The New England Journal of Medicine

Baker, Carol J.; Melish, Marian E.; Hall, Robert T.; Casto, Daniel T.; Vasan, Ushanalini; Givner, Laurence B.; ,

doi: 10.1056/NEJM199207233270401pmid: 1614462

AbstractBackground.Nosocomial infection is a major risk for premature infants with very low birth weights. One reason for their susceptibility to infection may be antibody deficiency, since there is little transfer of maternal IgG to the fetus before 32 weeks' gestation.Methods.We conducted a multicenter, double-blind study of neonates weighing 500 to 1750 g at birth. A total of 588 neonates were randomly assigned, with stratification for birth weight, to receive periodic intravenous infusions of either immune globulin (500 mg per kilogram of body weight per day) or a placebo. Mortality, morbidity, and nosocomial infection during the next 56 days were assessed.Results.The infusions were well tolerated; mild, reversible adverse reactions occurred in five infants in each group. There was a significant reduction in the risk of a first nosocomial infection in the recipients of immune globulin as compared with the placebo recipients (relative risk, 0.7; 95 percent confidence interval, 0.5 to 0.9). About 85 percent of the nosocomial infections were bacterial; the majority of these were caused by coagulase-negative staphylococci or Staphylococcus aureus. The neonates who received immune globulin had fewer mean days of hospitalization than the controls (62 vs. 68, P = 0.15); among the infants with infections, the difference in the mean length of the hospital stay was even greater (80 days vs. 101 days, P = 0.02).Conclusions.For premature infants weighing between 500 and 1750 g at birth, treatment with intravenous infusions of immune globulin is safe and reduces the risk of nosocomial infection. (N Engl J Med 1992;327: 213–9.)

Pyzdrowski, Kathryn L.; Kendall, David M.; Halter, Jeffrey B.; Nakhleh, Raouf E.; Sutherland, David E.R.; Robertson, R. Paul

doi: 10.1056/NEJM199207233270402pmid: 1614463

AbstractBackground.Transplantation of pancreatic islets, rather than whole pancreas, has been introduced as a treatment for diabetes mellitus. We studied five patients ranging in age from 12 to 37 years who had severe chronic pancreatitis for which they underwent total pancreatectomy followed by isolation and hepatic transplantation of their own islets.Methods.All patients had remained insulin-independent for 1 to 7 1/2 years after transplantation. The numbers of islets transplanted ranged from 110,000 to 412,000. Islet function was assessed by measuring the plasma insulin responses to intravenous glucose and arginine and the plasma glucagon responses to hypoglycemia and arginine. In one patient, islet function was studied during catheterization of the hepatic vein, portal vein, and splenic artery and by analysis of a liver-biopsy specimen.Results.After transplantation, the mean (±SD) fasting plasma glucose concentration was 122±47 mg per deciliter (6.8±2.6 mmol per liter) and the hemoglobin A1c concentration was 6.0±0.8 percent in the five patients. The values were most abnormal — 214 mg per deciliter (11.9 mmol per liter) and 7.3 percent, respectively — in the patient who received only 110,000 islets. The acute plasma insulin responses to glucose and to arginine in the five patients were 23±13 and 26±10 μU per milliliter (168±94 and 184±70 pmol per liter), respectively, as compared with 58±6 and 37±8 μU per milliliter (416±44 and 267±61 pmol per liter) in the normal subjects. The peak plasma glucagon responses to insulin and arginine were 21±4 and 65±36 pg per milliliter, respectively, as compared with 125±28 and 156±99 pg per milliliter in the normal subjects. All five patients had plasma epinephrine but not pancreatic polypeptide responses to hypoglycemia. The results of the hepatic-vein catheterization in one patient indicated that the transplanted islets released insulin and glucagon in response to arginine. Immunoperoxidase staining of this patient's liver-biopsy specimen showed that the islets contained insulin, glucagon, and somatostatin but not pancreatic polypeptide.Conclusions.Intrahepatic transplantation of as few as 265,000 islets can result in the release of insulin and glucagon at appropriate times and in prolonged periods of insulin independence. (N Engl J Med 1992;327: 220–6.)

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doi: 10.1056/NEJM199207233270403pmid: 1377359

AbstractBackground.The Cardiac Arrhythmia Suppression Trial (CAST) tested the hypothesis that the suppression of asymptomatic or mildly symptomatic ventricular premature depolarizations in survivors of myocardial infarction would decrease the number of deaths from ventricular arrhythmias and improve overall survival. The second CAST study (CAST-II) tested this hypothesis with a comparison of moricizine and placebo.Methods.CAST-II was divided into two blinded, randomized phases: an early, 14-day exposure phase that evaluated the risk of starting treatment with moricizine after myocardial infarction (1325 patients), and a long-term phase that evaluated the effect of moricizine on survival after myocardial infarction in patients whose ventricular premature depolarizations were either adequately suppressed by moricizine (1155 patients) or only partially suppressed (219 patients).Results.CAST-II was stopped early because the first 14-day period of treatment with moricizine after a myocardial infarction was associated with excess mortality (17 of 665 patients died or had cardiac arrests), as compared with no treatment or placebo (3 of 660 patients died or had cardiac arrests); and estimates of conditional power indicated that it was highly unlikely (<8 percent chance) that a survival benefit from moricizine could be observed if the trial were completed. At the completion of the long-term phase, there were 49 deaths or cardiac arrests due to arrhythmias in patients assigned to moricizine, and 42 in patients assigned to placebo (adjusted P = 0.40).Conclusions.As with the antiarrhythmic agents used in CAST-I (flecainide and encainide), the use of moricizine in CAST-II to suppress asymptomatic or mildly symptomatic ventricular premature depolarizations to try to reduce mortality after myocardial infarction is not only ineffective but also harmful. (N Engl J Med 1992;327:227–33.)

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doi: 10.1056/NEJM199207233270404pmid: 1614464

AbstractBackground.Infections and their sequelae are a major cause of death among patients admitted to the surgical intensive care unit (ICU). Studies of passive immunotherapy with standard intravenous immune globulin and hyperimmune globulin directed against gram-negative core lipopolysaccharide to prevent gram-negative infections and their serious systemic complications have had equivocal results in such patients.Methods.We performed a double-blind study to assess the efficacy of standard immune globulin and core-lipopolysaccharide hyperimmune globulin in preventing infections in surgical patients at high risk. The patients received standard immune globulin (400 mg per kilogram of body weight), hyperimmune globulin (400 mg per kilogram), or placebo (25 percent albumin, 8 ml per kilogram) weekly, for a maximum of four doses while in the ICU.Results.A total of 352 patients were enrolled, and 329 could be evaluated. The number of patients in whom infections developed was significantly lower in the group receiving standard immune globulin than in the placebo group (36 of 109 vs. 53 of 112 patients, P = 0.03), as was the incidence of pneumonia (15 vs. 30 cases, P = 0.04), especially pneumonia due to gram-negative bacteria (5 vs. 16 cases, P = 0.02). The number of days spent in the ICU and the total days spent in the hospital were lower in the standard immune globulin group (medians of 2 and 7.5 days fewer; P = 0.02 and 0.06, respectively). In contrast, the hyperimmune globulin had no detectable prophylactic effect on infections (50 of 108 patients, with 25 cases of pneumonia). The rate of systemic infections and shock was similar in the three study groups, and hospital mortality did not differ significantly among them.Conclusions.Intravenous immune globulin given prophylactically to selected high-risk patients in the surgical ICU can reduce the incidence of infection. Core-lipopolysaccharide hyperimmune globulin is not effective in preventing gram-negative infections and their systemic complications. (N Engl J Med 1992;327:234–40.)

Lamas, Gervasio A.; Pfeffer, Marc A.; Hamm, Peggy; Wertheimer, John; Rouleau, Jean-Lucien; Braunwald, Eugene; ,

doi: 10.1056/NEJM199207233270405pmid: 1535419

AbstractBackground.Medical practice patterns change in response to a variety of stimuli, one of which may be the publication of the results of randomized clinical trials. We assessed the temporal association between the publication of clinical trials on myocardial infarction and changes in treatment practices for this disorder.Methods.We analyzed the use of aspirin before and after myocardial infarction and that of calcium antagonists after myocardial infarction in 2231 survivors of myocardial infarction enrolled in the Survival and Ventricular Enlargement (SAVE) study over a three-year period (from January 1987 through January 1990). The proportion of patients using these treatments was analyzed before and after the publication dates of three clinical trials: the Physicians' Health Study, published in January 1988, which supported the use of aspirin to prevent a first myocardial infarction; the Second International Study of Infarct Survival (ISIS-2), published in August 1988, which supported the use of aspirin after myocardial infarction; and the Multicenter Diltiazem Postinfarction Trial, published in August 1988, which reported a deleterious effect of diltiazem in some patients after myocardial infarction.Results.The use of aspirin before myocardial infarction increased from 16.2 percent to 23.9 percent between January 1987 and January 1990 (P<0.001 ). Enrollment in the study after the publication of the Physicians' Health Study independently predicted aspirin use before myocardial Infarction (odds ratio, 1.43; 95 percent confidence interval, 1.11 to 1.85). The use of aspirin after myocardial infarction increased from 38.8 percent to 71.9 percent (P<0.001) during the three-year study period. Enrollment in the study after the publication of ISIS-2 independently predicted the use of aspirin after myocardial infarction (odds ratio, 2.28; 95 percent confidence interval, 1.89 to 2.76). The use of calcium antagonists after myocardial infarction decreased from 57.1 percent to 33.1 percent (P<0.001) during the study period. Enrollment in the study after the publication of the Multicenter Diltiazem Postinfarction Trial independently predicted the use of calcium antagonists after myocardial infarction (odds ratio, 0.47; 95 percent confidence interval, 0.39 to 0.57).Conclusions.These observations suggest that randomized clinical trials have a measurable influence on medical practice patterns. (N Engl J Med 1992;327: 241–7.)

Lau, Joseph; Antman, Elliott M.; Jimenez-Silva, Jeanette; Kupelnick, Bruce; Mosteller, Frederick; Chalmers, Thomas C.

doi: 10.1056/NEJM199207233270406pmid: 1614465

AbstractBackground.The large volume of published randomized, controlled trials has led to a need for meta-analyses to track therapeutic advances. Performing a new meta-analysis whenever the results of a new trial of a particular therapy are published permits the study of trends in efficacy and makes it possible to determine when a new treatment appears to be significantly effective or deleterious. We describe the use of such a procedure, cumulative meta-analysis, to assess therapeutic trials among patients with myocardial infarction.Methods.We performed cumulative meta-analyses of clinical trials that evaluated 15 treatments and preventive measures for acute myocardial infarction.Results.An example of this method is its application to the use of intravenous streptokinase as thrombolytic therapy for acute infarction. Thirty-three trials evaluating this therapy were performed between 1959 and 1988. We found that a consistent, statistically significant reduction in total mortality (odds ratio, 0.74; 95 percent confidence interval, 0.59 to 0.92) was achieved in 1973, after only eight trials involving 2432 patients had been completed. The results of the 25 subsequent trials, which enrolled an additional 34,542 patients through 1988, had little or no effect on the odds ratio establishing efficacy, but simply narrowed the 95 percent confidence interval. In particular, two very large trials, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial in 1986 (11,712 patients) and the Second International Study of Infarct Survival trial in 1988 (17,187 patients) did not modify the already established evidence of efficacy. We used a similar approach to study the accumulating evidence of efficacy (or lack of efficacy) of 14 other therapies and preventive measures for myocardial infarction.Conclusions.Cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm and may be helpful in tracking trials, planning future trials, and making clinical recommendations for therapy. (N Engl J Med 1992;327:248–54.)

Clyne, Christopher A.; Estes, N.A. Mark; Wang, Paul J.

doi: 10.1056/NEJM199207233270407pmid: 1614466

MORICIZINE hydrochloride was first synthesized in the Soviet Union in 1964,1 2 3 and after pharmacologic and clinical evaluation in the United States4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 it was approved by the Food and Drug Administration in June 1990 to treat documented life-threatening ventricular arrhythmias. The drug (molecular weight, 464) is a phenothiazine derivative, with a carbamic ethol ester side chain attached to the second position of the phenothiazine ring (10-(3-morpholinopropionyl) phenothiazine-2-carbamic acid ethol ester hydrochloride) (Fig. 1). It is chemically unrelated to any currently approved antiarrhythmic drug,20 21 22 23 24 25 and despite having a phenothiazine structure, it lacks dopamine-antagonist activity and the behavioral and autonomic actions of neuroleptic . . .

Holtzman, D.; Hedley-Whyte, E.T.

doi: 10.1056/NEJM199207233270408pmid: 1614467

Presentation of Case A boy died at the age of 56 months after having had for most of his life a progressive neurodegenerative disorder, characterized by a gradual loss of motor and verbal skills, with generalized seizures, myoclonus, and final deterioration to a nonverbal, quadriparetic state. The patient was born by uncomplicated vaginal delivery after 42 weeks of gestation, the third pregnancy of a mother 33 years of age. His Apgar scores were 8 at one minute and 9 at five minutes; the birth weight was 4.2 kg. At four weeks of age the head circumference was 39.5 cm (97th . . .

Siber, George R.

doi: 10.1056/NEJM199207233270409pmid: 1614468

With the introduction of intravenous formulations, the use of immune globulins, once limited to IgG replacement in severe humoral immunodeficiencies, has been extended to include the prevention or treatment of a wide variety of infections and immunologic disorders.1,2 Though the role of immune globulin in the prevention of systemic and sinopulmonary bacterial infections in agammaglobulinemia is well established, its role in the management of more subtle humoral immunodeficiencies associated with B-cell neoplasms, bone marrow transplantation, and IgG-subclass deficiencies remains controversial.1,2 In premature babies, a physiologic hypogammaglobulinemia due to reduced transplacental transfer and endogenous synthesis of IgG provides a strong rationale . . .

Barker, Clyde F.; Naji, Ali

doi: 10.1056/NEJM199207233270410pmid: 1614469

The article by Pyzdrowski et al. on transplantation of pancreatic-islet autografts in this issue of the Journal1 raises several important questions. Is the transplantation of islet autografts appropriate therapy for patients disabled by painful chronic pancreatitis? What do these results tell us about the transplantation of islet allografts? What questions remain to be answered before transplantation of islets or the pancreas can become successful therapy for patients with insulin-dependent diabetes mellitus? If islet transplantation is ever to be acceptable therapy for any condition, it must first be demonstrated that free grafts of isolated islets can function in humans. Despite a . . .