Haemoglobinopathies thalassemia, prophyrias and sickle cell disease-
Moderator: Dr. Satish
Speaker: 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
Haemoglobin is a tetrameric protein consisting of two alpha
(a) and two nonalpha polypeptide chains attached to four
iron-containing heme complexes.
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
Intermittent vaso occlusive crises
Variable phenotypic expression.
Hb S gene is found primarily in populations of native tropical
Sickle cell disease (SCD) refers to a group of
- HbSS – Sickle cell anaemia
- HbSC disease
- HbSD disease
- HbS/β-thal - Sickle β-thalassemia
- 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
- 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
Also 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.
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
Note proliferative sickle retinopathy due to sickling, stasis and
occlusion of small blood vessels
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
Nocturnal enuresis not a sensitive predictor
Chronic renal insufficiency Present in 5–20% of adults
Urinary tract infection Increased incidence; may trigger
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
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
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.
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,
Osteonecrosis Up to 50% of adults
Osteomyelitis Salmonella and Staphylococcus aureus
are commonest pathogens.
Dactylitis Early onset is a marker of disease severity
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
Increased incidence of erythrocyte alloimmunization and
transfusion reactions consequent on perioperative
Nonspecific complications include
Death from causes other than SCD
History and examination- Establish organ damage, risk
Investigations: Investigations as indicated by patient and
Consider prophylactic transfusion: Transfusion
Crossmatch for Rhesus, Kell, and Lewis antigens,
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
Hospitalization-Marker of disease severity
Temporal clustering of ACS-Progression of lung disease
Abnormal lung fields on radiograph-Evidence of sickle chronic
Pregnancy-Increased risk of maternal complications
Pre-existing infection-Triggering agent for ACS
Haplotype-African haplotypes have more severe disease than
the Asian haplotype
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
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
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
Keep Hb around 10 gdl-1
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
Basic care : Early mobilization, pulmonary toilet, effective
Supplemental oxygen as required
Pain crisis: Pain scoring
Early effective analgesia—opioids
Adjuvant analgesics—nonsteroidal anti-inflammatory
Consider regional analgesia, incentive spirometry
ACS is typically detected 2–3 days postoperatively.
Difficult to diagnose but common characteristics:
- fever, dyspnoea, cough, chest pain and pulmonary
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
Pre-op measures to reduce risk of ACS:
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
Enhances formation of HbF
Lung function tests to assess respiratory fitness.
Controversial areas in managing patients with sickle cell
Past history of frequent complications, increased tissue
oxygenation, reduced blood viscosity, and a "margin of
Disadvantages include induction of hyperviscosity, significant
alloimmunization, delayed transfusion reactions, exposure to
infectious disease, cost, and provision of a false sense of
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
Postoperative complications such as chest syndrome,
fever, and alloimmunization with delayed transfusion
reactions are common
Autosomal recessive disorder of haemoglobin that results in
Frequently encountered in people of Mediterranean or South
Occurs because of a disruption of the normal 1:1 ratio of α–
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
Alpha thalassemia is characterized by the deficiency or
deletion of alpha–chains
Beta thalassemia is caused by reduced or absent
synthesis of beta-chains
Types 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
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
c) Beta-thalassemia major is also known as Cooley’s
anaemia and involves the absence of 4 beta–chain
Severe haemolytic anaemia,
These children require lifelong transfusion and the life
may be foreshortened by the cardiac complications of
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,
Serum iron level is unreliable, with ~78% sensitivity and
36% specificity in ICU management.
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
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.
A group of inherited or acquired enzymatic defects of home
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.
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
The gene encoding this enzyme is on chromosome 1.
The incidence of VP in South Africa is the highest in the
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
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,
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
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.
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
Drug may induce the transcription of ALA synthetase
directly through mRNA or may interfere negative
feedback control which haem exerts on ALA synthetase
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
(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
Drugs contraindicated in porphyrias
Barbiturates (hepatic porphyrias only)
All oral contraceptives
Alcohol in any form
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.
Removal of any known triggering factors
Adequate hydration and carbohydrate loading are
Sedation using a phenothiazine
Opioid for pain
Nausea and vomiting are treated with conventional
β-Blockers can be administered to control tachycardia
Since traditional anticonvulsants are regarded as unsafe,
seizures may be treated with a benzodiazepine or
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
Somatostatin decreases the rate of formation of ALA
synthetase and, in combination with plasmapheresis,
may effectively decrease pain and induce remission.