Prevalence and characteristics of medical emergency teams in Switzerland: a nationwide survey of intensive care units.

BACKGROUND: Medical Emergency Teams (METs) have been implemented in many hospitals worldwide and are considered an integral part of the hospital patient safety system. However, data on prevalence, staffing and activation criteria of METs are scarce. Such data are important as they may help to identify areas of quality improvement and barriers to implementation of rapid response systems (RRS). This survey aimed to analyze current characteristics, prevalence, and organization of METs in Switzerland. METHODS: We conducted a cross-sectional nationwide online survey, inviting physicians' and nurses' representatives from all registered adult intensive care units (ICU) in Switzerland. RESULTS: Of the 74 hospitals invited to participate in the survey, 57 responded (response rate 77%). We obtained 82 individual responses (from 50 physicians and 32 nurses). Twenty-five hospitals (44%) have a MET in place. In most Swiss hospitals, METs are composed of ICU consultants (64%) and ICU nurses (40%) and are activated by phone, with a usual response time of less than 10 minutes. The most common triggers are single abnormal vital signs (80%), while multiple-parameter warning scores are less commonly used (28%). While more than half of the nurses have regular trainings for their MET members (57%), most MET physicians (63%) do not. Systematic data collection of MET calls occurs in only 43% of institutions. Finally, the most common reasons for not having a MET are staff shortage (44%) and lack of funding (19%). CONCLUSIONS: Less than 50% of Swiss hospitals with an adult ICU have a MET in place. METs in Switzerland typically include an ICU doctor and an ICU nurse and are available 24/7. Major barriers to MET introduction are staff shortage and lack of funding.

Physiological changes after fluid bolus therapy in cardiac surgery patients: A propensity score matched case-control study.

Objective: Fluid bolus therapy (FBT) is ubiquitous in intensive care units (ICUs) after cardiac surgery. However, its physiological effects remain unclear. Design: : We performed an electronic health record-based quasi-experimental ICU study after cardiac surgery. We applied propensity score matching and compared the physiological changes after FBT episodes to matched control episodes where despite equivalent physiology no fluid bolus was given. Setting: The study was conducted in a multidisciplinary ICU of a tertiary-level academic hospital. Participants: The study included 2,736 patients who underwent Coronary Artery Bypass Grafting and/or heart valve surgery. Main Outcome Measures: Changes in cardiac output (CO) and mean arterial pressure (MAP) during the 60 minutes following FBT. Results: We analysed 3572 matched fluid bolus (FB) episodes. After FBT, but not in control episodes, CO increased within 10 min, with a maximum increase of 0.2 l/min (95%CI 0.1 to 0.2) or 4% above baseline at 40 min (p < 0.0001 vs. controls). CO increased by > 10% from baseline in 60.6% of FBT and 49.1% of control episodes (p < 0.0001). MAP increased by > 10% in 51.7% of FB episodes compared to 53.4% of controls. Finally, FBT was not associated with changes in acid-base status or oxygen delivery. Conclusion: In this quasi-experimental comparative ICU study in cardiac surgery patients, FBT was associated with statistically significant but numerically small increases in CO. Nearly half of FBT failed to induce a positive CO or MAP response.

A Rare Case of a Good Neurological Outcome following Traumatic Foix-Chavany-Marie Syndrome.

Traumatic brain injury (TBI) can have profound acute and chronic effects, leading to permanent disabilities and diminished quality of life. Pseudobulbar palsy and its infrequent subtype, Foix-Chavany-Marie Syndrome (FCMS), represent rare complications of TBI, manifesting as deficits in craniofacial motor function and automatic-voluntary dissociation. We present a case of a 58-year-old male who developed FCMS following severe TBI from a cycling accident. Initial imaging revealed extensive brain injury with subsequent development of FCMS characterised by bilateral cranial nerve dysfunction, notably facio-pharyngo-glosso-masticatory diplegia with preserved automatic motor function. This case contributes to the limited literature on traumatic FCMS, highlighting its distinct clinical features and potential for favourable outcomes compared to nontraumatic cases. Early recognition and comprehensive management, including supportive therapy and addressing underlying conditions, are paramount for optimising patient outcomes.

From the Operating Room to the Cave: Ultrasound-Guided Locoregional Anesthesia in the Setting of Cave Rescue-A Description of 2 Cases.

Caving accidents are rare, but when they occur, they represent a unique logistical and medical challenge. Retrieving the patient to the surface often means navigating stretchers through narrow corridors with limited options for monitoring and interventions. Because the patient is usually not fasting, opioids and sedatives should be used with extreme caution. Therefore, alternative analgesic techniques such as locoregional nerve blocks are a promising strategy to improve patient comfort and safety during cave rescues. In this article, we describe 2 cases in which portable point-of-care ultrasound equipment was used to supplement clinical assessment and provide locoregional anesthesia to facilitate patient evacuation and transport. In this context, we discuss the role of portable ultrasound-guided locoregional anesthesia in cave rescue and in the global preclinical context. In summary, our cases demonstrated that the administration of ultrasound-guided prehospital locoregional anesthesia is a safe, rapid, and effective procedure even in extreme situations such as cave rescues. The advent of portable, high-quality ultrasound equipment may open the door for more widespread application of this technique in the global preclinical setting.

Sodium glucose co-transporter-2 inhibitors in intensive care unit patients with type 2 diabetes: a pilot case control study.

BACKGROUND: Sodium glucose co-transporter-2 (SGLT2) inhibitors improve long-term cardiovascular and renal outcomes in individuals with type 2 diabetes. However, the safety of SGLT2 inhibitors in ICU patients with type 2 diabetes is uncertain. We aimed to perform a pilot study to assess the relationship between empagliflozin therapy and biochemical, and clinical outcomes in such patients. METHODS: We included 18 ICU patients with type 2 diabetes receiving empagliflozin (10 mg daily) and insulin to target glucose range of 10-14 mmol/l according to our liberal glucose control protocol for patients with diabetes (treatment group). Treatment group patients were matched on age, glycated hemoglobin A1c, and ICU duration with 72 ICU patients with type 2 diabetes exposed to the same target glucose range but who did not receive empagliflozin (control group). We compared changes in electrolyte and acid-base parameters, hypoglycemia, ketoacidosis, worsening kidney function, urine culture findings, and hospital mortality between the groups. RESULTS: Median (IQR) maximum increase in sodium and chloride levels were 3 (1-10) mmol/l and 3 (2-8) mmol/l in the control group and 9 (3-12) mmol/l and 8 (3-10) mmol/l in the treatment group (P = 0.045 for sodium, P = 0.059 for chloride). We observed no differences in strong ion difference, pH or base excess. Overall, 6% developed hypoglycemia in each group. No patient in the treatment group and one patient in the control group developed ketoacidosis. Worsening kidney function occurred in 18% and 29% of treatment and control group patients, respectively (P = 0.54). Urine cultures were positive in 22% of treatment group patients and 13% of control group patients (P = 0.28). Overall, 17% of treatment group patients and 19% of control group patients died in hospital (P = 0.79). CONCLUSIONS: In our pilot study of ICU patients with type 2 diabetes, empagliflozin therapy was associated with increases in sodium and chloride levels but was not significantly associated with acid-base changes, hypoglycemia, ketoacidosis, worsening kidney function, bacteriuria, or mortality.

Heterogeneous treatment effects of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia-Post hoc exploratory analyses of the COVID STEROID 2 trial.

BACKGROUND: Corticosteroids improve outcomes in patients with severe COVID-19. In the COVID STEROID 2 randomised clinical trial, we found high probabilities of benefit with dexamethasone 12 versus 6 mg daily. While no statistically significant heterogeneity in treatment effects (HTE) was found in the conventional, dichotomous subgroup analyses, these analyses have limitations, and HTE could still exist. METHODS: We assessed whether HTE was present for days alive without life support and mortality at Day 90 in the trial according to baseline age, weight, number of comorbidities, category of respiratory failure (type of respiratory support system and oxygen requirements) and predicted risk of mortality using an internal prediction model. We used flexible models for continuous variables and logistic regressions for categorical variables without dichotomisation of the baseline variables of interest. HTE was assessed both visually and with p and S values from likelihood ratio tests. RESULTS: There was no strong evidence for substantial HTE on either outcome according to any of the baseline variables assessed with all p values >.37 (and all S values <1.43) in the planned analyses and no convincingly strong visual indications of HTE. CONCLUSIONS: We found no strong evidence for HTE with 12 versus 6 mg dexamethasone daily on days alive without life support or mortality at Day 90 in patients with COVID-19 and severe hypoxaemia, although these results cannot rule out HTE either.

Characteristics and outcomes of medical emergency team calls in a Swiss tertiary centre - a retrospective observational study.

AIMS OF THE STUDY: To describe reasons for medical emergency team (MET) activation over time, to analyse outcomes, and to describe the circadian distribution of MET calls and Intensive Care Unit (ICU) admissions following MET activation. METHODS: Monocentric retrospective observational study of prospectively collected data on all MET calls between 1st of January 2012 until 31st of May 2019. We analysed data on baselines, referring wards, and disposition of all MET patients. In addition, we allocated all MET calls to the hourly intervals over the 24-hour cycle of the day in order to identify peak times of team activation. RESULTS: A total of 4068 calls in 3277 patients (37% female, n = 1210) were analysed. The mean age was 65.9 years (± 15.7). The MET dose (defined as MET calls/1000 hospital admissions) remained relatively stable over the years with a median of 8.0 calls/1000 hospitalisations (interquartile range [IQR] 7.0-10.0). A total of 2526 calls (62%) occurred out of hours (17:00 to 8:00). The hourly rate of MET activations was greatest during the evening shift (33.8% of calls in seven hours), followed by the day shift (35.8% calls in nine hours) and night shift (30.4% in eight hours). Over the years, staff concern was the main reason for a MET call (n = 1192, 34%), followed by low peripheral oxygen saturation (SpO2) not responding to oxygen therapy (n = 776, 22%). Abnormal respiratory rate was a trigger to call the MET in 44 cases (1.3%), and was not documented prior to 2017. Overall, in-hospital mortality was 22%. CONCLUSION: While most common reasons for MET calls over the years were staff concern and low SpO2, abnormal respiratory rate was the least frequent, but increased after the introduction of the quick sequential organ failure assessment (qSOFA) in 2016. Most MET calls occurred out of hours with peak hours during the evening shift, highlighting the importance of resource allocation during this shift when planning to introduce a MET system in a hospital. In-hospital mortality after a MET call was 22%.

Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia.

PURPOSE: We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. RESULTS: We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). CONCLUSION: Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.

Development of an electronic Poor Outcome Screening (ePOS) Score to identify critically ill patients with potential palliative care needs.

PURPOSE: To develop and validate an electronic poor outcome screening (ePOS) score to identify critically ill patients with potentially unmet palliative care (PC) needs at 48 hours after ICU admission. MATERIALS AND METHODS: Retrospective single-centre cohort study of 1'772 critically ill adult patients admitted to a tertiary academic ICU in Switzerland between 2017 and 2018. We used data available from electronic health records (EHR) in the first 48 hours and least absolute shrinkage and selection operator (LASSO) logistic regression to develop a prediction model and generate a score to predict the risk of all cause 6-month mortality. RESULTS: Within 6 months of the ICU admission, 598 patients (33.7%) had died. At a cut-off of 20 points, the ePOS score (range 0-46 points) had a sensitivity of 0.81 (95% CI 0.78 to 0.84) and a specificity of 0.51 (0.48 to 0.54) for predicting 6-month mortality and showed good discriminatory performance (AUROC 0.72, 0.67 to 0.77). CONCLUSIONS: The ePOS score can easily be implemented in EHR and can be used for automated screening and stratification of ICU patients, pinpointing those in whom a comprehensive PC assessment should be performed. However, it should not replace clinical judgement.

The hemodynamic effects of warm versus room-temperature crystalloid fluid bolus therapy in post-cardiac surgery patients.

INTRODUCTION: The contribution of fluid temperature to the effect of crystalloid fluid bolus therapy (FBT) in post-cardiac surgery patients is unknown. We evaluated the hemodynamic effects of FBT with fluid warmed to 40°C (warm FBT) versus room-temperature fluid. METHODS: In this single centre prospective before-and-after study, we evaluated the effects of 500 ml of warm versus room-temperature compound sodium lactate administered over <30 minutes, in 50 cardiac surgery patients admitted to ICU. We recorded hemodynamics continuous before and for 30 minutes after the first FBT. We defined CI responsiveness (CI-R) as an CI increase >15% of baseline immediately after FBT and effect dissipation if the CI returned to <5% of baseline and MAP responsiveness as >10% increase and dissipation as return to <3 mmHg of baseline. RESULTS: Hypotension (56%) and low CI (40%) typically triggered FBT. Temperature decreased >0.3°C in 13 (52%) patients after room-temperature FBT versus 0 (0%) after warm FBT (p < 0.01). CI and MAP responsiveness was similar (16 [64%] versus 11 [44%], p = 0.15 and 15 [60%] versus 17 [68%], p = 0.77, respectively). Among CI responders, CI increased more with room-temperature FBT (+0.6 [IQR, 0.5-1.1] versus +0.5 [IQR, 0.4-0.6] L/min/m2, p = 0.01). However, dissipation was more common after room-temperature versus warm FBT (9/16 [56%] versus 1/11 [9%], p = 0.02). CONCLUSION: In postoperative cardiac surgery patients, warm FBT preserved core temperature and induced smaller but more sustained CI increases among responders. Fluid temperature appears to impact both core temperature and the duration of CI response.

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial.

PURPOSE: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. METHODS: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. RESULTS: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. CONCLUSION: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial.

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

Should Vasopressors Be Started Early in Septic Shock?

Sepsis can influence blood volume, its distribution, vascular tone, and cardiac function. Persistent hypotension or the need for vasopressors after volume resuscitation is part of the definition of septic shock. Since increased positive fluid balance has been associated with increased morbidity and mortality in sepsis, timing of vasopressors in the treatment of septic shock seems crucial. However, conclusive evidence on timing and sequence of interventions with the goal to restore tissue perfusion is lacking. The aim of this narrative review is to depict the pathophysiology of hypotension in sepsis, evaluate how common interventions to treat hypotension interfere with physiology, and to give a resume of the results from clinical studies focusing on targets and timing of vasopressor in sepsis. The majority of studies comparing early versus late administration of vasopressors in septic shock are rather small, single-center, and retrospective. The range of "early" is between 1 and 12 hours. The available studies suggest a mean arterial pressure of 60 to 65 mm Hg as a threshold for increased risk of morbidity and mortality, whereas higher blood pressure targets do not seem to add further benefits. The data, albeit mostly from observational studies, speak for combining vasopressors with fluids rather "early" in the treatment of septic shock (within a 0-3-hour window). Nevertheless, the optimal resuscitation strategy should take into account the source of infection, the pathophysiology, the time and clinical course preceding the diagnosis of sepsis, and also comorbidities and sepsis-induced organ dysfunction.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial.

BACKGROUND: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. METHODS: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. RESULTS: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: -1.1 days, 95% CI -9.5 to 7.3, P = .79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. CONCLUSIONS: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Prolonged postoperative cerebral oxygen desaturation after cardiac surgery: A prospective observational study.

BACKGROUND: Near-infrared spectroscopy (NIRS) is used routinely to monitor cerebral tissue oxygen saturation (SctO2) during cardiopulmonary bypass (CPB) but is rarely employed outside the operating room. Previous studies indicate that patients are at risk of postoperative cerebral oxygen desaturation after cardiac surgery. OBJECTIVES: We aimed to assess perioperative and postoperative changes in NIRS-derived SctO2 in cardiac surgery patients. DESIGN: Prospective observational study. SETTING: The study was conducted in a tertiary referral university hospital in Australia from December 2017 to December 2018. PATIENTS: We studied 34 adult patients (70.6% men) undergoing cardiac surgery requiring CPB and a reference group of 36 patients undergoing non-cardiac surgical procedures under general anaesthesia. MAIN OUTCOME MEASURES: We measured SctO2 at baseline, during and after surgery, and then once daily until hospital discharge, for a maximum of 7 days. We used multivariate linear mixed-effects modelling to adjust for all relevant imbalances between the two groups. RESULTS: In the cardiac surgery group, SctO2 was 63.7% [95% confidence interval (CI), 62.0 to 65.5] at baseline and 61.0% (95% CI, 59.1 to 62.9, P = 0.01) on arrival in the ICU. From day 2 to day 7 after cardiac surgery, SctO2 progressively declined. At hospital discharge, SctO2 was significantly lower than baseline, at 53.5% (95% CI, 51.8 to 55.2, P < 0.001). In the reference group, postoperative SctO2 was not significantly different from baseline. On multivariable analysis, cardiac surgery, peripheral vascular disease and time since the operation were associated with greater cerebral desaturation, whereas higher haemoglobin concentrations were associated with slightly better cerebral oxygenation. CONCLUSION: After cardiac surgery on CPB, but not after non-cardiac surgery, most patients experience prolonged cerebral desaturation. Such postoperative desaturation remained unresolved 7 days after surgery. The underlying mechanisms and time to resolution of such cerebral desaturations require further investigation.

Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine.

A dysregulated response to systemic inflammation is a common pathophysiological feature of most conditions encountered in the intensive care unit (ICU). Recent evidence indicates that a dysregulated inflammatory response is involved in the pathogenesis of various ICU-related disorders associated with high mortality, including sepsis, acute respiratory distress syndrome, cerebral and myocardial ischemia, and acute kidney injury. Moreover, persistent or non-resolving inflammation may lead to the syndrome of persistent critical illness, characterized by acquired immunosuppression, catabolism and poor long-term functional outcomes. Despite decades of research, management of many disorders in the ICU is mostly supportive, and current therapeutic strategies often do not take into account the heterogeneity of the patient population, underlying chronic conditions, nor the individual state of the immune response. Fatty acid-derived lipid mediators are recognized as key players in the generation and resolution of inflammation, and their signature provides specific information on patients' inflammatory status and immune response. Lipidomics is increasingly recognized as a powerful tool to assess lipid metabolism and the interaction between metabolic changes and the immune system via profiling lipid mediators in clinical studies. Within the concept of precision medicine, understanding and characterizing the individual immune response may allow for better stratification of critically ill patients as well as identification of diagnostic and prognostic biomarkers. In this review, we provide an overview of the role of fatty acid-derived lipid mediators as endogenous regulators of the inflammatory, anti-inflammatory and pro-resolving response and future directions for use of clinical lipidomics to identify lipid mediators as diagnostic and prognostic markers in critical illness.

Cytokine and lipid metabolome effects of low-dose acetylsalicylic acid in critically ill patients with systemic inflammation: a pilot, feasibility, multicentre, randomised, placebo-controlled trial.

OBJECTIVE: The systemic inflammatory response syndrome (SIRS) is a dysregulated response that contributes to critical illness. Adjunctive acetylsalicylic acid (ASA) treatment may offer beneficial effects by increasing the synthesis of specialised proresolving mediators (a subset of polyunsaturated fatty acid-derived lipid mediators). DESIGN: Pilot, feasibility, multicentre, double-blind, randomised, placebo-controlled trial. SETTING: Four interdisciplinary intensive care units (ICUs) in Australia. PARTICIPANTS: Critically ill patients with SIRS. INTERVENTIONS: ASA 100 mg 12-hourly or placebo, administered within 24 hours of ICU admission and continued until ICU day 7, discharge or death, whichever came first. MAIN OUTCOME MEASURES: Interleukin-6 (IL-6) serum concentration at 48 hours after randomisation and, in a prespecified subgroup of patients, serum lipid mediator concentrations measured by mass spectrometry. RESULTS: The trial was discontinued in December 2017 due to slow recruitment and after the inclusion of 48 patients. Compared with placebo, ASA did not decrease IL-6 serum concentration at 48 hours. In the 32 patients with analysis of lipid mediators, low-dose ASA increased the concentration of 15-hydroxyeicosatetraenoic acid, a proresolving precursor of lipoxin A4, and reduced the concentration of the proinflammatory cytochrome P-dependent mediators 17-HETE (hydroxyeicosatetraenoic acid), 18-HETE and 20-HETE. In the eicosapentaenoic acid pathway, ASA significantly increased the concentration of the anti-inflammatory mediators 17,18-DiHETE (dihydroxyeicosatetraenoic acid) and 14,15-DiHETE. CONCLUSIONS: In ICU patients with SIRS, low-dose ASA did not significantly alter serum IL-6 concentrations, but it did affect plasma concentrations of certain lipid mediators. The ability to measure lipid mediators in clinical samples and to monitor the effect of ASA on their levels unlocks a potential area of biological investigation in critical care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN 12614001165673).