Sickle Cell Disease: Emergency Management Steven J. Ambrusko, MD, MS Assistant Professor of Pediatrics, Division of Hematology/Oncology Director – Sickle Cell & Hemoglobinopathy Center of Western New York

Introduction and Goals Review pathophysiology, epidemiology, and care approaches to sickle cell disease syndromes Discuss diagnosis and treatment of acute SCD complications Special regard to understanding pain and its management First… some cases!

Case #1: Child with fever 6yo Kurdish girl with SCD (HbSS) presents to ED with fever, cough, rhinorrhea, congestion T 38.7ºC, P 115, RR 28, SaO2 98% Not ill-appearing, lungs reported clear WBC 15.2K, Hb 9.4 g/dL (baseline), Retic 190/4.8% Diagnosis signed out by ED resident: URI Plan: Give ibuprofen, discharge to home ED Attending quickly sees patient, does blood culture, ceftriaxone, CXR before patient leaves ED Pediatric Hem/Onc not contacted

Case #1: Child with fever Upon later review, CXR shows RUL infiltrate Patient/family initially unable to be contacted Eventually, patient brought back to ED Repeat CBC: Hb 8.1 g/dL, Retic 210 (5.4%) Admit, given ceftriaxone, add azithromycin Becomes hypoxic, requires PRBC Actual Diagnosis? Acute Chest Syndrome

Case #2: Teen with Pain Crisis 18yo male HbSS, chronic pain issues, on HU Takes ibuprofen 600mg, oxycodone 10 mg PRN Baseline Hb ~8.5 g/dL, MCV ~101, WBC ~5K Presentation: acute right thigh/back pain, no relief with home tx, at another ER yesterday Exam and Labs T 36.7ºC, P 85, RR 22, BP nl, SaO2 94%, Wt 68kg Non-toxic but uncomfortable, pain to palpation Hb 7.1g/dL, MCV 103, WBC 15.6K, Retic 395/11%

Case #2: Teen with Pain Crisis Diagnosis: “Sickle Cell Crisis” Management Toradol 30mg – gives brief relief, pain 8/10 Morphine 3 mg IV x 1 – no relief Morphine 3 mg IV 2 hours later – no relief Asks for Dilaudid, is given 1mg IV x 1 – pain to 7/10 briefly Plan for admission Patient overhears staff say “another sickler just looking for drugs”, leaves AMA

Case #2: Teen with Pain Crisis Patient returns to ED 15 hours later Pain now 10/10, has spread to “whole body” Exam and Labs: T 37.5ºC, P 130, RR 32, SaO2 94% Jaundiced, ill-appearing Hb 4.7 g/dL, Retic 410/15%, CXR: enlarged heart, no infiltrates Diagnosis? Poorly-treated vaso-occlusive crisis Followed by hemolytic crisis

Person with Sickle Cell Disease Not a “Sickler” by Hertz Nazaire

SCD - Epidemiology United States (population: ~280 M) WNY: ~1000 SCD births/yr Prevalence: ~100K Sickle Trait 1 in 12 African 1 in 100 Latino WNY: ~140 Children >200? Adults Nigeria (population: ~90 M) 45,000 - 90,000 SCD births/year West Africa 25% prevalence of sickle trait 1-2% population with SCD

Distribution of SCD Sickle Cell Trait confers benefit in malarial regions Primary SCD regions Bantu Benin Senegal Arab-Indian Disease severity varies by region Illustrates more than just HbS is a disease variable Malaria Sickle Cell Disease

Sickle Cell Hemoglobinopathy: Hemoglobin S s-globin GAG → GTG Glutamine → Valine HbS: s-globin + -globin Deoxygenated HbS polymerizes into chains

Sickling of Erythrocytes HbS polymerizes: chains Reversibly, then irreversibly Higher %HbS in RBC leads to greater sickling deformity Presence of other hemoglobins impairs sickling (HbA, HbF) However, HbC (in HbSC) crystalizes, increases rigidity Results in vaso-occlusion and hemolysis

Vaso-Occlusion & Ischemia Rigid SCD cells damage vascular endothelium Inflammation WBC Adhesion Hypercoagulability RBC aggregation Thrombin generation Thromboembolic ischemia and damage Reperfusion injury

Hemolysis and Vasculopathy Sickled cells hemolyze at rate of ~10% of total RBCs per day (30% intravascular) Rate of hemolysis depends on HbS% (and subtype) Hemolytic anemia Decreased oxygen carrying capacity Requires constant erythropoiesis (reticulocytosis) Release of hemoglobin/other enzymes Scavenges/depletes nitric oxide Inflammatory changes and oxidative stress Endothelial dysfunction Chronic vessel damage: Vasculopathy

Sickle Cell Vasculopathic Changes even in Children Pulmonary arteriole showing circumferential intimal hypertrophy in an 8 year-old girl with sickle cell disease without clinical symptoms of pulmonary dysfunction.

Sickle Cell Syndromes HbSS HbS/0-thalassemia HbS/+-thalassemia HbSC “Sickle cell anemia” HbS/0-thalassemia HbS/+-thalassemia HbSC HbSD HbS/Oarab HbS_/HPFH* HbAS = Sickle cell trait *or with use of Hydroxyurea Disease S% F% A2% A% C% SS >90 <5 <3 - S/0thal >85 5-8 S/+thal ≥55 3-6 5-40 SC 40-50 SS/HPFH <85 >10 AS (trait) ≤45 <1

Sickle Cell - Complications Anemia Marrow hyperplasia Splenic Dysfunction Functional asplenia INFECTIONS Hypersplenism Sequestration Infarction Vaso-Occlusive/Pain Crises Acute Chest Syndrome Cerebrovascular Disease TIA Ischemic/Infarct Stroke Hemorrhagic Stroke* Aplastic Crises Avascular necrosis of bone Priapism Asthma Retinopathy Delayed/impaired growth Hyposthenuria Proteinuria/Renal Insufficiency Pulmonary Hypertension* Leg ulceration* Congestive heart failure* Sudden death* * Occur primarily in adults

Anemia: Emergent Sequelae “Baseline” Anemia ~7-9 g/dL in SS; ~8-10 g/dL in S/-thal; ~9-12 g/dL in SC Reticulocytosis (look at absolute, not just %) No routine indication for transfusion Aplastic Crisis Moderate/Severe anemia, low retic count (absolute retic!) Causes: Parvovirus B19, bone marrow infarction Treatment: PRBC to maintain adequate Hb level Hemolytic Crisis Known/unknown trigger for rapid hemolysis Rapid drop Hb, increased retic, high T Bili/LDH Treatment: PRBC, manage any underlying cause

Infectious Complications Functional asplenia (usually by ~2yo) Risk for encapsulated organism infections Bacteremia/Sepsis Pneumonia (Acute Chest Syndrome) Osteomyelitis (Staph > Salmonella) Meningitis Prevention Penicillin prophylaxis (BID, at least until 5yo) Vaccines: pneumococcal, meningococcal Aplastic Crisis: Parvovirus, Influenza, others

Fever Management: Rule-out Bacteremia/Sepsis T ≥101ºF (38.3ºC): immediate ED evaluation Prompt Work-up (within 30 minutes): CBC, Retic, Blood cx (through CVL, if present) Ceftriaxone x 1 (Unasyn or Clinda if allergic) CXR if any respiratory symptoms/hypoxia High risk signs/symptoms: ADMIT T ≥ 40ºC, history of bacteremia, significant drop Hb and/or low retic count, WBC ≥30K, positive CXR If not high risk, consider d/c with 2 days oral antibiotics (Amoxicillin or Omnicef)

Splenic Complications Splenic sequestration Acute blood pooling into enlarging spleen Abdominal pain, splenomegaly, Hb, Retic Transfuse PRN to maintain hemodynamic stability (often to Hb ~8-9 g/dL) Splenectomy: not done in acute setting (consider later, >2yo) Hypersplenism = Chronic mild sequestration Chronic enlarged spleen, Hb, WBC, Platelet Early (<4yo) in HbSS; later in milder sickle syndromes At risk for acute splenic sequestration and splenic infarction Splenic Infarction: severe LUQ pain, wedge infarcts on CT, treat pain well, consider splenectomy later

Vaso-Occlusive/Pain Crises Vaso-occlusion: Sickled RBC, endothelial damage, microthrombi, WBC/inflammation Post-capillary venules Pain – Mechanisms Inflammation (acute/chronic) Tissue Ischemia Reperfusion injury Neuropathic (acute/chronic) Chronic changes (rewiring) Psychological aspects “Ten Redefined”

Vaso-Occlusive/Pain Crises Causes/Triggers: Dehydration Exertion Immobility Dyspnea/Hypoxia Exposure to cold Infection Injury Psychological Stress Idiopathic At Tissue/Organ level Muscle/Bone Marrow Appendicular skeleton in younger patients Axial skeleton in older patients Dactylitis – “hand/foot syndrome” in infants Any organ/tissue can be affected

VOC: Home Management Supportive Care Medications Avoiding triggers Rest/Light activity Hydration Heating Pads Massage Distraction Meditation Prayer Medications NSAIDs!!! Opioids Short acting Long acting Transdermal Other meds Muscle relaxants Gabapentin Capsaicin Acetaminophen?

VOC: Emergency Evaluation Exam: rule-out/consider Fever Chest pain: ACS Osteomyelitis Abdominal pain Splenic complications Cholecystitis/stones Gut ischemia Abdominal VOC AVN/Pathologic fracture Compartment syndrome No lab test or scan will “diagnose” or “rule-out” VOC/pain Labs CBC/diff and Retic BMP/CMP and LDH Consider: Blood culture Type & Screen Scans: If indicated CXR if any respiratory symptoms/signs

VOC: Emergency Management IVFP (NS) 10 – 20 mL/kg Caution if severe anemia or cardiomegaly Oxygen – if hypoxia present No routine indication for transfusion for VOC Heat/Hot packs

VOC: Pain Medications NSAIDs: Ketorolac (Toradol) Opioid use: should be personalized! Opioid-naïve: typical starting dose effective Opioid-tolerant: consider home dose (give more!) Use Morphine FIRST – IV (or SQ) If initial dose ineffective, just give higher dose! (Do NOT change medication for “better effect”) Only consider hydromorphone if Uncontrolled side effects with morphine History of prior “superior efficacy” Morphine rationale : easier PCA dosing (fine tuning)

Opioid Equianalgesic Table Drug Onset (min) Duration of Action (hr) Equianalgesic Dose (mg) Parenteral:Oral Ratio IV PO Morphine IV: 10 – 30 PO: 20 – 30 IV: 2-4 PO: 4-6 10 30 1:3 Codeine 30 – 60 4 – 6 -- 200 Hydrocodone 20 – 30 Hydromorphone 10 – 20 (IV) 2 – 4 (IV) 1.5 7.5 1:5 Oxycodone 10 – 15 25 Methadone 6 – 8 (Long t½) 7.5 – 10 0.75 – 1.1

VOC: Pain Medications Treat pain aggressively and reevaluate often Morphine/Hydromorphone onset <30 min, so reevaluate then! Opioid dose Q30 – 60 minutes until relief (not 2+ hours) Treat opioid side effects Pruritis: Naloxone 0.1 – 0.3 mcg/kg Q1h PRN (Do not use Benadryl – causes sedation) Nausea/Emesis: Ondansetron/Granisetron Steroid use controversial: some benefit vs. risk

Acute Chest Syndrome New focal pulmonary infiltrate in patient with positive signs/symptoms Fever Chest pain Hypoxemia Sudden/significant drop in hemoglobin Cough Causes: bacterial/viral infections, fat emboli, pulmonary infarction

Acute Chest Syndrome High suspicion: CXR CBC/Retic, Type & Screen, Blood culture Hydration Avoid overhydration which may cause pulmonary edema Antibiotics Ceftriaxone Vancomycin if ill Azithromycin if >3yo O2 supplementation: if hypoxic/dyspneic Transfusion (if Hb drop, hypoxic, ill appearing) Simple PRBC Exchange transfusion indicated if Bilateral disease Severe hypoxemia Hb ≥10 g/dL Failure of simple PRBC

Cerebrovascular Disease Cerebrovascular Accident most widely defined as: Acute neurologic event due to arterial occlusion or hemorrhage resulting in ischemic event with clinical s/sx Includes TIA, infarctions, and hemorrhagic strokes Cerebrovascular Disease: includes wider spectrum of those with h/o CVA and those at significant risk Risk assessment: TCD screening (role for MRA?) Increased awareness of silent strokes CVA occurs in 7% of children w/SCD Incidence: 0.76%/yr during 1st two decades of life Hemorrhagic strokes: often due to aneurysms

Type of CVA by Age

CVA: Emergency Management Imaging CT: First line, delayed findings up to 6 hours MRI/MRA Visualizes infarcts sooner (within 2 – 4 hours) Detects stenosis, Moya-Moya, aneurysms, prior infarcts Treatment Ischemic CVA: Emergent Exchange Transfusion CBC, Retic, Type & Screen, call blood bank! Hemorrhagic CVA: Exchange transfusion, vascular surgery if aneurysm present

Priapism Painful erection with failure of detumescence Initial management: urination, analgesia, pseudoephedrine Emergency management Hydration Analgesics Irrigation (saline, epinephrine) Some patients require shunting procedures

Chronic Treatments for SCD? Hydroxyurea Decreases HbS% by increasing fetal Hb (HbF) Decreased sickling and hemolysis Higher hemoglobin, lower reticulocyte count Can cause cytopenias (neutropenia) Chronic RBC Transfusion Therapy Indicated for CVD/CVA prevention (10, 20), refractory to HU, other severe disease sequelae) Bone Marrow Transplant The only cure for sickle cell disease

SCHC Future Goal: Personalized Pain Plans Customized to patient’s past history of opioid need and supportive care Recommended medications and starting doses History of side effects, management (e.g. naloxone) Input from patient and family Updated for current outpatient pain regimen Monitoring those on hydroxyurea Improved care: More efficient/aggressive initial treatment May avoid some hospitalizations Affords greater patient satisfaction/decision making

Thank You! Questions