Quality of life in congenital diaphragmatic hernia survivors treated at a non-ECMO centre from 1998 to 2015: a cross-sectional study.

BACKGROUND: Survival of infants with congenital diaphragmatic hernia (CDH) has increased and more insight is warranted on the long-term issues of this condition. METHODS: We conducted a cross-sectional study on consecutively born infants with CDH treated at a non-extracorporeal membrane oxygenation centre (ECMO) from 1998 to 2015. Quality of life was evaluated using the Pediatric Quality of Life Inventory Generic Core Scale 4.0 (PedsQL(4.0)) Questionnaire and an interview was conducted to assess for CDH-related morbidity. RESULTS: 71 eligible CDH survivors were identified and 51 consented to participate: aged 5-21 years, 28 (54.9%) male, 42 (82.4%) with left-sided hernias, 10 (19.6%) needed patch repair, median length of stay in hospital was 27.96 days (IQR 18.54-61.56). Forty-nine completed the questionnaire with a median PedsQL total score for participants of 82.6 vs 83.7 of the total proxy parent score (p=0.04). Total score was significantly lower for participants aged 5-12 years compared with participants aged 13-21 years (p=0.04); however, when reported by domains, only the physical score remained significantly lower (p=0.048). Two (4.1%) participants' and 8 (16.7%) proxy parents' scores were below 70 and considered at risk of impaired quality of life. We identified the presence of CDH-related morbidity in our population, and confirmed an association between respiratory morbidity and lower PedsQL scores (p=0.04). CONCLUSION: We report an overall good quality of life in our population with CDH. However, a lower physical score was noted when compared with a national Danish cohort and individuals at risk of reduced quality of life were recognised. Structured follow-up programmes to identify and ensure early management of CDH-related issues may prevent a negative impact on quality of life.

Furosemide versus placebo for fluid overload in intensive care patients-The randomised GODIF trial second version: Statistical analysis plan.

BACKGROUND: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. METHODS: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. CONCLUSION: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. TRIAL REGISTRATIONS: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.

Adjusting perioperative methadone dose for elderly and fragile hip fracture patients (MetaHip-trial) - A statistical analysis plan for an adaptive dose-finding trial.

Background: The elderly population is expanding globally. This gives numerous challenges especially regarding hip fracture patients. In the US alone over 300.000 hip fracture patients are treated each year, and a large amount of those develop opoid addiction. Hip fractures require surgical intervention within 24 h and is associated with significant pain even at rest. Postoperative analgesic treatment need to be optimized to ensure adequate pain relief and to prevent subsequent opioid addiction. Previous studies have shown that methadone effectively decreases post-operative opioid consumption but the studies focused on younger patients undergoing elective surgery. This study focus on the use of methadone on the elderly, fragile patients undergoing acute surgery, by first determining the maximal tolerable dose.The hypothesis is the maximal tolerable doses of these hip-fracture patients lies between 0.10 mg/kg and 0.20 mg/kg. This trial aims to estimate the maximum tolerable dose of methadone when administered to elderly patients undergoing surgery for a hip fracture. Method: This project is an adaptive dose-finding trial. The continuous reassessment method will estimate the maximum tolerable dose of methadone. The primary outcome will be respiratory depression. The statistical analysis plan will be published a priori to the closure of patient recruitment and statistical analysis of database results. Conclusion: The results of this study will give valuable information about the maximally tolerated dose of methadone for postoperative pain relief for elderly patients with hip fractures and potential adverse events.This trial is registered on clinicaltrials.gov with trial registration: NCT05581901. Registered 17 October 2022, https://www.clinicaltrials.gov/ct2/show/NCT05581901?term=methadone&cond = hip&draw = 2&rank = 1.

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.

Abnormal serum levels of magnesium, phosphate, and zinc in ICU patients-Characteristics, management, and outcomes: The WhyTrace cohort study.

BACKGROUND: Abnormal serum levels of magnesium, phosphate, and zinc appear common in intensive care unit (ICU) patients, but the epidemiology, management, and associations with outcomes are less well described. We described these factors and estimated associations with outcomes in a large dataset of Danish ICU patients. METHODS: We included adults who were acutely admitted to 10 general ICUs in Denmark between October 2011 and January 2018. From the dataset, we obtained characteristics of patients who had serum levels measured of magnesium, phosphate, or zinc, including data on supplementation. We used joint models with death as a competing outcome to estimate the associations between abnormal serum levels and time to successful extubation and, for magnesium, also incident tachyarrhythmia. RESULTS: We included 16,517 of 36,514 patients in the dataset. The cumulative probability of hypomagnesemia within 28 days was 64% (95% confidence interval [CI] 62-66); of hypophosphatemia 74% (95% CI 72-75); and of hypozincemia 98% (95% CI 98-98). Supplementation of magnesium was used in 3554 out of 13,506 (26%) patients, phosphate in 2115 out of 14,148 (15%) patients, and zinc in 4465 out of 9869 (45%) patients. During ICU stay, 38% experienced hypermagnesemia, 58% hyperphosphatemia, and 1% hyperzincemia. Low serum levels of magnesium, phosphate, and zinc were associated with shorter time to successful extubation, and high serum magnesium and phosphate and low serum zinc with the competing risk of increased mortality, but too few serum measurements made the results inconclusive. CONCLUSION: In this multicenter cohort study of acutely admitted ICU patients, most experienced low serum levels of magnesium, phosphate, or zinc during ICU stay, many received supplementation, and experiencing both low and high serum levels during ICU stay was not uncommon. Associations between serum levels and clinical outcomes appeared inconclusive because the data proved unfit for these analyses.

Effect of 24 mg dexamethasone preoperatively on surgical stress, pain and recovery in robotic-assisted laparoscopic hysterectomy.

Background: Robotic-assisted hysterectomy is an alternative to laparoscopic surgery as part of a minimal invasive regimen. Several treatment strategies are followed to improve the overall outcome and minimize surgical stress. Glucocorticoids provide significant analgesic and antiemetic effects but their role in reducing inflammatory stress in a fast-track, multi-modal setting in patients undergoing minimally invasive surgery remains to be investigated in details. Methods: This study will evaluate in a randomized trial the effect of a single dose of 24 mg dexamethasone on 100 women undergoing robotic-assisted hysterectomy with regard to surgical stress, measured by c-reactive protein as primary outcome and, further, other stress markers like white blood cell subtypes. The postoperative recovery will be registered in validated charts and questionnaires for pain and analgesic use, quality of recovery, incontinence, sexual and work life. Furthermore, in a sub-analysis, transcriptional profiling will be performed to explore the mechanism of systemic innate and adaptive immune system perturbation induced by surgical stress. Conclusion: The study will provide solid evidence on markers of immunomodulation biomarkers and in addition the subjective effects and underlying mechanisms of perioperative glucocorticoid in women undergoing robotic hysterectomy. These include important aspects of life quality like pain, fatigue, freedom of medications, resuming work and sexual activities.

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.

Early Pre- and Postoperative Enteral Nutrition and Growth in Infants with Symptomatic Congenital Diaphragmatic Hernia.

OBJECTIVES: Nutritional support during the neonatal and postoperative period in congenital diaphragmatic hernia (CDH) is challenging and controversial. We aimed to report on early enteral nutritional support in symptomatic CDH patients during the pre- and postoperative period, including feasibility, associated factors with established full enteral nutrition, and weight at birth, discharge, and 18 months. METHODS: We retrospectively collected data on nutrition: type and volume of enteral nutrition and parental support. Enteral feeding was introduced preoperatively from day 1 after birth, increased step-wised (breastmilk preferred), and resumed after CDH repair on the first postoperative day. Baseline data were available from our CDH database. RESULTS: From 2011 to 2020, we identified 45 CDH infants. Twenty-two were girls (51.1%), 35 left sided (77.8%), and 40 underwent CDH repair (88.9%). Median (interquartile range) length of stay in the pediatric intensive care unit was 14.6 days (6.0-26.5), and 1-year mortality was 17.8%.Postoperatively, 120 and 160 mL/kg/d of enteral nutrition was achieved after a median of 6.5 (3.6-12.6) and 10.6 (7.6-21.7) days, respectively. In total, 31 (68.9%) needed supplemental parenteral nutrition in a median period of 8 days (5-18), and of those 11 had parenteral nutrition initiated before CDH repair. No complications to enteral feeding were reported. CONCLUSION: Early enteral nutrition in CDH infants is feasible and may have the potential to reduce the need for parental nutrition and reduce time to full enteral nutrition in the postoperative period.

Sleep quality and quantity determined by polysomnography in mechanically ventilated critically ill patients randomized to dexmedetomidine or placebo.

BACKGROUND: Abnormal sleep is commonly observed in the ICU and is associated with delirium and increased mortality. If sedation is necessary, it is often performed with gamma-aminobutyric acid agonists such as propofol or midazolam leading to an absence of restorative sleep. We aim to evaluate the effect of dexmedetomidine on sleep quality and quantity. METHODS: Thirty consecutive patients were included. The study was conducted as a double-blinded, randomized, placebo-controlled trial with two parallel groups: 20 patients were treated with dexmedetomidine, and 10 with placebo. Two 16 h of polysomnography recordings were done for each patient on two consecutive nights. Patients were randomized to dexmedetomidine or placebo after the first recording, thus providing a control recording for all patients. Dexmedetomidine was administered during the second recording (6 p.m.-6 a.m.). OBJECTIVE: To compare the effect of dexmedetomidine versus. placebo on sleep - quality and quantity. PRIMARY OUTCOME: Sleep quality, total sleep time (TST), Sleep efficiency (SE), and Rapid Eye Movement (REM) sleep determined by Polysomnography (PSG). SECONDARY OUTCOME: Delirium and daytime function determined by Confusion Assessment Method of the Intensive Care Unit and physical activity. Alertness and wakefulness were determined by RASS (Richmond Agitation and Sedation Scale). RESULTS: SE were increased in the dexmedetomidine group by; 37.6% (29.7;45.6 95% CI) versus 3.7% (-11.4;18.8 95% CI) (p < .001) and TST were prolonged by 271 min. (210;324 95% CI) versus 27 min. (-82;135 95% CI), (p < .001). No significant difference in REM sleep, delirium physical activity, or RASS score was found except for RASS night two. CONCLUSION: Total sleep time and sleep efficiency were significantly increased, without elimination of REM sleep, in mechanically ventilated ICU patients randomized to dexmedetomidine, when compared to a control PSG recording performed during non-sedation/standard care.

Effect of Interpectoral-Pectoserratus Plane (PECS II) Block on Recovery Room Discharge Time in Breast Cancer Surgery.

Background and Objectives: The increase in the incidence and diagnosis rate of breast cancer demands the optimization of resources. The aim of this study was to assess whether the supplementation of the interpectoral-pectoserratus plane block (PECS II) reduces surgery and post-anesthesia care unit (PACU) time in patients undergoing breast cancer surgery. Materials and methods: This was a retrospective data-analysis study. In 2016, PECS II block was introduced as a supplement to general anesthesia for all mastectomies with or without axillary resections in South Jutland regional hospital, Denmark. The perioperative data of patients operated 3 years before and 3 years after 2016 was retrieved through the Danish anesthesia database and patient journals and systematically analyzed. Female patients aged over 18 years, with no use of muscle relaxant, intubation, and inhalation agents, were included. The eligible data was organized into two groups, i.e., Block and Control, where the Block group received PECS II Block, while the Control group received only general anesthesia. Parameters such as surgery time, anesthesia time, PACU time, opioid consumption, and the incidence of postoperative nausea and vomiting (PONV) in PACU were retrieved and statistically analyzed. Results: A total of 172 patients out of 358 patients met eligibility criteria. After applying exclusion criteria, 65 patients were filtered out. A total of 107 patients, 51 from the Block and 56 from the Control group, were eligible for the final analysis. The patients were comparable in demographic parameters. The median surgery time was significantly less in the Block group (78 min (60-99)) in comparison to the Control group (98.5 min (77.5-139.5) p < 0.0045). Consequently, the median anesthesia time was also shorter in the Block group (140 min (115-166)) vs. the Control group (160 min (131.5 to 188), p < 0.0026). Patients from the Block group had significantly lower intraoperative fentanyl consumption (60 µg (30-100)) as compared with the Control group (132.5 µg (80-232.5), p < 0.0001). The total opioid consumption during the entire procedure (converted to morphine) was significantly lower in the Block group (16.37 mg (8-23.6)) as compared with the Control group (31.17 mg (16-46.5), p < 0.0001). No statistically significant difference was found in the PACU time, incidences of PONV, and postoperative pain. Conclusions: The interpectoral-pectoserratus plane (PECS II) block supplementation reduces surgery time, anesthesia time, and opioid consumption but not PACU time during breast cancer surgery.

Discrete-time survival analysis in the critically ill: a deep learning approach using heterogeneous data.

Prediction of survival for patients in intensive care units (ICUs) has been subject to intense research. However, no models exist that embrace the multiverse of data in ICUs. It is an open question whether deep learning methods using automated data integration with minimal pre-processing of mixed data domains such as free text, medical history and high-frequency data can provide discrete-time survival estimates for individual ICU patients. We trained a deep learning model on data from patients admitted to ten ICUs in the Capital Region of Denmark and the Region of Southern Denmark between 2011 and 2018. Inspired by natural language processing we mapped the electronic patient record data to an embedded representation and fed the data to a recurrent neural network with a multi-label output layer representing the chance of survival at different follow-up times. We evaluated the performance using the time-dependent concordance index. In addition, we quantified and visualized the drivers of survival predictions using the SHAP methodology. We included 37,355 admissions of 29,417 patients in our study. Our deep learning models outperformed traditional Cox proportional-hazard models with concordance index in the ranges 0.72-0.73, 0.71-0.72, 0.71, and 0.69-0.70, for models applied at baseline 0, 24, 48, and 72 h, respectively. Deep learning models based on a combination of entity embeddings and survival modelling is a feasible approach to obtain individualized survival estimates in data-rich settings such as the ICU. The interpretable nature of the models enables us to understand the impact of the different data domains.

Goal directed fluid removal with furosemide versus placebo in intensive care patients with fluid overload: A trial protocol for a randomised, blinded trial (GODIF trial).

BACKGROUND: Fluid overload is a risk factor for mortality in intensive care unit (ICU) patients. Administration of loop diuretics is the predominant treatment of fluid overload, but evidence for its benefit is very uncertain when assessed in a systematic review of randomised clinical trials. The GODIF trial will assess the benefits and harms of goal directed fluid removal with furosemide versus placebo in ICU patients with fluid overload. METHODS: An investigator-initiated, international, randomised, stratified, blinded, parallel-group trial allocating 1000 adult ICU patients with fluid overload to infusion of furosemide versus placebo. The goal is to achieve a neutral fluid balance. The primary outcome is days alive and out of hospital 90 days after randomisation. Secondary outcomes are all-cause mortality at day 90 and 1-year after randomisation; days alive at day 90 without life support; number of participants with one or more serious adverse events or reactions; health-related quality of life and cognitive function at 1-year follow-up. A sample size of 1000 participants is required to detect an improvement of 8% in days alive and out of hospital 90 days after randomisation with a power of 90% and a risk of type 1 error of 5%. The conclusion of the trial will be based on the point estimate and 95% confidence interval; dichotomisation will not be used. CLINICALTRIALS: gov identifier: NCT04180397. PERSPECTIVE: The GODIF trial will provide important evidence of possible benefits and harms of fluid removal with furosemide in adult ICU patients with fluid overload.

Patient-Important Outcomes Other Than Mortality in Contemporary ICU Trials: A Scoping Review.

OBJECTIVES: Randomized clinical trials (RCTs) conducted in adult ICU patients increasingly include patient-important outcomes other than mortality. This comes with challenges regarding outcome choices/definitions, handling of deceased patients and missing data in analyses, and choices of effect measures and statistical methods due to complex distributions. This scoping review aimed to characterize how these challenges are handled in relevant contemporary RCTs. DATA SOURCES: We systematically searched 10 selected journals for RCTs conducted primarily in adult ICU patients published between 1 January 2018 and 5 May 2022 reporting at least one patient-important outcome other than mortality, including "days alive without"…-type outcomes, functional/cognitive/neurologic outcomes, health-related quality of life (HRQoL) outcomes, and ordinal/other outcomes. STUDY SELECTION: Abstracts and full-texts were assessed independently and in duplicate by two reviewers. DATA EXTRACTION: Data were extracted independently and in duplicate by two reviewers using predefined and pilot-tested extraction forms and subsequently categorized to facilitate analysis. DATA SYNTHESIS: We included 687 outcomes from 167 RCTs, with 32% of RCTs using a patient-important outcome other than mortality as a (co-)primary outcome, most frequently "days alive without"…-type outcomes. Many different functional/cognitive/neurologic (103) and HRQoL (29) outcomes were reported. Handling of deceased patients varied, with analyses frequently restricted to survivors only for functional/cognitive/neurologic (62%) and HRQoL (89%) outcomes. Follow-up was generally longer and missing data proportions higher for functional/cognitive/neurologic and HRQoL outcomes. Most outcomes were analyzed using nonparametric tests (31%), linear regression/ t tests (27%), chi-square-like tests (12%), and proportional odds logistic regression (9%), often without presentation of actual treatment effects estimates (38%). CONCLUSIONS: In this sample of RCTs, substantial variation in practice and suboptimal methodological choices were observed. This calls for increased focus on standardizing outcome choices and definitions, adequate handling of missing data and deceased patients in analyses, and use of statistical methods quantifying effect sizes.

Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia.

PURPOSE: We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. RESULTS: We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). CONCLUSION: Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.

Senicapoc treatment in COVID-19 patients with severe respiratory insufficiency-A randomized, open-label, phase II trial.

BACKGROUND: The aim of the current study was to determine if treatment with senicapoc, improves the PaO2 /FiO2 ratio in patients with COVID-19 and severe respiratory insufficiency. METHODS: Investigator-initiated, randomized, open-label, phase II trial in four intensive care units (ICU) in Denmark. We included patients aged ≥18 years and admitted to an ICU with severe respiratory insufficiency due to COVID-19. The intervention consisted of 50 mg enteral senicapoc administered as soon as possible after randomization and again after 24 h. Patients in the control group received standard care only. The primary outcome was the PaO2 /FiO2 ratio at 72 h. RESULTS: Twenty patients were randomized to senicapoc and 26 patients to standard care. Important differences existed in patient characteristics at baseline, including more patients being on non-invasive/invasive ventilation in the control group (54% vs. 35%). The median senicapoc concentration at 72 h was 62.1 ng/ml (IQR 46.7-71.2). The primary outcome, PaO2 /FiO2 ratio at 72 h, was significantly lower in the senicapoc group (mean 19.5 kPa, SD 6.6) than in the control group (mean 24.4 kPa, SD 9.2) (mean difference -5.1 kPa [95% CI -10.2, -0.04] p = .05). The 28-day mortality in the senicapoc group was 2/20 (10%) compared with 6/26 (23%) in the control group (OR 0.36 95% CI 0.06-2.07, p = .26). CONCLUSIONS: Treatment with senicapoc resulted in a significantly lower PaO2 /FiO2 ratio at 72 h with no differences for other outcomes.

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.

Development of a core outcome set for general intensive care unit patients-A protocol.

INTRODUCTION: Different outcomes are reported in randomised clinical trials (RCTs) in intensive care unit (ICU) patients, and no core outcome set (COS) is available for ICU patients in general. Accordingly, we aim to develop a COS for ICU patients in general. METHODS: The COS will be developed in accordance with the Core Outcome Measures in Effectiveness Trials (COMET) Handbook, using a modified Delphi consensus process and semi-structured interviews involving adults who have survived acute admission to an ICU, family members, clinicians, researchers and other stakeholders. The modified Delphi process will include two steps. Step 1: conduction of a modified Delphi survey, developed and informed by combining the outputs of a literature search of outcomes in previous COSs and semi-structured interviews with key stakeholders. We plan at least two survey rounds to obtain consensus and refine the COS. Step 2: a consensus process regarding instruments or definitions to be recommended for the measurements of the outcomes selected in Step 1. A 'patient and public involvement panel' consisting of a smaller group of patients, family members, clinicians and researchers will be included in the development, analysis and interpretation of the COS. DISCUSSION: The outlined multiple method studies will establish a COS for ICU patients in general, which may be used to increase the standardisation and comparability of results of RCTs conducted in patients in the ICU setting.

Failure of non-sedation strategy in critically ill, mechanically ventilated patients - a retrospective, post-hoc analysis of the NONSEDA trial.

PURPOSE: There is a growing awareness on minimizing sedation in ICUs. In the NONSEDA trial 700 critically ill patients were randomized to light sedation or non-sedation during mechanical ventilation. Approximately 40% of patients randomized to non-sedation needed sedation. The aim of this study is to obtain knowledge on patients, who experienced failure of non-sedation. MATERIALS AND METHODS: This study is a retrospective post-hoc analysis of the NONSEDA trial. Patients, who were randomized to non-sedation are sub-divided into those who did not require sedation during mechanical ventilation ("non-sedation success"), and those who needed continuous sedation at least once ("non-sedation failure"). RESULTS: 348 patients were randomized to non-sedation, 199 experienced non-sedation success, whereas 149 experienced non-sedation failure. Patients in the two groups were comparable with regards to age, BMI, disease severity scores and admission diagnoses. Patients with non-sedation failure were more often male. Propofol was mainly used as rescue sedation. Patients with non-sedation failure had less days alive without sedation, coma, delirium, organ support, mechanical ventilation, ICU- and hospital admission. Mortality and long-term outcomes did not differ between groups. CONCLUSION: Patients with non-sedation success had better in-hospital outcomes, but mortality and long-term outcomes were not affected by success or failure of non-sedation.

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial.

PURPOSE: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. METHODS: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. RESULTS: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. CONCLUSION: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial.

BACKGROUND: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. METHODS: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. RESULTS: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: -1.1 days, 95% CI -9.5 to 7.3, P = .79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. CONCLUSIONS: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.