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Acute Complications of Sickle Cell Disease & Management Guidelines Emily Riehm Meier, M.D., M.S.H.S. September 28,2016 317.871.0000 or 877.256.8837 Objectives 1. Describe the most common complications of sickle cell disease, including acute chest syndrome, vaso-occlusive pain crisis, and stroke. 2. Recognize a patient with sickle cell disease who needs emergency care. 3. Develop a management plan for a patient with sickle cell disease who presents for an acute care visit. The Red Cell • Each red cell has 200- 300 • million hemoglobin molecules • Four globin chains per • hemoglobin molecule: • 2 α chains • 2 β chains • One heme moiety • within each globin chain • to bind oxygen Pathophysiology 1 : Polymer Formation • HbS is an abnormal β globin protein caused by a single amino acid substitution (Glu -> Val) • Polymerizes upon deoxygenation • HbS polymers pull cell into sickle shape • Other known triggers of polymerization: dehydration, cold temperatures. O2 O2 O2 O2 HbA HbS Pathophysiology 2: Vaso-Occlusion • Normal red blood cells are flexible enough for passage through microcirculation. • Sickle cells are rigid and become stuck in the capillaries. • Tissue is deprived of oxygen. • Over time organ damage occurs (i.e. spleen, retina) Pathophysiology 3: Nitric Oxide Depletion Hemolysis, endothelial dysfunction Viscosity, vaso-occlusion Pathophysiology 4: Inflammation • • • • Interplay of white cells and platelets Reperfusion injury Upregulation of cytokines Thrombosis Clinical Manifestations of Sickle Cell Disease Unpredictable severe pain • Tissue damage from lack of blood flow Anemia Damage to many organs: • Kidney, spleen, brain, lung, retina, bone Unpredictable hospitalizations & absences Leg ulcers Retinopathy Stroke SCD Manifestations Splenic Sequestration Pain-Dactylitis AVN Acute Chest Syndrome Survival of Children with Sickle Cell Disease Quinn CT, et al. Blood 2010;115:3447-3452 State Distribution of Hemoglobinopathies Over 50 cases 31-50 cases 16-30 cases 6-15 cases 1-5 cases State Distribution of Hemoglobinopathies Over 50 cases 31-50 cases 16-30 cases 6-15 cases 1-5 cases Emergencies in Sickle Cell Disease Fever of 101oF or higher (100.4oF in young infants) Acute Chest Syndrome: Respiratory symptoms/chest pain with abnormal chest Xray Stroke: Neurologic symptoms/deficits Priapism: Prolonged penile erection Splenic sequestration: Pallor, lethargy, hypotension, with increased size of the spleen Pain not responding to home pain control regimen Sickle Cell Interim History and ROS: • • • • • • • • • • Sickle genotype Baseline hemoglobin Acute chest syndrome –PICU care needed Stroke –recent TCD results Spleen complications – Sequestration, splenectomy History of Pneumococcal bacteremia, meningitis Priapism Transfusions – transfusion problems e.g. alloAntibodies Hydroxyurea and adherence Immunizations – esp Pneumovax, Prevnar 13, Flu Sickle Cell Emergency 1: Fever > 101⁰F Parents counseled to seek advice for all temperatures >38⁰C/100.4⁰F in infants and >101⁰F in older child Prompt assessment at PCP/ Heme office/ED for source of fever AND Empiric antibiotics even if source found or not Admit infants <1 year In children > 1 year, Ensure child will have outpatient follow up AND 2nd dose Ceftriaxone if necessary Infection Risk and SCD 1. Functional or Surgical Asplenia • Impaired clearance of IgG coated bacteria that are resistant to opsonization • Need an increased rate of opsonization to overcome infection risk • Delayed/decreased response to vaccines because of impaired production of IgM 2. Decreased Opsonization • Children with SCD have decreased rate of opsonization compared to healthy children Rubin and Schaffner, N Eng J Med 2014;371:349-356 Bjornson, Gaston & Zellner, J Pediatr 1977;91:371-378 Invasive Pneumococcal Disease and SCD Rate of IPD has declined since Prevnar • Rate of IPD 13.5/100 patient years in 1980s • 0.5-1/100 patient years in 2010 IPD still happens in children with Sickle Cell • Less than optimal adherence to Penicillin prophylaxis • Non-vaccine serotypes • Suboptimal vaccine response Rubin and Schaffner, N Eng J Med 2014;371:349-356 Obaro and Iroh Tam, Pediatr Blood Cancer 2016;63:781-785 Management of Fever in an Asplenic Patient Fever >101 Access to Medical Facility within 2 hours? Yes No CBC/Retic Aerobic Blood Culture + Chest Xray Physical Exam Take po antibiotics and immediately begin travelling to medical facility Ill appearing or abnormal labs or age <1 year? Yes Ceftriaxone im/iv Admit to hospital Broaden coverage based on clinical presentation No Ceftriaxone im/iv Discharge home provided that followup is arranged and reliable contact phone number available SCD Empiric Antibiotics, Fever > 101⁰F Ceftriaxone – 1st line for most fever • Active against S. pneumonia, H. influenzae, N. meningitidis, community-acquired gram negative Clindamycin – if allergic to ceftriaxone Vancomycin – add if sepsis is likely Azithromycin – add for Acute Chest Syndrome Sickle Cell Emergency 2: Acute Chest Syndrome Infiltrate on Chest Xray and > 1 of the any of the following: • • • • • • Fever Cough Chest Pain Hypoxia Wheezing Tachypnea Leading Cause of Death in SCD patients Wang et al. Lancet 2011; 377:1663-1672 Khoury et al. Hemoglobin 2011; 35:625-635 Acute Chest Syndrome Classically develops 2-3 days after admission for pain crisis and characterized by rapid (<12 hours) development of respiratory symptoms and decompensation Causes: • Fat emboli (from bone that is infarcted from red cell sickling) • Infection Gram positive cocci Atypical organisms (mycoplasma most common) • Lung infarction • Cause only identified in 38% of patients DeBaun MR, Struck RC. Lancet 2016;387:2545-2553 Desai PC, Ataga KI. Expert Opin Pharmacother 2013;14:991-999 Acute Chest Syndrome Much more commonly a subacute process that mimics: • Bacterial pneumonia • Bronchiolitis • Asthma exacerbation Children much more likely to present with cough and fever • 40% will have a normal physical exam, so high index of suspicion is necessary Adults more likely to present with chest pain, dyspnea, and multilobar involvement on chest Xray DeBaun MR, Struck RC. Lancet 2016;387:2545-2553 Treatment for Acute Chest Syndrome Broad spectrum antibiotics • IV Ceftriaxone (for S. pneumoniae) • PO Macrolide (for C. pneumoniae or M. pneumoniae) Adequate analgesia (but not over-sedation) Adequate hydration (to prevent subsequent sickling but also need to avoid fluid overload) Physical therapy Inhaled beta-agonists and corticosteroids Incentive spirometry Blood transfusion, exchange transfusion Oxygen, BiPAP, mechanical ventilation DeBaun MR, Struck RC. Lancet 2016;387:2545-2553 Desai PC, Ataga KI. Expert Opin Pharmacother 2013;14:991-999 Sickle Cell Emergency 3: Stroke • ISCHEMIC - blockage of blood flow to part of brain o vascular stenosis o microvascular sickling & thrombosis? • Symptoms include o motor or sensory deficit, >24hr (caveat: painless limp) • MRI / MRA / dWI Strokes • HEMORRHAGIC bleed, e.g. aneurysm • hypertension, increased ICP • “worst headache of my life” Non-contrast CT Treatment – Neurosurgical Prevention – control hypertension Stroke Risk in Children with SCD Adams RJ. Arch Neurol 2007;64:1567-1574 Age Distribution of Stroke by Age Ohene-Frempong K, et al. Blood 1998;91:288-294 Exchange Transfusion vs. Simple Transfusion at Time of Presentation Exchange Transfusion at Presentation Simple Transfusion at Presentation Hulbert ML, et al. J Pediatr 2006;149:710-712 Exchange Transfusion vs. Simple Transfusion at Time of Presentation Exchange Transfusion at Presentatio Patients who received a simple transfusion at the time of presentation were 5 times more likely to have a recurrent stroke in the future (RR=5.0; 95%CI 1.3-18.6) Simple Transfusion at Presentatio Hulbert ML, et al. J Pediatr 2006;149:710-712 Sickle Cell Emergency 4: Priapism • Prolonged, unwanted, painful erection of the penis • Onset between 5 and 35 years of age • Affects over 1/3 of males with SCD • Often recurrent • Stuttering Priapism: multiple, self-limited, lasts < 4 hours • Onset is often in the early morning, waking the patient Olujohungbe AB et al. J Androl 2011;32:375-382 Priapism – Treatment and Prevention Treatment includes: • Pain relief, hydration • Urination • Intercavernosal injection of alpha adrenergic agent (etilefrine or pseudoephedrine) • Surgical shunt procedures Prevention with: • Alpha adrenergic agents (etilefrine or pseudoephedrine) • Hydroxyurea • Possibly sildenafil Broderick GA. J Sex Med 2012;9:88-103 Montague DK, et al. J Urol 2003;170:1318-1324 Burnett AL, et al. Am J Hematol 2014;127:664-668 Sickle Cell Emergency 5: Splenic Sequestration • Most common from 6 mos-3 yrs of age in children with HbSS • Can occur into adulthood in people with HbSC or HbSβ+thalassemia • • • • • Drop in Hemoglobin by at least 2 g/dL Rapidly enlarging spleen Reticulocytosis (above baseline) Mild to moderate thrombocytopenia May be associated with fever, pain, tachycardia and respiratory symptoms. Emond AM, et al. J Pediatr 1985;107:201-206 Squiers JJ, et al. J Inv Med High Impact Case Rep 2016;1:1-3 Spleen Palpation Increases Incidence but Decreases Mortality Pre-Spleen Palpation Education Year No. of attacks Fatalities Child years of observation 1974 2 0 39 1975 7 2 74 1976 9 3 102 1977 7 2 130 1978 9 3 149 Incidence rate: 4.6 per 100 patient years of observation Mortality rate: 29.4 per 100 events Emond AM, et al. J Pediatr 1985;107:201-206 Spleen Palpation Increases Incidence but Decreases Mortality Pre-Spleen Palpation Education Post-Spleen Palpation Education Year No. of attacks Fatalities Child years of observation Year No. of attacks Fatalities Child years of observation 1974 2 0 39 1979 18 0 182 1975 7 2 74 1980 20 1 209 1976 9 3 102 1981 22 2 241 1977 7 2 130 1982 22 0 245 1978 9 3 149 1983 16 0 236 Incidence rate: 4.6 per 100 patient years of observation Incidence rate: 11.3 per 100 patient years of observation Mortality rate: 29.4 per 100 events Mortality rate: 3.1 per 100 events Emond AM, et al. J Pediatr 1985;107:201-206 Treatments of Splenic Sequestration Intravenous fluids Blood transfusion – typically 5 mL/kg pRBC aliquots Splenectomy – usually reserved for recurrent splenic sequestration • Review spleen palpation and signs/symptoms of worsening anemia with family members at each clinic visit Rhodes MM, et al. J Clin Gastroenterol 2014;48:99-105. Sickle Cell Emergency 6: Vaso-Occlusive Episode The most common symptom of SCD May start as early as first year of life. Recurs unpredictably through the life Frequency and severity of pain is variable among the patients Presents unique challenges for patients, families and health professionals Platt OS et al. New Eng J Med,1991;325: 11-16 Impact of Pain in Sickle Cell Disease Quality of life of patients and their caregivers Financial burden: • Direct cost : Admissions and treatment of VOC »over 75,000 hospitalizations »over $475 million in 2004 • Indirect cost : Lost productivity, missed work or school days Steiner and Miller. 2004. hcup-us.ahrq.gov African Tribal Names for Sickle Cell o Chwechweechwe (relentless perpetual chewing) o Adep (beaten up) o HemKom (body biting) Pain in SCD Starts Early Dactylitis: Painful swelling of hand and feet. Infarction of bone marrow due to occlusion of blood supply Presents as early as 6 months of age as fetal hemoglobin starts to decline Acute Vaso-Occlusive Pain Crisis The characteristic manifestation after early childhood Precipitated by temperature changes, stress, infection, dehydration and unknown factors Spine, pelvis, long and flat bones are commonly involved 39%: no episodes of severe pain; 1% had >6 episodes per year; 5% of SCD individuals accounted for >30% of episodes Platt r denotes the number of episodes of pain per patient-year, SS sickle cell anemia, SC hemoglobin SC disease, Sβ+ et al NEJM 1991; 325(1)11-6 sickleβ+-thalassemia, and Sβ0 sickle β0-thalassemia. Frequent Hospitalization for Pain is a Risk Factor for Early Mortality in SCD Darbari DS et al. PLoS One. 2013;8:e79923. Vaso-Occlusive Crises vs. Daily Pain Smith WR et al. Ann Intern Med 2008;148:94-101 Episodes of Daily Pain Smith WR et al. Ann Intern Med 2008;148:94-101 Episodes of Daily Pain Smith WR et al. Ann Intern Med 2008;148:94-101 Episodes of Daily Pain > 50% of patients experienced pain on >50% of the days; 30% experienced pain > 95% of the days Smith WR et al. Ann Intern Med 2008;148:94-101 Pain in Sickle Cell Disease Sickle cell pain: »Acute, severe and disabling (crisis) »Chronic pain of variable degrees » Rx: Ambulatory/ ED/ hospitalization Frequency of pain vary among SCD individuals for both severe and mild/ moderate ambulatory pain Outpatient Management of Pain Adequate hydration Avoid temperature extremes Anti-inflammatory (ibuprofen) alternating with oral opioid Adequate rest Non-pharmacologic techniques • • • • • • • • Distraction Deep Breathing Guided Imagery Acupuncture Massage Cognitive Behavioral Therapy Yoga Prayer Inpatient Management of Pain IV fluids IV opioids Anti-inflammatories Non-pharmacologic techniques • Deep breathing exercises to prevent pneumonia • Physical Therapy Therapeutic exercises Heat packs/whirlpool • • • • • • Distraction Guided Imagery Acupuncture Massage Cognitive Behavioral Therapy Prayer Summary Pain is the hallmark of sickle cell disease Acute chest syndrome is the leading cause of death in people with sickle cell disease Patients who present with acute, overt stroke should be treated with exchange transfusion to decrease risk of recurrent stroke. Gold standard of therapy for priapism is intercavernosal irrigation and injection of alpha adrenergic agonist. Splenic sequestration should be managed with iv fluids and pRBC transfusion. Thank you! Questions? [email protected] Challenges of Chronic Pain Management No long term (>1 year) studies of opioid effectiveness for chronic pain Mixed results with short term courses of opioid medications for chronic pain In 2014, 10 million Americans reported using a prescription opioid for a nonmedical reason Nearly 2 million Americans over age 12 years met diagnostic criteria for substance use disorder involving prescription opioids More than 165,000 deaths due to overdose of opioid pain medication in US from 1999-2014 Dowell D, et al. JAMA 2016;315:1624-45 Olsen Y. JAMA 2016; 315:1577-1578 CDC Recommendations for Chronic Pain Management 1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain 2. Establish treatment goals before initiating opioid therapy 3. Discuss risks and realistic benefits of opioid use with patient 4. Choose immediate-release over extended release or long acting opioids 5. Prescribe the lowest effective dose 6. Reassess risk/benefit ratio within 1-4 weeks of initiation 7. Continue to reassess risk factors for opioid related harms 8. Utilize state prescription drug monitoring programs 9. Consistent use of urine drug monitoring program 10. Do not prescribe opioids and benzodiazepenes concurrently Dowell D, et al. JAMA 2016;315:1624-45 If Opioids are not the best option for chronic pain, then What Are Other Therapeutic Options to Improve Chronic Pain in Patients with Sickle Cell Disease? Vitamin D and Pain in Patients with SCD Osunkwo, et al. Br J Haematol 2012;159:211-215 Other Micronutrients May Be Important Martyres, et al. Ped Blood Cancer 2016;63:1060-1064 Other Micronutrients May Be Important Martyres, et al. Ped Blood Cancer 2016;63:1060-1064 Complementary Medicine Approaches - Patients Thompson and Eriator, Pain Med 2014;241-246 Complementary Approaches - Provider Perspective Providers willing to try complementary medicine approaches for pain management Need more training and standardized protocols for its integration into standard inpatient pain management regimens More studies are needed to evaluate effectiveness Barriers: Insurance coverage and lack of knowledge about integrative medicine providers Neri CM, et al. Global Adv Health Med 2016;5:44-50 Evidence for Non-Pharmacologic Approaches Lee C, et al. Pain Med 2014;15:S76-S85 Stress Reduction vs. Cognitive Behavioral Therapy vs. Usual Care for Non-SCD Chronic Low Back Pain Global Improvement of Pain (Pain Much Better or Completely Gone) Week 8 26 52 Cherkin DC, et al. JAMA 2016;315:1240-1249