Sickle cell protocol

During normal working hours patients can be assessed and treated on the Ward 2B Day Care unit with admission to the ward as needed. Out of hours - see flow chart below. The Haematology Middle Grade On Call should be informed of their attendance and will arrange admission to the ward where necessary. 

Sickle Cell Disease (SCD): Out with day care hours

CLINICAL ASSESSMENT:

A full history and examination must be carried out, paying particular attention to symptoms/signs of life-threatening complications, including acute chest syndrome, sequestration of aplastic crisis, or septicaemia. Extreme pallor, weakness, lethargy, breathlessness, headaches, fits, and priapism require urgent attention.

Note:

• The site and intensity of the pain
• Any analgesia already taken
• Any focus of infection (including the urinary tract)
• Chest symptoms and signs, including respiratory rate
• Liver and spleen size (cm)
• Degree of pallor, blood pressure

DISCHARGE FROM CASUALTY OR WARD:

If there are no other indications for admission, following discussion with the Haematology Specialist Registrar, a child can be discharged from Casualty or from Day Care with:

• A supply of oral analgesia
• Instructions to drink a minimum of 50ml/kg/day
• Antibiotics if there is any evidence of infection (refer to hospital antibiotic policy)
• A follow-up appointment for review, within a week, either on Ward 2B Day Care (or the next Sickle Cell Clinic [Thursday PM])
• Folic acid
• Prophylactic Penicillin V (Erythromycin bd if Penicillin allergic) 

ROUTINE INVESTIGATIONS (ALL CASES):

Blood Tests

• FBC and retics
• Group, screen and save
• Urea and electrolytes, bone profile
• Creatinine
• LFTs, LDH
• CRP
• Blood cultures

HbS % (only if on regular transfusion programme)

Microbiological Screen

• Urine dipstick and MSU culture
• Clotted blood to store
• Other cultures as indicated (see below)

Other Tests

• Pulse oximetry (SaO2) in air
• Chest x-ray if indicated (ie symptoms/signs)

ADDITIONAL INVESTIGATIONS:

Certain tests are done if indicated, as follows:

*X-rays of bones and joints show little or no change in the first week of an acute illness and rarely differentiate between infarction and infection. Ultrasound should be considered for suspected osteomyelitis. X-rays can be useful in confirming avascular necrosis as a cause of chronic or intermittent pain

INVESTIGATIONS (IF NEW TO THE HOSPITAL):

New patients to the hospital require all the routine investigations.

Additional Blood Tests

• Hb electrophoresis, including %HbF
• Full red cell phenotype - Rh, Kell, Fy^a+b, Jk^a+b
• G6PD
• Ferritin
• Hepatitis B and C serology
• CMV IgG
• Parvovirus serology
• Vitamin D

         Consider HIV serology

Management is supportive unless there are indications for exchange transfusion.  The aim of treatment is to break the cycle of: sickling, hypoxia and acidosis - all exacerbated by dehydration.  

GENERAL MANAGEMENT INCLUDES:  

• reassurance that the patient’s pain will be relieved as soon as possible
• warmth and establishing a position of maximum comfort
• analgesia
• hydration
• intravenous access if required for fluids, analgesia, antibiotics
• identification and treatment of infection
• regular observations and reassessment

ANALGESIA – SEE FLOW CHART BELOW

• Pain is the commonest cause of hospital admission and needs to be addressed urgently. Analgesia should be administered within 30 minutes of arrival and aim for pain control within 60 minutes.

• Pain in sickle cell disease may be very severe, and is often underestimated by healthcare professionals.

• Assessment should include analgesia taken prior to attending hospital.

• Pain assessment should include the use of an age appropriate pain assessment score, which may be helpful as part of the overall assessment of the patient.

• Non Steroidal Anti-inflammatory Agents (NSAIDs) and Paracetamol may have synergistic effects and should be prescribed in addition to opiate analgesia.

Monitoring

The following should be monitored in all patients on analgesia:

• Severity of pain (use validated pain score)
• Sedation level
• Pulse, BP, temperature
• Respiratory rate
• Oxygen saturations in air

These observations should be performed at least every 30 minutes until the pain has been controlled and observations are stable, then according to local pain management protocols, or at least every 2 hours whilst the patient is on opiate analgesia.  If the respiratory rate falls below 10/minute then any opiate infusion should be discontinued and consider the use of naloxone.

FIRST DOSE ANALGESIA SHOULD BE ADMINISTERED WITHIN 30 MINUTES

(FOR DOSES OF DRUGS REFER TO INFORMATION BELOW)

SEVERE PAIN

Intra nasal Diamorphine (IND) – if patient presents in ED –see below:

(For full guideline refer to Pain in children, management in the ED- “Guideline for using Intra nasal Diamorphine” 2015: Author Joanne Stirling).

It should be noted that IND and 1^st dose of Oramorph should be given simultaneously. If IND contraindicated/unavailable, Oramorph or IV morphine should continue to be administered as per protocol.

Guideline for using Intranasal Diamorphine (to be used in conjunction with Emergency Department Pain Management Guideline)

Indications:

To be included as part of the first-line treatment of severe pain in a child (without IV access).  For example, in children with pain secondary to:

• Clinically suspected limb fractures
• Painful/distressing burns

Contraindications:

• Need for immediate IV access (use parenteral morphine)
• Significant nasal trauma
• Blocked nose or upper respiratory tract infection
• Age < 1 year (or weight <10kg)
• General contraindications/sensitivity to diamorphine or morphine use  Significant head injury

Protocol:

1. Weigh the child in kg, transfer to resuscitation area (if not already done), monitor O₂ sats
2. Prescribe diamorphine via intranasal route (in mg) based on child’s weight (see chart – round to nearest weight; final dose=0.1mg/kg) and use chart (below) to determine the volume of water to add to a 5mg diamorphine ampoule. Mix well.
3. Draw up 0.2 mls (0.1mg/kg) of the resultant solution into a 1ml syringe and discard the rest (following controlled drugs procedure).
4. Gently tip child’s head and instill 0.1ml into each nostril (total of 0.2mls in drops). Occlude the other nostril after each 0.1ml and ask the child to sniff.
5. Don’t forget to give supplementary oral analgesia (if not contra-indicated) and that the child may need ongoing IV analgesia once the initial pain is controlled.
6. Intranasal diamorphine is usually effective within 5-10 minutes but allow up to 20 minutes for maximal pain control.
7. Continue O₂ sats monitoring for 1 hour post administration. Analgesic effect lasts up to 4 hours. Providing the child is stable, they can be transferred elsewhere within the department for ongoing monitoring once diamorphine has been administered. 

Guideline for making up Intranasal Diamorphine Solution

Dilute 5mg of diamorphine powder with specific volume of sterile water

Oral morphine:

Stat IV bolus of morphine (if required) once access established. This will take 5-20 minutes to take effect.  Dose should be given by titration over at least 5 minutes to assess efficacy of dose.  

When pain control is established consider continuous infusion.  If PCA/NCA is felt to be more appropriate then the pain team should be contacted (where available).  MST may also be considered – see local pain management protocols.  Efficacy of analgesia should be assessed repeatedly over the first few hours and adjusted if necessary.  Patients will vary in their analgesic requirements.

Morphine infusion:

To reverse opiate-induced hypoventilation: Naloxone should always be available

(see BNFc for dosing recommendations).  

MODERATE PAIN

• Oral Morphine (Oramorph) - see above for doses
• Oral Codeine - Not used in RHC Glasgow

MILD PAIN

Oral Paracetamol:

 Oral Ibuprofen:

FLUIDS:

Dehydration occurs readily in children with sickle cell disease due to impairment of renal concentrating power (hyposthenuria). Diarrhoea and vomiting are thus of particular concern. An IV line should be established whenever parenteral opiates have been given, or if the patient is not taking oral fluids well.  In the less ill patient who is able to drink the required amount, hydration can be given orally.  As an alternative, consider a nasogastric tube in an alert patient.

A fluid chart should be commenced and careful monitoring of both input and output.

The ill child should be assessed for the degree of dehydration by the history; the duration of the illness; by clinical examination; and (if known) weight loss. Hb and PCV (Hct) may be elevated as compared with the child's steady state values.

Hyperhydration (150%) of normal requirements should be commenced on admission, as follows; fluid balance must be reviewed regularly; avoid fluid overload especially in those with respiratory or cardiac compromise.

For example:
An 8kg infant will require 150 x 8 = 1200ml per 24hrs (50ml/hr)
A 16kg child will require (150 x 10) + (75 x 6) = 1950ml per 24hrs (81ml/hr)
A 36 kg child will require (150 x 10) + (75 x 10) + (30 x 16) = 2730ml/24hrs (114ml/hr

• Electrolytes should be reviewed, remembering that a slightly raised urea will be significant as these children normally have a low blood urea.

• Check urea and U+Es at least daily and add KCl as required.

OXYGEN:

This is of doubtful use if the patient has only limb pain, but may be given if requested by the patient. The patient’s oxygen saturation (SaO₂) should be monitored by pulse oximetry with regular readings in air (minimum 4 hourly)  

• If SaO₂ < 95% in air, give O₂ by face mask.

• Check capillary or arterial gases if SaO₂ in air is <90%.

• Monitor SaO₂ while patient is on supplementary O₂, aiming to keep SaO₂ > 98%.

• Inform consultant if deteriorating respiratory condition and consult acute chest syndrome protocol.

PHYSIOTHERAPY:

All children with acute chest or back pain and those requiring opiate analgesia should be referred to physiotherapy with a view to incentive spirometry or other measures as appropriate for age. Contact the Resp physio team by telephone in the first instance. Follow up with trakcare referral.

ANTIBIOTICS:

Infection is a common precipitating factor of painful or other types of sickle crises. These children are immunocompromised. Functional asplenia or hyposplenia occurs, irrespective of spleen size, resulting in an increased susceptibility to infection, in particular with capsulated organisms such as pneumococcus, neisseria, Haemophilus influenzae and salmonella – all of which can cause life-threatening sepsis.

• In uncomplicated painful crisis without specific evidence of infection increase prophylactic Phenoxymethylpenicillin (Penicillin V) to 4 times per day after cultures (blood, urine and any other source that is indicated) have been taken.

• If penicillin allergic, use erythromycin 4 times per day.

• Any unwell child with sequestration syndrome, chest syndrome or obviously toxic should receive intravenous antibiotics as per local antibiotic policy. Mild to moderately unwell children with a temperature of >38.0 should also receive intravenous Piperacillin Tazabactam (Tazocin) (or according to local antibiotic policy) after appropriate cultures have been taken.

• Dosing regimen: Piperacillin Tazabactam (Tazocin) (90mg/kg/dose 4 times a day)

• If there are chest signs, or an abnormal CXR, give Piperacillin Tazabactam (Tazocin) (iv) and clarithromycin (IV or oral) or Azithromycin (oral).
  
  
• If symptoms/signs of focal infection are present (eg tonsillitis, UTI), treat appropriately according to local microbiological advice.
  
  
• If penicillin allergic with a reaction classified as non-serious, use Ceftazidime (IV).

• If penicillin allergic with a reaction classified as serious (serious allergy is one that causes an anaphylactic or urticarial reaction, 10% of patients with reactions to penicillin-based antibiotics will also have a reaction with cephalosporins) use erythromycin (IV) or clarythromycin (IV) +/- ciprofloxacin.

• Patients on desferrioxamine (DFO) who have diarrhoea should be started on ciprofloxacin immediately (after checking they are not G6PD deficient) and the DFO stopped. Ciprofloxacin can be stopped if Yersinia infection has been excluded. Siblings of children with Salmonella infections should be discussed with the microbiology team.

OTHER DRUGS:

Please prescribe:

a) Folic Acid (oral)

b) Antiemetic: eg Cyclizine (if required with opiate analgesia)

c) Laxatives, if receiving opiate analgesia e.g. Lactulose, Senna, Macrogols - doses adjusted according to response

Lactulose:

Senokot liquid (5mls=7.5mg):

d) Macrogols:

e) Antipruritic (if receiving opiate analgesia)

Oral Chlorphenamine Maleate (Piriton):

Consider non-sedating antihistamines if sedated with piriton

f) Iron chelation therapy – e.g. Desferrioxamine (if they would receive this normally)

g) Thromboprophylaxis - LMWH (Clexane): consider in those ≥13yrs of age.

Please refer to Appendix 1 and also section 5.10 of the Anti thrombotic protocol (HAEM-007)

ABDOMINAL CRISIS AND GIRDLE SYNDROME:

Abdominal crises often start insidiously with non-specific abdominal pain, anorexia and abdominal distension. As abdominal pain is not an infrequent symptom in children, it can be difficult to diagnose. Constipation may often co-exist, especially if codeine or other opiates have been used as analgesia. In an abdominal crisis, bowel sounds are diminished, and there is often generalised abdominal tenderness; rebound tenderness absent.  The abdomen is not rigid and moves on respiration.  Vomiting and diarrhoea are less common.

Girdle (or mesenteric) syndrome may be said to be present when there is an established ileus, with vomiting, a silent distended abdomen, and distended bowel loops and fluid levels on abdominal x-ray.  Some hepatic enlargement is common, and it is often associated with bilateral basal lung consolidation (early chest syndrome).

Differential diagnosis

Consider the possibility of surgical pathology such as acute appendicitis, pancreatitis, cholecystitis, biliary colic, splenic abscess, ischaemic colitis, peptic ulcer etc. Well localised or rebound tenderness, board-like rigidity or lack of movement on respiration are suggestive of these diagnoses.  Ultrasound may be helpful.  If surgical intervention is contemplated, exchange transfusion should be performed prior to laparotomy: this can be started pending clarification of the diagnosis.

Investigations

• FBC, biochemistry, CRP, blood cultures, group & save
• LFTs to exclude hepatic and biliary problems
• Serum amylase to exclude pancreatitis
• Plain abdominal x-ray & USS – as indicated
• Oxygen saturation & CXR

Management

• IV fluids: hyperhydration as for acute painful sickle crisis – monitor fluid balance carefully
• Analgesia: pain control as for acute painful sickle crisis
• Antibiotics eg cefuroxime and metronidazole (or as per hospital antibiotic policy)
• If there is vomiting, abdominal distension or absent bowel sounds, nil by mouth and consider nasogastric suction.
• Monitor abdominal girth (at umbilicus) 1-4 hourly; measure liver size bd.
• Monitor SaO₂ in air. Measure capillary blood gases if SaO₂ in air <90% repeat CXR and manage as per acute chest syndrome.
• Chest physiotherapy – incentive spirometry or other measures

Girdle syndrome may be an indication for top up or exchange transfusion – see ACS management.

ACUTE CHEST SYNDROME (ACS):

Acute sickle chest syndrome is an acute illness characterised by fever and/or respiratory symptoms accompanied by new infiltrates on chest x-ray.

It is likely to be multifactorial in origin. Sickling within the pulmonary vasculature leads to infarction and sequestration. Infection can precipitate or complicate ACS. The distinction between infection and sickling is difficult and management principles should be the same for the two conditions. Commonly pain in the thorax, upper abdomen or spine leads to hypoventilation, which may be exacerbated by opiate analgesia reducing respiratory drive. Basal hypoventilation leads to regional hypoxia, which triggers localised sickling with subsequent infarction and consolidation. Thus, a vicious circle is set up with sickling, leading to progressive hypoxia and in turn to further sickling. 

Acute chest syndrome is one of the major causes of death from sickle cell disease. A high index of suspicion is needed to detect and treat early. Patients should be treated aggressively irrespective of disease phenotype.

Triggers

• Infection
• Painful vaso-occlusive crisis
• Post operative
• Opiate induced hypoventilation
• Pulmonary embolus 
• Fluid overload

Symptoms

• Pain (often pleuritic) in chest wall, upper abdomen and/or thoracic spine (T-shirt distribution).
• Dyspnoea
• Wheeze and cough which may be a late symptom.

Signs

• Fever
• Tachypnoea, tachycardia, increased work of breathing
• Hypoxia - a useful predictor of severity and outcome
• Signs of lung consolidation, including wheeze and bronchial breathing
• Physical signs often precede x-ray changes.

Differential Diagnosis

Sickle lung and pneumonia are often clinically and radiologically indistinguishable.  However, consolidation in the upper and/or middle lobes, without basal changes, is suggestive of chest infection rather than sickle chest syndrome. Bilateral disease is most likely due to sickling, but atypical pneumonia should be considered.  Pleuritic pain may also be due to spinal/rib/sternal infarction, or from subdiaphragmatic inflammation.

Investigations

• Baseline FBC, UE and creatinine and LFT, CRP
• Blood, throat and sputum cultures
• Chest x-ray - repeat if normal initially but ongoing clinical suspicion
• Respiratory infection screen – nose and throat swabs in viral transport medium for respiratory viruses and mycoplasma. 
• Capillary blood gases if SaO₂ < 94% - recommended pulse oximetry and CBG to monitor CO₂/acid base if required
• Baseline HbS and extended phenotype cross-match
• Markers of severity include worsening hypoxia, increasing respiratory rate, falling platelet count (<200), falling Hb and multilobar changes on chest x-ray

Management - General Measures

• Inform the Consultant on call for haematology if chest syndrome suspected. Discuss patients with PICU as early as possible.
• Transfer of children in low prevalence paediatric units should be considered as soon as the condition is suspected. This may require transfer by the regional retrieval team dependent on the patient's clinical condition.
• Oxygenation. Maintenance of adequate oxygenation is essential. Options include face mask oxygen, nasal cannulae, CPAP and ventilation. Ideally maintain SaO₂ >96%.
• Monitor oximetry on air at least 4 hourly together with pulse, BP and respiratory rate. Consider continuous pulse oximetry if clinical concerns and CBG
• IV fluids individualised and guided by the patient's fluid balance and cardiopulmonary status. 
• Ensure adequate pain control but with care to avoid opiate induced hypoventilation (see acute pain management guideline).
• Antibiotics: IV Piperacillin Tazobactam and oral Azithromycin or Clarithromycin (or as per local antibiotic policy).
• Incentive spirometry or other measures in conjunction with the physiotherapist.
• Consider regular bronchodilators by nebuliser in patients with wheeze, demonstrable reversible airways obstruction or history of asthma
• Consider systemic steroids in severe ACS or acute asthma

Management - Transfusion

• The purpose of transfusion is to:
  • Enhance oxygen-carrying capacity and improve tissue oxygen delivery
  • Reduce HbS concentration to reduce sickling
  • Prevent progression to acute respiratory failure
• Transfusion commonly results in impressive improvement within hours
• Simple transfusion is indicated for patients with:
  • Mild or moderate chest syndrome, particularly with hypoxia and/or falling Hb levels
  • Aim for a post transfusion Hb level of 100-110g/l
• Exchange transfusions are used to:
  • Reduce the HbS concentration rapidly;
  • Avoid problems associated with increased fluid volume and viscosity
• Exchange transfusion is indicated when there is evidence of:
  • Clinical and or radiological deterioration despite simple transfusion
  • Worsening x-ray changes
  • Severe disease (see above)
• Automated RBC exchange transfusion may be performed if available or using a manual method (see below for manual exchange protocol).

APLASTIC CRISIS:

A temporary red cell aplasia caused by B19 (Parvovirus) can lead to a sudden severe worsening of the patient’s anaemia. A viral prodromal illness may have occurred, but classical erythema infectiosum (‘slapped cheek syndrome’) is uncommon. 

The main differential diagnosis is splenic sequestration.  Aplastic crisis may affect multiple members of a family concurrently or consecutively.

Diagnosis

• Rapidly falling Hb
• Reticulocytopenia (but retics may be increased if in early recovery phase)
• B19 (Parvovirus) IgM present (or PCR positive although this may not always indicate acute infection)

Management

• Urgent red cell transfusion may be necessary (if Hb < 6g/dl).
• Spontaneous recovery is heralded by return of nucleated RBCs and reticulocytes to peripheral blood.
• Reassure. Recurrence does not occur, as immunity to Erythrovirus is lifelong.

STROKE:

Stroke is a potentially devastating complication of sickle cell disease, most commonly occurring in individuals with homozygous disease (HbSS). Vaso occlusion of the cerebral vessels leads to infarction, generally in the territory of the middle cerebral artery, and untreated the majority of patients will have a recurrence.

Predictive factors for stroke include those with a history of transient ischaemic attacks, chest syndrome, hypertension, a family history of sickle related stroke, or those with a low Hb F and/or a low total haemoglobin. The Stroke Prevention Trial (STOP) showed that children with trans-cranial Doppler (TCD) velocities of >200cm/sec are also at significant risk.  

Investigations

• MRI/CT scan of brain without contrast may be useful to exclude haemorrhage, but may be negative in the very early stages. If clinical findings are consistent with stroke then treat according to clinical suspicion.
• If urgent MR is not available then treat according to clinical suspicion
• Pre-exchange investigations as per exchange transfusion protocol.

Lumbar puncture may be necessary to exclude infection or subarachnoid haemorrhage.

Management

• Immediate:
  • Rehydrate immediately.
  • Urgent neurological assessment.
  • Exchange transfusion urgently, aiming to achieve HbS % below 20% within 2-3 days.
  • Seizures may occur and require anticonvulsant therapy.
• Long-term:
  • A regular transfusion programme, keeping the HbS level preferably below 20%, should be instituted.
  • MR Angiography may help to determine the duration of the transfusion regimen. The risk of recurrent neurological events is greatest in those with abnormal cerebral vasculature.
  • Trans-cranial Doppler studies.

SUBARACHNOID HAEMORRHAGE:

• Uncommon in children, and often associated with multiple intracranial aneurysms.
• May present with headache or focal or generalised neurological signs. Differential diagnosis includes meningitis.

Investigation

• CT scan without contrast.
• Consider MR angiography later.

Management

• Exchange transfusion as for stroke.  Refer to neurosurgeons.

CONVULSIONS

Febrile convulsions may occur with high fevers, including after vaccination, however it is important to distinguish these from convulsions due to cerebral sickling. 

Convulsions are not uncommon following stroke, and may occur following administration of intravenous pethadine. 

Investigations

• EEG
• CT or MRI
• Consider MR angiography
• Blood cultures and other infection screen, as clinically indicated

Management

Immediate:

• Anticonvulsant, usually diazepam (slow IV injection or rectally)
• Antipyretic, such as paracetamol

Definitive:

• If no abnormality on EEG and CT/MRI, and no recurrence, watch and wait.
• If EEG abnormal, but CT/MRI and MR angio are both normal, consider anticonvulsants.
• If infarction on scanning, or vessel stenosis/occlusion on angiogram, exchange transfuse and consider hypertransfusion regime for ≥ 36 months.

SPLENIC SEQUESTRATION:

Splenic sequestration is more common in infants and young children (< 3 years old). 

It may be precipitated by fever, dehydration or hypoxia. Rapid sequestration of red cells can lead to sudden anaemia and even death from hypoxic cardiac failure with pulmonary oedema. In some patients it may have a more insidious onset and can be recurrent.

Symptoms

• Abdominal pain (pulling legs up to abdomen)
• Abdominal distension
• Sudden collapse

Signs

• Rapidly enlarging spleen (may or may not be painful)
• Pallor, shock (tachycardia, hypotension, tachypnoea)
• +/- Fever due to associated sepsis

Investigations

• FBC and retics (raised in sequestration, cf absent in aplastic crisis)
• Blood cultures and other infection screen, as clinically indicated
• Erythrovirus serology (differential diagnosis is aplastic crisis)
• Cross match half the patient's estimated blood volume immediately

Management

• Assess the need for volume expansion but crystalloid should be used with caution as it may exacerbate cardiac failure.
• Emergency top-up transfusion, if necessary with uncross-matched O Rh -ve blood
• Broad spectrum antibiotics eg Tazocin (or as per local antibiotic policy)
• Before discharge, teach parents to recognise the symptoms and to detect an increase in spleen size
• Consider a regular transfusion regime for 2-3 months
• Consider splenectomy if recurrent (>1 episode)

HEPATIC SEQUESTRATION

Symptoms

• Right hypochondrial pain, abdominal distension
• +/- Fever due to associated sepsis

Signs

• Enlarging tender liver, increasing jaundice
• Collapse/shock is less common than with splenic sequestration

Investigations

• Bilirubin may be very high
• Exclude gallstones/cholestasis by ultrasound
• Blood cultures and other infection screen, as clinically indicated

Management

• May need urgent top-up transfusion
• IV Tazocin or other broad spectrum antibiotic as per local antibiotic policy.
• If the patient becomes tachypnoeic, or develops chest signs, then check oxygen saturation and treat as for acute chest syndrome.

Priapism is defined as a sustained painful erection and is one of the vaso-occlusive complications of sickle cell anaemia. The prevalence of severe priapism in sickle cell is unknown, but a survey in young males suggested that 89% will experience priapism by 20 years of age and 25% of children with sickle cell disease related priapism are pre-pubertal.

Priapism can be acute/fulminant or stuttering:

ACUTE/FULMINANT PRIAPISM

• Severe pain
• Duration >4 hours
• Penis fully erect
• High risk of cavernosal fibrosis and impotence
• Urgent intervention indicated

STUTTERING PRIAPISM

• Recurrent
• Pain of variable intensity
• Lasting 30 minutes to <3 hours
• Penis may not be fully erect
• Risk of subsequent fulminant attack

The optimal management of priapism is still a subject of debate. This protocol is based on a recent review of the literature.

Aims of Treatment

The aim of treatment is threefold:

• Achieve rapid relief from pain and discomfort
• Preserve potency
• Prevent recurrence

Outcome is dependent on the pubertal status of the patient and length of time to detumescence. Poor long term outcome in terms of impotence is associated with post-pubertal males and a long duration of erection. The likelihood of responding to intervention is also related to duration of erection with most procedures being most effective in the first 6 hours and relatively ineffective after 24-48 hours.

Hence PRIAPISM IS A UROLOGICAL EMERGENCY requiring rapid assessment and treatment to prevent irreversible ischaemic penile injury, corporal fibrosis and impotence.

Patient Education

Male sickle cell patients and their families should be educated about priapism early after diagnosis or transfer to the service and written information should be given. Specific enquiry should be made about this symptom at follow-up.  They should be instructed to present to hospital immediately if an episode of priapism does not resolve within 2 hours. 

History and examination

• Duration of episode
• Pain severity (usually very painful)
• Medications including alcohol and recreational drugs, analgesia
• Prior episodes
• Crisis pain elsewhere
• Abdomen – masses, spleen, bladder, external genitalia
• Full set of observations including SaO₂

Investigations

• Full blood count
• Urea and electrolytes and creatinine
• Group and save with extended red cell phenotype

General Principles of Early Management

• Attempt to urinate (consider catheter if unsuccessful and a full bladder is present)
• Try a warm bath
• Gentle exercise
• Hydration
• Analgesia

Management Plan For Acute/Fulminant Priapism

1. A review of the literature suggests procedures such as exchange transfusion are of little value in the acute setting and only delay definitive treatment. The treatment of choice is aspiration and irrigation which should be performed with 4-6 hours of onset. Therefore urgent involvement of paediatric surgeons/urology is needed and this should not be delayed while initial supportive measures are carried out.
   
   
2. Initial management should be: intravenous hyperhydration (1.5-2 x normal maintenance fluids) and analgesia (morphine is usually needed). Sedation may be useful in some cases - take care with concomitant opiate use.
   
   
3. NB Acute exchange transfusion is generally not indicated and has been associated with an increased incidence of neurological events (ASPEN Syndrome). Top-up transfusion may be associated with similar concerns and should only be considered if otherwise indicated by the clinical picture. 
   
   
4. If there is no detumescence after 1-2 hours then aspiration and irrigation should be performed (see below for aspiration protocol)
   
   
5. Irrigation can be performed with epinephrine (1:1 000 000) OR 1% Phenylephrine OR 5mg of undiluted Etilefrine can be instilled intracavernosally at the end of the procedure. See Table 1.
   
   
6. Aspiration and irrigation is reported to be effective in more than 85% of cases. Failure is usually associated with prolonged episodes of priapism >24 hours. Second line management consists of exchange transfusion and/or formal surgical shunting operations such as Winter’s cavernosal shunt performed under general anaesthesia.
   
   
7. If aspiration is successful then the patient should be observed for a few hours and then, if well, discharged home.

8. If the patient has had previous episodes of priapism then medium to long term prophylaxis should be discussed (see stuttering priapism below).

Procedure for Aspiration and Irrigation

• Aspiration can be performed under sedation/general anaesthesia depending on the age of the patient.

• If not under GA then using an aseptic technique infiltrate 0.5ml 1% Lignocaine under the skin on the lateral aspect of the penis.

• Insert a 23-gauge needle or butterfly into the corpus cavernosum with a lateral approach taking care to avoid the dorsal vein (superior aspect) and the urethra (inferior aspect). Attach a 3-way tap and aspirate into a dry 10ml syringe: 3–5-mL aliquots should be aspirated until bright red (oxygenated) blood is seen (not exceeding 10% of the circulating blood volume; 7.5 mL/kg in children aged ≥1 year). The corpora should then be flushed with warmed 0.9% saline. The procedure is unilateral as there is a connection between the two corpora.
  
  
• If aspiration and irrigation do not achieve detumescence, sympathomimetic intracorporal injection should be performed with cardiovascular monitoring: pulse, BP and pulse oximetry should be monitored at 15 minute intervals until >30 minutes post-procedure. Side-effects are rare but include headache, dizziness, hypertension, reflex bradycardia, tachycardia, arrhythmias. Injections must stop when detumescence is achieved.

• If epinephrine is being used: then attach another 10ml syringe containing a 1:1 000 000 solution of epinephrine (i.e. 1ml of 1:1000 epinephrine diluted in 1 litre 0.9% sodium chloride) to the 3 way tap and irrigate with this solution. If needed additional blood can be aspirated until detumescence occurs.

• If etilefrine is being used: then attach a 10ml syringe containing 0.9% sodium chloride to the 3 way tap and irrigate. Additional blood can be aspirated until detumescence occurs. 5mg (0.5ml) of undiluted etilefrine can be instilled into the corpora via the 3 way tap at the end of the procedure (NB irrigation is not always required prior to etilefrine instillation).

• After withdrawal of the needle firm pressure should be applied for at least 5 minutes to prevent haematoma formation (the most common complication of the procedure).

Table 1 (adapted from Donaldson et al 2014)

Suggested sympathomimetic preparation for intracorporal injection (ICI). This is an unlicensed indication and route of administration. When available Phenylephrine should be used in boys aged ≥11 years; Epinephrine should be used in boys ≤10 years. There are no reliable data on ICI ≤2 years; we recommend using a reduced dose of Epinephrine (Adrenaline).

Management of Stuttering Priapism

1. Initial treatment out of hospital should consist of:
   • Increased fluid intake
   • Oral analgesia
   • Gentle exercise
   • Attempts to urinate soon after onset

2. If the episode lasts more than 2 hours then the patient should be advised to attend hospital at once and acute priapism protocol should be followed.

3. Prophylaxis should be discussed with the patient and parents. Options are:
   • Exchange Transfusion Programme
   • Oral Etilefrine (an α- agonist)
   • Hydroxyurea

An exchange transfusion programme has the disadvantages of potential iron overload, alloimmunisation, difficulties with venous access and repeated hospital visits but has the advantages of reducing other sickle related morbidity during the period of transfusion.

Etilefrine is a direct acting alpha-adrenergic agonist. In normal physiological circumstances adrenergic impulses keep the penis flaccid in the absence of sexual stimulation. 

Etilefrine has advantages over other alpha agonists such as epinephrine and phenylepinephrine in that it is rapidly absorbed orally and has a short half life (150 minutes) and it may have a lower risk of systemic hypertension. It appears effective in small trials but there is only limited experience in children. Systemic hypertension has not been seen in paediatric patients reported in the literature but should be assessed regularly on treatment.

Etilefrine is given in a dose of 0.5mg/kg daily. This can be given as one dose of 0.5mg/kg in the evening for patients with nocturnal priapism or 0.25mg/kg twice daily in other patients. It will not reduce other sickle cell related symptoms.

Hydroxycarbamide has been shown to be effective in reducing sickle related complications in children. There are case reports documenting its efficacy in treatment of recurrent priapism but this outcome was not studied in the large scale trials reported to date. It has the advantage of preventing other sickle related morbidity and reducing need for transfusion. Regular blood count monitoring is required throughout treatment and potential long term adverse effects are unknown.

HAEMATURIA:

Microscopic haematuria is common in sickle cell disease; macroscopic haematuria may be due to urinary infection or papillary necrosis.  Passing of renal papillae may cause renal colic and ureteric blockage.  Haematuria can also occur in patients with sickle trait.

Investigations

• MSU for culture to exclude infection
• Ultrasound scan
• hydrated intravenous urography may be necessary to establish the diagnosis, discuss with registrar or consultant first.

NOCTURIA AND ENURESIS:

Nocturia and enuresis are common in part due to obligatory high fluid intake, coupled with reduced urinary concentrating capacity. Cultural and familial influences may also play a part.

Reassurance, patience, and measures such as reward systems, bell and pad training, etc may be required. Referral to a local Enuresis Clinic or to the clinical psychologist may be appropriate.

URINARY TRACT INFECTIONS:

Not uncommon in sickle cell disease, in both sexes.  It should be vigorously investigated and treated to prevent serious renal pathology.  Haematuria, secondary to papillary necrosis, can precipitate UTI, but other factors must be excluded.

CHRONIC RENAL FAILURE:

Uncommon in children. Predictors include increasingly severe anaemia, hypertension, proteinuria, the nephrotic syndrome, and microscopic haematuria.

Investigations

• Urea and electrolytes, calcium, phosphate, bicarbonate; immunoglobulins and autoantibodies.
• FBC and reticulocytes
• MSU for M,C and S; 24 hour urine collections for protein and creatinine clearance
• Ultrasound of kidneys and urinary tract

Management

• Refer to renal team
• Consider erthropoietin and/or hypertransfusion regime

The ocular complications due to sickle cell disease are uncommon in children, however retinal vessel occlusion may begin in adolescence in particular in children with HbSC disease. Thus these children require annual ophthalmological assessment from puberty onwards. Also, children on regular transfusion regimens receiving desferrioxamine require annual ophthalmological assessment.

Management

• Refer to Ophthalmology

Laser therapy is the treatment of choice for proliferative sickle retinopathy.

Vitreous haemorrhage and retinal detachment may occur.

Surgical treatment should not be undertaken without prior exchange transfusion.

GALLSTONES:

Pigment gallstones due to ongoing haemolysis are common in sickle cell disease, occurring in at least 30% of children. It is often asymptomatic but can precipitate painful abdominal crises and the girdle syndrome. It can also cause:

• Acute cholecystitis
• Chronic cholecystitis
• Biliary colic
• Obstruction of the common bile duct
• Acute pancreatitis

Differential diagnosis of abdominal complications:

• Hepatic or splenic sequestration
• Acute chest syndrome
• Surgical pathology - consider e.g. acute appendicitis, splenic abscess, ischaemiccolitis, peptic ulcer etc. Well localised or rebound tenderness, board-like rigidity or lack of movement on respiration are suggestive of these diagnoses
• Constipation

Investigations

• FBC, Biochemistry, CRP, Blood cultures, Group & Save
• LFTs to exclude hepatic & biliary problems
• Serum amylase to exclude pancreatitis
• Plain abdominal X-ray & USS - as indicated (50% of gallstones are radio-opaque)
• Oxygen saturation & CXR chest

Management

Acute episode of cholecystitis:

• Analgesia
• Hydration
• Antibiotics - cefuroxime and metronidazole

Recurrent episodes of cholecystitis is an indication for cholecystectomy (see below):

Common bile duct obstruction:

Endoscopic retrograde chloangiopancreatography (ERCP) or emergency surgery. After one attack, refer for surgical opinion re elective cholecystectomy; generally laparoscopic, which does not require prior transfusion, however it may be best to exchange in case full laparotomy becomes necessary. 

INTRAHEPATIC CHOLESTASIS:

Some patients experience episodes of severe hyperbilirubinaemia (conjugated + unconjugated) with moderately raised alkaline phosphatase, associated with fever and hepatic pain in the absence of demonstrable stones. These episodes are thought to be due to severe intrahepatic sickling.

Management

• Analgesia (care as most opiate are metabolised in the liver)
• Hydration
• Antibiotics; e.g. cefuroxime
• Monitor liver function tests, and as for girdle syndrome/hepatic sequestration
• Hyperhaemolysis +/- sequestration may supervene, requiring frequent transfusion
• In severe cases, exchange transfusion may be needed.

This complication may start in adolescence and often gives rise to chronic pain and limitation of movement due to joint damage, rather than ongoing vaso-occlusion.

PRESENTATION:

• Pain in the hip, leg groin, knee or shoulder on movement; later at rest. Repeated or prolonged pain (>8 weeks) should be investigated for aseptic necrosis.
• Limitation of movement; particularly abduction and external rotation of the hip, external rotation of the shoulder.

DIFFERENTIAL DIAGNOSIS:

• Osteomyelitis
• Septic arthritis

These are suggested by swinging pyrexia, severe systemic disorder, positive blood cultures and toxic granulation in neutrophils.

Investigations

• X-ray
• MRI (This will show changes much earlier than x-ray)
• Isotope bone scan can be very difficult to interpret in the presence of active sickling

Management

• Analgesia with non-steroidal anti-inflammatory agents or codeine derivative.
• Rest and the avoidance of weight bearing (very difficult to implement).
• Transfusion cannot reverse the process but may prevent progression to the contralateral joint; it is performed pre-operatively and for 3 months postoperatively to maximise bone healing.
• Refer for orthopaedic assessment and treatment (Mr Duncan), which is likely to involve these types of treatment:
  • Osteotomy and/or decompression surgery may be considered.
  • Major joint surgery may be necessary if pain is continuous (>2 years) or very severe, or if the patient’s mobility is seriously affected.
  • Different types of prosthesis, hip fusion, or bone grafting are used depending on the individual case. Cemented prostheses are best avoided.  Loosening of the prosthesis is quite common.  Infection is not uncommon.
• The possibility of failure, the likelihood of some residual pain, the potential life of the prosthesis, and the limitations imposed must always be discussed with the patient pre-operatively.

DELAYED PUBERTY:

• Common, particularly in boys.
• Related to lower body mass for age in children with sickle cell disease.
• Reassure, as most will progress to puberty and achieve normal height despite the delay.

Management

• In the very thin patient, attempt to improve the appetite and quality of nutrition in order to increase the body weight.
• If an endocrine review is appropriate, or replacement therapy needed then refer to Prof Ahmed
• Regular transfusion for 6 - 12 months almost always initiates puberty delayed due to sickle cell disease.
  (Exceptionally, infarcts in the hypophysis and hypothalamus are responsible)

FERTILITY:

Girls are normally fertile, whereas many boys with HbSS and S/Beta thalassaemia have reduced sperm counts and reduced sperm motility - some may have erectile impotence because of past priapism.

Anaemia alone in an otherwise well child is not an indication for transfusion unless the haemoglobin falls to less than 5g/dl, in which case discuss with Senior Trainee/Consultant. To prevent red cell alloimmunisation Rh and kell compatible blood should be used whenever possible. All patients should have red cell phenotyping done at diagnosis.

Options for transfusion include simple additive transfusion, exchange transfusion and hypertransfusion regimens. All regularly/heavily transfused patients should be monitored for iron overload.

SIMPLE OR “TOP-UP” TRANSFUSION:

• This is indicated for acute symptomatic anaemia eg aplastic or sequestration crises or acute bleeding. It may also be indicated pre-operatively. Do not transfuse to above 11g/dl. Volume required:
  
  
  • Weight in kg x desired rise in Haemoglobin x 3 = volume in mls to transfuse.

EXCHANGE TRANSFUSION:

Exchange transfusion is undertaken to rapidly reduce the percentage of sickle cells in the circulation when a patient develops a life-threatening complication of the disease. It is not to be undertaken lightly, as the possible complications are considerable. However, patients with the following problems justify the risks:

• Severe chest syndrome - see ACS protocol for indications
• Girdle Syndrome
• A new CVA
• Multi-organ failure, e.g. associated with systemic fat embolism

Exchange transfusions should only be undertaken after discussion with the Haematology consultant on call:

Aim

1. To reduce the % HbS to < 20% over 2-3 days unless acutely ill, when more rapid exchange may be appropriate
   
   
2. To keep Hb < 100g/l initially (or at steady state level in those with higher baseline Hb, e.g. HbSC patients) and about 100-110g/l (PCV 0.36) by the end of the whole procedure.
   
   
3. To maintain a steady state blood volume throughout the procedures

• Use SAG-M blood, which is the freshest available (to prolong its life in the patient).

• Red cells should be phenotype compatible ie ABO, Kell and Rh compatible (rr or Ro as appropriate)

• Do not use diuretics.

• Continue to administer IV fluids at the standard rate between transfusions.

Critically ill patients may require exchanges to be more frequent than daily.  Where possible, leave a 4 - 8 hour break between exchanges.  In the very sick patient, the procedure is a continuous process.  In these patients, particular attention should be paid to PaO₂, CVP, acid-base balance, Ca⁺⁺, citrate load, core temperature and clotting.

Preliminary Investigations

• FBC

• % HbS (or S+C if HbSC disease) 

• Extended RBC phenotype (if not already known), cross-match

• Urea and electrolytes, creatinine, calcium

• Capillary or arterial blood gases - in those with symptoms suggestive of chest or girdle syndrome

• Baseline Serology for Hepatitis B and C and HIV, if not done recently.

Automated Exchange Transfusion

A national SNBTS SOP for automated red cell exchange exists and is available through SNBTS

Information required:

• Patient height and weight
• Pre-exchange Hb, Hct and HbS%
• Transfusion fluid Hct (or default 60%)
• Target values post red cell exchange
  • Hb 100g/l
  • Hct 0.35
  • HbS 15%
  • FCR - fraction of red cells remaining - can be calculated on apheresis instrument from pre and target post HbS %

Adequate venous access is required.  If it is anticipated that adequate access may not be obtained via peripheral access then insertion of a large bore double lumen catheter should be arranged.

Manual Exchange Transfusion

Volumes required

The initial aim is to exchange 1.5 - 2 times the child's blood volume, divided over 2-3 procedures. 28ml/kg is the approximate red cell mass from infancy to teenage years.

Volume (ml) of SAG-M blood for each exchange should be: 

                            28 x weight (in kg) = volume in mls

Venous Access

Two ports of venous access are required; one for venesection, the other for administering blood and crystalloid; in certain circumstances, an arterial line may be used.  

Procedure

The aim is that this should be an isovolaemic procedure with frequent, monitoring of blood pressure, heart rate and oxygen saturations every 15 minutes, and 1 hourly temperature monitoring. Exchanges are done in ‘aliquots’ of approximately 1/10 of the total to be exchanged.

• Give 10ml/kg of 0.9%saline as a bolus prior to venesection unless the child is receiving maintenance fluids. (If Hb < 6g/dl, then blood and 0.9%saline should be administered prior to the first venesection).

• Venesect an aliquot (i.e. 10% of total volume to be exchanged) over 10 to 15 minutes

• Transfuse the first aliquot at a rate of 5-7.5ml/kg/hr 

• Venesect second aliquot

• Transfuse the second aliquot

• Venesect third aliquot, and so on

• Finish the procedure by giving the last aliquot of blood as a top-up transfusion ie venesect the 9^th aliquot then transfuse 9^th and 10^th aliquots

At the end of the procedure check FBC, HbS %, urea and electrolytes including calcium.  If HbS not <20%, then consider continuing with further exchanges, to give a final Hb of 110g/l and Hb S ideally between 10% and 20%.

Ensure the child is well hydrated between successive exchanges, as the haematocrit of transfused packed cells is higher than that of the venesected blood. Keep PVC <0.4. In larger volume exchanges consider giving a break between 2^nd or 3^rd unit and giving dextrose/saline to rehydrate. 

Possible Immediate Complications

• Transfusion reactions - ABO incompatibility, febrile non-haemolytic reactions, TRALI etc

• 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 the PCV has not risen too high (>0.4).  Give anti-epileptics; ensure there is a large fluid intake; give oxygen.
  
  
• Hypertension is occasionally seen in patients with circulatory overload. If diastolic BP increases by > 20mmHg, slow down exchange, check PCV not >0.4. If diastolic BP is >100mmHg stop the exchange, venesect, and consider antihypertensives.

SICKLE CELL - CHRONIC TRANSFUSION

Aims

• Aim to achieve HbS <30% and suppress erythropoiesis
• Aim for Hb <110g/l post transfusion
• Transfusions of 10-20ml/kg are given 3-4 weekly to achieve the above targets and should be prescribed based on pre-transfusion Hb
• Patients should not wait longer than 1 hour for venepuncture, cannulation or transfusion and no more than 3 attempts at cannulation are recommended

Investigations

• Weekly
  • FBC if on deferiprone
• Monthly
  • Pre-transfusion FBC and HbS%
  • Cross match for RCC
  • U&E and creatinine (weekly for first 4 weeks on deferasirox)
  • LFT, Ferritin
  • Urine protein: Creatinine ratio, if on deferasirox 

Record results and transfusion volume (see Appendix 2: Transfusion Record)

• 3 monthly
  • Above +
  • Height and weight, record centiles
  • Random blood glucose (further investigations if abnormal)
  • Ca, Mg, PO4, Zinc
  • Review of chelation therapy
• Annually
  • Total transfusion requirement (ml/kg RCC transfused, mid-year weight)
  • Annually from 4-8 years (when tolerated without GA)
  • Liver MRI, Cardiac MRI
  • Audiology and Ophthalmology on chelation
• Annually from 10 years (or earlier if clinical concerns)
  • Pubertal assessment, TFTs, sex hormones
  • ECHO
  • DEXA scan (2 yearly)

Consult Trust Transfusions Policy [Staffnet link]

It is important to educate the patient and family about the potential complications of iron overload and the need for chelation therapy and monitoring.  Patients and other family members should be encouraged to be involved in the self-administration of medications at home. 

When to start:

For those on regular top-up transfusions with a rising ferritin chelation should commence when the ferritin reaches 1000mcg/l, usually after 10-20 transfusions. Ferritin is an acute phase reactant and should be elevated on 2 occasions when the patient is well.

What to start:

Chelators, dose, toxicities and drug safety monitoring - for full list of side effects and dosing consult BNF and SPC.

Drug and Dose adjustment:

• Adequacy of chelation depends on chelator dose, adherence and transfusion requirements. Children <6 years of age have a relatively greater transfusion requirement which decreases with age
• Aim to keep ferritin around 500-1000mcg/l and consider LIC ferriscan value when making dose adjustments

Dose increase:

• Monitor ferritin monthly and increase dose 3 monthly if ferritin consistently >1000 mcg/l and rising or >1500 mcg/l

When to change chelator: 

• Consider change of chelation therapy to alternative 1^st line or second line therapy if ferritin >1000 mcg/l and rising or consistently over 1500 mcg/l despite maximum tolerated dose of single agent
• Ensure adequate patient adherence
• Consider use of dual therapy with deferiprone and desferrioxamine particularly if there is significant cardiac iron overload
• Consider use of IV desferrioxamine if there is clinical cardiac impairment

Dose reduction:

• In general, chelator toxicities are increased when ferritin falls
• Consider dose reduction/onteruption when ferritin <500mcg/l

Iron overload toxicity monitoring

• Serum ferritin – monthly
• LFTs – monthly, Liver ferriscan - yearly
• Cardiac T2* MRI annually ; 6 monthly if T2* <10ms
• ECHO annually
• Ca, PO4 – 3 monthly, TFT, PTH Vitamin D – annually
• Random blood glucose – 3 monthly, Oral glucose tolerance test annually
• Growth - height and weight – 3 monthly
• Sitting and standing height and Tanner staging– annually
• FSH, LH E2 or testosterone - annually

Hydroxycarbamide has been shown, in a randomised controlled trial in young children, to be safe and to reduce the frequency of painful crisis, dactylitis and acute chest syndrome. In long-term studies in adults, it has been shown to similarly reduce episodes of pain and acute chest syndrome and to reduce mortality with no evidence of reduced fertility or increased incidence of malignancy, including leukaemia. 

The exact mechanism of action is under investigation but is likely to include the induction of Haemoglobin F production, inhibiting sickle haemoglobin polymerisation within the cell; reduction in adhesion molecule expression, thereby reducing red cell – endothelial interaction; reduction of white cell and platelet counts.

PATIENT ELIGIBILITY:

Patients with sickle cell disease (HbSS or S beta zero-thalassaemia or HbSC) who have:

• 3 admissions with painful crisis within the previous year, or
• >1 admission with painful crisis within the previous year and are symptomatic in the community, or
• >1 life threatening complication of the disease such as acute chest syndrome, or
• other indications including where chronic transfusion is indicated but not possible

PATIENT EXCLUSION CRITERIA:

Inability to attend clinic regularly for follow up and FBC monitoring:

• Abnormal liver function tests (AST or ALT > x 2 upper limit of normal, consult with Pharmacy)
• Pregnancy or not practicing effective contraception

BASELINE INFORMATION

Patients and their parents/carers should be given an information leaflet and the use of hydroxycarbamide should be discussed with them on at least 2 separate occasions. Current information about known side effects including myelosuppression and the possible risks of subfertility and malignancy risk should be discussed and documented in the notes. Male patients should be assessed for and offered sperm storage if appropriate.

CONSENT

Written consent should be obtained using the generic chemotherapy consent form (RHC-HAEM-ONC-TEMP-002) and filed in patient record.  Toxicity monitoring is carried out as detailed below and documented in the case record.

SIDE EFFECTS:

• Bone marrow suppression (dose dependent)
• Gastrointestinal disturbance – usually mild and short term
• Rash, skin and nail pigmentation
• Leg ulcers
• Liver dysfunction
• Possible Teratogenicity and subfertility

BASELINE INVESTIGATIONS

• Height and weight
• FBC, reticulocyte count, HbF%
• Renal and liver biochemistry

DOSE AND MONITORING:

• Start at 15mg/kg/day – tablets come as 500mg and dose should be rounded to the nearest 500mg whenever possible. A suspension can be prepared for younger patients
• Increase dose by increments of 5mg/kg/day every 4-8 weeks (max: 35mg/kg/day)
• Monitor FBC weekly for 4 weeks, then every 2 weeks until stable dose. FBC should be checked every 4 weeks when on a stable dose
• Monitor reticulocyte count and HbF 4 weekly until stable dose
• Monitor biochemistry profile at day 14 then at least 4 weekly (renal excretion and hepatic toxicity)
• Only dispense enough tablets to last to next clinic visit. Never issue more than 4 weeks supply at a time
• Patients/parents should be advised to present if febrile/unwell or symptoms of worsening anaemia or bleeding. Stop treatment if any of the following occur:
  • Neutrophils <1.0 x 109/l
  • Platelets 100 x 109/l
  • Hb <55g/l, retics <10x 109/l or Hb falls by more than 20g/l from last dose adjustment
• If treatment is interrupted, check FBC weekly and restart after counts recover, at a dose 5mg/kg lower than the patient was on at the time toxicity developed:
  • Assess clinical response, HbF and adverse events 3 monthly
  • If HbF increment _ 2.5 fold continue therapy
  • If HbF increment <2.5 and/or clinical response not apparent after 6-9 months then consider discontinuation of therapy
• Aim to give the maximum tolerated dose (MTD), but if haematological and clinical responses are achieved at a lower dose consider using this dose (minimal effective dose, MED)

Over 100 stem cell transplants for sickle cell disease have been performed to date.

In the UK and other developed countries, childhood mortality has been considerably reduced through neonatal screening programmes, parent education, the introduction of penicillin prophylaxis and comprehensive health care provision by haemoglobinopathy counsellors, health visitors, social workers and haematologists.

Nonetheless, SCD remains a heterogeneous condition in its manifestations and impact on patients and their families. A subset of children experience major life-threatening disease-related complications in childhood and even with optimal medical care the majority of patients with SCD will have sustained some major organ or tissue damage by the age of 30.  This has led several centres to offer HSCT to selected children with SCD who are at risk of major morbidity or premature death, either as a consequence of serious complications sustained early in childhood or because they live in parts of the world where access to good quality medical care is limited.  

Current results from Europe and the US give a survival of 90-95% and cure of SCD of around 85%. HSCT is also associated with improved growth, stable CNS imaging and improved pulmonary function in the majority of patients.

CRITERIA FOR SELECTION OF SICKLE CELL PATIENTS FOR SCT:

* There is increasing evidence of the efficacy of hydroxyurea in children with SCD in the prevention of recurrent chest syndrome and recurrent painful crises, and the reduction in blood transfusion requirement, thus it should be considered as an alternative to SCT in the first instance.

General anaesthesia in patients with sickle cell disease is associated with a significant risk for post-operative complications, especially acute chest syndrome. Surgery should be undertaken with close liaison and good communication between the surgeon, anaesthetist and medical and nursing staff.

Preoperative Management

Patients should be scheduled early on the operating list to ensure that they avoid prolonged fasting time and are unlikely to be cancelled.  Consider IV hydration whilst fasting.

Transfusion

Most patients with sickle cell anaemia (HbSS, Sβthal) are relatively asymptomatic with an Hb around 65g/l.  This chronic steady state anaemia itself is not an indication for transfusion. The decision to transfuse a patient preoperatively depends on the type of operation and the patient’s past sickle related complications. Patients with a history of recurrent chest crises or central nervous system disease or patients undergoing major surgery are at greater risk of developing sickle related problems peri-operatively. A three-tiered approach can be taken:

• Children with no risk factors, having short procedures with minimal risk of perioperative complications – consider no transfusion. Extended phenotype crossmatched blood should be available if required.
• Children having intermediate risk surgery eg tonsillectomy, splenectomy, cholecystectomy, or children with a history of chest syndrome or other chronic complications – top-up transfusion to Hb of about 100-110g/l, regardless of S levels.
• Children having high risk surgery eg thoracic, major abdominal surgery, neurosurgery, eye surgery, hip/knee replacement or surgery involving hypothermia or tourniquet use, or children with severe sickle related problems eg recurrent chest syndrome or CVA- exchange transfusion to reduce HbS to less than 30% with Hb 100-120g/l.

Note that exchange transfusion needs to be planned well in advance of the expected date of surgery.  Early liaison with the Haematology team is essential.

Children requiring emergency surgery should be treated similarly if time allows. If this is not possible surgery should proceed and suitable blood should be cross-matched to allow exchange transfusion post-operatively if the patient experiences sickle related complications. 

The need for pre-operative transfusion in children with HbSC should be considered on a case-by-case basis dependent on past history of complications and surgical risk.

Intraoperative Management

• Care should be taken to avoid factors that may precipitate a sickle crisis. These include hypoxia, cold, dehydration, pain and acidosis. The majority of crises in the peri-operative period occur post-operatively
• Minimum 50% oxygen with anaesthetic agent
• Avoid hypoxia, (continuous pulse oximetry), hypercarbia, hyperventilation, overhydration
• Avoid or minimise tourniquets, avoid cold packs

Post-operative Management

• Consider IV hydration if oral intake delayed post-operatively
• Supplemental oxygen to maintain oxygen saturations >95% for 18-24 hours postoperatively
• Incentive spirometry
• Aggressive pain management
• Encourage early ambulation
• Consider thromboprophylaxis especially in older children if immobility anticipated for >72h

THE AIMS OF THE CINIC ARE TO:

• Monitor progress of the children: medical, educational and psychosocial.
• Establish baseline observations for comparison in acute illness.
• Educate parents and children in the management of sickle- related problems.
• Genetic counselling.

NEW PATIENTS:

• Confirm diagnosis with quantitative Hb electrophoresis HbS, A₂ and F estimation. Check also FBC, retics, U + Es, LFTs and LDH. This should be repeated at 1 year of age when the blood group, red cell phenotype and G6 PD level should also be checked.  

• Check baseline virology – Hep A, B, C and HIV (with consent).

• Take full personal and family history including names and ages of parents and siblings. Parents and all siblings should have a full blood count, and quantitative Hb electrophoresis, if this has not already been performed. Also plans for future children can be discussed.

• Explain to parents the probable diagnosis and its implications.

• Weigh, measure height and examine the child.

• Check immunisations.

• Discuss acute complications in infancy including dactylitis, acute splenic sequestration.

• Prescribe Penicillin and Folic Acid if appropriate and give follow-up appointment.

• Ensure that the patient and family have contact details for the hospital, the Ward 2B Day Care Unit, ward 2A and the consultant’s secretary.

• Check that the child is known to the Health visitor and GP.

• Issue a splenectomy/hyposplenism card if available.

RETURN PATIENTS

1. On arrival, FBC and reticulocytes.
   
   
2. Measurement of BP, Pulse and SaO2
   
   
3. Weight and height. Each patient should have a growth chart.
   
   
4. Document of any sickle-related or other disease since last visit, immunisation up to date, school progress and attendances and holiday plans. Ask about bed-wetting and symptoms of upper airways obstruction.
   
   
5. Examination: check especially for jaundice, heart for size and murmurs, liver and spleen size (measure).
   
   
6. Any questions from parents, involve children as appropriate, any letters to be written.
   
   
7. Check compliance and dose of Penicillin, folic acid and Vitamin D.
   
   
8. Make follow-up appointment for clinic (4 month for SS or 6 month SC)
   
   
9. Annual review. All patients should have liver function tests, electrolytes, urea and creatinine, serum urate and Vitamin D level

PROPHYLAXIS AGAINST PNEUMOCOCCAL INFECTION:

There is now very good evidence that penicillin prophylaxis protects against pneumococcal septicaemia / meningitis PROVIDED IT IS TAKEN REGULARLY.  It is essential that all children with sickle cell disease take penicillin twice daily continuously, starting at the age of three months.  Make sure that the parents are prepared to give it continuously and keep this under review. Try and get the children taking tablets as early as possible (crushed and mixed with fruit juice if needed). Pharmacies may be prepared to dispense the dry suspension or receive a batch of prescriptions from the surgery to avoid collecting a weekly script for the suspension.

Penicillin V

If truly Penicillin allergic Erythromycin  can be used instead:

Folic Acid

Management of Nutritional Vitamin D deficiency in children & adolescents

Working Definition of Rickets

Raised Alkaline Phosphatase (ALP) and classic X-ray changes

Classic biochemical picture - Ca (↔/↓), P(↔/↓), ALP(↑), PTH (↔/↑), 25HCC (↓)

Baseline Investigations

• Height and weight
• Left wrist X-ray
• Serum - U&E’s, calcium, LFT, FBC, PTH, 25(OH)D

Summary of Suggested Treatment

* range of doses given to allow for use of liquid and solid dose forms

**if hypocalcaemic

Full guideline can be found at: 

http://www.clinicalguidelines.scot.nhs.uk/ggc-paediatric-guidelines/ggc-guidelines/endocrinology/nutritional-vitamin-d-deficiency-in-children-adolescents-management-of/

Appointments

Children with Sickle cell disease are seen at least 4 monthly until 2 years of age and four to six-monthly thereafter, unless there are medical, educational or psychosocial concerns in which case they should be seen more frequently.

Vaccination Schedule

In addition to routine childhood vaccinations children with sickle cell disease require:

Pneumococcal polysaccharide (23 valent) vaccine should be given from the age of 2 years at a dose of 0.5ml IM at least 2 months after PCV13. This should be repeated at 5 yearly intervals thereafter. Pneumococcal antibody titres can be checked if the immunisation status is unknown.

Children presenting late for vaccination should receive 2 doses (separated by at least 1 month) of the 13 valent Pneumococcal polysaccharide conjugate vaccine (Prevenar) before 12 months and a 3^rd dose at 13 months (See "Green Book" for further information on dosing in those presenting after 12 months of age). 

Hepatitis B Vaccine (recommended for all children with HbSS and HbSBthal, mandatory for children receiving blood transfusions).

All children requiring blood transfusions, whether as an elective or emergency procedure should receive Hepatitis B vaccination. Hepatitis B antibody levels should be checked 2-4 months after 3^rd dose to ensure an adequate response (>100 iu/ml). 

BCG vaccination should be given according to national guidelines and will be indicated at birth in many children from this patient population.

Influenza vaccine is also recommended to be given each Autumn.

Meningococcal Vaccination: Meningitis B vaccination is now given as part of the Routine Childhood vaccination programme as is Meningitis ACWY. Where vaccination status in unclear or absent, a catch up programme should be given in accordance with the "Green Book" - Immunisation against Infections.

Malaria Prophylaxis is recommended

• Depends on area to be visited. Consult with GP or Hospital for Tropical Diseases.
  
  
• Check G6PD status.
  
  
• To be commenced one week prior to departure and to be continued throughout visit and until 4 weeks after return. Patients going to live in malarial areas should be advised remain on prophylaxis life-long if possible.
  
  
• General advice re preventing bites -mosquito nets, clothing and repellents, additional travel vaccinations

Click here to open a pdf of the Adolescent Risk Assessment for VTE form. 

Click here to open a pdf copy of the Transfusion Record form.