In a randomized, double-blinded, placebo-controlled trial, we compared the therapeutic effect of oral acyclovir (400 mg five times daily for 10 days) with that of placebo in patients with marrow transplants and culture-proven recurrent mucocutaneous herpes simplex. Twelve patients received acyclovir and nine received placebo. Acyclovir treatment significantly shortened the median duration of viral shedding, new lesion formation, and time to first decrease in pain, resolution of pain, 50% healing, and total healing. These results compared favorably with those previously obtained with intravenous or topical acyclovir preparations. Oral acyclovir is highly effective for the treatment of recurrent mucocutaneous infections caused by herpes simplex virus in immunocompromised patients.

A randomized controlled trial was done to assess the ability of continuing medical education to change physicians' knowledge and behavior in the care of patients with acute myocardial infarction. Patient care practices on eight objectives were audited 6 months before and after physicians completed a 2-hour educational program. Sixty-three physicians from eight randomly selected communities constituted the experimental group and 40 physicians from four similar communities served as controls. The average score for desired care practices over all objectives increased from 48.5% to 60% (p less than 0.001). Three objectives showed significantly greater gains for physicians in the experimental group. The generalizability of these effects was also studied in two additional educational contexts: a multitopic and a unitopic university-based continuing medical education program. Similar significant changes in behavior resulted in both contexts. Significant overall increases in knowledge occurred and persisted for all groups. Continuing medical education can effect changes in physicians' knowledge and care practices that can persist for at least 6 months.

Recently the Food and Drug Administration approved cimetidine for the treatment of benign gastric ulcer. Approval was based in part on the results of our large multicenter trial involving 172 patients with benign gastric ulcer between 0.5 and 2.5 cm in diameter: 87 were randomly assigned to receive cimetidine (300 mg four times daily) and 85 to receive placebo. Cimetidine treatment resulted in significantly more rapid healing than placebo; after 2 and 6 weeks of therapy, 10.0% and 44.8% of patients receiving placebo were healed, as compared to 22.6% and 65.1% receiving cimetidine. The results of our study were compared with the time-response curve previously published (0, 4, and 8 weeks of therapy). The combined data yielded linear healing rates for the first 8 weeks of therapy (r greater than 0.99 for both cimetidine and placebo). These studies can be used to define expectations for healing of benign gastric ulcer, and we recommend follow-up intervals of 8 and, if unhealed, 16 weeks.

An intervention was developed to increase patient involvement in care. Using a treatment algorithm as a guide, patients were helped to read their medical record and coached to ask questions and negotiate medical decisions with their physicians during a 20-minute session before their regularly scheduled visit. In a randomized controlled trial we compared this intervention with a standard educational session of equal length in a clinic for patients with ulcer disease. Six to eight weeks after the trial, patients in the experimental group reported fewer limitations in physical and role-related activities (p less than 0.05), preferred a more active role in medical decision-making, and were as satisfied with their care as the control group. Analysis of audiotapes of physician-patient interactions showed that patients in the experimental group were twice as effective as control patients in obtaining information from physicians (p less than 0.05). Results of the intervention included increased involvement in the interaction with the physician, fewer limitations imposed by the disease on patients' functional ability, and increased preference for active involvement in medical decision-making.

Twenty-six patients participated in a randomized, double-blind study of the efficacy of total lymphoid irradiation in the treatment of intractable rheumatoid arthritis. All 26 patients, for whom therapy with gold compounds and penicillamine had failed, would ordinarily have been considered candidates for cytotoxic or antimetabolite drug therapy. Thirteen patients randomly assigned to receive full-dose total lymphoid irradiation (2000 rad) and 11 patients assigned to receive control low-dose total lymphoid irradiation (200 rad) completed radiotherapy. Alleviation of joint disease activity was significantly greater in the high-dose group as judged by morning stiffness, joint tenderness, and functional assessment (global composite score) at 3 and 6 months after radiotherapy. The high-dose group had a marked reduction in both T-lymphocyte function and numbers, but this finding was not observed in the low-dose group. Complications seen in the high-dose but not low-dose group included transient neutropenia, thrombocytopenia, pericarditis, and pleurisy.

Five intensively treated, insulin-dependent diabetics exercised for 45 minutes after fasting while receiving basal insulin injections. Plasma glucose concentrations remained stable during exercise but then declined, resulting in clinical hypoglycemia 1 to 2 hours later. Efficacies of three pre-exercise snacks in preventing the hypoglycemia were compared in a randomized crossover design. Orange juice, whole milk, and skim milk, each containing 13 g of carbohydrate, all prevented postexercise hypoglycemia. However, the more rapidly absorbed snacks, orange juice and skim milk, caused a greater increase in plasma glucose concentrations and the area under the glucose curve during exercise. From the recognized glucose profiles that occur after consumption of different carbohydrates, snacks as well as exercise and insulin can now be programmed for intensively treated, insulin-dependent diabetics. Because plasma glucose levels remain stable during exercise done after fasting and only fall late after exercise, a "lente" carbohydrate snack, such as whole milk, is an appropriate pre-exercise snack.

In a randomized crossover trial, 38 women with recurrent urinary tract infections were assigned to use either continuous prophylaxis with trimethoprim-sulfamethoxazole or intermittent self-administered therapy (single-dose trimethoprim-sulfamethoxazole taken for acute urinary symptoms). The infection rate for patients on prophylaxis was 0.2 episodes/patient-year compared with 2.2 infections/patient-year for patients on self-administered therapy (p less than 0.001). Thirty-five of thirty-eight symptomatic episodes diagnosed by patients as infection were confirmed microbiologically, and 30 of the 35 infections responded clinically and microbiologically to patient-administered therapy with single-dose trimethoprim-sulfamethoxazole. No complications were seen in the 5 patients in whom therapy failed. The annual costs of prophylaxis and self-therapy were similar ($256 and $239, respectively) and both were less expensive than conventional therapy in women having 2 or more infections per year. In selected women, self-therapy is efficacious and economical compared with conventional therapy or prophylaxis.

The amplitude of ventricular fibrillation found initially in 394 patients was compared to clinical and logistical findings at the time of cardiac arrest. Peak-to-peak amplitude averaged 0.55 +/- 0.25 mV; a very low amplitude (0.2 mV or less) or "fine" fibrillation was present in 66 patients (17%). The amplitude was not found to be related to clinical histories, but depended on the length of the period from collapse until start of basic life support (p = 0.004) and the delay until assessment by paramedics (p = 0.001). Survival rates were strongly associated with amplitude: only 4 patients (6%) with fine ventricular fibrillation survived, compared to 117 or 328 patients (36%) in whom the initial amplitude was higher (p less than 0.001). Patient outcome related to amplitude even after adjusting for clinical history and logistical delays (p less than 0.005). We conclude that fine ventricular fibrillation is in part the result of delay in initiation of treatment, and that fibrillation amplitude is a powerful indicator of outcome after cardiac arrest.

At six centers, 203 patients with stabilized hypoxemic chronic obstructive pulmonary disease were evaluated hemodynamically during a continuous or 12-hour oxygen therapy program. Neither oxygen therapy program resulted in correction or near-correction of the baseline hemodynamic abnormalities. The continuous oxygen therapy group did show improvement in pulmonary vascular resistance, pulmonary arterial pressure, and stroke volume index. The improvement in pulmonary vascular resistance was associated with improved cardiac function, as evidenced by an increase in baseline and exercise stroke volume index. The nocturnal oxygen therapy group showed stable hemodynamic variables. For both groups, changes in mean pulmonary artery pressure during the first 6 months were associated with subsequent survival after adjustment for association with the baseline mean pulmonary artery pressure. Continuous oxygen therapy can improve the hemodynamic abnormalities of patients with hypoxic chronic obstructive pulmonary disease. The hemodynamic response to this treatment is predictive of survival.

Impedance plethysmography is an accurate noninvasive method to test for proximal vein thrombosis, but it is insensitive to calf-vein thrombi. We randomly assigned patients on referral with clinically suspected deep-vein thrombosis and normal impedance plethysmographic findings to either serial impedance plethysmography alone or combined impedance plethysmography and leg scanning (which has been shown to be essentially as sensitive as venography) and compared the long-term outcomes. During the initial surveillance, deep-vein thrombosis was detected in 6 of 311 patients (1.9%) tested by serial impedance plethysmography alone and in 30 of 323 patients (9.3%) (most with calf-vein thrombi) tested by the combined approach (p less than 0.001). During long-term follow-up, no patient died from pulmonary embolism; but 6 patients (1.9%; 95% confidence limits, 0.7% to 4.2%) tested by serial impedance plethysmography developed deep-vein thrombosis compared with 7 patients (2.2%; 95% confidence limits, 0.9% to 4.4%) tested by the combined approach. Serial impedance plethysmography used alone is an effective strategy to evaluate such symptomatic patients.

Gentamicin and tobramycin were compared for cost effectiveness in the treatment of adult patients with serious infections in a general medical service. We used data from a randomized double-blind trial in which the only observed difference between the clinical effects of these aminoglycosides was the incidence of nephrotoxicity (26% with gentamicin and 12% with tobramycin). According to 1984 cost data, the combined average drug and nephrotoxicity costs per patient were $127 for tobramycin and $72 for gentamicin. An extensive sensitivity analysis--varying frequency and cost of nephrotoxicity, dialysis requirements, aminoglycoside acquisition costs, and length of hospitalization--showed gentamicin to be more cost effective than tobramycin, unless hospitalization is prolonged by an average of at least 15 days for patients with severe nephrotoxicity or at least 3 days for all patients with moderate or severe nephrotoxicity.

Two hundred twenty patients were randomly assigned to receive either ceforanide or cephalothin as perioperative antibiotic prophylaxis during cardiovascular surgery. More infections were seen among cephalothin recipients (8 deep, 32 total) than among ceforanide recipients (1 deep, 17 total). Among patients who had only coronary artery bypass grafting, more cephalothin recipients had infection than did ceforanide recipients (19 of 82 as opposed to 7 of 83; p = 0.001; relative risk, 2.7; 95% confidence interval, 1.22 to 6.18). The difference between the two regimens was attributable to fewer blood, wound, and urinary tract infections. Among patients who had other procedures, there was no difference in the efficacy of the two regimens. Cephalothin recipients who developed wound or blood stream infections had lower antibiotic levels in their atrial appendages than recipients not developing such infections (p = 0.02). If one assumes that cephalothin does not increase the risk of infection, then these data show that antibiotic prophylaxis prevents infection after coronary artery bypass surgery, and, in the dosages used, that ceforanide is superior to cephalothin.

We compared the outcome of marrow transplantation with that of continued chemotherapy for adults with acute nonlymphoblastic leukemia who achieve a first remission. From May 1977 to July 1982, 111 consecutive adults (ages 17 to 50) with newly diagnosed acute nonlymphoblastic leukemia were treated with induction chemotherapy. Ninety patients (81%) had a complete remission. Forty-four remission patients had available donors: 33 received a transplant and 11 did not. Forty-six patients in remission without matched donors were treated with continued chemotherapy. Kaplan-Meier estimates of 5-year, disease-free survival from complete remission are 49% +/- 18% for the transplant group and 20% +/- 13% for the chemotherapy group. When compared to the chemotherapy group, patients undergoing transplantation had a higher risk of dying during the first 6 months after remission induction but a lower risk of dying thereafter. Within the transplant group, only age influenced survival. Within the chemotherapy group, a leukocyte count of greater than 10 000 mm3 at diagnosis, a French-American-British (FAB) Cooperative Group morphologic status of M-4, M-5, or M-6, and the presence of infection at diagnosis were all associated with shorter survival.

In a prospective, randomized, double-blind study, we compared cefotaxime with nafcillin plus tobramycin in the treatment of serious bacterial infections. Of 195 patients with suspected or proven infections who were not neutropenic, definite bacterial infections were identified in 81; 34 of 38 patients given cefotaxime and 26 of 43 given nafcillin plus tobramycin (p less than 0.01) responded to treatment. The difference in response rates occurred primarily in patients with rapidly fatal underlying disease or with an infection outside the urinary tract. A logistic regression analysis showed that treatment with cefotaxime was still associated with a higher response rate after adjusting for several potential confounding factors. Among patients treated for 3 days or more, our criteria for nephrotoxicity were met in 2 of 68 (2.9%) given cefotaxime and 16 of 57 (28.1%) given nafcillin plus tobramycin (p less than 0.001). Prolongation of the prothrombin time and enterococcal colonization did not occur more frequently with cefotaxime. We conclude that cefotaxime may be more effective and less toxic than nafcillin plus tobramycin for patients with serious bacterial infections.

Two chemotherapy regimens for treatment of patients with advanced Hodgkin's disease, BCVPP (carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone) and MOPP (mechlorethamine hydrochloride, vincristine, procarbazine, and prednisone), were compared in a randomized prospective study. Two hundred ninety-three patients were evaluable in the induction phase of this study. The complete remission rate with BCVPP was 76% (112/147) and with MOPP, 73% (106/146) (p = 0.51). The duration of complete remissions for previously untreated patients given BCVPP was significantly longer than that for previously untreated patients given MOPP (p = 0.02). Although hematologic toxicities were similar, BCVPP caused less gastrointestinal (p = 0.0001) and neurologic toxicity (p = 0.01) than MOPP. Previously untreated patients achieving complete remission with BCVPP survived significantly longer than those receiving MOPP (p = 0.03). As primary induction chemotherapy for advanced Hodgkin's disease, BCVPP is an effective alternative to MOPP, having equal or greater therapeutic benefit with less toxicity.

y composition was studied in 31 patients receiving chemotherapy for small-cell lung cancer. Patients were randomly assigned to receive either 4 weeks of total parenteral nutrition (study group) or to continue a self-regulated oral diet (control group). The relationship between height and total body nitrogen was altered initially for patients who had lost more than 5% of body weight. During the 4 weeks of parenteral nutrition, body weight, total body fat, and total body potassium, but not total body nitrogen, increased significantly in the study group (p less than 0.001). However, after parenteral nutrition was stopped, body weight and potassium levels in the study group fell significantly and to the same extent as in the control group. Nitrogen levels showed an overall fall in the 32 weeks of observation for both groups. After the period of parenteral nutrition, the decrease in body fat was significantly greater in the control group than in the study group (p less than 0.05). Thus, parenteral nutrition increased body fat and total body potassium, but not total body nitrogen.

In a double-blind study, 12 patients on chronic hemodialysis received daily an average of 1.3 meq/kg body weight of oral sodium citrate for 8 weeks and a placebo solution for 8 weeks. Sodium citrate corrected predialysis metabolic acidosis (plasma pH 7.41 compared to 7.35; serum bicarbonate, 21.1 compared to 17.0 meq/L) and the plasma arterial PCO2 was higher (33.8 compared to 31.2). Postdialysis serum bicarbonate was slightly higher, 22.7 compared to 21.0 but there was no significant difference in arterial pH. Weight gain between dialysis periods was 0.4 kg higher with sodium citrate (2.9 compared to 2.5 kg). There were no significant differences in other routine values, blood pressure, or symptoms during dialysis. Similar results were found in patients on acetate dialysate and in patients on bicarbonate dialysate.

The indications for treating patients with subclinical hypothyroidism (normal serum thyroxine and free thyroxine levels, but elevated serum thyrotrophin levels) are poorly defined. In this study, 33 patients with subclinical hypothyroidism were randomly assigned in a double-blind manner to receive placebo or L-thyroxine therapy and were followed for 1 year with thyroid function tests, serum lipid measurements, basal metabolic rate and systolic time interval determinations, and a questionnaire on hypothyroid symptoms. The placebo group showed no changes in thyroid function or peripheral indices of thyroid hormone action. In the thyroxine-treated group, serum lipids and the mean systolic time interval did not change, but the systolic time intervals became normal in the 5 patients with the most abnormal baseline values. Symptoms improved in 8 of 14 patients receiving thyroxine and in 3 of 12 patients receiving placebo (p less than 0.05). L-Thyroxine therapy may be useful for patients with subclinical hypothyroidism with abnormal myocardial contractility or symptoms consistent with mild hypothyroidism, or both.

In a double-blind trial, we randomly assigned 1330 high-risk health care personnel to receive three 20-micrograms doses of hepatitis B vaccine or placebo. Among vaccine recipients 58% responded within 1 month and 97% within 9 months; there was no difference in immune response to the vaccine between men and women. Efficacy was evaluated after a mean follow-up of only 13.2 months, just before the vaccine was released commercially. Five hepatitis B infections were identified in placebo recipients and one in a vaccine recipient. Although the number of infections was too small to allow confident conclusions about protective efficacy of the vaccine, we saw a 67% reduction in the need for hepatitis B immune globulin after accidental hepatitis B inoculation in the vaccine group (relative risk, 5.08; 95% confidence intervals, 1.3 to 19.9). Minor side effects occurred with equal frequency after vaccine (28.7%) and placebo (27.2%) injections; no participant had a severe adverse reaction. Vaccination with the 20-micrograms hepatitis B vaccine was highly immunogenic and safe in health care workers.