(Circulation. 1996;94:1316-1324.)
© 1996 American Heart Association, Inc.
Articles |
Placebo-Controlled, Randomized, Double-Blind Study of Intravenous Enalaprilat Efficacy and Safety in Acute Cardiogenic Pulmonary Edema
the Service de Reanimation Medicale (Universite Paris V), Hopital Raymond Poincare, Garches, France (D.A., P.G.); Laboratoire de Pharmacologie Clinique (Universite Rennes I), Faculte de Medecine, Rennes, France (E.B.); Service de Pharmacologie Clinique (Universite Paris XI), Hopital de Bicetre, Le Kremlin Bicetre, France (E.P., J.-F.G.); Service de Medecine I (Universite Paris V), Hopital Broussais, Paris, France (R.A., M.S.); Laboratoires Merck Sharp & Dohme-Chibret, Paris, France (F.L., O.M.); and SAMU 92, Hopital Raymond Poincare, Garches, France (E.L.).
Correspondence to Djillali Annane, MD, Service de Reanimation Medicale, Hopital Raymond Poincare, 104 Boulevard Raymond Poincare, 92380 Garches, France.
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Abstract |
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Background Converting enzyme inhibitors meet most of the criteria required to be used in acute pulmonary edema. However, they could also induce deleterious effects on renal function and electrolytes. The purpose of this study was to evaluate the efficacy and safety of a single intravenous 2-hour infusion of enalaprilat (1 mg) after an acute pulmonary edema.
Methods and Results This was a placebo-controlled, randomized, double-blind study performed in 20 congestive heart failure patients (New York Heart Association class III or IV). Systemic and regional hemodynamic parameters, biological parameters, and blood gases were measured before and repeatedly after the onset of infusion. Compared with placebo, enalaprilat decreased pulmonary capillary wedge pressure (-37% versus -10%, P=.001), diastolic and mean systemic blood pressures (-21% versus 0%, P=.009, and -18% versus -1%, P=.026, respectively), diastolic and mean pulmonary blood pressures (-21% versus -8%, P=.040; -18% versus -9%, P=.046), and brachial and renal resistances (-44% versus -14%, P=.017, and -22% versus -2%, P=.014, respectively); increased brachial and renal blood flows (+77% versus +8%, P=.036, and +12% versus 0%, P=.043, respectively), arterial oxygen tension (+2% versus -16%, P=.041), and arterial oxygen saturation (+1% versus -2%, P=.045); and tended to decrease rate-pressure product (-19% versus -7%, P=.076), increase brachial artery diameter (+13% versus 0%, P=.081), and improve intrapulmonary shunt (-18% versus +16%, P=.080). Enalaprilat did not affect cardiac output or carotid or hepatosplanchnic hemodynamics.
Conclusions Early administration of enalaprilat is effective and well tolerated in acute pulmonary edema.
Key Words: heart failure • drugs • hemodynamics • pharmacology • regional blood flow
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Introduction |
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The use of ACE inhibitors has grown, and they are now established therapy in hypertension1 and congestive heart failure.2 There is strong evidence that ACE inhibitors reduce mortality in end-stage heart failure3 as well as in less seriously ill patients.4 5 There is similarly strong evidence that ACE inhibitors improve survival of patients with left ventricular dysfunction after acute myocardial infarction.6
Acute cardiogenic pulmonary edema is the most frequent reason for admission of congestive heart failure patients to the intensive care unit. Because patients are hemodynamically unstable and have a high renin state during such episodes,7 the clinician usually stops ACE inhibitors temporarily to avoid deleterious effects on renal function and electrolytes. However, ACE inhibitors have immediate alleviating effects on both increased preload and afterload without unfavorable effects on myocardial oxygenation,8 and they improve myocardial energy balance.9 Several reports indicate that oral or intravenous ACE inhibitors may relieve pulmonary congestion and maintain both cardiac function and arterial oxygenation in the postinfarct period.10 11 Recently, similar findings have been shown12 in critically ill patients with acute intractable heart failure after myocardial infarction. Thus, if ACE inhibitors meet most of the criteria for a drug devoted to the treatment of cardiogenic pulmonary edema in theory, their efficacy and safety in this acute context remain to be evaluated in practice. Therefore, we decided to investigate the effects of early administration of intravenous enalaprilat on systemic hemodynamics, regional hemodynamics (of the brachial, carotid, renal, and hepatosplanchnic territories), the major hormones that regulate the cardiovascular system, plasma and urinary electrolytes, and arterial and venous oxygenation parameters during an acute cardiogenic pulmonary edema unrelated to acute myocardial infarction. We chose the intravenous form of enalapril to ensure a complete disposition of the drug and thus to optimize treatment.
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Methods |
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This was a placebo-controlled, randomized, double-blind study performed on two groups of congestive heart failure patients who received a single intravenous 2-hour infusion of either enalaprilat (1 mg) or placebo.
The study protocol was approved by our hospital ethics committee. Informed written consent was obtained from all patients.
Selection of Patients
The aim of the recruitment process was to enroll congestive heart failure patients with acute cardiogenic pulmonary edema. To ensure uniform management of these patients, selection was based on a two-stage procedure.
First, patients above the legal age of consent were preincluded if they fulfilled all of the following criteria: (1) mild to severe congestive heart failure (NYHA class III or IV), (2) acute cardiogenic pulmonary edema (respiratory rate >30 breaths per minute, bilateral lung rales, bilateral alveolointerstitial syndrome on chest roentgenogram, arterial oxygen tension <80 mm Hg at room air, and PCWP >25 mm Hg), (3) SBP >80 mm Hg, and (4) plasma creatinine <180 µmol/L. Patients were excluded if they met one of the following criteria: (1) need for mechanical ventilation, (2) evidence of recent (<3 months) myocardial infarction or unstable angina pectoris, (3) evidence of severe stenotic valve disease, (4) evidence of active infection or hematological or hepatic disorders, (5) known history of cancer or AIDS, (6) treatment with ACE inhibitors during the 2 weeks preceding the pulmonary edema episode, or (7) previous digoxin treatment.
All patients who were determined to be eligible for preinclusion then received a standardized intravenous treatment that included a single furosemide dose, isosorbide dinitrate, and if needed, dobutamine, with oxygen supplementation through a face mask at FIO2=0.40. All other treatments except amiodarone were stopped. This first period lasted at least 6 hours, did not exceed 12 hours, and was ended by the search for inclusion criteria.
We then reviewed eligible patients for the following inclusion criteria: (1) substantial improvement as a result of the initial treatment (respiratory rate <25 breaths per minute, substantial regression of lung rales, arterial oxygen tension >80 mm Hg at FIO2=0.40, and PCWP <25 mm Hg), (2) SBP always >80 mm Hg, and (3) provision of informed, written consent.
Treatments
Two indistinguishable formulations, containing either enalaprilat or placebo, were supplied for the study by Merck Sharp & Dohme-Chibret Laboratories (Paris, France). Placebo formulations were presented as vials of 2.5 mL sodium chloride 0.9%. Enalaprilat formulations were presented as identical vials of 2.5 mL sodium chloride 0.9% that contained 2.5 mg enalaprilat (1 mg/mL). The treatment (enalaprilat 1 mg or placebo) was administered intravenously (infusion of 100 mL of sodium chloride 0.9%) in the antecubital fossa of the left arm. The infusion was performed over a 2-hour period with an electric pump.
Investigated Parameters
Systemic and Pulmonary Hemodynamics
SBP and DBP were measured by use of a brachial sphygmomanometer. HR was determined from RR intervals from lead II of the ECG. Systolic and diastolic pulmonary blood pressures, RAP, and PCWP were measured by use of a flow-directed thermodilution pulmonary artery catheter (Baxter Healthcare Corp, Edwards Division) introduced via the right internal jugular vein and connected to a monitor (Hewlett Packard 78353B fitted to a 78342A multichannel recorder). We determined CO by thermodilution technique using a CO computer (Baxter COM-2TM, Edwards Division).
The following parameters were calculated by use of standard formulas: MBP and pulmonary blood pressures, rate-pressure product, CI, SVI, and systemic and pulmonary vascular resistance indexes.
These parameters were recorded or calculated at baseline and 2, 4, and 8 hours after onset of infusion. For each measured parameter, the final value was the mean of five consecutive measurements.
Regional Hemodynamics
Brachial and carotid artery diameters, BBF, and CBF were measured by use of two-dimensional pulsed Doppler (Echovar Doppler pulse 8 MHz, Alvar Electronics) as previously described and validated in hypertensive patients13 and as widely used in healthy volunteers14 15 and congestive heart failure patients.16 17 BVR and CVR and the corresponding regional distribution ratios (%) were calculated as BVR=MBPx60/BBF, CVR=MBPx60/CBF, BBF/CO, and CBF/CO.
Plasma renal flow was determined from the para-aminohippuric acid clearance,18 and RBF was calculated as RBF=Plasma Renal Flow(1-hematocrit). Plasma hepatosplanchnic flow was determined from indocyanine green clearance,19 and HBF was calculated as HBF=Plasma Hepatosplanchnic Flow(1-hematocrit). Renal and hepatosplanchnic vascular resistances and the corresponding regional distribution ratios (%) were calculated as Renal Vascular Resistance=(MBP-RAP)x60/RBF, Hepatosplanchnic Vascular Resistance=(MBP-RAP)x60/HBF, RBF/CO, and HBF/CO.
These parameters were recorded or calculated at baseline and 4 hours after the onset of infusion.
Hormonal Parameters
Plasma ACE activity was measured by use of a spectrophotometric method.20 Plasma renin activity, aldosterone, antidiuretic hormone, and, after extraction, ANF were determined by use of radioimmunoassays.21 22 23 24 Finally, plasma norepinephrine and epinephrine were measured by high-performance liquid chromatography.25
These parameters were recorded at baseline and 4 and 8 hours after the onset of infusion.
Blood Gas Parameters
Arterial and mixed venous oxygen tensions (PaO2 and P
2) and saturations (SaO2 and S2) were measured by use of standard techniques. The following derived oxygenation variables were calculated by use of standard formulas: arterial and mixed venous oxygen content (CaO2 and C2), arteriovenous oxygen difference (mL/L), DO2, 
O2, EO2, and Qs/Qt.
These parameters were recorded or calculated at baseline and 2, 4, and 8 hours after the onset of infusion.
Safety Evaluation
SBP, DBP, and HR were monitored every 10 minutes during the first 2 hours of treatment infusion and then hourly until the end of the study. Serum concentrations of sodium, potassium, nitrogen, and creatinine were determined at baseline and 4 and 8 hours later. Urine volume and concentrations of sodium, potassium, nitrogen, and creatinine were determined during the corresponding time intervals from 4 hours before the onset of infusion to 8 hours afterward. Urine output and clearances during the corresponding time intervals were calculated by use of standard formulas.
Study Protocol
The study comprised three consecutive periods. The first period, the duration of which was between 6 and 12 hours, allowed us to establish the diagnosis of cardiogenic pulmonary edema, carry out a standardized treatment, and assess each patient's response to that treatment. This first period, which began with the search for preinclusion criteria, ended with the search for inclusion criteria. The second period, the duration of which was 6 hours, was a wash-out period that consisted of withdrawal of the standardized treatment, except oxygen (FIO2=0.40). This second period ended with measurement of the baseline values of the investigated parameters and with randomization of patients. The third period, the duration of which was 8 hours, allowed us to perform the intravenous infusion (enalaprilat or placebo) for 2 hours and to assess repeatedly for 6 hours its safety and its efficacy on the investigated parameters. This period ended for all patients with the administration of a 2.5-mg oral dose of enalapril. In the succeeding days, the doses of enalapril and of diuretics and nitrates were adapted so that patients were discharged from the hospital with an appropriate long-term treatment.
Sample-Size Calculation
The primary end points for efficacy were PCWP and RBF. According to previous studies,16 17 26 we assumed standard deviations of 6 mm Hg for PCWP and 200 mL/min for RBF. Under these conditions, with the type I error (
) set at .05, we calculated that 20 patients would be necessary to detect a 12 mm Hg decrease in PCWP and a 450 mL/min increase in RBF with a 95% power (ie, a type II error (ß)=.05).
Statistical Analysis
Statistical analysis was performed with BMDP statistical software.27 Homogeneity of pretreatment means between groups was tested by use of Student's t test (BMDP 3D). Comparison of treatment effects between groups was performed by ANCOVA (BMDP 1V for parameters that were evaluated once; BMDP 2V for parameters evaluated more than once), with the pretreatment value used as the covariate. For parameters that were only evaluated once (ie, at 4 hours), treatment effect was analyzed only when the parallelism test was not significant. For parameters evaluated more than once (ie, at 2, 4, and 8 hours or at 4 and 8 hours), treatment effect was analyzed only when the time-treatment interaction was not significant. For each analysis, values of P
.05 were considered statistically significant.
In "Results," reported percentages of variation for a given parameter were computed for each treatment between the values observed at peak effect and at baseline.
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Results |
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Description of the Study Population
Twenty patients were included in the study between September 1992 and May 1993. Eleven patients received enalaprilat and 9 received placebo. The imbalanced distribution between the two groups is owing to the fact that the randomization was prepared according to groups of 6. This ensured a balanced distribution between the two groups up to the 18th patient, but the 19th and 20th patients were both allocated to the same treatment (enalaprilat).
Table 1
shows the clinical characteristics of the patients, including age, weight, height, sex, NYHA functional class, causes of their congestive heart failure, their isotopic or angiographic left ventricular ejection fraction, left ventricular end-diastolic dimension, cardiothoracic index, and treatments received during the first period. The patients were suffering from advanced congestive heart failure (40% NYHA class III and 60% NYHA class IV), and their cardiomyopathies were predominantly (80%) of ischemic origin.
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Table 2 shows the clinical and biological quantitative parameters recorded at entry (to determine preinclusion) and at the end of the standardized treatment period (to determine inclusion). At the time of inclusion, all patients had shown a substantial response to the standardized treatment, with decreases of respiratory rate (-46%), HR (-16%), and PCWP (-47%) and an increase in PaO2 (+44%).
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At baseline, after the 6-hour wash-out period, both preload and afterload had deteriorated substantially in all patients. The evolution was similar in the two groups. As a matter of fact, the investigated parameters were comparable between the two groups for all parameters except ANF. Data recorded at baseline and the corresponding statistical analyses are presented in Tables 3 through 9 together with the effects observed during the investigational period.
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Treatment Evaluation
Systemic Hemodynamic Effects
Compared with placebo, enalaprilat significantly decreased DBP (-21% versus 0% at 8 hours) and MBP (-18% versus -1% at 8 hours). No significant difference was observed between the two groups for SBP, HR, CI, SVI, or systemic vascular resistance index. Finally, enalaprilat tended to decrease rate-pressure product (-19% versus -7% at 8 hours), but this effect failed to reach the level of statistical significance (P=.076). (See Table 3
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Pulmonary Hemodynamic Effects
Compared with placebo, enalaprilat significantly decreased diastolic pulmonary BP (-21% versus -8% at 4 hours), mean pulmonary BP (-18% versus -9% at 4 hours), and PCWP (-37% versus -10% at 4 hours). No significant difference was observed between the two groups for systolic pulmonary BP, RAP, or pulmonary vascular resistance index. Nevertheless, it should be observed that enalaprilat tended to decrease RAP (-42% versus -11% at 4 hours). (See Table 4.)
Regional Hemodynamic Effects
Compared with placebo, enalaprilat tended to increase brachial artery diameter (+13% versus 0%), but this effect failed to reach the level of statistical significance (P=.081). Moreover, enalaprilat significantly increased BBF (+77% versus +8%) and decreased BVR (-44% versus -14%). Finally, no significant difference was observed between the two groups for the BBF/CO distribution ratio. In contrast, compared with placebo, enalaprilat did not modify carotid artery diameter and slightly (and nonsignificantly) increased CBF and the CBF/CO distribution ratio and decreased CVR. (See Table 5.)
Compared with placebo, enalaprilat significantly increased RBF (+12% versus 0%) and decreased renal vascular resistance (-22% versus -2%) and did not modify the RBF/CO distribution ratio. In contrast, compared with placebo, enalaprilat did not modify HBF, hepatosplanchnic vascular resistance, or the HBF/CO distribution ratio. (See Table 6.)
Hormonal Effects
Compared with placebo, enalaprilat significantly decreased plasma ACE activity (-81% versus -30% at 4 hours) and tended to increase plasma renin activity and decrease aldosterone plasma levels between 4 and 8 hours, but these effects remained nonsignificant. Moreover, enalaprilat did not modify antidiuretic hormone, ANF, norepinephrine, or epinephrine plasma levels. (See Table 7.)
Blood Gases and Oxygenation-Derived Variables
Compared with placebo, enalaprilat significantly improved PaO2 (+2% versus -16% at 8 hours) and SaO2 (+1% versus -2% at 8 hours) and tended to improve Qs/Qt (-18% versus +16% at 8 hours), but this latter effect failed to reach the level of statistical significance (P=.080). In contrast, compared with placebo, enalaprilat did not modify P2 or S2, arteriovenous oxygen difference, DO2, O2, or EO2. (See Table 8.)
Biochemical Variables
Compared with placebo, enalaprilat significantly decreased serum sodium (-4% versus -1% at 8 hours) but did not modify serum potassium, nitrogen, or creatinine concentrations. Similarly, no significant difference was observed between the two groups for urine output or sodium, potassium, nitrogen, or creatinine clearances. (See Table 9.)
Treatment Safety
During the study period, no patient suffered from excessive hypotension or reported any adverse effect. At the end of the study period, in addition to oral enalapril, diuretics, and nitrates, 4 of the 9 patients randomized to placebo and 2 of the 11 assigned to enalaprilat also required inotropic drugs (ie, dobutamine). Two patients in the placebo group and 1 in the enalaprilat group died of intractable heart failure.
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Discussion |
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To evaluate the efficacy and safety of a single intravenous infusion of 1 mg enalaprilat in acute cardiogenic pulmonary edema, we selected patients with severe congestive heart failure during an exacerbation of their illness unrelated to acute myocardial infarction. However, for ethical purposes, the study was performed 12 to 18 hours after the acute episode, ie, when the condition of these patients was less severe but they were still in pulmonary edema. The dose and infusion rate of enalaprilat were those used in the CONSENSUS II study.28
Regarding central hemodynamics, enalaprilat reduced both preload and afterload from 2 to at least 8 hours after the start of infusion. We observed a strong decrease in PCWP and reductions in DBP and MBP that reflected both venous and arteriolar vasodilation in the context of no change in CI. Enalaprilat induced similar effects in the right circulation as evidenced by the tendency for RAP to decrease and by reductions in diastolic pulmonary BP and mean pulmonary BP. These similar effects on MBP and RAP on the one hand and on mean pulmonary BP and PCWP on the other also explain, in the context of no change in CI, why calculated systemic and pulmonary vascular resistance indexes were not significantly modified. The fact that CI was not modified is the result of unchanged HR and SVI. Whereas the lack of effect on HR was expected with an ACE inhibitor,29 30 the lack of effect on SVI was more surprising in the context of afterload reduction. In fact, the possible rise of SVI may have been counteracted by the inhibition of angiotensin II formation.31 Finally, enalaprilat tended to decrease rate-pressure product, which indicates a probable reduction in myocardial oxygen requirements. These effects on central hemodynamics are in line with those reported in chronic stable congestive heart failure16 32 and, more recently, in open trials in postinfarct heart failure.11 12
Regarding regional hemodynamics, enalaprilat induced favorable effects in the brachial and renal vascular beds and had no deleterious effects in the cerebral and hepatosplanchnic territories.
Concerning renal hemodynamics, it must be stressed that RBF, which is the chief determinant of renal function in patients with severe congestive heart failure,33 is generally increased with ACE inhibitors.16 26 32 34 35 36 However, in theory, in situations of hyperreninemia and of massive and quick diuresis, as usually observed in acute heart failure, administration of ACE inhibitors is regarded as potentially deleterious for renal function. In fact, in this acute context, the enalaprilat-induced effects on RBF and renal vascular resistance were comparable qualitatively to those observed in chronic stable congestive heart failure.16 26 32 34 35 Moreover, because neither creatinine or nitrogen clearances were modified, we can assume that enalaprilat did not alter glomerular filtration.
Concerning brachial hemodynamics, enalaprilat induced both arteriolar and large-artery vasodilation as evidenced by the decrease in BVR and the increase in brachial artery diameter, respectively. As a result, BBF increased. In the context of a decrease in MBP and as previously reported in stable chronic congestive heart failure patients,16 hypertensives,37 and healthy volunteers,38 vasodilation of the brachial artery is an active phenomenon that reflects an increase in arterial compliance. Moreover, because impaired brachial artery function may increase impedance to left ventricular performance,39 the enalaprilat-induced large-artery vasodilation may contribute to decreased left ventricular end-systolic stress. Finally, although BBF/CO did not increase significantly, the fact that enalaprilat significantly increased BBF without changing CO suggests that it probably induced some redistribution of CO toward the musculocutaneous territory.
Concerning carotid hemodynamics, our study shows that in our patients and compared with healthy volunteers38 40 and/or hypertensives,37 41 carotid artery diameter and CBF were markedly decreased and CVR was increased at baseline. These observations are similar to those reported in the brachial territory in stable chronic congestive heart failure.16 17 39 In contrast with the effects previously reported with ACE inhibitors in healthy volunteers38 40 and hypertensives,37 enalaprilat did not significantly modify carotid artery hemodynamics. However, CBF and CVR were increased by 15% and decreased by 29%, respectively. In fact, hemodynamics of the common carotid artery represent those of two different vascular beds, the facial musculocutaneous one, which depends on the external carotid artery, and the intracerebral one, which is a tributary of the internal carotid artery. In healthy volunteers, it has been shown that ACE inhibitors affect only the external carotid territory and do not modify the internal one, which is autoregulated.42 In our study, because enalaprilat strongly increased musculocutaneous blood flow (as shown, for instance, in the brachial vascular bed), the fact that CBF was only slightly increased probably can be accounted for by an unchanged intracerebral blood flow.
Finally, it appears from our data that enalaprilat had no significant effect on hepatosplanchnic hemodynamics, thus confirming previously reported data with ACE inhibitors in chronic stable congestive heart failure.16 26 32 34
Regarding hormonal effects, as expected, enalaprilat induced a strong inhibition of plasma ACE activity 4 hours after onset of the infusion, and this effect lasted for at least 8 hours. The simultaneous tendencies of plasma renin activity to increase and of aldosterone to decrease are in line with the lowering of angiotensin II concentrations. In contrast, enalaprilat did not significantly affect antidiuretic hormone, ANF, norepinephrine, or epinephrine. These results, which are similar to those recently reported in acute intractable heart failure after myocardial infarction,12 contrast with most of those previously reported in chronic stable congestive heart failure, in which decreases in norepinephrine16 26 32 43 and in ANF43 plasma levels were observed. Concerning ANF, the lack of a large reduction in atrial stretch, well reflected by the nonsignificant decrease in RAP, may account for this discrepancy.
Regarding tissue oxygenation, our study indicates that as a result of the lack of variation in CO, oxygen delivery remained unchanged. The balance between DO2 and O2 was well maintained, as shown by the lack of variation of S2 and EO2. The decrease in PCWP induced by enalaprilat was probably associated with a reduction in edema fluid filtration and consequently with an improvement of PaO2 and SaO2. Moreover, enalaprilat slightly improved Qs/Qt. This result is of great clinical importance because other vasodilators, such as sodium nitroprusside or nitrates, which inhibit hypoxic pulmonary vasoconstriction and thus increase Qs/Qt, usually cause hypoxemia.44
Finally, as previously reported in critically ill patients,11 12 45 enalaprilat was well tolerated. SBP and diuresis were maintained throughout the study period. The observed decrease in serum sodium was moderate and never required any specific treatment. Moreover, serum potassium was never altered.
In conclusion, in cardiogenic pulmonary edema, an early intravenous administration of a 1-mg dose of enalaprilat alleviates both preload and afterload, improves musculocutaneous and renal hemodynamics and arterial oxygenation, and tends to reduce Qs/Qt while maintaining cardiac function, cerebral and hepatosplanchnic hemodynamics, and creatinine and electrolyte clearances. These results suggest that there is a clinical advantage to the use of intravenous enalaprilat in the early course of acute cardiogenic pulmonary edema in congestive heart failure.
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Acknowledgments |
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This work was partly supported by a medical school grant from Merck Sharp & Dohme-Chibret Laboratories (Bluebell, New Jersey, 1992).
Received September 11, 1995; revision received February 14, 1996; accepted March 20, 1996.
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