Steroid Treatment for Sickle Cell Pain Crisis

In the United States, 9% of African Americans have sickle cell trait and 1 in 600 has sickle
cell disease. Vaso- occlusive crises in sickle cell disease remain a frequent cause of severe
pain, leading to emergency room visits, hospitalizations, and dependence upon narcotics for
analgesia. Current treatments for vaso-occlusive crises includes IV analgesia with narcotics,
NSAIDS, and hydration. Admissions can be frequent, prolonged, and can significantly diminish
quality of life.

Understanding the pathophysiology of vaso-occlusive crises helps to find possible treatments.
The etiology of vaso- occlusive crises includes HbS polymerization; sickle erythrocyte
polymerization; endothelial damage; and inflammation, reperfusion injury, and oxidant radical
production (Steinberg et al, Hematology, 2004). For example, hydroxyurea works by increasing
the amount of fetal hemoglobin (HbF) and thus inhibiting polymerization, and reduces the
incidence of pain by nearly 50%. Glucocorticoids would be expected to exert effects on the
endothelium and inflammation.

Vaso-occlusive crises share similar features with other inflammatory processes, including
clinical symptoms of swelling, erythema, and warmth; and laboratory findings of leukocytosis
and elevated ESR. It has previously been theorized that glucocorticoids, which are used in
many other inflammatory disorders, could decrease the duration or severity of vaso-occlusive
crises. Methylprednisolone is a corticosteroid which decreases inflammation by suppression of
migration of polymorphonuclear leukocytes and reversal of increased capillary permeability
(Takemoto, et al 2004). A randomized, placebo-controlled study of 2 doses of intravenous
methylprednisolone for vaso-occlusive crisis showed that the duration of severe pain and the
need for inpatient analgesia was decreased in patients who received methylprednisolone;
however the intervention patients had more rebound attacks than those who received placebo.
(Griffin et al, NEJM, 1994)

Previous studies have examined long-term administration of steroid hormones including
testosterone, progesterone, and medroxyprogesterone to patients with sickle cell disease. In
placebo-controlled crossover trials, patients who received steroids had fewer vaso-occlusive
episodes than placebo-treated patients (Isaacs et al, Lancet,1972; DeCeulaer et al, Lancet,
1982). Initial reports of glucocorticoids for vaso-occlusive crisis include an uncontrolled
report of hydrocortisone as adjunctive therapy for VOC (Araujo et al, Blood, 1990). A case
report showed efficacy of dexamethasone for vaso-occlusive crisis in children (Robinson et
al, Lancet, 1979). The mechanism of steroids effect is uncertain.

In acute chest syndrome, which shares many clinical features with vaso-occlusive crises,
intravenous therapy with dexamethasone has been shown to reduce the length of hospital stay,
prevent clinical deterioration, and reduce the need for blood transfusion (Bernini et al,
Blood, 1998).

In a placebo-controlled trial of high-does methylprednisolone for VOC, patients with severe
pain requiring hospital admission were randomized to receive methylprednisolone or placebo
(15 mg/kg to maximum 1 gram) at admission and again 24 hours later. The duration of inpatient
analgesia was significantly shorter in patients who received methylprednisolone. However,
patients who received methylprednisolone were much more likely to be readmitted shortly after
finishing therapy. In addition, the study was criticized because patients did not rate their
pain, and very few patients received patient-controlled analgesia while hospitalized.

Since this trial was published, there have been other advances in the standard management of
VOC. Ketorolac, a non-steroidal analgesic, is now a standard adjunctive therapy, and most
patients are quickly placed on patient-controlled analgesia. In addition, more patients now
receive chronic, preventative therapies such as hydroxyurea and chronic transfusions.

We are therefore interested in repeating and expanding upon the results obtained several
years ago and in evaluating the role of steroids if given over a slightly longer period of
time.

The primary objective of this study is to determine whether the use of high-dose
methylprednisolone followed by steroid taper decreases the duration of hospitalization and
severity of pain in VOC of sickle cell disease.

Primary Hypothesis: The experimental group treated with high-dose methylprednisolone and
steroid taper plus conventional therapy will have a lesser duration and and lower severity of
pain in VOC than the control group.

In addition, the secondary objectives will be:

1. to determine whether this methylprednisolone regimen will decrease the number of
inpatient admissions.

2. to examine the number and type of complications and side effects (including infection,
hypertension, and GI bleeding)

3. to determine rate of recurrent episodes of pain within one month of treatment.

4. to determine whether the amount of analgesic used will decrease during the
hospitalization.

Inclusion Criteria:

Sickle cell and acute pain Age 8 and up English or Spanish-speaking

Exclusion Criteria:

Fever greater than 101 Acute chest syndrome or pneumonia Other SS complications
(sequestration, aplastic crisis) Other explanation for pain (chronic, AVN, surgical)
History of GI bleeding, HTN, or hyperglycemia/DM