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).

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.

Higher versus lower oxygenation targets in COVID-19 patients with severe hypoxaemia (HOT-COVID) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Respiratory failure is the main cause of mortality and morbidity among ICU patients with coronavirus disease 2019 (COVID-19). In these patients, supplemental oxygen therapy is essential, but there is limited evidence the optimal target. To address this, the ongoing handling oxygenation targets in COVID-19 (HOT-COVID) trial was initiated to investigate the effect of a lower oxygenation target (partial pressure of arterial oxygen (PaO2 ) of 8 kPa) versus a higher oxygenation target (PaO2 of 12 kPa) in the ICU on clinical outcome in patients with COVID-19 and hypoxaemia. METHODS: The HOT-COVID is planned to enrol 780 patients. This paper presents the protocol and statistical analysis plan for the conduct of a secondary Bayesian analysis of the primary outcome of HOT-COVID being days alive without life-support at 90 days and the secondary outcome 90-day all-cause mortality. Furthermore, both outcomes will be investigated for the presence heterogeneity of treatment effects based on four baseline parameters being sequential organ failure assessment score, PaO2 /fraction of inspired oxygen ratio, highest dose of norepinephrine during the 24 h before randomisation, and plasma concentration of lactate at randomisation. CONCLUSION: The results of this pre-planned secondary Bayesian analysis will complement the primary frequentist analysis of the HOT-COVID trial and may facilitate a more nuanced interpretation of the trial results.

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.

Hyperoxia affects the lung tissue: A porcine histopathological and metabolite study using five hours of apneic oxygenation.

BACKGROUND: Oxygen is a liberally dosed medicine; however, too much oxygen can be harmful. In certain situations, treatment with high oxygen concentration is necessary, e.g. after cardiopulmonary resuscitation. The amount of oxygen and duration of hyperoxia causing pulmonary damage is not fully elucidated. The aim of this study was to investigate pathophysiological and metabolite changes in lung tissue during hyperoxia while the lungs were kept open under constant low pressure. METHODS: Seven pigs were exposed to 100% oxygen for five hours, using an apneic oxygenation technique with one long uninterrupted inspiration, while carbon dioxide was removed with an interventional lung assist. Arterial blood samples were collected every 30 minutes. Lung biopsies were obtained before and after hyperoxia. Microscopy and high-resolution magic angle spinning nuclear magnetic resonance spectroscopy were used to detect possible pathological and metabolite changes, respectively. Unsupervised multivariate analysis of variance and paired sample tests were performed. A two-tailed p-value ≤ 0.05 was considered significant. RESULTS: No significant changes in arterial pH, and partial pressure of carbon dioxide, and no clear histopathological changes were observed after hyperoxia. While blood glucose and lactate levels changed to a minor degree, their levels dropped significantly in the lung after hyperoxia (p ≤ 0.04). Reduced levels of antioxidants (p ≤ 0.05), tricarboxylic acid cycle and energy (p ≤ 0.04) metabolites and increased levels of several amino acids (p ≤ 0.05) were also detected. CONCLUSION: Despite no histological changes, tissue metabolites were altered, indicating that exposure to hyperoxia affects lung tissue matrix on a molecular basis.

Can a central blood volume deficit be detected by systolic pressure variation during spontaneous breathing?

BACKGROUND: Whether during spontaneous breathing arterial pressure variations (APV) can detect a volume deficit is not established. We hypothesized that amplification of intra-thoracic pressure oscillations by breathing through resistors would enhance APV to allow identification of a reduced cardiac output (CO). This study tested that hypothesis in healthy volunteers exposed to central hypovolemia by head-up tilt. METHODS: Thirteen healthy volunteers were exposed to central hypovolemia by 45° head-up tilt while breathing through a facemask with 7.5 cmH2O inspiratory and/or expiratory resistors. A brachial arterial catheter was used to measure blood pressure and thus systolic pressure variation (SPV), pulse pressure variation and stroke volume variation . Pulse contour analysis determined stroke volume (SV) and CO and we evaluated whether APV could detect a 10 % decrease in CO. RESULTS: During head-up tilt SV decreased form 91 (±46) to 55 (±24) mL (mean ± SD) and CO from 5.8 (±2.9) to 4.0 (±1.8) L/min (p < 0.05), while heart rate increased (65 (±11) to 75 (±13) bpm; P < 0.05). Systolic pressure decreased from 127 (±14) to 121 (±13) mmHg during head-up tilt, while SPV tended to increase (from 21 (±15)% to 30 (±13)%). Yet during head-up tilt, a SPV ≥ 37 % predicted a decrease in CO ≥ 10 % with a sensitivity and specificity of 78 % and 100 %, respectively. CONCLUSION: In spontaneously breathing healthy volunteers combined inspiratory and expiratory resistors enhance SPV during head-up tilted induced central hypovolemia and allow identifying a 10 % reduction in CO. Applying inspiratory and expiratory resistors might detect a fluid deficit in spontaneously breathing patients. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02549482 Registered September 10(th) 2015.