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.

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.).

Effect of Intravenous Interferon ß-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) ß-1a may prevent the underlying event of vascular leakage. Objective: To determine the efficacy and adverse events of IFN-ß-1a in patients with moderate to severe ARDS. Design, Setting, and Participants: Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018. Interventions: Patients were randomized to receive an intravenous injection of 10 µg of IFN-ß-1a (144 patients) or placebo (152 patients) once daily for 6 days. Main Outcomes and Measures: The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error. Results: Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-ß-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-ß-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-ß-1a group and 33 [21.7%] in the placebo group). Conclusions and Relevance: Among adults with moderate or severe ARDS, intravenous IFN-ß-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-ß-1a in the management of ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02622724.

Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU)-Protocol for a randomised clinical trial comparing a lower vs a higher oxygenation target in adults with acute hypoxaemic respiratory failure.

BACKGROUND: Acutely ill adults with hypoxaemic respiratory failure are at risk of life-threatening hypoxia, and thus oxygen is often administered liberally. Excessive oxygen use may, however, increase the number of serious adverse events, including death. Establishing the optimal oxygenation level is important as existing evidence is of low quality. We hypothesise that targeting an arterial partial pressure of oxygen (PaO2 ) of 8 kPa is superior to targeting a PaO2 of 12 kPa in adult intensive care unit (ICU) patients with acute hypoxaemic respiratory failure. METHODS: The Handling Oxygenation Targets in the ICU (HOT-ICU) trial is an outcome assessment blinded, multicentre, randomised, parallel-group trial targeting PaO2 in acutely ill adults with hypoxaemic respiratory failure within 12 hours after ICU admission. Patients are randomised 1:1 to one of the two PaO2 targets throughout ICU stay until a maximum of 90 days. The primary outcome is 90-day mortality. Secondary outcomes are serious adverse events in the ICU, days alive without organ support and days alive out of hospital in the 90-day period; mortality, health-related quality-of-life at 1-year follow-up as well as 1-year cognitive and pulmonary function in a subgroup; and an overall health economic analysis. To detect or reject a 20% relative risk reduction, we aim to include 2928 patients. An interim analysis is planned after 90-day follow-up of 1464 patients. CONCLUSION: The HOT-ICU trial will test the hypothesis that a lower oxygenation target reduces 90-day mortality compared with a higher oxygenation target in adult ICU patients with acute hypoxaemic respiratory failure.

Targeting two different levels of both arterial carbon dioxide and arterial oxygen after cardiac arrest and resuscitation: a randomised pilot trial.

PURPOSE: We assessed the effects of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2) and normoxia or moderate hyperoxia after out-of-hospital cardiac arrest (OHCA) on markers of cerebral and cardiac injury. METHODS: Using a 23 factorial design, we randomly assigned 123 patients resuscitated from OHCA to low-normal (4.5-4.7 kPa) or high-normal (5.8-6.0 kPa) PaCO2 and to normoxia (arterial oxygen tension [PaO2] 10-15 kPa) or moderate hyperoxia (PaO2 20-25 kPa) and to low-normal or high-normal mean arterial pressure during the first 36 h in the intensive care unit. Here we report the results of the low-normal vs. high-normal PaCO2 and normoxia vs. moderate hyperoxia comparisons. The primary endpoint was the serum concentration of neuron-specific enolase (NSE) 48 h after cardiac arrest. Secondary endpoints included S100B protein and cardiac troponin concentrations, continuous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) results and neurologic outcome at 6 months. RESULTS: In total 120 patients were included in the analyses. There was a clear separation in PaCO2 (p < 0.001) and PaO2 (p < 0.001) between the groups. The median (interquartile range) NSE concentration at 48 h was 18.8 µg/l (13.9-28.3 µg/l) in the low-normal PaCO2 group and 22.5 µg/l (14.2-34.9 µg/l) in the high-normal PaCO2 group, p = 0.400; and 22.3 µg/l (14.8-27.8 µg/l) in the normoxia group and 20.6 µg/l (14.2-34.9 µg/l) in the moderate hyperoxia group, p = 0.594). High-normal PaCO2 and moderate hyperoxia increased NIRS values. There were no differences in other secondary outcomes. CONCLUSIONS: Both high-normal PaCO2 and moderate hyperoxia increased NIRS values, but the NSE concentration was unaffected. REGISTRATION: ClinicalTrials.gov, NCT02698917. Registered on January 26, 2016.

The predictive value of NT-proBNP and hs-TnT for risk of death in cardiac surgical patients.

BACKGROUND: European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) is used for risk stratification before cardiac surgery, but whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) may add prognostic information to EuroSCORE II is not known. METHODS: Preoperative (n=640) and postoperative (n=629) blood samples were available from cardiac surgical patients with 961-day follow-up (FINNAKI Heart study; cohort #1). The accuracy of a parsimonious risk model with NT-proBNP measurements was also tested in 90 patients with respiratory failure after cardiac surgery (FINNALI study; cohort #2). RESULTS: Sixty-one patients (9.5%) died during follow-up in cohort #1. Preoperative NT-proBNP and hs-TnT concentrations correlated (rho=0.58; p<0.001) and were higher in non-survivors compared to survivors: median 2027 (Q1-3 478-5387) vs. 373 (134-1354) ng/L [NT-proBNP] and 39 (16-191) vs. 13 (8-32) ng/L [hs-TnT]; p<0.001 for both. Preoperative NT-proBNP concentrations were associated with time to death after adjustment for EuroSCORE II (HR [lnNT-proBNP] 1.33 [95% CI 1.08-1.64]), p=0.008 and reclassified patients on top of EuroSCORE II (net reclassification index 0.39 [95% CI 0.14-0.64], p=0.003). Pre- and postoperative NT-proBNP concentrations were closely correlated (rho=0.80, p<0.001) and postoperative NT-proBNP concentrations were also associated with long-term mortality after adjustment for EuroSCORE II. A parsimonious risk model that included age, creatinine clearance, chronic pulmonary disease, and NT-proBNP measurements provided comparable prognostic accuracy as EuroSCORE II in cohort #1 and #2 for risk of long-term mortality. hs-TnT measurements did not add to NT-proBNP measurements CONCLUSION: NT-proBNP measurements could improve and simplify risk prediction in cardiac surgical patients.

Circulating chromogranin B levels in patients with acute respiratory failure: data from the FINNALI Study.

PURPOSE: Circulating chromogranin B (CgB) levels are increased in situations characterized by systemic and myocardial stress, but whether CgB provides prognostic information in patients with acute respiratory failure (ARF) is unknown. METHODS: We included 584 patients with ARF, defined as ventilatory support >6 h, and with blood samples available on Intensive Care Unit (ICU) admission and day 3 (n = 479). CgB levels were measured by radioimmunoassay and follow-up was 90 days. RESULTS: One-hundred-sixty-nine patients (29%) died during follow-up. Admission CgB levels separated non-survivors from survivors: median 1234 (Q1-3 989-1742) vs. 917 (753-1224) pmol/L, respectively, p < 0.001. CgB levels on ICU admission (logarithmically transformed) were associated with time to death after adjustment for established risk indices available on ICU admission, including N-terminal pro-B-type natriuretic levels: HR 2.62 (95%C.I. 1.82-3.77), p < 0.001. Admission CgB levels also improved prognostication on top of SOFA and SAPS II scores as assessed by Cox regression analyses and the category-free net reclassification index. The area under the curve (AUC) for admission CgB levels to separate survivors and non-survivors was 0.72 (95%CI 0.67-0.76), while the AUC on day 3 was 0.60 (0.54-0.66). CONCLUSIONS: CgB levels measured on ICU admission provided additional prognostic information to established risk indices in ARF patients.

Prognostic Value of Secretoneurin in Patients with Acute Respiratory Failure: Data from the FINNALI Study.

BACKGROUND: We examined whether secretoneurin (SN), a biomarker associated with cardiomyocyte Ca(2+) handling, provides prognostic information in patients with acute respiratory failure (ARF). METHODS: We included 490 patients with ARF, defined as ventilatory support >6 h, with blood samples available on admission to the intensive care unit (ICU). SN concentrations were measured by RIA. RESULTS: A total of 209 patients (43%) were hospitalized with cardiovascular (CV)-related ARF, and 90-day mortality rates were comparable between CV- and non-CV-related ARF (n = 281): 31% vs 24%, P = 0.11. Admission SN concentrations were higher in nonsurvivors than in survivors in both CV-related (median 148 [quartile 1-3, 117-203] vs 108 [87-143] pmol/L, P < 0.001) and non-CV-related ARF (139 [115-184] vs 113 [91-139] pmol/L, P < 0.001). In patients with CV-related ARF, SN concentrations on ICU admission were associated with 90-day mortality [odds ratio (OR) 1.97 (95% CI, 1.04-3.73, P = 0.04)] after adjusting for established risk indices, including N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentrations. SN also improved patient classification in CV-related ARF as assessed by the net reclassification index: 0.32 (95% CI, 0.04-0.59), P = 0.03. The area under the curve (AUC) of SN to predict mortality in patients with CV-related ARF was 0.72 (95% CI, 0.65-0.79), and the AUC of NT-proBNP was 0.64 (0.56-0.73). In contrast, SN concentrations on ICU admission did not provide incremental prognostic value to established risk indices in patients with non-CV-related ARF, and the AUC was 0.67 (0.60-0.75). CONCLUSIONS: SN concentrations measured on ICU admission provided incremental prognostic information to established risk indices in patients with CV-related ARF, but not in patients with non-CV-related ARF.

SuPAR and PAI-1 in critically ill, mechanically ventilated patients.

PURPOSE: SuPAR (soluble urokinase plasminogen activator receptor) and PAI-1 (plasminogen activator inhibitor 1) are active in the coagulation-fibrinolysis pathway. Both have been suggested as biomarkers for disease severity. We evaluated them in prediction of mortality, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sepsis and renal replacement therapy (RRT) in operative and non-operative ventilated patients. METHODS: We conducted a prospective, multicenter, observational study. Blood samples and data of intensive care were collected. Mechanically ventilated patients with baseline suPAR and PAI-1 measurements were included in the analysis, and healthy volunteers were analysed for comparison. Receiver operating characteristics (ROC), logistic regression, likelihood ratios and Kaplan-Meier analysis were performed. RESULTS: Baseline suPAR was 11.6 ng/ml (quartiles Q1-Q3, 9.6-14.0), compared to healthy volunteers with suPAR of 0.6 ng/ml (0.5-11.0). PAI-1 concentrations were 2.67 ng/ml (1.53-4.69) and 0.3 ng/ml (0.3-0.4), respectively. ROC analysis for suPAR 90-day mortality areas under receiver operating characteristic curves (AUC) 0.61 (95 % confidence interval (CI): 0.55-0.67), sepsis 0.68 (0.61-0.76), ALI/ARDS 0.64 (0.56-0.73) and RRT 0.65 (0.56-0.73). Patients with the highest quartile of suPAR concentrations had an odds ratio of 2.52 (1.37-4.64, p = 0.003) for 90-day mortality and 3.16 (1.19-8.41, p = 0.02) for ALI/ARDS. In non-operative patients, the AUC's for suPAR were 90-day mortality 0.61 (0.54-0.68), RRT 0.73 (0.64-0.83), sepsis 0.70 (0.60-0.80), ALI/ARDS 0.61 (0.51-0.71). Predictive value of PAI-1 was negligible. CONCLUSIONS: In non-operative patients, low concentrations of suPAR were predictive for survival and high concentrations for RRT and mortality. SuPAR may be used for screening for patients with potentially good survival. The association with RRT may supply an early warning sign for acute renal failure.

Plasma cell-free DNA in patients needing mechanical ventilation.

INTRODUCTION: Concentrations of plasma cell-free DNA are increased in various diseases and have shown some prognostic value in many patient groups, including critically ill patients. Pathophysiological processes behind the need for mechanical ventilation and the treatment itself could raise plasma levels of cell-free DNA. We evaluated levels of plasma cell-free DNA and their prognostic value in patients needing mechanical ventilation. METHODS: We studied prospectively 580 mechanically ventilated critically ill patients. Blood samples were taken at study admission (Day 0) and on Day 2. Plasma cell-free DNA concentrations were measured by real-time quantitative PCR assay for the ß-globin gene and are expressed as genome equivalents (GE)/ml. RESULTS: Median (interquartile range, IQR) plasma cell-free DNA concentration was 11,853 GE/ml (5,304 to 24,620 GE/mL) at study admission, and 11,610 GE/mL (6,411 to 21,558 GE/mL) on Day 2. Concentrations at admission were significantly higher in 90-day non-survivors than survivors, 16,936 GE/mL (7,262 to 46,866 GE/mL) versus 10,026 GE/mL (4,870 to 19,820 GE/mL), P < 0.001. In a multivariate logistic regression analysis plasma cell-free DNA concentration over 16,000 GE/ml remained an independent predictor of 90-day mortality (adjusted odds ratio 2.16, 95% confidence interval CI 1.37 to 3.40). Positive likelihood ratio of plasma cell-free DNA at admission for the prediction of 90-day mortality was 1.72 (95% CI 1.40 to 2.11). CONCLUSIONS: Plasma levels of cell-free DNA were significantly higher in non-survivors than survivors. Plasma DNA level at baseline was an independent predictor of 90-day mortality. However, its clinical benefit as a prognostic marker seems to be limited.

Acute respiratory failure in intensive care units. FINNALI: a prospective cohort study.

OBJECTIVE: To evaluate the incidence, treatment and mortality of acute respiratory failure (ARF) in Finnish intensive care units (ICUs). STUDY DESIGN: Prospective multicentre cohort study. METHODS: All adult patients in 25 ICUs were screened for use of invasive or non-invasive ventilatory support during an 8-week period. Patients needing ventilatory support for more than 6 h were included and defined as ARF patients. Risk factors for ARF and details of prior chronic health status were assessed. Ventilatory and concomitant treatments were evaluated and recorded daily throughout the ICU stay. ICU and 90-day mortalities were assessed. RESULTS: A total of 958 (39%) from the 2,473 admitted patients were treated with ventilatory support for more than 6 h. Incidence of ARF, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) was 149.5, 10.6 and 5.0/100,000 per year, respectively. Ventilatory support was started with non-invasive interfaces in 183 of 958 (19%) patients. Ventilatory modes allowing triggering of spontaneous breaths were preferred (81%). Median tidal volume/predicted body weight was 8.7 (7.6-9.9) ml/kg and plateau pressure 19 (16-23) cmH2O. The 90-day mortality of ARF was 31%. CONCLUSIONS: While the incidence of ARF requiring ventilatory support is higher, the incidence of ALI and ARDS seems to be lower in Finland than previously reported in other countries. Tidal volumes are higher than recommended in the concept of lung protective strategy. However, restriction of peak airway pressure was used in the majority of ARF patients.