Steven M. Banks

Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial.

Infection with the hepatitis C virus may result in chronic liver disease for which no effective therapy is now available. We studied the effects of recombinant human interferon alfa in a prospective, randomized, double-blind, placebo-controlled trial in patients with well-documented chronic hepatitis C. Forty-one patients were enrolled in the trial, 37 of whom were later found to have antibody to hepatitis C virus. Twenty-one patients received interferon alfa (2 million units) subcutaneously three times weekly for six months, and 20 received placebo. The mean serum aminotransferase levels and the histologic features of the liver improved significantly in the patients treated with interferon but not in the patients given placebo. Ten patients treated with interferon (48 percent) had a complete response, defined as a decline in mean serum aminotransferase levels to the normal range during therapy; three others had a decrease in mean aminotransferase levels of more than 50 percent. After treatment ended, however, serum aminotransferases usually returned to pretreatment levels; 6 to 12 months after the discontinuation of interferon therapy, only two patients (10 percent) still had normal values. We conclude that interferon alfa therapy is beneficial in reducing disease activity in chronic hepatitis C; however, the beneficial responses are often transient.

Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: A meta-analysis

CONTEXT Hemoglobin-based blood substitutes (HBBSs) are infusible oxygen-carrying liquids that have long shelf lives, have no need for refrigeration or cross-matching, and are ideal for treating hemorrhagic shock in remote settings. Some trials of HBBSs during the last decade have reported increased risks without clinical benefit. OBJECTIVE To assess the safety of HBBSs in surgical, stroke, and trauma patients. DATA SOURCES PubMed, EMBASE, and Cochrane Library searches for articles using hemoglobin and blood substitutes from 1980 through March 25, 2008; reviews of Food and Drug Administration (FDA) advisory committee meeting materials; and Internet searches for company press releases. STUDY SELECTION Randomized controlled trials including patients aged 19 years and older receiving HBBSs therapeutically. The database searches yielded 70 trials of which 13 met these criteria; in addition, data from 2 other trials were reported in 2 press releases, and additional data were included in 1 relevant FDA review. DATA EXTRACTION Data on death and myocardial infarction (MI) as outcome variables. RESULTS Sixteen trials involving 5 different products and 3711 patients in varied patient populations were identified. A test for heterogeneity of the results of these trials was not significant for either mortality or MI (for both, I2 = 0%, P > or = .60), and data were combined using a fixed-effects model. Overall, there was a statistically significant increase in the risk of death (164 deaths in the HBBS-treated groups and 123 deaths in the control groups; relative risk [RR], 1.30; 95% confidence interval [CI], 1.05-1.61) and risk of MI (59 MIs in the HBBS-treated groups and 16 MIs in the control groups; RR, 2.71; 95% CI, 1.67-4.40) with these HBBSs. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication. CONCLUSION Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI.

The impact of overtime and long work hours on occupational injuries and illnesses : new evidence from the United States

Aims: To analyse the impact of overtime and extended working hours on the risk of occupational injuries and illnesses among a nationally representative sample of working adults from the United States. Methods: Responses from 10 793 Americans participating in the National Longitudinal Survey of Youth (NLSY) were used to evaluate workers’ job histories, work schedules, and occurrence of occupational injury and illness between 1987 and 2000. A total of 110 236 job records were analysed, encompassing 89 729 person-years of accumulated working time. Aggregated incidence rates in each of five exposure categories were calculated for each NLSY survey period. Multivariate analytical techniques were used to estimate the relative risk of long working hours per day, extended hours per week, long commute times, and overtime schedules on reporting a work related injury or illness, after adjusting for age, gender, occupation, industry, and region. Results: After adjusting for those factors, working in jobs with overtime schedules was associated with a 61% higher injury hazard rate compared to jobs without overtime. Working at least 12 hours per day was associated with a 37% increased hazard rate and working at least 60 hours per week was associated with a 23% increased hazard rate. A strong dose-response effect was observed, with the injury rate (per 100 accumulated worker-years in a particular schedule) increasing in correspondence to the number of hours per day (or per week) in the workers’ customary schedule. Conclusions: Results suggest that job schedules with long working hours are not more risky merely because they are concentrated in inherently hazardous industries or occupations, or because people working long hours spend more total time “at risk” for a work injury. Strategies to prevent work injuries should consider changes in scheduling practices, job redesign, and health protection programmes for people working in jobs involving overtime and extended hours.

A classification tree approach to the development of actuarial violence risk assessment tools

Since the 1970s, a wide body of research has suggested that the accuracy of clinical risk assessments of violence might be increased if clinicians used actuarial tools. Despite considerable progress in recent years in the development of such tools for violence risk assessment, they remain primarily research instruments, largely ignored in daily clinical practice. We argue that because most existing actuarial tools are based on a main effects regression approach, they do not adequately reflect the contingent nature of the clinical assessment processes. To enhance the use of actuarial violence risk assessment tools, we propose a classification tree rather than a main effects regression approach. In addition, we suggest that by employing two decision thresholds for identifying high- and low-risk cases--instead of the standard single threshold--the use of actuarial tools to make dichotomous risk classification decisions may be further enhanced. These claims are supported with empirical data from the MacArthur Violence Risk Assessment Study.

Meta-Analysis: The Effect of Steroids on Survival and Shock during Sepsis Depends on the Dose

Despite effective antibiotics, septic shock remains the most common cause of death in the intensive care unit, incurring a mortality rate of 30% to 50% (1, 2). Several therapies targeting the upregulated inflammatory pathways of sepsis have been studied to improve survival. However, few therapies have proven beneficial (3-10). In the 1960s, preclinical studies reported that high doses of glucocorticoids in models of Escherichia coli and endotoxic shock improved survival. These studies prompted the initiation of human sepsis trials (11-13). Subsequently, more than 50 human trials have examined the role of high-dose steroid therapy in sepsis. These trials administered doses of methylprednisolone as high as 30 to 120 mg/kg of body weight over 24 hours. Because the reported results of these trials were inconsistent, there was little consensus on the appropriate use of steroids in patients with septic shock. To clarify the treatment effects of high-dose steroids, 3 meta-analyses performed in the 1990s examined the more rigorously conducted randomized, controlled clinical trials of sepsis (7, 14, 15). The meta-analysis by Lefering and colleagues (14) incorporated 10 trials and found no overall beneficial effect of glucocorticoid therapy on mortality in septic patients (absolute difference in mortality rates between treatment and control groups, 0.2 percentage point [95% CI, 9.2 percentage points to 8.8 percentage points]). A second meta-analysis by Cronin and colleagues (15) examined 9 trials with variable effects (P= 0.02) and reported no evidence of a beneficial effect of high-dose steroids on mortality from sepsis (relative risk for death with treatment, 1.13 [CI, 0.99 to 1.29]). A third meta-analysis, performed by our group (7), examined the trials included in the previous meta-analyses. Nine trials, which were the same as those investigated by Cronin and colleagues (15), met inclusion criteria for that analysis (7). In this group of trials, we identified 1 study (16) as a statistical outlier that accounted for the variability reported by Cronin and colleagues. After exclusion of this outlier, our analysis revealed a homogenous group of 8 studies (P> 0.2) that demonstrated an overall increase in mortality associated with the use of high-dose steroids in septic patients (odds ratio of survival with treatment, 0.70 [CI, 0.55 to 0.91]; P= 0.008) (7). The increased mortality in these studies may have been due to the immunosuppressive effects of steroids, which led to more severe secondary infections (17-19). In response to these overall discouraging results, the use of high-dose glucocorticoids in septic patients decreased in the late 1980s and 1990s. Recently, interest in examining the role of the adrenal axis in sepsis has been renewed. Briegel and colleagues (20) reported that septic patients have an attenuated response to corticotropin stimulation testing during their acute illness. Furthermore, Annane and colleagues (21) demonstrated that a high cortisol level and an attenuated response to corticotropin stimulation indicate relative adrenal insufficiency during sepsis that may increase mortality. On the basis of these findings, several clinical trials have been performed to determine whether administering glucocorticoids in dosages similar to the amount produced physiologically during a stressful state (that is, 300 mg of cortisol per day) affects outcome in septic patients. We performed the current study to update our previous meta-analysis and compare recent clinical trials with previous clinical trials of steroid use in patients with sepsis (22). Methods Literature Search We searched MEDLINE for medical literature published from 1988 to December 2003 by using the following keywords: steroids and sepsis, steroids and septic shock, glucocorticoids and sepsis, glucocorticoids and septic shock, corticosteroids and sepsis, and corticosteroids and septic shock. Studies were included if they met all of the following criteria: randomized, controlled trial design; enrollment of adult patients who met criteria for sepsis or septic shock; and a primary end point, including either the discontinuation of vasopressor therapy or a change in survival comparing glucocorticoid treatment with a control group with or without placebo. Included studies must have administered similar treatments to both the control and steroid groups, with the exception of the administration of a predetermined glucocorticoid regimen. Criteria for sepsis or septic shock needed to be clearly defined in each study and be consistent with the American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference (23) definition for sepsis (including documented site or strong suspicion of infection, temperature > 38 C or < 36 C, heart rate > 90 beats/min, respiratory rate > 20 breaths/min, and leukocyte count > 12 109 cells/L), severe sepsis (sepsis plus organ dysfunction; hypotension or hypoperfusion, including oliguria, altered mental status, or lactate acidosis), and septic shock (hypotension despite fluid resuscitation plus hypoperfusion abnormalities) (23). Data Collection Two investigators trained in critical care medicine independently reviewed the included studies by using a standardized protocol and data collection form. A third author trained in critical care medicine evaluated and resolved discrepancies. We collected data on patient characteristics, study characteristics, treatment interventions, and treatment outcomes. Abstracted data included the presence of sepsis, severe sepsis, or septic shock; type, dose, and duration of glucocorticoid administered; incidence and severity of secondary infections; response to corticotropin stimulation testing; the number of patients with shock reversal; and the number of patient deaths. We evaluated the quality of the included trials by assessing the method and adequacy of randomization, blinding protocols, completeness of follow-up, adherence to treatment protocols, and co-interventions or treatments to each group in the studies. Our primary goal was to compare the effect of glucocorticoid administration on survival in the recent studies with the effects reported in the previously analyzed trials (22). Since the glucocorticoid regimen differed among the trials, we converted all dosages to hydrocortisone equivalents (24). Statistical Analysis Survival data were analyzed by using a Cochran-Mantel-Haenszel test to estimate the pooled effect of steroids (25). The similarity of the effect across studies was assessed by using a Breslow-Day test and reported with an I2 value (26, 27). When statistically significant heterogeneity of treatment effects was observed, studies were partitioned (for example, early vs. late studies) to decrease the heterogeneity of studies in a particular partition and increase the differences among the partitions, which can be seen when the I2 value is substantially lower in each partition as compared with the overall I2 value (28). One study increased the I2 value substantially in the set of early studies and was removed from all subsequent analyses. Partitioning variables were determined by regressing study characteristics (for example, steroid dose in first 24 hours) on mortality, specifically the log relative survival benefit (29). Regression was performed by using an inverse-variance-weighted restricted maximum likelihood random-effects method. When the regression was performed by using log steroid dose in the first 24 hours as the independent variable, 1 study was observed to be both a statistical outlier and influential. An indicator variable for this study was included in the regression analysis. Similar estimates of the slope associated with the effect of log steroid dose in the first 24 hours were observed when the influential study was removed and for early and late studies separately. A regression analysis that included control group mortality rate as an additional independent variable did not change the relationship between steroid dose in the first 24 hours and relative survival benefit. All pooled relative survival benefits are reported with associated 95% CIs by using a fixed-effects model. Random-effects estimates of survival were also calculated and reported. Statistically significant differences in characteristics between early and late studies were assessed by using analysis of variance (ANOVA) (when a weighted analysis was needed) or a 2-sample Wilcoxon test (when an unweighted analysis was performed). To analyze the different types of severity of illness scores used in the studies, we computed an effect size for each. This effect size was calculated by determining the difference between the mean steroid severity score and the mean control severity score, divided by the control standard deviation in each study. Role of the Funding Sources The Warren G. Magnuson Clinical Center at the National Institutes of Health, Bethesda, Maryland, provided intramural funds for this study. The funding source played no role in the design, conduct, or reporting of the study or decision to submit the manuscript for publication. Data Synthesis Comparison of Study Methods Since 1988, more than 1300 articles on steroids and sepsis have been published. Five randomized, controlled trials, all published after 1997, met inclusion criteria and were included in our analysis (30-34) (Figure 1). Four of these studies were published manuscripts, and 1 study was reported in abstract form (33). Figure 1. Flow diagram of the published articles evaluated for inclusion in this meta-analysis. The 5 studies published after 1997 were randomized, double-blind, placebo-controlled trials (Table 1). Each study listed specific inclusion and exclusion criteria that were consistent with American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference definitions of sepsis and septic shock (23). Each study used a severity of illness score (Simplified Ac

Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3–6 months after immunization

Formalin-inactivated (FI) RSV, purified F glycoprotein in alum, and RSV infection (intranasal) were compared for their immunogenicity, efficacy, and ability to enhance pulmonary histopathology during RSV infection 3 and 6 months following immunization by the intramuscular route. Purified influenza virus in alum was used as a control immunogen. At 1 month following immunization with one dose of purified F glycoprotein (5 micrograms), cotton rats developed levels of F antibodies (ELISA) higher than the other groups, but these antibodies had the lowest level of neutralizing activity, Little increase in antibody titre was seen following a second dose of FI-RSV or purified F vaccine given at 1 month. Animals that received 5 micrograms F, 0.5 microgram F, or were almost completely resistant to pulmonary RSV infection following challenge at 3 months, but were susceptible by 6 months. Animals immunized with 5 micrograms of purified F glycoprotein developed alveolar and bronchiolar histopathology following RSV challenge at 3 or 6 months which was comparable to that of animals immunized with FI-RSV. These levels significantly exceeded those in animals previously immunized with influenza A virus vaccine which exhibited little histopathology. Animals previously infected with RSV also developed bronchiolar, but not alveolar, histopathology suggesting that the bronchiolar histopathology seen in RSV challenged cotton rats is a normal component of the immune resolution of RSV infection. These results suggest that the immune response of cotton rats to immunoaffinity purified F glycoprotein can result in enhanced bronchiolar and alveolar histopathology following RSV challenge. Thus, caution should be exercised in studies in humans using a purified F glycoprotein subunit vaccine.

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin.

During intravascular hemolysis in human disease, vasomotor tone and organ perfusion may be impaired by the increased reactivity of cell-free plasma hemoglobin (Hb) with NO. We experimentally produced acute intravascular hemolysis in a canine model in order to test the hypothesis that low levels of decompartmentalized or cell-free plasma Hb will severely reduce NO bioavailability and produce vasomotor instability. Importantly, in this model the total intravascular Hb level is unchanged; only the compartmentalization of Hb within the erythrocyte membrane is disrupted. Using a full-factorial design, we demonstrate that free water-induced intravascular hemolysis produces dose-dependent systemic vasoconstriction and impairs renal function. We find that these physiologic changes are secondary to the stoichiometric oxidation of endogenous NO by cell-free plasma oxyhemoglobin. In this model, 80 ppm of inhaled NO gas oxidized 85-90% of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous NO scavenging by cell-free Hb. As a result, the vasoconstriction caused by acute hemolysis was attenuated and the responsiveness to systemically infused NO donors was restored. These observations confirm that the acute toxicity of intravascular hemolysis occurs secondarily to the accelerated dioxygenation reaction of plasma oxyhemoglobin with endothelium-derived NO to form bioinactive nitrate. These biochemical and physiological studies demonstrate a major role for the intact erythrocyte in NO homeostasis and provide mechanistic support for the existence of a human syndrome of hemolysis-associated NO dysregulation, which may contribute to the vasculopathy of hereditary, acquired, and iatrogenic hemolytic states.

Experimental human endotoxemia increases cardiac regularity: Results from a prospective, randomized, crossover trial

OBJECTIVE To determine whether human endotoxemia is associated with a loss of the physiologic beat-to-beat variability of heart rate. DESIGN Prospective, randomized, crossover, single-blind study. SETTING Clinical research center in a federal, nonuniversity hospital. SUBJECTS Healthy volunteers. INTERVENTIONS Intravenous administration of reference (Escherichia coli) endotoxin or saline placebo, with or without previous administration of oral ibuprofen. MEASUREMENTS AND MAIN RESULTS Electrocardiograms were continuously recorded and digitized using series of 1000 beat epochs of R-R intervals over 8 hrs. Analyses included measures in the time domain (standard deviation), frequency domain (power spectra), and a measure of regularity (approximate entropy). Endotoxin administration was associated with loss of variability by all measures. This loss of variability remained significant even with administration of ibuprofen, which blocked the development of fever and endotoxin-related symptoms. CONCLUSIONS Infusion of endotoxin into human volunteers causes loss of heart rate variability, as measured by standard deviation and power spectra, as well as an increase in heart rate regularity, as measured by approximate entropy. Changes in approximate entropy occurred earlier than changes in other heart rate variability measures and may be a useful means of detecting early sepsis. This reduction in regularity is consistent with a model in which the pathogenesis of multiple organ system dysfunction syndrome involves the physiologic uncoupling of vital organ systems.

Bundled care for septic shock: An analysis of clinical trials

Context: Sepsis bundles have been developed to improve patient outcomes by combining component therapies. Valid bundles require effective components with additive benefits. Proponents encourage evaluation of bundles, both as a whole and based on the performance of each component. Objective: Assess the association between outcome and the utilization of component therapies in studies of sepsis bundles. Data Source: Database searches (January 1980 to July 2008) of PubMed, Embase, and the Cochrane Library, using the terms sepsis, bundles, guidelines, and early goal directed therapy. Data Extraction: Inclusion required comparison of septic adults who received bundled care vs. nonprotocolized care. Survival and use rates for individual interventions were abstracted. Main Results: Eight unblinded trials, one randomized and seven with historical controls, were identified. Sepsis bundles were associated with a consistent (I2 = 0%, p = .87) and significant increase in survival (odds ratio, 1.91; 95% confidence interval, 1.49–2.45; p < .0001). For all studies reporting such data, there were consistent (I2 = 0%, p ≥ .64) decreases in time to antibiotics, and increases in the appropriateness of antibiotics (p ≤ .0002 for both). In contrast, significant heterogeneity was seen across trials for all other treatments (antibiotic use within a specified time period; administration of fluids, vasopressors, inotropes, and packed red blood cells titrated to hemodynamic goals; corticosteroids and human recombinant activated protein C use) (all I2 ≥ 67%, p < .002). Except for antibiotics, sepsis bundle components are still being investigated for efficacy in randomized controlled trials. Conclusion: Bundle use was associated with consistent and significant improvement in survival and antibiotic use. Use of other bundle components changed heterogeneously across studies, making their impact on survival uncertain. However, this analysis should be interpreted cautiously as these studies were unblinded, and only one was randomized.

Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock.

Using different types of bacteria and a canine model simulating human septic shock, we investigated the role of endotoxin in cardiovascular dysfunction and mortality. Either Escherichia coli (a microorganism with endotoxin) or Staphylococcus aureus (a microorganism without endotoxin) were placed in an intraperitoneal clot in doses of viable or formalin-killed bacteria. Cardiovascular function of conscious animals was studied using simultaneous radionuclide heart scans and thermodilution cardiac outputs. Serial plasma endotoxin levels were measured. S. aureus produced a pattern of reversible cardiovascular dysfunction over 7-10 d that was concordant (P less than 0.01) with that of E. coli. Although this cardiovascular pattern was not altered by formalin killing (S. aureus and E. coli), formalin-killed organisms produced a lower mortality and less myocardial depression (P less than 0.01). S. aureus, compared to E. coli, produced higher postmortem concentrations of microorganisms and higher mortality (P less than 0.025). E. coli produced significant endotoxemia (P less than 0.01), though viable organisms (versus nonviable) resulted in higher endotoxin blood concentrations (P less than 0.05). Significant endotoxemia did not occur with S. aureus. Thus, in the absence of endotoxemia, S. aureus induced the same cardiovascular abnormalities of septic shock as E. coli. These findings indicate that structurally and functionally distinct microorganisms, with or without endotoxin, can activate a common pathway resulting in similar cardiovascular injury and mortality.