Sickle Cell Disease

Lauren V. Ready, MD, MPHa, Mary Carroll Lee, MD

b
,
John C. Perkins Jr, MDc,*

KEYWORDS
 Sickle cell disease  Vaso-occlusive crisis  Acute chest syndrome
 Acute pain episode  Splenic sequestration  Stigma  Quality of life

KEY POINTS
 Aggressive management of acute pain episodes with opioid analgesics in an objective
manner is a primary role for the emergency provider.
 All patients with sickle cell disease who present to the emergency department are at risk of
life-threatening pathology in addition to an acute pain episode.
 Stigmatizing language and nonobjective treatment of acute pain episodes in the Emer-
gency Department are barriers to optimal care of patients with Sickle Cell Disease.
 Acute chest syndrome has diagnostic overlap with numerous other serious cardiopulmo-
nary pathologies which leads to delays in diagnosis and treatment.
 All patients with sickle cell disease have some degree of immune compromise and delays
in diagnosis are common due to atypical presentations confounded by acute pain
episodes.

INTRODUCTION

Emergency providers (EPs) practicing in North America must be familiar with sickle cell
disease (SCD) and its complications. SCD is the most common genetic disease in the
United States: 1 in 13 black or African American babies are born with the autosomal
recessive mutation, and approximately 1 in 365 Black or African Americans born
has the disease.1 There are now more than 100,000 people living in the United States
with SCD and when they present to the emergency department (ED), it is most
commonly due to an acute complication of SCD.1 While many EPs are familiar with
the hallmark presentation known as a vaso-occlusive crisis (VOC), there is a wide vari-
ation in approach to treatment which may lead to inadequate management of severe
pain. And while VOC is the most common presentation in the ED for those patients
with SCD, much more ominous pathology may occur. It is essential for every SCD

a
Department of Emergency Medicine, Oregon Health Sciences University, Portland, OR, USA;
b
Oregon Health Sciences University, Portland, OR, USA; c Virginia Tech Carilion School of
Medicine, Roanoke, VA, USA
* Corresponding author.
E-mail address: [email protected]

Emerg Med Clin N Am 43 (2025) 391–406

https://doi.org/10.1016/j.emc.2025.03.007 emed.theclinics.com
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392 Ready et al

Abbreviations
ACS acute coronary syndrome
CT computed tomography
ED emergency department
EP emergency provider
ESI emergency severity index
FDA Food and Drug Administration
HbS hemoglobin S
IVF intravenous fluid
LBF long bone fractures
LRA local regional anesthesia
PAH pulmonary artery hypertension
PCA patient-controlled analgesia
POCUS point-of-care ultrasound
PRBC packed red blood cell
SCD sickle cell disease
VOC vaso-occlusive crisis

patient to receive a thorough evaluation complete with consideration of life-

threatening pathology as well as VOC.

EPIDEMIOLOGY

More than 90% of the people living in the United States with SCD are non-Hispanic
black or African American with roughly 3% to 9% identified as Latino.1 Despite
numerous advances in the recent decades in medical care for patients with SCD,
the average life expectancy is 20 years less than would be expected and quality-
adjusted life expectancy is more than 30 years less than expected.2 Unfortunately,
some of the explanation for early mortality involves lack of access to care, stigma
when SCD patients attempt to access care, and health systems barriers to integrate
SCD patients into a comprehensive patient care team both inside and outside the
hospital.3
Clinical Presentations in the Emergency Department
Vaso-occlusive crisis and non-vaso-occlusive crisis acute pain episode
Vaso-occlusive crisis (VOC) is the most common ED presentation of SCD.3 Microvas-
cular occlusion (the cardinal pathophysiologic cause of acute pain) leads to ischemia
and hypoxia. This stage is followed by tissue and vascular damage and inflammation
with release of inflammatory mediators, all of which activate nociceptors. Reperfusion
intensifies the inflammation and resultant pain.4–9
Classically, acute pain from VOC is described in the back or extremities, although it
may occur elsewhere.10 It may be migratory and is usually continuous and progres-
sive. VOC pain may less frequently occur elsewhere, such as in the chest, where it
may create diagnostic overlap with acute chest syndrome (abbreviated here as
AChS to avoid confusion with acute coronary syndrome [ACS]), pulmonary embolism
and acute coronary syndrome. Pain from VOC should be distinguished from 2 other
patterns of pain experienced by patients with SCD: acute flare of chronic pain and
neuropathic pain. Generally, the major focus for the provider is management of acute
pain caused by VOC and best practice is for the EP to assume that a VOC is the cause
of the acute pain episode while evaluating for concurrent pathology that may be life-
threatening.
Acute pain episodes caused by VOC are usually diagnosed by patients themselves.
The treating EP will be challenged by having to identify other causes of an acute pain
 Sickle Cell Disease 393

episode (such as AChS), identifying conditions that could be masked by the severe
pain, and aggressively treating VOC pain, which necessitates an individualized treat-
ment approach.
There are no reliable aspects of the history, examination, or laboratory testing that
indicate the presence or absence of VOC or pain associated with VOC. Patients’ self-
reported pain scores do not reliably correlate with changes in vital signs, such as
tachycardia, hypertension, or tachypnea, which are associated with pain in other clin-
ical contexts. Hemoglobin, hematocrit, and reticulocyte measurements do not serve
as markers for pain either. Further, EPs may believe patient behavior is inconsistent
with reported pain. Patients may have a VOC and yet are able to walk, engage in con-
versations, or have a calm appearance while reporting high levels of pain.5,7,11,12 Lab-
oratory tests should be ordered for patients who are being admitted, and to evaluate
when suspicion of a diagnosis other than an acute pain episode is being considered
such as ACS or sepsis.

Acute pain episode clinical management

Whether a patient with SCD has a VOC or another etiology for their presentation with
an acute pain episode, pain management is critically important, and unfortunately, is
often inadequately addressed for a myriad of reasons. Opioids have been the main-
stay of analgesia for VOCs and acute pain episodes over the past century. Morphine,
fentanyl, and hydromorphone are all commonly used in EDs, and there are specific
considerations for each agent. Meperidine has been the subject of much debate,
but it should not be used, as it has been associated with behavioral changes and
seizures.12–15
Contemporary management of acute pain episodes is outlined in Table 1. Key goals
include prioritization of these patients in triage, early and adequate analgesia, frequent
reassessments, and repeat dosing until pain is controlled.5,8,16–18 EPs should consider
implementing patient-controlled analgesia (PCA) when feasible and especially if the
patient is being admitted.5,7,9,10,19–25 The intramuscular route should be avoided in
favor of the intravenous, subcutaneous, or oral routes. Fluids are no longer considered
a mainstay of treatment but may be beneficial if the physical examination suggests
hypovolemia. Hypovolemia increases deoxygenated hemoglobin S (HbS) forms and
leads to decreased red cell flexibility and decreased plasma volume, which increases
the sickle cell red blood cell morphology.26
Patients with acute pain episodes may be discharged if their pain is adequately
controlled and there is an outpatient plan of care involving early follow up and an
appropriate pain management regimen. There is no literature to support a fixed num-
ber of doses of opioid medications (eg, 3 doses of intravenous opioids) for an EP to
use as an admission threshold. Optimal pain management treatment incorporates
an individualized treatment plan formulated by the patient’s hematologist (Table 2).
Individualized treatment plans provide consistent and objective guidelines that ac-
count for the patient’s home analgesic regimen and what has been successful for
them previously in controlling their acute pain episodes. Admission guidelines are
often incorporated into individualized treatment plans, but it is important to note
that this only addresses one clinical inquiry related to pain. Other factors should be
incorporated into a decision on admission such as alternative or additional pathology
being considered, social and clinical support outside the ED, and perceived clinical
benefit of admission. If deciding to discharge, it is important to discuss out-of-
hospital pain management with the patient and family/caregiver. This can include
avoiding dehydration or overexertion, and employing folic acid supplementation
with multimodal pain control—acupuncture, heat, massage, and meditation.12 We
394 Ready et al

Table 1
Management options in the emergency department

Opioids: initiate within 30 min of patient Review records of prior dosing for guidance
arrival on initial and subsequent dosing
Avoid intramuscular route if possible
(unpredictable pharmacokinetics)
Morphine 0.1 mg/kg intravenously every 20 min then
maintenance with 0.05–0.1 mg/kg q 2–4 h.
Hydromorphone 0.015 mg/kg IV every 20 min
Alternative analgesia:
Patient-controlled analgesia Consider if persistent pain despite opioid
bolus dosing
Local regional anesthesia Local regional block to reduce opioid use;
long-lasting (12–16 h), risks include
infection, neurologic injury, hematoma
Intranasal fentanyl If avoiding or unable to perform intravenous
cannulation
Non-steroidal anti-inflammatories Used in addition to opioids, help with
inflammation, limit use to <72 h in patients
with no contraindication
Ketamine Consider as an adjunct using pain control
dosing: 0.1 mg/kg–0.2 mg/kg intravenously
Antihistamines Anecdotal evidence for opioid-sparing effect
and reduction in pruritus. Avoid
intravenous administration if possible to
avoid euphoric effect.
Nitric oxide Limited data
Steroids Reduction in pain scores and length of stay,
high rates of pain recurrence
Intravenous magnesium Limited data, vasodilator, anti-inflammatory,
can have pain with drug delivery
Adjunctive Therapy:
Supplementary oxygen Only if pulse oximetry <92%
Intravenous fluids Only if hypovolemic

*This is for consideration in patients without an individualized treatment plan.

also strongly encourage communication with the patient’s hematologist (if applicable)
to ensure follow up and address any consultant concerns for their patient.
Alternative treatments include magnesium and ketamine which act as N-methyl-D-
aspartate (NMDA) receptor noncompetitive antagonists.17,27 Ketamine can be used as
an adjunct to, but not in place of, opioid medications.3 Magnesium may help with
discomfort, but does not reduce opioid requirements, length of stay, or improve qual-
ity of life.28 Intranasal fentanyl should be considered in patients in whom intravenous
access is delayed for any reason.3 Local regional anesthesia (LRA) has been shown to
help reduce inflammation and improve vasodilation.17,29 One study demonstrated a
75% mean reduction in opioid requirements for an acute pain episode.17 LRA was
also noted to aid in transition to oral analgesia. A dose of 1 to 2 mg/kg of ropivacaine
was employed in the study using the following regional areas for targeted therapy: axil-
lary nerve, brachial plexus, femoral nerve, transversus abdominis plane, and popliteal
sciatic nerve.17 Bupivacaine can also be used for LRA with dexmedetomidine as an
adjunct.17
 Sickle Cell Disease 395

Table 2
Examples of an individual treatment plan for acute pain episode

Patient X  Ketorolac 15 mg IV x 1  If the patient requires

 Hydromorphone 1 mg IV q1 hour x hydromorphone PCA, please do
two doses NOT order a continuous rate.
 Intravenous fluids 1000 mL bolus  Continuous settings cause
oversedation and confusion.
 PCA to be started at 0.0 mg
continuous, 0.6 mg demand with a
15-min lockout, and 10 mg q4 hours
maximum
Patient Y  Ketorolac 15 mg IV x 1  If pain is unrelieved after second
 Fentanyl 100mcg IV x 1 dose of fentanyl, consider
 Fentanyl 150mcg IV x1 2 h later if admission, PCA and consult
necessary hematology as well as the pain
 Intravenous fluids 1000 mL bolus (if management service
not contraindicated)

Acute Chest Syndrome

AChS is defined as the appearance of a new pulmonary infiltrate on chest radiography
accompanied by a fever (80%) and respiratory symptoms, including cough (62%–
74%), tachypnea, rales (48%–76%), and chest pain.12,30–34 It is hypothesized that
AChS is the result of hypoxia and an inflammatory mediator-induced increase in adhe-
sion of the pulmonary microvasculature to sickled erythrocytes. This process is
coupled with a reduction in nitric oxide, which would normally counteract such pathol-
ogy.31,35 Incidence is highest in young children (2–4 years), but symptoms are more
significant in older adults.33
Although a significant portion (45.7%) of AChS cases have unknown causes, 30%
occurred in the setting of an active infection.36 Approximately 9% were attributed to
a pulmonary fat embolism (which could be the result of infection), and 16% were asso-
ciated with pulmonary infarction (not caused by infection or fat embolism).36 Hypoven-
tilation caused by splinting (secondary to pain) or somnolence (secondary to opioids)
places the patient at risk for AChS.31 Pulmonary edema caused by intravenous hydra-
tion may lead to AChS, but the data is inconclusive. Pulmonary thrombosis (note: pul-
monary thrombosis is being distinguished from pulmonary embolism discussed later
in the article) occurs in about 17% of cases with AChS, but it is unclear if it is a cause or
consequence of AChS.37

AChS treatment
Initial management of AChS should prioritize treatment of infection and pain, given that
the presentation will necessitate consideration of numerous pathologies.38 Suggested
antibiotics include a cephalosporin and macrolide, as is typical for community-
acquired pneumonia. Supplemental oxygen should be used to treat hypoxia.31,38
Incentive spirometry plays a significant role in the prophylaxis and treatment of
AChS and is something that can be initiated in the ED. Intravenous fluids should be
administered judiciously, as there is a risk of pulmonary edema which would worsen
AChS.
Exchange transfusion has been used effectively in the United States for treatment of
AChS, but a mortality benefit has not been noted when compared with Europe, where
exchange transfusion is not used routinely.31 There is not clear evidence in literature
regarding definitive indications for exchange transfusion, so we suggest using clinical
judgment to assess each patient uniquely; areas of concern include increasing oxygen
396 Ready et al

requirement and abnormal findings on chest x-ray.39 Transfusion-associated rise in

hemoglobin levels can increase viscosity, thereby increasing the risk of complications.
Exchange transfusion may be considered in patients with a baseline high hemoglobin
levels or those with “multi-lobe involvement, persistent or worsening hypoxemia,
neurologic abnormalities, or multi-organ failure.”31 It is important to note that due to
the lower lobe predilection of AChS, it can be confused for pneumonia on chest
x-ray.33
The use of mechanical ventilation has been associated with improved out-
comes.36 Indications for intubation would be similar to other patients experiencing
respiratory distress. If you have concerns for worsening oxygenation status, in-
crease your patient’s respiratory support to noninvasive ventilation prior to intuba-
tion and consider a bronchodilator.40 Anticoagulation in patients with pulmonary
thrombosis will not improve outcomes from AChS; however, it is considered stan-
dard of care and should be initiated. Inhaled nitric oxide and steroids may also be
used in the management of AChS, but these therapies are still considered
experimental.31
Increasing age is associated with worse outcomes for AChS, and, overall, roughly
3% of patients with AChS die.36 Predictors of worse outcomes are extensive lung
involvement on radiograph, a platelet count of less than 199,000/mm3, and co-
morbid coronary artery disease.36 All patients with AChS should be admitted to a
monitored setting, but not necessarily an intensive care unit.

Can’t miss pathology in the emergency department

Pulmonary embolism. Pulmonary embolism can be a challenging diagnosis in patients
with SCD as the presentation will overlap with AChS, pneumonia, VOC, and ACS. Pul-
monary embolism should be considered as part of the differential diagnosis in patients
presenting to the ED with any cardiopulmonary complaints. We do not recommend the
use of the pulmonary embolism rule out criteria in SCD patients, as the study popula-
tion used to derive this clinical decision rule was not strictly in SCD patients. Secondly,
patients with SCD are at higher risk for venous thromboembolism, making it more diffi-
cult to place them in a low-risk category when they present with a cardiopulmonary
complaint. In fact, there is a 50-fold to 100-fold increase in annual incidence of pulmo-
nary embolism in patients with SCD compared with those without SCD.41,42 Sending a
d-dimer is potentially problematic for a few reasons. First, there is a strong likelihood
the d-dimer will be elevated (>90% likelihood) and computed tomography (CT) pulmo-
nary angiography will be necessary to exclude pulmonary embolism.43,44 Thus, there
will be a delay in definitive imaging while awaiting d-dimer results. However, more
importantly, multiple pathologies can be evaluated using CT pulmonary angiography
which makes it reasonable to pursue aggressive imaging earlier in the ED course for
patients with a cardiopulmonary complaint. Finally, while point-of-care ultrasound
(POCUS) is advisable in patients with SCD and may be beneficial, it is also fraught
with pitfalls when used for signs of right heart strain due to the prevalence of underly-
ing pulmonary artery hypertension (PAH) in patients with SCD. Thus, evidence of right
heart strain on POCUS may reflect pre-existing PAH and should be interpreted in
conjunction with a review of prior records and previous echocardiography. We
encourage liberal use of adjunctive serum troponin and brain natriuretic peptide as
the results may be valuable in determining treatment modalities for new pulmonary
embolism in patients with SCD. Early engagement of consultants (eg, pulmonary,
interventional radiology, hematology) is highly recommended when a new diagnosis
of pulmonary embolism is made in patients with SCD as the approach to intervention
may change in patients with SCD.45
 Sickle Cell Disease 397

Stroke. Although ischemic strokes are unusual in the pediatric population, they are
more common in children with SCD.46,47 Children with SCD as young as 2 years old
have been diagnosed with ischemic strokes.47 Symptoms of stroke in children may
be atypical such as seizures or lethargy. Adults are more likely to suffer a hemorrhagic
stroke as opposed to an ischemic stroke. In adults, large vessels are more likely to be
involved which increases the importance of early use of the National Institute of Health
stroke scale and consideration of thrombolytics and thrombectomy. However, the
added complexity of an acute cerebrovascular accident (CVA) in patients with SCD
is that they may need a blood transfusion or exchange transfusion. Therefore, early
consultation with neurology, hematology, and interventional radiology are strongly
recommended. Early transfer to a center that can provide exchange transfusion as
well as aggressive stroke reperfusion therapy is essential.48

Pulmonary hypertension. The exact pathogenesis of PAH in SCD is not fully under-
stood. However, it is a particularly serious complication of long-term SCD that affects
up to 10% of adult patients with SCD.47 Quality of life decreases significantly in pa-
tients with PAH, and median survival for those patients diagnosed with PAH is less
than 10 years. Symptoms of PAH overlap with other cardiopulmonary pathology
and include dyspnea on exertion, lower extremity edema, fatigue, dizziness, syncope,
and chest pain. One of the potential etiologies of PAH in SCD is chronic pulmonary
embolism, which is important to understand if a bedside POCUS is suggestive of right
heart strain, or PAH is documented during a right-heart catheterization. Treatments
focused on PAH are largely similar to those patients with PAH without SCD, and focus
on pulmonary artery vasodilation and supplemental oxygenation to prevent further
vasoconstriction as a consequence of hypoxemia.49

Splenic sequestration. Splenic sequestration is a potentially catastrophic complication

of SCD, and is characterized by an acute decrease in hemoglobin level, which can
result in circulatory collapse. It is more common in the pediatric population because
they have not yet auto-infarcted their spleen.5,50 The mechanism for this entity involves
sickled erythrocytes becoming trapped within the spleen and thereby being removed
from the circulatory system; this is seen on laboratory testing as a profound or
acute-on-chronic anemia. EPs must consider this entity when presented with an adult
or child with acute splenic enlargement and circulatory collapse. Splenic sequestration
can be differentiated from other causes of anemia associated with SCD (hemolysis, red
cell aplasia) based on a combination of laboratory tests: severe anemia, increased
reticulocyte count, and findings of hemolysis (increased indirect bilirubin, alanine trans-
aminase, and lactate dehydrogenase).5 Patients should be resuscitated with intrave-
nous fluids and emergent blood transfusion. A subsequent splenectomy is critical,
because splenic sequestration recurs at a rate of nearly 50%.50
Infectious complications. Patients with SCD are at higher risk for infectious pathology
and in particular infection as a result of encapsulated organisms because of their func-
tional asplenia.5 Patients with SCD are considered to have a functionally immunocom-
promised state as a result of increased bone marrow turnover and altered
complement activation.5 In children, routine penicillin prophylaxis and widespread
use of the pneumococcal vaccine have decreased the incidence of bacterial infections
and sepsis. It is imperative to consider infectious complications in every ED patient
with SCD, as normal screening tools for sepsis (eg, systemic inflammatory response
syndrome) will not be as sensitive. In particular, a febrile response to infection or
leukocytosis may not manifest in SCD patients who are septic. Similar to other pa-
tients who are immunocompromised, the EP should consider both typical (eg,
398 Ready et al

pulmonary, genitourinary, skin, blood, viral) sources of infection as well as nontypical

sources, such as port/line, joint, intra-abdominal, and central nervous system. The
threshold to initiate broad-spectrum antibiotics should be lowered in both adult and
pediatric populations. Furthermore, consultation with hematology and a detailed re-
view of prior admissions is strongly encouraged to obtain more information that
may illuminate considerations for infectious etiologies needing investigation.51

Special considerations for the pediatric sickle cell disease population. About 200 chil-
dren are born each year with SCD.52 These children grow up with reduced quality of
life due to pain, psychosocial impact, and other complications from SCD.52 In the last
decade, new treatment options have allowed children with SCD to live longer; these
include the pneumococcal vaccine, antibiotic prophylaxis, hydroxyurea, and chronic
red blood cell transfusions.53,54 Despite these progressions, this population, largely
of African descent, still has a higher chance of neurologic complications and health
care use. One study noted children with SCD are 4 times more likely to experience in-
tellectual disability.52 Common SCD complications in the pediatric group include
stroke, acute chest syndrome, avascular necrosis, leg ulcers, anxiety, depression, pri-
apism, and multi-organ failure (Table 3).54
Pre-adolescence is when SCD patients often transition from episodic to chronic
pain, usually requiring opioid administration when they present to the ED.60–62 Depres-
sion, leading to poor social engagement with peers and falling behind on academics,
is another frequent presentation.63 Transfusion is often employed to treat anemia in
these patients and to help with VOC symptoms.64 In a study by Anderson and col-
leagues, the major cause of death in their pediatric patients was iron overload with
chronic organ damage.54 Consequently, all transfusions should be discussed with he-
matology in stable patients to evaluate risk and potential benefit.
It is also important to understand the impact on caregivers of children who have
SCD. The average yearly medical cost for a child with SCD is $10,000.65 Studies
have shown that parents of children with SCD are 3 times more likely to lose employ-
ment.65 Thus, it is optimal for EPs to consider the social, economical, and psycholog-
ical well-being of the patient as well as the caregivers. Social work, case management,
and mental health services may be valuable adjunctive resources in many pediatric
SCD presentations to the ED.

Management of pediatric sickle cell disease acute pain episodes. When children with
SCD present to the ED, they are frequently in severe pain, and will require prompt initi-
ation of opioids for analgesia. As mentioned in the adult section, if the pediatric patient
has an individualized treatment plan, that should be prioritized. EPs should rely on pa-
tient and caregiver reports of pain and treat aggressively, avoiding the pitfall of subjec-
tively ascertaining pain level based on laboratory values or vital signs.58,66 It is
reasonable to consider starting with morphine 0.1 mg/kg IV every 20 minutes with a
transition to maintenance dosing after 2 to 4 hours once the initial acute pain episode
has diminished in severity. EPs are at risk of under-dosing or even avoiding opioids in
pediatric patients, but research has identified morphine clearance to be almost twice
the rate compared to subjects without SCD, which provides a strong argument for
early and aggressive dosing to achieve adequate analgesia.67 Pruritus is common
with morphine administration in higher doses and can be mitigated with antihista-
mines. Pruritus is less common with hydromorphone which can be initiated at
0.015 mg/kg IV with similar dosing intervals as morphine.67
A 2020 pediatric randomized controlled trial assessed the efficacy of IV acetamin-
ophen as a means to decrease opioid requirements in acute pain episodes.66 Patients
 Sickle Cell Disease 399

Table 3
Pediatric pathology to consider in SCD

Organ System Pathology Treatment Pearls

Pulmonary  Bacterial infectious pathology Penicillin V Potassium: prevents
(especially Pneumococcus) 84% of life-threatening
 Viral infectious pathology streptococcus pneumoniae
 Acute Chest Syndrome sepsis.
Acute chest often associated with:
mycoplasma pneumoniae,
chlamydia pneumoniae, and
strep pneumoniae.12
Skin Ulcerations Leg ulcers are 10x more common
in patients with SCD as
compared to general
population.55
Genitourinary Priapism Occurs in approximately 35% of
men with SCD.56
Mean age of onset: 15 years56
Precipitated by sexual activity,
fever, or dehydration.56
Musculoskeletal  Avascular Necrosis Dactylitis is usually bilateral with
 Osteomyelitis dorsal swelling.57
 Dactylitis
Splenic  Severe anemia from splenic For sequestration crisis, expect
sequestration hypotension and the affected
 Splenic infarction organ to be enlarged and
tender.57
Most common to see between age
6 months old and 3 years.12
Renal  Acute kidney injury Hyperfiltration (GFR elevation)
 Chronic nephropathy seen in 43% of children with
SCD58
Neurologic  Stroke 11% of SCD patients experience
stroke by age 20.58
Ophthalmology Retinopathy Sickled erythrocytes occlude small
eye vessels causing ocular
lesions. Retinopathy present in
approximately 33%–40% of
sickle cell patients and can be
diagnosed during teenage
years.59

in this study who received IV acetaminophen in addition to opioids did not have clin-
ically or statistically different pain scores than those with volume equivalent normal sa-
line placebo.66 Additionally, the addition of acetaminophen did not lower admission
rates.66 Another adjunctive medication option is ketorolac (0.5 mg/kg IV); a random-
ized controlled trial demonstrated ketorolac is successful in shortening the duration
of hospitalization.68 As in adult patients with SCD, intranasal fentanyl can be effica-
cious in the short term while waiting for intravenous access. If pain is refractory and
admission is likely, consider initiating a PCA or a local regional nerve block. Nitric oxide
has very limited data in acute pain episodes in the pediatric population. Finally, keta-
mine may be used in children as an analgesic adjunctive medication.
400 Ready et al

Sickle cell disease: impact of years of bias toward this patient population. For de-
cades, one of the major barriers to health care among patients with SCD was the
stigma simply associated with that diagnosis. In the ED, patients with SCD almost
invariably will present with pain as a major feature of their encounter. In the past
few decades, the entire ED culture toward aggressive opioid pain management has
shifted dramatically and left some patients in a position where their analgesic needs
are scrutinized by ED providers, nurses, and other members of the care team. This
is especially problematic in smaller hospitals or communities where SCD is less prev-
alent. Literature in the past decade highlights how stigma may contribute to substand-
ard treatment for some patients with SCD and an acute pain episode.
In 2016, Haywood and colleagues examined ED wait times for SCD patients versus
patients with long bone fractures (LBF).69 They found that although patients with LBF
were assigned a lower emergency severity index (ESI) score at triage than SCD pa-
tients on average, patients with LBF were evaluated quicker with faster analgesia. Au-
thors also discovered that SCD patients wait longer than other patients with a similar
ESI.69
Stigmatizing language also contributes to substandard medical care and may lead
to avoiding a health care system based on interactions with just a few providers. For
example, the term “sickler” is strongly stigmatizing and can define the patient with
SCD as their disease rather than a human suffering from a chronic and disabling dis-
ease in need of health care. In a 2018 study, emergency medicine residents were
asked to read 2 fictional vignettes of a man with SCD presenting to an ED with an
acute pain episode.70 Residents were significantly less likely to use aggressive anal-
gesia and reported more negative attitudes toward this fictional patient when reading
a vignette with stigmatizing language than compared to a vignette with neutral lan-
guage.70 Some examples of stigmatizing language included phrases that cast doubt
on pain level (ie, “patient insists his pain is still a 10” vs “still has 10/10 pain”) and
phrases that suggested a patient was not cooperative (ie, “refusing to wear his oxygen
mask” vs “not tolerating the oxygen mask”).70 A powerful summary statement from the
authors is as follows: “Language used in medical records to describe patients can
directly influence subsequent physicians-in-training who read the notes, in terms of
both their attitudes toward the patient and their medication-prescribing behavior.”70

Treatment management beyond analgesia

Intravenous fluids. Providing intravenous fluids (IVF) for SCD patients who present
with an acute pain episode has been commonly employed as an adjunct to opioid
analgesia. While hypovolemia can trigger a VOC, there is potential harm in providing
IVF to SCD patients who are euvolemic or hypervolemic as it can cause fluid overload
and pulmonary edema; these can increase a patient’s length of stay and morbidity.71 A
2017 study noted that among 400 SCD patients, those who received more than or
equal to 5 mL/kg IVF given rapidly over 30 to 60 minutes were admitted at a higher
rate, had worse pain control, and had a longer length of stay in the ED.72 Additional
studies have linked excessive fluid administration to atelectasis and AChS.36,73 This
presents a dilemma for EPs who need to identify SCD patients who are hypovolemic
prior to providing IVF and then correctly determine how much fluids will return the pa-
tient to a euvolemic status. While there is no ideal method to achieve this balance, it
would be prudent to reassess SCD patients more frequently as they may only require
500 mL or 1000 mL to achieve euvolemia. Added caution should be taken in SCD pa-
tients who are determined to be septic, as most such patients may not tolerate a
30 mL/kg bolus and should instead receive smaller IVF boluses with frequent reas-
sessments to determine need and benefit of additional fluid.
 Sickle Cell Disease 401

Hydroxyurea. Starting in 2014, patients with SCD were given access to hydroxyurea
at around 9 months of age.60 Many patients who present to the ED will be on this medi-
cation. It functions by stimulating fetal hemoglobin and raising red cell mean corpus-
cular volume, with a goal of decreasing acute pain episodes.32 Patients presenting to
the hospital could also be experiencing toxicity from their medication regimen. Hy-
droxyurea has been shown to cause neutropenia, rash, gastrointestinal upset, and
hair loss.57 This drug is dosed at 20 mg/kg titrated up to tolerable dosing.12 Benefits
include decreased sickling of red blood cells and decreased vascular inflammation
with improved blood flow.12 It is not a practical option for acute ED management as
it takes time to generate a therapeutic benefit.

Blood transfusion. Packed red blood cell (PRBC) transfusions or exchange transfu-
sions are common treatment methods for splenic sequestration, AChS, stroke, aplas-
tic crisis, or kidney failure.12 However, over years, patients with SCD who have
received numerous transfusions are at high risk of iron overload with significant poten-
tial morbidity and mortality. This is in addition to the risk of alloimmunization, hyperhe-
molysis, transfusion associated cardiac overload, transfusion-associated acute lung
injury, and immune suppression. Fortunately, most patients with SCD do not require
emergent PRBC transfusion for hemorrhagic shock, and time is available for hemato-
logic consultation. Chronic transfusion therapy is now employed to decrease compli-
cations of SCD and reduce HbS to less than 30%.12 Transfusion is not indicated for
treatment of acute pain episodes.

Biologics. Biologics include L-glutamine, crizanlizumab, and voxelotor, which can be

taken on their own or in addition to hydroxyurea. L-glutamine was approved by the
Food and Drug Administration (FDA) in 2017 for those 5 years old and above, and is
dosed by weight.58 It protects blood cells from oxidative stress to reduce VOC and
AChS.58 Common side effects may include constipation, nausea, headache, cough,
and abdominal pain. Crizanlizumab was approved by the FDA in 2019 for those
16 years old and above, to help with VOC.58 Its dosing regimen is a 5 mg/kg/dose
IV initial dose that is repeated at 2 weeks before a monthly injection regimen is initi-
ated.58 Associated side-effects include nausea, back pain, fever, and arthralgias.
Finally, voxelotor is a therapy aimed at improving anemia and was approved by the
FDA for those 12 years old and above, at a dose of 1500 mg orally daily.58 Although
it works to decrease hemolysis and sickle polymerization, 20% or more of patients
experience headache or diarrhea or other less common side effects such as nausea,
abdominal pain, rash, fever and fatigue.58 Importantly, the EP should consistently ask
each patient with SCD about disease specific medications and identify biological
medications while considering whether the presentation may be associated with these
side effects. Consideration should also be given to the additional immune compromise
generated by many biological agents with the understanding this will expand the dif-
ferential diagnosis for potential infection-related presentations, including some
nontraditional pathology (eg, tuberculosis).
The next phase in optimal patient care. Sickle cell disease should be recognized as a
complex, chronic disease that has implications for patients well beyond the ED. Pa-
tients with SCD may have chronic or intermittent struggles with mental health, difficulty
with employment, endure familial stress, or have difficulty accessing primary care and
outpatient pain management services. Consequently, SCD patients may benefit from
a comprehensive care model such as a medical home where primary care, hematol-
ogy, pain management, psychological, and social support services can be addressed
under one healthcare umbrella. The medical home model has been successful in
402 Ready et al

demonstrating decreased use of the ED and decreased rate of hospitalization.73 The

medical home model will also provide more consistent development of individualized
treatment plans.

SUMMARY

With more than 100,000 people living in the United States with SCD, EPs can expect to
provide care for SCD patients in every practice setting. Despite advances in outpatient
treatment options, early mortality, chronic pain, and limitations in quality of life indices
remain substantial for those living with SCD. The ED encounter for any SCD patient is
often fraught with concern over inadequate treatment of an acute pain episode, and
the EP may experience the pitfall of diagnostic anchoring on a VOC while failing to
search for concurrent and more deadly pathology. It is imperative for EPs to under-
stand their challenging and dual obligation for every encounter when treating a patient
with SCD. The EP must first aggressively manage the acute pain episode in an objec-
tive manner and utilize the patient’s individualized treatment plan when available. Sec-
ondly, it is equally important to consider concurrent pathology that cannot be missed,
such as AChS, pulmonary embolism, sepsis, and splenic sequestration. Finally, the EP
should prioritize compassionate care that avoids reinforcing any stigma associated
with SCD, thus preventing subsequent avoidance of the ED and potential patient
harm. The Emergency Department will always be an integral facet of the SCD health
care network, and optimal management of SCD patients in the ED is an important
aspect of improved quality of life and decreased mortality in SCD patients.

CLINICS CARE POINTS

 Patients presenting with a VOC should receive early and aggressive analgesics primarily with
opioids. If the patient has an individualized care plan, that should be followed precisely.
 Fever in a patient with SCD requires a diligent search for a source and a high suspicion for
sepsis given the inherent immune compromise that is associated with SCD. Non-infectious
sources of fever such as pulmonary embolism should also be considered.
 Packed red blood cell (PRBC) transfusion in the anemic patient with SCD must be considered
carefully as repeated PRBC transfusion may lead to iron overload chronically. If
hemodynamically stable, PRBC transfusion should be discussed with the patient’s
hematologist.

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