1 st Paediatric Emergency Conference Kuwait October 2011

1. 1st Paediatric Emergency ConferenceKuwait October 2011 Sickle Cell Disease – Optimising Paediatric Emergency Care Dr. D. A Jarvis

2. Disclaimer I have no actual or potential conflict of interest to declare. Photographs, images, charts and information were selected from The Hospital for Sick Children teaching file, my personal collection or downloaded from the internet. Dr. D. A. Jarvis

3. Learning Objectives In this session participants will: • Review the common presentations of Sickle Cell Disease and emergency management • Learn some of the new emerging information on approaches to management • Be stimulated to review the care Sickle Cell patients receive in their practice settings

4. What is Sickle Cell Disease? 1910 James Herrick described RBCs distorted by polymerized, deoxygenated hemoglobin as “sickle shaped” 1922 Mason named condition “sickle cell anemia” • a single missence mutation B globin gene • (sixth codon) • thiamine substituted for adenine results in valine residue replacing glutamic acid

5. Sickle Cell Genetics

6. How do patients present? • Newborn screening program • Recurrent crises: vaso occlusive (pain) bacteremia/septicaemia acute chest syndrome splenic/hepatic sequestration stroke aplastic

7. Pathophysiology and Presentations • recurrent ischemia due to vaso-occlusion • acute and chronic inflammation • haemolysis – associated vasculopathy Clinical presentations: gallstones,retinopathy, priapism pulmonary hypertension, avascular bone necrosis Individual clinical severity based on interaction of genetic/environmental factors and HbF levels

8. Vaso-Occlusive (Pain) Crisis: • cause: ischemic tissue injury results from obstructed blood flow by sickled RBCs • precipitants: infection, fever, acidosis, hypoxia, dehydration, sleep apnea, extremes of heat and cold • clinical: bone, back, abdomen infants dactylitis (hand/foot syndrome)

9. Vaso-Occlusive (Pain) Crisis: • Management: accurate ongoing pain assessments maintain hydration 1½ x maintenance 10 ml/kg bolus if morphine RX adequate pain control ± antipyretics and antihistamines rule out other pathologies • discharge planning: to ensure continued symptom relief and appropriate follow up health care

10. Pain Scales

11. Pain Scales

12. RT 8 Year Old Boy • known “sickler” HbSS • presented with painful, swollen right upper arm, unable to feed himself • pain on and off for one week treated at home with acetaminophen and ibuprofen • family denies fever – concerned arm is swelling and skin feels warm On examination: pain 10/10 Temp 37.8°Celsius Emergency staff called Child Protection Services when x-ray showed “new bone formation” Was this appropriate? What is the diagnosis?

13. RT 8 Year Old Boy • family contacted Sickle Clinic Nurse for help On further investigation: multifocal osteomyelitis Salmonella species Admitted to hospital: intravenous antibiotics and surgical drainage Further history: diarrhea one month earlier on visit to Caribbean, denied rectal bleeding or fever There may be more than 1 pathological process present! SickKids Toronto suggests any axillary temperature > 37.5°C be investigated

14. Bacteremia / Septicemia • sickle disorders result in susceptibility to overwhelming infection with encapsulated organisms (pneumococcus / salmonella) • prophylactic antibiotics save lives • vaccinations essential • prompt evaluation with ANY rise in temperature, appropriate cultures and broad spectrum antibiotics within 30 minutes of arrival in Emergency Department • admission to hospital in most cases

15. JJ 6 Month Old Boy • newborn Sickle Screen positive, confirmed at four months of age • family doctor referred baby to tertiary centre • before first visit developed a “cold” and temperature of 38°C • family treated with acetaminophen • found lifeless in crib • post mortem diagnosis Pneumococcal Sepsis Could this have been prevented? How are newly diagnosed sicklers managed in your Emergency?

16. Acute Chest Crisis: causes:infectious – bacteria, viruses non-infectious – pulmonary infarction hypoventilation, fat embolus, pulmonary oedema clinical: young children – fever + cough adults – severe pain, dysnoea, chills chest crises cause 25% SCD fatalities may result in restrictive chronic lung disease

17. Chest Syndrome Management • oxygen saturation and/or oxygen Rx • blood culture + CBC diff + reticulocytes • chemistry + X match CXR + arterial gas • iv N/S 1-1 ½ maintenance, bolus only if in shock DO NOT OVER HYDRATE • iv antibiotics • measure pain + morphine iv • review old records and consult expert may need an exchange transfusion – must be in ICU

18. Acute Sequestration Clinical: • sudden increase in spleen size, decrease in haemoglobin and increase in reticulocytes • child may present with pallor, decreased activity or irritability • after attack, spleen decreases in size In Jamaican cohort: accounted for 24% deaths in first ten years of study Sergeant

19. Acute Splenic Sequestration Management: • parental detection reduces mortality • after 2nd attack, further events occur at shorter intervals, each associated with mortality • prophylactic splenectomygenerally indicated after 2nd attack • no demonstrated disadvantages of splenectomy in terms of post-splenectomy infections or deaths • beware of over-transfusion

20. Cerebrovascular Accidents and SCD Clinical: • 11% risk of stroke in HbSS patients by 20 years age 16% have “silent strokes” • presentation may be subtle and transient: visual field defects / aphasia acute changes in behaviour motor dysfunction First indication of stroke(s) may be school or behavioural difficulties Hulbert et al Blood 2011 .... Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy....

21. Cerebrovascular Accidents and SCD Management: • CT study early may be normal • MRI investigation of choice • always rule out meningitis and other causes of altered mental status • exchange transfusion Note: educational implications and need for multidisciplinary follow up

22. AC 6 Year Old Girl • A camp counsellor at Summer Camp notices 6 year old AC is watching activities today • AC states she is “fine, just don’t feel like playing today” How should the counsellor proceed? What do you think is happening?

23. Sickle Cell Crisis Challenges • wide spectrum of presentations • stoic / calm patients versus distressed patients • low grade fever at home, “well” looking • patient with normal temperature in emergency • young patients reported to be “quieter” than usual or “not usual selves” Note: avoid underestimations of pain severity early signs of sepsis, hypersplenism and aplastic crises may be subtle multiple pathologies may be present

24. New emerging information • can clinical severity be predicted? • do all febrile “sicklers” need admission? • how much fluid is enough? • what is that heart murmur? • how long do sicklers live? • nitric oxide inhalation during pain crisis

25. Can clinical Severity be Predicted? VandenTweel Am J Hematol 2010; 85: 746-51 Validated a pediatric severity index for sickle cell patients: • Bone necrosis • Cerebral infarcts or vasculopathy • Hepatic / Splenic sequestration • Pneumococcal sepsis and / or meningitis • Priapism • Acute chest syndrome / Painful crises • Lab values: Hb ≤ 6.6 g/dl HbF ≤ 3.0% LDH 700 U/I WBC ≥ 15.2

26. Do all febrile “sicklers” need admission? Rogovik et al Am J Emerg Med 2010; 28: 511-4 • retrospective chart review 692 emergency visits during 2 year period – Toronto SickKids • 77 % febrile Sickle Cell children admitted • 1.3% positive blood cultures no S. pneumoniae • most children had received 7 valentpneumoccal conjugate vaccine Ramakrishnan M et al Lancet InfDis 2010 Increased risk of invasive bacterial infections in Africa.... Suggest: CAUTION continue to treat and admit febrile sickle cell patients until “low risk” criteria for discharge are validated

27. How much fluid is enough? Miller Pediatr Blood Cancer 2010; 54;265-8 1928 Dr. Hugh Josephs first noted that urine concentration defect common in sickle cell anaemia • defect may be reversible with transfusions • clinically nocturia, enuresis and tendency to dehydration seen BABY HUG ongoing double blind, placebo controlled trial to evaluate efficacy of hydroxyurea in young sickle children to prevent end organ damage Results: infants 7.5 to 17.9 months able to concentrate urine after fluid deprivation before enrolment retesting of same children planned in 2 years Note: avoid over hydration of young infants

28. What is that murmur? • chronic anaemia • fluid overload • pulmonary hypertension: tricuspid regurgitation • pathology not related to sickle cell anaemia Johnson 2010 Blood Left ventricular hypertrophy and diastolic dysfunction... are related to asleep and waking oxygen saturation Liem 2010 Am J Hematology Reproducibility of tricuspid jet velocity measurements Arslankoylu 2010 J Tropical Pediatrics Assessment of cardiac functions... doppler myocardial performance index

29. How long do Sicklers live? • depends on genetics, severity of disease, environment and access to medical care Jamaican Cohort 6 Age 30 years Age 3 months

30. References Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis: a randomized trial Gladwin MT, Kate GJ, Weiner D et al JAMA 2011; 305 (9): 893-902 Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG) Wang WC et al, BABY HUG investigators The Lancet 2011; 377: 1663-72 Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with Sickle Cell Disease Hulbert ML, McKinstry RC, Lacey JL et al Blood 2011; 117: 772-79 The PediatricHydroxyurea Phase III Clinical Trial (BABY HUG) Challenges of Study Design Thompson BW, Miller ST, Rogers ZR, Rees RC et al Pediatr Blood Cancer 2010; 54: 250-55

31. References Urine Concentration Ability in Infants with Sickle Cell Disease: Baseline Data from the Phase III Trial of Hydroxyurea (BABY HUG) Miller ST, Wang WC, Iyer R et al Pediatr Blood Cancer 2010; 54: 265-68 Outcome of children with sickle cell disease admitted to intensive care – a single institution experience Bartram JL, Thein SL, Gardner K et al Br J Haematol 2010; 150: 614-7 Left ventricular hypertrophy and diastolic dysfunction in children with sickle cell disease are related to asleep and waking oxygen desaturation Johnson MC, Kirkham FJ, Redline S et al Blood 2010; 116(1): 16-21 Assessment of cardiac functions in Sickle Cell Anemia with doppler myocardial performance index Arslankoylu AE, Hallioglu O, Yilgor E, Duzovali O J TropPediatr 2010; 56(3):195-7

32. References Improved survival of children and adolescents with sickle cell disease Quinn CT, Rogers RR, McCavit TL, Buchanan GR Blood 2010; 115: 3447-52 Development and validation of a pediatric severity index for sickle cell patients van Den Tweel XW, van der Lee JH, Heijboer H, Peters M, Fijnvandraat K Am J Hematol 2010; 85: 746-51 The risks and benefits of long term use of hydroxyurea in sickle cell anaemia: A 17.5 year follow up Steinberg MH, McCarthy WF, Castro O et al; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients' Follow-Up Am J Hematal 2010; 85: 403-8 Bacterial blood cultures in children with sickle cell disease Rogovik AL, Friedman JN, Persaud J, Goldman RD Am J Emerg Med 2010; 28: 511-14

33. References Increased risk of invasive bacterial infections in African people with sickle-cell disease: a systemic review and meta-analysis Ramakrishnan M, Moisi JC, Klugman KP et al Lancet InfDis 2010; 10:329-37 Pulmonary Complications of Sickle Cell Disease Gladwin MT, Vichinsky E NEJM 2008; 359: 2254-65 Sickle Cell Disease Driscoll MC Pediatrics in Review 2007; 28(7): 259-68 Sickle Cell Disease Graham R Sergeant Oxford Medical Publications