sepsis – pathophysiology and management

COMPILED BY MODERATOR

Dr. Bharat Arora Dr. Abhijit Tarat

PG Trainee Associate Professor

Department Of Anesthesiology And Critical Care

Silchar medical college And Hospital, Silchar

• The condition characterized by signs of systemic

Inflammation(eg . fever & leucocytosis) is called

Systemic Inflammatory response syndrome (SIRS).

•When SIRS is the result of an infection, the condition is called Sepsis.

•When sepsis is accompanied by dysfunction of

one or more vital organs, the condition is called

Severe sepsis.

•When sepsis is accompanied by hypotension that is refractory to volume infusion, the condition is called

Septic shock.

Diagnostic Criteria For SIRS The diagnosis of SIRS requires at least 2 of the

following:

1)Temperature > 380 C or < 360 C

2)Heart rate > 90 beats/ min

3)Respiratory rate > 20 breaths/ min

or

Arterial PCO2< 32 mm of Hg

4)WBC count > 12,000/mm3 or <4000 mm3

or

>10 % immature (band ) forms

1)Infections in the aged and malnourished

2)Inadequate immune response due to hepatic or renal failure, diabetes mellitus, malignancy, HIV infection, lymphoma.

3)Iatrogenic infections

4)Virulent gram negative and gram positive infections

5)Oppurtunistic infections (fungal, viral)following organ transplants, HIV infections and lymphoma.

6)Fulminant tetanus

7)Disseminated haematogenous tuberculosis

8)Severe Pl. falciparum infections

9)Fulminant B. typhosus, salmonella, amoebic infection

10) Trauma , crush injuries, burns, pancreatitis.

Severe SEPSIS :Sepsis accompanied by hypo-perfusion or

organ dysfunction.Cardiovascular : SBP<90mmhg/MAP<70 for at least 1 hr

despite adequate volume resuscitation or the use of vasopressors to achieve the same goals.

Renal : Urine output <0.5ml/kg/hr or Acute Renal

Failure.Pulmonary : PaO2/FiO2 <250if other organ dysfunction

is present or <200 if the lungs is the only dysfunctional organ.

Gastrointestinal :

Hepatic dysfunction (hyperbilirubinemia, Elevated transaminases

CNS :

Alteration in Mental status (delirium)

Hematologic :

Platelet count of <80,000/mm3 or decreased by 50% over 3 days/DIC

Metabolic :

PH<7.30 or base deficit >5.0mmol/L

Plasma lactate >1.5 upper limit of normal.

BASIC PATHOPHYSIOLOGY

Nidus of infection

Blood stream invasion

Release of mediators

Peripheral vascular effects

Myocardial depression Cellular Injury

Poor tissue perfusion and metabolic acidosis

Multiple organ dysfunction Death

Classically septic shock is due to endotoxins released by gram negative bacteria though it can occur with fungal and protozoal infections. Endotoxin is a lipopolysaccharide component of the outer membrane of the bacterial cell. It contains Lipid A which is highly antigenic and is responsible for features of sepsis syndrome.

Endotoxin interacts with normal host defense system and triggers release of numerous mediators notably cytokines like TNF from mononuclear cells.

Endotoxins also activates neutrophils with the release of proteases and oxidants which promote endothelial cell damage.

Arachidonic acid in the cell wall undergoes degradation through phospholipase leading to formation of prostaglandins, leucotrienes and thromboxanes.

Phospholipase A2 release membrane bound phospholipids which are converted to platelet activating factor which increases vascular permeability, produces free radicals and activates platelets and phagocytes.

Endotoxins also activates the coagulation factors in the serum stimulating the coagulation pathway.

Fibrinolysis normally counters procoagulant factors but is suppressed in sepsis due to increased levels of plasminogen activator inhibitor-1(PAI-1), thrombin activatable fibrinolysis inhibitor(TAF.1a)and decreased levels of Protein C.

This haemostatic mechanism prevailing in sepsis is believed to lead to micro-vascular thrombi in various organ system.

In summary, invasion by microorganisms and their toxins elicit a strong response from the host defenses, which is characterized by activation of cellular elements and the plasma protein system. The cells activated are mononuclear cells , macrophages, neutrophils and endothelial cells. These activated cells produce numerous cytokines and mediators . The host defense system also activates the complement , coagulation cascades and the kallikrein-kinin system

• If the host defense system is disorganized , un-orchestrated , unbalanced and unchecked it fails to defend the host and paradoxically enough inflicts injury on the host .

• This injury is widespread because of the toxic effect of numerous mediators , and also because of endothelial cell damage and the dominance of procoagulant factors leading to micro vascular thrombi in various organ systems.

Infection

Endotoxin(LPS)

Cellular activation

Direct cell injury

Plasma protein system

PMN Macrophage Lymphocyte Monocyte Endothelial cell

Pro inflammatory mediators

Activation of complement coagulation

cascade& kallikrein kinin

TNF IL-6,IL-1

Leucotrienes, Prostaglandin

Superoxide,H2O2,OH-

G-CSFSelectins,ICAMS

NO

Cell injury

Organ failure

• The typical result is a high output hyper dynamic

circulatory state with tachycardia and

hypotension.

• Septic shock in addition is characterized by SBP≤ 90 mm of Hg not responding to fluid replenishment. It is associated with evidence of hypo perfusion and/or organ dysfunction.

• This state may be a compensatory response to increased tissue metabolism.

1)Arterial and venous tone markedly decreases

-venous and arteriolar dilatation

- fall in peripheral vascular resistance

- fall in SBP.

Vasodialating substances :- TNF,IL-1,NO,EDRF and PAF.

Catecholamine receptor down regulation may also occur and causes poor response to vasopressors.

2) Generalized increase in vascular permeability

- increase in interstitial fluid and

-tissue edema.

Peripheral pooling , hepatosplanchnic pooling and loss from GIT leads to low circulatory volume.

3)Combined effect of 1 & 2 leads to hypovolemia which may mask the hyper dynamic state.

4)Pattern of blood flow distribution changes . Some organs receive supernormal O2 supply and some get ischemic .Especially the splanchnic circulation is affected . Hepatovenous desaturation has been reported in septic patients.

Myocardial depression occurs in all patients.

Decreased compliance with decreased left ventricular diastolic function.

Left ventricular systolic dysfunction also occurs

evidenced by dilated cardiomyopathy with low

ejection fraction.

Cardiac output increases because of marked

tachycardia.

Beta receptor downgrading occurs and causes a

poor response to inotropic drugs.

Pulmonary hypertension due to increased pulmonary vascular resistance can occur when septic shock produces ARDS.

When pulmonary hypertension is significant , right ventricular function may be markedly affected due to an increased after load.

1)Early stage:-Tachycardia , hypotension , low PCWP,

high CI , low SVR

2)With progression and deteriorating cardiac function

hypotension , high PCWP , normal or slightly low

CI , normal to rising SVR

3) Late (pre terminal stage):-hypotension , high PCWP,

low and progressively decreasing CI and increased

SVR

4) Rarely very low CI , high PCWP and high SVR is

seen at the start of fulminant septic shock.

• Early and evolving phase of sepsis and septic shock

is characterized by increase in DO2 and VO2.

• In spite of increased O2 consumption , tissue needs

may not be satisfied and tissue hypoxia may occur.

• In late phase of septic shock,O2 consumption may fall even though DO2 is satisfactory resulting in a low O2 extraction ratio causing hypoxia and acidosis.

• Critical threshold of oxygen delivery

• Reasons are:-

1)Damaged endothelial cells in capillaries ,get edematous resulting in increased distance necessary for diffusion of O2 into tissue cells.

2) Damaged tissue cells find it difficult to utilize O2 for their metabolic needs.

3)Tissue oxygenation may not be impaired at all in sepsis as PO2 is increased in sepsis . Defect may be in the O2 utilization in the mitochondria which challenges aerobic metabolism. The culprit may be endotoxin ,which blocks the enzyme pyruvate dehydrogenase which moves pyruvate into mitochondria . Pyruvate accumulates in the cytoplasm where it is converted into lactate.

4) There is persistent hypotension following ischemic insult to an organ. This can be explained due to calcium influx within the vascular smooth muscles during hypoxia, which leads to persistent vasoconstriction even after CO and BP are restored to normal, leading to progressive multi-organ dysfunction.

5) Reperfusion Injury

6)Oxygen debt leading to Hyper carbonic acidosis in tissues.

7)Assessment of Stress by Gastric tonometry .

General Sign and Symptoms Rigor – fever (sometimes hypothermia)

Tachypnea /respiratory alkalosis

Positive fluid balance – edema

General inflammatory reaction

Altered white blood cell count

Increased CRP, IL-6, PCT concentrations

Hemodynamic alterations

Arterial hypotension

Tachycardia

Increased cardiac output/low SVR/high SvO2

Altered skin perfusion

Decreased urine output

Hyperlactatemia – increased base deficit

Signs of organ dysfunction

Hypoxemia

Coagulation abnormalities

Altered mental status

Hyperglycemia

Thrombocytopenia, DIC

Altered liver function (hyperbilirubinemia)

Intolerance to feeding (altered GI motility)

MODSMultiple organ dysfunction syndrome (MODS)-

failure of two or more organ systems

Homeostasis cannot be maintained without intervention-Results from SIRS

SIRS and MODS represent ends of a continuum

Transition from SIRS to MODS DOES NOT occur in a clear-cut manner

MODS occurs late and is the most common cause of death in patients with Sepsis.

Lactic acidosis led investigators to think that this is due to tissue ischemia.

Recovery from Sepsis is associated with near complete

recovery of organ function, even in organs whose cells

have poor regenerative capacity.

PATHOPHYSIOLOGY OF MODS MITOCHONDRIAL DYSFUNCTION

INCREASED CELLULAR APOPTOSIS

ENDOTHELIAL AND EPITHILIAL DYSFUNCTION

LATE ACTING MEDIATORS OF INFLAMMATION like MIF.

MANAGEMENT

1)Leucocytosis or leucopenia.

2)Deranged coagulation profile which includes elevated PT , thrombocytopenia , decreased fibrinogen and increased FDP .

3)Hyperglycemia is common . Hypoglycemia may also occur in pre terminal or terminal stage signifying hepatic dysfunction.

4)Slight rise in bilirubin , SGOT,SGPT and alk.phosphatase.

5)Increase in urinary urea or urinary nitrogen over 24 hrs and a negative nitrogen balance.

6)Low arterial pH due to presence of metabolic acidosis

7)Recently cytokines (esp. IL-6 and IL-8),

C-reactive proteins and Procalcitonin (PCT) levels have been noted to rise significantly following sepsis.PCT is reported to be superior to other markers in the diagnosis of a bacterial focus complicated by symptoms of severe sepsis and septic shock ( more than 2SD above normal values).

Principles of Therapy

1)To find out and eradicate the infection or sepsis responsible for the state of septic shock.

2)To reverse shock using volume infusion and inotropic support.

3)Ventilator support to all critically ill patients

4)To use recombinant human activated protein C in selected patients with severe sepsis.

5)Provide support to other organ systems

6)Provide nutritional support

7)Provide metabolic support

8)Prophylaxis for DVT and stress ulcers.

• Both eradication of infection and shock reversal are set into motion together . In severe shock , resuscitation takes place of prime , yet resuscitation would come to a standstill if prompt use and continuation of antibiotics are delayed , or if a pocket of pus remains undetected and not drained.

• Septic shock needs to be urgently treated and reversed . Though the patient should be urgently shifted to ICU , treatment should commence wherever the patient is at the time of diagnosis(in the ambulance , emergency dep't. or ward)

SEPSIS RESUSCITATION BUNDLE

TO BE COMPLETED WITHIN 3 HOURS:

1) Measure lactate level

2) Obtain blood cultures prior to administration of antibiotics

3) Administer broad spectrum antibiotics

4) Administer 30 mL/kg crystalloid for hypotension or lactate 4mmol/L

TO BE COMPLETED WITHIN 6 HOURS:

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation)

to maintain a mean arterial pressure (MAP) 65 mm Hg

6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate 4 mmol/L (36 mg/dL):

- Measure central venous pressure (CVP)

- Measure central venous oxygen saturation (ScvO2)

7) Re measure lactate if initial lactate was elevated

1)Management of severe sepsis(EGDT)

A) Initial Resuscitation(first 6 hours)

Begin resuscitation immediately in pts with hypotension and elevated lactate(>4 mmol/l).Do not delay pending ICU admission.

Resuscitation goals

CVP 8-12 mm of Hg

MAP≥65 mm of Hg

Urine output ≥ 0.5 ml/kg/hr

Central venous(superior vena cava)oxygen saturation ≥ 70% or mixed venous saturation ≥ 65%

If venous oxygen saturation target is not achieved:-

Consider further fluid

Transfuse packed red blood cells if required to a haematocrit of ≥ 30%

Start dobutamine infusion , maximum 20 mcg/kg/min

B)Diagnosis Obtain appropriate cultures before starting antibiotics provided it does not significantly delay antibiotic administration. Obtain two or more blood cultures1) One or more blood cultures may be percutaneous2) One blood culture from each vascular access device in place > 48 hrs. Culture other sites as clinically indicated like urine CSF , wounds, respiratory secretions etc. Perform imaging studies if safe to do so

Use of 1,3 beta D glucan assay , mannan and anti-mannan antibodies for diagnosis of invasive candidiasis and fungal infections.(If Available)

C)Antibiotic Therapy Begin i.v. antibiotic therapy as early as possible and always within the first hour of recognizing severe sepsis and septic shock. Broad spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration in the presumed source.Reassess antimicrobial regimen daily to optimize efficacy , prevent resistance , avoid toxicity and minimize costs.• Consider combination therapy in Pseudomonas

infection.

• Consider combination empiric therapy in

neutropenic patients

• Combination therapy ≤ 3-5 days and de-escalation following susceptibilities.

Duration of therapy typically limited to 7-10 days,

longer if response is slow or there are an un-drainable

foci of infection or immunologic deficiencies.

D)Source identification and control

A specific anatomic site of infection must be must be established within first 6 hrs of presentation.

Formally evaluate a patient for a focus of infection amenable to source control measures(eg. abscess drainage , tissue debridement)

Implement source control measure soon after resuscitation.(except infected pancreatic necrosis).

Choose source control measure with maximum efficacy and minimum physiological upset

Remove i.v. access devices if potentially infected.

Infection prevention by oral decontamination using chlorhexidine gluconate solution.

E)Fluid Therapy

Fluid resuscitation using crystalloid, the fluid of choice.

Target a CVP of 8mm of Hg( ≥12 mm of Hg if mechanically ventilated)

Give fluid challenges of 1000 ml of crystalloids or

30 ml/ kg. More rapid and larger volumes needed in sepsis induced tissue hypo perfusion

Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement.

Against the use of heta starch for resuscitation.

Albumin can be used if patient require substantial amount of crystalloids.

F)Vasopressors:

Maintain MAP ≥ 65 mm of Hg

Nor epinephrine and dopamine administered centrally are the initial vasopressors of choice.

Vasopressin (0.03 units/min) may be subsequently

administered with the anticipation of an effect equivalent to nor epinephrine alone.

Use epinephrine as the first alternative agent when blood pressure is poorly responsive to nor epinephrine or dopamine

Do not use low dose dopamine for renal protection

Insert an arterial line as soon as practical

G)Inotropic therapy:

Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output.

Do not increase cardiac index to predetermined supernormal levels

H)Steroids: i.v. hydrocortisone to be considered in hypotension not responding to fluids and vasopressors.ACTH stimulation is not recommended for identifying which patients should receive hydrocortisone.Hydrocortisone is preferred to dexamethasoneFludrocortisone (50μg orally OD)may be used if an alternative to hydrocortisone is used lacking mineralocorticoid activity.Hydrocortisone dose should be ≤ 300 mg/dayShould not be used in absence of shock unless the endocrine or corticosteroid history warrants it

I)Recombinant human activated protein C

Once Considered the use of rh -APC in adult patients with sepsis induced organ dysfunction with high risk of death(APACHE II ≥25 or MODS) if there are no contraindications.

Adult patients with severe sepsis and low risk of death(APACHE II ≤ 20 or one organ failure) should not receive rhAPC

PROWESS SHOCK Trail in 2011 shows no benefit of rhAPC in patients with septic shock, following which it was withdrawn from the market.

Supportive Therapy Of Severe Sepsis

J)Blood Product Administration:

RBC’s to be administered when Hb<7 gm/dl to target Hb at 7-9gm/dl . A higher level may be required in conditions like MI , severe hypoxemia , hemorrhage, cyanotic heart diseases or lactic acidosis.

Do not use erythropoietin

Do not use FFP to correct clotting defects unless there is bleeding or planned invasive procedures

Do not use antithrombin therapy

Administer platelets when:

• Counts < 10000/mm3

• Counts <20000 and there is significant bleeding risk

• Higher platelet counts(>50000) are required for surgery or

invasive procedures

K) Mechanical ventilation of sepsis induced ALI/ARDS

Target a tidal volume of 6ml/kg body weight

Target an initial upper limit plateau pressure ≤ 30 cm H2O.Chest wall compliance to be considered.

Allow PACO2 to rise above normal , if needed to

minimize plateau pressures and tidal volume.

Set PEEP to avoid excessive lung collapse.

Consider prone position for patients requiring potentially injurious levels of FIO2

Maintain mechanically ventilated patients in semi-recumbent position between 30o-45o

Noninvasive ventilation may be considered in minority of patients with ALI/ARDS.

Recruitment maneuvers, beta agonists only if required.

Use a weaning protocol and an SBT to evaluate the potential for discontinuing mechanical ventilation.

SBT options include a low level of pressure support with continuous CPAP of 5 cm of H2O or a T-piece.

Before SBT patients should be:-

•Be arousable

•Be haemodynamically stable without vasopressors

•Have no new potentially serious conditions

•Have low ventilatory and end expiratory requirements

•Require FIO2 levels that can be safely delivered through face mask or nasal cannula.

Use a conservative fluid management strategy for patients who do not have evidence of tissue hypoperfusion

Sedation , analgesia and neuromuscular blockade in sepsis.

Use either intermittent bolus sedation or continuous infusion sedation to predetermined end points(sedation scales) with daily interruptions/ lightening to produce awakening . Re-titrate if necessary.

Avoid neuromuscular blockade whenever possible. Monitor depth of blockade whenever with TOF when using continuous infusions.

Glucose Control

Use intravenous insulin to control hyperglycemia in patients with severe sepsis following stabilization in ICU.

Aim to keep blood glucose levels < 180 mg/dl using a validated protocol for insulin dose adjustment.

Provide a glucose calorie source and monitor blood glucose values every 1-2 hours(4 hours when stable) in patients receiving i.v. insulin.

Renal replacement

Intermittent hemodialysis and CRRT are considered equivalent.

CRRT offers easier management in haemodynamically unstable patients.

Bicarbonate Therapy

Do not use bicarbonate therapy to improve haemodynamics or reduce vasopressor requirements when treating hypoperfusion induced lactic acidemia with pH ≥ 7.15

Deep vein thrombosis prophylaxis

Use either low dose UFH or LMWH , unless contraindicated.

Use either a mechanical prophylactic device , such as compression stockings or an intermittent compression device , when heparin is contraindicated.

Use a combination of pharmacologic and mechanical therapy for patients at very high risk for developing DVT.

In patients at very high risk , use LMWH rather than UFH.

Stress ulcer prophylaxisProvide stress ulcer prophylaxis using H2 blocker or proton pump inhibitor . Benefits of prevention of upper gastrointestinal bleeding must be weighed against the potential for development of ventilator-acquired pneumonia.

NUTRITION:

•Administer oral/ enteral feed ,amount as tolerated.

•Avoid mandatory full caloric feeds, suggesting low caloric feeds, advancing only as tolerated.

•Combine i.v glucose/ enteral nutrition/ par-enteralnutrition as required during 1st week of diagnosis.

•No immunomodulating supplementation required.

Consideration for limitation of supportDiscuss advance care planning with patients and families . Describe likely outcomes and set realistic expectations.

1)Central venous pressure monitoring is done through a central venous line.

2)Arterial pressure to be monitored through a catheter inserted preferably in the radial artery-so that beat to beat pressures are displayed.

3)Septic shock is a prime indicator for use of a Swan- Ganzcatheter . The parameters which can be recorded are:-

-PvO2 -CI

-Svo2 -PAP

-CO -PVR

-PCWP

•Arrhythmias can occur in septic hypotensive patients who are on inotropic support and who have indwelling intracardiac catheters . Electrolyte disturbances contribute to or often causes dangerous ventricular arrhythmias . So constant monitoring of the cardiac rhythm with ECG is mandatory to recognize and correct these abnormalities.

THOUGH THESE GUIDELINES ARE HELPFUL,

RECOMMENDATIONS FROM THESE GUIDELINES CANNOT REPLACE THE CLINICIAN

DECISION MAKING CAPACITY , WHEN HE OR SHE IS PRESENTED WITH PATIENTS UNIQUE SET

OF CLINICAL VARIABLES.

Thank

You