Eight hundred twelve men with presumed acute myocardial infarction and left ventricular filling pressure of at least 12 mm Hg participated in a randomized double-blind placebo-controlled trial to assess the efficacy of a 48-hour infusion of sodium nitroprusside. The mortality rates at 21 days (10.4 per cent in the placebo group and 11.5 per cent in the nitroprusside group) and at 13 weeks (19.0 per cent and 17.0 per cent, respectively) were not significantly affected by treatment. The efficacy of nitroprusside was related to the time of treatment: the drug had a deleterious effect in patients whose infusions were started within nine hours of the onset of pain (mortality at 13 weeks, 24.2 per cent vs. 12.7 per cent; P = 0.025) and a beneficial effect in those whose infusions were begun later (mortality at 13 weeks, 14.4 per cent vs. 22.3 per cent; P = 0.04). Nitroprusside should probably not be used routinely in patients with high left ventricular filling pressures after acute myocardial infarction. However, the results in the patients given late treatment suggest that those with persistent pump failure might receive sustained benefit from short-term nitroprusside therapy.

We gave sodium nitroprusside by intravenous infusion to 163 randomly selected patients during the first 24 hours after hospitalization for typical acute myocardial infarction, and we studied its effects on mortality at one week, on the incidence of cardiogenic shock, on clinical signs of left ventricular failure, and on peak levels of creatine kinase isoenzyme MB. A control group of 165 patients received standard medical treatment and infusion of 5 per cent glucose. The end point of the study was a significant reduction in mortality in the nitroprusside group; this was reached when five deaths had occurred in this group, as compared with 18 among the controls (P less than 0.05). The incidence of cardiogenic shock, clinical signs of left-heart failure, and mean peak levels of creatine kinase isoenzyme MB were all reduced (P less than 0.05). The results indicate that infusion of nitroprusside in the early phase of acute infarction limits complications, possibly by reducing infarct size. The drug was particularly effective in anterior-wall infarction.

Although oral glucose-electrolyte solutions containing 90 mmol of sodium per liter have been widely used in the treatment of acute diarrhea among under-nourished children in the developing world, they have rarely been studied in well-nourished children. We therefore conducted a controlled randomized study among well-nourished children three months to two years who were hospitalized with acute diarrhea (52 in the United States, and 94 in Panama), to compare the efficacy of this solution with that of one containing 50 mmol of sodium per liter and with standard intravenous therapy. Oral rehydration with both solutions according to protocol was successful in 97 of 98 children (one required unscheduled intravenous therapy), and in 87 (89 per cent) no intravenous therapy was required. All of six children admitted with hypernatremia were successfully treated with oral therapy alone. We conclude that glucose-electrolyte oral solutions containing either 50 or 90 mmol of sodium per liter are effective and safe in the treatment of well-nourished children hospitalized with acute diarrhea, and that they may completely replace the intravenous fluids in the majority of such children.

In a controlled trial conducted to assess the biologic value of High Nitrogen Vivonex, we compared this "elemental" diet with predigested protein--Product MJ7041--and with solid food during eight-day balance periods. Each formula was evaluated in three patients with malabsorption and one without it, by measuring apparent absorption of nitrogen and energy, nitrogen balance, and blood and urinary urea nitrogen. Overall energy and nitrogen absorption in the patients with malabsorption was better with either special diet than with solid food; net intestinal uptake of Vivonex tended to be higher but not consistently so in al patients. However, nitrogen balance differed consistently during the three diets; with solid food and MJ7041, retention of absorbed nitrogen was respectively, nine and 16 times greater than with Vivonex. Moreover, institution of each Vivonex period led to a prompt increase in urea nitrogen--a trend quickly reversed by the alternative diets. Although the mechanism for the impairment of nitrogen use caused by High Nitrogen Vivonex is unknown, its low biologic value and tendency to cause azotemia should be kept in mind.

Twenty-four depressed patients with heart disease were treated for four weeks in a double-blind trial of imipramine, doxepin, or placebo to assess the effects of tricyclic antidepressants on ventricular function and rhythm. The tricyclic antidepressants had no effect on left ventricular ejection fraction at rest or during maximal exercise, as measured by radionuclide ventriculograms obtained before and after treatment. Premature ventricular contractions were reduced by imipramine but were not consistently changed by doxepin or placebo. Treatment with imipramine and doxepin, but not placebo, was associated with significant improvement (P less than 0.001) in standard ratings of depression. Our findings underscore the need for a reappraisal of the cardiovascular risks of tricyclic antidepressants and suggest that in the absence of severe impairment of myocardial performance, depressed patients with preexisting heart disease can be effectively treated with these agents without an adverse effect on ventricular rhythm or hemodynamic function.

Hypoglycemia (blood glucose less than 45 mg per deciliter [less than 2.5 mmol per liter]) occurred in seven of 19 healthy men who exercised to exhaustion on a cycle ergometer at 60 to 65 per cent of maximal aerobic power. The hypoglycemic subjects exercised for 15 to 70 minutes despite blood glucose levels of 25 to 48 mg per deciliter (1.4 to 2.7 mmol per liter), and their exhaustion time (mean +/- S.E.M., 142 +/- 15 minutes) was not significantly different from that of the euglycemic group (165 +/- 11). Plasma epinephrine was inversely related to blood glucose (P less than 0.01) and was three times higher in the hypoglycemic subjects (P less than 0.05). Glucose ingestion (40 or 80 g per hour) prevented the hypoglycemia and resulted in a smaller rise in plasma epinephrine but did not alter perceived exertion or consistently delay exhaustion. We conclude that hypoglycemia occurs in normal subjects during prolonged exercise and results in an exaggerated rise in plasma epinephrine. However, hypoglycemia fails to effect endurance, and its prevention does not consistently delay exhaustion.

We assessed the efficacy of adding nifedipine to the conventional treatment of unstable angina in 138 patients in a prospective, double-blind, randomized, placebo-controlled trial. There was no difference between the two groups in the dose of conventional antianginal medication or in age, prior myocardial infarction, ejection fraction, or other risk factors. Failure of medical treatment (defined as sudden death, myocardial infarction, or bypass surgery within four months) occurred in 43 of 70 patients given placebo and in 30 of 68 given nifedipine. Kaplan-Meier survival-curve analysis of the number and time dependence of treatment failures demonstrated a benefit of nifedipine over placebo (P = 0.03). The benefit was particularly marked in patients with ST-segment elevation during angina (P = 0.02). Side effects (transient hypotension or diarrhea) required withdrawal of the drug from four patients given nifedipine and from one given placebo. We conclude that the addition of nifedipine to conventional therapy is safe and effective in unstable angina.

Of 75 consecutive patients with Stage IV Hodgkin's disease, we assigned 38 to receive MOPP alone (mechlorethamine, vincristine, procarbazine, and prednisone) and 37 to receive MOPP alternating monthly with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) - a combination of drugs not cross-resistant with MOPP. Complete remission was documented in 71 percent of the patients receiving MOPP alone and in 92 per cent of those receiving the alternating regimen (P = 0.02). At five years, there was no progression of disease in 37 per cent of the MOPP group and in 70 per cent of the MOPP-plus-ABVD group (P less than 0.0001). After chemotherapy, the median relapse-free survival period was 20 months in the MOPP group and over 31 months in the MOPP-plus-ABVD group (P less than 0.01). Five-year survival with no evidence of disease was 84 per cent in patients given MOPP and ABVD and 54 per cent in those given MOPP alone (P less than 0.005). We conclude than alternating non-cross-resistant combinations appear promising in the management of advanced Hodgkin's disease and are worthy of trial in other malignant diseases.

Human leukocyte interferon was evaluated as a treatment for varicella in a randomized double-blind, placebo-controlled study carried out in two phases. A total of 44 children being treated for cancer were enrolled within 72 hours of the appearance of the exanthem. The mean number of days of new lesion formation was 3.8 +/- 1.89 (+/- S.D.) in the interferon recipients and 5.3 +/- 2.56 in the placebo recipients (P less than 0.05). Eighty-one per cent of the interferon recipients had had no new lesions for 24 hours by Day 7, as compared with 56 per cent of the placebo recipients (P less than 0.025). In the second, higher-dose phase of the study 92 per cent of the interferon recipients had had no new lesions for 24 hours by Day 6, as compared with 45 per cent of the placebo recipients (P less than 0.025). Three of 21 placebo recipients died of progressive varicella. Two of the 23 interferon recipients died two to three weeks after the onset of varicella; viral cultures were negative in one of these patients, and the second had recurrent viremia at the end of the treatment period. Among the survivors, treatment with interferon reduced the number of patients who had life-threatening dissemination (none of 21 vs. three of 18; P = 0.053). We conclude that interferon had an antiviral effect against varicella virus in immunocompromised patients.

The view that digitalis clinically benefits patients with heart failure and sinus rhythm lacks support from a well-controlled study. Using a randomized, double-blind, crossover protocol, we compared the effects of oral digoxin and placebo on the clinical courses of 25 outpatients without atrial fibrillation. According to a clinicoradiographic scoring system, the severity of heart failure was reduced by digoxin in 14 patients; in nine of these 14, improvement was confirmed by repeated trials (five patients) or right-heart catheterization (four patients). The other 11 patients had no detectable improvement from digoxin. Patients who responded to digoxin had more chronic and more severe heart failure, greater left ventricular dilation and ejection-fraction depression, and a third heart sound. Multivariate analysis showed that the third heart sound was the strongest correlate of the response to digoxin (P less than 0.0001). These data suggest that long-term digoxin therapy is clinically beneficial in patients with heart failure unaccompanied by atrial fibrillation whose failure persists despite diuretic treatment and who have a third heart sound.

Beta-blocking drugs are increasingly prescribed in coronary heart disease, but controversy surrounds the hemodynamic relevance of their ancillary pharmacologic properties--cardioselectivity and intrinsic sympathomimetic activity. We therefore compared the effects of four intravenous beta-adrenoreceptor antagonists with different ancillary properties on left ventricular function in 24 patients with coronary heart disease. All four drugs depressed the relation between left ventricular filling pressure and cardiac output at rest and during exercise. However, practolol and oxprenolol, which have intrinsic sympathomimetic activity, induced significantly less depression of left ventricular function than either propranolol or metoprolol, which do not have this activity. Cardioselectivity, a property of both practolol and metoprolol, had no discernible hemodynamic advantage. Beta-blocking drugs that have intrinsic sympathomimetic activity appear to be more effective in maintaining cardiac function than drugs without this property, when given intravenously to patients with coronary heart disease.

To determine whether continuing medical education affects the quality of clinical care, we randomly allocated 16 Ontario family physicians to receive or not receive continuing-education packages covering clinical problems commonly confronted in general practice. Over 4500 episodes of care, provided before and after study physicians received continuing education, were compared with preset clinical criteria and classified according to quality. Although objective tests confirmed that the study physicians learned from the packages, there was little effect on the overall quality of care. When the topics were of relatively great interest to the physicians, the control group (who did not receive the packages) showed as much improvement as did the study group. When the topics were not preferred, however, the documented quality of care provided by study physicians rose (P less than 0.05) and differed from that provided by control physicians (P = 0.01). Finally, there was no spillover effect on clinical problems not directly covered by the program. In view of the trend toward mandatory continuing education and the resources expended, it is time to reconsider whether it works.