Abstract 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 (PaO 2 ) of 8 kPa (lower oxygenation group) or a PaO 2 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 PaO 2 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.
Abstract 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 β 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.
An animal model is presented that provides constant and controllable conditions for approaching gradually, and within reasonable time, different stages of iron overload and, probably, an iron-induced mitochondrial disorder. Thirty-five rats were infused with ferric citrate, sodium citrate and saline at constant rates for 6-24 h. In the 200-3200 micrograms Fe h-1 loading range, the iron-incorporation capacity of the liver was not saturable and the fractional iron uptake by the liver remained at approximately 30% even at a loading rate of 3200 micrograms Fe h-1. Up to a loading rate of 200 micrograms Fe h-1, iron storage was not associated with toxic effects. Beyond this loading rate, however, the liver was no longer able to prevent a massive plasma iron increase on one side and hyperlactataemia on the other. These signs most probably represent hepatocellular decompensation with respect to a critical iron-storage rate. The product of plasma iron x exposition time was significantly correlated with increased plasma lactate levels (r = 0.89, P less than 0.005), whereas increased plasma iron levels per se were not. Hyperlactataemia was associated with hyperkalaemia and progressive cardiac conduction defects leading to cardiac arrest at lactate concentration of 9.1 +/- 4.3 mmol l-1. The hypothesis is discussed that toxicity in acute iron overload may entirely be due to hepatocellular (mitochondrial) damage, and not to multiple organ iron overload.
Abstract. Rydberg E, Erhardt L, Brand B, Willenheimer R (Malmö University Hospital, University of Lund, Malmö, Sweden). Left atrioventricular plane displacement determined by echocardiography: a clinically useful, independent predictor of mortality in patients with stable coronary artery disease. J Intern Med 2003; 254: 479–485. Background. Echocardiographically determined left atrioventricular plane displacement (AVPD) is strongly related to prognosis in patients with chronic heart failure and in postmyocardial infarction patients. We aimed at exploring whether AVPD, unlike ejection fraction, is related to mortality in patients with stable coronary artery disease (CAD). Methods and results. Atrioventricular plane displacement was assessed by two dimensionally guided M‐mode echocardiography in the four and two chamber views, in 333 consecutive patients with stable CAD and an abnormal coronary angiogram. Patients were followed up for an average of 41 months. AVPD was lower in patients who died ( n = 30, 9.0 %) compared with survivors (9.0 ± 2.2 vs. 11.5 ± 2.1 mm, P < 0.0001). Amongst patients with prior myocardial infarction ( n = 184) AVPD was 8.7 ± 2.3 mm in those who died ( n = 17) and 11.2 ± 2.3 mm in the survivors ( P < 0.0001). In patients without prior myocardial infarction ( n = 149), AVPD was 9.4 ± 2.1 ( n = 13) and 11.8 ± 1.8 mm, respectively ( P < 0.0001). Age, AVPD and four other echocardiographical variables correlated significantly with prognosis in univariate logistic regression analysis. In multiple logistic regression analysis only AVPD ( P < 0.0001) correlated independently with mortality. Conclusion. Echocardiographically determined AVPDis a clinically useful, independent prognostic tool in patients with stable CAD. The presence of a documented previous myocardial infarction does not influence this observation.
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 Pa o 2 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 Pa o 2 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 Pa o 2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pa o 2 of 90 mm Hg. Trial Registration ClinicalTrials.gov Identifier: NCT04425031
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.
Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear.In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization.A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups.Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621 .).
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