PHANEENDRA NATH THOTA

ANAESTHESIA UPDATE

and

16 ANAESTHESIA POSTGRADUATEth

ACADEMIC PROGRAMME

Department of Anaesthesiology

Kasturba Medical College, Manipaland

ISA, Udupi City branch

2018

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Our thoughts….

Change is inevitable. May be for good or worse, we know not now. Let time

judge it, as we have seen again and again in history.

Our academic feast APGAP 2018 is here with changes, some subtle, some

striking. Let us be a part of this process, an endeavor to make learning better.

Editorial Team

Editorial Team

Krishna HM, Shaji Mathew, Pawan N, Ajith KP, Shiyad M, Nisha SJ, Sushma TK, Eeshwar MV

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Contents

LECTURES Page Number

1 Stewart’s approach to ABG…………………………………………………………… 3

2 Pediatric sedation outside OT………………………………………………………. 19

3 Labour analgesia-what is new?......................................................... 28

4 Low flow anesthesia-practical considerations……………………………….. 49

5 Statistical analysis, sample size and power estimation………………….. 57

6 Ventricular dysfunction and anesthetist………………………………………… 71

FOCUS SESSIONS

1 High flow oxygen therapy………………………………………………………………. 92

2 Perioperative fluid management in the renal transplant recipient…. 98

HOW I DO IT

1 Awake craniotomy…………………………………………………………………………. 105

INTERACTIVE SESSIONS

1 Malignant hyperthermia…………………………………………………………………. 112

2 Aspiration under anesthesia-decision making…………………………………. 118

3 Anaphylaxis……………………………………………………………………………………… 131

4 Management of diabetic ketoacidosis……………………………………………… 142

5 Airway fire………………………………………………………………………………………… 150

6 Local anesthesia systemic toxicity…………………………………………………….. 154

POSTGRADUATE SESSIONS

1 Obstetric hemorrhage………………………………………………………………………. 160

2 Pulmonary embolism………………………………………………………………………… 170

3 Pacemaker and the anesthetist………………………………………………………… 191

4 Mitral stenosis and perioperative acute atrial fibrillation…………………. 207

5 MRI and the anesthetist……………………………………………………………………. 224

VIDEO SESSIONS

1 Transforaminal and facet block………………………………………………………… 229

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Stewart’s approach to acid-base balance

Anitha Nileshwar

Professor and Head, Department of Anesthesiology

Kasturba Medical College, Manipal

INTRODUCTION

Acid-base status and its analysis have always perplexed clinicians. It is one of the most common

investigations obtained in the ICU and has become an integral part of management of a critically

ill patient, especially those on ventilator. Blood gases are obtained at least once a day and after

any major change in the situation or management of the patient.

The most commonly used method, also called the traditional method uses the Henderson

Hasselbalch equation. A step-wise approach using the pH, partial pressure of carbon dioxide and

serum bicarbonate level are used to deduce the abnormality.1 The main assumption in this

approach is that the hydrogen ion concentration depends on the partial pressure of carbon

dioxide and the bicarbonate level. While this concept is easy to understand and is user-friendly

at the bedside, it may not be complete. The disorder may be named but the reason for the

disorder may not be very clear.

Stewart’s approach, called the modern approach, was proposed in 1983.2 It is more complex but

can explain the reason for the changes seen. It uses the base excess as the main parameter to

evaluate acid-base disorders. In this physico-chemical approach, the changes in base excess are

not only due to changes in arterial carbon dioxide concentration but are also due to changes in

electrolyte concentrations, albumin and serum phosphate as also changes in unmeasured anions

and cations.

Many comparisons have been made between the traditional and the Stewart methods and the

advantages of one over the other have not been proved.3-11 There are strong proponents of both

approaches. Although Stewart’s approach has been largely ignored by physiologists, it is

increasingly used by anesthesiologists and intensive care specialists. Many find the original

Stewart approach difficult to understand and tend to ignore it. In 2016, David Story proposed a

simplified Stewart approach and claimed that this is likely to be more clinically useful and at the

bedside.12-13 The Stewart method has been called the ‘Gold standard’ in a recent article.14

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The following write-up aims to explain the Stewart approach in a simple way for easier

understanding and provides an insight into the topic. The choice of which method to adopt will

be up to the reader/user. Perhaps one would find a familiar method more useful than a new one

but there will be a few instances where the traditional method might fall short of explanations

and the Stewart approach might be able to help. It is important to have an open mind and

enthusiasm to look at things in a new light, in a new way.

STEWART APPROACH

Basic Principle

The Stewart approach is based on three basic principles or physicochemical properties of body

fluids.

1. Dissociation: Strong ions completely dissociate in solution (e.g., sodium chloride),

whereas weak acids partially dissociate and therefore exist in both ionized and unionized

forms.

2. Electroneutrality: In aqueous solution, the sum of all the positive charged ions in any

compartment must equal the sum of all negatively charged ions.

3. Mass conservation: The amount of a substance remains constant unless it is added,

removed, generated or destroyed.

According to Stewart, three independent factors contribute to acid-base disturbances in the

body:

1) PCO2

2) Strong ion difference (SID)

3) Weak acids in the plasma (albumin and phosphate)

Acid-base disturbances in the body can be respiratory or metabolic. The respiratory changes are

detected by examining changes in partial pressure of carbon dioxide and the metabolic changes

are explained by change in base excess.

According to law of neutrality, the neutrality of the plasma must be maintained and the sum of

all cations must equal sum of all anions. It can be written as:

[Na+] + [K+] + [Ca++] + [Mg++] = [Cl-] + [HCO3-] + [Lactate] + [ATotal]

Where ATotal represents weak acids including albumin and other unmeasured anions.

This can be illustrated using a Gamblegram (Figure 1), developed by a physiologist John Gamble.

It consists of paired columns, one representing the cations and the other anions. It can be seen

that the major cation is sodium and the major anion is chloride.

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Figure 1. Gamblegram

Strong Ion Difference (SID)

In plasma, the strong cations (sodium mainly) are more in number than the strong anions

(Chloride – Cl mainly and lactate). The difference between the measured strong cations and

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measured strong anions is termed the ‘Strong Ion Difference - SID’. Since [K+], [Ca++], [Mg++] are

small or often not measured, they can be ignored.

Accordingly, the strong ion difference can be written as:

SID = [Na+] – ([Cl-]);

Normal SID would be 34-35 mmol/l.

The state of ionization of water into hydrogen and hydroxyl ions depends on the SID (Figure 2).

If the SID decreases, hydrogen ions increase (pH decreases) and the patient will have acidosis. If

the SID increases, the hydroxyl ions increase and the patient will have alkalosis.

Figure 2. The relationship between SID and H+/pH

The Gamblegram is very useful to understand the effects of changes in SID. Changes in SID could

be because of any of the following:

Change in sodium: If the sodium concentration increases, the amount of cations will increase.

Chloride concentration does not change but to maintain electroneutrality, bicarbonate

concentration increases. This increases the SID (difference between sodium and chloride

concentration increases) and produces alkalosis. Any change in sodium concentration in the body

is mostly due to change in water content. An increase in sodium concentration is due to decrease

in water content (dehydration). Hence, an increase in sodium concentration produces a state

called ‘contraction alkalosis’ (Figure 3). The converse would be true if the sodium concentration

decreases.

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Figure 3. Change in SID due to change in sodium concentration. An increase in sodium

concentration has caused an increase in bicarbonate to maintain electroneutrality. The SID

increases and results in alkalosis.

Change in chloride concentration

An increase in chloride concentration will cause an increase in the number of anions and to

maintain electroneutrality, the bicarbonate gets squeezed out (bicarbonate concentration

decreases). The SID decreases and the patient will have hyperchloremic acidosis. The converse

will be true if the chloride concentration reduces.

Rapid infusion of large amounts of saline during resuscitation can cause hyperchloremic acidosis

as compared to Ringer lactate. A study done by Scheingraber et al. demonstrated these effects.15

They measured the pH, sodium concentration, chloride concentration, base excess and SID after

rapid infusion of saline or Ringer lactate. The patients in the group that received saline had a

lower pH, higher base deficit, higher sodium and chloride concentrations and lower SID,

indicating development of hyperchloremic acidosis (Figure 4).

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Figure 4. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing

gynecological surgery

This is explained using the following example:

Take for instance a litre of plasma (Sodium 140 mmol/l and Chloride 102 mmol/l, SID = 38 mmol/l)

and a litre of saline (sodium 154 mmol/l and chloride 154 mmol/l, SID = 0), and when these are

mixed, two litres of volume is obtained (Figure 4). The resultant fluid will have a sodium

concentration of 147 mmol/l, which is still within normal limits but the chloride concentration

increases to 128 mmol/l and the SID decreases to 19 mmol/l. This is hyperchloremic acidosis.

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Figure 4. Effect of mixing one litre of plasma and one litre of saline and effect on SID

The effect of mixing one litre of plasma with one litre of Ringer lactate is also shown in Figure 5.

Figure 5. Effect of infusion of mixing one litre of Ringer lactate with one litre of plasma

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One litre of plasma (Sodium 140 mmol/l and Chloride 102 mmol/l, SID = 38 mmol/l) and a litre of

Ringer lactate (sodium (all strong ions put together) 137 mmol/l and Chloride 109 mmol/l, lactate

28 mmol/l, SID = 0 because lactate is a strong anion), when mixed, two litres of volume is

obtained (Figure 4). The resultant fluid will have a sodium concentration of 139 mmol/l, and a

chloride concentration of 105 mmol/l and the SID decreases to 34 mmol/l. This is within normal

limits.

The effect of infusion of various crystalloids available in the market can be similarly predicted. As

shown in Figure 6, Ringer lactate, Ringer acetate and Ringer fundin have a SID (with a

metabolizable anion) equal to plasma SID and hence infusion of large amounts of these do not

change the acid-base balance unlike isotonic saline.

Figure 6. Composition of various crystalloids available in the market and comparison with

plasma.

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Effect of albumin and phosphate

Figure 7. Effect of albumin on acid-base balance

Albumin and phosphate are weak anions that contribute to the electrical status of plasma.

Consequently, if the albumin level reduces, to maintain electroneutrality, bicarbonate

concentration increases and the condition is called hypoalbuminemic alkalosis (Figure 7). This will

not cause a change in SID because sodium and chloride values are unchanged. However, the pH

and the base excess will increase. The converse is all true. Similar changes can be expected with

change in phosphate concentrations.

Apparent SID and Effective SID

SID can be calculated in two ways. When SID is obtained by subtracting chloride concentration

from sodium concentration, it is called apparent SID (SIDa). When SID is obtained as a sum of the

concentrations of bicarbonate, albumin and phosphate, it is called effective SID (SIDe). Normally,

SIDa must equal SIDe or the difference between them, which is also called the Strong Ion Gap

(SIG) must be zero (Figure 8). SIDapparent – SIDeffective = Strong Ion Gap; Normal = 0

Unmeasured weak acids in the plasma

Acidosis can also be caused due to accumulation of weak acids such as sulfate, ketoacetate and

other unknown anions. The Gamblegram shows that an increase in the weak acid concentration

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also can have the same effect of squeezing out the bicarbonate and cause acidosis (Figure 8).

Accumulation of these weak acids will manifest as an increase in Strong Ion Gap (SIG).

Figure 8. Illustration of SIDa, SIDe and SIG

Comparison of Strong ion gap (SIG) with Anion Gap (Traditional method)

Anion gap is defined as the amount of unmeasured anions in the sample. It can be calculated as

follows:

AG = ([Na+] + [K+]) – ([Cl-] + [HCO3-])

Ignoring [K+], the equation can be written as

AG = [Na+] – ([Cl-] + [HCO3-])

Metabolic acidosis can be classified into two types based on the anion gap: high anion gap

metabolic acidosis and normal anion gap acidosis.

In Stewart approach, the high anion gap acidosis will have high SIG whereas the normal anion

gap acidosis will have zero or low SIG.

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Causes of high anion gap acidosis (low SID, high SIG): MUDPILES (Methanol, Uremia, Diabetic

ketoacidosis, Paracetamol/propylene glycol, Iron/Isoniazid, Lactic acidosis, Ethylene glycol,

Salicylate poisoning)

Causes of normal anion gap acidosis (low SID, low/zero SIG): Diarrhea, isotonic saline infusion,

early renal failure, renal tubular acidosis, ureteroenterostomy.

Figure 9 summarizes the effect of changes in the concentration of electrolytes, albumin and

unmeasured anions in the plasma.

Figure 9. Summary of changes in the concentration of electrolytes, albumin and unmeasured

anions in the plasma

Following is an algorithm that can be followed while using Stewart’s approach (Figure 10).

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Figure 10. Algorithm to use Stewart’s approach to acid-base

Although Stewart’s approach is quantitative and explains the cause of acid-base change better

than Henderson method, it has not gained wide-spread popularity because of its complexity. It is

being increasingly used by intensivists and many anesthesiologists.

SIMPLIFIED STEWART APPROACH (BY DAVID STORY) TO BE USED AT THE BEDSIDE

The Stewart approach, looks at acid base problems from a different angle, is essentially similar

to the Henderson approach but provides more information. David Story proposed a simplified

Stewart approach which is user-friendly and can be used at the bedside. This can be easily

remembered as the SALT approach, where S – Sodium chloride effect, A – Albumin effect, L –

Lactate effect and T – oTher ions effect.

The simplified approach is as follows:

This will require arterial blood gas analysis, measurement of lactate and albumin.

Step 1: Calculate the Sodium Chloride Base Excess effect

= Measured Na – Measured Cl – 35

Step 2: Calculate Lactate Base Excess effect = 1 – measured lactate (mmol/l)

(Conversion of mg% to mmol/l 1 mg/dl = 0.11 mmol/l);

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Step 3: Calculate Albumin Base Excess effect

= 0.25 (42 - Measured albumin in g/l)

Step 4: Calculate oTher Ions effect

BE = NaCl base excess effect + Lactate base excess effect + albumin base excess effect + Other

ions (OI) effect

OI = BE – (NaCl base excess effect + Lactate base excess effect + albumin base excess effect)

BE = S + A + L + T; or T = BE – (S + A + L)

Any abnormality in the base excess can be analyzed critically to see whether the contribution to

it is mainly from sodium, chloride, lactate, albumin or other ions.

Other ions that can affect acid-base include measured and unmeasured cations and anions.

Measured cations include potassium, calcium and magnesium. Unmeasured cations are proteins,

lithium or aluminium. Other anions include phosphate (may be measured), acetate and sulphate

(unmeasured). A multitude of currently unknown anions may also be present.

Thus, the simplified Stewart approach is expected to not only diagnose acidosis or alkalosis but

also identifies the cause and quantifies the abnormality.

Sample Case study:

78 year old female with AAA post op; [Na+] = 142 mmol/l, [Cl-] = 117 mmol/l, Albumin = 26 g/l,

Lactate = 6 mmol/l, SBE = - 8 mmol/l

Analysis:

S (NaCl) effect = 142 - 117 - 35 = - 10 mmol/l

A (Albumin) effect = 0.25 x (42-26) = 0.25 x (16) = 4 mmol/l

L (Lactate) effect = 1 - 6 mmol/l = - 5 mmol/l

T (Other ions effect) = BE – (S + A + L)

= - 8 – [- 10 + 4 + (- 5)] = - 8 – (- 11) = 3 mmol/l

This case is a good illustration of the utility of David Story’s simplified Stewart approach. If we

were to concentrate only on the base excess without further analysis, this patient with a base

excess of -8 mmol/l might have been administered sodium bicarbonate. However, the above

analysis shows that the patient has multiple problems: hyperchloremic acidosis,

hypoalbuminemic alkalosis (masking some of the acidosis), some lactic acidosis and some

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unaccounted alkalosis. The patient would require chloride free fluids, and possibly cardiovascular

support to improve perfusion (to reduce lactic acidosis). A detailed history and physical

examination, evaluation of other reports would contribute to a clear diagnosis and management.

COMPARISON OF THE TRADITIONAL AND STEWART APPROACH

Many studies have compared the traditional and the Stewart approaches and the opinion is

divided as to which is better and which one provides more information.

Lloyd and Freebairn in their review of using quantitative acid-base analysis in the ICU, described

how the quantitative acid-base Strong ion calculator quantifies the three independent factors

that control acidity, calculates the concentration and charge of these unmeasured ions, produces

a report based on these calculations and displays a Gamblegram depicting measured anion

species.3 They went on to opine that when the Stewart approach is used together with the

medical history, quantitative acid-base analysis has advantages over traditional approaches.

Dubin et al published their prospective, observational study comparing three different methods

of evaluation of metabolic acid-base disorders.4 They compared the traditional Henderson

Hasselbalch method, anion gap method and the Stewart method in 935 patients admitted to the

ICU. The Stewart approach detected an arterial metabolic alteration in 131 (14%) of patients with

normal HCO− 3 and BE, including 120 (92%) patients with metabolic acidosis. However, 108 (90%)

of these patients had an increased AGcorrected. The Stewart approach permitted the additional

diagnosis of metabolic acidosis in only 12 (1%) patients with normal HCO3−, BE, and AGcorrected. On

the other hand, the Stewart approach failed to identify 27 (3%) patients with alterations

otherwise observed with the use of HCO− 3, BE, and AGcorrected (16 cases of acidosis and 11 of

alkalosis). SID and BE, and strong ion gap (SIG) and AGcorrected, were tightly correlated (R2 = .86

and .97, p < .0001 for both) with narrow 95% limits of agreement (8 and 3 mmol/l, respectively).

Areas under receiver operating characteristic curves to predict 30-day mortality were 0.83, 0.62,

0.61, 0.60, 0.57, 0.56, and 0.67 for Sepsis-related Organ Failure Assessment (SOFA) score, SIG,

AGcorrected, SID, BE, HCO− 3, and lactates, respectively (SOFA vs. the rest, p < .0001). They concluded

that in this large group of critically ill patients, diagnostic performance of the Stewart approach

exceeded that of HCO− 3 and BE. However, when AGcorrected was included in the analysis, the

Stewart approach did not offer any diagnostic or prognostic advantages.

Badr and Nightingale published an excellent review of the Stewart’s approach, calling it an

alternative approach to acid-base abnormalities in critically ill patients. One of the key points in

the article was that the Stewart’s approach adds to our understanding and management of

underlying acid-base abnormalities.5

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Kurtz et al published a critique of the Stewart and bicarbonate-centred approaches and

concluded that both approaches are quantitatively identical.6

Rastegar in his article on Clinical utility of the Stewart’s method in the diagnosis and management

of acid-base disorders states that the Stewart’s method does not provide any greater utility in

either the diagnosis, management or prognostication of the patient condition.7

Seifter JL describes a method of analysing acid-base disorders integrating both approaches and

published a few case vignettes to describe the method.8

Szrama et al after their study on 990 patients concluded that the Stewart approach is more

effective in detecting acid-base disturbances and quantifying individual components of acid-base

abnormalities and provides a detailed insight into their pathogenesis.9

Masevicious F and Dubin in their mini-review on whether Stewart approach has improved our

ability to diagnose acid-base disorders in critically ill patients, opine that the Stewart system has

not improved our ability to diagnose acid-base disorders in critically ill patients.10

Todorovic et al published an article titled ‘The assessment of acid-base analysis: comparison of

the ‘traditional’ and the ‘modern’ approaches’. He wrote that Stewart’s approach must be used

whenever albumin and phosphate are abnormal.11

David Story attempted to take Stewart from bench to bedside, at first in his article in 2004 and

then further simplified it in his article in 2016.12,13

The protocol of the Study of impact of Phosphate-balanced crystalloid infusion on acid-base

homeostasis (PALANCE study) was published in 2017 in Trials, in which the investigator describes

the Stewart approach as the gold standard.14

CONCLUSIONS

The Stewart approach is a method of evaluating acid-base distinct from the traditional Henderson

Hasselbalch equation. In this method, base excess depends on the partial pressure of carbon

dioxide, electrolytes, albumin and other ions. This analysis helps not only to diagnose the disorder

but also provides an insight into the cause of the disorder. More and more anesthetists and

intensivists are adopting this in their daily work. David Story’s simplification of Stewart approach

is a great aid in the shift of analytical method to Stewart.

REFERENCES

1. Marino P. The ICU book. 3rd ed. 2007 Lippincott Williams Wilkins: Philadelphia.p.559-574. 2. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol

1983;61:1444-61.

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3. Lloyd P, Freebairn R. Using quantitative acid-base analysis in the ICU. Critical Care and Resuscitation 2006;8:19-30.

4. Dubin, Arnaldo MD; Menises, María M. PhD; Masevicius, Fabio D. MD; Moseinco, Miriam C. MD; Kutscherauer, Daniela Olmos MD; Ventrice, Elizabeth MD; Laffaire, Enrique MD; Estenssoro, Elisa MD. Comparison of three different methods of evaluation of acid-base disorders. Critical Care Medicine 2007;35(5):1264-70

5. Badr A, Nightingale P. An alternative approach to acid-base abnormalities in critically ill patients. CEACCP 2007;7(4):107-111.

6. Kurtz I, Krant J, Ornekiam V, Nguyen MK. Acid-base analysis: a critique of the Stewart and bicarbonate-centred approaches. Am J Physiol Renal Physiol 2008;294:F1009-31.

7. Rastegar A. Clinical utility of Stewart’s method in diagnosis and management of acid-base disorders. Am J Am Soc Nephrol 2009;4:1267-74.

8. Seifter JL. Integration of acid-base and electrolyte disorders. N Engl J Med 2014;371:1821-31.

9. Szrama J, Smuszkiewicz P, Trojanowska I. Acid-base disorders according to the Stewart approach in septic patients. Critical Care 2014;1891:P429.

10. Masevicious F and Dubin in their mini-review on whether Stewart approach has improved our ability to diagnose acid-base disorders in critically ill patients. WJCCM 2015;4(1):62-70.

11. Todorovic J, Nesovic-Ostojic JN, Milanovic A, Brkic P, Ille M amd Cemerikic D. 2018 Med Glas (Zenica) 2015;12(1):7-18.

12. Story D. Bench to bedside review: A brief history of acid-base. Critical Care 2004;8:253-8.

13. Story D. Stewart acid-base – A simplified bedside approach. Anesth Analg 2016;123(2):511-5

14. Pagel JI, Hulde N, Kammerer T, Schwarz M, Chappell D, Burges A, Hofmann-Kiefer K, Rehm M. The impact of phosphate-balanced crystalloid infusion on acid-base homeostasis (PALANCE study): study protocol for a randomized controlled trial. Trials 2017;18_313.

15. Scheingraber et al. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecological surgery. Anesthesiology 1999;90:1247-9.

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Sedation for pediatric patients outside operation theatres

Ekta Rai

Professor, Department of Anesthesiology Christian Medical College, Vellore

More and more sick patients at extremes of age are being anesthetized for various procedures in remote locations. The main reasons for this are the development of minimally invasive diagnostic and interventional techniques, and economical advantage these techniques offer. A number of minor procedures are performed in the emergency ward and outpatient clinics under the cover of sedation and analgesia. Thus, the role of the anesthetist is expanding from providing anesthesia in the well-equipped operating rooms to sedation in remote locations. These areas may not be as well-equipped and may have a dearth of equipment, monitoring tools and personnel. In many hospital, non-anesthesia personnel are providing sedation. Hence knowledge about sedation techniques, monitoring and rescue airway techniques must be mandatory skills for these providers. Sedation in pediatric patients is especially challenging, as they have higher incidence of complications such as hypoventilation, apnea, airway obstruction, laryngospasm, and impairment of cardiorespiratory function. For all these reasons, providing anesthesia in remote locations is a complex and challenging task requiring skill and expertise. Guidelines regarding the personnel, equipment, monitoring tools, as well as selection of procedures and patients should be developed and instituted so as to provide safe remote location sedation or anesthesia. Here, we will discuss sedation provided by qualified anesthetists, since non-anesthetists require individual training for demonstrating knowledge of drugs, sedation techniques and methods of airway rescue. SEDATION

The overall care of a patient undergoing sedation can be divided into:

Pre sedation phase

Intra-sedation phase including management of sedation related complications

Post sedation phase Aims of Sedation

The following are the aims of sedation in pediatric patients, for both therapeutic and diagnostic procedures:

1. Minimizing pain and physical discomfort.

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2. Ensure safety and well-being. 3. Allay anxiety, minimize secondary injuries due to uncooperative behavior. 4. Minimize psychological trauma. 5. Prevent long-term behavioral disorders such as nightmares. 6. Complete the investigation or procedure without interruption. 7. Safely discharge the child as per discharge criteria

In order to achieve these goals successfully, different levels of sedation are given depending on the procedure, patient and environment.

The Spectrum of Sedation

During procedural sedation, the patient is able to tolerate the uncomfortable or painful diagnostic/ interventional surgical or radiological procedure. It is desirable to have a lack of memory of distressing events; however, lack of response to painful stimulation is not assured. Practitioners who administer procedural sedation and/or analgesia should be aware that the transition from complete consciousness through the various depths of sedation to general anesthesia is a continuum and not a set of discrete, well-defined stages (Table1).

In 2002, the American Society of Anesthesiologists (ASA) defined the four levels of sedation

Minimal Sedation (Anxiolysis): A state induced by medication in which

patients respond normally to verbal commands.

cognitive function and coordination may be impaired,

ventilatory and cardiovascular functions are not affected. Moderate Sedation or ‘‘Conscious Sedation’’: A state induced by medications in which

there is a decrease in consciousness; the patient responds purposefully to verbal commands, which may be isolated or accompanied by light tactile stimuli.

no intervention is necessary to maintain airway patency and spontaneous ventilation is adequate.

cardiovascular function is usually maintained. Deep Sedation: A state induced by medications in which

there is a decrease in consciousness from which patients cannot be easily awakened, but respond to repeated or painful stimuli.

there is an inability to maintain ventilatory function independently.

assistance is required to maintain airway patency and spontaneous ventilation may be inadequate.

cardiovascular function is generally maintained. General Anesthesia: A state induced by medications where

there is loss of consciousness from which patients are not aroused, even with painful stimuli.

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ventilatory function is impaired and assistance is required to maintain airway with positive pressure ventilation.

there is impaired cardiovascular function.

Table 1. Summary of levels of sedation and clinical response

Pediatric Sedation vs. Adult Sedation

Sedation of children is different from sedation of adults. Sedation in children often is administered to control behavior to allow the safe completion of a procedure. The ability of a child to control his or her own behavior to cooperate for a procedure depends both on his/her chronologic and developmental age. Often, children younger than six years and those with developmental delay require deep levels of sedation to gain control over their behavior. Therefore, the need for deep sedation should be anticipated in such patients. Children in this age group are particularly vulnerable to the sedating medication’s effects on respiratory drive, patency of the airway, and protective reflexes. Studies have shown that it is common for children to pass from the intended level of sedation to a deeper, unintended level of sedation. For older, cooperative children, other modalities, such as parental presence, hypnosis, distraction, topical local anesthetics, and guided imagery may reduce the need for deeper level of pharmacologic sedation

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Complications

Sedation of pediatric patients is associated with serious risks such as hypoventilation, apnea, airway obstruction, laryngospasm and cardiopulmonary impairment. These adverse responses which may occur during and after sedation may be minimized, but not completely eliminated, by a careful pre-procedure review of the patient’s underlying medical conditions and consideration of how the sedation process might affect or be affected by these conditions. The severity of injuries for remote location claims was greater than those associated with operating room claims. The proportion of death was almost double in remote location. Appropriate drug selection for the intended procedure as well as the presence of an individual with the skills needed to rescue a patient from an adverse response are essential. The most common serious complications of sedation involve compromise of the airway or depressed respiration resulting in airway obstruction, hypoventilation, hypoxemia and apnea. Hypotension and cardiopulmonary arrest may occur, usually from inadequate recognition and treatment of respiratory compromise. Other rare complications may also include seizures and allergic reactions. REMOTE LOCATIONS

Remote locations, where anesthesiologists may be required to administer anesthesia or sedation outside the operating theatres, include: • Radiology suites e.g. cardiac angiography, interventional radiology, CT scan, MRI • Endoscopy suites • The dental clinic • The burns unit • Psychiatric unit for electroconvulsive therapy • Renal unit for lithotripsy • The gynecology unit for in-vitro fertilization.

Who should provide sedation in remote location?

Trained anesthesiologist should provide anesthesia in remote locations. However, trained doctors should be allowed to provide conscious sedation as demand for an anesthesiologist is more than the supply in any hospital. Non–anesthesiologist should be able to

1. Understand the spectrum of sedation and have knowledge of the drugs and equipment involved.

2. Know their limitations 3. Perform BLS and ACLS

Complicated or challenging cases should performed under the supervision of an anesthesiologist. These include:

Abnormal airway

Raised intra-cranial pressure or depressed level of consciousness

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History of sleep apnea

Major organ dysfunction including congenital cardiac anomalies

Gastro-esophageal reflux disease

Neuromuscular disorders.

Bowel obstruction

Polytrauma patients Young children and infants, premature babies

CONDUCT OF SEDATION (Pre Sedation phase, Intra sedation phase and post sedation phase)

Pre-sedation Preparation Phase

Checklist

Equipment Monitors Drugs Support staff Safety features Recovery area with staff Adequate fasting

Equipment

SOAP ME- Acronym for the equipment check list

S (suction) – Appropriate size suction catheters and functioning suction apparatus. O (oxygen) – Reliable oxygen sources with a functioning flow meter. At least one spare E-type oxygen cylinder. A (airway) – appropriate airway equipment for the child:

Face mask Nasopharyngeal and oropharyngeal airways Laryngoscope blades Endotracheal tube (ETT)

Stylet

Bag-valve-mask or equivalent device

P (pharmacy) – Basic drugs needed for life support during emergency: Epinephrine (adrenaline) Atropine Glucose Naloxone (reversal agent for opioid drugs) Flumazenil (reversal agent for benzodiazepines)

M (monitors): Pulse oximeter (SpO2) Non-invasive blood pressure (NIBP)

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End-tidal CO2 (EtCO2) Temperature

ECG E (equipment):

Defibrillator with paddles Gas scavenging Safe electrical outlets (earthed) Adequate lighting (torch with battery backup) Means of reliable communication to main theatre site

Difficult Airway Cart with different sizes ETT, LMA, bougie, tube exchanger, various sizes of laryngoscope blades. All equipment should be checked prior to starting the sedation procedure.

• Oxygen –delivery masks, AMBU mask, resuscitation bag and masks • Head down tipping trolley and suction equipment. • Oral, nasopharyngeal, laryngeal mask airways and appropriately sized endotracheal tubes. • Defibrillator with appropriate pediatric pads • Reversal agents –flumazenil (and naloxone if patient receiving opiates) must be readily available.

Monitors

A trained, vigilant anesthetist or a trained doctor is the most important monitor, who will be monitoring parameters such as level of consciousness, heart rate (HR), SpO2, NIBP and ventilation (respiratory rate and ETCO2). Monitors should be compatible with the remote location with cables of adequate length.

Drugs

Resuscitation Drugs: Emergency cart must have all resuscitation drugs diluted.

Amnesia / Sedation: Various drugs cause differing effects. Some of the effects of these drugs are described below:

Sedative: A sedative decreases activity, moderates excitement and calms the patient.

Hypnotic: A hypnotic produces drowsiness and facilitates the onset and maintenance of sleep.

Analgesic: An analgesic relieves pain by altering perception of nociceptive stimuli.

Anxiolytic: An anxiolytic relieves apprehension and fear due to an anticipated act or illness.

Amnesic (ante grade): An amnestic agent affects memory incorporation such that the patient is unable to recall events following delivery of the drug.

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Sedative drugs result in central nervous system depression. Use of these drugs may result in loss of protective reflexes, with subsequent respiratory and/or cardiac dysfunction. Many of the clinical effects of medications administered to achieve sedation are dose-related and must be assessed individually for each child. Sedative drugs may be administered orally, intra-nasally, rectally, intravenously or by inhalation.

Some common drugs used in pediatric sedation: Oral Agents

Chloral hydrate Dose: 50 mg/kg (mild sedation) - 100 mg/kg (moderate- deep sedation)

Beware of cardiac arrhythmias and respiratory depression with loss of airway reflexes at high doses.

Must be given 45-60 minutes prior to procedure.

Unpleasant taste – can be mixed with blackcurrant flavor, etc.

There is NO reversal agent.

Midazolam Dose: 0.5 mg/kg (Max 20 mg)

Beware of respiratory depression/hypotension/loss of airway reflexes at high doses

Short acting benzodiazepine causing sedation, hypnosis, anxiolysis, anterograde amnesia

Can lead to a distressing paradoxical excitement in children

ORALLY give 30-60 minutes before procedure. BUCCALLY give 15 minutes pre-procedure

No easily available oral preparation. Please use injection orally (diluted in apple or orange juice, squash etc..

Reversal agent is Flumazenil

Inhalational Agents

Nitrous oxide (up to 70% with oxygen).

Self-administration via demand valve OR via anaesthetic machine if trained.

Beware diffusion hypoxia post procedure. Additional oxygen should be given for 5-10 minutes to prevent this.

Colorless, odorless gas with analgesic and anxiolytic effects with rapid onset and offset.

Useful for short painful procedures and very effective in cooperative school aged children ('Laughing gas").

Delivered as Entonox – 50:50 mix with oxygen (minimal sedation).

Delivered as a 70:30 mix with oxygen (moderate sedation).

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Intravenous Agents

Propofol

Dose: 100-200 mcg/kg/min IV

Ideal agent for non painful diagnostic procedures.

Only for use by expert airway managers with good back up systems

Propofol with fentanyl Dose: fentanyl 1-2 mcg/kg IV + propofol 50-150 mcg/kg IV

Best for deep sedation/anesthesia/analgesia

Risk of requiring advanced airway management is high

Ketamine Dose: 3 - 4 mg/kg IM

1 – 2 mg/kg IV

Effective analgesia and sedation for painful procedures

Nausea and vomiting are the common complaints post-procedure

Laryngospasm and copious saliva have been reported. Best combined with an anti-cholinergic for secretions. Midazolam may be used in an attempt to decrease emergence dysphoria (rare in children)

Dexmedetomidine

Dose: 1 mcg/kg bolus with 0.5-0.7 mcg/kg/h infusion

Used for cardiac catheterization, awake craniotomies, burns dressing etc

Postoperative Nausea and Vomiting (PONV) Prevention:

Prevention of PONV with 5HT3 antagonists and dexamethasone is recommended for quality care in remote locations. A large number of procedures in remote locations are day-care procedures and PONV is one of the major culprits in delayed discharge.

Pre-sedation Assessment

Similar to preoperative assessment. Details should include the co-morbidities, allergies, previous anesthesia related events, airway assessment, medication status and any life threatening issues.

Fasting- ASA guidelines are followed for sedation except when only entonox is planned.

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In emergency situations, weigh the risk versus the benefit and explain to the relatives about the risk of aspiration and urgency of the procedure.

Consent- Informed consent should be obtained before sedating the child.

Documentation

Time based vital signs recording every 5 minutes during the procedure and every 15 minutes post procedure in recovery phase

All events should be reported

Dye instillation time should be mentioned, if applicable All sedation drugs with dosages should be mentioned.

Complications- Anticipation and Prevention

In procedures involving dye instillations, the sedation provider should be prepared to deal with anaphylaxis.

When dealing with diagnostic scans for patients with neuromuscular diseases, measures to manage malignant hyperthermia must be available.

Remote areas with radiation exposure should have appropriate lead aprons and shields for medical staff.

Post Sedation Care

Following sedation, the child should be kept in the recovery area, close to the procedure area. The recovery area should be equipped with O2 supply, suction, and facility to monitor at least SpO2 and HR. Depending on procedure and comorbidity, the level of monitoring may need to be upgraded. The equipment required for resuscitation and airway management should be readily available.

Discharge Criteria: For patients who have undergone sedation at remote location, discharge criteria should be same as that from the recovery room of the operating room. Modified Aldrete Score can be followed as discharge criteria.

The standards of anesthesia care and patient monitoring are the same regardless of location.

FURTHER READING

1. Coté CJ, Wilson S; American Academy of Pediatrics; American Academy of Pediatric Dentistry. Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures: Update 2016. Pediatrics 2016;138(1). pii: e20161212. doi: 10.1542/peds.2016-1212. PubMed PMID: 27354454.

2. Jacob R, Ilamurugu K, Amar N. Paediatric procedural sedation - a review and an update. Indian J Anaesth 2007;51(3):169-175.

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Labour analgesia – What is new?

Gurudutt C L Professor and Head, Department of Anesthesiology

JSS Medical College, Mysuru The delivery of the infant into the arms of a conscious and pain free mother is one of the most exciting and rewarding moments in medicine – Moir DD INTRODUCTION James Young Simpson, the Professor of midwifery in Edinburgh, Scotland was among the first to use ether for the relief of labour pain. On January 1847, he used ether to ameliorate the pain of labour in a young woman with rickets & severely deformed pelvis, who was at grave risk of dying. She survived the complicated delivery pain free. But his concept of etherization of labour was strongly condemned by the clergy. Queen Victoria was given relief from pain during labour by John Snow using chloroform on a folded handkerchief. The Queen abruptly terminated the religious debate over the appropriateness of analgesia for labour. Since then labour analgesia has gained popularity and neuraxial analgesia has become the gold standard for the same. Recent Trends in Labour Analgesia

1. Intravenous use of Remifentanyl and Dexmedetomidine 2. Inhalational sevoflurane 3. Use of adjuvants like clonidine, neostigmine, dexmedetomidine epidurally along with

local anesthetics 4. Use of Ropivacaine, Levobupivacaine instead of bupivacaine for epidural 5. Continuous spinal analgesia 6. Computer integrated patient controlled epidural analgesia 7. Programmed Intermittent or automated mandatory epidural boluses 8. Dural puncture epidurals 9. Walking epidural 10. Ultrasound guided neuraxial technique

CHARACTERISTICS AND PHYSIOLOGY OF LABOUR PAIN Perception of pain, including pain of uterine contractions, is a complex process that involves interaction of both central and peripheral mechanisms, and continuous interchange of information among ascending nociceptive and descending antinoceptive pathways. Pain perception involves sensory, emotional, behavioral, and environmental factors. Most women rate pain of childbirth as the most painful experience of their lives. Pain during the first stage of labor is visceral in nature and arises primarily from the contracting uterus and dilating cervix, supplied by sympathetic afferent fibers. The visceral pain of uterine

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contractions is transmitted to the T10 - L1 segments of the spinal cord by A delta and C visceral afferent fibers that originate in the lateral wall and the fundus of the uterus (Table 1). The sequence of afferent nociceptive transmission from the uterus and cervix to the spinal cord is conducted through the uterine and cervical, hypogastric and aortic plexuses. From there, the nociceptive afferent impulses cross to the lumbar sympathetic chain and travel cephalad to the thoracic sympathetic chain, and via the white rami communicantes associated with the T10 - L1 spinal nerves. Finally, the pain-conducting fibers cross through the posterior nerve roots and synapse with interneurons within the dorsal horn of the spinal cord where they undergo further modulation.

Stage of labor

Pain characteristics Pain pathways

First Visceral pain: diffuse and poorly

localized Spinal nerve roots

(T10-L1)

Second Somatic pain: sharp and well-

localized

Pudendal nerve

(S2-S4 sacral roots)

Table 1. Pain perception in labour

Nociceptive stimulation from uterine body contractions and distension of the lower uterine segment continues during the second stage of labor when the cervix has reached full dilatation. Additionally, the increasing pressure of the fetal presenting part on pelvic structures gives rise to somatic pain, with stretching of fascia and subcutaneous tissues of the lower birth canal, distention of the perineum, and pressure on perineal muscle. The somatic pain of the second stage of labour is transmitted via the pudendal nerve derived from the S2, S3, and S4 sacral roots (Table 1). In contrast to the visceral pain of the first stage of labour, somatic pain experienced during the second stage of labour is more intense and well localized. The visceral pain of uterine contractions of the first stage of labour is diffuse in nature, poorly localized, and is commonly referred to the lower back, abdomen, and rectum. Descent of the foetal presenting part during the late phase of the first and second stages of labour produces sharp, well-localized somatic pain in the regions innervated by the pudendal nerve. Pain is perceived most acutely in the perineum, vagina, rectum, and the lower part of the sacrum. The increased knowledge of neurophysiology and neuropharmacology of pain and improved understanding of nociceptive processing in the spinal cord may bring us closer to the development of the ideal management of the pain of labour and delivery. This may allow the use of anaesthetic agents that are capable of altering neural transmission in such a way as to afford analgesia without sympathetic, sensory, or motor block.

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WHY LABOUR ANALGESIA IS REQUIRED? It has long been known that painful labour produces several adverse changes in maternal physiology & biochemistry. Some changes have important implications for the baby also. 1. Maternal respiration increases by 75-150% during 1st stage of unmodified labour.

This is associated with a number of maternal changes that may have adverse fetal effects

a. Hypocarbia & respiratory alkalosis b. Increased O2 consumption c. Under-ventilation between contractions, resulting in episodes of hemoglobin desaturation which are more pronounced when systemic opioids are given. d. Compensatory metabolic acidosis which appears to be transferred readily to the fetus. e. Vasoconstriction which affects the uterine arteries f. A shift in the maternal oxyhemoglobin dissociation curve counteracting the Double Bohr Effect. 2. Maternal hyperventilation lowers the umblical artery PCO2, but as labour progresses this change is overtaken by metabolic acidosis of increasing severity. Such that the longer the second stage of labour, the lower the cord pH at birth.

3. Maternal pain & stress have adverse fetal effects. Maternal anxiety is associated with increased plasma catecholamines, cortisol, ACTH & lipoprotein. Increased sympathoadrenal activity may lead to uncoordinated uterine activity & reduce uterine perfusion. 4. Metabolic outcome is hyperglycemia with a poor insulin response, lipolysis with increased fatty acids, ketones & lactate. These acids cross the placenta and produce fetal acidosis & increase fetal O2 requirement.

CHARACTERISTICS OF THE IDEAL LABOUR ANALGESIC AND AVAILABLE TECHNIQUES

Safe for the mother and fetus

Easy to administer

Have a consistent, predictable, rapid onset of action

Maternal composure & control during both the 1st & 2nd stages of labour

Provide analgesia in all stages of labour

Devoid of motor blockade, enabling ambulation & various birthing positions

Preserve the stimulus for expulsive efforts during the 2nd stage of labour

Retain maternal expulsive efforts

Facilitate the administration of supplemental analgesia without additional invasive procedures

Facilitate the delivery of anesthesia for surgery to avoid the need for general anesthesia Methods of labour analgesia can be classified into non pharmacological methods & pharmacological methods.

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Non-pharmacological methods include hypnosis, psychoprophylaxis, acupuncture, transcutaneous electrical nerve stimulation (TENS), sterile water blocks, hydrotherapy and maternal position Pharmacological methods may be classified as systemic medications and regional analgesic techniques. SYSTEMIC MEDICATIONS FOR LABOUR AND DELIVERY All systemic medications used can cross the placenta and can produce a depressant effect on the fetus. The amount of depression depends on the dose, route and time of administration before delivery and presence of maternal complications. Systemic medications can be used in places where the facilities for regional analgesia are not there and in patients whom central neuraxial block is contraindicated. Systemic drugs can be classified as 1. Opioids 2. Tranquilizers 3. Dissociative or amnesic drugs 4. Alpha 2 agonists Opioids Opioids are probably the most commonly used medications for labour analgesia. In many centres where epidural analgesia is unavailable or maternal condition contraindicates its use, opioids remain the analgesics of choice for labour pain. The common opioids used systemically are pethidine, fentanyl & Remifentanil. Fentanyl – because of its rapid onset of action, profound analgesic capabilities & lack of active metabolites, fentanyl is a popular IV or IM analgesic for labour. Fentanyl 100mcg is equianalgesic to morphine 10 mg. The usual IM dose is 50 to 100 mcg and the IV dose is 25 to 50 mcg. IV fentanyl produces analgesia almost instantaneously. The peak effect follows within 3 to 5 mins and the duration of action is 30 to 60 minutes. After IM administration, analgesia begins in 7 to 8 minutes, peaks at about 30 minutes and lasts 1 to 2 hours. Fentanyl crosses the placenta rapidly & appears in the fetal blood within 1 minute after IV administration, and peaks at 5 minutes. In maternal blood 60-80% of fentanyl is bound to plasma albumin and only 1/3 is available for placental transfer. Fentanyl also can be used as patient controlled IV analgesic. Compared to pethidine the side effects on the fetus and neonate are much less with fentanyl. Sufentanyl & Alfentanyl are the more lipid soluble opioids and have not gained popularity for labour analgesia as systemically administered drugs as they have little advantage over fentanyl.

Remifentanil – is an ultra-short acing -1 opioid receptor agonist with a rapid onset of action and is hydrolysed by non-specific tissue and blood esterases to an inactive metabolite. Context sensitive half time is 3.5 min and is independent of duration of infusion. The analgesic half life is 6 min, thus allowing effective analgesia for several consecutive painful uterine contractions.

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Remifentanil plasma concentration in pregnant women are approximately half those found in non-pregnant patients because of the greater volume of distribution & higher clearance. Optimal dosing regimen – The efficiency of remifentanil may depend on both the dose and manner in which it is administered. It can be given as an intermittent patient administered bolus (PCIA) with a lockout interval and with or without background infusion. The timing of dose administration, the rate of bolus delivery and the lockout interval are important to analgesia outcome. Usual dose is 0.5 mcg/kg with a 2 min lockout interval. It can also be given as a PCIA bolus dose of 0.25 mcg/kg (2 min lockout) with a background infusion of 0.025 to 0.1 mcg/kg/min (Table 2). The context sensitive half time is 3.5 minutes in both mother as well as fetus. Maternal effects - Sedation, nausea & vomiting and maternal desaturation requiring O2 supplementation that is short lived. Fetal & Neonatal effects – Because of the remifentanil’s rapid metabolism & redistribution in the neonate after placental transfer, the side effects are very few.

Informed consent

No opioid use in the previous 4 hrs Eligibility

Dedicated IV cannula for Remifentanil infusion

PCIA protocol PCIA bolus – 0.25 mcg/kg

Lockout interval : 2 min

Continuous observations SaO2 (pulse oximetry)

Nursing supervision : one to one

Respiratory rate

30 min observations Sedation score

Pain score

Excessive Sedation score( not arousable to voice) Indications for contacting the

anesthesia personnel

Respiratory rate < 8 breaths/min

SaO2<90% while breathing room air.

Table-2. Suggested Guidelines for Patient controlled IV Analgesia (PCIA) with remifentanil

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Optimal remifentanil PCIA regimens may well require titration against individual patient response as well as a titration in dose requirements as labour progresses. Further developments may include synchronization of the remifentanil PCIA bolus dose to the tocodynamometer recording so that the maximum analgesic effect of the drug can occur at the peak of the uterine contraction. Administration of the bolus during the period between contractions may also potentially improve efficacy. Dexmedetomidine Dexmedetomidine, a highly selective α2 agonist with negligible placental transfer, may be a valuable adjunct to PCIA by providing additional analgesia without the respiratory depression associated with increasing opioid usage. The successful use of a dexmedetomidine infusion as an adjunct to unsatisfactory fentanyl PCIA is reported in a 31-year-old parturient with spina bifida occulta and a tethered spinal cord reaching L5-S1. Dexmedetomidine significantly improved the analgesic quality; increased sedation was observed, but the patient was easily rousable to verbal stimuli. No episodes of maternal hypotension or bradycardia, or fetal heart rate irregularities occurred. Ketamine Ketamine is a N-Methyl-D-aspartate receptor antagonist, with excellent analgesic property even in subanesthetic doses. It is readily available and is being used currently, even by non-anesthesiologists, to provide “sedation” for minor procedures. Low-dose ketamine infusion in the perioperative period has shown to produce analgesia and decrease the requirements of opioid analgesics. In obstetrics, it is being used as an adjunct to an inadequately functioning spinal anesthesia for caesarean section, as an induction agent for caesarean section and also to provide analgesia during labour in intermittent boluses. In a study conducted by Sam Joel et al a low-dose ketamine infusion (loading dose of 0.2 mg/kg delivered over 30 min, followed-by an infusion at 0.2 mg/kg/h) could provide acceptable analgesia during labour and delivery. INHALATION AGENTS Only inhalation agent still popular in some places is entonox- a 50% nitrous oxide in oxygen. Other agents like desflurane and sevoflurane have also been in use. Entonox: Intermittent inhalation of nitrous oxide can provide analgesia for labor, but it does not completely eliminate the pain of contractions. Suitable equipment must be available to provide safe and satisfactory inhalation analgesia with nitrous oxide. An apparatus that limits the concentration of nitrous oxide (e.g., a nitrous oxide/oxygen blender or a premixed 1:1 cylinder) is required, and it must be checked periodically to prevent the unintentional administration of a high concentration of nitrous oxide and a hypoxic concentration of gas. Inhalation may occur through a mask or a mouthpiece with a one-way valve to limit pollution of the labor suite with unscavenged gases.

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Sevoflurane: Sevoflurane is potentially an attractive inhalation agent for use as an analgesic during labour. Subanaesthetic concentrations offer advantages to mothers including a lack of irritation to the respiratory tract and a pleasant odour. In addition, sevoflurane has a low blood-gas partition coefficient of 0.65 that enables rapid uptake into the central nervous system together with fast washout which results in swift clinical effect and recovery. It has been found that sevoflurane at a concentration of 0.8% provides optimum pain relief in labour. Disadvantage of inhalational anesthetics – pollution of labour suit, mother may lose protective airway reflexes, nausea and vomiting. REGIONAL ANALGESIA FOR LABOUR PAIN Regional techniques provide excellent analgesia with minimal depressant effects on mother & fetus. The regional techniques most commonly used in obstetric analgesia include central neuraxial blocks - spinal, epidural, combined spinal/epidural(CSE), paracervical, pudendal blocks & less frequently lumbar sympathetic blocks. Neuraxial analgesia – is the only technique that can completely relieve the pain of labour. It is the gold standard for labour analgesia, although the technique is not without its own inherent complications. The indications for neuraxial analgesia are 1.Maternal request 2.Hypertensive disorders of pregnancy 3.Preexisting medical disease 4.Multiple pregnancy 5.Previous caesarean section with trial labour 6.Prolonged labour 7.Deterioration in foetal well-being Contraindications - 1. Maternal refusal 2. Coagulopathy & thrombocytopenia 3. Local or systemic infection 4. Inadequate staffing or facilities In modern obstetric anesthetic practice, the aim is to produce a selective sensory block from T10 to L1 while at the same time sparing the motor supply to the lower limbs (L2-L5), the “Mobile Epidurals or Walking Epidurals”. This sparing of motor fibres has been achieved by decreasing the concentration of local anesthetics used by the addition of opioid, most commonly fentanyl. Bupivacaine ranging from 0.0625% to 0.1% with fentanyl 2 mcg/ml is the most popular solution used till recently. Techniques of neuraxial analgesia are elaborated in the following paragraphs. Lumbar Epidural Analgesia Once labour is well established, epidural analgesia can be appropriate at virtually any time of labour when the parturient experiences painful contractions, providing there are no contraindications. In the past, epidural analgesia had been withheld until parturient was in the

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active phase of labour (4 to 6 cm dilated). Now with the introduction of low concentration of local anesthetics with opioids one can start even in the latent phase itself. Drug regimen 1. Epidural catheter is positioned & placement verified 2. Initial block – 10 – 15 ml bupivaciane 0.1% with fentanyl 2 mcg/ml 10 – 15 ml ropivacaine 0.125% - 0.2% with fentanyl 2 mcg/ml 3. Maintenance of analgesia – a. Intermittent bolus technique 10 ml bupivacaine 0.1% with fentanyl 2 mcg/ml injected once in 60 to 90 minutes 10 ml ropivacaine 0.125% - 0.2% with fentanyl 2 mcg/ml injected once in 60 - 90 minutes Advantage - better spread of the local anesthetic in the epidural space with better analgesia. Disadvantage - is the breakthrough pain b. Continuous infusion technique 0.0625% Bupivacaine with fentanyl 2 mcg/ml at 8 – 15 ml/hr Advantages are i. Maintenance of a stable level of analgesia ii. A more stable maternal heart rate and blood pressure with decreased risk of hypotension. iii. A less frequent need to give bolus doses of local anesthetic which may reduce the risk of systemic local anaesthetic toxicity iv. Satisfactory perineal analgesia Disadvantages – continuous infusion may limit the spread of drug to a small number of segments and hence may produce inadequate analgesia. c. Continuous infusion with intermittent bolus technique 0.0625% Bupivacaine with fentanyl 2 mcg/ml at 8-15 ml/hr + intermittent bolus dose of 5 to 10 ml of 0.1% bupivacaine with fentanyl 2 mcg/ml whenever there is breakthrough pain. The advantages of both intermittent bolus and continuous infusion techniques will be there without any disadvantage. d. Patient controlled epidural analgesia (PCEA) Initial bolus dose as above Basal infusion – 6 ml/h of 0.0625% bupivacaine with fentanyl 2 mcg/ml Demand bolus dose – 3 to 5 ml 0.0625 – 0.1% bupivacaine with fentanyl 2 mcg/ml Lock out interval – 10 minutes 0.125% ropivacaine with fentanyl 2 mcg/ml can also be used instead of bupivacaine in the same dose Advantages 1. Effective labour analgesia 2. Excellent patient satisfaction 3. Decreases the total amount of LA used

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4. Lessens unwanted effects like hypotension & motor block 5. Reduces the demands on staff 6. Gives many parturient with a feeling of empowerment Combined Spinal Epidural Analgesia (CSE) The CSE technique is widely used in obstetric practice. It offers effective, rapid- onset analgesia with minimal risk of toxicity or impaired motor block. It also provides the ability to prolong the duration of analgesia as required through the use of an epidural catheter. If operative delivery is required, the same catheter can be used for providing anesthesia. Many methods may be used to perform a CSE block a. Epidural catheter insertion followed by spinal needle placement at a lower interspace b. An epidural needle beside the spinal needle at the same interspace with specially designed needles. The most commonly used “needle- through- needle technique, which involves identification of epidural space & insertion of a long fine-bore pencil point spinal needle through the epidural needle until the tip of spinal needle pierces the dura. Free flow of CSF confirms correct placement & the opioid alone (25 mcg of fentanyl) or in combination with local anesthetic (0.5 ml of 0.5% bupivacaine heavy + fentanyl 25 mcg) is injected. After spinal injection, the spinal needle is withdrawn & the epidural catheter is placed 3 to 5 cm into the epidural space via the epidural needle. CSE technique potentially provides the advantages of a spinal anesthetic with a fast onset of analgesic action, reliable anesthesia of sacral roots, a high quality of analgesia especially during the second stage of labour, high maternal satisfaction and low maternal and cord blood drug concentrations. It also allows the anesthetist to supplement and titrate analgesia using the indwelling epidural catheter An increased frequency of non reassuring FHR tracings & fetal bradycardia occurs with CSE. The etiology of fetal bradycardia may be related to an acute reduction in circulating maternal catecholamine levels after to quick onset of analgesia leading to uterine hypertonicity. The typical fetal bradycardia resolves within 5 to 8 minutes. Computer Integrated PCEA (CI-PCEA) Is a novel epidural drug delivery system that automatically adjusts the background infusion rate based on the number of PCEA demands. A laptop computer with a programmed algorithm is connected to a standard epidural pump. The computer programme automatically adjusts the background infusion rate based on the number of patient’s PCEA demands in the previous hour (Table 3). It has been found that women on CI-PCEA technique had similar local anesthetic consumption compared with demand only PCEA. It was found that CI-PCEA was associated with increased maternal satisfaction.

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CSE: Intrathecal fentanyl 15 mcg + Ropivacaine 2 mg + EP 1.5% lidocaine 2 mg ↓ No infusion ↓ Demand dose: 5 ml*, lockout 10min ↓ Change infusion to 5 ml/h ↓ 2nd Demand within 1 h ↓ Change infusion to 10 ml/h ↓ 3rd Demand within 1 h ↓ Change infusion to 15 ml/h ↓ 4th Demand within 1 h→ Stop infusion and activate alarm (* 0.1% Ropivacaine + fentanyl 2 mcg/ml)

Table 3. Computer integrated PCEA (CI-PCEA)

Programmed Intermittent or Automated Mandatory Epidural Boluses (PIEB) With programmed intermittent epidural boluses (PIEB), the hourly total amount of local anesthetic solution normally used in a continuous epidural infusion is administered as intermittent boluses (eg., two 5 ml boluses every 30 minutes as opposed to a continuous epidural infusion of 10 ml/h). Studies have shown that PIEB resulted in similar analgesia, higher maternal satisfaction, less need for unscheduled rescue boluses and a reduced consumption of Bupivacaine when compared to a continuous epidural infusion. This reduced dose of Bupivacaine is probably related to the better & more uniform spreads of larger volumes of local anaesthetic solution, compared to the slow spread achieved with a continuous infusion. Ultrasound Guided Neuraxial Technique Ultrasound imaging is becoming an increasingly popular aid for performing neuraxial blockade. It may help to identify the midline, localize the epidural space, measure the skin-to-epidural space distance & estimate the angle of needle insertion. Prepuncture lumbar ultrasound assessment provides useful information which may facilitate the placement of epidural needles not only in healthy parturients but also in obese pregnant women and patients with scoliosis. It also has been shown that Ultrasonography used as a teaching tool, improves the epidural placement learning curve by increasing epidural success rate & reducing the number of epidural attempts & catheter replacement for failed labour analgesia. Ultrasound technology can help in better

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understanding of the physiology & pharmacology of neuraxial blockade and the development of a “difficult spine score”. To Walk or Not to Walk in Labour: Ambulatory Labour Analgesia (Walking Epidurals) CSEA performed with subarachnoid opioids (with or without local anesthetic) causes minimal or no motor block and has been referred as the "walking epidural". For ambulatory labor analgesia the CSEA technique offers the possibility of combining rapid onset of subarachnoid analgesia with the flexibility of continuous epidural analgesia. This approach with the application of low-dose local anesthetic and/or opioid can provide a very selective sensory block with minimal motor blockade, allowing parturients to ambulate. The initial subarachnoid dose of bupivacaine, 2.5 mg, and fentanyl, 5-10 mcg is extremely efficacious, abolishing most severe labor pain in 2-3 minutes. Although the initial dose is usually a low-dose mixture of local anesthetic and opioid, fentanyl or sufentanil alone may also be used. Before making the woman ambulate she should be assessed for motor blockade, sensory blockade, postural hypotension and must be accompanied by the attendant or the nurse (Table 4).

Assessment Task

Leg strength (supine) Straight leg raise (both legs)

Postural hypotension sit at bedside

Leg strength & postural hypotension stand at bedside

Leg strength (standing) partial deep knee bend

Ambulation six unassisted steps

Table 4. Motor assessment to determine ability to ambulate unassisted

Patients who have full motor strength may ambulate with assistance of an IV pole on one side and support person (usually her nurse or her partner) on the other. Most patients usually walk around the room or to the bathroom, where they void, spending approximately 10-15 minutes out of bed on each occasion. If the patient is receiving an oxytocin infusion ambulation in close proximity to her bed or sitting in the armchair is usually recommended. It is very important to provide a suitable, safe environment for ambulating parturient (safe floors, no cables, and the like). To avoid epidural catheter displacement an anesthesiologist needs to ensure good fixation of the epidural catheter to skin. Suitable (remote, cordless) foetal monitoring is recommended to ensure foetal well-being.

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There are few reliable data to determine if ambulation in labour is harmful, helpful, or has no effect on the progress of labour and maternal and foetal outcome. Purported advantages of ambulation in labour include parturient's enjoyment of mobility, autonomy and self-control in labour, increased uterine activity and increased intensity of contractions, decreased frequency of contractions, decreased pain, decreased duration of the first stage of labour, decreased incidence of fetal heart rate abnormalities and decreased incidence of operative and/or assisted deliveries. Only small number of studies have failed to demonstrate advantages of ambulation during labour. However, to date no study has shown detrimental effects from ambulation in labour. Test Dose for Epidural Catheter Position Epidural catheter placement may be complicated by blood vessel or dural puncture. The usual test dose given is lidocaine 1.5% 3 ml with 1:200000 adrenaline. If intravascular, increase in the heart rate of more than 10 beats/min will occur within 60 seconds. If intrathecal, then motor block of the lower limbs will occur in 3 – 4 minutes. The test dose should be given at the end of a contraction as the pain of contraction can increase the heart rate. Use of hypobaric lidocaine can produce a very high block when given with the patient in sitting posture. Use of adrenaline also raises a few controversies as adrenaline can produce vasoconstriction of the uterine vessels and can decrease the uteroplacental circulation if the catheter tip is inside a vessel. The second thing is that adrenaline can relax the uterus and can decrease the contractions. Since the concentration of local anesthetic used for labour analgesia is very low, there is an argument saying that test dosing is not necessary. Test dose is necessary for epidural injection for operative delivery, where higher concentration and larger volumes of local anesthetics are used. An alternate means of testing the catheter for intravascular placement is injection of 1-2 ml of air into the epidural catheter while listening over the precordium with the maternal external Doppler monitor for evidence of air. Regardless of the technique used, the safe practice of epidural labour analgesia dictates – 1. Observing for the passive return of blood or CSF through the catheter 2. Aspirating before each injection 3. Giving the test dose after a uterine contraction 4. Maintaining verbal contact with the patient, & looking for the subjective symptoms & objective signs of intravenous or subarachnoid injection of the local anesthetic. 5. Not injecting more than 5 ml of local anesthetic as a single bolus. 6. Having a low threshold for replacing the epidural catheter if uncertainty exists regarding the catheter location Use of Levobupivcaine and Ropivacaine Burke et al. evaluated levobupivacaine and bupivacaine when used to provide epidural analgesia in 137 patients and found both drugs to have equivalent analgesic potency. Convery et al. compared the efficacy of a continuous infusion of levobupivacaine 0.125% and bupivacaine 0.125% in 80 patients requesting labour analgesia. Levobupivacaine and bupivacaine were found

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to be equally effective in provision of labour analgesia in their study. McLeod et al. concluded that when using levobupivacaine in clinical practice, a simple substitution for the same concentration of bupivacaine is all that is required. It would appear, however, that levobupivacaine has not yet significantly displaced bupivacaine for the management of labour pain. This may be due to a lack of perceived safety benefit and/or consideration of the additional costs that are associated with changing to levobupivacaine, which is approximately 2 - 4 times more expensive than bupivacaine. Ropivacaine, a left-turning molecule, was the first new local anesthetic to reach the market. Studies in volunteers and patients suggest that ropivacaine is similar to bupivacaine in onset, duration and extent of sensory block, although motor block is less intense and of shorter duration. Dural Puncture Epidural Technique The dural puncture epidural (DPE) technique is performed by creating a single dural perforation via a spinal needle placed through the shaft of an epidural needle, followed by placement of a catheter into the epidural space. However, unlike the CSE technique, where medications are directly administered through the spinal needle into the subarachnoid space, all medications for analgesia or anesthesia are introduced through the epidural catheter into the epidural space. The dural puncture creates a conduit for translocation of medications from the epidural to subarachnoid spaces, a process that is believed to be responsible for the unique characteristics that are observed with the DPE technique. When compared with the epidural technique, the DPE technique has been demonstrated to improve sacral block onset and spread of anesthesia and analgesia, these properties are particularly advantageous in obstetric patients. In addition, the process of creating a dural puncture with a spinal needle through an epidural needle uses cerebrospinal fluid (CSF) return as a “confirmatory,” definitive end point for the likely positioning of the epidural needle tip within the epidural space. Furthermore, by avoiding direct intrathecal administration of medication, the DPE technique may have fewer adverse effects compared with the CSE technique. Continuous Spinal Analgesia Technique Continuous spinal analgesia can provide excellent labour analgesia & surgical anesthesia if required & is a very reliable, flexible technique. Fear of PDPH is the primary reason it is infrequently used; however, the relative risk of this treatable side effect should be weighed against the many advantages of the technique in specific challenging populations. Although standard epidural catheters (20 G) may be used for continuous spinal analgesia, pediatric epidural catheters (24 G) that can be placed via 20 G needles are available and can be used. Microcatheters of size smaller than 24 G may produce higher incidence of neurological problems due to laminar flow of local anaesthetics & improper distribution in the CSF. Advantage of using a larger sized catheter is that the CSF can be easily aspirated and the intrathecal position can be confirmed.

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Care must always be taken to clearly identify the spinal catheter as such, to avoid the possibility that it may be mistaken for an epidural catheter. When possible, different infusion pumps and tubing should be used for management of the spinal catheter. Ideally pumps and tubing should be reserved solely for this purpose. When connecting, disconnecting, or injecting the catheter, strict adherence to “clean” technique should be used to decrease the risk of contamination. The timing of removal of the intrathecal catheter is a matter of some controversy. It was observed that a much lower incidence of PDPH after intrathecal catheter placement (20 G catheter placed via an 18 G Tuohy needle) if the catheter was left in place for 24 hours after delivery rather than immediately after delivery. Until further evidence is available, it is difficult to recommend a single practice regarding the timing of removal. The catheter should be left in place only if maintenance of sterility can be assured. Suggested solutions for maintenance of Continuous Spinal catheter analgesia are given in Table 5.

Technique Solution

Plain bupivacaine 1.75 -2.5 mg + Fentanyl 15-20 mcg as

Intermittent bolus needed (roughly each 1 -2 h)

0.05% - 0.125% bupivacaine + Fentanyl 2-5 mcg/ml at 0.5

Continuous infusion to 3 ml/h

Surgical anesthesia Preservative free 0.5% bupivacaine 5 mg (1 ml) + fentanyl

15 mcg for the initial dose followed by 0.5 ml boluses of

0.5% bupivacaine until the desired height is obtained

Table 5. Suggested Solutions for maintenance of Continuous Spinal catheter analgesia

Indications – 1. Previous spinal surgery – identification of epidural space and spread of the drug in the epidural space if identified are the problems in such patients. Use of CSA can overcome this problem. 2. Significant cardiac disease – CSA for labour can be managed with intrathecal opioids alone which usually have negligible hemodynamic effects. 3. Morbid obesity – In this group the rate of failed induction, caesarean delivery & the rate of epidural failure is higher. CSA provides a highly reliable route to induce analgesia & anesthesia if required. The incidence of PDPH has been found to be lower in this population.

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4. Difficult epidural catheter placement – covers situations in which an unintended dural puncture occur or when the palpable landmarks for epidural placement are so poor that it becomes essentially a “blind”, best guess needle placement. 5. Difficult airway – Though somewhat controversial, placement of a spinal catheter in a parturient with a difficult airway provides a reliable route to safely induce surgical anesthesia, very rapidly if necessary, without worry about loss of the airway.

Adjuvants with Local Anesthetics Other Than Opioids The COMET group study has demonstrated that low dose bupivacaine-based neuraxial analgesia for labour pain reduces the rate of instrumental vaginal delivery. Such ‘mobile’ epidurals can give adequate labour analgesia provided the drug regimen includes adjuvants that will reduce pain transmission in an additive or synergistic fashion. Lipophilic opioids such as fentanyl & sufentanil have proven their efficacy & safety profile in millions of pregnant women. However undesirable side effects such as nausea, vomiting, pruritis, sedation required to search for alternative adjuvants, that might provide a local anesthetic sparing effect without producing unwanted side-effects. Epidurally administered clonidine (an α2 receptor agonist that modulates pain perception at spinal level) and neostigmine (an acetylcholinesterase inhibitor, that indirectly stimulates both muscarinic & nicotinic receptors in the spinal cord) are promising agents for labour analgesia. Studies have confirmed that a combination of clonidine 75 mcg & neostigmine 500 mcg administered epidurally as a part of CSE technique with ropivacaine & sufentanil prolonged the initial analgesic effect of the spinal component of the CSE, provided a subsequent local anesthetic sparing effect and did not result in any maternal adverse effects such as hypotension, nausea or sedation, or in any neonatal adverse outcome. But clonidine alone when administered without neostigmine produced significant maternal hypotension. Van de Velde et al administered neostigmine (500 mcg) and clonidine (75 mcg) epidurally after performing combined spinal-epidural analgesia in labour. The duration of initial analgesia was extended from 95 to 144 minutes and overall local anesthetic consumption was less. Interestingly, nearly a quarter of the women in the neostigmine/clonidine group delivered before additional analgesia was required. This may serve to be a useful technique in the future but caution is advised on a number of levels: the mixing and dilution of drugs at the bedside raises sterility and error issues and this technique has a number of ethical and medico-legal implications. Low concentration of epidural ropivacaine (0.125%) combined with dexmedetomidine (0.5 mcg/kg) has been found to reduce the feeling of pain, and not showing the problems of motor blockade, hemodynamic instability, extension of production process and complications such as nausea and vomiting. Side Effects & Complications of Regional Techniques While neuraxial analgesia is usually safe, complications can occur. Some may be directly attributable to drugs or techniques (Table 6). Inadequate analgesia – Neuraxial analgesia failure is defined as epidural or CSE procedures resulting in inadequate analgesia or no sensory block after adequate dosing at any time after

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initial placement, inadvertent dural puncture, intravascular placement or any technique requiring replacement or alternative management. Analgesia may be absent, asymmetrical or unilateral. To solve the problem, it may be appropriate to administer a low-dose large volume bolus or to pull the epidural catheter back one or more centimeters. However, if adequate analgesia has not been established within an hour, consideration should be given to replacing the catheter with the woman’s consent.

Table 6. Complications of neuraxial analgesia Failed Epidural Blocks – is related to several factors – technique related factors, catheter related factors & patient factors.

Complications

Epidural

CSE

Failure rate

14%

10%

PDPH

0.21% - 1.6%

0.2% - 1.7%

Nerve damage

0.6/100000

3.9/100000

Epidural abscess

0.2 – 3.7/100000

3/100000

Meningitis

0 – 3.5/100000

0 – 3.5/100000

Epidural hematoma

1 in 168000

Foetal H.R abnormalities

5.5%

31.7%

Pruritis

4.7%

8.3%

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Technique related factors- 1. Specialists versus trainees performing the block – more failures with the trainees. 2. Length of the catheter inserted inside the epidural space. Catheter should be inserted only for 3-4 cm. Increased failure rates occur when introduced for more than 5 cm. The engorged veins in the epidural space direct the catheter to move out through the intervertebral foramen. 3. The loss of resistance technique used - more failures when air was used compared to saline. It is said that epidural air bubbles may cause incomplete block by preventing spread of local anaesthetics and also more likely to cause headache as a result of pneumocephalus. 4. CSE versus epidurals – less failure rates when CSE is used compared with only epidurals. Catheter related factors – multiorifice catheters may be less safe because they can be sited partially subdurally and allow multicompartmental spreads of local anesthetic, but they are less likely to get occluded & requiring re-sitting. Bloody taps are more common with multi-orificial catheters and missed segments are more common when single orifice catheters are used. Patient factors 1. Spinal deformity, disease or previous spinal surgery – are associated with patchy or unilateral blocks. 2. The midline barrier – dorsal connective tissue band in the midline called as plica mediana dorsalis in the epidural space can produce partial block. The band in most of the patients is incomplete. Failed blocks can be managed by partial withdrawal of the catheter, additional fractional doses of local anesthetics with opioid to cross the barrier & change of posture. Accidental Dural Puncture & PDPH Classically the headache which can be severe occurs 24-72 h after the dural puncture & is postdural in nature. The definitive treatment is epidural blood patch, which should be performed without delay once the headache is diagnosed and not getting relieved by non-invasive conservative management. Nerve Damage Epidural catheters may injure nerve roots either because they are inappropriately rigid or because they are threaded too deeply & may compress a root, although a flexible catheter is unlikely to do lasting damage to a nerve root in the epidural space. Infection Epidural Abscess & Meningitis These are infrequent complications of neuraxial techniques. Epidural hematoma inspite of the engorgement of epidural veins during pregnancy causing neurologic deficits is very rare in the obstetric population & perhaps the hypercoagulable state of pregnancy acts as a protective factor. Backache

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Many studies have shown that epidural analgesia in labour does not result in postpartum backache. Short term (5-7 days) local tenderness at the site of the needle puncture occurs in about 50% of mothers. Maternal Fever In recent years there has been much discussion on the association of epidural analgesia during labour & maternal fever. Nulliparity, dysfunctional labour are significant co-factors in the fever attributed to epidural analgesia. It has been found that labour epidural analgesia was associated with maternal intrapartum fever which increased neonatal sepsis evaluation (NSE) rates, necessitating neonatal antibiotic treatment. Fever which is rarely >38°C, related to epidural analgesia should not be the impetus to carry out sepsis screening in neonate. Bladder dysfunction In some mothers epidural analgesia can result in difficulty in passing urine. Bladder distension must not be allowed to occur during labour & the insertion of a urinary catheter should be considered for mothers who are having difficulty passing urine or whose epidural analgesia has been in progress for greater than 6 h. Effect of Epidural Analgesia On the Progress and Outcome of Labour NICE guidelines on intrapartum care which are based on best available evidence, indicate that epidural analgesia - is not associated with a longer first stage of labour or an increased risk of a caesarean birth. -is not associated with a longer second stage of labour and an instrumental birth. The most important factors determining labour outcome however are anesthetic & obstetric management. Therefore -Low concentrations of local anesthetic should be used to minimize motor block. -Oxytocin should be used to augment labour when required. -Maternal pushing in the second stage of labour should, if possible be delayed until the presenting part is visible or until 1 hr after reaching full cervical dilatation. Breast Feeding The benefits of breastfeeding on neonate & infant wellbeing are well established. Breast milk provides adequate nutrients to the newborn while protecting the baby against infectious disease improving neonatal cognitive development & enhancing maternal-infant bonding. Whether or not neuraxial analgesia may impact breast feeding initiation & duration is controversial. Studies have found that neither epidural analgesia alone or epidural analgesia with fentanyl had any adverse effect on the initiation or duration of breast feeding. Low dose local anesthetic/fentanyl regimens do not clinically affect breast feeding. PHARMACOGENETICS

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Clinicians are consistently confronted with variability in patient’s sensitivity to pain stimuli & their response to analgesic drugs. The relevance of pharmacogenetics in labour analgesia has been explored by examining the effect of single nucleotide polymorphism (SNP) 304A>G located in the opioid mu-receptor (OPRM1) gene, on the response to intrathecal fentanyl in parturient in labour. Women with this mutant gene required less fentanyl and also requested supplemental analgesia at a greater cervical dilatation. 304A>G mutation in OPRM1 gene not only affected the potency of intrathecal fentanyl for labour analgesia, bur also modulated pain tolerance. A thorough knowledge & understanding of pharmacogenetics is likely to help in the future to tailor analgesic therapy to suit patients’ needs. CONCLUSION Modern epidural techniques & medications have resulted in more consistent, predictable & effective analgesia during labour. Recent innovations in drug combinations and delivery systems have resulted in a flexible technique that meets the needs of most parturients in a safe and effective manner. The use of low concentrations of local anesthetics, combined with lipid-soluble opioids does not impede the progress of labor or depress the newborn. The addition of patient-controlled epidural analgesia and innovations using new technologies enhance patient satisfaction. REFERENCES

1. Sunil T Pandya. Labour analgesia: Recent advances. Indian J Anaesth 2010;54;400-8.

2. Roanne Preston. Walking epidurals for labour analgesia: do they benefit anyone? Can J Anaesth 2010;57(2);103-6.

3. Silva M, Halpern SH. Epidural analgesia for labor: Current techniques. Local Reg Anaesth. 2010;03:143-53.

4. Yeo ST, Holdcraft A, Yentis SM, Stewart A. Analgesia with sevoflurane during labour: Determination of the optimum concentration. Br J Anaesth. 2007;98(1):105-9.

5. Mhyre JM. What’s new in obstetric anesthesia? Int J Obstet Anesth 2011;20(2);149-59.

6. Volikas I, Butwick A, Wilkinson C, Pleming A, Nicholson G. Maternal and neonatal side-effects of remifentanil patient - controlled analgesia in labour. Br J Anaesth 2005;95(4):504-9.

7. Palmer CM. Continuous spinal anesthesia and analgesia in Obsterics. Anesth Analg 2010;111(6);1476-79.

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8. Preston R. The role of combined spinal epidural analgesia for labour: is there still a question? Can J Anesth 2007; 54(1):9-14.

9. Landolt AS, Milling LS. The efficacy of hypnosis as an intervention for labor and delivery pain: a comprehensive methodological review. Clin Psychol Rev 2011; 31(6):1022-31.

10. Cambic CR, Wong CA. Labour analgesia and obstetric outcomes. Br J Anaesth 2010;105 Suppl 1:I50-60.

11. Horlocker TT. Complications of regional anesthesia and acute pain management. Anesthesiol Clin 2011;29(2):257-78.

12. Landau R. Pharmacogenetics and obstetrics anesthesia. Anesthesiol Clin 2008;26(1):183-95.

13. Toledo P. What’s new in obstetric anesthesia: the 2011 Gerard W. Ostheimer lecture. Int J of Obstet Anesth 2012;21(1);68-74.

14. Dewandre PY, Decurninge V, Bonhomme V, Hans P, Brichant JF. Side effects of the addition of clonidine 75 microg or sufentanil 5 microg to 0.2% ropivacane for labour epidural analgesia. Int J of Obstet anesth 2010;19(2):149-54.

15. Joel S, Joselyn A, Cherian VT, Nandhakumar A, Raju N, Kaliaperumal l. Low dose ketamine infusion for labor analgesia: A double-blind, randomized placebo controlled clinical trial. Saudi J Anaesth 2014;8(1):6-10.

16. Van de Velde M, Berends N, Kumar A, Devroe S, Devlieger R, Vandermeersch E et al. Effects of epidural clonidine and neostigmine following labour analgesia: a randomised, double-blind, placebo-controlled trial. Int J Obstet Anesth 2009;18(3):207-14.

17. Paech MJ, Pavy TJ, Orlikowski CE, Evans SF. Patient-controlled epidural analgesia in labor: the addition of clonidine to bupivacaine-fentanyl. Reg Anesth Pain Med 2000;25(1):34-40.

18. Paech M, Pan P. New recipes for neuraxial labor analgesia: simple fare or gourmet combos? Int J of obstet Anesth 2009;18(3):201-3.

19. Convery P, Bogod D, Young A, McLeod G, Burke D, Russell R et al. Continuous infusion during labour: levobupivacaine vs. bupivacaine. Eur J Anaesth 2000;17:159.

20. Zhao Y, Xin Y, Liu Y, Yi X, Liu Y. Effect of epidural dexmedetomidine combined with ropivacaine in labor analgesia: a randomized double-blinded controlled study. Clin J Pain 2017;33(4):319-24.

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21. COMET Study Group UK. Effect of low-dose mobile versus traditional epidural techniques on mode of delivery: a randomised controlled trial. Lancet 2001;358:19–23.

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Low flow anesthesia – practical considerations

Aruna Parameswari Professor and Head, Department of Anesthesiology, Critical Care and Pain Medicine

Sri Ramachandra University, Porur INTRODUCTION AND THEORY Low flow anesthesia refers to any technique utilizing a fresh gas flow that is less than the alveolar ventilation. The term “low flow anesthesia” was introduced by F. Foldes, inaugurating an anesthetic technique performed with a fresh gas flow of 1 L/min. R. Virtue recommended the use of an even lower flow of 500 ml/min and introduced the term “Minimal flow anesthesia”. Baum et al had defined low flow anesthesia as an anesthetic technique in which a semiclosed breathing system is used recirculating atleast 50% of the exhaled air back to the patient after CO2 absorption. This can be achieved with modern rebreathing systems using a fresh gas flow less than 2 L/min. Low flow anesthesia has also been defined as fresh gas flow of less than half the minute volume, usually less than 3 L/min. Baker, in his editorial has suggested the following modification of Simionescu’s classification of flow rates of gases into anesthetic circuits:

Metabolic flow: 250 ml/min

Minimal flow: 250 – 500 ml/min

Low flow: 500 – 1000 ml/min

Medium flow: 1 – 2 L/min

High flow: 2 – 4 L/min

Very high flow: > 4 L/min There is a limit for reducing the fresh gas flow to avoid gas volume deficiency. Atleast that gas volume has to be delivered into the breathing system, that is definitely taken up by the patient. UPTAKE OF OXYGEN, NITROUS OXIDE AND INHALATIONAL ANESTHETICS During the course of anesthesia, oxygen uptake is constant and is given by the Brody formula. VO2 = 10 x body weight (kg)3/4

More commonly, oxygen uptake can easily be calculated as 3.0 ml/kg/min and is about 250 ml/min in a normal adult. The uptake of nitrous oxide is given by Severinghaus’ formula VN2O = 1000 x t -1/2

And the uptake of inhalational anesthetics may be calculated by Lowe’s formula VAN = f x MAC x λB/G x Q x t -1/2

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Where f x MAC is desired anesthetic concentration, fraction of MAC, Q is cardiac output and t is time. The uptake of nitrous oxide and volatile anesthetics follows a power function. Assuming a constant gas composition circulating within the breathing system, the total gas uptake, the sum of oxygen, nitrous oxide and inhalational anesthetic uptake, follows a power function. Initially it is high and declines sharply during the first 30 min, but it is comparatively low and decreases only slowly during the following course of anesthesia. This is because the partial pressure difference of anesthetic gases between the alveoli and blood is initially high but thereafter decreases continuously with increasing saturation of blood and the tissues. If the anesthesiologist could succeed in approximating the total gas uptake, anesthesia with a closed rebreathing system would be realized. THE PRACTICE OF LOW FLOW ANESTHESIA Premedication and induction can be done using routine techniques with no procedure specific requirements for the practice of low flow anesthesia. Initial High Flow Rate A high fresh gas flow (3 L/min of N2O and 1.5 L/min of O2) has to be used in the initial 10 to 15 min with 1.5% isoflurane, 2.5% sevoflurane or 4 – 6% desflurane. With these settings, an expired concentration of 0.7 – 0.8 MAC of the respective agent will be gained. In addition to a nitrous oxide MAC of about 0.6, corresponding to a nitrous oxide concentration of 60%, this will result in a common MAC of 1.3, guaranteeing sufficient anesthetic depth to tolerate skin incision. A high fresh gas flow initially also ensures sufficient denitrogenation and wash in of the aspired gas composition into the whole gas containing space. If the flow is reduced too early to low values, gas volume deficiency would result compromising adequate ventilation. Flow Reduction After 10 min, the fresh gas flow can be reduced to 1 L/min. With flow reduction, the inspired gas contains a markedly increased proportion of the exhaled gas which already had passed the patient’s lung and contains less oxygen. This decrease in the oxygen content of the gas mixture can be compensated by increasing the fresh gas oxygen fraction, which must be higher, the lower the flow. To maintain a safe inspired concentration of about 30% in low flow anesthesia, the fresh gas oxygen concentration has to be increased to 50%. Also, with flow reduction, the amount of anesthetic vapor delivered into the system is markedly reduced. For example, with a fresh gas flow rate of 5 L/min and sevoflurane vaporizer at 2%, 100 ml/min of sevoflurane vapor is added, whereas with a fresh gas flow rate of 1 L/min and sevoflurane at 2%, only 20 ml/min of sevoflurane vapor is added to the circuit. So with low flow, this reduction in anesthetic vapor concentration has to be compensated by a corresponding increase of the agent’s concentration in the fresh gas; 2 vol% of isoflurane and 3 vol % of sevoflurane is used with flow reduction. Due to its specific pharmacokinetic properties, only the fresh gas desflurane concentration can be

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maintained unchanged. With these standardized schemes, the expired anesthetic concentrations will be maintained in the aspired range of 0.7 to 0.8 times the MAC. Time Constant The time constant is a measure for the time it takes, that alterations of the fresh gas composition will lead to corresponding alterations of the gas composition within the breathing system. According to a formula given by Conway, the time constant can be calculated by dividing the system’s volume (VS) by the difference between the amount of anesthetic agent delivered into the system with the fresh gas (VD) and the individual gas uptake (VU). T = VS/ (VD – VU) A given volume of the system and a given individual gas uptake assumed, the time constant is inversely proportional to the fresh gas flow. This marked increase in time constant has to be taken into account while switching from high to low fresh gas flows. Whenever the gas composition within the breathing system has to be changed rapidly, the fresh gas flow has to be increased for adequately accelerating the wash in of the newly aspired gas composition. For newer volatile agents like sevoflurane and desflurane, the time constants will be significantly shorter as VD can be raised considerably and VU is extremely low. Recovery Phase If low flow is maintained, due to the long time constant, the washout and hence the decrease of anesthetic concentration is delayed and slow. Towards the end of the anesthesia, a high flow of gas can thus be used to flush out the anesthetic agents which accelerates their washout. The other method is to use activated charcoal which when heated to 220 deg C adsorbs the potent vapors almost completely. So, a charcoal containing canister with a bypass is placed in the circuit. Towards the end of anesthesia, the gas is directed through the activated charcoal canister. This results in rapid recovery and at the same time, reduction in theatre pollution. Nitrous oxide is washed off towards the end by using 100% oxygen. TECHNICAL REQUIREMENTS FOR SAFE CONDUCT OF LOW FLOW ANESTHESIA Monitoring With flow reduction, the composition of the fresh gas flow does not reliably indicate the composition of the inspired gas mixture. Thus, monitoring of inspired oxygen concentration is absolutely indispensable. The same applies for volatile anesthetics, if fresh gas flow lower than 1 L/min is used. Airway pressure and minute volume also need to be monitored to indicate the gas filling of the breathing circuit. Sodalime consumption increases fourfold if low flow techniques are consistently performed. By monitoring inspired CO2 concentrations, soda lime exhaustion can be reliably detected and replaced when necessary. Anesthetic Apparatus

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The flow control system must feature needle valves to measure very low gas flows. The flowmeter tubes must be calibrated to work reliably even in the low flow range. The vaporizers must feature fresh gas flow compensation. The rebreathing system has to be sufficiently gas tight; the leakage must not exceed 100 ml/min at a pressure of 20 mbar. The reservoir bag or ventilator bellows indicate the volume of the circuit gas. If the volume of gas entering the circuit is less than the total patient uptake plus any leaks, then the reservoir bag or bellos will refill less with each breath. This gives an indication of the total volume of gas flow needed, while oxygen, nitrous oxide and aneshthetic analyzers indicate the composition of the circuit contents. Omission of Nitrous Oxide Without nitrous oxide, the conduction of low flow anesthesia is simpler. As only oxygen and anesthetic agent are absorbed, total gas uptake is noticeably reduced and denitrogenation is no longer necessary. By eliminating N2O, the breathing system filling is improved following the reduction of fresh gas flow. The omission of nitrous oxide in low flow anesthesia

Facilitates a reduction in fresh gas flow by the resulting excess in gas volume and, thus, the increase in gas volume circulating within the breathing system

Reduces the risk of gas volume deficiency

Makes it possible to keep the initial high-flow phase very short since this is only determined by the wash in characteristics of the anesthetic agent used

Makes it possible to achieve closed system anesthesia with conventional anesthetic machines in routine clinical practice

Impedes the further use of anesthetic agents with high blood solubility, such as halothane, since it becomes impossible to deliver sufficient amounts of these anesthetics into the breathing system with the aid of agent specific vaporizers outside the circuit

Augments the concern about Compound A as it becomes possible to use extremely low fresh gas flows. Long lasting closed system sevoflurane anesthesia should be performed using calcium hydroxide lime (non – caustic absorbents).

ADVANTAGES OF LOW FLOW ANESTHESIA OVER CONVENTIONAL HIGH FLOW ANESTHESIA There are several advantages to the use of low flow anesthesia that are obvious and indisputable and were listed in the original Waters’ paper namely, the reduction of anesthetic gas and vapor consumption, the decrease in atmospheric pollution with inhalation anesthetics, the improvement of anesthetic gas climate and the significant reduction of costs. Economic Use of low flow anesthesia reduces the fresh gas flow and anesthetic vapor consumption. This assumes more significance with the use of newer agents like sevoflurane and desflurane which

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are more expensive compared to the older inhalational agents, halothane and isoflurane. Also, the low potency of desflurane mandates the use of more anesthetic vapor and the amount of consumption with conventional fresh gas flows can significantly escalate the costs. Environmental

There are stringent regulations on the maximum acceptable workspace concentrations of anesthetic gases in USA, Europe and Canada. Even with the extremely low anesthetic gas concentrations stipulated by the US National Institute of Occupational Safety and Health, this can be achieved easily only by the use of low flow techniques. The use of gas scavenging systems ensures there is no theatre pollution and permissible workspace levels can be maintained as per the requirements. However, all gases delivered from the anesthetic machines are ultimately lost to the atmosphere. The chlorinated hydrocarbons (halothane, isoflurane and enflurane) are broken down by ultraviolet radiation releasing chlorine atoms that have been shown to deplete the protective ozone layer in the stratosphere. Nitrous oxide also depletes ozone through nitric oxide production, and also reflects heat back to the earth, contributing directly to global warming. The inhalational anesthetics are only responsible for 0.1 - 1% of the global release of chlorofluorocarbons and nitrous oxide accounts for only 3 – 12% of global nitrous oxide release; nevertheless it becomes the responsibility of anesthesiologists to prevent this contribution to environmental degradation. Use of low flow anesthesia would significantly decrease this environmental damage. Desflurane and Sevoflurane are chlorine free, and have less potential for ozone depletion, but may contribute considerably to the greenhouse effect. Improvement of Anesthetic Gas Climate

Inspiration of cool dry gases impairs mucociliary function, with subsequent microatelectasis, potential for infection and impaired gas exchange. Use of low fresh gas flow conserves heat and humidity and improves inspired gas humidification and temperature and is useful in improving the anesthetic gas climate, especially in places where the practice of using heat and moisture exchangers is not routine.

Efficiency of Inhalational Anesthesia

The most striking argument in favour of low flow anesthesia is the marked increase in the efficiency of inhalational anesthesia. The efficiency can be calculated by dividing the amount of anesthetic agent taken up by the patient (VU) by the amount of anesthetic agent delivered into the breathing system (VD). Efficiency = VU/VD As the amount of agent delivered into the system directly depends on the fresh gas flow, the efficiency of the inhalational anesthetic technique is lesser with use of higher fresh gas flows. This is especially applicable to inhalational agents with low solubility and anesthetic potency. If desflurane, for instance, is used with a fresh gas flow of 4.5 L/min at an inspired concentration

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of 6% for a period of 2 hours, the overall efficiency will decline to 0.07. Only 7% of the total amount of agent delivered into the system is really needed and taken up by the patient, whereas 93% is wasted with the excess gas escaping from the breathing system. Only if this agent is applied with low fresh gas flow rates, the efficiency can be increased to an acceptable range of about 30%. The use of anesthetic agents with low solubility and potency can only be justified if judicious use is made of rebreathing techniques.

DISADVANTAGES OF LOW FLOW ANESTHESIA Accumulation of Unwanted Gases in The Breathing System

It is axiomatic that if you put little gas into the breathing system, then little or none will come out. Due to the failure to flush gases out of the breathing system, any gases that are introduced but not taken up by the patient or absorbed chemically will tend to accumulate. Such gases may be exhaled by the patient, be a contaminant of the medical gases or result from a reaction with the chemical agents used for carbon di oxide absorption.

Substances exhaled by the patient These include alcohol, acetone, carbon monoxide and methane. Use of low fresh gas flow is hence contraindicated in patients who are in uncompensated diabetic states, intoxicated, or who are suffering from carbon monoxide poisoning. Carbon monoxide is produced as a metabolite of proteins and during low flow anesthesia, there is a steady and small rise in carboxyhemoglobin. This is unlikely to exceed 3 – 4% even after several hours. Methane is produced by the action of Methanobacterium ruminatum in the large bowels of about 30% of the population and will equilibrate with the circuit gases during low flow anesthesia. It is biologically inert. The amount that accumulates is much less than its lower flammability limit. The only issue with methane is that it absorbs infra red light at 3.3 micrometer about 10 times as strongly as halothane. This can lead to a “mixed agent” warning or will cause inaccuracy of the analyser. Acetone is produced by hepatic metabolism, excreted in the expired gas, and equilibrates in the anesthetic circuit. During prolonged anesthesia, blood acetone concentration can increase, especially in patients with preoperative starvation or increased production (diabetes, cirrhosis). Concentrations more than 50 ppm may cause nausea, vomiting and slow emergence. Contaminants of medical gases Potential contaminants of medical gas supplies include the lethal gases carbon monoxide and nitric oxide. More benignly, nitrogen and argon may accumulate and cannot be detected by infra red analyzers. Argon is biologically and chemically inert. Products of reaction with absorbents

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Chemicals used to absorb CO2 may react with volatile inhalational anesthetics. Trilene was known to break down to phosgene (COH2), which is lethally toxic. Halothane reacts with soda lime to produce hydrofluoric acid and bromochlorodifluoroethylene (‘BCDFE’ BrClC=CF2), though no harm has been attributed to this. Desflurane, enflurane and isoflurane (which contain a difluoromethoxy group: F2HCO-) react with dry baralyme producing carbon monoxide. More degradation of the anesthetic agents and more CO production occur with increased absorbent temperature, high anesthetic concentration and with dry absorbent. Sevoflurane reacts with sodalime to produce an olefin “Compound A” which was considered to pose a risk of renal toxicity. It is accepted that prolonged sevoflurane anesthesia with low fresh gas flows results in proteinuria, glycosuria and enzymuria. However, this has not been shown to be associated with any clinical manifestations, even in patients with pre-existing biochemical renal abnormalities. Much of the laboratory work on renal toxicity was undertaken on rats, where compound A causes acute tubular necrosis at concentrations in excess of 250 ppm. It is now clear that these studies are invalid due to the marked differences between human and rat renal biochemistry. The generally held view is that compound A has a considerable margin of safety in humans at the concentrations typically found during low flow sevoflurane anesthesia (around 15 ppm). Due to the above concern, the FDA (USA) has set a 2 L/min lower limit for fresh gas flow during sevoflurane anesthesia. This was revised to 1 L/min in December 1997 with a 2 MAC hour exposure limit for fresh gas flows between 1 and 2 L/min. Canada and Australia still have a 2 L/min limit while Switzerland and Israel have adopted the US FDA revised guideline. There are no flow restrictions in UK. With the discovery that strong alkalis in carbondioxide absorbents were responsible for the production of both CO and compound A, manufacturers have taken a lot of measures. Removal of all KOH was widely adopted and NaOH levels were reduced. Other approaches included the addition of a zeolite. Molecular sieves are a reusable alternative to soda lime or Baralyme. These are alumino-silicate zeolites, tetrahedral with 4 – 7 Angstrom pores, which retain CO2 by Van der Waal’s forces, and can be regenerated for reuse. In 1999, a novel absorbent was introduced (Amsorb) which contains no strong alkali. Amsorb utilizes hygroscopic agents to ensure that the calcium hydroxide does not become dry. The main claimed benefits of Amsorb are that it produces no CO or compound A, though with the disadvantages of increased cost and reduced efficiency. Danger of Hypoxia and Hypercapnia There is a danger of hypoxemia if an inspired oxygen concentration of 33% is used in low flow anesthesia using nitrous oxide. This is because with time, the nitrous oxide uptake decreases, while oxygen uptake continues, resulting in relatively more nitrous oxide in the expired gas, leading to a hypoxic inspired mixture. Increasing the inspired oxygen concentration to 50%

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prevents this. Also, oxygen analyzers monitor and display the FIO2 and their use during low flow anesthesia would help identify delivery of hypoxic inspired gas mixture and thus rectify it. Soda lime is consumed more when low flow anesthesia is used. A rise in inspired CO2 indicates that absorbent should be replaced. Monitoring endtidal and inspired CO2 concentration thus helps prevent hypercapnia. Inability to Quickly Change Inspired Gas Mixture Due to the long time constant with low flow anesthesia, any change in the fresh gas flow composition takes time to be reflected in the inspired gas mixture. CONCLUSION There is a resurgence of low flow anesthesia technique with the introduction of more expensive inhalational agents of low potency and solubility. The advantages compared to conventional flow anesthesia are enormous and the apparent disadvantages are easily overcome. Understanding the concepts behind low flow anesthesia would allow a safe practice of this technique. REFERENCES

1. Baum JA. Low-flow anesthesia: Theory, practice, technical preconditions, advantages and foreign gas accumulation. J Anesth 1999; 13:166-174.

2. Baxter AD. Low and minimal flow inhalational anesthesia. Can J Anaesth 1997;44:643-653.

3. Baum JA. Nitrous oxide: use in low-flow systems/economics. Best Pract Res Clin Anaesthesiol 2001;15:377-388.

4. Nunn Geoffrey. Low-flow anaesthesia. CEACCP 2008;8:1-4. 5. Yumiko Ishizawa. General anesthetic gases and the global environment. Anesth Analg

2011;112:213-7.

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Statistical analysis, sample size and power estimation

Bala Bhaskar S

Professor, Department of Anesthesiology Vijayanagar Institute of Medical Sciences, Ballari

PART 1: DATA, VARIABLES AND MEASUREMENT THE VARIABLES

During research, many outcomes and observations as defined in the methodology are observed and noted for the sample studied. The types of data are specifically defined during the planning stage and will determine which statistical tests will eventually be used. They could be related to the patients’ clinical status, monitored parameters, laboratory tests or others (manikin, simulations, field studies, etc.). They are identified in a manner to make them measurable in as precise (free of random errors) and accurate (free of systematic errors) as possible. This makes them ‘valid’ and helps to be analyzed statistically.

In general, these observations of interest in a research study are also referred to as variables, in that they can have different values (i.e. they can vary). Basically, there are two types of data/variables. The first type of data includes those which are defined by some characteristics or quality and are referred to as qualitative data. They cannot be quantified. The second type of data includes those which are measured on a numerical scale and are referred to as quantitative data.

Categorical/Qualitative Variables

There are 2 subtypes - ordinal and nominal

Ordinal data have an order, are measured in categories that are ranked in terms of a graded order (or in categories that have specific order). The differences among the categories are not necessarily equal and often are not even measurable. The symbols assigned to represent the categories are not important as long as the ranking system is preserved. Ordinal scale is easy to use, may not require any sophisticated device and in many times easily understood by all.

Examples: Pain score (0 = no pain, 1 = mild pain, 2 = moderate pain 3 = severe pain, 4 = unbearable pain), Extent of Motor block (Bromage scale Gr 0 - Gr 3), Patients status or condition- unimproved, stable or improved, Age- child, adult and old.

Nominal data are measured on scales of names, numbers or other symbols to assign each measurement to one of the limited number of categories that cannot be ordered one above the other.

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Example- Measurement of Blood type – A, B, AB, O, Gender – male or female, Outcome of a Disease – survival, death, diagnosis as hepatitis, cirrhosis, etc., Site of Malignancy- lung, mouth, breast, or ovary, Occupation – farming, business, labor, service etc.

The categories of a nominal scale must be exhaustive and mutually exclusive; each measurement must fall into only one category. Within any category, the members are assumed to be equivalent (not superior or inferior) with respect to the characteristic being scaled.

Numerical/Quantitative Variables

There are 2 subtypes – discrete and continuous

Discrete data takes a countable number of values or distinct values or have only intermittent values over a range. The scale units are limited to integers. Example- number of patients admitted to a hospital, number of deaths recorded in a particular area, number of attacks of diarrhea in a child during a year etc.

Continuous data can take any value over a particular range. They are quantified on an infinite scale. The scale units are not specific integers but have decimals. The number of possible values of body weight, for example, is limited only by the sensitivity of the machine that is used to measure it. Continuous variables are rich in information. Example- Height, Weight, Age, Level of protein in blood, Body temperature, Pulse rate etc.

Discrete variables can have a considerable number of possible values and can resemble continuous variables in statistical analyses and can be equivalent for the purpose of designing measurements.

Dichotomous data have only two possible values (e.g. dead or alive) whereas polychotomous data have more than two categories according to the type of information they contain.

The same variable can be expressed in different ways e.g. smoking status can be recorded as smoker/non-smoker (categorical data), heavy smoker/light smoker/ex-smoker/non-smoker (ordinal data), or by the number of cigarettes smoked per day (discrete data).

Studies generally include more than one type of data. For example, in a study comparing analgesia characteristics of bolus vs. patient controlled analgesia for major surgery, the following may be recorded: pain score (0-4 scale, 0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain and 4 = unbearable pain- these are ordinal data), incidence of respiratory depression (categorical data), total morphine consumption (continuous data) and serum cortisol level (continuous data).

Methodological Classification of Variables

It is necessary to identify the variables that will be involved in the research project being designed; mainly the independent and the dependent variables.

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Independent (predictor) variable is the one that is varied or manipulated by the researcher- any variable whose value determines that of others; it represents the treatment or experimental variable that is manipulated by the researcher to create an effect on the dependent variable.

Dependent variable is the response that is measured. It represents a response, behavior or outcome that the researcher wishes to predict or explain.

“Independent variable causes a change in Dependent variable and it isn’t possible that Dependent variable could cause a change in Independent variable.”

Example-1. A study comparing two local anesthetics on the duration of analgesia: The independent variable is the use of two LAs and the dependent variable is the duration of analgesia.

Example-2. Comparison of two doses of dexmedetomidine to attenuate the intubation response: Independent variable- dose of dexmedetomidine and the dependent variable is the blood pressure/heart rate changes.

Confounding variable (third variable) is a 'confounding factor' - something, other than the thing being studied that could be influencing the results seen in a study which has to be identified and discussed.

Measurement of Variables and Distribution

The categorical variables are expressed as frequency- proportions, percentages and the quantitative variables as mean/median, standard deviation, range (max, min) and interquartile range.

The observed variables are measured for distribution of data and for comparison. They can be distributed uniformly around a central value or may be dispersed away from the central value. This may be checked mathematically or by plotting in a graph (Figure 1). They are expressed in terms of measures of central tendency/location - a single value that attempts to describe a set of data by identifying the central position within that set of data (Mean, Median, Mode) and in terms of measures of dispersion (Standard Deviation, Standard Error, Range, Variance, Percentile).

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Figure 1. Distribution of Data; Mean, Median, Mode; Standard Deviation

PART 2: TYPES OF STATISTICS, DATA DISTRIBUTION, P VALUE AND CONFIDENCE INTERVAL

Statistics is the process of measuring and analyzing data from a sample, in order to estimate certain characteristics of a population. These estimates of a population are most commonly an average value or proportion and these estimates are usually compared with those of another group to determine whether one group differs significantly from the other.

Thus, there are two broad categories of statistics: Descriptive statistics and Inferential Statistics.

Descriptive Statistics

The collected data are summarized in order to characterize features of its distribution. They are measured in terms of central location and of dispersion (discussed already). The mean is the average value (μ), median the middle value and mode the most common value. The descriptive statistics are not “decision” oriented. Pilot studies are descriptive.

Inferential Statistics

The summary data (used for descriptive statistics) are processed in order to estimate or predict characteristics of another (usually larger) group i.e., the tests extrapolate sample data to generalizations, usually with calculated degrees of certainty. Inferences are drawn from the sample data for generalization to the larger population, with some degree of certainty.

1. Number of Variables and Analysis Univariate - is the analysis of one (“uni”) variable at a time. It doesn’t deal with causes or relationships and its major purpose is to describe. It summarizes data and finds patterns in the data. The variable in univariate analysis is just a condition or subset that the data falls into. It can be taken as a “category.” For example, the analysis might look at a variable of “age” or it might look at “height” or “weight”.

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Bivariate - is the analysis of exactly two variables at a time

Multivariate- is the analysis of more than two variables at a time

2. Distribution of Data The distribution (Figure 2) of data could be uniform around the central area (when mean, median, mode assume same value) or non-uniform with mean, median and mode not aligned as the same value. In a skewed distribution, the median is a better measure of central tendency.

Figure 2. Distribution of data

The uniform distribution is referred to as the Gaussian/symmetrical distribution; it is a symmetrical bell-shaped curve with a mean (μ) of 0 and a standard deviation (sigma-σ) of 1. This is also known as the z distribution (Figure 3a). The non-uniform distribution is referred to as the Non-Gaussian distribution or asymmetrical distribution (Figure 3b). The data representation and the statistical test applied varies with Gaussian and Non-Gaussian data. Gaussian Data has better validity with respect to statistical tests.

Figure 3. a (to the left) Gaussian Distribution (Mean SD) b (to the right). Non Gaussian Distribution [Median- Range (IQR)]

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In a normal distribution, one SD either side of the mean includes 68% of the total area, two standard deviations 95.4% and three standard deviations 99.7%. 95% of the population lies within 1.96 standard deviations (Figure 4).

Figure 4. Standard Deviation

Standard deviation (SD) is therefore a measure of variability and should be quoted when describing the distribution of sample data. Standard error (SE) is the SD of sample means (from 2 or more groups) used to calculate 95% confidence intervals (CI) and so is a measure of precision (of how well sample data can be used to predict a population parameter). SE is a much smaller value than SD and is often presented (wrongly) for this reason.

3. Inferences from data: The role of p values & Confidence Interval

p value

Once data are gathered from a study, statistical testing is performed and the statistical test looks at the likelihood that a certain result would have occurred based on some assumptions/hypothesis about the underlying population and outcomes being studied. However, certain proportion of results favoring the hypothesis could occur by chance despite the best methodology and this is the p-value; a measure of the effect of chance within a study. It is not the probability that the result of the study is true or correct. This ‘chance’ occurrence is universal but the aim is to keep this to a minimum; an average value of 0.05 is universally accepted. That is, the result could occur by chance in 5 out of 100 instances. The p value lies outside of the 2 SD (Figure 5).

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Figure 5. p value and the SD (outside the 95%)

Confidence Interval (CI)

Confidence interval is the range of likely values for a population parameter, such as the population mean. It is an estimate to provide a range that is likely to include the true value; the boundaries of a CI give values within which there is a high probability (95% by convention with a p value of 5%) that the true population value can be found. Calculation of a CI considers the standard deviation of data and the number of observations. Thus, a CI narrows as the number of observations increase or its variance (dispersion) decreases. The 95% CI, by convention is indicative of 2 SD (Figure 6a and 6b).

Figure 6a. Confidence Interval (within 95% with 2 SD)

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Figure 6b. Confidence Interval

Statistical Significance - p and CI

The choice of a specific cut off point for a p-value or degree of confidence for CI, as mentioned already is arbitrary but conventional (p-value of 0.05, 95% CI). There is no particular reason why a different p-value e.g. 0.02 and a corresponding 98 % CI could not be the standard for calling a result "statistically significant". Different values may be targeted based on the importance of the hypothesized outcome; for example, minimal p and maximal CI may need to be targeted in mortality related studies.

It is important not to draw too many conclusions from the p value; there may not be correlative practical implications of p values on either side of the chosen p value. The value of 0.01 (rather than 0.05) need not be clearly indicative of a result of the study being tightly restricted to avoid results occurring by ‘chance’. Also, marginally higher value e.g. 0.06 need not also mean that the errors have possibly been higher, leading to higher rates of events occurring by chance. Despite this loss of predictability, it is common and logical to take very small p-values as a stronger evidence in support of a hypothesis than p-values close to 0.05.

PART 3: CHOOSING THE STATISTICAL TEST

The following factors influence the choice of the test (the basic tests are covered).

1. Type of variable considered and how they are measured:

Numerical/Quantitative (Discrete/Continuous, normally Mean & SD)

Categorical/Qualitative (Ordinal/Nominal, normally proportions-frequencies/percentages)

2. Distribution of Data: Gaussian or non-Gaussian.

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Gaussian distribution is demonstrated either a. graphically, b. by comparing the values of Mean and Median/Mean and SD

a. The data can be plotted on a graph and distribution assessed

b. Difference between the mean and median values of variable are checked if the difference is more than 1.5% or the SD is more than 40%, it represents non-Gaussian distribution (Mathematical) 3. If the Distribution is Gaussian, data is more amenable to statistical analysis and parametric tests are applied. If the Distribution is Non-Gaussian, non-normal or skewed, data can be transformed so that they approximate a normal distribution; commonly by log transformation, whereby the natural logarithms of the raw data are analyzed to calculate a mean and standard deviation (data transformation). The antilogarithm of the mean of this transformed data is known as the geometric mean. One of the ‘goodness of fit’ tests, Kolmogorov- Smirnov or Shapiro-Wilk test is applied for this to see if the transformed data approximate to a normal distribution. If they do, they can then be analyzed with parametric tests. If the Non-Gaussian characteristic stays, non-parametric tests are applied. 4. Check what type of variables to compare:

A. Numerical data B. Categorical data

5. Check whether the data are related or unrelated:

Related means comparison within the same group, of a variable, before or after an event or intervention- also called ‘dependent variable’ comparison. Unrelated means comparison of variables, between groups- also called ‘independent variable’ comparison. 6. Define X – the number of groups and Y- normal or non-normal distribution and choose one of the statistical tests as per the figures below (Figure. 7, 8).

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Figure 7. Numerical data and the choice of statistical test

Figure 8. Categorical data and the choice of statistical test

PART 4: SAMPLE SIZE AND POWER

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Sampling is the process of selecting a group of people from a larger population and subjecting that group for the research. The study outcome is then extrapolated to large population group as research cannot be viable/economical/ethical to be conducted in the bigger population/group.

WHAT IS THE CORRECT SAMPLE SIZE?

The sample size has to be adequate- smaller size will not reflect significant, true & valid differences in outcome. Larger size will be difficult, time consuming, uneconomical and unethical. It also represents a number, beyond which additions are quite unlikely to change the conclusion.

Thus, under-sampling

- may not achieve statistical significance

- results may not be consistent when trial is repeated

- questionable validity of research

Larger sampling

- may show statistical significance even if the clinical significance is minimal

- unnecessary exposure of population to new drug

- greater economical and ethical burden.

There are numerous formulae for sample size calculation but can now be obtained from statistical software easily. Basics principles and considerations related to sample size calculation are discussed below.

1. The Primary Outcome Criteria

2. The hypothesis/assumptions and errors (Alfa, Beta, Power and CI)

3. Effect size

4. Measures of primary outcome: Mean, Proportion, Percentages

Primary Outcome Criteria

Aim for ONLY one Primary outcome measure e.g. study on post-operative analgesia – primary outcome measure can be duration of analgesia or 24 hour analgesic requirement (only one chosen).

Hypothesis and Errors

Before the study is started, while methodology is created, assumptions are done with respect to the outcomes. The assumptions, for example, can be that a new analgesic as compared to a standard analgesic has SAME outcomes or has IMPROVED outcomes (duration of analgesia). Such

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assumptions/hypotheses are referred to as null hypothesis (assumes no difference between the control and the study group) or alternative hypothesis (assumes that there is a difference among the groups or there is some association between the predictor and the outcome). Majority of the studies in anesthesia use alternate hypothesis as new drugs, routes, doses, new techniques, devices, etc. are studied.

The Errors

The hypothesis need not be and will not always be correct because there can be some errors, reflected in the form of false positives or false negatives.

For example, in a study comparing spinal bupivacaine and ropivacaine (30 sample size each) for post-operative analgesia, the assumption could be that ropivacaine ‘produces longer duration of sensory block’ as compared to bupivacaine, by about 25%. Let us check with one group; if 22/30 patients in ropivacaine group had prolonged analgesia, it could be that 20/22 had actual prolongation (true +ve) but 2/22 (false +ve) reported prolongation but this could be because of errors/chance. This incorrect claim of statistical significance (false +ve) is a Type 1 error (α); the probability of Type I error in any hypothesis test is FIXED traditionally at 0.05 or 5% (CI= 95%).

If 8/30 patients in ropivacaine group showed reduced duration compared to bupivacaine group, it could be that 5/8 had actually reduced duration (true –ve) but 3/8 (false –ve) reported reduction, could be because of errors / chance. This incorrect claim of statistical significance (false -ve) is a Type 2 error (β); probability of Type II error in any hypothesis test is FIXED traditionally at 20%.

The impact of a false positive error (Type I) is more detrimental than that of false negative (Type II) error; hence, the error rate of Type I error (α, at 5%) is customarily set lower than Type II error (β, at 20%).

When we say that we allow up to 20% of false negatives, that means this 20% should have been positives, but only 80% is shown as positives. This is the basis of Power of a study; a power of 80% means that the hypothesis would definitely be correct in 80/100 instances. Greater the power, greater the likelihood of true positive outcomes and lesser the false negatives. That is, the probability of minimizing the type 2 error, represented as the complement of β; 1-β (100-20) =80% (traditionally).

Effect size

This is the minimum difference that the investigator wants to detect between the groups. This can be obtained from pilot study, previous studies, clinical judgment or expert advice. Continuing with the previous example, we can assume the duration of sensory block with ropivacaine to be longer than that with bupivacaine by 30% (or 60 min). This is called the ‘effect size’.

Measures of Primary Outcome

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Define primary outcome in terms of mean/proportion/percentages. Example: duration of sensory block as Mean - 216 ± 34 min, anti-emetic efficacy - Incidence of PONV as percentages / proportions - 30% or 60/200 patients.

Calculation of Sample Size

The parameters mentioned above are used as input for calculation of sample size using formulae or software. The formulae are incorporated into the software either online or offline and the input values are provided. The software/online system will display the sample size. Software for the calculation of sample size for different designs of study are available at http://powerandsamplesize.com, www.openepi.com, www.stata.com, www.spss.com, www.poweranalysis.com, www.nmaster.com. The last one is available from the department of biostatistics of CMC Vellore for use with Windows OS. openepi.com is a totally free website and is user friendly.

Statement of Sample Size Calculation

When all above criteria as required for sample size calculation are obtained and used for calculation, the sample size is calculated and a statement as below is made (example) -

“Assuming a duration of analgesia of 150 min and standard deviation of 15 min in first group, keeping power at 80% and confidence intervals at 95% (alpha error at 0.05), a sample of 24 patients would be required to detect a minimum of 20% (30 min) difference in the duration of analgesia between the two groups, we included 27 patients in each group to compensate for possible drop outs.”

Summary

Statistics is a field of assumptions and relations, not decisions and final validations. Knowledge about the basic principles of statistics is useful so that the right input of right data is provided to the bio statistician. Wrong analysis of right data can lead to wrong outcome decisions. It is advised to involve the bio-statistician from planning stage of the study itself.

Understanding the types of variables, distribution of the data, errors, basics of descriptive and inferential statistics will help in choosing the best statistical test. Sample size calculation should take into consideration the type of variable, the groups, the hypothesis, type 1 and type 2 errors along with the primary outcome parameter with effect size.

REFERENCES

1. Myles PS, Gin T (editors). Statistical methods for anaesthesia and intensive care. 1st ed. Oxford [England], Butterworth-Heinemann. 2000;1-176.

2. Garg R. Methodology for research I. Indian J Anaesth 2016;60:640-45. 3. Bhaskar SB, Manjuladevi M. Methodology for research II. Indian J Anaesth 2016;60:646-

51.

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4. Ali Z, Bhaskar SB. Basic statistical tools in research and data analysis. Indian J Anaesth 2016;60:662-69.

5. Das S, Mitra K, Mandal M. Sample size calculation: Basic principles. Indian J Anaesth 2016;60:652-56.

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Ventricular dysfunction and the anesthetist

Rajesh Shetty Lead Consultant, Multidisciplinary Critical Care Unit

Manipal Hospital, Bengaluru

INTRODUCTION

Ventricular dysfunction can be broadly classified into two categories-left ventricular (LV) dysfunction and right ventricular (RV) dysfunction. Left ventricular dysfunction can be further categorized into systolic and diastolic dysfunction. In this lecture we will discuss perioperative assessment and management of LV and RV dysfunction.

LEFT VENTRICULAR DYSFUNCTION

Definitions

Systolic Dysfunction

Systolic dysfunction is characterized by increased ventricular volume and reduced ejection fraction (EF).

Diastolic Dysfunction

In diastolic dysfunction patients have abnormal pattern of left ventricular [LV] filling and elevated filling pressures, but normal or near normal LVEF and LV volume.

Risk Factors

The most common causes of systolic dysfunction are ischemic heart disease, valvular heart disease, idiopathic dilated cardiomyopathy, and hypertension. Causes of diastolic dysfunction include ischemic heart disease, hypertension, hypertrophic obstructive cardiomyopathy and restrictive cardiomyopathy.

Clinical Features

The history, including assessment of New York Heart Association (NYHA) functional class, provides a reasonable estimate of the severity of the heart disease.

Symptoms of heart failure (HF) include decreased exercise tolerance, paroxysmal nocturnal dyspnea, cough, orthopnea, peripheral edema, and nocturia. Poor exercise tolerance is defined as the inability to walk at least four blocks or climb two flights of stairs without having to pause.

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Worsening exercise tolerance or recent use of additional pillows in order to sleep without dyspnea may indicate progression of disease.

Lack of heart failure symptoms is not necessarily reassuring. Asymptomatic patients with known heart failure have often made behavioral adjustments to minimize their symptoms. However, clinical manifestations may develop in these patients with the stress of surgery. Therefore, it is important to evaluate all patients for a prior diagnosis of heart failure (e.g., ischemic cardiomyopathy, idiopathic [nonischemic] dilated cardiomyopathy, familial cardiomyopathy) and known risk factors for heart disease (e.g., atherosclerotic disease, hypertension, obesity, diabetes, drug or alcohol toxicity).

Physical examination in patients with heart failure may reveal a third heart sound (S3), elevated jugular venous pressure, hepatomegaly, ascites, rales, wheezing, diminished breath sounds and a laterally displaced apical impulse.

Pre-Operative Assessment and Optimization

Basic Cardiac Testing

As per 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for perioperative cardiovascular evaluation, a preoperative resting 12-lead electrocardiogram should be obtained in patients with known atherosclerotic disease, significant arrhythmia, or other significant structural heart disease, except for those undergoing low-risk surgery.1 It is reasonable to obtain a metabolic panel (sodium, potassium, chloride, carbon dioxide, glucose, blood urea nitrogen and creatinine) since heart failure patients often have electrolyte imbalances due to administration of loop diuretics, and may have renal insufficiency due to cardio-renal syndrome.

Chest radiograph should be obtained in patients with acute decompensated heart failure to look for evidence of pulmonary vascular congestion and pulmonary edema.

Specialized Cardiac Testing

2014 ACC/AHA guidelines for perioperative cardiovascular evaluation state that LV function should be evaluated preoperatively in patients with dyspnea of unknown origin, worsening dyspnea, or other change in functional clinical status.1

Echocardiography

In patients with symptoms or signs of new or worsening HF, echocardiography may be useful to establish the etiology. Echocardiographic quantification of the severity of both systolic and diastolic dysfunctions may guide perioperative management in patients with symptomatic HF. For example, if severe systolic dysfunction is identified, then inotropic therapy might be preferable to fluid administration for ensuring end-organ perfusion, and anesthetic agents causing myocardial depression might be avoided or administered in low doses. If severe diastolic dysfunction in a small non-compliant LV is identified, then it is important to maintain adequate

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preload. Under filling the LV may result in decreased cardiac output and concomitant hypotension, even if the LV ejection fraction (EF) is normal.

Noninvasive Exercise Testing or Pharmacological Stress Testing

Although cardiopulmonary exercise testing or dobutamine stress echocardiography may add predictive value in HF patients with poor functional capacity, screening with such noninvasive stress testing is not indicated unless management would be changed. These tests are valuable for detection of inducible ischemia, rather than LV dysfunction.

In all patients with clinical signs and symptoms of heart failure, cardiac status is optimized to the extent possible prior to surgery. Consultation with the patient's cardiologist in the immediate preoperative period is desirable.

Medications

In patients already taking the following medications for treatment of HF, considerations for anesthetic care include:

Beta-blockers – Chronically administered beta-blockers are continued perioperatively.

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers – Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are generally continued perioperatively unless there is evidence of hemodynamic instability, hypovolemia or acute elevation of creatinine.

However, patients receiving chronic ACE inhibitor or ARB therapy are more likely to develop hypotension during anesthesia, particularly during induction. The probable mechanism for hypotension is volume depletion with inability to activate the sympathetic nervous system. Treatment of perioperative hypotension includes careful volume expansion and/or administration of vasopressor or inotropic agents.

Some clinicians administer the evening dose of an ACE inhibitor or ARB on the day before surgery (but not on the morning of surgery), particularly if significant perioperative fluid shifts are anticipated. One observational study in patients undergoing non-cardiac surgery found that withholding an ACE inhibitor or ARB for 24 hours was associated with reduced risk of intraoperative hypotension and adverse outcomes. However, the clinical applicability of this retrospective analysis for patients with chronic HF is unknown, and postoperative hypertension is more likely if these agents are withheld on the day of surgery.

Importantly, ACE inhibitors or ARBs are resumed early in the postoperative period. Failure to restart these agents within 48 h after surgery has been associated with increased 30-day mortality.

Aldosterone antagonists -- In HF patients receiving an aldosterone antagonist, hyperkalemia is the most important potential adverse effect, especially if aldosterone antagonists have been

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chronically administered in combination with ACE inhibitor. Thus, the preoperative potassium level should be checked.

If the patient is hyperkalemic (e.g., potassium ≥ 6.0 mEq/l), the optimum approach is based upon the urgency of surgery. If there are no ECG changes and the patient is otherwise stable, emergency surgery may proceed with continuous intraoperative monitoring of the ECG and frequent monitoring of the potassium level. If ECG features of hyperkalemia are present, medical management should be initiated. Aldosterone antagonists are typically resumed in the perioperative period.

Diuretics -- Perioperative hypovolemia and hypokalemia are the major physiologic effects of concern in patients receiving chronic diuretic therapy. Close attention to electrolytes is necessary.

Digoxin -- The role of digoxin in the perioperative period is not well defined. Although administration of digoxin may decrease the incidence of postoperative supraventricular arrhythmias, the anesthesiologist must be prepared to treat other digoxin-induced arrhythmias.

Anticoagulants -- Perioperative management of anticoagulation balances thromboembolic risk and bleeding risk to determine the optimum timing of anticoagulant interruption and whether to use bridging anticoagulation.

Implantable Cardioverter Defibrillators and Pacemakers

Patients with HF frequently have a pacemaker and/or implantable cardioverter defibrillator or a biventricular pacemaker inserted to provide cardiac resynchronization therapy. Perioperative management of these devices is discussed elsewhere.

Intraoperative Management

Risks

Patients with HF are at risk for hypotension, hypertension and arrhythmias during surgery. These hemodynamic aberrations are due, in part, to the stress response induced by surgery, with release of catecholamines, steroids and inflammatory mediators, which increase metabolic demand. The increased metabolic demand must be met by an adequate increase in oxygen delivery, typically achieved by an increase in cardiac output.

Cardiac output is determined by heart rate, preload, afterload, and contractility. These factors can be manipulated intraoperatively by:

Control of heart rate and rhythm

Fluid replacement and diuretics

Vasopressor and vasodilator drugs

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Administration of positive and negative inotropic drugs

Hemodynamic Monitoring

Hemodynamic monitoring in patients with ventricular dysfunction depends on patient-specific and surgery-specific factors.

Electrocardiography (ECG)

Continuous ECG monitoring is necessary to detect arrhythmias and/or myocardial ischemia. In patients with ischemic cardiomyopathy, computerized ST-segment trending is superior to visual clinical interpretation in the identification of ST-segment changes and multiple-lead monitoring is more sensitive than single-lead monitoring.

Intra-Arterial Catheter

Invasive measurement of arterial blood pressure is used when moment-to-moment blood pressure changes are anticipated and rapid detection is vital. These conditions apply to patients with pre-existing severe ventricular dysfunction or hemodynamic instability, as well as those undergoing surgical procedures that are likely to cause rapid blood loss or large fluid shifts. The Australian Incident Monitoring Study established the superiority of direct arterial BP monitoring over indirect monitoring techniques for the early detection of intraoperative hypotension.

Monitoring of respirophasic variation in the intra- arterial pressure waveform during positive pressure ventilation is useful as a dynamic parameter to determine fluid therapy. An intra-arterial catheter is also useful to guide management of vasoactive drugs, including vasopressors, vasodilators, and inotropic agents, as well as facilitating the anesthesiologist's ability to obtain frequent arterial blood gas measurements. If possible, the intra-arterial catheter should be inserted prior to induction of anesthesia.

Central Venous Catheter

The decision to place a central venous catheter is based on the potential for significant blood loss and/or large fluid shifts, likelihood of administration of continuous infusions of vasoactive drugs, and challenges in obtaining reliable intravascular access. Measurement of central venous pressure (CVP) provides supplemental data regarding intravascular volume status. CVP is a poor predictor of volume responsiveness in most patients. However, monitoring the trend in CVP values may be helpful to avoid extremes to enable maintenance of adequate preload while preventing volume overload, particularly in patients with right-sided HF.

Pulmonary Artery Catheter (PAC)

PAC monitoring is not routinely recommended for monitoring patients with cardiovascular disease, even those with elevated risk, since there appears to be no benefit and possible harm from PAC use in most patients undergoing either cardiac or non-cardiac surgery. In selected patients (e.g., severe HF that cannot be corrected before major surgery with expected large fluid

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shifts or significant pulmonary hypertension), it is reasonable to insert a PAC to monitor CVP and pulmonary artery pressure as well as determine cardiac outputs, if the practice setting is appropriate (i.e., extensive PAC experience to reduce the risk of potentially harmful incorrect interpretation).

Transesophageal Echocardiography (TEE)

Emergency use of intraoperative or perioperative TEE is indicated to determine the cause of any unexplained persistent or life-threatening hemodynamic instability ("rescue echo") when equipment and expertise are available. TEE may identify hypovolemia, LV and/or RV dysfunction, pericardial effusion or tamponade, intrapulmonary emboli, valvular regurgitation or LV outflow tract obstruction. Also, transthoracic echocardiography is increasingly being used in the operating room by the anesthesiologist or cardiology consultant in emergency situations.

TEE monitoring is also useful to guide fluid management and vasoactive therapy during major surgical procedures, because it allows evaluation of LV and RV size, global and regional systolic and diastolic ventricular function, valvular regurgitation and estimation of pulmonary artery pressure.

In patients at high risk for myocardial ischemia, continuous intraoperative TEE monitoring may be useful to detect new regional wall motion abnormalities suggestive of ischemia. TEE monitoring has higher sensitivity for detecting myocardial ischemia than ECG or PAC monitoring. However, new regional wall motion abnormalities in a high-risk patient may not improve with resolution of ischemia and data regarding the value of TEE in predicting cardiac morbidity in non-cardiac surgical patients are limited.

Choice of Anesthetic Technique

The choice of anesthetic technique for patients with heart failure should be primarily guided by the requirements of the surgical procedure and the patient's preferences. However, when either regional (including peripheral nerve or neuraxial) anesthesia or general anesthesia is surgically appropriate, there may be some benefits to regional anesthesia, such as pre-emptive postoperative analgesia and a decreased risk of pneumonia. In a 2014 review of systematic reviews of neuraxial versus general anesthesia in a wide spectrum of patients, neuraxial blockade reduced zero to 30-day mortality (relative risk [RR] 0.71, 95% CI 0.53-0.94; 20 studies, 3006 participants) in patients undergoing surgery with intermediate to high risk for adverse cardiac events, although there was no overall difference in the incidence of myocardial infarction.

The potential beneficial effects of a regional technique must be balanced on a case-by-case basis against the potential for hypotension (e.g., the sympathectomy induced by neuraxial anesthesia), and other patient-specific factors (e.g., anxiety, reluctance to be awake, inability to cooperate or communicate, inability to lie supine comfortably if necessary for the surgical procedure, or recent antithrombotic drug use precluding neuraxial anesthesia).

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Technique for neuraxial anesthesia -- The goal of neuraxial anesthesia in heart failure patients is to produce adequate anesthesia without inducing hypotension. Neuraxial anesthesia can decrease cardiac preload due to sympathetic blockade, with resultant hypotension; this is more likely to occur in patients with HF and/or diastolic dysfunction who are dependent upon adequate preload. Although titrated volume administration in increments of 250 ml may be helpful in restoring BP, fluid overload should be avoided to avoid postoperative sequelae (e.g., pulmonary edema). Thus, if hypotension develops, administration of alpha1 receptor agonists (e.g., phenylephrine) or direct/indirect sympathomimetics (e.g., ephedrine) is preferred to significant volume loading in heart failure patients.

Modified neuraxial anesthetic techniques are a reasonable option (e.g., a low-dose combined spinal-epidural with or without intrathecal opioids, or a very slowly titrated epidural anesthetic), even in HF patients susceptible to hypotension (e.g., recently decompensated HF).

Technique for general anesthesia -- The goal of general anesthesia in HF patients is to produce an unconscious state without inducing hypotension due to relative "overdosing" of the selected induction agent.

Induction — A reasonable approach to induction of general anesthesia is use of a short-acting hypnotic (e.g., etomidate 0.15 to 0.3 mg/kg, ketamine 1 to 2 mg/kg, or a low dose of propofol 1 to 2 mg/kg); a moderate dose of an opioid (e.g., fentanyl, 1 to 2 mcg/kg) and/or lidocaine 50 to 100 mg may be administered to blunt the tachycardia response to laryngoscopy and intubation; and a muscle relaxant with rapid onset. Anesthetic induction in patients unable to lie supine because of orthopnea may be accomplished with elevation of the back of the operating room table.

The choice of short-acting hypnotic is based on patient-specific factors:

Etomidate: In heart failure patients with hemodynamic instability, etomidate is useful since it has minimal hemodynamic side effects. Although etomidate transiently inhibits cortisol biosynthesis, the preponderance of evidence suggests that this is not harmful in most clinical settings and does not preclude its use.

Ketamine: In heart failure patients with severely decreased ventricular function, ketamine is a useful agent because it usually results in significant increases in BP, heart rate, and plasma epinephrine levels due to centrally mediated sympathetic nervous system stimulation. This stimulatory effect depends upon the presence of adequate sympathetic reserve. In patients who have maximally activated their sympathetic response (e.g., hemorrhage or cardiogenic shock), ketamine may decrease BP due to its mild direct myocardial depressant effect. Also, in patients with cardiomyopathy due to ischemia, the tachycardia effect of ketamine is undesirable.

Propofol: If propofol is used for induction, the induction dose should be reduced and bolus injections should be administered slowly. An induction dose of propofol, administered as a bolus, may result in profound reduction in BP due to decreased systemic resistance (by inhibiting sympathetic vasoconstriction), decreased preload and direct depression of myocardial

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contractility. This is particularly likely in patients receiving ACE inhibitors or ARBs. Patients with acute decompensated HF who arrive in the operating room already intubated and sedated may not need any IV induction agent, although low doses of opioids, sedatives or a volatile anesthetic agent will be necessary to maintain anesthesia during the surgical procedure.

Maintenance: Use of either a volatile anesthetic agent or total IV anesthesia is reasonable. The cardioprotective effects of volatile anesthetics may be useful in patients with HF caused by ischemic heart disease. However, usual doses of volatile agents should be reduced because these agents are myocardial depressants.

Fluid management

The main goal of intraoperative fluid therapy is to maintain adequate tissue perfusion by optimizing intravascular volume status and stroke volume.

Perioperative fluid management in HF patients is challenging. Prior to surgery, patients may have either intravascular volume overload due to their underlying disease or, conversely, volume depletion due to diuretic administration. During surgery, fluid shifts and/or bleeding may significantly decrease preload.

Adequate preload is necessary for maintenance of adequate cardiac output, particularly in patients with HF due to diastolic dysfunction. However, over hydration has an independent deleterious effect on various organ systems, even in patients who remain hemodynamically stable.

Monitoring volume status

Standard monitors of static parameters including heart rate, arterial blood pressure, peripheral oxygen saturation, as well as supplemental information provided by urine output or CVP in selected patients are used to guide fluid and diuretic administration. Also, total fluid balance is calculated at regular intervals (e.g., every 30 minutes) in an attempt to avoid hypovolemia or hypervolemia.

Dynamic hemodynamic parameters provide superior assessment of response to a fluid challenge (i.e., volume responsiveness), compared with traditional static parameters. Examples include dynamic parameters based on respiratory variation in the intra-arterial pressure waveform (e.g., visual estimation of systolic blood pressure [SBP] variation in the intra-arterial pressure waveform, or devices that analyze and automatically calculate SBP variation, pulse pressure [PP] variation, or stroke volume (SV) variation in this waveform, esophageal Doppler devices that estimate SV, or TEE estimates of left ventricular cavity size provide superior assessments of response to small fluid challenges (e.g., 1 to 2 ml/kg). These monitors may be particularly useful to titrate fluid administration and/or vasoactive drug administration.

A goal-directed therapeutic approach to fluid therapy employs invasive monitoring of these dynamic hemodynamic indices of volume responsiveness. However, it is important to avoid

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hypervolemia, and no studies specifically address the influence of goal-directed therapy on perioperative outcomes in patients with chronic or acute HF.

An indicator of reduced global tissue perfusion is lactic acidosis, which may be due to low cardiac output and inadequate tissue perfusion with resultant anaerobic metabolism. However, these laboratory values do not provide information regarding contemporaneous clinical intravascular volume status since they are measured intermittently and do not immediately reflect acute changes.

Hypovolemia — Hypovolemia leads to low cardiac output and decreased tissue perfusion, and, if severe, can lead to shock and multiorgan failure.

Prevention and treatment of hypovolemia include:

Crystalloids and colloids: Fluids used to optimize volume status are broadly classified as crystalloids and colloids. Intraoperative fluid management with crystalloids and/or colloids is primarily based upon the invasiveness of the surgical procedure. Minimal to moderately invasive surgical procedures not associated with significant fluid shifts or blood loss requires a baseline crystalloid infusion of 1 to 2 ml/kg/h. This infusion may be supplemented as needed with slow administration of smaller than usual (1 to 2 ml/kg) crystalloid boluses in a heart failure patient. For major surgical procedures with significant fluid shifts and hemodynamic lability, large volumes of crystalloids may be detrimental, particularly in a patient with HF. It is preferable to use an approach that combines crystalloids and colloids, with a goal of limiting the total amount of fluid administered.

Blood transfusion: Colloids may be used initially to replace blood loss (on a volume to volume basis) until blood transfusion is indicated by a low hemoglobin level. Although a restrictive transfusion strategy is usually appropriate, transfusion of red blood cells is generally necessary in HF patients with borderline hemoglobin levels (< 8 g/dl), particularly with ongoing bleeding, coagulopathy, or evidence of inadequate perfusion of vital organs. Anemia is common in patients with HF. Whenever significant infusions of fluid or blood are necessary, slow administration may be necessary to avoid exacerbation of HF. Also, warming of blood and/or fluids prior to administration assists in maintaining normothermia to avoid the increased oxygen consumption associated with shivering.

Hypervolemia: Resuscitation with fluids and/or blood may result in volume overload. In HF patients, fluid may rapidly accumulate within the lung's interstitial and alveolar spaces, due to acutely elevated cardiac filling pressures (cardiogenic pulmonary edema). In such cases, diuretics may need to be administered.

Administration of vasoactive agents

If vasodilator, inotropic, and vasopressor infusions are administered, an intra-arterial catheter is necessary for continuous BP monitoring during titration, particularly during ongoing surgical interventions.

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Vasodilator and inodilator agents: In patients with acutely decompensated HF and systemic hypertension or severely symptomatic fluid overload, use of vasodilators (e.g., nitroglycerin, nitroprusside) or inodilators (e.g., milrinone) is reasonable to significantly reduce LV end-diastolic pressure and myocardial oxygen consumption. The choice of a specific agent depends on factors such as presence of myocardial ischemia, severity of hypertension, and need for concomitant inotropic effect with an inodilator such as milrinone. Specific options include levosimendan, an inodilator that increases the sensitivity of the heart to calcium, thus increasing cardiac contractility, and opens adenosine triphosphate channels in vascular smooth muscle. Thus, systolic myocardial contractility is enhanced, while diastolic relaxation is preserved or improved. Vasodilation occurs in the peripheral vasculature, which may result in hypotension. The 2016 European Society of Cardiology (ESC) heart failure guidelines suggest levosimendan (or a phosphodiesterase inhibitor) rather than dobutamine if reversal of the effects of beta-blockade is necessary to treat hypoperfusion. A 2012 meta-analysis noted reduced mortality in medical and cardiac surgical patients receiving levosimendan compared with dobutamine or placebo. However, studies in cardiac surgical patients with a reduced ejection fraction (EF) have not shown benefits in reducing mortality, perioperative myocardial infarction, renal replacement therapy, or need for a ventricular assist device compared with placebo. Also, the vasodilatory effect of levosimendan renders it unsuitable for treating patients with hypotension (systolic BP < 85 mmHg) or cardiogenic shock unless it is combined with other inotropes or vasopressors.

Inotropic agents: In heart failure patients with severe LV systolic dysfunction and low cardiac output syndrome, inotropic agent options include;

Milrinone: 0.375 to a maximum of 0.75 mcg/kg/minute. A loading dose of 50 mcg/kg administered over 10 to 30 minutes is usually omitted to avoid hypotension. Milrinone is often selected because it is a nonadrenergic agent with inotropic and vasodilatory actions, with a lower incidence of dysrhythmias than dobutamine. Milrinone may be particularly efficacious in HF patients who are at risk for beta-receptor down-regulation. However, its vasodilatory properties limit its use in hypotensive patients.

Dobutamine: 1 to 20 mcg/kg/minute. Dobutamine is an inotrope that causes inotropy, chronotropy, and some degree of vasodilation, predominantly by beta adrenergic effects. The net effect is usually increased cardiac output, with decreased systemic vascular resistance (SVR), with or without a small reduction in BP. Due to its chronotropic effect; dobutamine may be preferred in cases where an increase in heart rate is desired. However, dysrhythmias may occur due to the beta1 adrenergic effect.

Vasopressors: Vasopressor therapy is used as a temporizing measure to preserve systemic BP in patients with decompensated HF, marked hypotension and evidence of end-organ hypoperfusion, despite the potential for vasopressor administration to increase afterload and decrease cardiac output. It is reasonable to initially administer IV boluses of ephedrine (5 to 50 mg), epinephrine 4 to 16 mcg, norepinephrine 4 to 16 mcg, or phenylephrine (40 to 100 mcg) to maintain systemic BP while a continuous vasopressor infusion is prepared.

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The following drugs are administered as continuous infusions;

Dopamine: 5 to 20 mcg/kg/minute. Dopamine is an inotrope and a vasopressor. Dopamine doses at 5 to 10 mcg/kg/minute stimulate beta-1 adrenergic receptors and increase cardiac output, with variable effects on heart rate. At doses >10 mcg/kg/minute, the predominant effect is stimulation of alpha-adrenergic receptors, resulting in vasoconstriction and increased SVR. The overall effect of dopamine is weaker than that of norepinephrine and dysrhythmias may occur due to the beta1 adrenergic effect.

Norepinephrine: 1 to 30 mcg/minute; 0.01 to 0.3 mcg/kg/minute. Norepinephrine is a potent inotrope and vasopressor. Norepinephrine acts on both alpha1 and beta1 adrenergic receptors, thus producing potent vasoconstriction as well as a modest increase in cardiac output.

Vasopressin: 1 to 6 units/hour; 0.01 to 0.1 units/minute. Vasopressin is a vasopressor without inotropic properties; it is a very potent direct peripheral vasoconstrictor. Vasopressin administration may be necessary to treat vasodilatory shock (e.g., low systemic vascular resistance due to ACE inhibitor therapy or septic shock) that is severe and/or refractory to other medications.

Management of arrhythmias

Arrhythmias are not uncommon in patients with cardiomyopathy. In patients with acute decompensated heart, external defibrillation/pacing pads should be placed, since defibrillation, cardioversion, or pacing may become necessary. Intraoperative management of serious arrhythmias is summarized below.

Ventricular fibrillation or ventricular tachycardia is life threatening, requiring immediate cardioversion or defibrillation. If the arrhythmia recurs after conversion, antiarrhythmic therapy, particularly amiodarone, may be effective.

Atrial fibrillation is a common arrhythmia, particularly in patients with underlying heart disease. In patients who are hemodynamically unstable (e.g., myocardial ischemia, hypotension, pulmonary edema) due to atrial fibrillation with a rapid ventricular response, treatment options include IV rate control medications and/or cardioversion. Often, management of atrial fibrillation in hemodynamically stable patients may be accomplished with ventricular rate control, using short-acting drugs such as esmolol or diltiazem, or amiodarone. However, if the atrial fibrillation is associated with hypotension or evidence of cardiogenic shock, or is clearly the cause of pulmonary edema, immediate cardioversion to restore sinus rhythm may be necessary.

Bradycardia resulting in signs and symptoms of inadequate perfusion (e.g., hypotension, altered mental status) is usually treated with atropine, while simultaneous preparations are made for transcutaneous pacing and/or a chronotropic agent. (e.g., dopamine, isoproterenol, epinephrine). However, administration of atropine may cause tachycardia, which is undesirable in the setting of myocardial ischemia.

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Postoperative Management

Medical therapy should be resumed in the postoperative period. Patients with heart failure are more likely to develop postoperative complications, including pulmonary edema, myocardial infarction, ventricular fibrillation and cardiac arrest.

Acute decompensated HF typically manifests as respiratory distress with or without pulmonary edema, and may be accompanied by hypertension due to hypervolemia, or hypotension due to cardiogenic shock. Any postoperative patient with evidence of pulmonary edema should be evaluated for new or unstable myocardial ischemia, including continuous monitoring of the ECG and obtaining a 12-lead ECG and troponin measurements.

RIGHT VENTRICULAR DYSFUNCTION

Introduction

RV dysfunction is often present in patients with pulmonary hypertension, with the most common etiology being left heart disease. A single disease process (e.g., myocardial infarction) or concurrent disease processes may affect both ventricles. Other causes of RV dysfunction include cardiomyopathy (e.g., arrhythmogenic RV cardiomyopathy), tricuspid regurgitation, pulmonic stenosis and pulmonic regurgitation.

Pressure and volume overload and/or direct myocardial injury leads to dilatation and increased wall tension, impairment of perfusion, and reduced contractility of the RV, with eventual development of right-sided HF. Patients with severe right HF and/or pulmonary hypertension (PH) may present with oxygen dependence or other overt signs and symptoms of right-sided volume overload.

Patients with right and/or left-sided HF are at greater risk for mortality and major adverse cardiac events in the perioperative period than those with coronary artery disease.

Preanesthetic Assessment

General Considerations

The goals of the preanesthetic consultation are targeted assessment of the severity of PH and/or right-sided HF, functional status and any modifiable factors that would optimize the patient's condition.

Due to increased perioperative risk for mortality and morbidity in patients with severe disease, the anesthesiologist should consult with the surgeon and other treating physicians (e.g., cardiologist or pulmonologist) to ensure that careful consideration has been given to the indications and benefits of surgery, and that potential risks have been discussed with the patient. In selected cases, these consultants may explore nonsurgical alternatives. Examples include minimally invasive or interventional radiology procedures, or cancer treatment with chemotherapy or radiotherapy if appropriate.

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Preoperative medical preparation of these patients may be complex. Occasionally, advanced hospitalization may be needed to optimize intravascular volume status, hemodynamic management, or logistical support for vasoactive infusions. For patients with severe PH and RV dysfunction, necessary surgical procedures are ideally performed in centers with surgical teams, anesthesiologists, cardiologists, pulmonologists and intensivists with expertise in handling these high-risk patients, including the availability of personnel and equipment to provide RV mechanical circulatory support if necessary.

History and Physical Examination

The history is reviewed to assess the patient's symptoms (such as fatigue, dyspnea, chest pain, or syncope), the functional significance of PH (determined by measuring exercise capacity), and the patient's New York Heart Association (NYHA) functional class. Other cardiac, pulmonary, renal, hepatic and hematologic comorbidities are identified.

The physical examination should include assessment of the presence and severity of signs of left- and right-sided HF including assessment of evidence of congestion and an initial assessment of intravascular volume status. Recent changes in the presence or severity of peripheral edema, jugular venous distention, hepatojugular reflux, hepatosplenomegaly, ascites, or tricuspid regurgitation should be noted. If worsened status is detected, the patient's cardiologist is consulted for further management.

Preoperative Testing

Preoperative tests may be ordered by the consulting cardiologist or pulmonologist in selected patients with PH and/or HF (e.g., ECG, chest radiograph, echocardiogram, natriuretic peptide levels, stress exercise testing), depending on the clinical indication, recent prior testing, and the likelihood that such testing might impact decisions regarding perioperative management, timing of the surgical procedure or choice of surgical technique. As an example, an echocardiogram is helpful in patients with symptoms or signs of worsening HF. If a diuretic has been chronically administered, serum electrolytes should be checked for abnormalities that may lead to cardiac arrhythmias (e.g., hypokalemia)

Preoperative Optimization

The anesthesiologist and consulting physicians ensure that intravascular volume status, oxygenation, BP, and HR are in an optimal range, treatable factors exacerbating PH or right-sided HF are managed and essential chronic mediations are continued uninterrupted.

Management of Chronic Medications

Chronically administered medications to ameliorate PH and the underlying diseases leading to PH and/or right-sided HF are generally continued throughout the perioperative period without interruption.

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Medications to Manage Heart Failure

Chronically administered medications to manage right-sided or left-sided HF such as beta blockers, ACE inhibitors, ARBs, mineralocorticoid receptor antagonists and digoxin are generally continued. An ACE inhibitor or ARB can generally be safely administered in the perioperative period. However, since established benefits are from chronic use, brief temporary discontinuation is acceptable when fluid shifts might cause excessive hypotension. Some clinicians administer the evening dose of ACE inhibitor or ARB on the day before surgery (and withhold the dose on the morning of surgery) to avoid intraoperative hypotension.

Diuretics: Chronic diuretic administration is common in patients with PH and/or HF. Administration in the immediate preoperative period (e.g., on the morning of surgery) depends on assessment of the patient's intravascular volume status.

Anticoagulant medications: Chronically administered anticoagulants (e.g., to treat chronic thromboembolic PH) must be managed according to agent-specific, patient-specific, and procedure-specific considerations.

Optimal Intravascular Volume Status

Patients with RV failure and/or PH have poor tolerance for either intravascular volume overload or reduced preload, and the optimal range for preload is narrow. Patients with fluid retention and hypervolemia due to RV failure may benefit from diuretic therapy, but these agents must be administered cautiously to avoid over-diuresis and hypovolemia. In patients with potential or actual hemodynamic instability, intraoperative invasive monitoring is typically employed to establish and maintain optimal intravascular volume status (e.g., central venous catheter [CVC], pulmonary artery catheter [PAC] or TEE]).

The RV has anatomical and physiological differences from the LV, and is designed to pump a large volume of blood against a small pressure gradient. Thus, even small elevations in pulmonary artery pressure can lead to marked decreases in CO in patients with RV failure. Hypervolemia with RV volume overload also causes a leftward shift in the interventricular septum, thereby decreasing LV preload and contributing to the decrease in CO. However, hypovolemia may also result in decreased CO since patients with RV failure are preload-dependent; thus, under filling of the RV decreases RV stroke volume.

Control of Exacerbating Factors

Continuous oxygen administration -- Oxygen therapy is indicated in patients with hypoxemia including those with HF and/or PH

Treatment of exacerbations of lung disease -- e.g., bronchodilators, inhaled and systemic steroids, respiratory support to relieve hypoxemia and hypercarbia, antimicrobial therapy for acute infection.

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Treatment of OSA -- with respiratory support devices.

Lifestyle modifications -- in selected patients (e.g., exercise, cessation of smoking), if time allows.

Mechanical circulatory support -- during the perioperative period in rare cases. Intra-aortic balloon pump (IABP) counterpulsation provides modest hemodynamic support for refractory left HF and is also used as a temporizing measure for acute mitral regurgitation. Other mechanical circulatory assist devices (percutaneous axial and centrifugal pumps and non-percutaneous centrifugal pumps) were designed to provide greater hemodynamic support than an IABP. Non-percutaneous centrifugal pumps can be used as an LV assist device (LVAD), RV assist device (RVAD), or biventricular device (BiVAD). Very rarely, venoarterial extracorporeal membrane oxygenation (ECMO) is initiated to bypass the RV by placing the cannulas into the right atrium (or central venous circulation) for venous drainage, and into a systemic artery (e.g., the femoral artery) for arterial inflow.

Preoperative Sedation Considerations

Preoperative sedation may be useful to attenuate increases in sympathetic tone due to pain and/or anxiety. Thus, sedatives (e.g., midazolam) or opioids (e.g., fentanyl) should be administered in very small doses, and are titrated very gradually. It is particularly important to avoid over sedation with consequent hypoventilation in patients with PH or HF, since hypoxemia and/or hypercapnia may acutely increase PVR and exacerbate RV dysfunction. This may result in rapid progression to hemodynamic collapse.

Intraoperative Management

General Principles

Anesthetic management goals: Anesthetic management goals include avoiding factors that increase baseline pulmonary vascular resistance (PVR), maintaining preload in an optimal range while avoiding fluid overload, and maximizing RV oxygen supply (i.e., RV perfusion and subendocardial blood flow), while minimizing RV oxygen demand (i.e., RV afterload, tachycardia). The failing RV is exquisitely afterload sensitive, so one of the key goals is to maintain PAP as low as possible to maintain forward flow. Various factors during anesthesia and surgery can precipitate rapid hemodynamic decompensation.

Choice of Anesthetic Technique

Choice of anesthetic technique is based on procedure-specific requirements and the likely impact of anesthetic agents and interventions on PVR and RV function.

Peripheral nerve blocks and/or sedation with monitored anesthesia care (MAC) – These are typically selected for more minor surgical procedures when feasible. These techniques are not likely to have significant hemodynamic effects so long as over sedation (with consequent hypercarbia and hypoxemia) is carefully avoided.

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Neuraxial anesthesia – These may cause an acute reduction in SVR, resulting in decreased preload and systemic perfusion pressure that may adversely impact RV perfusion and function, and may also cause bradycardia due to blockade of the cardioaccelerator fibers. Fluid management in this situation can be particularly challenging in patients with HF and PH. If a neuraxial technique is selected, an epidural technique is preferred to spinal anesthesia. The goal is to gradually establish the neuraxial block with very slow titration of the local anesthetic selected for epidural administration (e.g., 3 to 5 ml every five minutes), or small incremental doses of bupivacaine for a continuous spinal technique (e.g., 3 mg increments), with attainment of the minimum block level necessary to complete the surgical procedure. If systemic BP begins to fall, administration of volume should be judicious, while bolus doses of vasopressors and inotropes (e.g., phenylephrine boluses of 40 to 100 mcg, or ephedrine boluses of 5 to 20 mg) are administered. Gentle titration of an infusion of phenylephrine or low-dose vasopressin or norepinephrine infusion is other options.

General anesthesia incurs significant risks for precipitation of adverse hemodynamic and respiratory effects.

Surgical Technique Considerations

For patients with PH and/or RV failure, potential adverse effects caused by a laparoscopic approach typically outweigh any advantages compared with an open approach (e.g., lesser fluid shift and hemodynamic lability, blood loss, pain, systemic stress). Increased risks include hypercarbia caused by carbon dioxide (CO2) insufflation to create a pneumoperitoneum, greater likelihood of hypoxemia due to the pneumoperitoneum and typically steep Trendelenburg positioning, and greater risk of venous embolization of air, thrombi, or tissue matter. Also, RV preload is reduced and RV afterload is increased by the pneumoperitoneum, Trendelenburg position, and potential need for relatively high peak inspiratory pressure (PIP) and positive end-expiratory pressure (PEEP). Furthermore, hemodynamic monitoring may be challenging since the pneumoperitoneum and positioning may create artifacts and inaccuracies in measured values. Finally, duration of laparoscopic surgery may be prolonged compared with open procedures.

Monitoring

Standard monitoring -- All patients have standard noninvasive monitoring, including ECG, pulse oximetry (SpO2), and intermittent noninvasive blood pressure (NIBP) cuff measurements. ECG monitoring with leads II and V5, with computerized ST-segment trending to detect myocardial ischemia and/or arrhythmias is preferred.

Particular attention is paid to continuous monitoring of the fraction of inspired oxygen (FiO2) concentration and end-tidal carbon dioxide (ETCO2) measurements to avoid hypoxemia or hypercarbia and to mechanical ventilatory parameters to avoid high inspiratory pressures.

Intra-arterial catheter – An intra-arterial catheter is usually inserted in patients with significant PH and RV dysfunction, unless the surgical procedure is minor. Invasive intra-arterial monitoring is often initiated prior to anesthetic induction.

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Central venous catheter -- For major surgical procedures, insertion of a central venous catheter (CVC) provides:

A reliable intravascular conduit for administration of vasopressor, inotropes, or pulmonary vasodilators.

The ability to monitor CVP. Monitoring the trend in CVP values may be helpful for maintaining adequate preload while preventing volume overload, particularly in patients with right-sided HF. Although CVP is a poor predictor of volume responsiveness in most patients, it provides supplemental data regarding intravascular volume status. Also, new-onset or worsening of tricuspid insufficiency may manifest as an increase in CVP.

Pulmonary artery catheter – The potential risks and benefits of pulmonary artery catheter (PAC) use should be evaluated for each patient. Although outcome data are lacking, a PAC is often inserted for major surgical procedures to prevent or recognize exacerbations of PH due to hypoxemia or hypercarbia, hypovolemia due to blood loss, or, conversely, hypervolemia due to fluid overload. Specifically, monitoring hemodynamic parameters with a PAC provides:

The ability to calculate PVR if required to detect acute changes.

The ability to monitor trends in CVP, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and mixed venous oxygen saturation (SvO2).

Monitoring these parameters may be helpful to recognize and manage any acute exacerbation of PH and/or RV dysfunction so that appropriate therapies may be initiated, and resulting effects may be assessed.

Transesophageal echocardiography – Intraoperative TEE monitoring is often employed in patients with severe PH or RV failure. Baseline measurements include:

Qualitative evaluation of RV function, as well as quantitative assessment of RV function by fractional area change (FAC), measurement of three-dimensional RV ejection fraction (RVEF), measurement of tricuspid annular plane systolic excursion (TAPSE), and the myocardial performance index (MPI).

Qualitative evaluation of left ventricular (LV) function.

Evaluation of valvular pathology, particularly qualitative assessment of tricuspid valve and pulmonic valve function.

Estimation of systolic or mean PAP

Subsequent intraoperative changes can be rapidly detected with transesophageal echocardiography (TEE) monitoring. Emergency use of TEE is indicated to determine the cause of acute decompensation (e.g., due to severe RV or LV dysfunction, pulmonary embolism, or hypovolemia).

Induction and Maintenance Of General Anesthesia

Anesthetic agents are selected based on their effects on systemic and pulmonary vascular resistance. A slow rate of administration and incremental dosing are critically important.

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Induction – A reasonable approach to induction of general anesthesia is use of a short-acting hypnotic (e.g., etomidate 0.15 to 0.3 mg/kg) together with a moderate dose of an opioid (e.g., fentanyl, 1 to 2 mcg/kg) and/or lidocaine 50 to 100 mg to blunt increases in sympathetic tone during airway manipulation, as well as a muscle relaxant with rapid onset. Maintenance of adequate oxygenation and ventilation is critically important during mask ventilation, laryngoscopy and endotracheal intubation or insertion of a laryngeal mask airway (LMA).

Maintenance – Selection of inhaled anesthetic agents is based on their effects on systemic and pulmonary hemodynamics, although specific data regarding effects on PVR are scant. Nitrous oxide should be avoided because it can mildly increase PVR, as well as potential risk of hypoxia.

If a total intravenous anesthetic (TIVA) technique is preferred, a balanced anesthetic regimen is typically selected, and may include infusions of a sedative-hypnotic component (e.g., propofol 50 to 150 mcg/kg/min), an opioid (e.g., remifentanil 0.05 to 0.3 mcg/kg/min, fentanyl 1 to 2 mcg/kg/h, or sufentanil 0.5 to 1.5 mcg/kg/h, and/or adjuvant agents (e.g., dexamethasone 0.05 to 0.6 mcg/kg/h). Ketamine infusion should be avoided due to concern for increases in PVR.

Management of ventilation — Ventilation strategies should balance maintenance of adequate oxygenation and ventilation with the need to avoid lung over distention. Hypoxemia, hypercarbia and acidosis should be avoided; since these abnormalities worsen PVR and RV function. Atelectasis and factors that compress extra-alveolar vessels (e.g., positioning) decrease functional residual capacity (FRC) with resultant hypoxemia and increased PVR. However, positive pressure ventilation may reduce venous return and right-sided CO, and higher PEEP levels (e.g., > 8 cm H2O) may lead to increased PVR and worsening of RV function.

Pressure-control ventilation is typically selected, with an optimal level of PEEP to minimize atelectasis. High inspiratory pressures and auto-PEEP are avoided.

Hemodynamic Management

Fluid management — RV preload is maintained in a tight optimal range, with avoidance of either intravascular volume overload causing RV distention or hypovolemia causing RV under filling. If a CVC is in place, CVP is typically maintained at 6 to 10 mmHg in patients with well-controlled chronic right HF or PH. However, the optimal range for RV preload varies and may be higher in some patients, which may be noted in preoperative records of data obtained during right heart catheterization or echocardiography studies.

Abrupt changes in intravascular volume status are avoided or immediately treated. Invasive hemodynamic monitoring is often useful to detect early changes in preload, allowing immediate initiation of appropriate therapy with avoidance of overtreatment.

Vasopressors and inotropes: Treatment of exacerbations of RV dysfunction and/or PH typically require combinations of the following agents:

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Vasopressors – Vasopressors (norepinephrine, phenylephrine, and vasopressin) to maintain RV perfusion pressure are the first line of support for RV dysfunction, and are also employed to treat acute decompensation. The concern with these agents is that while they increase systemic BP and support RV perfusion by increasing SVR, they also increase PVR and RV afterload.

Norepinephrine or vasopressin may reduce the PVR to SVR ratio more successfully than phenylephrine, which can cause unopposed pulmonary vasoconstriction as well as reflex bradycardia. Low-dose vasopressin infusion actually decreases PVR through release of nitric oxide from the pulmonary vascular endothelium and activation of the V2 receptors in vascular smooth muscle. However, the dose-dependent coronary vasoconstrictor effects of vasopressin may produce or exacerbate RV ischemia and contribute to RV contractile dysfunction at higher doses. Thus, use of vasopressin in patients with PH and RV failure is generally limited to a low-dose infusion (e.g., 0.03 to 0.07 units/minute).

Inotropes – Inotropes used to improve the contractility of the RV and LV during the perioperative period include milrinone, dobutamine, dopamine and epinephrine.

Benefits of inotropes depend on the agent:

Inodilators such as milrinone or dobutamine are typically selected to support RV contractility. Milrinone is also a pulmonary vasodilator, while dobutamine may improve ventricular-vascular coupling. These agents are often used in combination with vasopressors (e.g., norepinephrine, vasopressin) to increase coronary perfusion pressure.

Epinephrine supports the systemic circulation, but increases PVR. Also, it is associated tachycardia, proarrhythmic effects, and increased myocardial oxygen consumption may negate its benefits. Thus, epinephrine is typically reserved for severe refractory cardiogenic shock.

Calcium sensitizers, such as levosimendan, are inodilators that increase myocardial sensitivity to calcium, thereby increasing cardiac contractility, and these agents also open adenosine triphosphate channels in vascular smooth muscle, which causes vasodilation. Levosimendan is often used in the perioperative treatment of PH and RV failure, although consistent evidence of benefit is lacking.

Treatment of arrhythmias — Arrhythmias should be controlled. Typically, a slower heart rate (e.g., 60 to 80 beats/minute) is optimal to improve RV perfusion and filling, and tachycardia is avoided. Ideally, sinus rhythm should be maintained. Arrhythmias such as atrial fibrillation or atrioventricular block are treated immediately as they may lead to hemodynamic decompensation.

Acute hemodynamic decompensation — Acute increases in PVR and increases in RV systolic pressure of 30 to 40 percent may cause acute decompensated RV failure. For example, increased sympathetic tone due to pain and stress, persistent RV ischemia, or new embolic phenomena may acutely increase PVR and RV systolic and end-diastolic pressure, causing myocardial ischemia, RV distention, and septal displacement that affects LV filling, with acutely reduced CO,

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hypotension, and cardiogenic shock. Urgent treatment of the primary cause is critical, and targeted therapies may be appropriate for selected types of pulmonary hypertension as described above.

Options for patient’s refractory to medical therapy include mechanical circulatory support (e.g., RV assist device [RVAD], extracorporeal membrane oxygenation [ECMO].

Emergence from General Anesthesia

Emergence from anesthesia is a critical period with potential hemodynamic and respiratory instability. The goal is a smooth emergence with adequate pain control to prevent abrupt increases in sympathetic tone and RV afterload, as well as adequate oxygenation and ventilation to avoid hypoxia and hypercarbia. A reasonable approach is use of a pressure support (PS) mode of ventilation as the patient awakens, with gradual weaning of this support as anesthetic effects dissipate and the patient recovers normal respiratory mechanics.

Pain and temperature derangements are treated during and after transfer to the postoperative anesthesia care unit. Pain or hypothermia typically causes sympathetic stimulation with hypertension and/or tachycardia, increased myocardial oxygen consumption, and exacerbation of myocardial ischemia, particularly if shivering occurs. Hyperthermia also increases heart rate and leads to shivering.

Postoperative Management

In the immediate postoperative period, control of pain, preload, HR, systemic BP, ventilation, and temperature remain critically important. Administration of vasoactive infusions and PH -targeted therapies should not be abruptly interrupted. The patient's chronic regimen for treatment of PH should be reinstated as soon as feasible. For example, oral agents such as sildenafil can be restarted when the patient is hemodynamically stable and can tolerate oral intake, or intravenous sildenafil can be administered if such patients are unable to take oral medications.

Selected patients may require postoperative monitoring in an intensive care unit. Examples include patients with significant intraoperative hemodynamic instability, hypoxemia or hypercarbia at the end of the procedure, and those who require ongoing infusion or inhalation of a pulmonary vasodilator agent. Such patients may need continued controlled mechanical ventilation until cardiopulmonary function has stabilized, as well as sedative-analgesic medications to alleviate pain, dyspnea and anxiety.

REFERENCES

1. Fleisher L A, Fleischmann K E, Auerbach A D, Barnason S A, Beckman J A, Bozkurt B, et al. 2014 ACC/AHA Guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac Surgery: A report of the American College of

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Cardiology/American Heart Association Task Force on practice guidelines. Circulation 2014;130:e278-e333.

2. Kristensen S D, Knuuti J, Saraste A, Anker S, Bøtker H E, De Hert S, et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). European Heart Journal 2014;35:2383-2431.

3. Anderson J L, Halperin J L, Albert N M, Bozkurt B, Brindis R G, Curtis L H, et al. Perioperative beta blockade in noncardiac surgery: A systematic review for the 2014 ACC/AHA Guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Circulation 2014;130:2246-64.

4. Chassot P-G, Delabays A, Spahn DR. Preoperative evaluation of patients with, or at risk of, coronary artery disease undergoing non-cardiac surgery. Br J Anaesth 2002;89:747-59.

5. Karthikeyan G, Bhargava B. Managing patients undergoing non-cardiac surgery. Heart 2006;92:17-20.

6. Forrest P. Anaesthesia and right heart failure. Anaesth Intensive Care 2009;37:370-385. 7. Meyer T E. Perioperative management of heart failure in patients undergoing noncardiac

surgery. Gottelib S S, Yeon S B, ed. UpToDate. Waltham, MA: Up to date Inc. http://www.uptodate.com (accessed on 3rd and 5th September 2018).

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High flow oxygen therapy

Madhusudan Upadya Professor, Department of Anesthesiology,

Kasturba Medical College, Mangaluru

The conventional oxygen delivery systems generally belong to low flow (variable performance, eg, nasal cannulae or masks) and high flow (fixed performance, eg, Venturi masks, nonrebreathers). The conventional devices are generally poorly tolerated for prolonged periods due to inadequate warming and humidification of inspired gas. The fraction of inspired oxygen is also limited and non-reliable. Critically ill patients often require high-flow devices to meet their oxygen needs. The peak inspiratory flow rate demand is usually high in respiratory failure and often exceeds the oxygen flow delivered by the traditional oxygen devices. High-flow nasal oxygen therapy (HFNOT) is an innovative high-flow system that allows for delivering up to 60 L/min of heated and fully humidified gas with a FiO2 ranging between 21% and 100%.

The administration of HFNO requires the following: a) High pressure sources of oxygen and air b) An air-oxygen blender or a high-flow ’Venturi’ system (which permits delivery of an

accurate FiO2 between 21% and 100%) c) A humidifying and heating system for conditioning the gas to optimal temperature (37OC)

and humidity (44 mg H2O/L) d) A sterile water reservoir e) A non-condensing circuitry f) An interface

THE PHYSIOLOGICAL BENEFITS PROVIDED BY EACH FEATURE OF HFNO DELIVERY SYSTEMS

Feature of HFNOT Physiological Effect

Warmed humidified gas Reduced airway surface dehydration

Improved secretion clearance

Decreased atelectasis

Gas flow of up to 60 L/min CO2 washout, reduction in anatomical dead space

Provides an oxygen reservoir

Allows FiO2 close to 1.0 to be delivered

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PEEP Increased end-expiratory lung volume

Alveolar recruitment

ADVANTAGES AND DISADVANTAGES OF HFNOT

Advantages Disadvantages

Easy to implement and manage

Minimal risk of skin breakdown

Lower nurse workload in comparison with non-invasive ventilation

Stability of the nasal cannula in comparison with conventional high-flow facemask

No claustrophobia

Eating, drinking, communicating permitted

Nasal mucosal irritation (infrequent) Discomfort (infrequent)

Runny nose

Pneumothorax in newborns (air-leak syndrome)

Feeling hot

Alteration of smell (infrequent)

Dislocation of the nasal cannula (infrequent) Noise

Limited movement

Risk of delayed intubation

PRACTICAL SETTINGS OF HFNOT

Prongs Prongs should not totally occlude nostrils

Flow rate Start at 30-40 L/min and increase to meet the patient’s demand

Temperature Set at 37oC

FiO2 Increase the FiO2 until satisfactory SaO2 is achieved

Flow Increase the delivered flow until a reduction in respiratory rate and stable SaO2 is achieved

Water reservoir Place as high as possible above the humidifier

Monitoring Continuous monitoring of heart rate, respiratory rate, SaO2

Positive response and weaning Gas flow rate and FiO2 adjusted according to the clinical response (expected within 1 h).

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Reduce FiO2 by 5-10% and reassess after 1-2 h. Reduce the flow rate by 5 L/min and reassess after 1-2 h.

Consider weaning from HFNOT with flow rates 25 L/min and FiO2 <0.40.

Ineffective response If there is no improvement after 60-120 min, treatment escalation must be considered.

ROLE OF HFNOT IN SPECIFIC SCENARIOS

During Intubation and Post Extubation in Susceptible Patients There is a place for HFNOT in emergency and elective airway management which includes preoxygenation, to denitrogenate the lungs and to provide an oxygen reservoir for use during apnea. This is a core principle in airway management, not just in the anticipated difficult airway. Increasing the viable apneic window is highly desirable in the management of the difficult airway, and in those patients with a reduced functional residual capacity, or increased metabolic demand for oxygen. These patients will have a limited oxygen reservoir, and reduced time to desaturation. Obstetric, bariatric, and septic patients represent potential groups where preoxygenation with HFNOT may be beneficial. It has been used successfully in awake fiberoptic intubation, where a major advantage appears to be its ability to provide FiO2 of nearing 1.0 via soft nasal cannulae that allow the passage of a fiberoptic scope. Postoperative hypoxemia is common in patients undergoing major abdominal surgery, due to derecruitment of lung alveoli, atelectasis, and altered respiratory mechanics secondary to pain. The use of HFNOT in the postoperative population was shown to reduce respiratory rate, and increase end-expiratory lung volume. It can reduce the requirement for CPAP via a facemask interface and re-intubation rates. This effect extends to the critical care population requiring intubation, where fewer and less severe episodes of arterial desaturation are seen when preoxygenated with HFNOT, rather than high-flow oxygen using a conventional facemask.

To Treat Respiratory Failure (hypoxic respiratory failure) HFNOT is useful for the treatment of Acute Respiratory Failure (ARF) due to its ability to provide FiO2 of close to 1.0, PEEP of ∼5cm H2O, and humidified gases through a comfortable interface. HFNOT can be particularly useful in ARF patients with increased work of breathing who do not tolerate facemask therapy or those who have a high secretion load. HFNOT has also been used in patients with hypoxemia due to cardiogenic pulmonary edema, where the application of PEEP resulting from HFNOT led to improved breathing comfort and arterial oxygen tension. Its use in chronic obstructive pulmonary disease (COPD) patients requires further evaluation, particularly in the setting of acute exacerbations. It has been shown, however, that high-flow nasal cannulae oxygen therapy reduces respiratory rate and increases minute volume in COPD patients both at rest and during exercise. Carbon dioxide (CO2) is cleared to some extent in apneic application of HFNOT possibly due to diffusion after washout of CO2 from the anatomical dead space. However, it is important

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to remember that periods of apnea in excess of 15 min can be achieved with HFNOT, but arterial CO2 levels may increase to dangerous levels, resulting in severe acidosis.

Airway Instrumentation The HFNOT has been studied as an adjunct to airway instrumentation during manipulation of the airway (e.g., bronchoscopy, intubation) in patients with both low and high risk (i.e., hypoxemia, morbid obesity).

Immune Compromised Patients Immune compromised patients have higher mortality rates than those with no immune compromise when intubated for respiratory failure. Studies have provided conflicting results regarding mortality and intubation rates when NIV (as a modality to prevent intubation) is used in this population. Patients who needed endotracheal intubation had higher rates of bacterial pneumonia and death than those who required HFNT alone. Another post-hoc analysis of adult ICU patients admitted with respiratory failure yielded quite the opposite result; the intubation rate among patients treated with HFNT was 80% and the mortality rate was 73% vs. 26.7% in intubated patients. The major reason for HFNT failure was pneumonia. None of these studies adjusted for variables that may have driven the choice of treatment (e.g., selection of NIV in patients who were a-priori worse or avoidance of intubation due to futility). Thus, the data regarding use of the HFNT in immune compromised patients are not only conflicting but also of poor quality.

End-of-Life Care In 2004, the expert working group of the scientific committee of the association of palliative medicine proposed that oxygen therapy be prescribed for patients with advanced cancer if it can alleviate the symptom of breathlessness. The justification for palliative therapy with the HFNT includes both ethical considerations (beneficence) and economic considerations (justice). The benefit to be considered is alleviation of suffering. The justice to be considered is the cost of care.

CONTRAINDICATIONS Contraindications to the use of HFNOT are much the same as for NIV delivered via a facemask or hood. HFNOT should not delay mechanical ventilation in those with severe respiratory failure, particularly in type II respiratory failure. Any contraindication to the application of PEEP should prompt alternative methods of respiratory support to be sought. Additionally, it should not be used on those with reduced levels of consciousness, or uncooperative patients. In addition, epistaxis, facial injury, or airway obstruction should preclude its use.

LIMITATIONS OF HFNOT (i) Expense and complexity (air/O2 blender, humidifier and requirement for a large

oxygen supply) (ii) Mobility (limited ambulation) (iii) Leak mitigating positive airway pressure effect and inability to compensate for leaks (iv) Nasopharyngeal airway pressure and positive end-expiratory pressure warrant more

exploration (v) Potential for delayed intubation

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(vi) Potential for (inappropriate) delay of end-of-life decisions

FUTURE APPLICATIONS The applications for HFNOT are already extending beyond its use in critical care. In some centers, it is used hospital-wide and may become a replacement for conventional nasal cannula, allowing administration of warmed humidified oxygen to those not necessarily requiring high-flow gas. We anticipate that it may be of use in prehospital care and inter-hospital transfers, primarily for its ability to deliver FiO2 of close to 1.0. Alongside the clinical advantages, HFNOT offers practical benefits such as improved patient compliance and the ability to eat, drink, and communicate while receiving therapy. In our experience, these have a significant impact on patient morale. We anticipate growth in the use and acceptance of HFNOT and envisage that high flow, cold dry gases administered via a facemask may become a relic of the past.

CONCLUSIONS Several studies indicate that HFNO is more effective than conventional oxygen therapy in improving oxygenation in patients with hypoxemic ARF. The patients most likely to benefit from HFNO are those with mild-to-moderate forms of hypoxemic ARF. A stepwise approach has been proposed, which reserves HFNO for patients in whom standard oxygen fails and escalating to NIV prior to invasive mechanical ventilation if HFNO also fails. Compared with standard techniques, HFNO improves safety in patients with known or anticipated difficult airways undergoing elective intubation, and it may help in avoiding or limiting hypoxemia during invasive diagnostic procedures, making it advisable for operating theatres to have access to this technique. The HFNOT seems more effective than conventional oxygen therapy and non-inferior to NIV in most studies. The quality of data on the HFNOT is slightly better regarding patients post-extubation, but there is need for more studies even in this clinical setting to generate a clearer signal. The HFNOT seems to hold promise for apneic oxygenation during airway instrumentation but the studies performed on this topic have largely been underpowered. With regards to provision of HFNOT therapy to immune compromised patients and those requiring palliative care, the retrospective nature of the studies performed thus far precludes determination of any causative association between patient management and outcome. However, there may be ethical considerations for providing this treatment in some cases.

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(A) Vapotherm Precision Flow generating up to 40 L/min. 1A, Oxygen-air sources. 2A, Water reservoir. 3A, Electronic flow-meter, FiO2 controller and a humidifier system as a vapor transfer cartridge (vtc) are assembled in one module. The device has a hinged door (hd). 4A, Non-condensing triple lumen heated circuit, able to maintain the breathing gas (bg) in the center lumen with warmed water (ww) around it. 5A, Patient interface. (B) Optiflow Fisher and Pykel Healthcare generating up to 60 L/min.1B, Oxygen-air sources. 2B, Water reservoir. 3B, Air-oxygen blender. 4B, Flow-meter. 5B, Humidifier and heating system. 6B, Heated non-condensing circuit. 7B, Patient interface.

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Fluid management in the renal transplant recipient

Lakshmi Kumar Professor and Head, Department of Anesthesiology

AIMS, Kochi INTRODUCTION

The outcomes after renal transplant are determined by surgical technique supported by an optimal fluid management. Intuitively fluid management during surgery is guided by hemodynamic signs and urine output. However, in renal recipient hemodynamic responses are exaggerated with sodium and extracellular fluid retention and activation of the renin angiotensin aldosterone axis. The absence of urine output leaves the clinician with limited choice on techniques for optimal fluid management.

The central venous pressure is no longer considered accurate to represent fluid status and dynamic tests of fluid responsiveness such as the stroke volume or pulse pressure variations are recommended as a guide during surgery. However, in the management of ESRD (end stage renal disease) patients, clinicians often recourse to the CVP as a guide to fluid management. The challenges of fluid management are in identifying a balance between the most optimal fluid balance that preserves the mean arterial pressure without pushing the patient into a volume overloaded situation resulting in pulmonary edema.

Healthy vascular endothelium is coated by transmembrane syndecans and membrane-bound glypicans containing heparan sulfate and chondroitin sulfate side chains, which together constitute the endothelial glycocalyx. Bound plasma proteins, solubilized glycosaminoglycans and hyaluronic acid constitute the glycocalyx of the endothelial surface layer (ESL), which is subject to periodic constitution and degradation. The glycocalyx seems to act as a molecular filter, retaining proteins and increasing the oncotic pressure within the endothelial surface layer. The commonest cause for disruption of the glycocalyx is iatrogenic hypervolemia associated with perioperative transfusion. This results in the release of atrial natriuretic peptide and denudation of the ESL resulting in fluid movement in to the interstitial space.

CHOICE OF FLUIDS IN RENAL TRANSPLANTATION

Patients presenting for renal transplant are presumed to be in an optimal fluid state following dialysis that needs to be performed ideally within 12 h prior to transplant. Some patients undergoing hemodialysis are fluid depleted to their bone weight prior to dialysis. Such dehydrated patients are more susceptible to DGF (delayed graft function) following transplant: hence the recommendation is to dialyse a patient to 2-3 kg above bone weight prior to dialysis. The targets for fluid are to maintain a CVP between 10-12 mm Hg prior to reperfusion. The

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limits of CVP may vary from individual to individual and hence between 1.0 L to 3.5 L may be needed until the time of reperfusion.

Normal saline has traditionally been the fluid of choice for ESRD patents as the occurrence of hyperkalemia can predispose to the occurrence of arrhythmias and contribute to delayed graft function. DGF has been defined as derangement graft functions postoperatively manifesting as uremic and electrolyte disturbances and needs renal replacement therapy. The major contributor to this are donor age, comorbidity, duration of cold ischemia time, immunosuppressive regimen but hyperkalemia could be a contributor.

The deterrent to the use of normal saline came in with the awareness the normal saline is not “normal” or physiologic as it contains a mix of two electrolytes sodium and chloride in water. This translates to the fact that administration of 1.0 L of normal saline will dilute the body’s stores of bicarbonate by 1.0 L. The dilutional hyperchloremic acidosis that results could affect renal function by causing constriction of afferent renal arterioles and activation of the renin angiotensin aldosterone axis.

The alternate crystalloid solutions available are Ringer’s lactate, Ringer’s acetate, Plasmalyte and Sterofundin (Ringerfundin). Of all, Plasmalyte is the most physiologic with the plasma as the chloride and sodium content are closest to normal. This is increasingly being used in patients with end organ disease. Preliminary use suggests that the acetate buffer may be safe for liver and renal disease patients.

O’ Malley conducted a study in patients undergoing renal transplants with a mix of live and cadaveric donors and randomised 51 patients with baseline potassium values less than 5.5 mEq/l to receive either Ringer’s lactate (RL) or normal saline as fluid during the study. This study was terminated after the initial interim analysis revealed a significantly higher number of patients in the group receiving normal saline developed hyperkalemia (K > 6.0 mEq/l) and needed treatment for the correction of metabolic acidosis.

Hadimioglu evaluated the effects of three different solutions, normal saline (NS), Ringer’s lactate and Plasmalyte administered at a dose of 30 ml/kg during 90 living donor renal transplants. They concluded that there were no differences in serum creatinine or potassium levels but the NS group had much higher chloride levels and lowered base excess than the other groups.

Khajavi and co workers evaluated the effects of administration of normal saline versus Ringer’s lactate in 52 living donor renal transplants. While they could document decreased acidosis and hyperkalemia with the RL group, they also found higher raised serum creatinine on the 4th postoperative day and a higher incidence of graft loss due to renal artery thrombosis in the RL group implying that caution with the routine use of RL is needed during renal transplantation. Kim and co workers have evaluated the effects of normal saline versus Plasmalyte on the Stewarts equation with similar results.

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Potura and co workers evaluated the effects of normal saline versus acetate buffered solution prospectively in 150 cadaver recipients. Their study confirmed the findings of hyperchloremia and acidosis in the NS group and also a higher requirement of catecholamines in the NS group.

Based upon the above results, it can be concluded that the use of a balanced salt solution provided a better metabolic profile and reduces the incidence of hyperkalemia and hyperchloremia. However, the effects on vascular complications or vasopressor requirement needs to be validated further.

COLLOID SOLUTIONS IN RENAL DISEASE The colloid solutions used in surgery are the synthetic colloids (hydroxyethyl starches) and the natural colloid albumin. Hydroxyethyl starches are prepared from waxy maize or potato starch. Although the first and second generation hetastarches were associated with issues relating to renal function, coagulation and tissue storage, reductions in molecular weight and molar substitution, have led to products with shorter half-lives, improved pharmacokinetic and pharmacodynamics properties, and fewer side effects. Colloids are retained in the intravascular compartment dependent upon the molecular weight, oncotic pressure metabolism and elimination rate. The red blood cell adhesive property is a side effect of the colloid and their effects on the red blood cells dependent upon the molecular weight and substitution of the carbon atom. Hydroxyethyl starch (HES) macromolecules interact with platelets and the coagulation cascade, causing a decrease in factors such as Factor VIII and von Willebrand factor, but the exact mechanisms have still not been fully elucidated. These may have implications in patients with renal diseases but of coagulopathy with starches does not appear to be of concern clinically. The third generation of HES, the tetrastarch was developed with lower molar substitution MS

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(0.4) to enhance degradation and to minimize retention in the circulation and tissues. These are considered to be safe without contributing to coagulopathy with a safety profile up to 50 ml/kg/24 hours. HES however fell into disrepute after a large number of studies established beyond doubt that their use in patients with sepsis was associated with a higher incidence of renal failure and mortality. This was documented with even the lower molecular weight versions of the product. The PRAC society of Great Britain has banned the use of starches in the UK, while countries such as the United states and Australia have allowed their use in patient who are not critically ill. Gelatins are also associated with some degree of renal dysfunction in addition to their effects on coagulation besides having a higher incidence of anaphylaxis. The administration of HES in renal donors was associated with poorer graft outcomes after renal transplant and its administration in brain dead donors with the appearance of osmotic nephrosis like lesions in the graft kidney. Hence the routine use of HES in renal transplant is not recommended. Gelatins are used in some centres although reports of anaphylaxis exist. Albumin is the only naturally occurring colloid and is commercially available as 20% and 5% solution. As it is prepared from human plasma, risks of immunogenic reactions and disease transmission may occur. The indications considered for its use include liver surgery, patients with cirrhosis and resistant ascites and burns. There is insufficient scientific evidence to recommend its routine use during surgery. The SAFE study evaluated the safety of albumin used as a resuscitation fluid versus saline administration in 6997 patients admitted to the ICU. They concluded that there was no difference in the 28 days mortality or number of ventilator days, renal dysfunction or new organ dysfunction in the two groups. They concluded that 4% albumin could be safely used for resuscitation of patients admitted to the ICU. The same investigators looked at the use of albumin in traumatic brain injury. Four hundred and sixty patients with severe brain injury defined by GCS score 3 - 8 were resuscitated by randomization to receive either albumin or saline. The end point, death at 24 months was significantly higher in the albumin group versus the saline group. The differences were largely due to the differences at 28 days. They concluded that saline could be more appropriate fluid for initial resuscitation of traumatic brain injury patients. Albumin is available as different formulations, 5 %, 10% and 20% albumin, of which 20 % is the most popularly available commercial version. It is rarely used intraoperatively in renal transplant surgery as a volume expander but can be used to maintain the CVP before and after reperfusion. MANNITOL IN RENAL DISEASE

The renal cortex receives 90-95% of renal blood flow while the medulla only 5-10%. The inner medullary flow is 5 times less than the outer medullary flow making it more sensitive to hypoxic insults. The medullary mechanisms of solute and water reabsorption are controlled by Na - K ATPase with a high requirement of oxygen. Perioperative renal dysfunction therefore most commonly occurs because of acute tubular necrosis (ATN) secondary to hypoxic damage of

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medullary nephrons, usually because of hypotension, hypovolemia, or dehydration. In addition, oxygen delivery to the renal medulla may be reduced during hypoxemia, endothelial cell swelling, and sludging of cell debris and casts in the renal tubules.

Mannitol is filtered by the kidneys but is not reabsorbed resulting in an increased delivery of sodium to the distal tubules and continued diuresis. This results in a flushing out of tubules and debris and mannitol improves renal blood flow by improving pressure flow responses within the kidney resulting in improved flow for the same perfusion pressure. Osmotic diuresis is ineffective once the ischemic insult sets in and mannitol is not recommended after anuria has set in. Secondary to the improvement in the renal blood flow is an increase in oxygen consumption due to the energy expended in tubular transport. Mannitol also reduces post-ischemic endothelial cell swelling and decreases ischemic reperfusion injuries through scavenging of hydroxyl and other free radicals. Mannitol was presumed to decrease the incidence of post transplantation acute renal failure. Studies have shown that although mannitol reduces the requirements for post transplantation dialysis it does not have any long term effect on graft survival in the absence of adequate intravascular hydration. The explanation for the above is that although mannitol temporarily increases intravascular volume this effect is lost by arterial and venous dilation that accompanies its use.

Mannitol is used as part of the triple drug preparation prior to renal transplant.

FUROSEMIDE IN RENAL TRANSPLANT

Furosemide is a loop diuretic often used in renal transplant. Loop diuretics increase urinary sodium and electrolyte losses and extracellular fluid volume and are useful in the context of volume overloaded states. Furosemide acts in the thick ascending limb of the loop of Henle both in the medullary and cortical aspects including the macula dense in the early distal tubule. It combines with the chloride site of the Na K Cl carrier located in the luminal membrane and causes natriuretic and calciuresis. A questionnaire on furosemide use across 18 transplant centres showed variability in the use and did not demonstrate any improvement in graft survival or reduction in acute tubular necrosis. The strategy is to combine hydration with adequate use of diuretics to minimize the incidence of acute tubular necrosis and graft dysfunction following renal transplant. However most transplant units in the country include furosemide in their perioperative management.

DOPAMINE

Dopamine once popular as an inotrope has limited indications for its use today. The ‘renal dose’ of < 5.0 mcg/kg/min is believed to increase renal blood flow, reduce resistive index and improve GFR. A retrospective study of 254 cadaver renal transplants showed that dopamine treatment in the donor resulted in improved graft outcomes. Similar results were shown in a prospective trial in brain dead donors where the grafts from the dopamine treated group had a significantly lesser need for renal replacement therapy. Dopamine is unlikely to result in graft improvement in transplanted kidneys that are not innervated. A prospective controlled trial

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with 20 patients failed to demonstrate a decrease in resistive index or increase in renal flow velocity at renal doses of dopamine.

Fenoldopam is a selective DA 1 agonist that produces vasodilatory effects in beds rich in dopaminergic receptors as in the kidney. An infusion of 0.1 mcg/kg/min versus 3 mcg/kg/min dopamine infusion during renal transplantation from living donors showed improved renoprotective effects with fenoldepam in urinary excretion of sodium, potassium and chloride.

Dopamine infusions in brain dead donors improves graft survival. Dopamine is not useful in increasing graft function in the transplant recipient. Fenoldopam may be superior to dopamine in its renoprotective effects during living donor transplants.

CONCLUSION

The most optimal management of fluids in renal transplant surgery will continue to be a matter of debate as newer knowledge and technology emerge. Integrating available evidence with supervised care will translate into best outcomes for the patient.

REFERENCES

1. Gonzalez-Castro A, Ortiz-Lasa M, Penasco Y, González C, Blanco C, Rodriguez-Borregan JC. Choice of fluids in the perioperative period of kidney transplantation. Nefrologia 2017;37(6):572-578.

2. Guidet B, Soni N, Della Rocca G, Kozek S, Vallet B, Annane D, James M. A balanced view of balanced solutions. Crit Care 2010;14(5):325.

3. Doherty M, Buggy DJ. Intraoperative fluids: how much is too much? Br J Anaesth 2012;109(1):69-79.

4. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares.Chest 2008;134(1):172-8.

5. O’Malley CM, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, et al. A randomized, double-blind comparison of lactated Ringer’s solution and 0.9% NaCl during renal transplantation. Anesth Analg 2005;100:1518–24.

6. Khajavi MR, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, et al. Effects of normal saline vs. lactated Ringer’s during renal transplantation. Ren Fail 2008;30:535–9.

7. Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect of different crystalloid solutions on acid–base balance and early kidney function after kidney transplantation. Anesth Analg 2008;107:264–9.

8. Potura E, Lindner G, Biesenbach P, Funk GC, Reiterer C, Kabon B, et al. An acetate-buffered balanced crystalloid versus 0.9% saline in patients with end-stage renal disease undergoing cadaveric renal transplantation: a prospective randomized controlled trial. Anesth Analg 2015;120:123–9.

9. Gillies MA, Habicher M, Jhanji S, Sander M, Mythen M, Hamilton M, Pearse RM. Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and meta-analysis. Brit J of Anaesth 2014;112(1):25-34.

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10. Myburgh JA, Finfer S, Bellomo R, Billot L, Gattas D, McGuiness S, Rajbhandari D, Taylor CB, Webb S. Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care: N Engl J Med 2012;367:1901-11.

11. Hanif F, Macrae AN, Littlejohn MG, Clancy MJ, Murio E. Outcome of renal transplantation with and without intra-operative diuretics. International Journal of Surgery. 2011;9: 460-463.

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Awake craniotomy

Krishna H M

Professor and Unit Head, Department of Anesthesiology Kasturba Medical College, Manipal, MAHE, Manipal

Awake craniotomy is an example of perfect confluence of science and art in anesthesia. Patient needs to be awake during specific time period during the craniotomy to elicit certain responses from the awake patient that will facilitate successful and safe surgery.

1. DISCUSS WITH THE SURGEON. COMMUNICATION IS VERY IMPORTANT

It is important to know the indication for which awake craniotomy is being done. The common indications for awake craniotomy are to allow mapping for resection of brain tumors near eloquent (motor, sensory and speech) regions of cerebral cortex, for epilepsy surgery and deep brain stimulation. It may also be done to reduce the risk of general anesthesia and for early hospital discharge. When the expectations of the surgeon during the procedure are clearly understood anesthesia can be tailored accordingly. The surgeon should be notified beforehand to inform the anesthesiologist as to when he wants the patient to be awake and when asleep. Even with the drugs that have fast onset and offset there would be some lag period. Hence the surgeon has to be reminded to inform well in advance. Any differences in opinion regarding preoperative medications and intraoperative technique has to be creased out preoperatively. Let the surgeon know about the anesthetic plan and be prepared to modify it to suit the needs. Remind the surgeon that the local anesthetic acts for about 3 hours (only!).

2. PATIENT COOPERATION. SPARE EVERY EFFORT TO GET IT

Having a cooperative patient makes awake craniotomy much easier. It is worth spending extra time to counsel the patient preoperatively than struggle with an uncooperative patient in the intraoperative period. Patient has to be explained about the uniqueness of the surgery where he would be woken up in between to elicit some responses. Explaining to the patient as to why this is being done will convince him about its importance. Encourage the patient to get even the smallest of his/her doubts cleared, as often, these trivial points are major causes of anxiety in the patient. Rehearsal of the intended response to be elicited intraoperatively can be done a couple of times to ensure that there is no communication barrier.

3. ARE THERE ANY FACTORS WHICH COULD MAKE AWAKE CRANIOTOMY DIFFICULT?

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Awake craniotomy is not just a procedure under sedation. Airway assessment has to be meticulous and the ability to secure the airway with suboptimal positioning of the patient in the intraoperative period has to be determined. One should have at least 3 plans of airway management if the need arises because the likelihood of one plan failing is very high. There could be situations when awake craniotomy might not be a feasible option or carry high risk like certainly difficult airway, uncompensated cardiac or pulmonary failure, uncooperative patient. Optimize the management of comorbidities as much as possible. Verify the control of seizures/epilepsy, if any, with the current medications. History of snoring and features of obstructive sleep apnea are important.

4. PREOPERATIVE PREPARATION AND ADVICE

The patient is counselled and optimized with respect to the comorbidities. Decision to continue or withhold the medications for the comorbidities is as for any other surgery. Review the anticonvulsant medications. On the morning of the surgery the dose of anticonvulsants (commonly levetiracetam) is often doubled by the surgical team because the surgery involves a high risk of intraoperative seizures and the protective effect of general anesthesia might not be there. Acid aspiration prophylaxis is recommended (Tab ranitidine 150 mg and metoclopramide 10 mg). In addition to the standard fasting advice it is better to write a feeding prescription asking the patient to drink as much water (with glucose or any other clear fluid) as he wants two hours before the surgery. Thirst and tiredness are the common complaints heard from the patient intraoperatively. This small step helps in making the patient (and hence the anesthesiologist comfortable). Despite counselling patient would be anxious and hence it is common practice to give anxiolytic (Tab alprazolam 0.25 mg when body weight is less than 50 kg and 0.5 mg when body weight is more than 50 kg) on the morning of the surgery. Arrange blood products as required for the surgery.

5. ANESTHETIC TECHNIQUES FOR AWAKE CRANIOTOMY

Traditionally two techniques are described for awake craniotomy: asleep-awake-asleep technique and sedation technique.

After confirming the fasting status of the patient (and ensuring that the patient had his drink of clear fluids 2 hours back), receipt of anticonvulsant medications the patient is shifted into the prepared operating room. A placard on the door of the operating room indicating to maintain silence in view of awake craniotomy will be a good reminder to the personnel. Standard monitoring is initiated. Invasive arterial blood pressure monitoring is considered by many as a standard for craniotomy but my choice is made on the type of surgery and patient comorbidities. Central venous pressure monitoring may rarely be required. Depth of anesthesia monitoring with entropy or BIS can be useful unless the electrode placement interferes with the surgical site. Appropriate intravenous access is secured. Often the morning dose of anticonvulsant will still be on flow; it is important not to discard it. IV midazolam 1-2 mg can be administered if the patient is found to be anxious but remember that at times midazolam can cause a release phenomenon especially in calm and quiet people making them more talkative after midazolam. Ensure that the operating table mattress is soft and smooth, the drapes on it

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don’t have creases to trouble the patient and there is nothing poking and pressing the patient. Repeatedly confirm in the very beginning from the patient that the position is comfortable or not (unless you want to keep checking for that tiny trouble maker throughout the intraoperative period when the patient keeps complaining about it!). The surgeries may be done with the head fixed by pins or resting on the horse shoe head holder. In either case make sure that the neck is well supported because neck pain is another common intraoperative complaint. All patients are given a systemic non-opioid analgesic IV paracetamol 1 g or IV diclofenac 75 mg to reduce the musculoskeletal discomfort. Patients also receive antiemetic prophylaxis. The scalp is topicalized as shown in figure 1.

Figure 1. Scalp block

Ropivacaine 0.2%, levobupivacaine 0.25% or bupivacaine 0.25% can be used for the scalp block. On most of the occasions bilateral block has to be given (to account for the crossing fibres even if the surgery is on one side) and requires considerable volume of local anesthetic. Calculate maximum permissible dose of local anesthetic for the patient (the toxic dose). This would be 2.5-3 mg/kg (maximum and nothing more) for the solutions mentioned above. Epinephrine is added to this solution to obtain a concentration of 5 mcg/mL (1:200000 solution) and the surgeon could use the same solution for infiltration along the line of incision for hemostasis. There are reports of adding additives like clonidine, dexmedetomidine and dexamethasone to prolong the duration of action but it is not in my practice. About 40-50 mL of local anesthetic

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will be required during awake craniotomy for scalp block, additional infiltration by the surgeons and for infiltration of the dura (because dura mater is another pain sensitive structure after the scalp). For pterional craniotomy infiltration into the temporalis muscle is required. If enough volume of the solutions with concentrations mentioned above cannot be obtained then they can be diluted with normal saline to get the required volume. Talk to the patient as the block is being given because slurred speech is one of the earliest signs of local anesthetic systemic toxicity. Be prepared to manage local anesthetic toxicity as you are literally taking the patient towards toxic levels. Make sure diazepam/lorazepam/thiopentone and lipid emulsion solution (intralipid solution) are readily and immediately available if required. Give at least 10 minutes for the block to act (Other preparations, urinary bladder catheterization can be done during this time). Check for the adequacy of block and supplement the individual block again where found to be inadequate.

The patient is positioned for the surgery (pins are applied or the head is positioned on the horse shoe head rest). Head to toe assessment of the position is done again and make sure the patient is comfortable in this position and would be comfortable for next three hours. Usually bladder catheterization is done. But if for any reason it is not planned then ensure that the patient has passed urine before going in to the operating room. Pay attention to keep the patient warm from the moment he has entered the operating room (using warm linen, convective warmers, fluid warmers).

Asleep-Awake-Asleep Technique

In this technique, after initiating standard monitoring and securing IV access, general anesthesia is induced using propofol and fentanyl. Appropriate sized supraglottic airway is inserted (Proseal LMA/Classic LMA/I gel) and controlled ventilation is initiated. A muscle relaxant is usually not required. Anesthesia can be maintained with TIVA (propofol infusion) or sevoflurane/desflurane/isoflurane targeting a MAC of 1-1.3 or as guided by entropy/BIS value. Spontaneous ventilation is better avoided because the accompanying increase in ETCO2 can increase the surgical bleeding and increase intracranial tension. Scalp block may be given after inducing general anesthesia (advantage is that patient will not feel the multiple pricks) or before inducing general anesthesia (advantage is that the success of block can be checked and confirmed). The surgeon is notified to inform the anesthesiologist about 30 min before the patient needs to be awake. Depending on the agent used (sevoflurane or desflurane or isoflurane or propofol infusion) anesthetics are tapered and cut off at right time intervals to wake up the patient. Patient is repeatedly told to stay calm, giving reassurance and woken up. LMA is removed, suctioning is done if required. Functional cortical mapping and any verbal, motor or other response that needs to be checked intraoperatively or electrocorticography or deep brain stimulation is done once the patient is awake. When this phase of the surgery is completed general anesthesia is induced again with propofol and supraglottic device is inserted. Controlled ventilation is initiated maintaining anesthesia with same agents.

The challenges with this technique are (a) timing the patient’s waking up – The right time to taper and cut off the agents is learnt by having a thorough understanding of pharmacology of these agents and practical experience. Otherwise time may get wasted in waking the patient.

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Remember not to wake up the patient in a hurry applying painful stimuli. The patient should wake up to verbal commands only (b) patient agitation at the time of waking up – Despite thorough explanation to the patient, the patient may be agitated while waking up and this can be troublesome when the head is fixed with pins. This can be prevented by ensuring adequate analgesia at the time of waking up (right dose of fentanyl at the right time) and unhurried waking up with constant reassurance. If agitated, small doses of propofol help in sedating the patient and waking up again a little later (c) Airway related issues – The patient may cough, buck while waking up which may cause unwanted effects at the surgical field. A small dose of fentanyl, about 25 mcg, given 15 min before waking up can reduce this (but at times may prolong the waking up also). Preservative free lignocaine 1.5 mg/kg given 3-5 min before LMA removal may be helpful (remember the dose of local anesthetic given for block, this adds up directly). Patients may vomit. A wide bore suction must be readily available. There can be airway obstruction, laryngospasm. Airway can be managed and manipulated, now, not from the head end but from one side of the patient. (d) securing airway from unconventional location – After checking the patient responses the patient is anesthetized again and supraglottic device is inserted again, but this time standing by the side of the patient. So one may require some practice with this.

The advantage of asleep – awake – asleep technique is that the patient is comfortable for most of the procedure being under general anesthesia. There is also some protection from convulsions by the general anesthesia. Controlling ETCO2 by controlled ventilation may provide better surgical conditions. Airway is secured (at least to some extent) during most of the surgery.

Sedation Technique

In this technique airway is not secured. The patient is sedated during the surgery. The level of sedation is decreased during the phase of the surgery when patient response needs to be elicited. After this is done, the patient is sedated again. The availability of dexmedetomidine in India has made this technique popular and preferred. Dexmedetomidine infusion is started at the time of giving the scalp block or just before it. A bolus dose of 0.5-1 mcg/kg is administered over 10 min. Following this the maintenance infusion is continued at a rate of 0.1-0.9 mcg/kg/h. It is a good practice to make the calculations of the range in which the infusion can be administered for a particular patient and then titrate the infusion rate within this range to achieve the desired sedation level. The advantage of dexmedetomidine is that there is no respiratory depression and it potentiates analgesia. So airway obstruction is rarely a problem with dexmedetomidine infusion. Dryness of mouth and bradycardia are frequently encountered problems with dexmedetomidine. Propofol infusion is another alternative for sedation and used to be commonly used before the advent of dexmedetomidine. Infusion rate for sedation is between 50-150 mcg/kg/min. One has to be cautious to avoid drifting of patients from deep sedation to light general anesthesia. Propofol can cause airway obstruction which can be managed by lightening the level of sedation or using a nasopharyngeal airway in a prepared nostril. Both dexmedetomidine and propofol have a definite context sensitive half- life which needs to be kept in mind to stop the infusion at the right time to wake up the patient.

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Irrespective of the drug chosen for sedation all patients receive supplemental oxygen through nasal prongs. The benefits of ETCO2 monitoring during sedation are well known.

6. PROBLEMS TO ANTICIPATE AND THEIR MANAGEMENT

Airway access is restricted from the head end of the patient. But a free access from the side/caudad end has to be ensured. The draping for the surgery should be done accordingly. Securing the airway with supraglottic device is the easier option when the need arises. Use the supraglottic device that is familiar to you and test if this device can reach the mouth without hindrance after draping. Practice of inserting supraglottic device and intubation with video laryngoscopes from the side of the patient on manikins can increase the skill and confidence. Airway obstruction and its management has been mentioned in the preceding section.

Convulsions can be a problem at any point of time in the perioperative period. Giving priority to airway, breathing and circulation convulsions are controlled with IV midazolam 1-3 mg or IV diazepam 5-10 mg or IV thiopentone 25-100 mg. Irrigation of surgical field (if dura has been opened) with cold saline is a simple first step that can control the seizures. Hence cold saline should readily be available in the refrigerator. It may be difficult to decide if the convulsions are due to local anesthetic systemic toxicity but the supportive management remains the same.

Local anesthetic toxicity can occur while injecting the local anesthetic or after minutes to hours. As emphasized earlier intralipid should be readily available.

Pain at the surgical site or elsewhere in the body is common. Additional local anesthetic infiltration, small dose of fentanyl (25 mcg), IV paracetamol or diclofenac may alleviate this problem.

Raised intracranial tension can be managed by IV mannitol and furosemide. Surgical bleeding is usually not excessive in these cases.

Dryness of mouth can be a big little problem. Small sips of water can be given during the surgery to wet the mouth.

Inability to perform the desired response or elicit the desired response during intraoperative testing has to be immediately notified to the surgeon to prevent any further surgical damage.

CONCLUSION

Awake craniotomy has been in practice for decades. Availability of better drugs for sedation and newer techniques of airway management have refined the anesthetic management for awake craniotomy. Acknowledging that no discomfort of patient is trivial and preparedness for the worst is key to uneventful awake craniotomy.

SUGGESTED READING

1. Lobo FA, Wagemakers M, Absalom AR. Anaesthesia for awake craniotomy. Br J Anaesth 2016;116 (6): 740–4 doi:10.1093/bja/aew113.

2. Venkatraghavan L. Anesthesia for awake craniotomy. Up ToDate.

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3. Rath GP, Mahajan C, Bithal PK. Anaesthesia for awake craniotomy. J Neuroanaesthesiol Crit Care 2014;1:173-7.

4. Stevanovic A, Rossaint R, Veldeman M, Bilotta F, Coburn M (2016) Anaesthesia management for awake craniotomy: Systematic review and meta-analysis. PLOS ONE 11(5): e0156448. doi:10.1371/journal.pone.0156448.

5. Burnand C, Sebastian J. Anaesthesia for awake craniotomy. Continuing Education in Anaesthesia, Critical Care & Pain 2014;14(1):6-11.

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Management of malignant hyperthermia

Vamsidhar Chamala1, Krishna HM2

1Assistant Professor, 2Professor, Department of Anesthesiology Kasturba Medical College, Manipal, MAHE, Manipal

A. Diagnosis

B. Acute phase treatment

C. Post-acute phase treatment

DIAGNOSIS

Signs of Malignant Hyperthermia (MH)

Increasing ETCO2 (despite hyperventilation)

Trunk or total body rigidity

Masseter spasm or trismus

Tachycardia/tachypnea

Mixed respiratory and metabolic acidosis (MH can occur without significant metabolic acidosis)

Increased temperature (may be an early or a late sign)

Myoglobinuria

Sudden/Unexpected Cardiac Arrest in Young Male Patients

Presume hyperkalemia and initiate treatment

Measure blood gases and electrolytes

Measure CK, myoglobin, ABGs, until normalized

Usually secondary to occult myopathy (e.g., muscular dystrophy)

Resuscitation may be difficult and prolonged

Myoglobinuria is common

Trismus or Masseter Spasm with Succinylcholine

Early sign of MH in many patients

If limb muscle rigidity, begin treatment with dantrolene

For emergency procedures, continue with non-triggering agents, evaluate and monitor the

patient and consider dantrolene treatment

Check CK immediately and at 6-8 hour intervals until returning to normal. Observe for dark- or

cola-colored urine. If present, liberalize fluid intake and test for serum and urine myoglobin

Observe in PACU or ICU for at least 24 hours if metabolic signs of MH were present

ACUTE PHASE TREATMENT

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GET HELP. GET DANTROLENE. NOTIFY SURGEON.

Discontinue volatile agents and succinylcholine

Hyperventilate with 100% oxygen at flows of 10 L/min to flush volatile anesthetics and lower

ETCO2. If available insert activated charcoal filters into the inspiratory and expiratory limbs of the

breathing circuit. Halt the procedure as soon as possible; if it is not possible to stop surgery,

continue with non-triggering anesthetic technique

Don’t waste time changing the circle system and CO2 absorbent

1

DANTRIUM®/REVONTO®/RYANODEX®: 2.5 mg/kg RAPID IV, IF POSSIBLE THROUGH LARGE-BORE IV

Dantrium/Revonto – Each 20 mg vial should be reconstituted with at least 60 ml sterile water for

injection. There are 3 grams of mannitol in each 20 mg vial of Dantrium and Revonto

Ryanodex – Each 250 mg vial should be reconstituted with 5 ml sterile water for injection and

shaken to ensure an orange-colored uniform, opaque suspension. There are 125 mg of mannitol

in each 250 mg vial of Ryanodex

Repeat until signs of MH are reversed

Sometimes more than 10 mg/kg (up to 30 mg/kg) of dantrolene is necessary

2

BICARBONATE FOR METABOLIC ACIDOSIS

Obtain blood gas (venous or arterial) to determine degree of metabolic acidosis

Consider administration of sodium bicarbonate, 1-2 mEq/kg dose, for base excess greater than 8

(maximum dose 50 mEq)

3

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COOL THE PATIENT

If core temperature > 39°C apply ice to surface

Infuse cold saline intravenously

Lavage open body cavities

Stop cooling if temperature < 38°C and falling to prevent hypothermia

4

DYSRHYTHMIAS: USUALLY RESPONDS TO TREATMENT OF ACIDOSIS AND HYPERKALEMIA

Use standard drug therapy EXCEPT avoid calcium channel blockers— (may cause hyperkalemia or

cardiac arrest in the presence of dantrolene)

5

HYPERKALEMIA: TREAT WITH HYPERVENTILATION, BICARBONATE, GLUCOSE/INSULIN, CALCIUM

Bicarbonate 1-2 mEq/kg IV

For pediatric, 0.1 units regular insulin/kg and 2 ml/kg 25% dextrose

For adult patients, 10 units regular insulin IV and 50 ml 50% dextrose

Calcium chloride 10 mg/kg IV or calcium gluconate 10-50 mg/kg IV for life-threatening

hyperkalemia

Check glucose levels hourly

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POST-ACUTE PHASE TREATMENT

FOLLOW...

ETCO2, minute ventilation electrolytes, blood gases, CK, core temperature, urine output and color,

coagulation studies

If CK and/or K+ rise more than transiently or urine output falls to less than 0.5 ml/kg/h, induce

diuresis to >1 ml/kg/h and give bicarbonate to alkalinize urine and prevent myoglobinuria induced

renal failure

Venous blood gas (e.g., femoral vein) values may document hypermetabolism earlier than arterial

values

Central venous or PA monitoring as needed

Place Foley’s catheter and monitor urine output

7

Watch for MH relapse by continuously evaluating the patient for at least 24 hours following cessation of

signs of MH. 25% of MH events relapse, which can be fatal. Treat immediately if relapse occurs. Signs of

MH relapse include:

Increasing muscular rigidity in the absence of shivering

Inappropriate hypercarbia with respiratory acidosis

Metabolic acidosis without other cause

Inappropriate temperature rise

1

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Give dantrolene, 1 mg/kg IV q 4-6 h or 0.25 mg/kg/h by infusion and continue for at least 24 h and

sometimes longer as clinically indicated

Dantrolene can be stopped, or the interval between doses increased to q8 h or q12 h if all of the following

criteria are met:

Metabolic stability for 24 hours

Core temp is less that 38°C

CK is decreasing

No evidence of myoglobinuria

Muscle is no longer rigid

2

Follow vital signs and labs:

Frequent blood gases as per clinical signs

CK every 6 hours; less often as the values trend downward

3

Follow urine myoglobin and institute therapy to prevent myoglobin and the subsequent

development of acute renal failure. CK levels above 10,000 IU/L is a presumptive sign of

rhabdomyolysis and myoglobinuria

Follow standard intensive care therapy for acute rhabdomyolysis and myoglobinuria by hydration

and diuretics (urine output >2 mL/kg/hour along with alkalinization of urine with Na-bicarbonate

infusion and careful attention to both urine and serum pH values

4

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REFERENCES

1. 2015 guidelines of Malignant Hyperthermia Association of the United States (MHAUS)

Counsel the patient and family regarding MH and further precautions and send a letter to the

patient and her/his physician

Refer patient to the nearest Biopsy Center for follow-up and definitive diagnosis

5

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ASPIRATION UNDER ANESTHESIA: DECISION MAKING

Aruna Parameswari Professor and Head, Department of Anesthesiology, Critical Care and Pain Medicine

Sri Ramachandra University, Porur INTRODUCTION The prevention of pulmonary aspiration remains the cornerstone of anesthesia practice, as this is a direct anesthesia related complication and is associated with significant mortality and morbidity (pneumonitis, ARDS, MODS, brain damage). In the NAP4 data published in 2011, over 50% of airway related deaths in anesthesia were due to aspiration. Aspiration was first recognized as a cause of an anesthetic related death in 1848 by James Simpson, but it was Mendelson in 1946, who described the potential consequences of abolished reflexes under anesthesia and subsequent aspiration in 66 obstetric patients, leading to pulmonary aspiration of gastric contents and the resulting chemical pneumonitis becoming synonymous with Mendelson’s syndrome. The incidence of this complication is between 1 in 900 to 1 in 10,000 general anesthetics and is higher with emergency surgery. DEFINITION Pulmonary aspiration is defined by the inhalation of oropharyngeal or gastroesophageal contents below the vocal cords into the larynx and tracheobronchial tree. NORMAL PHYSIOLOGICAL MECHANISMS TO PREVENT ASPIRATION OF GASTRIC CONTENTS There are normal physiologic mechanisms to prevent aspiration of gastric contents and include the gastro-esophageal junction, the upper esophageal sphincter and the protective laryngeal reflexes. Gastroesophageal Junction The lower esophageal sphincter is a section of the distal esophagus that protects the esophagus from gastric acid reflux. The anatomical lower esophageal sphincter (LES) consists of 2 sphincters—the intrinsic sphincter involving the semicircular clasp muscles and the oblique sling muscle and the external sphincter, the crural diaphragm. In addition, the oblique entrance of the esophagus into the stomach creates a sharp, acute angle on the greater curvature aspect of the gastroesophageal junction (GOJ), the angle of His. This angle creates a flap valve effect that

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contributes to the GOJ competency. Resting LES pressure ranges from 10 – 30 mmHg with a generous reserve capacity because only a pressure of 5 – 10 mm Hg is necessary to prevent gastroesophageal reflux (GER). The LES maintains a high-pressure zone by the intrinsic tone of its muscle and by cholinergic excitatory neurons. The LES resting pressure exceeds gastric pressure, creating a physiological barrier to GER, known as barrier pressure. Reflux of gastric contents into the esophagus occurs in both healthy individuals and those with pathological gastroesophageal reflux disease (GERD) when the LES transiently relaxes in the absence of swallowing. In hiatus hernia, the proximal stomach enters the thorax, diminishing the acute angle between the esophagus and the stomach and preventing the reinforcement of the LES by the diaphragmatic crura. So the maximal LES pressure reduces thus decreasing the barrier pressure and increases likelihood of reflux. During anesthesia, drugs like anticholinergics, opioids, thiopental and inhalational anesthetics cause pharmacologic relaxation of the LOS, reducing the barrier pressure and may lead to reflux. Upper Esophageal Sphincter The upper esophageal sphincter (UES) is formed by the cricopharyngeus, the thyropharyngeus, the inferior constrictor muscle of the pharynx and the cervical esophagus. The UES acts to prevent the reflux of esophageal contents into the pharynx in conscious individuals. UES tone is reduced in patients with reduced consciousness and is attenuated by most drugs used for the induction and maintenance of anesthesia with the exception of ketamine. Both depolarizing and nondepolarizing neuromuscular blocking drugs (NMBDs) reduce UES tone. Residual neuromuscular block significantly reduces UES tone for a significant time after emergence, increasing the risk of aspiration during the recovery phase. Protective Airway Reflexes Protective airway reflexes include coughing, expiration and laryngospasm. These reflexes can be affected by reduced levels of consciousness and may be reduced at any stage during the perioperative period, including after emergence. Elderly patients are particularly prone to higher risks of aspiration under anesthesia, because they in general have less active airway reflexes. Regurgitation, Vomiting and Aspiration Regurgitation is a passive process whereby the stomach contents are brought up into the esophagus, while vomiting is an active process. Aspiration is the inhaling of those contents into the lungs, where the acidic contents may damage the lung tissue. In the setting of aspiration, regurgitation occurs three times more commonly than active vomiting. RISK FACTORS

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The vast majority of anesthetic techniques attenuate the protective physiological mechanisms that prevent regurgitation and aspiration. Inadequate depth of anesthesia or unexpected responses to surgical stimulation may evoke gastrointestinal motor responses, such as gagging or recurrent swallowing, increasing gastric pressure over and above LES pressure, facilitating reflux. An unprotected airway and one or more predisposing risk factors for aspiration combine to significantly increase the risk of aspiration. Poor assessment of patient, operative risks and failure to use airway devices or techniques offering greater protection against aspiration can also lead to this. Risk Factors For Aspiration Patient Factors

Full stomach o Emergency surgery o Inadequate fasting time o Gastrointestinal obstruction

Delayed gastric emptying o Systemic diseases (Diabetes mellitus, Chronic kidney disease) o Recent trauma o Opioids o Raised intracranial pressure o Previous gastrointestinal surgery o Pregnancy (including active labor)

Incompetent lower esophageal sphincter o Hiatus hernia o Recurrent regurgitation o Dyspepsia o Previous upper GI surgery o Morbid obesity

Depressed protective airway reflexes o Geriatric patients o Depressed consciousness

Surgical Factors

Upper GI surgery

Lithotomy or head down position

Laparoscopy

Cholecystectomy

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Anesthetic Factors

Light anesthesia

Supraglottic airways

Positive pressure ventilation

Length of surgery > 2 h

Difficult airway

Improperly positioned/displaced airway devices (SGD and ETT) Device Factors

First generation supraglottic devices In pregnancy, the gravid uterus displaces the stomach, altering the angle formed between the esophagus and stomach. Progesterone reduces barrier pressure by relaxing the LOS, while decreased concentration of the peptide hormone motilin delaying the gastric emptying. Aspiration of blood can occur with tonsillectomy, cleft palate and other intraoral surgeries. Aspirated blood may clot, causing total airway obstruction. PATHOPHYSIOLOGY The pulmonary consequences of gastric aspiration fall into three groups:

Particle-related

Acid-related

Bacterial Particle-Related Acute airway obstruction leading to arterial hypoxemia may cause immediate death. Prompt removal of inhaled particles, oxygenation of patient and prevention of further aspiration by tracheal intubation are essential. Acid-Related Complications (Aspiration Pneumonitis) Originally it was believed that the critical pH of 2.5 and critical volume of 0.4 ml/kg body weight (approximately 25 ml) was associated with aspiration related chemical pneumonitis. Instillation of hydrochloric acid into the trachea of monkeys did not result in death at volumes of 0.4 and 0.6ml/kg and the LD50 was 1 ml/kg. Extrapolation of these data would give a critical volume for severe aspiration in adult humans of approximately 50 ml. The harmful effects of acid aspiration may occur in two phases: Immediate direct tissue injury and subsequent inflammatory response. Immediate direct tissue injury occurs as a chemical burn in 5 seconds with desquamation of superficial cell layer in 6 hours. Regeneration is seen after 3 days with complete recovery after 7 days. Alveolar type II cells are markedly sensitive and degenerate in 4 hours. A rapid increase

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in lysophosphatidyl choline leads to an increased alveolar permeability and increased lung water that causes decreased compliance, ventilation perfusion mismatch and hypoxemia. The second phase is characterized by acid mediated induction and release of proinflammatory cytokines such as TNF alpha and IL-8, which trigger expression of adhesion molecules on neutrophils and lung endothelium promoting inflammation. Localized aspiration can also lead to a generalized systemic inflammatory response. Bacterial-Related Complications (Aspiration Pneumonia) Gastric contents are not sterile and community acquired lung infections after aspiration are usually caused by anaerobes. Mixed aerobes-anaerobes are found in hospital acquired aspiration pneumonia. Pseudomonas aeruginosa, Klebsiella and Escherichia coli account for most gram-negative nosocomial pneumonias whereas Staphylococcus aureus is the main gram-positive pathogen. PREVENTION Risk Assessment Risk assessment for aspiration was originally with the use of only history and examination to identify the presence of risk factors as there was no objective tool to assess gastric content at the bedside. Gastric ultrasound is now an emerging point-of-care tool that provides bedside information on gastric content and volume. Gastric Ultrasound Point of care ultrasound can help with aspiration risk assessment by providing bedside information on both the type of gastric content (nothing, clear fluid, thick fluid, or solid particulate matter) and the volume. It may be particularly useful in clinical settings where gastric content is questionable or uncertain. An I-AIM framework is a suitable paradigm for using and teaching gastric ultrasound.

Indication: Gastric ultrasound is performed when the gastric content is unknown based on clinical information

Acquisition: Ultrasound images are acquired in a standardized manner

Interpretation: Once an adequate image is obtained, it is interpreted based on qualitative and quantitative findings

Medical decision-making: The interpretation of the findings is then used to guide airway or anesthetic management

Indication

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o Uncertain or contradictory information regarding nil per oral status (e.g., decreased level of consciousness)

o Medical comorbidities or physiologic conditions that may prolong gastric emptying despite adequate fasting (diabetes, achalasia, renal failure, liver failure, parkinsonism, recent trauma, labor)

o Emergency procedures where patient may not have had an opportunity to fast or may have delayed gastric emptying due to pain, opioids, sympathetic activation etc.

Acquisition A curved array low-frequency transducer (2-5 MHz) is used for adult patients and a linear high-frequency transducer can be used for pediatric patients under 40 kg. The probe is placed in a sagittal plane in the epigastric area, immediately inferior to the xiphoid process and superior to the umbilicus. The patient is scanned consecutively in the supine and the right lateral decubitus (RLD) position. When examination in the RLD position is not possible (e.g. Critically ill, trauma), a semi-recumbent position (head elevated 45°) may be an acceptable as “second best”, with the supine position being the least sensitive and least accurate patient position. The gastric antrum (the distal portion of the stomach) is particularly amenable to ultrasound examination. This is because of its consistent location in the epigastric area, superficial position and favorable soft tissue window through the left lobe of the liver. An evaluation of the antrum provides accurate information about the content in the entire organ. The antrum appears as a superficial hollow viscus with a thick multilayered wall, anterior to the body of the pancreas. The IVC and the aorta are posterior to the antrum. The gastric wall is approximately 4-6 mm thick in the adult patient and has five distinct sonographic layers (best seen with high frequency transducer in the empty state) which are as follows from the inner to the outer surface: i) mucosal-air interface, ii) muscularis mucosa, iii) submucosa, iv) muscularis propria, and v) serosa. With the low frequency transducer, only the muscularis propria is consistently observed. This thick muscularis layer, along with the characteristic location of the antrum, allows differentiating the stomach from other portions of the GIT, with their thinner smooth muscle layer. Interpretation Identification of content

When the stomach is empty, the antrum is either flat or round with juxtaposed anterior and posterior walls. When it is round or ovoid, its appearance has been compared with a “bull’s eye” or “target” pattern (Figure 1).

Thick fluid, milk or suspensions have a hyper echoic, usually homogenous aspect.

With solid food ingestion, the air mixed with the solid bolus during chewing forms a mucosal-air interface along the anterior wall of the distended antrum. This large area of “ring-down” air artifacts blurs the gastric content, the posterior wall of the antrum, the pancreas and the aorta. This is often referred to as a “frosted-glass” pattern (Figure 2).

After a variable time interval, this air is displaced, and the antrum appears distended with better appreciable content of typically mixed echogenicity (Figure 3).

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Normal gastric secretions and clear fluids (e.g., water, tea, apple juice, black coffee) appear anechoic or hypo echoic. The antrum becomes round and distended with thin walls as the volume increases (Figure 4). Immediately after fluid intake, gas bubbles can be appreciated as small punctuate echoes, but they disappear rapidly within minutes of ingestion (starry night appearance)

Figure 1. Ultrasound image showing empty antrum. A – Antrum, P – Pancreas, Sma – Superior mesenteric artery, Ao – Aorta, D – Duodenum, L – Liver, R – Rectus abdominis muscle

Figure 2. Ultrasound image showing solid gastric contents with a “frosted glass” appearance. R

– Rectus abdominis muscle, A – Antrum, Ao- Aorta, L - Liver

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Figure 3. Ultrasound image showing late stage solid gastric contents. R – Rectus abdominis muscle, A – antrum, Ao- Aorta, L – Liver, P – pancreas, Sma – superior mesenteric artery, L –

liver, S - spine

Figure 4. Ultrasound image showing clear fluid gastric contents. R – Rectus abdominis muscle, A

– antrum, Ao- Aorta, L – Liver, P – pancreas, L – liver

Grading based on volume

Grade 0 antrum: Completely empty antrum, with no content visible in either the supine or the RLD position

Grade 1 antrum: Small, negligible volume of baseline secretions (typically < 1.5 ml/kg) which is appreciated only in the RLD position

Grade 2 antrum: Appreciable amount of clear fluid (in excess of 1.5 ml/kg) in both the supine and the RLD positions or any amount of solid or particulate content in the stomach.

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The upper limit of normal baseline gastric volume is still somewhat controversial. The mean value is approximately 0.6 ml/kg and volumes of up to 100 -130 ml (about 1.5 ml/kg) are common in healthy fasted subjects and do not pose a significant risk for aspiration. Previously suggested thresholds of “risk” (0.4 ml/kg and 0.8 ml/kg) were extrapolations from volumes of hydrochloric acid directly instilled into the tracheas of animals and are not supported by a plethora of human data, demonstrating that such volumes of gastric secretions are well within the normal range for healthy fasted individuals with a low risk for aspiration. Conversely, a volume of clear fluid in excess of 1.5 ml/kg or any amount of solid or particulate content in the stomach suggests a non-fasting state (or a “full stomach”), and is likely to increase the risk of aspiration. It has been consistently shown that a single cross-sectional area (CSA) of the gastric antrum measured in a standardized manner correlates with the total gastric volume and this correlation is stronger in the RLD position. Several mathematical models have been reported that describe this numerical relationship. One such model accurately predicts gastric volume up to 500 ml as follows: Gastric volume (ml) = 27 + 14.6 × Right-lateral CSA – 1.28 × age For a volume evaluation, the antral area is obtained at the level of the aorta, with the antrum at rest (that is, between peristaltic contractions), and measured using a free-tracing tool of the equipment following the serosa. A mean of 3 readings is recommended to minimize error. A cut off value of 9.6 cm2 discriminates ingested volumes > 1.5 ml/kg Medical decision-making Point-of-care gastric ultrasound (POCUS) is used to stratify individual risk for aspiration and to tailor airway and anesthetic management in situations where nil per oral status is not clear. A Grade 0 or Grade 1 antrum is consistent with a fasting state and suggests a low risk. Grade 2 antrum denotes solid content or a high volume of clear fluid and indicates a nonfasted state and suggests a higher than baseline risk for aspiration. The clinical context of each individual patient needs to be taken into account when making a medical decision. Specific risk factors for aspiration need to be considered, such as the patient’s history and physical examination, type of procedure (elective or emergency), nature of the last meal, time interval since the last meal, as well as other risk factors for aspiration. Ultrasound findings can help in diagnosing a “likely full” or “likely empty” situation, thus guiding anesthetic management accordingly (Figure 5).

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Figure 5. Flow chart for medical decision making based on gastric ultrasound findings

Limitations of Gastric Ultrasound In Risk Assessment Of Aspiration From a technical standpoint, gastric ultrasound has been validated in patients with normal gastric anatomy and may therefore not reliable or accurate in subjects with previous gastric surgery (partial gastrectomy, gastric bypass) or large hiatus hernias. Regarding the conceptual framework for the use of gastric ultrasound, it is important to consider that this test evaluates only one of the determinants of aspiration risk, that is gastric content. The risk of aspiration is however also influenced by other factors, such as coexisting diseases of the upper GIT (achalasia, GERD), anesthetic technique and events related to airway management (unexpected difficult intubation requiring prolonged manual ventilation). So point of care gastric ultrasound evaluates an important, but not the only determinant of risk. The other issue is that 3-5% of all examinations may be inconclusive and the diagnostic accuracy of GUS to detect a full stomach (sensitivity, specificity, positive and negative predictive values) remains to be studied. The negative predictive value of POCUS is arguably of most importance. Also, gastric content is dynamic and changes quickly over time. So the information will be accurate only at the time of the test. For example, the information at induction may not be applicable at emergence. Risk Reduction Strategies

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Reducing Gastric Volume Preoperative fasting Nasogastric aspiration Prokinetic premedication Reducing pH Of Gastric Contents Antacids H2 receptor antagonists Proton pump inhibitors Avoidance Of General Anesthesia Regional anesthesia Airway Protection Tracheal intubation Second-generation supraglottic airway devices Prevent Regurgitation Cricoid pressure Rapid sequence induction Extubation Awake after return of airway reflexes Position (Lateral, head down or upright) MANAGEMENT Initial management involves the recognition of aspiration by way of visible gastric contents in the oropharynx, or more subtle indications such as hypoxia, increased inspiratory pressure, cyanosis, tachycardia or abnormal auscultation. A list of differentials must be thought of, few of which include

Bronchospasm

Laryngospasm

Endotracheal obstruction

Pulmonary edema

ARDS

Pulmonary embolism Aspiration will more commonly affect the right lung because the right main bronchus is more vertical than the left main bronchus. Once the diagnosis is made, patient should be positioned head down to limit pulmonary contamination, and suctioning performed to clear the oropharynx. Some advocate the left lateral position, but this may cause difficulty in managing

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the airway. Oxygen (100%) must be administered, followed by immediate RSI and securing the airway with an endotracheal tube. At this point, tracheal suctioning should ideally precede positive pressure ventilation to avoid any aspirate being forced further down the bronchial tree. Early bronchoscopy is recommended if aspiration of particulate matter is suspected to prevent distal atelectasis. Symptomatic treatment of bronchospasm with bronchodilators may be necessary. A clinical decision should be made whether or not to proceed with surgery depending on the condition of the patient, the extent of aspiration and urgency of the surgery. A chest X ray should be done, though in about 25% of cases, there are no radiographic changes initially. In 75% of cases, CXR will show consolidation. Aspiration may lead to chemical pneumonitis, bacterial pneumonia or ARDS and mechanical ventilation may be required for prolonged periods and patients should be managed in the ICU. Empirical antibiotic therapy is strongly discouraged unless it is apparent that the patient has developed a subsequent pneumonia, as occurs in 20-30%. Treatment should only be prescribed once the organism has been identified. Inappropriate administration of antibiotics has been linked to ventilator-associated pneumonia with virulent organisms such as Pseudomonas aeruginosa and Acinetobacter. Corticosteroids should not be given prophylactically in the acute phase following aspiration, as there is no evidence to support a reduction in the inflammatory response. They may even have an adverse effect on mortality in critically ill patients. WHY DO PATIENTS STILL DIE FROM ASPIRATION UNDER ANESTHESIA? TRAINEES, TRAINING, OR CULTURE? The NAP4 study showed ongoing evidence of aspiration occurring in patients with recognized risk factors. There have been instances where classical indications for RSI were present but RSI was not used. There have been instances where first generation laryngeal mask airways have been used in patients with definite risk for aspiration. Failure of risk assessment is another persistent theme found in the NAP4 aspiration cases. Poor decision-making, poor handovers, poor supervision and poor support for trainees have been other reasons cited for this complication developing. CONCLUSION Gastric aspiration is a dreaded complication under anesthesia and its prevention remains an important aspect of anesthesia care. In addition to history and physical examination, point of care gastric ultrasound may aid in decision-making and appears to be a novel, valuable tool to be used for this purpose. REFERENCES

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1. Robinson M, Davidson A. Aspiration under anaesthesia: Risk assessment and decision-making. CEACCP 2014;14:171-75.

2. Janda M, Scheeren TWL, Noldge-Schomburg GFE. Management of pulmonary aspiration. Best Prac Res Clin Anaesthesiol 2006;20:409-27.

3. Perlas A, Arzola C, Van de Putte P. Point-of-care gastric ultrasound and aspiration risk assessment: a narrative review. Can J Anaesth 2018;65:437-48.

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Anaphylaxis

Dr Bala Bhaskar S Professor, Department of Anesthesiology

Vijayanagar Institute of Medical Sciences, Ballari INTRODUCTION The reported incidence of anaphylaxis during anesthesia ranges from 1 in 10,000 to 1 in 20,000 procedures with an increased incidence of 1 in 5200 to 1 in 6500 in cases involving administration of neuromuscular blocking drugs (NMBDs). Anaphylaxis also accounts for up to 3% of perioperative deaths that are totally or partially related to anesthesia. The National Audit Project 6 (NAP6), the largest study of life-threatening peri-operative anaphylaxis, puts the figure of perioperative anaphylaxis at 1 in 10,000 anesthetics.

DEFINITION Allergic reactions are immunologically mediated reactions (not caused by pharmacologic idiosyncrasy, direct toxicity or drug over dosage or by drug interaction). Anaphylaxis / Anaphylactic Reaction is a severe life-threatening allergic reaction. It is a systemic, immediate hypersensitivity reaction (type 1) caused by immunoglobulin- Ig E dependent activation of effector cells of the immune system-predominantly mast cells and basophils. The new endogenous substances by themselves are not damaging (pollen, foodstuffs or drugs) but cause the production of IgE antibodies that fix to the surface of mast cells or basophils. On subsequent exposure, the antigen binds to the cell-fixed IgE, resulting in degranulation of the cell and liberation of vasoactive mediators, which are responsible for the syndrome of anaphylaxis (Figure 1).

Figure 1. Mechanism of Anaphylaxis

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Anaphylactoid reaction denotes an identical or very similar clinical response that is not mediated by IgE or (usually) an antigen-antibody process but a result of direct degranulation of mast cells and basophils with release of the same mediators as in anaphylactic reactions. There may be no history of sensitization to the substance, and it is not necessary for re-exposure to occur. PATHOPHYSIOLOGY The reaction, anaphylactic or anaphylactoid, regardless of the triggering agent is a consequence of overwhelming mast cell or basophil activation. The onset of reactions is usually immediate but may be delayed depending on the route of exposure. The triggering agent in anaphylactic reactions can be an injected or inhaled or ingested substance. The offending substance may be the parent compound, a non-enzymatically generated product, or a metabolic product formed in the patient’s body. When an allergen binds to immune-specific IgE antibodies on the surface of basophils in the blood and the mast cells in the tissues, histamine and eosinophilic chemotactic factors of anaphylaxis are released from storage granules in a calcium and energy dependent process (Figure 1). Other chemical mediators are rapidly synthesized and are subsequently released in response to cellular activation. These mediators include slow-reacting substance of anaphylaxis, which is a combination of three leukotrienes, other leukotrienes, kinins, platelet-activating factors, adenosine, chemotactic factors, heparin, tryptase, chymase and prostaglandins, including the potent bronchoconstrictor prostaglandin D2, eosinophil growth and activating factors, mast cell growth factors and pro-inflammatory and other factors that contribute to the IgE isotype switch. Usually, a first wave of symptoms including those caused by vasodilation and a feeling of impending doom is quickly followed by a second wave as the cascade of mediators amplify the reactions. In a sensitized patient, onset of the signs and symptoms caused by these mediators is usually immediate but may be delayed for up to 2 to 15 minutes or in rare instances as long as 2.5 hours after the parenteral injection of antigen. After oral administration, manifestations may occur at unpredictable times. Mast cell proliferation, together with severe progressive inflammation contributes to the worsening of symptoms that occur even after the allergen load is no longer present. The antigen present in cells and lymphocytes, as well as activated mast cells start to induce the production of cytokines. These pro inflammatory cytokines recruit more inflammatory cells, a process that leads to tissue edema and mediates a second wave of mast cell degranulation. This second wave can promote the recurrence of severe symptoms 6 to 8 hours later and necessitates at least 8 hours of continued ICU-like observation. In addition, biologically active mediators can be generated by multiple effector processes to produce an anaphylactoid reaction. Activation of the blood coagulation and fibrinolytic systems, the kinin-generating sequence, or the complement cascade can produce the same inflammatory substances that result in an anaphylactic reaction. In addition, histamine can be liberated independent of immunologic reactions. Mast cells and basophils release histamine in response to chemicals or drugs.

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MANIFESTATIONS OF ANAPHYLAXIS Patient may manifest cutaneous signs, hives, itching with dizziness and breathlessness. The respiratory and cardiovascular manifestations set in and generally progress rapidly. In the operating room, cardiovascular symptoms (73.6%), cutaneous symptoms (69.6%) and bronchospasm (44.2%) are the most common clinical features. The cutaneous symptoms may be missed because of surgical drapes and patient position. Perioperative anaphylaxis usually occurs within 1 minute after anesthetic induction and is primarily related to medications administered intravenously. As per NAP6, considering all cases, the onset time was <5 min in 66%, <10 min in 83%, <15 min in 88% and <30 min in 95%. Rashes and airway problems were very rare in the NAP6 results. The spectrum of clinical features varies (Figure 2, Table 1) but only grade 3 and more are life threatening.

Figure 2. Pathophysiology of Anaphylactic Shock Cardiovascular Effects: Histamine causes

a. venodilatation - increase in vascular capacity b. dilation of the arterioles, resulting in greatly reduced arterial pressure c. increased capillary permeability, with rapid loss of fluid and protein into the tissue

spaces. The net effect is a reduction in venous return and sometimes severe shock that the person dies within minutes (anaphylactic shock). Circulating blood volume may decrease by as much as 35% within 10 minutes. Chemical mediators can cause acute coronary spasm which results in a myocardial infarction and acute coronary syndromes. Hypotension and tachycardia may rapidly progress into severe arrhythmias and cardiovascular collapse if not treated quickly. The faster

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the onset of anaphylaxis the severe the reaction. PEA and severe bradycardia precede cardiac arrest. Respiratory effects: Anaphylaxis precipitates smooth muscle spasm in the respiratory tract. Signs and symptoms include copious secretions from the mouth and nose, shortness of breath, laryngeal edema, elevated ETCO2 and an increase in the peak airway pressure. This quickly progresses to bronchospasm, desaturation, hypoxia and pulmonary oedema. Angioedema: This is most apparent in the head and neck including the face, lips, floor of the mouth, tongue and larynx but edema may involve any area of the body. Angioedema, if untreated will advance to complete airway obstruction and death caused by laryngeal edema.

Grade Definition

1 Generalised cutaneous signs: erythema, urticaria with or without angioedema

2 Presence of measurable but not life-threatening symptoms, including cutaneous effects, arterial hypotension (defined as a decrease of more than 30% in blood pressure associated with unexplained tachycardia), bronchial hyper-reactivity (cough, ventilatory impairment)

3 Presence of life-threatening reactions, including profound hypotension (defined as a decrease of more than 50% from baseline), collapse, tachycardia, bradycardia, severe bronchospasm

4 Circulatory or respiratory arrest (PEA arrest or arrhythmia associated with no cardiac output) and or inability to ventilate

5 Death due to a lack of response to cardiorespiratory resuscitation

[Minor or moderate reactions (Grade 1 and Grade 2) are correctly termed ‘hypersensitivity’ and should not be called ‘anaphylaxis’ as only Grade 3, 4 and 5 hypersensitivity can correctly be termed anaphylaxis (NAP6)].

Table 1. Degrees of Anaphylaxis ANAPHYLAXIS / ANAPHYLACTOID TRIGGERS IN ANESTHESIA Virtually all nondepolarizing NMBDs can evoke anaphylaxis in anesthesia practice and they are the commonest cause (Table 2) (NAP6 revealed highest incidence with antibiotics). Anaphylaxis to nondepolarizing NMBDs can occur in patients without any previous exposure to nondepolarizing NMBDs. Cross-reactivity occurs between NMBDs and food, cosmetics, disinfectants and industrial materials. Sensitization to non-depolarizing NMBDs may be related to pholcodine, a cough-relieving medicine. Cross-reactivity is seen in 70% of patients with a history of anaphylaxis to NMBD. d-tubocurarine has the highest histamine releasing potential (followed by atracurium) but 3 times the ED95 doses are needed. Rocuronium and atracurium carry intermediate levels of risk for causing allergic reactions, whereas rocuronium and succinylcholine are in high-risk category.

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Four times the ED95 of rocuronium (1.2 mg/kg) causes no significant histamine release. The increased incidence sometimes attributed to rocuronium may be related to its increased market share.

Succinylcholine-induced anaphylaxis, mainly presenting with bronchospasm, was two-fold more likely than other neuromuscular blocking agents (NAP6). The NAP6 showed that the culprit neuromuscular blocking agents were rocuronium (42% of cases), atracurium (35%), succinylcholine (22%) and mivacurium (1.5%). There were no cases of anaphylaxis caused by vecuronium, pancuronium or cisatracurium. Sugammadex was suspected in two cases and confirmed in one in NAP6 study (out of 64,121 annual exposures to sugammadex!). All NMBDs can cause noncompetitive inhibition of histamine-N-methyltransferase but the concentrations required for that inhibition greatly exceeds those that would be used clinically, except in the case of vecuronium, with which the effect manifests at 0.1 to 0.2 mg/kg. This finding could explain the occurrence of occasional severe bronchospasm in patients after receiving vecuronium. Sugammadex (SGX) per se is an extremely rare cause of anaphylaxis; some reports suggest that SGX reversal of NM blockade could be useful in treating anaphylaxis induced by steroid NMBDs (NAP6). However, ANZAAG-ANZCA (2013, updated 2016) guidelines caution against this, citing the absence of proof of immunological mediation. Sugammadex could lessen a reaction if given before an anaphylactic event but once a reaction has been triggered, subsequent administration of SGX is unlikely to terminate it (NAP6).

Substance Incidence of Perioperative anaphylaxis (%)

Most commonly associated with perioperative anaphylaxis

Muscle relaxants 69.2

High risk: rocuronium (56%), succinylcholine (21%) Intermediate risk: vercuronium (11%), atracurium, and pancuronium Low risk: mivacurium and cisatracurium

Natural rubber latex

12.1

Latex gloves, tourniquets, Foley’s catheters Patients with multiple prior surgical procedures can be sensitized to latex Healthcare workers also at increased risk Recognized cross-sensitivity to bananas, avocado and chestnuts.

Antibiotics 8 Penicillin, cephalosporin, vancomycin

Hypnotics 3.7 Propofol, thiopental, midazolam

Colloids 2.7 Dextran, gelatin

Opioids 1.4 Morphine, pethidine, codeine

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Other substances 2.9 a. Radio contrast Dyes b. Paracetamol, aprotinin, chymopapain, protamine c. Bupivacaine d. Blood Products (1:20,000-1:47,000 components transfused) e. Direct skin contact: chloroprep, iodine, hibiclens, chlorhexidine f. Sugammadex?

Table 2. Drugs involved in perioperative anaphylaxis

Latex is the second most common precipitant of anaphylaxis during anesthesia. Although the rate of latex sensitization continues to increase, the development of better ways to identify at-risk patients has led to a decreased incidence of latex-induced anaphylaxis. Among antibiotics, penicillins and cephalosporins are the most common cause of anaphylaxis. A small risk of cross-reactivity exists between penicillins and cephalosporins but most of these reported reactions involve rashes, not anaphylaxis. NAP6 showed the majority of cases to be caused by co-amoxiclav or teicoplanin. Reported allergies to vancomycin should be distinguished from “red man syndrome”, a histamine-induced side effect associated with rapid injection of vancomycin, consisting of flushing, pruritus, erythematous rash and hypotension. Overall, the NAP6 reports that antibiotics contribute to the highest incidence of perioperative anaphylaxis (47%), followed by the NMBDs (33%). Local anesthetic agents: Anaphylactic reactions to amide local anesthetics are extremely rare. Most true anaphylactic reactions following exposure to ester local anesthetics do not involve an allergy to the local anesthetic but rather to associated preservatives (e.g., para- aminobenzoic acid). No reports of anaphylactic reactions to volatile anesthetics have been published. Halothane can elicit hepatic injury due to immune mediated toxicity. Antibodies are produced against the trifluoroacetyl metabolite (Ag) of halothane. Enflurane and isoflurane may be associated with similar events but may occur without previous exposure as seen with halothane. Most reactions to commonly used antiseptic solutions such as bacitracin or povidone-iodine involve contact dermatitis; in contrast, true anaphylactic reactions have only rarely been reported. Timing of Occurrence of anaphylaxis: This depends on the situation and the drugs administered to the patients. As per the NAP6, most (58%) anaphylactic events occurred in the operating theatre and 3% were before the induction of anesthesia, 81% after the induction and before surgery, 13% during surgery and 3% after surgery. Biphasic Anaphylaxis: After successful recovery from the original anaphylactic episode, a recurrence of anaphylactic symptoms can occur in approximately 20% of patients 1 to 72 hours after the original episode with no re-exposure to allergen. If the patient had a near fatal anaphylactic response with original exposure, the risk of a fatal or near fatal biphasic reaction

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can occur in up to 1/3 of patients. The biphasic reaction can be less severe but can also be as severe as the original episode. Systemic corticosteroids do not seem to be able to prevent recurrence. Multiple chemical sensitivity disorder (idiopathic environmental intolerance syndrome) - There is no clear acceptance of this status. It is associated with chronic, diffuse, nonspecific symptoms with low levels of multiple chemical substances. Symptoms involve multiple organ systems, not generally accompanied by biologic test abnormalities or changes on physical examination but they are frequently associated with psychiatric symptoms. This disorder is also often associated with fibromyalgia. DIAGNOSTIC TESTS FOR ANAPHYLACTIC REACTIONS In vitro: Biochemical tests should be performed rapidly after occurrence of an anaphylactic reaction. An early increase in plasma histamine is observed 60 to 90 minutes after anaphylactic reactions (not usually measured because of short half-life). Serum tryptase concentrations typically reach a peak between 15 and 120 minutes, depending on the severity of the reaction, highly suggestive of mast cell activation. The half-life is approximately 2.5 h. The levels become normal in 6-8 h. Tryptase is a mast cell protease, signaling an immune mediated reaction. Approximately 99% of the body’s total enzyme is located within the mast cell. It is not present in red or white cells and therefore plasma concentrations are not affected by hemolysis. The basal tryptase concentration is 0.8 to 1.5 ng/ml with the normal value usually <1 ng/ml. Increase in tryptase does not differentiate between anaphylactic or anaphylactoid reactions. C3 and C4 complement levels can also be assessed. Radioallergosorbent test (RAST) measures the IgE Abs in serum; it is highly specific but sensitivity is low for many drugs. In Vivo: Skin testing is useful only for IgE mediated reactions and remains the gold standard for detection of the culprit agent during anaphylaxis. It is also useful in selected cases where clear diagnosis of a specific allergy is required to guide perioperative management. For nondepolarizing NMBDs, a dilution of 1:1000 is widely accepted, with higher concentrations being associated with false positives and for others, 1:100 has been recommended. At least 0.2-0.3 ml is injected intradermally and the test performed 4-6 weeks after an episode because of mast cell and basophil mediator-depletion. PREOPERATIVE EVALUATION OF PATIENTS FOR ANAPHYLAXIS History of allergies and adverse drug reactions should be elicited and documented with correct differentiation between true anaphylactic reactions from adverse side effects (e.g., nausea with opioid use). Those with history of atopy or allergic rhinitis should be suspected of being at risk. Latex allergy during preoperative evaluation can be diagnosed based on a careful history. Individuals at particular risk for latex allergy include those with a history of multiple surgical procedures, health care workers and those with atopic histories. When latex allergy is identified, the operative team should be notified in advance to ensure that all appropriate equipment is available.

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MANAGEMENT OF ANAPHYLAXIS Prevention: It is better to avoid drugs that are likely to trigger anaphylactic or anaphylactoid reactions in patients with previous history. Premedication with histamine blockers and steroids is not generally recommended. Even if the patient is not specifically known as allergic to a substance, high risk drugs such as morphine, antibiotics and nondepolarizing muscle relaxants should be administered as slowly as possible. Diagnostic tests are helpful only in IgE-mediated reactions. They are also useful in selected cases where clear diagnosis of a specific allergy is required to guide perioperative management. For contrast agent related reactions, pretesting is not useful. Pretreatment with diphenhydramine, cimetidine (or ranitidine) and corticosteroids has been reported to be useful in preventing or ameliorating anaphylactoid reactions to intravenous contrast material as well as perhaps to narcotics. Anaphylactic and anaphylactoid reactions to contrast media occur 5 to 10 times more frequently in patients with a previously suspected reaction. They might benefit from low-osmotic agents and both H1 and H2-receptor antagonists for 16 to 24 hours before exposure

to a suspected allergen. H1-receptor antagonists appear to require this much time to act on the

receptor. Maintenance of volume status and high doses steroids (1 g of hydrocortisone) are other measures to be used prior to exposure. Patients with a history of an anaphylactic or anaphylactoid reaction must not receive a substance suspected of producing such a reaction (e.g., iodinated contrast material). Readymade management protocols and guideline should be immediately accessible in operation theatres with lamination. There could be designated ‘anaphylaxis-packs’. Anaphylaxis shock pack should consist of minimum two ampoules of epinephrine 1 in 1000, 4 graduated 1 ml syringes, four 23G needles and an algorithm for reference. Smartphone technology can also be utilised to access online resources. Latex use in the operating room should be brought down and made totally latex- free. In allergic patients, care should be taken to ensure that no latex-containing products are present in the operating room. The ANZAAG-ANZCA (2013, updated 2016) anaphylaxis management cards have been designed for use in the event of anaphylaxis in perioperative period purely mentioning role of anesthesiologists. At least three members are included with specific roles: Team Leader, Card Reader and Adrenaline (epinephrine) preparation. It may be necessary to enlist the assistance of non-anesthesia staff members. Drawing blood for later analysis, especially of tryptase can be useful in clarifying the diagnosis. TREATMENT

e. Immediate measures – a. Stop further administration of offending agent, call for help b. Assess ABC, intravenous access and adequacy of mentation (if applicable)

Epinephrine: 1:1000 (1 mg/ml) - drug of choice.

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- IV dose: 50-100 mcg (0.5-1 ml from 10 ml of 1:10,000) boluses. Three bolus doses are administered at 3-5 min intervals and should be followed by infusion as necessary

- IM route for healthcare workers out of OT, Emergency medicine and ICU The benefits of IM adrenaline for the management of anaphylaxis far exceed the risks (Level 1 evidence) and can be used when IV line is not ready or is lost (World Allergy Organisation) > 12 years: 500 mcg IM (0.5 ml of 1:1000 preparation) i.e. same as adult dose > 6 – 12 years: 300 mcg IM (0.3 ml) > 6 months – 6 years: 150 mcg IM (0.15 ml) < 6 months: 150 mcg IM (0.15 ml) - SC dose not advised: 50–100 mcg or 0.01 mg/kg in children; repeat as needed but less effective

f. General measures a. Expedite surgery, position the patient supine and elevate lower extremities b. Establish and maintain the airway (Supraglottic airway device, endotracheal tube or front of neck access as necessary) c. Administer 100% oxygen- high flow useful (10 L/min) d. Fluid Resuscitation- Crystalloids (normal saline)/Colloids. Increased vascular permeability can transfer 50% of intravascular fluid into the extravascular space within 10 minutes. The amount of fluid administered should be based on haemodynamic parameters. Dextrose solutions avoided - risk of tissue edema. a. Specific measures

Epinephrine: 1:1000 (1 mg/ml)- drug of choice in treatment of anaphylaxis (α1- for improvement in BP & β2- for bronchodilatation) 1 mg in 250 ml of normal saline or D5W (4 mcg/ml) at a rate of 0.5–2 mcg/min.

b. H1 antagonists: Useful

i.Chlorphenaramine- >12 years and adults: 10 mg IM or IV slowly > 6 – 12 years: 5 mg IM or IV slowly > 6 months - 6 years: 2.5 mg IM or IV slowly < 6 months: 250 mcg/kg IM or IV slowly ii. Diphenhydramine 25–100 mg IV iii. Promethazine 50 mg IV (children 0.3–1.0 mg/kg given IV/IM)

c. Glucocorticoids: Steroids may have no effect for 4–6 hours, but may prevent persistent or biphasic anaphylaxis. i. Hydrocortisone: Adult or child more than 12 years – 200 mg, Child 6 - 12 years- 100 mg, Child 6 months to 6 years- 50 mg Child < 6 months- 25mg ii. Methylprednisolone: 80mg /1–2 mg/kg IV; repeat q 4–6 hourly as needed (Children: Methylprednisolone 2 mg/kg IV).

d. H2 antagonists: ranitidine 1 mg/kg IV, not much useful

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e. Glucagon: 1–5 mg IV. Glucagon (1–5 mg IV) in severe reactions. Glucagon directly activates adenylyl cyclase and bypasses the β-adrenergic receptor. It may reverse refractory hypotension and bronchospasm. Glucagon or atropine should be used in β-blocked patients to increase an inappropriately slow heart rate.

f. Vasopressin, a potent vasoconstrictor has been reported to be effective in refractory cases (2-10 units, when no response to epinephrine).

g. Nebulized β2-agonists: 12 puffs of 100 mcg of salbutamol can be administered in an

adult using a metered dose inhaler into the anesthesia circuit h. Aminophylline: 5 mg/kg IV over 30 min, then 0.9 mg/kg/h IV; follow serum levels

(therapeutic range 8–15 mcg/ml) i. Volatile anesthetics can also be used (if that is not already the case and if the blood

pressure allows) for their bronchodilating properties. j. Military antishock trousers (MAST) - In case of refractory hypotension, MAST may

significantly improve hemodynamics. g. Supervening cardiac arrest, in addition to ACLS protocol

a. Rapid volume expansion b. Prolonged resuscitative efforts

(Adapted with permission from Kemp SF: Current concepts in pathophysiology, diagnosis and management of anaphylaxis. Immunol Allergy Clin Am. 2001;21:611–34) Monitoring of various systems should include oxygenation, capnography, temperature, ECG monitoring, blood pressure and invasive pressures when necessary, airway pressures, blood gas analysis, echocardiogram, etc. CAN THE SURGERY CONTINUE AFTER RESUSCITATION FROM AN ANAPHYLACTIC EPISODE? The case can probably be allowed to proceed after rapid resolution of the event. Upper airway edema should be excluded prior to extubation. The presence of a leak around the endotracheal tube should be determined by deflating the endotracheal tube cuff and occluding the tube manually. However, anaphylaxis may respond poorly to treatment and acute respiratory distress syndrome (ARDS) and myocardial ischemia or infarction can ensue. The 2013 Australia and New Zealand Anaesthetic Allergy Group (ANZAAG) recommendations (update 2016) for the management of intra-operative acute hypersensitivity reaction include the statement that, after stabilisation of the patient’s condition, consideration be made whether surgery should be completed, postponed or abandoned. A retrospective case control study from Australia reports that once initial resuscitation has been achieved and if resuscitative efforts can be re-instituted if required, continuing with planned surgery in grade 1, 2 and 3 immediate hypersensitivity was not associated with poorer outcomes. After grade 3 reactions, there was a significant incidence of complications attributable to acute hypersensitivity regardless of whether surgery proceeded or was abandoned. Surgery was frequently abandoned in grade 4 immediate hypersensitivity and was associated with a high rate of complications. The NAP6 study showed that in one-third of cases the procedure was unchanged but in more than half of cases the intended surgery was not started. In a small proportion of cases the

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procedure was modified or abandoned. Median severity was Grade 4 in the abandoned cases and Grade 3 in continued cases. Balancing the risks of deferring or proceeding with surgery after perioperative anaphylaxis will often require careful multidisciplinary discussion. WHAT TO TELL THE PATIENT POSTOPERATIVELY? The patient should be given a letter detailing the reaction and specifically naming the medication involved and instructed to wear a bracelet indicating his allergy. Patient may be referred to allergy specialists for skin tests to identify the causative drug, but the tests themselves are not without risk. Communication is very important to transfer the details to the patients. The NAP6 panel judged that there were considerable shortcomings in communication between the anesthetist and the patient after the anaphylaxis event. The patient should be told that the administration of any β-lactam antibiotic might be fatal and referred to an allergy specialist for desensitisation and assessment. REFERENCES

1. Hepner DL, Castells MC. Anaphylaxis during perioperative period. Anesth Analg 2003;97:1381-95.

2. Kemp SF. Anaphylaxis: Current concepts in pathophysiology, diagnosis and management of anaphylaxis. Immunol Allergy Clin North Am 2001;21:611–34.

3. Kroigaard M, Garvey LH, Gillberg L, Johansson SG, Mosbech H, Florvaag E, et al. Scandinavian Clinical Practice Guidelines on the diagnosis, management and follow-up of anaphylaxis during anaesthesia. Acta Anaesthesiol Scand 2007;51: 655-70.

4. Australian and New Zealand Anaesthetic Allergy Group. 2013. ANZAAG Anaphylaxis Management Guidelines. http://www.an zaag.com/Mgmt% 20 Resources.aspx

5. Sadleir PHM, Clarke RC, Bozic B, Platt PR. Consequences of proceeding with surgery after resuscitation from intra-operative anaphylaxis. Anaesthesia 2018;73:32–39.

6. Harper NJN, Cook TM, Garcez T, Lucas DN, Thomas M, Kemp H.et al. Anaesthesia, surgery and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth 2018;121:172-88.

7. Harper NJN, Cook TM, Garcez T, Farmer L, Floss K, Marinho S. et al. Anaesthesia, surgery, and life-threatening allergic reactions: Epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6). Br J Anaesth 2018;121:159-71.

8. Perioperative Anaphylaxis Management Guidelines. http://www.anzca.edu.au/ documents/bp-anaphylaxis-2016.pdf.

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Management of diabetic ketoacidosis

Rajesh Shetty

Lead Consultant, Multidisciplinary Critical Care Unit Manipal Hospital, Bengaluru

1. WHAT ARE THE CHARACTERISTIC METABOLIC DERANGEMENTS IN DIABETIC KETOACIDOSIS (DKA)? The accumulation of ketoacids leads to an elevated anion gap. This is a key feature of DKA. Initially as the blood sugar rises there is a shift of fluid from the intracellular to the extracellular compartment with subsequent dilution. Once the blood sugar level exceeds the renal threshold for glucose (around 12 mmol/l) glycosuria occurs followed by an obligatory osmotic diuresis, resulting in a loss of water from the extracellular compartment. This hyperglycemia induced osmotic diuresis as well as causing a urinary loss of water and glucose will also cause a loss of, ketones, sodium, potassium and phosphate in the urine. At presentation patients are often severely dehydrated with marked serum electrolyte disturbances.

2. WHAT ARE THE BASIC PRINCIPLES IN THE MANAGEMENT OF A PATIENT WITH DKA? The basic principles of DKA management are

rapid restoration of adequate circulation and perfusion with isotonic intravenous fluids

gradual rehydration and restoration of depleted electrolytes

insulin to reverse ketosis and hyperglycemia

careful, regular monitoring of clinical sings and laboratory tests to detect and treat complications

3. WHAT IS THE OPTIMAL RATE OF FALL OF PLASMA GLUCOSE IN THE MANAGEMENT OF DKA?

A reasonable target for the fall in plasma glucose is 50-70 mg/dl/h, if the blood glucose fails to fall at this rate the insulin rate should be doubled every hour until the target decrease is reached. In those in whom the rate of fall of plasma glucose exceeds 90 mg/dl/h the rate should be reduced to 0.05 units/kg/h but only for a short time as a rate of 0.1 units/kg/h is needed to switch off ketone production. When the blood glucose falls to below 250 mg/dl a dextrose containing fluid should be commenced. If hypoglycemia occurs prior to complete resolution of DKA the insulin infusion should not be stopped instead extra glucose should be added to the IV fluids.

4. WHAT ARE THE RISK FACTORS FOR AND EARLY SIGNS OF CEREBRAL EDEMA COMPLICATING DKA TREATMENT? Monitoring for any signs of cerebral edema should start at the time of admission of patients with DKA and continue for at least the first 12 hours of treatment, it typically presents within 2 – 24 hours of treatment for DKA. Early signs are headache, confusion and irritability. Later signs include reduced conscious level and seizures. The exact pathophysiology is poorly understood

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but risk is related to severity and duration of DKA. Other suggested associated factors include overzealous fluid administration, the administration of sodium bicarbonate and too rapid fall in the blood glucose. If cerebral edema is suspected due to an altered level of consciousness hypoglycemia must be excluded initially. Intravenous mannitol (1.0 g/kg = 5.0 ml/kg 20% mannitol) should be given immediately. Fluids should be restricted to 2/3 maintenance and the fluid deficit should be replaced over 72 hours. Transfer the patient to the Intensive Care Unit for intubation, mechanical ventilation and arrangements made for an urgent CT head. If cerebral edema is present liaise with a neurosurgeon regarding the possibility of intra-cranial pressure monitoring.

5. WHEN IS IT APPROPRIATE TO CONVERT A PATIENT WHO HAS BEEN TREATED FOR DKA FROM INTRAVENOUS INSULIN INFUSION TO A SUBCUTANEOUS REGIME? Once plasma glucose is < 180 mg/dl and the acidosis has resolved the insulin infusion should be changed from a constant rate to a sliding scale. Oral diet should be resumed as soon as the patient is able to. Subcutaneous insulin regimes may be commenced when the patient is tolerating an oral diet and the level of ketonuria has fallen to 1+ or 0. This usually corresponds to a pH of > 7.3. Twenty to thirty minutes before meal subcutaneous insulin should be given and the intravenous insulin continued for another 2 hours.

6. WHAT IS DIABETIC KETOACIDOSIS? Diabetic ketoacidosis (DKA) is a life threatening medical emergency. It is characterized by hyperglycemia, dehydration, metabolic acidosis and ketonuria. The criteria for the diagnosis of DKA includes a blood sugar >250 mg/dl, presence of urinary or plasma ketones, a pH< 7.3 and a serum bicarbonate of less than 18 mmol/l. The main differential diagnosis is the hyperosmolar hyperglycemic syndrome which differs in the extent of dehydration, acidosis and ketosis. Patients with hyperosmolar hyperglycemic syndrome tend to present with a pH>7.3.

7. WHAT ARE THE PRECIPITATING CAUSES OF DKA? Diabetic ketoacidosis (DKA) primarily occurs in patients with Type I diabetes mellitus but it is being recognized in some Type II diabetics as well. The incidence of DKA is estimated at between 4.6 and 8 episodes per 100 patient years of diabetes. DKA may be the first presentation of diabetes or may follow a precipitating event. The most common precipitant is an infection however in a large number of cases no identifiable cause can be found.

Common precipitating causes of DKA are;

a. Infections (commonly urinary tract) b. Non-compliance with treatment c. New diagnosis of type I diabetes d. Other stresses (MI, alcohol, pancreatitis, drugs) e. No cause found (40%)

8. EXPLAIN THE PATHOPHYSIOLOGY OF DKA.

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DKA is due to an insulin deficiency, together with an excess of the counter-regulatory hormones, glucagon, growth hormone and the catecholamines. The absence of insulin results in poor glucose utilization by peripheral tissues. Glucagon, growth hormone and the catecholamines increase triglyceride breakdown into free fatty acids and promote glucose production from hepatic gluconeogenesis. The Ketones, acetoacetate and β hydroxybutyrate are formed by the beta oxidation of the free fatty acids. Hence resulting in hyperglycemia and the formation of ketoacids which are the primary metabolic derangements in DKA. The secondary consequences of these primary derangements include metabolic acidosis and an osmotic diuresis. Metabolic acidosis is caused by the production of H+ ions by the dissociation of ketoacids. The accumulation of ketoacids leads to an elevated anion gap. This is a key feature of DKA. Initially as the blood sugar rises there is a shift of fluid from the intracellular to the extracellular compartment with subsequent dilution. Once the blood sugar level exceeds the renal threshold for glucose, around 210 mg/dl, glycosuria occurs followed by an obligatory osmotic diuresis, resulting in a loss of water from the extracellular compartment. This hyperglycemia induced osmotic diuresis as well as causing a urinary loss of water and glucose will also cause a loss of, ketones, sodium, potassium and phosphate in the urine. At presentation patients are often severely dehydrated with marked serum electrolyte disturbances.

9. WHAT ARE THE CLINICAL FEATURES OF DKA? There is a wide spectrum of severity of illness in patients presenting with DKA. Classically patients present with a history of thirst, polyuria and polydipsia although these are not invariably present. Diabetes Mellitus may not have been previously diagnosed. Other symptoms may include weakness and lethargy, nausea and vomiting, abdominal pain and weight loss. Common general physical signs are:

Evidence of dehydration

Tachycardia and hypotension

Kussmaul respiration (deep rapid respiration to provide respiratory compensation for metabolic acidosis)

Ketotic breath (fruity acetone smell due to exhaled ketones)

Temperature is usually normal or low even in the presence of an underlying infection

Altered consciousness and confusion

10. DESCRIBE BASIC INVESTIGATIONS YOU WILL UNDERTAKE FOR A PATIENT PRESENTING WITH FEATURES OF DKA. Initial investigations are aimed at confirming the diagnosis, estimating the severity and identifying underlying causes.

Blood Glucose

Blood glucose is measured hourly. This will be grossly elevated at presentation but can rarely be normal if there has been administration of insulin, resulting in correction of the blood sugar

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but not the acidemia. When the blood sugar is grossly elevated at presentation, point of care testing can be inaccurate and therefore samples should be sent to the laboratory initially.

Urine Ketones

If the nitroprusside method is used β hydroxybutyrate will not be measured. As β hydroxybutyrate is the main ketone produced in DKA for on-going assessment of ketonemia direct measurement of serum β hydroxybutyrate is recommended but is dependent on laboratory availability. Serum urea and electrolytes should be measured every 2-4 hours initially.

Serum Sodium

Hyperglycemia will cause a dilutional hyponatremia. The measured serum Na can be corrected by adding 1.6 mmol/l for each 100 mg/dl elevation of serum glucose over 100 mg/dl. Correction formula: Corrected Na = Measured Na + 1.6 [Plasma Glucose (mg/dl) – 100/ 100]

Serum Potassium

In DKA there is a total body deficit of potassium but because of acidosis and dehydration initial serum levels may be within the normal range or be elevated. Serum levels must be regularly checked because correction of the acidosis and administration of insulin can result in a precipitous drop in serum potassium because of the intracellular movement of potassium.

Serum Urea and Creatinine

Renal impairment may be present at presentation. Elevated acetoacetate levels may cause a falsely elevated creatinine level if the colorimetric method is used to measure the serum creatinine. Serum osmolality calculated as 2(Na) + Glucose + Urea. If a patient in DKA is comatose with an osmolality less than 330 mOsm/kg then other sources for coma should be sought.

Venous or Arterial Blood Gas

This is required every 2-4 hours. Venous blood gases or venous serum bicarbonate are an acceptable alternative to arterial blood gas sampling in the initial management of DKA as studies have confirmed that venous blood pH closely reflects arterial blood pH in these patients. The venous pH is 0.02-0.03 units lower than the arterial pH.

Anion Gap

An elevated anion gap metabolic acidosis is a key feature of DKA. Anion gap is calculated as (Serum Na + K) – (Serum HCO3 + Cl). Normal values are 8 – 12 mmol/l.

Full Blood Count

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An increased white blood cell count in the range 10000-15000/mm3 is characteristic of DKA and is not indicative of infection. However, a count >25000/mm3 should raise concern that an infection is present.

Serum Amylase

Amylase is often raised in the absence of pancreatitis. This may cause diagnostic confusion, especially in the presence of abdominal pain.

Other Investigations

Chest X-ray, blood cultures, urine cultures, ECG and cardiac enzymes should be considered to investigate potential underlying causes.

11. BRIEFLY DESCRIBE THE MANAGEMENT OF PATIENTS PRESENTING WITH DKA Initial Assessment and Resuscitation: Patients with DKA may be severely unwell and comatose. Initial assessment involves confirmation of the diagnosis and a rapid assessment of Airway, Breathing, Circulation and Disability. Intravenous access is obtained as soon as possible and blood tests taken for urgent analysis including blood for culture. 100% oxygen should be provided via a face mask with a reservoir bag.

The Basic Principles of DKA Management are;

rapid restoration of adequate circulation and perfusion with isotonic intravenous fluids

gradual rehydration and restoration of depleted electrolytes

insulin to reverse ketosis and hyperglycemia

careful, regular monitoring of clinical sings and laboratory tests to detect and treat complications

Fluids

Initially fluid therapy is aimed at rapid restoration of the intravascular volume. In the first hour 0.9% saline is given at a rate of 15-20 ml/kg or an average 1-1.5 L. Thereafter further fluid therapy should be administered at a rate sufficient to maintain adequate blood pressure, urine output and mental status. The aim is to correct the estimated water deficit over 24 hours, in general a rate of 4-14 ml/kg/h will suffice. Patients in cardiogenic shock will require inotropes and hemodynamic monitoring. Although some have argued that Hartmann’s solution is a better fluid to give during the initial resuscitation as it avoids the hyperchloremic acidosis. However adverse sequelae from Hartmann’s include an increase in the blood glucose from the lactate load, the potassium it contains (5 mmol/l) can elevate the serum potassium dangerously in those already hyperkalemic and lastly the hypotonicity could precipitate cerebral edema. Following the initial period of resuscitation the subsequent choice of fluid will depend on the corrected serum sodium. If normal or elevated then 0.45% saline should be given, if low then saline should be continued. When the blood glucose is 14 mmol/l the fluid should be changed to 5% dextrose with 0.45% saline until the acidosis and ketosis have resolved. Slow correction of metabolic abnormalities, particularly elevated serum sodium and glucose is a goal of

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treatment. Until the resolution of DKA the insulin infusion should not be stopped instead extra glucose should be added to the IV fluids if patient is hypoglycemic.

Potassium Replacement in DKA

There is a total body deficit of potassium but despite this at presentation mild to moderate hyperkalemia is not uncommon. Serum levels will fall once insulin and fluids are started. Adding 20-40 mmol/l KCl will usually result in adequate replacement, keeping the serum potassium around 4.5 mmol/l. If the initial serum potassium is low initially, omit potassium and continue to check the serum potassium every 2 h.

Sodium Bicarbonate

Sodium bicarbonate is rarely, if ever, necessary. If administered, deleterious effects include risk of hypokalemia, cerebral edema and reduced tissue oxygenation by its effects on the oxygen dissociation curve. Acidosis will improve with fluid replacement and insulin. Continuing acidosis usually means insufficient resuscitation. Sodium bicarbonate should only be considered in patients with profound acidosis (pH < 6.9) and circulatory failure resistant to inotropes.

Location of Care

Patients with DKA require close nursing and medical supervision. This may be best provided in a high dependency or intensive therapy environment if facilities are available. Regular clinical assessment is required to guide fluid therapy and ensure adequate resolution of shock.

Antibiotic Therapy

Occult infections are common precipitants of DKA. Evidence of infection should be actively sought and investigations should include blood cultures and urine dipstick testing and cultures. Suspected bacterial infections should be treated aggressively with appropriate antibiotics.

Thromboprophylaxis

Patients with DKA are at increased risk of thromboembolism. Prophylactic heparin has an accepted role in the management of patients with DKA. It should be continued until the patients are mobile with no evidence of dehydration or elevated serum osmolality. Unfractionated heparin or low molecular weight heparin are suitable treatments.

Nasogastric Tube Drainage

DKA causes gastric stasis. Aspiration pneumonitis may occur if vomiting is combined with a reduced level of consciousness. Nasogastric tube drainage should therefore be considered in all patients with DKA. It is mandatory in those with markedly impaired conscious level.

Urinary Catheterization

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Strict fluid balance is required in the management of DKA. Measurement of urinary output is simplified by urinary catheterization.

Continuous ECG Monitoring

This is indicated in the presence of significant underlying cardiac disease, significant hyper- or hypokalemia or severe DKA.

Adequate recording of regular clinical assessments and laboratory test results is vital. This allows staff to rapidly and accurately assess patient progress. All DKA patients should be referred to a member of the diabetes team in order to help determine the cause of the DKA and to review the patient’s diabetes knowledge and education.

REFERENCES

1. Wittlesey CD. Case study: Diabetic ketoacidosis complications in type 2 Diabetes. Clinical Diabetes 2000;18:88-90.

2. Chiasson J-L, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ékoé J-M et al. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. CMAJ: Canadian Medical Association Journal 2003;168(7):859-866.

3. Kitabaci AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycaemic crises in adult patients with diabetes. A consensus statement from the American diabetes association. Diabetes Care 2006;29:2739-2748.

4. Brandenburg MA, Dire DJ. Comparison of arterial and venous blood values in the initial emergency evaluation of patients with diabetic ketoacidosis. Ann Emerg Med 1998;31:459—465.

5. Glaser NS, Wooton-Gorges SL, Buonocore MH, Marcin JP, Rewers A, Strain J, DiCarlo J, Neely EK, Barnes P, Kuppermann N. Frequency of sub-clinical cerebral edema in children with diabetic ketoacidosis. Pediatric Diabetes 2006;2:75–80.

6. Southwest Diabetes Regional Network Integrated Care Pathway for Children with Diabetic Ketoacidosis 2007.

7. Kyle GC. Diabetes and pregnancy. Ann Intern Med 1963;59(suppl 3):1-8.

8. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2011; 34(Suppl 1), S62–S69. http://doi.org/10.2337/dc11-S062.

9. English W, Ford P. Diabetic ketoacidosis anaesthesia tutorial of the week 128. 2009. https://www.wfsahq.org/components/com_virtual_library/media/35223c6b4d6680dc81f9fd2d

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25cf451c-4a76d422b60582cfc313ba559de6ed60-128-Diabetic-Ketoacidosis.pdf (accessed on 4th September 2018).

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Airway fire

Ramkumar Venkateswaran Chief Medical Officer, Mission Smile

Manipal

INTRODUCTION Fires can break out either in the open or inside any building, and operation theatres are no exception. While the basic reasons why a fire breaks out remain the same irrespective of whether the building is a commercial complex, auditorium or an operating room, the implications of a fire in each area are quite different. It is no surprise then that legally-constructed building needs to have a fire safety protocol in place that not only focuses on preventing fires but also what to do in the event of a fire that breaks out despite all precautions. The following discussion presented in a “question-and-answer format” will attempt to cover specific issues of a fire occurring within the breathing tract of a patient (hence termed “airway fire”). Such a patient is often under anesthesia and therefore unable to neither protect nor evacuate himself/herself from the scene of fire. What are the factors needed to start a fire and keep it going? There are 3 prerequisites that are necessary to start and keep a fire going – fuel, oxidizer and ignition source. These components are often collectively referred to as the “triad of fire”. If sufficient heat energy is supplied to a substance that has a potential to burn, it will start burning. A fire that gets started thus will keep burning as long as there is an ongoing supply of an oxidizer. What do you understand by the term “airway fire”? An airway fire is one that happens close to or within the breathing tract of a patient. More often than not, the surgical site happens to be within or near the patient’s airway. With reference to airway surgery, what are the specific factors that create the “triad of fire”? Fuel is provided by combustible substances such as endotracheal tubes, surgical drapes and dry sponges. Gases used to maintain anesthesia such as oxygen and nitrous oxide are the oxidizers that support combustion. The ignition source that is often responsible for starting a fire in the operating room is either the electrocautery or the laser. Which surgeries are associated with “airway fires”? Surgeries at or around the glottic inlet that utilize the laser beam for cutting or coagulation create a situation that can result in an airway fire. Such an occurrence was common in the days when unprotected or improperly shielded tracheal tubes made of polyvinyl chloride (PVC) or red rubber were in use for laser surgery. Better understanding of the causation of airway fires has helped to bring down the incidence of such mishaps. Airway fires can also occur when a tracheostomy is being done on a patient in whom long-term ventilator support is being contemplated. Careless use of the electrocautery or laser to open the

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trachea or cut the tracheal cartilages can produce the right combination of predisposing factors to cause an airway fire during a tracheostomy. What steps can be taken to prevent an airway fire? During laser surgery of the airway, keeping the oxygen concentration in the anesthetic mixture to less than 40% provides the safe balance between avoiding hypoxia on one hand and creating a gas mixture that supports combustion on the other. An inspired oxygen concentration of around 40% is achieved by mixing air and oxygen in a proportion of 3:1. Nitrous oxide is best avoided in the anesthetic mixture during laser surgery of the airway because at temperatures

above 450C (which could be produced by electrocautery or laser), nitrous oxide breaks down into oxygen and nitrogen (with the former supporting combustion). Flooding the surgical site with carbon dioxide makes logical sense as carbon dioxide is known to be the best quencher of a fire. However, modern anesthesia machines do not provide carbon dioxide flowmeters and hence, such a practice is not possible. Use of special laser-compatible tubes is one way of preventing airway fires. Damage to the tracheal tube cuff by the laser beam can be detected early by inflating the cuff with saline mixed with methylene blue. Damage of the cuff results in coloured saline flooding the surgical field, not only giving an early warning of such a mishap but also helping to douse and put out the fire early. A 50-ml syringe filled with saline should always be kept in readiness on the anesthesia table top. Should a fire occur, saline can be flushed onto the surgical site, helping not only to put out the fire and but also providing immediate cooling of the surrounding soft tissues. An additional tracheal tube 0.5 to 1.0 mm smaller in diameter than the original tube should be always available for reintubation. The laser should be used in short bursts and the beam activated only when the surgeon is working on the surgical site. If lead shielding is being used on a PVC tube because laser-compatible tubes are not available, care must be taken that the wrapping is done correctly and that the tracheal tube that is lying close to the surgical area is well shielded with saline-soaked gauze. What are the tell-tale signs of an airway fire? Sparks, pops and flashes are often indicators that worse is to follow. An airway fire is often seen as a flame accompanied by smoke. If the entire thickness of the tracheal tube has been breached and ventilation continues with oxygen-rich gas mixture, the airway fire may become more serious and take on features of a “blow torch”. What does one do if an airway fire occurs despite all precautions and preventive steps? Once the team is aware of the possibility of an airway fire, the surgeon should immediately stop the use of the laser or electrocautery while the anesthesiologist turns off oxygen and nitrous oxide (if accidentally in use). The patient is immediately extubated and the “burning tube” dropped into a bucket of water (which should ideally be kept ready). An exception to this rule is when the patient also has a documented difficult airway. In such a situation, the anesthesiologist

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is literally caught between the proverbial “devil and the deep blue sea”. Retaining the tube and courting damage to the airway (that can be dealt with later) would be a better option in such situations where removal of the tube would definitely result in irreversible loss of the airway (and possible morbidity or mortality related to an inability to reintubate). Another option is to quickly pass a tube exchanger through the damaged tube and rail-roading a fresh tracheal tube over the tube exchanger. Saline is immediately flushed onto the area from the preloaded 50-ml syringe. Though rare, the fire may extend onto the surgical drapes. To tackle such a situation, a conventional fire extinguisher should always be kept ready inside the operating room where laser airway surgery is in progress. What is the management plan once the airway fire is extinguished? Once the burning tube is removed, the patient must be ventilated with 100% oxygen using a face mask or a supraglottic airway device. The patient should then undergo inspection of the airway with the help of a rigid bronchoscope to determine the extent of damage. Should the clinical condition demand continued ventilatory support, the patient should be reintubated and shifted to an intensive care unit for such ventilatory and other supportive therapy until the patient is ready for extubation. Occasionally, a tracheostomy may be needed to provide a longer period of ventilatory support. CONCLUSION Though airway fires are rare, such an accident can not only be unforgettable but may also have devastating consequences. The answers to the last 3 questions provide the sequential basis of how an airway fire can be prevented, efficiently dealt with should it occur, and what diagnostic and supportive care needs to be given following such a dramatic event. The steps of management can be remembered as the 4E’s – extract, eliminate, extinguish and evaluate. Extreme vigilance and being mentally and physically prepared for such a critical incident (though rare) is the key to success. Remember, calamities strike when they are least expected! RECOMMENDED READING 1. Doyle DJ. Airway fire. In Doyle DJ, Abdelmalek B, eds. Clinical airway management – An

illustrated case-based approach. Cambridge: Cambridge University Press 2017, 304-9. 2. Kazanjian PE, Doyle AR. Fires in the operating room. In Atlel JL, ed. Complications in anesthesia,

2nd Ed. Philadelphia: Saunders Elsevier 2007, 562-6. 3. Klarr PS. Laser complications. In Atlel JL, ed. Complications in anesthesia, 2nd Ed. Philadelphia:

Saunders Elsevier 2007, 567-9. 4. Doyle DJ. Anesthesia for ear, nose and throat surgery. In Miller RD, Cohen NH, Eriksson LI,

Fleischer LA, Wiener-Kronish JP, Young WL, eds. Miller’s Anesthesia, 8th Ed. Philadelphia : Elsevier Saunders 2015, 2523-49.

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5. Apfelbaum JL, Caplan RA, Barker SJ, Connis RT, Cowles C, Ehrenwerth J et al. Practice advisory for the prevention and management of operating room fires: An updated report by the American Society of Anesthesiologists Task Force on operating room fires. Anesthesiology 2013;118:271-90.

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Local anesthetic systemic toxicity (LAST)

Rammurthy Consultant Anesthesiologist

People Tree Hospital, Bengaluru

CASE SCENARIO A 76 year old elderly lady weighing 48 kg was scheduled for an urgent surgical treatment of a right hip fracture after a mechanical fall. Her medical history included hypertension and coronary artery disease. She was taking amlodipine, metoprolol and aspirin. Her baseline heart rate was 51 beats/min, BP- 150/90 mmHg. ECG showed occasional atrial premature complexes and 2D echo revealed an ejection fraction of 55%, moderate aortic stenosis, mild mitral regurgitation and normal pulmonary artery pressures. Her blood reports were unremarkable.

After discussion and obtaining informed consent, hip surgery was planned under combined psoas-compartment block and sciatic nerve block. In the operating room, all standard monitors were connected and an IV line was secured. Both blocks were performed using peripheral nerve stimulator (PNS) guidance. 25 ml (12.5 ml of 2% lidocaine + 12.5 ml of 0.5% bupivacaine) of local anesthetic solution was used for psoas compartment block and 15 ml (7.5 ml of 2% lidocaine + 7.5 ml of 0.5% bupivacaine) for sciatic nerve block.

Fifteen minutes after the block procedure, during positioning, patient became unresponsive to verbal and tactile stimuli, and developed a fixed gaze. Vital signs remained unchanged. In the next 2 minutes, she developed generalised convulsions. HR and BP were 110 beats/min and 180/110 mmHg respectively. IV midazolam was administered to stop the seizures and airway was secured with an endotracheal tube. Approximately seven minutes later, patient developed severe bradycardia (HR- 30 beats/min). IV atropine was administered following which the HR increased to 50 beats/min. However, within a minute, the rhythm deteriorated to pulseless electrical activity. ACLS algorithm was initiated.

POSSIBLE DIAGNOSES

Causes of Altered sensorium / Hemodynamic compromise in Orthopedic patients

1. Acute decompensation of valvular heart disease 2. Acute MI 3. Alcohol use or withdrawal / illicit drug withdrawal 4. Anaphylaxis 5. Cerebrovascular accident (stroke, TIA)

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6. Drugs- Local anesthetics, psychotropics, theophylline 7. Pulmonary embolism, fat embolism

LOCAL ANESTHETIC SYSTEMIC TOXICITY (LAST)

The estimate of clinically significant LAST ranges from 7.5-20 per 10,000 blocks performed.

Risk Factors for Toxicity: 1

The risk factors for developing LAST may be related to the local anesthetic, the type of block and the patient.

1. Local Anesthetic a. Type of local anesthetic

Bupivacaine is known to be more cardiotoxic than the lignocaine, levobupivacaine and possibly ropivacaine. It is a racemic mixture of both S and R enantiomers whereas levobupivacaine is only S enantiomer. Ropivacaine and levobupivacaine have intrinsic vasoconstrictor properties which may slow systemic absorption and hence lessen the possibility of systemic toxicity.

An important concept in the study of LAST is the ratio of the dose required to produce cardiovascular collapse to that required to induce seizures, the so-called CC/CNS ratio. Bupivacaine has a CC/CNS ratio of 2.0 compared with 7.1 for lidocaine. Therefore, progression from CNS signs and symptoms to cardiovascular collapse can occur more readily with bupivacaine than with lidocaine.

b. Dose of local anesthetic:

The total dose of local anesthetic should never cross the upper limit. If two different drugs are mixed together, then the dose of each drug should be halved as the mixture of two local anesthetic have an additive effect.

2. Block Related

a. Site of the block:

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Some block sites are more vascular than others, making blocks at these sites more vulnerable for producing toxicity. The order of LAST from low risk to high risk site is subcutaneous, brachial plexus, epidural, caudal, intercostal and topical.

b. Single shot vs. continuous catheter:

Continuous infusion can cause accumulation of local anesthetic over a period of time and can lead to LAST.

c. Conduct of the block:

Undertaking precautions such as Injecting test dose, frequent aspiration at every 3-5 ml interval, dye confirmation under fluoroscopy, and use of ultrasound guidance can reduce the incidence of LAST

3. Patient Related Factors

a. Liver and renal diseases- reduced clearance of local anaesthetic. b. Cardiac diseases- may increase the risk of arrhythmias, myocardial depression. c. Pregnant patients- low levels of alpha-1 acid glycoprotein and hence increased free

fraction of drug. d. Elderly patients- reduced clearance, increased neuronal sensitivity for blockade,

associated comorbidities. Pediatric patients- newborns and infants have reduced alpha-1 acid glycoprotein levels.

Signs and Symptoms of Local Anesthetic Toxicity 2

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Management of Local anesthetic systemic toxicity2

Steps for management of LAST: 3,4

1. Stop injecting local anesthetic 2. Get help

a. Consider lipid emulsion therapy at the first sign of a serious LAST event

b. Call for the LAST rescue kit 3. Ventilation management- 100% oxygen, avoid hypoxia, hypercarbia and acidosis.

Effective airway management is crucial. 4. Lipid emulsion therapy: administer at first sign of LAST, after airway management

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5. Control seizures a. Benzodiazepines b. Avoid large doses of propofol, especially in hemodynamically unstable patients.

6. Treat hypotension and bradycardia- if pulseless, start CPR 7. In the event of a cardiac arrest as a result of LAST, management differs in the following

aspects: a. Reduce individual epinephrine boluses to < 1 mcg/kg b. Avoid vasopressin, CCBs, beta-blockers, other local anesthetics. c. Amiodarone is the preferred anti-arrhythmic agent.

8. If there is no response to lipid therapy or vasopressors, cardiopulmonary bypass should be instituted.

9. Continue monitoring post-event:

a. At least 4-6 hours after cardiovascular event b. At least 2 hours after limited CNS event

Risk Reduction

1. Use the least dose of local anesthetic needed to achieve the desired effect and duration of blockade.

2. Identify the patients at risk of LAST- infants < 6 months, small patient size, old and fragile patient, heart failure, liver and kidney disease, mitochondrial disease, acidosis.

3. Consider using a pharmacologic marker / test dose - epinephrine 2.5 - 5 mcg/ml. 4. Inject the local anesthetic in incremental doses. 5. Aspirate frequently to check any blood in the syringe or the extension tubing. 6. Consider discussing the dose of local anesthetic to be used in the pre-anesthesia

checklist (timeout) 7. Use of ultrasound guidance for peripheral nerve blocks

Techniques for Early Detection of LAST

1. Monitor the patient during and after the block 2. Use ASA standard monitors

Communicate frequently with the patient for any symptoms of toxicity. Consider LAST if

there is altered mental status, neurologic symptoms or signs of cardiovascular instability

REFERENCES

1. Christie LE, Picard J, Weinberg GL. Local anaesthetic systemic toxicity. BJA Educ.

2015;15(3):136–142.

2. Vadi MG, Patel N, Stiegler MP. Local anesthetic systemic toxicity after combined psoas

compartment–sciatic nerve block: analysis of decision factors and diagnostic delay.

Anesthesiology 2014;120:987-96.

3. Neal JM, Barrington MJ, Fettiplace MR, Gitman M, Memtsoudis SG, Mörwald EE. et al.

The third American society of regional anesthesia and pain medicine practical advisory

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on local anesthetic systemic toxicity. Executive summary 2017. Reg Anesth Pain Med

2018;43:113-123.

4. Cave G, Harrop-Griffiths W, Harvey M, Meek T, Picard J, Short T, Weinberg G. AAGBI

safety guideline. Management of severe local anaesthetic toxicity. 2010. Available from

https://www.aagbi.org/sites/default/files/la_toxicity_2010_0.pdf.

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Obstetric hemorrhage

P S Balakrishna Achar Assistant Professor, Department of Anesthesiology

Father Muller Medical College, Mangaluru

CASE SCENARIO You are paged by the obstetrician regarding cesarean section for a 36 year old G3P2 at 37 weeks gestation with placenta previa. She has started to labor but is not bleeding. She requests regional anesthesia for her surgery. She has had 2 prior cesarean sections. Obstetric hemorrhage is one of the leading causes of maternal mortality in developing countries and morbidity in developed countries. WHO statistics puts the figure at 25-30% globally, 13% in developed countries and 34% in Africa. There is no universally accepted definition of obstetric hemorrhage though a few criteria are laid down - Sudden blood loss > 1500 ml (25% of blood volume) - Blood loss > 3000 ml in less than 3 hours (50% of blood volume) - Blood loss of 150 ml/minute in 20 minutes (>50% of blood volume) - Requirement of acute transfusion of > 4 units of packed red blood cells Though the clinical applications of these criteria could vary from case to case basis.

TYPES/ CAUSES OF OBSTETRIC HEMORRHAGE

1. Antepartum Hemorrhage- Bleeding into the genital tract after 24 weeks of gestation till delivery is called antepartum hemorrhage. Before 24 weeks, bleeding could be due to ectopic pregnancy or miscarriages. Causes

Most Common causes & Risk Factors

1.Placenta Previa Elderly Primi Previous LSCS Multipara Past Uterine Surgery

2.Placental Abruption Maternal Hypertension Severe Pre-Eclampsia Advanced Age PROM

Less Common causes 1.Uterine rupture 2.Cervical and Vaginal lesion

2. Postpartum Hemorrhage- Incidence is approximately 10% deliveries. It can be either

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Primary PPH

Within 24 hours Tone (uterine atony) Tissue (retained products) Trauma (cervical and genital tract damage during delivery) Thrombin (coagulation disorder)

Secondary PPH

After 24 hours to 6 weeks post delivery

Uterine atony, retained products, genital tract trauma, uterine inversion

RISK FACTORS

CONDITION DEFINITION RISK FACTORS

UTERINE ATONY

Defined as lack of efficient uterine contractility after placental separation

Uterine atony, retained products, genital tract trauma, uterine inversion

ABNORMAL PLACENTATION

Abnormal attachment of placenta to uterine wall.

Low lying Placenta, Prev LSCS, Placenta Praevia

MANAGEMENT 1. Anticipated Obstetric Hemorrhage A. Role of Anesthesiologist- -To identify patients who are at risk of obstetric hemorrhage by a. Discussion with obstetrician b. Reviewing patient’s investigations (Hb, PCV, Platelet count, PT, aPTT, INR, etc.) ultrasound report for any missed findings -Pre-op patient consultation focusing on important areas like a. Previous uterine surgeries, b. Various anesthetic options c. Need to convert to GA from RA if need arises d. NPO status e. Possibility of blood transfusions, f. Post op mechanical ventilation -Select Regional anesthesia in c/o intervention with stable hemodynamics and normal coagulation parameters (placenta previa, PPH, and abruption) - To make sure adequate compatible blood products are reserved in blood bank. - To be prepared for emergency intervention like -Arterial cannulation, CVC - Major fluid resuscitation, blood transfusion, inotrope management - Continue patient monitoring to look for signs of hypovolemia in case of on going bleed/oozing

1. Hypotension 2. Heart rate > 120 beats/minute

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3. Urine output < 0.5 ml/kg/minute 4. Capillary refill time < 5 seconds

- Targets for resuscitation during major hemorrhage to focus on Hemoglobin > 8 g% Platelet count > 75 x 109 /liter Prothrombin time (PT) < 1.5 x mean control Activated prothrombin time (APTT) < 1.5 x mean control Fibrinogen > 1.0 g/l

B. Obstetric Management - To plan the optimal intervention based on patient condition - Normal delivery vs. Cesarean delivery - Term gestation vs pre-term gestation - Clinical condition- Placenta previa (Complete vs. Incomplete), Abruption (Concealed vs. revealed), PPH - Intervention in c/o atony/abruption/rupture uterus like bimanual compression, B-Lynch sutures, hysterectomy - Discuss with the patient and the patient’s relatives about the need for hospitalization, observation, options of delivery, blood transfusion, obstetric hysterectomy and ICU care in case of obstetric hemorrhage - To plan the various uterotonics administration if PPH is anticipated - To co-ordinate with anesthesiologist, blood bank officer and other intermediaries, for proper planning if need for massive transfusion arises - Consider interventional procedures like IIA ligature/embolization if facility for the same is in place as a remedial measure for major bleed. - Monitor vitals in case of bleeding to plan and execute various strategies depending on the degree of hemorrhage 2. Unanticipated Obstetric Hemorrhage A. Anesthetic Management Degree and urgency of resuscitation depends on the extent of bleed Minor bleeding (Up to 100-1000 ml blood loss, no s/o clinical shock)

Gain intravenous access (14 G cannula x1) Commence crystalloid infusion.

In massive hemorrhage (> 1000ml/ continuing blood loss, or patient in clinical shock) mothers need active resuscitation. Following factors need to be addressed;

Assess airway, breathing and circulation Oxygen by mask @ 10-15 liters/minute Intravenous access – large bore cannulas-16 or 14 G cannula x 2, Central venous cannulation in collapsed patient not only provides a vascular access but may

also aid in monitoring the central venous pressure and guide fluid resuscitation. Flat position Keep the mother warm using appropriate available measures

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Until blood is available, infuse up to 3.5 liters of warm crystalloid (RL 2 liters, avoid hypertonic solutions) and/or colloid (1-2 liters) as rapidly as possible

If group specific packed cells and FFP are arranged, start transfusion earliest or else send blood for grouping and cross matching to make blood available very soon

If concerned group blood products are not available O-ve blood products can be transfused as an urgent rescue measure

Point of care results of adequacy of resuscitation like HemoCue, TEG can be used

Consider administering GA if hemorrhage develops during normal delivery/cesarean or in case of abruption and atonic PPH

To be prepared to shift the patient to radiology suite for interventional balloon embolization Monitoring: - Clinical signs of hypovolemia/shock - Parameters for adequacy of resuscitation/correction of coagulation parameters/blood oxygen carrying capacity -Document the entire intervention with clinical scenario in a chart for further analysis B. Obstetric Management - Involve the fellow colleagues/senior in quick decision making - Involve anesthesiologist/blood bank/radiologist in urgent patient care related decisions and interventions - Consider the various uterotonic administration for managing the uterine contraction - Plan for next level care if 1st line management fails to give the desired results like bi-manual compression, B-lynch sutures, IIA ligatures - Consider radiological intervention if facilities for the same is available - Last life saving option to be considered is obstetric hysterectomy

3. Hemorrhagic Shock and Management Stages of shock

CLASS 1 CLASS 2 CLASS 3 CLASS 4

BLOOD LOSS % <15 15-30 30-40 >40

HEART RATE/MIN

<100 >100 >120 >140

SBP(mmHg) Normal Normal ↓ ↓

Pulse Pressure N/↑ ↓ ↓ ↓

RESP RATE/MIN

14-20 20-30 30-40 >35

MENTAL STATE Slightly anxious

Mildly anxious

Anxious, Confused

Confused lethargic

General Resuscitation Principles The management of hemorrhage in parturient depends upon - Antecedent condition - Vitals - Existing resources, manpower, blood and blood products

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A few general principles are -Resuscitation with I.V fluids to be used only for hypotensive patients and only till blood arrives - Blood and blood products to be given as soon as need for transfusion is recognized -Blood products like (PRBC, plasma, platelets) to be given in equivalent proportions (preferably in 1:1:1) ratio -Point of care investigations like HemoCue, thromboelastogram to be used as a guide to assess the adequacy of resuscitation during major obstetric hemorrhage Prevention

A. Identify the risk factors for uterine atony- The following are risk factors for Atony which has to be assessed, addressed, avoided if possible and reviewed

OBSTETRIC MANAGEMENT Induced Labor, Augmented Labor, Cesarean delivery

OBSTETRIC CONDITIONS Multiple gestation, Macrosomia, Polyhydromnios, High parity, Prolonged labor, Precipitous labor,Chorioamnionitis

MATERNAL CO-MORBIDITIES Advanced maternal age, Hypertensive disease, Diabetes

OTHERS Tocolytic drugs*(β-agonist, MgSO4), High concentration of volatile anesthetic agents

B. Identify the risk factors for abnormal placentation like placenta previa, low lying placenta, and previous LSCS. Anticipate atony/PPH/obstetric hemorrhage and take necessary measures to manage the same C. Scheduled Cesarean Hysterectomy is the definitive treatment of choice for obstetric hemorrhage when medical and other invasive therapies fail. Indications-1. Uterine atony 2. Placenta Accreta 3. History of multiple previous sections increases risk for atony and accreta subsequently ending with peripartum hysterectomy. Obstetric challenges-1. Enlarged uterus 2. Engorged vessels due to pregnancy vascularity 3. Adhesions from previous surgery 4. Risk of bleed, ooze leading to massive blood transfusion 5. Ureteric/Bladder injury 6. Late complications such as wound infection, DVT, Transfusion related complications Morbidity and Mortality- 56% & 2.6% Anesthetic Challenges and Considerations-1. Dedicated experienced team need to manage the anesthetic & circulatory challenge that can arise during the procedure. 2. If circulatory and coagulation disturbance is absent – combined spinal epidural or epidural anesthesia or spinal anesthesia with a block height of T4 to be maintained to prevent adverse responses during surgery.

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3. Sympatholysis induced before the onset of hemorrhage could reduce bleed, sympathetic stimulation from stress of bleed. However in established hypovolemia during major bleed, it could worsen hypotension leading to end organ dysfunction/cardio respiratory collapse. 4. GA preferable if -Spinal anesthesia for section is wearing off below T4 - Ongoing bleed with circulatory instability - Anticipated difficult airway/circulatory instability (Placenta accreta) - Major fluid and blood products transfusion leading to generalized/airway edema, disturbance in oxygenation/ventilation 5. Securing large bore cannulas/CVC cannulation anticipating bleed for massive fluid and blood resuscitation 6. Role of invasive arterial monitoring for real time blood pressure monitoring and drawing repeat blood samples for investigations 7. Reserving at least 4 PRBC for immediate transfusion along with FFP, platelets. 8. Prevention of hypothermia 9. Inotropes like dopamine, epinephrine to be loaded and kept ready D. Role of interventional radiology- One of the options in advanced centers is internal iliac artery embolization through occlusive balloon catheters via fluoroscopy to avoid peripartum hysterectomy. If epidural catheter is used for labor analgesia, bolus or infusion can be continuous or else sedation analgesia maybe required for the procedure. The attending anesthesiologist should accompany patient to the radiology suite and manage the patient with full care. DISCUSSION 1. CHOICE OF ANAESTHETIC MANAGEMENT- GA vs. REGIONAL

GA REGIONAL

1.Anaesthetic of choice in -Placental Abruption - Hemodynamically unstable - Placenta accreta/percreta - Associated difficult airway - Suspected coagulopathy - Patchy/wearing off of spinal anesthesia 2.Advantages- - Control over hemodynamics - Can prolong anesthetic duration - Airway protection - Can institute ICU ventilation if need arises -Easier to secure Lines

1.Anaesthetic of choice in - Pt consenting - Placenta previa (Hemodynamically stable ) - Other hemodynamic stable patient - Coagulations parameters normal

2.Advantages- - Better stress response control and analgesia - Lesser hemorrhage from vasodilatation and sympatholysis - Epidural catheter for labor analgesia can be converted to anesthesia for surgery - Prolongation of anesthesia with Epidural Infusions/top ups - Lesser risk of DVT 3.Disadvantages

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3.Disadvantages - Polypharmacy - Analgesic quality inferior to regional techniques - Awareness - Risk of uterine atony with >0.5 MAC inhalational agent - N2O could be harmful for fetus if there is existing fetal distress 4.Drugs- - Analgesics-Short acting opioids. No consensus regarding timing of administration before or after delivery of baby - Induction Agents- titrated doses of thiopentone/propofol/etomidate If hemodynamically unstable, ketamine /etomidate - Technique-RSI consider full stomach - N20- Preferable after extraction of baby -Inhalational Agent- 0.5 MAC for awareness/avoiding atony

- No Airway protection - Spinal anesthetic cannot be prolonged if procedure takes time -Insertion of vascular lines more challenging in awake patient - Circulatory instability from hemorrhage could worsen with additional regional anesthetic drugs 4.Drugs- - Block height of T4 required - Choice of Spinal/Epidural/CSE depending on the procedure -Monitor for hypotension/bradycardia/ bleeding - Rule out coagulopathy/hemodynamic disturbance before administering anesthesia - Be prepared for conversion to GA anytime during the procedure

2. Anesthetic challenges for bleeding Parturient-Various challenges are -Minimal time frame for pre-anesthetic checkup, investigations review, optimization - Patient evaluation, resuscitation, preparation for operative delivery to undergo simultaneously - Status of Airway, NPO, Intravascular volume secondary to bleed, cause of the bleed are add on challenges - Aggressive resuscitation with 2 large bore cannulas and non-dextrose crystalloids, colloids till the right group cross matched blood products are made available - Making sure adequate blood products are available in case of massive transfusion scenario - Choice of Anesthesia shall be GA with RSI assuming full stomach. Challenges pertaining to drug selection, dosage, role of N20 and inhalational agent are anesthetic challenges - Different uterotonics administration to ensure uterine contraction in case of atony, cesarean for placenta previa, abruption, accreta. - Role of Invasive monitors like CVC, Arterial cannula for improving real time monitoring, drawing blood for repeat Investigations. - Ensuring patient is kept warm and hypothermia to be prevented

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- Ensuring all the above instituted measures are initiated and synchronized with the obstetric team in ensuring the bleed and parturient both are taken care off - The situation may turn more challenging when none of the medical and other invasive techniques fail to take care of the bleeding and peripartum hysterectomy becomes final option 3. Uterotonic drugs and surgical techniques

DRUGS DOSE & ROUTE

RELATIVE C/I SIDE EFFECTS NOTES

OXYTOCIN 0.3-0.6 IU/min I.V infusion

None Tachycardia, hypotension, MI, free water retention

Short duration of action

Methyl Ergonovine (Methergine)

0.2 mg IM HTN,PIH,CAD N/V, arteriolar vasoconstriction HTN

Long duration of action. Repeat every 1 hour

15-Methyl PGF2α

0.25 mg IM

Reactive Airway Disease,PAH,Hypoxia

N/V, bronchospasm, diarrhea, chills

Repeat every 15 min to max 2 mg

Surgical techniques for management of PPH

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REFERENCES

1. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum hemorrhage: a systematic review. Best Pract Res Clin Obstet Gynaecol. 2008;22:999-1012. 2. Chhabra S, Sirohi R. Trends in maternal mortality due to hemorrhage: two decades of Indian rural observations. J Obstet Gynaecol. 2004;24(1):40–43. 3. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PFA. WHO analysis of causes of maternal death: a systematic review. The Lancet. 2006;367:1066-1074. 4. Rath WH. Post partum hemorrhage- Update on problems of definitions and diagnosis. Acta Obstet Gynecol Scand. 2011;90(5):421-28. 5. Mayer D, Spielman FJ, Bell EA. Antepartum and postpartum hemorrhage. In: Chestnut DH, (editor). Obstetric anesthesia. Principles and practice. 3rd edition. Philadelphia: Elsevier Mosby; 2004:Chapter 38.662–82. 6. Camann WR, Biehl DH. Antepartum and postpartum hemorrhage. In: Hughes SC, Levinson G, Rosen MA, (editors). Shnider and Levinson’s anesthesia for obstetrics. 4th edition. Philadelphia: Lippincott Williams & Wilkins;2002:361–71. 7. You WB, Zahn CM. Postpartum hemorrhage: abnormally adherent placenta, uterine inversion and puerperal hematomas. Clin Obstet Gynecol. 2006;49:184-97. 8. Mitty HA,Sterling KM, Alvarez M, Gendler R. Obstetric hemorrhage:prophylactic and emergency arterial catheterization and embolotherapy.Radiology.1993;188:183-7.

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9. The Royal College of Obstetricians and Gynaecologists (RCOG). Postpartum hemorrhage: Prevention and Management (Green-top Guidelines No. 52). London: RCOG;2009. Available on https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg52/ 10. Reyal F, SibonyO, Oury JF, Luton D, Bang J, Blot P. Criteria for transfusion in severe postpartum hemorrhage: analysis of practice and risk factors. Eur J Obstet Gynecol Reprod Biol 2004;112:61–4. 11. Jansen AJ, van Rhenen DJ, Steegers EA, Duvekot JJ. Postpartum hemorrhage and transfusion of blood and blood components. Obstet Gynecol Surv 2005;60:663-71. 12. Magann EF, Evans S, Hutchinson M, Collins R, Howard BC, Morrison JC. Postpartum hemorrhage after vaginal birth: an analysis of risk factors. Southern Med J.2005;98(4):419–422. 13. Tsu V. Postpartum hemorrhage in Zimbabwe: a risk factor analysis. Br J Obstet Gynaecol.1993;100:327–333. 14. American College of Surgeons Trauma Committee. Advanced Trauma Life Support for Doctors. 8th edition. Chicago, American College of Surgeons, 2008.

15. Bauer ST, Bonanno C. Abnormal placentation. Semin Perinatol 2009;33:88-95. 16. Hudon L, Belfort MA, Broome DR: Diagnosis and management of placenta percreta: A review. Obstet Gynecol Surv 1998:53;509-517. 17. Levy D, Obstetric hemorrhage, In:Johnston I,Harrop-Griffiths,W Gemmell, L, eds. AAGBI Core Topics in Anesthesia ,Chichester: Wiley-Blackwell Ltd,2012;105–23. 18. Parekh N, Husaini SWU, Russell IF. Caesarean section for placenta praevia: a retrospective study of anesthetic management, Br J Anaesth.2000;84:725–30. 19. Bhavani-Shankar K, Lynch EP, Datta S: Airway changes during Cesarean hysterectomy. Can J Anesth.2000:47;338-341. 20. Chestnut DH, Redick LF: Continuous epidural anesthesia for elective cesarean hysterectomy. South Med J.1985:78;1168-1169. 21. Bonnar J. Massive obstetric hemorrhage. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000:14(1);1-18. 22. Mok M, Heidemann B, Dundas K, Gillespie I, Clark V. Interventional radiology in women with suspected placenta accreta undergoing caesarean section. Int J Obstet Anesth 2008:17;255-261. 23.O’Rourke N, McElrath T, Baum R, Camann W, Tuomala R, Stuebe A, et al. Cesarean delivery in the interventional radiology suite: A novel approach to obstetric hemostasis. Anesth Analg 2007:104;1193-1194.

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Pulmonary embolism

Sripada G Mehandale1, Sakshi Tikkoo2

1Professor and Head, 2Junior Resident, Department of Anesthesiology & Critical Care K S Hegde Medical Academy, Nitte University, Mangaluru

CASE SCENARIO

A 54 year old male with fracture shaft of femur (L) following road traffic accident is posted for intramedullary nailing. There is no history of other comorbidities, no history suggestive of head injury or other injuries. Subarachnoid block was planned and performed uneventfully. Shortly after intramedullary nailing patient became unresponsive. There is a drop in the end tidal carbon dioxide levels, oxygen saturation levels and blood pressure associated with sinus tachycardia. What is the likely diagnosis and plan of management?

1. What is the differential diagnosis? a. Fat embolism b. Thromboembolism c. Pulmonary embolism of other origin d. Thrombotic thrombocytopenic purpura e. Pulmonary edema f. High spinal

2. What is fat embolism?

Fat embolism refers to the presence of circulating fat globules in circulation and pulmonary parenchyma. Fat embolism syndrome (FES) is the clinical manifestation of fat embolism. It is associated with a complex alteration of hemostasis, usually presenting as a triad of respiratory insufficiency, altered sensorium and petechiae.

3. What is the etiology of fat embolism?

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Table 1. Causes of FES

The other forms of trauma that may be rarely responsible for FES include massive soft tissue injury, severe burn, bone marrow biopsy, bone marrow transplant, cardiopulmonary resuscitation, liposuction, and median sternotomy. Other possible etiological factors are as in Table 1.

4. What are the risk factors for fat embolism? a. Young age (10 to 40 years) b. Closed fractures c. Multiple fractures d. Conservative therapy for long-bone fractures

5. What are the aggravating factors during surgery? a. Overzealous nailing b. Reaming medullary cavity c. Increased velocity of nailing d. Gap between nail and bone

6. Are fat embolism and fat embolism syndrome synonymous? No. Almost all patents show fat emboli in systemic circulation who sustain pelvic or femoral fractures. Fat embolism syndrome (FES) is physiologic reaction to fat in systemic circulation and incidence is less than 1%.

7. What are the clinical manifestations of fat embolism? FES can manifest with respiratory, neurological, cardiovascular, hematological manifestations. The manifestations may evolve gradually over 24 to 72 h or may be fulminant leading to acute respiratory distress and cardiac arrest.

8. What are the pathognomonic signs of FES? A petechial rash is pathognomonic of FES. Rashes usually present over conjunctiva, oral mucosa, skin folds of neck and axilla. This has highest diagnostic value (Table 2).

CSl no. Trauma related Non trauma related

1. Long bone fracture Pancreatitis

2. Pelvic fracture Diabetes mellitus

3. Fracture of other marrow-containing bones

Osteomyelitis and panniculitis

4. Orthopedic procedures Bone tumor lysis

5. Soft tissue injuries (e.g., chest compression with or without rib fracture)

Sickle cell hemoglobinopathies

6. Burns Alcoholic liver disease

7. Liposuction Cyclosporine A solvent

8. Bone marrow harvesting and transplant Steroid therapy

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Presence of fat globules is not diagnostic as even healthy volunteers may have them in their blood. Daily assessment of fat droplets in blood may be of prognostic value as they may indicate severity of symptoms. However, recent evidence does not support this and negates the notion that it can predict onset of ARDS.

9. What are the diagnostic criteria for fat embolism? Gurd and Wilson (1974) suggested diagnostic criteria for FES. They consist of major, minor and laboratory features. One major, four minor and presence of fat macroglobulinemia was required for diagnosis.

Table 2. Causes of FES

Schonfeld fat embolism index (1983) is a quantitative tool for diagnosis. A score exceeding 5 is diagnostic.

Sl no. Criteria Score

1. Petechiae 5

2. Diffuse alveolar infiltrates on x-ray chest 4

3. Hypoxemia (PaO2<70 mmHg @ 100% O2) 3

4. Confusion 1

5. Fever > 38° C (>100°F) 1

6. Hear rate > 120 BPM 1

7. Respiratory rate > 30 BPM 1

Table 3. Schonfeld index

Lindeque et al (1978) proposed criteria for diagnosis of FES with only respiratory parameters. A positive diagnosis is proposed if at least one criterion is met.

Major criteria Minor criteria Laboratory criteria

Petechial rash Tachycardia Fat macroglobulinemia

Respiratory insufficiency (with radiological changes)

Fever Thrombocytopenia

Cerebral involvement (unrelated to trauma)

Retinal changes Anemia

Jaundice High ESR

Renal signs

Sl no. Criteria Value

1. Sustained hypoxia < 60 mm Hg

2. Sustained hypercarbia >55 mm Hg

3. Sustained tachypnea in spite of sedation >35 BPM

4. Increased work of breathing (dyspnea, accessory muscle action, tachycardia, anxiety)

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Table 4. Lindeque's criteria 10. Describe the pathophysiology of FES.

Pathophysiology still remains unclear. However, two theories are proposed.

a. Mechanical theory: Fat globules from bone marrow or adipose tissue enter circulation via disrupted venules to travel to pulmonary circulation or systemic circulation through arteriovenous shunts. Direct evidence for this phenomenon can be witnessed by echocardiographic finding of echogenic material traversing right ventricle during orthopedic procedures including reaming and bone cement application. These globules obstruct the circulation to cause increased load on right heart, create dead space in the lungs, alveolar collapse, micro-infarcts in brain, heart and other organs. These phenomena partly explain respiratory manifestations, CNS changes and myocardial depression.

b. Biochemical theory: However, the mechanical theory does not explain the development of FES after a delay of 2–3 days post injury. There are many biochemical mechanisms involved in the progression of FES. Most widely accepted explanation is release of free fatty acids and resultant response. The lung (pneumocytes) responds to the presence of fat emboli by secreting lipase, which hydrolyses the fat into free fatty acids and glycerol. The free fatty acids act locally to produce an increase in the permeability of the capillary bed, a destruction of the alveolar architecture, and damage to lung surfactant. Local ischemia and inflammation leads to concomitant release of inflammatory mediators and vasoactive amines and platelet aggregation. Acute-phase reactants, such as C-reactive proteins cause the chylomicrons to coalesce initiating inflammatory response. Free fatty acids migrate to other organs via the systemic circulation, causing multi-organ dysfunction including decreased cardiac contractility.

c. Coagulation theory: This is a recent theory. It proposes that tissue thromboplastin released with marrow elements activate the complement system and extrinsic coagulation cascade via direct activation of factor VII which in turn leads to production of intravascular coagulation by fibrin and fibrin degradation products.

11. What are the complications of fat embolism syndrome? a. Acute respiratory failure b. Cor pulmonale c. Neurological deficits ranging from disorientation, drowsiness to coma, DIC, d. Acute coronary syndromes, sudden circulatory collapse and death

12. What are the clinical presentations? a. Subclinical: Very common among long bone fractures. Decreased PaO2, minor

hematological changes with no clinical signs or symptoms of respiratory insufficiency are the usual presentation. However, tachypnea, tachycardia, and fever may be seen.

b. Subacute or nonfulminant: Consisting of respiratory (tachypnea to ARDS), CNS (confusion, stupor to coma) and petechiae, beginning to improve from third day. Changes similar to Purtscher's Retinopathy may be present.

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c. Fulminant: Though rare, may present with onset within hours of injury. Respiratory failure and altered mental status may progress to death, usually due to right ventricular failure.

13. What are the other causes of pulmonary embolism? Embolization of deep vein thrombosis from legs is the commonest cause. However, other veins like femoral, pelvic, abdominal, upper limb, cervical as well as right ventricle may contribute to pulmonary embolism. Though not as frequent, other sources of pulmonary embolism include fat, amniotic fluid, air, infected material, foreign bodies and tumors.

14. What is the incidence of pulmonary embolism? In USA, one in one thousand population is affected by pulmonary embolism every year. In Indian context, it is estimated that a million are affected every year, though exact figures are difficult to collect.

15. What are the risk factors for thromboembolism? In essence the risk factors can be classified as (Table 5)

a. Conditions that impair venous return, including bed rest and confinement without walking

b. Conditions that cause endothelial injury or dysfunction c. Underlying hypercoagulable (thrombophilic) disorders

Surgery Major joint surgery, lower limb surgery, abdominal or pelvic surgery for cancer, major gastrointestinal tract surgery, multi-trauma, spinal cord injury with paresis

Acute and chronic medical illness Chronic heart failure, myocardial infarction, inflammatory bowel disease, active rheumatic disease, nephrotic syndrome, acute respiratory failure, chronic lung disease

Malignancy-related factors Active malignancy, myeloproliferative neoplasms, cancer treatment

Hormonal-related factors Pregnancy or early postpartum, oral contraceptive pill, hormone replacement therapy

Known thrombophilia

Other Body mass index >30 kg/m2, venous stasis/varicose veins, past history of deep venous

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Table 5. Risk factors for pulmonary embolism

16. Describe the pathophysiology of pulmonary embolism. Under normal conditions, micro thrombi (tiny aggregates of red cells, platelets, and fibrin) are formed and lysed continually within the venous circulatory system. If there is any factor favoring stabilization of micro thrombi or increase in its size, would cause formation of thrombus. This thrombus may break in to fragments and gets dislodged to travel along veins to reach right heart and then in to pulmonary circulation. It may lodge at the bifurcation of main pulmonary artery or any lobar artery branches to cause hemodynamic compromise. Small emboli may have no acute physiologic effects and may begin to lyse immediately and resolve within hours or days. Larger emboli can cause a reflex increase in ventilation (tachypnea), hypoxemia due to ventilation / perfusion (V/Q) mismatch, and low mixed venous oxygen content as a result of low cardiac output, atelectasis due to alveolar hypocapnia and abnormalities in surfactant, and an increase in pulmonary vascular resistance caused by mechanical obstruction and vasoconstriction. Most of the emboli lyse owing to internal mechanism, but some may organize and persist. As per the severity it can be classified as,

a. Massive: Impaired right ventricular function with hypotension, as defined by systolic BP < 90 mm Hg or a drop in systolic BP of ≥ 40 mm Hg from baseline for a period of 15 min and predicts a significant risk of death within hours or days

b. Submassive: Impaired right ventricular function without hypotension c. Small: Absence of right ventricular impairment and absence of hypotension

Nonthrombotic pulmonary embolism may present with clinical conditions different from thrombotic pulmonary embolism. Diagnosis depends upon individual clinical criteria.

17. What is saddle pulmonary embolus? A pulmonary embolus that lodges in the bifurcation of the main pulmonary artery and into the right and left pulmonary arteries; saddle PEs are usually submassive or massive.

18. What is chronic pulmonary thromboembolic hypertension? Often the emboli resolve over a period of time due to internal lytic mechanisms. However, some of them (3-4%) may remain and cause residual chronic obstruction to pulmonary blood flow leading to pulmonary hypertension that can result in right heart failure.

19. What is the clinical presentation of pulmonary embolism? Clinical presentation may vary according to the severity of embolism. Physiologically insignificant emboli may be asymptomatic. Even if they are significant, clinical features may be nonspecific and may depend on extent, location and pre-existing

thrombosis or pulmonary embolism, prolonged immobilization/travel

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cardiopulmonary disease. Typically, dyspnea of acute onset, pleuritic chest pain and cough may be present. Concomitant symptoms and signs of DVT may present and support diagnosis. Tachypnea, tachycardia may also be present.

20. What are the investigations to establish diagnosis? Investigations include ECG, blood tests and imaging. Useful tests include:

a. ECG may show S1Q3T3, or a new onset right bundle branch block (indicative of effect of sudden rise in RV pressure on RV conduction), right axis deviation (R>S in V1), P pulmonale (Tall, narrow, peaked P waves in leads II, III, and aVF and often a prominent initial positive P wave component in V1), T inversion in V1-4 may be seen. Tachycardia and T wave inversions are most common.

S1Q3T3 pattern

b. D-dimer testing c. Ischemia-modified albumin level d. Total count e. Arterial blood gases f. Serum troponin levels g. Brain natriuretic peptide

D- dimer is a by-product of intrinsic fibrinolysis. Elevated levels occur if there is recent thrombosis. A negative D-dimer levels (<0.4µg/mL) are highly sensitive for absence of pulmonary embolism if there is no possibility of thrombosis prior to the incident (NPV>95%). Elevated levels being nonspecific, calls for further testing for confirmation.

Ischemia-modified albumin level has similar predictive value as D-dimer. Total count may be elevated. Arterial blood gases (ABG) may show hypoxia, and respiratory alkalosis. Serum troponin levels may be of prognostic value as elevated levels indicate myocardial injury. Brain natriuretic peptide (BNP) alone and in combination with Troponin I can be of prognostic value. Elevated BNP indicate poorer prognosis including need for ICU admission. BNP elevation disproportionate to troponin I may indicate higher mortality. N-terminal prohormone of brain natriuretic peptide (NT-proBNP or BNPT) may be useful in differentiating patients attending emergency department with acute dyspnea of chronic heart failure and pulmonary embolism.

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h. X-ray chest: though nonspecific may have abnormal findings in most occasions of pulmonary embolism. They include: atelectasis, focal infiltrates, an elevated hemi diaphragm or pleural effusion. Classical findings like Hamptons hump (a peripheral wedge-shaped density), Westermark sign (focal loss of vascular markings), Palla’s sign (enlargement of the right descending pulmonary artery) may be seen but infrequently.

i. Echo cardiograph: Right ventricular dilation, right ventricular hypo kinesis and high right atrial pressures may confirm the presence of massive pulmonary emboli. Advantage of echocardiograph is that, it can be performed bedside, even when the patient is hemodynamically unstable. Also, Doppler and ultrasound can detect and confirm deep vein thrombosis (DVT), supporting the diagnosis. Duplex, combination of traditional ultrasound (for blood vessels) and Doppler scan (blood flow) is used for detecting DVT by looking for lack of compressibility and alteration in flow pattern in the venous system (95% or more sensitivity and specificity).

Trans esophageal echocardiography can detect emboli in central pulmonary veins, hence useful in cases where other modalities of imaging are not available or contraindicated.

j. CT pulmonary angiography (CTPA): Currently standard criteria for diagnosis are computed tomography angiography, demonstrating filling defect in pulmonary arterial tree. May not be feasible in unstable patients.

k. Venography: Criterion standard for diagnosis of DVT. Requires a stable patient without renal compromise.

l. MRI chest: Spin gated or standard gated MRI chest to detect hyper intense signal within pulmonary artery.

m. Pulmonary angiography: Is standard diagnostic tool in the absence of CTPA, to demonstrate flow defects in the vascular tree.

n. Ventilation perfusion (V/Q) scan: Was a standard modality prior to CT scan. However, if there is a need to reduce exposure to radiation like in pregnant patient, perfusion only scans may be performed, especially in cases of normal chest x-ray.

21. What are the risk stratification tools for pulmonary embolism? There are numerous clinical decision rules, including the Wells score (Table 6), modified Wells score, simplified Wells score, revised Geneva score, Charlotte rule and Pulmonary Embolism Rule-out Criteria (PERC) rule. The Wells score and PERC rule are the most validated tools of these studies, are simple to use, and can be incorporated into the assessment of patients with suspected pulmonary embolism.

22. Describe Well’s criteria.

Sl no. Clinical feature Wells score

1. Clinical signs and symptoms of DVT 3

2. Pulmonary embolism most likely diagnosis 3

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3. Heart rate >100 beats per minute 1.5

4. Immobilization at least three days or surgery within past four weeks

1.5

5. Previous DVT or pulmonary embolism 1.5

6. Hemoptysis 1

7. Malignancy treatment within six months or palliative 1

Table 6. Wells criteria

A Well’s score >4 warrant imaging

Limitations of Wells score: Wells score can only be applied if symptoms have been present for <30 days, and is not validated for use if

a. Upper limb DVT is suspected as a source of pulmonary embolism b. The patient has been on anticoagulants for >72 hours c. The patient has been asymptomatic for 72 hours prior to presentation d. The patient is pregnant

23. What is PERC rule? If the probability of pulmonary thromboembolism is low with Wells score, then the Pulmonary Embolism Rule-out Criteria (PERC) rule (Table 7) can be applied:

Aged <50 years

Pulse <100 beats per minute

SaO2 ≥95%

No hemoptysis

No estrogen use

No surgery or trauma requiring hospitalization within four weeks

No prior venous thromboembolism

No unilateral leg swelling

Table 7. PERC Rule

If the answer to all of the above criteria is ‘Yes’, then the PERC rule is negative. No further testing is required and pulmonary embolism is safely excluded. The PERC rule has not been validated for people with:

a. Active cancer, thrombophilia or a strong family history of thrombophilia b. Transient tachycardia or beta-blocker use that may mask tachycardia c. Leg amputations d. Morbid obesity (leg swelling not easily determined) e. Baseline hypoxemia when oximetry reading <95% is longstanding.

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If the patient’s PERC score is > 0, then an enzyme-linked immunosorbent assay (ELISA)-type D-dimer is recommended. If this is negative, pulmonary embolism is ruled out and no further investigation is required; if positive, then imaging is recommended.

24. Lay out the approach to the investigations in a suspected case of pulmonary embolism.

Figure 1. Approach to the investigation in suspected pulmonary embolism.

25. How do you proceed with diagnosis of pulmonary embolism with the help of imaging? Following algorithm may be useful in proceeding with diagnosis of pulmonary embolism when imaging is indicated.

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Chest CT

Diagnostic

Stop

Non diagnostic/unavailable

or unsafe

lung scan

Diagnostic

Stop

Nondiagnostic

Venous ultrasound

Positive

Treat for PE

Negative

TEE/MRI/invasive angiography

Positive

Treat for PE

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Figure 2. Diagnostic approach to suspected pulmonary embolism.

26. What is the management for pulmonary embolism?

Mainstay of management in pulmonary embolism is three pronged approach:

a. Prevention of further embolization b. Destruction of embolus c. Stabilization and supportive therapy

Algorithm for pulmonary embolism management:

Figure 3. Decision making in pulmonary embolism

Rapid assessment and supportive therapy: Need for supportive treatment should be quickly assessed. Hypoxia being common among symptomatic patients, supplemental oxygenation to be initiated. In hypotensive patients maintaining preload by infusing about a liter of Lactated Ringer’s solution is an age-old strategy. If the response is inadequate, vasopressors like noradrenaline to be initiated urgently.

Pulmonary vasodilators: Pulmonary vasodilators improve right-sided cardiac output by reducing RV afterload. Conventional vasodilators such as nitroglycerin, nitroprusside, and hydralazine have a vasodilatory effect on the pulmonary vasculature that leads to reduction in PVR and RV afterload. However, they have a more profound vasodilatory effect on the systemic vasculature, ultimately leading to a higher risk of decreasing SVR and worsening RV ischemia.

Risk stratification

Nornotension+ Normanl RV

Anticoagulation alone

IVC filter

Normotension+ Hypokinetic RV

Individualize therapy

Hypotension

Anticoagulation+ thrombolysis

Embolectomy (Catheter/Surgical)

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Pulmonary vasodilators such as prostacyclin (epoprostenol and prostaglandin I2) and inhaled nitric oxide (NO) are shown to have a promising role in management of RV failure due to various etiologies.

If cardiac output remains low despite vasopressors and inotropes, a pulmonary vasodilator trial with inhaled nitric oxide may be beneficial when pulmonary hypertension is present.

Veno-arterial extracorporeal membrane oxygenation (ECMO) may be used as a rescue procedure in severely ill patients with acute PE, regardless of what other therapies are used.

Anticoagulation: Consists of intravenous unfractionated heparin, subcutaneous low molecular weight heparin, subcutaneous fondaparinux, Factor Xa inhibitors (apixaban and rivaroxaban), intravenous argatroban for patients with heparin-induced thrombocytopenia, oral warfarin

Unfractionated heparin: Traditionally heparin is used as an intravenous bolus followed by infusion to maintain aPTT 2-3 times the upper limit of control. Advantages of this are short half-life in the face of risk of bleeding and easy reversibility with protamine if there is bleeding risk. However, individual response to the dose is unpredictable mandating close monitoring with frequent dose adjustment.

Subcutaneous low molecular weight heparin: Has several advantages over unfractionated heparin including superior bioavailability, weight-based dosing results in a more predictable anticoagulation effect than does weight-based dosing of unfractionated heparin, ease of administration (can be given sc once or twice daily), decreased incidence of bleeding, potentially better outcomes, the potential for patients to self-inject (thereby allowing earlier discharge from the hospital), lower risk of heparin-induced thrombocytopenia compared with standard, unfractionated heparin.

LMWH Treatment dose Prophylactic dose

Dalteparin 100 units/kg sc q 12 h or

200 units/kg once/day

2500–5000 units once/day

Enoxaparin 1 mg/kg sc q 12 h or 1.5 mg/kg sc once/day

After abdominal surgery: 40 mg sc once/day

After hip replacement surgery: 40 mg sc once/day or 30 mg sc q 12 h; after knee replacement: 30 mg sc q 12 h

For unstable angina or non-Q wave MI:

1 mg/kg sc q 12 h

For other (medical) patients not undergoing surgery: 40 mg sc once/day

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Tinzaparin 175 units/kg sc once/day (in patients with or without PE)

3500 units once/day

Table 8. Dosage of LMWH

Dose adjustment is required in patients with renal failure.

For maintenance rivaroxaban 15 mg twice daily for three weeks followed by 20 mg once daily is sufficient. Newer agents like fondaparinux (factor Xa antagonist), apixaban, rivaroxaban and edoxaban are also effective. Direct thrombin inhibitor dabigtran is also effective.

Maintenance anticoagulation is indicated to reduce the risk of clot extension or embolization and to reduce the risk of new clot formation. Drug choices for maintenance anticoagulation include

a. Oral vitamin K antagonist (warfarin in the US) b. Oral factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) c. Oral direct thrombin inhibitor (dabigatran) d. Subcutaneous low molecular weight heparin, primarily for high-risk cancer patients

or patients with recurrent PE despite other anticoagulants

Warfarin for long-term anticoagulation (prophylaxis) is started on same day as heparin so they overlap for five days so that the INR of 2-3 is achieved for at least 24 hours.

Destruction of embolus: Clot elimination by means of embolectomy or dissolution with IV or catheter-based thrombolytic therapy should be considered for acute PE associated with hypotension (massive PE). Patients who are hypotensive and require vasopressor therapy are obvious candidates. Patients with a systolic BP < 90 mm Hg lasting at least 15 min are hemodynamically compromised and are also candidates. Although only anticoagulation is generally recommended for patients with very mild RV dysfunction (based on clinical, ECG or echocardiographic findings), thrombolytic therapy or embolectomy may be needed when RV compromise is severe even when hypotension is not present.

Systemic thrombolytic therapy is the rapid way to restore pulmonary blood flow. Tissue plasminogen activator (tPa, alteplase), streptokinase or urokinase are used. There is definitive risk of hemorrhage, hence risk benefit to be weighed before initiating therapy. Some indications for thrombolytic therapy are numerous or large clots, very severe RV dysfunction, marked tachycardia, significant hypoxemia, and other concomitant findings such as residual clot in the leg, positive troponin values, and/or elevated BNP values. There are some contraindications for thrombolysis.

Absolute contraindications to thrombolytics include

a. Prior hemorrhagic stroke b. Ischemic stroke within 1 year

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c. Active external or internal bleeding from any source d. Intracranial injury or surgery within 2 months e. Intracranial tumor

Relative contraindications include

a. Hemorrhagic diathesis (as in hepatic insufficiency) b. Pregnancy c. Recent punctures of large no compressible veins (subclavian or internal jugular veins) d. Recent femoral artery catheterization (e.g., ≤ 10 days) e. Recent surgery (≤ 10 days) f. Peptic ulcer disease or other conditions that increase the risk of bleeding g. Severe hypertension (systolic BP > 180 mm Hg or diastolic BP > 110 mm Hg)

Catheter directed therapy: Can be thrombolytic or embolectomy. Typically the catheter is passed in to pulmonary artery via venous system. In catheter based thrombolytic therapy, thrombolytics are delivered directly to large proximal emboli in pulmonary artery via the catheter. High frequency low powered ultrasound accelerates the thrombolysis by disaggregating fibrin strands and increasing permeability of lytic drug in to the clot. When wide bore catheters are used vortex-suction embolectomy can be performed for larger clots. Blood thus sucked may need to be returned in to systemic circulation via extracorporeal circuit.

Surgical embolectomy: Indicated in patients with hypotension despite fluid, oxygen and vasopressor therapy or on the verge of cardiorespiratory collapse. Contraindication for thrombolysis is also a consideration. However, catheter vortex embolectomy may be tried, depends on local factors like expertise and infrastructure.

27. Name the devices used prophylactically for reducing pulmonary embolism.

Inferior vena cava filters, intermittent pneumatic compression (also known as sequential compression devices [SCD]), and graded elastic compression stockings may be used alone or in combination with drugs to prevent PE. Whether these devices are used alone or in combination depends on the specific indication.

An inferior vena cava filter (IVCF) may help prevent PE in patients with DVT in the leg, but IVCF placement may risk long-term complications. Benefits outweigh risk if a second PE is predicted to be life threatening; however, few clinical trial data are available. A filter is most clearly indicated in patients who have:

a. Proven DVT and contraindications to anticoagulation b. Recurrent DVT (or emboli) despite adequate anticoagulation c. Undergone pulmonary thromboendarterectomy d. Marginal cardiopulmonary function, causing concern for their ability to tolerate

additional small emboli (occasionally)

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Intermittent pneumatic compression (IPC) with SCDs provides rhythmic external compression to the legs or to the legs and thighs. It is more effective for preventing calf than proximal DVT. It is insufficient as sole prophylaxis after hip or knee replacement but is often used in low-risk patients after other types of surgery or in medical patients who have a low-risk of DVT or who are at high risk of bleeding. IPC can theoretically trigger PE in immobilized patients who have developed occult DVT while not receiving DVT prophylaxis.

Graded elastic compression stockings are less likely effective than external pneumatic leg compression, but one systematic meta-analysis suggested that they reduced the incidence of DVT in postoperative patients from 26% in the control group to 13% in the compression stockings group.

Anticoagulant Recommendations to minimize risk of hematoma following regional analgesic/anesthetic procedures

T1/2 Anticoagulant type

AC-RA/CM RA/CM-AC Monitoring and precautions

Heparin (unfractionated) intravenous

1.5–2 hours

Pro-antithrombin III (anti II, X)

2–4 hours, or aPTT WNL

1–2 hours nontraumatic; 6–12 hours if traumatic

aPTT, anti-Xa/IIa, ACT

Heparin SQ BID ≤10,000 U/d

1.5–2 hours

Pro-antithrombin III (anti II, X)

None; Caution: peaks 1–4 hours post dose

No restriction Platelets for HIT

Heparin SQ TID ≥10,000 U/d

1.5–2 hours

Pro-antithrombin III (anti II, X)

Insufficient data and caution

Insufficient data (many choose nadir of

Platelets for HIT

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advised, >6 hours

effect at >6 hours)

Enoxaparin (Lovenox) QD prophylaxis (0.5 mg/kg) (40 mg daily)

3–6 hours

LMWH Anti-Xa

12 hours 2 hours; 24 hours posttraumatic needle puncture

Anti-Xa

Enoxaparin (Lovenox) BID prophylaxis (0.5 mg/kg) (30 mg BID)

3–6 hours

LMWH Anti-Xa

12 hours Not recommended with catheter. Initiate ≥2–4 hours post removal

Anti-Xa

Enoxaparin BID therapeutic dose (≥0.5 mg/kg)

3–6 hours

LMWH Anti-Xa

24 hours Not recommended with catheter. Initiate ≥10–12 hours post removal

Anti-Xa

Warfarin (Coumadin)

20–60 hours

Vitamin K-dependent factor inhibition

INR ≤1.5, 4–5 days

INR <1.5 INR

Aspirin 6 hours Antiplatelet None No restrictions

Clopidogrel (Plavix)

6–8 hours

Irreversible platelet aggregation inhibitor

5–7 days; may be OK for superficial PNA SSRA

Not recommended with catheter. Initiate ≥2 hours post

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without discontinuation

catheter removal

Ticlopidine (Ticlid)

4–5 days

Irreversible platelet aggregation inhibitor

14 days Not recommended with catheter. Initiate ≥2 hours post removal

Prasugrel (Effient)

7–8 hours

Irreversible platelet aggregation inhibitor

7–10 days 6 hours

Ticagrelor (Brilinta)

7–8.5 hours

ADP reversible receptor blocker

5–7 days 6 hours

Abciximab (ReoPro)

0.5 hour

Glycoprotein IIb/IIIa inhibitor

48 hours Not recommended with catheter. Initiate ≥2 hours post removal

Eptifibatide (Integrilin)

1–2.5 hours

Glycoprotein IIb/IIIa inhibitor

8 hours Not recommended with catheter. Initiate ≥2 hours post removal

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Tirofiban (Aggrastat)

2 hours Glycoprotein IIb/IIIa inhibitor

8 hours Not recommended with catheter. Initiate ≥2 hours post removal

Bivalirudin (Angiomax), lepirudin, desirudin

0.5–3 hours

Thrombin (II) inhibitor

Not recommended for neuraxial/deep-PNB Insufficient data

Not recommended for neuraxial/deep-PNB Insufficient data

aPTT

Argatroban 35–40 minutes

Thrombin (II) inhibitor

Not recommended for neuraxial/deep-PNB Insufficient data

Not recommended for neuraxial/deep-PNB Insufficient data

aPTT

Dabigatran (Pradaxa)

12–15 hours

Thrombin (II) inhibitor (oral)

4–5 days 6 hours aPTT

Fondaparinux (Arixtra)

17–21 hours

Anti-Xa through binding to antithrombin III

3–4 days; SSRA only

Contraindicated for indwelling catheters. Initiate ≥12 hours post removal

Anti-Xa

Rivaroxaban (Xarelto)

5–9 hours

Anti-Xa 3 days 6 hours Anti-Xa, PT

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Apixaban (Eliquis)

10–15 hours

Anti-Xa 3–5 days 6 hours Anti-Xa, PT

Table 9. Anticoagulants and central nueraxial block – guidelines in brief

(Abbreviations for Table 9: AC-RA/CM, duration from last anticoagulant dosing to regional anesthesia needle puncture or catheter manipulation; RA/CM-AC, duration from regional anesthesia needle puncture or catheter manipulation to next anticoagulant dosing; QD, once daily; BID, twice daily; TID, three times daily; aPTT, activated partial thromboplastin time; WNL, within normal limits; anti-Xa, anti-factor Xa activity; LMWH, low-molecular-weight heparin; PT/INR, prothrombin–time/international normalized ratio; ACT, activated clotting time; SQ, subcutaneous; SSRA, single-shot regional anesthesia; PNB, peripheral nerve block; HIT, heparin-induced thrombocytopenia; ASRA, American Society of Regional Anesthesia; ADP, adenosine diphosphate; T1/2, medication half-life.)

Treatment of FES:

a. ICU care b. Correction of hypoxia with O2 with mask, non-rebreathing mask, CPAP, NIV or

mechanical ventilation (if FiO2 of >60% and CPAP >10 cm are required to maintain oxygenation)

c. CVP monitoring to detect RV failure d. Maintaining BP by correcting fluid deficit with RL or normal saline or dextran e. Albumin may be preferred as it is more lipophilic f. Dobutamine may be a better inotrope than noradrenaline g. ECHMO may have role in severe lung injury leading to refractory hypoxemia h. Corticosteroids have no proven role

CONCLUSION

Eternal vigilance, high index of suspension and judicious use of investigations and aggressive management are key in prevention and successful management pulmonary embolism.

REFERENCES

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2. Honorio T. Benzon, Rasha S. Jabri, Tom C. Van Zundert. Neuraxial Anesthesia & Peripheral Nerve Blocks in Patients on Anticoagulants. @ https://www.nysora.com/neuraxial-anesthesia-peripheral-nerve-blocks-patients-anticoagulants.

3. Laryea J, Champagne B. Venous Thromboembolism Prophylaxis. Clinn Colon Rectal Surg. 2013 Sep;26(3):153–159. doi: 10.1055/s-0033-1351130.

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4. Kaya Z, Kayrak M, Gul EE, et al. The Role of Ischemia Modified Albumin in Acute Pulmonary Embolism. Heart Views: The Official Journal of the Gulf Heart Association. 2014;15(4):106-110. doi:10.4103/1995-705X.151083.

5. Meyer G. Effective diagnosis and treatment of pulmonary embolism: Improving patient outcomes. Arch Cardiovasc Dis 2014;107(6-7):406-14. doi: 10.1016/j.acvd.2014.05.006. Epub 2014 Jul 9.

6. Lewis TC, Cortes J, Altshuler D, Papadopoulos J. Venous Thromboembolism Prophylaxis: A Narrative Review With a Focus on the High-Risk Critically Ill Patient. J Intensive Care Med 2018;30:885066618796486. doi: 10.1177/0885066618796486. [Epub ahead of print].

7. Doherty S. Pulmonary embolism: An update. Chest pain 2017;46(11):816-820. 8. Bondarsky E, Schaikewitz M, Filopei J, Steiger D. Brain Natriuretic Peptide/Troponin I Ratio

in Pulmonary Embolism. Chest 2017;152(4):Supplement, Page A1040 9. George J, George R, Dixit R, Gupta RC, Gupta N. Fat embolism syndrome. Lung India : Official

Organ of Indian Chest Society 2013;30(1):47-53. doi:10.4103/0970-2113.106133. 10. Shaikh N. Emergency management of fat embolism syndrome. Journal of Emergencies,

Trauma and Shock 2009;2(1):29-33. doi:10.4103/0974-2700.44680. 11. Uransilp N, Muengtaweepongsa S, Chanalithichai N, Tammachote N. Fat Embolism

Syndrome: A Case Report and Review Literature. Case Reports in Medicine 2018;2018:1479850. doi:10.1155/2018/1479850.

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Pacemaker and its anesthetic implications

Meghna Mukund1, Harshita Tayi2, Anupa Negandhi2

1Associate Professor, 2Junior Resident, Department of Anesthesiology Yenepoya Medical College Hospital, Mangaluru

1. What is a pacemaker? How does it work?

A pacemaker is a device capable of generating artificial pacing impulses and delivering them to the heart. This device uses electrical pulses to prompt the heart to beat at a normal rate.

Pacemakers can:

Speed up a slow heart rhythm.

Help control an abnormal or fast heart rhythm.

Coordinate electrical signalling between the upper and lower chambers of the heart. 2. What are the parts of a pacemaker?

Pulse Generator: It includes the energy source (battery) and electric circuits for pacing and sensory function. Most commonly Lithium-iodide batteries are being used which have longer life (5–10 years) and high energy density.

Leads: These are insulated wires connecting the pulse generator.

Electrode: It is an exposed metal end of the lead in contact with the endocardium or epicardium.

Unipolar Pacing: There is one electrode, the cathode (negative pole) or active lead. Current flows from the cathode, stimulates the heart and returns to anode (positive pole) on the casing of pulse generator via the myocardium and adjacent tissue to complete the circuit. A unipolar pacemaker is more likely to pick up extracardiac signals and myopotentials, as the circuit is larger than the bipolar. Pacemaker spikes are large in this pacing.

Bipolar Leads: Two separate electrodes, anode (positive pole) and cathode (negative pole), both located close to each other within the chamber that is being paced. As the electrodes are very close, the circuit is small, and the possibility of extraneous noise disturbance is less, and

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the signals are sharp. Pacemaker spikes are small in this type of pacing.

3. What are the codes or nomenclature used in pacemakers?

The Pacemaker Coding system was developed originally by the International Conference on Heart Disease, and subsequently modified by the NASPE/BPEG (North American Society of pacing and electrophysiology/British pacing and electrophysiology group) alliance.

Pacing Modes

1. Asynchronous: (AOO, VOO, and DOO): It is the simple form of a fixed rate pacemaker which discharges at a pre-set rate irrespective of the intrinsic heart rate.

2. Single Chamber demand pacing (AAI, VVI): the mode in which the pacemaker paces at a preset rate when spontaneous rate falls below pre-set rate. The firing of pacemaker is inhibited by electrical activity in the chamber sensed.

3. Dual chamber pacing: It requires two pacemaker leads, one in the atrium and one in the ventricle. The atrium is stimulated first to contract, and after an adjustable PR interval the ventricle is stimulated to contract. Dual chamber pacing allows for A-V synchronicity

LETTER 1

LETTER 2

LETTER 3 LETTER 4

LETTER 5

Chamber paced

Chamber sensed Mode of response to sensing

Programmability Rate modulation

Multisite pacing

O=None A=Atrium V=Ventricle D=Dual(A+V)

O=None A=Atrium V=Ventricle D=Dual(A+V)

O=None T=Triggered I=Inhibited D=Dual(T+I)

O=None R=Rate modulation

O=None A=Atrium V=Ventricle D=Dual(A+V)

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Single chamber pacing

Dual chamber pacing

AP-VP: Pacemaker spike before the P waveAtrium paced. Pacemaker spike before the QRS Ventricle is paced (Wide QRS).

Pacemaker spike

before QRS after P

wave - VOO

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AP-VS: Pacemaker spike before the P waveAtrium paced, followed by normal QRS (ventricle sensed) intrinsic ventricular depolarization

AS-VS: Atrium and ventricle sensed, no pacing.

4. What are the types of pacemakers?

Endocardial Pacing: Also called as “Transvenous pacing” which implies that the leads/electrodes system has been passed through a vein to the right atrium or right ventricle. It can be unipolar or bipolar.

Epicardial Pacing: This type of pacing is accomplished by inserting the electrode through the epicardium into the myocardium and is generally done following cardiac surgery. This can also be unipolar or bipolar.

Transesophageal pacing: Atrial pacing of patients is done in the proximity between the oesophagus and the posterior aspect of the atria.

Transcutaneous pacing: Method of choice in prophylactic and emergent applications. Large patches are placed anteriorly over the cardiac apex and posteriorly over the scapula.

5. What are the indications for a pacemaker?

• Symptomatic bradycardia from sinus node disease.

• Symptomatic bradycardia from atrioventricular node disease

• Long QT syndrome

• Hypertrophic obstructive cardiomyopathy (HOCM)

• Dilated cardiomyopathy (DCM)

6. What are some common pacemaker terminologies?

Pacing Threshold: This is the minimum amount of energy required to consistently cause depolarization and contraction of the heart.

Sensitivity: The minimal voltage level of the patient’s intrinsic R wave or P wave that must be exceeded for the pacemaker to sense that R or a P wave to activate the sensing circuit of the pulse generator, resulting in inhibition or triggering of the pacing circuit.

Hysteresis: It is the difference between intrinsic heart rate at which pacing begins (about 60 beats/min) and pacing rate (e.g. 80-100 beats/min)

Runaway Pacemaker: It is the acceleration in paced rates due to aging of the pacemaker or damage produced by leakage of the tissue fluids into the pulse generator. Leads to pacemaker failure.

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7. What are the factors affecting pacing threshold in a pacemaker?

Increases pacing threshold Decreases pacing threshold

1–4 weeks after implantation, Myocardial ischemia /infarction Hypothermia, Hypothyroidism Hyperkalaemia, Acidosis/Alkalosis Antiarrhythmic agents (class IA, IB, IC) Severe hypoxia/ hyperglycaemia

Increased catecholamines Stress Anxiety Sympathomimetic drugs Anticholinergics Glucocorticoids Hyperthyroidism Hypermetabolic status

8. What is the plan of anesthesia for a patient posted for pacemaker insertion?

• Pre- anesthetic evaluation including indications and other co-morbid conditions.

• Written informed consent.

• Pacemaker is generally inserted under local anesthesia with Monitored Anesthesia Care (MAC)

• Intravenous Midazolam and Fentanyl can be administered alone or in combination.

• In case of an uncooperative patient under General Anesthesia, nitrous oxide is best avoided as it could cause pacemaker malfunction by increasing gas in the pectoral pacemaker pocket which leads to loss of a nodal contact and pacing malfunction.

• Emergency equipment like airways, endotracheal tubes, defibrillators, should be kept nearby.

• Emergency drugs e.g. Atropine, Isoprenaline, Amiodarone, Noradrenaline, etc should be readily available.

9. How are pacemakers affected by magnets?

• Often, it is assumed that just placing a magnet on a pacemaker intraop is the right way to manage a patient with a PM.

• However, most pacemaker manufactures warn that magnets were NEVER intended to treat pacemaker emergencies or to prevent EMI effects.

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• Every pacemaker has a metallic “Reed switch” and an external magnet can put this switch ON and OFF.

• The circuit is such that, once switched ON makes the sensing function null and void. It functions as ASYNCHRONOUS mode pacemaker converts to a mandatory pacing mode.

• All sensing related issues are immediately removed.

• Asynchronous pacing without rate- responsiveness using parameters cannot possibly be in the patient’s best interest at 85-100 bpm.

• Unexpected behaviour, no effect on PM, continuous or transient loss of pacing, etc are risks that are unnecessary to undertake.

• ASA shuns magnet use in favour of Reprogramming

• Appropriate reprogramming might be the safest way to avoid intra-operative problems.

• Reprogramming the device to asynchronous pacing at a rate greater than the patients underlying rate ensures that EMI will not affect pacing.

• It must be kept in mind that reprogramming to asynchronous mode will not protect it from internal damage or reset cause by EMI

• Reprogramming the pacemaker to asynchronous fixed mode puts patient at risk of

developing R on T phenomenon and ventricular tachycardia especially for patients with good underlying rate.

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• Sometimes placing a magnet over the generator can have NO effect whatsoever for the following reasons:

1. Not ALL pacemakers switch to a continuous asynchronous mode eg: Medtronic “Micra” leadless IC-PM no magnet sensor

2. Programming of the pacemaker or “Default Mode”

3. Safety Mode.

4. EMI caused electrical reset.

5. Component/battery failure.

6. Magnet mode completely disabled (Biotronic, St Jude Medical, Boston Scientific.

• Other problems with magnets: Difficulty in maintaining the position of the magnet in lateral/ prone position

can compromise the operative field.

Sterility and presence of surgical drapes can hinder access to the magnet

• CAUTION: MAGNETS SHOULD ONLY BE USED BY THE PACEMAKER TECHNICIANS OR BY DOCTORS HAVING KNOWLEDGE HOW TO MANAGE THE RESULTANT RHYTHM.

10. How can we evaluate a patient with pacemaker pre-operatively posted for an elective surgery?

Pre-operative evaluation:

• Detailed evaluation of the underlying cardiovascular disease responsible for the insertion of pacemaker

• Other associated co-morbidities: since substantial number of these patients suffer from coronary artery disease (50%), hypertension (20%) and diabetes (10%), one should know:

• Severity of the cardiac disease

• Current functional status

• Medications the patient is on.

• Relevant history regarding the elective surgery

• Thorough clinical examination Physical examination for scars, palpating the device

• The initial indication for the pacemaker

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• Preimplantation symptoms such as light-headedness, dizziness or fainting. If these symptoms occur even after the pacemaker insertion, cardiology consultation is needed.

• Bruits, signs of CCF Investigations: 12 lead ECG: Determine if the patient is pacemaker dependant:

• 40% or greater pacing burden • ECG predominantly paced rhythm – examine P waves and QRS complexes A pacing

spike before every P-wave and/or QRS complex suggests that the patient is pacemaker dependent

• In the above ECG: Red dots Pacemaker spikes

Chest X-Ray:

• Information about lead numbers and configuration whether the device is a SINGLE or DUAL chamber pacemaker, a BIVENTRICULAR device, or an ICD

• Can also determine whether the device will function as intended.

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ICD PACEMAKER

In the above X-rays: The red arrows indicate the radio-opaque sections high voltage coils of the ICD

Other investigations include:

Routine biochemical and haematological investigations should be performed as indicated on an individual basis

• Measurement of serum electrolytes (especially K+) should be performed

About the pacemaker:

• Pacemaker – check INFORMATION CARD

Shows: Device, Model No, Indications and current settings:

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PACEMAKER DEVICE INTERROGATION: to reconfirm rhythm and functioning done by PM technicians ONLY

• (Heart Rhythm Society recommends device interrogation within 12 months for PPM)

Algorithm for PPM patient for elective surgery:

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11 What are the measures to be taken intra-operatively in a patient with a pacemaker?

INTRA-OPERATIVE MANAGEMENT:

Anesthetist identifies PPM and its

manufacturer through history-taking,

clinical records and PPM information

card

Contact cardiology and Pacemaker technician to obtain details on PPM check records - If patient’s last PPM check is 6 months ago, a repeat check is not needed - If patient’s last PPM check is > 6 months ago, PPM check should be

conducted to determine pacing dependence.

Is the patient PPM-dependent?

PPM should be reprogrammed to asynchronous pacing mode

preoperatively on day of scheduled procedure and if expecting EMI

interference

Proceed with elective procedure with cardiac device magnet on standby

Post-procedure, contact cardiology and PM technician to check PPM to ensure optimal

function and to reprogram PPM back to baseline settings.

YES NO

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• Main concern is the interference with device function from EMI. Any apparatus that emits radiofrequency waves between 0 and 109 Hz can generate EMI and therefore interfere with proper device function

• Vigilance must not be suspended, even if the patient is dependant and the mode is asynchronous.

• Skeletal myopotentials; fasciculations encountered with succinylcholine, or direct muscle stimulation can inhibit or trigger pacemaker and should be avoided.

• Avoid perioperative hypothermia as muscle activity caused by shivering may affect pacemaker functioning. PM perceives it as an intrinsic impulse; stops pacing and can cause bradycardia leading to asystole

• Induction agent’s etomidate and ketamine should be avoided as these can sometimes cause myoclonic movements

• In patients with long QT syndrome, drugs which cause QT prolongation such as methadone, haloperidol, ondansetron and high doses of inhalation agents are best avoided due to the theoretical risk of polymorphic ventricular tachycardia

MONITORING:

• Monitoring of the patient must include the ability to detect mechanical systoles since EMI and devices like Nerve stimulator, can interfere with QRS complex and pacemaker spikes on the ECG

• Can be achieved by Palpation of the pulse, pulse oximetry, plethysmography or arterial waveform display

• Continuous ECG monitoring is essential to monitor pacemaker functioning.

• The “artefact” filter on the ECG monitor should be disabled in order to detect the pacing spikes. The filter in the monitor should be set at ‘diagnostic’ so that the pacing spikes can be appreciated.

• Special equipment to keep ready for every case:

• Defibrillator with pacing capacity

• Transcutaneous pacing

• Special Drugs e.g.: Isoprenaline

• PM Technician on standby

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• Available Cardiologist

12. How can EMI be managed peri-operatively in a pacemaker patient?

• Bipolar cautery should be used as much as possible as it has less EMI

• If unipolar cautery is to be used during operation, the grounding plate should be placed close to the operative site (active cautery tip) and as far away as possible from the site of pacemaker, usually on the thigh and should have good skin contact.

• Electrocautery should not be used within 15 cm of pacemaker

• Frequency of electrocautery should be limited to 1-second bursts in every 10 seconds to prevent repeated asystolic periods. Short bursts with long pauses of cautery are preferred

• During the use of cautery, magnet should not be placed on pulse generator as it may cause pacemaker malfunction.

• EMI issues are the least with Harmonic scalpel

• Coagulation electrosurgical unit (ESU) will likely cause more problems than non-blended cutting ESU

• The dispersive electrode should be placed such that the presumed current path does not cross the chest

13. Can Regional anesthesia for patients with pacemakers be given?

• Remember that a paced heart cannot compensate for hypotension with tachycardia as the pacemaker is in fixed asynchronous mode.

• Spinal anesthesia should be used cautiously and preferably avoided in cases of anticipated blood loss or fluid shift.

• Spinal anesthesia aimed for block below T12 level.

• Graded epidural analgesia can be used.

14. What are the post-operative considerations in pacemaker patients?

• Shivering and fasciculations should be avoided, in the postoperative period.

• If the pacemaker is ‘activity’ rate responsive- ventilation should be kept controlled and constant and temperature must be kept constant in ‘temperature’ rate responsive pacemakers.

• Any device that has been reprogrammed for the perioperative period should be re-evaluated and programmed appropriately.

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• For non-reprogrammed devices most, manufacturers recommend interrogation to ensure proper functioning and battery life if any monopolar ESU was used.

• ASA recommendation:

Device interrogation before patient discharge from monitored care

• HRS/ASA suggests:

Immediate postoperative interrogation is needed only for the haemodynamically challenging cases or when significant EMI occurs superior to the umbilicus while operating

15. What are the considerations in a patient with pacemaker posted for an emergency surgery?

• Pre-anesthetic evaluation with brief history regarding the pacemaker and evaluate the patient for the cause of surgery.

• Intraoperatively, transcutaneous pacing pads are placed on the patient’s chest for backup pacing or external defibrillation, if necessary cardiac device magnet is then taped over the patient’s pacemaker pulse generator

• Post-procedure, cardiac device magnet is removed, followed by the defibrillation pads.

• Ensure that cardio-pulmonary resuscitation and the ability to perform temporary pacing in accordance with ALS guidance are available. Defibrillator’s with pacing potential and emergency drugs eg; Atropine; Isoprenaline, Noradrenaline, Amiodarone, etc. are available.

• Cardiologist on standby

• In the event of defibrillation following precautions to be undertaken:

• If defibrillation is required in a patient with pacemaker, paddles should be positioned as far away as possible from the pacemaker generator. If possible, anterior to posterior positioning of paddles should be used

• In elective cardioversion, the lowest voltage necessary should be utilized.

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16. What are the specific perioperative considerations one should be aware of when dealing with a pacemaker implanted patient?

1. Transuretheral Resection of Prostate (TURP) and Uterine Hysteroscopy Cutting current at high frequencies (up to 2500 kc/sec) can suppress the output of a bipolar demand ventricular pacemaker

2. Electroconvulsive Therapy It is safe due to high tissue impedance, but the post ECT seizure may generate myopotentials which may inhibit the pacemaker.

3. Radiation

Therapeutic radiation can damage the complementary metal oxide semiconductors (CMOS) that are the parts of most modern pacemakers.

Generally, doses more than 5000 rads are required to cause pacemaker malfunction but doses of 1000 rads may induce pacemaker failure or cause runaway pacemaker.

4. Nerve Stimulator Testing or Transcutaneous Electronic Nerve Stimulator Unit (TENS) TENS unit consists of several electrodes placed on the skin and connected to a pulse generator that applies 20 μsec at a frequency of 20 to 110 Hz. This repeated frequency is similar to the normal range of heart rates, so it can create a far field potential that may inhibit a cardiac pacemaker.

5. Magnetic Resonance Imaging (MRI): Magnetic field- may exert a torque effect leading to discomfort at the pacemaker pocket.

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Reed switch activation can result in switching of pacemaker to a non-sensing asynchronous pacing.

Causes inappropriate sensing and triggering because of the induced voltages.

Only MRI compatible pacemaker patients should be taken for these procedures, otherwise it is contraindicated.

6. Lithotripsy: High-energy vibrations can cause closure of reed switch leading to asynchronous pacing.

Focal point of the lithotriptor should be kept at least six inches (15 cm) away from the pacemaker.

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Mitral stenosis and perioperative acute atrial fibrillation

Vasantha Shetty1, Ananya P2, Tamanna Ahemad2

1 Assistant Professor, 2 Junior Resident, Department of Anesthesiology AJ Institute of Medical Sciences, Mangaluru

ANATOMY AND PHYSIOLOGY

Mitral valve apparatus is a bicuspid valve consisting of annulus, valve leaflets, chordae tendinae and antero-medial and postero-lateral papillary muscle. Normal mitral valve function prevents regurgitation during systole, yet allowing diastolic passage of blood into the left ventricle with a minimal pressure gradient across the valve. Abnormality in any of these structures contributes to MS, MR and MVP.

Normal ventricular pressure volume loop created by plotting points on a curve representing ventricular pressure at varying volumes during a single cardiac cycle, help in understanding the mitral valve function.

Figure 1. Normal left ventricular pressure volume loop

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Phase 1: Depicts ventricular preload before systole. In early to mid-diastole, ventricular filling depends on gradient between LA and LV pressure. In late ventricular diastole, atrial systole occurs. This atrial kick accounts for 15-20% of ventricular preload in a normal patient and may even contribute more to cardiac output in diseased mitral valve states (D to A).

Phase 2: Isovolumetric period of systole. Large increase in intra-ventricular pressure occurs but volume remains unchanged (A to B).

Phase 3: It is a portion of systole, when the intra-ventricular pressure exceeds that in the aorta. Aortic valve opens (B to C).

Phase 4: Isovolumetric relaxation occurs (C to D).

ETIOLOGY

1. Most commonly rheumatic in origin. Women are affected twice as frequently as males, usually associated with valvular regurgitation

2. Calcification of the Mitral Valve 3. Functional MS

LA myxoma

LA ball valve thrombus

Cortriatriatum

HOCM with obstruction to left ventricular outflow 4. Congenital - rare 5. Associated with ASD 6. Hurlers syndrome 7. Endomyocardial fibrosis

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Figure 2. Normal chamber pressures (mmHg) at various phases of cardiac cycle

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Table 1. Degree of mitral stenosis based on valve area and diastolic pressure half time. [1]

The GORLIN’S formula which is used to determine the valve area using pressure gradient in mitral stenosis as follows -

Valve area = K × cardiac output

DFP × HR × 44.3 √MPG

DFP- Diastolic flow period, HR- Heart rate, MPG- Mean pressure gradient, K= 0.85 for mitral valve.

PATHOPHYSIOLOGY

1. Natural progression The disease process includes thickening, commissural fusion and increased rigidity of the mitral valve leaflets, as well as thickening, fusion, and contracture of the chordae and the papillary heads. Long standing disease leads to some degree of calcification of the valve apparatus.

Symptoms can occur if the valve area is less than 2.5 cm2 and can be precipitated by clinical events associated with increased cardiac output and consequent increased flow across the valve which include stress, exercise, anemia, pregnancy and febrile illness. Symptoms do not usually occur at rest unless the MVA is less than 1.5 cm2.

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Mitral stenosis

LA pressure increases

Enlargement of the left atrium

Pulmonary venous and pulmonary capillary pressure increases - exertional dyspnea

Pulmonary edema- reactive pulmonary hypertension

Elevated pulmonary arterial pressure

Pulmonary arterial pressure greater than 50 mmHg

Increased RV afterload

RV hypertrophy

RV dilatation

RV failure

Causes of Pulmonary arterial hypertension (PHTN) in MS

Passive backward transmission of LA pressure

Pulmonary arteriolar constriction due to LA and pulmonary venous HTN

Obliterative changes in the pulmonary vascular bed

Aggravated by co-existing pulmonary disease

Clot formation and

thromboembolic

complications

Atrial fibrillation

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Pathophysiology of pulmonary arterial hypertension

Initially pulmonary arterial pressure will be reversibly elevated but PVR will remain normal. With the progression of the disease, pulmonary arterial constriction, pulmonary intimal hyperplasia and pulmonary medial hypertrophy eventually leads to increased PVR and chronic PHTN. Severe chronic PH will lead to RVH, RV dilatation and failure- ‘second stenosis’.

The dilated RV can cause a leftward shift of interventricular septum, reducing the LV size and further impairing stroke volume. Further RV dilation results in TR and signs of peripheral congestion.

A mitral area of 0.3 - 0.4 cm is the smallest area compatible with life.

2. Cardiac remodelling and left ventricular changes Patients with significant mitral stenosis have a reduced LVEDV and LVEDP (Figure 3). Stroke volume is also reduced. The actual LV contractility is usually normal, but may be reduced due to chronic LV deconditioning. LV dysfunction may be present in 30% of cases. It may be due to reduced filling of LV, muscle atrophy, inflammatory fibrosis leading to RWMA, scarring of sub-valvular apparatus, abnormal contraction, reduced compliance, right-to-left septal shift secondary to effect of pulmonary HTN on RV and coexistent diseases like

systemic HTN. Figure 3: Left ventricular pressure volume loop in mitral stenosis

3. Pressure wave disturbances

Mitral stenosis produces a large ‘A’ wave on the PCWP tracing in patients with preserved sinus rhythm. Prominent ‘V’ wave is present if associated with MR. The ‘A’ wave may become small on impairment of LA contractility and will be absent in AF.

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PREGNANCY AND MS

Pregnancy worsens the features of MS.

When the blood volume increases by 30-50% at around 20-24 weeks of gestation, the increase in cardiac output increases the trans-valvular gradient significantly leading to substantial raise of LA pressure. The risk of pulmonary oedema increases due to increase in pulmonary capillary hydrostatic pressure. The NYHA grade of symptoms increases by 1 class.

SVR decreases.

Increase in HR by 10-20 bpm further reduces the diastolic filling time of LV.

Decompensation results during labour and delivery due to auto-transfusion and IVC decompression.

Enlarged atrial dimensions can trigger atrial arrhythmias including AF.

Increased thromboembolic risk due to procoagulant state of pregnancy. Symptoms

Fatigue

Dyspnoea

Palpitations

Syncope

Chest pain

Cough

Hemoptysis

Peripheral edema

Orthopnea

PND

Neurological changes- systemic embolization

Symptoms due to dilated LA- dysphagia, hoarseness SIGNS

Pulse- could be normal, low volume pulse, irregularly irregular rhythm- in AF

Tachypnea could be present.

BP- could be normal or on the lower side

Peripheral oedema, raised JVP

Peripheral cyanosis CVS EXAMINATION

Inspection

Mitral facies: malar flush, cyanosis of lips

Prominent jugular venous pulse may be seen

Pulsation in the second left intercostal space in PHTN

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Palpation

Tapping apex beat

Left parasternal heave

Palpable P2

Mid-diastolic or pre-systolic thrill at the apex may be present

Percussion

Right border of the heart may be percussed beyond the right side of the sternum

Dullness in the second left intercostal space due to PHTN

Auscultation

Loud S1- increased LAP keeps the valve wide open at the beginning of the ventricular contraction.

Opening snap (OS) - Occurs early in diastole, short high pitched sound after A2. Time interval from A2 to OS reflects the abnormal pressure gradient across the mitral valve. Smaller the A2 - OS interval, more severe is the disease.

Low pitched mid diastolic murmur best heard at the apex with the bell of the stethoscope with the patient in the left lateral position at the end of expiration.

Pre-systolic accentuation of the murmur- Precedes S1 due to increased flow during LA contraction. Usually lost in AF.

PRE-OPERATIVE EVALUATION AND OPTIMISATION

Investigations

Complete blood count- R/O anemia, infection

Serum electrolytes- If on diuretics, digoxin, Beta blockers.

Coagulation profile- anticoagulants

ECG- Bifid P waves- P mitrale Wide notched P waves in leads I and II Inverted or biphasic P waves in lead III Right axis deviation RVH- Significant R wave in lead V1 and large S wave in lead V6 ST depression, T wave inversions If in AF- absent P waves, irregularly irregular rhythm

CHEST X-RAY

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Straightening of the left heart border- left atrial enlargement- double atrial shadow Right ventricular hypertrophy Cardiomegaly Perihilar flare- bat wing appearance Kerley A,B,C lines Pleural effusion, small LV Increased angle at the carina- displacement of the left main stem bronchus Calcified mitral valve Calcified ball valve thrombus PHTN - right ventricular enlargement, prominence of upper zone veins-‘Antlers sign’,

prominent pulmonary conus, enlarged main pulmonary artery

ECHO M-mode ECHO- decreased diastolic closing (E-F) slope, abnormal motion of the

posterior mitral valve leaflet and thickening of the mitral valve leaflets. Two dimensional (B mode) ECHO- diastolic doming, quantitating the degree of mitral

stenosis by measuring the valve area, left atrial dimensions, documenting the presence of thrombus, paradoxical septal motion due to rapid RV filling.

Doppler - To assess the transvalvular flow and quantify the pressure gradient across the valve and to know the TV pressure gradient to estimate the severity of pulmonary hypertension.

ROLE OF TEE - TEE is an excellent tool for assessing intra-operative hemodynamics. However, it needs some expertise. The valve leaflets appear thickened, calcified and have limited mobility. The diastolic dooming of the body of the anterior mitral valve leaflet is described as the 'hockey- stick' appearance. Low flow state in the enlarged left atrium- 'smoke in LA' on echo contrast should prompt examination for thrombus formation, most common location being the left atrial appendage.

Angiography - Often not required Coexisting CAD - suspected, symptomatic Patient with dyspnoea which is out of proportion of that due to valve lesion Pulmonary artery angiogram- If pulmonary embolism is suspected in a normal coronary

artery, no evidence of pulmonary disease, normal PVR MEDICAL MANAGEMENT

Restriction of physical activity

Cardiac failure- diuretics, digitalis

Arrhythmias- Rate, rhythm control and thromboprophylaxis (described later under atrial fibrillation)

Prophylaxis against rheumatic fever- Inj. Benzathine penicillin 1.2 MU I M every 4 weeks

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Infective endocarditis prophylaxis

Correction of any electrolyte imbalance SURGICAL MANAGEMENT

Mitral valvotomy- closed or open valvotomy

Balloon valvuloplasty (transcutaneous balloon dilatation)

Mitral valve replacement PRE-OP MEDICATIONS

Anticoagulation The duration of interruption and timing of resumption of anticoagulation after the procedure are guided by individualized consideration of the risk of thrombotic events and the severity of the operative and perioperative bleeding risk. [2]

Stop warfarin 5 days pre-operatively. Initiate bridging therapy with heparin from day 3 of stoppage.

LMWH Heparin has to be stopped 24 hours before the surgery. In case of unfractionated heparin, it is enough to stop them 6 hrs before surgery. Both heparin and warfarin to be restarted at least 24 hrs post-surgery. Heparin to be continued for the next 3-4 days until the warfarin action resumes.[3] Digoxin- Has to be continued if it is for ventricular rate control till surgery. Morning dose

has to be given if the HR > 80/min and avoided in the presence of electrolyte imbalance. PERIOPERATIVE MANAGEMENT

Premedication:

Avoid excessive sedation- can cause hypoxemia and aggravate pulmonary HTN. All patients should receive oxygen from the time of sedative premedication until arrival into the OR.

Morphine 0.05 – 0.1 mg/kg (reduce in critically ill) IM

Diazepam 0.035 mg/kg P/O

Midazolam 0.03 mg/kg IM Anticholinergic drugs with least effect on HR like glycopyrrolate should be used.

HAEMODYNAMIC GOALS

A). LV preload- Maintain adequate preload. However, patients with MS already have an elevated LA pressures and are prone to pulmonary vascular congestion. Overly aggressive use of fluids can lead to florid pulmonary oedema. Intraoperative TEE is the best to assess the volume status.

B). HR- Avoid tachycardia- blood flow across MV depends on diastole time and avoid excessive bradycardia since stroke volume is relatively fixed. Maintain HR at 70 to 90 BPM.

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C). Contractility- Do not depress myocardial contractility. Chronic under filing of the LV may lead to reconditioning and depressed ventricular contractility even in the face of restored filling. Depression of RV contractility limits left atrial filling and eventually cardiac output.

D). SVR - It will be increased in order to maintain cardiac output. Maintenance of afterload is essential to maintain the blood pressure. Fall in BP will lead to reflex tachycardia.

E). PVR - Avoid excessive increase in PVR due inadequate depth of anesthesia, acidosis, hypoxia or hypercapnia.

MONITORING:

CVP – guidance for volume status and RV function

Arterial BP monitoring

Pulse oximetry

ECG monitoring

PCWP – in normal HR, it gives reliable left sided filling pressure.

TEE GENERAL ANESTHESIA

Induction

Inhalational anesthetics- Well tolerated in mild to moderate MS as long as there is no change in HR. Isoflurane is best avoided.

N2O- may be risky. It increases PVR. It causes myocardial depression and may produce wall motion abnormalities.

Narcotics- Opioids have a central vagotonic effect and they blunt the sympathetic responses of intubation and surgery. Best given in titrated doses.

Barbiturates- Venodilation and reduction in preload cause significant decrease in stroke volume. As the BP falls, it can activate baroreceptor reflex leading to increase in HR. Probably should be avoided in patients with severe MS.

Non barbiturate IV anesthetic- Benzodiazepines combined with narcotics should be carefully titrated due to

depression in myocardial contractility. Its best avoided in severe MS. Ketamine should be avoided. Propofol in small doses may be tolerated. However due to its decreasing effect

on SVR and direct myocardial depressant action, induction doses may decrease the SBP by 40%. Even the preload decreases.

Etomidate- Hemodynamic stability maintained. Minimal changes in SBP, PAP, CVP, PCWP, SVR, CI. A small decrease in HR and decrease in PVR may occur.

Muscle relaxant- chosen based on their effect on heart rate Vecuronium and cisatracurium have least CVS effects. They are the preferred

choice of muscle relaxants.

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Pancuronium causes tachycardia and atracurium may decrease BP due to histamine release. For the above reasons these are best avoided in MS.

Intra-operative maintenance

BP and SVR should be maintained with sympathomimetic drugs

Ephedrine- Direct beta agonist effect– increases BP, myocardial contractility and decreases pulmonary HTN. However, it increases the HR.

Phenylephrine – It is an alpha-1 agonist. It causes vasoconstriction, increase in ventricular afterload and increase in BP. This can cause reflex bradycardia. However, it can also increase the pre-existing PHTN.

Maintain adequate depth of anesthesia. Avoid hypercarbia, hypoxemia, hyperinflation of the lungs and fluid overload- can precipitate PHTN and RVH. Ionotropic support may be required.

Treatment of severe pulmonary HTN

Sodium nitroprusside is a potent dilator of veins and systemic and pulmonary arterioles. There is a substantial risk of systemic hypotension due to decrease in SVR and preload. So caution is advised.

Phosphodiesterase inhibitors: Milrinone, a nonglycoside, noncatecholamine inotropic agent with additional vasodilatory and lusitropic effect is an inhibitor of phosphodiesterase-3 that metabolizes cAMP. By increasing intracellular cAMP, it increases intracellular calcium, thus enhancing myocardial contractility.

Inhaled nitric oxide- It causes cGMP mediated reduction in intracellular calcium resulting in smooth muscle relaxation. It decreases PVR while not significantly lowering systemic BP.

Reversal agents- Glycopyrrolate is preferred over atropine.

POSTOPERATIVE CONCERNS

Changes in the pulmonary vasculature lead to a decrease in lung compliance and an increase in the work of breathing. This leads to an increased risk of post-operative pulmonary complications. Mechanical ventilation may be required in post-operative period. Hypercarbia, hypoxemia and pain can lead to increases in systemic/ pulmonary artery pressures, tachycardia resulting in pulmonary edema or right sided failure or both. Providing adequate analgesia is of utmost importance.

ROLE OF REGIONAL ANESTHESIA

It presents a formidable problem as it decreases both preload and afterload.

Spinal anesthesia- Rapid decrease in sympathetic tone can cause a sudden, severe decrease in SV and precipitous fall in the SBP.

Epidural anesthesia- Can be used in mild MS, but becomes more difficult with increasing severity due to hemodynamic considerations. Volume overload along with return of

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sympathetic tone may precipitate pulmonary oedema. Invasive monitoring is essential. Low concentration of local anesthetic combined with opioid may provide adequate pain relief with minimal hemodynamic effect.

Indication:

In disease conditions where GA carries additional risks. Eg., severe pulmonary diseases.

Post-operative analgesia

Epidural labour analgesia. AF IN MITRAL STENOSIS- PERIOPERATIVE PERIOD

Preoperative optimization

Preoperative medications: to be continued, as mentioned earlier

Correction of electrolyte imbalances, if any Significance

Loss of atrial kick

Atrial thrombi after 24 hr

Tachycardia Signs:

Irregularly irregular pulse, apex pulse deficit, varying intensity 1st heart sound, loss of presystolic accentuation, absence of ‘a’ wave on CVP tracing.

ECG findings (Figure 4)

Figure 4. ECG findings in AF

Treatment of Atrial fibrillation

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In hemodynamically stable patients in whom the duration of AF is unknown or greater than 48 hrs, rate control is preferred until adequate anticoagulation is achieved. It aims to control the ventricular rate without restoring the rhythm to sinus (Table 2). Beta blockers- including esmolol, propranolol, and metoprolol are effective in

the setting of acute AF. Nondihydropyridine calcium channel blockers- Diltiazem and verapamil safe and

effective in controlling ventricular rate. Digoxin is not usually first-line therapy for ventricular rate control in patients

with AF, onset of action requires >1 hour and the effect does not peak until approximately 6 hours after initial administration. It is beneficial in patients with low myocardial contractility.

Amiodarone- it is less effective than nondihydropyridine calcium channel blockers.

In hemodynamically unstable patients- Electrical cardioversion is the treatment of choice. TEE can be used to rule out LA thrombus before attempting a cardioversion, although

atrial thrombi is unlikely and the chance of thromboembolism is very rare in acute AF. Synchronised biphasic shock of 100 - 200 J is delivered. It is reasonable to administer heparin (intravenous bolus of UFH followed by infusion,

or LMWH) or new anticoagulant and to continue this after cardioversion unless contraindicated.

Pharmacological cardioversion- Flecainide, dofetilide, propafenone, and IV ibutilide are useful for cardioversion of AF, provided contraindications to the selected drug are absent. Amiodarone is reasonable for pharmacological cardioversion of AF (Table 3).

An ABG analysis can be done to look for the cause of AF- electrolyte imbalance, acidosis and hypoxia.

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Table 2. Drugs used for controlling rate and their dosages[2]

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Table 3. Drugs used for pharmacological cardioversion[2]

REFERENCES

1. Paul A, Das S. Valvular heart disease and anaesthesia. Indian J Anaesth 2017;61:721-7. 2. January CT, Wann LS, Alperts JS, Calkins H et al. 2014 AHA/ACC/HRS guidelines for the

management of patients with atrial fibrillation- a report of the American College of Cardiology/American Heart Association Task force on Practice guidelines and the heart rhythm society.2014;64:e1-76.

3. Douketis JD.2012 AHA. Bridging anticoagulation, is it needed? Circulation. 2012;125:e496-98.

4. Goldstein S, Taragin SM. Mitral Valve Disease. In: Simpson JI, editor. Anaesthesia and the patient with co-existing heart disease. 4th ed.

5. Nussmeier NA, Sarwar MF, Searles BE. Anesthesia for cardiac surgical procedures. In: Miller RD, Eriksson LI, Fleisher LA. In Miller RD, editor. Miller’s Anesthesia. 8th ed. Philadelphia: Elsevier Saunders; 2015. p. 2007-95.

6. Hensley FA, Martin DE, Gravlee GP. A practical approach to cardiac anaesthesia. 4th ed. Philadelphia: Lippincott Williams and Wilkins; 2008.

7. Herrera A. Valvular heart disease. In: Hines RL, Marschall KE, editors. Anesthesia and co-existing disease. 7th ed. Philadelphia: Elsevier; 2018.p. 107-28.

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8. Fontes M, Heerdt PM. Systemic and pulmonary arterial hypertension. In: Hines RL, Marschall KE, editors. Anesthesia and co-existing disease. 7th ed. Philadelphia: Elsevier; 2018. p. 183-98.

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MRI and the anesthetist

Shaji Mathew1, Malavika2, Arun P3, Aamuktha3 1Professor, 2Associate Professor, 3Junior Resident, Department of Anesthesiology

Kasturba Medical College, Manipal

In recent times anesthetist’s involvement in imaging areas is highly increasing. As an attending anesthesiologist one must know about Magnetic resonance imaging (MRI), its complications & hazards. One must be prepared to safeguard the patient from the complications with proper MRI compatible equipment & resuscitation tools.

WHAT IS MRI?

It is an imaging modality of choice for the diagnosis of neurosurgical & orthopedic cases. MRI does not use ionizing radiation to generate images but the information is generated from the spin of magnetically susceptible nuclei in a high magnetic field.

BASIC PRINCIPLE OF MRI MRI is based on the interaction between a static magnetic field generated by the scanner and the tiny fields that arise from individual atomic nuclei. Atoms like hydrogen, phosphorous inside human body have an odd unpaired proton. These nuclei have charge causing a spin, resulting in a local magnetic field and allowing them to act like small magnets. Usually, there will be random alignment of these nuclei, but they tend to align themselves when strong magnetic field is applied to the body. Application of short bursts of radiofrequency energy creates an electromagnetic field at right angle to the first magnetic field resulting in non-alignment of nuclei with the first magnetic field. On removal of the electromagnetic field, the nuclei relax back into alignment because of the release of radiofrequency energy. The emitted signals depend on the molecular properties of the tissue. This radiofrequency radiation that is emitted induces an electrical signal and these signals are transformed into a three-dimensional image of the body.

MAGNETIC FIELD

The most prominent hazard in the MR suite is the magnetic field generated by the imaging equipment itself. This magnet will cause any environmental item containing ferrous materials to become dangerous projectiles and poses great risk to the patient or personnel. Newer MRI

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machines are shielded so that the effects of the magnetic field is decreased significantly. However, it remains critically important that no equipment is brought into the MRI vicinity to assure successful imaging and safety of the patient, personnel, and equipment.

NEED FOR THE ANESTHETIST When MRI is used for diagnostic or therapeutic procedures, the patient must remain immobile, sometimes for longer periods. Patient’s cooperation is required which may not be possible in many cases. Thus an anesthetist is necessary to keep the patient calm, sedated, for airway management and reactions due to dye injections if any. HAZARDS No clear mechanism for damage to biological tissues within the large static magnetic field of MRI suites has far been reported, likely because the human body is only weakly diamagnetic and no body functions are dependent on magnetic fields. When possible, the anesthesiologist should remain at least 0.5 to 1 m from the bore of the scanner and should move slowly when it is necessary to be near the bore. Rapid patient motion in the strong magnetic field near the MRI scanner produces an electrical current within the body, which may cause symptoms such as nausea, vertigo, headache, light flashes, loss of proprioception, or a metallic taste, which the anesthesiologist may also experience. MRI SUITE IS DIVIDED INTO 4 ZONES Zone 1 - public zone with free access. Zone 2 - interface between public zone and MRI suite. Zone 3 - Consists of MR control room and/or computer room. Ferromagnetic objects should not be allowed to this zone Zone 4 - Scanner room itself. Access into the MR scanner room Should only be available by passing through Zone Three TYPES OF ANAESTHESIA Considerable debate exists regarding the relative merits of sedation and general anesthesia for MRI. Mild sedation can be administered though failed scans due to inadequate sedation are common. If the patient’s an aesthetic requirements exceed conscious sedation, it is our experience that a formal general anesthesia with LMA or ETT is preferable to deep sedation. ANAESTHETIC CONCERNS

Limited patient visibility and accessibility

Absolute need to exclude ferromagnetic components

Use of lithium batteries and plastic laryngoscopes

Interference/malfunction of monitoring equipment

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Potential degradation of the imaging caused by the stray RF currents from monitoring equipment and leads

Limited access to the MRI suite for emergency personnel

BASIC SETUP

Central gas supply and suction should be installed into wall systems during construction of the MR suite. Electrical power sources consisting of isolated duplex power circuits with filtered 120V (AC) to prevent electrical noise artefacts from interfering with the images should be available in the magnet room.

ANESTHESIA EQUIPMENT

Anesthesia machines can be modified for use in a magnetic field by replacing their ferromagnetic components to less than 2% of the total weight. Currently, MRI compatible machines made largely of stainless steel, brass, aluminum and plastic are available. Vaporizers are affected little by the magnetic field and function accurately within the magnetic field.

Medical gas cylinders made of aluminum should be used in the MRI suite. No non-aluminum oxygen tanks should be brought into the scanner area, as multiple incidents of injury from projectile tanks have been reported. Not only are injuries to patients and personnel reported, but the scanner must be turned off to remove the items from the magnet bore and resuming the magnetic field is very costly and may take several days.

Total intravenous anesthesia with a continuous infusion of propofol may be selected, necessitating use of infusions pumps. Commercially available computerized infusion pumps contain ferromagnetic circuitry, which can malfunction in the presence of a high magnetic field. However, several pumps have been tested and found to be accurate outside the gauss line and new pumps are being developed specifically for use in the MRI suite.

Regardless of the mode of anesthetic for critical care patients, mechanical ventilation may be required. Ventilators with FDA approval for use in the MR suite are linked with anesthesia delivery systems.

Plastic battery operated laryngoscopes can be used for intubation or airway can be secured using conventional laryngoscopes before the patient is moved into the scanner room.

MONITORING CONCERNS

Oxygenation

Although many pulse oximeters function well in the magnet, severe burns to extremities have been caused by the induction of current within a loop of wire. This may be avoided by placing the

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probe distally, away from the magnetic bore preferably on a toe, keeping its wires free of coils, and protecting the digits with clear plastic wrap. Alternatively, MR-specific pulse oximeters use heavy fiberoptic cables, which do not overheat and cannot be looped.

The magnet superconductors are kept cool in liquid nitrogen. As the coolant evaporates due to leaky housing (“quench”), the ambient oxygen supply of the room can drop precipitously, causing hypoxia and the potential for cryoinjury. Quench monitors within each MRI suite recognize changes in room oxygen concentration. Providers should be aware of the emergency procedures in each location should a quench occur.

Ventilation

Because of the magnet depth, it is often virtually impossible to visualize the patient’s face and chest for adequacy of ventilation during scanning. Noise levels of 95 dB make auscultation of the lungs during scanning almost impossible. Ear plugs are recommended for anesthetized or sedated patients for noise protection. However, direct visualization of the airway may be possible by observing the scan and respiratory capnography.

Electrocardiography

ECG monitoring is particularly problematic. Maximum voltage charges are induced in any column of conducting fluid when the fluid flow is 90 degrees to the field. The superimposed potentials are greatest in ST segments and T waves and these changes in the ECG waveform make it essentially impossible to reliably monitor for ischemia or to interpret arrhythmias. In patients highly susceptible to ischemia, a 12-lead ECG pre and post MRI is recommended. Several MRI-compatible ECG systems are currently available, using electrodes made of carbon graphite to lower resistance, eliminate ferromagnetism, and minimize RF interference. These systems use coaxialized cables to avoid any coils that could result in patient burns.

Blood pressure

MR approved monitoring systems use automated oscillometric blood pressure monitoring because it is based on pneumatic principles, avoids electromagnetic interference. For invasive blood pressure monitoring, conventional disposable transducers may function adequately outside the gauss line.

Temperature

During MRI, body temperature may increase from heating caused by RF within the magnetic field or decrease from the cool environment necessary to protect superconductors. Intermittent temperature monitoring has been recommended to reduce the possibility of thermistor induced skin burns for critical patients or during long scanning procedures.

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NEWER ADVANCES IN MRI AND ANESTHESIA

Intraoperative MRI

Intra-operative MRI (iMRI) is a newer development in the field of MRI. A typical iMRI suite has 2 areas - an inner controlled area and a larger MR controlled area, the latter has physical access being controlled with self-locking doors/entry cards. During surgical procedures, MRI responsible person usually controls the flow of staff and equipment through the environment.

Layout of iMRI suite

Advantages

Scanning during surgery at appropriate intervals

Provides real time navigation accuracy for accurate resection of lesion

Reduces the need for postoperative scan

Economic savings for the patient as repeated surgeries can be avoided Uses

Tumor surgeries (Gliomas, ventricular & difficult pituitary tumors)

Deep brain stimulation in epilepsy surgeries

Liver and breast biopsies for early and accurate diagnosis

MR guided thermal ablation- an alternative to open surgery for oncological procedures

Endoluminal MR interventions Anesthetic concerns specific for iMRI

The routine an aesthetic implications for the procedure for which the patient is posted will remain the same. Additional concerns in an iMRI suite demands extra attention.

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An extended long ventilator circuit with a straight connector should be used since the patient can be turned 180 degrees.

Intravenous tubing extensions should be placed to assure adequate distance between the intravenous pump and the MRI unit.

Reinforced endotracheal tubes should not be used

MRI compatible temperature probes should be used

Surgical equipment and instruments must be MRI-compatible

Electrical cords should not touch the patient's skin as this can cause burns

Checklist can be used to ensure adequate safety before the use of iMRI

Relocation of machines and equipments away from the MRI suite may be needed before iMRI imaging

CONCLUSION

Given available scientific data, MRI seems to be intrinsically ‘safe’ for humans. As the demand for MRI scans increase, so will be the requirement of anesthesia and anesthetic personnel in this environment. With increasing use of iMRI, anesthetists are exposed to newer challenges in this field. All anesthetists should remain familiar with these challenges for ensuring patient care and safety.

REFERENCES

1. Ugan Reddy, Mark J White, Sally R Wilson; Anesthesia for magnetic resonance imaging. Continuing Education in Anesthesia Critical Care & Pain 2012;12:140–144.

2. ATOTW 177 – Understanding Magnetic Resonance Imaging. 3. Association of Anesthetists of Great Britain and Ireland. Provision of anesthetic services

in magnetic resonance units. May 2002. 4. Bell C. Anesthesia in the MRI Suite, Anesthesia Patient Safety Foundation.

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Facet joint block and transforaminal block

Rammurthy Consultant Anesthesiologist

People Tree Hospital, Bangalore

FACET JOINT BLOCK

Introduction and Anatomy of Facet Joints

1. Lumbar facet joint blocks are the most commonly done interventions in chronic pain management.

2. Lumbar facet joint pain constitutes about 40 - 45% of all low back pain cases. 3. Facet joints or zygapophyseal joints are formed by the articulation of superior articular

process of one vertebra with the inferior articular process of vertebra immediately above. (Figure. 1, 2).

4. These joints are true synovial joints- they are lined by synovial membrane, covered by a capsule and contain synovial fluid.

5. The lumbar facet joints receive innervations from medial branch of the dorsal ramus of spinal nerve

6. Each lumbar facet joint has dual innervation- one from the nerve of same level and one

from the level immediately above. For example, L4-5 facet joint is supplied by medial

branch of L4 and L3 spinal nerve dorsal rami. This rule applies to all lumbar facet joints.

Lumbar facet joints help in transmitting the load of upper body to the lower limbs, and are involved in extension of the lumbar spine, lateral bending and lateral rotation.

Figure 1 Figure 2

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Causes of Facet Joint Pain

1. Degenerative osteoarthritis 2. Inflammatory arthritis- Rheumatoid arthritis, spondyloarthropathy

Diagnosis of Facet Joint Pain 1. Axial low back pain in middle age or elderly 2. Radiating to flanks, buttocks, thighs 3. Rarely radiating beyond knees 4. Pain worsened by extension, lateral rotation, lateral bending of lumbar spine 5. Pain decreased by sitting and lying down 6. No associated neurological deficits 7. Local pressure over the facet joints cause pain (tenderness) 8. X-ray and MRI are not specific in diagnosis making

Management

1. Conservative Simple analgesics- paracetamol, tramadol, short course of NSAIDs Back and core muscle strengthening exercises, avoiding lumbar braces

2. Interventions Facet joint block

Facet joint block

It is usually done under C-arm guidance. Both intra-articular and medial branch blocks can be performed.

Although there is strong evidence for medial branch block, intra-articular facet block has the advantage of single needle prick. The medial branch block requires needle placement at two levels for each facet joint (dual nerve supply).

Prerequisites for the Block Procedure 1. Explain the procedure to the patient and obtain consent 2. Patient should be off analgesics for at least 24 hours before the procedure so as to

appreciate the pain relief after the block. More than 50% reduction in pain is considered as block success

3. Pain score at the time of procedure should be at least 4/10 on the Numeric Rating Scale (NRS)

4. Check whether the patient is on anti-platelet agents as well as the coagulation status 5. Patient should be accompanied by an attender

Technique of the Facet Joint Block

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1. Patient is asked to lie prone on the operating table, with a pillow under the abdomen/belly to reduce the lumbar lordosis

2. Standard monitors are connected and IV line is secured 3. C-arm is oriented to take an antero-poestrior (AP) image of the lumbar spine. Ensure the

spinous processes are in the midline (the true AP view) (Figure 3). 4. Next, rotate the C-arm obliquely to the ipsilateral side (side of blockade) till the Scotty

dog image is seen clearly (Figure 4). This angle may vary in each individual. 5. Identify the facet joint lines. This is the target for intra-articular block (Figure 5). For

medial branch block, the junction between the superior articular process and transverse process is the target (Figure 6).

6. Infiltrate the target on the skin with local anaesthetic and insert the 22G block needle in line with the x-ray beam. This is called “needle in tunnel view”. When the needle is in tunnel view, only the hub will be visualised as a dot in the fluoro-image.

7. Slowly advance the needle towards the target and check the image for tunnel view at regular intervals.

8. Once the target is reached (bone is encountered), manipulate the needle to enter the joint in the intra-articular technique (feel for give away or pop of the joint capsule).

9. Check the needle position in both AP and lateral view to confirm correct needle placement and to rule out needle entering the spinal canal.

10. Inject 0.5-0.8 ml of local anesthetic with 5-10 mg deposteroid and remove the needle. 11. Monitor the patient for 30 min post procedure for any adverse events such as

neurological deficits, hematoma. Also assess the degree of pain relief. Discharge the patient with instructions.

Figure 3. True AP view Figure 4. Oblique view

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Figure 5. Figure 6.

Complications Facet joint block is usually a safe block to perform with no major complications. Nevertheless, if not properly conducted, it can lead to serious complications such as

a. Inadvertent intrathecal and epidural injection b. Injury to nerve root c. Intravascular injection d. Hematoma formation

TRANSFORAMINAL BLOCK

Indications

1. To diagnose radicular pain 2. Disc herniation with radiculopathy 3. Dorsal root ganglion lesion 4. Post herpetic neuralgia

Prerequisites for the Block

1. Explain the procedure to the patient and obtain consent. 2. Patient should be off anti-neuropathic medications at least 24 hours before the

procedure, so as to appreciate the pain relief after the block. More than 50% reduction in pain is considered as block success.

3. Pain score at the time of procedure should be at least 4/10 on NRS. 4. Check whether the patient is on anti-platelet agents as well as the coagulation status 5. Patient should be accompanied by one attender

Technique of Transforaminal Epidural Block

Transforaminal epidural block is different from conventional inter-laminar epidural injection. In case of inter-laminar technique (both midline and paramedian approaches), the loss of resistance

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method with Tuohy needle is used to find the epidural space. This method is blind and pierces the ligamentum flavum. In transforaminal approach, a regular 22G spinal needle is used to enter the epidural space via the intervertebral foramen under fluoroscopy guidance.

Transforaminal technique selectively targets a single nerve root, unlike the inter-laminar approach. Thus, risk of hypotension is negligible. Since the needle enters the epidural space via, the foramen, the needle tip lies close to the anterior epidural space (where the inflamed nerve root is present). The needle tip in the inter-laminar approach lies in the posterior epidural space and hardly any drug injected in this area will reach the anterior space.

Procedure 1. Patient is asked to lie prone on the operating table, with a pillow under the

abdomen/belly to reduce the lumbar lordosis 2. Standard monitors are connected and IV line is secured 3. C-arm is oriented to take an antero-posterior (AP) image of the lumbar spine. Ensure

that the spinous processes are in the midline (true AP view) (Figure 7) 4. Next, rotate the C-arm obliquely to the ipsilateral side (side of blockade) till the Scotty

dog image is seen clearly (Figure 8). This angle may vary in each individual 5. Identify the pedicle (eye of Scotty dog). The six o’ clock position of the pedicle is the

target for the transforaminal epidural injection (Figure 8) 6. Infiltrate the target on the skin with local anesthetic and insert the 22 G block needle in

line with the X-ray beam. This is called “needle in tunnel view”. When the needle is in tunnel view, only the hub will be visualized as a dot in the fluoro-image (Figure 9)

7. Slowly advance the needle towards the target and check the image for tunnel view at regular intervals

8. Once the target is reached (6 o’clock edge of the pedicle is encountered), manipulate the needle just to slip off the bone

9. Check the needle depth in lateral view. Advance the needle further till the tip lies in postero-superior quadrant of the intervertebral foramen (Figure 10)

10. Next, take AP view image to confirm correct needle placement. The needle tip should be along an imaginary line which bisects the pedicle perpendicularly (also called mid-pedicular line). Needle tip should never be medial to this line. This will rule out needle tip entering the spinal canal (Figure 11).

11. Inject 0.5 ml of contrast (radio-opaque dye) and confirm that the dye is spreading along the nerve root and also in the epidural space (Figure 11). Next inject 5-6 ml of local anesthetic with 10-20 mg deposteroid and confirm the washout of the dye

12. Monitor the patient for 30 minutes post- procedure for any adverse events such as neurological deficits and hematoma. Assess the pain relief. Discharge the patient with instructions

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Figure 7. True AP view Figure 8. Oblique view

Figure 9. Needle in tunnel view Figure 10.

Figure 11.

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Complications

1. Dural puncture 2. Nerve root injury 3. Intravascular injection 4. Intradiscal injection 5. Infection 6. Epidural hematoma

REFERENCES

1. Brummet CM, Chen SP. Pathogenesis, diagnosis, and treatment of zygapophyseal (facet) joint pain In: Benzon HT, Rathmell JP, Wu CL, Turk DC, Argoff CE, Hurley RW, editors. Practical Management of Pain. 5th ed. Philadelphia: Elsevier; 2014. p. 816-45.

2. Raj P, Erdine S. Pain-Relieving Procedures. The Illustrated Guide. Hoboken, N.J. Wiley-Blackwell ;2012.

3. Van Kleef M, Vanelderen P, Cohen SP, Lataster A, Zundert JV, Mekhail N. Pain originating from the lumbar facet joints. Pain Practice 2010;10(5):459-46.

4. Boxem KV, Cheng J, Patijn J, Van Kleef M, Lataster A, Mekhail N, Zundert JV. Lumbosacral radicular pain. Pain Practice 2010;10(4):339–58.