PRECISION-TBI: a study protocol for a vanguard prospective cohort study to enhance understanding and management of moderate to severe traumatic brain injury in Australia.

INTRODUCTION: Traumatic brain injury (TBI) is a heterogeneous condition in terms of pathophysiology and clinical course. Outcomes from moderate to severe TBI (msTBI) remain poor despite concerted research efforts. The heterogeneity of clinical management represents a barrier to progress in this area. PRECISION-TBI is a prospective, observational, cohort study that will establish a clinical research network across major neurotrauma centres in Australia. This network will enable the ongoing collection of injury and clinical management data from patients with msTBI, to quantify variations in processes of care between sites. It will also pilot high-frequency data collection and analysis techniques, novel clinical interventions, and comparative effectiveness methodology. METHODS AND ANALYSIS: PRECISION-TBI will initially enrol 300 patients with msTBI with Glasgow Coma Scale (GCS) <13 requiring intensive care unit (ICU) admission for invasive neuromonitoring from 10 Australian neurotrauma centres. Demographic data and process of care data (eg, prehospital, emergency and surgical intervention variables) will be collected. Clinical data will include prehospital and emergency department vital signs, and ICU physiological variables in the form of high frequency neuromonitoring data. ICU treatment data will also be collected for specific aspects of msTBI care. Six-month extended Glasgow Outcome Scores (GOSE) will be collected as the key outcome. Statistical analysis will focus on measures of between and within-site variation. Reports documenting performance on selected key quality indicators will be provided to participating sites. ETHICS AND DISSEMINATION: Ethics approval has been obtained from The Alfred Human Research Ethics Committee (Alfred Health, Melbourne, Australia). All eligible participants will be included in the study under a waiver of consent (hospital data collection) and opt-out (6 months follow-up). Brochures explaining the rationale of the study will be provided to all participants and/or an appropriate medical treatment decision-maker, who can act on the patient's behalf if they lack capacity. Study findings will be disseminated by peer-review publications. TRIAL REGISTRATION NUMBER: NCT05855252.

Association Between Early External Ventricular Drain Insertion and Functional Outcomes 6 Months Following Moderate-to-Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading global cause of morbidity and mortality. Intracranial hypertension following moderate-to-severe TBI (m-sTBI) is a potentially modifiable secondary cerebral insult and one of the central therapeutic targets of contemporary neurocritical care. External ventricular drain (EVD) insertion is a common therapeutic intervention used to control intracranial hypertension and attenuate secondary brain injury. However, the optimal timing of EVD insertion in the setting of m-sTBI is uncertain and practice variation is widespread. Therefore, we aimed to assess if there is an association between timing of EVD placement and functional neurological outcome at 6 months post m-sTBI. We pooled individual patient data for all relevant harmonizable variables from the Erythropoietin in Traumatic Brain Injury (EPO-TBI) and Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR) randomized control trials, and the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) Core Study version 3.0 and Australia-Europe NeuroTrauma Effectiveness Research in TBI (Oz-ENTER) prospective observational studies to create a combined dataset. The Glasgow Coma Scale (GCS) score was used to define TBI severity and we included all patients admitted to an intensive care unit with a GCS ≤12, who were 15 years or older and underwent EVD placement within 7 days of injury. We used hierarchical multi-variable logistic regression models to study the association between EVD insertion within 24 h of injury (early) compared with EVD insertion more than 24 h after injury (late) and 6-month functional neurological outcome measured using the Glasgow Outcome Score Extended (GOSE). In total, 2536 patients were assessed. Of these, 502 (20%) underwent early EVD insertion and 145 (6%) underwent late EVD insertion. Following adjustment for the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) score extended (Core + CT), sex, injury severity score, study and treatment site, patients receiving a late EVD had higher odds of death or severe disability (GOSE 1-4) at 6 months follow-up than those receiving an early EVD adjusted odds ratio; 95% confidence interval, 2.14; 1.22-3.76; p = 0.008. Our study suggests that in patients with m-sTBI where an EVD is needed, early (≤ 24 h post-injury) insertion may result in better long-term functional outcomes. This finding supports future prospective investigation in this area.

Anti-Factor-Xa and Activated Partial Thromboplastin Time Concordance and Outcomes in Adults Undergoing Extracorporeal Membrane Oxygenation: A Secondary Analysis of the Pilot Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation Randomized Trial.

OBJECTIVES: To determine the concordance between activated partial thromboplastin time (aPTT) and anti-factor-Xa (anti-Xa) in adults undergoing extracorporeal membrane oxygenation (ECMO) and to identify the factors associated with discordant paired aPTT/anti-Xa. DESIGN: Pre-planned secondary analysis of the Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation pilot randomized unblinded, parallel-group controlled trial. SETTING: Two ICUs in two university hospitals. PATIENTS: Thirty-two critically ill patients who underwent ECMO and who had at least one paired aPTT and anti-Xa assay performed at the same time. INTERVENTIONS: We analyzed the concordance between aPTT and anti-Xa and identified factors associated with discordant paired aPTT/anti-Xa based on their respective therapeutic ranges. We also compared biological parameters between heparin resistance episode and no heparin resistance. MEASUREMENTS AND MAIN RESULTS: Of the 32 patients who were included in this study, 24 (75%) had at least one discordant paired aPTT/anti-Xa. Of the 581 paired aPTT/anti-Xa that were analyzed, 202 were discordant. The aPTT was relatively lower than anti-Xa in 66 cases (32.7%) or relatively higher than anti-Xa in 136 cases (67.3%). Thirty-three heparin resistance episodes were identified in six patients (19%). CONCLUSIONS: In these critically ill patients undergoing ECMO, one third of paired aPTT/anti-Xa measures was discordant. Coagulopathy and heparin resistance might be the reasons for discordance. Our results support the potential importance of routinely monitoring both tests in this setting.

Systematic reviews and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative: mortality, morbidity, and organ failure.

BACKGROUND: Mortality, morbidity, and organ failure are important and common serious harms after surgery. However, there are many candidate measures to describe these outcome domains. Definitions of these measures are highly variable, and validity is often unclear. As part of the International Standardised Endpoints in Perioperative Medicine (StEP) initiative, this study aimed to derive a set of standardised and valid measures of mortality, morbidity, and organ failure for use in perioperative clinical trials. METHODS: Three domains of endpoints (mortality, morbidity, and organ failure) were explored through systematic literature review and a three-stage Delphi consensus process using methods consistently applied across the StEP initiative. Reliability, feasibility, and patient-centredness were assessed in round 3 of the consensus process. RESULTS: A high level of consensus was achieved for two mortality time points, 30-day and 1-yr mortality, and these two measures are recommended. No organ failure endpoints achieved threshold criteria for consensus recommendation. The Clavien-Dindo classification of complications achieved threshold criteria for consensus in round 2 of the Delphi process but did not achieve the threshold criteria in round 3 where it scored equivalently to the Post Operative Morbidity Survey. Clavien-Dindo therefore received conditional endorsement as the most widely used measure. No composite measures of organ failure achieved an acceptable level of consensus. CONCLUSIONS: Both 30-day and 1-yr mortality measures are recommended. No measure is recommended for organ failure. One measure (Clavien-Dindo) is conditionally endorsed for postoperative morbidity, but our findings suggest that no single endpoint offers a reliable and valid measure to describe perioperative morbidity that is not dependent on the quality of deli-vered care. Further refinement of current measures, or development of novel measures, of postoperative morbidity might improve consensus in this area.

Medication-related Medical Emergency Team activations: a case review study of frequency and preventability.

OBJECTIVES: Despite recognition of clinical deterioration and medication-related harm as patient safety risks, the frequency of medication-related Rapid Response System activations is undefined. We aimed to estimate the incidence and preventability of medication-related Medical Emergency Team (MET) activations and describe the associated adverse medication events. METHODS: A case review study of consecutive MET activations at two acute, academic teaching hospitals in Melbourne, Australia with mature Rapid Response Systems was conducted. All MET activations during a 3-week study period were assessed for a medication cause including identification of the contributing adverse medication event and its preventability, using validated tools and recognised classification systems. RESULTS: There were 9439 admissions and 628 MET activations during the study period. Of these, 146 (23.2%) MET activations were medication related: an incidence of 15.5 medication-related MET activation per 1000 admissions. Medication-related MET activations occurred a median of 46.6 hours earlier (IQR 22-165) in an admission than non-medication-related activations (p=0.001). Furthermore, this group also had more repeat MET activations during their admission (p=0.021, OR=1.68, 95% CI 1.09 to 2.59). A total of 92 of 146 (63%) medication-related MET activations were potentially preventable. Tachycardia due to omission of beta-blocking agents (10.9%, n=10 of 92) and hypotension due to cumulative toxicity (9.8%, n=9 of 92) or inappropriate use (10.9%, n=10 of 92) of antihypertensives were the most common adverse medication events leading to potentially preventable medication-related MET activations. CONCLUSIONS: Medications contributed to almost a quarter of MET activations, often early in a patient's admission. One in seven MET activations were due to potentially preventable adverse medication events. The most common of these were omission of beta-blockers and clinically inappropriate antihypertensive use. Strategies to prevent these events would increase patient safety and reduce burden on the MET.

High arterial oxygen levels and supplemental oxygen administration in traumatic brain injury: insights from CENTER-TBI and OzENTER-TBI.

PURPOSE: The effect of high arterial oxygen levels and supplemental oxygen administration on outcomes in traumatic brain injury (TBI) is debated, and data from large cohorts of TBI patients are limited. We investigated whether exposure to high blood oxygen levels and high oxygen supplementation is independently associated with outcomes in TBI patients admitted to the intensive care unit (ICU) and undergoing mechanical ventilation. METHODS: This is a secondary analysis of two multicenter, prospective, observational, cohort studies performed in Europe and Australia. In TBI patients admitted to ICU, we describe the arterial partial pressure of oxygen (PaO2) and the oxygen inspired fraction (FiO2). We explored the association between high PaO2 and FiO2 levels within the first week with clinical outcomes. Furthermore, in the CENTER-TBI cohort, we investigate whether PaO2 and FiO2 levels may have differential relationships with outcome in the presence of varying levels of brain injury severity (as quantified by levels of glial fibrillary acidic protein (GFAP) in blood samples obtained within 24 h of injury). RESULTS: The analysis included 1084 patients (11,577 measurements) in the CENTER-TBI cohort, of whom 55% had an unfavorable outcome, and 26% died at a 6-month follow-up. Median PaO2 ranged from 93 to 166 mmHg. Exposure to higher PaO2 and FiO2 in the first seven days after ICU admission was independently associated with a higher mortality rate. A trend of a higher mortality rate was partially confirmed in the OzENTER-TBI cohort (n = 159). GFAP was independently associated with mortality and functional neurologic outcome at follow-up, but it did not modulate the outcome impact of high PaO2 levels, which remained independently associated with 6-month mortality. CONCLUSIONS: In two large prospective multicenter cohorts of critically ill patients with TBI, levels of PaO2 and FiO2 varied widely across centers during the first seven days after ICU admission. Exposure to high arterial blood oxygen or high supplemental oxygen was independently associated with 6-month mortality in the CENTER-TBI cohort, and the severity of brain injury did not modulate this relationship. Due to the limited sample size, the findings were not wholly validated in the external OzENTER-TBI cohort. We cannot exclude the possibility that the worse outcomes associated with higher PaO2 were due to use of higher FiO2 in patients with more severe injury or physiological compromise. Further, these findings may not apply to patients in whom FiO2 and PaO2 are titrated to brain tissue oxygen monitoring (PbtO2) levels. However, at minimum, these findings support the need for caution with oxygen therapy in TBI, particularly since titration of supplemental oxygen is immediately applicable at the bedside.

Incidence of death or disability at 6 months after extracorporeal membrane oxygenation in Australia: a prospective, multicentre, registry-embedded cohort study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is an invasive procedure used to support critically ill patients with the most severe forms of cardiac or respiratory failure in the short term, but long-term effects on incidence of death and disability are unknown. We aimed to assess incidence of death or disability associated with ECMO up to 6 months (180 days) after treatment. METHODS: This prospective, multicentre, registry-embedded cohort study was done at 23 hospitals in Australia from Feb 15, 2019, to Dec 31, 2020. The EXCEL registry included all adults (≥18 years) in Australia who were admitted to an intensive care unit (ICU) in a participating centre at the time of the study and who underwent ECMO. All patients who received ECMO support for respiratory failure, cardiac failure, or cardiac arrest during their ICU stay were eligible for this study. The primary outcome was death or moderate-to-severe disability (defined using the WHO Disability Assessment Schedule 2.0, 12-item survey) at 6 months after ECMO initiation. We used Fisher's exact test to compare categorical variables. This study is registered with ClinicalTrials.gov, NCT03793257. FINDINGS: Outcome data were available for 391 (88%) of 442 enrolled patients. The primary outcome of death or moderate-to-severe disability at 6 months was reported in 260 (66%) of 391 patients: 136 (67%) of 202 who received veno-arterial (VA)-ECMO, 60 (54%) of 111 who received veno-venous (VV)-ECMO, and 64 (82%) of 78 who received extracorporeal cardiopulmonary resuscitation (eCPR). After adjustment for age, comorbidities, Acute Physiology and Chronic Health Evaluation (APACHE) IV score, days between ICU admission and ECMO start, and use of vasopressors before ECMO, death or moderate-to-severe disability was higher in patients who received eCPR than in those who received VV-ECMO (VV-ECMO vs eCPR: risk difference [RD] -32% [95% CI -49 to -15]; p<0·001) but not VA-ECMO (VA-ECMO vs eCPR -8% [-22 to 6]; p=0·27). INTERPRETATION: In our study, only a third of patients were alive without moderate-to-severe disability at 6 months after initiation of ECMO. The finding that disability was common across all areas of functioning points to the need for long-term, multidisciplinary care and support for surviving patients who have had ECMO. Further studies are needed to understand the 180-day and longer-term prognosis of patients with different diagnoses receiving different modes of ECMO, which could have important implications for the selection of patients for ECMO and management strategies in the ICU. FUNDING: The National Health and Medical Research Council of Australia.

AUS-TBI: The Australian Health Informatics Approach to Predict Outcomes and Monitor Intervention Efficacy after Moderate-to-Severe Traumatic Brain Injury.

Predicting and optimizing outcomes after traumatic brain injury (TBI) remains a major challenge because of the breadth of injury characteristics and complexity of brain responses. AUS-TBI is a new Australian Government-funded initiative that aims to improve personalized care and treatment for children and adults who have sustained a TBI. The AUS-TBI team aims to address a number of key knowledge gaps, by designing an approach to bring together data describing psychosocial modulators, social determinants, clinical parameters, imaging data, biomarker profiles, and rehabilitation outcomes in order to assess the influence that they have on long-term outcome. Data management systems will be designed to track a broad range of suitable potential indicators and outcomes, which will be organized to facilitate secure data collection, linkage, storage, curation, management, and analysis. It is believed that these objectives are achievable because of our consortium of highly committed national and international leaders, expert committees, and partner organizations in TBI and health informatics. It is anticipated that the resulting large-scale data resource will facilitate personalization, prediction, and improvement of outcomes post-TBI.

People in intensive care with COVID-19: demographic and clinical features during the first, second, and third pandemic waves in Australia.

OBJECTIVE: To compare the demographic and clinical features, management, and outcomes for patients admitted with COVID-19 to intensive care units (ICUs) during the first, second, and third waves of the pandemic in Australia. DESIGN, SETTING, AND PARTICIPANTS: People aged 16 years or more admitted with polymerase chain reaction-confirmed COVID-19 to the 78 Australian ICUs participating in the Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) Australia project during the first (27 February - 30 June 2020), second (1 July 2020 - 25 June 2021), and third COVID-19 waves (26 June - 1 November 2021). MAIN OUTCOME MEASURES: Primary outcome: in-hospital mortality. SECONDARY OUTCOMES: ICU mortality; ICU and hospital lengths of stay; supportive and disease-specific therapies. RESULTS: 2493 people (1535 men, 62%) were admitted to 59 ICUs: 214 during the first (9%), 296 during the second (12%), and 1983 during the third wave (80%). The median age was 64 (IQR, 54-72) years during the first wave, 58 (IQR, 49-68) years during the second, and 54 (IQR, 41-65) years during the third. The proportion without co-existing illnesses was largest during the third wave (41%; first wave, 32%; second wave, 29%). The proportion of ICU beds occupied by patients with COVID-19 was 2.8% (95% CI, 2.7-2.9%) during the first, 4.6% (95% CI, 4.3-5.1%) during the second, and 19.1% (95% CI, 17.9-20.2%) during the third wave. Non-invasive (42% v 15%) and prone ventilation strategies (63% v 15%) were used more frequently during the third wave than during the first two waves. Thirty patients (14%) died in hospital during the first wave, 35 (12%) during the second, and 281 (17%) during the third. After adjusting for age, illness severity, and other covariates, the risk of in-hospital mortality was similar for the first and second waves, but 9.60 (95% CI, 3.52-16.7) percentage points higher during the third than the first wave. CONCLUSION: The demographic characteristics of patients in intensive care with COVID-19 and the treatments they received during the third pandemic wave differed from those of the first two waves. Adjusted in-hospital mortality was highest during the third wave.

Comparison of 6-month outcomes of sepsis versus non-sepsis critically ill patients receiving mechanical ventilation.

BACKGROUND: Data on long-term outcomes after sepsis-associated critical illness have mostly come from small cohort studies, with no information about the incidence of new disability. We investigated whether sepsis-associated critical illness was independently associated with new disability at 6 months after ICU admission compared with other types of critical illness. METHODS: We conducted a secondary analysis of a multicenter, prospective cohort study in six metropolitan intensive care units in Australia. Adult patients were eligible if they had been admitted to the ICU and received more than 24 h of mechanical ventilation. There was no intervention. RESULTS: The primary outcome was new disability measured with the WHO Disability Assessment Schedule 2.0 (WHODAS) 12 level score compared between baseline and 6 months. Between enrollment and follow-up at 6 months, 222/888 (25%) patients died, 100 (35.5%) with sepsis and 122 (20.1%) without sepsis (P < 0.001). Among survivors, there was no difference for the incidence of new disability at 6 months with or without sepsis, 42/106 (39.6%) and 106/300 (35.3%) (RD, 0.00 (- 10.29 to 10.40), P = 0.995), respectively. In addition, there was no difference in the severity of disability, health-related quality of life, anxiety and depression, post-traumatic stress, return to work, financial distress or cognitive function. CONCLUSIONS: Compared to mechanically ventilated patients of similar acuity and length of stay without sepsis, patients with sepsis admitted to ICU have an increased risk of death, but survivors have a similar risk of new disability at 6 months. Trial registration NCT03226912, registered July 24, 2017.

Comparison of 6-Month Outcomes of Survivors of COVID-19 versus Non-COVID-19 Critical Illness.

Rationale: The outcomes of survivors of critical illness due to coronavirus disease (COVID-19) compared with non-COVID-19 are yet to be established. Objectives: We aimed to investigate new disability at 6 months in mechanically ventilated patients admitted to Australian ICUs with COVID-19 compared with non-COVID-19. Methods: We included critically ill patients with COVID-19 and non-COVID-19 from two prospective observational studies. Patients were eligible if they were adult (age ⩾ 8 yr) and received ⩾24 hours of mechanical ventilation. In addition, patients with COVID-19 were eligible with a positive laboratory PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Measurements and Main Results: Demographic, intervention, and hospital outcome data were obtained from electronic medical records. Survivors were contacted by telephone for functional outcomes with trained outcome assessors using the World Health Organization Disability Assessment Schedule 2.0. Between March 6, 2020, and April 21, 2021, 120 critically ill patients with COVID-19, and between August 2017 and January 2019, 199 critically ill patients without COVID-19, fulfilled the inclusion criteria. Patients with COVID-19 were older (median [interquartile range], 62 [55-71] vs. 58 [44-69] yr; P = 0.019) with a lower Acute Physiology and Chronic Health Evaluation II score (17 [13-20] vs. 19 [15-23]; P = 0.011). Although duration of ventilation was longer in patients with COVID-19 than in those without COVID-19 (12 [5-19] vs. 4.8 [2.3-8.8] d; P < 0.001), 180-day mortality was similar between the groups (39/120 [32.5%] vs. 70/199 [35.2%]; P = 0.715). The incidence of death or new disability at 180 days was similar (58/93 [62.4%] vs. 99/150 [66/0%]; P = 0.583). Conclusions: At 6 months, there was no difference in new disability for patients requiring mechanical ventilation for acute respiratory failure due to COVID-19 compared with non-COVID-19. Clinical trial registered with www.clinicaltrials.gov (NCT04401254).

Evaluation of medical emergency team medication management practices in acute hospitals: A multicentre study.

BACKGROUND: Medical emergency teams use medications to rescue deteriorating patients. Medication management is the system of steps and processes, including prescribing, distribution, administration, and monitoring, to achieve the best outcomes from medication use. Systems or standards for medication management by medical emergency teams have not been defined. OBJECTIVES: The aim of the study was to propose potential solutions to improve medical emergency team medication management by evaluating medication supply and related medication management practices during medical emergency team activations and understanding clinicians' perceptions about medical emergency team medication management in acute hospitals. METHODS: A prospective multicentre audit of intensive care unit-equipped hospitals in Victoria, Australia, was conducted. After advertisement and invitation via scheduled email newsletters to hospitals, a representative of the medical emergency team from each hospital self-administered an online audit tool during December 2019 and January 2020. Audit data were analysed descriptively, and perceptions were analysed using content analysis. RESULTS: Responses were received from 32 of the 44 (72.7%) eligible hospitals. At 17 of the 32 (53.1%) hospitals, arrest trolleys provided medications for medical emergency team activations, in addition to arrest calls. At 15 of the 32 (46.9%) hospitals, separate, dedicated medical emergency team medication supplies were used to care for deteriorating patients. Dedicated medical emergency team supplies contained a median of 20 (range = 8-37) medications, predominantly cardiovascular (median = 8, mode = 7, range = 4-16) and neurological medications (median and mode = 6, range = 0-11). Variation was observed in all storage and other supply-related medication management practices studied. The four most frequent categories of clinicians' perceptions described systematic challenges with availability of the right medication in the right place at the right time. CONCLUSIONS: Current supply and related medication management practices and clinicians' perceptions demonstrated further development is necessary for medication management to meet the needs of medical emergency team clinicians and their patients.

The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study.

BACKGROUND: There are few reports of new functional impairment following critical illness from COVID-19. We aimed to describe the incidence of death or new disability, functional impairment and changes in health-related quality of life of patients after COVID-19 critical illness at 6 months. METHODS: In a nationally representative, multicenter, prospective cohort study of COVID-19 critical illness, we determined the prevalence of death or new disability at 6 months, the primary outcome. We measured mortality, new disability and return to work with changes in the World Health Organization Disability Assessment Schedule 2.0 12L (WHODAS) and health status with the EQ5D-5LTM. RESULTS: Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51-70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06-13.77]; p < 0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, - 0.19 [- 0.28 to - 0.10]; p < 0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty. CONCLUSIONS: At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning. Clinical trial registration NCT04401254 May 26, 2020.

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.

Measured energy expenditure in mildly hypothermic critically ill patients with traumatic brain injury: A sub-study of a randomized controlled trial.

BACKGROUND & AIMS: Prophylactic hypothermia, often used in critically ill patients with traumatic brain injury, reduces energy expenditure and may affect energy delivered by nutrition therapy. The primary objective of this study was to measure energy expenditure in hypothermic patients over the first 3 days after traumatic brain injury (TBI). Secondary objectives included comparison of measured energy expenditure and nutrition delivery to day 7. METHODS: A prospective sub-study of a randomized controlled trial conducted in patients with severe TBI, investigating prophylactic hypothermia (33-35 °C) as a neuroprotective therapy. In two centers, indirect calorimetry was initiated within 24 h of randomization and repeated up to twice daily to day 7. Data are presented as n (%), mean (standard deviation (SD)), median [interquartile range (IQR)], and mean difference (95% confidence interval (CI)). RESULTS: Forty patients were included (20 in each group), with 17 patients in the hypothermic and 16 in the normothermic group having an indirect calorimetry measurement in the first 3 days. Over the first 3 days, the mean temperature in the hypothermic and normothermic groups was 33.5 (0.6) ºC (n = 17) and 37 (0.5) ºC (n = 16), p < 0.0001, and the mean measured energy expenditure, was 21 (5) and 27 (4) kcal/kg, p = 0.002, representing a mean difference of 5 (95% CI: 2-8) kcal/kg. Energy expenditure was 20% (95% CI: 9.5-29%) less in hypothermia patients compared to normothermia patients. Hypothermia patients also had higher gastric residual volumes across the 7 day study period (438 (237) mls vs 184 (103) mls, p < 0.0001) and higher use of metoclopramide and erythromycin as prokinetics. Despite enteral nutrition intolerance, hypothermia patients received 93% of measured energy expenditure over 7 days. CONCLUSION: In TBI patients, energy expenditure was 20% less when receiving prophylactic hypothermia compared to normothermia. Greater gastric residual volumes, use of prokinetics and energy delivery that approximated measured energy expenditure was also observed in hypothermia patients. TRIAL REGISTRY NUMBER: POLAR-RCT: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235. This sub-study was not registered separately.

Age of red blood cells is not associated with in-hospital mortality in massively transfused patients.

BACKGROUND: Studies comparing mortality following massive transfusion (MT) with fresher versus longer-stored red blood cells (RBCs) have focused on trauma patients. The Australian and New Zealand Massive Transfusion Registry collects data on all adult MT cases (≥5 RBCs within 4 hours, any bleeding context, ≥18 years) at participating hospitals. METHODS: Years 2007 to 2018 data from 29 hospitals were analyzed to quantify the association between mortality and RBC storage time in adult MT cases. We ran three logistic regression models separately on each of seven bleeding contexts, with in-hospital mortality as the outcome and, in turn, (1) mean storage time (STmean) quartiles, (2) proportion of RBCs ≥30 days old (propOLD), and (3) scalar age of blood index as predictors. RESULTS: A total of 8,685 adult MT cases involving transfusion of 126,622 RBCs were analyzed with Australian and New Zealand data analyzed separately. Mean storage times for these cases were (by quartile in ascending order) as follows: Australia, 12.5 days (range, 3.1-15.5 days), 17.7 (15.5-19.9), 22.3 (19.9-24.9), and 29.8 (24.9-41.7); New Zealand, 11.3 days (3.6-13.7), 15.3 (13.7-16.8), 18.7 (16.8-20.7), and 24.5 (20.7-35.6). The odds ratios comparing in-hospital mortality for each quartile with that of the control first quartile (freshest blood), proportion of longer-stored (≥30 days) RBCs, and scalar age of blood index were not statistically significant across all bleeding contexts. CONCLUSION: We find no correlation between in-hospital mortality and storage time of transfused RBCs in a large cohort of adult MT patients representing all bleeding contexts. These results are consistent with those of recent large multicenter trials. LEVEL OF EVIDENCE: Epidemiologic, level III; Therapeutic, level IV.

Characteristics, management and outcomes of patients with severe traumatic brain injury in Victoria, Australia compared to United Kingdom and Europe: A comparison between two harmonised prospective cohort studies.

OBJECTIVE: The aim of this manuscript is to compare characteristics, management, and outcomes of patients with severe Traumatic Brain Injury (TBI) between Australia, the United Kingdom (UK) and Europe. METHODS: We enrolled patients with severe TBI in Victoria, Australia (OzENTER-TBI), in the UK and Europe (CENTER-TBI) from 2015 to 2017. Main outcome measures were mortality and unfavourable outcome (Glasgow Outcome Scale Extended <5) 6 months after injury. Expected outcomes were compared according to the IMPACT-CT prognostic model, with observed to expected (O/E) ratios and 95% confidence intervals. RESULTS: We included 107 patients from Australia, 171 from UK, and 596 from Europe. Compared to the UK and Europe, patients in Australia were younger (median 32 vs 44 vs 44 years), a larger proportion had secondary brain insults including hypotension (30% vs 17% vs 21%) and a larger proportion received ICP monitoring (75% vs 74% vs 58%). Hospital length of stay was shorter in Australia than in the UK (median: 17 vs 23 vs 16 days), and a higher proportion of patients were discharged to a rehabilitation unit in Australia than in the UK and Europe (64% vs 26% vs 28%). Mortality overall was lower than expected (27% vs 35%, O/E ratio 0.77 [95% CI: 0.64 - 0.87]. O/E ratios were comparable between regions for mortality in Australia 0.86 [95% CI: 0.49-1.23] vs UK 0.82 [0.51-1.15] vs Europe 0.76 [0.60-0.87]). Unfavourable outcome rates overall were in line with historic expectations (O/E ratio 1.32 [0.96-1.68] vs 1.13 [0.84-1.42] vs 0.96 [0.85-1.09]). CONCLUSIONS: There are major differences in case-mix between Australia, UK, and Europe; Australian patients are younger and have a higher rate of secondary brain insults. Despite some differences in management and discharge policies, mortality was less than expected overall, and did not differ between regions. Functional outcomes were similar between regions, but worse than expected, emphasizing the need to improve treatment for patients with severe TBI.

Outcomes for patients with COVID-19 admitted to Australian intensive care units during the first four months of the pandemic.

OBJECTIVES: To describe the characteristics and outcomes of patients with COVID-19 admitted to intensive care units (ICUs) during the initial months of the pandemic in Australia. DESIGN, SETTING: Prospective, observational cohort study in 77 ICUs across Australia. PARTICIPANTS: Patients admitted to participating ICUs with laboratory-confirmed COVID-19 during 27 February - 30 June 2020. MAIN OUTCOME MEASURES: ICU mortality and resource use (ICU length of stay, peak bed occupancy). RESULTS: The median age of the 204 patients with COVID-19 admitted to intensive care was 63.5 years (IQR, 53-72 years); 140 were men (69%). The most frequent comorbid conditions were obesity (40% of patients), diabetes (28%), hypertension treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (24%), and chronic cardiac disease (20%); 73 patients (36%) reported no comorbidity. The most frequent source of infection was overseas travel (114 patients, 56%). Median peak ICU bed occupancy was 14% (IQR, 9-16%). Invasive ventilation was provided for 119 patients (58%). Median length of ICU stay was greater for invasively ventilated patients than for non-ventilated patients (16 days; IQR, 9-28 days v 3 days; IQR, 2-5 days), as was ICU mortality (26 deaths, 22%; 95% CI, 15-31% v four deaths, 5%; 95% CI, 1-12%). Higher Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores on ICU day 1 (adjusted hazard ratio [aHR], 1.15; 95% CI, 1.09-1.21) and chronic cardiac disease (aHR, 3.38; 95% CI, 1.46-7.83) were each associated with higher ICU mortality. CONCLUSION: Until the end of June 2020, mortality among patients with COVID-19 who required invasive ventilation in Australian ICUs was lower and their ICU stay longer than reported overseas. Our findings highlight the importance of ensuring adequate local ICU capacity, particularly as the pandemic has not yet ended.

Thromboelastography to Assess Coagulopathy in Traumatic Brain Injury Patients Undergoing Therapeutic Hypothermia.

Therapeutic hypothermia has been a treatment option for patients with severe traumatic brain injury (TBI) for many years. There has, however, been uncertainty whether hypothermia in this context also increased clinical bleeding risk, perhaps due to platelet dysfunction. Standard coagulation tests do not allow accurate assessment of in vivo coagulation. We studied specific coagulation abnormalities in patients undergoing therapeutic hypothermia for severe TBI using bedside thromboelastography (TEG).We studied 20 patients with severe blunt TBI from a single tertiary ICU who were enrolled in the prophylactic hypothermia to lessen traumatic brain injury (POLAR) trial. Ten patients had been randomized to hypothermia, and 10 were controls receiving normothermic standard care. TEG was undertaken during and after therapeutic hypothermia, and at the same time points in controls. Coagulation profiles were then compared between the hypothermic and control patients, and also between hypothermia and later normothermia in the study patients. Patients were primarily young (mean age 34 years) and male (85%). Measures of injury severity, including Glasgow coma score and injury severity scale, were not different between groups. Using TEG, the median alpha angle was reduced in hypothermic patients compared with controls (69.2° vs. 72.0°, p = 0.02), although both were within the normal range. LY30 was also reduced (0.0% vs. 0.5%, p < 0.01). Both differences persisted when hypothermic patients were compared with themselves during later normothermia. Therapeutic hypothermia during severe TBI causes a small decrease in the rate of clot formation. However, this decrease is within the normal range, and is unlikely to be clinically significant.