A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension
Robyn J. Barst, M.D., Lewis J. Rubin, M.D., Walker A. Long, M.D., Michael D. McGoon, M.D., Stuart Rich, M.D., David B. Badesch, M.D., Bertron M. Groves, M.D., Victor F. Tapson, M.D., Robert C. Bourge, M.D., Bruce H. Brundage, M.D., Spencer K. Koerner, M.D., David Langleben, M.D., Cesar A. Keller, M.D., Srinivas Murali, M.D., Barry F. Uretsky, M.D., Linda M. Clayton, Pharm.D., Maria M. Jöbsis, B.A., Shelmer D. Blackburn, B.A., Denise Shortino, M.S., James W. Crow, Ph.D., for The Primary Pulmonary Hypertension Study Group
Background Primary pulmonary hypertension is a progressive diseasefor which no treatment has been shown in a prospective, randomizedtrial to improve survival.
Methods We conducted a 12-week prospective, randomized, multicenteropen trial comparing the effects of the continuous intravenousinfusion of epoprostenol (formerly called prostacyclin) plusconventional therapy with those of conventional therapy alonein 81 patients with severe primary pulmonary hypertension (NewYork Heart Association functional class III or IV).
Results Exercise capacity was improved in the 41 patients treatedwith epoprostenol (median distance walked in six minutes, 362m at 12 weeks vs. 315 m at base line), but it decreased in the40 patients treated with conventional therapy alone (204 m at12 weeks vs. 270 m at base line; P<0.002 for the comparisonof the treatment groups). Indexes of the quality of life wereimproved only in the epoprostenol group (P<0.01).
Hemodynamics improved at 12 weeks in the epoprostenol-treatedpatients. The changes in mean pulmonary-artery pressure forthe epoprostenol and control groups were -8 percent and +3 percent,respectively (difference in mean change, -6.7 mm Hg; 95 percentconfidence interval, -10.7 to -2.6 mm Hg; P<0.002), and themean changes in pulmonary vascular resistance for the epoprostenoland control groups were -21 percent and +9 percent, respectively(difference in mean change, -4.9 mm Hg per liter per minute;95 percent confidence interval, -7.6 to -2.3 mm Hg per literper minute; P<0.001). Eight patients died during the study,all of whom had been randomly assigned to conventional therapy(P = 0.003). Serious complications included four episodes ofcatheter-related sepsis and one thrombotic event.
Conclusions As compared with conventional therapy, the continuousintravenous infusion of epoprostenol produced symptomatic andhemodynamic improvement, as well as improved survival in patientswith severe primary pulmonary hypertension.
Primary pulmonary hypertension is a disease characterized bythe progressive elevation of pulmonary-artery pressure and vascularresistance, ultimately producing right ventricular failure anddeath.1,2,3 A variety of treatments have been used, includingvasodilators,4,5,6,7 anticoagulant agents,6,8 and lung or heart–lungtransplantation,9,10,11,12,13 but none have resulted in improvedsurvival in a prospective, randomized trial.
Epoprostenol (formerly called prostacyclin or prostaglandinI2) is a potent, short-acting vasodilator and inhibitor of plateletaggregation that is produced by vascular endothelium. Short-terminfusions of epoprostenol decrease pulmonary vascular resistancein a dose-dependent manner in patients with primary pulmonaryhypertension, and this response has been used to determine whetherlong-term oral vasodilator therapy is warranted.14
In an eight-week prospective, randomized trial, the continuousintravenous infusion of epoprostenol produced hemodynamic andsymptomatic improvement.15 Patients treated with epoprostenolfor up to three years appeared to live longer than historicalcontrols from the Registry on Primary Pulmonary Hypertensionof the National Institutes of Health (NIH) who received standardtherapy.16 The objective of this study was to evaluate the effectsof the continuous infusion of epoprostenol on exercise capacity,quality of life, hemodynamics, and survival in a 12-week open-label,prospective, randomized, multicenter study of patients withsevere primary pulmonary hypertension who continued to be inNew York Heart Association (NYHA) functional class III or IVdespite conventional therapy.
Methods
After giving their informed consent, 81 patients with primarypulmonary hypertension entered the study. We established a diagnosisin all patients before they entered, using the criteria of theRegistry on Primary Pulmonary Hypertension of the NIH.1 Patientswere in NYHA functional class III or IV despite optimal medicaltherapy, which consisted of the administration of anticoagulants,oral vasodilators, diuretic agents, cardiac glycosides, andsupplemental oxygen. The primary objective was to evaluate theeffects of the continuous infusion of epoprostenol on exercisecapacity. Other major, prospectively defined objects of studywere the effects of epoprostenol on survival and its effectson the quality of life. We also evaluated the effects of epoprostenolon hemodynamics.
Sterile, lyophilized epoprostenol sodium powder, synthesizedby Upjohn (Kalamazoo, Mich.), was formulated by Wellcome ResearchLaboratories (Beckenham, Kent, United Kingdom) as flolan. Immediatelybefore administration, epoprostenol was reconstituted with sterileglycine buffer (pH 10.5) and filtered.
Right-heart catheterization was performed in all patients withthe use of standard techniques. After base-line hemodynamicvariables were measured, epoprostenol was infused at an initialrate of 2 ng per kilogram of body weight per minute, with incrementsof 2 ng per kilogram per minute every 15 minutes. The infusionwas discontinued at the dose that produced one or more of thefollowing effects: a decrease of more than 40 percent in systemicarterial pressure, an increase of more than 40 percent in heartrate, or signs or symptoms deemed sufficient to warrant discontinuationof the infusion — that is, nausea, vomiting, severe headache,lightheadedness, or severe restlessness and anxiety. The infusionwas subsequently reduced by 2 ng per kilogram per minute, andhemodynamic measurements were recorded at this maximal tolerateddose.
Randomization and Treatment
Eighty-one patients completed the short-term dose-ranging phaseof the study and entered the 12-week study. One additional patient,in whom a pneumothorax developed during the base-line cardiaccatheterization, was not enrolled in the study. A computer-generated,adaptive randomization was performed, with stratification accordingto the functional class, study center, and base-line vasodilatoruse.17 Forty-one patients were randomly assigned to receiveepoprostenol plus conventional therapy, and 40 patients wererandomly assigned to receive conventional therapy alone. Allthe patients received oral anticoagulant agents during the study,with the exception of one patient in each treatment group. Adjustmentsin concomitant medications were allowed during the study onthe basis of clinical judgment.
Venous access for the infusion of epoprostenol in the epoprostenolgroup was obtained by the insertion of a permanent catheterinto a subclavian or jugular vein. Epoprostenol was infusedcontinuously with the use of a portable infusion pump (CADD-1Model 5100 HF, Pharmacia Deltec, St. Paul, Minn.). Before beingdischarged from the hospital, patients were trained in steriletechnique, catheter care, and drug preparation and administration.Epoprostenol therapy was initiated at a dose of 4 ng per kilogramper minute below the maximal tolerated dose determined duringdose ranging. Dose adjustments during the 12-week study weremade on the basis of signs or symptoms consistent with clinicaldeterioration or the occurrence of adverse events. Hemodynamicmeasurements were repeated at the end of the study.
Exercise capacity was assessed at base line and at 1, 6, and12 weeks with the use of the unencouraged six-minute-walk test.18The patients' quality of life was evaluated at base line andat 6 and 12 weeks with the Chronic Heart Failure Questionnaire,the Nottingham Health Profile, and the Dyspnea-Fatigue Rating.19,20,21Both the walk test and the quality-of-life instruments wereadministered by personnel not directly involved in patient carewho were unaware of the treatment groups to which patients hadbeen assigned. At the completion of the study, all patientswere given the option of entering an open-label study of continuousepoprostenol therapy.
Statistical Analysis
Data are presented as means ±SE, medians, and 95 percentconfidence intervals. Six-minute-walk data were analyzed intwo intention-to-treat analyses: a nonparametric analysis ofcovariance and a parametric analysis of variance.22 In the nonparametricanalysis of covariance, patients who were unable to walk atbase line were assigned a value of 0 m. Patients who had diedor were unable to walk because of illness at week 12 were alsoassigned a value of 0 m. Patients who underwent transplantationduring the study completed the exercise test at week 12, andthe data on this test were included in the nonparametric analysisof covariance. An ordinary least-squares regression of the ranksof walking distance at week 12 was performed, with adjustmentfor covariates. The resulting residuals were analyzed with theuse of the Cochran–Mantel–Haenszel procedure.
The parametric analysis of variance evaluated the changes frombase line to week 12 in the distances walked. In this analysis,patients who died or received transplants before week 12 hadtheir last observations (or six-minute-walk values before transplantation)carried forward and used as their values at week 12.
Survival was analyzed with the use of a log-rank test and includedall the randomized patients. Survival analyses, adjusted forcovariates, were based on the Cox regression model23 and wereperformed both with data on some patients censored at transplantationand with such data not censored. For hemodynamic and quality-of-lifemeasures, we determined the change from base line and constructedtwo-sided 95 percent confidence intervals24,25 for the differencesbetween treatment groups. In the Spearman analyses of the correlationbetween the changes from base-line six-minute-walk values andlong-term hemodynamic effects, the last observation carriedforward was used for patients who died or received transplants.A P value of less than 0.05 was considered to indicate statisticalsignificance.
Results
The base-line demographic and hemodynamic characteristics ofthe two groups are shown in Table 1. There were no significantdifferences between the groups in the severity of pulmonaryhypertension, duration of illness, use of concomitant medication,or NYHA functional class. The base-line distance in the six-minutewalk was greater, though not significantly greater, in the epoprostenolgroup.
Table 1. Demographic and Hemodynamic Characteristics at Base Line, According to Treatment Group.
Effects of the Short-Term Infusion
The maximal short-term hemodynamic responses to infused epoprostenolare shown in Table 2. Only changes in stroke volume and systemicvascular resistance were significantly different in the twotreatment groups. The mean maximal tolerated dose of epoprostenolwas 9.2±0.5 ng per kilogram per minute in the group subsequentlyassigned to receive epoprostenol and 7.6±0.5 ng per kilogramper minute in the conventional-therapy group. The initial dosein the patients treated with a long-term infusion of epoprostenolwas 5.3±0.5 ng per kilogram per minute; the dose wasincreased to 9.2±0.8 ng per kilogram per minute by theend of the study.
Table 2. Short-Term Hemodynamic Effects of Epoprostenol at the Maximal Tolerated Dose during Short-Term Dose Ranging.
Exercise Capacity
Exercise capacity was evaluated by measuring the change in thedistance the patient could walk in six minutes from base lineto week 12. The nonparametric analysis of covariance, with adjustmentfor the six-minute-walk values and the use of vasodilators atbase line, showed that the median change from base line wasan increase of 31 m in the epoprostenol-treated patients (mediandistance walked, 362 m at week 12 as compared with 315 m atbase line) and a decrease of 29 m in the patients receivingconventional therapy (204 m at week 12 as compared with 270m at base line; P<0.002 for the comparison of the treatmentgroups). Exercise capacity remained significantly improved (P<0.02)in the epoprostenol-treated patients after adjustment for both(1) the hemodynamic changes in stroke volume and systemic vascularresistance that resulted from the short-term infusion of epoprostenol(the only significant differences between the treatment groups)and (2) six-minute-walk values and vasodilator use at base line.
The mean distance walked increased by 32 m in the epoprostenolgroup (mean distance walked, 348±17 m at week 12 as comparedwith 316±18 m at base line) and decreased by 15 m inthe conventional-therapy group (257±24 m at week 12 ascompared with 272±23 m at base line; P<0.003 for thecomparison of the treatment groups, as determined with a parametricanalysis of variance).
There were significant inverse correlations between the changein the distance the patient could walk in six minutes and thecorresponding changes in mean pulmonary-artery pressure, rightatrial pressure, mean systemic-artery pressure, pulmonary vascularresistance, and systemic vascular resistance from base lineto week 12. There were also significant correlations betweenthe change in the six-minute-walk value and the correspondingchanges in cardiac index and stroke volume from base line toweek 12.
Clinical and Hemodynamic Measures
The results of assessments of quality of life are shown in Table 3.Patients who received epoprostenol for 12 weeks had significantimprovements in all four parts of the Chronic Heart FailureQuestionnaire, in two of the six parts of the Nottingham HealthProfile, and in the Dyspnea-Fatigue Rating (P<0.01).
Table 3. Effects on the Quality of Life of Treatment with Epoprostenol as Compared with Conventional Therapy.
Functional class was assessed in all patients who were aliveand had not received transplants by the end of the 12-week studyperiod (40 in the epoprostenol group and 31 in the conventional-therapygroup). In the epoprostenol group, the functional class improvedin 16 patients (40 percent), worsened in 5 (13 percent), andwas unchanged in 19 (48 percent). In the conventional-therapygroup, in contrast, the functional class improved in only 1patient (3 percent), worsened in 3 (10 percent), and was unchangedin 27 (87 percent;P<0.02 for the comparison of the treatmentgroups).
The changes in the hemodynamic measures from base line to week12 are shown in Table 4. Comparisons of the treatments showedthat the epoprostenol-treated patients had significant improvementin mean pulmonary-artery pressure, cardiac index, and pulmonaryvascular resistance. The changes in mean pulmonary-artery pressurefor the epoprostenol and control groups were -8 percent and+3 percent, respectively (P<0.002), and the mean changesin pulmonary vascular resistance were -21 percent and +9 percent,respectively (P<0.001).
Table 4. Hemodynamic Effects of Epoprostenol or Conventional Therapy at 12 Weeks.
Transplantation and Survival
Three patients underwent lung transplantation during the 12-weekstudy: one epoprostenol-treated patient at 11 days and two patientstreated with conventional therapy at 63 and 68 days. All threewere alive at the end of the study. Therapy for two patientsrandomly assigned to receive epoprostenol was discontinued beforethe end of the study: in one patient, because of adverse effects(jaw pain and diarrhea), and in the other, because the patientwas unable to manage the drug-delivery system.
Eight patients died during the 12-week study; all were in theconventional-therapy group (P = 0.003) (Figure 1). Among thosewho died, there was an equal distribution of patients in NYHAfunctional classes III and IV. The six-minute-walk values atbase line were significantly lower in these 8 patients thanin the 73 survivors in both groups (195±63 m vs. 305±14m, P<0.03). There were, however, no significant differencesin base-line hemodynamic variables or short-term responses duringdose ranging between the survivors in both treatment groupsand the eight patients who died. Performance in the six-minutewalk at base line was an independent predictor of survival (P<0.05);however, survival remained significantly improved in the epoprostenolgroup after adjustment for that variable (P<0.002). Survivalalso remained significantly improved in the epoprostenol group(P<0.001) after adjustment for the changes in stroke volumeand in systemic vascular resistance in response to the short-terminfusion of epoprostenol (the only significant differences betweentreatment groups).
Figure 1. Survival among the 41 Patients Treated with epoprostenol and the 40 Patients Receiving Conventional Therapy.
Data on patients who underwent transplantation during the 12-week study were censored at the time of transplantation. Estimates were made by the Kaplan–Meier product-limit method. The two-sided P value from the log-rank test was 0.003. Survival analysis with data on patients receiving transplants not censored at transplantation resulted in the same level of significance (two-sided P = 0.003 by the log-rank test).
Complications
Minor complications related to the use of epoprostenol werefrequent and included jaw pain, diarrhea, flushing, headaches,nausea, and vomiting. Serious complications were most oftendue to the delivery system and included four episodes of nonfatal,catheter-related sepsis and one nonfatal thrombotic event (aparadoxical embolism). There were 26 episodes of malfunctionof the drug-delivery system resulting in temporary interruptionof the infusion. These included occlusions, perforations, anddislodgements of the catheter and pump malfunction. While epoprostenoltherapy was interrupted, patients experienced an increase intheir symptoms. Additional problems related to the deliverysystem included irritation or infection at the catheter sitein seven patients, bleeding at the catheter site in four, andcatheter-site pain in four.
Discussion
Since the description of the characteristic hemodynamic abnormalitiesover 40 years ago, primary pulmonary hypertension has been regardedas a progressive disease that is usually refractory to treatment.26In the present study, a randomized, controlled trial, we documentedimprovement in exercise capacity and survival in patients withsevere primary pulmonary hypertension who were treated withepoprostenol in addition to conventional therapy, as comparedwith patients treated with conventional therapy alone. The eightpatients who died had been randomly assigned to the conventional-therapygroup, and all died as a result of their underlying pulmonaryvascular disease. Even when these patients were excluded fromthe analyses of exercise-test results, exercise capacity remainedsignificantly improved in the epoprostenol-treated patientsas compared with the conventional-therapy group. In addition,hemodynamic function and exercise capacity tended to deteriorateor remain unchanged with conventional therapy, whereas it wasconsistently improved with the use of epoprostenol.
The rationale for using continuous epoprostenol infusion totreat primary pulmonary hypertension was based initially onthe demonstration that epoprostenol is a potent pulmonary vasodilatorwhen administered to laboratory animals with acute pulmonaryvasoconstriction induced by constrictor stimuli.27,28 Our results,consistent with these findings, indicate that the short-terminfusion of epoprostenol reduces pulmonary-artery pressure andpulmonary vascular resistance in patients with primary pulmonaryhypertension. However, randomization in this and in our previousstudy15 was performed independently of the short-term responsesto epoprostenol during dose ranging, and we have previouslyobserved that long-term effects are frequently seen even inthe patients in whom no short-term changes were manifested.15,16Thus, the long-term effects of epoprostenol in primary pulmonaryhypertension may be only partially related to its vasodilatorproperties and may be due, at least in part, to poorly definedeffects on vascular growth, remodeling, or platelet function.29,30,31,32Unlike the use of other vasodilators to treat pulmonary hypertension(which should be reserved for patients who have short-term pulmonaryvasoreactivity),4,6,7 the use of continuous intravenous epoprostenolmay be worth investigating in patients who continue to havesevere symptoms despite conventional therapy, even if they haveno short-term response to epoprostenol or if their conditionhas deteriorated with conventional therapy.
Several factors have been shown to determine survival in patientswith primary pulmonary hypertension, including hemodynamic variablesand functional class.2,8 Determining the status of these factorsmay be helpful when one is selecting and timing a more aggressiveapproach to treatment, such as transplantation. In this study,we found that performance in the six-minute walk at base linewas also an independent predictor of survival. Thus, assessingexercise capacity in this inexpensive and noninvasive way maybe useful in determining whether alternative treatment optionsshould be considered in individual patients.
Since epoprostenol is unstable at pH values below 10.5, it cannotbe given orally, and continuous intravenous infusion is necessarybecause of its short half-life in the circulation.33 Althoughthe delivery system for continuous infusion is complex, mostpatients were capable of learning how to prepare and infusethe drug. Only one patient was withdrawn from this study becauseof the inability to master drug delivery. Despite the cumbersomenature of treatment with epoprostenol, the patients' qualityof life was significantly improved. Thus, the complexity ofthe treatment may be offset by the overall improvement in well-beingin most patients.
Continuous intravenous epoprostenol therapy is not, however,devoid of potentially serious complications (most of which areattributable to the delivery system), including catheter-relatedinfections, thrombosis, and temporary interruption of the infusiondue to malfunction of the pump. Although these adverse eventswere not associated with death in this study, they are potentiallylife-threatening and underscore the need for an alternativemode of drug delivery.
The principal limitation of this study was that it was not adouble-blind, placebo-controlled trial. Therefore, we cannotcompletely exclude the possibility of investigator or patientbias, particularly with regard to exercise capacity. We feltwe could not design this study as a double-blind, placebo-controlledtrial because of ethical considerations based on the known incidenceof sepsis caused by central venous catheters in control patients34,35and because unique or highly predictable symptoms during long-termepoprostenol treatment — that is, jaw pain and diarrhea— prevented the blinding of physicians and patients.
The changes in stroke volume and systemic vascular resistanceduring the short-term infusion of epoprostenol were greaterin the group subsequently assigned to receive the drug, raisingthe possibility that these patients had greater vasoreactivityat base line. However, none of the hemodynamic variables thatare predictors of survival (pulmonary-artery pressure, rightatrial pressure, cardiac index, and mixed venous oxygen saturation)2,8and none of the markers of pulmonary vasoreactivity with short-termvasodilator testing (short-term changes in pulmonary-arterypressure, cardiac index, and pulmonary vascular resistance)4,6,7were different in the two groups.
An additional limitation of this study is the suggestion thatthe base-line exercise capacity of the patients randomly assignedto receive conventional therapy was slightly worse than thatof the patients assigned to receive epoprostenol. Although thesedifferences were not statistically significant, it is possiblethat the epoprostenol-treated patients may have been less impairedat base line. On the basis of our observation that exercisecapacity is an independent predictor of survival in patientswith primary pulmonary hypertension, future trials should includerandomization based on performance in the six-minute walk atbase line in addition to other known predictors of survival.
In conclusion, the continuous intravenous infusion of epoprostenolplus conventional therapy for primary pulmonary hypertensionresulted in better hemodynamics, exercise endurance, qualityof life, and survival than conventional therapy alone. Althoughwe did not address the long-term effects of therapy, our previousstudy suggests that the beneficial effects of epoprostenol onhemodynamics and exercise capacity persist with long-term therapy.16When epoprostenol is used as a bridge to transplantation, stabilizingthe patient's hemodynamics could lower perioperative rates ofmorbidity and mortality. The continuous intravenous infusionof epoprostenol may be useful in the management of severe primarypulmonary hypertension when it is refractory to conventionalmedical therapy.
Supported in part by Burroughs Wellcome, Research Triangle Park,N.C. Dr. Rubin is the recipient of an academic award in vasculardisease from the National Heart, Lung, and Blood Institute.Dr. Badesch is the recipient of a clinical investigator awardfrom the National Institutes of Health.
We are indebted to the study coordinators and pharmacists whoparticipated in this trial for their technical assistance.
* The members of the Primary Pulmonary Hypertension Study Groupare listed in the Appendix.
Source Information
From the Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York (R.J.B.); the Department of Medicine, University of Maryland, Baltimore (L.J.R.); the Department of Pediatrics, University of North Carolina, Chapel Hill (W.A.L.); the Department of Medicine, Mayo Medical Center, Rochester, Minn. (M.D.M.); the Department of Medicine, University of Illinois at Chicago (S.R.); the Department of Medicine, University of Colorado Health Sciences Center, Denver (D.B.B., B.M.G.); the Department of Medicine, Duke University Medical Center, Durham, N.C. (V.F.T.); the Department of Medicine, University of Alabama, Birmingham (R.C.B.); the Department of Medicine, Harbor–UCLA Medical Center, Torrance, Calif. (B.H.B.); the Department of Medicine, Cedars–Sinai Medical Center, Los Angeles (S.K.K.); the Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal (D.L.); the Department of Medicine, Baylor College of Medicine, Houston (C.A.K.); the Department of Medicine, Presbyterian–University Hospital, University of Pittsburgh, Pittsburgh (S.M., B.F.U.); and the Medical Division, Burroughs Wellcome, Research Triangle Park, N.C. (L.M.C., M.M.J., S.D.B., D.S., J.W.C.).
Address reprint requests to Dr. Barst at the Division of Pediatric Cardiology, Department of Pediatrics, BH 262N, Columbia University College of Physicians and Surgeons, 3959 Broadway, New York, NY 10032.
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Appendix
Other participants in the North American Primary Pulmonary HypertensionStudy included E. Horn and J. Kirkpatrick, Columbia–PresbyterianMedical Center, New York; K. Wynne, University of Colorado HealthSciences Center, Denver; W. Knight, University of Alabama MedicalCenter, Birmingham; D. Georgiou and J. Beckman, Harbor–UCLAMedical Center, Torrance, Calif.; W.R. Clarke, D. Ralph, andP. Schrader, Children's Hospital and University Hospital, Universityof Washington, Seattle; E.J. Caldwell, W. Williams, and B. Vogel,Maine Medical Center, Portland; N.A. Ettinger and D. Canfield,Barnes Hospital, Washington University, St. Louis; N.S. Hilland C. Carlisle, Rhode Island Hospital, Providence; A. Hinderliterand P.W. Willis IV, University of North Carolina Hospitals,Chapel Hill; A.E. Frost and K. Chafizedah, Methodist Hospital,Baylor College of Medicine, Houston; D. Ross and D. Claire,Cedars–Sinai Medical Center, Los Angeles; E. Shalit, SirMortimer B. Davis Jewish General Hospital, McGill University,Montreal; B. Edwards, C. Severson, and K. Kosberg, Mayo MedicalCenter, Rochester, Minn.; T. Tokarczyk, Presbyterian–UniversityHospital, University of Pittsburgh, Pittsburgh; L. Kaufman,University of Illinois at Chicago; L. Hartle, University ofMaryland School of Medicine, Baltimore; W.R. Summer, B. deBoisblanc,and B. Everett, Charity Hospital, Louisiana State UniversityMedical Center, New Orleans; and A. Krichman, Duke UniversityMedical Center, Durham, N.C.
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