Haemoglobinopathies thalassemia, prophyrias and sickle cell disease-
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Transcript of Haemoglobinopathies thalassemia, prophyrias and sickle cell disease-
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
Thank you