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.

Mitochondrial dysfunction in peripheral blood mononuclear cells in early experimental and clinical acute pancreatitis.

BACKGROUND/OBJECTIVES: Mitochondrial dysfunction occurs in vital organs in experimental acute pancreatitis (AP) and may play an important role in determining severity of AP. However, obtaining vital organ biopsies to measure mitochondrial function (MtF) in patients with AP poses considerable risk of harm. Being able to measure MtF from peripheral blood will bypass this problem. Furthermore, whether mitochondrial dysfunction is detectable in peripheral blood in mild AP is unknown. Therefore, the objective was to evaluate peripheral blood MtF in experimental and clinical AP. METHOD: Mitochondrial respiration was measured using high resolution oxygraphy in an experimental study in caerulein induced AP and in a separate study, in patients with mild AP. Superoxide, cytochrome c, mitochondrial membrane potential (ΔΨ) and adenine triphosphate (ATP) were also measured as other markers of MtF. RESULTS: Even though some states of mitochondrial respiration were increased in both experimental and clinical AP, this did not lead to an increase in net ATP in patients with AP. The increased leak respiration in both studies was further proof of dyscoupled mitochondria. In the clinical study there were also features of mitochondrial dysfunction with increased leak flux control ratio, superoxide, ΔΨ and decreased cytochrome c. CONCLUSION: There is evidence of mitochondrial dysfunction with dyscoupled mitochondria, increased superoxide and decreased cytochrome c in patients with mild acute pancreatitis. Further studies should now determine whether mitochondrial function alters with severity in AP and whether mitochondrial dysfunction responds to treatments.

Dysnatremia and 6-Month Functional Outcomes in Critically Ill Patients With Aneurysmal Subarachnoid Hemorrhage: A Prospective Cohort Study.

OBJECTIVES: To investigate the association between plasma sodium concentrations and 6-month neurologic outcome in critically ill patients with aneurysmal subarachnoid hemorrhage. DESIGN: Prospective cohort study. SETTING: Eleven ICUs in Australia and New Zealand. PARTICIPANTS: Three-hundred fifty-six aneurysmal subarachnoid hemorrhage patients admitted to ICU between March 2016 and June 2018. The exposure variable was daily measured plasma sodium. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six-month neurologic outcome as measured by the modified Rankin Scale. A poor outcome was defined as a modified Rankin Scale greater than or equal to 4. The mean age was 57 years (± 12.6 yr), 68% were female, and 32% (n = 113) had a poor outcome. In multivariable analysis, including age, illness severity, and process of care measures as covariates, higher mean sodium concentrations (odds ratio, 1.17; 95% CI, 1.05-1.29), and greater overall variability-as measured by the sd (odds ratio, 1.53; 95% CI, 1.17-1.99)-were associated with a greater likelihood of a poor outcome. Multivariable generalized additive modeling demonstrated, specifically, that a high initial sodium concentration, followed by a gradual decline from day 3 onwards, was also associated with a poor outcome. Finally, greater variability in sodium concentrations was associated with a longer ICU and hospital length of stay: mean ICU length of stay ratio (1.13; 95% CI, 1.07-1.20) and mean hospital length of stay ratio (1.08; 95% CI, 1.01-1.15). CONCLUSIONS: In critically ill aneurysmal subarachnoid hemorrhage patients, higher mean sodium concentrations and greater variability were associated with worse neurologic outcomes at 6 months, despite adjustment for known confounders. Interventional studies would be required to demonstrate a causal relationship.

Statistical analysis plan for the POLAR-RCT: The Prophylactic hypOthermia trial to Lessen trAumatic bRain injury-Randomised Controlled Trial.

BACKGROUND: The Prophylactic hypOthermia to Lessen trAumatic bRain injury-Randomised Controlled Trial (POLAR-RCT) will evaluate whether early and sustained prophylactic hypothermia delivered to patients with severe traumatic brain injury improves patient-centred outcomes. METHODS: The POLAR-RCT is a multicentre, randomised, parallel group, phase III trial of early, prophylactic cooling in critically ill patients with severe traumatic brain injury, conducted in Australia, New Zealand, France, Switzerland, Saudi Arabia and Qatar. A total of 511 patients aged 18-60 years have been enrolled with severe acute traumatic brain injury. The trial intervention of early and sustained prophylactic hypothermia to 33 °C for 72 h will be compared to standard normothermia maintained at a core temperature of 37 °C. The primary outcome is the proportion of favourable neurological outcomes, comprising good recovery or moderate disability, observed at six months following randomisation utilising a midpoint dichotomisation of the Extended Glasgow Outcome Scale (GOSE). Secondary outcomes, also assessed at six months following randomisation, include the probability of an equal or greater GOSE level, mortality, the proportions of patients with haemorrhage or infection, as well as assessment of quality of life and health economic outcomes. The planned sample size will allow 80% power to detect a 30% relative risk increase from 50% to 65% (equivalent to a 15% absolute risk increase) in favourable neurological outcome at a two-sided alpha of 0.05. DISCUSSION: Consistent with international guidelines, a detailed and prospective analysis plan has been developed for the POLAR-RCT. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses and methods for exploratory analyses. Application of this statistical analysis plan to the forthcoming POLAR-RCT trial will facilitate unbiased analyses of these important clinical data. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00987688 (first posted 1 October 2009); Australian New Zealand Clinical Trials Registry, ACTRN12609000764235 . Registered on 3 September 2009.

Validation of a classification system for causes of death in critical care: an assessment of inter-rater reliability.

OBJECTIVE: Trials in critical care have previously used unvalidated systems to classify cause of death. We aimed to provide initial validation of a method to classify cause of death in intensive care unit patients. DESIGN, SETTING AND PARTICIPANTS: One hundred case scenarios of patients who died in an ICU were presented online to raters, who were asked to select a proximate and an underlying cause of death for each, using the ICU Deaths Classification and Reason (ICU-DECLARE) system. We evaluated two methods of categorising proximate cause of death (designated Lists A and B) and one method of categorising underlying cause of death. Raters were ICU specialists and research coordinators from Australia, New Zealand and the United Kingdom. MAIN OUTCOME MEASURES: Inter-rater reliability, as measured by the Fleiss multirater kappa, and the median proportion of raters choosing the most likely diagnosis (defined as the most popular classification choice in each case). RESULTS: Across all raters and cases, for proximate cause of death List A, kappa was 0.54 (95% CI, 0.49-0.60), and for proximate cause of death List B, kappa was 0.58 (95% CI, 0.53-0.63). For the underlying cause of death, kappa was 0.48 (95% CI, 0.44-0.53). The median proportion of raters choosing the most likely diagnosis for proximate cause of death, List A, was 77.5% (interquartile range [IQR], 60.0%-93.8%), and the median proportion choosing the most likely diagnosis for proximate cause of death, List B, was 82.5% (IQR, 60.0%-92.5%). The median proportion choosing the most likely diagnosis for underlying cause was 65.0% (IQR, 50.0%-81.3%). Kappa and median agreement were similar between countries. ICU specialists showed higher kappa and median agreement than research coordinators. CONCLUSIONS: The ICU-DECLARE system allowed ICU doctors to classify the proximate cause of death of patients who died in the ICU with substantial reliability.

Protocol for a multicentre randomised controlled trial of early and sustained prophylactic hypothermia in the management of traumatic brain injury.

INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Prophylactic hypothermia is effective in laboratory models, but clinical studies to date have been inconclusive, partly because of methodological limitations. Our Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR) randomised controlled trial is currently underway comparing early, sustained hypothermia versus standard care in patients with severe TBI. We describe our study protocol and the challenges in conducting prophylactic hypothermia research in TBI. DESIGN: We aim to randomise 500 patients to either prophylactic 33°C hypothermia initiated within 3 hours of injury and continued for at least 72 hours, or standard normothermic management. Patients will be enrolled by paramedic services in the prehospital setting, or by emergency department staff at participating sites in Australia, New Zealand and Europe. The primary outcome will be the eight-level extended Glasgow outcome scale (GOSE), dichotomised to favourable and unfavourable outcomes at 6 months after injury. Secondary outcomes will include mortality at hospital discharge and at 6 months, ordinal analyses of 6-month GOSE outcomes, quality of life with health economic evaluations and the differential proportion of adverse events. We will predefine subgroup and interaction analyses. DISCUSSION: After a run-in phase, recruitment for our main study began in December 2010. When the study is completed, we aim to provide evidence on the efficacy of prophylactic hypothermia in TBI to guide clinicians in their management of this devastating condition.

Cost of medical injury in New Zealand: a retrospective cohort study.

OBJECTIVE: To estimate the cost of treating medical injury associated with hospital admissions in New Zealand and the patient characteristics of costly adverse events. METHODS: As part of the New Zealand Quality in Healthcare Study (NZQHS), a retrospective examination of medical records in 13 public hospitals identified the occurrence of clinical procedures and hospital bed days attributable to adverse events. The prices charged to foreign patients were used to estimate the cost of the health care resources used. RESULTS: 850 adverse events were identified in the NZQHS which cost an average of $NZ 10,264 per patient. For New Zealand, adverse events are estimated to cost the medical system $NZ 870 million, of which $NZ 590 million went toward treating preventable adverse events. The results suggest that up to 30% of public hospital expenditure goes toward treating an adverse event. The results also suggest that older patients, neonates and those with moderately serious co-morbidity tended to have more costly adverse events. CONCLUSIONS: Adverse events lead to a significant use of health care resources in New Zealand. These findings suggest that substantial resources could be saved by eliminating preventable adverse events.