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''Originally from Update in Anaesthesia | www.wfsahq.org/resources/update-in-anaesthesia''

Based in part upon Locke, C. Anaesthetic management of sickle cell disease in children. Anaesthesia Tutorial
of the Week 153 (2009).

Tanya Smith and Christie Locke* (*Correspondence email: christielocke@me.com)

Tanya Smith
::Specialist Registrar in Anaesthesia,
::Northwick Park Hospital, UK


Christie Locke
::Consultant Anaesthetist,
::East Surrey Hospital,
::UK
----
Summary
Sickle cell disease may
cause serious perioperative
complications.
Management of these
patients requires careful
preparation, and close
attention to those factors
that could precipitate
a sickle crisis. The basic
principles of oxygenation,
hydration, analgesia,
avoidance of hypothermia
and acidosis, and blood
transfusion where
indicated, are essential.
----
=INTRODUCTION=
Sickle cell disease (SCD) is a congenital
haemoglobinopathy inherited in an autosomal recessive
manner. It is a multisystem disease which affects
approximately 4 million people worldwide. Surgery
and anaesthesia carry a high risk for these patients, and
meticulous perioperative care is essential to prevent
complications of SCD.1

=PATHOPHYSIOLOGY=
Adult red blood cells normally contain three different
types of haemoglobin; Haemoglobin A (HbA) which
makes up 96-98% of total haemoglobin, haemoglobin
A2 (HbA2) which accounts for 1.5-3% of the total,
and foetal haemoglobin (HbF) which accounts for
0.5-0.8% of the total.

Haemoglobin S (HbS) occurs as a result of a single
DNA base change (adenine to thymidine) that results
in the substitution of valine for glutamic acid in the
ß-globin chain.

Sickle cell diseases are inherited in an autosomal
recessive fashion, with homozygous expression of the
abnormal gene (HbSS) producing SCD. These patients
have no normal adult haemoglobin (HbA) and only
have HbS, HbA2 and HbF, with approximately 95%
haemoglobin as HbS. Patients who are heterozygous
for HbS (HbSA) are carriers but are asymptomatic and
have a normal life expectancy.

Sickle haemoglobin (HbS) polymerises into insoluble
microfibrils in the deoxygenated state. It is thought
that these parallel microfibrils cause red cell membrane
damage and result in the classical sickle cell deformity
(Figure 1). The deformed red cells are more rigid and
less capable of passing through the microcirculation,
causing increased blood viscosity and impaired blood
flow. The cells also have a shortened survival time (5-
15 days in homozygous sickle cell disease) with the
resulting haemolytic anaemia that is characteristic of
SCD.

There is increasing evidence that the primary event in
SCD is oxidative damage to the arterial endothelium
(the lining of the vessel wall) due to the effects of
sickle haemoglobin breakdown. The vascular damage
caused by HbS, may be due to its extremely unstable
nature, rather than its insolubility. Biochemical markers
of endothelial damage are present and suggest that
perhaps the disease should be considered as a chronic
inflammatory disorder.

The spectrum of sickling disorders is widened by the
combination of HbS with other haemoglobinopathies
such as thalaessaemia and haemoglobin C and
haemoglobin D. This is because polymerisation of
HbS is affected by the presence of other haemoglobins,
but in varying degrees. For example, patients with
HbSD are severely affected, while patients with
HbSC are less affected by sickling, and suffer more
thrombotic complications. The combination of α and
β thalassaemia with HbS result in disease ranging in
severity depending on the nature of the thalassaemia
mutation.

=EPIDEMIOLOGY=
SCD affects approximately 4 million people worldwide
and it is most common in West African and Caribbean
populations. In Equatorial Africa the sickle cell trait
occurs in up to 30% of the population. This is due
to a phenomenon called balanced polymorphism,
which is when the heterozygote for two alleles of a
gene has an advantage over either of the homozygous
states. Heterozygotes for sickle cell anaemia show a
marked resistance to malaria. The mechanism for this
is unknown but could be explained by the fact that
sickle cell trait red cells deform when infected by the
parasite, and are then targeted for destruction by phagocytes. The
destruction of these cells decreases the parasite burden Because of this
relative resistance, people with sickle cell trait in high malaria areas
are more likely to reach reproductive age and pass on their genes to
the next generation.

In North America approximately 8% of the black population has sickle
cell trait, and up to 1.3% has SCD. The majority of SCD in the UK
is found in African-Caribbean populations in large cities where up to
10% individuals carry the gene.

The HbS gene also occurs in some areas in Mediterranean regions such
as Greece, southern Italy, Turkey, and in Saudi Arabia and central India.

=DIAGNOSIS=
The gold standard for the diagnosis of SCD is haemoglobin
electrophoresis.

The simpler Sickledex test confirms the presence of HbS, however
electrophoresis is required to distinguish between HbSA (sickle cell
trait) and HbSS (sickle cell disease).

The Sickledex test uses sodium metabisulphite as a reducing agent
that causes HbS to precipitate in a hyperosmolar phosphate buffer
solution to produce a cloudy suspension.

The Sickledex test is not reliable in the neonatal period where low
levels of HbS and high levels of HbF (with normal solubility) may
result in false negative results. It becomes reliable after 6 months of
age when the HbF levels have dropped.

Haemoglobin electrophoresis separates molecules on the basis of their
charge at a given pH (Figure 2). Electrophoresis of umbilical cord
blood can be used for diagnosis in the newborn.

=CLINICAL MANIFESTATIONS OF SCD IN CHILDREN=
SCD has a variety of clinical presentations.

==Anaemia==
This is universal in patients with HbSS. Patients usually have a
haemoglobin level of 6-9g.dL-1. The anaemia is usually well tolerated,
and adequate tissue oxygenation is maintained due to a compensatory
increase in cardiac output and increased effective release of oxygen
to the tissues due to the low affinity of HbS for oxygen. A systolic
flow murmur (non-pathological murmur as a result of increased
cardiac output) is a frequent finding, and congestive heart failure
with cardiomegaly on clinical examination/chest radiograph can
occur in adults. Children with SCD should receive iron and folic
acid supplementation.

==Painful crises==
This is associated with the sudden onset of severe pain, most commonly
arising in bone and joints due to ischaemia and infarction in the
marrow or cortical bone. Dactylitis (painful swelling of small bones
of hands and feet) occurs in up to half of children by the age of two
years and is a sign of severe disease. Abdominal pain occurs in older
children and can be caused by bowel dysfunction, organ infarction
or referred pain from the ribs. These abdominal crises can be difficult
to distinguish from other common acute surgical disorders. 1% of
patients have more than six episodes of pain per year. Precipitants
for acute painful crises include infection, dehydration, cold, hypoxia
and stress.

==Acute chest syndrome==
This is defined as a fever of more than 38.5°C, respiratory distress or
chest pain and the appearance of new lung lobar infiltration on chest
X-ray. Hypoxia is common and ventilatory support is occasionally
needed in severe sickle chest crisis. The majority of patients are
managed with oxygen therapy, hydration and blood transfusion. The
incidence of acute chest syndrome in the postoperative child may be
as high as 10% in those with severe disease undergoing major surgery.
Risk factors for sickle chest crisis are age between 2-4 years and a
persistently raised white cell count. Multiple episodes of acute chest
syndrome in children are likely to result in pulmonary fibrosis and
chronic lung disease as the child gets older.

==Cerebrovascular accidents (CVA)==
The majority of CVAs in patients with SCD occur during childhood
(5% of children with sickle cell disease have overt CVAs due to
ischaemia). These are typically caused by vascular lesions in the cerebral
vessels and may present as watershed infarctions during a sickle crisis
(infarction occurring at the more vulnerable regions between major
cerebral arterial zones). Transcranial Doppler ultrasonography can
identify children at risk of cerebral infarction, by detecting reduced
blood flow in cerebral vessels. It has been shown that treating patients
at risk with regular transfusion programmes significantly reduces
the incidence of stroke. Children are also at risk of intracerebral and
subarachnoid haemorrhage.

==Aplastic crisis==
This is usually precipitated by infection, parvovirus being an important
pathogen. There is suppression of erythropoiesis (red blood cell
formation) in the bone marrow and a dramatic fall in haemoglobin 
levels. Early diagnosis and treatment with blood transfusion is essential.

==Acute splenic sequestration==
This is a rare complication that is most common in children under the
age of five. Large numbers of red cells are sequestered in the spleen
and the haemoglobin level drops precipitously. This may present
with acute collapse and shock, and may require resuscitation and
blood transfusion. Children who suffer repeat episodes of splenic
sequestration may require splenectomy.

More commonly, splenic infarction occurs as a result of repeated
sickling episodes, which results in functional hyposplenism. Patients
are at increased risk of infections, particularly with encapsulated
bacteria such as Streptococcus pneumoniae, Neisseria meningitides, and
Haemophilus influenza B. All children with homozygous SCD should
receive prophylactic penicillin V from birth.

==Osteomyelitis==
Patients are at higher risk of osteomyelitis than the rest of the
population, with the most common pathogens being salmonella and
staphylococci.

==Priapism==
Attacks start as young as the age of eight and are reported by up to
30% of male sufferers of SCD. It can occur in the postoperative
period. Treatment includes hydration, exchange transfusion and intracavernous
injections of an alpha-adrenergic agent.

==Avascular necrosis==
Intravascular sickling of the red blood cells in the microcirculation of
the bone results in intramedullary sludging, stasis, thrombosis, and
progressive ischaemia, most often of the femoral head. These patients
present with pain in the affected joint. Orthopaedic management may
be conservative or surgical.

==Long-term complications of SCD in adults==
Recurrent sickle cell crises may cause many complications including
gall stones, sickle retinopathy, leg ulcers, chronic renal failure due to
renal parenchymal scarring, pulmonary hypertension, chronic lung
disease, and neurological impairment. Chronic bone damage may
occur, leading to avascular necrosis, impaired growth and joint damage.

=ANAESTHETIC MANAGEMENT OF CHILDREN WITH SCD=

==Pre-operative screening==
All children in a high-risk population or those with a positive family
history should be screened for SCD.

==Pre-operative assessment and preparation==
Patients with a history of chest crisis, stroke, frequent painful crises,
or those with severe obstructive sleep apnoea have a higher risk of
perioperative complications. All patients with SCD require meticulous
perioperative care.3 4

Pre-operative assessment should involve a careful review of all systems.
::• Multiple episodes of acute chest syndrome may result in reduced lung volumes, pulmonary infarction and pulmonary hypertension with low oxygen saturation. It is important to check the baseline oxygen saturation before surgery.
::• Although more commonly seen in adults, cardiomegaly may be seen on chest X-ray, and echocardiography may be indicated to assess cardiac function.
::• Careful neurological examination is essential and any preexisting neurological deficit from previous CVAs should be documented.
• Renal and hepatic function should also be assessed for signs of endorgan damage. Even children with HbAS have a renal concentrating defect and may not tolerate dehydration.
• If there is any evidence of active infection, elective surgery should be postponed.

Where possible, children with SCD should be scheduled first on the
operating theatre list to avoid prolonged starvation and dehydration.
Patients should be encouraged to drink free clear fluids until two
hours before surgery.

==Blood transfusion and SCD==
Preoperative blood transfusion is a controversial area,5 particularly
now that standards of anaesthetic care have improved for patients with
SCD. The pathophysiology of the disease is better understood and
many of the precipitating factors for sickle crisis in the perioperative
period can be avoided (see below). The NHS Blood and Transplant
service in the UK recently undertook a randomized controlled trial to
evaluate whether blood transfusion should be given to patients with
SCD pre-operatively (so-called TAPS trial). Although the recruitment
target was 400 patients, the trial was ended early (after 70 patients)
as a review of patient safety identified that there were more serious
complications in patients who did not receive pre-operative blood
transfusion6 (unpublished data)
.
Theoretically, reducing the percentage of HbSS by prophylactic
transfusion should prevent complications. However, aggressive
transfusion regimens are associated with a high incidence of
transfusion-associated complications.

In resource poor areas where screening for infection and highly specific
blood cross matching is limited, the balance of the risks versus the
benefits of blood transfusion needs to be carefully considered.
Management plans for transfusion therefore need to be individualised
for each patient, taking into account the patient’s medical history
and type of surgery, in consultation with the anaesthetist, surgeon,
paediatrician and haematologist, as well as the patient’s family.
Guidelines may vary between hospitals and between regions.
Transfusion may be used to increase the haemoglobin level; repeated
top-up transfusion will also reduce the percentage of HbS in the
blood. Below are current transfusion guidelines at Great Ormond
Street Children’s Hospital in London.

::• Children with no special risk factors having short procedures such as insertion of myringotomy tubes or minor dental work: no transfusion, provided the haemoglobin is at the normal baseline
level (Hb >6g.dL-1)
::• Children with no special risk factors having intermediate risk surgery such as tonsillectomy or laparotomy: top-up transfusion to Hb 9-11g.dL-1
::• Children who have had a chest crisis, CVA or suffer frequent painful crises, or children undergoing major surgery such as thoracic or neurosurgery: sequential top-ups or exchange
transfusion to achieve a Hb of 9-11g.dL-1 and a HbS level of <30%
::• As it is essential to avoid increased tissue viscosity, the Hb should not exceed 12g.dL-1
::• For emergency surgery, patients should ideally be treated the same, but if time does not allow, then blood should be crossmatched and ready for surgery. All cases should be discussed with a haematologist if possible.

=INTRAOPERATIVE MANAGEMENT=

==Oxygenation==
The primary goal is to maintain good oxygenation during the
perioperative period. Perioperative pulse oximetry monitoring is
essential as patients may have impaired oxygen delivery resulting from
chronic anaemia or chronic lung damage, and may have a limited
ability to maintain tissue perfusion and oxygenation during hypoxic
episodes. Even short periods of hypoxia must be avoided. Postoperative
continuous positive airway pressure (CPAP) or a nasopharyngeal
airway may be indicated in those with obstructive sleep apnoea (see
below).

==Dehydration==
Dehydration is poorly tolerated. Dehydration may lead to increased
tissue viscosity, poor perfusion, acidosis and increased sickling.
Adequate hydration is essential and must be maintained before, during
and after surgery. The patient should be encouraged to drink clear
fluids up until 2 hours before surgery, or if this is not possible, to have
intravenous fluids during the preoperative fasting period. Intravenous
fluids should be used during surgery, and postoperative intravenous
fluids should be prescribed until oral intake is re-established.

==Acidosis==
Avoid acidosis. Acidosis causes increased sickling, with subsequent
increased blood viscosity and impaired tissue perfusion. This will cause
the tissues to become more acidotic, causing further sickling, which
may result in a sickle crisis.

==Temperature management==
Avoid hypothermia. Hypothermia causes vasoconstriction,
hypoperfusion, increased blood viscosity, and decreased venous oxygen
tension which all lead to increased sickling.

==Vascular stasis==
Avoid vascular stasis by maintaining a good circulating volume,
careful positioning, and the use of thromboembolic deterrent (TED)
stockings. Pneumatic calf compression devices can be used during
prolonged surgery. These should be avoided if there is evidence of
peripheral vascular occlusive disease.

==Tourniquets==
Studies reporting outcomes after tourniquet use are scarce in patients
with sickle cell disease. A recent systematic review concluded that
tourniquets may be used with relative safety in most patients, as long
as other peri-operative precautions are taken. The use of tourniquets
in patients with SCD should therefore be considered on an individual
basis weighing up the risks and benefits.

Tourniquet after exsanguination of the limb may be used safely in
patients with sickle cell trait.

==Cell saver devices==
The high incidence of sickling in cell savers prevents their use in SCD.

=POSTOPERATIVE MANAGEMENT=

==Oxygen therapy==
Oxygen saturation should be monitored continuously and
supplemental oxygen should be given to maintain saturations >92%.

==Fluid management==
Continue intravenous maintenance fluids until the child is tolerating
oral fluids.

==Postoperative analgesia==
Management of post-operative pain is challenging. Patients may
have very high perioperative analgesic requirements, and may have
developed tolerance to opioids. A multimodal approach should be
used with a combination of opioids where indicated, paracetamol and
NSAIDs, and regional anaesthesia when possible.

==Physiotherapy==
Physiotherapy and early ambulation are important to avoid vascular
stasis.

==Nasopharyngeal airway==
Obstructive sleep apnoea secondary to adenotonsillar hypertrophy
is common in children with SCD. Careful attention should be
paid to these patients postoperatively to avoid airway obstruction,
hypoventilation or hypoxia. A nasopharyngeal airway may be used
after tonsillectomy or in those with severe obstructive sleep apnoea to
prevent post-operative airway obstruction and hypoxia.

==Postoperative complications==
Patients should be monitored carefully for early signs of complications
as serious post-operative complications usually occur within 48hrs of
surgery. These include:
::• Painful crisis
::• Cerebrovascular accident
::• Acute chest syndrome.

==Management of sickle complications==
The anaesthetic team may be involved in managing the acute
complications of sickle cell disease, both when they present postoperatively,
and when the patient presents to the hospital with an
acute crisis.
::• The management of all sickle crises includes the same principles of establishing intravenous fluids, oxygen therapy, analgesia, and antibiotics.
::• Analgesia may require high doses of opiates, as well as the use of regular paracetamol and NSAIDs such as ibuprofen or diclofenac.
::• Transfusion to an Hb>10g.dL-1 is important, but over transfusion (>12g.dL-1) must be avoided. Exchange transfusion to reduce HbS <20-30% may be indicated in certain situations such as acute
chest syndrome or CVA. As a guide, transfusion of 4ml.kg-1 of packed cells or of 8 ml.kg-1 of whole blood raises the haemoglobin concentration by 1g.dL-1.
::• Ventilatory support (continuous positive airway pressure (CPAP), or intubation and ventilation) may be required for acute chest syndrome. Patients should be carefully monitored for signs
of respiratory decompensation.
::• Acute sequestration crisis is an important cause of death in children with sickle cell disease. Acute hypovolaemia can occur due to pooling of blood in the spleen. Treatment is
transfusion of blood and intravenous 0.9% saline for volume replacement.

=CONCLUSIONS=
Anaesthetists need to be aware of the possible serious complications
of SCD in the perioperative period. Management of these patients
requires careful preparation, and close attention to those factors that
could precipitate a sickle crisis.7 The basic principles of oxygenation,
hydration, analgesia, avoidance of hypothermia and acidosis, and
blood transfusion where indicated, are essential.

=REFERENCES=
::[http://www.wfsahq.org/components/com_virtual_library/media/e0645e0e5cce77faef81cd00f0a0efa4-134dcf42c0b8f21e61db61b943aa0c8b-153-Sickle-cell-disease-inchildren.pdf Locke C. Anaesthetic management of sickle cell disease in children. ATOTW (2009) 153.] Available at: http://www.wfsahq.org/components/com_virtual_library/media/e0645e0e5cce77faef81cd00f0a0efa4-134dcf42c0b8f21e61db61b943aa0c8b-153-Sickle-cell-disease-inchildren.pdf [NOTE: This link is broken. Needs to be fixed.]

::1. Marchant WA, Walker I. Anaesthetic management of the child with sickle cell disease. Paediatr Anaesth 2003;13:473-89.
::2. Nandi R, Martin R. Haematology. In: Bingham R L-TA, Sury M, editor. Hatch and Sumner’s Textbook of Paediatric Anaesthesia. 3rd ed, 2008.
::3. Firth PG, Head CA. Sickle cell disease and anesthesia. Anesthesiology 2004;101:766-85.
::4. Frietsch T, Ewen I, Waschke KF. Anaesthetic care for sickle cell disease. Eur J Anaesthesiol 2001;18:137-50.
::5. Hirst C, Williamson L. Preoperative blood transfusions for sickle cell disease. Cochrane Database Syst Rev 2012;1:CD003149.
::6. http://www.sicklecellsociety.org/websites/123reg/LinuxPackage22/si/ck/le/sicklecellsociety.org/public_html/news/view/22
::7. Davies SC, Oni L. Management of patients with sickle cell disease. BrMed J 1997;315:656-60. Update

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