To identify the risk factors for the development of postoperative septic complications in patients with intestinal perforation after abdominal trauma, and to compare the efficacies of single-drug and dual-drug prophylactic antibiotic therapy, we studied 145 patients who presented with abdominal trauma and intestinal perforation at two hospitals between July 1979 and June 1982. Logistic-regression analysis showed that a higher risk of infection (P less than 0.05) was associated with increased age, injury to the left colon necessitating colostomy, a larger number of units of blood or blood products administered at surgery, and a larger number of injured organs. The presence of shock on arrival, which was found to increase the risk of infection when this factor was analyzed individually, did not add predictive power. Patients with postoperative sepsis were hospitalized significantly longer than were patients without infection (13.8 vs. 7.7 days, P less than 0.0001). Both treatment regimens--cefoxitin given alone and clindamycin and gentamicin given together--resulted in similar infection rates, drug toxicity, duration of hospitalization, and costs.

Accelerated progression of atherosclerosis is known to occur in surgically bypassed coronary arteries in which the preoperative stenosis was greater than 50 per cent. To assess the effect of coronary bypass on vessels with lesser degrees of stenosis, we studied 85 men who had undergone coronary bypass surgery. In this group we identified bypass grafts placed in 37 arteries with minimal atherosclerosis, which was defined as less than 50 per cent stenosis of the vessel diameter. In the same 85 men there were 93 coronary vessels with minimal atherosclerosis for which a bypass graft had not been placed. Progression of atherosclerosis, defined as further loss of at least 25 per cent of the lumen, during an average follow-up period of 37 months was more than 10 times as frequent (38 per cent vs. 3 per cent) in bypassed arteries with minimal atherosclerosis as in comparable arteries that were not bypassed. These findings support the view that minimally diseased coronary arteries should not be bypassed.

We studied the effects of the bacterial urease inhibitor acetohydroxamic acid on the growth of struvite stones in the urinary tract. Eighteen patients who received acetohydroxamic acid (15 mg per kilogram of body weight per day, in divided oral doses) for a mean of 15.8 months were compared in a randomized double-blind study with 19 patients who received placebo for a mean of 19.6 months. Seven patients given placebo reached a pre-determined end point: a 100 per cent increase in the two-dimensional surface area of their stones. No patient who received acetohydroxamic acid had a doubling of stone size (P less than 0.01). Nine patients receiving the drug and one patient receiving placebo required a decrease in dosage or cessation of treatment because of adverse effects (P less than 0.01). Episodes of tremulousness (n = 5, P less than 0.05), which reversed with a decrease in drug dose, and phlebothrombosis (n = 3, P not significant) were limited to the group given acetohydroxamic acid. We conclude that acetohydroxamic acid effectively inhibits the growth of struvite stones in the short term in patients infected with urea-splitting bacteria, but the prevalence of adverse reactions appears to be high and the toxicity and effectiveness of long-term therapy for struvite nephrolithiasis remain to be defined.

Three hundred seventy patients with recently healed duodenal ulcer entered into a one-year, double-blind, randomized multicenter trial comparing placebo with three different dose schedules of cimetidine (200 mg twice a day, 300 mg twice a day, and 400 mg at bedtime) for the prevention of recurrent duodenal ulcer. By the end of one year, the cumulative symptomatic recurrence rate as demonstrated by endoscopy was similar for the patients receiving the three dosages of cimetidine (19 per cent, 15 per cent, and 13 per cent, respectively; not significant), whereas the placebo-treated group had a 34.7 per cent symptomatic recurrence rate (P less than 0.01 as compared with each cimetidine group). Cigarette smoking was found to be an important variable; among the placebo recipients ulcer recurrence was significantly more likely in smokers (72 per cent) than in nonsmokers (21 per cent, P less than 0.001). The frequency of ulcer recurrence in smokers was significantly reduced by treatment with cimetidine (from 72 per cent to 34 per cent, P less than 0.). Smokers who received cimetidine were at least as likely to have a recurrence as were nonsmokers who received placebo (34 per cent vs. 21 per cent, not significant). Thus, smoking appears to be a major factor in recurrence of duodenal ulcer, and in smokers, giving up smoking may be more important in the prevention of ulcer recurrences than administration of cimetidine.

Psychosocial interviews with 2320 male survivors of acute myocardial infarction, participants in the beta-Blocker Heart Attack Trial, permitted the definition of two variables strongly associated with an increased three-year mortality risk. With other important prognostic factors controlled for, the patients classified as being socially isolated and having a high degree of life stress had more than four times the risk of death of the men with low levels of both stress and isolation. An inverse association of education with mortality in this population reflected the gradient in the prevalence of the defined psychosocial characteristics. High levels of stress and social isolation were most prevalent among the least-educated men and least prevalent among the best-educated. The increase in risk associated with stress and social isolation applied both to total deaths and to sudden cardiac deaths and was noted among men with both high and low levels of ventricular ectopy during hospitalization for the acute infarction.

We conducted a randomized, double-blind, crossover study comparing the antiemetic efficacy of dexamethasone and prochlorperazine in 42 patients with cancer who were receiving outpatient chemotherapy, mainly without cisplatin. Patients experienced significantly less nausea and vomiting with dexamethasone than with prochlorperazine (P less than 0.02 and less than 0.03, respectively). Twenty-five patients experienced no nausea with dexamethasone, as compared with 14 patients taking prochlorperazine (P less than 0.001). Similarly, 29 patients receiving dexamethasone did not vomit, as compared with 18 receiving prochlorperazine (P less than 0.001). Somnolence was the most frequent side effect, occurring in 60 per cent of patients receiving prochlorperazine and in 12 per cent of those receiving dexamethasone (P less than 0.001). Patients also experienced less suppression of appetite while receiving dexamethasone (P less than 0.02). We conclude that dexamethasone is an effective and safe antiemetic in patients receiving cancer chemotherapy without cisplatin.

We evaluated the immunogenicity and efficacy of hepatitis B vaccine (Heptavax-B) in a randomized, double-blind, placebo-controlled trial involving 1311 patients receiving hemodialysis in the United States. After three doses of vaccine (40 micrograms each) had been administered, 63 per cent of the patients were antibody-positive. After correction for possible passive transfer of antibodies by blood transfusion, only 50 per cent of vaccine recipients were considered vaccine responders. The incidence of hepatitis B viral infection during the 25 months of the trial was much lower than had been anticipated and was virtually the same in the vaccine and placebo recipients (6.4 and 5.4 per cent, respectively). Four cases of hepatitis B occurred in patients who had an apparent antibody response to the vaccine, but in each case either antibody had reached low or undetectable levels before hepatitis B surface antigen was detected or the patient had been receiving immunosuppressive therapy. This study did not demonstrate the efficacy of the vaccine in a population of patients receiving dialysis in whom both the rate of antibody response to hepatitis B vaccine and the viral attack rate were low. Other measures to control transmission of hepatitis B virus in dialysis units, including surveillance for hepatitis B surface antigen and isolation of patients who are positive for the antigen, must be continued.

We enrolled 479 patients with subarachnoid hemorrhage in a multicenter, randomized, double-blind, placebo-controlled trial to determine whether treatment with the antifibrinolytic agent tranexamic acid improves outcome by preventing rebleeding. At three months there was no statistical difference between the outcomes in the tranexamic acid group and the control group. Of the 173 patients who died, 84 had received tranexamic acid and 89 placebo (95 per cent confidence interval for the difference in mortality rate, -6 to 11 per cent). Similarly, when analysis was restricted to patients with an angiographically demonstrated aneurysm, there was no significant difference between the groups. This absence of effect was not due to a lack of antifibrinolytic action, since the rate of rebleeding was reduced from 24 per cent in the control group to 9 per cent in the tranexamic acid-treated group (chi-square = 18.07, P less than 0.001), but resulted from a concurrent increase in the incidence of ischemic complications (15 per cent in the control group and 24 per cent in the tranexamic acid group; chi-square = 8.07, P less than 0.01). We conclude that until some method can be found to minimize ischemic complications, tranexamic acid is of no benefit in patients with subarachnoid hemorrhage.

We conducted a prospective multicenter randomized trial to determine both the feasibility of maintaining blood glucose control at differing levels and the effect of improved control on diabetic microangiopathy and albuminuria. Seventy patients with diabetes (low C-peptide level) with nonproliferative retinopathy were randomly assigned to continuous subcutaneous insulin infusion or unchanged conventional injection treatment. At entry, both groups had similar demographic, clinical, and glycemic characteristics. Over the succeeding eight months, mean 24-hour glucose concentrations (175 +/- 9 mg per deciliter) and glycosylated hemoglobin levels (10.0 +/- 0.3 per cent) remained elevated during conventional treatment but fell to nearly normal levels (117 +/- 6 mg per deciliter and 8.1 +/- 0.2 per cent, respectively) with continuous insulin infusion. The frequency of biochemical hypoglycemia (less than 40 mg of blood glucose per deciliter) was similar in both groups, but ketoacidosis occurred only during continuous infusion. The level of retinopathy, assessed from photographs, progressed in both groups. Continuous infusion was associated with slightly more deterioration, mainly because of the appearance of soft exudates and intraretinal microvascular abnormalities. In contrast, elevated albumin-excretion rates fell during continuous infusion but not during conventional treatment. We conclude that maintenance of differing levels of blood glucose is feasible in a multicenter trial and that a nearly normal blood glucose level for eight months does not retard progression of, and may initially worsen, established retinopathy. These preliminary observations indicate the need for longer trials (particularly of primary prevention).

Previous studies have suggested that the early application of positive end-expiratory pressure (PEEP) reduces the incidence of the adult respiratory-distress syndrome. We randomly assigned 92 patients with a known risk for this syndrome to receive mechanical ventilation either without PEEP (control) or with early PEEP at 8 cm H2O. These therapies continued for 72 hours unless respiratory distress developed or arterial oxygen tension was above 140 (fractional inspired oxygen concentration, 0.5) at 24 hours or later and remained at that level after removal of PEEP. The study was designed to have an 80 per cent probability of detecting a 60 per cent reduction in the incidence of the syndrome. The treatment groups were comparable in age, severity of injury, number and type of risk factors for adult respiratory-distress syndrome, and initial oxygenation. The syndrome developed in 11 of 44 patients given early PEEP (25 per cent) and in 13 of 48 control patients (27 per cent). The incidence of atelectasis, pneumonia, and barotrauma was the same in both groups, as was mortality. We found that the early application of PEEP at 8 cm H2O in high-risk patients had no effect on the incidence of the adult respiratory-distress syndrome or other, associated complications.

A multicenter randomized single-blind study was performed to evaluate the effects of propranolol administered during the evolution of myocardial infarction. Five centers enrolled a total of 269 patients, with 134 receiving propranolol and 135 placebo. Propranolol or placebo was given intravenously upon randomization (0.1 mg per kilogram of body weight) and then orally for nine days to keep the heart rate between 45 and 60 beats per minute. Less than 2 per cent of patients were treated within 4 hours after the onset of symptoms, but 50 per cent received therapy within 8 hours of onset of chest pain, and the remainder between 8 and 18 hours. The heart rates in the propranolol-treated group were significantly lower than those in the placebo group (P less than 0.001). Base-line characteristics, including the mean heart rate (79.6 vs. 81.3) and the left ventricular ejection fraction (49.0 vs. 49.5), were similar in the two groups. The primary end point evaluated--infarct size as estimated from plasma MB creatine kinase activity--was virtually identical in the two groups, averaging 13.3 and 13.6 gram-equivalents of MB creatine kinase per square meter of body-surface area. Peak plasma levels of the enzyme were also similar in the two groups. No significant difference was observed between the propranolol and placebo groups in the change in left ventricular ejection fraction, extent of area involved in pyrophosphate uptake, R-wave loss on electrocardiograms, or mortality (after three years). These results do not support the use of propranolol administered four or more hours after the onset of symptoms to limit infarct size.

Cimetidine is known to impair the hepatic microsomal oxidation of diazepam, reducing its clearance and prolonging its half-life. We studied the clinical importance of this effect in 10 patients, who were receiving long-term treatment with diazepam for anxiety, tension, or difficulty in sleeping, in an eight-week double-blind controlled study during which the diazepam dosage remained constant. The study was in four two-week phases: base-line or adaptation, coadministration of cimetidine (300 mg) or matching placebo four times daily, crossover to the opposite treatment (placebo or cimetidine), and recovery treatment with diazepam alone. During the cimetidine phase, plasma concentrations of diazepam plus desmethyldiazepam rose an average of 57 per cent (P less than 0.005), then fell when cimetidine was withdrawn. However, there were no significant changes in scores on the digit-symbol-substitution test, a tracking task, or a reaction-time test. Clinical self-ratings indicated no increases in sedation, fatigue, or drowsiness. Patients experienced shortening of sleep latency (P less than 0.05) and an increase in self-rated depth or soundness of sleep (P less than 0.001) during the cimetidine period, but there were no changes in sleep duration or in the number of nocturnal awakenings. Although coadministration of cimetidine to diazepam-treated patients causes a large increase in plasma diazepam and desmethyldiazepam concentrations, the increase is of minimal clinical importance.

Patients with frequently recurring genital herpes were enrolled in a double-blind placebo-controlled trial comparing 200-mg acyclovir capsules, given five or two times daily, with placebo. Of 47 placebo recipients, 44 (94 per cent) had recurrences during the 120-day treatment period, compared with 13 (29 per cent) of 45 patients treated with acyclovir five times daily and 18 of 51 (35 per cent) treated with acyclovir twice daily (P less than 0.001 for each regimen compared with placebo). The median time to the first clinical recurrence was 18 days in placebo recipients, compared with over 120 days in both acyclovir-treated groups (P less than 0.001 for both groups compared with placebo). The mean monthly recurrence rate during the medication period was 0.86 in placebo recipients, compared with 0.13 in patients treated with acyclovir five times daily and 0.14 in patients treated with acyclovir twice daily (P less than 0.001 for both groups compared with placebo). While receiving therapy, 86 of 96 acyclovir-treated patients had over a 50 per cent reduction in their pretreatment recurrence rate. Breakthrough recurrences in acyclovir recipients were of shorter duration and associated with a lower frequency of viral shedding than recurrences in placebo recipients. After medication was discontinued, the subsequent recurrence rate returned to pretreatment frequencies. Daily oral acyclovir was well tolerated. We conclude that oral acyclovir given for four months markedly reduces but does not completely prevent recurrences of genital herpes and does not influence the long-term natural history of the disease.

We studied 35 otherwise healthy adults with frequently recurring genital herpes (greater than or equal to 1 episode per month), in a double-blind trial comparing oral acyclovir with placebo capsules for suppression of recurrent infection. The patients were treated for 125 days unless herpes recurred. Among 32 evaluable patients, there were significantly fewer recurrences during acyclovir treatment (4 of 16) than during placebo treatment (16 of 16, P less than 0.001). The mean duration of therapy was significantly longer for patients receiving acyclovir than for those receiving placebo (114.9 vs. 24.8 days, P less than 0.001). Of 19 patients who had recurrences in the blind trial, only 2 had recurrences when given acyclovir in a second, open-study phase. All patients had recurrences after completing acyclovir treatment. The therapy was well tolerated, with minimal gastrointestinal upset and one hypersensitivity reaction. Studies of the viral isolates demonstrated that lesions developing in patients receiving acyclovir contained drug-resistant virus. Later recurrences in these patients were associated with drug-sensitive virus. We conclude that oral acyclovir suppresses genital herpes in patients with frequent recurrences, but the potential for problems with drug resistance and the long-term safety need to be more fully explored.

Does a prepaid group practice deliver less care than the fee-for-service system when both serve comparable populations with comparable benefits? To answer this question, we randomly assigned a group of 1580 persons to receive care free of charge from either a fee-for-service physician of their choice (431 persons) or the Group Health Cooperative of Puget Sound (1149 persons). In addition, 733 prior enrollees of the Cooperative were studied as a control group. The rate of hospital admissions in both groups at the Cooperative was about 40 per cent less than in the fee-for-service group (P less than 0.01), although ambulatory-visit rates were similar. The calculated expenditure rate for all services was about 25 per cent less in the two Cooperative groups (P less than 0.01 for the experimental group, P less than 0.05 for the control group). The number of preventive visits was higher in the prepaid groups, but this difference does not explain the reduced hospitalization. The similarity of use between the two prepaid groups suggests that the mix of health risks at the Cooperative was similar to that in the fee-for-service system. The lower rate of use that we observed, along with comparable reductions found in non-controlled studies by others, suggests that the style of medicine at prepaid group practices is markedly less "hospital-intensive" and, consequently, less expensive.

Forty patients with Type I membranoproliferative glomerulonephritis were treated for one year with dipyridamole, 225 mg per day, and aspirin, 975 mg per day, in a prospective, randomized, double-blind, placebo-controlled study. At the base line, the half-life of 51Cr-labeled platelets was reduced in 12 of 17 patients. The platelet half-life became longer and renal function stabilized in the treated group, as compared with the placebo group, suggesting a relation between platelet consumption and the glomerulopathy. The glomerular filtration rate, determined by iothalamate clearance, was better maintained in the treated group (average decrease, 1.3 ml per minute per 1.73 m2 of body-surface area per 12 months) than in the placebo group (average decrease, 19.6). Fewer patients in the treated group than in the placebo group had progression to end-stage renal disease (3 of 21 after 62 months as compared with 9 of 19 after 33 months). The data suggest that dipyridamole and aspirin slowed the deterioration of renal function and the development of end-stage renal disease.

To determine whether cigarette smoking affects the results of drug treatment for angina, we studied 10 cigarette smokers with angina who were given placebo, nifedipine (60 mg per day), propranolol (240 mg per day), and atenolol (100 mg per day), each for one week. The four-week double-blind study was repeated with the same randomly determined order of drug sequences, after all 10 subjects had stopped smoking. Before and after the subjects stopped smoking, all three drugs significantly reduced the frequency of angina, as measured with angina diaries, and improved the results of maximal exercise testing and 48-hour ambulatory monitoring of ST segments (P less than 0.01). However, during the nonsmoking phase of the study, there was an overall decline in the frequency of angina and an improvement in performance on exercise testing (P less than 0.05) as compared with the smoking period, although the results of 48-hour ambulatory monitoring remained unchanged. The improvement after patients stopped smoking was greater during treatment with nifedipine than during administration of the other two drugs or placebo. Blood levels of propranolol were increased when patients stopped smoking; levels of nifedipine and atenolol were unchanged. Our data show that smoking had direct and adverse effects on the heart and interfered with the efficacy of all three anti-anginal drugs, but with nifedipine the most.

Sixty-seven adults with idiopathic membranous nephropathy and the nephrotic syndrome were randomly assigned to symptomatic treatment only or to a six-month course of methylprednisolone alternated with chlorambucil every other month. Patients were followed for one to seven years. At the end of follow-up (mean of 31.4 +/- 18.2 months for the treated group and 37.0 +/- 22.0 for the control group) 23 of 32 treated patients were in complete or partial remission, as compared with 9 of 30 control patients (P = 0.001). Twelve of the treated patients were in complete remission, as compared with only two of the controls. In the treated group there were no changes in renal function during follow-up, whereas in the control group the reciprocal of the plasma creatinin level, which is proportional to the creatinine clearance, decreased significantly (P = 0.00017) after two years of follow-up. Side effects were minimal in all treated patients except two, who were dropped from the study because of peptic ulcer and gastric intolerance to chlorambucil. We conclude that steroid and chlorambucil treatment for six months favors remission of the nephrotic syndrome in adults with idiopathic membranous nephropathy and can preserve renal function for at least some years.

The long-term benefit of coronary bypass surgery in terms of longevity and prevention of major ischemic events in patients who have mild angina is not well defined. The randomized Coronary Artery Surgery Study (CASS) was designed to evaluate this issue; it consists of 780 patients who were considered operable and who had mild stable angina pectoris or who were free of angina after infarction. As a result of the randomization process there were no significant differences in base-line variables between patients randomly assigned to medical and to surgical therapy. The likelihood of death in the five-year period after randomization was only 8 per cent in the medical cohort, as compared with 5 per cent in the surgical cohort (not significant). The likelihood of nonfatal Q-wave myocardial infarction was 11 and 14 per cent, respectively (not significant). The five-year probability of remaining alive and free of infarction was 82 per cent in the patients assigned to medical therapy and 83 per cent in the patients assigned to surgery (not significant). There were no statistically significant differences in the survival rate or in the myocardial-infarction rate between subgroups of patients randomly assigned to medical and to surgical therapy when they were analyzed according to initial group assignment, number of diseased vessels, or ejection fraction. Therefore, as compared with medical therapy, coronary bypass surgery appears neither to prolong life nor to prevent myocardial infarction in patients who have mild angina or who are asymptomatic after infarction in the five-year period after coronary angiography.