Haemoglobinopathies- Thalassemia, Porphyrias and Sickle cell disease-

Anaesthetic implications

Moderator: Dr. SatishSpeaker: Dr. Deepa

The hazards of surgery in these patients are not always those which are attendant on conditions suggesting emergency surgery. . .The presence of the basic disease increases the hazard of surgery, and of course, of anesthesia. —In ANESTHESIOLOGY, 1955

Haemoglobinopathies are diseases involving abnormalities of the structure or production of haemoglobin

Structure of Haemoglobin

Haemoglobin is a tetrameric protein consisting of two alpha (a) and two nonalpha polypeptide chains attached to four iron-containing heme complexes.

Sickle Cell Disease:

An autosomal recessively inherited disorder of the

β-haemoglobin chain caused by substitution of Valin

for Glutamic Acid in β-globin subunit. This disease is

characterized by

Haemolytic anaemia,

Intermittent vaso occlusive crises

Variable phenotypic expression.

Hb S gene is found primarily in populations of

native tropical African origin

Sickle cell disease (SCD) refers to a group of

haemoglobinopathies.

- HbSS – Sickle cell anaemia

- HbSC disease

- HbSD disease

- HbS/β-thal - Sickle β-thalassemia

Pathology: - HbS polymerization depends upon the haemoglobin concentration per cell, i.e. high MCHC. - Decreased pH reduces the oxygen affinity to Oxygen, thereby increasing deoxygenated Hb and increasing sickling- Duration of Red cell exposed to low oxygen

Cellular response of haemoglobin S is due to both

unstability and insolubility of HbS as a result of

the loss of the negative charge resulting in

stickling and sickling during extreme state of

deoxygenating by aggregation and

polymerization

Vaso-occlusive crisisAlso known as Pain crisis is the hallmark of SCD, represent episodes of hypoxia injury and infraction associated with severe pain in the affected region triggered by infection, dehydration and acidosis.

Clinical Features of Sickle Cell Disease

Neurological

Pain crisis Occurs in 70% of patients

Stroke 10% of children; subclinical microvascular

occlusion in more than 20%. Cause of 20% deaths.

Peripheral neuropathy unusual complication

Chronic pain syndrome in a small subset of

patients

Strokes are much more common in children than in adults. Frequently, large arteries such as the internal carotid or the

middle cerebral are occluded In adults, haemorrhagic strokes occur more frequently than

arterial occlusive strokes Subarachnoid haemorrhages are most common. Exchange transfusion followed by maintenance

hypertransfusion is a prudent course of action. Pre-op management for uncovering previous ischaemic injury: Transcranical Doppler studies MRI Note proliferative sickle retinopathy due to sickling, stasis

and occlusion of small blood vessels

Pulmonary

Acute Chest Syndrome Occurs in 40% of patients;

mortality rate of 1.1% for children and 4.8% for

adults.

Airway hyperreactivity 35% of children

Restrictive lung disease 10–15% of patients

Genitourinary

Nocturnal enuresis not a sensitive predictor

Chronic renal insufficiency Present in 5–20% of

adults

Urinary tract infection Increased incidence; may

trigger ACS

Priapism 10–40% of men

Sickle cell nephropathy, characterised by Defective renal concentration and acidification. Lesions are consequence of sickling in vasa recta (supplies blood

to collecting ducts, medullary structures etc.) of renal medulla. Concentrating defect results due to obliteration of vasa recta

which forms part of the counter-current multiplication system in loops of Henle.

Because of the slow blood flow and decreased local oxygen tension, the renal medulla is particularly vulnerable to infarction and necrosis

Papillary renal necrosis, 2° to medullary ischaemia, may be manifest by unilateral haematuria.

UTI and pyelonephritis due to structural abnormalities and scarring.

Gastrointestinal

Cholelithiasis Up to 70% of adults

Liver disease: Viral hepatitis from transfusion in up

to 10% of adults. Liver failure 2%.

Dyspepsia Mucosal ischemia, rather than increased

acid production, is thought to be the cause.

Reflux is not a complication of SCD.

Haematological

Haemolytic anaemia Typical baseline

haemoglobin levels are 6–9 g/dl in SS disease,

higher in SC disease and Arab phenotype.

Acute aplastic anaemia Parvovirus B19 infections

trigger acute severe exacerbations of anaemia

Splenic enlargement/fibrosis Less affected: SC

disease, Arab haplotype

Orthopaedic

Osteonecrosis Up to 50% of adults

Osteomyelitis Salmonella and Staphylococcus

aureus are commonest pathogens.

Dactylitis Early onset is a marker of disease

severity

Vascular

Leg ulcers

Immunological

Immune dysfunction Increased susceptibility to

infections

Erythrocyte auto/alloimmunization Increased

incidence of transfusion

Haemolytic transfusion reactions

Alloimmunization

Anaesthetic Implication

Although sickle cell trait does not cause a marked

increase in perioperative morbidity or mortality.

Management of SCD focuses on controlling

symptoms and minimizing crises.

SCD-specific complications, or “sickle events,”

include

- Pain crisis

- ACS

Complications include:

Increased incidence of erythrocyte alloimmunization

and transfusion reactions consequent on

perioperative transfusion

Nonspecific complications include

Fever

Infection

Bleeding

Thrombosis

Embolism

Death from causes other than SCD

Guidelines for Management

Preoperative: History and examination- Establish organ

damage, risk factors Investigations: Investigations as indicated by

patient and procedure Consider prophylactic transfusion: Transfusion Crossmatch for Rhesus, Kell, and Lewis antigens, alloantibodies

Predictors of Postoperative SCD complications Type of surgical procedure-Low, moderate or high risk Increased age-Associated with disease progression Frequency of recent complications-Current activity of

disease state Hospitalization-Marker of disease severity Temporal clustering of ACS-Progression of lung disease Abnormal lung fields on radiograph-Evidence of sickle

chronic lung disease Pregnancy-Increased risk of maternal complications Pre-existing infection-Triggering agent for ACS Haplotype-African haplotypes have more severe disease

than the Asian haplotype

Intraoperative Hydration: Modify according to renal pathology Oxygenation : Modify according to organ pathology Thermoregulation: Normothermia; hypothermia if indicated

under deep anaesthesia. Normothermia maintenance. Fever increases the rate of gel formation by S haemoglobin. Although hypothermia retards gel formation, the decreased

temperature also produces peripheral vasoconstriction. Consequently, normothermia is desirable.

Increasing ambient temperature in operating room. Transfusion: As indicated by haemorrhage and organ

pathology Aesthetic technique As indicated by procedure

Use of a tourniquet (depending on surgery

planned) is controversial in both the homo- and

heterozygote during surgery to prevent stasis of

blood.

- If essential ensure careful wrapping of extremity,

normothermia, short compression time,

hyperoxygenation

Prevent sickling by avoiding Hypoxaemia By measuring oxygen saturation using pulse

oximetry and giving prophylactic oxygen. Oxyhaemoglobin dissociation curve is shifted to

the left. Low arterial saturation in SCD. During surgery and the postoperative period, the

inspired oxygen concentration should be increased to around 40% to maintain or increase the arterial oxygen tension

Hyperviscosity

Keep Hb around 10 gdl-1

Maintain hydration

Acidosis

Positive pressure ventilation during surgery to

achieve normocarbia and avoid acidosis.

Aim for mild respiratory alkalosis (pH ≈ 7.45)

To avoid dehydration (i.e. to prevent circulatory

stasis)

An IV infusion should always be set up pre-

operatively.

Allow oral fluids as late as possible and give pre-

and post-operative IV fluids

Postoperative Basic care : Early mobilization, pulmonary toilet,

effective analgesia Supplemental oxygen as requiredPain crisis: Pain scoring Early effective analgesia—opioids Adjuvant analgesics—nonsteroidal anti-

inflammatory drugs, acetaminophen Consider regional analgesia, incentive spirometry Pulmonary monitoring Psychological support

Acute Chest Syndrome ACS is typically detected 2–3 days postoperatively. Difficult to diagnose but common characteristics:- fever, dyspnoea, cough, chest pain and pulmonary infiltrates Pneumonia can trigger and complicate ACS, broad-

spectrum antibiotics e.g. cephalosporin and erythromycin in combination are indicated if infection occurs.

Arterial blood oxygen saturation commonly falls with ACS, therefore monitor arterial blood gases rigorously

Management of ACS

Pre-op measures to reduce risk of ACS:

Transfusion

Aims to increase HbS level to ≈30% and haemoglobin

>10g/dl before major surgery. The need to reduce

HbS to these levels has recently been questioned

Hydroxyurea

Enhances formation of HbF

Lung function tests to assess respiratory fitness.

Preoperative Transfusion

Controversial areas in managing patients with sickle cell

disease.

Past history of frequent complications, increased tissue

oxygenation, reduced blood viscosity, and a "margin of

safety".

Disadvantages include induction of hyperviscosity,

significant alloimmunization, delayed transfusion

reactions, exposure to infectious disease, cost, and

provision of a false sense of security.

A recent cooperative study of preoperative transfusion demonstrates that sickle cell patients should have simple transfusions to raise the patient's haemoglobin to 10 gm/dL before surgery.

safer and as effective in preventing postoperative complications as are exchange or aggressive transfusions to decrease the haemoglobin S level below 30%

Postoperative complications such as chest syndrome, fever, and alloimmunization with delayed transfusion reactions are common

Thalassemia

Autosomal recessive disorder of haemoglobin that

results in haemolytic anaemia

Frequently encountered in people of Mediterranean or

South Asian ancestry

Occurs because of a disruption of the normal 1:1 ratio of

α– and β-chains.

There are multiple forms of thalassemias. Imbalance of

α– and β–chains results in rapid erythrocyte destruction

and turnover with a chronic haemolytic anaemia

Inheritance of thalassemia mutations with

haemoglobin S will produce a sickle-thal disease

very similar to sickle cell anaemia.

Types:

Alpha thalassemia is characterized by the

deficiency or deletion of alpha–chains

Beta thalassemia is caused by reduced or absent

synthesis of beta-chains

Alpha ThalassemiaTypes of Alpha Thalassemia: Alpha thalassemia major, also called haemoglobin

Bart’s, occurs when 4 alpha–chains are replaced by gamma-chains; this results in hydrops fetalis syndrome.

Absence of 3 alpha–chains results in alpha-thalassemia intermedia which has four beta-chains and haemolytic anaemia. These excess beta-chains form unstable tetramers called haemoglobin H with abnormal oxygen dissociation curves.

When 2 alpha–chains are involved, the patients

have alpha thalassemia minor and a mild

anaemia; a single alpha–chain involvement

results in the alpha thalassemia carrier state

Types of Beta Thalassemia:

a) Beta Thalassemia Minor: Single gene defect.

Patients are asymptomatic and have mild

anaemia.

b) Beta thalassemia intermedia is intermediate

between minor and major; patients require only

occasionally require transfusions

c) Beta-thalassemia major is also known as Cooley’s anaemia and involves the absence of 4 beta–chain production. Severe haemolytic anaemia, Poor growth, Skeletal abnormalities, Hepatosplenomegaly, jaundice Vascular damage These children require lifelong transfusion and

the life may be foreshortened by the cardiac complications of iron overload.

Investigation: CBC with differential count, peripheral smear for

schistocytes, reticulocyte count, PT/PTT, LFTs, metabolic profile, TSH, iron, TIBC, folate, ferritin, B12, transferrin, blood type/screen, ESR, CRP, lactate, DIC panel, haptoglobin, LDH.

Serum iron level is unreliable, with ~78% sensitivity and 36% specificity in ICU management.

Reticulocyte index Iron levels and other serum studies may be

inaccurate if recent transfusions have been given.

Urine analysis, creatinine, BUN, glucose

CPK and troponin (for rhabdomyolysis and

ongoing ischemia from anaemia)

CXR, EKG, ABG, SvO2

Low MCV with high reticulocyte count may be the

first indirect evidence for thalassemia

Serum iron studies: High, with extremely elevated saturation levels, >70-80%; TIBC elevated Ferritin: High, but levels need to be taken into consideration in face of acute illness. Some patients may have iron overload.

Peripheral smear: Usually done by automated systems in lab, but ask for specific haemolysis and anaemia profiling. Great source for identification of abnormal cell types, inclusion bodies (Heinz), morphology

Anaesthetic Consideration

Severity of Thalassemia is critical determinant.

Chronic anaemia is major concern.

Bony malformations that may disturb tracheal

intubation

Complications of Iron over load leading to

cirrhosis, right sided heart failure and

endocrinopathies.

Porphyria

A group of inherited or acquired enzymatic defects

of home biosynthesis.

Each type of porphyria has a characteristic

pattern of overproduction and accumulation of

home precursors based upon the location of the

dysfunctional enzyme in the home synthetic

pathway.

Types Acute Intermittent Porphyria (AIP), Variegate Porphyria (VP), Hereditary Coproporphyria (HCP) and the very rare Plumboporphyria (PP).

With the exception of PP, which is recessive, these porphyrias are inherited as non‐sex‐linked, autosomal dominant conditions with variable expression

a) Acute Intermittent Porphyria: The defective enzyme in this condition is porphobilinogen deaminase and the gene encoding this enzyme is located on chromosome 11. PBG deaminase deficiency can, in most cases, be detected in red cells between attacks. the most severe symptoms, and is the one in

which an acute attack is most likely to be fatal hypertension and impaired renal function are

significantly more common in porphyric subjects

b) Variegate porphyria: This condition is characterized by cutaneous photosensitivity in which bullous skin eruptions occur on exposure to sunlight as a result of the conversion of porphyrinogens to porphyrins. The characteristic skin lesion is one of excessive

fragility, especially on sun‐exposed surfaces such as the face and hands, where bullae and erosions with subsequent pigmented ‘tissue paper’ scarring are frequently seen.

The enzyme defect is at the level of protoporphyrinogen oxidase but there is also a reduced amount of PBG deaminase.

The gene encoding this enzyme is on chromosome 1. The incidence of VP in South Africa is the highest in the world.

c) Hereditary coproporphyria: This condition is far less common than VP and AIP. Acute attacks appear to be considerably less severe, and the prognosis better. The defective enzyme is coproporphyrinogen oxidase, encoded by a gene on chromosome 9. As in VP, cutaneous photosensitivity is characteristic, though it tends to be less severe in the interval between acute attacks than it is in VP.

d) Plumboporphyria: This, the rarest of the acute porphyrias, results from a deficiency of ALA dehydratase, which is encoded by a gene on chromosome 9. It is associated with an excess of urinary ALA analogous to that found in lead poisoning (hence the name), although lead concentrations in the blood are normal. Unlike the other acute porphyrias, the mutation is recessive, and the disease presents early in life, with all clinically manifest cases being homozygotes. No references to anaesthesia for patients with this condition have been published

Signs:Classical case presents with colicky abdominal pain, muscular weakness, paralysis, psychiatric manifestations, and red coloured urine. Insomnia is a frequent symptom and may lead to the administration of barbiturates and a subsequent precipitation of an attack

Acute Abdomen and porphyria : The following symptoms should raise suspicion of porphyria in patients with acute abdominal pain: mental status changes

(confusion, hysteria), peripheral neuropathy (motor > sensory), dark coloured

(red to purple) urine, and known family History of porphyria. Of special concern is the parturient

with acute abdominal pain. Greater than 50% of pregnant women who have porphyria will experience a crisis during pregnancy or puerperium, probably due to ALA sythetase induction by hormonal changes of pregnancy. If the patient with an acute abdomen, pregnant or not, does not have suggestive symptoms of porphyria, anaesthetic drugs and therapies should not be modified

Known acute porphyria : In the setting of known acute porphyria, perhaps the most difficult situation is when an acute attack is caused by and is concurrent with a disease process which mandates surgical intervention; i.e. the infection, pyrexia, and anorexia of acute appendicitis inducing ALA sythetase and precipitating crisis. Neurologic evaluation should focus on mental

status and peripheral neuropathy. If an acute crisis is suspected, attention to cranial

dysfunction and bulbar symptomatology may predict impending respiratory failure.

Premedication is important, as psychological stress alone has been reported to precipitate crises.

Numerous reports have implicated benzodiazepines, and their use is discussed below. Narcotics are safe in porphyria, with the exception of pentazocine, a partial agonist. Scoplamine and atropine are considered safe. Acceptable non-narcotic sedative include droperidol, promethazine, chloral hydrate, and diphenhydramine

Most porphyric can be anaesthetized with relative safety provided that appropriate precautions are taken.

Mainstay of the safe anaesthetic management of these patients depends on the detection of susceptible individuals, and the identification of potentially porphyrinogenics agents

Preoperative Evaluation

A careful family history should be obtained and a thorough physical examination performed (although there is often no clinical evidence or only subtle skin lesions), and the presence or absence of peripheral neuropathy and autonomic nervous system instability should be noted.

When a case of porphyria is present, it is important for us to know the factors and agents that precipitate an acute attack. It is also important to choose a drug which will be safe.

Anaesthetic Management

Drugs may trigger acute attack mostly which depends on an increased demand for haem production or a failure of haem inhibitory feedback as the final common pathway.

Drug may induce the transcription of ALA synthetase directly through mRNA or may interfere negative feedback control which haem exerts on ALA synthetase production.

Drug may interfere with the haem synthetic pathway, thus reducing the level of haem, or may increase the demand by increasing utilization.

Multitude of pathways and variety of drug structures make it impossible to predict prophyrinogenic agent.

The only property of drug that links between porphyria is lipid solubility and membrane fluidization

Guidelines for drug selection include the following:

(1) There is evidence that a single exposure to a potent inducer can be well tolerated, but not during an acute attack. (2) Exposure to multiple potential inducers is more dangerous than exposure to any single agent. (3) Lists of “safe” and “unsafe” anaesthetic drugs and adjuncts may be based on animal or cell culture experiments

Drugs contraindicated in porphyrias Barbiturates (hepatic porphyrias only) diazepam chlordiazepoxide hydrochloride phenytoin sodium Sulfonamides Estrogen All oral contraceptives Ergot preparations methyldopa Alcohol in any form pentazocine

Drugs Recommendation

INHALED ANESTHETICS Nitrous oxide- Safe Isoflurane- Probably safe Sevoflurane- Probably safe Desflurane- Probably safe

INTRAVENOUS ANESTHETICS Propofol- safe Ketamine: Probably safe Thiopental: Avoid Thiamylal: Avoid Methohexital: Avoid Etomidate: Avoid (No proper study is available)

ANALGESICS Acetaminophen: Safe Aspirin: Safe Codeine: Safe Morphine: Safe Fentanyl: Safe Sufentanil: Safe Ketorolac: Probably avoid Phenacetin: Probably avoid Pentazocine: Avoid

NEUROMUSCULAR BLOCKING DRUGS Succinylcholine: Safe Pancuronium: Safe Atracurium: Probably safe Cisatracurium: Probably safe Vecuronium: Probably safe Rocuronium: Probably safe Mivacurium: Probably safe

OPIOID ANTAGONIST Naloxone: SafeANTICHOLINERGICS Atropine: Safe Glycopyrrolat: SafeANTICHOLINESTERASE Neostigmine Safe

LOCAL ANESTHETICS Lidocaine: Safe (Theoretically unsafe but no

evidence present) Tetracaine: Safe Bupivacaine: Safe Mepivacaine: Safe Ropivacaine: No data

SEDATIVES AND ANTIEMETICS Droperidol: Safe Midazolam: Probably safe Lorazepam: Probably safe Cimetidine: Probably safe Ranitidine: Probably safe Metoclopramide: Probably safe Ondansetron: Probably safe

CARDIOVASCULAR DRUGS Epinephrine: Safe α-Agonists: Safe β-Agonists: Safe β-Antagonists: Safe Diltiazem: Probably Safe Nitroprusside: Probably safe Nifedipine: Avoid

Regional Anaesthesia: No absolute contraindication If a regional anaesthetic is being considered, it is

essential to perform a neurologic examination before initiating the blockade to minimize the likelihood that worsening of any pre-existing neuropathy.

Autonomic nervous system blockade induced by the regional anaesthetic could unmask cardiovascular instability, especially in the presence of autonomic neuropathy, hypovolemia, or both.

Treatment of a Porphyric Crisis

Removal of any known triggering factors Adequate hydration and carbohydrate loading are

necessary Sedation using a phenothiazine Opioid for pain Nausea and vomiting are treated with

conventional antiemetics. β-Blockers can be administered to control

tachycardia and hypertension

Since traditional anticonvulsants are regarded as unsafe, seizures may be treated with a benzodiazepine or propofol

Electrolyte disturbances, including hypomagnesaemia, must be treated aggressively.

Administration of home (3 to 4 mg/kg IV daily for 4 days) is indicated after a day or two of the crisis if the patient is no better after receiving conservative therapy. Hemet may be administered as haematin, haem albumin, or haem arginine

Somatostatin decreases the rate of formation of

ALA synthetase and, in combination with

plasmapheresis, may effectively decrease pain

and induce remission.

Reference1. Robbins and Cortan Pathologic Basis of Disease

7Th Edition2. Miller’s Anesthesia 7th Edition3. Stoelting’s Anesthesia & Co-Existing Disease 5th

Edition4. Br. J. Anasthesia 2000; 85: 143-535. Anesthesiology 2004; 101:766–85 Sickle Cell

Disease and Anesthesia Paul G. Firth, M.B., Ch.B.,* C. Alvin Head, M.D.†© 2004 American Society of Anesthesiologists

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