Single-cell RNA sequencing reveals peripheral blood leukocyte responses to spinal cord injury in mice with humanised immune systems.

Next-generation humanised mouse models and single-cell RNA sequencing (scRNAseq) approaches enable in-depth studies into human immune cell biology. Here we used NSG-SGM3 mice engrafted with human umbilical cord haematopoietic stem cells to investigate how human immune cells respond to and/or are changed by traumatic spinal cord injury (SCI). We hypothesised that the use of such mice could help advance our understanding of spinal cord injury-induced immune depression syndrome (SCI-IDS), and also how human leukocytes change as they migrate from the circulation into the lesion site. Our scRNAseq experiments, supplemented by flow cytometry, demonstrate the existence of up to 11 human immune cell (sub-) types and/or states across the blood and injured spinal cord (7 days post-SCI) of humanised NSG-SGM3 mice. Further comparisons of human immune cell transcriptomes between naïve, sham-operated and SCI mice identified a total of 579 differentially expressed genes, 190 of which were 'SCI-specific' (that is, genes regulated only in response to SCI but not sham surgery). Gene ontology analysis showed a prominent downregulation of immune cell function under SCI conditions, including for T cell receptor signalling and antigen presentation, confirming the presence of SCI-IDS and the transcriptional signature of human leukocytes in association with this phenomenon. We also highlight the activating influence of the local spinal cord lesion microenvironment by comparing the transcriptomes of circulating versus infiltrated human immune cells; those isolated from the lesion site were enriched for genes relating to both immune cell activity and function (e.g., oxidative phosphorylation, T cell proliferation and antigen presentation). We lastly applied an integrated bioinformatics approach to determine where immune responses in humanised NSG-SGM3 mice appear congruent to the native responses of human SCI patients, and where they diverge. Collectively, our study provides a valuable resource and methodological framework for the use of these mice in translational research.

EARLY PERSISTENT LYMPHOPENIA AND RISK OF DEATH IN CRITICALLY ILL PATIENTS WITH AND WITHOUT SEPSIS.

ABSTRACT: Purpose: To examine the relationship of early persistent lymphopenia with hospital survival in critically ill patients with and without sepsis to assess whether it can be considered a treatable trait. Methods: Retrospective database analysis of patients with nonelective admission to intensive care units (ICUs) during January 2015 to December 2018. Patients were classified as having sepsis if the Acute Physiology and Chronic Health Evaluation III admission diagnostic code included sepsis or coded for an infection combined with a Sequential Organ Failure Assessment score of ≥2. We defined early persistent lymphopenia at two thresholds (absolute lymphocyte count [ALC] <1.0 and <0.75 × 10 9 /L) based on two qualifying values recorded during the first 4 days in ICU. The main outcome measure was time to in-hospital death. Results: Of 8,507 eligible patients, 7,605 (89.4%) had two ALCs recorded during their first 4 days in ICU; of these, 1,482 (19.5%) had sepsis. Persistent lymphopenia (ALC <1.0) was present in 728 of 1,482 (49.1%) and 2,302 of 6,123 (37.6%) patients with and without sepsis, respectively. For ALC <0.75, the results were 487 of 1,482 (32.9%) and 1,125 of 6,123 (18.4%), respectively. Of 3,030 patients with persistent lymphopenia (ALC <1.0), 562 (18.5%) died compared with 439 of 4,575 (9.6%) without persistent lymphopenia. Persistent lymphopenia was an independent risk factor for in-hospital death in all patients. The hazard ratios for death at ALC <1.0 were 1.89 (95% confidence interval, 1.32-2.71; P = 0.0005) and 1.17 (95% confidence interval, 1.02-1.35; P = 0.0246) in patients with and without sepsis respectively. Conclusions: Early persistent lymphopenia is common in critically ill patients and associated with increased risk of death in patients with and without sepsis. Although the association is stronger in patients with sepsis, lymphopenia is a candidate to be considered a treatable trait; drugs that reverse lymphopenia should be trialed in critically ill patients.

Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. METHODS: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2], 50 to 55 mm Hg) or normocapnia (target Paco2, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. RESULTS: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. CONCLUSIONS: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.).

PREdiction and Diagnosis using Imaging and Clinical biomarkers Trial in Traumatic Brain Injury (PREDICT-TBI) study protocol: an observational, prospective, multicentre cohort study for the prediction of outcome in moderate-to-severe TBI.

INTRODUCTION: Traumatic brain injury (TBI) is a heterogeneous condition with a broad spectrum of injury severity, pathophysiological processes and variable outcomes. For moderate-to-severe TBI survivors, recovery is often protracted and outcomes can range from total dependence to full recovery. Despite advances in medical treatment options, prognosis remains largely unchanged. The objective of this study is to develop a machine learning predictive model for neurological outcomes at 6 months in patients with a moderate-to-severe TBI, incorporating longitudinal clinical, multimodal neuroimaging and blood biomarker predictor variables. METHODS AND ANALYSIS: A prospective, observational, cohort study will enrol 300 patients with moderate-to-severe TBI from seven Australian hospitals over 3 years. Candidate predictors including demographic and general health variables, and longitudinal clinical, neuroimaging (CT and MRI), blood biomarker and patient-reported outcome measures will be collected at multiple time points within the acute phase of injury. The predictor variables will populate novel machine learning models to predict the Glasgow Outcome Scale Extended 6 months after injury. The study will also expand on current prognostic models by including novel blood biomarkers (circulating cell-free DNA), and the results of quantitative neuroimaging such as Quantitative Susceptibility Mapping and Dynamic Contrast Enhanced MRI as predictor variables. ETHICS AND DISSEMINATION: Ethical approval has been obtained by the Royal Brisbane and Women's Hospital Human Research Ethics Committee, Queensland. Participants or their substitute decision-maker/s will receive oral and written information about the study before providing written informed consent. Study findings will be disseminated by peer-review publications and presented at national and international conferences and clinical networks. TRIAL REGISTRATION NUMBER: ACTRN12620001360909.

Improving the handover of complex trauma patients by implementing a standardised process.

BACKGROUND: Patient handover continues to be an international health priority in the prevention of patient harm. Transitioning patients from the intensive care unit (ICU) to the ward is complex, particularly for trauma patients, due to the multifaceted aspects of their care requirements as a result of multiple injuries and different speciality teams. OBJECTIVES/AIM: To design, implement, and evaluate the efficacy of a standardised handover process and tool for the transfer of ICU trauma patients. METHODS: A multimethod before/after study design was used. This included observations before and after an implemented transfer process and semistructured interviews with ICU and ward nurses caring for trauma patients. Comparisons were made of data before and after the intervention. RESULTS: Eleven patient handovers were observed, and 21 nurses (11 from the ICU and 10 from the ward) were interviewed. Patients and family members were included during the handover following the intervention (n = 0/10 [0%] vs n = 4/11 [36%]) and the ward nurses were asked if they had any concerns (n = 5/10 [50%] vs n = 10/11 [91%]). Improvements in patient observations handed over were reported following the intervention. However, omissions remained in some key areas including patient introduction, patient identity, fluid balance, and allergies/alerts. Thematic analysis of interviews revealed that the new handover process was perceived advantageous by both ICU and ward nurses because of its structured and comprehensive approach. Identified future improvements included the need for hospital service managers to ensure integration of ICU and ward electronic health record systems. CONCLUSION: Precise, accurate, and complete handover remains a patient safety concern. Improvements were achieved using a standardised process and handover tool for the transfer of complex trauma patients. Further improvements are required to reduce the failure to hand over essential patient information.

Optimal Settings at Initiation of Veno-Venous Extracorporeal Membrane Oxygenation: An Exploratory In-Silico Study.

The Extracorporeal Life Support Organisation (ELSO) recommends initiating veno-venous extracorporeal membrane oxygenation (ECMO) with sweep gas flow rate () of 2 L/min and extracorporeal circuit blood flow () of 2 L/min. We used an in-silico model to examine the effect on gas exchange of initiating ECMO with different and , and the effect of including 5% in sweep gas. This was done using a set of patient examples, each with different physiological derangements at baseline (before ECMO). When ECMO was initiated following ELSO recommendations in the patient examples with significant hypercapnia at baseline, sometimes fell to < 50% of the baseline , a magnitude of fall associated with adverse neurological outcomes. In patient examples with very low baseline arterial oxygen saturation (), initiation of ECMO did not always increase to > 80%. Initiating ECMO with of 1 L/min and of 4 L/min, or with sweep gas containing 5% , of 2 L/min, and of 4 L/min, reduced the fall in and increased the rise in compared to the ELSO strategy. While ELSO recommendations may suit most patients, they may not suit patients with severe physiological derangements at baseline.

Soft collar for acute cervical spine injury immobilisation -patient experiences and outcomes: A single centre mixed methods study.

BACKGROUND: Cervical collars are used as standard care for neck immobilisation after cervical spine injury. Although evidence for the most effective type of collar is lacking, there is evidence regarding adverse patient outcomes when managed in a semi or rigid collar. In response to the evidence of complications and adverse effects when using a hard collar, a large Australian adult trauma hospital that specializes in spinal care, changed its policy from hard to soft collars when managing acute cervical spine injury. OBJECTIVE: The aim of this study was to investigate patients' experiences and outcomes when wearing a soft collar for acute cervical spine injury management in hospital. METHOD: A single centre mixed method sequential study design was used. RESULTS: Medical records from 136 patients were examined and no adverse events resulting from collar use were recorded. Interviews with 20 patients revealed that they understood the value of wearing a soft collar. The soft collars were considered supportive and well tolerated, with good adherence to recommendations for use. CONCLUSIONS: Understanding the patients' experiences informs better care management. This study suggests that soft collars are well tolerated, do not result in pressure injuries or other adverse events and are suitable for managing acute cervical spine injury.

Case Report: Preliminary Images From an Electromagnetic Portable Brain Scanner for Diagnosis and Monitoring of Acute Stroke.

Introduction: Electromagnetic imaging is an emerging technology which promises to provide a mobile, and rapid neuroimaging modality for pre-hospital and bedside evaluation of stroke patients based on the dielectric properties of the tissue. It is now possible due to technological advancements in materials, antennae design and manufacture, rapid portable computing power and network analyses and development of processing algorithms for image reconstruction. The purpose of this report is to introduce images from a novel, portable electromagnetic scanner being trialed for bedside and mobile imaging of ischaemic and haemorrhagic stroke. Methods: A prospective convenience study enrolled patients (January 2020 to August 2020) with known stroke to have brain electromagnetic imaging, in addition to usual imaging and medical care. The images are obtained by processing signals from encircling transceiver antennae which emit and detect low energy signals in the microwave frequency spectrum between 0.5 and 2.0 GHz. The purpose of the study was to refine the imaging algorithms. Results: Examples are presented of haemorrhagic and ischaemic stroke and comparison is made with CT, perfusion and MRI T2 FAIR sequence images. Conclusion: Due to speed of imaging, size and mobility of the device and negligible environmental risks, development of electromagnetic scanning scanner provides a promising additional modality for mobile and bedside neuroimaging.

Prognostic value of early leukocyte fluctuations for recovery from traumatic spinal cord injury.

BACKGROUND: Acute traumatic spinal cord injury (SCI) induces a systemic immune response involving circulating white blood cells (WBCs). How this response is influenced by overall trauma severity, the neurological level of injury and/or correlates with patient outcomes is poorly understood. The objective of this study was to identify relationships between early changes in circulating WBCs, injury characteristics and long-term patient outcomes in individuals with traumatic SCI. METHODS: We retrospectively analysed data from 161 SCI patients admitted to Brisbane's Princess Alexandra Hospital (exploration cohort). Logistic regression models in conjunction with receiver operating characteristic (ROC) analyses were used to assess the strength of specific links between the WBC response, respiratory infection incidence and neurological outcomes (American Spinal Injury Association Impairment Scale (AIS) grade conversion). An independent validation cohort from the Trauma Hospital Berlin, Germany (n = 49) was then probed to assess the robustness of effects and disentangle centre effects. RESULTS: We find that the extent of acute neutrophilia in human SCI patients is positively correlated with New Injury Severity Scores but inversely with the neurological outcome (AIS grade). Multivariate analysis demonstrated that acute SCI-induced neutrophilia is an independent predictor of AIS grade conversion failure, with an odds ratio (OR) of 4.16 and ROC area under curve (AUC) of 0.82 (P < 0.0001). SCI-induced lymphopenia was separately identified as an independent predictor of better recovery (OR = 24.15; ROC AUC = 0.85, P < 0.0001). Acute neutrophilia and increased neutrophil-lymphocyte ratios were otherwise significantly associated with respiratory infection presentation in both patient cohorts. CONCLUSIONS: Our findings demonstrate the prognostic value of modelling early circulating neutrophil and lymphocyte counts with patient characteristics for predicting the longer term recovery after SCI.

Fibrinogen Early In Severe Trauma studY (FEISTY): results from an Australian multicentre randomised controlled pilot trial.

Background: Haemorrhage is a major cause of death in severe trauma. Fibrinogen plays a critical role in maintaining haemostasis in traumatic haemorrhage, and early replacement using fibrinogen concentrate (FC) or cryoprecipitate (Cryo) is recommended by several international trauma guidelines. Limited evidence supports one product over the other, with widespread geographic and institutional variation in practice. Two previous trials have investigated the feasibility of rapid FC administration in severely injured trauma patients, with conflicting results. Objective: To compare the time to fibrinogen replacement using FC or Cryo in severely injured trauma patients with major haemorrhage and hypofibrinogenaemia. Design, setting, patients and interventions: A multicentre controlled pilot trial in which adult trauma patients with haemorrhage were randomly assigned (1:1) to receive FC or Cryo for fibrinogen replacement, guided by FIBTEM A5 (functional fibrinogen assessment at 5 minutes after clot formation, using rotational thromboelastometry). Main outcome measures: The primary outcome was time to commencement of fibrinogen replacement. Secondary outcomes included effects of the intervention on plasma fibrinogen levels and clinical outcomes including transfusion requirements and mortality. Results: Of the 100 randomly assigned patients, 62 were hypofibrinogenaemic and received the intervention (n = 37) or Cryo (n = 25). Median (interquartile range [IQR]) time to delivery of FC was 29 min (23-40 min) compared with 60 min (40-80 min) for Cryo (P = 0.0001). All 62 patients were hypofibrinogenaemic before receiving FC or Cryo (FC: median FIBTEM A5, 8 mm [IQR, 7-9 mm]; Cryo: median FIBTEM A5, 9 mm [IQR, 5-10 mm]). In the FC arm patients received a median of 3 g FC (IQR, 2-4 g), and in the Cryo arm patients received a median of 8 units of Cryo (IQR, 8-14 units). Restoration of fibrinogen levels was achieved in both arms after the intervention. Blood product transfusion, fluid resuscitation and thromboembolic complications were similar in both arms. Overall mortality was 15.3%, with more deaths in the FC arm. Conclusion: Fibrinogen replacement in severely injured trauma patients with major haemorrhage and hypofibrinogenaemia was achieved substantially faster using FC compared with Cryo. Fibrinogen levels increased appropriately using either product. The optimal method for replacing fibrinogen in traumatic haemorrhage is controversial. Our results will inform the design of a larger trial powered to assess patient-centred outcomes.

Effect of in-bed cycling on acute muscle wasting in critically ill adults: A randomised clinical trial.

PURPOSE: To examine whether in-bed cycling assists critically ill adults to reduce acute muscle wasting, improve function and improve quality of life following a period of critical illness. MATERIALS AND METHODS: A single-centre, two-group, randomised controlled trial with blinded assessment of the primary outcome was conducted in a tertiary ICU. Critically ill patients expected to be mechanically ventilated for at least 48 h were randomised to 30 min daily in-bed cycling in addition to usual-care physiotherapy (n = 37) or usual-care physiotherapy (n = 37). The primary outcome was muscle atrophy of rectus femoris cross-sectional area (RFCSA) measured by ultrasound at Day 10 following study enrolment. Secondary outcomes included manual muscle strength, handgrip strength, ICU mobility score, six-minute walk test distance and health-related quality of life up to six-months following hospital admission. RESULTS: Analysis included the 72 participants (mean age, 56-years; male, 68%) who completed the study. There were no significant between-group differences in muscle atrophy of RFCSA at Day 10 (mean difference 3.4, 95% CI -6.9% to 13.6%; p = .52), or for secondary outcomes (p-values ranged p = .11 to p = .95). CONCLUSIONS AND RELEVANCE: In-bed cycling did not reduce muscle wasting in critically ill adults, but this study provides useful effect estimates for large-scale clinical trials. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12616000948493.

Handover practices of nurses transferring trauma patients from intensive care units to the ward: A multimethod observational study.

Poor-quality patient handover leads to adverse patient outcomes. Consequently, handover has been identified as a national and international priority for preventing patient harm. Risks are exacerbated during transfers of trauma intensive care unit (ICU) patients to a ward because of the complexity of their injuries coupled with a de-escalation in care and monitoring. This study assessed current handover practices for ICU trauma patients, identifying barriers and facilitators to best practice handover. A multimethod design was used, including naturalistic observations of clinical handover of trauma patients transferred to a ward and semistructured interviews with both the ICU and ward nurses caring for the trauma patient. The study was conducted at an Australian metropolitan public adult teaching hospital ICU. Purposive maximal sampling of patient handover opportunities was sought. Recruitment continued until data saturation was reached using thematic analysis. Ten ICU and ward nurses were recruited, with 10 observations of handover and 20 interviews conducted. Observations of the handovers identified multiple issues, including deficits and discrepancies in the information communicated that could impact patient safety, variable handover processes, and poor patient and family involvement. Interviews elicited two major themes around the handover: practices and processes. Nurses identified that interruptions, time, and workload pressures presented barriers to handover, whilst teamwork, using a structured and systematic approach, preparation time for handover, and communication before transfer facilitated effective handover and transfer. Nurses suggested a structured tool to aid handover. This study identified clinically significant deficits and discrepancies in the information communicated to the ward nurses. Nurses identified that interruptions, time, and workload pressures presented barriers to effective handover. Teamwork where preparation and the handover event are prioritised over other activities is needed. A minimum data set for handover in conjunction with patients and family members is recommended.

Continuous renal replacement therapy and its impact on hyperammonaemia in acute liver failure.

OBJECTIVE: Hyperammonaemia contributes to complications in acute liver failure (ALF) and may be treated with continuous renal replacement therapy (CRRT), but current practice is poorly understood. DESIGN: We retrospectively analysed data for baseline characteristics, ammonia concentration, CRRT use, and outcomes in a cohort of Australian and New Zealand patients with ALF. SETTING: All liver transplant ICUs across Australia and New Zealand. PARTICIPANTS: Sixty-two patients with ALF. MAIN OUTCOME MEASURES: Impact of CRRT on hyperammonaemia and patient outcomes. RESULTS: We studied 62 patients with ALF. The median initial (first 24 h) peak ammonia was 132 µmol/L (interquartile range [IQR], 91-172), median creatinine was 165 µmol/L (IQR, 92-263) and median urea was 6.9 mmol/L (IQR, 3.1-12.0). Most patients (43/62, 69%) received CRRT within a median of 6 hours (IQR, 2-12) of ICU admission. At CRRT commencement, three-quarters of such patients did not have Stage 3 acute kidney injury (AKI): ten patients (23%) had no KDIGO creatinine criteria for AKI, 12 (28%) only had Stage 1, and ten patients (23%) had Stage 2 AKI. Compared with non-CRRT patients, those treated with CRRT had higher ammonia concentrations (median, 141 µmol/L [IQR, 102-198] v 91 µmol/L [IQR, 54-115]; P = 0.02), but a nadir Day 1 pH of only 7.25 (standard deviation, 0.16). Prevention of extreme hyperammonaemia (> 140 µmol/L) after Day 1 was achieved in 36 of CRRT-treated patients (84%) and was associated with transplant-free survival (55% v 13%; P = 0.05). CONCLUSION: In Australian and New Zealand patients with ALF, CRRT is typically started early, before Stage 3 AKI or severe acidaemia, and in the presence hyperammonaemia. In these more severely ill patients, CRRT use was associated with prevention of extreme hyperammonaemia, which in turn, was associated with increased transplant-free survival.

Acceptability, safety, and feasibility of in-bed cycling with critically ill patients.

BACKGROUND: In-bed cycling is a promising intervention that may assist critically ill patients to maintain muscle mass and improve their trajectory of recovery. The acceptability of in-bed cycling from the different perspectives of patients, clinicians, and families are unknown. In addition, the safety and feasibility of in-bed cycling in an Australian tertiary intensive care unit (ICU) is relatively unknown. OBJECTIVES: The objective of this study was to examine the acceptability, safety, and feasibility of in-bed cycling in an Australian tertiary, adult, mixed medical, surgical, trauma ICU. METHODS: An observational process evaluation was embedded in one arm of a two-arm parallel phase II randomised controlled trial that was conducted in an Australian tertiary ICU. The process evaluation was of the acceptability, safety, and feasibility of passive and active in-bed cycling for participants allocated to the trial intervention group. In-bed cycling acceptability questionnaires were designed through a three-step Delphi process. Questionnaire responses from patients, family members, and clinicians who participated in or observed the intervention during the Critical Care Cycling Study (CYCLIST) were evaluated to determine the acceptability of in-bed cycling. The congruence of responses between respondents was also compared. Safety and feasibility of the in-bed cycling intervention were assessed against predetermined criteria. RESULTS: Acceptability questionnaire responses demonstrated that in-bed cycling was an acceptable intervention from the perspectives of patients, family members, and clinicians. Questionnaire responses were congruent across the respondent groups. Safety was demonstrated with two minor transient adverse events occurring during 276 in-bed cycling sessions (adverse event rate: 0.7%). In-bed cycling sessions were feasible with 276 of 304 (90%) planned sessions conducted. CONCLUSIONS: Acceptability questionnaire responses found that in-bed cycling was regarded as an acceptable intervention to patients, family members, and clinicians. The implementation of in-bed cycling was safe and feasible to complete with critically ill patients during the early stages of their critical illness in an Australian tertiary ICU setting.

Inducing ketogenesis via an enteral formulation in patients with acute brain injury:a phase II study.

Objective: Although extensively studied in children, the safety and tolerability of ketone supplementation in adults is unclear, particularly in the acute brain injury population. The purpose of this study was to examine the feasibility and safety of inducing ketosis using an enteric ketogenic formulation and determine its impact on intracranial and cerebral perfusion pressures and metabolic parameters.Methods: Prospective interventional Phase II trial of ventilated critically ill patients with acute brain injury administered a ketogenic feed over a 6 day period.Results: 20 patients were recruited, 5 females and 15 males, 3 with stroke, 2 with subarachnoid haemorrhage and 15 with traumatic brain injury. Feeds were well tolerated with 19 patients completing study. There was a significant increase in both plasma beta-hydroxybutyrate and acetoacetate from 0.24± 0.31 mmol/l and 0.19 ± 0.16 mmol/l to 0.61 ± 0.53 mmol/l (p =0.0005) and 0.52 ± 0.40 mmol/l (p<0.0001) respectively over the 6 day period. Total daily Ketocal® caloric intake was positively correlated with plasma beta-hydroxybutyrate concentrations (p=0.0011). There was no significant correlation between the cerebral hypertension and cerebral hypoperfusion indices and plasma ketone concentrations. In 95% of patients there were no clinically significant changes in acid/base status over the 6 days with pH remaining within normal range.Conclusion: In patients with acute brain injury, an enterally administered ketogenic formulation increased plasma ketone concentrations, was well tolerated, did not impact on cerebral hemodynamics and can be safely administered.Clinical trial registered at the Australian New Zealand Clinical Trials Registry (ACTRN12616000332426)Abbreviations: BHB: betahydroxybutyrate; AcAc: acetoacetate; ABI: acute brain injury; TBI: traumatic brain injury; CSF: cerebrospinal fluid; SAH: subarachnoid injury; CVA: cerebrovascular accidents; ICP: intracranial pressure; CPP: cerebral perfusion pressure; ICU: intensive care unit; EVD: external ventricular device; CHI: cerebral hypoperfusion index; IHI: intracranial hypertension index; GCS: Glasgow Coma Scale.

Coagulation abnormalities, bleeding, thrombosis, and management of patients with acute liver failure in Australia and New Zealand.

BACKGROUND AND AIM: To study the management of coagulation and hematological derangements among severe acute liver failure (ALF) patients in Australia and New Zealand liver transplant intensive care units (ICUs). METHODS: Analysis of key baseline characteristics, etiology, coagulation and hematological tests, use of blood products, thrombotic complications, and clinical outcomes during the first ICU week. RESULTS: We studied 62 ALF patients. The first day median peak international normalized ratio was 5.5 (inter-quartile range [IQR] 3.8-8.7), median longest activated partial thromboplastin time was 62 s (IQR 44-87), and median lowest fibrinogen was 1.1 (IQR 0.8-1.6) g/L. Fibrinogen was only measured in 85% of patients, which was less than other tests (P < 0.0001). Median initial lowest platelet count was 83 (IQR 41-122) × 109 /L. Overall, 58% of patients received fresh frozen plasma, 40% cryoprecipitate, 35% platelets, and 15% prothrombin complex concentrate. Patients with bleeding complications (19%) had more severe overall hypofibrinogenemia and thrombocytopenia. Thrombotic complications were less common (10% of patients), were not associated with consistent patterns of abnormal hemostasis, and were not immediately preceded by clotting factor administration and half occurred only after liver transplantation surgery. CONCLUSION: In ALF patients admitted to dedicated Australia and New Zealand ICUs, fibrinogen was measured less frequently than other coagulation parameters but, together with platelets, appeared more relevant to bleeding risk. Blood products and procoagulant factors were administered to most patients at variable levels of hemostatic derangement, and bleeding complications were more common than thrombotic complications. This epidemiologic information and practice variability provide baseline data for the design and powering of interventional studies.

Exercise interventions are delayed in critically ill patients: a cohort study in an Australian tertiary intensive care unit.

OBJECTIVES: This study aims to (i) describe the time to exercise commencement (sitting and upright activities) relative to ICU admission and relative to achievement of initial neurological, respiratory and cardiovascular stability; (ii) examine factors associated with whether sitting and upright activities occurred in ICU; and (iii) examine factors associated with time taken to commence these activities after stability has been achieved. DESIGN: Five-year historical cohort study. SETTING: An Australian tertiary mixed medical, surgical, trauma ICU. PARTICIPANTS: The cohort (n=3222, mean (SD) age 54 (18) years, 67% male) included consecutive ICU patients with length of stay over 48hours admitted to a tertiary ICU who achieved stability. MAIN OUTCOME MEASURES: Time from stability to patients' first completed sitting and upright activities was calculated. Logistic regression (and Cox proportional hazard models) examined whether sitting and upright activities in ICU occurred (and time to these events). INTERVENTIONS: None. RESULTS: For patients who completed exercise interventions (n=1845/3222, 57%), this commenced a median (IQR) 2.3 (1.3-4.4) days after stability for upright activities and 2.7 (1.5-5.7) days for sitting. A large proportion of patients did not complete exercise interventions despite achieving stability (n=1377/3222, 43%). Elective surgical admissions, lower illness severity and older age were associated with completion (and earlier completion) of sitting and upright activity (P<0.01). CONCLUSIONS: Many stable patients did not commence sitting or upright activity in ICU despite known benefits, or commencement was somewhat delayed. Opportunities may exist to improve patient outcomes through timely implementation of exercise-based interventions.

Low volume ECMO results study.

Objectives: To report extracorporeal membrane oxygenation (ECMO) experience at Princess Alexandra and Gold Coast University hospitals and compare mortality with benchmarks. Design: Case series of patients treated with ECMO. Setting: Two adult tertiary Australian intensive care units with low ECMO case volumes. Participants: Patients treated with ECMO, aged > 18 years. Main outcome measures: Patients were categorised into respiratory, cardiac, and extracorporeal cardiopulmonary resuscitation (eCPR) groups. Observed mortality was compared with mortality predicted using individual risk of death predictions from the Survival after Veno-arterial ECMO (SAVE) and Respiratory ECMO Survival Prediction (RESP) scores; mortality predicted when mortality predictions of the SAVE score were modified to be consistent with the validation cohort in the SAVE study (Alfred Hospital); and with mortality predicted when eCPR patients were all assigned a risk of death equal to Extracorporeal Life Support Organization (ELSO) Registry eCPR mortality. Results: Over 10 years, 86 patients were treated with ECMO. Eight deaths were observed in 49 patients with respiratory failure, below the 95% CI (13-24) for the deaths predicted by the RESP score (P < 0.001). Nine deaths were observed in 27 patients with cardiac failure, below the 95% CI (14-23) for the deaths predicted by the SAVE score (P < 0.001), but within the 95% CI (9-17) for the deaths predicted by the SAVE score modified to be consistent with the Alfred Hospital cohort (P > 0.05). Seven deaths were observed in the ten eCPR patients, within the 95% CI (4-10) predicted using the risk of death derived from the ELSO Registry. Conclusions: Mortality in two low volume ECMO centres was not inferior to benchmarks.

Characteristics, management and outcomes of patients with acute liver failure admitted to Australasian intensive care units.

OBJECTIVE: Acute liver failure (ALF) leads to severe illness and usually requires admission to the intensive care unit (ICU). Despite its importance, little is known about patients with ALF in Australia and New Zealand. DESIGN: Binational observational study to evaluate the aetiology, baseline characteristics, patterns of illness, management, and outcomes for patients with ALF admitted to Australian and New Zealand ICUs. SETTING: All six Australian and New Zealand ICUs in liver transplant centres submitted de-identified data for ten or more consecutive patients with ALF. Data were obtained from the clinical record and included baseline characteristics, aetiology, mode of presentation, illness severity, markers of liver failure, critical care interventions, utilisation of transplantation, and hospital outcome. RESULTS: We studied 62 patients with ALF. Paracetamol overdose (POD) was the underlying cause of ALF in 53% of patients (33/62), with staggered ingestion in 42% of patients (14/33). Among patients with POD, 70% (23/33) were young women, most had psychiatric diagnoses, and most presented relatively early with overt liver failure. This group were transplanted in only 6% of cases (2/33) and had an overall mortality of 24% (8/33). The remaining patients with ALF had less common conditions, such as hepatitis B and non-paracetamol drug-induced ALF. These patients presented later and exhibited less extreme evidence of acute hepatic necrosis. Transplantation was performed in 38% of patients (11/29) in this subgroup. The mortality of nontransplanted non-POD patients was 56% (10/18). Illness severity at ICU admission, initial requirement for organ support therapies and length of hospital stay were similar between patients with POD and non-POD ALF. CONCLUSION: POD is the major cause of ALF in Australian and New Zealand liver transplant centres and is a unique and separate form of ALF. It has a much lower associated mortality and treatment with liver transplantation than non-POD ALF. Non-POD patients have a poor prognosis in the absence of transplantation.

Clinical management practices of life-threatening asthma: an audit of practices in intensive care.

OBJECTIVE: Lack of management guidelines for lifethreatening asthma (LTA) risks practice variation. This study aims to elucidate management practices of LTA in the intensive care unit (ICU). DESIGN: A retrospective cohort study. SETTING: Thirteen participating ICUs in Australia between July 2010 and June 2013. PARTICIPANTS: Patients with the principal diagnosis of LTA. MAIN OUTCOME MEASURES: Clinical history, ICU management, patient outcomes, ward education and discharge plans. RESULTS: Of the 270 (267 patients) ICU admissions, 69% were female, with a median age of 39 years (interquartile range [IQR], 26-53 years); 119 (44%) were current smokers; 89 patients (33%) previously required ICU admission, of whom 23 (25%) were intubated. The median ICU stay was 2 days (IQR, 2-4 days). Three patients (1%) died. Seventy-nine patients (29%) received non-invasive ventilation, with 11 (14%) needing subsequent invasive ventilation. Sixty-eight patients (25%) were intubated, with the majority of patients receiving volume cycled synchronised intermittent mechanical ventilation (n = 63; 93%). Drugs used included ß2-agonist by intravenous infusion (n = 69; 26%), inhaled adrenaline (n = 15; 6%) or an adrenaline intravenous infusion (n = 23; 9%), inhaled anticholinergics (n = 238; 90%), systemic corticosteroids (n = 232; 88%), antibiotics (n = 126; 48%) and antivirals (n = 22; 8%). When suitable, 105 patients (n = 200; 53%) had an asthma management plan and 122 (n = 202; 60%) had asthma education upon hospital discharge. Myopathy was associated with hyperglycaemia requiring treatment (odds ratio [OR], 31.6; 95% CI, 2.1-474). Asthma education was more common under specialist thoracic medicine care (OR, 3.0; 95% CI, 1.61-5.54). CONCLUSION: In LTA, practice variation is common, with opportunities to improve discharge management plans and asthma education.