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Background New-onset atrial fibrillation or flutter (NOAF) is a common arrhythmia in adult intensive care unit (ICU) patients. Intravenous amiodarone is one of the most used anti-arrhythmic drugs, despite its risk of inducing acute amiodarone-induced pulmonary toxicity (APT). We aimed to outline the body of evidence on acute APT in ICU patients with NOAF. Methods We performed a systematic search using the population, intervention, comparison, and outcome (PICO) approach. We included studies of adults admitted to the ICU, who developed NOAF during their ICU stay, were treated with amiodarone, and reported on acute APT, irrespective of research design. The CASE guidelines were applied to evaluate the quality of the included studies, and study results are reported in accordance with the preferred reporting items for systematic reviews and meta-analyses. Results No randomised controlled trials or observational studies were identified. Nine case reports and one retrospective case series of fatal outcomes in ICU patients treated with amiodarone for NOAF constituted the evidence base. The quality of the included studies was high with a mean of 10 (range 8–12) of the 13 CASE guideline criteria fulfilled. The studies included a total of 16 critically ill adults who was diagnosed with acute APT after a mean of 9 days (range 2–20 days) following initiation of amiodarone with a mean total dose of amiodarone of 4553 mg (range 1100–13,500 mg) predominantly administrated intravenously. Three out of nine patients in the case reports died in the ICU during the amiodarone treatment. No long-term follow-up was conducted for the survivors. Conclusion Acute APT in adult ICU patients treated with amiodarone for NOAF is poorly described and is based on a total of 16 reported cases. Additional studies assessing the safety of amiodarone in critically ill adults with NOAF in the ICU is warranted., Background: New-onset atrial fibrillation or flutter (NOAF) is a common arrhythmia in adult intensive care unit (ICU) patients. Intravenous amiodarone is one of the most used anti-arrhythmic drugs, despite its risk of inducing acute amiodarone-induced pulmonary toxicity (APT). We aimed to outline the body of evidence on acute APT in ICU patients with NOAF. Methods: We performed a systematic search using the population, intervention, comparison, and outcome (PICO) approach. We included studies of adults admitted to the ICU, who developed NOAF during their ICU stay, were treated with amiodarone, and reported on acute APT, irrespective of research design. The CASE guidelines were applied to evaluate the quality of the included studies, and study results are reported in accordance with the preferred reporting items for systematic reviews and meta-analyses. Results: No randomised controlled trials or observational studies were identified. Nine case reports and one retrospective case series of fatal outcomes in ICU patients treated with amiodarone for NOAF constituted the evidence base. The quality of the included studies was high with a mean of 10 (range 8–12) of the 13 CASE guideline criteria fulfilled. The studies included a total of 16 critically ill adults who was diagnosed with acute APT after a mean of 9 days (range 2–20 days) following initiation of amiodarone with a mean total dose of amiodarone of 4553 mg (range 1100–13,500 mg) predominantly administrated intravenously. Three out of nine patients in the case reports died in the ICU during the amiodarone treatment. No long-term follow-up was conducted for the survivors. Conclusion: Acute APT in adult ICU patients treated with amiodarone for NOAF is poorly described and is based on a total of 16 reported cases. Additional studies assessing the safety of amiodarone in critically ill adults with NOAF in the ICU is warranted.

Background Oxygen supplementation is ubiquitous in intensive care unit (ICU) patients with chronic obstructive pulmonary disease (COPD) and acute hypoxaemia, but the optimal oxygenation target has not been established. Methods This was a pre-planned subgroup analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) trial, which allocated patients with acute hypoxaemia to a lower oxygenation target (partial pressure of arterial oxygen [Pao2] of 8 kPa) vs a higher target (Pao2 of 12 kPa) during ICU admission, for up to 90 days; the allocation was stratified for presence or absence of COPD. Here, we report key outcomes for patients with COPD. Results The HOT-ICU trial enrolled 2928 patients of whom 563 had COPD; 277 were allocated to the lower and 286 to the higher oxygenation group. After allocation, the median Pao2 was 9.1 kPa (inter-quartile range 8.7–9.9) in the lower group vs 12.1 kPa (11.2–12.9) in the higher group. Data for arterial carbon dioxide (Paco2) were available for 497 patients (88%) with no between-group difference in time-weighted average; median Paco2 6.0 kPa (5.2–7.2) in the lower group vs 6.2 kPa (5.4–7.3) in the higher group. At 90 days, 122/277 patients (44%) in the lower oxygenation group had died vs 132/285 patients (46%) in the higher (relative risk 0.98; 95% confidence interval 0.82–1.17; P=0.67). No statistically significant differences were found in any secondary outcome. Conclusions In ICU patients with COPD and acute hypoxaemia, a lower vs a higher oxygenation target did not reduce mortality. There were no between-group differences in Paco2 or in secondary outcomes., Background: Oxygen supplementation is ubiquitous in intensive care unit (ICU) patients with chronic obstructive pulmonary disease (COPD) and acute hypoxaemia, but the optimal oxygenation target has not been established. Methods: This was a pre-planned subgroup analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) trial, which allocated patients with acute hypoxaemia to a lower oxygenation target (partial pressure of arterial oxygen [PaO2] of 8 kPa) vs a higher target (PaO2 of 12 kPa) during ICU admission, for up to 90 days; the allocation was stratified for presence or absence of COPD. Here, we report key outcomes for patients with COPD. Results: The HOT-ICU trial enrolled 2928 patients of whom 563 had COPD; 277 were allocated to the lower and 286 to the higher oxygenation group. After allocation, the median PaO2 was 9.1 kPa (inter-quartile range 8.7–9.9) in the lower group vs 12.1 kPa (11.2–12.9) in the higher group. Data for arterial carbon dioxide (PaCO2) were available for 497 patients (88%) with no between-group difference in time-weighted average; median PaCO2 6.0 kPa (5.2–7.2) in the lower group vs 6.2 kPa (5.4–7.3) in the higher group. At 90 days, 122/277 patients (44%) in the lower oxygenation group had died vs 132/285 patients (46%) in the higher (relative risk 0.98; 95% confidence interval 0.82–1.17; P=0.67). No statistically significant differences were found in any secondary outcome. Conclusions: In ICU patients with COPD and acute hypoxaemia, a lower vs a higher oxygenation target did not reduce mortality. There were no between-group differences in PaCO2 or in secondary outcomes. Clinical trial registration: NCT 03174002, EudraCT number 2017-000632-34.

Importance Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial. Objective To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU). Design, Setting, and Participants Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023. Interventions Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU. Main Outcomes and Measures The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days. Results Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adver, IMPORTANCE: Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial.OBJECTIVE: To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU).DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023.INTERVENTIONS: Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU.MAIN OUTCOMES AND MEASURES: The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days.RESULTS: Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse eve

Background In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings There were differences in mortality at day 28 (RD for Europe −8.3% (99% CI: −17.7 to 1.0) vs. India 0.1% (99% CI: −10.0 to 10.0)), mortality at day 90 (RD for Europe −7.4% (99% CI: −17.1 to 2.0) vs. India −1.4% (99% CI: −12.8 to 9.8)), mortality at day 180 (RD for Europe −6.7% (99% CI: −16.4 to 2.9) vs. India −1.0% (99% CI: −12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: −1.3 to 13.4) vs. India 1.7 days (99% CI: −8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe −1.0% (99% CI: −7.1 to 5.2) vs. India −5.3% (99% CI: −16.2 to 5.0). Interpretation Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding., Background: In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods: In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings: There were differences in mortality at day 28 (RD for Europe −8.3% (99% CI: −17.7 to 1.0) vs. India 0.1% (99% CI: −10.0 to 10.0)), mortality at day 90 (RD for Europe −7.4% (99% CI: −17.1 to 2.0) vs. India −1.4% (99% CI: −12.8 to 9.8)), mortality at day 180 (RD for Europe −6.7% (99% CI: −16.4 to 2.9) vs. India −1.0% (99% CI: −12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: −1.3 to 13.4) vs. India 1.7 days (99% CI: −8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe −1.0% (99% CI: −7.1 to 5.2) vs. India −5.3% (99% CI: −16.2 to 5.0). Interpretation: Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding. Funding: None for this analysis. The COVID STEROID 2 trial was funded by The Novo Nordisk Foundation and supported by Rigshospitalet's Research Council.

The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) was to provide evidence-based clinical guidance about the use of higher versus lower oxygenation targets for adult patients in the intensive care unit (ICU). The guideline panel comprised 27 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines, including the use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and used the Evidence-to-Decision framework to generate recommendations. A recently published updated systematic review and meta-analysis constituted the evidence base. Through teleconferences and web-based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients' values and preferences, costs and resources, equity, feasibility, acceptability, and research priorities. The updated systematic review and meta-analysis included data from 17 randomized clinical trials with 10,248 participants. There was little to no difference between the use of higher versus lower oxygenation targets for all outcomes with available data, including all-cause mortality, serious adverse events, stroke, functional outcomes, cognition, and health-related quality of life (very low certainty of evidence). The panel felt that values and preferences, costs and resources, and equity favored the use of lower oxygenation targets. The ICM-RPG panel issued one conditional recommendation against the use of higher oxygenation targets: “We suggest against the routine use of higher oxygenation targets in adult ICU patients (conditional recommendation, very low certainty of evidence). Remark: an oxygenation target of SpO2 88%–92% or PaO2 8 kPa/60 mmHg is relevant and safe for most adult ICU patients.”, The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) was to provide evidence-based clinical guidance about the use of higher versus lower oxygenation targets for adult patients in the intensive care unit (ICU). The guideline panel comprised 27 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. We adhered to the methodology for trustworthy clinical practice guidelines, including the use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and used the Evidence-to-Decision framework to generate recommendations. A recently published updated systematic review and meta-analysis constituted the evidence base. Through teleconferences and web-based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients' values and preferences, costs and resources, equity, feasibility, acceptability, and research priorities. The updated systematic review and meta-analysis included data from 17 randomized clinical trials with 10,248 participants. There was little to no difference between the use of higher versus lower oxygenation targets for all outcomes with available data, including all-cause mortality, serious adverse events, stroke, functional outcomes, cognition, and health-related quality of life (very low certainty of evidence). The panel felt that values and preferences, costs and resources, and equity favored the use of lower oxygenation targets. The ICM-RPG panel issued one conditional recommendation against the use of higher oxygenation targets: “We suggest against the routine use of higher oxygenation targets in adult ICU patients (conditional recommendation, very low certainty of evidence). Remark: an oxygenation target of SpO2 88%–92% or PaO2 8 kPa/60 mmHg is relevant and safe for most adult ICU patients.”.

Background: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers. Methods: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice. Results: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF. Conclusions: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF.

Background: This is an updated review concerning 'Higher versus lower fractions of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit'. Supplementary oxygen is provided to most patients in intensive care units (ICUs) to prevent global and organ hypoxia (inadequate oxygen levels). Oxygen has been administered liberally, resulting in high proportions of patients with hyperoxemia (exposure of tissues to abnormally high concentrations of oxygen). This has been associated with increased mortality and morbidity in some settings, but not in others. Thus far, only limited data have been available to inform clinical practice guidelines, and the optimum oxygenation target for ICU patients is uncertain. Because of the publication of new trial evidence, we have updated this review. Objectives: To update the assessment of benefits and harms of higher versus lower fractions of inspired oxygen (FiO2) or targets of arterial oxygenation for adults admitted to the ICU. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, BIOSIS Previews, and LILACS. We searched for ongoing or unpublished trials in clinical trial registers and scanned the reference lists and citations of included trials. Literature searches for this updated review were conducted in November 2022. Selection criteria: We included randomised controlled trials (RCTs) that compared higher versus lower FiO2 or targets of arterial oxygenation (partial pressure of oxygen (PaO2), peripheral or arterial oxygen saturation (SpO2 or SaO2)) for adults admitted to the ICU. We included trials irrespective of publication type, publication status, and language. We excluded trials randomising participants to hypoxaemia (FiO2 below 0.21, SaO2/SpO2 below 80%, or PaO2 below 6 kPa) or to hyperbaric oxygen, an

Platformsforsøg er kliniske forsøg, der fokuserer på en sygdom, f.eks. brystkræft eller COVID-19, eller en del af sundhedsvæsnet, f.eks. intensivafdelingerne. Modsat konventionelle forsøg, der ofte tester én behandling og så afsluttes, er platformsforsøg blivende og tester løbende flere behandlinger [1]. F.eks. har I-SPY 2-platformsforsøget siden 2010 testet 23 nye behandlinger mod brystkræft [2]., Platform trials focus on the perpetual testing of many interventions in a disease or a setting. These trials have lasting organizational, administrative, data, analytic, and operational frameworks making them highly efficient. The use of adaptation often increases the probabilities of allocating participants to better interventions and obtaining conclusive results. The COVID-19 pandemic showed the potential of platform trials as a fast and valid way to improved treatments. This review gives an overview of key concepts and elements using the Intensive Care Platform Trial (INCEPT) as an example.

BACKGROUND Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. METHODS In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. RESULTS A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P=0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. CONCLUSIONS Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo.

Background: ICU admission due to COVID-19 may result in cognitive and physical impairment. We investigated the long-term cognitive and physical status of Danish ICU patients with COVID-19. Methods: We included all patients with COVID-19 admitted to Danish ICUs between March 10 and May 19, 2020. Patients were the contacted prospectively at 6 and 12 months for follow-up. Our primary outcomes were cognitive function and frailty at 6 and 12 months after ICU admission, estimated by the Mini Montreal Cognitive Assessment, and the Clinical Frailty Scale. Secondary outcomes were 6- and 12-month mortality, health-related quality of life (HRQoL) assessed by EQ-5D-5L, functional status (Barthel activities of daily living and Lawton–Brody instrumental activities of daily living), and fatigue (Fatigue Assessment Scale). The study had no information on pre-ICU admission status for the participants. Results: A total of 326 patients were included. The 6- and 12-month mortality was 37% and 38%, respectively. Among the 204 six-month survivors, 105 (51%) participated in the 6-month follow-up; among the 202 twelve-month survivors, 95 (47%) participated in the 12-month follow-up. At 6 months, cognitive scores indicated impairment for 26% (95% confidence interval [CI], 11.4–12.4) and at 12 months for 17% (95% CI, 12.0–12.8) of participants. Frailty was indicated in 20% (95% CI, 3.4–3.9) at 6 months, and for 18% (95% CI, 3.3–3.8) at 12 months. Fatigue was reported by 52% at 6 months, and by 47% at 12 months. For HRQoL, moderate, severe, or extreme health problems were reported by 28% at 6 months, and by 25% at 12 months. Conclusion: Long-term cognitive, functional impairment was found in up to one in four of patients surviving intensive care for COVID-19. Fatigue was present in nearly half the survivors at both 6 and 12 months. However, pre-ICU admission status of the patients was unknown.

Background: Although supplemental oxygen can be lifesaving, liberal oxygen administration causing hyperoxaemia may be harmful. The targets for oxygenation in patients with acute hypoxaemic respiratory failure acutely admitted to the intensive care unit (ICU) are strongly debated, and consensus on which targets to recommend has not been reached. The Handling Oxygenation Targets in the ICU (HOT-ICU) trial is a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure. In this study, we aim to evaluate the effects of these targets on long-term cognitive and pulmonary function in Danish patients, enrolled in the HOT-ICU trial and surviving to 1-year follow-up. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. Methods: All patients enrolled in the HOT-ICU trial at Danish sites and surviving to 1 year after randomisation are eligible to participate. The last patient is expected to be included by November 2021. A Repeatable Battery for the Assessment of Neuropsychological Status and a body plethysmography, including diffusion capacity for carbon monoxide, both pre-planned secondary long-term outcomes of the HOT-ICU trial, will be obtained. Conclusion: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on cognitive and pulmonary function in adult ICU patients with acute hypoxaemic respiratory failure.

Background Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). Methods In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. Results We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P=0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. Conclusions Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, .)

Background Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. Methods In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. Results A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P=0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. Conclusions Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo.