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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 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” 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 Consider alternative to morphine eg. Fentanyl, oxycodone Consider PCA Consult hospital pain team Pain controlled Stop morphine s/c Change to oramorph Continue MST and reduce after further 24 hours 6 Note 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: 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 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 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% 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 If apyrexial continue prophylactic antibiotics: Penicillin V 250 mg bd po (Erythromycin 250mg bd po if allergic) If temperature greater than 38C, 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: 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 Chest signs Oxygen desaturation New infiltrate on CXR (Often fever, Decreased Hb) Institute basic management Inspired Oxygen, maintain sats >95% Optimize standard analgesia protocol. IV fluids, correct dehydration, avoid fluid overload Bronchodilators. Salbutamol nebs Antibiotics: Co-amoxiclav and clarithromycin Physiotherapy assessment. Incentive spirometry Blood tests: FBC, biochem, Group and Save 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 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: 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 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; 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 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 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