Sickle Cell Disorders in Leeds Children's Hospital - Guidelines For Management of Children with

Publication: 01/05/2012  --
Last review: 15/04/2020  
Next review: 18/03/2021  
Clinical Guideline
CURRENT 
ID: 2931 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2020  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guidelines For Management of Children with Sickle Cell Disorders in Leeds Children's Hospital

Acute presentation with sickle cell disease

Mechanism for referral

Urgent concern regarding child or young person <18 years old with possible sickle cell disease?

Ring :

0900-1700 Monday to Friday 0113 3927179
All other times and Bank Holidays 0113 3927431  
If no answer to the above numbers 0113 2432799 (Leeds Teaching Hospitals switchboard)

Ask for specialist registrar covering paediatric haematology or consultant on call for paediatric haematology/oncology.

Unless there is a specific contraindication, all such patients should be cared for on the paediatric haematology/oncology wards.

All new patients who may have sickle cell disease or thalassaemia who are <18 years old who are not presenting unwell and need outpatient referral should be discussed with/referred to the Paediatric Haematology Department, Leeds Children’s Hospital, Martin Wing, Leeds General Infirmary, LS1 3EX. This includes infants identified through the neonatal haemoglobinopathy screening programme.

Tel 0113 3928776
Fax 0113 3928488

When to refer from the community

Emergency referral

Potential symptoms or signs in a child at risk of sickle cell disease include serious infection, unexplained pain often in limbs or back but any site possible, acute chest symptoms, acute abdominal symptoms, central neurological deficits, dactylitis, anaemia, jaundice, skin ulceration, priapism, visual disturbance.

If patient presents to Emergency Department call ward 31/33 as referral (tel. 27431, 27433) but measure oxygen saturation and offer analgesia – see protocol for details.

Outpatient referral

Possible new case of sickle cell disease presenting through neonatal screening, new presentation at an older age or following movement of a family to the Leeds area.

 Essential longer term management in the community

Guidance for management in the community will be described in clinic letters/discharge summaries but ongoing interventions in partnership with the sickle cell clinic will include:

  • Prescription of and support to ensure adherence to twice daily administration of penicillin/ alternative prophylaxis against enveloped bacterial infections
  • Prescription of escalating analgesia (paracetamol and ibuprofen) at home for sickle cell pain.
  • Ensuring adherence to the immunisation programme including pneumococcal and influenza vaccinations.
  • Provision of support for the family at home and in school to ensure good hydration, dissemination of appropriate advice in the community and school and facilitation of regular review or emergency presentation at Leeds Children’s Hospital or the local paediatric unit.
  • Supporting the Sickle Cell centre in providing ongoing treatment with vitamin D or zinc supplementation.

Treatment with hydroxycarbamide, iron chelation or more complex management will be provided by the Sickle Cell centre.

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Sickle cell disease

Assessment and management of patient with sickle cell disease with a crisis

Referral pathway

Existing patients have open access to wards 31/32/33, Clarendon Wing in Leeds Children’s Hospital at Leeds General Infirmary and do not have to present to the Emergency Department.
Families should ring the paediatric haematology clinic (0113 3927379) or ward 31 (0113) 3927431 for assessment and or admission.
If patients present to the general paediatric unit or emergency department, refer to ward 31.

Presentation
Diagnosis of sicking disorder confirmed?
Sickle trait does not result in vaso-occlusive crisis other than in very low ambient pO2
(Sickle test is positive in trait but is associated with insignificant anaemia, no irreversibly sickle cells on blood film, and Haemoglobin electrophoresis AS pattern)
Sicking disorder may be due to following homozygous/heterozygous states
SS/ SC /SB thal trait /S O arab/ S D Punjab
(For diagnosis confirmation ensure two test results are available confirming the diagnosis including one after the age of 6 months
Organise the testing of parents and siblings unless already available)

Possible forms of crisis

Pain
Sequestration
Chest syndrome
Abdominal crisis
Stroke
Aplastic

Any other form of paediatric presentation may coexist with sickle cell disease

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Assessment

  • Basic paediatric assessment
  • Is patient shocked/ dehydrated?
  • Is there a neurological compromise - consider cerebral infarct, cerebral haemorrhage, transient ischaemic attack, seizure?
  • Is there enlarged liver or spleen - consider sequestration crisis?
  • Abdominal pain/ distension
    • consider abdominal crisis
    • consider surgical abdomen
    • consider constipation
  • Is there fever, tachypnoea, chest pain, hypoxia, chest signs - consider acute chest syndrome?
  • Is there severe anaemia?
  • Is there priapism?
  • Is there evidence of infection?
  • Is there pain?

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Initial assessment of emergency presentation of patient with sickle cell disease

Management

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Painful crisis +/- fever

Admission
Observe child for a minimum of 4 hours. Admit overnight if febrile, pain cannot be controlled with standard analgesia or the child cannot tolerate oral hydration at maintenance rate. Standard analgesia includes regular paracetamol and ibuprofen. Dihydrocodeine may be used in addition but with careful observation of tolerability. (Many painful crises can be managed at home however, referral to hospital is often a call for help)

  1. Introduce analgesia
    Score pain
    On admission, 30 minutes after introduction or change in analgesia and 2 hrly as per poorly bear score or linear analogue scale depending on maturity of child.
    Record score on the PAWS (Paediatric Advanced Warning Score) chart.
    Administer analgesia
    Follow Trust intranet Leeds Health Pathways pain guideline ‘Paediatric Acute Pain Management Manual for Children’.

  2. Assess need for intravenous fluids.
    if mild pain oral hydration at maintenance rate may suffice. If need for opiate analgesia patients should be started on 2L/m2 intravenous fluids (0.45% sodium chloride, 5% glucose). Increase rate to 3L/m2 if pain does not improve. Patients with sickle cell disease are unable to concentrate urine appropriately but close fluid balance and chest examination is important to avoid pulmonary oedema.

    Cannulation of veins in the legs, ankles and feet should be avoided because of the risk of venous thrombosis and leg ulceration. Central lines, including femoral lines, should be avoided unless needed for life-saving blood transfusions, because of the high rate of complications.

  3. Assess need for Oxygen 
    Oxygen should be given if pulse oximetry shows the oxygen saturation is
    below the patient’s known steady-state level. If a patient’s steady-state oxygen saturation is not known, then oxygen should be given when the pulse oximetry shows
    oxygen saturation is below 95% or within 3% of the patient's baseline (specific indication for sickle cell patients).

  4. Assess need for incentive spirometry
    Incentive spirometry should be used in children with acute chest and back
    pain since it has been demonstrated to reduce the risk of chest crisis. Please refer to the ward physiotherapy team.

  5. Assess need for antibiotics
    Start oral or intravenous co-amoxiclav if the patient is febrile (temperature
    >38oC), generally unwell, has chest symptoms or signs, or infection is suspected for some other reason. If penicillin allergic please consult with on call microbiologist. (Cephalosporins not recommended for patients on the paediatric haematology ward because of previous ward related clostridium difficile infection)
    If chest signs are present, a macrolide should also be given, e.g. clarithromycin.
    If a patient is receiving iron chelation with desferrioxamine or deferiprone and has abdominal pain or diarrhoea, the chelation should be stopped, blood and stool cultures sent, and ciprofloxacin given to treat possible Yersinia infections.

    All children should be taking penicillin V prophylaxis and this should be continued unless alternative antibiotics providing cover for encapsulated organisms have been started.
    If patient is systemically compromised with sepsis or shock or deteriorating despite first line antibiotics discuss with microbiology for advice
    It is established that sickle cell patients are more susceptible to serious infection, particularly from Streptococcus pneumoniae, Haemophilus influenza B, meningococcus and Salmonella species, related to hyposplenism and more subtle alterations in immunity.
    White cell counts are routinely elevated in SCD and leucocytosis does not always equate with infection.

  6. Assess need for blood transfusions
    Avoid blood transfusion if possible given the general risks of transfusion and the specific risks of alloantibody formation in sickle cell disease. Always discuss the request for transfusion with the consultant on call.

    Indications for acute transfusion
    • Acute anaemia
      Parvovirus B19 infection (often accompanied by reticulocytopenia).
      Acute splenic or hepatic sequestration
    • Acute chest syndrome – early top-up transfusion may avoid the need for exchange transfusion
    • Stroke or acute neurological deficit – exchange transfusion is usually necessary to reduce the HbS to less than 30%, Hb 100-110g/L.
    • Multi-organ failure
    • Preparation for urgent significant surgery

Urgent red cell transfusion should be used in children with rapidly progressive acute chest syndrome and acute neurological symptoms aiming to achieve HbS level below 30% and Hb 100-110g/dl. This will often require an exchange transfusion.

Haemoglobin may fall 10–20 g ⁄ dl in an uncomplicated painful crisis, but blood transfusion is not routinely indicated. Blood transfusions should be used if the patient develops signs or symptoms which may be due to anaemia, including unexplained tachycardia, tachypnoea, dyspnoea and fatigue. A low reticulocyte count (< 100x109 ⁄ dl) and falling haemoglobin make transfusion more appropriate.

Typically, blood transfusion will not be necessary unless the haemoglobin has fallen more than 20 g ⁄ dl and is below 50 g⁄ dl, and should aim to return the haemoglobin to the steady-state level.

Blood should be leucocyte depleted, HbS negative, and matched for Rh (C, D and E) and Kell antigens. Less than 14 days old for top up and less than 7 days old for exchange and ideally large volume packs if exchange needed. Use standard SAG-M blood, usual haematocrit is (0.45- 0.55).
Volume required (ml) = desired increment (g/ L) x body weight (kg) x 0.35*
*This factor may be reviewed - refer to paediatric haematology transfusion guidance

Exchange transfusions are indicated for severe chest crises, suspected cerebrovascular events and multi-organ failure.

Whole blood viscosity increases with increasing haemoglobin so oxygen carrying capacity of sickle cell patient peaks at haematocrit 0.35- 0.4 then falls whilst risk of further vasoocclusion increases. Therefore do not exceed this level of haematocrit - if top up transfusion not effective for clinical presentation consider exchange transfusion instead.
See details for exchange transfusion on page 23.

  1. Clinical monitoring 
    Monitor for pain, complications of sickle cell disease and complications of treatment throughout admission.

    Monitor pain every 30 minutes until controlled. Once controlled on a stable analgesic regimen monitor 2 hrly for pain (using a pain chart), sedation, respiratory rate and
    oxygen saturation.

    Monitor temperature and pulse, blood pressure every 4 hours or as indicated clinically or on the PAWS chart.

    Review fluid balance every 12 hours if receiving intravenous fluid replacement

  2. Investigations

    On admission
    All patients
    • Full blood count and reticulocytes
    • Urea, creatinine and electrolytes, liver function tests (LFTs)

Investigations for selected patients

  • Chest radiograph
    if febrile, breathless, tachypnoeic, chest pain, chest signs or oxygen saturations reduced below baseline or <95%
  • Amylase
    if increased jaundice, abdominal pain
  • Blood and urine cultures
    if febrile, rigors, hypotensive
  • Ultrasound abdomen
    abnormal LFTs, abdominal pain,
    splenomegaly/ hepatomegaly
  • Parvovirus B19 serology
    reticulocytopenia
  • Magnetic resonance imaging (MRI) scans of brain
    if seizure, transient ischaemic attack, stroke, severe headache - CT scan will miss early signs of ischaemic stroke
  • MRI scanning imaging or ultrasound looking for sub-periosteal fluid collection and surgical drainage may help to differentiate between limb ischaemia and osteomyelitis
    Limb radiographs should not be performed unless there are other worrying features, such as a history of trauma or persistent, unexplained swelling. Sickling may cause localized, painful swelling, and differentiation from osteomyelitis is difficult. High fevers, positive blood cultures and high C-reactive protein (CRP) level should increase the suspicion of osteomyelitis. Bone scans are generally unhelpful.
  • Malaria films should be sent if there is any suspicion of malaria or if a patient has returned from a malarious region in the previous year.

Monitoring

Check FBC alternate days and other tests as required clinically

Discharge

Patients may suitable for discharge when clinically well, afebrile, sustaining at least maintenance fluid oral intake and requiring only standard analgesia. Please arrange routine follow up on a Tuesday afternoon clinic within 2 weeks of discharge.

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Acute chest Syndrome

Definition
New pulmonary infiltrate involving at least one complete lung segment suggesting alveolar consolidation but excluding atelectasis with one or more of the following; chest pain, temperature greater than 38.5oC, tachypnoea, wheeze, cough.

Treatment

This is a serious complication - ring consultant on call

First line:

Analgesia - as per protocol for painful crisis and infection
Hydration - as per protocol for painful crisis and infection
Incentive spirometry - as per protocol for painful crisis and infection
Antibiotics - as per protocol for painful crisis and infection
Oxygenation - maintain 100% oxygen saturation on pulse oximetry
Bronchodilators if evidence of airway hyper reactivity.
Assess twice daily for fluid overload

If evidence of deterioration:

Change to broad-spectrum antibiotics: discuss with microbiology but consider piperacillin/tazobactam or meropenem in addition to macrolide

Check blood gases

Inform the PICU staff

Consider transfer to HDU or PICU

Consider blood transfusion aiming to correct anaemia and reduce HbS percentage, no advantage to exchange transfusion over simple transfusion but exchange indicated for patients with higher haemoglobin, such as patients with HbSC disease. Consider use of top up transfusion to correct anaemia and exchange transfusion for those who deteriorate despite this.

Anecdotal evidence for benefit from continuous positive airways pressure (CPAP), dexamethasone.

Causes
It may be a complication of admission with other sickle cell disorders including pain or have no specific cause identified.
Other causes include infection, fat embolism, vaso-occlusion.
Infections associated with acute chest syndrome, Chlamydia pneumonia: 7%, mycoplasma: 7% respiratory syncytial virus: 4%, streptococcus pneumonia: 2%, legionella: 0.6%. Others include tuberculosis, atypical mycobacteria, salmonella, influenza, pandemic influenza A (H1N1).

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Acute neurological complications

This is an emergency - Call consultant on call

Start 2L/m2 per 24 hours intravenous fluids

Arrange an urgent CT and/or MRI scan to define the event and exclude a haemorrhagic component.

Inform on call paediatric neurology consultant

Inform intensive care staff if respiratory depression

Intracerebral or subarachnoid bleeds defined by such imaging may need to be followed by lumbar puncture (if safe), and, in some situations, surgical intervention. Although stroke in a child with SCD is likely to be secondary to cerebrovascular pathology, it is important to remember that stroke in childhood can result from alternative pathology.

Symptoms suggestive of meningitis require urgent investigation, including lumbar
puncture, blood culture and prompt antibiotic treatment.

In children with sickle cell disease and arterial ischaemic stroke:

i) Arrange urgent exchange transfusion to reduce HbS to <10% and raise haemoglobin to 100–125 g/L. For website see below:

http://hospital.blood.co.uk/patient-services/therapeutic-apheresis-services/how-to-make-patient-referrals-to-tas/

Within hours contact

Floor 3 Bexley Wing
St James University Hospital
Beckett Street
Leeds
LS9 7TF
Tel: 0113 206 8131
Fax: 0113 206 8131
Leeds.TAS@nhsbt.nhs.uk

TAS Lead Consultant - Dr Marina Karakantza MBBS, MD
Consultant in Haematology NHS Blood & Transplant
TAS Lead Nurse - Abby Wilson

Outside normal working hours

Telephone the Leeds NHSBT Hospital Services Department on 0113 820 8607and ask to be transferred to the on call patient clinical team consultant. The on call consultant will discuss your patient referral with you and make the necessary arrangements to treat your patient.

ii) if the patient has had a neurological event in the context of severe anaemia (eg splenic sequestration or aplastic crisis), or if exchange transfusion is going to be delayed for more than four hours, urgent top-up blood transfusion should be undertaken.

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Fulminant priapism

This is an emergency - Call consultant on call

Priapism is the persistence of erection that does not result from sexual desire and fails to subside despite orgasm. There are two kinds: low-flow ischaemic, which is the form seen in sickle cell disease (SCD) and high-flow priapism, which is associated with external trauma causing damage to the cavernosal artery (see appendix 1). Priapism is usually accompanied by pain and tenderness. It can occur in all age groups and onset can be anytime between 5 and 45 years, with the peak incidence among young adults (aged 20 - 25 years). A prolonged attack, lasting more than 3 hours should be treated as a surgical emergency as, if untreated, cavernosal fibrosis and impotence may ensue.

Treatment

Patients may be able to abort an attack early by increasing fluid intake, taking analgesia (eg paracetamol + dihydrocodeine +/- NSAID if no contra-indication), warm baths and moderate exercise.  If unsuccessful and priapism persists >3 hours, patients must immediately attend the paediatric unit since early presentation (<4 hours) is essential for good outcome.  The importance of early presentation should be reinforced at least annually at clinic visits.  Patients with stuttering priapism should be encouraged to empty their bladder last thing at night and on first awakening.  Those who have had aspiration should be encouraged to refrain from sexual activity until the pain and swelling has resolved.

Management of a fulminant episode
This should be treated as a medical emergency. Admission should be via paediatric haematology at LGI.

Start 2-3L/m2 per 24 hrs intravenous fluids

Call on call paediatric surgical registrar

In patients known to have SCD presenting with fulminant priapism, diagnostic procedures such as intracorporeal blood sampling and duplex ultrasound should not delay therapeutic intervention.

Establish the duration of priapism, measures taken to relieve priapism at home, precipitating factors (dehydration, alcohol, medication, infection), previous history and frequency of priapism and previous surgical treatment (eg shunt). Confirm priapism.

  • Initial treatment (irrespective of duration of priapism) should include analgesia (this will often be opiates as per the patient’s usual sickle cell treatment) and an anxiolytic (eg diazepam).  Bladder emptying should be encouraged (consider catheterisation).  Oral hydration, or if unable to tolerate this, IV fluids.  Moderate exercise.  Ice should NOT be used.  If these measures relieve priapism, admit under urology for observation and check routine blood tests (U&E, LFT, FBC, CRP, G&S).  Patients must be seen in the haematology clinic within 2 weeks to assess efficacy and tolerance.
  • If initial treatment not effective seek advice form urology team on call.
  • Consider use of pseudoephidrine, seek pharmacy advice but suggested doses : adults 30-60mg qds; children 15-60 mg qds according to age as per BNF.   
  • If priapism does not rapidly settle with initial management or if priapism already >6 hours, the patient should receive intracorporeal aspiration (+/- irrigation with 0.9% sodium chloride) and injection with phenylephrine or dilute epinephrine.
  • If intracorporeal treatment is unsuccessful, consider on-call exchange transfusion (this will require insertion of a femoral line if venous access is poor, target Hb < 100 g/L)
  • If exchange transfusion ineffective, consider epidural analgesia.  Plan for a surgical shunt.  A distal procedure is preferred first line.

 

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Osteomyelitis / bone infarction

Osteomyelitis most commonly affects the diaphyses of the femur, tibia or humerus. Leukocytosis, raised inflammatory markers and periosteal and paraosteal soft tissue enhancement cannot differentiate between osteomyelitis and acute infarction, most helpful investigation is a positive culture.

A special form of bone infarction can occur in infants who have dactylitis.

Investigation
Discuss with radiologist regarding benefits of ultrasound vs. MRI. If ultrasound performed showing a greater than 4mm depth of periosteal fluid elevation aspiration and gram stain should be considered. If ultrasound is negative but the pain persists discuss with radiology regarding MRI or 3 phase bone isotope scan.

Treatment
As per painful crisis/ infection
Consider need for cover for bone specific organisms eg. Salmonella - discuss with microbiologist

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Splenic or liver sequestration

Features
Significant fall in haemoglobin
Reticulocytosis
Abdominal pain, enlarged liver or spleen with associated organ dysfunction

Treatment
As per painful/ infective crisis and top up transfusion
If no resolution with top up transfusion consider exchange transfusion

Children with two or more episodes of acute splenic sequestration, should be
considered for splenectomy.

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Changes in vision

Unexpected changes in vision in a child with sickle cell disease requires urgent ophthalmic review to exclude ocular disorders.

NOTE this symptom may represent a visual cortical event so management of an acute stroke may be needed.

Sickle cell disease

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Out patient management

Aims
Encourage adherence to treatment – particularly prophylaxis and immunisation programmes; to continue education; to offer screening tests; and to monitor general health, nutrition and growth

Features to address in clinic

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Diagnosis

All parents/carers of an infant who has been diagnosed via the new-born screening programme should be given the result by the time the child has reached 4 weeks.

Babies are to be registered by eight weeks by the designated healthcare professional within the haemoglobinopathy team. This registration will include a request for diagnostic testing and confirmation that penicillin has been prescribed. Ensure referral sent to the Leeds sickle cell community service if transferred from out of area.

First consultation should include following investigations:

  • Full blood count
  • Haemoglobin electrophoresis for confirmatory result by 3 months (and one sample after 6 months if there is doubt)
  • Reticulocyte count
  • Blood group and extended red cell phenotype
  • G6PD level

As G6PD deficiency is common in the same ethnic groups and also induces haemolysis, it is advisable to test for G6PD at the first new-born visit when the degree of reticulocytosis is unlikely to produce falsely elevated results.

Confirm that the testing of parents and siblings is undertaken and offer genetic counselling,

Confirmatory results should be sent to the new-born screening laboratories for quality control.

DNA analysis should be requested in cases where the diagnosis is unclear.

Penicillin prophylaxis should be started before 3 months of age; start while waiting for clarification of diagnosis, if this is delayed

Appropriate written information should be made available regarding the diagnosis, important clinical signs and management plans. Information regarding the key contacts for advice and queries should be provided. The family should additionally be given the contact details for local or national patient help groups.

Annual review in the Leeds.centre should be offered in conjunction with regular review at the local centre.

Send information regarding diagnosis and management plan to the general practitioner and shared care paediatrician and community nurses as appropriate.
A copy should also be sent to the parents / patient as appropriate.
If patients move a referral letter and copy letters will be sent to the new consultant.
As well as organising regular routine review please make a specific annual review clinic appointment at 6 months of age and annually thereafter.

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Review of Patients Previously Treated Outside the UK

Immediate assessment

Full history and examination

Immediate investigations

Full blood count
Haemoglobin electrophoresis
Reticulocyte count
ABO and full red cell phenotype and antibody screen. (If recently transfused, DNA studies for red cell antigens, via Reference Laboratory of National Blood Service)G6PD level

Serum or plasma ferritin assay

Hepatitis B & C serology to include Hep B surface antibody titre

HIV serology preceded by pre-test counselling

Full renal, liver, bone, random glucose, TFTs,

Other specialist assessments

If diabetic, specialist diabetic clinic - arrange GTT if glucose tolerance uncertain

If other endocrinopathies, endocrine clinic

If hepatitis B antigen or C antibody positive, hepatology clinic

Patient and family should be offered genetic counselling, as appropriate

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Further general clinic review

 

Examination

Investigations

Management considerations

Routine review

First 2 years : 3-monthly
2- 5 years : 6-monthly
>5 years annually

ensure follow up of patient who was not brought to clinic by liaison with the haematology Nurse Specialist and social worker

Height and weight

General exam. Including pallor, jaundice, heart murmur

 

Spleen size - educate parents in assessing spleen size

Blood pressure

FBC

Not needed at every visit but a series is needed to confirm baseline haemoglobin levels

See narrative: include

Symptom review
Days lost from school/work
School progress
Prophylaxis adherence

Management of pain at home
Access to ward / clinic

Travel plans
Nocturnal enuresis

Snoring and obstructive apnoea, restlessness at night, kicking off bed clothes, sweating, tired on waking all suggestive of reduced nocturnal pO2
If symptoms are suggestive refer for O2 oximetry by paediatric community nurses
Review growth
Need for psychology input for patient or family?

Annual review
for all patients in the centre and shared care centres

As above + assessment of puberty ≥ 10 yrs

FBC
Zinc
Vitamin D
Hepatitis C serology if transfused
Record results of trans cranial Doppler study

Oxygen saturation
U and E, LFT

As above +
TCD results
O2 results
Hydroxycarbamide?
Stem cell transplantation? Surgery?
Splenectomy?
Need for Zn/ Vit D?
Evidence of pulmonary hypertension – need for echo?
School attendance issues?
Need for psychology input?
Request appropriate asplenia vaccinations from GP surgery as per DOH Immunisation against
infectious disease ‘Green Book’
Health promotion and sexual advice at appropriate age
Initiate transition pathway from aged 12 years

Features to address in clinic
History

  • Record symptoms since last review:
    Number of and a review of painful episodes, illnesses, A & E attendances and hospital admissions since the last consultation
  • Number of days lost from school/ college or work
  • A systematic enquiry about symptoms eg. abdominal pain, pica, priapism, headaches, snoring, other neurological symptoms suggestive of ischaemia
  • Adherence to penicillin prophylaxis
  • How pain and fever is managed at home
  • Outcome of developmental screening tests, school progress and achievement in national tests (eg SATs, GCSEs)
  • Travel plans
  • Nocturnal enuresis if present over the age of 6 years
    Snoring and obstructive apnoea should be documented and overnight oxygen saturations measured if the history is suggestive of obstructive apnoea, and a referral made for ENT opinion. Restlessness at night, kicking off bed clothes, sweating, tired on waking all suggestive of reduced nocturnal pO2 refer to community nurses for overnight O2 monitoring
  • Growth and development
    Puberty may be delayed by about 6 months in Hb SC and by 2-3 years in HbSS. Delayed skeletal maturation during adolescence allows for a longer growth period in the long bones. This results in normal adult height, and hence children and their parents can usually be reassured. Seek endocrinology advice if marked developmental delay.
    An endocrinology opinion should be sought if there are no physical signs of puberty in a girl at 14 years and a boy at 14.5 years

Advice for carers

  • Importance of penicillin
  • Importance of staying up-to-date with all vaccinations
  • Management of pain at home
  • Need to seek early advice for fevers, respiratory symptoms or other signs of infection, and how to access advice and admission if necessary
  • Recognition of unusual pallor and need to seek early treatment
  • Need to seek early medical advice if weakness (without pain), tingling, or loss of speech are observed
  • Detection of an enlarged spleen by palpation
  • Recognition of dactylitis and other painful crises
  • When to consult the GP
  • When to come to hospital in an emergency and contact numbers
  • Need for reporting any visual symptoms
  • Need to report any developmental concerns or falling-off in school achievement
  • General advice regarding keeping warm and avoiding sudden changes in temperature, care when swimming, maintaining a good fluid intake
  • Information that should be shared with child’s school
  • The need for any planned surgery to be managed jointly with the surgeon, anaesthetist and the SCD team
  • Travel advice
  • Genetic counselling, contraception
  • Specific advice of risks to future pregnancies
  • Avoidance of smoking and alcohol
  • Discussion to cover consideration of interventions including hydroxycarbamide, red cell transfusion and stem cell transplantation

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Treatment

Anti infective prophylaxis
Penicillin V should be offered to all children by the age of 3 months
<1 yr : 62.5mg po bd,
1-5 yr : 125mg po bd,
6 - 18 yrs : 250mg po bd

Erythromycin is a suitable alternative if penicillin allergy is documented

Vaccination schedule

All children should be fully vaccinated according to the national routine immunisation schedule. See The Green Book (Vaccination Guidance) for further information or for those with an incomplete vaccination history.

Ideally live vaccines should be avoided in patients receiving hydroxycarbamide. These include the MMR, yellow fever and live influenza vaccines. Ideally complete the MMR vaccination course before starting hydroxycarbamide. An option is to administer MMR at 12months of age and the second dose 3 months later. For children presenting after 2 years of age refer to Green Book

Additional vaccinations required in addition to the routine schedule outlined below:

Vaccine

Age

MenACWY

3 months

PCV13 +MenACWY

5 months

PCV13 + MenACWY

Between 14 months & 22months

PPV23

2 years

PPV23

7 years

PPV23

12 years

PPV23

17 years and 5 yearly thereafter

Influenza
Recommend the inactivated influenza
vaccine for patients receiving
hydroxycarbamide

Annually from 6 months

*Preschool booster contains the live MMR vaccine which should ideally be avoided in
patients taking hydroxycarbamide; this may have been given before commencing treatment.

Travel requirements
The yellow fever vaccine is live therefore advise caution in children on hydroxycarbamide. An individual risk benefit assessment is needed.
When travelling abroad to areas that are endemic for meningococcal disease, a further dose of MenACWY should be offered if a dose has not been given within the last 5 years (Note MenACWY also given with routine immunisations aged 14 years). This is in addition to other recommended travel vaccinations and malaria prophylaxis - seek destination specific advice.

 Supplements

Zinc sulphate replacement in zinc deficiency may lead to fewer infections and improved growth.

Iron supplementation should be given only if iron deficiency is documented.

There is no evidence that folic acid supplementation is beneficial, although this remains controversial.

Vitamin D deficiency is very prevalent. Recommended intake is 400 units vitamin D daily in the first year of life, regardless of manner of feeding, and 200 units to the age of 50 years. Refer to GP and Leeds Health Pathways for advice regarding supplementation.

 Specific system toxicity

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Neurology

In a multicentre sickle cell cooperative study in the USA, the overall incidence of stroke in SCD (HbSS) was 0.6/100 patient years. The highest incidence was between 2 and 5 years (1.02/100 patient years) and by the age of 20, about 11% of people with SCD had a clinically evident stroke.

Another important indicator of risk for stroke is a history of transient ischaemic attacks. Other reported risk factors – such as low baseline haemoglobin, high baseline leukocyte count, low overnight oxygen saturation, acute chest syndrome in the previous 2 weeks, frequent episodes of acute chest syndrome and high systolic blood pressure – are too insensitive to be of any value in evaluating a child, although high blood pressure obviously requires appropriate investigation and management.

Stroke is more prevalent in HbSS and HbS/ ß0 thalassaemia compared to HbSC and HbS/ß+ thalassaemia, although there is limited information regarding HbS/ß0 thalassaemia.

A large prospective follow-up study showed that a high-risk group for stroke can be identified by time-averaged mean velocities (TCDi) in the ICA/MCA/ACA segments >180cm/sec. The risk is also increased to a lesser extent in those with conditional velocities (155-179cm/sec) and in those with absent or low signal. This randomised, controlled trial showed that a first stroke could be prevented by regular blood transfusions in children with sickle cell anaemia and abnormal TCD scans.
(Note recent recommendation refer to a threshold of >200cm/sec)

About 17% of children with sickle cell anaemia have silent infarcts on MRI scan that are not associated with overt neurological episodes or symptoms. These are relatively small white-matter lesions, often in the anterior watershed distribution. They are associated with mild cognitive impairment, which may be picked up by neurocognitive screening tests. TCD screening in these patients shows normal results in 75% of cases; and there is, as yet, no evidence that silent infarcts can be prevented by blood transfusion or other intervention.

The relative hazard for overt stroke in a patient with a silent infarct is approximately 14 times those with a normal MRI. This compares to 18 times normal in a patient with a high-risk TCD.

Chronic transfusion has been established as effective secondary stroke prevention, reducing the risk of recurrent stroke from 50-75% to about 13%. The aim of the transfusion regimen is to maintain haemoglobin S below 30%. Some patients may be able to reduce the intensity of transfusions after 3 years to maintain haemoglobin S at 50%.

Trans Cranial Doppler scanning
-See algorithm in appendix
- Request MRI/A if high risk TCD after MDT discussion.

Appropriate imaging studies to assess the extent of cerebrovascular disease should also be arranged if there is evidence of cerebral vessel narrowing on TCD, learning difficulties, atypical symptoms such as unusual behaviour during acute pain, frequent headaches, fits, or other unexplained neurological, psychiatric or psychological symptoms.

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Respiratory

If oxygen saturations are <95%, overnight oxygen saturation monitoring should be performed. If the mean overnight oxygen saturation is <95%, the child should be investigated for cerebrovascular disease and obstructive sleep. Formal pulmonary function tests and echocardiography should also be arranged.

If pulmonary function tests suggest chronic sickle lung, the child should be monitored with regular pulmonary function tests and overnight pulse oximetry and high-resolution CT scan of the lungs should be considered. Treatment with home oxygen, hydroxycarbamide or regular blood transfusions should be considered in cases of deterioration

Echocardiography to assess pulmonary hypertension should be arranged if there is evidence of chronic sickle lung, chronic unexplained hypoxia (oxygen saturations <95%) or other symptoms/signs suggestive of pulmonary hypertension

A child with significant pulmonary hypertension should be referred to a
respiratory physician with an interest in sickle cell disease (Dr. Tim Lee).

 Renal

Enuresis above age of 6 years - refer to enuresis clinic (Dr J Darling) and check overnight oxygen saturations. Desmopressin may be an option.

Ophthalmology

Patients with HbSC and HbS/ßThal are more likely than those with HbSS to have serious ocular problems. Given the uncertainty about the natural history of this complication, there is no evidence to support routine ophthalmologic screening of children. Children and their carers should report any change in vision and be referred for an ophthalmologic opinion as a matter of urgency.

Gallstones.
There is no evidence to recommend cholecystectomy in asymptomatic
cases, but cholecystectomy is advised in symptomatic biliary disease.

Avascular necrosis
An MRI scan should be carried out where there is persistent acute pain in the hip or Shoulder.
A referral to an orthopaedic surgeon with an interest in sickle cell disease should be undertaken if pain persists
Initial treatment should be conservative, with analgesia, partial weight-bearing on crutches, and physiotherapy support.

Leg ulcers
Debridement of the ulcer and antibiotic therapy should be started if infection is present
Compression bandaging and physiotherapy should be arranged to improve ankle mobility
Oral zinc sulphate should be considered in children with persistent leg ulcers

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Hydroxycarbamide
(Alternative name hydroxyurea)

See Guidelines for the use of hydroxycarbamide in children and adults with sickle cell disease (Qureshi et al British Journal of Haematology (2018) 181, 460–475.)

First tested in SCD -1984
EMEA approval in 2007 – for children & adults with SCD

Clinical effects

Decreases clinical episodes of : Laboratory :
Painful episodes
Acute chest syndrome
Hospitalizations
Need for transfusion
Mortality
↑ Hb &MCV
↑ HbF & F cells
↓ Neutrophils
↓ Platelets
↓ Dense cells
↓ Reticulocytes
↓ LDH & Bilirubin

Mechanism of action
HbF induction
Reduces red cell adhesion
Improves cell hydration
Nitric Oxide donor
Reduces contribution of white cells, platelets & reticulocytes

Potential side effects

Short term
Some patients may experience mild gastrointestinal symptoms or hyperpigmentation of the skin and darkening of nails, which is not dose-dependent. Some patients note hair thinning. Marrow suppression, which is transient and reversible, is the most expected short-term effect. This side effect also contributes to the clinical benefits

Leukaemia
There is now compelling evidence that hydroxycarbamide, when used in the treatment of patients with haemoglobinopathies, carries no increased risk of leukaemogenesis.

Fertility
A number of studies addressing the effects of hydroxycarbamide on fertility have been published. These studies are small, and it is not possible to confirm the degree to which hydroxycarbamide impairs spermatogenesis and the reversibility of its effects, however abnormalities seen in sperm parameters in men with sickle cell disease do seem to be increased by hydroxycarbamide. The association of abnormal sperm parameters and fertility is not clear as men with low sperm number and abnormal morphology can still be fertile and the effect of hydroxycarbamide on male fertility have not been evaluated. The effect of hydroxycarbamide on male spermatogenesis and fertility when the drug is started in pre-pubertal children are unknown. In view of potential risks of teratogenicity the use of contraception is recommended for both male and female patients whilst taking hydroxycarbamide.

Indications
Recent guidelines addressing the use of hydroxycarbamide make the following recommendations (with level of grading)

  • The benefits of hydroxycarbamide, including preventing end organ damage (renal/splenic and retinopathy) +/- priapism (2D) should be discussed with all parents of children, adolescents and adults with SS/Sb0 to enable informed joint decision-making. There should be on-going discussion between provider and patient (1B)

  • Ongoing informed consent should be confirmed for all patients on hydroxycarbamide, at least at each Annual Review (1D)

Offer treatment with hydroxycarbamide to:

  • Infants with SS/Sb0 aged 9–42 months, regardless of clinical severity to reduce sickle cell complications (pain, dactylitis, acute chest syndrome (ACS), anaemia (1A)

  • Children aged >42 months, adolescents and adults with SS/Sb0, in view of the impact on reduction of mortality (1B)

Treat with hydroxycarbamide

  • Adults and children with SS/Sb0 who have 3 or more sickle cell-associated moderate to severe pain crisis in a 12-month period (1A)
  • Adults and children with SS/Sb0 who have sickle cell pain that interferes with daily activities and quality of life (1C)
  • Adults and children with SS/Sb0 and a history of severe and/or recurrent Acute Chest Syndrome (1A)
  • Children with TCD velocities in the range 170–200 cm/s (conditional risk category) to help prevent progression from conditional to abnormal TCD velocity (1B). The dose should be escalated to maximum tolerated dose (1C)
  • Children and adults with SS/Sb0 and symptomatic chronic anaemia that interferes with daily activities or quality of life (1C)
  • Children and adults with chronic hypoxia (1C)
  • Children who have started regular blood transfusions for abnormal Transcranial Doppler (TCD) can be switched to hydroxycarbamide therapy (with or without venesection) if they have received at least 1 year of regular transfusions and have no magnetic resonance angiography-defined severe vasculopathy (1A). Transfusion should be continued until they have reached maximum tolerated dose of hydroxycarbamide (1C)
  • In children and adults with a previous history of acute ischaemic stroke or infarcts, hydroxycarbamide should be recommended as second line therapy for secondary stroke prevention when transfusions are contraindicated or unavailable (1B)

Consider treatment with hydroxycarbamide

  • In patients with sickle nephropathy with persisting proteinuria despite angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker therapy (2C)
  • There is insufficient evidence to treat patients with SS/ Sb0 with pulmonary hypertension and avascular necrosis with hydroxycarbamide but it should be considered on a case-by-case basis (2C)
  • Adults and children with sickle cell disease (SCD) with genotypes other than SS and Sb0 thalassaemia who have recurrent acute pain, acute chest syndrome or episodes of hospitalisation and other indications on a case by-case basis (2C)

Considerations regarding fertility

  • Post-pubertal male patients should be considered for sperm analysis and cryopreservation prior to starting treatment with hydroxycarbamide (1C)
  • Consider stopping hydroxycarbamide pre-conception in male and female patients and in pregnant women (1C) if the patient is not at high risk of serious complications relating to sickle cell disease
  • Prenatally and during pregnancy, consider a transfusion programme if there is a severe clinical phenotype as an alternative to hydroxycarbamide treatment. (1C)
  • Contraception is advised for patients on hydroxycarbamide (1C)

Dosing of hydroxycarbamide
Perform baseline renal and liver function
Perform pregnancy test in post -pubertal females

In children who have not yet received their pre-school MMR booster consider giving this prior to commencing hydroxycarbamide (at least 3 months after the first dose) as ideally live vaccines should be avoided whilst taking hydroxycarbamide.

  • Commence at 20 mg/kg
    Use 5–10 mg/ kg/day as the starting dose if the patient has chronic kidney disease (estimated glomerular filtration rate [eGFR] < 60 ml/ min/1.73 m2) and hydroxycarbamide should be avoided if eGFR < 30 ml/min/1.73 m2.
    Single oral daily dose
  • Monitor FBC at 2 weeks and 8 weeks and renal and liver function every 8 weeks
    At two weeks review FBC, follow guidance below if haematological toxicity has occurred
    If neutrophil or platelet counts or Hb has dropped by more than 33%, review more frequently either in one or two weeks depending on degree of reduction of blood counts
    If neither of the above review in 6 weeks
  • If at 8 weeks of stable hydroxycarbamide dose

    Neutrophils > 2 × 10 9/l and
    Platelets > 150 × 10 9/l and
    Hb > 60 g/l and
    Retics > 80 × 10 9/l (unless Hb >90 g/l)
    And no deterioration in renal and liver function
    Increase hydroxycarbamide by 5mg/kg/day until maximum dose of 35 mg/kg/day

  • Monitor FBC and at 2 and 8 weeks and renal and liver function every 8 weeks after each dose increase and follow guidance as with initiation of treatment
  • Once a stable dose is established, safety monitoring should include FBC and reticulocyte count, U&E and LFT every 2-3 months.

Haematological toxicity

  • Neutrophils <1 ×109/l or
    Platelets < 80 ×109/l or
    Hb < 45 g/l or
    Retics < 80 × 109/l (unless Hb >90 g/l)

If toxicity as defined occurs, stop hydroxycarbamide and repeat FBC weekly until 2 weeks with:

Neutrophils >1×109/l and
platelets > 80 × 109/l and
Hb >45 g/l and
retics > 80 × 10 9/l (unless Hb >90 g/l)

But note caution above if >33% drop in blood counts

  • Start same dose if transient drop, or reduce by 5 mg/kg/day and monitor as per new dose instructions

 

  • Achieving clinical response may take many months

The patient and/or their parents should be given a patient’s information sheet and the use of hydroxycarbamide should be discussed with them on at least two separate occasions. Current knowledge about side effects, should be discussed. This discussion should be documented in the patient’s notes and written consent obtained.

See next page for parent/patient information.

Hydroxyurea (also known as Hydroxycarbamide) Use in sickle cell disease Guidance for parents and young adults

Traditionally the treatment for sickle cell disease (SCD) had been limited to pain relief and fluid for pain episodes, antibiotics for infection, and blood transfusions for serious complications. It was not possible to alter the course of the condition, except by bone marrow transplant. However, for the past 30 years a medication called hydroxycarbamide has been found to help a large number of patients.

What is hydroxycarbamide?

For decades, hydroxycarbamide has been regularly used in the treatment of different blood disorders. Recently it has been used for SCD and thalassaemia. There is a growing body of research evidence for use of Hydroxycarbamide in children and adults. The National standards of care: “Standards for the Clinical Care of Adults with Sickle Cell Disease in the UK” and “Sickle cell Disease in Childhood - Standards and Guidelines for Clinical Care” recommend the use of hydroxycarbamide in a variety of situations.

What does hydroxycarbamide do for a patient with the SCD?

The best evidence we have comes from two large multicentre studies conducted in America. In the first (published in 1994), a large group of patients received either hydroxycarbamide capsules or an identical looking dummy drug (placebo). In the second study known as the BABY HUG trial (published in 2012), either placebo or hydroxycarbamide was given to new-borns with sickle cell disease. In both studies, neither the patients/parents nor the doctors knew which drug they were taking, so that the benefits and any side effects could be monitored objectively. All patients were carefully followed up for a period of nearly two years. Following both studies, significant improvement in the health was noted in a majority of the patients receiving hydroxycarbamide, compared to those taking the dummy drugs.

The experiences were:

  • A longer pain-free period after starting treatment
  • Even longer period before the next painful episode
  • Fewer episodes of chest crises/sickle lung
  • Fewer blood transfusions

Overall, the treated patients had fewer and less severe crises. About 8 out of 10 patients improved substantially. Unfortunately, it is not possible to predict which patients are likely to benefit most. More recently the BABY HUG study showed beneficial effects in babies treated from birth.

How does hydroxycarbamide work?

It appears to work in at least three ways:

  • It increased the production of foetal haemoglobin. This takes some months or weeks to be effective.
  • It decreased the stickiness of the young red blood cells. When they stick to the blood vessel lining, they may start a sickle cell crisis. This is thought to be the reason why some people notice that they feel better quite soon after starting treatment.
  • It decreases the number of white blood cells and platelet, which are often raised in people with SCD. White blood cells produce a substance that cause inflammation and may worsen a sickle cell crisis. Having fewer white cells makes this less likely.

Platelets also contribute to stickiness.

How do I take it and what monitoring and precautions are needed?

Hydroxyurea come in a liquid (for children) or a capsule and is taken by mouth. Treatment will begin on a low dose daily, usually 20 mg/kg. The dose will be gradually increased every two months until the right dose is achieved. This will be the dose that gives you the most benefits. The decision will be based on your symptoms and he results of your blood tests. This process may take several months to complete, after which you will need blood test every two to three months. If there any unwanted effects for you or in your blood tests, the hydroxycarbamide may be stopped or recommenced at a lower dose.

Patients who are sexually active must use contraception while taking hydroxycarbamide as it has not been formally tested in such settings. Patient unwilling to be monitor regularly will not be eligible to use hydroxycarbamide.

Giving consent (permission)

If you or your child agrees to take hydroxycarbamide, you will need to sign a consent form. If you are under 18 years of age, a parent or guardian may be required to sign the consent form, though you can sign it too.

What to expect and side effects

Most patients remain well, and have very little or no side effects. Hydroxyurea affects blood cells being produced so noticing any difference may take a few weeks. It is important that you do not give up taking your medication - it may take a couple of months before you reach the right treatment dose and can benefit from the effects of the medication.

Hydroxyurea occasionally causes sickness and vomiting, skin rashes, hair loss, diarrhoea, liver damage, weight gain, and if the blood count drops significantly, infection or bleeding. It may also cause darkening of the nails.

Many people ask if hydroxycarbamide increases the risk of cancer. We all have a risk of developing cancer during our lifetime. Some medications increase this risk a little, and this is true of a number of medications which work in a similar way to hydroxycarbamide. However, there is no evidence that the risk of cancer is increased in patients with sickle cell disease who take hydroxycarbamide.

Effects on fertility

The evidence that hydroxycarbamide affects fertility is as yet unclear. Small studies have demonstrated a reduction in sperm count in male adults taking the drug. However it is not clear whether this change will affect the ability to have children or is reversed when the drug is stopped. The effects on fertility in younger children have not been established. As it has not been tested in large trials on pregnant women, hydroxycarbamide should be avoided when planning to start a family. Adolescents should discuss fertility, sperm bank collection and birth control on an individual basis with their consultant before starting this drug.

The doctors and nurses will be happy to discuss these issues with you in clinic.

Mike Richards
Consultant Paediatric Haematologist
Leeds Children’s Hospital
October 2018

Red cell transfusion

Indications for regular, long-term transfusion

We follow NICE guidance and recommend red cell exchange as preferred method of long term transfusion.

  • Primary and secondary stroke prevention
  • Recurrent acute chest syndrome not prevented by Hydroxyurea 
  • Progressive organ failure

In monthly top-up transfusions (e.g. for the management of stroke where the haemoglobin S is being maintained <30%), the target haemoglobin is between 120 and 130g/L.

First transfusion should aim to rise the Hb to 95g/L.
Check the post transfusion Hb and Hct and HbS% and ensure Hct has not exceeded 40%. If a higher Hct has been achieved admit overnight for Intravenous fluids.

2 weeks later second transfusion with a target Hb of 110 g/L. Check the post transfusion Hb and Hct and and HbS% and ensure Hct has not exceeded 40%. If a higher Hct has been achieved admit overnight for Intravenous fluids.

2 weeks later administer third transfusion with a target Hb of 130 g/L. Check the post transfusion Hb and Hct and and HbS% ensure Hct has not exceeded 40%. If a higher Hct has been achieved admit overnight for Intravenous fluids.

Further transfusions should occur monthly aiming for nadir Hb 110 g/L and Hb S% ≤30%. Initial target Hb should be 130 g/L but this may be increased to 145g/L if the target HbS% is not being achieved.

Iron loading should be monitored and chelation should be started in all children on a regular blood transfusion programme. Please refer to ‘Guidelines For Management of Children with Thalassaemia in Leeds Children’s Hospital’ on Leeds Health Pathways.

  • Immunisation against hepatitis A and B should be offered to all those on long term transfusion programmes.
  • Children receiving regular monthly blood transfusion should have a specific annual review.

Protocol for transfusion

Formula: Refer to unit guidance
Matched red cells for Rh (D, C, c, E, e) and Kell (K) blood group antigens

Large volume units should be chosen, preferably greater than 300 mls (for adults and children when one or more full unit is required), and wherever possible units should be less than 2 weeks old. No more than 3 attempts to site a cannula should be made by any one individual

Record dates of transfusion, the patient weight, the volume of blood transfused at each episode and the estimated haematocrit of the transfused blood (available from the blood transfusion laboratory)

Pre-operative transfusion

The optimal pre-operative transfusion policy in sickle cell disease is not clear. There is only one randomised controlled trial, which showed that a conservative transfusion regimen which raised haemoglobin to 100g/L was as effective in preventing peri-operative complications as an aggressive exchange regimen which reduced HbS to <30%. Transfusion may not be necessary at all for many procedures, including cholecystectomy and adenotonsillectomy.

Exchange transfusion in sickle cell disease

Ensure the patient is well hydrated prior to exchange
Do not use diuretics prior to transfusion
Continue to administer intravenous fluids between transfusions at the standard rate of 2.5-3L/m2 per 24 hours

Automated erythropheresis

The safest form of exchange transfusion in patients with Sickle Cell disease is an automated erythropheresis procedure undertaken by the National Blood Service.  This is available within hours and also as a 24 hour service in an emergency. See guidance in transfusion section. It is important the apheresis team is contacted early in the day for time to make appropriate preparations. Unless the child is large with excellent peripheral venous access, a femoral or jugular catheter will require insertion by the anaesthetist.  Therefore, if an exchange is predictable, keep the child nil by mouth and contact the On Call Registrar for anaesthetics or the Paediatric Intensive Care unit.

Targets

  1. Reduce haemoglobin S percentage to less than 20%.
  2. Keep haemoglobin less than 100g/L
  3. Maintain steady blood volume in patient throughout the procedure

Red cell requirements
Freshest available blood.
ABO compatible, rhesus negative, E negative and Kell compatible (or Kell negative) red cells.

Investigations before exchange transfusion
Full blood count,
Percentage Haemoglobin S,
Extended red blood cells group phenotyping (if not already known)
Urea and electrolytes
Calcium

Venous access
Two ports of venous access needed - one for venesection the other for transfusion.

Reliable access for transfusion is essential so that hypovolaemia does not occur; in an emergency it is often advisable to use a central line.
Do not remove blood until venous access for transfusion is secure

Principles of a manual exchange:

  • An exchange transfusion should be an isovolaemic procedure i.e. equal volumes in and out.
  • Ensure the child is well hydrated between successive exchanges
  • Continue to administer intravenous fluids between transfusions at the standard rate of 2.5-3L/m2 per 24 hours
  • Do not use diuretics prior to transfusion
  • Meticulous documentation essential
  • Throughout, the haemoglobin should be less than 100g/L aiming to reduce the haemoglobin S percentage to less than 30%.

Preparation for an emergency manual exchange transfusion procedure:

  • If not already done
    • Call for senior help
    • Stabilise the patient
    • Ensure senior nursing team aware
    • Ensure laboratory aware
      • Request volume of packed red cells (mls)
    • Inform PICU of a critically unwell child
    • If the starting Hb<60g/L then discuss with a consultant haematologist (may need to start with a top up)
  • Prepare Equipment:
    • Site 2 cannulas (as large as possible) or an arterial line and cannula (may require anaesthetic support)
    • Obtain empty venesection bags from blood bank
    • Prepare a trolley with 3 way taps and 50ml syringes, flushes and swabs
    • Prepare a detailed fluid balance chart: advisable to document volumes in and out every 15 minutes to avoid errors
    • Take baseline bloods if not already done
      • FBC, HbS%, Electrolytes, Arterial Blood Gas, hepatitis serology
      • It is not necessary to wait for a pre-exchange HbS% results before starting the exchange

Calculations and Procedure:

  • Total volume exchanged: 30mls/kg
  • Volume of blood to remove: 30mls/kg
  • To be replaced with 30mls/kg of
    • Packed red cells: 15mls/kg
    • 0.9% sodium chloride: 15mls/kg
  • All procedures take 4 hours
  • Rate of red cells or fluid going in: 7.5mls/kg/hour
    • Matched by rate of whole blood removal

1st Hour:

  • Venesect 7.5mls/kg of blood in aliquots of 10-50mls using a large syringe.  The venesected blood can be discarded into a venesection bag using a 3-way tap (see photo).
  • Simultaneously (using another IV line) infuse 0.9% sodium chloride at the same rate (7.5mls/kg/hour) to maintain isovolaemia. 

2nd hour:

  • Venesect 7.5mls/kg in 10-50ml aliquots and discard
  • Simultaneously (using another IV line) transfuse red blood cells at the same rate (7.5mls/kg/hour) to maintain isovolaemia.  Do not allow blood to be

transfused without being certain that the patient’s blood can be venesected out.
3rd Hour:

  • Venesect 7.5mls/kg in 10-50ml aliquots and discard 
  • Simultaneously (using another IV line) infuse 0.9% sodium chloride at the same rate (7.5mls/kg/hour) to maintain isovolaemia. 

4th Hour:

  • Venesect 7.5mls/kg in 10-50ml aliquots and discard 
  • Simultaneously (using another IV line) transfuse red blood cells at the same rate (7.5mls/kg/hour) to maintain isovolaemia.  Do not allow blood to be transfused without being certain that the patient’s blood can be venesected out.

At end of any/each exchange procedure:

  • Check FBC, HbS%, Electrolytes, Calcium, Clotting
  • Ensure final Hb does not go over 100g/L and the final Hct remains <0.4.  If the post transfusion results are above these then further venesection may be required.
  • A top up transfusion of packed red cells can be given at the end of the final procedure to give a final Hb of 100g/L (but no higher)

Example calculations for 2 patients:

Patient = 15kg.  Volume to be exchanged = 30mls/kg = 450mls.  Rate = 7.5mls/kg/hour

 

Blood Out

Red cells In

0.9% sodium chloride Saline In

1st Hour

112mls

Nil

112mls

2nd Hour

112mls

112mls

Nil

3rd Hour

112mls

Nil

112mls

4th Hour

112mls

112mls

Nil

Totals

448mls
30mls/kg

224mls
15mls/kg

224mls
15mls/kg

Patient = 45kg.  Volume to be exchanged = 30mls/kg = 1350mls.  Rate = 7.5mls/kg/hour

 

Blood Out

Red cells In

0.9% sodium chloride In

1st Hour

337mls

Nil

337mls

2nd Hour

337mls

337mls

Nil

3rd Hour

337mls

Nil

337mls

4th Hour

337mls

337mls

Nil

Totals

1348mls
30mls/kg

674mls
15mls/kg

674mls
15mls/kg

Monitoring:
Meticulous monitoring, documentation of volumes exchanged, fluid balance and observations is mandatory.

  • Every 15 minutes:
    • Pulse, Bp, Oxygen saturations, Temp

Subsequent exchange transfusion procedures:
In critically ill patients exchange procedures may need to be continuous to reduce the HbS% to less than 25%.  Where possible, however, at least 4-6 hours should be left between each exchange procedure.

With very large volume exchanges it is possible to induce coagulation abnormalities because the procedure involves the removal of whole blood (including plasma containing coagulation factors) whereas the replacement fluid (packed red cells or 0.9% sodium chloride) has essentially no coagulation factors.

For subsequent procedures whilst it is reasonable to use the above calculations, it may be necessary to adjust the volumes of transfused blood and infused 0.9% sodium chloride in order to prevent the final Hb from rising too high.  This decision should be discussed with the Paediatric  Haematology consultant when planning the procedure.

Possible immediate complications of exchange transfusion:

Please document in the notes that these have been explained to the parents.

  • Anaphylactoid reactions due to HLA antibodies
    • Treat with antihistamine and/or corticosteroid
  • Metabolic disturbances are rare, occurring usually in small children, or in association with visceral sequestration requiring continuous exchange
  • Convulsions are very rare. They are usually a sign of cerebral sludging, often in patients with previous CNS problems
  • Check that Hb has not risen too high (> 100g/L)
  • Give anticonvulsants according to APLS
  • Ensure patient is well hydrated (but avoiding fluid overload)
  • Give oxygen
  • Hypertension is occasionally seen in patients with circulatory overload
  • If diastolic BP increases by > 20 mmHg
    • Slow down exchange rate
    • Check Hb not >100g/L or Hct not > 0.4
  • If diastolic BP is > 100 mmHg stop the exchange
  • Venesect
  • Consider antihypertensives and/or prophylactic anticonvulsants

Troubleshooting

Problem

Action

Patient unstable

May require PICU transfer.  Continue exchange whilst arranging.

Transfusion reaction

Manage as per Trust Transfusion guidelines

Unable to withdraw blood but red cells have already been transfused into patient

Stop giving red cells.  May need to venesect excess blood to re-establish equivalence.  Monitor volumes exchanged more closely to avoid large inequalities between in and out

Diastolic Bp >100mgHg

Stop exchange.  Consider venesection.  Check FBC and Hct

Seizures

Stop exchange. Manage as per APLS. Check blood for causes or metabolic disturbances

Photographs: Manual Exchange Transfusion

Assessment of iron loading and chelation in children on long term transfusion programmes

Please refer to ‘Guidelines For Management of Children with Thalassaemia in Leeds Children’s Hospital’ on Leeds Health Pathways

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Bone marrow or stem cell transplantation

Bone marrow/stem-cell transplantation is the only treatment for SCD which is potentially curative.

Published experience describes a 92-94% survival rate and a 75-84% disease-free survival rate.There is no recurrence of clinical vaso-occlusive events in patients with stable engraftment, but 10% of patients experience rejection or recurrent SCD.

The majority of patients have an excellent quality of life after bone marrow transplantation (BMT).

There are, however, significant risks associated with BMT. The most common early complications are acute graft-versus-host disease (GVHD) and neurological events, including intracerebral haemorrhage and seizures. Chronic GVHD is the most common cause of late mortality and morbidity, with an incidence of 5% in the UK. Other late complications include gonadal dysfunction and an increased risk of malignancy.

Unlike thalassaemia major, where the clinical course is fairly predictable, there is a large variation of severity in SCD. In view of this, and the high risk of mortality and morbidity from the procedure, BMT is not appropriate in every patient. The British Paediatric Haematology Forum suggested criteria for selection

Acceptance
UK acceptance criteria do change so referral to the stem cell consultant lead is indicated for any family contemplating this procedure.
Indications as of 2018 are as follows:

  • <17 years with HLA-identical sibling and informed consent
  • One or more of these SCD-related complications:
    vaso-occlusive crisis despite hydroxycarbamide (≥4 episodes / year requiring hospitalisation or impacting schooling), recurrence of acute chest syndrome despite hydroxycarbamide, CNS disease (stroke, abnormal transcranial Doppler [TCD] ultrasound and silent infarct or abnormal psychometric tests / poor school performance on formal assessment, silent infarcts with cognitive deficiency, significant abnormalities in MRA despite transfusions, abnormal TCD and generation of red cell alloantibodies, CNS disease requiring transfusions leading to significant iron overload despite optimum chelation treatment), or suboptimal medical care
    Problems relating to future care – to be decided on case-by-case basis

Exclusions

  • Donor with a major haemoglobinopathy
  • One or more of the following:
    Karnofsky performance <70%
    Portal fibrosis (moderate or severe)
    Renal failure (GFR <30%)
    Major intellectual impairment
    Stage III or IV chronic sickle lung disease
    Cardiomyopathy
    HIV infection

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Transition to adult services

Transition policy

Transition is ‘the purposeful planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adult-oriented health care systems.’1

The importance of transitional care has been highlighted in the Children’s National Service Framework Hospital Standards 2, Improving the transition of young children with long term conditions to adult health services 3 and the intercollegiate report, Bridging the gaps: health care for adolescents4. This includes a requirement for children and adult services to take the needs of this group of patients into consideration when planning and developing services.

Here at Leeds we follow the “Ready, Steady, Go” programme developed by Southampton University Hospital5. This is a generic programme, as many of the problems faced by each sub-speciality group during transition are similar. Through this program we ensure the medical, psychosocial and vocational needs of the young person are being addressed by following a structured, but adaptable, transition plan. A key principle throughout the process is ‘empowering’ the young person to take control of their lives and equipping them with the necessary skills to be able to function independently and confidently in adult services.

The transition programme starts with a “Moving to Adults” information leaflet and a questionnaire which, through a series of structured questions, is designed to establish when the patient is likely to be ready to move to adult services and what needs to be done to get “Ready” for the move to adult services. In due course this is followed up by a questionnaire to assess progress and keep them “Steady” and ensure that they have all the skills to “Go” to adult services at a time which has been mutually agreed by the patient, medical professionals and where appropriate parents.

The programme is facilitated through our Annual Review Clinic. The idea of transition and the gradual switch of focus from parent to young person, should be introduced at the first Annual review visit, as part of an overview of what parents can expect from annual review sessions (see annual review clinic policy)

The Moving to Adults Leaflet should be given to the young person when they move from primary to secondary education. Progress should then be assessed at each visit until the patient is ready to move to adult services.

At the point of transition to adult services, the annual review session will be attended by both Adult and paediatric Haematologists together with the Adult specialist nurse for red cell disorders and Charge Nurse for Paediatric Haematology.

Before the first appointment with adult services, the patient will attend a “Welcome to adult services” session. This session will include, a tour of the unit (outpatient clinic, day unit, in patients wards); information about how to book or rearrange an appointment and who to contact in an emergency.

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Haemoglobinopathy and Thalassaemia Specialist Centre

Leeds Children’s Hospital

Service Organisation Standard Operational Procedure

‘Fail-safe’ arrangements for ensuring all children with significant haemoglobinopathy disorders who have been identified through screening programmes are followed up by a Specialist Haemoglobinopathy Centre.
On identification of a new diagnosis of a thalassaemia or haemoglobinopathy patient the Lead BMS of the Screening Laboratory, Lisa Farrar, will e-mail and write to the Lead Consultant of the Leeds  Specialist Haemoglobinopathy Centre alerting him/her to this new diagnosis. Documents to complete on review of the patient in clinic and repeat haemoglobin electrophoresis are forwarded to the Lead Consultant.

Ensuring all patients are reviewed by a senior haematology decision-maker within 14 hours of acute admission.
A consultant led ward round of all the paediatric and young adult haematology and oncology in-patients each morning assuring review of all newly admitted patients by midday. Sickle/thalassaemia patients are managed against a clear protocol so ensuring that delegation for the 14 hour standard is achieved even if physical review by a consultant has not occurred.

Patient discussion at multi-disciplinary team meetings
All children and young adults with thalassaemia or a haemoglobinopathy attending clinic are discussed with all clinic consultants and junior doctors and the lead haemoglobinopathy nurse or another senior nurse at a pre-clinic meeting.  Support from a named social worker is available as needed. Regular multidisciplinary review of red cell exchange patients is undertaken at meetings attended by a lead apheresis nurse, the lead haemoglobinopathy nurse and lead haemoglobinopathy consultant. Regular multidisciplinary review of patients potentially eligible for stem cell transplantation is undertaken with the stem cell transplant team. The commissioning arrangements for the community service is currently under review, it is a priority to establish a multi-disciplinary meeting with community clinical teams, acute Trust teams, laboratory  and screening teams once arrangements have been finalised.

Arrangements for liaison with community paediatricians and with schools
Joint care with community paediatricians is arranged as required through written referral and telephone conversations as needed. Care plans are sent to schools and liaison including school visits is organised when a new starter with a haemoglobinopathy or thalassaemia diagnosis first attends. Specific intervention is undertaken if a specific need is identified. Reports from schools are important as part of the annual review data set.

Fail-safe’ arrangements for ensuring all children and young people have Trans-Cranial Doppler ultrasound when indicated
The Lead Consultant and Lead Nurse are notified in writing of cases who fail to attend TCD scans by the paediatric radiology department. Direct contact with the families is made by the Lead Nurse to explore reasons for non-attendance and re referral to TCD service is completed by lead Consultant.

Follow up of patients who do not attend
Case notes of patients who fail to attend clinic are reviewed by the Lead Consultant who will offer a further routine appointment or liaise with the GP/ Local consultant. The Lead Nurse will contact the family directly as they may have moved out of the area or need support. A social worker will be  informed if safeguarding concerns exist.

Transfer of care of patients who move to another area, including communication with all SHC, LHTs and community services involved with their care before the move and communication and transfer of clinical information to the SHC, LHT and community services who will be taking over their care.
There is written +/- verbal communication to identified new haemoglobinopathy teams and GP and apheresis unit as needed if a patient is transferred to another centre.

Accessing specialist advice
All specialist services are available in Leeds Children’s Hospital, written referral to relevant service is undertaken or telephone contact is made if urgent referral is necessary.

Two-way communication of patient information between SHC and LHTs
Clinic copy letters are sent to LHT consultants and well as phone/e-mail  conversations when indicated. GPs also receive copy letters as do parents/patients if significant changes in treatment planned. Blood results from many local hospitals are available on Open-net ICE pathology server and are  reviewed in Leeds on an ongoing basis eg. serum ferritin. Copies of Leeds Children's Hospital haemoglobinopathy guidelines are circulated when updated/reviewed.

M Richards
Lead Clinician
Leeds Children’s Hospital
Specialist Haemoglobinopathy Centre

Provenance

Record: 2931
Objective:

To provide evidence-based recommendations for appropriate diagnosis, investigation and management of sickle cell disorders

Clinical condition:

Sickle cell disorders

Target patient group: Children
Target professional group(s): Allied Health Professionals
Secondary Care Doctors
Secondary Care Nurses
Primary Care Doctors
Adapted from:

Evidence base

References:

Society for Adolescent Health and Medicine, 1993. www.adolescenthealth.org

Getting the right start: National Service Framework for Children, Young People and Maternity Services: Standard for hospital services, 2003 Department of Health (Gateway reference 2003, product number 31352) (accessed 6 August 2010) http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_4067251.pdf

Improving the transition of young children with long-term conditions to adult health services, 2006 Department of Health (Gateway reference 5914, product number 271588) (accessed 6 August 2010) http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/Browsable/DH_4132944

Royal College of Paediatrics and Child Health. Bridging the gaps: health care for adolescents. London: RCPCH; 2003.

Southampton University Hospital trust. Ready steady go programme. www.uht.nhs.uk/ OurServices/Childhealth/TransitiontoadultcareReadySteadyGo/Transitiontoadultcare.aspx

Rees DC, Olujohungbe AD, Parker NE, et al; British Committee for Standards in Haematology. Guidelinesfor the management of the acute painful crisis in

sickle cell disease. Br J Haematol. 2003;120:744-52.

Sickle cell disease in childhood

Standards and guidelines for clinical care

2nd edition October 2010

Sickle cell acute painful episode. NICE clinical guideline 143 (June 2012)   1 

Issue date: June 2012

NICE clinical guideline 143 Developed by the Centre for Clinical Practice at NICE

The evidence was reviewed in August 2016, no major studies were identified  that would affect the recommendations in the next 3–5 years.

Stroke in childhood

Clinical guidelines for diagnosis, management and rehabilitation

Prepared by the Paediatric Stroke Working Group

November 2004

Clinical Effectiveness

& Evaluation Unit

Royal College of Physicians

NIH Recommendations for use of HU in patients with sickle cell disease

Guidelines for the use of hydroxycarbamide in children and adults with sickle cell disease (Qureshi et al. British Journal of Haematology (2018) 181, 460–475.)

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.2

Related information

Not supplied

Equity and Diversity

The Leeds Teaching Hospitals NHS Trust is committed to ensuring that the way that we provide services and the way we recruit and treat staff reflects individual needs, promotes equality and does not discriminate unfairly against any particular individual or group.