Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

BACKGROUND: Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODS: In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTS: We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONS: Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

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.).

Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial.

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 Pao2 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 Pao2 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 Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg. Trial Registration: ClinicalTrials.gov Identifier: NCT04425031.

A survey of preferences for respiratory support in the intensive care unit for patients with acute hypoxaemic respiratory failure.

BACKGROUND: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers. METHODS: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice. RESULTS: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF. CONCLUSIONS: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF.

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.

Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU.

BACKGROUND: Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 .).

Characteristics, management and survival of ICU patients with coronavirus disease-19 in Norway, March-June 2020. A prospective observational study.

BACKGROUND: Norwegian hospitals have operated within capacity during the COVID-19 pandemic. We present patient and management characteristics, and outcomes for the entire cohort of adult (>18 years) COVID-19 patients admitted to Norwegian intensive care units (ICU) from 10 March to 19 June 2020. METHODS: Data were collected from The Norwegian intensive care and pandemic registry (NIPaR). Demographics, co-morbidities, management characteristics and outcomes are described. ICU length of stay (LOS) was analysed with linear regression, and associations between risk factors and mortality were quantified using Cox regression. RESULTS: In total, 217 patients were included. The male to female ratio was 3:1 and the median age was 63 years. A majority (70%) had one or more co-morbidities, most frequently cardiovascular disease (39%), chronic lung disease (22%), diabetes mellitus (20%), and obesity (17%). Most patients were admitted for acute hypoxaemic respiratory failure (AHRF) (91%) and invasive mechanical ventilation (MV) was used in 86%, prone ventilation in 38% and 25% of patients received a tracheostomy. Vasoactive drugs were used in 79% and renal replacement therapy in 15%. Median ICU LOS and time of MV was 14.0 and 12.0 days. At end of follow-up 45 patients (21%) were dead. Age, co-morbidities and severity of illness at admission were predictive of death. Severity of AHRF and male gender were associated with LOS. CONCLUSIONS: In this national cohort of COVID-19 patients, mortality was low and attributable to known risk factors. Importantly, prolonged length-of-stay must be taken into account when planning for resource allocation for any next surge.

The handling oxygenation targets in the intensive care unit (HOT-ICU) trial: Detailed statistical analysis plan.

BACKGROUND: No solid evidence exists on optimal oxygenation targets in intensive care patients. The handling oxygenation targets in the intensive care unit (HOT-ICU) trial assesses the effects of a targeted arterial oxygen tension of 8 vs 12 kPa on 90-day mortality in acutely admitted adult patients with hypoxaemic respiratory failure. This article describes the detailed statistical analysis plan for the predefined outcomes and supplementary analyses in the HOT-ICU trial. METHODS: The trial will include 2928 patients to be able to detect or reject a true 20% relative risk reduction in the primary outcome of 90-day all-cause mortality with an α of 5% and a ß of 10%. Analyses of the primary and secondary outcomes will be conducted according to the intention-to-treat principle and adjusted for stratification variables. The primary outcome and dichotomous secondary outcomes will be analysed using a generalised linear model with a log-link and binomial error distribution. For the primary outcome, a 95% confidence interval (CI) not including 1.00 for the risk ratio will be considered statistically significant. Continuous secondary outcomes will be analysed using a generalised linear model or nonparametric test. CIs adjusted for the multiple secondary outcomes not including the null effect will be considered statistically significant. One planned interim analysis has been conducted. CONCLUSIONS: The HOT-ICU trial and the pre-planned statistical analyses are designed to minimise bias and produce high quality data on the effects of a lower vs a higher oxygenation target throughout ICU admission in acutely admitted adult patients with hypoxaemic respiratory failure. REGISTRATION: ClinicalTrials.gov identifier: NCT03174002, date of registration: June 2, 2017. European clinical trials database, EudraCT number 2017-000632-34.

Spontaneous versus controlled mechanical ventilation in patients with acute respiratory distress syndrome - Protocol for a scoping review.

BACKGROUND: In caring for mechanically ventilated adults with acute respiratory distress syndrome (ARDS), clinicians are faced with an uncertain choice between controlled or spontaneous breathing modes. Observational data indicate considerable practice variation which may be driven by differences in sedation and mobilisation practices. The benefits and harms of either strategy are largely unknown. METHODS: A scoping review will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. We will review the clinical literature on controlled vs spontaneous breathing in mechanically ventilated patients with ARDS of any severity. Studies reporting on qualitative and/or quantitative data from any world region will be considered. For inclusion, studies must include data on mechanically ventilated patients with ARDS who are allowed spontaneous (triggered ventilation). Searches will be conducted in four electronic databases without any limitation on publication date and language. We will assess the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, where appropriate. CONCLUSION: We will perform a scoping review of the clinical literature on controlled vs spontaneously breathing in mechanically ventilated patients who fulfil ARDS criteria (including acute lung injury). This is to elucidate if a pragmatic clinical trial comparing controlled and spontaneous mechanical ventilation is warranted and will allow us to formulate relevant research questions.

Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial.

BACKGROUND: In patients with septic shock, mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes. AIM: To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. METHODS: In this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, health-related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. DISCUSSION: With this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.

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.

Pantoprazole in ICU patients at risk for gastrointestinal bleeding-1-year mortality in the SUP-ICU trial.

BACKGROUND: The long-term effects of stress ulcer prophylaxis with pantoprazole are unknown in ICU patients. We report 1-year mortality outcome in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. METHODS: In the SUP-ICU trial, acutely admitted adult ICU patients at risk of gastrointestinal bleeding were randomised to intravenous pantoprazole 40 mg vs placebo (saline) once daily during their ICU stay. We assessed mortality at 1 year and did sensitivity analyses according to the trial protocol and statistical analysis plan. RESULTS: A total of 3261 of the 3291 patients with available data (99.1%) were followed up at 1 year after randomisation; 1635 were allocated to pantoprazole and 1626 to placebo. At 1 year after randomisation, 610 of 1635 patients (37.3%) had died in the pantoprazole group as compared with 601 of 1626 (37.0%) in the placebo group (relative risk, 1.01; 95% confidence interval 0.92-1.10). The results were consistent in the sensitivity analysis adjusted for baseline risk factors and in those of the per-protocol population. We did not observe heterogeneity in the effect of pantoprazole vs placebo on 1-year mortality in the predefined subgroups, that is, patients with and without shock, mechanical ventilation, liver disease, coagulopathy, high disease severity (SAPS II > 53) or in medical vs surgical ICU patients. CONCLUSION: We did not observe a difference in 1-year mortality among acutely admitted adult ICU patients with risk factors for gastrointestinal bleeding allocated to stress ulcer prophylaxis with pantoprazole or placebo during the ICU stay. (The SUP-ICU trial was funded by Innovation Fund Denmark and others; ClinicalTrials.gov number, NCT02467621).

Gender Parity in Critical Care Medicine.

Clinical practice guidelines are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. These documents inform and shape patient care around the world. In this Perspective we discuss the importance of diversity on guideline panels, the disproportionately low representation of women on critical care guideline panels, and existing initiatives to increase the representation of women in corporations, universities, and government. We propose five strategies to ensure gender parity within critical care medicine.

Nurse-led implementation of an insulin-infusion protocol in a general intensive care unit: improved glycaemic control with increased costs and risk of hypoglycaemia signals need for algorithm revision.

BACKGROUND: Strict glycaemic control (SGC) has become a contentious issue in modern intensive care. Physicians and nurses are concerned about the increased workload due to SGC as well as causing harm through hypoglycaemia. The objective of our study was to evaluate our existing degree of glycaemic control, and to implement SGC safely in our ICU through a nurse-led implementation of an algorithm for intensive insulin-therapy. METHODS: The study took place in the adult general intensive care unit (11 beds) of a 44-bed department of intensive care at a tertiary care university hospital. All patients admitted during the 32 months of the study were enrolled. We retrospectively analysed all arterial blood glucose (BG) results from samples that were obtained over a period of 20 months prior to the implementation of SGC. We then introduced an algorithm for intensive insulin therapy; aiming for arterial blood-glucose at 4.4 - 6.1 mmol/L. Doctors and nurses were trained in the principles and potential benefits and risks of SGC. Consecutive statistical analyses of blood samples over a period of 12 months were used to assess performance, provide feedback and uncover incidences of hypoglycaemia. RESULTS: Median BG level was 6.6 mmol/L (interquartile range 5.6 to 7.7 mmol/L) during the period prior to implementation of SGC (494 patients), and fell to 5.9 (IQR 5.1 to 7.0) mmol/L following introduction of the new algorithm (448 patients). The percentage of BG samples > 8 mmol/L was reduced from 19.2 % to 13.1 %. Before implementation of SGC, 33 % of samples were between 4.4 to 6.1 mmol/L and 12 patients (2.4 %) had one or more episodes of severe hypoglycaemia (< 2.2 mmol/L). Following implementation of SGC, 45.8 % of samples were between 4.4 to 6.1 mmol/L and 40 patients (8.9 %) had one or more episodes of severe hypoglycaemia. Of theses, ten patients died while still hospitalised (all causes). CONCLUSION: The retrospective part of the study indicated ample room for improvement. Through the implementation of SGC the fraction of samples within the new target range increased from 33% to 45.8%. There was also a significant increase in severe hypoglycaemic episodes. There continues to be potential for improved glycaemic control within our ICU. This might be achieved through an improved algorithm and continued efforts to increase nurses' confidence and skills in achieving SGC.

Excessive innate immune response and mutant D222G/N in severe A (H1N1) pandemic influenza.

AIM: Explore the role of viral factors and immune response in patients with severe pandemic pdmH1N1 illness without significant co-morbidity. MATERIALS: Seven patients with pdmH1N1 influenza, bilateral chest X-rays infiltrates, requiring mechanical ventilator support were consecutively recruited. Seven age- and gender-matched healthy individuals served as controls. RESULTS: Four patients were viremic, two with the mutant D222G/N pdmH1N1.Microarray analyses of peripheral blood leukocytes suggested a marked granulocytes activation, but no up-regulation of inflammatory cytokine mRNA. Patients with severe pdmH1NI had a marked systemic complement activation, and in contrast to the lack of cytokine mRNA up-regulation in blood leukocytes, plasma levels of a broad range of inflammatory mediators, including IP-10, and mediators involved in pulmonary remodelling were markedly elevated. Patients with mutant virus had particularly high IP-10 levels, and the most pronounced complement activation. CONCLUSIONS: In severe pdmH1N1, viremia was common and the D222G/N mutant was found in half of the viremic patients. Host immune response was characterized by strong activation of the innate immune system, including complement and granulocytes activation, increased serum levels of inflammation and pulmonary remodelling markers, possibly contributing to the observed tissue damage. However, few patients were included and further studies are needed to characterize the immune response in severe pdmH1N1 infection.