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.

Pain distress: the negative emotion associated with procedures in ICU patients.

PURPOSE: The intensity of procedural pain in intensive care unit (ICU) patients is well documented. However, little is known about procedural pain distress, the psychological response to pain. METHODS: Post hoc analysis of a multicenter, multinational study of procedural pain. Pain distress was measured before and during procedures (0-10 numeric rating scale). Factors that influenced procedural pain distress were identified by multivariable analyses using a hierarchical model with ICU and country as random effects. RESULTS: A total of 4812 procedures were recorded (3851 patients, 192 ICUs, 28 countries). Pain distress scores were highest for endotracheal suctioning (ETS) and tracheal suctioning, chest tube removal (CTR), and wound drain removal (median [IQRs] = 4 [1.6, 1.7]). Significant relative risks (RR) for a higher degree of pain distress included certain procedures: turning (RR = 1.18), ETS (RR = 1.45), tracheal suctioning (RR = 1.38), CTR (RR = 1.39), wound drain removal (RR = 1.56), and arterial line insertion (RR = 1.41); certain pain behaviors (RR = 1.19-1.28); pre-procedural pain intensity (RR = 1.15); and use of opioids (RR = 1.15-1.22). Patient-related variables that significantly increased the odds of patients having higher procedural pain distress than pain intensity were pre-procedural pain intensity (odds ratio [OR] = 1.05); pre-hospital anxiety (OR = 1.76); receiving pethidine/meperidine (OR = 4.11); or receiving haloperidol (OR = 1.77) prior to the procedure. CONCLUSIONS: Procedural pain has both sensory and emotional dimensions. We found that, although procedural pain intensity (the sensory dimension) and distress (the emotional dimension) may closely covary, there are certain factors than can preferentially influence each of the dimensions. Clinicians are encouraged to appreciate the multidimensionality of pain when they perform procedures and use this knowledge to minimize the patient's pain experience.

Protocol summary and statistical analysis plan for the intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX).

BACKGROUND: The balance of risks and benefits of conservative v standard care oxygen strategies for 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 ICU randomised trial comparing two approaches to oxygen therapy (ICU-ROX). DESIGN, SETTING AND PARTICIPANTS: Protocol for a multicentre, randomised, participant and outcome assessor-blinded, standard care-controlled, parallel-group, two-sided superiority trial to be conducted in up to 22 ICUs in Australia and New Zealand. 1000 adults who are mechanically ventilated in the ICU and expected to remain ventilated beyond the day after recruitment will be randomly assigned to conservative oxygen therapy or standard care in a 1:1 ratio. ICU-ROX began with an internal pilot phase in September 2015. It is anticipated that recruitment will be completed in 2018. MAIN OUTCOME MEASURES: The primary endpoint will be alive, ventilator-free days to Day 28. Secondary outcomes include 90- and 180-day all-cause mortality, survival time to 180 days, and quality of life and cognitive function at 180 days. All analyses will be conducted on an intentionto- treat basis. RESULTS AND CONCLUSIONS: ICU-ROX will compare the effect of conservative v standard oxygen therapy in critically ill mechanically ventilated adults who are expected to be ventilated beyond the day after recruitment on ventilatorfree days to Day 28. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12615000957594).

Intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX): results of the pilot phase.

OBJECTIVE: The objective of the intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX) pilot phase, which included the first 100 patients of an overall sample of 1000, was to examine feasibility. DESIGN: Investigator-initiated, prospective, parallel-group, pilot randomised controlled trial. SETTING: Six medical-surgical intensive care units (ICUs) in Australia and New Zealand, with participants recruited from September 2015 through June 2016. PARTICIPANTS: 100 patients ≥ 18 years of age who required invasive mechanical ventilation in the ICU and were expected to be receiving it beyond the next calendar day at the time of randomisation. INTERVENTIONS: Conservative oxygen therapy or standard care. MAIN OUTCOME MEASURES: Eligibility, recruitment rate, and separation in oxygen exposure (fraction of inspired oxygen [FiO2] and oxygen saturation measured by pulse oximetry [SpO2Z]). RESULTS: 94 of 99 participants (94.9%) were confirmed by study monitors to fulfil the study eligibility criteria. 3.6 patients per site per month were enrolled (95% confidence interval [CI], 2.5-4.7). Patients allocated to conservative oxygen therapy spent significantly more time on an FiO2 of 0.21 in the ICU; median, 31.5 hours (interquartile range [IQR], 7-63.5) for conservative oxygen therapy patients v 0 hours for standard oxygen therapy patients (IQR, 0-10; midpoint difference, 21.5 hours; 95% CI, 9-34; P < 0.0001). Patients allocated to conservative oxygen therapy spent less time in the ICU with an SpO2Z of ≥ 97% than patients allocated to standard oxygen therapy; median, 18.5 hours (IQR, 5-46) for conservative oxygen therapy patients v 32 hours for standard oxygen therapy (IQR, 17-80; midpoint difference, 13.5 hours; 95% CI, 2-25; P = 0.02). CONCLUSIONS: Our findings confirm the feasibility of completing the ICU-ROX trial without the need for substantive changes to the study protocol for the remaining 900 trial participants. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12615000957594).

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.

Determinants of procedural pain intensity in the intensive care unit. The Europain® study.

RATIONALE: Intensive care unit (ICU) patients undergo several diagnostic and therapeutic procedures every day. The prevalence, intensity, and risk factors of pain related to these procedures are not well known. OBJECTIVES: To assess self-reported procedural pain intensity versus baseline pain, examine pain intensity differences across procedures, and identify risk factors for procedural pain intensity. METHODS: Prospective, cross-sectional, multicenter, multinational study of pain intensity associated with 12 procedures. Data were obtained from 3,851 patients who underwent 4,812 procedures in 192 ICUs in 28 countries. MEASUREMENTS AND MAIN RESULTS: Pain intensity on a 0-10 numeric rating scale increased significantly from baseline pain during all procedures (P < 0.001). Chest tube removal, wound drain removal, and arterial line insertion were the three most painful procedures, with median pain scores of 5 (3-7), 4.5 (2-7), and 4 (2-6), respectively. By multivariate analysis, risk factors independently associated with greater procedural pain intensity were the specific procedure; opioid administration specifically for the procedure; preprocedural pain intensity; preprocedural pain distress; intensity of the worst pain on the same day, before the procedure; and procedure not performed by a nurse. A significant ICU effect was observed, with no visible effect of country because of its absorption by the ICU effect. Some of the risk factors became nonsignificant when each procedure was examined separately. CONCLUSIONS: Knowledge of risk factors for greater procedural pain intensity identified in this study may help clinicians select interventions that are needed to minimize procedural pain. Clinical trial registered with www.clinicaltrials.gov (NCT 01070082).

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.

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).

Therapeutic drug monitoring when using cefepime in continuous renal replacement therapy: seizures associated with cefepime.

Ensuring effective, safe drug dosing in critically ill patients can be difficult, due to variable and dynamic organ function. An 82-year-old man was admitted to the intensive care unit with severe community-acquired pneumonia, septic shock and progressive organ failure. He required ventilation and continuous renal replacement therapy. He developed seizures which we believe were due to cefepime toxicity. Following the first seizure, we took serial measurements of plasma cefepime levels, and a single measurement of the cerebrospinal fluid (CSF) cefepime level. The peak plasma cefepime concentration was 73.8 µg/mL (minimum inhibitory concentration of target enterobacteriaceae is 8 µg/mL) and the CSF level was 6.1 µg/mL. The patient had four seizures during the period of high plasma cefepime concentration, but no more episodes once the drug level decreased to non-toxic levels. This case highlights the difficulty in predicting pharmacokinetics in critically ill patients, particularly those receiving renal replacement therapy. We suggest that therapeutic drug monitoring in critically ill patients may be a useful intervention to avoid antibiotic-related toxicities.

Radiation exposure of ventilated trauma patients in intensive care: a retrospective study comparing two time periods.

OBJECTIVE: To describe the cumulative effective dose of radiation that was received during the initial Emergency Department assessment and ICU stay of patients admitted with trauma, who required mechanical ventilation, during two time periods. METHOD: A retrospective analysis of radiological and clinical data, set in a regional nonurban ICU. Two cohorts (starting 1 January 2004 and 1 January 2009), each comprising 45 adult patients admitted with trauma who were mechanically ventilated in intensive care, were studied. Frequency and type of radiological examinations, demographic information, and clinical data were collated from the radiological database, hospital admission record and Australian Outcomes Research Tool for Intensive Care database. Cumulative effective doses were calculated and expressed as a total dose and average daily dose for each cohort. RESULTS: The median cumulative effective dose per patient (in milliSieverts) increased from 34.59 [interquartile range (IQR) 9.08-43.91] in 2004 to 40.51 (IQR 22.01-48.87) in 2009, P=0.045. An increased number of computed tomography examinations per patient was also observed over the same interval from an average of 2.11 (median 2, IQR 1-3) in 2004 to an average of 2.62 (2, 2-4) in 2009, P=0.046. CONCLUSION: The radiation exposure of mechanically ventilated trauma patients in intensive care has increased over time. Radiation exposure should be prospectively monitored and staff should be aware of the increased risk resulting from this change in practice.

Leptospirosis presenting to an intensive care unit in provincial New Zealand: a case series and review.

BACKGROUND: Leptospirosis is a disease associated with meat and agricultural workers which is endemic in New Zealand and Australia. During 2003-2005, it resulted in 207 hospitalisations in New Zealand. Hawke's Bay had the highest regional incidence in 2004 and 2005. While admission to intensive care units with leptospirosis is not infrequent, no such cases have been described in the literature from New Zealand, and only five from Australia. METHODS: A chart review of all patients admitted to the intensive care/high dependency unit of a regional hospital in New Zealand with a diagnosis of leptospirosis from June 1999 to May 2005. Admission features, progress and diagnostic tests were collated, and APACHE II score on admission and daily Sequential Organ Failure Assessment (SOFA) score were calculated. RESULTS: 15 cases were identified; median age was 44 years (range, 27-62), and 13 were men. Myalgia, headache, nausea and vomiting were common; nine had conjunctival suffusion. Ten had hypotension and 14 had renal failure before ICU admission. Eleven received vasoactive support, and three received renal replacement therapy. Median length of ICU stay was 4 days (range, 2- 11; mean, 4 days). Median hospital stay was 6 days (range, 2-13; mean, 7.6 days). All patients survived and were discharged free of dialysis. CONCLUSION: Leptospirosis presents to the ICU with a variety of signs and symptoms. Renal failure is the most common organ dysfunction requiring intensive care, and its severity is disproportionate to other signs of severe sepsis. Leptospirosis has a good prognosis with early management in an ICU.

Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis.

Drotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to drotrecogin alfa (activated) at 24 microg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-observation-carried-forward (LOCF) method of imputation for missing observations was the prospectively defined statistical method. The results were also analyzed with only the observed values without imputation for missing data (repeated measures analysis). With both statistical methods, drotrecogin alfa (activated)-treated patients demonstrated antithrombotic (reduced markers of thrombin generation and accelerated normalization of anticoagulant factor, protein C and fibrinolytic factors) and anticoagulant (prolonged PT and APTT) effects compared with placebo. A profibrinolytic (reduction in plasminogen activator inhibitor-1) effect was significant only with the LOCF imputation method in observed case and percent change from baseline analyses. An anti-inflammatory (reduction in interleukin-6) effect was significant only with the LOCF imputation method in change from baseline and percent change from baseline analyses. Drotrecogin alfa (activated) is a new and promising agent for treatment of patients with severe sepsis. The extensive analysis of systemic biomarkers confirms the previously published antithrombotic effects. However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of drotrecogin alfa (activated).

Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated).

Clinical trials with novel therapeutic agents for severe sepsis have suggested that patients might respond differently depending on causative microorganism. Data from a large, placebo-controlled trial of recombinant human drotrecogin alfa (activated) (DrotAA) were analyzed by type of causative microorganism for treatment-associated differences in mortality, coagulopathy, and inflammatory response. Compared with placebo, mortality rates associated with DrotAA were consistently reduced for each microorganism group (gram-positive bacteria, gram-negative bacteria, mixed bacteria, fungi, other, and unknown microbial etiology), with a stratified relative risk (RR) of 0.80 (95% confidence interval [CI], 0.69-0.94). The greatest reduction in the mortality rate was for Streptococcus pneumoniae infection (RR, 0.56; 95% CI, 0.35-0.88). Levels of coagulation and inflammation biomarkers varied with different pathogens at study entry. Results demonstrate that DrotAA, administered as an adjunct to standard anti-infective therapy, can improve the rate of survival for patients who develop severe sepsis regardless of causative microorganism.

Oxygen therapy for hypercapnic patients with chronic obstructive pulmonary disease and acute respiratory failure: a randomized, controlled pilot study.

OBJECTIVE: To investigate the effect of oxygen therapy on outcome and on symptomatic hypercapnia. DESIGN: Randomized, controlled, single-blind study. SETTING: Multidisciplinary intensive care unit of a university teaching hospital. PATIENTS: Patients admitted with a clinical diagnosis of an acute exacerbation of chronic obstructive pulmonary disease and a PaO2 <6.6 kPa (50 mm Hg) and PaCO2 >6.6 kPa (50 mm Hg) on air. INTERVENTIONS: Patients received oxygen therapy titrated to increase arterial oxygen tension to >6.6 kPa (50 mm Hg) or >9 kPa (70 mm Hg). Patients in the low-oxygen tension group also received doxapram if they developed an acidosis with pH <7.2, whereas those in the high-oxygen tension group received doxapram if they developed symptomatic acidosis. Bronchodilator, steroid, and antibiotic therapy was standardized. MEASUREMENTS AND MAIN RESULTS: Two patients in the low-oxygen tension group (n = 17) required mechanical ventilation and another one died. No patients in the high-oxygen group (n = 17) had a poor outcome, but this difference was not significant. No patient in either group became comatose or developed an acute cardiac arrhythmia. CONCLUSIONS: Traditional teaching related to oxygen therapy for hypercapnic patients with an acute exacerbation of chronic obstructive pulmonary disease may be incorrect. A large randomized, controlled study is required to confirm this impression.