1. Acute Complications of Sickle Cell Disease & Management Guidelines Emily Riehm Meier, M.D., M.S.H.S. September 28,2016

2. Objectives
Describe the most common complications of sickle cell disease, including acute chest syndrome, vaso-occlusive pain crisis, and stroke.
Recognize a patient with sickle cell disease who needs emergency care.
Develop a management plan for a patient with sickle cell disease who presents for an acute care visit.

3. 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
Also carries CO2

4. 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.
Valine for glutamine
stress, menses. O2
HbA O2 O2
HbS O2

5. 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)

6. Pathophysiology 3: Nitric Oxide Depletion
Hemolysis, endothelial dysfunction
Viscosity, vaso-occlusion
Arginine converts nitric oxygenase to NO
Free hemoglobin binds with high affinity to nitric oxide

7. Pathophysiology 4: Inflammation
Interplay of white cells and platelets
Reperfusion injury
Upregulation of cytokines
Thrombosis

8. 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

9. SCD Manifestations Leg ulcers Retinopathy Stroke Splenic Sequestration
Complications of SCD – Pain is the hallmark, but every organ system is affected, including:
Brain Stroke, neurocognitive dysfunction
Lungs Acute chest syndrome, pulmonary hypertension
Heart Cardiac failure, infarction
Kidneys Hyposthenuria, papillary necrosis
Spleen Splenic infarction, sequestration
Hepatobiliary Cholecystitis, hepatic failure
Joints Avascular necrosis
Pain-Dactylitis
AVN
Acute Chest Syndrome 9

10. Survival of Children with Sickle Cell Disease
Quinn CT, et al. Blood 2010;115:

11. State Distribution of Hemoglobinopathies
Over 50 cases
31-50 cases
16-30 cases
6-15 cases
1-5 cases
So here is a visual showing the distribution of cases throughout the state since
When the program was initiated we requested the NBS results for child born 1.5 years prior to help ensure they have been notified and were receiving treatment. During this look back we found several children whose parents were not aware of their diagnosis. Those we could find then and when we expanded received sickle safe services.
The darker colors represent areas with a high prevalence while the lighter color represents fewer.
As you see here we do have areas where there are no children referred with a hemoglobinopathy.

12. State Distribution of Hemoglobinopathies
Over 50 cases
31-50 cases
16-30 cases
6-15 cases
1-5 cases
Most of the children live in 4 counties or areas.
We have had the highest number of children from Marion County.
Lake county which includes Gary, Hammond, East Chicago, Munster, Merrillville
And St Joseph- South Bend, Mishawaka, Elkhart account for the second largest
And Allen county- Ft Wayne- Followed by Tippecanoe- Lafayette and Vanderburgh- Evansville.

13. 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

14. 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

15. 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
2nd dose Ceftriaxone if necessary
Ceftriaxone – 1st line, broad spectrum, mg/kg/dose
Clindamycin – if allergic to ceftriaxone
Azithromycin – add for chest infiltrate.
Vancomycin – add if sepsis is likely

16. Infection Risk and SCD 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
Decreased Opsonization
Children with SCD have decreased rate of opsonization compared to healthy children
Rubin and Schaffner, N Eng J Med 2014;371:
Bjornson, Gaston & Zellner, J Pediatr 1977;91:

17. 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
70-90% reduced rate of IPD with PCV7
18% rate of IPD in mid-1980s, decreased to 2-10% from
Rubin and Schaffner, N Eng J Med 2014;371:
Obaro and Iroh Tam, Pediatr Blood Cancer 2016;63:

18. Management of Fever in an Asplenic PatientNo
Yes
Fever >101
Access to Medical Facility within 2 hours?
Take po antibiotics and immediately
begin travelling to medical facility
CBC/Retic
Aerobic Blood Culture
+ Chest Xray
Physical Exam
Ill appearing or abnormal labs or age <1 year?
Ceftriaxone im/iv
Discharge home provided
that followup is arranged and
reliable contact phone number available
Admit to hospital
Broaden coverage
based on clinical presentation

19. 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

20. 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:
Khoury et al. Hemoglobin 2011; 35:

21. 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:
Desai PC, Ataga KI. Expert Opin Pharmacother 2013;14:

22. 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:

23. Factors in the Development of Acute Chest Syndrome
Sedation from opioid pain medications
Splinting because of pain (chest/back/abdomen)
Decreased mobility because of pain which can lead to atelectasis
Fluid overload
Late recognition of the change in clinical status
Lack of Incentive Spirometry use

24. 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:
Desai PC, Ataga KI. Expert Opin Pharmacother 2013;14:

25. Sickle Cell Emergency 3: Stroke
ISCHEMIC - blockage of blood flow to part of brain
vascular stenosis
microvascular sickling & thrombosis?
Symptoms include
motor or sensory deficit, >24hr (caveat: painless limp)
MRI / MRA / dWI

26. Strokes HEMORRHAGIC bleed, e.g. aneurysm hypertension, increased ICP
“worst headache of my life”
Non-contrast CT
Treatment – Neurosurgical
Prevention – control hypertension

27. Stroke Risk in Children with SCD
Adams RJ. Arch Neurol 2007;64:

28. Age Distribution of Stroke by Age
Ohene-Frempong K, et al. Blood 1998;91:

29. 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:

30. Exchange Transfusion vs. Simple Transfusion at Time of Presentation
Exchange Transfusion at Presentation
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 )
Simple Transfusion at Presentation
Hulbert ML, et al. J Pediatr 2006;149:

31. 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
The mechanistic causes of priapism are multi-factorial and include polymerization of HbS and erythrocyte sickling within penile venules which prevents blood from escaping the corpus cavernosum, increased adhesion of the sickled erythrocytes to the penile vasculature, as well as decreased nitric oxide (NO) availability caused by increased uptake by free plasma hemoglobin and decreased production by the penile endothelial tissue
Olujohungbe AB et al. J Androl 2011;32:

32. 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:
Burnett AL, et al. Am J Hematol 2014;127:

33. 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:
Squiers JJ, et al. J Inv Med High Impact Case Rep 2016;1:1-3

34. Spleen Palpation Increases Incidence but Decreases Mortality
Pre-Spleen Palpation Education
Year
No. of attacks
Fatalities
Child years of observation
1974 2 39
1975 7 74
1976 9 3
102
1977
130
1978
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:

35. Spleen Palpation Increases Incidence but Decreases Mortality
Pre-Spleen Palpation Education
Post-Spleen Palpation Education
Year
No. of attacks
Fatalities
Child years of observation
1974 2 39
1975 7 74
1976 9 3
102
1977
130
1978
149
Incidence rate:
4.6 per 100 patient years of observation
Mortality rate:
29.4 per 100 events
Year
No. of attacks
Fatalities
Child years of observation
1979 18
182
1980 20 1
209
1981 22 2
241
1982
245
1983 16
236
Incidence rate:
11.3 per 100 patient years of observation
Mortality rate:
3.1 per 100 events
Emond AM, et al. J Pediatr 1985;107:

36. 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:

37. 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

38. 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 hcup-us.ahrq.gov

39. African Tribal Names for Sickle Cell
Chwechweechwe (relentless perpetual chewing)
Adep (beaten up)
HemKom (body biting)

40. 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

41. 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

42. Pain Rates are Variable in SCD
39%: no episodes of severe pain; 1% had >6 episodes per year;
5% of SCD individuals accounted for >30% of episodes
r denotes the number of episodes of pain per patient-year, SS sickle cell anemia, SC hemoglobin SC disease, Sβ+ sickleβ+-thalassemia, and Sβ0 sickle β0-thalassemia.
Platt et al NEJM 1991; 325(1)11-6

43. Frequent Hospitalization for Pain is a Risk Factor for Early Mortality in SCD
Darbari DS et al. PLoS One. 2013;8:e79923.

44. Vaso-Occlusive Crises vs. Daily Pain
Smith WR et al. Ann Intern Med 2008;148:94-101

45. Episodes of Daily Pain Smith WR et al. Ann Intern Med 2008;148:94-101
Pain Intensity, by Percentage of Pain Days*
Smith WR et al. Ann Intern Med 2008;148:94-101

46. Episodes of Daily Pain Smith WR et al. Ann Intern Med 2008;148:94-101
Pain Intensity, by Percentage of Pain Days*
Smith WR et al. Ann Intern Med 2008;148:94-101

47. Episodes of Daily Pain
Pain Intensity, by Percentage of Pain Days*
> 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

48. 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

49. 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

50. 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

51. 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.

52. Thank you!
Questions?

53. 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
Dowell D, et al. JAMA 2016;315:
Olsen Y. JAMA 2016; 315:

54. CDC Recommendations for Chronic Pain Management
Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain
Establish treatment goals before initiating opioid therapy
Discuss risks and realistic benefits of opioid use with patient
Choose immediate-release over extended release or long acting opioids
Prescribe the lowest effective dose
Reassess risk/benefit ratio within 1-4 weeks of initiation
Continue to reassess risk factors for opioid related harms
Utilize state prescription drug monitoring programs
Consistent use of urine drug monitoring program
Do not prescribe opioids and benzodiazepenes concurrently
Dowell D, et al. JAMA 2016;315:

55. 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?

56. Vitamin D and Pain in Patients with SCD
Osunkwo, et al. Br J Haematol 2012;159:

57. Other Micronutrients May Be Important
Martyres, et al. Ped Blood Cancer 2016;63:

58. Other Micronutrients May Be Important
Zinc insufficiency correlated with more home VOC and admissions for VOC
Martyres, et al. Ped Blood Cancer 2016;63:

59. Complementary Medicine Approaches - Patients
Thompson and Eriator, Pain Med 2014;

60. 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

61. Evidence for Non-Pharmacologic Approaches
Lee C, et al. Pain Med 2014;15:S76-S85

62. Stress Reduction vs. Cognitive Behavioral Therapy vs
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: