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MANAGEMENT GUIDELINES FOR
ADULT PATIENTS WITH
SICKLE CELL DISEASE AND
THALASSAEMIA
1
Contents
Page number(s)
1. Use of Hydroxycarbamide in Adults
with Sickle Cell Disorders
3-4
2. Management of Acute Painful Crisis in
Sickle Cell Disease
5-8
3. Perioperative Management of Patients
with Sickle Cell Disease
9 - 13
4. Acute Chest Syndrome in Sickle Cell
Disease
14 -16
5. Red Cell Exchange Protocol
17 - 20
6. Sickle Cell Outpatient Management
21 – 23
7. Thalassaemia Outpatient Management
24
8. Management of Priapism
25 - 28
9. Management of Hyperhaemolysis in
patients with Sickle Cell Disease,
including the use of intravenous
immunoglubulins
29 – 31
2
GUIDELINE FOR THE USE OF HYDROXYCARBAMIDE IN ADULTS WITH SICKLE CELL DISORDERS
Hydroxycarbamide has been shown in a large randomised-controlled study to decrease the frequency of
painful vaso-occulusive crises and of chest crises in adults with homozygous sickle cell disease. It is not yet
known whether it will lessen the risk of other sickle-related complications. There is early evidence to indicate
a survival benefit, probably because of a reduction in fatal chest crises in patients taking hydroxycarbamide.
Side effects include bone marrow suppression, gastro-intestinal disturbances, and increased skin and nail
pigmentation. It is potentially teratogenic and there is concern about an increased risk of malignancy, but this
risk remains theoretical and has not been confirmed with follow-up of patients on the drug to date.
Indications for use
Moderate or severe
 >3 admissions with painful crises in the previous 12 months, or
 >1 admission with painful crisis in the previous 12 months, and are symptomatic in the community such
that lifestyle is affected, or
 >1 life threatening complications of the disease, such as acute chest syndrome
 other indications (such as secondary stroke prevention, pulmonary hypertension, prevention of renal
disease) should be discussed with consultant colleagues within the network
Exclusions
 Pregnancy or not practicing active contraception (if sexually active)
 Active hepatitis
 Hb<60g/l, WCC<1x10^9/l, Plts<100x10^9/l Prior to commencing drug
Requirements prior to starting therapy
 The benefits and hazards of using hydroxycarbamide should be considered for each patient individually,
and discussed
 Ensure that the patient is willing to attend regularly to monitor blood counts
 Discuss the possibility of infertility with male patients. Offer sperm banking
 It is important to discuss the possible (small but not quantifiable) risk of malignancy
Baseline investigations
 FBC and reticulocytes
 HbF%
 U+Es, LFTs, Urate, LDH
Monitoring
 Weekly FBC for first 4 weeks
 Fortnightly FBC for next 8 weeks
 Monthly FBC thereafter if counts stable
 3 monthly U+Es, LFTs, Urate, LDH and HbF%
Regimen details:
 Commence at 15mg/kg/day orally to nearest 500mg
 If there is a good clinical response continue on this dose (minimal effective dose)
 If clinical response is sub-optimal, increase by 2.5mg/kg/day every 8 weeks until limited by toxicity
Approved August 2014
Review August 2016
3
Toxicity
 Neutrophils
 Platelets
 Retics
 Haemoglobin


< 1.5 x 109/l
< 80 x 109/l
< 10 x 109/l
<30g/l from baseline
If any of the above problems with FBC encountered, stop hydroxycarbamide, until full blood count has
recovered
Restart at 2.5mg/kg/day (or 1 capsule – 500mg) lower. This is the maximum tolerated dose (MTD)
Caution
 If there is a significant rise in Hb (>110g/l in HbSS) stop the hydroxycarbamide and consider venesection
 If there is a downwards trend in FBC parameters, increase frequency of monitoring
 Use with caution in renal impairment: start at a lower dose and increment more cautiously
 If Creatinine Clearance < 60ml/min, commence at 50% dose (7.5mg/kg/day)
Toxicities
Common:
Bone marrow suppression and cytopenias.
Hyperpigmentation of nails and skin
Nausea and vomiting
Diarrhoea
Skin rash
Uncommon: Alopecia
Teratogenicity
Leg ulcers
Decreased sperm count and function
Low risk of second malignancy
Dose modifications
Neutrophils
≥ 1.5 x 109/L
< 1.5 x 109/L
&
or
Platelets
≥ 80 x 109/L
< 80x 109/L
Hydroxycarbamide
100% dose
Stop treatment and recheck FBC
until N>1.5 and Plt >80. Restart
treatment at 2.5mg/kg/day or
500mg daily lower.
Renal Impairment : Use with caution. If Creatinine Clearance < 60ml/min, commence at 50% dose
(7.5mg/kg/day)
Hepatic Impairment:
Use with caution
References: Charache S, Terrin ML, Moore RD et al. Effect of hydroxycarbamide on the frequency of painful
crises in sickle cell anaemia. Multicentre Study of Hydroxyurea. N Engl J Med 1995: 332: 1317-1322
Acknowledgements:
Thank you to the Haematology Departments of The Royal London Hospital, Manchester Royal Infirmary and
St.Thomas’s Hospital for allowing reference and adaptation of their guidelines for the management of Adults
with Sickle Cell Disease.
4
GUIDELINE FOR THE MANAGEMENT OF ACUTE PAINFUL CRISIS IN SICKLE CELL DISEASE
Introduction
The painful crisis is the commonest manifestation of sickle cell disease requiring hospital assessment and
admission. The pain can be extremely severe and should be addressed urgently, with patients triaged as high
priority and contact should be made with the on-call Haematology team.
Management is supportive (i.e. conservative) unless there are indications for exchange transfusion.
 Acute cerebro-vascular event
 Acute chest syndrome
 Multi-organ failure
The aim of treatment is to break the vicious cycle of sickling, hypoxia and acidosis leading to more
sickling — all exacerbated by dehydration.
Prompt treatment of painful crises can reduce suffering and prevent further sickle related complications.
Analgesia should be given within 30 minutes of the patient presenting.
Principals of management
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Effective analgesia
Hydration
Oxygenation
Antimicrobials – prophylactic or therapeutic if pyrexial
Ongoing assessment of analgesic efficacy
Assessment
Routine Investigation (*Urgent requests)
 FBC, reticulocytes *
 Group & screen (state on form that patient has Sickle Cell Disease. Request full red cell phenotype if new
patient)
 Urea, creatinine electrolytes *
 LFT's, LDH
 Baseline pulse oximetry ON AIR
Haemoglobin electrophoresis in NEW patients only
If indicated
 Blood cultures
 Viral serology
 Urine dipstick + MSU
 Throat swab
Additional Investigations
 If there are chest signs or temperature >38o:
– Chest X-ray
 If O2 sats on air < 94%
– Arterial gases on air
 Appropriate microbiological specimens (sputum, stool, wound, etc.)
 Note: Patients on Desferrioxamine (DFO), admitted with diarrhoea/abdominal pain, should have blood
and stool screened for Yersinia and the DFO stopped.
Approved August 2014
Review August 2016
5
Analgesia
Aim is to achieve safe, effective analgesia whilst avoiding IV opiates if possible.
Patients with end stage renal failure, consider alternative opiate e.g. Fentanyl
Some patients will have individualised pain protocols which should be referred to if available, otherwise
follow chart below.
Assessment of severity of pain in A & E
Establish what analgesia patient has
taken already/is on regularly at home.
Pain Mild/moderate
Pain moderate/severe or
Patient not used oral
analgesia
Patient used analgesic “ladder”
Analgesic “ladder”

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Add
Paracetamol Ig QDS
NSAIDs-eg. Ibuprofen
400mg/Diclofenac 50 mg
Dihydrocodeine 60 mg
Reassess after 30 mins
Pain control unacceptable

Morphine 5-10mg s/c
stat OR Oramorph 5-10
mg stat
Reassess 20-30 mins post
dose and titrate with pain
Pain persisting
Pain controlled
Pain controlled

Continue on oral
medication


Consider changing to oral
analgesia if tolerated
Morphine 5-10mg s/c or
Oramorph 5-10mg
Consider addition of MST
1mg/kg 12 hourly
Hourly observations
Pain persisting

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Consider alternative to
morphine eg. Fentanyl,
oxycodone
Consider PCA
Consult hospital pain team
Pain controlled
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Stop morphine s/c
Change to oramorph
Continue MST and
reduce after further
24 hours
6
Note
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Paracetamol and NSAIDS should be used in addition to opiates as required, as they have a synergistic
effect
All patients will have different analgesic requirements and many know what they have required to
achieve pain relief in the past. Analgesia should be titrated with pain
Patients should be monitored every 30 mins until pain is controlled and patient is stabilised and every 2
hours thereafter
Monitoring must include pain, sedation, vital signs, respiratory rate, O2 Saturation
Naloxone should be available for reversal of sedation and/or respiratory depression (RR<12/min)
Pethidine is not recommended because of risk of seizures at high doses
Consider additional therapies:
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Antipruritics: Hydroxyzine 25 mg bd po
Antiemetics: e.g. Cyclizine 50 mg tds
Laxatives if opioid analgesia is to continue
Folic acid 5mg od
Prophylactic Low Molecular Weight Heparin
Prophylactic antibiotics (usually penicillin V 250mg bd)
Fluids
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Adequate fluid intake is essential.
Patients should be encouraged to drink at least 3 litres of water-based fluids per 24 hours.
Every patient must have a fluid balance chart which should be completed by the nursing staff or by the
patient (if able).
Intravenous or nasogastric fluids may be required if the patient is unable to tolerate oral fluids
Oxygen

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
Oxygen saturations on air should be monitored regularly
Many patients have a symptomatic benefit from Oxygen therapy, and it should be prescribed and be
available whatever the oxygen saturations (even if >98%) if the patient requests
Oxygen saturations on air should be >94%
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If 0xygen saturations on air <94% Call Haematologist
Check Arterial Blood Gases (ABGs) on air
Administer humidified oxygen at 2-4 L/min by mask or nasal cannulae
Increase frequency of observations to hourly or more frequently if clinical picture dictates
Arterial Blood Gases: Consider a diagnosis of Acute Chest Syndrome if worsening hypoxia
Remember that excessive use of opioids can cause respiratory suppression. (Naloxone is occasionally
required).
7
Antimicrobials

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If apyrexial continue prophylactic antibiotics: Penicillin V 250 mg bd po (Erythromycin 250mg bd po if
allergic)
If temperature greater than 38C, undertake blood cultures/septic screen and commence Co-amoxiclav
(Unless penicillin allergic). Prophylactic antibiotics should be stopped.
If patient is on Hydroxycarbamide (Hydroxyurea), check FBC urgently and stop the Hydroxycarbamide if
the platelet count <100x109/l, reticulocytes <100x109/l or neutrophils <1x109/l
Consider:
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Pneumococcal sepsis (especially if not taking prophylaxis and not vaccinated)
Gram negative sepsis
Lower respiratory tract infection
Urinary tract infection
Osteomyelitis
Malaria if travelled recently
Parvovirus B19 if low reticulocyte count
Yersinia if on DFO and have diarrhoea
Reference: Management of Acute painful crises in sickle cell disease BCSH GUIDELINE 2003
Acknowledgements:
Thank you to the Haematology Departments of The Royal London Hospital, Manchester Royal Infirmary and
St. Thomas’s Hospital for allowing reference and adaptation of their guidelines for the management of Adults
with Sickle Cell Disease.
8
GUIDELINE ON PERIOPERATIVE MANAGEMENT OF PATIENTS WITH SICKLE CELL DISEASE
Principles of management
The Haematology Team should be informed as far in advance of elective surgery as possible.
Preparation for surgery will usually require AT LEAST a weeks notice.
Patients should be managed jointly between Haematology, Surgery and Anaesthetics. The Anaesthetic Team
should be made fully aware of the patients needs.
An individual management plan should be in place prior to surgery which takes into account the patients’
particular risk factors and the type of procedure planned. This should be circulated to all relevant individuals
prior to an elective surgical procedure.
If a period in HDU/ICU is anticipated the necessary arrangements should be made in advance.
Sickle patients should be placed near the beginning of the theatre list to minimize time fasting and reduce
likelihood of cancellation.
Ensure the patient is well informed and involved in their management plan when possible.
Fluid balance must be managed with great care in sickle patients as they dehydrate easily due to impaired
renal concentrating ability.
These patients may have a history of chronic pain and be relatively insensitive to opiate analgesia. This should
be taken into account when prescribing in the post-operative period.
Avoid factors which may precipitate the development of a sickle crisis;
Hypoxia
Dehydration
Acidosis
Cold
Pain
Day case surgery may not be suitable for this patient group due to the above considerations.
Approved August 2014
Review August 2016
9
Pre-operative Care
Ensure Haematology Team is made aware of admission as soon as possible.
Blood transfusion is not always indicated prior to surgery (see Page 12). Where indicated blood transfusion
will be arranged by the haematology team and arranged during the week before surgery for elective
procedures. Do not transfuse without prior discussion with Haematology.
In addition to FBC, HbS level and routine bloods, a sample for Group and Save, antibody screening
and red cell phenotyping (if not performed previously) should be sent at the pre-op assessment
visit and BTS informed of the date and nature of the planned procedure.
Admit the day before surgery if possible.
Hydration
Maintenance IV fluids should be commenced the evening before surgery unless the patient is drinking freely.
IV fluids must be started if nil by mouth for >2 hours.
Maintenance fluids may need to run at a higher rate than usual to avoid dehydration. Monitor fluid balance
closely.
Thromboprophylaxis
This should be considered for all procedures, particularly for major surgery or if patient will be immobile for
>24 hours post procedure.
Follow local guidelines on VTE prophylaxis.
Oxygenation
Avoidance of hypoxia is vital to prevent sickling and tissue ischemia.
Document baseline O2 saturation (may have pre-existing cardio-respiratory disease)
Consider use of incentive spirometry.
Oxygen saturation should be monitored continuously once premedication given.
Consider giving supplemental oxygen from the time of premedication.
Hyper- oxygenate at induction of anaesthesia.
Temperature Regulation
Hypothermia can trigger peripheral stasis and sickling. Attention should be paid to keeping the patient
normothermic during surgery. This may require the use of warmed intravenous fluids, warm air blankets and
adjustment to the ambient temperature in theatre. Ensure the anaesthetic team is made aware
of these requirements in advance.
Infection Management
These patients are functionally hyposplenic and are therefore at increased risk of perioperative infection. If
additional antibiotic prophylaxis is needed this should be detailed in the patients management plan.
Elective surgery should not proceed in the presence of active infection as this will greatly increase the risk of
serious sickle related complications.
10
Intra-operative Care
Hydration
Volume status must be monitored closely throughout the procedure and hypovolaemia avoided at all costs
through the prompt use of volume replacement. Again these patients are more prone to dehydration due to
impaired renal concentrating ability.
Positioning
As prolonged venous stasis can lead to sickling, the patient should be repositioned periodically where possible
during long procedures.
Tourniquet
These are contra indicated in patients with Sickle Cell disease and relatively contra indicated in Sickle Cell
Trait
Oxygenation
Pulse oximetry should be monitored continuously throughout the procedure.
Temperature Regulation
Ensure the patient remains normothermic. Warmed IV fluids are particularly important during long
procedures.
Cell Salvage
Intra-operative cell salvage is contraindicated in patients with Sickle Cell Disease.
Post-op Care
Hydration
Continue IV fluids until the patient is able to tolerate a sufficient oral intake
Avoid fluid overload post-op as this may increase the risk of complications in high risk patients.
Analgesia
Prescribe post-op analgesia as per local guidelines. Sickle patients with a history of chronic pain may be
relatively opiate resistant and require higher doses for adequate analgesia. There is a high incidence of painful
crises in the post-op period (see separate guideline).
Oxygenation
Pulse oximetry should continue for at least 24 hours or until stable.
Maintain saturations >95% or above baseline whichever is higher.
Continue incentive spirometry, encourage patient to take regular deep breaths (every 10minutes) if not
available.
Temperature regulation
Ensure the patient is normothermic until able to regulate body temperature independently.
Infection Management
If patient develops a fever (>38.0°c) ensure blood cultures are taken and start intravenous antibiotics as per
local antimicrobial policy. (NB hyposplenic)
Check cannula and line sites daily for signs of infection.
Monitor for symptoms such as productive cough, shivering or myalgia.
11
Thromboprophylaxis
This should be considered for all procedures, particularly for major surgery or if patient will be immobile for
>24 hours post procedure.
Follow local guidelines on VTE prophylaxis.
Encourage early mobilisation with physiotherapy input if appropriate.
Should the patient develop new symptoms suggestive of a sickle related complication, such as a
painful crisis, chest crisis or CVA the haematology Team MUST be informed immediately.
Blood Transfusion Guidance
Transfusion Prior to Elective Surgery
Patients undergoing major surgery and those with a history of previous sickle related complications are at
higher risk in the perioperative period. Conversely over aggressive transfusional support may unnecessarily
expose low risk patients to transfusion related hazards. Transfusion should therefore be considered
dependant on patient factors and the nature of surgery.
The recent TAPS1 trial has shown benefit for pre-operative transfusion in patients undergoing low and
medium risk surgery. See appendix for comprehensive list of surgical procedures classified by risk1. Numbers
of patients included who were for low-risk procedures was small but transfusion should still be considered.
Likewise few patients were included in the pre-operative exchange transfusion arm but this should be
considered for those with a baseline Hb>90g/l. The trial excluded patients with HbSC disease and S/β+, but in
most cases it would be reasonable to follow the principles below:
1. Low and Medium-Risk Surgery
Even patients undergoing low-risk procedures under general anaesthetic require discussion with
Haematology.
Top up transfusion should be considered (irrespective of HbS level) in most cases. Aim for a pre-op
Hb of approximately 100g/l. Avoid top-up if baseline Hb >90g/l.
Patients undergoing medium-risk surgery.
Top-up transfusion aiming for Hb of 100g/l, or partial exchange (see Exchange Transfusion
guideline) if baseline Hb >90g/l (target HbS <60%). Hb should be kept below 110g/l.
3. High-Risk Surgery
High-risk procedures e.g. thoracic, major upper abdominal surgery, neurosurgery or previous serious sickle
related complications eg severe chest crisis, CVA.
Exchange transfusion aiming for a pre-op HbS % of <30 (see Exchange Transfusion guideline). Hb
should be kept below 110g/l.
In patients with a high baseline Hb of >90g/l top-up transfusion should be used with caution to avoid
hyperviscosity. Particular care is needed in patients with HbSC disease as they are more likely to develop
hyperviscosity related complications with top-up transfusion.
Blood should be sickle negative and matched for Rh and Kell antigens as a minimum.
These principles are also applicable to patients undergoing emergency surgery if time permits. As a minimum
these patients should have suitable cross-matched blood available should an emergency exchange procedure
be needed (see Exchange Transfusion guideline). Haematology Team and Blood Transfusion Laboratory
should be informed on admission if surgery is deemed likely.
12
1. Howard J, Malfroy M, Llewelyn C et al. The Transfusion Alternatives Preoperatively in Sickle Cell
Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2103; 381: 930–38.
13
ACUTE CHEST SYNDROME IN SICKLE CELL DISEASE
Acute Chest Syndrome is the leading cause of mortality in adults with HbSS.
• CONTACT HAEMATOLOGY REGISTRAR ON CALL as soon as suspected
Acute Chest Syndrome can develop rapidly and clinicians should have a high index of suspicion.
Key Features (patient may not have all of these)
• SaO2 Sats on air <94% or PaO2 <8kPa
• Fever, Cough, Chest pain
• Respiratory distress/hypoxemia
• New opacity on chest x-ray
• Worsening anaemia
• Bilirubin stained sputum
• Antecedent painful crisis
Symptoms and Signs
• Hypoxia
• Pain in chest wall, upper abdomen, and/or thoracic spine.
• Signs of lung consolidation; usually bilateral and, generally, starting at the
bases (can progress in hours).
• Fever
• Tachypnoea
• Tachycardia
• Shortness of breath
• Cough may be a late symptom
• Physical signs often precede X-ray changes
Initial investigations
• Arterial blood gases on air
• Chest X-ray
• Blood cultures, sputum cultures, respiratory viral screen, respiratory atypical serology (including
Chlamydia, legionella, mycoplasma).
• Group and save – please state patient has ‘Sickle cell disease’ on form
• Full blood count and reticulocytes initially and then daily until improving
(compare patients baseline values)
• Renal and liver function tests
Analgesia (as per painful crisis)
Initial Management
• Call Haematology Registrar/Consultant
• IV fluids – with close monitoring of fluid balance
• IV Co-amoxiclav 1.2g tds (plus Clarithromycin 500mg bd if atypical
pneumonia suspected), for 5-7 days (consult local antibiotic policy if penicillin
allergic)
• Monitor SaO2 on air, pulse, respiratory rate, Hb
• Oxygen therapy to increase oxygen saturations >95%
• Bronchodilators if there is evidence of wheeze or reversible airways disease, or a history of asthma.
• Analgesia
Approved August 2014
Review August 2016
14
• PaO2 Room Air
< 10.0 kPa - Oxygen, and monitor oxygen saturations on air, hourly
< 8 kPa – give oxygen and consider transfusion (top up or exchange)
• Discuss transfer to HDU with HDU team if:
Worsening hypoxia or developing hypercapnia
Patient is deteriorating/tiring
Additional supportive management
• Incentive spirometry – 10 deep breaths 1-2 hourly when awake
• Consider positive pressure ventilation (nasal CPAP or mask BiPAP) for
patients with poor respiratory effort or reduced ventilation
• Analgesia (as per painful crisis)
• Consider one dose of frusemide 0.5-1mg/kg if signs of fluid overload
• Prophylactic Low Molecular Weight Heparin
Transfusion
N.B. Sickle cell patients should ideally have Rh and Kell matched sickle negative blood
• Simple transfusion for moderately severe illness, but do not transfuse
acutely to >100g/l, or take the haematocrit above 30%
• If the patient's Haemoglobin has fallen to <60 g/l consider initial top up
transfusion.
• Exchange blood transfusion can be done by the automated or manual
method. (See Exchange Transfusion guideline)
For both types of exchange transfusion:
- Cross match 8 units of blood.
- Ensure adequate venous access.
- Source blood warmer
Consider femoral line insertion if peripheral access is poor. If femoral line is
inserted, use a vascath double lumen for automated exchanges.
Monitoring
• Ensure that vital signs are taken and documented hourly (more frequently if patients’ condition is
deteriorating)
• Continuous oxygen saturation monitoring. Record Sa02 and if <92% or if deteriorating, repeat ABG’s
• Inform haematology team urgently if respirations increase or Sa02 falls
• Record temperature 2-4 hourly and if >38°c take cultures and review antibiotics
• Maintain strict fluid balance
Discharge Criteria – only in consultation with Haematologist
• Improved pulmonary symptoms and adequate oxygenation on room air
• Afebrile >24hours and negative cultures if applicable
• Stable/rising haemoglobin
• Tolerating adequate oral fluids and able to take medications orally
• Adequate pain relief on oral analgesia
15
MANAGEMENT OF ACUTE SICKLE CHEST SYNDROME
Establish diagnosis and severity

Chest pain
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Chest signs
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Oxygen desaturation
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New infiltrate on CXR

(Often fever, Decreased Hb)
Institute basic management
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Inspired Oxygen, maintain sats >95%
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Optimize standard analgesia protocol.

IV fluids, correct dehydration, avoid fluid overload
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Bronchodilators. Salbutamol nebs
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Antibiotics: Co-amoxiclav and clarithromycin
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Physiotherapy assessment. Incentive spirometry
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Blood tests: FBC, biochem, Group and Save
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Hourly nursing observations
No or mild resp distress
Mod-severe
respiratory distress

Consider top-up
transfusion
(Hb not more than
100g/l)
Post transfusion (Hb not
more than 10g)
Consider exchange transfusion
No improvement or deterioration
No improvement
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Contact ITU/HDU:
Consider CPAP or need for ventilation
Intensify physiotherapy
Review analgesia
Deterioration
Consider ITU for ventilation.
16
GUIDELINE FOR RED CELL EXCHANGE TRANSFUSION IN SICKLE CELL DISEASE
Most patients with sickle cell anaemia are relatively asymptomatic despite baseline Hb concentrations
between 50-120g/l as HbS is a low-affinity haemoglobin and oxygen delivery to tissues is enhanced. Chronic
steady state anaemia alone is not an indication for transfusion. Top-up transfusion increases whole
blood viscosity and may aggravate sickling. Top up transfusion is not indicated for uncomplicated sickle crises
(see separate guideline on perioperative management).
Exchange transfusion is a potentially life saving procedure that allows correction of anaemia without
increasing blood viscosity and may improve tissue oxygenation whilst reducing microvascular sickling.
The aim of exchange transfusion is to lower the HbS level to 30% or less while keeping the Haemoglobin close
to 100g/l. Clinical benefit may be seen even with a partial manual exchange.
Prior to embarking on an exchange procedure the case must be discussed with the Consultant
Haematologist on call.
Indications for Exchange Transfusion
Acute cerebro-vascular event
Acute chest syndrome
Multi-organ failure
Preoperatively in selected cases
Manual Red Cell Exchange Transfusion

Background
This procedure should only be performed by suitably qualified staff under the supervision of the responsible
Consultant Haematologist.
Staff should be familiar with the procedure and management of associated complications.
In some units automated exchange using an apheresis machine may be available. (Check local policy).
However manual exchange should not be delayed if it is clinically indicated.
Adult patients may require insertion of a femoral or internal jugular line but those with good peripheral
access can be managed with one or preferably two large bore IV cannulae.
Trust policies for safe blood transfusion must be adhered to at all times.

Patient work up
Consent
Ensure the patient is consented for the exchange procedure. Often verbal consent alone will be practical
when the patient is seriously ill.
Aspects which should be specifically mentioned include:
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Access (peripheral vs vascath)
Vasovagal episodes
Blood transfusion reactions and alloimmunisation
Transfusion related infection
Approved August 2014
Review August 2016
17
Inform Transfusion Laboratory of planned exchange and check for history of previous transfusion reactions or
allo-antibodies. Make them aware of degree of urgency of exchange.
Baseline Blood tests
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Full blood count
HbS percentage
Urea and electrolytes
Calcium
Magnesium
Liver function tests
Virology – HIV, hepatitis B and C
Ferritin levels, glucose, thyroid and endocrine function if appropriate (not relevant in emergency setting)
Cross match 6-8 units of packed red cells (depending on size of patient). These should be;
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Sickle negative
Phenotypically matched (Rh and Kell as minimum),
Ideally less than 5 days old (not essential in an emergency)
Nb patients should have full red cell phenotype performed if not already known and not
had recent transfusion
N.B. It may be several hours before compatible blood is available for patients with
allo-antibodies
Patient Assessment
Prior to the procedure, check:
Review baseline observations (blood pressure, heart rate, temperature and oxygen saturations)
Patient weight (estimate in an emergency when accurate measurement not feasible).
Ensure adequate venous access

Equipment and supplies
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Baxter infusion pump
Blood giving set
Blood warmer
500mls normal saline (several packs)
Packed red cells (amount dependant on patient’s size and condition, usually 6-8 units)
Dynamap and tympanic thermometer
Calcium gluconate in case of hypocalcaemia or hyperkalaemia
18
Equipment for Peripheral Access/Venesection
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












Sterile gloves
16g Kimal access needle x1
18g or 20g cannula
Chloraprep/skin preparation
4x10ml syringes
20mls of normal saline for flush
Tegaderm dressing to secure cannula
Mepore tape to secure kimal needle
Gauze swabs
Consent form (if applicable)
Blood collection form, observation chart and nursing documentation
Large sharps box
Weighing scales (to assist calculation of volume venesected)
3 way tap (useful in patients with limited peripheral access)
Sterile bungs (to allow repeated access of large bore venesection pack needle into 3 way tap extension
set)
Venesection packs
Patients requiring a central line
Follow local line insertion protocol

Method
Perform the venepuncture for the access (venesection) line and return lines. Ensure access on both sides is
secured and both lines are flushed with normal saline prior to commencing the procedure.
Set up the giving set for the return line so that fluid/blood administered is warmed in the blood warmer.
Do not start until compatible blood is available on the ward
1. Set up a bag of normal saline and run 500mls over 15 to 30 minutes to ensure the patient is adequately
pre-hydrated (reduce rate/and or volume if concern over fluid overload or cardiovascular compromise).
2. Ensure the blood is warmed prior to infusing.
3. To venesect: remove 450-500mls of blood over 15-30minutes.
4. Ensure local transfusion policies are adhered to and documentation completed.
5. Calculate the amount to be exchanged, dependant on the starting haemoglobin, as follows:

Hb >80g/l 5-8 units

Hb 60-79g/l 4-6 units

Hb <60g/l up to 4 units
19
Exchange Procedure if starting Hb >80g/l
Venesect 1st unit
whilst
Replacing with 500mls normal saline stat
Venesect 2ndunit
then
Transfuse 1st unit over 30-40 minutes
Venesect 3rd unit
then
Transfuse 2nd unit over 1 hour
Venesect 4th unit
then
Transfuse 3rd unit over 2 hours
Re-check FBC, HbS and electrolytes at this stage
If repeat Hb<90g/l
If repeat Hb>90g/l
Transfuse 4th unit and consider 5th unit (3hrs each)
Restart from “venesect 1st unit”
N.B. By removing two units of blood before transfusing the 1st unit, this method results in more efficient
lowering of the HbS %. However if the patient is cardiovascularly unstable, or becomes hypotensive during the
venesection, the replacement transfusion should be started sooner, i.e. after venesection of the 1st unit.
If starting Hb 60-79g/l
Venesect 1st unit
whilst
Transfusing 1st unit
Venesect 2ndunit
then
Transfuse 2nd unit over 1hr and 3rd and 4th units over 3hrs
Further exchange may be required (see “Hb 80g/l”) if insufficient clinical improvement/impact on HbS level
If starting Hb<60g/l
Top up transfusion to 80-100g/l (rate depending on clinical condition and baseline Hb) initially, discuss with
Consultant Haematologist.
Formal exchange may be required (see “Hb 80g/l”) if insufficient clinical improvement/impact on HbS%

Post procedure
Leave cannula in, flush with normal saline.
Monitor vital signs at 15 and 30 minutes post procedure
Take bloods 30 minutes post procedure for:
Full blood count
HbS percentage
Electrolytes, calcium and magnesium
Avoid final Hb of >110g/l (risk of hyper viscosity) or <70g/l
Watch for development of hyperkalaemia and hypocalcaemia during the exchange.
Ensure all transfusion documentation is completed correctly and returned to blood transfusion as per
local policy.
Acknowledgements:
Thank you to the Haematology Department, Manchester Royal Infirmary, for allowing reference and
adaptation of their guidelines for the management of Adults with Sickle Cell Disease.
20
SICKLE CELL OUTPATIENT MANAGEMENT
Routine Clinic review
The following issues should be discussed at each clinic visit:









General wellbeing
Sickle related complications and their current and proposed management
Recent hospital admissions
Number of hospitalisations or days off work or school related to illness
Current medications, side effects and any compliance issues
Social issues (work, housing, benefit related issues)
Infection prophylaxis
Need for specialist treatment eg exchange transfusion programme or hydroxycarbamide, if
appropriate
Any other issues of concern for the patient
Examination


Weight
Other systems as clinically indicated
Investigations




FBC
Biochemistry
Urinalysis
G&S, if transfused since last review
Approved February 2013
Review February 2015
21
SICKLE CELL OUTPATIENT MANAGEMENT
Annual review
The following issues should be discussed at each annual review visit:








The issues listed above for “Routine clinic visit”
Compliance with folic acid and penicillin V
Immunisation status, especially flu vaccine, pneumovax and Hep B
Contraception
Family planning, including the need for antenatal screening
Review of specialist treatment
Upcoming surgical procedures or outstanding referrals
Any other issues of concern for the patient
Examination






Weight
Height
Blood pressure
Oxygen saturation
Cardiovascular, respiratory and abdominal examination
Urinalysis – send for MSSU if proteinuria present
Investigations





FBC, U&E, LFTs, Ferritin
Urine for microalbuminuria or protein-creatinine ratio (PCR)
If PCR raised, 24 hour urine for creatinine clearance and protein excretion and liaise with renal team
ECHO (every 18-24 months)
PFTs, if symptomatic
Specialist Referrals






Consider ophthalmology review - annual screening for retinopathy
Consider renal review if proteinuria with PCR > 50 or ACR > 5 or worsening U&E
o Prior to referral, arrange US kidneys, HIV testing, AI screen, dsDNA, PPE/Igs and 24 hour urine
for creatinine clearance and protein excretion
Consider orthopaedic review, if AVN
Consider respiratory review, if CSL
Consider cardiology review, if pulmonary hypertension
Consider psychology and/or social work referral
22
SICKLE CELL OUTPATIENT MANAGEMENT
New Patient Attendance













General wellbeing
Sickle related complications and their current and proposed management including priapism
Recent hospital admissions and transfusions
Number of hospitalisations or days off work or school related to illness
Current medications, side effects and any compliance issues
Immunisation status
Social issues (work, housing, benefit related issues)
Family planning and contraception
Discussion re partner testing and extended family screening, if not previously done
Need for specialist treatment eg exchange transfusion programme or hydroxycarbamide, if
appropriate
Details of previous clinicians and hospitals where treated
Country of origin and any travel plans
Any other issues of concern for the patient
Examination








Weight
Height
Blood pressure
Oxygen saturation
Cardiovascular, respiratory and abdominal examination
Leg ulcers
Fundoscopy
Urinalysis – send for MSSU if proteinuria present
Investigations








FBC, U&E, LFTs, Ferritin, HPLC (for diagnostic clarification if from outwith UK)
G&S and extended RC phenotype – ensure local blood bank aware of SCD status
HIV and Hepatitis screen
G6PD screening
Urine for microalbuminuria or protein-creatinine ratio (PCR)
If PCR raised, 24 hour urine for creatinine clearance and protein excretion and liaise with renal team
ECHO (every 18-24 months)
PFTs, if symptomatic
23
THALASSAEMIA OUTPATIENT MANAGEMENT
Annual Review
The following should be discussed at each annual review visit:










General wellbeing
Transfusion issues: frequency, pre-transfusion Hb, venous access issues, transfusion reactions
Chelation issues: drugs, dose, compliance
Episodes of hospitalisation
Current medications, side effects and compliance issues
Immunisation status: Hep B status, ? had splenectomy
Outcomes of other specialist reviews eg endocrinology, cardiology, ophthalmology, audiology
Upcoming surgical procedures
Any other issues of concern for the patient
Family planning and screening
Examination
 Height
 Weight
 Cardiovascular examination
 Abdominal examination for organomegaly
Investigations
 FBC (pre-transfusion Hb)
 U&E
 Calcium & phosphate
 LFTs
 TFTs
 Ferritin
 Zinc
 Virology – Hep B, Hep C, HIV serology
 Glucose Tolerance Test
 Audiometry
 MRI assessment of liver iron stores – Ferriscan, preferred method
 MRI assessment of cardiac iron stores – T2*, preferred method
 DEXA Bone Scan (18-24 months)
Specialist review
 Cardiology, if appropriate
 Endocrinology, if appropriate
 Ophthalmology, if on desferrioxamine
Approved February 2013
Review February 2015
24
GUIDELINE FOR THE MANAGEMENT OF PRIAPISM IN SICKLE CELL DISEASE
Introduction
Priapism is defined as a pathologically prolonged erection in the absence of sexual stimulation. Stuttering
priapism may last a few minutes but by definition less than three hours and can herald a fulminant episode.
Fulminant episodes last more than three hours and are a medical emergency; without prompt treatment
erectile dysfunction and penile scarring may occur. The longer the duration, the greater the chance of a poor
outcome.
Patients with sickling disorders are at particular risk of priapism with an annual incidence in adults of 29-42%.
Children may also be affected albeit less commonly. Up to 90% of patients will have had an episode by the age
of 20. Priapism may develop with any sickling disorder but the risk appears highest in HbSS.
95% of cases in sickle patients are ischaemic. Due to dysregulation of penile circulation, blood becomes
trapped at increased pressure within the corpus cavernosum. This creates a hypoxic, hypercapneoic, acidotic
environment analogous to a compartment syndrome. If left untreated permanent tissue damage will occur.
Pathophysiology is poorly understood but abnormal blood rheology and alterations in NO metabolism may
contribute to the high incidence in sickle patients.
Patient education
Priapism is often under reported. Male sickle patients should be educated about the dangers of priapism at
their first visit and given written information. They should be instructed to present to hospital immediately if
the priapism does not resolve within two hours.
The following supportive measures can be started whilst the patient is at home but patients must be aware
not to delay seeking help:






Plentiful oral hydration
Pain relief (as per patients usual for crisis pain)
Advise the patient to empty their bladder
Encourage gentle exercise if able (“steal syndrome” may help resolve stuttering episodes)
A warm shower or bath may be helpful but evidence is lacking
Ice/cold packs must not be applied
Principles of management
Inform Urology Registrar on call immediately if a patient presents with suspected priapism. Do not delay
whilst initial supportive measures are being carried out. Prompt surgical intervention may be required.
Diagnosis
Focused history
 Duration/time of onset must be documented
 Pain severity (fulminant priapism usually very painful)
 Medication:
o intracavernosal drugs, sildenafil, antihypertensives, antipsychotics and anticoagulants are
associated with development of priapism
o analgesia taken prior to arrival
 Recreational drugs: alcohol, marijuana, cocaine
Approved June 2014
Review June 2016
25
Prior episodes
 Pre-existing erectile dysfunction
 History of genital trauma
 Crisis pain elsewhere
Examination
 Brief general examination
 Full set of observations
 External genitalia
o Degree of tumescence
o Abdominal examination: organomegaly, masses etc
Initial management




Opiate analgesia as required (sedation may be needed if severe)
IV fluids
Supplemental oxygen should be considered in all patients ( mandatory if saturations <94% on air )
Catheterise only if bladder palpable
Initial investigations
 FBC, reticulocyte count, film
 Haemoglobin electrophoresis and sickle solubility test (if not known to unit)
 Group and Save (in case needs exchange transfusion, blood loss usually minimal with shunt
procedures)
 Electrolytes, CRP
 Consider toxicology screen
Further management
If the priapism has been present for less than two hours a trial of an oral alpha or beta adrenergic agonist may
be appropriate:
 Etilifrine 50mg po stat, Ephedrine 15-30mg po stat or Terbutaline 5mg po stat depending on local
policy and availability.
 If used monitor for hypertension and/or tachycardia.
 Contraindicated in patients with uncontrolled hypertension or cardiac disease.
 If possible patient should be made aware that these are unlicensed indications.
If detumescence does not occur within 30 minutes of oral therapy, or duration of priapism greater than four
hours, penile aspiration and/or irrigation of the corpus cavernosum will be required as per advice of on-call
Urologist.
 Penile aspiration:
o
This should be performed by a Urologist but if this is not possible in an emergency situation
Medical staff may aspirate if competent to do so
o
Clean the penis with antiseptic solution as per local policy.
o
Using a 19G butterfly needle and a heparinised 20ml syringe, blood should be aspirated from
the corpus cavernosum with a lateral approach (10 or 2 o’clock position), taking care to avoid
26
the dorsal vein (superior aspect) and the urethra (inferior aspect). This will often provide
immediate relief.
o
Aspirated blood should be sent for blood gas analysis to confirm ischaemic priapism (pO2
<30mmHg and pCO2 >60mmHg, pH <7.25 expected in ischaemic priapism)
o
50-500mls should be aspirated until detumescence is achieved and the cannula then flushed
with saline.
o
Leave cannula in situ for thirty minutes before removing.
 If no resolution with aspiration, 200 to 500micrograms of phenylephrine may be given as an
intracavernosal injection- this may cause transient hypertension.
 If still no resolution, intracavernosal irrigation with saline +/- a sympathomimetic agent can be
performed (ECG and continuous BP monitoring required).
 If this fails the patient may require a penile shunt procedure.
 Late presentations with a duration of >72 hours where the risk of total loss of sexual function and
penile scarring is high may benefit from an immediate penile implant procedure.
Should the patient require surgery, the need for a top-up or partial exchange transfusion should be
considered as per the peri-operative guideline, but beware the association of sickle cell disease with
priapism, exchange transfusion and neurological events (ASPEN syndrome).
THE DECISION TO TRANSFUSE SHOULD BE MADE BY A CONSULTANT HAEMATOLOGIST.
THERE IS NO EVIDENCE FOR THE USE OF TRANSFUSION AS AN AID TO DETUMESCENCE.
Secondary Prevention
Advice





Avoid alcohol at night
Awareness of the link between illicit drugs and priapism (cocaine, marijuana)
Maintain good fluid intake
Empty bladder before bed
Inform doctor about stuttering episodes
Outpatient management of stuttering priapism
Management should be in conjunction with a Sexual Health specialist with an interest in priapism.
Psychosocial aspects should also be considered.
Pharmacological therapy should be reserved for patients with recurrent episodes or who have previously
suffered a fulminant priapism.
Options include:




Regular oral alpha adrenergic agonist- monitor BP every 2 weeks and discontinue if > 150/90
Hormonal therapies- side effects include loss of libido and impotence
Trial of PDE5 inhibitor eg Sildenafil
Hydroxycarbamide or regular transfusion programme if previous severe episodes - discuss at SPAH
MCN MDT prior to commencement
27
References
Olujohungbe A., Burnett A. (2013) How I manage priapism due to sickle cell disease. British Journal of
Haematology 160, 754-765.
Montague D.K., Jarow J., Broderick G.A., Dmocochowski R.R., Heaton J.P., Lue T.F., Nehra A.J., Sharlip I.D.
(2003). Guideline on the management of priapism. American Urological Association.
Acknowledgements:
Thank you to the Haematology Departments of Manchester Royal Infirmary and St. Thomas’s Hospital for
allowing reference and adaptation of their sickle cell disease priapism guidelines.
28
CLINICAL GUIDELINE FOR THE MANAGEMENT OF HYPERHAEMOLYSIS IN PATIENTS WITH SICKLE
CELL DISEASE, INCLUDING THE USE OF INTRAVENOUS IMMUNOGLOBULINS (IVIg)
Summary
Hyperhaemolysis is a well-recognised but rare complication of blood transfusion in patients with sickle cell
disease (SCD).
It is characterised by rapid haemolysis following a blood transfusion, and the post-transfusion haemoglobin
(Hb) will often be lower than the pre-transfusion Hb, implying the destruction of recipient as well as donor red
cells.
This Guideline describes the management of this complication, including the use of immunoglobulin, which is a
'grey' indication according to the Department of Health Immunoglobulin Demand Management Programme.
Document Detail
Document Type
Document name
Clinical Guideline
Guidelines for the management of
hyperhaemolysis in patients with Sickle Cell
Disease, including the use of intravenous
immunoglobulins (IVIg)
GTi Clinical Guidance Database
2.0
22 May 2012
22 May 2014
Oncology and Haematology Directorate
Dr Jo Howard, Consultant Haematologist
Drug and Therapeutics Committee, March
2012
1.0
Document location
Version
Effective from
Review date
Owner
Author
Approved by, date
Superseded documents
Related documents
Keywords
Sickle cell disease, immunoglobulins, IVIg,
hyperhaemolysis
Relevant external law, regulation, standards
Change History
Date
Change details, since approved
Approved by
Background
Hyperhaemolysis is a well-recognized but rare complication of blood transfusion in patients with sickle cell
disease (SCD).
It is characterised by rapid haemolysis following a blood transfusion, and the post-transfusion haemoglobin
(Hb) will often be lower than the pre-transfusion Hb, implying the destruction of recipient as well as donor red
cells. It may be associated with a fever and with pain typical of sickle cell disease. The direct antiglobulin test
(DAT) is usually negative and no new red cell allo-antibodies are identified. There may be a reticulocytopenia.
29
Additional transfusion has been associated with increasing haemolysis and worsening anaemia, and should be
avoided if possible. The haemolysis can be treated with intravenous immunoglobulins (IVIg) and IV
Methylprednisolone.
In cases where there is very rapid haemolysis and critical anaemia, additional transfusion will be required and
this should be preceded by IVIg and IV Methylprednisolone.
Erythropoetin, iron replacement, B12 and folate replacement should also be considered.
Hyperhaemolysis can recur following blood transfusions several months or years after the initial episode, and
patients should be retreated with IVIg and Methylprednisolone prior to future transfusion.
IVIg use for this indication has been approved by IVIg Assessment Panel, 30 November 2010.
Patient Groups
1) IVIg and IV Methylprednisolone should be considered in patients with SCD who present with evidence of
severe haemolysis following a blood transfusion.
2) Patients with SCD and hyperhaemolysis who continue to haemolyse despite initial treatment and have
worsening anaemia may need a further transfusion. This should be preceded by IVIg and IV
Methylprednisolone.
3) Patients with SCD and a history of hyperhaemolysis are at risk of recurrence and if transfusion is necessary
should be pre-treated with IVIg and IV Methylprednisolone.
Diagnosis
Hyperhaemolysis should be considered in any patient with SCD who presents with increasing haemolysis after
a blood transfusion. It typically presents at 1 week post- transfusion, but may occur sooner than this if the
patient is re-challenged with transfusion
Clinical features: Increasing jaundice, dark urine (‘coca-cola’ coloured), anaemia. They may also have a fever,
back leg or abdominal pain, hepatomegaly or hepatic discomfort.
Investigations:
Increasing anaemia – Hb may often fall to below the pre-transfusion level
Haemolysis – raised bilirubin, raised LDH
Reticulocytes may be raised (in keeping with haemolysis) or decreased, due to suppression of red cell
production
Direct Antiglobulin Test (DAT) is negative, and no new allo-antibodies are found on testing.
Differential diagnosis is a delayed haemolytic transfusion reaction due to new allo-antibodies and blood must
be sent to the transfusion laboratory for the investigation of new allo-antibodies.
Treatment
Discuss with Haematology Consultant (Contact the on-call Consultant if out-of-hours)
Prescribe Folic acid 5mg.
Primary treatment is with immunosuppression: IV Methylprednisolone and IVIg
Consider treatment with erythropoietin and IV iron replacement
Consider B12 replacement.
Blood transfusion should only be given after discussion with the Haematology Consultant.
Blood transfusion may be necessary if clinically indicated (profound symptomatic anaemia)
Phenotyped blood should be given (CDE and Kell matched).
Dosage
Intravenous immunoglobulin (IVIg) – Adult and paediatric dose (Unlicensed indication)
1g/kg once daily for 2 days (total dose = 2g/kg)
Round dose to nearest vial size (5g or 10g vials available)
Administration and preparation as per trust guidance
30
The prescribing doctor (Specialist Registrar or Consultant) MUST complete an IVIg form on EPR. This must be
printed out and given to pharmacy at the same time as a copy of the prescription. Pharmacy cannot supply
IVIg without this form.
Methylprednisolone
Adults: 500mg IV for 2 days
Paediatrics 10mg/kg IV for 2 days (maximum dose 500mg)
Review dose after 2 days.
Erythropoietin
NeoRecormon® 300units/kg once daily for 5 days.
Then 300units/kg once daily alternate days (i.e. 3 times per week)
Ferritin, B12 and Folate
Erythropoietin needs adequate haematinics to work properly.
If ferritin <100ng/ml – prescribe IV Ferinject® (ferric carboxymaltose) (dose is based on the patient weight and
Hb; refer to full Summary of Product Characteristics for dosing information)
If ferritin >100ng/ml – prescribe oral iron (ferrous sulphate)
B12: prescribe if B12 <200 pg/ml (i.e. Hydroxocobalamin 1mg IM 3 times a week for 2 weeks)
Folate: prescribe Folic acid 5mg once daily
Monitoring of treatment:
Haemoglobin:
Stop if haemoglobin returns to baseline or if lack of response after full treatment dose.
Target is return of haemoglobin to baseline
Monitoring of this Guideline
Use of IVIg for this indication will be monitored via the DH Immunoglobulin Demand Management Programme
Database.
References
Cullis JO, Win N, Dudley JM, Kaye T. Post-transfusion hyperhaemolysis in a patient with Sickle Cell Disease: Use
of Steroids and Intravenous Immunoglobulin to prevent further red cell destruction. (1995). Vox Sang. 69; 355357
Talano JM, Hillery CA, Gottschall JL, Baylerian DM, Scott JP. Delayed haemolytic Transfusion
Reaction/Hyperhaemolysis Syndrome in Children with Sickle Cell Disease. (2003) Paediatrics; 111; 661-665
Win N, Tullie Y, Needs M, Chen FE, Okpala I. Use of intravenous immunoglobulin and intravenous
methylprednisolone in hyperhaemolysis syndrome in sickle cell disease. (2004) Haematology. 9; 433-6
Win N, New H, Lee E, De La Fuente J. Hyperhemolysis syndrome in sickle cell disease: case report (recurrent
episode) and literature review. (2008) Transfusion. 48; 1231-1238
Acknowledgement:
Thank you to the Haematology and Oncology Departments of Guy’s & St Thomas’ Hospital, London for
allowing us to reference their guideline.
31