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OBJECTIVE: To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis. SETTING: Ninety-one academic medical center intensive care units in North America and Europe. PATIENTS: Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo. INTERVENTIONS: Patients were randomized to receive either rhIL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/kg/hr) or placebo. MEASUREMENTS AND MAIN RESULTS: The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. No excess number of adverse reactions or microbial superinfections were attributable to rhIL-1ra treatment in this study. CONCLUSIONS: A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

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OBJECTIVES: To investigate a novel anticytokine therapy in patients with sepsis syndrome, and the relationship between a patient's baseline mortality risk and survival benefit. DESIGN: Data from a recent phase III, double-blind, placebo-controlled, multicenter clinical trial with patients randomized to three treatment arms: an intravenous loading dose of recombinant human interleukin-1-receptor antagonist (rhIL-1ra) or placebo, followed by a continuous infusion of rhIL-1ra (1.0 mg/kg/hr, or 2.0 mg/kg/hr), or placebo for 72 hrs. SETTING: Sixty-three investigative centers in eight countries. PATIENTS: The study population consisted of 893 patients: 302 placebo patients; 298 patients treated with 1.0 mg/kg/hr of rhIL-1ra; and 293 patients treated with 2.0 mg/kg/hr of rhIL-1ra. MEASUREMENTS AND MAIN RESULTS: An independent, sepsis-specific, log-normal regression model that predicts the risk of mortality over 28 days was applied to all patients enrolled into the rhIL-1ra sepsis study. The ability of the Predicted Risk of Mortality model to predict 28-day mortality in the placebo patients was determined and the relationship between mortality risk and efficacy of rhIL-1ra was investigated. The trial data were also analyzed using two other risk-assessment models for comparison with Predicted Risk of Mortality. A significant increase in survival time was demonstrated for all patients treated with rhIL-1ra (n = 893, p < .02 Predicted Risk of Mortality log-normal), but patients with a Predicted Risk of Mortality of < 24% derived little benefit. Retrospective examination of time-to-death data demonstrated that rhIL-1ra reduced risk of death in the first 2 days for patients with > or = 24% Predicted Risk of Mortality (n = 580, p < .005 Predicted Risk of Mortality log-normal). This same effect was not present in patients with a Predicted Risk of Mortality of < 24% on entry into the study. The Predicted Risk of Mortality model predicted a 28-day mortality rate of 35% for placebo patients compared with 34% observed and accurately stratified patients along the full range of risks. There was a wide distribution of individual patient risks for 28-day mortality for all patients, as well as within categorical subgroups, such as shock and organ system dysfunction. Two alternate risk models were assessed and the Acute Physiology Score of Acute Physiology and Chronic Health Evaluation III also demonstrated a statistically significant survival benefit for rhIL-1ra (p = .04 Predicted Risk of Mortality log-normal) for all patients treated. CONCLUSIONS: Using an appropriate analytic model, a statistically significant increase in survival time from rhIL-1ra was measured. A direct relationship was found between a patient's Predicted Risk of Mortality at study entry to efficacy of rhIL-1ra. Individual risk or severity assessment may be a useful tool for evaluating the clinical benefit of new therapeutic approaches to sepsis and for monitoring outcomes at the bedside.

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Clinical trials of anticytokines in sepsis have not been as straightforward as had been anticipated from results in animal models of sepsis and the role of cytokines in sepsis is now in question. Retrospective analysis of the results of a phase III trial of interleukin-1 (IL-1) receptor antagonist suggests that sepsis-induced adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), renal dysfunction, and shock are valuable markers of patients in whom IL-1 is a pathogenic mediator and in whom IL-1ra can reduce mortality. A re-examination of the effects of IL-1ra in animal models of sepsis supports the validity of this analysis. A new phase III clinical trial will confirm or disprove the hypothesis that IL-1 is a mediator of pathology, and IL-1ra is a valuable therapy for sepsis complicated by ARDS, DIC, renal dysfunction, or shock.

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The virulence of 24 strains of Mycobacterium avium complex (MAC) isolated from patients with acquired immune deficiency syndrome (AIDS) was assessed using the beige mouse model. Most changes in colony forming unit (cfu) counts in spleen and lungs, and spleen weights occurred between days 1 and 14, with comparatively smaller changes 14-28 days postinfection. The virulence was assessed by a score formulated from the four most useful parameters: mortality, spleen cfu, lung cfu and spleen weights at 28 days. The scores of the 24 strains showed a normal distribution; four strains falling above one standard deviation from the mean were classified as high virulent, those four falling below one standard deviation as low virulent, and the remaining 16 as of intermediate virulence. Virulence was associated with the total number of plasmids and the occurrence of large plasmids (greater than 100 MDa) in the MAC strains. There was an inverse correlation between virulence and the organism's capacity to trigger the release of oxygen metabolites from peritoneal macrophages. Macrophages from mice infected with the MAC strains of different degrees of virulence released superoxide anion (O2-) with a peak at two weeks, the peak levels bearing an inverse correlation to virulence. No association was seen between virulence and source of specimens, biochemical characteristics, drug susceptibility, serotypes or phage types.

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Abnormalities in fitness in asthmatic children are assumed to derive from illness severity. We studied 90 children with moderately severe to severe but stable asthma for (1) fitness levels using bicycle ergometry, (2) measures of asthma severity, (3) clinician's impression of child (Child Global Assessment Scale), and (4) mother's rating of child's behavior (Child Behavior Checklist). Fitness values ranged from 15% to 120% of normal values for age, sex, and body surface area: 48% were abnormal (less than 2 SD below mean) and 5% were borderline (1 to 2 SD below mean). Associations between levels of fitness and medical and psychologic criteria were tested using regression analyses. Of the 11 medical variables used to define the severity of asthma, recent exacerbation of disease, forced expiratory volume in 1 second, and specific airway conductance together accounted for 8.1% of the variability in the workload ratios (ie, R2 = 0.081). The importance of the psychologic factors in determining the variability in the workload ratios was tested after the importance of the medical variables had been considered: Child Global Assessment Scale accounted for a significant amount of variability, improving the R2 to 0.180 (an increase to 0.100, P = .003). These data suggest that, within the spectrum of disease presented by the patients in this study, adjustment to the disease is at least as important as severity of disease in determining fitness.

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We have documented performance on standardized academic achievement tests for reading and mathematics in 99 children with moderately severe to severe chronic asthma. Academic performance and intelligence test scores indicated that, overall, the academic capabilities of the children with asthma were average to above average. A stepwise regression analysis was used to examine relationships between the dependent variables of reading and mathematics and the independent variables of socioeconomic status, school attendance, medical factors relating to asthma, age, and emotional and behavioral problems of the children. Factors that were associated significantly with low performance scores were low socioeconomic status, older age, history of continuous oral steroid use (prednisone or methyl prednisolone taken at least every other day for the year prior to evaluation), and presence of emotional and behavioral problems. School absenteeism, use of medical resources, oral steroid dosage, other medications used to treat asthma, and pulmonary functions were not associated with academic performance. Investigation of poor classroom performance of a child with chronic asthma should include investigation of the roles of socioeconomic status, oral steroid therapy, and emotional and behavioral problems.

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Children whose asthma continues to be poorly controlled with outpatient management are often referred to a long-term hospital program for care. Although these programs have been in existence since the 1950s, there has been no systematic study of their effectiveness. The purpose of the present study was to determine outcome in 103 children discharged consecutively after a long-term hospitalization. These children had both severe asthma and significant psychologic problems. Eighty-three of the 103 children had required continuous or frequent intermittent steroids for asthma control. In the year before admission, they had been hospitalized for asthma a mean of 2.6 times for 11.8 days and had had 4.6 visits to emergency rooms and 6.6 visits to physician offices for acute wheezing. Use of medical resources for asthma decreased significantly in the year after long-term hospitalization compared to the year before hospitalization (hospitalization: -34%, p less than 0.0001; hospital days: -39%, p less than 0.0002; emergency room visits: -46%, p less than 0.00001; physician office visits for acute asthma, -42%; p less than 0.00001; and a composite score giving increasing weight to more intensive and costly care: -30%, p less than 0.0001). Long-term hospitalization for children with asthma not responsive to outpatient management is associated with improvement in their use of medical resources.

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We explored the potential proinflammatory effect of prostaglandins of the E series (PGE's) in a rabbit model of acute pulmonary inflammation. The instillation of fragments of the fifth component of complement (C5f) into the lung resulted in a localized area of inflammation, the extent of which was quantified by the total number of neutrophils and protein recoverable by bronchoalveolar lavage (BAL). Utilizing 111In-labeled neutrophils and serial scintigraphy, neutrophil localization in the area of inflammation was detected as early as 20 min after C5f instillation and reached a maximum between 2 and 4 h. The simultaneous intrabronchial administration of 100 micrograms of PGE2 resulted in a twofold increase in the accumulation of neutrophils in the area of inflammation as determined scintigraphically, a fivefold increase in BAL neutrophils, and a threefold increase in BAL protein. A proinflammatory effect on lavage constituents was also seen with the intravenous administration of PGE2 (100 ng.kg-1.min-1) and PGE1 (50 ng.kg-1.min-1) as well as in animals pretreated with a PGH synthase inhibitor, meclofenamate, and a thromboxane synthase inhibitor, dazmegrel. The effect of intrabronchial PGE2 to potentiate the inflammatory response was attenuated by the intravenous administration of a vasoconstrictor (angiotensin II) and mimicked by a vasodilator (nitroprusside), suggesting an effect of vasodilation per se. Using radiolabeled microspheres, it was determined that in response to the C5f alone, there was a 50% decrease in local blood flow to the area of inflammation, a pattern different from that seen in the systemic circulation. This decrease was prevented by the concomitant administration of PGE2 or nitroprusside. We conclude that vasodilation induced by PGE2 is associated with enhancement of pulmonary inflammation.

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Several reports have documented characteristics of children who die of asthma; however, to the best of our knowledge, no studies have used case controls to clarify the clinical characteristics associated with death. We conducted a case-controlled study of 21 patients with severe asthma hospitalized between 1973 and 1982 who died of asthma sometime following discharge. Average age at death was 13 years (range, 8 to 18 years). Twenty-one asthmatic control cases were matched for age at the time of hospitalization, sex, and severity of illness. Hospital records were evaluated for 57 physiologic and psychological variables. A stepwise discriminant analysis determined that the following eight variables could discriminate the two groups effectively: history of seizures associated with an asthma attack; conflicts between the patient's parents and hospital staff regarding medical management of the patient; self-care of asthma while in the hospital that was not appropriate for age; prednisone dosage having been decreased by more than 50% during the course of hospitalization; inhaled beclomethasone dipropionate required for treatment; increased asthmatic symptoms during the week preceding discharge; depressive symptoms; and disregard of asthmatic symptoms. Most of the clinical characteristics previously thought to place patients at greater risk for a fatal asthmatic attack were found as often in the control cases as in the children who died. This study indicates that psychologic risk factors were prominent in severely asthmatic children who subsequently died of asthma. The variables defined in this study may be important in identifying patients who are at high risk for dying of asthma and in developing treatment plans to prevent deaths.

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Liquefied natural gas (LNG) densities can be measured directly but are usually determined indirectly in custody transfer measurement by using a density correlation based on temperature and composition measurements. An LNG densimeter test facility at the National Bureau of Standards uses an absolute densimeter based on the Archimedes principle, while a test facility at Gaz de France uses a correlation method based on measurement of composition and density. A comparison between these two test facilities using a portable version of the absolute densimeter provides an experimental estimate of the uncertainty of the indirect method of density measurement for the first time, on a large (32 L) sample. The two test facilities agree for pure methane to within about 0.02%. For the LNG-Iike mixtures consisting of methane, ethane, propane, and nitrogen with the methane concentrations always higher than 86%, the calculated density is within 0.25% of the directly measured density 95% of the time.