Steve Webb

Acetaminophen for Fever in Critically Ill Patients with Suspected Infection.

BACKGROUND Acetaminophen is a common therapy for fever in patients in the intensive care unit (ICU) who have probable infection, but its effects are unknown. METHODS We randomly assigned 700 ICU patients with fever (body temperature, ≥38°C) and known or suspected infection to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from the need for intensive care) from randomization to day 28. RESULTS The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges-Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P=0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P=0.84). CONCLUSIONS Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. (Funded by the Health Research Council of New Zealand and others; HEAT Australian New Zealand Clinical Trials Registry number, ACTRN12612000513819.).

Bench-to-bedside review: the evaluation of complex interventions in critical care.

Complex interventions, such as the introduction of medical emergency teams or an early goal-directed therapy protocol, are developed from a number of components that may act both independently and inter-dependently. There is an emerging body of literature advocating the use of integrated complex interventions to optimise the treatment of critically ill patients. As with any other treatment, complex interventions should undergo careful evaluation prior to widespread introduction into clinical practice. During the development of an international collaboration of researchers investigating protocol-based approaches to the resuscitation of patients with severe sepsis, we examined the specific issues related to the evaluation of complex interventions. This review outlines some of these issues. The issues specific to trials of complex interventions that require particular attention include determining an appropriate study population and defining current treatments and outcomes in that population, defining the study intervention and the treatment to be used in the control group, and deploying the intervention in a standardised manner. The context in which the research takes place, including existing staffing levels and existing protocols and procedures, is crucial. We also discuss specific details of trial execution, in particular randomization, blinded outcome adjudication and analysis of the results, which are key to avoiding bias in the design and interpretation of such trials.These aspects of study design impact upon the evaluation of complex interventions in critical care. Clinicians should also consider these specific issues when implementing new complex interventions into their practice.

The impact of bacterial and viral co-infection in severe influenza

Please cite this paper as: Blyth et al. (2013) The impact of bacterial and viral co‐infection in severe influenza. Influenza and Other Respiratory Viruses 7(2) 168–176.

Effect of length of stay in intensive care unit on hospital and long-term mortality of critically ill adult patients

BACKGROUND Critical illness leading to prolonged length of stay (LOS) in an intensive care unit (ICU) is associated with significant mortality and resource utilization. This study assessed the independent effect of ICU LOS on in-hospital and long-term mortality after hospital discharge. METHODS Clinical and mortality data of 22 298 patients, aged 16 yr and older, admitted to ICU between 1987 and 2002 were included in this linked-data cohort study. Coxs regression with restricted cubic spline function was used to model the effect of LOS on in-hospital and long-term mortality after adjusting for age, gender, acute physiology score (APS), maximum number of organ failures, era of admission, elective admission, Charlsons co-morbidity index, and diagnosis. The variability each predictor explained was calculated by the percentage of the chi(2) statistic contribution to the total chi(2) statistic. RESULTS Most hospital deaths occurred within the first few days of ICU admission. Increasing LOS in ICU was not associated with an increased risk of in-hospital mortality after adjusting for other covariates, but was associated with an increased risk of long-term mortality after hospital discharge. The variability on the long-term mortality effect associated with ICU LOS (2.3%) appeared to reach a plateau after the first 10 days in ICU and was not as important as age (35.8%), co-morbidities (18.6%), diagnosis (10.9%), and APS (3.6%). CONCLUSIONS LOS in ICU was not an independent risk factor for in-hospital mortality, but it had a small effect on long-term mortality after hospital discharge after adjustment for other risk factors.

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

BACKGROUND Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between‐group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal‐replacement therapy, and the incidence of new‐onset bacteremia or fungemia. CONCLUSIONS Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90‐day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109.)

The Efficacy of Earplugs as a Sleep Hygiene Strategy for Reducing Delirium in the Icu: A Systematic Review and Meta-analysis*

Objective:A systematic review and meta-analysis to assess the efficacy of earplugs as an ICU strategy for reducing delirium. Data Sources:MEDLINE, EMBASE, and the Cochrane Central Register of controlled trials were searched using the terms “intensive care,” “critical care,” “earplugs,” “sleep,” “sleep disorders,” and “delirium.” Study Selection:Intervention studies (randomized or nonrandomized) assessing the efficacy of earplugs as a sleep hygiene strategy in patients admitted to a critical care environment were included. Studies were excluded if they included only healthy volunteers, did not report any outcomes of interest, did not contain an intervention group of interest, were crossover studies, or were only published in abstract form. Data Extraction:Nine studies published between 2009 and 2015, including 1,455 participants, fulfilled the eligibility criteria and were included in the systematic review. Studies included earplugs as an isolated intervention (n = 3), or as part of a bundle with eye shades (n = 2), or earplugs, eye shades, and additional sleep noise abatement strategies (n = 4). The risk of bias was high for all studies. Data Synthesis:Five studies comprising 832 participants reported incident delirium. Earplug placement was associated with a relative risk of delirium of 0.59 (95% CI, 0.44–0.78) and no significant heterogeneity between the studies (I2, 39%; p = 0.16). Hospital mortality was reported in four studies (n = 481) and was associated with a relative risk of 0.77 (95% CI, 0.54–1.11; I2, 0%; p < 0.001). Compliance with the placement of earplugs was reported in six studies (n = 681). The mean per-patient noncompliance was 13.1% (95% CI, 7.8–25.4) of those assigned to receive earplugs. Conclusions:Placement of earplugs in patients admitted to the ICU, either in isolation or as part of a bundle of sleep hygiene improvement, is associated with a significant reduction in risk of delirium. The potential effect of cointerventions and the optimal strategy for improving sleep hygiene and associated effect on patient-centered outcomes remains uncertain.

Urinary proteases degrade albumin: implications for measurement of albuminuria in stored samples:

Background Previous studies have shown that albumin in stored urine samples degrades over time, and that albumin losses are greatest in samples with low pH conditions (pH < 5). Furthermore, the high-performance liquid chromatography (HPLC) assay for urinary albumin has been shown to be particularly susceptible to the effects of prolonged storage. Methods Frozen urine samples, stored for 12 months at −70 and −20°C, were analysed for albumin fragmentation. Urinary protease activity was investigated in vitro in urine adjusted to pH 2.3–2.5. Albumin was measured by nephelometry, HPLC and sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Results In the unadjusted samples, albumin was degraded in 11 out of 40 samples stored at −20°C. In the in vitro experiments, both endogenous albumin and exogenous albumin added to urine were rapidly degraded into large fragments within minutes after adjustment to low pH. The fragments produced were consistent with those produced during digestion with pepsin and urinary degradation was completely inhibited by pepstatin. Albumin concentration measured by HPLC was most dramatically affected, with near-complete loss of albumin-sized material within one hour of incubation at pH 2.3–2.5. Sample reactivity with antiserum in a nephelometry assay initially declined then increased, possibly due to exposure of internal epitopes during albumin digestion. Conclusions This study demonstrated that proteases are present and active in stored human urine samples. Urinary albumin digestion occurred in a manner consistent with activity of endogenous urinary proteases. Adjustment to neutral pH or addition of protease inhibitors may be useful techniques for sample preservation.

Variation in risk and mortality of acute kidney injury in critically ill patients: A multicenter study

Background: Despite standardized definitions of acute kidney injury (AKI), there is wide variation in the reported rates of AKI and hospital mortality for patients with AKI. Variation could be due to actual differences in disease incidence, clinical course, or a function of data ascertainment and application of diagnostic criteria. Using standard criteria may help determine and compare the risk and outcomes of AKI across centers. Methods: In this cohort study of critically ill patients admitted to the intensive care units at six hospitals in four countries, we used KDIGO criteria to define AKI. The main outcomes were the occurrence of AKI and hospital mortality. Results: Of the 15,132 critically ill patients, 32% developed AKI based on serum creatinine criteria. After adjusting for differences in age, sex, and severity of illness, the odds ratio for AKI continued to vary across centers (odds ratio (OR), 2.57-6.04, p < 0.001). The overall, crude hospital mortality of patients with AKI was 27%, which also varied across centers after adjusting for KDIGO stage, differences in age, sex, and severity of illness (OR, 1.13-2.20, p < 0.001). The severity of AKI was associated with incremental mortality risk across centers. Conclusions: In this study, the absolute and severity-adjusted rates of AKI and hospital mortality rates for AKI varied across centers. Future studies should examine whether variation in the risk of AKI among centers is due to differences in clinical practice or process of care or residual confounding due to unmeasured factors.

The pressure effects of facemasks during noninvasive ventilation : a volunteer study

Noninvasive ventilation by facemask is commonly used for patients with respiratory failure. We evaluated the pressure exerted by two types of facemask on the faces of 12 healthy volunteers while they were being given different levels of continuous or bi‐level positive airway pressure ventilation. The mean (SD) pressure recorded on the bridge of the nose was much higher than that on the cheek (nose: 65.8 (21.2) vs cheek 15.4 (7.2) mmHg, p < 0.0001). Progressive tightening of the harness and increasing of the volume of air in the facemask cushions increased the pressure on the bridge of the nose, and the effect of these two factors was additive. Some commercially available facemasks can produce substantial pressure on the bridge of the nose and this explains why pressure complications on the bridge of the nose are common during noninvasive ventilation.

The ICU Mobility Scale Has Construct and Predictive Validity and Is Responsive. A Multicenter Observational Study

RATIONALE The ICU Mobility Scale (IMS) is a measure of mobility milestones in critically ill patients. OBJECTIVES This study aimed to determine the validity and responsiveness of the IMS from a prospective cohort study of adults admitted to the intensive care unit (ICU). METHODS Construct and predictive validity were assessed by comparing IMS values at ICU discharge in 192 patients to other variables using Spearman rank correlation coefficient, Mann-Whitney U tests, and logistic regression. Responsiveness was assessed using change over time, effect size, floor and ceiling effects, and percentage of patients showing change. MEASUREMENTS AND MAIN RESULTS The IMS at ICU discharge demonstrated a moderate correlation with muscle strength (r = 0.64, P < 0.001). There was a significant difference between the IMS at ICU discharge in patients with ICU-acquired weakness (median, 4.0; interquartile range, 3.0-5.0) compared with patients without (median, 8.0; interquartile range, 5.0-8.0; P < 0.001). Increasing IMS values at ICU discharge were associated with survival to 90 days (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.14-1.66) and discharge home (OR, 1.16; 95% CI, 1.02-1.32) but not with return to work at 6 months (OR, 1.09; 95% CI, 0.92-1.28). The IMS was responsive with a significant change from study enrollment to ICU discharge (d = 0.8, P < 0.001), with IMS values increasing in 86% of survivors during ICU admission. No substantial floor (14% scored 0) or ceiling (4% scored 10) effects were present at ICU discharge. CONCLUSIONS Our findings support the validity and responsiveness of the IMS as a measure of mobility in the ICU.