1. 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

2. 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!

3. 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

4. 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

5. 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%

6. 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

7. 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

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

9. 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 SCD births/year
West Africa
25% prevalence of sickle trait
1-2% population with SCD

10. 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

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

12. 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

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

15. 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

16. 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.

17. 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

18. 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

19. 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

20. 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

21. 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)

22. 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

23. 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”

24. 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

25. 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?

26. 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

27. 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

28. 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)

29. 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

30. 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

31. 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

32. 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

33. 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

34. Type of CVA by Age

35. 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

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

37. 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

38. 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

39. Thank You! Questions