Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial.

Importance: After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes. Objective: To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury. Design, Setting, and Participants: The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018. Interventions: There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician. Main Outcomes and Measures: The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury. Results: Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI, -9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively. Conclusions and Relevance: Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury. Trial Registration: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235.

Goal-directed resuscitation for patients with early septic shock.

BACKGROUND: Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain. METHODS: In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization. RESULTS: Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (±SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964±1415 ml vs. 1713±1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay. CONCLUSIONS: In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.).

Using Clinically Accessible Tools to Measure Sound Levels and Sleep Disruption in the ICU: A Prospective Multicenter Observational Study.

OBJECTIVES: To use clinically accessible tools to determine unit-level and individual patient factors associated with sound levels and sleep disruption in a range of representative ICUs. DESIGN: A cross-sectional, observational study. SETTING: Australian and New Zealand ICUs. PATIENTS: All patients 16 years or over occupying an ICU bed on one of two Point Prevalence study days in 2015. INTERVENTIONS: Ambient sound was measured for 1 minute using an application downloaded to a personal mobile device. Bedside nurses also recorded the total time and number of awakening for each patient overnight. MEASUREMENTS AND MAIN RESULTS: The study included 539 participants with sound level recorded using an application downloaded to a personal mobile device from 39 ICUs. Maximum and mean sound levels were 78 dB (SD, 9) and 62 dB (SD, 8), respectively. Maximum sound levels were higher in ICUs with a sleep policy or protocol compared with those without maximum sound levels 81 dB (95% CI, 79-83) versus 77 dB (95% CI, 77-78), mean difference 4 dB (95% CI, 0-2), p < 0.001. There was no significant difference in sound levels regardless of single room occupancy, mechanical ventilation status, or illness severity. Clinical nursing staff in all 39 ICUs were able to record sleep assessment in 15-minute intervals. The median time awake and number of prolonged disruptions were 3 hours (interquartile range, 1-4) and three (interquartile range, 2-5), respectively. CONCLUSIONS: Across a large number of ICUs, patients were exposed to high sound levels and substantial sleep disruption irrespective of factors including previous implementation of a sleep policy. Sound and sleep measurement using simple and accessible tools can facilitate future studies and could feasibly be implemented into clinical practice.

A Multicenter Randomized Trial of Continuous versus Intermittent ß-Lactam Infusion in Severe Sepsis.

RATIONALE: Continuous infusion of ß-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with intermittent dosing. OBJECTIVES: To evaluate the efficacy of continuous versus intermittent infusion in patients with severe sepsis. METHODS: We conducted a randomized controlled trial in 25 intensive care units (ICUs). Participants commenced on piperacillin-tazobactam, ticarcillin-clavulanate, or meropenem were randomized to receive the prescribed antibiotic via continuous or 30-minute intermittent infusion for the remainder of the treatment course or until ICU discharge. The primary outcome was the number of alive ICU-free days at Day 28. Secondary outcomes were 90-day survival, clinical cure 14 days post antibiotic cessation, alive organ failure-free days at Day 14, and duration of bacteremia. MEASUREMENTS AND MAIN RESULTS: We enrolled 432 eligible participants with a median age of 64 years and an Acute Physiology and Chronic Health Evaluation II score of 20. There was no difference in ICU-free days: 18 days (interquartile range, 2-24) and 20 days (interquartile range, 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156 of 210) and 72.5% (158 of 218); hazard ratio, 0.91 (95% confidence interval, 0.63-1.31; P = 0.61). Clinical cure was 52.4% (111 of 212) and 49.5% (109 of 220); odds ratio, 1.12 (95% confidence interval, 0.77-1.63; P = 0.56). There was no difference in organ failure-free days (6 d; P = 0.27) and duration of bacteremia (0 d; P = 0.24). CONCLUSIONS: In critically ill patients with severe sepsis, there was no difference in outcomes between ß-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886).

Hydroxyethyl starch or saline for fluid resuscitation in intensive care.

BACKGROUND: The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS: We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. RESULTS: A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001). CONCLUSIONS: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).

Increased hospital costs associated with red blood cell transfusion.

BACKGROUND: Red blood cell (RBC) transfusion is independently associated in a dose-dependent manner with increased intensive care unit stay, total hospital length of stay, and hospital-acquired complications. Since little is known of the cost of these transfusion-associated adverse outcomes our aim was to determine the total hospital cost associated with RBC transfusion and to assess any dose-dependent relationship. STUDY DESIGN AND METHODS: A retrospective cohort study of all multiday acute care inpatients discharged from a five hospital health service in Western Australia between July 2011 and June 2012 was conducted. Main outcome measures were incidence of RBC transfusion and mean inpatient hospital costs. RESULTS: Of 89,996 multiday, acute care inpatient discharges, 4805 (5.3%) were transfused at least 1 unit of RBCs. After potential confounders were adjusted for, the mean inpatient cost was 1.83 times higher in the transfused group compared with the nontransfused group (95% confidence interval, 1.78-1.89; p < 0.001). The estimated total hospital-associated cost of RBC transfusion in this study was AUD $77 million (US $72 million), representing 7.8% of total hospital expenditure on acute care inpatients. There was a significant dose-dependent association between the number of RBC units transfused and increased costs after adjusting for confounders. CONCLUSION: RBC transfusions were independently associated with significantly higher hospital costs. The financial implication to hospital budgets will assist in prioritizing areas to reduce the rate of RBC transfusions and in implementing patient blood management programs.

Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial.

BACKGROUND: Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. METHODS: This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival. RESULTS: Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). CONCLUSIONS: Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.

Critical care services and 2009 H1N1 influenza in Australia and New Zealand.

BACKGROUND: Planning for the treatment of infection with the 2009 pandemic influenza A (H1N1) virus through health care systems in developed countries during winter in the Northern Hemisphere is hampered by a lack of information from similar health care systems. METHODS: We conducted an inception-cohort study in all Australian and New Zealand intensive care units (ICUs) during the winter of 2009 in the Southern Hemisphere. We calculated, per million inhabitants, the numbers of ICU admissions, bed-days, and days of mechanical ventilation due to infection with the 2009 H1N1 virus. We collected data on demographic and clinical characteristics of the patients and on treatments and outcomes. RESULTS: From June 1 through August 31, 2009, a total of 722 patients with confirmed infection with the 2009 H1N1 virus (28.7 cases per million inhabitants; 95% confidence interval [CI], 26.5 to 30.8) were admitted to an ICU in Australia or New Zealand. Of the 722 patients, 669 (92.7%) were under 65 years of age and 66 (9.1%) were pregnant women; of the 601 adults for whom data were available, 172 (28.6%) had a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 35. Patients infected with the 2009 H1N1 virus were in the ICU for a total of 8815 bed-days (350 per million inhabitants). The median duration of treatment in the ICU was 7.0 days (interquartile range, 2.7 to 13.4); 456 of 706 patients (64.6%) with available data underwent mechanical ventilation for a median of 8 days (interquartile range, 4 to 16). The maximum daily occupancy of the ICU was 7.4 beds (95% CI, 6.3 to 8.5) per million inhabitants. As of September 7, 2009, a total of 103 of the 722 patients (14.3%; 95% CI, 11.7 to 16.9) had died, and 114 (15.8%) remained in the hospital. CONCLUSIONS: The 2009 H1N1 virus had a substantial effect on ICUs during the winter in Australia and New Zealand. Our data can assist planning for the treatment of patients during the winter in the Northern Hemisphere.

Critical care services and the H1N1 (2009) influenza epidemic in Australia and New Zealand in 2010: the impact of the second winter epidemic.

INTRODUCTION: During the first winter of exposure, the H1N1 2009 influenza virus placed considerable strain on intensive care unit (ICU) services in Australia and New Zealand (ANZ). We assessed the impact of the H1N1 2009 influenza virus on ICU services during the second (2010) winter, following the implementation of vaccination. METHODS: A prospective, cohort study was conducted in all ANZ ICUs during the southern hemisphere winter of 2010. Data on demographic and clinical characteristics, including vaccination status and outcomes, were collected. The characteristics of patients admitted during the 2010 and 2009 seasons were compared. RESULTS: From 1 June to 15 October 2010, there were 315 patients with confirmed influenza A, of whom 283 patients (90%) had H1N1 2009 (10.6 cases per million inhabitants; 95% confidence interval (CI), 9.4 to 11.9) which was an observed incidence of 33% of that in 2009 (P < 0.001). The maximum daily ICU occupancy was 2.4 beds (95% CI, 1.8 to 3) per million inhabitants in 2010 compared with 7.5 (95% CI, 6.5 to 8.6) in 2009, (P < 0.001). The onset of the epidemic in 2010 was delayed by five weeks compared with 2009. The clinical characteristics were similar in 2010 and 2009 with no difference in the age distribution, proportion of patients treated with mechanical ventilation, duration of ICU admission, or hospital mortality. Unlike 2009 the incidence of critical illness was significantly greater in New Zealand (18.8 cases per million inhabitants compared with 9 in Australia, P < 0.001). Of 170 patients with known vaccination status, 26 (15.3%) had been vaccinated against H1N1 2009. CONCLUSIONS: During the 2010 ANZ winter, the impact of H1N1 2009 on ICU services was still appreciable in Australia and substantial in New Zealand. Vaccination failure occurred.

Early observational research and registries during the 2009-2010 influenza A pandemic.

As a critical care community, we have an obligation to provide not only clinical care but also the research that guides initial and subsequent clinical responses during a pandemic. There are many challenges to conducting such research. The first is speed of response. However, given the near inevitability of certain events, for example, viral respiratory illness such as the 2009 pandemic, geographically circumscribed natural disasters, or acts of terror, many study and trial designs should be preplanned and modified quickly when specific events occur. Template case report forms should be available for modification and web entry; centralized research ethics boards and funders should have the opportunity to preview and advise on such research beforehand; and national and international research groups should be prepared to work together on common studies and trials for common challenges. We describe the early international critical care research response to the influenza A 2009 (H1N1) pandemic, including specifics of observational study case report form, registry, and clinical trial design, cooperation of international critical care research organizations, and the early results of these collaborations.

Landmark survival as an end-point for trials in critically ill patients--comparison of alternative durations of follow-up: an exploratory analysis.

INTRODUCTION: Interventional ICU trials have followed up patients for variable duration. However, the optimal duration of follow-up for the determination of mortality endpoint in such trials is uncertain. We aimed to determine the most logical and practical mortality end-point in clinical trials of critically ill patients. METHODS: We performed a retrospective analysis of prospectively collected data involving 369 patients with one of the three specific diagnoses (i) Sepsis (ii) Community acquired pneumonia (iii) Non operative trauma admitted to the Royal Perth Hospital ICU, a large teaching hospital in Western Australia (WA cohort). Their in-hospital and post discharge survival outcome was assessed by linkage to the WA Death Registry. A validation cohort involving 4609 patients admitted during same time period with identical diagnoses from 55 ICUs across Australia (CORE cohort) was used to compare the patient characteristics and in-hospital survival to look at the Australia-wide applicability of the long term survival data from the WA cohort. RESULTS: The long term outcome data of the WA cohort indicate that mortality reached a plateau at 90 days after ICU admission particularly for sepsis and pneumonia. Mortality after hospital discharge before 90 days was not uncommon in these two groups. Severity of acute illness as measured by the total number of organ failures or acute physiology score was the main predictor of 90-day mortality. The adjusted in-hospital survival for the WA cohort was not significantly different from that of the CORE cohort in all three diagnostic groups; sepsis (P = 0.19), community acquired pneumonia (P = 0.86), non-operative trauma (P = 0.47). CONCLUSIONS: A minimum of 90 days follow-up is necessary to fully capture the mortality effect of sepsis and community acquired pneumonia. A shorter period of follow-up time may be sufficient for non-operative trauma.

Determinants of long-term survival after intensive care.

OBJECTIVE: To identify prognostic determinants of long-term survival for patients treated in intensive care units (ICUs) who survived to hospital discharge. DESIGN: An ICU clinical cohort linked to state-wide hospital records and death registers. SETTING AND PATIENTS: Adult patients admitted to a 22-bed ICU at a major teaching hospital in Perth, Western Australia, between 1987 and 2002 who survived to hospital discharge (n = 19,921) were followed-up until December 31, 2003. MEASUREMENTS: The main outcome measures are crude and adjusted survival. MAIN RESULTS: The risk of death in the first year after hospital discharge was high for patients who survived the ICU compared with the general population (standardized mortality rate [SMR] at 1 yr = 2.90, 95% confidence interval [CI] 2.73-3.08) and remained higher than the general population for every year during 15 yrs of follow up (SMR at 15 yrs = 2.01, 95% CI 1.64-2.46). Factors that were independently associated with survival during the first year were older age (hazard ratio [HR] = 4.09; 95% CI 3.20-5.23), severe comorbidity (HR = 5.23; 95% CI 4.25-6.43), ICU diagnostic group (HR range 2.20 to 8.95), new malignancy (HR = 4.60; 95% CI 3.68-5.76), high acute physiology score on admission (HR = 1.55; 95% CI 1.23-1.96), and peak number of organ failures (HR = 1.51; 95% CI 1.11-2.04). All of these factors were independently associated with subsequent survival for those patients who were alive 1 yr after discharge from the hospital with the addition of male gender (HR = 1.17; 95% CI 1.10-1.25) and prolonged length of stay in ICU (HR = 1.42; 95% CI 1.29-1.55). CONCLUSIONS: Patients who survived an admission to the ICU have worse survival than the general population for at least 15 yrs. The factors that determine long-term survival include age, comorbidity, and primary diagnosis. Severity of illness was also associated with long-term survival and this suggests that an episode of critical illness, or its treatment, may shorten life-expectancy.

C-reactive protein concentration as a predictor of in-hospital mortality after ICU discharge: a prospective cohort study.

OBJECTIVE: The objective was to assess the ability of potential clinical predictors and inflammatory markers within 24 h of intensive care unit (ICU) discharge to predict subsequent in-hospital mortality. DESIGN AND SETTING: A prospective cohort study of 603 consecutive patients who survived their first ICU admission, between 1 June and 31 December 2005, in a 22-bed multidisciplinary ICU of a university hospital. MEASUREMENTS AND RESULTS: A total of 26 in-hospital deaths after ICU discharge (4.3%) were identified. C-reactive protein (CRP) concentrations at ICU discharge were associated with subsequent in-hospital mortality in the univariate analysis (mean CRP concentrations of non-survivors=174 vs. survivors=85.6 mg/l, p=0.001). CRP concentrations remained significantly associated with post-ICU mortality (a 10-mg/l increment in CRP concentrations increased the odds ratio [OR] of death: 1.09, 95% confidence interval [CI]: 1.03-1.16); after adjusting for age, the Acute Physiology and Chronic Health Evaluation (APACHE) II predicted mortality, and the Delta Sequential Organ Failure Assessment (Delta SOFA) score. The area under the receiver operating characteristic curve of this multivariate model to discriminate between survivors and non-survivors after ICU discharge was 0.85 (95% CI: 0.73-0.96). The destination and timing of ICU discharge, and the Discharge SOFA score, white cell counts and fibrinogen concentrations at ICU discharge were not significantly associated with in-hospital mortality after ICU discharge. CONCLUSIONS: A high CRP concentration at ICU discharge was an independent predictor of in-hospital mortality after ICU discharge in our ICU.

Bench-to-bedside review: Bacterial virulence and subversion of host defences.

Bacterial pathogens possess an array of specific mechanisms that confer virulence and the capacity to avoid host defence mechanisms. Mechanisms of virulence are often mediated by the subversion of normal aspects of host biology. In this way the pathogen modifies host function so as to promote the pathogen's survival or proliferation. Such subversion is often mediated by the specific interaction of bacterial effector molecules with host encoded proteins and other molecules. The importance of these mechanisms for bacterial pathogens that cause infections leading to severe community-acquired infections is well established. In contrast, the importance of specialised mechanisms of virulence in the genesis of nosocomial bacterial infections, which occur in the context of local or systemic defects in host immune defences, is less well established. Specific mechanisms of bacterial resistance to host immunity might represent targets for therapeutic intervention. The clinical utility of such an approach for either prevention or treatment of bacterial infection, however, has not been determined.

Cefepime versus ceftazidime: considerations for empirical use in critically ill patients.

Sepsis and nosocomial infections continue to be a significant problem in intensive care, contributing heavily to mortality and prolonged hospital stay. Early and appropriate antibiotic therapy is critical for optimising outcomes. However, the emergence of highly resistant bacteria, coupled with reduced development of novel antibiotics, means that there is a real threat of development of untreatable nosocomial infections. Cefepime and ceftazidime are broad-spectrum cephalosporins that are widely used to treat Gram-negative nosocomial infections in critically ill patients. Available data suggest that cefepime may have advantages over ceftazidime owing to a broader spectrum of activity and reduced potential for development of bacterial resistance. However, whether either of these agents is superior can only be determined by a head-to-head study evaluating clinical and bacteriological outcomes. Such a study to determine whether apparent differences translate into clinically relevant differences in outcome is indicated.

Quality sleep using earplugs in the intensive care unit: the QUIET pilot randomised controlled trial.

OBJECTIVE: To assess the feasibility of a definitive, randomised controlled trial of earplugs as a noise-abatement strategy to improve sleep and reduce delirium in patients admitted to the intensive care unit. DESIGN AND SETTING: An open-label trial of 40 patients randomised in a 1:1 ratio to receive earplugs in addition to standard care, or standard care alone, conducted in a 10-bed ICU of a large, private hospital in Perth, Western Australia. PARTICIPANTS AND INTERVENTION: Patients were eligible for participation if they were expected to be undergoing mechanical ventilation (MV) on admission to the ICU. Patients assigned to receive earplugs had earplugs placed on admission to the ICU and were offered earplug placement between 10 pm and 6 am for the first night in the ICU once they were extubated. Earplugs were not provided for patients assigned to standard care. MAIN OUTCOME MEASURE: The primary outcome of study feasibility was assessed using criteria for acceptability of the intervention and protocol compliance. RESULTS: Of the 20 participants randomised to receive earplugs, 19 had earplugs placed within 6 hours of ICU admission, corresponding to 76% of the MV time (mean time with earplugs, 7.5 hours [SD, 5.3 hours]). Earplugs were placed for 18 of 20 participants during their first full night after extubation, corresponding to 78% of the total overnight time (mean time with earplugs, 6.2 hours [SD, 2.5 hours]). CONCLUSION: A definitive study of earplugs as a noiseabatement strategy for patients admitted to the ICU is feasible on the basis of participant acceptability of the intervention and protocol compliance. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615001125516.

Association between augmented renal clearance and clinical outcomes in patients receiving ß-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial.

Augmented renal clearance (ARC) is known to influence ß-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive ß-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144-198) mL/min]. ARC patients were younger (P <0.001), more commonly male (P = 0.04) and had less organ dysfunction (P <0.001). There was no difference in ICU-free days at Day 28 [ARC, 21 (12-24) days; no ARC, 21 (11-25) days; P = 0.89], although clinical cure was significantly greater in the unadjusted analysis in those manifesting ARC [33/45 (73.3%) vs. 115/209 (55.0%) P = 0.02]. This was attenuated in the multivariable analysis. No difference was noted in 90-day mortality. There were no statistically significant differences in clinical outcomes in ARC patients according to the dosing strategy employed. In this substudy of a large clinical trial of ß-lactam antibiotics in severe sepsis, ARC was not associated with any differences in outcomes, regardless of dosing strategy.