Anaesthetic management of children with sickle cell disease

Key points.

• •Sickle cell disease is an inherited disorder, with multisystem complications resulting from vaso-occlusion and chronic haemolysis.
• •Long-term management involves education; early vaccination and prophylaxis with penicillin; and prevention of end-organ damage.
• •Common life-threatening complications include infections, acute chest syndrome, splenic sequestration, and stroke.
• •Perioperative management involves careful planning and optimisation to ensure adequate oxygenation, hydration, tissue perfusion, and pain control.
• •Prompt pain assessment and multimodal analgesia are essential in treating acute painful events.

Learning objectives.

By reading this article, you should be able to:

• •Describe the pathogenesis of sickle cell disease (SCD).
• •Recognise the acute complications that occur in children with SCD.
• •Illustrate the key issues in the perioperative management of a child with SCD.
• •Explain the available strategies and rationale behind multimodal analgesia for children with SCD presenting with acute pain.

Sickle cell disease (SCD) is an inherited disorder with multisystem complications, often presenting in childhood.¹ Anaesthetists are frequently involved throughout perioperative care, in the management of acute pain and acute complications.

SCD results from inheriting genes coding for an abnormal β-globin chain from both parents, where at least one is the sickle cell gene. Sickle cell anaemia (SCA), the most severe and common form of SCD, results from inheriting sickle β-globin genes from both parents, leading to a homozygous HbSS state.2, 3 Other disease forms include heterozygous states involving other abnormal β-globin alleles such as β-thalassaemia (HbSß), C (HbSC), and D-punjabi (HbSD). Inheriting one sickle cell and one normal haemoglobin gene leads to sickle cell trait (SCT), which usually has no clinical consequences.

SCD is a significant global public health issue. The WHO reports that the sickle cell gene is responsible for more than 80% of all inherited haemoglobinopathies, with 85% of SCD cases in Africa.⁴ SCD also occurs in the Mediterranean, Arabia, South Asia, and elsewhere mainly as a result of migration.3, 4 The distribution of SCD closely matches the distribution of malaria, because the heterozygous states are protective against Plasmodium falciparum infection.⁴ However, those with SCA are more susceptible, and more likely to develop life-threatening malaria.

There is a disparity between the availability of healthcare resources for the treatment of SCD relative to its geographical distribution. Resources are most limited in many African countries, where prevalence is highest, and consequently mortality here is also highest.⁵ Children aged under 5 yr are particularly at risk of death.⁵ In more developed healthcare systems such as Europe and North America, the prevalence is lower, survival rates higher, and child mortality rare. This is mostly attributable to the success of neonatal screening, immunisation, and penicillin prophylaxis.³

Pathogenesis

In adult life, HbA (containing two α and two β polypeptide chains) is the predominant haemoglobin type.⁴ In sickle cell disorders, chromosome 11, which codes for the β chain, has a valine substituted for glutamic acid at codon 6; this results in a hydrophobic β chain that tends to polymerise at lower oxygen tensions.³ Polymers bundle together to create the red cell ‘crescent-shape’ causing microcirculatory occlusion.³ At birth, fetal haemoglobin (HbF) predominates containing γ rather than β chains.⁴ Therefore, haemoglobin is essentially normal and clinical features rare until the child begins to produce HbA at 4–6 months of age.

Despite each inherited sickle cell gene having the same codon defect, there can be considerable difference in clinical severity. This suggests that although genotypes are the same, individual phenotypes are determined by other modifiers, and red blood cell sickling may not be the only pathology. There is evidence that the endothelium is abnormally hyperactive leading to increased cellular adhesion, involving both leukocytes and platelets.6, 7 Platelets are thought to contribute significantly, through increased production of inflammatory cytokines and expression of cell-surface adhesion molecules.⁷ Abnormal vasomotor tone resulting in relative vasoconstriction has also been suggested, increasing the risk of microcirculatory occlusion as well as pulmonary hypertension. This may result from chronic release of free haemoglobin which scavenges nitric oxide.⁶ Nitric oxide deficiency may also contribute to increased endothelial dysfunction and the risk of thrombosis.⁶

Diagnosis

Since 2006, children in the UK have been diagnosed through universal newborn blood spot screening.8, 9, 10 Antenatal screening is also offered to all pregnant women.⁹ Newborn screening reports cases of SCD and carriers.⁸ The newborn blood spot is analysed using high-performance liquid chromatography, isoelectric focusing, capillary electrophoresis, or tandem mass spectrometry.¹⁰ After a positive result, the test is repeated using another of these techniques to confirm the diagnosis. A recent evaluation of newborn sickle cell screening has reported an estimated birth prevalence of SCD in England of 1 in 2,564.¹⁰ Other countries have instituted partial screening, including Canada, the USA, France, Ghana, and Uganda, but are not yet at the stage of universal testing. However, most children living with SCD are in countries without screening and so late diagnosis contributes to early mortality in these areas.

In regions with neonatal screening, routine screening of all children presenting for surgery who are at risk because of their ethnicity is no longer recommended; duplicate testing has a very low yield of new positive diagnoses and may require unnecessary venepuncture.¹¹ Epidemiological studies have confirmed that the routine preoperative testing of children who underwent screening at birth is ineffective.¹²

In SCA, full blood count shows low haemoglobin concentrations secondary to chronic haemolysis; high mean cell volume and red cell distribution width reflect early release of reticulocytes in response to anaemia. Red cell shape is often a key indicator, so a peripheral blood film is valuable in regions where other diagnostic tests are unavailable. In SCA, sickle-shaped cells and reticulocytes are common (Fig. 1). Folate deficiency occurs because of high cell turnover and limited folate stores. Iron deficiency is rare but can be seen in menstruating adolescents and breast-fed infants of iron-deficient mothers.³ Iron overload is a risk after multiple transfusions.

Fig 1.

Microscopy of a blood film of a patient with sickle cell anaemia showing poikilocytosis (variation in cell shape), specifically sickle-cells. Reproduced with permission from Dr Janaki Pearson.

Chronic management

The management of children with SCD requires a multidisciplinary approach. Early diagnosis allows for parent education, vaccination, and prophylactic penicillin before the expected fall in HbF concentrations. End-organ damage includes cerebrovascular disease, heart failure secondary to thrombotic disease or pulmonary hypertension, and early signs of chronic kidney disease caused by ischaemic damage and loss of renal tubules. These complications are increasingly rare because of early diagnosis and improved chronic management. Protection against encapsulated organisms, particularly Streptococcus pneumoniae, is routine practice. Children in the UK are vaccinated according to the UK immunisation schedule, which includes vaccination against Haemophilus influenzae (Hib), Neisseria meningitidis (Men C), and hepatitis B.¹³ In addition, children with SCD receive the pneumococcal, meningitis ACWY, the annual influenza vaccine, and an additional dose of HiB and Men C vaccines.¹³ Oral penicillin prophylaxis is continued from 3 months to 5 yr of age and significantly reduces pneumococcal infection.³ In endemic areas, malaria prophylaxis is also indicated. Folate and micronutrient supplementation are also given routinely and these limit the consequences of rapid cell turnover.

HbF production can be prolonged pharmacologically with hydroxyurea (hydroxycarbamide). A multicentre randomised controlled trial of infants aged 9–18 months with HbSS or HbSβ⁰ compared hydroxyurea with placebo and showed preserved haemoglobin and HbF concentrations, and a significant decrease in painful events and dactylitis in the treatment group.¹⁴ Of note, there were no significant differences between groups in the primary endpoints of the study: splenic and renal function.¹⁴ Hydroxyurea is now offered routinely to all children in the UK aged >1 yr with HbSS or HbSβ⁰.

Acute complications

The most common acute complications are infection and vaso-occlusive episodes.³ Multiple splenic microinfarcts secondary to sickling is an early complication of SCA, with 90% of affected children reported to have functional asplenia by age 6 yr. This leads to an increased risk of bacterial infections, most notably with S. pneumoniae in addition to atypical organisms.³ Parvovirus B19 is also an infective cause of acute complications in SCD, the most severe being aplastic crisis.

The most common presenting symptom of a vaso-occlusive episode is pain. Vaso-occlusion can also lead to infection, as the hypoxic environment enables bacterial proliferation. Vaso-occlusion is treated supportively, with i.v. fluids, oxygen, and early multimodal analgesia.

Acute chest syndrome (acute CS) is a common and life-threatening complication of SCD defined as ‘an acute illness characterised by fever, respiratory symptoms, or both, accompanied by new pulmonary infiltrate on chest X-ray’.¹⁵ It is more common in children between 2 and 4 yr of age, and in hospital inpatients admitted for another complication.³ An association with asthma is also reported.¹⁶ Acute CS occurs when there is an area of poor ventilation within the lung, which becomes hypoxic, with mismatching of ventilation and perfusion. Hypoxia and acidosis then cause firstly sickling of red blood cells, leading adhesion of these sickle cells to other red blood cells, leukocytes and vascular endothelium, and secondly pulmonary vasoconstriction.¹⁶ These effects combine to result in poor pulmonary perfusion, thereby worsening the hypoxia and acidosis. A vicious spiral occurs and the child can deteriorate rapidly. Often the precipitant in children is infection, most commonly respiratory syncytial virus.¹⁵ Other precipitants include atelectasis following abdominal surgery or an ‘acute abdomen’, or vaso-occlusion resulting in rib, sternal, or vertebral microinfarctions.¹⁷ Children most commonly present with fever and cough, followed by wheeze.¹⁵ Tachycardia, tachypnoea, and signs of increased work of breathing may be seen.¹⁵ Chest X-ray findings may not be evident at presentation. Predictors of severity include worsening hypoxia, increasing respiratory rate, neurological symptoms, deteriorating haemoglobin concentration or platelet count, and multilobar lung involvement.¹⁵ Treatment is supportive, using oxygen (high-flow humidified devices are particularly useful) and analgesia adequate to prevent hypoventilation.¹⁵ Broad-spectrum i.v. antibiotics with atypical cover are given and children should also receive a transfusion aiming for a haemoglobin concentration of 10 g dl⁻¹, reducing the percentage of HbSS.¹⁵ Two-hourly daytime incentive spirometry is used for both prevention and treatment. Cautious fluid management is required, with care to avoid pulmonary oedema. These children should be managed in a critical care environment.

Splenic sequestration occurs mostly in infants. This occurs secondary to vaso-occlusion in the spleen leading to rapid enlargement and sequestration of blood, which may result in hypovolaemic shock and pancytopenia. Treatment involves restoring volume status, using blood products as first-line, and antibiotics. Teaching parents the technique of splenic palpation allows earlier presentation, improving outcome.³

Stroke is a common complication of SCD, reported to occur with clinical neurology in 11% of HbSS patients by the age of 20, with silent ischaemia in 22%.³ This complication occurs most commonly between 2 and 10 yr of age.³ Ischaemic stroke is more common than haemorrhagic stroke.³ Most commonly stroke is a macrovascular complication occurring when sickling occurs at areas of turbulent flow at bifurcations within the circle of Willis. The Stroke Prevention Trial in Sickle Cell Anaemia (STOP) strongly suggested that identifying children at high risk of stroke using transcranial Doppler ultrasonography and entering them into a long-term transfusion programme to reduce their percentage of circulating sickle-haemoglobin significantly reduces the incidence of primary stroke.¹⁸ Subsequently, screening of all children using transcranial Doppler ultrasonography is recommended from 2 yr of age.³

Other acute complications secondary to vaso-occlusion include priapism and renal tubular necrosis. Gallstones (mostly seen in older children) occur secondary to chronic high circulating unconjugated bilirubin concentrations, conjugated in the liver and excreted into the biliary tract. Orthopaedic complications are also common. Osteomyelitis often occurs secondary to a vaso-occlusive episode commonly involving Staphylococcus aureus or Salmonella.³ Pathological fractures and avascular necrosis of the femoral and humeral heads occur.

Anaesthetic considerations

Common requirements for surgery for children with SCD (Table 1) are different to the non-sickle population. The most common postoperative complications are vaso-occlusive episodes and acute CS.¹⁹ Postoperative sepsis is also a concern, but has substantially decreased since the introduction of early vaccination.¹⁹ There is considerable variation in the reported incidences of postoperative acute CS. A study of paediatric patients discharged from hospitals in the USA reported an incidence of acute CS of 3.08% after elective surgery.¹⁷ Acute CS was commonest following appendicectomy (8.73%) and Caesarean section (5.75%) suggesting that intraabdominal surgery and acute presentations are risk factors. The incidence was also high after umbilical hernia repair (4.24%), cholecystectomy (3.9%), and splenectomy (2.76%). Stroke and death were reported in 0.2% and <0.2% of postoperative cases, respectively.¹⁷

Table 1.

Most common surgeries undergone by children (<18 yr) with sickle cell disease, with common indications also listed. Data from Hyder and colleagues (2013).¹⁷ The commonest procedures as a proportion of all children undergoing surgery were cholecystectomy, splenectomy, and hip replacement

Procedure	Common indications in children <18 yr with SCD
Cholecystectomy	Gallstones occur in SCD secondary to chronic high circulating unconjugated bilirubin
Tonsillectomy and adenoidectomy	Hypertrophy of lymphoid tissues causing obstructive symptoms
Splenectomy	More than two episodes of splenic sequestration Chronic hypersplenism with secondary pancytopaenia
Umbilical hernia repair	As in non-SCD patients
Appendicectomy	As in non-SCD patients
Myringotomy	As in non-SCD patients
Caesarean section	Increased incidence of maternal and fetal complications in pregnancy including antepartum haemorrhage and delivery by caesarean section
Inguino-femoral hernia repair	As in non-SCD patients
Hip replacement	Avascular necrosis of the hip

Importantly, collective experience with laparoscopic techniques has increased over recent years. A retrospective comparative study of children with SCD undergoing splenectomy reported a decreased incidence of acute CS in those undergoing laparoscopic compared with open surgery.²⁰ Most institutions now report routine use of laparoscopic techniques for intraabdominal surgery. Although the risk reduction reported varies between papers, there is consensus that laparoscopic techniques are likely to be beneficial in the sickle population.

Postoperative stroke is also a risk. After splenectomy for hypersplenism, thrombocytosis is common because the effects of chronic bone marrow hyperactivity are no longer opposed.¹⁹ This study found a high incidence of abnormal and borderline transcranial Doppler measurements after surgery, although routine preoperative screening had not been performed to enable comparisons to be made. The authors suggested that increased platelet activity and cellular adhesion within the cerebral vasculature contribute to the risk of stroke risk after splenectomy.¹⁹

Preoperative

The key to the anaesthetic management of children with SCD is planning and optimisation, ensuring adequate oxygenation, hydration, and pain control throughout the perioperative period. Surgery should be performed at a centre with a multidisciplinary sickle cell team. Day-case surgery is not recommended, excepting for minor body surface procedures in a child whose disease is well controlled.²¹

Preoperative assessment should assess for complications of SCD including end-organ damage. Full blood count should be checked. Neutropenia is common as a complication of hydroxyurea therapy.¹⁵ Haemoglobin electrophoresis may determine the percentage of HbS. Urea and electrolyte measurement may reveal chronic kidney disease. Blood should be screened for antibodies and cross-matched blood made available; this may take considerably longer to cross-match than usual if the child has received multiple transfusions in the past and the transfusion history should be noted. If the child has a history of multiple chest infections or acute CS, a chest X-ray and spirometry should be considered. Echocardiography may be warranted in children with a history of cardiac disease or obstructive sleep apnoea. The child should have had an assessment with transcranial Doppler ultrasonography within the last 12 months.

Children should be kept hydrated before surgery to decrease blood viscosity and the tendency for sickling. Wherever possible, the child should be scheduled first on the operating list. Allowing children scheduled for elective surgery to drink clear fluids freely until they are called to the operating theatre does not appear to increase the risk of aspiration.²² This approach may be beneficial in SCD. Some hospital-based guidelines for children with SCD recommend supplementing oral fluids with i.v. maintenance fluids during the fasting period.²¹

There has been a considerable change in practice regarding preoperative transfusion in children with SCD over recent years. The most important recent study is the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study, a multicentre randomised controlled trial of patients over 1 yr of age with either HbSS or HbS/β⁰ thalassaemia, undergoing low- or medium-risk elective surgery.²³ Patients received either preoperative blood transfusion or no transfusion. The transfusion group received packed red cells up to a haemoglobin concentration of 10 g dl⁻¹ if their presenting haemoglobin was <9 g dl⁻¹, or, if higher, received an exchange transfusion to an estimated HbSS percentage of <60%. Some 60% of the study participants were aged under 17 yr. The study reported a significantly higher rate of perioperative complications (most commonly acute CS) in patients not transfused.²³ There were no transfusion-related reactions in the transfused group. More children in the non-transfused group required blood transfusions during or after surgery, the common indication being acute CS.²³

Since this study, it has become common practice to transfuse children presenting for low- or medium-risk surgery to the same protocol before surgery. Children presenting for high-risk surgery (for example neurosurgical, cardiothoracic, or complex orthopaedic surgery) or high-risk children (previous stroke, acute CS, or end-organ damage), who were not included in this study, commonly receive an exchange transfusion or top-up transfusion, aiming for a preoperative haemoglobin concentration of 10 g dl⁻¹ and Hb SS <30%. There is less evidence available for the role of transfusion in children with other forms of SCD.

Intraoperative

During surgery, the goals of anaesthesia are to maintain oxygenation and hydration, avoid acidosis, and maintain normocarbia, normotension, and normothermia. Hypothermia increases the risk of sickling by increasing blood viscosity and the tendency towards vasoconstriction.

Measures should be used to prevent postoperative nausea and vomiting (PONV). Although there are few specific data on the prevalence of PONV in children with SCD, the general consensus is that the anaesthetic technique should be tailored and multiple antiemetics advised to prevent PONV and enable the early resumption of eating and drinking.

The use of tourniquets during surgery has been controversial, but the current consensus is that the benefits of reducing blood loss in children with SCD in high-risk orthopaedic procedures, so preventing hypovolaemia, outweigh the risk of a crisis. The risks of a tourniquet are that a vaso-occlusive episode may occur in the operative limb distal to the tourniquet secondary to local hypoxia and acidosis; and that release of the tourniquet may result in systemic acidosis and increase the possibility of a vaso-occlusive episode elsewhere. Steps to reduce the risk include ensuring the patient is well hydrated with normal acid-base balance before application and throughout the surgery, the limb is exsanguinated well, and an experienced surgeon ensuring the shortest possible tourniquet time.

Cell salvage is considered contraindicated as the hypoxic extracorporeal circuit leads to a high proportion of sickling. In children undergoing cardiac surgery on cardiopulmonary bypass (CPB), exchange transfusion is used to reduce the HbS fraction and the child is kept warm during CPB.

SCT alone does not cause an increase in perioperative morbidity and mortality except in extreme physiological circumstances, for example hypothermia or CPB.¹² Despite this, it is good practice to avoid known triggers of vaso-occlusion in these children.

Postoperative

After surgery, maintenance fluids should be continued until the child is drinking well. Oxygen should be used to maintain SpO₂>94% and two-hourly incentive spirometry can be useful. Admission to critical care should be considered in all cases of high-risk or emergency surgery, or surgery for medically high-risk children. Children with obstructive sleep apnoea or chronic lung disease need an environment able to deliver high-flows of humidified oxygen or CPAP. Postoperative physiotherapy can improve respiratory function and mobilisation.

Multimodal analgesia is recommended, where possible involving regional techniques to maximise analgesia and minimise opioid use, thereby reducing the likelihood of sedation and PONV. Pain increases the risk of atelectasis and subsequently acute CS.¹⁵ Transversus abdominis plane or rectus sheath blocks (including catheter-based techniques) may be useful for patients undergoing splenectomy or open cholecystectomy.

A study of opioid use in children undergoing laparoscopic cholecystectomy with and without a history of SCD reported that children with SCD had higher postoperative pain scores and requirement for both opioid and non-opioid analgesics.²⁴ The authors suggested that the SCD results in a proinflammatory state that is further upregulated after surgery leading to increased pain and that children with SCD often have chronic pain, which is known to be associated with hyperalgesia. They proposed that epidural anaesthesia and N-methyl-D-aspartate-receptor antagonists may be useful to prevent further central sensitisation.²⁴

Acute pain management

The most common acute pain-related presentation of a child with SCD is a vaso-occlusive episode where the management is to treat precipitating factors, manage pain, and prevent complications. To prevent further deterioration and for the child's comfort, analgesia should be administered promptly and regularly reviewed for effect.

Vaso-occlusive pain is commonly severe and occurs in the long bones, back, chest, and abdomen. Young children may present with dactylitis, a manifestation of vaso-occlusion in the hands and feet. A history of this presenting pain, in comparison with previous vaso-occlusive episodes, may help to differentiate between vaso-occlusion and another complication, for example infection or ACS. Signs suggesting an alternative complication include abnormal observations or examination findings, worsening anaemia, or abnormal biochemical tests.

Paracetamol and NSAIDs are useful. Supportive measures include heat pads that promote local vasodilation and flow. Mild pain can be treated with regular paracetamol and ibuprofen, escalating to oral morphine if there is no improvement in the pain score at 30 min. Oral morphine or oral morphine and intranasal diamorphine are recommended for moderate and severe pain, respectively, in combination with paracetamol and ibuprofen. In the case of persistent severe pain, PCA or nurse-controlled analgesia (NCA) is recommended. Adjuncts recommended for further escalation include clonidine and ketamine. Children receiving daily opioids for the treatment of chronic pain, who present with moderate or severe pain, should be treated with oral morphine and intranasal diamorphine, escalated to PCA or NCA if required. Common adverse effects from opioid use, for example constipation and pruritus, should be anticipated and managed. Oversedation and hypoventilation should be anticipated and prevented.

Declaration of interest

The authors declare that they have no conflicts of interest.

MCQs

The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.

Biographies

Sonia Akrimi FRCA MRCP PGCME is a speciality trainee in anaesthesia in the Health Education Kent, Surrey and Sussex Deanery. She has interests in medical education and global surgery.

Victoria Simiyu MMed Anaesthesia is a consultant anaesthetist at the Kenyatta National Hospital in Nairobi who is an active member of the scientific committee of the Kenya Society of Anaesthesiologists. Her major clinical and research interests are in the promotion of safe anaesthesia in low-income settings.

Matrix codes: 1D02, 2D02, 3D00