Download Evidence-Based Management Of Sickle Cell Disease In The

Evidence-Based Management
Of Sickle Cell Disease In The
Emergency Department
Abstract
Professor, UT College of Medicine,
Chattanooga, TN
Andy Jagoda, MD, FACEP
Professor and Chair, Department of
Nicholas Genes, MD, PhD
Emergency Medicine, Mount Sinai
Assistant Professor, Department of
School of Medicine; Medical Director,
Emergency Medicine, Mount Sinai
Mount Sinai Hospital, New York, NY
School of Medicine, New York, NY
Author
Jeffrey Glassberg, MD
Instructor of Emergency Medicine, Mount Sinai School of
Medicine, New York, NY
Peer Reviewers
Sohan Parekh, MD, RDMS
Sickle cell disease (SCD) is the most common genetic disease
in the US, affecting approximately 100,000 individuals. In SCD,
genetically mutated hemoglobin (HbS) forms rigid polymers
when deoxygenated, giving red blood cells a characteristic sickled shape. Increased blood viscosity and cell adhesion produce
intermittent vaso-occlusion. The vaso-occlusive phenotype of SCD,
which is marked by higher hemoglobin, manifests with frequent
painful crises and is associated with a higher risk for developing
acute chest syndrome. The hemolytic phenotype is characterized
by lower baseline levels of hemoglobin and elevated markers of
hemolysis. There are no reliable markers of vaso-occlusive crisis
(VOC), ie, vital signs and laboratory tests are normal. After intravenous (IV) opiate titration, patient-controlled anesthesia (PCA)
pumps are encouraged. Excess IV fluids have been associated with
development of atelectasis, a risk factor for acute chest syndrome.
Acute chest syndrome has clinical symptoms similar to pneumonia; these patients will develop progressive hypoxemia, acute
respiratory distress syndrome, and death if exchange transfusion
is not initiated.
Editor-in-Chief
August 2011
Volume 13, Number 8
Clinical Assistant Professor of Emergency Medicine,
University of Texas Medical Branch, Galveston TX; University
Medical Center Brackenridge and Dell Children’s Medical
Center, Austin TX
William Zempsky, MD
Head, Division of Pain and Palliative Medicine, Connecticut
Children’s Medical Center; Professor of Pediatrics, University
of Connecticut School of Medicine, Hartford, CT
CME Objectives
Upon completing this article, you should be able to:
1.
2.
3.
4.
Discuss the most common complications of SCD and
their presentations.
Discuss current and developing treatments for the
management of complications related to SCD.
Discuss age-related strategies for the management of
stroke in patients with SCD.
Distinguish between the different forms of SCD based
on hemoglobin electrophoresis.
Date of original release: August 1, 2011
Date of most recent review: July 10, 2011
Termination date: August 1, 2014
Medium: Print and Online
Method of participation: Print or online answer form and
evaluation
Prior to beginning this activity, see “Physician CME
Information” on page 21.
Shkelzen Hoxhaj, MD, MPH, MBA
Scott Silvers, MD, FACEP
Chief of Emergency Medicine, Baylor Chair, Department of Emergency
College of Medicine, Houston, TX
Medicine, Mayo Clinic, Jacksonville, FL
Keith A. Marill, MD
Assistant Professor, Department of
Emergency Medicine, Massachusetts
General Hospital, Harvard Medical
School, Boston, MA
International Editors
Peter Cameron, MD
Academic Director, The Alfred
Emergency and Trauma Centre,
Monash University, Melbourne,
Australia
Corey M. Slovis, MD, FACP, FACEP
Professor and Chair, Department
of Emergency Medicine, Vanderbilt
University Medical Center; Medical
Giorgio Carbone, MD
Michael
A.
Gibbs,
MD,
FACEP
Editorial Board
Director, Nashville Fire Department and
Chief, Department of Emergency
Professor
and
Chief,
Department
of
William J. Brady, MD
International Airport, Nashville, TN
Charles
V.
Pollack,
Jr.,
MA,
MD,
Medicine Ospedale Gradenigo,
Emergency Medicine, Maine Medical
Professor of Emergency Medicine
FACEP
Jenny Walker, MD, MPH, MSW
Torino, Italy
Center,
Portland,
ME;
Tufts
University
and Medicine Chair, Resuscitation
Chairman, Department of Emergency
Assistant Professor, Departments of
School of Medicine, Boston, MA
Amin Antoine Kazzi, MD, FAAEM
Committee & Medical Director,
Medicine, Pennsylvania Hospital,
Preventive Medicine, Pediatrics, and
Associate Professor and Vice Chair,
Emergency Preparedness and
Steven A. Godwin, MD, FACEP
University of Pennsylvania Health
Medicine Course Director, Mount
Department of Emergency Medicine,
Response, University of Virginia
Associate Professor, Associate Chair
System, Philadelphia, PA
Sinai Medical Center, New York, NY
University of California, Irvine;
Health System Operational
and Chief of Service, Department
Michael
S.
Radeos,
MD,
MPH
Ron M. Walls, MD
American University, Beirut, Lebanon
Medical Director, Charlottesvilleof Emergency Medicine, Assistant
Assistant
Professor
of
Emergency
Professor
and
Chair,
Department
of
Albemarle Rescue Squad &
Dean, Simulation Education,
Hugo Peralta, MD
Medicine, Weill Medical College
Emergency Medicine, Brigham and
Albemarle County Fire Rescue,
University of Florida COMChair of Emergency Services, Hospital
of Cornell University, New York;
Women’s Hospital, Harvard Medical
Charlottesville, VA
Jacksonville, Jacksonville, FL
Italiano, Buenos Aires, Argentina
Research Director, Department of
School, Boston, MA
Peter DeBlieux, MD Gregory L. Henry, MD, FACEP
Emergency Medicine, New York
Dhanadol Rojanasarntikul, MD
Scott
Weingart,
MD,
FACEP
Louisiana State University Health
CEO, Medical Practice Risk
Hospital Queens, Flushing, New York
Attending Physician, Emergency
Associate Professor of Emergency
Science Center Professor of Clinical
Assessment, Inc.; Clinical Professor
Medicine, King Chulalongkorn
Medicine, Mount Sinai School of
Medicine, LSUHSC Interim Public
of Emergency Medicine, University of Robert L. Rogers, MD, FACEP,
Memorial Hospital, Thai Red Cross,
FAAEM, FACP
Medicine; Director of Emergency
Hospital Director of Emergency
Michigan, Ann Arbor, MI
Thailand; Faculty of Medicine,
Assistant Professor of Emergency
Critical Care, Elmhurst Hospital
Medicine Services, LSUHSC
Chulalongkorn University, Thailand
John M. Howell, MD, FACEP
Medicine, The University of
Center, New York, NY
Emergency Medicine Director of
Clinical Professor of Emergency
Maryland School of Medicine,
Maarten Simons, MD, PhD
Faculty and Resident Development
Senior Research Editor
Medicine, The George Washington
Baltimore, MD
Emergency Medicine Residency
Wyatt W. Decker, MD
University, Washington, DC; Director
Joseph D. Toscano, MD
Director, OLVG Hospital, Amsterdam,
Professor of Emergency Medicine,
of Academic Affairs, Best Practices, Alfred Sacchetti, MD, FACEP
Emergency Physician, Department
The Netherlands
Assistant Clinical Professor,
Mayo Clinic College of Medicine,
Inc, Inova Fairfax Hospital, Falls
of Emergency Medicine, San Ramon
Department of Emergency Medicine,
Research Editor
Church, VA
Rochester, MN
Regional Medical Center, San
Thomas Jefferson University,
Matt Friedman, MD
Ramon, CA
Francis M. Fesmire, MD, FACEP
Philadelphia, PA
Emergency Medicine Residency,
Director, Heart-Stroke Center,
Mount Sinai School of Medicine,
Erlanger Medical Center; Assistant
New York, NY
Accreditation: EB Medicine is accredited by the ACCME to provide continuing medical education for physicians. Faculty Disclosure: Dr. Glassberg, Dr. Parekh, Dr. Zempsky, Dr. Jagoda,
and their related parties report no significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation.
Commercial Support: This issue of Emergency Medicine Practice did not receive any commercial support.
Case Presentation
•
In the middle of a busy evening shift, you encounter a
25-year-old man with a chief complaint of sickle cell crisis.
He states that he has had an upper respiratory infection
for about a week, followed by progressive pain to his lower
back and legs. At home, he has been taking 4-mg tablets
of hydromorphone every 3 hours, which reduces his pain
score from a 10 to a 9. His vital signs are as follows: heart
rate of 77, blood pressure of 115/70 mm Hg, respiratory
rate of 14 breaths per minute, and temperature of 36.9°C
(98.4°F). He does not appear to be uncomfortable and is
sitting in bed using a cellular phone. The nurse has placed
a peripheral IV, delivering a 1-L bolus of NS. You get the
CBC results, and his hemoglobin is 10.2 mg/dL. You ask
yourself several questions: • Can this patient be having a crisis without a drop in
hemoglobin?
• Is there a blood test I can do to confirm that he is
truly having a crisis?
• Is the patient addicted to opiates or drug-seeking?
• What fluids should I administer?
• What kind of opiates should I administer?
• Should I administer supplemental oxygen?
You are surprised that despite many years of practice you
are not sure of the answers and wonder why that is.
Introduction
Sickle cell disease is the most common genetic
disease in America,1 affecting approximately 100,000
individuals.2 Since the discovery of SCD 100 years
ago, our understanding of the disease has changed
dramatically. Research has revealed that the genetic
mutations underlying SCD not only result in sickleshaped red blood cells (RBCs) but also completely
alter the rheologic properties of the blood, causing clinical manifestations in every organ system.
Despite major advances in our understanding of
the disease, literature to guide clinical decisions in
the treatment of SCD is sorely lacking. This issue of
Emergency Medicine Practice presents a synopsis of
the latest evidence regarding the pathophysiology,
diagnosis, and treatment of emergent complications
of SCD.
Critical Appraisal Of The Literature
Table Of Contents
A literature search was performed using PubMed,
using the search terms pain, vaso-occlusion, acute
chest syndrome, stroke, avascular necrosis, priapism,
sepsis, osteomyelitis, transient red cell aplasia, pulmonary
hypertension, hyphema, fat embolism, splenic sequestration, hepatic sequestration, hemolysis, and iron overload.
A total of 596 articles from 1964 to the present were
reviewed. The Cochrane Database was searched
for systematic reviews using the key term sickle cell,
which identified 35 reviews. Guidelines released by
the National Institutes of Health (National Heart,
Lung, and Blood Institute) in 2002 and the American
Pain Society (APS) in 1999 were also reviewed. Both
of these guidelines represent consensus statements
and are not systematic, evidence-based guidelines.
Using standard evidence-level scales, the majority of clinical evidence in SCD falls into the weaker
and moderately-strong categories. There are several
reasons for this. First, SCD is a rare disorder, and
properly designed clinical trials are often too resource-intensive to perform. Second, SCD research is
severely underfunded (cystic fibrosis, a disease that
is one-third as common as SCD, receives millions
of dollars more in funding each year). A third and
final issue is the effect of medical advances on our
knowledge of the disease. For example, many observational studies of SCD were performed before the
development of the pneumococcal vaccine. This and
other advances in preventive medicine may call into
question results of earlier observational and interventional trials. When available, recommendations
Abstract........................................................................ 1
Case Presentation.......................................................2
Introduction................................................................2
Critical Appraisal Of The Literature.......................2
Etiology........................................................................ 3
Pathophysiology........................................................3
Differential Diagnosis................................................4
Prehospital Care.........................................................4
Emergency Department Evaluation........................ 5
Diagnostic Studies...................................................... 6
Treatment Of Vaso-Occlusion...................................6
Controversies And Cutting Edge For
Vaso-Occlusive Crisis.............................................8
Disposition For Vaso-Occlusive Crisis.................... 9
Special Circumstances: Other Complications
Of SCD..................................................................... 9
Clinical Pathway For Management Of Pain
In SCD.................................................................... 10
Risk Management Pitfalls For SCD....................... 14
Time- And Cost-Effective Strategies For
Patients With SCD................................................ 16
Summary................................................................... 16
Case Conclusion....................................................... 16
References..................................................................17
CME Questions......................................................... 20
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Should I give him IV ketorolac? Are there any other
medications that might help?
2
ebmedicine.net • August 2011
in this article are evidence-based. Recommendations
based on accepted practice or expert consensus are
explicitly noted as such.
vascular occlusion. Some speculate that venous and
arterial thrombosis also play a role.
Of the 5 SCD genotypes listed in Table 1, HbSS
is the most severe. The genotype HbSC is associated
with a higher level of total hemoglobin and a lesssevere course; however, these patients are at greater
risk for avascular joint necrosis. In patients with HbS
beta thalassemia, the severity of disease is determined by the severity of the thalassemia mutation.
Patients with mild HbS beta+ thalassemia will have
near-normal lives, whereas the natural history of
HbS beta0 thalassemia is similar to HbSS.
An important caveat when diagnosing SCD is
the fact that the results of the electrophoresis cannot
be interpreted for diagnostic purposes if the patient
has been transfused within 90 days before blood is
drawn. Transfusion is used in patients with SCD to
prevent complications of surgery, strokes, and painful crises as well as to manage acute complications
such as acute chest syndrome and priapism. Often,
the goal of transfusion therapy is to reduce the HbS
level to less than 30%; therefore, a patient with SCD
who has recently received a transfusion will appear
to have sickle cell trait on electrophoresis. For this
reason, it is important to obtain a transfusion history from all patients with SCD. If the diagnosis of
SCD is in doubt for a patient who has recently been
transfused, other secondary clinical and laboratory
indicators must be used to confirm for the presence
of SCD.
Etiology
Sickle cell disease arises from genetic mutations on
the beta-globin subunit of the protein hemoglobin.
Offspring receive 1 gene from each parent, and both
genes must carry the sickle cell mutation in order to
have sickle cell disease. The most common mutation
is the substitution of valine for glutamine at codon
6, which results in an abnormal hemoglobin called
HbS. Other beta-globin mutations that result in SCD
include HbC (substitution of lysine for glutamine
at codon 6) and beta thalassemia. The laboratory
test used to diagnose SCD, hemoglobin electrophoresis, provides the fractional percents of each type
of hemoglobin produced by an individual. Typical
hemoglobin electrophoresis patterns are provided in
Table 1.
Differentiating between sickle cell trait (HbAS)
and HbS beta thalassemia can be challenging
because there will be varying amounts of normal
hemoglobin (HbA) in both conditions. In general,
if there is more HbA than abnormal HbS, then the
diagnosis is sickle cell trait. If the reverse is true, the
diagnosis is more likely to be HbS beta thalassemia.
Sickle cell trait has been associated with increases
in sudden death upon strenuous physical exertion
or maternal labor3-11 as well as ocular complications
after minor eye trauma12,13; however, there is no
evidence that patients with sickle cell trait manifest
vaso-occlusion or pain. Many experts believe that
the propensity towards sudden death during intense
anaerobic exercise is due to systemic acidosis and
hypoxia that promotes sickling and diffuse micro-
Pathophysiology
The abnormal hemoglobins produced in individuals
with SCD form rigid polymers in response to deoxygenation. These polymers give red blood cells their
characteristic sickled shape.3 Although it was origi-
Table 1. Genotypes And Phenotypes Of Different Sickling Disorders
% of hemoglobin type/total hemoglobin in a typical patient
Genotype
HbS
HbA
HbF
HbC
HbA2
Clinical Course
-
96%
2%
-
2%
No manifestations
50%
2%
-
2%
No manifestations*
Not Sickle Cell Disease
HbAA (normal)
HbAS (trait)
45%
Sickle Cell Disease
HbSS
95%
-
3%
-
2%
Severe
HbSC
48%
-
3%
47%
2%
Moderate
HbS beta0
93%
-
2%
-
5%
Severe
HbS beta (moderate)
85%
6%
5%
-
4%
Moderate
HbS-beta (mild)
70%
23%
3%
-
4%
Mild
+
+
*Patients with sickle cell trait are at risk for delayed hemorrhage after eye trauma, sudden death upon exhausting physical exertion, and possibly venous thrombosis. Sickle cell trait is associated with none of the manifestations of sickle cell disease and does not cause painful crises.
August 2011 • ebmedicine.net
3
Emergency Medicine Practice © 2011
nally postulated that the manifestations of SCD were
due to the peculiar shape of the RBCs, this theory
has been rejected as our understanding of the pathophysiology of SCD progressed.4 Today, we know
that the blood in individuals with SCD behaves
abnormally at all times, whether or not sickled cells
are present. Several systems are abnormally activated at baseline and during a sickle cell crisis including platelet activation,5,6 endothelial activation,7-9
leukocyte activation,8,10 acute phase reactants,11 and
cell adhesion molecule activation.7,12-15 The result of
these processes is an increase in both blood viscosity
and cell adhesion that causes intermittent vaso-occlusion which manifests most frequently as an acute
painful episode or VOC.
mia, with baseline hemoglobin levels ranging from as
low as 4 mg/dL to as high as 14 mg/dL along with a
compensatory reticulocytosis. Markers of hemolysis,
including increased serum lactate dehydrogenase
(LDH), indirect hyperbilirubinemia, and low haptoglobin will be present to varying degrees. Many
patients with SCD are placed on chronic transfusion
regimens to mitigate or prevent severe complications, resulting in iron overload. Laboratory findings
include markedly elevated ferritin levels and low
total iron binding capacity. Clinical findings of iron
overload include liver, pancreas, and heart failure.
Phenotypic Variation In Sickle Cell Disease
The VOC is the hallmark manifestation of SCD and
is the most common reason for presenting to the
emergency department (ED)21 and hospital admissions.22 It can manifest as excruciating pain to any
part of the body, although the lower back and legs
are the most common.23,24 Triggers include infection,
stress, dehydration, and changes in weather, but
frequently there is no discernable precipitant.25,26,27
For the emergency clinician, the keys are to form an
appropriate differential diagnosis, aggressively manage pain, and avoid contraindicated therapies. Table
2 lists the common and rare complications of SCD.
Differential Diagnosis
The severity of SCD presentations varies tremendously. Some patients exhibit incredibly mild courses and survive into the eighth decade of life, while
others have a relentless and progressive course and
do not live past early childhood. The clinical manifestations of SCD affect every organ system. The
hallmark of SCD is the VOC. Other manifestations
include acute chest syndrome, stroke, splenic and
hepatic sequestration, progressive renal injury and
failure, avascular necrosis, osteomyelitis, sepsis,
pulmonary hypertension, skin ulcers, priapism,
retinopathy, and several others.
The factors that determine why some patients
have severe presentations while others do not are
poorly understood; however, certain markers of SCD
severity are well-accepted. The persistence of elevated fetal hemoglobin (HbF) levels (an alternative
hemoglobin that can function in place of the defective HbS) is associated with decreased morbidity.
Elevated baseline leukocyte counts, elevated inflammatory markers, and the presence of a comorbid diagnosis of asthma16-18 are associated with increased
SCD morbidity.
Based on these manifestations, patients with SCD
generally fall into 2 phenotypic groups: hemolytic
and vaso-occlusive.19 Vaso-occlusion is the process
that results in the manifestations of SCD that are best
known to the emergency clinician (VOC pain crises,
acute chest syndrome, stroke); however, hemolysis also
makes an important contribution. The vaso-occlusive
phenotype, marked by relatively higher hemoglobin levels, typically manifests with frequent painful
crises and higher risk for the development of acute
chest syndrome or stroke. In contrast, the hemolytic
phenotype is associated with lower baseline levels of
hemoglobin and elevated markers of hemolysis. These
patients tend not to have painful crises or acute chest
syndrome. Instead, they present with leg ulcers and
pulmonary hypertension.19
Patients with SCD exhibit a range of laboratory
findings. All patients will have some degree of aneEmergency Medicine Practice © 2011
Prehospital Care
An extensive review of the literature uncovered no
evidence with which to make specific recommendations about the prehospital care of individuals with
SCD. Based on accepted standards of practice, the
following recommendations can be made:
• Avoid oxygen unless the patient is in respiratory
distress.
• Administer IV fluid boluses only to hypotensive
patients.
• Administer IV opioids by emergency medical
services personnel if the patient is in pain and
venous access is obtained.
• Transport patients who are already being followed by a specific hematology service to that
hospital whenever possible.
Table 2. Acute Complications Of Sickle Cell
Disease
4
Common
Rare
Extremely Rare
Vaso-occlusive
crisis
Infection
Stroke
Cholelithiasis
Priapism
Acute coronary
syndrome
Splenic sequestration
Osteomyelitis
Transient red cell
aplasia
Hepatic sequestration
Renal infarction
Splenic infarction
Retinal detachment
Mesenteric ischemia
ebmedicine.net • August 2011
Emergency Department Evaluation
visual analog scale,29 and the Wong-Baker FACES™
Pain Rating Scale for children.30 Important elements of the history for complaints other than pain
are discussed in the Special Circumstances: Other
Complications of SCD section on page 9.
History
Obtaining a history on an individual with SCD can
be divided into 2 parts: addressing the acute complaint and characterization of the severity of the
patient’s disease.
Table 3 lists the key components for evaluation
of ED patients with SCD. The hematologist should
be alerted to all ED visits, as follow-up has been associated with reduced bounce-back visits. The first
step is to form an appropriate differential diagnosis.
For example, pain is the most common complaint associated with ED visits for SCD, but VOC must be a
diagnosis of exclusion; once other causes have been
sufficiently ruled out, proceed with a pain evaluation. What follows is a discussion of the evaluation
for a patient with the chief complaint of pain. Specific elements of the evaluation for other complaints
(infection, neurologic complaints) are discussed in
their component sections.
Opiate Addiction And Drug-Seeking Behavior In
Sickle Cell Disease
Many emergency clinicians are concerned that their
SCD patients are addicted to opiates or are seeking
drugs. Furthermore, there is widespread belief that
prescribing opiates in the ED will foster addiction
and enable drug-seeking behavior.31 Qualitative32
and quantitative33 studies of opiate use in SCD
patients indicate that rates of true addiction are low
(below 5%). For the emergency clinician, the following recommendations can be made: unless there is
clear evidence that the patient does not actually have
SCD, take the patient’s complaint seriously and use
opiates aggressively. It is true that a small fraction
of people with SCD exhibit drug-seeking behavior
to feed addiction or divert drugs to supplement
income. It is also true that an attempt by the emergency clinician to identify drug-seeking patients and
deny them analgesia will inevitably result in denial
of analgesia for patients who deserve pain relief and
compassionate care. Patients in need of treatment
for addiction or diversion should be identified at
follow-up with hematology or primary care, not in
the ED.
Historical Evaluation Of Pain
Key questions include the locations, severity, and
duration of pain; the exact amount of oral opiates
taken at home; and the effect these opiates had on
the pain score. Any validated pain assessment tool
is acceptable, and there is insufficient evidence to
recommend any particular one. Well-validated pain
assessment tools include the verbally administered
0-10 numerical rating scale,29 the 100-millimeter
Physical Examination
The physical examination on an individual with
SCD should focus on several areas. Examine the eyes
and mucous membranes for jaundice, and if present, ask the patient if this is significantly changed
from baseline. Auscultate for cardiac murmurs and
focal pulmonary abnormalities. When examining the
abdomen, pay close attention to the liver and spleen,
as both can be a site of significant red cell sequestration. For each pain location, examine carefully for
signs of infection (tenderness, erythema, fluctuance)
as cellulitis, osteomyelitis, and abscess often masquerade as vaso-occlusive pain.
Table 3. Elements Of The Sickle Cell Disease
History
Determine Severity of Patient’s SCD
What complications of SCD have you had?
Pain
Acute chest syndrome
Stroke
Infections
Avascular necrosis
Priapism
Cholecystitis
Splenic sequestration
Renal failure
Pulmonary hypertension
Pulmonary disease
Leg ulcers
Vision loss
Use Of Vital Sign Abnormalities To Assess Pain
Severity
Many emergency clinicians use the presence or
absence of abnormal vital signs to help objectively
quantify the severity of a patient’s pain. Few studies
specifically address this question; however, vital sign
data from interventional clinical trials are sufficient to
recommend against this practice. In a recent randomized controlled trial of inhaled nitric oxide for VOC
that included 150 subjects, mean blood pressure measurements were below 120/70 mm Hg.34 In another
randomized controlled trial of ketoprofen for the
management of VOC pain, only one of the patients in
What surgeries have you had?
Cholecystectomy
Splenectomy
Joint replacement
Tonsillectomy
How often do you have pain?
How often do you come to the ED for pain?
Have you ever been on chronic transfusions?
Do you take hydroxyurea or other medications?
What medicines do you take for pain at home?
What is your baseline hemoglobin level?
Abbreviations: ED, emergency department; SCD, sickle cell disease.
August 2011 • ebmedicine.net
5
Emergency Medicine Practice © 2011
the trial presented with tachycardia.35 A single-center,
retrospective review of 459 VOC episodes specifically
looked at blood pressure during crisis and found
zero episodes of hypertension associated with VOC.36
Thus, individuals with SCD will usually not exhibit
vital sign abnormalities, and many will not manifest
distress even when in excruciating pain.
tive observational cohort, elevations in hs-CRP were
significantly associated with the presence of VOC.43
Standard institutional CRP assays are unreliable because elevations occur days after the onset of crisis.
The LTE4 has also shown correlation with presence
of VOC in a small prospective cohort,37 but this test
is not readily available.
Diagnostic Studies
Treatment Of Vaso-Occlusion
In all but the simplest cases, laboratory evaluation
for ED patients with SCD should include CBC, liver
function studies, and reticulocyte count. In patients
with worsened scleral icterus, back pain, fever,
or signs that suggest hemolysis, additional tests
would include alanine aminotransferase (ALT),
lactate dehydrogenase (LDH), and bilirubin fractionation. Blood typing and screening is necessary
if hemoglobin has dropped more than 1 mg/dL
below baseline or if there is concern that the patient
may need a transfusion.
Triage
All SCD patients with a complaint of pain should be
triaged as an Emergency Severity Level (ESI) level
2 and moved into the ED immediately. Assignment
to the waiting room after triage is inappropriate.
Patients should be assessed by an emergency clinician and given initial analgesia within 30 minutes of
arrival.44,45
Opiate Therapy
The cornerstone of VOC management is administration of IV opiates. Available evidence with respect
to the type of opiate, method of administration, and
use of adjuvant therapies is presented in this review.
In the absence of IV access, subcutaneous or oral
administration is preferred over intramuscular, as
altered tissue perfusion in SCD results in unreliable
absorption of opiates from muscular beds. The NIH
and APS guidelines for the management of acute
pain recommend IV opiate administration and reassessment every 15-30 minutes until the pain is significantly improved (typically a drop in pain score of
2 or more).45,46 Limited ED resources may make this
guideline difficult to follow; however, pain usually
improves after 2 to 3 doses of IV opiates if administered in rapid succession.
Can Laboratory Studies Be Used To
Objectively Identify Vaso-Occlusive Crisis?
Laboratory tests are ordered to determine severity of
disease and to compare clinical markers of disease
with baseline values. Laboratory tests do not assist
the clinician in determining whether or not the patient is having VOC (ie, they cannot help determine
whether or not a patient is being untruthful about
his pain).
Several studies have explored the patterns
of various laboratory markers during VOC, and
although there are promising experimental assays,
there are no commercially available laboratory
tests that can objectively identify VOC. Two small
observational cohort studies found no relationship
between the presence of VOC and hemoglobin
level, white blood cell (WBC) count, reticulocyte
count, or change in hemoglobin from baseline.37,38
Larger prospective interventional clinical trials
have noted hemoglobin concentrations of 8-10 mg/
dL during crisis, which are not significantly different from baseline.34,35,39 Furthermore, there is
evidence that reductions in hemoglobin are actually
associated with decreased VOC. A before-and-after
study of 7 patients found that regular phlebotomy
significantly reduced frequency of VOC.40 The presence or absence of sickled RBCs is also unreliable as
an objective measure of crisis. Although there have
been no formally designed observational studies to
test this, it is well known that sickled RBCs will be
present in patients with SCD regardless of whether
they are in crisis.41,42
Experimental assays for objective identification
of VOC have included markers of inflammation
such as high-sensitivity c-reactive protein (hs-CRP)
and urinary leukotriene E4 (LTE4). In one prospecEmergency Medicine Practice © 2011
Type Of Opiate – Available Evidence
In a 66-patient factorial design pediatric study of
continuous infusion morphine versus intermittent bolus codeine or meperidine, continuous
infusion morphine was associated with superior
analgesia.47 In a phase I pediatric trial of intranasal diamorphine in conjunction with oral or IV
opiates, rapid reductions in pain scores with few
adverse effects were observed.48 A small randomized trial comparing PCA to continuous infusion of
morphine showed similar pain scores but reduced
opiate consumption and opiate side effects in the
PCA group.49 A 45-patient trial of bolus dose IV
morphine versus morphine PCA in the ED found
similar analgesic efficacy but shorter time to pain
relief and shorter ED length of stay with PCA.50 In
a placebo-controlled randomized trial of children
admitted for VOC, after an initial dose of IV morphine, oral morphine was equivalent (with trends
towards superiority) to IV morphine.51
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pain is accomplished by developing individualized
pain control plans for patients who are known to
the hematology service. In the past, this was done
by keeping a 3-ring binder in the ED. Today, many
electronic medical records software packages can
accomplish the same thing in a paperless fashion.
Type Of Opiate – Recommendations And
Commentary
Because of the renal abnormalities prevalent in
patients with SCD, meperidine should be avoided.
Almost all patients with SCD will have some degree
of renal insufficiency owing to chronic medullary
infarctions. Patients with SCD have supranormal
proximal tubule function, which causes increased
creatinine secretion. Consequently, the serum creatinine level underestimates the degree of renal dysfunction so that a patient with a creatinine level of 1.0
mg/dL may have significant renal dysfunction with
decreased glomerular filtration rate (GFR). Compared
with other opioids, meperidine is a relatively poor
analgesic; however, it is often requested because of
its euphoric effects. The metabolite of meperidine,
normeperidine, is a renally cleared cerebral irritant,
and upon accumulation in the blood, adverse effects ranging from dysphoria to seizures can result.
Because renal dysfunction in SCD is so common, meperidine should be reserved for only brief treatment
courses (no more than 48 hours at doses no higher
than 600 mg/24 hours) for patients who have allergies or uncorrectable intolerances to other opioids.
Morphine, fentanyl, and hydromorphone are acceptable opiate options. Initially, administer opiates
via IV push every 15 minutes until the patient’s pain
is moderately improved (at least a 2-point reduction on a 0-10 scale, preferably below 5). Intranasal
diamorphine is an acceptable alternative in children.
After initial IV opiate titration, place the patient on
PCA pump, if available, even if the patient might be
discharged. The PCA pumps should be programmed
with a basal rate in addition to demand boluses.
(See Table 4).
In the author’s opinion, optimal treatment for
Non-Opiate Therapies
For a summary of non-opiate therapies for VOC, see
Table 5 on page 8.
Acetaminophen
There is no clinical evidence regarding the use of
acetaminophen for VOC. Anecdotal reports suggest
an opiate-sparing effect. Acetaminophen is generally a safe medicine, even in the setting of liver
dysfunction; thus, it is recommended as an adjuvant
medication in the management of VOC. In patients
with iron overload from transfusion regimens, avoid
prolonged use of acetaminophen.
Antihistamines
There is no clinical evidence regarding the use of
antihistamines in the treatment of VOC. Since antihistamines may mitigate the histaminergic effects of
morphine administration and are anecdotally associated with opiate-sparing effects, they can be used as
adjuvant therapy.
Non-Steroidal Anti-Inflammatory Drugs – Available
Evidence
Case reports have associated the use of NSAIDs with
renal failure in children with SCD52 and without
SCD.53 Four studies have compared NSAIDs to
placebo as adjunctive treatment for VOC. The largest
and most rigorously designed study of 102 adults
Table 4. Opiate Dosing Strategies For Patients > 50 kg With Vaso-Occlusive Crisis
Initial Opiate Titration*
IV hydromorphone
1-2 mg IV push every 15 min until pain score < 5
IV morphine
8-12 mg IV push every 15 min until pain score < 5
Intranasal diamorphine (children)
0.1 mg/kg
Around-the-Clock Opiate Dosing After Initial Titration
PCA analgesia with hydromorphone (1 mg/mL)
Basal 0.1 mg/hr
Demand 0.1-0.3 mg every 8 minutes
PCA with morphine (4 mg/mL)
Basal 0.7 mg/hr
Demand 0.7-2 mg every 8 minutes
Long-acting opioid agonist (controlled-release
morphine or oxycodone or transdermal
fentanyl)
Base initial dosing on short-acting opioid requirements
Rescue doses of 10% to 15% of the total 24-hour dose or 50% of the 4-hour dose should be the
same opioid as the around-the-clock medication, available every 1-2 hours as needed
Tapering opioids
Wean dose by 10% to 20% every 8 hours as tolerated to keep pain score < 5. Once opioid dose
is 25% to 30% of initial level, can switch to equianalgesic oral opioids and consider discharge
*Place patient on monitor.
Abbreviations: IV, intravenous; PCA, patient-controlled analgesia.
August 2011 • ebmedicine.net
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Emergency Medicine Practice © 2011
transfusion requirements.63 Supplemental oxygen is
recommended only if the patient’s oxygen saturation
is below 92%.
with VOC found no differences with respect to pain
scores, opiate requirements, or hospital length of
stay with the addition of IV ketoprofen.37 Of the 3
smaller studies, 2 found no differences with respect
to pain score, opiate dose, and length of stay.54,55
One study of 21 patients treated with meperidine
found reductions in meperidine requirements with
IV ketorolac.56 A Cochrane Review on this topic was
unable to make definitive recommendations.57
Incentive Spirometry
A randomized trial of 29 patients with VOC found that
the addition of incentive spirometry during hospitalization for VOC was associated with a 37% decrease
in the incidence of pulmonary infiltrates and atelectasis.64 Incentive spirometry should be included in the
treatment protocol for all SCD patients admitted for
VOC. Acute chest syndrome typically develops during
inpatient admissions for VOC and pulmonary infiltrate
is a clinical finding required for the diagnosis of acute
chest syndrome. This low-risk intervention decreases
the incidence of pulmonary infiltrates.
Non-Steroidal Anti-Inflammatory Drugs –
Recommendations And Commentary
• Use acetaminophen and antihistamines as initial
adjuvant therapy.
• When using NSAIDs, only short courses (less
than 72 hours) are indicated.
• When discharging a patient with a prescription
for NSAIDs, use short courses (preferably less
than 72 hours).
Controversies And Cutting Edge For
Vaso-Occlusive Crisis
It is likely that NSAIDs have small analgesic benefits for patients with SCD. The long-term effects of
NSAIDs on patients with SCD have not been wellstudied; thus, they should be used judiciously.
Steroids
A placebo-controlled randomized controlled trial of
56 episodes of VOC found that high-dose methylprednisolone was associated with decreased length of
hospital stay and severity of pain but was associated
with increased frequency of readmission for recurrence of pain.65 Steroids are not recommended in the
treatment of VOC. If the patient has a concurrent
reason for the administration of steroids (eg, asthma
exacerbation), steroids would not be contraindicated.
Intravenous Fluid Choice – Available Evidence
In vitro and in vivo studies have shown that lowering
of serum osmolality with hypotonic fluid can reduce
erythrocyte sickling.58,59 Excess IV fluids have been
anecdotally associated with the development of atelectasis.60 A prospective observational cohort of 3751
patients with SCD identified atelectasis as a risk factor
for the development of acute chest syndrome.61
Magnesium
A single-arm study of 19 children with acute VOC
compared hospital length of stay for patients admitted either with or without the administration of
Intravenous Fluid Choice – Recommendations And
Commentary
• Use D5 ½ normal saline (NS) at a maintenance
rate for the management of all complications
related to SCD unless there is a specific indication to do otherwise.
• Boluses of IV fluid should not be given unless patients are overtly hypovolemic (sepsis,
diarrheal illness, vomiting). In these situations,
resuscitate only to euvolemia with isotonic
crystalloid. While it is thought that dehydration
may precipitate VOC, overhydration — especially with isotonic crystalloid — does not cure
crisis and may have detrimental effects. One
additional undesirable effect of normal saline
is that large amounts can cause hyperchloremic
metabolic acidosis, and lowering the serum pH
promotes sickling.
Table 5. Non-Opiate Therapies For VasoOcclusive Crisis
Recommended
•
Hypotonic fluids: D5 ½ NS at maintenance rate
•
Acetaminophen
•
Antihistamines (diphenhydramine, hydroxyzine)
•
Incentive spirometry
Relatively contraindicated
•
Isotonic fluid (unless patient is overtly hypovolemic, eg, diarrhea
or sepsis)
•
Supplemental oxygen (unless saturation is below 92%)
•
NSAIDs
•
Steroids (unless indicated for a concurrent illness)
Supplemental Oxygen
Administration of supplemental oxygen has been
shown in real time to reduce circulating levels of
erythropoietin in nonhypoxic individuals with
SCD,62 and case reports have associated the administration of oxygen with marrow hypoplasia and
Emergency Medicine Practice © 2011
Experimental
•
Intravenous magnesium (40mg/kg)
•
Low-dose ketamine infusion (0.06 mg/kg/h to 0.1 mg/kg/h)
•
Morphine and naloxone infusion
Abbreviations: D5, dextrose 5%; NSAIDs, non-steroidal anti-inflammatory drugs; NS, normal saline.
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ebmedicine.net • August 2011
Special Circumstances: Other
Complications Of Sickle Cell Disease
magnesium. The use of magnesium was associated
with a decreased length of stay. A prospective randomized trial of magnesium for VOC is now underway. Until the results are available, current evidence
is not sufficient to recommend its use in VOC.
Acute Chest Syndrome
Acute chest syndrome is a life-threatening clinical
entity that occurs in individuals with SCD and is
defined by a combination of at least 2 of the following signs or symptoms46:
• Chest pain
• Fever higher than 38.5°C (101.3°F)
• Pulmonary infiltrate or focal abnormality on
ventilation/perfusion scan
• Respiratory symptoms
• Hypoxemia
Ketamine
A retrospective case series of a subdissociative dose
of ketamine for VOC suggested an improvement in
pain control and a decrease in the need for opiate
administration.66 A prospective trial to investigate
the effects of ketamine is currently underway. Until
further evidence is available, low-dose ketamine for
VOC should be administered only after consultation
with pain management experts.
This constellation of findings is also consistent
with the more widely known clinical entity, pneumonia. This overlap can be confusing to healthcare
providers, but the two may be distinguished by how
they respond to treatment. Pneumonia typically
responds to antibiotics, whereas with acute chest
syndrome, progressive hypoxemia, acute respiratory
distress syndrome, and death will develop if exchange transfusion is not initiated. Acute chest syndrome is one of the most common causes of death
in patients with SCD, and it should be considered
whenever these patients present with respiratory
signs or symptoms.
Naloxone
A pilot study of 18 children with VOC receiving
continuous morphine infusion showed that concurrent infusion of naloxone was associated with a
reduction in opiate side effects with no reduction in
analgesic efficacy.67
Nitric Oxide
Nitric oxide was recently evaluated in one of the
largest trials of an acute intervention for VOC. In
150 patients at 11 centers, no differences were found
with respect to duration of crisis, pain scores, or opiate consumption with the inhalation of nitric oxide.34
Etiology And Pathophysiology For Acute Chest
Syndrome
The best evidence regarding the etiology of acute
chest syndrome comes from the Multicenter Acute
Chest Syndrome Study (MACSS). Of 364 episodes
of acute chest syndrome, 33% were due to infection,
another 33% were found by exclusion to be due to
pulmonary infarction, and 16% were due to pulmonary fat embolism.69 The most frequently isolated
organisms are Chlamydophila (formerly Chlamydia)
pneumoniae and Mycoplasma pneumoniae. The majority of acute chest syndrome cases will not present to
the ED61; instead, they typically develop during an
admission for VOC. Thus, the emergency clinician’s
greatest role in acute chest syndrome is prevention
with incentive spirometry and avoidance of overhydration. All non-SCD-related causes of chest pain
should be considered in the differential diagnosis prior to making the diagnosis of acute chest syndrome.
Disposition For Vaso-Occlusive Crisis
There are no rigid guidelines regarding which
patients with simple VOC should be admitted. The
standard practice in many EDs is to give the patient
3 doses of IV opiates followed by admission if additional analgesia is required. This practice of limiting
the number of opiate doses a patient can receive
without being admitted is often used to discourage
patients from casually visiting the ED to receive IV
opiates. There is indirect evidence that a more lenient approach may reduce hospital admissions and
return visits to the ED. Between 1989 and 1993, the
Bronx (New York) Comprehensive Sickle Cell Center
at the Montefiore Medical Center operated an acutecare day hospital dedicated to treating SCD patients
with simple VOC. Implementing a standardized,
aggressive, opiate-based treatment protocol dramatically reduced hospital admissions and recidivism.68
Although certain features of the day hospital can
never be replicated in the ED, a policy of aggressive
pain control without reflexively admitting after 3
doses of IV opiates is possible and may lead to fewer
admissions and return visits to the ED. The author
recommends that the patient with VOC be involved
in the decision to admit and only those patients
whose pain is refractory to IV hydration and aggressive pain control should be admitted to the hospital.
August 2011 • ebmedicine.net
Emergency Department Evaluation For Acute Chest
Syndrome
In addition to laboratory studies, the evaluation
of patients with SCD who have chest pain should
include chest radiography. Cardiac enzyme and
D-dimer levels should be ordered at the emergency
clinician’s discretion. The use of arterial blood gas
measurements is somewhat controversial. In one
observational study of 44 patients with acute chest
9
Emergency Medicine Practice © 2011
Clinical Pathway For Management Of Pain In Sickle Cell Disease
Patient presents with acute pain
•
•
Perform history and physical examination
Determine probable cause and precipitating factors for pain
Related to SCD?
NO
Perform appropriate work-up and management
YES
Start D5 ½ normal saline at the maintenance rate (Class III)
NO
Currently on chronic opiate therapy?
Administer IV dose of opiate (Class II)
•
Morphine 0.1-0.15 mg/kg
•
Hydromorphone 0.015 -0.02 mg/kg
YES
•
•
Administer IV equivalent of home oral opiate dose (Class III)
Administer APAP and antihistamine (Class III)
Assess degree of relief every 15-30 minutes (Class III)
NO
Moderate pain relief?
Repeat IV opiate at half of initial dose
YES
Abbreviations: APAP, acetaminophen; IV, intravenous; PCA, patient-controlled analgesia; SCD, sickle cell disease.
Begin around-the-clock dosing
•
Long-acting oral opiate
•
PCA
•
Opiate infusion (Class III)
Disposition with short opiate prescription with hematology follow-up
Class Of Evidence Definitions
Each action in the clinical pathways section of Emergency Medicine Practice receives a score based on the following definitions.
Class I
• Always acceptable, safe
• Definitely useful
• Proven in both efficacy and
effectiveness
Level of Evidence:
• One or more large prospective
studies are present (with rare
exceptions)
• High-quality meta-analyses
• Study results consistently positive and compelling
Class II
• Safe, acceptable
• Probably useful
Level of Evidence:
• Generally higher levels of
evidence
• Non-randomized or retrospective studies: historic, cohort, or
case control studies
• Less robust RCTs
• Results consistently positive
Class III
• May be acceptable
• Possibly useful
• Considered optional or alternative treatments
Level of Evidence:
• Generally lower or intermediate
levels of evidence
• Case series, animal studies, consensus panels
• Occasionally positive results
Indeterminate
• Continuing area of research
• No recommendations until
further research
Level of Evidence:
• Evidence not available
• Higher studies in progress
• Results inconsistent, contradictory
• Results not compelling
Significantly modified from: The
Emergency Cardiovascular Care
Committees of the American
Heart Association and represen-
tatives from the resuscitation
councils of ILCOR: How to Develop Evidence-Based Guidelines
for Emergency Cardiac Care:
Quality of Evidence and Classes
of Recommendations; also:
Anonymous. Guidelines for cardiopulmonary resuscitation and
emergency cardiac care. Emergency Cardiac Care Committee
and Subcommittees, American
Heart Association. Part IX. Ensuring effectiveness of communitywide emergency cardiac care.
JAMA. 1992;268(16):2289-2295.
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual
needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright © 2011 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine.
Emergency Medicine Practice © 2011
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ebmedicine.net • August 2011
syndrome, the alveolar-arterial gradient was the
best predictor of clinical severity and the need for
blood transfusion.70 Based on this evidence, the
NIH guidelines recommend exchange transfusion
for patients with Pa O2 below 70 mm Hg on room
air. Contrary to the NIH guidelines, the decision
to transfuse can usually be made clinically without the evaluation of arterial blood. Patients with
pulmonary infiltrate and marked respiratory distress
or pulse oximetry below 90% will almost always
require transfusion, and measurements of arterial
blood gases should not delay therapy.
ment in clinical outcomes (transfusion, length of
stay, pain scores) and was associated with significant
patient discomfort. Noninvasive ventilation was
associated with more rapid improvement in physiological indices of oxygenation. To date, evidence is
not sufficient to recommend noninvasive ventilation
for acute chest syndrome.
Steroids
Steroids are not recommended for the treatment
of acute chest syndrome unless there is concurrent
exacerbation of asthma. One randomized trial of 43
episodes of acute chest syndrome showed a decrease
in length of stay, duration of pain, and opiate administration with administration of steroids. Steroids
were also associated with increased rates of readmission within 72 hours.74 A retrospective review of
129 episodes of acute chest syndrome confirmed the
association between steroids and readmisssions.75
Treatment For Acute Chest Syndrome
Evidence for the various therapies is discussed below.
Treatment of acute chest syndrome includes all the
treatments for simple VOC including analgesia, maintenance fluids, and incentive spirometry, in addition
to standard therapies including IV antibiotics and exchange transfusion. Emergent hematology consultation is indicated for all cases of acute chest syndrome.
Disposition For Acute Chest Syndrome
The NIH guidelines recommend that serial arterial blood gases be measured in patients with acute
chest syndrome and that all patients with worsening alveolar-arterial gradients be managed in an
intensive care setting.70 These recommendations
are based on somewhat circular logic. In the study
that led to these particular guidelines, patients were
triaged to the intensive care unit (ICU) on the basis
of clinical assessments, not blood gas data. Of all objective indicators, worsening of the alveolar-arterial
gradient correlated most closely with the clinical
decision to admit the patient to the ICU. This finding
suggests that arterial blood gas evaluation can assist
but should never supersede clinical judgment and
that patients can be assigned to an appropriate level
of care without the repeated use of this invasive test.
Patients with confirmed or suspected acute chest
syndrome should not be discharged from the ED.
Oxygen
There is no specific evidence regarding oxygen
administration for patients with acute chest syndrome, thus the guidelines for VOC should be followed: administer supplemental oxygen to hypoxic
patients only.
Antibiotics
The MACSS identified Chlamydia (now Chlamydophila) pneumoniae as the organism most commonly
isolated from sputum in patients with acute chest
syndrome,69 and the cooperative study of SCD identified Streptococcus pneumonia as the organism most
frequently isolated from the blood.61 Antibiotics
should cover both typical and atypical organisms.
Transfusion
In patients with worsening respiratory distress,
hypoxemia, or arterial-alveolar gradient, exchange
transfusion is recommended with a goal of increasing hemoglobin A levels above 70%. If exchange
transfusion is not available, simple transfusion is
recommended. In observational studies, transfusion (simple or exchange) has been associated with
improvement of arterial blood gas indices of oxygenation69,71 and decreases in serum inflammatory
mediators.72 One nonrandomized comparison of
simple versus exchange transfusion did not show
difference in outcomes, but this may be due to the
fact that recipients of exchange transfusion were
more critically ill.65
Stroke
Stroke is one of the most devastating complications
of SCD. Children with SCD have an approximately
300-fold increase in the rate of stroke as compared
with children without SCD.76,77 Strokes occur most
commonly in children before the age of 10 and are
uncommon between 20 and 29 years of age, with a
second peak after the age of 29.78 Because there are
no prospective clinical data to help guide the acute
evaluation or management of stroke in individuals
with SCD, recommendations are based on indirect
evidence and expert consensus.
In contrast to conventional thrombotic or
embolic stroke, the mechanism for ischemic stroke
in children with SCD is thought to result from
abnormal cell adhesion, intravascular sickling, and
abnormal smooth muscle tone. In adults with SCD,
the etiology of stroke is thought to be due to the
Noninvasive Ventilation
An open-label randomized trial of 71 episodes of
acute chest syndrome found that early noninvasive
ventilation was not associated with any improveAugust 2011 • ebmedicine.net
11
Emergency Medicine Practice © 2011
same thromboembolic mechanisms that cause stroke
in the general population. For this reason, the recommendations for treatment of stroke are different for
children and adults.
For individuals with SCD, the evaluation of
suspected stroke should include a careful history
including potential precipitants of vaso-occlusion
(especially infection), time of onset, and the nature
of symptoms. Laboratory evaluation is the same as
for VOC, except a type and screen should be included immediately because transfusion is highly
likely. Emergent noncontrast or perfusion CT scan
is indicated in children and adults with suspected
acute stroke.
asplenia that predisposes to infections with encapsulated organisms. For this reason, fever in the SCD
patient must be approached with great caution. The
NIH clinical guidelines for the management of fever
are based mostly on expert consensus since clinical
evidence in this area is lacking.
In addition to sources of infection that are common in the general population, patients with SCD
are at increased risk for bacteremia, meningitis, and
osteomyelitis. The implementation of penicillin
prophylaxis followed by pneumococcal vaccines has
dramatically reduced the number of deaths due to
bacterial sepsis in patients with SCD. Data reported
in 2010 from the Dallas Newborn Cohort (the largest
cohort of individuals followed for SCD) indicated
that bacterial sepsis is no longer the most common cause of death in SCD.81 In cases of sepsis, the
most common cause of bacterial infection in SCD is
streptococcal pneumonia. Observational data in the
post-pneumococcal vaccine era suggest that while
serious bacterial infections with streptococcal pneumonia still occur, rates are much lower (44 infections
in 4108 patient-years of data).82
The ED evaluation of a patient with SCD who has
a fever should include a careful search for infectious
causes. Always consider meningitis, septic arthritis,
and osteomyelitis (specifically within the spine) in
addition to standard infections. The NIH guidelines
recommend the following studies in individuals with
SCD and fever when the source is not clear46:
• CBC
• Blood culture
• Urine culture
• Throat culture
• Chest radiograph
• Urinalysis
• Lumbar puncture (on toxic-appearing children)
• Subperiosteal fluid aspiration and culture in
patients with bone pain
• Arthrocentesis for acute arthritis
Treatment For Stroke
Recommendations for the management of stroke in
SCD are based almost entirely upon expert opinion.
In children with SCD, thrombolysis is contraindicated, and the treatment for acute stroke is exchange
transfusion. In one retrospective cohort, immediate
exchange transfusion was associated with lower
rates of recurrent stroke when compared to simple
transfusion.79
In adults with SCD who present with stroke, it
is recommended that patients receive conventional
therapy as indicated. Tissue plasminogen activator
(tPA) has never been studied in patients with SCD,
so it is recommended that administration of tPA be
in accordance with institutional guidelines and in
consultation with a neurologist and hematologist.
In children with transient ischemic attacks
(TIAs), recommended treatment is early initiation
of prophylactic exchange transfusion therapy. When
TIA is suspected, the diagnosis will usually be unclear; thus, semiemergent magnetic resonance imaging (MRI) is indicated. Transfusion has been shown
to prevent stroke in children with SCD who are at
increased risk because of cerebrovascular disease.80
The presence or absence of anatomical/vascular risk
factors on MRI will guide the hematologist’s decision to initiate secondary prevention by means of
chronic transfusions.
A single case report exists on the use of inhaled
nitric oxide in a child in whom postoperative stroke
occurred. Although the child made an excellent
recovery, no conclusions can be drawn with respect
to the efficacy of nitric oxide in acute stroke related
to SCD. Beyond this case report, there has been essentially no clinical investigation with regard to the
acute management of stroke in SCD. Several controversies exist with regard to the primary and secondary prevention of stroke, but these have limited
relevance for the emergency clinician.
The most controversial recommendation in this
guideline involves aspirating from infected bone
prior to administering antibiotics. This recommendation is based on the fact that radiographic appearance of noninfected bone and osteomyelitis may be
similar in patients with SCD, and infection may be
obscured by the administration of antibiotics prior to
culture of the affected area. Although use of antibiotics prior to culture in SCD patients with bone pain
may complicate later treatment decisions, this recommendation must be weighed against the possible
consequences of delaying antimicrobial coverage in
patients in whom the potential to deteriorate is significant, especially when a clinician skilled in bone
aspiration is not immediately available. In clinically
toxic patients, antibiotics should not be delayed to
obtain subperiosteal cultures.
Fever
Sickle cell disease represents a state of immunocompromise due to increased bone marrow turnover,
altered complement activation, and functional
Emergency Medicine Practice © 2011
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ebmedicine.net • August 2011
which can broadly be divided into 3 categories:
bleeding (both internal and external), decreased RBC
production, and increased RBC destruction. The key
differentiating point for the emergency clinician is to
determine whether the anemia is due to splenic sequestration, hemolysis, or transient red cell aplasia.
(See Table 6.) Splenic sequestration and hemolysis
will both cause elevated reticulocyte counts, with
only hemolysis showing elevations in indirect bilirubin, ALT, and LDH. Transient red cell aplasia will be
associated with low or zero reticulocyte counts.
Key points in the history include identifying the
baseline hemoglobin level, symptoms of anemia,
prior history of splenic sequestration, prior history
of transfusions, and possible precipitating events
(eg, infection, stress). Physical examination may
show the classic findings of anemia (pale conjunctiva
and mucous membranes) in addition to a palpably
enlarged spleen. Laboratory evaluation is the same
as for VOC, with inclusion of type and crossmatch
for 2 units of blood.
Treatment For Fever
For confirmed infections, standard treatment for the
specific infection is indicated. When a serious source
of infection cannot be identified in the ED, children
who meet the following criteria can be given 1 dose
of IV antibiotic that covers Haemophilus influenzae
and Streptococcus pneumonia (eg, ceftriaxone 75 mg/
kg) and discharged with follow-up in 24 hours,
provided:
• They have remained clinically stable for 3 hours
after the antibiotic dose;
• Endemic S pneumoniae in the community is
likely to be antibiotic-sensitive;
• The parents have been appropriately trained,
have a history of compliance with the prophylactic administration of penicillin, keep appointments reliably, and have emergency access to the
hospital;
• There is no infiltrate on chest radiograph or
abnormal oxygen saturation levels;
• The WBC count is not greater than 30,000/mcL
or less than 5,000/mcL and the platelet count is
less than 100,000/mcL;
• Hemoglobin level is greater than 5 g/dL; and
• The patient has no history of sepsis.
Treatment For Splenic Sequestration
All clinical trials relating to splenic sequestration in
SCD focus on primary and secondary prevention
measures; there are no studies regarding the acute
management of splenic sequestration. The keys to
management measures are as follows:
• Immediate packed red cell transfusion once the
condition is identified
• Serial blood count measurements after transfusion to evaluate for overcorrection of anemia
• Serial examinations to detect evidence of vasoocclusion after transfusion (stroke, pain, acute
chest syndrome)
Splenic Sequestration
Splenic sequestration is a life-threatening cause of a
rapid drop in hemoglobin in children with SCD.83 In
a retrospective Jamaican cohort, mortality associated
with this complication was 12%.84 Although splenic
sequestration usually occurs in children (as young
as 5 weeks85), it can be seen at any age. Adult cases
usually involve patients with HbSC or HbS beta
thalassemia.86-91 Estimates vary, but splenic sequestration accounts for 6.6% to 16.6% of deaths due to
SCD.92,93
Splenic sequestration is caused by the trapping and removal of intrasplenic red cells from the
systemic circulation. The risk is thought to be greatest in children because they produce sickled RBCs
but have not yet undergone splenic auto-infarction.
Massive amounts of blood can be sequestered in
the spleen, and the condition can be fatal within a
matter of hours. The disease can be thought of as
occurring in 2 equally dangerous phases: pre-transfusion and post-transfusion. In the pre-transfusion
phase, patients experience a rapid, life-threatening
fall in hemoglobin level as blood is sequestered in
the spleen. In the post-transfusion phase, red cells
sequestered in the spleen are remobilized, thus producing increases in hemoglobin levels well beyond
those expected with transfusion. In the post-transfusion phase, patients are at risk for vaso-occlusive
phenomena including pain, stroke, and acute chest
syndrome.
The differential diagnosis of acute splenic sequestration includes other causes of acute anemia,
August 2011 • ebmedicine.net
Most of the controversy concerning management of splenic sequestration centers on optimal
methods to prevent further attacks. Regimens include chronic transfusion, splenectomy, and partial
splenectomy. All patients with acute splenic sequestration should be admitted to a monitored bed
where CBCs and neurologic examinations can be
performed frequently (at least every 4 hours).
Table 6. Differentiating Common Causes Of
Acute Anemia In Sickle Cell Disease
13
Condition
Anemia
Markers of
Hemolysis
Reticulocyte
Count
Splenic sequestration
Severe
Absent
Elevated
Hemolysis
Severe
Present
Elevated
Transient red cell
aplasia
Severe
Absent
Decreased
Emergency Medicine Practice © 2011
Transient Red Cell Aplasia
parvovirus infection is estimated to be 11.3 events
per 100 patient-years, and 62% of these infections
result in TRCA.94
The history should elicit any symptoms of anemia (pallor, fatigue, dyspnea on exertion, chest pain),
and of recent infection (fever, cough, rash). The physical examination should focus on signs of anemia and
splenic enlargement. In rare cases, splenic sequestration can occur simultaneously with TRCA, leading to
catastrophic results if not recognized.95
Laboratory evaluation is the same as for VOC
(see Diagnostic Studies section on page 6), with the
Transient red cell aplasia (TRCA) is a common cause
of acute anemia in patients with SCD. Evidence to
guide therapy is based largely on anecdote, case report, and expert consensus. Most commonly caused
by acute infection with parvovirus B19, TRCA
infection results in a transient suppression of red
cell production (approximately 5-7 days) via a direct
cytotoxic effect on erythroid precursors. Because the
lifespan of red cells in SCD is markedly reduced,
this transient suppression can result in significant
decreases in hemoglobin levels. The incidence of
Risk Management Pitfalls For Sickle Cell Disease
1. “I thought it was just a pain crisis.”
Always consider non-SCD-related conditions
in your differential. For example, for right
lower quadrant pain, consider appendicitis,
kidney stone, and gynecological causes before
presuming VOC. For chest pain, consider acute
coronary syndromes, pulmonary embolism, or
pneumothorax before presuming acute chest
syndrome.
complications after blunt eye trauma, even if
hyphema is not apparent.
6. “I gave the patient a prescription for iron
because she was anemic. I didn’t realize this
would cause liver problems.”
Never prescribe iron for patients with SCD.
These patients are usually iron-overloaded.
7. “The creatinine was normal. How was I supposed to know the patient had kidney dysfunction?”
Assume that all patients with SCD have
some degree of renal dysfunction, even if
the creatinine level is normal. Supranormal
proximal tubule function creates falsely low
creatinine in this patient population. Take this
into consideration when prescribing NSAIDs
and when ordering imaging studies with IV
contrast.
2. “He’s had this back pain before, so it can’t be
anything dangerous.”
Consider epidural abscess and spinal
osteomyelitis in the differential of midline back
pain, even when fever is absent.
3. “The hemoglobin was low, so I gave blood. I
didn’t think this would cause a stroke.”
Never transfuse a patient simply because
hemoglobin is low. Elevating the hemoglobin
above baseline can cause hyperviscosity, pain,
acute chest syndrome, and stroke.
8. “I didn’t know that a few liters of normal saline could be harmful.”
Using bolus normal saline to treat sickle cell
crisis presents several problems. Excess IV fluid
can result in atelectasis, which may precipitate
acute chest syndrome. Large amounts of normal
saline can produce a hyperchloremic metabolic
acidosis, which may promote sickling.
4. “I thought the patient had sickle cell trait, so I
withheld pain medicines.”
When it appears that a patient has sickle cell
trait on hemoglobin electrophoresis, make sure
the patient did not receive a transfusion within
90 days of having the test performed. Recent
transfusion renders the electrophoresis useless
for diagnostic purposes.
9. “I thought the patient was just faking because
he had normal vital signs.”
Most patients with VOC will not exhibit vital
sign abnormalities.
5. “The patient doesn’t have SCD, so I never
thought to check intraocular pressure for such
minor eye trauma.”
In cases of direct eye trauma, patients with
SCD and sickle cell trait should be treated the
same way. Many patients do not know that
they carry the trait or will fail to mention it
unless prompted. Both SCD and sickle cell trait
increase the risk for catastrophic ophthalmologic
Emergency Medicine Practice © 2011
10. “The patient wasn’t black, and I thought SCD
only occurs in people of African descent.”
Sickle cell disease has been described in all races
and should no longer be considered exclusive to
black persons.
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ebmedicine.net • August 2011
inclusion of type and screen in the event the patient
requires transfusion. The hallmark finding of TRCA
is reticulocytopenia. Anemia and reticulocytopenia
will typically develop 5-7 days after exposure to the
virus. The decrease in hemoglobin will usually be less
precipitous and less severe than splenic sequestration,
although in one series mean nadir hemoglobin levels
were 3.9 mg/dL.96
Treatment For Ophthalmologic Complications
In 2002, a systematic review evaluated evidence to
guide management of hyphema in patients with
SCD or sickle cell trait. Recommendations are based
mostly on physiologic data from rabbit models with
few clinical trials having been performed.104 Treatment of traumatic hyphema, in addition to consultation with an ophthalmologist, should include the
following:
• Head-of-bed elevation to 30°
• Topical timolol: In one series, timolol did not
promote anterior chamber deoxygenation.105
• Topical brimonidine or apraclonidine as a second agent
• Topical dorzolamide as a third agent
The following treatments should be avoided
because of their potential to promote sickling or exacerbate the physiologic alterations present in SCD:
• Mannitol (increases serum osmolality)
• Glycerin (increases serum osmolality)
• Acetazolamide (increases serum osmolality and
lowers serum pH)
• Topical epinephrine (thought to promote anterior chamber deoxygenation)
Treatment For Transient Red Cell Aplasia
There are no experimental trials to guide management of TRCA. Management includes IV immune
globulin (IVIG) administration, red cell transfusion,
and isolation from pregnant patients and pregnant
healthcare workers. Unlike splenic sequestration,
for which transfusion should be immediate, NIH
guidelines recommend transfusion in TRCA only if
symptomatic anemia develops. Data to support the
use of IVIG come from a case report of a patient with
leukemia97,98 and a case series of patients with HIV
infection, all of whom had chronic parvovirus infection.99 In all patients, complete resolution of anemia
and viremia occurred after IVIG treatment. Because
maternal infection with parvovirus is associated with
a 10% rate of fetal hydrops,100 all patients with TRCA
should be isolated and contact with pregnant healthcare workers prohibited. All patients with TRCA
should be admitted for serial CBC and reticulocyte
counts, and they can be discharged when reticulocytosis has resumed and there are no significant symptoms of anemia.
A 2011 Cochrane Review found that the antifibrinolytic agent epsilon-aminocaproic acid is
associated with decreased incidence of secondary
hemorrhage after traumatic hyphema.106 Although
this agent has not been specifically tested in SCD
and sickle cell trait, experts speculate that it may be
beneficial since patients with SCD have increased
rates of fibrinolysis.
The threshold for admitting patients with SCD
(or sickle cell trait) and traumatic hyphema should
be extremely low. In the absence of clear evidence,
the author recommends ophthalmologic consultation, followed by admission for medical therapy and
serial intraocular pressure measurements.
Ophthalmologic Complications
Traumatic hyphema is an ophthalmologic emergency in patients with SCD. It is also an emergency
in patients with sickle cell trait. Because the rheologic properties of blood are altered in patients with
SCD, traumatic hyphema has been associated with
the development of acute narrow-angle glaucoma,
frequent rebleeding into the hyphema, and delayed
complications such as optic nerve atrophy and central retinal artery occlusion.101 Glaucoma is thought
to result from RBC vaso-occlusion in the trabecular
meshwork, and rebleeding is thought to result from
the increased steady-state thrombolysis in SCD.102
Evaluation of any eye trauma in the patient
with SCD or sickle cell trait should include a careful
history (to determine the mechanism and detect foreign bodies), visual-acuity and visual-field testing,
a slit-lamp examination, and intraocular pressure
measurements. The presence of hyphema warrants
emergent ophthalmologic consultation. Some advocate for consultation in all cases of direct trauma to
the eye, since elevated intraocular pressures have
been reported in the absence of hyphema.103
Standard laboratory studies are indicated for SCD
patients with eye trauma, since many will be admitted for serial intraocular pressure measurements.
August 2011 • ebmedicine.net
Priapism
Priapism, defined as sustained, undesired penile
erection, is a common complication for men with
SCD. According to a questionnaire in one study, the
cumulative incidence of priapism by the age of 20
was 89%.107 Recurrent episodes, even if properly
treated, can result in fibrosis and impotence. The etiology of priapism in SCD is vaso-occlusion. As such,
treatments that are effective for pain and acute chest
syndrome are likely to be effective for priapism.
Unfortunately, clinical trial data are lacking.
The history and physical examination focuses
on potential triggers, including infection, stress,
dehydration, and ingestion of certain medications
(trazodone or phosphodiesterase inhibitors such
as sildenafil). Onset and duration directs treatment. The physical examination specifically looks
15
Emergency Medicine Practice © 2011
Summary
for signs of local tissue ischemia. Recommended
laboratory studies include CBC, reticulocyte count,
basic metabolic panel, liver function tests, type and
screen, and lactate dehydrogenase. Serum lactate
is a marker for tissue ischemia but is optional in
evaluating these patients.
Sickle cell disease is a complex disease with manifestations that involve every organ system. Although
high-quality evidence is lacking, several recommendations have been made that will likely improve the
care of individuals with SCD who present to the ED.
Treatment For Priapism
Treatment is based on the duration of priapism
• Less than 2 hours: Analgesics, IV fluids
• More than 2 hours:
First-line therapy:
• Local intracavernosal aspiration and injection with 1:1,000,000 solution of epinephrine in saline. In a prospective single arm
study of 39 cases of priapism treated with
epinephrine injection, detumescence was
achieved in 37 of 39 patients. The procedure
was unsuccessful in 2 patients who presented with priapism of greater than 24 hours
duration.
Second-line therapies:
• Exchange transfusion: Successful detumescence with exchange transfusion has been
reported several times in the literature.108-111
However, since the use of this therapy has
been associated with adverse neurologic
events,112-114 it should be employed only
after conventional therapies have failed.
• Epidural anesthesia: There are 2 reports in
the literature of successful treatment of priapism with epidural anesthesia.115,116
Case Conclusions
You returned to the bedside of the young man with SCD
who presented with the complaint of sickle cell crisis.
After reviewing the literature, you now have answers to
the clinical questions that were raised:
• Can this patient be having a crisis without a
drop in hemoglobin? Yes. Painful crises are not
associated with drops in hemoglobin; furthermore,
high hemoglobin (10 mg/dL is very high for individuals with SCD) is associated with increased viscosity,
which may predispose to pain.
• Is there a blood test I can do to confirm that he
is truly having a crisis? No. Performing a peripheral smear to look for sickled cells will not yield any
information about whether the patient is in crisis, nor
will any other readily available laboratory test. The
patient had normal vital signs and looked comfortable, which initially made you skeptical about his
10/10 pain, but you realized that vital sign abnormalities are uncommon with VOC. The patient told you
he has regular follow-up in a hematology clinic and
access to dilaudid prescriptions through his hematolo­
gist. He assured you that he would not come to the
ED unless the pain was intractable.
• Is the patient addicted to opiates or drug-seeking? It is unlikely, but you realized that the ED is not
the time or the place to evaluate for addiction. You
treated the pa­tient’s pain aggressively and relayed
any concerns to the hematologist who will be following the patient.
Once priapism has been present for more than 2
hours, intracavernosal epinephrine injection should
be initiated immediately. If this fails, consider exchange transfusion or epidural anesthesia in consultation with urology and hematology.
Time- And Cost-Effective Strategies For Patients With Sickle Cell Disease
1. Limit the use of oxygen.
Oxygen may be detrimental because of the
potential for myelosuppression and has never
been shown to improve outcomes. Administer
supplemental oxygen only for hypoxic patients.
3. Limit laboratory testing.
In patients presenting with simple pain without
other symptoms – especially if discharge is
likely – laboratory tests are not necessary. Liver
function tests and markers of hemolysis are not
indicated unless patients have worsening icterus
or significant decreases in hemoglobin from
baseline.
2. Consider oral rehydration and oral opiates,
especially in children.
Oral opiates are associated with shorter timeto-opiates. Consider oral opiates and hydration
especially when pain is perceived to be mild
with potential for discharge.
Emergency Medicine Practice © 2011
4. Order an incentive spirometer for all admitted
patients.
This simple intervention may decrease the
incidence of inpatient acute chest syndrome,
which is a high-cost, high-mortality event.
16
ebmedicine.net • August 2011
• What fluids should I administer? You instructed
the nurse to stop the 1-L bolus of NS, and start an
infusion of D5 ½ NS at the mainte­nance rate.
• What kind of opiates should I give this patient?
You administered 2 doses of 2-mg IV hydromorphone
15 minutes apart, and the patient reported his pain
score was down to 6/10. You started the patient on a
hydromor­phone PCA with a basal rate of 0.1 mg/hr
and demand doses of 0.2 mg every 8 minutes.
• Should I administer supplemental oxygen?
No. The patient is not hypoxic, so you stopped all
supplemen­tal oxygen.
• Should I give him IV ketorolac? Are there any
other medications that might help? No. The
patient’s creatinine level came back at 0.9. Because
patients with SCD have supranormal proximal tubule function, you know that his renal function may
be sig­nificantly decreased even though his creatinine
is normal. You elected not to give NSAIDs. You gave
the patient acetaminophen, diphenhydramine, and an
incentive spirometer. You decided not to give magne­
sium or ketamine.
8.
9.
10.
11.
12.
13.
14.
After 3 hours in the ED, you reassessed the patient.
His pain was well controlled, but he did not think he
would be able to go home. You contacted the inpatient
service and admitted him to the hospital. Five days later,
he was transitioned to oral analgesics and discharged from
the hospital.
15.
16.
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in children with sickle cell disease. Pediatr Blood Cancer.
2008;50:1006-1012.
76. Leikin SL, Gallagher D, Kinney TR, et al. Mortality in children and adolescents with sickle cell disease. Cooperative
Study of Sickle Cell Disease. Pediatrics. 1989;84:500-508.
77. Fullerton HJ, Wu YW, Zhao S, et al. Risk of stroke in children: ethnic and gender disparities. Neurology. 2003;61:189194.
78. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91:288-294.
79. Hulbert ML, Scothorn DJ, Panepinto JA, et al. Exchange
blood transfusion compared with simple transfusion for first
overt stroke is associated with a lower risk of subsequent
stroke: a retrospective cohort study of 137 children with
sickle cell anemia. J Pediatr. 2006;149:710-712.
80. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first
stroke by transfusions in children with sickle cell anemia and
abnormal results on transcranial Doppler ultrasonography.
N Engl J Med. 1998;339:5-11.
81. Quinn CT, Rogers ZR, McCavit TL, et al. Improved survival
of children and adolescents with sickle cell disease. Blood.
2010;115:3447-3452.
82. Hord J, Byrd R, Stowe L, et al. Streptococcus pneumoniae
sepsis and meningitis during the penicillin prophylaxis era
in children with sickle cell disease. J Pediatr Hematol Oncol.
2002;24:470-472.
83. Neonato MG, Guilloud-Bataille M, Beauvais P, et al. Acute
clinical events in 299 homozygous sickle cell patients living
in France. French Study Group on Sickle Cell Disease. Eur J
Haematol. 2000;65:155-164.
84. Emond AM, Collis R, Darvill D, Higgs DR, Maude GH,
Serjeant GR. Acute splenic sequestration in homozygous
sickle cell disease: natural history and management. J Pediatr.1985;107:201-206.
85. Airede AI. Acute splenic sequestration in a five-week-old
infant with sickle cell disease. J Pediatr. 1992;120:160.
86. Aslam AF, Aslam AK, Dipillo F. Fatal splenic sequestration
crisis with multiorgan failure in an adult woman with sickle
cell-beta+ thalassemia. Am J Med Sci. 2005;329:141-143.
87. Hutchins KD, Ballas SK, Phatak D, et al. Sudden unexpected
death in a patient with splenic sequestration and sickle cellbeta+-thalassemia syndrome. J Forensic Sci. 2001;46:412-414.
88. Koduri PR. Acute splenic sequestration crisis in adults with
sickle cell anemia. Am J Hematol. 2007;82:174-5.
89. Koduri PR, Agbemadzo B, Nathan S. Hemoglobin S-C
disease revisited: clinical study of 106 adults. Am J Hematol.
2001;68:298-300.
90. Koduri PR, Kovarik P. Acute splenic sequestration crisis
in an adult with sickle beta-thalassemia. Ann Hematol.
2006;85:633-635.
91 Koduri PR, Nathan S. Acute splenic sequestration crisis in
adults with hemoglobin S-C disease: a report of nine cases.
August 2011 • ebmedicine.net
Ann Hematol. 2006;85:239-243.
92. Manci EA, Culberson DE, Yang YM, et al. Causes of death
in sickle cell disease: an autopsy study. Br J Haematol.
2003;123:359-365.
93. Fernandes AP, Januario JN, Cangussu CB, et al. Mortality of
children with sickle cell disease: a population study. J Pediatr
(Rio J). 2010;86:279-284.
94. Smith-Whitley K, Zhao H, Hodinka RL, et al. Epidemiology
of human parvovirus B19 in children with sickle cell disease.
Blood. 2004;103:422-427.
95. Mallouh AA, Qudah A. Acute splenic sequestration together
with aplastic crisis caused by human parvovirus B19 in
patients with sickle cell disease. J Pediatr. 1993;122:593-595.
96. Goldstein AR, Anderson MJ, Serjeant GR. Parvovirus associated aplastic crisis in homozygous sickle cell disease. Arch
Dis Child. 1987;62:585-588.
97. Kurtzman G, Frickhofen N, Kimball J, et al. Pure red-cell
aplasia of 10 years’ duration due to persistent parvovirus
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98. Kurtzman GJ, Cohen B, Meyers P, et al. Persistent B19
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99. Frickhofen N, Abkowitz JL, Safford M, et al. Persistent B19
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100. Miller E, Fairley CK, Cohen BJ, et al. Immediate and long
term outcome of human parvovirus B19 infection in pregnancy. Br J Obstet Gynaecol. 1998;105:174-178.
101. Mowatt L, Chambers C. Ocular morbidity of traumatic hyphema in a Jamaican hospital. Eur J Ophthalmol. 2010;20:584589.
102. Nasrullah A, Kerr NC. Sickle cell trait as a risk factor for
secondary hemorrhage in children with traumatic hyphema.
Am J Ophthalmol. 1997;123:783-790.
103. Coats DK, Paysse EA, Kong J. Unrecognized microscopic
hyphema masquerading as a closed head injury. Pediatrics.
1998;102:652-654.
104. Walton W, Von Hagen S, Grigorian R, et al. Management of
traumatic hyphema. Surv Ophthalmol. 2002;47:297-334.
105. Pakalnis VA, Rustgi AK, Stefansson E, et al. The effect of
timolol on anterior-chamber oxygenation. Ann Ophthalmol.
1987;19:298-300.
106. Gharaibeh A, Savage HI, Scherer RW, et al. Medical interventions for traumatic hyphema. Cochrane Database Syst Rev.
2011:CD005431.
107. Mantadakis E, Cavender JD, Rogers ZR, et al. Prevalence of
priapism in children and adolescents with sickle cell anemia.
J Pediatr Hematol Oncol. 1999;21:518-522.
108. Karayalcin G, Imran M, Rosner F. Priapism in sickle cell
disease: report of five cases. Am J Med Sci. 1972;264:289-293.
109. Rifkind S, Waisman J, Thompson R, et al. RBC exchange
pheresis for priapism in sickle cell disease. JAMA.
1979;242:2317-2318.
110. Seeler RA. Intensive transfusion therapy for priapism in
boys with sickle cell anemia. J Urol. 1973;110:360-363.
111. Walker EM Jr, Mitchum EN, Rous SN, et al. Automated
erythrocytopheresis for relief of priapism in sickle cell hemoglobinopathies. J Urol. 1983;130:912-916.
112. Abboud MR, Musallam KM. Sickle cell disease at the dawn
of the molecular era. Hemoglobin. 2009;33 Suppl 1:S93-S106.
113. Rackoff WR, Ohene-Frempong K, Month S, et al. Neurologic
events after partial exchange transfusion for priapism in
sickle cell disease. J Pediatr. 1992;120:882-885.
114. Siegel JF, Rich MA, Brock WA. Association of sickle cell
disease, priapism, exchange transfusion and neurological
events: ASPEN syndrome. J Urol.1993;150:1480-1482.
115. McHardy P, McDonnell C, Lorenzo AJ, et al. Management of
19
Emergency Medicine Practice © 2011
6. In patients admitted for VOC, which treatment
is indicated to prevent the development of
acute chest syndrome?
a. IV fluids
b. Patient-controlled analgesia
c. Incentive spirometry
d. Supplemental oxygen
e. Exchange transfusion
priapism in a child with sickle cell anemia; successful outcome using epidural analgesia. Can J Anaesth. 2007;54:642645.
116. Labat F, Dubousset AM, Baujard C, et al. Epidural analgesia in a child with sickle cell disease complicated by acute
abdominal pain and priapism. Br J Anaesth. 2001;87:935-936
CME Questions
Take This Test Online!
7. Which treatment is indicated for patients with
pulmonary infiltrate and worsening dyspnea or
hypoxemia?
a. Steroids
b. Hydroxyurea
c. Thrombolysis
d. Exchange transfusion
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8.
1. In patients with SCD, painful crises are associated with a drop in hemoglobin.
a. True
b. False
The treatment for transient red cell aplasia is:
a. Supplemental oxygen
b. Hydroxyurea
c. IVIG
d. Exchange transfusion
9. Patients with sickle cell trait are at risk for:
a. Ophthalmologic complications after minor eye trauma
b. Pulmonary hypertension
c. Painful episodes
d. Stroke
2. The genotype of SCD associated with the highest risk for avascular necrosis is
a. HbSS
b. HbSC
c. HbS beta thalassemia0
d. Alpha thalassemia
10. In adults with SCD who present with acute
stroke, tPA is contraindicated.
a. True
b. False
3. The laboratory test that can be used to objectively determine if a patient with SCD is truly
having a painful episode is:
a. Hemoglobin
b. WBC
c. Peripheral smear with sickled cells
d. Troponin
e. There is no reliable laboratory test to identify painful episodes
11. After initial treatment with fluids and analgesics, first-line therapy for priapism in patients
with SCD is
a. Intracavernosal drainage and epinephrine injection
b. Exchange transfusion
c. Epidural anesthesia
d. Phlebotomy
4. Most SCD patients with true VOC will be
hypertensive.
a. True
b. False
5. Which treatment is indicated in the management of every VOC?
a. Normal saline
b. Supplemental oxygen
c. Opiates
d. NSAIDs
Emergency Medicine Practice © 2011
20
ebmedicine.net • August 2011
Board-Certified Emergency
Physicians: Are you prepared for
the ABEM LLSA Exam?
Physician CME Information
Date of Original Release: August 1, 2011. Date of most recent review: July 10,
2011. Termination date: August 1, 2014.
Accreditation: EB Medicine is accredited by the ACCME to provide continuing
medical education for physicians.
Credit Designation: EB Medicine designates this enduring material for a maximum
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is approved for 4 Prescribed credits. Credits may be claimed for 1 year from
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with the extent of their participation in the activity.
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Goals: Upon completion of this article, you should be able to: (1) demonstrate
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describe the most common medicolegal pitfalls for each topic covered.
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were asked to complete a full disclosure statement. The information received
is as follows: Dr. Glassberg, Dr. Parekh, Dr. Zempsky, Dr. Jagoda, and their
related parties report no significant financial interest or other relationship
with the manufacturer(s) of any commercial product(s) discussed in this
educational presentation.
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Emergency Medicine Practice CME article and complete the online post-test
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score 100% to receive credit.
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August 2011 • ebmedicine.net
21
Emergency Medicine Practice © 2011
In This Month’s Pediatric Emergency Medicine Practice
Evidence-Based
Emergent Management
of Bleeding Disorders
Authors:
Katherine Fullerton, MD
Department of Emergency Medicine, Inova
Fairfax Hospital for Children, Falls Church, VA;
Assistant Professor, Virginia Commonwealth
University School of Medicine, Richmond, VA
Rick Place, MD
Pediatric Medical Director, Department of
Emergency Medicine, Inova Fairfax Hospital for
Children, Falls Church, VA
Children with both congenital (eg, hemophilia
or von Willebrand disease) and acquired (eg,
immune thrombocytopenia [ITP]) bleeding
disorders frequently present to the emergency
department with a wide variety of bleedingrelated problems ranging from petechiae to
intracranial hemorrhage. In many instances, such
as hemophilia or von Willebrand disease, the
bleeding disorder has been previously diagnosed
because of an abnormal family history or bleeding
in infancy. However, in other instances, a patient
may present with abnormal bleeding symptoms
(such as a patient with ITP), and it is the role of
the emergency clinician to facilitate the diagnosis
and initiate therapy. This issue of Pediatric
Emergency Medicine Practice provides up-todate guidelines and an evidence-based review
of the most common bleeding disorders and
management of specific bleeding emergencies in
the ED.
Do You See
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Patients?
If your answer is yes, it’s time you subscribe to
Pediatric Emergency Medicine Practice.
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don’t know, the cutting edge and controversies,
and the essentials of caring for children in
emergency medicine.”
— Joseph Toscano, MD, San Ramon, CA
Pediatric Emergency Medicine Practice
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22
ebmedicine.net • August 2011
In This Month’s EM Critical Care
For the intensivist
inside every
emergency
physician...
Noninvasive Ventilation:
Update On Uses For
The Critically Ill Patient
Authors:
Jose Dionisio Torres, Jr., MD
Clinical Instructor in Emergency Medicine,
New York Hospital Queens, Flushing, NY
Michael S. Radeos, MD, MPH
Research Director, Department of Emergency
Medicine, Flushing, NY; Assistant Professor of
Emergency Medicine, Weill Cornell Medical
College, New York, NY
Noninvasive ventilation (NIV) is a method of
delivering oxygen by positive pressure mask
that allows the clinician to postpone or prevent
invasive tracheal intubation in patients who
present to the emergency department (ED)
with acute respiratory failure (ARF). There
are 2 primary modalities of NIV: continuous
positive airway pressure (CPAP) and bi-level
positive pressure ventilation (BPAP) where
the inspiratory positive airway pressure (IPAP)
is higher than the expiratory positive airway
pressure (EPAP). Continuous positive airway
pressure appears to be more effective in
reducing the need for tracheal intubation and
possibly mortality in patients presenting with
acute cardiogenic pulmonary edema (ACPE).
Bi-level positive pressure ventilation appears
to be more effective in reducing mortality and
the need for tracheal intubation in patients
with an acute decompensation of chronic
obstructive pulmonary disease (COPD). Proper
patient selection is critical in the use of NIV for
ED patients. They must be able to cooperate
with the respiratory therapist and tolerate the
often uncomfortable nasal or face mask. The
emergency clinician must be vigilant for signs of
clinical deterioration in these patients as they may
need an emergent definitive airway placed. This
issue of EMCC examines the evidence supporting
the use of NIV in various causes of ARF and
reviews potential complications.
EB Medicine is pleased to announce the launch
of the only publication dedicated to helping
emergency clinicians enhance their critically ill
patients’ care.
“EM Critical Care (EMCC) is the first-ever
peer-reviewed publication that provides
succinct content designed to resonate with the
intensivist that dwells inside every emergency
physician. Providing evidence-based reviews
on topics that define the emergency medicinecritical care interface, EMCC will be invaluable
to clinicians seeking to enrich their care and
understanding of the sickest, most complex
patients in their ED.”
— Robert Arntfield, MD, Editor-in-Chief
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August 2011 • ebmedicine.net
23
Emergency Medicine Practice © 2011
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