Manoj Saxena

Target temperature management after out-of-hospital cardiac arrest-a randomized, parallel-group, assessor-blinded clinical trial-rationale and design

BACKGROUND Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32°C to 34°C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known. METHODS The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33°C or 36°C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm. DISCUSSION The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.

Early mobilization and recovery in mechanically ventilated patients in the ICU: a bi-national, multi-centre, prospective cohort study.

The aim of this study was to investigate current mobilization practice, strength at ICU discharge and functional recovery at 6 months among mechanically ventilated ICU patients. This was a prospective, multi-centre, cohort study conducted in twelve ICUs in Australia and New Zealand. Patients were previously functionally independent and expected to be ventilated for >48 hours. We measured mobilization during invasive ventilation, sedation depth using the Richmond Agitation and Sedation Scale (RASS), co-interventions, duration of mechanical ventilation, ICU-acquired weakness (ICUAW) at ICU discharge, mortality at day 90, and 6-month functional recovery including return to work. We studied 192 patients (mean age 58.1 ± 15.8 years; mean Acute Physiology and Chronic Health Evaluation (APACHE) (IQR) II score, 18.0 (14 to 24)). Mortality at day 90 was 26.6% (51/192). Over 1,351 study days, we collected information during 1,288 planned early mobilization episodes in patients on mechanical ventilation for the first 14 days or until extubation (whichever occurred first). We recorded the highest level of early mobilization. Despite the presence of dedicated physical therapy staff, no mobilization occurred in 1,079 (84%) of these episodes. Where mobilization occurred, the maximum levels of mobilization were exercises in bed (N = 94, 7%), standing at the bed side (N = 11, 0.9%) or walking (N = 26, 2%). On day three, all patients who were mobilized were mechanically ventilated via an endotracheal tube (N = 10), whereas by day five 50% of the patients mobilized were mechanically ventilated via a tracheostomy tube (N = 18). In 94 of the 156 ICU survivors, strength was assessed at ICU discharge and 48 (52%) had ICU-acquired weakness (Medical Research Council Manual Muscle Test Sum Score (MRC-SS) score <48/60). The MRC-SS score was higher in those patients who mobilized while mechanically ventilated (50.0 ± 11.2 versus 42.0 ± 10.8, P = 0.003). Patients who survived to ICU discharge but who had died by day 90 had a mean MRC score of 28.9 ± 13.2 compared with 44.9 ± 11.4 for day-90 survivors (P <0.0001). Early mobilization of patients receiving mechanical ventilation was uncommon. More than 50% of patients discharged from the ICU had developed ICU-acquired weakness, which was associated with death between ICU discharge and day-90. ClinicalTrials.gov NCT01674608. Registered 14 August 2012.

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.).

Clinical review: Early patient mobilization in the ICU

Early mobilization (EM) of ICU patients is a physiologically logical intervention to attenuate critical illness-associated muscle weakness. However, its long-term value remains controversial. We performed a detailed analytical review of the literature using multiple relevant key terms in order to provide a comprehensive assessment of current knowledge on EM in critically ill patients. We found that the term EM remains undefined and encompasses a range of heterogeneous interventions that have been used alone or in combination. Nonetheless, several studies suggest that different forms of EM may be both safe and feasible in ICU patients, including those receiving mechanical ventilation. Unfortunately, these studies of EM are mostly single center in design, have limited external validity and have highly variable control treatments. In addition, new technology to facilitate EM such as cycle ergometry, transcutaneous electrical muscle stimulation and video therapy are increasingly being used to achieve such EM despite limited evidence of efficacy. We conclude that although preliminary low-level evidence suggests that EM in the ICU is safe, feasible and may yield clinical benefits, EM is also labor-intensive and requires appropriate staffing models and equipment. More research is thus required to identify current standard practice, optimal EM techniques and appropriate outcome measures before EM can be introduced into the routine care of critically ill patients.

A Binational Multicenter Pilot Feasibility Randomized Controlled Trial of Early Goal-Directed Mobilization in the ICU*

Objectives:To determine if the early goal-directed mobilization intervention could be delivered to patients receiving mechanical ventilation with increased maximal levels of activity compared with standard care. Design:A pilot randomized controlled trial. Setting:Five ICUs in Australia and New Zealand. Participants:Fifty critically ill adults mechanically ventilated for greater than 24 hours. Intervention:Patients were randomly assigned to either early goal-directed mobilization (intervention) or to standard care (control). Early goal-directed mobilization comprised functional rehabilitation treatment conducted at the highest level of activity possible for that patient assessed by the ICU mobility scale while receiving mechanical ventilation. Measurements and Main Results:The ICU mobility scale, strength, ventilation duration, ICU and hospital length of stay, and total inpatient (acute and rehabilitation) stay as well as 6-month post-ICU discharge health-related quality of life, activities of daily living, and anxiety and depression were recorded. The mean age was 61 years and 60% were men. The highest level of activity (ICU mobility scale) recorded during the ICU stay between the intervention and control groups was mean (95% CI) 7.3 (6.3–8.3) versus 5.9 (4.9–6.9), p = 0.05. The proportion of patients who walked in ICU was almost doubled with early goal-directed mobilization (intervention n = 19 [66%] vs control n = 8 [38%]; p = 0.05). There was no difference in total inpatient stay (d) between the intervention versus control groups (20 [15–35] vs 34 [18–43]; p = 0.37). There were no adverse events. Conclusions:Key Practice Points: Delivery of early goal-directed mobilization within a randomized controlled trial was feasible, safe and resulted in increased duration and level of active exercises.

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.

Fever management in intensive care patients with infections

With great interest we read the article by Dr Schoeneberg and colleagues regarding gender-specific differences with respect to outcome in patients with severe traumatic injury. The authors show that, apart from the acute phase after trauma, women have a more favorable trauma severity-adjusted outcome, with shorter ICU and hospital stay and lower sepsis rates. However, a possible mechanism of action behind this difference was not suggested. We hypothesize that, in view of the fact that morbidity and mortality in the post-acute phase after trauma are often caused by infectious complications, gender differences in immunity might explain the observed differences.

Patterns of intravenous fluid resuscitation use in adult intensive care patients between 2007 and 2014: An international cross-sectional study

Background In 2007, the Saline versus Albumin Fluid Evaluation—Translation of Research Into Practice Study (SAFE-TRIPS) reported that 0.9% sodium chloride (saline) and hydroxyethyl starch (HES) were the most commonly used resuscitation fluids in intensive care unit (ICU) patients. Evidence has emerged since 2007 that these fluids are associated with adverse patient-centred outcomes. Based on the published evidence since 2007, we sought to determine the current type of fluid resuscitation used in clinical practice and the predictors of fluid choice and determine whether these have changed between 2007 and 2014. Methods In 2014, an international, cross-sectional study was conducted (Fluid-TRIPS) to document current patterns of intravenous resuscitation fluid use and determine factors associated with fluid choice. We examined univariate and multivariate associations between patients and prescriber characteristics, geographical region and fluid type. Additionally, we report secular trends of resuscitation fluid use in a cohort of ICUs that participated in both the 2007 and 2014 studies. Regression analysis were conducted to determine changes in the administration of crystalloid or colloid between 2007 and 2014. Findings In 2014, a total of 426 ICUs in 27 countries participated. Over the 24 hour study day, 1456/6707 (21.7%) patients received resuscitation fluid during 2716 resuscitation episodes. Crystalloids were administered to 1227/1456 (84.3%) patients during 2208/2716 (81.3%) episodes and colloids to 394/1456 (27.1%) patients during 581/2716 (21.4%) episodes. In multivariate analyses, practice significantly varied between geographical regions. Additionally, patients with a traumatic brain injury were less likely to receive colloid when compared to patients with no trauma (adjusted OR 0.24; 95% CI 0.1 to 0.62; p = 0.003). Patients in the ICU for one or more days where more likely to receive colloid compared to patients in the ICU on their admission date (adjusted OR 1.75; 95% CI 1.27 to 2.41; p = <0.001). For secular trends in fluid resuscitation, 84 ICUs in 17 countries contributed data. In 2007, 527/1663 (31.7%) patients received fluid resuscitation during 1167 episodes compared to 491/1763 (27.9%) patients during 960 episodes in 2014. The use of crystalloids increased from 498/1167 (42.7%) in 2007 to 694/960 (72.3%) in 2014 (odds ratio (OR) 3.75, 95% confidence interval (CI) 2.95 to 4.77; p = <0.001), primarily due to a significant increase in the use of buffered salt solutions. The use of colloids decreased from 724/1167 (62.0%) in 2007 to 297/960 (30.9%) in 2014 (OR 0.29, 95% CI 0.19 to 0.43; p = <0.001), primarily due to a decrease in the use of HES, but an overall increase in the use of albumin. Conclusions Clinical practices of intravenous fluid resuscitation have changed between 2007 and 2014. Geographical location remains a strong predictor of the type of fluid administered for fluid resuscitation. Overall, there is a preferential use of crystalloids, specifically buffered salt solutions, over colloids. There is now an imperative to conduct a trial determining the safety and efficacy of these fluids on patient-centred outcomes. Trial registration Clinicaltrials.gov: Fluid-Translation of research into practice study (Fluid-TRIPS) NCT02002013

The effect of paracetamol on core body temperature in acute traumatic brain injury: a randomised, controlled clinical trial

Background Strategies to prevent pyrexia in patients with acute neurological injury may reduce secondary neuronal damage. The aim of this study was to determine the safety and efficacy of the routine administration of 6 grams/day of intravenous paracetamol in reducing body temperature following severe traumatic brain injury, compared to placebo. Methods A multicentre, randomised, blind, placebo-controlled clinical trial in adult patients with traumatic brain injury (TBI). Patients were randomised to receive an intravenous infusion of either 1g of paracetamol or 0.9% sodium chloride (saline) every 4 hours for 72 hours. The primary outcome was the mean difference in core temperature during the study intervention period. Results Forty-one patients were included in this study: 21 were allocated to paracetamol and 20 to saline. The median (interquartile range) number of doses of study drug was 18 (17–18) in the paracetamol group and 18 (16–18) in the saline group (P = 0.85). From randomisation until 4 hours after the last dose of study treatment, there were 2798 temperature measurements (median 73 [67–76] per patient). The mean ± standard deviation temperature was 37.4±0.5°C in the paracetamol group and 37.7±0.4°C in the saline group (absolute difference -0.3°C; 95% confidence interval -0.6 to 0.0; P = 0.09). There were no significant differences in the use of physical cooling, or episodes of hypotension or hepatic abnormalities, between the two groups. Conclusion The routine administration of 6g/day of intravenous paracetamol did not significantly reduce core body temperature in patients with TBI. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000444280

Fever and antipyresis in infection

Fever is an important mechanism of intrinsic resistance against infectious disease. A variety of studies point to a potential detrimental effect of temperature lowering in infectious disorders, but high‐quality evidence from randomised controlled trials is lacking. In ambulatory care settings, we need to know whether antipyretics influence the severity and duration of illnesses and, in critically ill patients, whether antipyretics affect mortality.