Vasooclusive Crisis of Sickle Cell Anemia: A New Therapy

Abstract & Commentary

Source: Orringer EP, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA 2001;286:2099-2106.

Purified poloxamer 188 (pp188) is a nonionic surfactant with properties that are thought to improve microvascular flow by reducing whole blood viscosity, erythrocyte aggregation, and adhesion to the vascular endothelium. The investigators of this randomized, double-blind, placebo-controlled trial hypothesized that PP188 would decrease the duration of acute, painful episodes in patients with sickle cell disease (SCD). At 40 medical centers, 250 patients (adults and children) with SCD who had a painful episode severe enough to require hospitalization and narcotic analgesics were enrolled in the study. Patients were randomly assigned to receive an intravenous infusion of PP188, 100 mg/kg for one hour followed by 30 mg/kg/hour for 47 hours, or a matching volume of saline placebo.

The mean duration of the painful episodes was 141.4 hours in the placebo group and 132.6 hours in the PP188 group, a nine-hour reduction (P = 0.04). Subset analyses indicated an even more pronounced PP188 effect in children ages 15 years or younger (21 hours; P = 0.01) and in patients who were receiving hydroxyurea (16 hours, P = 0.02). Secondary efficacy end points (time to discharge, pain, total analgesic use, and pharmacoeconomic costs) statistically were not different between the two treatment groups. There were no differences between the two groups in the overall incidence of adverse events, including increased risk of bleeding during PP188 treatment.

Commentary by Stephanie B. Abbuhl, MD, FACEP

This large-scale, well-executed study found a decrease in the duration of SCD painful episodes in patients treated with PP188 when compared to those who received placebo. Unfortunately, the difference, while statistically significant, was disappointingly modest (a 6.4% reduction; 5.9 vs 5.5 days) and may not be of clinical significance. The results for children and those patients receiving concurrent hydroxyurea were much more promising and deserve further investigation.

For the purposes of this study, the duration of a painful crisis was defined as the time from randomization to crisis resolution. It is interesting to note that the mean (SD) time from onset of crisis to randomization was 2.25 days (2.14) in the PP188 group and 1.87 days (1.84) in the placebo group (P = 0.12). After randomization, it took another approximately 2.2 hours for patients to receive the study drug infusion. The patients had already experienced two full days of pain at the time of initiation of study drug. Since established pain is more difficult to suppress than acute pain,1 it is possible that any physiologic improvement in microvascular blood flow might have been overshadowed by the "up-regulated" pain cycle.2 It also is possible that tissue ischemia and inflammation were so entrenched that the potential benefit from PP188 could not be optimized. There was no subset analysis based on the duration of pain before receiving the study drug.

Until there is more information from additional studies, it is unlikely that PP188 will be one of the therapies we use in the ED in the near future for acute vasoocclusive crisis. We must continue to be vigilant with sickle cell patients, relying on rapid pain assessment based on the patient’s report and prompt delivery of pain medication based on repeated pain assessments.

References

1. Carr DB, et al. Acute Pain Management: Operative or Medical Procedures and Trauma. Clinical Practice Guideline No 1. AHCPR Pub. No. 92-0032. Rockville, MD: Agency for Healthcare Policy and Research, Public Health Service, U.S. Department of Health and Human Services; 1992.

2. Ducharme J. Acute pain and pain control: State of the art. Ann Emerg Med 2000;35:592-603.

Dr. Abbuhl, Medical Director, Department of Emergency Medicine, The Hospital of the University of Pennsylvania; Associate Professor of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, is on the Editorial Board of Emergency Medicine Alert.