Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial.

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 events or in number of days alive and out of hospital. Conclusion and Relevance: In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg. Trial Registration: ClinicalTrials.gov Identifier: NCT04425031.

Platform trials.

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.

A survey of preferences for respiratory support in the intensive care unit for patients with acute hypoxaemic respiratory failure.

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.

Long-term outcomes in COVID-19 patients admitted to intensive care in Denmark: A nationwide observational study.

BACKGROUND: Among ICU patients with COVID-19, it is largely unknown how the overall outcome and resource use have changed with time, different genetic variants, and vaccination status. METHODS: For all Danish ICU patients with COVID-19 from March 10, 2020 to March 31, 2022, we manually retrieved data on demographics, comorbidities, vaccination status, use of life support, length of stay, and vital status from medical records. We compared patients based on the period of admittance and vaccination status and described changes in epidemiology related to the Omicron variant. RESULTS: Among all 2167 ICU patients with COVID-19, 327 were admitted during the first (March 10-19, 2020), 1053 during the second (May 20, 2020 to June 30, 2021) and 787 during the third wave (July 1, 2021 to March 31, 2022). We observed changes over the three waves in age (median 72 vs. 68 vs. 65 years), use of invasive mechanical ventilation (81% vs. 58% vs. 51%), renal replacement therapy (26% vs. 13% vs. 12%), extracorporeal membrane oxygenation (7% vs. 3% vs. 2%), duration of invasive mechanical ventilation (median 13 vs. 13 vs. 9 days) and ICU length of stay (median 13 vs. 10 vs. 7 days). Despite these changes, 90-day mortality remained constant (36% vs. 35% vs. 33%). Vaccination rates among ICU patients were 42% as compared to 80% in society. Unvaccinated versus vaccinated patients were younger (median 57 vs. 73 years), had less comorbidity (50% vs. 78%), and had lower 90-day mortality (29% vs. 51%). Patient characteristics changed significantly after the Omicron variant became dominant including a decrease in the use of COVID-specific pharmacological agents from 95% to 69%. CONCLUSIONS: In Danish ICUs, the use of life support declined, while mortality seemed unchanged throughout the three waves of COVID-19. Vaccination rates were lower among ICU patients than in society, but the selected group of vaccinated patients admitted to the ICU still had very severe disease courses. When the Omicron variant became dominant a lower fraction of SARS-CoV-2 positive patients received COVID treatment indicating other causes for ICU admission.

Haloperidol for the Treatment of Delirium in ICU Patients.

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. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).

Changes over time in characteristics, resource use and outcomes among ICU patients with COVID-19-A nationwide, observational study in Denmark.

BACKGROUND: Characteristics and care of intensive care unit (ICU) patients with COVID-19 may have changed during the pandemic, but longitudinal data assessing this are limited. We compared patients with COVID-19 admitted to Danish ICUs in the first wave with those admitted later. METHODS: Among all Danish ICU patients with COVID-19, we compared demographics, chronic comorbidities, use of organ support, length of stay and vital status of those admitted 10 March to 19 May 2020 (first wave) versus 20 May 2020 to 30 June 2021. We analysed risk factors for death by adjusted logistic regression analysis. RESULTS: Among all hospitalised patients with COVID-19, a lower proportion was admitted to ICU after the first wave (13% vs. 8%). Among all 1374 ICU patients with COVID-19, 326 were admitted during the first wave. There were no major differences in patient's characteristics or mortality between the two periods, but use of invasive mechanical ventilation (81% vs. 58% of patients), renal replacement therapy (26% vs. 13%) and ECMO (8% vs. 3%) and median length of stay in ICU (13 vs. 10 days) and in hospital (20 vs. 17 days) were all significantly lower after the first wave. Risk factors for death were higher age, larger burden of comorbidities (heart failure, pulmonary disease and kidney disease) and active cancer, but not admission during or after the first wave. CONCLUSIONS: After the first wave of COVID-19 in Denmark, a lower proportion of hospitalised patients with COVID-19 were admitted to ICU. Among ICU patients, use of organ support was lower and length of stay was reduced, but mortality rates remained at a relatively high level.

Long-term cognitive and functional status in Danish ICU patients with COVID-19.

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.

Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

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, NCT03668236.).

Agents intervening against delirium in the intensive care unit trial-Protocol for a secondary Bayesian analysis.

BACKGROUND: Delirium is highly prevalent in the intensive care unit (ICU) and is associated with high morbidity and mortality. The antipsychotic haloperidol is the most frequently used agent to treat delirium although this is not supported by solid evidence. The agents intervening against delirium in the intensive care unit (AID-ICU) trial investigates the effects of haloperidol versus placebo for the treatment of delirium in adult ICU patients. METHODS: This protocol describes the secondary, pre-planned Bayesian analyses of the primary and secondary outcomes up to day 90 of the AID-ICU trial. We will use Bayesian linear regression models for all count outcomes and Bayesian logistic regression models for all dichotomous outcomes. We will adjust for stratification variables (site and delirium subtype) and use weakly informative priors supplemented with sensitivity analyses using sceptical priors. We will present results as absolute differences (mean differences and risk differences) and relative differences (ratios of means and relative risks). Posteriors will be summarised using median values as point estimates and percentile-based 95% credibility intervals. Probabilities of any benefit/harm, clinically important benefit/harm and clinically unimportant differences will be presented for all outcomes. DISCUSSION: The results of this secondary, pre-planned Bayesian analysis will complement the primary frequentist analysis of the AID-ICU trial and facilitate a nuanced and probabilistic interpretation of the trial results.

Distribution of delirium motor subtypes in the intensive care unit: a systematic scoping review.

BACKGROUND: Delirium is the most common cerebral dysfunction in the intensive care unit (ICU) and can be subdivided into a hypoactive, hyperactive, or mixed motor subtype based on the clinical manifestation. The aim of this review was to describe the distribution, pharmacological interventions, and outcomes of delirium motor subtypes in ICU patients. METHODS: This systematic scoping review was performed according to the PRISMA-ScR and Cochrane guidelines. We performed a systematic search in six major databases to identify relevant studies. A meta-regression analysis was performed where pooled estimates with 95% confidence intervals were computed by a random effect model. RESULTS: We included 131 studies comprising 13,902 delirious patients. There was a large between-study heterogeneity among studies, including differences in study design, setting, population, and outcome reporting. Hypoactive delirium was the most prevalent delirium motor subtype (50.3% [95% CI 46.0-54.7]), followed by mixed delirium (27.7% [95% CI 24.1-31.3]) and hyperactive delirium (22.7% [95% CI 19.0-26.5]). When comparing the delirium motor subtypes, patients with mixed delirium experienced the longest delirium duration, ICU and hospital length of stay, the highest ICU and hospital mortality, and more frequently received administration of specific agents (antipsychotics, α2-agonists, benzodiazepines, and propofol) during ICU stay. In studies with high average age for delirious patients (> 65 years), patients were more likely to experience hypoactive delirium. CONCLUSIONS: Hypoactive delirium was the most prevalent motor subtype in critically ill patients. Mixed delirium had the worst outcomes in terms of delirium duration, length of stay, and mortality, and received more pharmacological interventions compared to other delirium motor subtypes. Few studies contributed to secondary outcomes; hence, these results should be interpreted with care. The large between-study heterogeneity suggests that a more standardized methodology in delirium research is warranted.

Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids.

BACKGROUND: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations. METHODS: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. CONCLUSION: This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.

Health-related quality of life, anxiety and depression and physical recovery after critical illness - A prospective cohort study.

BACKGROUND: Critical illness is often followed by mental and physical impairments. We aimed to assess the health-related quality of life (HRQoL), symptoms of anxiety and depression, and physical function in critically ill patients after discharge from the intensive care unit. METHODS: For this prospective cohort study we included all available adult patients admitted to the ICU for >24 h during a 12-month period. Home visits took place at 3 and 12 months after discharge from the hospital and included Short-Form Health Survey (SF-36), Hospital Anxiety and Depression Scale, and Chelsea Critical Care Assessment Too (CPAx). RESULTS: We visited 79 patients at 3 and 53 at 12 months. In patients with data from both visits the mental components SF-36 scores (median (IQR)) were 55 (43-63) at 3, and 58.5 (49.5-64) at 12 months; physical component SF-36 scores were 35 (28-45) at 3, and 36 (28-42) at 12 months. SF-36 subdomains of mental health, social functioning, and role emotional were close to normal. Vitality, bodily pain, general health, physical functioning, and role physical were severely affected. Incidences of anxiety and depression symptoms were 16%/8% at 3 and 13%/8% at 12 months) and physical function (CPAx) was 47 at both time points). CONCLUSION: We found no change in HRQoL, anxiety, and depression, or physical function from 3 months to 1 year. Physical health-related quality of life was impaired at both time points. Subdomain scores for physical health-related quality of life were affected more than mental domains at both time points.

Oxygenation targets in ICU patients with COVID-19: A post hoc subgroup analysis of the HOT-ICU trial.

BACKGROUND: Supplemental oxygen is the key intervention for severe and critical COVID-19 patients. With the unstable supplies of oxygen in many countries, it is important to define the lowest safe dosage. METHODS: In spring 2020, 110 COVID-19 patients were enrolled as part of the Handling Oxygenation Targets in the ICU trial (HOT-ICU). Patients were allocated within 12 h of ICU admission. Oxygen therapy was titrated to a partial pressure of arterial oxygen (PaO2 ) of 8 kPa (lower oxygenation group) or a PaO2 of 12 kPa (higher oxygenation group) during ICU stay up to 90 days. We report key outcomes at 90 days for the subgroup of COVID-19 patients. RESULTS: At 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58-1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups. Proning and inhaled vasodilators were used more frequently, and the positive end-expiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT-ICU population were insignificant. CONCLUSIONS: Targeting a PaO2 of 8 kPa may be beneficial in ICU patients with COVID-19. These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT-ICU trial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT03174002. Date of registration: June 2, 2017.

Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU trial: protocol and statistical analysis plan.

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.

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial.

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

Sleep-wake rhythms determined by actigraphy during in-hospital stay following discharge from an intensive care unit.

BACKGROUND: Sleep and circadian disturbances play a major role in recovery after critical illness. Ample research has shown sleep to be disturbed during the stay at the intensive care unit (ICU); however, the trajectory of sleep after ICU discharge is sparsely described. The current study aimed to describe the development of the sleep-wake rhythm in subjects discharged from ICU to a hospital ward. METHODS: Following discharge from the ICU to a general hospital ward, the participants were monitored with an ActiGraph for sleep assessment for 7 days or until hospital discharge or death. Data were analysed for day-to-day change with t-tests and for the whole period with repeated measures analysis. RESULTS: For the 38 included patients, repeated measures analysis showed no significant improvement in total sleep time and wake time. However, for secondary outcomes, improvements for wake after sleep onset (P = .02) and reduction in the number of naps (P = .03) both in the day-to-day and overall trend analysis were observed. CONCLUSION: The duration of sleep and wake time did not improve during ward stay. However, sleep became less fragmented and naps during the day declined. Due to the small sample size further, larger trials are needed.

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.

BACKGROUND: Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target. METHODS: In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTS: At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). CONCLUSIONS: Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).

Health care use before and after intensive care unit admission-A nationwide register-based study.

BACKGROUND: The aim of this study was to describe healthcare utilization of patients admitted to ICU before and after ICU admission. METHODS: Register-based study including adult patients discharged from ICU between January 1st, 2011 and December 31st, 2014. Reference group was a sex- and age-matched population not admitted to an ICU in the study period. Outcomes were hospital admissions, contacts to general practitioner or emergency services and municipality services from 1 year before ICU admission and up to 3 years after. RESULTS: The study included 82 384 patients and an equal number of reference persons. Of patients with ICU admission, 48% were married (reference group 57%), 48% had elementary school education (reference group 38%) and 18% had a Charlson co-morbidity score of 5+ (4% in reference group). We found that 51% of patients with an ICU admission had been admitted to hospital in the year before ICU admission (reference group 15%) and 97% had a contact to a general practitioner (reference group 89%) in the same period. CONCLUSIONS: Patients admitted to an ICU had increased use of both primary and secondary health care both before and for years after ICU treatment, even after adjustment for comorbidities and socio-economic factors.

The Agents Intervening against Delirium in the Intensive Care Unit Trial (AID-ICU trial): A detailed statistical analysis plan.

BACKGROUND: The AID-ICU trial aims to assess the benefits and harms of haloperidol for the treatment of delirium in acutely admitted, adult intensive care unit (ICU) patients. This paper describes the detailed statistical analysis plan for the primary publication of results from the AID-ICU trial. METHODS: The AID-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomized, blinded, parallel-group trial allocating 1000 adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. The primary outcome measure is days alive and out of hospital within 90 days post-randomization. Secondary outcome measures are days alive without delirium or coma, serious adverse reactions (SARs) to haloperidol, use of escape medicine, days alive without mechanical ventilation, and mortality, health-related quality-of-life measures and cognitive function 1-year post-randomization. Statistical analysis will be conducted in accordance with the current pre-specified statistical analysis plan. One formal interim analysis will be performed. The primary outcome will be adjusted for stratification variables (site and delirium motor subtype) and compared between treatment groups using a likelihood ratio test described by Jensen et al A secondary analysis will be conducted with additional adjustment of the primary outcome for prognostic variables at baseline. The primary conclusion of the trial will be based on the intention-to-treat analysis of the primary outcome adjusted for stratification variables. CONCLUSION: The AID-ICU trial will provide important, high-quality data on the benefits and harms of treatment with haloperidol in acutely admitted, adult patients with manifest delirium in the ICU.

Mortality and HRQoL in ICU patients with delirium: Protocol for 1-year follow-up of AID-ICU trial.

BACKGROUND: Intensive care unit (ICU)-acquired delirium is frequent and associated with poor short- and long-term outcomes for patients in ICUs. It therefore constitutes a major healthcare problem. Despite limited evidence, haloperidol is the most frequently used pharmacological intervention against ICU-acquired delirium. Agents intervening against Delirium in the ICU (AID-ICU) is an international, multicentre, randomised, blinded, placebo-controlled trial investigates benefits and harms of treatment with haloperidol in patients with ICU-acquired delirium. The current pre-planned one-year follow-up study of the AID-ICU trial population aims to explore the effects of haloperidol on one-year mortality and health related quality of life (HRQoL). METHODS: The AID-ICU trial will include 1000 participants. One-year mortality will be obtained from the trial sites; we will validate the vital status of Danish participants using the Danish National Health Data Registers. Mortality will be analysed by Cox-regression and visualized by Kaplan-Meier curves tested for significance using the log-rank test. We will obtain HRQoL data using the EQ-5D instrument. HRQoL analysis will be performed using a general linear model adjusted for stratification variables. Deceased participants will be designated the worst possible value. RESULTS: We expect to publish results of this study in 2022. CONCLUSION: We expect that this one-year follow-up study of participants with ICU-acquired delirium allocated to haloperidol vs. placebo will provide important information on the long-term consequences of delirium including the effects of haloperidol. We expect that our results will improve the care of this vulnerable patient group.