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).

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).

Effect of 0.9% Saline or Plasma-Lyte 148 as Crystalloid Fluid Therapy in the Intensive Care Unit on Blood Product Use and Postoperative Bleeding After Cardiac Surgery.

OBJECTIVE: To evaluate the effect of Plasma-Lyte 148 (PL-148) compared with 0.9% saline (saline) on blood product use and postoperative bleeding in patients admitted to the intensive care unit (ICU) following cardiac surgery. DESIGN: A post hoc subgroup analysis conducted within a multicenter, double-blind, cluster-randomized, double-crossover study (study 1) and a prospective, single-center nested-cohort study (study 2). SETTING: Tertiary-care hospitals. PARTICIPANTS: Adults admitted to the ICU after cardiac surgery requiring crystalloid fluid therapy as part of the 0.9% saline vs. PL-148 for ICU fluid therapy (SPLIT) trial. INTERVENTIONS: Blinded saline or PL-148 for 4 alternating 7-week blocks. MEASUREMENTS AND MAIN RESULTS: 954 patients were included in study 1; 475 patients received PL-148, and 479 received saline. 128 of 475 patients (26.9%) in the PL-148 group received blood or a blood product compared with 94 of 479 patients (19.6%) in the saline group (OR [95% confidence interval], 1.51 [1.11-2.05]; p = 0.008). In study 2, 131 patients were allocated to PL-148 and 120 patients were allocated to saline. There were no differences between groups in chest drain output from the time of arrival in the ICU until 12 hours postoperatively (geometric mean, 566 mL for the PL-148 group v 547 mL in the saline group; p = 0.60). CONCLUSIONS: The findings did not support the hypothesis that using PL-148 for fluid therapy in ICU following cardiac surgery reduces transfusion requirements compared to saline. The significantly increased proportion of patients receiving blood or blood product with allocation to PL-148 compared to saline was unexpected and requires verification through further research.

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.

Oxygenation targets, monitoring in the critically ill: a point prevalence study of clinical practice in Australia and New Zealand.

BACKGROUND: Many critically ill patients require supplemental oxygen. However, the optimal oxygen saturation measured by pulse oximetry (SpO2) in intensive care unit patients is unknown. OBJECTIVE: To evaluate clinical practice in Australia and New Zealand ICUs in relation to SpO2monitoring, prescription of SpO2targets by doctors, and upper and lower limits of tolerance of high and low SpO2levels by ICU bedside nurses. METHOD: Cross-sectional, observational study conducted on 2 days in 2013 involving adult patients in Australia and New Zealand ICUs. RESULTS: Data from 350 adult ICU patients were included. SpO2alarms were less likely to be disabled in patients who were invasively ventilated than in patients not receiving supplemental oxygen (4.8% v 15.1%; P = 0.02). In mechanically ventilated patients and non-ventilated patients receiving supplemental oxygen, the lower prescribed SpO2limit and the ICU bedside nurses' stated limits for action for low SpO2levels were 92% (interquartile range, 90%-94%). Upper SpO2limits were less frequently prescribed than lower SpO2limits (4.9% [95% CI, 3.0%- 7.7%] v 36.6% [95% CI, 31.7%-41.7%]); P < 0.01) and the observed SpO2exceeded the prescribed upper limit on 10/17 occasions (59%) when an upper limit was prescribed. CONCLUSION: Our findings suggest a relatively low level of vigilance in relation to prevention of high SpO2compared with low SpO2for adult patients in Australian and New Zealand ICUs.

Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial.

OBJECTIVE: To investigate the safety and efficacy of QMF149, a once-daily, fixed-dose combination of the long-acting ß2-agonist (LABA) indacaterol maleate and inhaled corticosteroid (ICS) mometasone furoate (MF) for the treatment of persistent asthma. The hypothesis was that QMF149 would not increase the risk of serious asthma exacerbations. SETTING: 174 research centres in nine countries. PARTICIPANTS: 1519 adolescents and adults with persistent asthma who were treated or qualified for treatment with combination LABA/ICS were randomised, and 1508 were included in the intention-to-treat analysis. INTERVENTION: Patients were randomised to QMF149 (indacaterol maleate 500 µg/MF 400 µg) or MF (400 µg) once daily via Twisthaler inhalation device in a double-blind, parallel-group study for 6-21 months. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary end point was time to first serious asthma exacerbation (resulting in hospitalisation, intubation or death). The key secondary end point was annual rate of exacerbations requiring systemic corticosteroids. RESULTS: Treatment with QMF149 resulted in no significant difference in time to first serious exacerbation compared to MF (2 (0.3%) vs 6 events (0.8%); difference -0.52 percentage point; 95% CI -1.25 to 0.21, p=0.160, HR=0.31; 95% CI 0.06 to 1.54, p=0.151). QMF149 significantly reduced the annual rate of exacerbations requiring systemic corticosteroids (rate ratio=0.71; 95% CI 0.55 to 0.90, p=0.005). Proportions of patients experiencing adverse events were similar across groups (74.0% in the QMF149 group and 73.4% in the MF group). Serious adverse events occurred in 4% and 5.8% of patients in the QMF149 and MF groups, respectively. CONCLUSIONS: No significant difference was observed in the primary outcome of time to first serious asthma exacerbation in patients treated with QMF149 compared with patients treated with MF. Long-term treatment with QMF149 once daily had a favourable safety/efficacy profile in adolescent and adult patients with persistent asthma. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT00941798.

Overview of the study protocols and statistical analysis plan for the Saline versus Plasma-Lyte 148 for Intravenous Fluid Therapy (SPLIT) research program.

BACKGROUND: 0.9% saline is the most commonly used intravenous (IV) fluid in the world but recent data raise the possibility that, compared with buffered crystalloid fluids such as Plasma-Lyte 148, the administration of 0.9% saline might increase the risk of developing acute kidney injury. OBJECTIVE: To provide an overview of the study protocols and statistical analysis plan for the six studies making up the (0.9% Saline v Plasma-Lyte 148 for Intravenous Fluid Therapy (SPLIT) research program. METHODS: The SPLIT study consists of six integrated clinical trials, including a double-blind, cluster, randomised, double-crossover study in intensive care unit patients, incorporating two nested studies within it; an open-label, before-and-after study in emergency department (ED) patients; a single-centre, double-blind, crossover trial in major surgical patients; and a randomised, double-blind study in ICU patients. All studies focus on biochemical and renal outcomes but will also provide preliminary data on patient-centred outcomes including inhospital mortality and requirements for dialysis. RESULTS AND CONCLUSION: The SPLIT study program will provide preliminary data on the comparative effectiveness of using 0.9% saline v Plasma-Lyte 148 for IV fluid therapy in ED, surgical and ICU patients.

A protocol for the 0.9% saline versus Plasma-Lyte 148 for intensive care fluid therapy (SPLIT) study.

BACKGROUND: 0.9% saline is the most commonly used intravenous (IV) fluid in the world. However, recent data raise the possibility that, compared with buffered crystalloid fluids such as Plasma-Lyte 148, the administration of 0.9% saline to intensive care unit patients might increase their risk of acute kidney injury (AKI). OBJECTIVE: To describe the protocol for the 0.9% Saline v Plasma-Lyte 148 for ICU Fluid Therapy (SPLIT) study. METHODS: This is a multicentre, cluster-randomised, double crossover feasibility study to be conducted in four New Zealand tertiary ICUs over a 28-week period and will enroll about 2300 participants. All ICU patients who need crystalloid IV fluid therapy (except those with established renal failure needing dialysis and those admitted to the ICU for palliative care) will be enrolled. Participating ICUs will be randomly assigned to 0.9% saline or Plasma-Lyte 148 as the routine crystalloid IV fluid, in a blinded fashion, in four alternating 7-week blocks. MAIN OUTCOME MEASURES: The primary outcome will be the proportion of patients who develop AKI in the ICU. Secondary outcomes will include the difference between the most recent serum creatinine level measured before study enrollment and the peak serum creatinine level in the ICU; use of renal replacement therapy; and ICU and in hospital mortality. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSION: The SPLIT study started on 1 April 2014 and will provide preliminary data on the comparative effectiveness of using 0.9% saline v Plasma- Lyte 148 as the routine IV fluid therapy in ICU patients.

Opinions and practice of stress ulcer prophylaxis in Australian and New Zealand intensive care units.

BACKGROUND: Intensivists frequently prescribe proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) to intensive care unit patients for stress ulcer prophylaxis (SUP). Despite the common use of SUP medicines, there is limited high-level evidence to support the choice between them. AIM: To describe self-reported practice of SUP by Australian and New Zealand intensivists. METHOD: An online questionnaire of intensivists between 13 January and 3 February 2014. RESULTS: Seventy-two intensivists responded to the survey: 61 (85%) practised in public metropolitan ICUs and 13/48 (27%) practised in paediatric ICUs. Fifty-two (72%) respondents indicated that PPIs were their preferred SUP medicine. Respondents estimated that an average of 84% of ventilated and 53% of non-ventilated patients received SUP medicines during their ICU admission. Seven respondents (9%) were concerned or very concerned about the possible increased risk of upper gastrointestinal bleeding associated with H2RBs versus PPIs. Ten respondents (14%) were concerned or very concerned about the possible greater risk of Clostridium difficile infection, and 15 respondents (21%) were concerned or very concerned about the possible greater risk or ventilator-associated pneumonia with PPIs versus H2RBs. Most respondents (64 [89%]) agreed or strongly agreed that there was insufficient evidence to support the choice of an optimal SUP medicine, and 58 respondents (81%) agreed or strongly agreed to patient enrollment in an RCT comparing PPIs with H2RBs. CONCLUSION: Most survey respondents felt that current evidence is insufficient to justify the preferential use of PPIs or H2RBs for SUP and would enroll patients in a comparative SUP RCT.

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).

A systematic review and meta-analysis of the cardioprotective effects of remote ischaemic preconditioning in open cardiac surgery.

OBJECTIVE: To investigate the cardioprotective efficacy of remote ischaemic preconditioning (RIPC) in cardiac surgery. DESIGN: We have performed a systematic search of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify randomized controlled trials involving RIPC. SETTING: Randomized controlled trials of RIPC in open cardiac surgery patients. MAIN OUTCOME MEASURES: Meta-analysis was performed with the primary outcome the standardized mean difference between intervention and control groups in 12 hour postoperative troponin concentration. Heterogeneity was examined by fixed effects meta-regression. RESULTS: Ten studies with a total of 693 participants were included in the meta-analysis. RIPC reduced troponin levels 12 hours after surgery compared with control. The fixed and random effects differences were 0.35 (95% CI 0.19 to 0.51) and 0.53 (95% CI 0.18-0.88) respectively. However, important heterogeneity was present. Fixed effects meta-regression partially accounted for heterogeneity based on whether studies had full blinding, comprising blinding of patients, surgeons, anaesthetists and investigators. Studies with incomplete or no blinding demonstrated a larger estimate of effect, 0.74 (95% CI 0.47 to 1.00) compared to those with full blinding, 0.13 (95% CI - 0.07 to 0.33). CONCLUSIONS: Although our analysis suggests RIPC may result in cardiac protection during cardiac surgery, the effect was most marked in studies without full blinding, with a smaller and statistically non-significant effect in fully blinded studies. We propose that further double blind randomized controlled trials investigating the cardioprotective effects of RIPC in cardiac surgery are required to resolve the current clinical uncertainty.

Fever and antipyresis in infection.

Fever is an important mechanism of intrinsic resistance against infectious disease. A variety of studies point to a potential detrimental effect of temperature lowering in infectious disorders, but high-quality evidence from randomised controlled trials is lacking. In ambulatory care settings, we need to know whether antipyretics influence the severity and duration of illnesses and, in critically ill patients, whether antipyretics affect mortality.

A hypothesis to phenotype COPD exacerbations by aetiology.

COPD exacerbations have traditionally been defined on the basis of symptoms or health-care utilization without specific reference to the suspected aetiology. Consequently, the term 'exacerbation' has been used to include all patients experiencing an acute deterioration of symptoms associated with COPD. However, exacerbations are known to result from a variety of causes and do not necessarily constitute an equivalent event in the same patient, between different patients or between individual research studies. We therefore hypothesize that phenotyping exacerbations by aetiology may identify exacerbation subgroups, clarify benefits of therapeutic intervention in the subgroups and overall improve clinical care. An acronym is proposed to facilitate phenotyping COPD exacerbations.

Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma and Allergies in Childhood Phase Three.

RATIONALE: There is epidemiological evidence that the use of acetaminophen may increase the risk of developing asthma. OBJECTIVES: To investigate the risk of asthma and other allergic disorders associated with the current use of acetaminophen in 13- to 14-year-old children in different populations worldwide. METHODS: As part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three, 13- to 14-year-old children completed written and video questionnaires obtaining data on current symptoms of asthma, rhinoconjunctivitis, and eczema, and a written environmental questionnaire obtaining data on putative risk factors, including acetaminophen use in the past 12 months. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was the odds ratio (OR) of current asthma symptoms associated with acetaminophen use calculated by logistic regression. A total of 322,959 adolescent children from 113 centers in 50 countries participated. In the multivariate analyses the recent use of acetaminophen was associated with an exposure-dependent increased risk of current asthma symptoms (OR, 1.43 [95% confidence interval, 1.33-1.53] and 2.51 [95% confidence interval, 2.33-2.70] for medium and high versus no use, respectively). Acetaminophen use was also associated with an exposure-dependent increased risk of current symptoms of rhinoconjunctivitis and eczema. CONCLUSIONS: Acetaminophen use may represent an important risk factor for the development and/or maintenance of asthma, rhinoconjunctivitis, and eczema in adolescent children.