Re-analysis of ventilator-free days (VFD) in acute respiratory distress syndrome (ARDS) studies.

BACKGROUND: Over recent decades, improvements in healthcare have reduced mortality and morbidity rates in many conditions. This has resulted, in part, from the identification of effective interventions in randomised trials, and in conducting such trials, a composite outcome measure (COM) with multiple components will increase event rates, which allows study completion with a smaller sample size. In critical care research, the COM "ventilator-free days" (VFD) combines mortality and duration of mechanical ventilation (MV) into a single continuous measure, which can be analysed in a variety of ways. This study investigates the usefulness of Poisson and two-part Poisson models compared to t-distribution for the analysis of VFD. METHODS: Data from four studies (ALbuterol for the Treatment of ALI (ALTA), Early vs. Delayed Enteral Nutrition (EDEN), Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute Lung Injury (ALI) to reduce pulmonary dysfunction (HARP-2), Statins for Acutely Injured Lungs from Sepsis (SAILS)) were used for analysis, with the VFD results summarised using mean, standard deviation (SD), median, interquartile range (25th and 75th percentiles) and minimum and maximum values. The statistical analyses that are compared used the t-test, Poisson, zero-inflated Poisson (ZIP) and two-part Logit-Poisson hurdle models. The analyses were exploratory in nature, and the significance level for differences in the estimates was set to 0.05. RESULTS: In HARP-2, which compared simvastatin and placebo, the mean (SD) VFD for all patients was 12.0 (10.2), but this mean value did not represent the data distribution as it falls in a zone between two peaks, with the lowest frequency of occurrence. The mean (SD) VFD after excluding patients who died before day 28 and patients who did not achieve unassisted breathing were 15.9 (8.7) and 18.2 (6.6), respectively. The mean difference (95% CI) between the two groups was 1.1 (95% CI: 0.7 to 2.8; p = 0.20) based on an independent t-test. However, when the two-part hurdle model was used, the simvastatin arm had a significantly higher number of non-zero values compared to the placebo group, which indicated that more patients were alive and free of mechanical ventilation in the simvastatin group. Similarly, in ALTA, this model found that significantly more patients were alive and free of MV in the control group. In EDEN and SAILS, there was no significant difference between the control and intervention groups. CONCLUSION: Our analyses show that the t-test and Poisson model are not appropriate for bi-modal data (such as VFD) where there is a large number of zero events. The two-part hurdle model was the most promising approach. There is a need for future research to investigate other analysis techniques, such as two-part quantile regression and to determine the impact on sample size requirements for comparative effectiveness trials.

Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9.

BACKGROUND & AIM: Ammonia is central in the pathogenesis of brain edema in acute liver failure (ALF) with infection and systemic inflammation expediting development of intracranial hypertension (ICH). Patients with acetaminophen-induced ALF have increased neutrophil TLR9 expression which can be induced by ammonia. We determined whether ammonia-induced brain edema and immune dysfunction are mediated by TLR9 and if this could be prevented in a TLR9-deficient mouse model. METHODS: Ammonium acetate (NH4-Ac; 4mmol/kg) was injected intraperitoneally in wild type (WT), Tlr9-/- and Lysm-Cre Tlr9fl/fl mice (TLR9 absent in neutrophils and macrophages including Kupffer cells) and compared to controls. Six hours after NH4-Ac injection, intracellular cytokine production was determined in splenic macrophages, CD4+ and CD8+ T cells. Brain water (BW) and total plasma DNA (tDNA) were also measured. The impact of the TLR9 antagonist ODN2088 (50µg/mouse) was evaluated. RESULTS: Following NH4-Ac injection, BW, macrophage and T cell cytokine production increased (P < .0001) in WT but not Tlr9-/- mice (P < .001). ODN2088 inhibited macrophage and T cell cytokine production (P < .05) and prevented an increase in BW (P < .0001). Following NH4-Ac injection, macrophage cytokine production and BW were ameliorated in Lysm-Cre Tlr9fl/fl mice compared to WT mice (P < .05) but there was no difference compared to Tlr9-/- mice. Following NH4-Ac injection, plasma tDNA levels increased in WT and Tlr9-/- mice (P < .05) suggesting that TLR9 may be activated by DNA released from ammonia-stimulated cells. CONCLUSION: Ammonia-induced brain edema requires macrophage and T cell expression of TLR9. Amelioration of brain edema and lymphocyte cytokine production by ODN2088 supports exploration of TLR9 antagonism in early ALF to prevent progression to ICH.

Transmission dynamics of methicillin-resistant Staphylococcus aureus in a medical intensive care unit in India.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a global pathogen and an important but seldom investigated cause of morbidity and mortality in lower and middle-income countries where it can place a major burden on limited resources. Quantifying nosocomial transmission in resource-poor settings is difficult because molecular typing methods are prohibitively expensive. Mechanistic statistical models can overcome this problem with minimal cost. We analyse the transmission dynamics of MRSA in a hospital in south India using one such approach and provide conservative estimates of the organism's economic burden. METHODS AND FINDINGS: Fifty months of MRSA infection data were collected retrospectively from a Medical Intensive Care Unit (MICU) in a tertiary hospital in Vellore, south India. Data were analysed using a previously described structured hidden Markov model. Seventy-two patients developed MRSA infections and, of these, 49 (68%) died in the MICU. We estimated that 4.2% (95%CI 1.0, 19.0) of patients were MRSA-positive when admitted, that there were 0.39 MRSA infections per colonized patient month (0.06, 0.73), and that the ward-level reproduction number for MRSA was 0.42 (0.08, 2.04). Anti-MRSA antibiotic treatment costs alone averaged $124/patient, over three times the monthly income of more than 40% of the Indian population. CONCLUSIONS: Our analysis of routine data provides the first estimate of the nosocomial transmission potential of MRSA in India. The high levels of transmission estimated underline the need for cost-effective interventions to reduce MRSA transmission in hospital settings in low and middle income countries.