A survey of Australian public opinion on using comorbidity to triage intensive care patients in a pandemic.

ObjectivesThis study aimed to determine which method to triage intensive care patients using chronic comorbidity in a pandemic was perceived to be the fairest by the general public. Secondary objectives were to determine whether the public perceived it fair to provide preferential intensive care triage to vulnerable or disadvantaged people, and frontline healthcare workers.MethodsA postal survey of 2000 registered voters randomly selected from the Australian Electoral Commission electoral roll was performed. The main outcome measures were respondents' fairness rating of four hypothetical intensive care triage methods that assess comorbidity (chronic medical conditions, long-term survival, function and frailty); and respondents' fairness rating of providing preferential triage to vulnerable or disadvantaged people, and frontline healthcare workers.ResultsThe proportion of respondents who considered it fair to triage based on chronic medical conditions, long-term survival, function and frailty, was 52.1, 56.1, 65.0 and 62.4%, respectively. The proportion of respondents who considered it unfair to triage based on these four comorbidities was 31.9, 30.9, 23.8 and 23.2%, respectively. More respondents considered it unfair to preferentially triage vulnerable or disadvantaged people, than fair (41.8% versus 21.2%). More respondents considered it fair to preferentially triage frontline healthcare workers, than unfair (44.2% versus 30.0%).ConclusionRespondents in this survey perceived all four hypothetical methods to triage intensive care patients based on comorbidity in a pandemic disaster to be fair. However, the sizable minority who consider this to be unfair indicates that these triage methods could encounter significant opposition if they were to be enacted in health policy.

Incorporating real-world evidence into the development of patient blood glucose prediction algorithms for the ICU.

OBJECTIVE: Glycemic control is an important component of critical care. We present a data-driven method for predicting intensive care unit (ICU) patient response to glycemic control protocols while accounting for patient heterogeneity and variations in care. MATERIALS AND METHODS: Using electronic medical records (EMRs) of 18 961 ICU admissions from the MIMIC-III dataset, including 318 574 blood glucose measurements, we train and validate a gradient boosted tree machine learning (ML) algorithm to forecast patient blood glucose and a 95% prediction interval at 2-hour intervals. The model uses as inputs irregular multivariate time series data relating to recent in-patient medical history and glycemic control, including previous blood glucose, nutrition, and insulin dosing. RESULTS: Our forecasting model using routinely collected EMRs achieves performance comparable to previous models developed in planned research studies using continuous blood glucose monitoring. Model error, expressed as mean absolute percentage error is 16.5%-16.8%, with Clarke error grid analysis demonstrating that 97% of predictions would be clinically acceptable. The 95% prediction intervals achieve near intended coverage at 93%-94%. DISCUSSION: ML algorithms built on observational data sources, such as EMRs, present a promising approach for personalization and automation of glycemic control in critical care. Future research may benefit from applying a combination of methodologies and data sources to develop robust methodologies that account for the variations seen in ICU patients and difficultly in detecting the extremes of observed blood glucose values. CONCLUSION: We demonstrate that EMRs can be used to train ML algorithms that may be suitable for incorporation into ICU decision support systems.

Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial.

Importance: Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown. Objective: To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis. Design, Setting, and Participants: Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital. Interventions: Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs). Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay. Results: Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group. Conclusions and Relevance: Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication. Trial Registration: anzctr.org.au Identifier: ACTRN12616000481471.

A multicentre point prevalence study of delirium assessment and management in patients admitted to Australian and New Zealand intensive care units.

Objective: To characterise the assessment and management of delirium in patients admitted to intensive care units (ICUs) in Australia and New Zealand. Methods: We conducted a multicentre observational point prevalence study across 44 adult Australian and New Zealand ICUs. Data were extracted for all patients in the ICU in terms of assessment and treatment of delirium. ICU-level data were collected regarding the use of explicit protocols related to delirium. Results: We studied 627 patients, with 54% (336/627) having at least one delirium screening assessment performed. The Confusion Assessment Method for the ICU (CAM-ICU) was the most frequently used tool (88%, 296/336). Of patients assessed, 20% (68) were identified to have delirium. Eighteen per cent (111) of patients were administered a drug to manage delirium, with 41% (46) of those receiving a drug having no recorded assessment for delirium on that day. Of the drugs used to treat delirium, quetiapine was the most frequently administered. Physical restraints were applied to 8% (48/626) of patients, but only 17% (8/48) of such patients had been diagnosed with delirium. Most physically restrained patients either did not have delirium diagnosed (31%, 15/48) or had no formal assessment recorded (52%, 25/48) on that day. Conclusions: On the study day, more than 50% of patients had a delirium screening assessment performed, with 20% of screened patients deemed to have delirium. Drugs that are prescribed to treat delirium and physical restraints were frequently used in the absence of delirium or the formal assessment for its presence.

Randomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial.

PURPOSE: It is unknown whether protocols targeting systematic prevention and treatment of fever achieve lower mean body temperature than usual care in intensive care unit (ICU) patients. The objective of the Randomised Evaluation of Active Control of temperature vs. ORdinary temperature management trial was to confirm the feasibility of such a protocol with a view to conducting a larger trial. METHODS: We randomly assigned 184 adults without acute brain pathologies who had a fever in the previous 12 h, and were expected to be ventilated beyond the calendar day after recruitment, to systematic prevention and treatment of fever or usual care. The primary outcome was mean body temperature in the ICU within 7 days of randomisation. Secondary outcomes included in-hospital mortality, ICU-free days and survival time censored at hospital discharge. RESULTS: Compared with usual temperature management, active management significantly reduced mean temperature. In both groups, fever generally abated within 72 h. The mean temperature difference between groups was greatest in the first 48 h, when it was generally in the order of 0.5 °C. Overall, 23 of 89 patients assigned to active management (25.8%) and 23 of 89 patients assigned to usual management (25.8%) died in hospital (odds ratio 1.0, 95% CI 0.51-1.96, P = 1.0). There were no statistically significant differences between groups in ICU-free days or survival to day 90. CONCLUSIONS: Active temperature management reduced body temperature compared with usual care; however, fever abated rapidly, even in patients assigned to usual care, and the magnitude of temperature separation was small. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry Number, ACTRN12616001285448.

A cluster randomised, crossover, registry-embedded clinical trial of proton pump inhibitors versus histamine-2 receptor blockers for ulcer prophylaxis therapy in the intensive care unit (PEPTIC study): study protocol.

BACKGROUND: The balance of risks and benefits with using proton pump inhibitors (PPIs) versus histamine-2 receptor blockers (H2RB) for stress ulcer prophylaxis in patients who are invasively ventilated in the intensive care unit (ICU) is uncertain. OBJECTIVE: To describe the study protocol and statistical analysis plan for the Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) study. DESIGN, SETTING AND PARTICIPANTS: Protocol for a prospective, multicentre, randomised, open-label, cluster crossover, registry-embedded trial to be conducted in 50 ICUs in Australia, Canada, Ireland, New Zealand and the United Kingdom. The PEPTIC study will compare two approaches to stress ulcer prophylaxis in mechanically ventilated adults implemented at the level of the ICU. One approach is to use PPIs as the default therapy and the other approach is to use H2RBs as the default therapy when stress ulcer prophylaxis is prescribed. Each ICU, by random allocation, will use one approach for 6 months and will then switch to the opposite approach for the next 6 months. The PEPTIC study began recruitment in August 2016 and will complete recruitment in January 2019. MAIN OUTCOME MEASURES: The primary end point will be in-hospital mortality. Secondary outcomes include clinically significant upper gastrointestinal bleeding, Clostridium difficile infection, ICU length of stay and hospital length of stay. RESULTS AND CONCLUSIONS: The PEPTIC study will compare the effect on in-hospital mortality of implementing, at the level of the ICU, the use of PPI as the preferred agent for stress ulcer prophylaxis in mechanically ventilated adults in the ICU with using H2RB as the preferred agent. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12616000481471).

A cross-sectional survey of Australian and New Zealand public opinion on methods totriage intensive care patients in an influenza pandemic.

BACKGROUND AND OBJECTIVE: An influenza pandemic has the potential to overwhelm intensive care resources, but the views of the general public on how resources should be allocated in such a scenario were unknown. We aimed to determine Australian and New Zealand public opinion on how intensive care unit beds should be allocated during an influenza pandemic. DESIGN, SETTING, AND PARTICIPANTS: A postal questionnaire was sent to 4000 randomly selected registered voters; 2000 people each from the Australian Electoral Commission and New Zealand Electoral Commission rolls. MAIN OUTCOME MEASURE: The respondents' preferred method to triage ICU patients in an influenza pandemic. Respondents chose from six methods: use a "first in, first served" approach; allow a senior doctor to decide; use pre-determined health department criteria; use random selection; use the patient's ability to pay; use the importance of the patient to decide. Respondents also rated each of the triage methods for fairness. RESULTS: Australian respondents preferred that patients be triaged to the ICU either by a senior doctor (43.2%) or by pre-determined health department criteria (38.7%). New Zealand respondents preferred that triage be performed by a senior doctor (45.9%). Respondents from both countries perceived triage by a senior doctor and by pre-determined health department criteria to be fair, and the other four methods of triage to be unfair. CONCLUSION: In an influenza pandemic, when ICU resources would be overwhelmed, survey respondents preferred that ICU triage be performed by a senior doctor, but also perceived the use of pre-determined triage criteria to be fair.

Protocol and statistical analysis plan for the Randomised Evaluation of Active Control of Temperature versus Ordinary Temperature Management (REACTOR) trial.

BACKGROUND: Body temperature can be reduced in febrile patients in the intensive care unit using medicines and physical cooling devices, but it is not known whether systematically preventing and treating fever reduces body temperature compared with standard care. OBJECTIVE: To describe the study protocol and statistical analysis plan for the Randomised Evaluation of Active Control of Temperature versus Ordinary Temperature Management (REACTOR) trial. DESIGN, SETTING AND PARTICIPANTS: Protocol for a phase II, multicentre trial to be conducted in Australian and New Zealand ICUs admitting adult patients. We will recruit 184 adults without acute brain injury who are expected to be ventilated in the ICU beyond the day after randomisation. We will use open, random, parallel assignment to systematic prevention and treatment of fever, or to standard temperature management. MAIN OUTCOME MEASURES: The primary end point will be mean body temperature, calculated from body temperatures measured 6-hourly for 7 days (168 hours) or until ICU discharge, whichever is sooner. Secondary end points are ICU-free days, in-hospital and cause-specific mortality (censored at Day 90) and survival time to Day 90 (censored at hospital discharge). RESULTS AND CONCLUSIONS: The trial will determine whether active temperature control reduces body temperature compared with standard care. It is primarily being conducted to establish whether a phase III trial with a patient-centred end point of Day 90 mortality is justified and feasible.

The Effect of Paracetamol on Core Body Temperature in Acute Traumatic Brain Injury: A Randomised, Controlled Clinical Trial.

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

A multicentre audit of temperature patterns after traumatic brain injury.

BACKGROUND: Elevation of body temperature is common after traumatic brain injury (TBI). Suppressing fever may be beneficial. HYPOTHESIS: In clinical practice, temperature is maintained _37°C. PARTICIPANTS, SETTING AND METHODS: A retrospective, multicentre, cohort study of patients with an intensive care unit admission diagnosis of TBI over a 6-month period. MAIN OUTCOME MEASURES: The mean proportion of time per day that temperature _37°C or _38°C (to correct for unequal measurements between patients, imputation was used between consecutive temperature measurements and a linear relationship was assumed); and the proportion of patients on each day with a peak temperature _37°C. RESULTS: 217 patients with TBI were admitted to eight ICUs. The mean Acute Physiology and Chronic Health Evaluation II score of the cohort was 15.7 (SD, 7.7) and intracranial pressure monitoring was done in 29% of patients. The mean proportion of time on each day that temperature was _37°C varied between 56% (SE, 2.6%) on Day 1 and 89% (SE, 3.7%) on Day 14. The mean proportion of time per day that temperature was > 38°C was between a minimum of 11% (SE, 1.5%) on Day 1 and a maximum of 25% (SE, 4.4%) Day 11. The proportion of patients for whom daily peak temperature was > 37°C ranged between a minimum of 73.2% (153/209) on Day 1 and a maximum of 97.4% (26/33) on Day 13. CONCLUSION: In patients with TBI, a substantial proportion of time is spent with a temperature _37°C. Prospective validation of these data are required.

Association between early peak temperature and mortality in neutropenic sepsis.

Fever is often the first sign of neutropenic infection, but its prognostic impact has not been established. We aimed to determine whether early peak temperature is associated with mortality in patients with neutropenic sepsis admitted to intensive care units (ICUs). We used a database of admissions to 157 ICUs in Australia and New Zealand between 2005 and 2013 to seek an association between peak temperature within the first 24 h in ICU and in-hospital mortality in neutropenic and non-neutropenic sepsis. Odds ratios for in-hospital death were calculated for four temperature bands, adjusting for illness severity. Two patient cohorts were identified: neutropenic sepsis (N = 4027) and non-neutropenic sepsis (N = 114,040). In-hospital mortality was higher in neutropenic sepsis than non-neutropenic sepsis. In both cohorts, early peak temperature below 36.5 °C was associated with significantly increased mortality compared to normothermia. Among non-neutropenic patients, an early peak temperature of 37.5 °C or higher was associated with reduced mortality compared to normothermia. In contrast, in patients with neutropenic sepsis, fever was not associated with reduced mortality compared to normothermia. Similar findings were seen in a subgroup of the neutropenic sepsis cohort with a documented haematological malignancy. In neutropenic sepsis patients admitted to ICU, a temperature below 36.5 °C is associated with increased mortality compared with normothermia. In contrast to non-neutropenic sepsis, fever was not associated with a significant reduction in mortality in neutropenic patients. Interventional studies are needed to determine whether physical or pharmacological measures to reduce fever influence outcomes during neutropenic infections.

A multicentre feasibility study evaluating stress ulcer prophylaxis using hospital-based registry data.

BACKGROUND: It is unclear whether histamine-2 receptor blockers (H2RBs) or proton pump inhibitors (PPIs) are preferred for stress ulcer prophylaxis (SUP) in intensive care unit patients. Suitably powered comparative effectiveness trials are warranted. OBJECTIVE: To establish the feasibility of collecting process-of-care and outcome data relevant to a proposed interventional trial of SUP using existing databases. DESIGN, SETTING AND PARTICIPANTS: A retrospective cohort study conducted in seven Australia and New Zealand tertiary ICUs, including all patients ≥18 years admitted between 1 January 2011 and 31 December 2012. MAIN OUTCOME MEASURES: Doses of dispensed PPIs and H2RBs, upper gastrointestinal bleeding events, upper respiratory tract colonisation with pathogenic bacteria, Clostridium difficile infections and inhospital mortality. RESULTS: All sites were able to contribute to the study and investigators reported that data were generally easy to obtain. A median dose/ICU of 477 g of PPIs (interquartile range [IQR], 430.5-865 g), and 408.5 g (IQR, 109-1630.2 g) of H2RBs, were dispensed over the 2 years of the study. The median proportion of patients/ICU with upper GI bleeding complicating admission was 1.4% (IQR, 0.3%-1.8%). Colonisation of the respiratory tract with gram-negative bacteria occurred in a median of 7.1% of patients/ICU (IQR, 6.3%-14.1%). Pseudomembranous colitis occurred in hospital in a median of 1.4% of patients (IQR, 0.9%-2%) and inhospital mortality was 10.6% (95% CI, 9.5%- 11.7%). CONCLUSIONS: It is feasible to use existing data sources to measure process-of-care and outcome data necessary for a registry-based interventional trial of SUP.

Individual patient data meta-analysis of hydroxyethyl starch 130/0.4-0.42 versus crystalloid for fluid resuscitation in patients with severe sepsis: a statistical analysis plan.

BACKGROUND: The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) and the Scandinavian Starch in Severe Sepsis/ Septic Shock (6S) trial reported that 6% hydroxyethyl starch (HES) is associated with increased use of renal replacement therapy and death in critically ill patients. Data collection was harmonised between the two trials in order to facilitate a preplanned individual patient data meta-analysis (IPDMA) of patients with severe sepsis. OBJECTIVES AND RATIONALE: To publish a statistical analysis plan (SAP) for an IPDMA of patients with severe sepsis enrolled in the 6S trial and the CHEST. METHODS AND OUTCOMES: The SAP is described in broad detail with specific information regarding baseline characteristics and process of care. The outcomes for the trial have been described and are presented as primary, secondary and exploratory outcomes with appropriate comparisons between groups detailed. Subgroups have been defined based on pre-randomisation variables. CONCLUSION: We developed a preanalysis SAP to combine data on patients with severe sepsis from the 6S trial and the CHEST. Prepublication of our SAP will reduce the risk of bias in the reporting of the results and improve confidence in the estimates of effects, allowing comparisons with conventional meta-analyses and assisting in the translation of research findings into clinical practice.

Statistical analysis plan for the HEAT trial: a multicentre randomised placebo-controlled trial of intravenous paracetamol in intensive care unit patients with fever and infection.

BACKGROUND AND OBJECTIVE: We describe the statistical analysis plan (SAP) for the Permissive Hyperthermia through Avoidance of Paracetamol in Known or Suspected Infection in the Intensive Care Unit (HEAT) trial, a 700-patient, prospective, randomised, Phase 2b, multicentre, double-blind, parallel-groups, placebo-controlled trial of paracetamol administration for the treatment of fever in critically ill patients with known or suspected infection. METHODS: The data fields described are those outlined in the study protocol published previously. We describe the plan for the presentation and comparison of baseline characteristics, process measures and outcomes. We describe baseline characteristics, and define and categorise trial outcomes according to their assigned importance. RESULTS AND CONCLUSIONS: We developed an SAP for the HEAT trial, and produced a mock Consolidated Standards of Reporting Trials diagram and tables. Our prespecified SAP accords with high-quality standards of internal validity and should minimise future analysis bias.

Temperature management of non-elective intensive care patients without neurological abnormalities: a point prevalence study of practice in Australia and New Zealand.

OBJECTIVE: To determine the frequency of pharmacological and physical cooling in non-elective general intensive care unit patients without neurological abnormalities in Australia and New Zealand, and to establish the indications for antipyretics, the prevalence of fever, and the methods of temperature measurement. DESIGN, SETTING AND PARTICIPANTS: A point prevalence study conducted on two days in 2010, in 38 ICUs in Australia and New Zealand, examining non-elective (emergency) patients admitted with sepsis and other inflammatory abnormalities but without neurological abnormalities. RESULTS: Of 506 general ICU patients surveyed on the study days, 311 had sepsis or other inflammatory abnormalities and no neurological abnormalities. These patients had a mean peak temperature of 37.3°C (SD, 0.8°C). In 100 patients (32.2%), the peak temperature was above 38°C. Paracetamol was the most common antipyretic used (152/311; 48.9%) and was administered for pain in 92/152 patients (60.5%), for pain and fever in 26/152 patients (17.1%), and for fever alone in 14/152 patients (9.2%). Patients who received paracetamol for fever had a mean peak recorded temperature of 38.3°C (SD, 0.8°C). Temperature measurements were mainly non-core (251/ 311; 81%) with axillary (116/311; 37%) and tympanic (110/ 311; 35%) measurements the most common. CONCLUSION: Pharmacological antipyretics are used regularly for pain management rather than fever management, with paracetamol the most common antipyretic therapy. The use of NSAIDS and physical cooling is rare. Non-core temperature measurements were common.

Temperature management in patients with acute neurological lesions: an Australian and New Zealand point prevalence study.

BACKGROUND: Given the scientific uncertainty of the efficacy and safety of normothermia (36.0°C to 37.5°C) on disability and death after acute neurological lesions, we sought to understand how temperature is managed in usual clinical care for this patient population in Australia and New Zealand. OBJECTIVE: To describe temperature management in patients with acute neurological lesions. DESIGN: Prospective, observational, multicentre, single-day point-prevalence study. PARTICIPANTS, SETTING AND METHODS: Observational data of usual practice were recorded for all patients with an intensive care admission diagnosis of acute neurological lesions and who were present in 33 intensive care units at 10:00 on the study day. Data were collected prospectively for the ensuing 24-hour period. MAIN OUTCOME MEASURES: Achieved temperature, interventions used to modify temperature and target temperature. RESULTS: There were 106 patients with acute neurological lesions (61% with either stroke or traumatic brain injury) with a mean APACHE (Acute Physiology and Chronic Health Evaluation) II score of 19.3 ± 7.4, age of 53.5 ± 19.0 years and median time from intensive care admission to data capture of 3 days (interquartile range, 1-9). A target temperature was specified in 24% of patients. Although paracetamol was commonly used (56%), it was infrequently used at the maximum licensed dose and there was no use recorded of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors. Physical cooling was used in 25% of patients and core temperature was measured in 32%. Measured temperature often exceeded 37.0°C (62% of readings), 37.5°C (43%) and 38.0°C (22%). CONCLUSIONS: Temperature readings above 37.5°C are common. Further cohort studies are required to validate these preliminary, exploratory findings.

The HEAT trial: a protocol for a multicentre randomised placebo-controlled trial of IV paracetamol in ICU patients with fever and infection.

BACKGROUND AND OBJECTIVE: Paracetamol is commonly administered to febrile critically ill patients with infection. However, there is limited information on the efficacy and safety of using paracetamol in this setting. We describe the study protocol for a Phase IIb multicentre randomised controlled trial (the Permissive Hyperthermia Through Avoidance of Paracetamol in Known or Suspected Infection in ICU [HEAT] trial) comparing intravenous paracetamol to placebo in the treatment of fever in critically ill adults with known or suspected infection. DESIGN AND SETTING: A pilot study followed by the main trial from November 2012. 700 patients will be recruited for concealed, random, parallel assignment of either 1 g of intravenous paracetamol or placebo (100mL of 5% dextrose) 6-hourly to treat fever while they remain on antimicrobial therapy in the intensive care unit. The primary end point will be ICU support-free survival at 28 days after randomisation. Secondary end points will include peak daily and mean daily body temperatures, prevalence of liver dysfunction requiring cessation of study treatment, degree of renal injury (based on delta creatinine), other organ failures, and Day 28 and Day 90 mortality. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSIONS: The HEAT trial should generate results that will inform and influence the prescribing of paracetamol. It will also determine if a large-scale Phase III trial of paracetamol is required in this patient group and whether such a trial is feasible. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12612000513819).

A systematic review of measurements of physical function in critically ill adults.

BACKGROUND: Patients who recover from critical illness may be left with significant limitations to their physical function that can have important consequences for their quality of life. Measures of physical function may be useful end points to consider in studies conducted in critically ill patients and are particularly attractive in studies investigating early mobilisation and rehabilitation. OBJECTIVE: To describe measurements of physical function used in studies investigating early mobilisation and rehabilitation in critically ill adults. METHODS: A systematic search of Ovid MEDLINE, Embase, CINAHL, Cochrane Library and PEDro was undertaken to identify studies investigating early mobilisation and rehabilitation in critically ill adults. Two researchers independently extracted data from identified studies that described measurements of physical function and that evaluated the available evidence for the measurement properties and risk of bias associated with the identified end points. RESULTS: We identified 11 studies of early mobilisation and rehabilitation in critically ill patients, involving 19 distinct measures of physical function. The ability to perform activities such as sitting and standing and the maximum distance ambulated were the most commonly used end points. Only one end point in the included studies, the Functional Status Score for the ICU (FSS-ICU), was designed for use in the ICU setting. Of the end points used, only the Short Form 36 (SF-36), the Medical Research Council (MRC) scale score and handheld dynamometers have proven interrater reliability and population validity in the ICU setting. CONCLUSION: A wide range of end points have been used to evaluate physical function in critically ill patients. However, further studies are needed to establish the measurement properties of the most commonly used end points in order to recommend their use in clinical trials.