Walker Long

A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension

BACKGROUND Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. METHODS We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). RESULTS Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; 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 of catheter-related sepsis and one thrombotic event. CONCLUSIONS As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension

OBJECTIVES The aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH). BACKGROUND Primary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized. METHODS Echocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone. RESULTS During the mean follow-up period of 36.9 +/- 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis. CONCLUSIONS Pericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation.

Treatment of Primary Pulmonary Hypertension with Continuous Intravenous Prostacyclin (Epoprostenol): Results of a Randomized Trial

STUDY OBJECTIVE To determine the efficacy of continuous intravenous infusion of prostacyclin (epoprostenol) in primary pulmonary hypertension. DESIGN Randomized trial with 8-week treatment periods and nonrandomized treatment for up to 18 months. SETTING Four referral centers. PATIENTS Sequential sample of 24 patients with primary pulmonary hypertension. Nineteen patients completed the study. Four patients died and one left the study because of adverse effects (pulmonary edema). INTERVENTIONS Continuous intravenous prostacyclin administered by portable infusion pump at doses determined by acute responses during baseline catheterization in ten patients. Nine patients were treated with anticoagulants, oral vasodilators, and diuretics. MEASUREMENTS AND MAIN RESULTS Starting with a baseline value for total pulmonary resistance of 21.6 units, there was a decrease of 7.9 units (95% CI, -13.1 to -2.2; P = 0.022) in the prostacyclin-treated group after 8 weeks; there was virtually no change in the conventional therapy group (from 20.6 to 20.4 units, not significant). Six of ten prostacyclin-treated patients who completed the 8-week study period had reductions in mean pulmonary artery pressure of greater than 10 mm Hg, whereas only one of nine in the conventional treatment group had a similar response (P = 0.057). Nine patients receiving prostacyclin for up to 18 months have persistent hemodynamic effects, although dose requirements have increased with time. Complications have been attributable to the drug delivery system. CONCLUSIONS Prostacyclin produces substantial and sustained hemodynamic and symptomatic responses in severe primary pulmonary hypertension and may be useful in the management of some patients with this disease.

Aerosolized Surfactant in Adults with Sepsis-Induced Acute Respiratory Distress Syndrome

BACKGROUND Patients with acute respiratory distress syndrome (ARDS) have a deficiency of surfactant. Surfactant replacement improves physiologic function in such patients, and preliminary data suggest that it may improve survival. METHODS We conducted a prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 725 patients with sepsis-induced ARDS. Patients were stratified according to the risk of death at base line (indicated by their score on the Acute Physiological and Chronic Health Evaluation [APACHE III] index) and randomly assigned to receive either continuously administered synthetic surfactant (13.5 mg of dipalmitoylphosphatidylcholine per milliliter, 364 patients) or placebo (o.45 percent saline; 361 patients) in aerosolized form for up to five days. RESULTS The demographic and physiologic characteristics of the two treatment groups were similar at base line. The mean (+/- SD) age was 50 +/- 17 years in the surfactant group and 53 +/- 18 years in the placebo group, and the mean APACHE III scores at randomization were 70.4 +/- 25 and 70.5 +/- 25, respectively. Hemodynamic measures, measures of oxygenation, duration of mechanical ventilation, and length of stay in intensive care unit did not differ significantly in the two groups. Survival at 30 days was 60 percent for both groups. Survival was similar in the groups when analyzed according to APACHE III score, cause of death, time of onset and severity of ARDS, presence or absence of documented sepsis, underlying disease, whether or not there was a do-not-resuscitate order, and medical center. Increased secretions were significantly more frequent in the surfactant group; the rates of other complications were similar in the two groups. CONCLUSIONS The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function.

Survival in Primary Pulmonary Hypertension with Long-Term Continuous Intravenous Prostacyclin

Primary pulmonary hypertension is characterized by a progressive elevation in pulmonary arterial pressure that eventually leads to right ventricular failure and death [1-3]. The median survival of patients who were prospectively entered into the National Institutes of Health (NIH) Registry on Primary Pulmonary Hypertension was 2.8 years after diagnosis [4]. No known cure exists for primary pulmonary hypertension; however, treatment for this disease has improved substantially over the past decade. Medical approaches include therapy with vasodilators [5-12], anticoagulant agents [13], inotropic agents [7], and diuretic agents and oxygen [14]. Nevertheless, some patients are refractory to medical therapy and require transplantation (heart and lung, single lung, and bilateral lung) [15-17]. In these patients with severe pulmonary vascular disease, the waiting time for transplantation may exceed their expected survival. Prostacyclin is a potent, short-acting vasodilator and inhibitor of platelet aggregation that is produced by the vascular endothelium. Prostacyclin decreases pulmonary vascular resistance and increases cardiac output and systemic oxygen delivery when acutely administered to patients with primary pulmonary hypertension [18]. We have previously reported that at the end of an 8-week randomized study, patients treated with prostacyclin had increased exercise capacity and improved hemodynamics compared with those who received conventional therapy [19]. The objective of this study was to evaluate the effects of long-term intravenous infusion of prostacyclin on exercise capacity, hemodynamics, and survival in patients with primary pulmonary hypertension. Methods In a previous 8-week randomized study [19], 11 of 25 patients were randomly assigned to receive prostacyclin plus conventional therapy, and 14 of the 25 patients were randomly assigned to receive conventional therapy alone. At the completion of the 8-week study, all survivors were eligible to enter this open, multicenter, uncontrolled trial of long-term intravenous infusion of prostacyclin regardless of their baseline hemodynamic response to prostacyclin or the treatment group to which they were initially assigned. The clinical diagnosis of primary pulmonary hypertension was established in all patients before entry on the basis of the criteria of the NIH Registry [3]. Thromboembolic disease was excluded on clinical grounds by perfusion lung scanning, or, when this was inconclusive, by pulmonary angiography. Patients with associated conditions such as portal hypertension, human immunodeficiency virus infection, collagen vascular diseases, and pulmonary vasculitides were excluded from this study. Sterile, lyophilized prostacyclin sodium powder (Flolan, epoprostenol sodium), synthesized by the Upjohn Co. (Kalamazoo, Michigan) and formulated by the Wellcome Research Laboratories (Beckenham, Kent, United Kingdom), was refrigerated until use. Immediately before administration, prostacyclin was reconstituted with a sterile buffer (pH, 10.5) at a concentration of 5 mg/mL and was filtered. All patients were treated with warfarin. Hemodynamic measurements were obtained by catheterization of the right side of the heart using standard techniques. After baseline hemodynamic measurements were obtained, an intravenous infusion of prostacyclin was begun at a rate of 2 ng/kg of body weight per minute and increased by increments of 2 ng/kg per minute every 10 to 15 minutes. Hemodynamic measurements were repeated at the end of the infusion of each dose. The acute infusion dose was not further increased when one or more of the following occurred: a greater than 40% decrease in systemic arterial pressure, a greater than 40% increase in heart rate, or symptoms such as nausea, vomiting, or severe headache. After the acute dose-ranging study, the dose of prostacyclin was decreased to a dose that did not result in any adverse effects. The long-term infusion dose was adjusted based on results of the most recently completed dose-ranging study or clinical needs of the patient. Patients were allowed to continue prostacyclin therapy until transplantation or death. Six-minute walk tests were done to assess exercise capacity [19]. Tests were carried out before long-term prostacyclin therapy was initiated and after 6, 12, and 18 months of long-term therapy. Venous access for the infusion of prostacyclin was obtained by inserting a permanent intravenous catheter into a jugular or subclavian vein and tunneling subcutaneously. Prostacyclin was infused continuously through a portable pump (Autosyringe AS2F, Travenol Inc., Hooksett, New Hampshire or CADD-1 Model 5100 HF, Pharmacia Deltec Inc., St. Paul, Minnesota). Before hospital discharge, patients were thoroughly trained in catheter care, sterile technique, and drug preparation and administration. Safety was monitored by physical examination, routine hematologic and chemical profiles, electrocardiograms, and adverse experience assessments. The prostacyclin doses and hemodynamic and exercise data are presented as the mean SD. Changes in exercise capacity and hemodynamics were analyzed using the Wilcoxon signed-rank test for paired data [20]. Survival analysis was done using a proportional hazards regression model [21] that models survival time against group (the 17 NYHA class III and IV patients treated with prostacyclin compared with the 31 NYHA class III and IV patients [historical controls] who were treated with anticoagulant agents). The model stratifies patients according to transplantation status and NYHA class and controls through a confounder score for baseline mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. These three hemodynamic variables have been shown to be associated with survival in patients with primary pulmonary hypertension [4], and the particular covariate used here as a confounder score is the predicted survival at 1 year, which is a function of the three hemodynamic variables mentioned above. Patients were censored at the time of transplantation. We constructed Kaplan-Meier curves for the patients treated with prostacyclin and for the historical controls [22]. A two-sided P value of 0.05 was considered statistically significant. The Equation developed from the NIH Primary Pulmonary Hypertension Registry [4] was used to predict survival for the patients treated with prostacyclin as well as for the historical controls. The formula P(t) = H(t) A(x,y,z) H(t) = 0.88 0.14 t + 0.01t2 A(x,y,x) = e(0.007325x + 0.0526y 0.3275 z) where x = mean pulmonary artery pressure; y = mean right-atrial pressure; z = cardiac index; and t = 1, 2, or 3 years, estimates a patients chances for survival (P[t]) at 1, 2, and 3 years given the values of the patients three hemodynamic variables: mean pulmonary artery pressure, mean right-atrial pressure, and cardiac index. Results Patients Eighteen patients with primary pulmonary hypertension (17 adults and 1 child) were entered into this long-term study after informed consent was obtained. From the 25 patients enrolled in the preceding 8-week randomized study [19], the 10 surviving patients already receiving prostacyclin plus conventional therapy and 8 of the 11 survivors from the group receiving conventional therapy alone elected to enter this long-term study. The clinical and demographic characteristics are shown in Table 1. The mean age was 35.9 13.4 years. Twelve patients were female and 6 patients were male. Seventeen of the 18 patients were NYHA class III or IV despite conventional therapy, which consisted of vasodilators, oxygen, diuretic agents, cardiac glycosides, and anticoagulant agents as deemed necessary. Six patients were receiving oral vasodilator agents before entering this study, and 5 of these patients continued this therapy. Table 1. Clinical Characteristics and Baseline Hemodynamics Treatment Regimen Before long-term treatment with continuous intravenous prostacyclin was started and during the baseline acute dose-ranging study, the range of maximal tolerated doses of prostacyclin for the 18 patients was 4 to 22 ng/kg per minute. After the acute dose-ranging study, the dose of prostacyclin was decreased until it did not result in any adverse effects. The initial dose of the long-term prostacyclin infusion ranged from 2 to 8 ng/kg per minute (mean, 6.9 3.0 ng/kg per minute). Sixteen patients had repeat hemodynamic evaluation and dose-ranging study after 6 months of therapy, and the hemodynamics of 14 patients were re-evaluated at 12 months. Three patients had transplantation at 6, 10, and 12 months, respectively, before repeat hemodynamic measurements were obtained. One patient declined catheterization at 12 months. One patient had catheterization at 12 months but not at 6 months. The mean dose of long-term prostacyclin was 17.6 11.2 ng/kg per minute (n = 14) at 1 year, 36.7 21.2 ng/kg per minute (n = 11) at 2 years, and 52.9 30.2 ng/kg per minute (n = 7) at 3 years. Exercise Capacity Exercise endurance evaluated on the basis of the 6-minute walk test is shown in Figure 1. At 6 and 18 months, patients could walk, on average, more than 100 meters farther than they could before prostacyclin therapy was started. The length of the 6-minute walk increased from 264 160 meters at baseline to 370 119 meters at 6 months, 348 142 meters at 12 months, and 408 138 meters at 18 months (P < 0.001 at 6 months and P = 0.02 at 18 months compared with baseline). Figure 1. Effect of prostacyclin on exercise capacity. P P Hemodynamics Mean hemodynamic measurements at baseline (n = 18), 6 months (n = 16), and 12 months (n = 14) are shown in Table 2. In the patients who had follow-up cardiac catheterization at 6 months, the cardiac index increased 18% (CI, 0.1% to 36.7%), mean pulmonary artery pressure decreased 9% (CI, 1.4% to 15.7%), and total pulmonary resistance improved 26% (CI, 6.1% to 46.3%). Among patients re-evaluated at 12 months, a 27% increase remain

Effects of Long-term Infusion of Prostacyclin (Epoprostenol) on Echocardiographic Measures of Right Ventricular Structure and Function in Primary Pulmonary Hypertension

Background Right heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationships of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy. Methods and Results The 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n=41) or conventional therapy alone (n=40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricul...

Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: A multicenter controlled trial

To determine whether a single prophylactic dose of synthetic surfactant would reduce mortality and morbidity rates, we performed a randomized, controlled trial of Exosurf Neonatal at 19 hospitals in the United States. The Exosurf preparation (5 ml/kg) was instilled into the endotracheal tube of premature infants weighing 700 to 1100 gm during mechanical ventilation, as soon as practical after birth. Control infants were treated with air (5 ml/kg). Dose administration was performed in secrecy by clinicians who did not reveal for 2 years what they had instilled. A total of 222 infants received air and 224 received the synthetic surfactant; 36 infants with congenital pneumonia or malformations were excluded from the primary efficacy analysis. By the age of 28 days, there were 44 deaths in the air group and 27 deaths in the surfactant group (p = 0.022). By the age of 1 year after term there were 61 deaths in the air group and 35 deaths in the surfactant group (p = 0.002). Although there was no reduction in the incidence of respiratory distress syndrome, a significant reduction in the number of deaths attributed to respiratory distress syndrome, a significant reduction in the incidence of pulmonary air leaks, and significantly lower requirements for oxygen and mean airway pressure indicated that lung disease was less severe in the Exosurf-treated infants. There were no significant differences in the incidence of complications such as bronchopulmonary dysplasia, intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, and infection. The results indicate that a single prophylactic dose of Exosurf, in high-risk premature infants treated soon after birth, reduces the number of deaths from respiratory distress syndrome and the overall mortality rate.

Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700- to 1350-gram infants with respiratory distress syndrome

In a multicenter, double-blind, placebo-controlled rescue trial conducted at 21 American hospitals, two 5 ml/kg doses of a synthetic surfactant (Exosurf Neonatal) or air were administered to 419 infants weighing 700 to 1350 gm who had respiratory distress syndrome and an arterial/alveolar oxygen pressure ratio less than 0.22. The first dose was given between 2 and 24 hours of age; the second dose was given 12 hours later to those infants remaining on ventilatory support. Infants were stratified at entry by birth weight and gender. Among infants receiving synthetic surfactant, improvements in alveolar-arterial oxygen pressure gradient, arterial/alveolar oxygen pressure ratio, and oxygen and ventilator needs through 7 days of age were apparent. Death from respiratory distress syndrome was reduced by two thirds (21 vs 7; p = 0.007), and the overall neonatal mortality rate was reduced by half (50 vs 23; p = 0.001). Although there was no significant reduction in the incidence of bronchopulmonary dysplasia (39 vs 31; p = 0.107), the hypothesis that survival through 28 days without bronchopulmonary dysplasia would be enhanced by two rescue doses of synthetic surfactant was proved true (21% improvement, from 132 to 156 patients; p = 0.001). In addition, the incidence of pneumothorax was reduced by one third (62 vs 40; p = 0.022), and the incidence of pulmonary interstitial emphysema was reduced by half (102 vs 51; p = 0.001). The only side effect identified was an increase in the incidence of apnea (102 vs 134; p = 0.001). These findings indicate that rescue use of a synthetic surfactant can improve the morbidity and mortality rates for premature infants with respiratory distress syndrome.

A Controlled Trial of Synthetic Surfactant in Infants Weighing 1250 G or More with Respiratory Distress Syndrome

Background Surfactant-replacement therapy is now recognized as a life-saving and safe intervention in small premature infants, but there is little evidence concerning its risks and benefits in larger premature infants. Methods We conducted a placebo-controlled, blinded trial in 1237 infants with respiratory distress who were enrolled at 23 hospitals in the United States and 13 hospitals in Canada. At entry all the infants weighed at least 1250 g, were receiving mechanical ventilation, and had a ratio of arterial to alveolar oxygen tension below 0.22. The initial dose of either the synthetic surfactant (Exosurf, 5 ml per kilogram of body weight) or air (the placebo) was administered less than 24 hours after birth, with a second dose given 12 hours later. A total of 614 infants were assigned to receive surfactant, and 623 to receive placebo. Results Fewer infants in the surfactant group than in the placebo group died before 28 days of age or survived at 28 days with bronchopulmonary dysplasia (7 percent vs. 12 percent, P = 0.002). In the first 28 days of life, there were fewer deaths due to respiratory distress syndrome in the surfactant group (1 percent vs. 3 percent, P = 0.043), lower overall neonatal mortality (4 percent vs. 7 percent, P = 0.04), and a lower incidence of bronchopulmonary dysplasia (3 percent vs. 6 percent, P = 0.008). There was also a significantly lower incidence of pulmonary air leaks, intraventricular hemorrhage, patent ductus arteriosus, seizures, hypotension, and pulmonary hypertension in the surfactant group. The infants treated with surfactant were weaned from oxygen and mechanical ventilation significantly sooner than those given placebo, and they less often required high-frequency ventilation or extracorporeal membrane oxygenation. The primary side effect observed more frequently among the infants who received surfactant treatment was pulmonary hemorrhage (six infants vs. one infant, P = 0.055). Conclusions In infants weighing at least 1250 g at birth who have respiratory distress syndrome, treatment with two doses of synthetic surfactant improves survival and reduces perinatal morbidity.

Improved outcome at 28 days of age for very low birth weight infants treated with a single dose of a synthetic surfactant

Two identical double-blind, controlled, randomized trials were initiated to determine whether the administration of a single 5 ml/kg dose of a synthetic surfactant (Exosurf Neonatal), soon after the delivery of infants with birth weights 700 to 1350 gm, would improve rates of survival without bronchopulmonary dysplasia. Both trials were terminated before enrolling their planned sample sizes because of the availability of Exosurf under the provisions of a Treatment Investigational New Drug program. We report the combined results of these trials. Study infants were stratified according to birth weight and gender before random assignment to a treatment regimen. One hundred ninety-two infants received Exosurf and 193 received an air placebo. The study groups were similar when a variety of demographic features describing the mothers, their pregnancies, the circumstances of the births, and the infants were compared. Exosurf-treated infants required significantly less oxygen and respiratory support during the first 3 days of life in comparison with the air-treated infants. Fewer infants in the Exosurf group had pulmonary interstitial emphysema (26 vs 13; p = 0.028). In the Exosurf group, there was a significant reduction in the combined outcome, neonatal death or survival with bronchopulmonary dysplasia (57 vs 39; p = 0.042), and there was a significant increase in rates of survival without this disease (128 vs 137; p = 0.042). There were no differences between treatment groups in the incidences of a variety of complications of prematurity, including apnea, patent ductus arteriosus, intraventricular hemorrhage, and necrotizing enterocolitis. We conclude that improvements in respiratory physiology after a single prophylactic dose of Exosurf result in an increased likelihood of neonatal survival without bronchopulmonary dysplasia.