Daily change of intravenous (i.v.) infusion administration sets has been recommended by the Center for Disease Control since 1973 to reduce the risk of infusion bacteremia. To evaluate this recommendation, we undertook a prospective, randomized, controlled trial that compared the rates of i.v.-associated bacteremia, in-use i.v. fluid contamination, and phlebitis in 300 patients whose administration sets were changed every 24 h with those in 300 patients whose administration sets were changed every 48 h. No i.v.-associated bacteremia occurred. Twelve of 600 infusions (2%) had positive infusion-fluid cultures: five in one group and seven in the other. Both groups had comparable rates of phlebitis. In this study population with low rates of fluid contamination, no benefit accrued from changing the administration sets every 24 h instead of every 48 h. In hospitals with low rates of fluid contamination, the routine changing of i.v. administration sets every 48 h will result in substantial financial savings.

The clinical implications of newly acquired left bundle-branch block (LBBB) were examined prospectively in the Framingham Study population. During 18 years of observation 55 people developed LBBB. The mean age at the onset of LBBB was 62; LBBB occurred largely in people with antecedent hypertension, cardiac enlargement, coronary heart disease, or a combination of these. Coincident with or subsequent to the onset of LBBB, 48% developed clinical coronary disease or congestive failure for the first time. Throughout the entire period of observation only 11% remained free of clinically apparent cardiovascular abnormalities. Within 10 years of the onset of LBBB, 50% had died from cardiovascular diseases. In men, the appearance of LBBB contributed independently to an increased risk of cardiovascular disease mortality. Comparison with age- and sex-matched control subjects free from LBBB confirmed that in the general adult population, newly acquired LBBB is most often a hallmark of advanced hypertensive or ischemic heart disease, or both.

We compared low-dose insulin regimens in a prospective randomized trial in 30 patients with diabetic ketoacidosis. One group received a loading dose of 0.44 U/kg body weight of regular insulin half intramuscularly and half intravenously followed by 7 U/h intramuscularly, whereas the other group received a loading dose of 0.44 U/kg intravenously followed immediately by a constant infusion of 7 U/h in albumin-free saline. The time for metabolic control of the ketoacidosis was not significantly different in the two groups. Five patients in each group developed mild hypokalemia (serum potassium, 3.0 to 3.4 meq/litre). No patient became hypoglycemic, and there were no deaths within the follow-up period (24 h). In the treatment of diabetic ketoacidosis, low doses of insulin administered by the priming dose-intermittent intramuscular route are as effective as the constant infusion method.

Laminar air flow isolation and decontamination procedures were evaluated in a prospective randomized study in patients with aplastic anemia or acute leukemia undergoing marrow transplantation from HLA-matched siblings. Patients transplanted in the laminar air flow group had significantly less septicemia and major local infections than did patients in the control group. Nineteen of 46 laminar air flow patients and six of 44 control patients are alive at present. In patients with aplastic anemia the survival was 13 of 17 in the laminar air flow group compared with four of 17 in the control group. In patients with acute leukemia the survival was six of 29 in the laminar air flow group versus two of 27 in the control group. These differences were not statistically significant. Death in both the laminar air flow and control groups was predominantly due to interstitial pneumonitis or recurrent leukemia, which were unaffected by isolation and decontamination.

In recent years in-vitro and in-vivo studies have greatly advanced our understanding of the action of antimicrobial agents and have opened new potential avenues for treatment of infectious diseases. Unfortunately, little interest or financial support has been available to test these observations in rigid, controlled clinical studies. New regimens have thus been used without proof of increased efficacy of reduced toxicity over old regimens. Carefully controlled clinical trials are particularly needed to evaluate the efficacy, toxicity, and cost of newly developed regimens in the therapy of chronic bacterial and fungal infections.

The network for development of a new antimicrobial drug, from discovery of the compound to submission of the New Drug Application, is reviewed. The key problems encountered during this process, as elucidated through a survey of 62 American pharmaceutical companies, include difficulties in discovering new and significant antimicrobial drugs, the unpredictability of in-vitro and animal studies, lack of specific criteria for the bacteriologic response to therapy, difficulties in setting up well-controlled clinical studies, and difficulty with the timely enrollment of suitable patients with precise microbiologic diagnosis before treatment.

The philosophy of drug regulation as expressed by Congress has progressively embraced concepts of misbranding and adulteration, safety, efficacy, and, most recently, control of the investigational process. The intent of Congress has been implemented by a series of regulations intended to protect the public health and to assure that available drugs are safe and effective. This has resulted in more centralized, standardized, uniform government control, with a slowdown in the development and approval of new drugs, an increase in the cost of developing and marketing new drugs, and costly control procedures. It is time to ask whether the benefit of more centralized government control is being exceeded by its cost.

The Food and Drug Administration recently has published general guidelines for the clinical evaluation of drugs used in adults and in infants and children. Specific guidelines for a number of drug classes, including anti-infective drugs, are also available. Marketing approval of a new drug requires that its benefits be judged to exceed its risks, that it be accurately and truthfully labeled, and that it be manufactured properly. Foreign studies are commonly accepted in support of new drugs, but approval requires at least one domestic trial unless the disease does not occur in the United States (for examply, tropical diseases).

After 5 years of use, cefazolin can be considered similar to cephalothin as a therapeutic agent and in its potential for adverse reactions. When cefazolin and cephalothin are compared by appropriately designed clinical trials, neither cefazolin's slightly greater in-vitro susceptibility to staphylococcal beta-lactamase inactivation, nor its slightly greater microbiologic activity for some enterobacteraciae has been shown to result in any readily apparent therapeutic differences. The important differences between cefazolin and cephalothin--and this is also probably true with respect to cephapirin and cephradine--are not in therapeutic effectiveness, microbiologic activity, or toxicity but rather in pharmacokinetics and cost-effectiveness.

In 14 healthy men we assessed the effects of smoking marihuana cigarettes containing 6 mg of delta-9-tetrahydrocannabinol on ultrasound measures of left ventricular function. Four of this group and four additional subjects also had measurements of plasma norepinephrine. Both heart rate and left ventricular performance (mean rate of internal diameter shortening [mean Vcf]) were significantly increased for at least 1 h after drug exposure compared with these values after placebo cigarettes. The immediate tachycardia and increase in mean Vcf were not accompanied by raised plasma norepinephrine levels. However, by 30 min after marihuana exposure, sympathetic neurotransmitter levels were significantly greater than both control values and those after placebo cigarettes, and they remained elevated for at least 2 h. Excessive sympathoadrenal discharge, as evidenced by augmented left ventricular function and prolonged catecholamine release, could adversely affect patients with heart disease.

To ascertain whether exercise could prevent involutional bone loss, we studied 18 postmenopausal women, half of whom exercised for 1 h three times a week. Total and regional bone mass were measured before and after 1 year of exercise by the techniques of total-body neutron activation analysis (total body calcium) and photon absorptiometry (bone mineral content) of the distal radius. Total body potassium was measured by whole body counting. Bone mineral content and total body potassium did not change significantly in either group. Total body calcium increased in the exercise group from 781 +/- 95 g of 801 +/- 118 g (SD). In contrast, total body calcium decreased in each subject in the sedentary group. The daily calcium balance derived from the difference in total body calcium measurements was significantly different in the two groups of women (P less than 0.001). These data support the hypothesis that exercise can modify involutional bone loss.

Alcoholism is a frequent complication of methadone treatment and is one of the few behaviors found to correlate with methadone treatment failure. To eliminate drinking among severely alcoholic patients, we tested the efficacy of incorporating methadone into a behavioral contingency to reinforce disulfiram ingestion. Methadone was dispensed to alcoholic narcotic addicts contingent upon their ingesting disulfiram, and as a control patients were urged to take disulfiram but received methadone regardless of whether they took disulfiram. The results indicated that the reinforced disulfiram treatment was highly successful in controlling alcoholism. In addition, nonstatistically significant trends suggested that the reinforced disulfiram treatment resulted in a superior adjustment, as reflected in arrest rate, unemployment, and illicit drug use. There appeared to be no significant physiologic or behavioral adverse effects.

Phleborheography, a recently described noninvasive test for deep venous thrombosis, was compared with leg venography in 75 patients. Acute deep venous thrombosis was accurately diagnosed by phleborheography in 24 patients, with no false-positive diagnoses. External venous compression without thrombosis was diagnosed correctly in two patients. The remaining patients appeared normal or had chronic venous disease by phleborheography; however, 11 of these had acute deep venous thrombosis by venography, for a false-negative rate of 31%. Most undetected thrombi were in small calf veins. The specificity of phleborheography is thus 100%, but the sensitivity is only 69%. Similarly, its positive predictive value is 100% and the negative predictive value is 78%. When phleborheography shows acute deep venous thrombosis, this diagnosis may be accepted with confidence and therapy chosen accordingly, without venographic confirmation. Venography may still be required to withhold anticoagulation when phleborheography is negative.

A controlled clinical trial compared three-drug and four-drug combination chemotherapy in 109 patients with advanced small-cell anaplastic carcinoma of the lung. The combination of vincristine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), cyclophosphamide, and methotrexate was significantly superior to the combination of the last three drugs alone with regard to median survival (230 versus 176 days) (P less than 0.01) and to duration of response (186 versus 112 days) (P less than 0.01). Objective response occurred in 78% and 75%, respectively. No significant difference in these values was observed in the comparison of the three subtypes of small-cell anaplastic carcinoma using the World Health Organization classification.

Cromolyn is a prototype of a new series of drugs, the pharmacologic activities of which may offer an entirely new approach in the treatment of asthma. Whereas bronchodilator drugs and steroids act primarily at tissue sites to counteract the effects of various toxic mediators released from tissue mast cells, cromolyn prevents the release of such mediators from mast cell membranes. The advent of cromolyn sodium therapy has been recognized as a significant advance by the pharmaceutical industry, which is rapidly developing a series of cromolyn-like drugs with similar properties. Many of these compounds are active orally, and some preliminary investigations suggest that they also could be clinically effective. Cromolyn has therapeutic value in immunologic and nonimmunologically induced bronchospasm, being particularly suited for conditions amenable to long-term prophylactic therapy. The risk-to-benefit ratio of cromolyn sodium therapy is excellent. Cromolyn sodium is an important adjunct in the treatment of asthma. By topical administration the drug has been effective in seasonal and perennial rhinoconjunctivitis and in selected cases of gastrointestinal allergy to foods.

Forty-seven patients with cholestatic jaundice were evaluated for extrahepatic biliary obstruction by ultrasonic cholangiography and the results verified by contrast cholangiography, celiotomy, or autopsy. Sonograms were evaluated both with ("official" reading) and without ("blind" reading) clinical information. By showing dilated bile ducts, sonography correctly diagnosed extrahepatic obstruction in 26 of 30 patients on "official" reading and 23 of 30 on "blind" reading. In all 17 patients without extrahepatic obstruction, sonography revealed the absence of dilated bile ducts. Among patients with extrahepatic obstruction, those with larger bile ducts had higher bilirubin concentrations, longer duration of jaundice, and were more reliably detected by sonography. In these patients, 94% with total bilirubin concentration greater than 10 mg/dl were detected by sonography, while 47% with total bilirubin concentration less than 10 mg/dl were detected. Although we recognize the limited sensitivity of sonography in early extrahepatic obstruction, we find it to be a valuable screening test in cholestatic jaundice.

To assess the value of continuous ambulatory electrocardiogram (ECG) monitoring for detecting coronary artery disease in symptomatic patients, we evaluated 70 patients with chest pain and normal resting ECGs prospectively by calibrated ambulatory monitoring, graded treadmill exercise, and selective coronary cineangiography. Ischemic-type ST-wave changes were detected by monitoring in 24 of the 39 patients with coronary artery disease (62% sensitivity). Twenty-six of the 39 patients had a positive treadmill (67% sensitivity). Of the 31 patients without coronary disease on angiography, 19 had negative monitoring studies (61% specificity). The treadmill was negative in 23 of these 31 patients (75% specificity). When the results of both tests were combined, 85% of the cases of coronary artery disease were detected, but only 52% of the patients without disease had negative studies. We conclude that continuous ambulatory monitoring is of limited value for detecting or excluding coronary artery disease in symptomatic patients with normal resting ECGs.