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 an improvement in pain scores using a 10-point scale.

In addition, the secondary objectives were:

1. duration of inpatient admissions
2. to examine the number and type of complications and side effects (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, as measured by the # of days in which IV opioids were given.