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Anaesthesia and Sickle Cell Disease


What is Sickle Cell Anaemia – US National Heart, Lung and Blood Institute.

 

Authors: Dr James Craig and Dr Martin Culwick, Department of Anaesthesia, Royal Brisbane and Women’s Hospital.

Summary

Whilst still relatively uncommon in Australiathe incidence of Sickle Cell Disease (SCD) is likely to increase as migrants from the Mediterranean , sub continental Asia and Africa become more numerous.

SCD provides a unique set of challenges for the anaesthetist and surgical team and this review will describe the pathophysiology and natural history of SCD, and then consider the current evidence for anaesthetic management of such cases.

A brief look at future therapies will be examined.

Introduction

Sickle Cell Disease is a congenital disorder of haemoglobin (Hb) synthesis in which there is a propensity for erythrocytes to sickle in the presence of deoxygenated haemoglobin. This is due to the relative insolubility of deoxygenated sickle haemoglobin (HbS).

The most common complications in SCD are acute pain episodes (vaso-occlusive crises) and the acute chest syndrome (ACS). Due to its affect on the vascular system SCD is a ubiquitous disease affecting most organs and causing a reduced life expectancy. It is inherited in an autosomal recessive manner, and a less severe sickle cell trait exists. SCD refers to all genotypes containing at least one sickle gene, in which HbS makes up at least half the haemoglobin present; therefore SCD is not limited to the homozygous HbSS (sickle cell anaemia.)

The perioperative period is recognised as a time of high risk for exacerbations of the disease and for this reason anaesthetists need to be familiar with the disease.

Prevalence

Sickle Cell disease is most common in sub-Saharan Africa (excluding South Africa ), the Middle East , and some areas of the Indian subcontinent (Indiaand Pakistan ). Population migration to North America , Brazil , the Caribbean , Central America and Southern Europe [1] has resulted in these areas having a variable frequency of SCD[2]. The survival advantage conferred by sickle cell trait against plasmodium falciprum malaria[3] explains the preponderance for the carrier state in these areas. It should be noted that inheritance of sickle cell anaemia (HbSS) confers no such advantage, and malaria is a major cause of morbidity and mortality in children with sickle cell anaemia in Africa .

It is believed there have been at least 5 separate spontaneous mutations of the allele in history four in Africa and one in Southeast Asia , areas recognized for a high prevalence of malaria.[4]

A recent study from Nigeria demonstrated the prevalence of sickle cell anaemia (genotype HbSS) as 1.5%, whereas the HbAS or sickle cell trait was 19.6%[5].

It has been estimated to be present in the heterozygous form in 8% of American blacks and in the homozygous form in 1:400-600[6]. There are about 60,000 people suffering SCD in the United States . About 10,000 people suffer the disease in the United Kingdom .[7] After the introduction of universal screening in the UK Streetly et al recently showed a much higher prevalence of the disease than previously described, the birth prevalence being 1:2000 which is more common than Cystic Fibrosis (1:2500). The carrier rate in newborn babies was shown to be almost 1%.[8]

Life expectancy for people with SCD is 25-30years lower than the population average[9].

A 2006 World Health Organization report described a prevalence of carriers for the genes responsible for haemoglobinopathies (which includes sickle cell disease and the thalassaemias) as 5% of the world’s population. Each year about 200,000 infants are born in Africa with sickle cell anaemia.[10] There is wide variation in the prevalence of sickle cell trait ranging from 10-40% across equatorial Africa , to between 1-2% across the north African coast, and less than 1% in South Africa .

Statistics for Australia are difficult to obtain specifically for sickle cell disease given that the classification from the Australian Institute of Health and Welfare (AIHW) refers to “other non-deficiency genetically inherited anaemias”. This classification includes:

  • Hb H (a form of alpha thalassemia) which usually results in moderate anaemia and
  • sickle cell diseases (Hb S homozygote’s, Hb SC , Hb SD , Hb S0 and Hb S-beta heterozygote’s).

The most recent data obtainable are from 1999 and the figures show an incidence of 328 cases for the year leading to an incidence per 100,000 population of 1.79 cases. Unfortunately prevalence data is not available.

Table 1 – Australia ’s estimated resident population, Selected countries of birth (1996-2009)Source: Summary Chart produced by James Craig and Martin Culwick, using data downloaded from Australian Bureau of Statistics – http://www.abs.gov.au/AUSSTATS/abs@.nsf/DetailsPage/3412.02008-09?OpenDocument

3412.0 – Migration, Australia – Estimated resident population, Selected countries of birth, age and sex—30 June 1996to 2009

Statistics are in Supertable format.

The importance for Australian clinicians is that immigration from areas with endemic SCD is increasing. The most useful data from the Australian Bureau of Statistics (ABS) gives figures for estimated resident population by country of birth and this is shown in Table 1. Although these figures do not directly measure immigration from the countries it does provide the number of people in Australia born in endemic areas.

As can be seen there has been a substantial increase in the number of people born in countries with a higher incidence of SCD.

Considering Nigeria alone, which seems to be recognized as the country with the highest prevalence of the disease it can be seen that the number of people born in Nigeria who are currently residing in Australia has increased from 1450 in 1996 to 4020 in 2009.

It will thus become increasingly more likely that individual Australian anaesthetists throughout their career will provide anaesthesia for patients with SCD and as such a working knowledge of the disease is required.

The haemoglobin molecule

Figure 1 – Schematic representation of the haemoglobin molecule

Source: http://themedicalbiochemistrypage.org/hemoglobin-myoglobin.html

Haemoglobin (Hb) is a tetramer consisting of two alpha(a) (141 amino acid) and two beta(b)(or non-a) (146 amino acid) protein chains, each enfolding a haem moiety. Haem contains a single iron atom in the Ferrous (Fe2+) state and is positioned to allow optimal reversible binding of oxygen.

Each haem can bind a single molecule of oxygen (O2) hence each molecule of haemoglobin can bind four molecules of O2.

The exterior surface of the tetramer is highly polar and water-soluble, while the interior haem pockets are non-polar and hydrophobic. This means that the haemoglobin molecule itself is highly soluble, but unpaired globin chains are insoluble and will precipitate in solution.

The most vital function of haemoglobin is oxygen transport, and this depends upon the tetrameric structure and the proper arrangement of the charged amino acids. Haemoglobin displays positive co-operativity, which refers to the increased affinity of the remaining haem subunits to O2 when O2 binds to one subunit. This allows for ease of binding in areas of high oxygenation and easy unloading in areas of lower O2 tension.

Normal adult haemoglobin is designated HbA and consists of two alpha and two beta chains (a2b2), Foetal haemoglobin is designated HbF, consisting of two alpha and two gamma chains (a2g2). The non-alpha chain may also be e (embryonic) or d (HbA2 – normal minor Hb). The usual concentrations in an adult are: HbA – 95%, HbA2 – 2.5%, HbF – 2.5%.[11] Beta chain production commences after birth and gamma chain production ceases, resulting in adult haemoglobin concentrations achieved by 4 months.

Haemoglobin in Sickle Cell Disease

Herrick first described sickle cell disease in 1910[12]. It is a structural haemoglobinopathy resulting from the substitution of valine for glutamic acid at the 6th amino acid of the b-globin gene (HbS – a2b26GluàVal) on chromosome 11.

This single amino acid substitution causes three interrelated effects on haemoglobin function, these are[13]:

  1. The HbS molecule is unstable and degrades more rapidly – the average lifespan of an HbS RBC is 12 days compared with 120 days for an HbA RBC .
  2. The deoxygenated form is insoluble and precipitates out of solution
  3. As a consequence the expression of HbF is upregulated.

HbS polymerises when deoxygenated to form a gelatinous network of polymers, which stiffen the RBC membrane giving the “sickled” appearance on microscopy. These RBC are not as pliable for transport through the microcirculation. The also have a “sticky” membrane which adhere to small vessels. This “stickiness” occurs because the intracellular polymers cause extracellular exposure of “sticky” proteins and glycolipids that are normally found inside the cell.13 There is also abherrent expression of adhesion molecules on reticulocytes.[14]

The determinants of sickling include;

  • intracellular HbS concentration,
  • degree of deoxygenation,
  • pH, and
  • intracellular HbF concentration (HbF inhibits HbS polmerization by stabilizing the HbS polymers)[15].

The instability of HbS causes chronic haemolytic anaemia and results in release of free iron and haemoglobin into the circulation which in turn consumes nitric oxide (NO) and exposes the vascular endothelium to oxidant damage.[16] Hence people with SCD may be in a chronic state of NO deficiency leading to a chronic inflammatory vasculopathy.

This leads to unpredictable episodes of microvascular occlusion and subsequent infarction of affected organs. Clinically these episodes present as tissue ischaemia, acute pain, priapism, ankle ulcers, gallstones, and end-organ damage.[17] The organs at most risk include the spleen, CNS , bones, liver, kidneys, and lungs.

Due to the recessive nature of the gene a carrier state exists causing a milder form of the disease (HbAS) – sickle cell trait. Usually these carriers produce about 30-40% HbS and the remainder as HbA, and clinically tend to sickle only under extreme physiological insult.

Inheritance of two mutant genes leads to the homozygous sickle cell anaemia (HbSS). SCD also includes a number of other genotypes involving HbS these can be seen in Table 2. There is significant heterogeneity in the clinical manifestations of SCD.

Genotype Clinical Course
HbSS Severe/Moderately severe disease
HbS/b0 thalassaemia Severe/Moderately severe disease
HbSC Intermediate severity
HbS/b+ thalassaemia Variable, mild-moderate severity
HbS/ hereditary persistence of foetal Hb (HbS/HPHP) Very mild/asymptomatic
HbS/HbE Rare and very mild severity

Table 2 – Genotypes in Sickle Cell Disease and associated disease severity.

Source: Stuart MJ & Nagel RL. Sickle Cell Disease. The Lancet 2004; 364: Panel 1 Page 1344.

Note: b0- thalassemia – occurs in b thalassemia trait where there is complete absence of production of the defective b-globin protein, and hence worse disease when combined with the defective HbS protein.

b+-thalassemia – occurs in b-thalassemia trait resulting in reduced (but not absent) production of the b-globin protein.

Natural history of SCD

SCD is characterised by a reduced life-span, chronic haemolytic anaemia, extensive vascular damage and progressive end-organ damage. Acute exacerbations occur and the most common forms of these are pain crises and acute chest syndrome.[18] The most common causes of morbidity and mortality in SCD are neurologic and pulmonary disease.

A substantial prospective cohort study following over 4000 patients with SCD was commenced in the United States in 1979. It was referred to as the Cooperative Study of Sickle Cell Disease (CSSCD). Information obtained from this study has been heavily published[19] and has allowed for a more detailed understanding of the natural history and treatments for the disease. A good summary of the natural history of SCD can be found in Bonds’ Review article published in 2005[20]. Some key points from the article include:

Painful Crises[21]

Defined as an acute episode of pain not attributable to any pathology apart from SCD.[22] These crises are a principal symptom of SCD, the CSSCD determined the frequency of painful crises was 0.8 episodes per patient year for HbSS, 1.0 for sickle b0-thallasaemia and 0.4 in HbSC and sickle b+ thallasemia. Patients with high pain rates tended to die earlier, had a higher hematocrit level and lower HbF level.

  • Bone pain is usually due to marrow infarction, and commonly presents in the lumbar spine, femoral shaft or knee.[23]
  • Abdominal pain may be due to gastrointestinal dysfunction, Spleen or Liver infarction or be referred from the ribs.[24]

Laboratory values[25]

Packed cell volume lower for males than females until 17-18years of age in HbSS, and then becomes consistently higher for males. Leucocyte count higher in HbSS than in normal individuals (making infective diagnoses more difficult). Platelet counts are above normal and show a gradual decline with age. Creatinine rises progressively with age, indicating declining renal function associated with end-organ damage.

Major organ dysfunction

 

Spleen

Multiple infarctions lead to functional asplenia in 94% of patients with SCD by the age of five years.[26] Dysfunction occurred within the first 6-12 months in HbSS and HbS/b0 Thalassemia, less frequently and later in HbS/b+ Thallasemia and HbSC resulted in intermediate dysfunction.

This causes susceptibility to encapsulated bacterial infections and sepsis which are the leading causes of death in young patients with SCD.[27] Splenic sequestration and splenic pooling can be a major cause of morbidity and mortality in children with SCD. Splenectomy is commonly performed in these patients.[28]

Leg Ulcers

Incidence higher among males than females and a sharp rise after the second decade of life. 3.1 per 100 person years at age 10-19 jumping to 14.6 per 100 person years after this age. If the HbF concentration >5% the incidence is reduced.

Osteonecrosis of bones[29]

Bone infarction causes painful crises, growth disturbance and susceptibility to osteomyelitis. The CSSCD examined patients over 5 years of age. At study entry 9.8% were found to have osteonecrosis of one or both femoral heads. HbSS and a-thallasemia phenotype were at greatest risk. Risk factors include; frequent painful crises, high hematocrit, lower MCV, lower AST. Results of hip arthroplasty are poor à 5 of 27 patients requiring re-operation within 11-53 months. Osteonecrosis also occurs in the humeral head (see Figure 3)à present in 5.6% at study entry.

Brain

Patients with SCD have a high incidence of stroke. 11% of patients with SCD will go on to develop a clinically apparent stroke by 20yo, and 24% by age of 45 years.[30] Several studies have been conducted. Conclusions included:

  • neurological development relatively normal until about 3yo when potential ischaemic insults may occur. [31]
  • Silent infarcts present in 17% HbSS children between the ages of 6 and 14 years[32],
  • Risk factors for silent infarcts include[33]: – history of seizures, low painful event rate, low Hb concentration, higher WBC count.
  • Risk factors for stroke[34] –prior TIA, low Hb concentration, recent acute chest syndrome, hypertension.
  • 4% of people with HbSS had a history of a stroke

Lung

 

  • Acute Chest Syndrome (ACS) à The ACS is pneumonia like illness (new symptoms – fever >38.5°C, cough, sputum, dyspnoea, hypoxia), with new pulmonary infiltrates on CXR .[35] It is typically detected 2-3 days post-operatively. Occurred at least once in 1085 of 3751 patients.
    • Incidence highest in younger children 2-4yo (25.3 per 100 patient years) and lowest in adults (8.8 per 100 patient years)
    • Higher rates of ACS à higher all cause mortality.
    • Risk factors – high [Hb], low [HbF], high leucocyte count.
    • Presentation – Children 2-4 years old à fever, cough, negative physical examination, adults à afebrile, SOB, chills and pain.
    • Death rate – children 1.1%, adults 4.3%.
    • Causes of ACS :
      • children – milder disease and usually infective cause,
      • adults – severe disease and commonly pulmonary thrombotic events leading to hypoxia, prolonged hospitalization and a higher death rate.

Figure 2 – Acute Chest Syndrome. Frontal chest radiograph demonstrates bilateral diffuse airspace disease (blue circle) in a patient with sickle cell disease, fever and hypoxemia. There is avascular necrosis of the left humeral head (red arrow) and replacement of the right humeral head (white arrow) because it was affected by avascular necrosis as well.Source: http://www.learningradiology.com/archives2008/COW%20296-Acute%20Chest%20Syndrome/acutechestsynccorrect.html

Reproduced with permission

Heart

Echocardiograms were conducted on 191 HbSS patients.[36] Chamber dimensions were inversely related to Hb concentration à this was significantly dependent upon age. Stable patients have dilated chambers, septal hypertrophy, and normal contractility. The cardiomegaly is usually due to chronic anaemia.

Pulmonary hypertension is often present and likely due to recurrent pulmonary infarctions.

Kidneys

The environment of the inner renal medulla is hypoxic, acidotic, and hyperosmolar, all of which promote sickling. Sickle cell nephropathy is due to reduced medullary blood flow and microinfarctions/papillary necrosis. This leads to the inability to concentrate urine, renal tubular acidosis and impaired potassium secretion. Proteinuria, nephrotic syndrome and progressive chronic renal failure have all been reported.[37]

Alloimmunzation

Refers to the development of antibodies to non-ABO blood groups.[38] SCD patients were shown to have a rate of alloimmunisation after transfusion of 18.6%[39], this increased exponentially with the number of transfusions.

  • This rate can be reduced by extended phenotypic matching, and this should be a standard for transfusions in SCD patients
  • Avoidance of unnecessary transfusions is the optimal way to minimise the risk.

Mortality in SCD

30 years ago childhood mortality from SCD was high and survival into adulthood uncommon. In 1974 Diggs estimated a median survival of 14.3 years with 1 in five patients dying within the first two years of life.[40]

In 1994 the figures had improved significantly, the CSSCD showed that in patients who were 20 years or older with sickle cell anaemia the mean age of death was 42 years for males and 48 years for females.[41] This still equates to a 25-30 year loss of life expectancy.

The circumstances of death involved chronic organ failure (renal failure, congestive heart failure or debilitating CVA) in relatively few patients – 38 out of 209 patients. Whilst a relatively sudden death with no evidence of chronic organ failure was more common (134 patients) and usually associated with a sickle cell crisis. 45 patients died during an acute pain crisis, 20 of whom had a simultaneous ACS while 9 patients suffered the ACS only. Acute stroke occurred in 15 patients, and 13 patients died of infection, that unlike in children was due to a varied array of pathogens. Of interest to anaesthetists there were 14 perioperative deaths.

Risk factors for early deaths were identified as:

  • More symptomatic disease, in particular pain episodes, the ACS , acute anaemia, seizures and renal failure.
  • HbF level – the lower the level the higher the risk of early death
  • White cell count – > 15,000/ml3
  • Haemoglobin <7.1g/dL

In SCD patients <20 years of age.

Children and SCD

The CSSCD[42] has shown the following issues in children with SCD:

  • Lower birth weight, and ongoing lower weight
  • Delayed sexual maturation
  • Peak incidence of death between 1-3 years of age, mostly due to infection ( mostly Streptococcus pneumoniae sepsis), risk factors include lower [Hb], higher WBC counts (>15,000), and lower HbF levels.
  • Over 10 years of age – CVA and trauma were leading causes of death.

Prevention of SCD[43]

Due to the presence of reliable and inexpensive tests for identification of at-risk couples, and chorionic villous sampling which can occur from the 9th week of gestation, SCD can be prevented. Genetic counselling and the offer of prenatal diagnosis can lead to large-scale reductions in birth of affected children. In order to identify at-risk individuals a carrier screening program is required, these programs are active in multiple countries for thalassemia prevention.

It is essential for these programs to adhere to the principles of medical genetics namely, autonomy of the couple, their right to complete information, and confidentiality.

Neonatal diagnosis also allows for provision of protective measures; education for the parents, penicillin, transfusion therapy and anti-malarial prophylaxis all leading to a better quality of life for the affected child.[44]

Current therapies in SCD

 

Therapies aimed at prevention of sickling

As mentioned earlier sickling (polymerization of HbS molecules) is more likely with:

  • a high intracellular HbS concentration,
  • a high degree of deoxygenated Hb,
  • a low pH, and
  • a low intracellular HbF concentration.

As such therapies are aimed at addressing these issues.

Chemical Inhibition of HbS polymerization

At present no drug has been found that provides a useful therapeutic effect without significant toxicity. Tested compounds include: potassium cyanate and diaspirins.[45]

Reduction in intracellular Hb concentration

Reducing [Hb] reduces the rate of HbS polymerization. The simplest way to achieve this is by inducing hyponatraemia and hence causing osmotic swelling of the RBC ’s. While this is effective it is very labour/cost intensive and hence too cumbersome and risky for long-term outpatient use.

Clotrimazole – (an antifungal agent) acts via inhibtion of the Gardos channel which is a calcium activated potassium channel, and as such prevents the efflux of potassium and concomitant cellular dehydration. This in turn reduces the intracellular HbS concentration and reduces sickling complications[46]. Unfortunately the side effects which include GIT, urinary, and cutaneous manifestations secondary to activation of the cytochrome P450 enzymes have prevented widespread use.

HbF induction

It has been shown that people with a higher HbF concentration in SCD are more likely to have milder clinical manifestations. The CSSCD showed an inverse correlation with painful crises and HbF concentration[47]. As such any drugs that increase the production of HbF can be expected to benefit patients in SCD.

Hydroxyurea(HU) is the most commonly used drug for this purpose in SCD.

HU is an antimetabolite that prevents DNA replication via inhibition of the enzyme ribonucleotide diphosphate reductase. The molecular mechanism causing hydroxyurea to stimulate HbF production is not known.

Upon treatment with hydroxyurea SCD patients were found to have higher haemoglobin levels, mean corpuscular volumes, and HbF levels. They had a reduced white cell, platelet, and reticulocye count.33

Side effects of hydroxyurea are minimal but can include reversible myelosuppression. The use of HU had been shown to reduce haemolysis and cause a slight increase in Hb concentration. Studies involving the use of HU in SCD have shown HU to be[48],[49]:

  • a relatively non-toxic drug,
  • useful in reducing frequency and severity of painful crises,
  • useful in reducing the incidence of ACS and need for transfusions.

A study was also conducted to ensure the safety of HU in paediatric populations. This HUG -KIDS[50] study showed that HU was safe in children aged between 5-15 years when directed by a paediatric hematologist.

Therapies aimed at minimization of complications

 

Penicillin

Two Randomized Controlled Trials have occurred regarding penicillin use in SCD.

The first (PROPS I)[51] was to determine the efficacy of daily oral penicillin use in infants (under 3 years old) with SCD in preventing severe infection due to Streptococcus pneumoniae, and a secondary endpoint as the prevention of H influenzae infection or any other bacterial organism. This was terminated 8 months early due to an 84% reduction in the incidence of infection being observed in the penicillin group. The recommendation was that after positive screening all infants with SCD should be placed on penicillin by 3 months of age.

The second (PROPS II)[52] was to determine the age at which penicillin treatment could be safely ceased in children with SCD. It was found that no additional benefit was obtained with continuation of penicillin beyond five years of age.

Pneumococcal immunisation is also recommended in SCD due to the risk of poor adherence to daily prophylaxis and the development of penicillin resistant Streptococcus pneumoniae strains.[53]

Stroke prevention

Transfusion therapy

Children with SCD and history of stroke were found to have a very high incidence of recurrence within 3 years.[54] Chronic transfusion therapy has been found to reduce this risk from 46-90% to less than 10%.[55] The goal of transfusion was to achieve a total sickle cell haemoglobin value less than 30%. Conclusive data does not exist on when transfusion therapy should be ceased but a suggested guideline[56] is to continue for at least 5 years after a stroke or until the age of 18 years.

The Stroke prevention trial in sickle cell anemia (STOP 1)[57] tested whether long-term use of transfusion therapy could reduce the risk of first stroke in children identified as high risk based on transcranial Doppler (TCD) ultrasonography. The trial was terminated early due to the significant improvement seen in the transfusion group (11 events in the untreated group versus 1 event in the treated group). As a result it is recommended that TCD screening occur in children with SCD annually between the ages of 2-16 years.[58]

Iron overload is a risk with long-term transfusion therapy and iron chelation treatment is required.

Other treatments:

Tissue plasminogen activator is appropriate to use in ischaemic stroke patients with SCD provided no other contraindications exist.

Hydration, normothermia, and euglycaemia are all important, as is the avoidance of hypotension in acute stroke.

The use of oral anticoagulants and antiplatelet agents are unproven however given the general benefit it is reasonable for their use in SCD when no other specific stroke prevention strategy is available.[59]

Folate supplementation

Folate is given in order to allow for an increased production of RBC ’s secondary to the chronic haemolytic anaemia

Curative therapy

 

Bone Marrow Transplantation(BMT)

At present BMT is the only curative therapy available for SCD. Indications for BMT in SCD have been empirically determined from studies of the natural history of SCD.[60] These include factors like:

  • Stroke, Central Nervous System(CNS) haemorrhage or neurological event lasting > 24hours
  • ACS with a history of recurrent hospitalisations
  • Recurrent vaso-occlusive pain (3 or more episodes per year for 3 or more years)

Currently recommendations consider BMT for patients who are 16 years of age or younger with an HLA-identical sibling. Unfortunately this limits this therapy to less than 15% of sufferers.[61] Unrelated-donor BMT is considered unacceptable due to the high regimen related toxicity, this includes a mortality of 30% and a high incidence of chronic Graft versus Host Disease (27%)[62].

The outcomes of BMT in patients with matched siblings are excellent with an overall survival of 93-97% and an event free survival of 85%.[63]

Stabilization or reversal of organ damage after successful BMT has been documented.[64] If stable engraftment occurs SCD related complications resolve and there are no further episodes of pain, stroke or ACS .

Anaesthetic management of SCD

SCD patients are more likely than the general population to undergo operative procedures, and usually do so at a younger age.[65] The perioperative period is recognised as a high-risk time for SCD patients. The CSSCD found that the overall mortality within 30 days of surgery was 1.1%.[66]

Traditionally anaesthetic management of SCD has involved:

  • pre-emptive RBC transfusion,
  • aggressive hydration, and
  • avoidance of:
    • hypoxia,
    • hypothermia and
    • acidosis.

Complications after surgery depend on the type of procedure, patient age, disease severity, and pre-existing organ dysfunction.

Acute sickle exacerbations were noted to occur in 0% of tonsillectomies, 2.9% of hip surgery, 3.9% of myringotomies,, 7.8% intra-abdominal (non-obstetric) surgery, 16.9% of caesarian sections, and 18.6% of dilatation and curettage.[67]

Anaesthetic issues during the perioperative period

 

Pre-anaesthetic assessment

Thorough pre-operative assessment, ideally week’s prior to the operation to allow for any therapeutic interventions that may be required.

History and examination should consider frequency, pattern, and severity of recent exacerbations, and the presence and extent of end organ damage.[68]

The most commonly affected organs are the lungs, kidney and brain.

Investigations that are likely to be useful include a full blood count and chest x-ray. Depending on the patient it may be beneficial to consider respiratory function tests, an electrocardiogram, and an arterial blood gas. For all but the most minor of cases a group and hold should be taken.

Perioperative hydration

Hydration is regarded as an important issue in SCD due to polymerization being closely related to intracellular [HbS][69]. Given most SCD patients have stable Hb levels between 5-10g/dL the blood viscosity is usually less than or similar to normal HbA blood, (despite HbS haemoglobin having a higher viscosity than HbA haemoglobin). To induce haemoconcentration that would cause sickling of erythrocytes would require profound dehydration not commonly seen in surgical patients. Nevertheless appropriate education of the patient regarding fasting periods and allowing clear fluids up to 2 hours before the operation is useful.

Given the lack of evidence implicating dehydration as a cause of sickling in SCD, and the associated risk of complications with invasive pressure monitoring, the best pre-operative hydration therapy should be based more on the surgical procedure and degree of renal dysfunction rather than the presence of SCD. It is unlikely pre-operative admission for hydration and invasive monitoring provides any benefit.

Nevertheless it may be prudent to minimise fasting times by placing the patient first on the list and by placing IV access and commencing fluids on arrival. Hypertonic fluids should be avoided due to the risk of additional dehydration of the sickle cells. Isotonic crystalloids are the fluid of choice.[70]

Transfusions

Studies have been conducted showing the benefit of transfusions for patients with SCD. The benefit derives from allowing correction of the low oxygen carrying capacity due to anaemia, and also by reducing the proportion of sickle RBC ’s in the circulation.

Although blood transfusion itself is associated with risks (alloimmunization, infection, iron overload, lung injury), these risks can now be minimised by use of more sensitive infectious screening, use of iron chelators and of phenotypically matched blood.

Transfusions in SCD patients should be individualized taking into account baseline hematocrit, end-organ dysfunction, and intra-operative blood loss. Both autologous transfusions and cell-salvage has been reported.[71]

The use of transfusions as a preventative measure in order to dilute the HbS concentration is controversial. One study[72] showed the use of an aggressive transfusion strategy (to reduce the HbS concentration to below 30%) when compared with a conservative strategy (to achieve a total Hb concentration of > 10g/dL) provided no additional benefit. However it was noted that less transfusion associated complications occurred in the conservative group.

If blood is to be given to a SCD patient thorough cross-matching for minor blood groups should be performed to minimise alloimmunisation risks.[73]

It is therefore reasonable to transfuse patients perioperatively to a Hb concentration of > 10g/dL, when taken in the context of the surgery to be performed and individual patient condition.

Intraoperatively

The anaesthetic goal intraoperatively is to provide conditions, which prevent any of the precipitants to sickling.

Oxygenation

Despite the traditional view that hypoxia leads to an increased rate of sickling and sickle related complications, the evidence supporting this is poor.

As with any anaesthetic hypoxia should be avoided. The use of hyperoxia or supplemental oxygen in SCD patients to maintain oxygen saturation above the patients baseline level have no direct evidence of benefit.

Due to a higher concentration of methaemoglobin in SCD patients, pulse oximetry will tend to underestimate the true haemoglobin saturation by about 2%.[74]

Interestingly a study has been conducted[75] which exposed SCD patients to acute severe hypoxia (to PaO2 of 33.1 +/- 6.9mmHg) and did not induce any acute complications. Tourniquet use has also been described without initiation of sickle complications.

Temperature management

It has been suggested hypothermia is a trigger for perioperative sickling based on non-hospital settings[76]. Unfortunately there is an absence of studies able to demonstrate a direct link between hypothermia and sickle cell disease complications.[77]

The apparent cause for sickling associated with SCD is due to hypothermia induced vasoconstriction. Which would lead one to believe that vasodilation associated with general anaesthesia would in fact be protective.

Surgical procedures requiring hypothermia like cardiac and neurosurgical cases have been conducted in SCD patients without complication.[78]

Standard care in anaesthesia includes the maintenance of normothermia, this should also be the case in SCD.

Tourniquets

The use of tourniquets in SCD is controversial. Benefits to using tourniquets include; reduced blood loss and transfusion requirements, improved surgical visualization, and a more rapid operating time.

However tourniquets also cause haemostasis, acidosis, and hypoxia in the distal tissues all of which are recognised triggers for sickling.[79]

One study has shown an increase in complications when tourniquets have been used.[80] While a more recent study concluded that even though evidence is limited, with appropriate peri-operative management, and necessary precautions tourniquets can be used with relative safety in most patients with SCD.[81]

The precautions recommended by this study were; adequate preoperative hydration, use of Esmarch for exsanguination (over elevation), oxygenation, and keeping the pH balance above 7.0. Provided appropriate care is taken there is no reason tourniquets cannot be used in SCD.

Analgesia

Management of pain crises in SCD patients involves an initial assessment of pain usually with an analogue scoring system. Treatment with oral analgesics may be sufficient in a mild episode. Intravenous opioids are usually required and a patient controlled analgesic technique is often the most effective delivery method. A background infusion may be required. [82]

It is important to recognise that SCD patients may have had recurrent episodes of painful crises and have developed a tolerance to opioids[83], and an adjustment to dosing may be required.

The use of a multimodal approach is appropriate. Paracetamol and Non-steroidal anti-inflammatory drugs (NSAIDS) are useful adjuncts, however caution should be exercised with NSAIDs due to potential renal compromise and in the COX -2 selective agents potential for coagulation.

High dose methylprednisolone has been shown to reduce opioid requirements, likely due to reducing the marrow swelling and pressure on the cortex. Unfortunately a high relapse rate exists on withdrawal of the steroid.[84]

Regional anaesthesia is highly effective in the treatment of pain crises and should be used when appropriate.[85]

Aggressive hydration and oxygen therapy are often prescribed but there is an absence of evidence for their use. Transfusions are not indicated unless complications are present.

Regional Anaesthesia

Neuraxial anaesthesia has been heavily utilised in SCD, commonly in pregnancy[86] and as treatment for acute pain episodes.[87]

An initial study conducted by the CSSCD showed a higher incidence of postoperative complications associated with regional anaesthesia compared with general anaesthesia (23.8% versus 6.6%).[88] This study was not controlled for obstetric procedures and probably just indicated the known higher complication rate associated with obstetric intervention.

Subsequently it has been shown that quite the opposite may be the case in obstetric patients.[89] Camous et al showed the use of regional anaesthesia reduced the incidence of postnatal sickling complications.

Arguments for the use of regional anaethesia include; inducing vasodilation and enhancing blood flow while providing optimal pain relief.

Acute Chest Syndrome

A study has shown that symptoms of the ACS typically present about 3 days after surgery, and last for 8 days.[90] Treatments include incentive spirometry, bronchodilators, supplemental oxygen, analgesia, and broad spectrum antibiotics.[91] Transfusion has been shown to improve oxygenation in ACS . In its most severe form patients may require mechanical ventilation.

Sickle cell disease in pregnancy

Pregnancy is recognised as a high-risk period for morbidity and mortality in women with SCD[92]. Although non-sickle related complications were similar to non-SCD women the CSSCD showed the rate of sickle related complications to be high. Camous et al showed that 25% of parturients suffered sickling complications after delivery; other studies have showed sickling complications in 7.7%[93] and 17%[94] (CSSCD). Despite this higher risk the vast majority of pregnant women with SCD will go on to have a favourable outcome.

Rates of LSCS in SCD are higher than the general population however studies show a wide variation in rates from 15 to 59%.

Studies have demonstrated that countries with modern obstetric care and medical management of SCD have improved pregnancy outcomes. In particular the USA [95], and UK [96] versus Nigeria [97].

A more recent study considered morbidity associated with pregnancy in women who were homozygous HbSS[98], the results can be seen in Table 1.

Of note there was a significantly higher rate of ante-natal anaemia, chest infections, IUGR, and PIH, and severe pre-eclampsia. The rate of eclampsia was not significantly different. The rate of sickle cell crisis was even higher than previous studies with 44% of patients suffering a crisis, most of these were painful crises.

Another study showed that SCD parturients were also more likely to suffer abruption, antepartum haemorrhage, and deep vein thromboses.[99]

It was also shown that women with SCD had an increased risk of preterm delivery[100]. The higher rates of Small for Gestational Age and IUGR in SCD may be due to the compromised utero-placental bloodflow in SCD[101]

Identified risk factors for post-natal sickling complications include: The use of general anaesthesia (versus regional – OR 16.0; 95% CI 1.6-165.6) in LSCS, and a leucocyte count >15 x 109/L (OR 8.4; 95%CI 1.6-44.5). Importantly regional anaesthesia and the use of ephedrine were not found to contribute to complications.

Anaesthetic management of SCD parturients is equivocal. One study suggesting that regional versus general anaesthesia depends on the patient’s general condition and anaesthetic preference, rather than any specific indication.[102] Given the evidence that regional anaesthesia may be preferable to general a reasonable approach to SCD parturients may to insert an epidural early in an attempt to avoid exposure to general anaesthesia in this higher risk population.

As with all SCD patients during anaesthetic care parturients need to be closely monitored to avoid hypothermia, hypoxaemia, acidosis, and hypotension.

Vasopressors in SCD are controversial; they may cause vasoconstriction and stasis and hence increase sickling risks.[103] They may also activate red cell adhesion which has been postulated as a trigger for vaso-occlusive crises.[104]

Nevertheless the use of ephedrine was not found to increase the risk of postnatal sickling complications[105], and a suitable approach would be to avoid if possible but use judiciously when needed.

Table 3 – Pregnancy outcomes in SCD – See text for sources

Maternal SCD Control Maternal SCD Control
Anaemia 84% 12.8% Intrauterine Growth Retardation 20.8% 4.6%
Sickle Cell Crises 44% N/A Stillbirths 4.9% 0.8%
Urinary Tract Infection 17% 6.8% Perinatal Mortality Rate 78/1000 deliveries 18.1/1000 deliveries
Chest Infection 11% 0.6% Birth Weight <2500g 16.5% 8.3%
Pregnancy Induced Hypertension 10% 4.0% Preterm births 12.6% 5.2%
Severe pre-eclampsia 8% 3.6%
Eclampsia 2.4% 0.6%
LSCS wound infection 8.2% 2.4%

Future Treatment for SCD

There exists a significant amount of potential improvement to SCD therapy in the future, some of the more promising therapies include:

Butyrate – This is a short chain fatty acid that was found to prevent the switch from ϒ-globin to b-globin production, resulting in increased HbF levels. This is achieved by improving the efficiency of ϒ-globin mRNA.[106] Trials have shown that with IV therapy a mean increase in HbF of 7-21% was achieved.[107] Attempts to achieve a similar response from oral sodium phenylbutyrate required the consumption of 30-40 capsules/day which was regarded as prohibitive.[108]

Gene therapy – Has the potential to be a curative therapy in SCD. A successful study[109] involved the transplantation of b globin gene variant (via a lentivirus vector) that resembled HbF into a sickle transgenic mouse. Long term expression occurred and eryhtroid specific accumulation of this anti-sickling protein was achieved. This resulted in inhibition of RBC dehydration and sickling with correction to anaemia and splenomegaly. At present there are concerns over the safety of gene therapy[110], but the potential for this therapy is enormous.

Phytomedicines – These are plant-derived medicines, Niprisan was developed in Nigeria and despite having an unknown active ingredient in vitro studies have shown inhibition of cell sickling.

Studies have been conducted in transgenic mice, which showed that in the presence of hypoxia, there was a dose-dependent reduction in sickled erythrocytes and a prolonged survival.[111] Human studies at this stage have shown a reduction in the frequency of severe pain crises, with the only side effect noted as headache.[112]

Cord-blood transplantation[113] – The advantages of umbilical cord blood transplantation over BMT include[114]:

  • Ease and safety of collection
  • Low risk of viral contamination of the graft
  • Prompt availability when an unrelated donor is employed
  • Reduced incidence and severity of graft versus host disease

The Eurocord cooperative group recently analysed transplants with UCB cells from a related sibling and found that out of 11 paitents with SCD only one did not have sustained engraftment, the event free survival rate was 90%.[115]

Steroids – Given the chronic inflammatory state present in SCD it is reasonable to expect steroids to be of benefit. Dexamethasone has been given to paediatric patient suffering ACS and was found to reduce the length of hospitalization, reduce analgesic requirements, and reduce oxygen requirements.[116] But there was a high rate of readmission when steroids were ceased, presumably due to a rebound effect. A study to see whether a tapering dose of dexamethasone reduces readmission rates was unfortunately ceased due to low enrolment.[117]Further studies would be useful.

Nitric Oxide – NO is continuously produced in the endothelium and induces relaxation of smooth muscle and vasodilation. In SCD there is a chronic state of NO deficiency.[118] This is due to the rapid scavenging by free haemoglobin[119], and free oxygen radicals.[120], and the low concentrations of the substrate, L-arginine[121]. The lung is most at risk of reduced NO concentration, and it causes pulmonary hypertension and a predisposition to the ACS .[122] It also may be responsible for vaso-occlusion due to dysregulation of vasomotor tone. [123]

NO has been studied in transgenic mice[124] and has shown benefit in the ACS . It was also used in children with vaso-occlusion and resulted in a trend toward lower opioid requirements and lower pain scores.[125]

The delivery of inhaled NO is cumbersome, however oral L-arginine seems to increase NO levels and improve endothelial function.[126]

Summary

Providing anaesthesia to patients suffering SCD is a unique challenge. As migration to Australia from countries with a higher prevalence of the disease continues it is more likely such patients will present for operative procedures. The peri-operative period is recognised as a high-risk time for such patients, and it is important to be able to understand, recognise and treat morbidity associated with the disease.

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