Long-term mortality and health-related quality of life with lower versus higher oxygenation targets in intensive care unit patients with COVID-19 and severe hypoxaemia.

PURPOSE: The aim of this study was to evaluate one-year outcomes of lower versus higher oxygenation targets in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We conducted pre-planned analyses of one-year mortality and health-related quality of life (HRQoL) in the Handling Oxygenation Targets in COVID-19 trial. The trial randomised 726 ICU patients with COVID-19 and hypoxaemia to partial pressure of arterial oxygen targets of 8 kPa (60 mmHg) versus 12 kPa (90 mmHg) during ICU stay up to 90 days, including readmissions. HRQoL was assessed using EuroQol visual analogue scale (EQ-VAS) and 5-level 5-dimension questionnaire (EQ-5D-5L). Outcomes were analysed in the intention-to-treat population. Non-survivors were assigned the worst possible score (zero), and multiple imputation was applied for missing EQ-VAS values. RESULTS: We obtained one-year vital status for 691/726 (95.2%) of patients and HRQoL data for 642/726 (88.4%). At one year, 117/348 (33.6%) of patients in the lower-oxygenation group had died compared to 134/343 (39.1%) in the higher-oxygenation group (adjusted risk ratio: 0.85; 98.6% confidence interval (CI) 0.66-1.09; p = 0.11). Median EQ-VAS was 50 (interquartile range, 0-80) versus 40 (0-75) (adjusted mean difference: 4.8; 98.6% CI - 2.2 to 11.9; p = 0.09) and EQ-5D-5L index values were 0.61 (0-0.81) in the lower-oxygenation group versus 0.43 (0-0.79) (p = 0.20) in the higher-oxygenation group, respectively. CONCLUSION: Among adult ICU patients with COVID-19 and severe hypoxaemia, one-year mortality results were most compatible with benefit of the lower oxygenation target, which did not appear to result in more survivors with poor quality of life.

Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU and HOT-COVID trials: A protocol update.

BACKGROUND: The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial was 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; the Handling Oxygenation Targets in coronavirus disease 2019 (HOT-COVID) tested the same oxygenation targets in patients with confirmed COVID-19. In this study, we aim to evaluate the long-term effects of these oxygenation targets on cognitive and pulmonary function. 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: This is the updated protocol and statistical analysis plan of two pre-planned secondary outcomes, the long-term cognitive function, and long-term pulmonary function, in the HOT-ICU and HOT-COVID trials. Patients enrolled in both trials at selected Danish sites and surviving to 1 year after randomisation are eligible to participate. A Repeatable Battery for the Assessment of Neuropsychological Status score and a full-body plethysmography, including diffusion capacity for carbon monoxide, will be obtained. The last patient is expected to be included in the spring of 2024. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on long-term cognitive and pulmonary functions in adult ICU patients with acute hypoxaemic respiratory failure.

Pleural effusion and thoracentesis in ICU patients: A longitudinal observational cross-sectional study.

BACKGROUND: Pleural effusion is common among patients in the intensive care unit (ICU) but reported prevalence varies. Thoracentesis may improve respiratory status, however, indications for this are unclear. We aimed to explore prevalence, development, and progression of pleural effusion, and the incidence and effects of thoracentesis in adult ICU patients. METHODS: This is a prospective observational study utilizing repeated daily ultrasonographic assessments of pleurae bilaterally, conducted in all adult patients admitted to the four ICUs of a Danish university hospital throughout a 14-day period. The primary outcome was the proportion of patients with ultrasonographically significant pleural effusion (separation between parietal and visceral pleurae >20 mm) in either pleural cavity on any ICU day. Secondary outcomes included the proportion of patients with ultrasonographically significant pleural effusion receiving thoracentesis in ICU, and the progression of pleural effusion without drainage, among others. The protocol was published before study initiation. RESULTS: In total, 81 patients were included of which 25 (31%) had or developed ultrasonographically significant pleural effusion. Thoracentesis was performed in 10 of these 25 patients (40%). Patients with ultrasonographically significant pleural effusion, which was not drained, had an overall decrease in estimated pleural effusion volume on subsequent days. CONCLUSION: Pleural effusion was common in the ICU, but less than half of all patients with ultrasonographically significant pleural effusion underwent thoracentesis. Progression of pleural effusion without thoracentesis showed reduced volumes on subsequent days.

Lower versus higher oxygenation targets in hypoxaemic ICU patients after cardiac arrest.

AIM: To investigate the effects of lower versus higher oxygenation targets in adult intensive care unit (ICU) patients with hypoxaemic respiratory failure after cardiac arrest. METHODS: Subgroup analysis of the international Handling Oxygenation Targets in the ICU (HOT-ICU) trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygenation of 8 kPa or 12 kPa in the ICU for up to 90 days. Here, we report all outcomes up to one year in the subgroup of patients enrolled after cardiac arrest. RESULTS: The HOT-ICU trial included 335 patients after cardiac arrest: 149 in the lower-oxygenation group and 186 in the higher-oxygenation group. At 90 days, 96/147 patients (65.3%) in the lower-oxygenation group and 111/185 patients (60.0%) in the higher-oxygenation group had died (adjusted relative risk (RR) 1.09, 95% confidence interval (CI) 0.92-1.28, p = 0.32); similar results were found at one year (adjusted RR 1.05, 95% CI 0.90-1.21, p = 0.53). Serious adverse events (SAEs) in the ICU occurred in 23% of patients in the lower-oxygenation group and 38% in the higher-oxygenation group (adjusted RR 0.61, 95% CI 0.43-0.86, p = 0.005); the difference was mainly due to more new episodes of shock in the higher-oxygenation group. No statistically significant differences were observed in other secondary outcomes. CONCLUSION: A lower oxygenation target in adult ICU patients with hypoxaemic respiratory failure after cardiac arrest did not result in lower mortality, but fewer SAEs occurred in this group compared to the higher-oxygenation group. All analyses are exploratory only, large-scale trials are needed for confirmation. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov number NCT03174002 (registered May 30, 2017); EudraCT 2017-000632-34 (registered February 14, 2017).

Association between days alive without life support/out of hospital and health-related quality of life.

BACKGROUND: Trials in critically ill patients increasingly focus on days alive without life support (DAWOLS) or days alive out of hospital (DAOOH) and health-related quality of life (HRQoL). DAWOLS and DAOOH convey more information than mortality and are simpler and faster to collect than HRQoL. However, whether these outcomes are associated with HRQoL is uncertain. We thus aimed to assess the associations between DAWOLS and DAOOH and long-term HRQoL. METHODS: Secondary analysis of the COVID STEROID 2 trial including adults with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial including adult intensive care unit patients with acute hypoxaemic respiratory failure. Associations between DAWOLS and DAOOH at day 28 and 90 and long-term HRQoL (after 6 or 12 months) using the EuroQol 5-dimension 5-level survey (EQ VAS and EQ-5D-5L index values) were assessed using flexible models and evaluated using measures of fit and prediction adequacy in both datasets (comprising internal performance and external validation), non-parametric correlation coefficients and graphical presentations. RESULTS: We found no strong associations between DAWOLS or DAOOH and HRQoL in survivors at HRQoL-follow-up (615 and 1476 patients, respectively). There was substantial variability in outcomes, and predictions from the best fitted models were poor both internally and externally in the other trial dataset, which also showed inadequate calibration. Moderate associations were found when including non-survivors, although predictions remained uncertain and calibration inadequate. CONCLUSION: DAWOLS and DAOOH were poorly associated with HRQoL in adult survivors of severe or critical illness included in the COVID STEROID 2 and HOT-ICU trials.

Patient and public involvement in contemporary large intensive care trials: A meta-epidemiological study.

BACKGROUND: Patient and public involvement in randomised clinical trials has received increased focus, including in intensive care trials, but the frequency, method and extent is unknown. This meta-epidemiological study investigated patient and public involvement in contemporary, large ICU trials. METHODS: We systematically searched PubMed for large (≥225 randomised patients), contemporary trials (published between 1 January 2019 and 31 January 2022) assessing interventions in adult patients in ICU settings. Abstracts and full-text articles were assessed independently and in duplicate. Data were extracted using a pre-defined, pilot-tested data extraction form with details on trials, patient and public involvement including categories and numbers of individuals involved, methods of involvement, and trial stage(s) with involvement. Trials authors were contacted as necessary. RESULTS: We included 100 trials, with 18 using patient and public involvement; these were larger and conducted in more centres than trials without patient and public involvement. Among trials with patient and public involvement, patients (in 14/18 trials), clinicians (13 trials), and family members (12 trials) were primarily involved, mainly in the development of research design (15 trials) and development of research focus (13 trials) stages and mostly by discussion (12 trials) and solo interviews (10 trials). A median of 65 individuals (range 1-6894) were involved. CONCLUSIONS: We found patient and public involvement in a fifth of large, contemporary ICU trials. Primarily patients, families, and clinicians were included, particularly in the trial planning stages and mostly through interviews and discussions. Increased patient and public involvement in ICU trials is warranted.

Long-term effects of lower versus higher oxygenation levels in adult ICU patients-A systematic review.

BACKGROUND: Oxygen therapy is a common treatment in the intensive care unit (ICU) with both potentially desirable and undesirable long-term effects. This systematic review aimed to assess the long-term outcomes of lower versus higher oxygenation strategies in adult ICU survivors. METHODS: We included randomised clinical trials (RCTs) comparing lower versus higher oxygen supplementation or oxygenation strategies in adults admitted to the ICU. We searched major electronic databases and trial registers. We included all non-mortality long-term outcomes. Prespecified co-primary outcomes were the long-term cognitive function measures, the overall score of any valid health-related quality of life (HRQoL) evaluation, standardised 6-min walk test, and lung diffusion capacity. The protocol was published and prospectively registered in the PROSPERO database (CRD42021223630). RESULTS: The review included 17 RCTs comprising 6592 patients, and six trials with 825 randomised patients reported one or more outcomes of interest. We observed no difference in cognitive evaluation via Telephone Interview for Cognitive Status (one trial, 409 patients) (mean score: 30.6 ± 4.5 in the lower oxygenation group vs. 30.4 ± 4.3 in the higher oxygenation group). The trial was judged at overall high risk of bias and the certainty of evidence was very low. Any difference was neither observed in HRQoL measured via EuroQol 5 dimensions 5 level questionnaire and EQ Visual Analogue Score (one trial, 499 patients) (mean score: 70.1 ± 22 in the lower oxygenation group vs. 67.6 ± 22.4 in the higher oxygenation group). The trial was judged as having high risk of bias, the certainty of evidence was very low. No trial reported neither the standardised 6-min walk test nor lung diffusion test. CONCLUSION: The evidence is very uncertain about the effect of a lower versus a higher oxygenation strategy on both the cognitive function and HRQoL. A lower versus a higher oxygenation strategy may have a little to no effect on both outcomes but the certainty of evidence is very low. No evidence was found for the effects on the standardised 6-min walking test and diffusion capacity test.

Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia.

PURPOSE: We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia. METHODS: Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients. RESULTS: We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93-1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50-80) in the lower oxygenation group versus 67 (50-80) in the higher oxygenation group (p = 0.98). None of the five EQ-5D-5L dimensions differed between groups. CONCLUSION: Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa).

Health-related quality of life and days alive without life support or out of hospital: Protocol.

BACKGROUND: Mortality is often the primary outcome in randomised clinical trials (RCTs) conducted in critically ill patients. Due to increased awareness on survivors after critical illness and outcomes other than mortality, health-related quality of life (HRQoL) and days alive without life support (DAWOLS) or days alive and out of hospital (DAAOOH) are increasingly being used. DAWOLS and DAAOOH convey more information than mortality, are easier to collect than HRQoL, and are usually assessed at earlier time points, which may be preferable in some situations. However, the associations between DAWOLS-DAAOOH and HRQoL are uncertain. METHODS: We will assess associations between DAWOLS-DAAOOH at day 28 and 90 (independent variables/predictors) and HRQoL assessed using the EuroQol EQ-5D-5L questionnaire (EQ-VAS and EQ-5D-5L index values) at 6 or 12 months (dependent variables) in two RCTs: the COVID STEROID 2 RCT conducted in adult patients with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) RCT conducted in adult intensive care patients with acute hypoxaemic respiratory failure. We will describe associations using best-fitting fractional polynomial transformations separately in each dataset, with the resulting models presented and assessed in both datasets graphically and using measures of fit and prediction adequacy (i.e., internal performance and external validation). We will use multiple imputation if missingness exceeds 5%. DISCUSSION: The outlined study will provide important knowledge on the associations between DAWOLS-DAAOOH and HRQoL in adult critically ill patients, which may help researchers and clinical trialists prioritise and select outcomes in future RCTs conducted in this population.

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.

The long-term effects of lower versus higher oxygenation levels in adult ICU patients - protocol for a systematic review.

BACKGROUND: Many organs can remain impaired after discharge from the intensive care unit (ICU) leading to temporal or permanent dysfunctions. Long-term impairments may be affected by supplemental oxygen, a common treatment in ICU, having both potential beneficial and harmful long-lasting effects. This systematic review aims to assess the long-term outcomes of lower versus higher oxygen supplementation and/or oxygenation levels in adults admitted to ICU. METHODS: We will include trials differentiating between a lower and a higher oxygen supplementation or a lower and a higher oxygenation strategy in adults admitted to the ICU. We will search major electronic databases and trial registers for randomised clinical trials. Two authors will independently screen and select references for inclusion using Covidence and predefined data will be extracted. The methodological quality and risk of bias of included trials will be evaluated using the Cochrane Risk of Bias tool 2. Meta-analysis will be performed if two or more trials with comparable outcome measures will be included. Otherwise, a narrative description of the trials' results will be presented instead. To assess the certainty of evidence, we will create a 'Summary of findings' table containing all prespecified outcomes using the GRADE system. The protocol is submitted on the PROSPERO database (ID 223630). CONCLUSION: No systematic reviews on the impact of oxygen treatment in the ICU on long-term outcomes, other than mortality and quality of life, have been reported yet. This systematic review will provide an overview of the current evidence and will help future research in the field.

Handling oxygenation targets in ICU patients with COVID-19-Protocol and statistical analysis plan in the HOT-COVID trial.

BACKGROUND: Coronavirus disease (COVID-19) primarily affects the lungs and lower airways and may present as hypoxaemic respiratory failure requiring admission to an intensive care unit (ICU) for supportive treatment. Here, supplemental oxygen remains essential for COVID-19 patient management, but the optimal dosage is not defined. We hypothesize that targeting an arterial partial pressure of oxygen of 8 kPa throughout ICU admission is superior to targeting 12 kPa. METHODS: The Handling Oxygenation Targets in ICU patients with COVID-19 (HOT-COVID) trial, is an investigator-initiated, pragmatic, multicentre, randomized, parallel-group trial comparing a lower oxygenation target versus a higher oxygenation target in adult ICU patients with COVID-19. The primary outcome is days alive without life-support (use of mechanical ventilation, renal replacement therapy or vasoactive therapy) at day 90. Secondary outcomes are 90-day and 1-year mortality, serious adverse events in the ICU and days alive and out of hospital in the 90-day period, health-related quality-of-life at 1 year, and health economic analyses. One-year follow-up of cognitive and pulmonary function is planned in a subgroup of Danish patients. We will include 780 patients to detect or reject an absolute increase in days alive without life-support of 7 days with an α of 5% and a ß of 20%. An interim analysis is planned after 90-day follow-up of 390 patients. CONCLUSIONS: The HOT-COVID trial will provide patient-important data on the effect of two oxygenation targets in ICU patients with COVID-19 and hypoxia. This protocol paper describes the background, design and statistical analysis plan for the trial.

Patient and public involvement in contemporary large intensive care trials: Protocol for a meta-epidemiological study.

BACKGROUND: Patient and public involvement (PPI) in randomized clinical trials (RCTs) has increased in recent years but remains the exception rather than the rule. We aim to assess the frequency and extent of PPI in large, contemporary RCTs conducted in an intensive care setting. METHODS AND DESIGN: We will conduct a meta-epidemiological study of RCTs conducted in intensive care settings published since 2019 and assess their use of PPI. We will extract trial characteristics and verify the use of PPI with trial authors unless specifically stated in the published paper. The primary outcome will be the proportion of trials that use PPI. Secondary outcomes will explore which groups are consulted, at which stage of the trial process this occurs, and by what means these opinions are collected and implemented. DISCUSSION: This meta-epidemiological study will provide an important insight into the use of PPI in large, contemporary intensive care trials. We wish to reveal ways in which patient involvement could be incorporated more broadly and purposefully here and help to empower clinicians, researchers and patients to collaborate further on future research processes and goals.

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.).

Tolerability of ambulatory blood pressure monitoring (ABPM) in cognitively impaired elderly.

OBJECTIVE: Recent guidelines have widened clinical indications for out-of-office blood pressure measurement, including home blood pressure monitoring and ambulatory blood pressure monitoring (ABPM), suggesting the latter as recommended method in cognitively impaired patients. There is, however, a widespread belief that ABPM could be poorly tolerated in dementia, often leading to withdraw from its use in these patients. AIM: To assess the actual tolerability of ABPM in a group of cognitively impaired elderly, affected by dementia or mild cognitive impairment (MCI). METHODS: We evaluated 176 patients aged 65 + years, recruited in two different memory clinics, with a Mini Mental State Examination (MMSE) between 10 and 27. Behavioral and psychological symptoms were assessed with Neuropsychiatric Inventory (NPI). A patient was considered tolerant if able to keep the device on continuously for 24 h. The minimum number of correct measurements required was 70% of the predicted total number. RESULTS: 16% of patients wore the device for less than 24 h. Dividing the study population in tertiles of MMSE performance, 29% failed to tolerate the device in the lowest, 12% in the middle and 7% in the highest tertile (p < 0.01). Dividing the study population in tertiles of NPI performance, 30% of patients failed in the highest, 19% in the middle and 8% in the lowest tertile (p = 0.02); 31% of patients who tolerated the device did not achieve the minimum number of measurements required, with a mean number of 63% of predicted measurements. CONCLUSION: The ABPM proved a generally well-tolerated technique even in cognitively impaired elderly. Only a minority of subjects with poorer cognitive performances and greater behavioral symptoms did not tolerate the monitoring. Among most patients who failed to achieve the minimum number of measurements needed, the number of valid measurements was very close to the minimum required.