Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza.

In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.

Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza.

Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death ('bacterial') pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this 'bacterial' signature but was able to enhance its development while attenuating the early 'viral' signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.

Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure.

Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae, modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. An analysis of large K. pneumoniae genome collections, encompassing major healthcare-associated clones, revealed the recurrent emergence of a synonymous cytosine-to-thymine transition at position 25 (25c > t) in ompK36. We show that the 25c > t transition increases carbapenem resistance through depletion of OmpK36 from the outer membrane. The mutation attenuates K. pneumoniae in a murine pneumonia model, which accounts for its limited clonal expansion observed by phylogenetic analysis. However, in the context of carbapenem treatment, the 25c > t transition tips the balance toward treatment failure, thus accounting for its recurrent emergence. Mechanistically, the 25c > t transition mediates an intramolecular messenger RNA (mRNA) interaction between a uracil encoded by 25t and the first adenine within the Shine-Dalgarno sequence. This specific interaction leads to the formation of an RNA stem structure, which obscures the ribosomal binding site thus disrupting translation. While mutations reducing OmpK36 expression via transcriptional silencing are known, we uniquely demonstrate the repeated selection of a synonymous ompK36 mutation mediating translational suppression in response to antibiotic pressure.

UK clinicians' attitudes towards the application of molecular diagnostics to guide antibiotic use in ICU patients with pneumonias: a quantitative study.

BACKGROUND: Molecular diagnostic tests may improve antibiotic prescribing by enabling earlier tailoring of antimicrobial therapy. However, clinicians' trust and acceptance of these tests will determine their application in practice. OBJECTIVES: To examine ICU prescribers' views on the application of molecular diagnostics in patients with suspected hospital-acquired and ventilator-associated pneumonia (HAP/VAP). METHODS: Sixty-three ICU clinicians from five UK hospitals completed a cross-sectional questionnaire between May 2020 and July 2020 assessing attitudes towards using molecular diagnostics to inform initial agent choice and to help stop broad-spectrum antibiotics early. RESULTS: Attitudes towards using molecular diagnostics to inform initial treatment choices and to stop broad-spectrum antibiotics early were nuanced. Most (83%) were positive about molecular diagnostics, agreeing that using results to inform broad-spectrum antibiotic prescribing is good practice. However, many (58%) believed sick patients are often too unstable to risk stopping broad-spectrum antibiotics based on a negative result. CONCLUSIONS: Positive attitudes towards the application of molecular diagnostics to improve antibiotic stewardship were juxtapositioned against the perceived need to initiate and maintain broad-spectrum antibiotics to protect unstable patients.

Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae.

Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen, Klebsiella pneumoniae (KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36. We identified L3 insertions in 3588 (24.1%) of 14,888 KP genomes with an intact ompK36 gene from a global collection. GD insertions were most common, with a high concentration in the ST258/512 clone that has spread widely in Europe and the Americas. Aspartate (D) and Threonine-Aspartate (TD) insertions were prevalent in genomes from Asia, due in part to acquisitions by KP sequence types ST16 and ST231 and subsequent clonal expansions. By solving the crystal structures of novel OmpK36 variants, we found that the TD insertion causes a pore constriction of 41%, significantly greater than that achieved by GD (10%) or D (8%), resulting in the highest levels of resistance to selected antibiotics. We show that in the absence of antibiotics KP mutants harbouring these L3 insertions exhibit both an in vitro and in vivo competitive disadvantage relative to the isogenic parental strain expressing wild type OmpK36. We propose that this explains the reversion of GD and TD insertions observed at low frequency among KP genomes. Finally, we demonstrate that strains expressing L3 insertions remain susceptible to drugs targeting carbapenemase-producing KP, including novel beta lactam-beta lactamase inhibitor combinations. This study provides a contemporary global view of OmpK36-mediated resistance mechanisms in KP, integrating surveillance and experimental data to guide treatment and drug development strategies.

Continuous vs Intermittent ß-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial.

Importance: Whether ß-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective: To evaluate whether continuous vs intermittent infusion of a ß-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants: An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention: Eligible patients were randomized to receive an equivalent 24-hour dose of a ß-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results: Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance: The observed difference in 90-day mortality between continuous vs intermittent infusions of ß-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03213990.

Prolonged vs Intermittent Infusions of ß-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis.

Importance: There is uncertainty about whether prolonged infusions of ß-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. Objective: To determine whether prolonged ß-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. Data Sources: The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Study Selection: Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of ß-lactam antibiotics in critically ill adults with sepsis or septic shock. Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. Main Outcomes and Measures: The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. Results: From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of ß-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of ß-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Conclusions and Relevance: Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged ß-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. Trial Registration: PROSPERO Identifier: CRD42023399434.

Apnoeic oxygenation in morbid obesity: a randomised controlled trial comparing facemask and high-flow nasal oxygen delivery.

BACKGROUND: Obesity is a risk factor for airway-related incidents during anaesthesia. High-flow nasal oxygen has been advocated to improve safety in high-risk groups, but its effectiveness in the obese population is uncertain. This study compared the effect of high-flow nasal oxygen and low-flow facemask oxygen delivery on duration of apnoea in morbidly obese patients. METHODS: Morbidly obese patients undergoing bariatric surgery were randomly allocated to receive either high-flow nasal (70 L min-1) or facemask (15 L min-1) oxygen. After induction of anaesthesia, the patients were apnoeic for 18 min or until peripheral oxygen saturation decreased to 92%. RESULTS: Eighty patients were studied (41 High-Flow Nasal Oxygen, 39 Facemask). The median apnoea time was 18 min in both the High-Flow Nasal Oxygen (IQR 18-18 min) and the Facemask (inter-quartile range [IQR], 4.1-18 min) groups. Five patients in the High-Flow Nasal Oxygen group and 14 patients in the Facemask group desaturated to 92% within 18 min. The risk of desaturation was significantly lower in the High-Flow Nasal Oxygen group (hazard ratio=0.27; 95% confidence interval [CI], 0.11-0.65; P=0.007). CONCLUSIONS: In experienced hands, apnoeic oxygenation is possible in morbidly obese patients, and oxygen desaturation did not occur for 18 min in the majority of patients, whether oxygen delivery was high-flow nasal or low-flow facemask. High-flow nasal oxygen may reduce desaturation risk compared with facemask oxygen. Desaturation risk is a more clinically relevant outcome than duration of apnoea. Individual physiological factors are likely to be the primary determinant of risk rather than method of oxygen delivery. CLINICAL TRIAL REGISTRATION: NCT03428256.

Escalation to intensive care for the older patient. An exploratory qualitative study of patients aged 65 years and older and their next of kin during the COVID-19 pandemic: the ESCALATE study.

BACKGROUND: older people comprise the majority of hospital medical inpatients so decision-making regarding admission of this cohort to the intensive care unit (ICU) is important. ICU can be perceived by clinicians as overly burdensome for patients and loved ones, and long-term impact on quality of life considered unacceptable, effecting potential bias against admitting older people to ICU. The COVID-19 pandemic highlighted the challenge of selecting those who could most benefit from ICU. OBJECTIVE: this qualitative study aimed to explore the views and recollections of escalation to ICU from older patients (aged ≥ 65 years) and next of kin (NoK) who experienced a COVID-19 ICU admission. SETTING: the main site was a large NHS Trust in London, which experienced a high burden of COVID-19 cases. SUBJECTS: 30 participants, comprising 12 patients, 7 NoK of survivor and 11 NoK of deceased. METHODS: semi-structured interviews with thematic analysis using a framework approach. RESULTS: there were five major themes: inevitability, disconnect, acceptance, implications for future decision-making and unique impact of the COVID-19 pandemic. Life was highly valued and ICU perceived to be the only option. Prior understanding of ICU and admission decision-making explanations were limited. Despite benefit of hindsight, having experienced an ICU admission and its consequences, most could not conceptualise thresholds for future acceptable treatment outcomes. CONCLUSIONS: in this study of patients ≥65 years and their NoK experiencing an acute ICU admission, survival was prioritised. Despite the ordeal of an ICU stay and its aftermath, the decision to admit and sequelae were considered acceptable.

Exploring the working environment of Hospital Managers: a mixed methods study investigating stress, stereotypes, psychological safety and individual resilience.

BACKGROUND: Hospital managers are responsible for the delivery of organisational strategy, development of clinical services and maintaining quality standards. There is limited research on hospital managers, in particular how stress manifests and impacts managers and the presence of individual resilience. Managers must work closely with clinical colleagues, however these relationships can be hindered by the perception of stereotyping and differing priorities. This study aimed to explore the working environment of hospital managers, focusing upon the unique stresses faced, psychological safety and the presence of resilience. METHODS: This study utilised mixed methodology using an embedded approach. Participants were purposively recruited from all levels of hospital management within one National Health Service Trust in London, United Kingdom. An exploration of managers experiences was undertaken using semi-structured qualitative interviews. Psychological safety and individual resilience were additionally assessed using validated surveys. Qualitative data were analysed iteratively using inductive thematic analysis, and triangulated with quantitative data. Kruskal-Wallis statistical analysis was performed to evaluate differences in resilience and psychological safety according to seniority and background experience. RESULTS: Twenty-two managers were recruited and interviewed, with 20 returning completed surveys. Key findings from the thematic analysis included the importance of good working relationships with clinical colleagues, the persistence of some stereotyping, and feeling unsupported in times of challenge. Stresses described included the bureaucracy involved when delivering change, conflict with colleagues and target driven expectations. Participants described their own psychological safety as lower than desired, supported by quantitative data; but recognised its importance and strived to create it within their own teams. Sixteen participants had 'normal' scores for resilience, with senior managers more likely to have higher scores than those more junior (p=0.011). CONCLUSION: Positive working relationships, high psychological safety and individual resilience are important for organisational safety and individual wellbeing. Our data illustrate unique stressors faced by hospital managers, provide detail on sometimes challenging working relationships, and demonstrate scope to improve both the psychological safety and resilience of those in managerial positions. A map for senior healthcare leaders was constructed, facilitating the identification of modifiable areas within their organisation to promote good working relationships and improve the working environment of hospital managers.

Descriptors of Sepsis Using the Sepsis-3 Criteria: A Cohort Study in Critical Care Units Within the U.K. National Institute for Health Research Critical Care Health Informatics Collaborative.

OBJECTIVES: To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records. DESIGN: Retrospective cohort study using electronic health records. SETTING: Ten ICUs from four U.K. National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative. PATIENTS: A total of 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical). MEASUREMENTS AND MAIN RESULTS: Twenty-nine thousand three hundred forty-three episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. A total of 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate greater than 2.0 mmol/L, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%; 95% CI, 21.9-25.6%), followed by hospital-acquired sepsis (18.6%; 95% CI, 17.5-19.9%), and community-acquired sepsis (12.9%; 95% CI, 12.1-13.6%) (p for comparison less than 0.0001). CONCLUSIONS: We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding.

Long-term outcomes after critical illness: recent insights.

Intensive care survivors often experience post-intensive care sequelae, which are frequently gathered together under the term "post-intensive care syndrome" (PICS). The consequences of PICS on quality of life, health-related costs and hospital readmissions are real public health problems. In the present Viewpoint, we summarize current knowledge and gaps in our understanding of PICS and approaches to management.

Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial.

RATIONALE: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration, but conflicting survival effects. Two transcriptomic sepsis response signatures (SRSs) have been identified. SRS1 is relatively immunosuppressed, whereas SRS2 is relatively immunocompetent. OBJECTIVES: We aimed to categorize patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock. METHODS: A post hoc analysis was performed of a double-blind, randomized clinical trial in septic shock (VANISH [Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock]). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined by a previously established model using seven discriminant genes. MEASUREMENTS AND MAIN RESULTS: Samples were available from 176 patients: 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (P = 0.50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (P = 0.02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (odds ratio = 7.9; 95% confidence interval = 1.6-39.9). CONCLUSIONS: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immunocompetent SRS2 endotype had significantly higher mortality when given corticosteroids compared with placebo. Clinical trial registered with www.clinicaltrials.gov (ISRCTN 20769191).

The Association between Supraphysiologic Arterial Oxygen Levels and Mortality in Critically Ill Patients. A Multicenter Observational Cohort Study.

Rationale: There is conflicting evidence on harm related to exposure to supraphysiologic PaO2 (hyperoxemia) in critically ill patients.Objectives: To examine the association between longitudinal exposure to hyperoxemia and mortality in patients admitted to ICUs in five United Kingdom university hospitals.Methods: A retrospective cohort of ICU admissions between January 31, 2014, and December 31, 2018, from the National Institute of Health Research Critical Care Health Informatics Collaborative was studied. Multivariable logistic regression modeled death in ICU by exposure to hyperoxemia.Measurements and Main Results: Subsets with oxygen exposure windows of 0 to 1, 0 to 3, 0 to 5, and 0 to 7 days were evaluated, capturing 19,515, 10,525, 6,360, and 4,296 patients, respectively. Hyperoxemia dose was defined as the area between the PaO2 time curve and a boundary of 13.3 kPa (100 mm Hg) divided by the hours of potential exposure (24, 72, 120, or 168 h). An association was found between exposure to hyperoxemia and ICU mortality for exposure windows of 0 to 1 days (odds ratio [OR], 1.15; 95% compatibility interval [CI], 0.95-1.38; P = 0.15), 0 to 3 days (OR 1.35; 95% CI, 1.04-1.74; P = 0.02), 0 to 5 days (OR, 1.5; 95% CI, 1.07-2.13; P = 0.02), and 0 to 7 days (OR, 1.74; 95% CI, 1.11-2.72; P = 0.02). However, a dose-response relationship was not observed. There was no evidence to support a differential effect between hyperoxemia and either a respiratory diagnosis or mechanical ventilation.Conclusions: An association between hyperoxemia and mortality was observed in our large, unselected multicenter cohort. The absence of a dose-response relationship weakens causal interpretation. Further experimental research is warranted to elucidate this important question.

Chronic pain in critical care survivors: a narrative review.

Chronic pain is an important problem after critical care admission. Estimates of the prevalence of chronic pain in the year after discharge range from 14% to 77% depending on the type of cohort, the tool used to measure pain, and the time point when pain was assessed. The majority of data available come from studies using health-related quality of life tools, although some have included pain-specific tools. Nociceptive, neuropathic, and nociplastic pain can occur in critical care survivors, but limited information about the aetiology, body site, and temporal trajectory of pain is currently available. Older age, pre-existing pain, and medical co-morbidity have been associated with pain after critical care admission. No trials were identified of interventions to target chronic pain in survivors specifically. Larger studies, using pain-specific tools, over an extended follow-up period are required to confirm the prevalence, identify risk factors, explore any association between acute and chronic pain in this setting, determine the underlying pathological mechanisms, and inform the development of future analgesic interventions.

Perceptions of Risk and Safety in the ICU: A Qualitative Study of Cognitive Processes Relating to Staffing.

OBJECTIVES: The aims of this study were to 1) examine individual professionals' perceptions of staffing risks and safe staffing in intensive care and 2) identify and examine the cognitive processes that underlie these perceptions. DESIGN: Qualitative case study methodology with nurses, doctors, and physiotherapists. SETTING: Three mixed medical and surgical adult ICUs, each on a separate hospital site within a 1,200-bed academic, tertiary London hospital group. SUBJECTS: Forty-four ICU team members of diverse professional backgrounds and seniority. INTERVENTIONS: None. MAIN RESULTS: Four themes (individual, team, unit, and organizational) were identified. Individual care provision was influenced by the pragmatist versus perfectionist stance of individuals and team dynamics by the concept of an "A" team and interdisciplinary tensions. Perceptions of safety hinged around the importance of achieving a "dynamic balance" influenced by the burden of prevailing circumstances and the clinical status of patients. Organizationally, professionals' risk perceptions affected their willingness to take personal responsibility for interactions beyond the unit. CONCLUSIONS: This study drew on cognitive research, specifically theories of cognitive dissonance, psychological safety, and situational awareness to explain how professionals' cognitive processes impacted on ICU behaviors. Our results may have implications for relationships, management, and leadership in ICU. First, patient care delivery may be affected by professionals' perfectionist or pragmatic approach. Perfectionists' team role may be compromised and they may experience cognitive dissonance and subsequent isolation/stress. Second, psychological safety in a team may be improved within the confines of a perceived "A" team but diminished by interdisciplinary tensions. Third, counter intuitively, higher "situational" awareness for some individuals increased their stress and anxiety. Finally, our results suggest that professionals have varying concepts of where their personal responsibility to minimize risk begins and ends, which we have termed "risk horizons" and that these horizons may affect their behavior both within and beyond the unit.

The Effect of ICU Out-of-Hours Admission on Mortality: A Systematic Review and Meta-Analysis.

OBJECTIVES: Organizational factors are associated with outcome of critically ill patients and may vary by time of day and day of week. We aimed to identify the association between out-of-hours admission to critical care and mortality. DATA SOURCES: MEDLINE (via Ovid) and EMBASE (via Ovid). STUDY SELECTION: We performed a systematic search of the literature for studies on out-of-hours adult general ICU admission on patient mortality. DATA EXTRACTION: Meta-analyses were performed and Forest plots drawn using RevMan software. Data are presented as odds ratios ([95% CIs], p values). DATA SYNTHESIS: A total of 16 studies with 902,551 patients were included in the analysis with a crude mortality of 18.2%. Fourteen studies with 717,331 patients reported mortality rates by time of admission and 11 studies with 835,032 patients by day of admission. Admission to ICU at night was not associated with an increased odds of mortality compared with admissions during the day (odds ratio, 1.04 [0.98-1.11]; p = 0.18). However, admissions during the weekend were associated with an increased odds of death compared with ICU admissions during weekdays (1.05 [1.01-1.09]; p = 0.006). Increased mortality associated with weekend ICU admissions compared with weekday ICU admissions was limited to North American countries (1.08 [1.03-1.12]; p = 0.0004). The absence of a routine overnight on-site intensivist was associated with increased mortality among weekend ICU admissions compared with weekday ICU admissions (1.11 [1.00-1.22]; p = 0.04) and nighttime admissions compared with daytime ICU admissions (1.11 [1.00-1.23]; p = 0.05). CONCLUSIONS: Adjusted risk of death for ICU admission was greater over the weekends compared with weekdays. The absence of a dedicated intensivist on-site overnight may be associated with increased mortality for acute admissions. These results need to be interpreted in context of the organization of local healthcare resources before changes to healthcare policy are implemented.

Copeptin reflects physiological strain during thermal stress.

PURPOSE: To prevent heat-related illnesses, guidelines recommend limiting core body temperature (T c) ≤ 38 °C during thermal stress. Copeptin, a surrogate for arginine vasopressin secretion, could provide useful information about fluid balance, thermal strain and health risks. It was hypothesised that plasma copeptin would rise with dehydration from occupational heat stress, concurrent with sympathoadrenal activation and reduced glomerular filtration, and that these changes would reflect T c responses. METHODS: Volunteers (n = 15) were recruited from a British Army unit deployed to East Africa. During a simulated combat assault (3.5 h, final ambient temperature 27 °C), T c was recorded by radiotelemetry to differentiate volunteers with maximum T c > 38 °C versus ≤ 38 °C. Blood was sampled beforehand and afterwards, for measurement of copeptin, cortisol, free normetanephrine, osmolality and creatinine. RESULTS: There was a significant (P < 0.05) rise in copeptin from pre- to post-assault (10.0 ± 6.3 vs. 16.7 ± 9.6 pmol L-1, P < 0.001). Although osmolality did not increase, copeptin correlated strongly with osmolality after the exposure (r = 0.70, P = 0.004). In volunteers with maximum T c > 38 °C (n = 8) vs ≤ 38 °C (n = 7) there were significantly greater elevations in copeptin (10.4 vs. 2.4 pmol L-1) and creatinine (10 vs. 2 µmol L-1), but no differences in cortisol, free normetanephrine or osmolality. CONCLUSIONS: Changes in copeptin reflected T c response more closely than sympathoadrenal markers or osmolality. Dynamic relationships with tonicity and kidney function may help to explain this finding. As a surrogate for integrated physiological strain during work in a field environment, copeptin assay could inform future measures to prevent heat-related illnesses.

Effect of a Strategy of a Supraglottic Airway Device vs Tracheal Intubation During Out-of-Hospital Cardiac Arrest on Functional Outcome: The AIRWAYS-2 Randomized Clinical Trial.

Importance: The optimal approach to airway management during out-of-hospital cardiac arrest is unknown. Objective: To determine whether a supraglottic airway device (SGA) is superior to tracheal intubation (TI) as the initial advanced airway management strategy in adults with nontraumatic out-of-hospital cardiac arrest. Design, Setting, and Participants: Multicenter, cluster randomized clinical trial of paramedics from 4 ambulance services in England responding to emergencies for approximately 21 million people. Patients aged 18 years or older who had a nontraumatic out-of-hospital cardiac arrest and were treated by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017; follow-up ended in February 2018. Interventions: Paramedics were randomized 1:1 to use TI (764 paramedics) or SGA (759 paramedics) as their initial advanced airway management strategy. Main Outcomes and Measures: The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred sooner. Modified Rankin Scale score was divided into 2 ranges: 0-3 (good outcome) or 4-6 (poor outcome; 6 = death). Secondary outcomes included ventilation success, regurgitation, and aspiration. Results: A total of 9296 patients (4886 in the SGA group and 4410 in the TI group) were enrolled (median age, 73 years; 3373 were women [36.3%]), and the modified Rankin Scale score was known for 9289 patients. In the SGA group, 311 of 4882 patients (6.4%) had a good outcome (modified Rankin Scale score range, 0-3) vs 300 of 4407 patients (6.8%) in the TI group (adjusted risk difference [RD], -0.6% [95% CI, -1.6% to 0.4%]). Initial ventilation was successful in 4255 of 4868 patients (87.4%) in the SGA group compared with 3473 of 4397 patients (79.0%) in the TI group (adjusted RD, 8.3% [95% CI, 6.3% to 10.2%]). However, patients randomized to receive TI were less likely to receive advanced airway management (3419 of 4404 patients [77.6%] vs 4161 of 4883 patients [85.2%] in the SGA group). Two of the secondary outcomes (regurgitation and aspiration) were not significantly different between groups (regurgitation: 1268 of 4865 patients [26.1%] in the SGA group vs 1072 of 4372 patients [24.5%] in the TI group; adjusted RD, 1.4% [95% CI, -0.6% to 3.4%]; aspiration: 729 of 4824 patients [15.1%] vs 647 of 4337 patients [14.9%], respectively; adjusted RD, 0.1% [95% CI, -1.5% to 1.8%]). Conclusions and Relevance: Among patients with out-of-hospital cardiac arrest, randomization to a strategy of advanced airway management with a supraglottic airway device compared with tracheal intubation did not result in a favorable functional outcome at 30 days. Trial Registration: ISRCTN Identifier: 08256118.