An evidence-based intervention resulted in a large and sustained reduction (up to 66%) in rates of catheter-related bloodstream infection that was maintained throughout the 18-month study period.

Background Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. Methods In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d -dimer level. Results The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d -dimer cohort, 92.9% in the low d -dimer cohort, and 97.3% in the unknown d -dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. Conclusions In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589 , NCT04505774 , NCT04359277 , and NCT02735707 .)

These results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death. (ClinicalTrials.gov number, NCT00295269.).

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BACKGROUND There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522.)

Objectives To evaluate the extent to which intensive care units participating in the initial Keystone ICU project sustained reductions in rates of catheter related bloodstream infections. Design Collaborative cohort study to implement and evaluate interventions to improve patients' safety. Setting Intensive care units predominantly in Michigan, USA. Intervention Conceptual model aimed at improving clinicians' use of five evidence based recommendations to reduce rates of catheter related bloodstream infections rates, with measurement and feedback of infection rates. During the sustainability period, intensive care unit teams were instructed to integrate this intervention into staff orientation, collect monthly data from hospital infection control staff, and report infection rates to appropriate stakeholders. Main outcome measures Quarterly rate of catheter related bloodstream infections per 1000 catheter days during the sustainability period (19-36 months after implementation of the intervention). Results Ninety (87%) of the original 103 intensive care units participated, reporting 1532 intensive care unit months of data and 300 310 catheter days during the sustainability period. The mean and median rates of catheter related bloodstream infection decreased from 7.7 and 2.7 (interquartile range 0.6-4.8) at baseline to 1.3 and 0 (0-2.4) at 16-18 months and to 1.1 and 0 (0.0-1.2) at 34-36 months post-implementation. Multilevel regression analysis showed that incidence rate ratios decreased from 0.68 (95% confidence interval 0.53 to 0.88) at 0-3 months to 0.38 (0.26 to 0.56) at 16-18 months and 0.34 (0.24-0.48) at 34-36 months post-implementation. During the sustainability period, the mean bloodstream infection rate did not significantly change from the initial 18 month post-implementation period (−1%, 95% confidence interval −9% to 7%). ConclusionsThe reduced rates of catheter related bloodstream infection achieved in the initial 18 month post-implementation period were sustained for an additional 18 months as participating intensive care units integrated the intervention into practice. Broad use of this intervention with achievement of similar results could substantially reduce the morbidity and costs associated with catheter related bloodstream infections.

Objective It has been suggested that fluid accumulation may delay recognition of acute kidney injury (AKI). We sought to determine the impact of fluid balance on the incidence of non-dialysis requiring AKI in patients with acute lung injury and to describe associated outcomes, including mortality. Design Analysis of the Fluid and Catheter Treatment Trial, a factorial randomized clinical trial of conservative versus liberal fluid management and of management guided by a central venous versus pulmonary artery catheter. Setting and Patients 1000 patients at ARDS Network hospitals. Measurements and Main Results The incidence of AKI, defined as an absolute rise in creatinine of ≥ 0.3 mg/dL or a relative change of > 50% over 48 hours, was examined before and after adjustment of serum creatinine for fluid balance. The incidence of AKI before adjustment for fluid balance was greater in those managed with the conservative fluid protocol (57 versus 51%, p = 0.04). After adjustment for fluid balance, the incidence of AKI was greater in those managed with the liberal fluid protocol (66 versus 58%, p = 0.007). Patients who met AKI criteria after adjustment of creatinine for fluid balance (but not before) had a mortality rate that was significantly greater than those who did not meet AKI criteria both before and after adjustment for fluid balance (31 versus 12%, p < 0.001) and those who had AKI before but not after adjustment for fluid balance (31 versus 11%, p = 0.005). The mortality of those patients meeting AKI criteria after but not before adjustment for fluid balance was similar to patients with AKI both before and after adjustment for fluid balance (31% versus 38%, p = 0.18). Conclusions Fluid management influences serum creatinine and therefore the diagnosis of AKI using creatinine-based definitions. Patients with “unrecognized” AKI that is identified after adjusting for positive fluid balance have high mortality rates, and patients who have AKI before but not after adjusting for fluid balance have low mortality rates. Future studies of AKI should consider potential differences in serum creatinine caused by changes in fluid balance and the impact of these differences on diagnosis and prognosis.

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