Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU and HOT-COVID trials: A protocol update.

BACKGROUND: The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial was a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2 ] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure; the Handling Oxygenation Targets in coronavirus disease 2019 (HOT-COVID) tested the same oxygenation targets in patients with confirmed COVID-19. In this study, we aim to evaluate the long-term effects of these oxygenation targets on cognitive and pulmonary function. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. METHODS: This is the updated protocol and statistical analysis plan of two pre-planned secondary outcomes, the long-term cognitive function, and long-term pulmonary function, in the HOT-ICU and HOT-COVID trials. Patients enrolled in both trials at selected Danish sites and surviving to 1 year after randomisation are eligible to participate. A Repeatable Battery for the Assessment of Neuropsychological Status score and a full-body plethysmography, including diffusion capacity for carbon monoxide, will be obtained. The last patient is expected to be included in the spring of 2024. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on long-term cognitive and pulmonary functions in adult ICU patients with acute hypoxaemic respiratory failure.

Ambulance and helicopter response time. Association with patient outcome and illness severity: Protocol of a systematic literature review and meta-analysis.

BACKGROUND: Response time for emergency medical service units is a key performance indicator. Studies have shown reduced response time association with improved outcome for specific critical conditions. To achieve short response time, emergency vehicles utilize lights and sirens, and crews are allowed to be non-compliant with traffic rules, posing a risk for accident. The purpose of the systematic review and meta-analysis is to provide an overview of the current body of evidence regarding the association, if any, between ambulance and helicopter response time and major complications and mortality in patients conveyed by ambulance and/or helicopter. Our secondary aim will be to enhance knowledge in the field of criteria-based dispatch to provide decision makers with evidence to optimize dispatch of limited resources. RESEARCH QUESTIONS: What is the association between overall emergency medical services unit response time and patient outcomes, major complications, and time-critical conditions? What is the internal and external validity of the included literature? METHODS: We plan the systematic review and meta-analysis to be in accordance with the Cochrane Handbook and Joanna Briggs Institute Manual for Systematic Reviews. The methodology will include formulating the review questions using a Population, Exposure, and Outcome framework. Every study design is eligible, including qualitative, quantitative, and mixed-methods designs. We will include all articles in English, Scandinavian, German, French and Portuguese in this systematic review. RESULTS: We will publish results from the systematic review and meta-analysis in a peer-reviewed journal and we will present the results at scientific conferences and meetings. Results will also be available at www.ahrtemis.dk. CONCLUSION: We will base our conclusions on the findings of the review and meta-analysis.

Association of intraosseous and intravenous access with patient outcome in out-of-hospital cardiac arrest.

Here we report the results of a study on the association between drug delivery via intravenous route or intraosseous route in out-of-hospital cardiac arrest. Intraosseous drug delivery is considered an alternative option in resuscitation if intravenous access is difficult or impossible. Intraosseous uptake of drugs may, however, be compromised. We have performed a retrospective cohort study of all Danish patients with out-of-hospital cardiac arrest in the years 2016-2020 to investigate whether mortality is associated with the route of drug delivery. Outcome was 30-day mortality, death at the scene, no prehospital return of spontaneous circulation, and 7- and 90-days mortality. 17,250 patients had out-of-hospital cardiac arrest. 6243 patients received no treatment and were excluded. 1908 patients had sustained return of spontaneous circulation before access to the vascular bed was obtained. 2061 patients were unidentified, and 286 cases were erroneously registered. Thus, this report consist of results from 6752 patients. Drug delivery by intraosseous route is associated with increased OR of: No spontaneous circulation at any time (OR 1.51), Death at 7 days (OR 1.94), 30 days (2.02), and 90 days (OR 2.29). Intraosseous drug delivery in out-of-hospital cardiac arrest is associated with overall poorer outcomes than intravenous drug delivery.

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock.

PURPOSE: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. METHODS: We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. RESULTS: Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) - 4.8 to 7.8]. Mean differences were 0.00 (99% CI - 0.06 to 0.05) for EQ-5D-5L index values, - 0.65 for EQ VAS (- 5.40 to 4.08), and - 0.14 for Mini MoCA (- 1.59 to 1.14) for the restrictive-fluid group versus the standard-fluid group. The results for survivors only were similar in both groups. CONCLUSIONS: Among adult ICU patients with septic shock, restrictive versus standard IV fluid therapy resulted in similar survival, HRQoL, and cognitive function at 1 year, but clinically important differences could not be ruled out.

Thromboembolic and bleeding events in ICU patients with COVID-19: A nationwide, observational study.

BACKGROUND: Intensive care unit (ICU) patients with Coronavirus disease 2019 (COVID-19) have an increased risk of thromboembolic complications. We describe the occurrence of thromboembolic and bleeding events in all ICU patients with COVID-19 in Denmark during the first and second waves of the pandemic. METHODS: This was a sub-study of the Danish Intensive Care Covid database, in which all patients with SARS-CoV-2 admitted to Danish ICUs from 10th March 2020 to 30th June 2021 were included. We registered coagulation variables at admission, and all thromboembolic and bleeding events, and the use of heparins during ICU stay. Variables associated with thrombosis and bleeding and any association with 90-day mortality were estimated using Cox regression analyses. RESULTS: We included 1369 patients in this sub-study; 158 (12%, 95% confidence interval 10-13) had a thromboembolic event in ICU and 309 (23%, 20-25) had a bleeding event, among whom 81 patients (6%, 4.8-7.3) had major bleeding. We found that mechanical ventilation and increased D-dimer were associated with thrombosis and mechanical ventilation, low platelet count and presence of haematological malignancy were associated with bleeding. Most patients (76%) received increased doses of thromboprophylaxis during their ICU stay. Thromboembolic events were not associated with mortality in adjusted analysis (hazard ratio 1.35 [0.91-2.01, p = .14], whereas bleeding events were 1.55 [1.18-2.05, p = .002]). CONCLUSIONS: Both thromboembolic and bleeding events frequently occurred in ICU patients with COVID-19. Based on these data, it is not apparent that increased doses of thromboprophylaxis were beneficial.

An increased potential for organ donors may be found among patients with out-of-hospital cardiac arrest.

INTRODUCTION: A prehospital system where obvious futile cases may be terminated prehospitally by physicians may reduce unethical treatment of dying patients. Withholding treatment in futile cases may seem ethically sound but may keep dying patients from becoming organ donors. The objective of this study was to characterise the prehospital patients who underwent organ donation. The aim was to alert prehospital physicians to a potential for an increase in the organ donor pool by considering continued treatment even in some prehospital patients with obvious fatal lesions or illness. METHODS: This is a retrospective register-based study from the Region of Southern Denmark. The prehospital medical records from patients who underwent organ donation after prehospital care from 1st of January 2016-31st of December 2020 were screened for inclusion. The outcome measures were prehospital diagnosis, vital parameters, and critical interventions. RESULTS: In the five year period, one-hundred-and-fifty-one patients were entered into a donation process in the health region following prehospital care. Sixteen patients were excluded due to limitations in data availability. Of the 135 patients included, 36.3% had a stroke. 36.7% of these patients were intubated prehospitally. 15.6% had subarachnoideal haemorrhage. 66.7% of these were intubated prehospitally. 10.4% suffered from head trauma. 64.3% of these patients were intubated at the scene. In 21.5% of the patients, the prehospitally assigned tentative diagnosis was missing or included a diverse spectrum of medical and surgical emergencies. Twenty-two patients (16.3%) were resuscitated from cardiac arrest. 81.8% were intubated at the scene. CONCLUSION: The majority of the patients who became organ donors presented prehospitally with intracranial pathology. However, 30% of the patients that later underwent an organ donation process had other prehospital diagnoses. Among these, one patient in six had out-of-hospital cardiac arrest. Termination of treatment in patients with cardiac arrest is not uncommon in physician-manned prehospital emergency medical systems. An organ donation process cannot be initiated prehospitally but can be shut down if treatment is withheld or terminated. We contend that there is a potential for enlarging the donor pool if the decision processes in out-of-hospital cardiac arrest include considerations concerning future procurement of organ donors.

International initiation and termination of resuscitation practices: Protocol of a cross-sectional survey.

BACKGROUND: Substantial variation in survival following out-of-hospital cardiac arrest (OHCA) is described both internationally and nationally. The Utstein factors account for half of the variation, but the remaining is not fully understood. Local regulations or guidelines concerning the withholding and termination of resuscitation may influence the reporting of cardiac arrests when comparing outcomes between different Emergency Medical Service systems. METHOD: We have developed an online cross-sectional mixed-methods explanatory design survey aimed at describing the international and national variations in the initiation, the termination of resuscitation, and the refraining from resuscitation of adult patients (>18 years of age) suffering from non-traumatic OHCA. The respondents will be national experts and the questionnaire will be distributed among members of European Prehospital Research Alliance, the International Liaison Committee of Resuscitation, the European Resuscitation Council, and the Resuscitation Academy. Each invited country will have to identify at least two national experts with special expertise in prehospital resuscitation practices. We exclude countries with less than two respondents. RESULTS: The survey will provide both quantitative and qualitative data. Quantitative data will be presented as frequencies and proportions. Qualitative data will be analyzed using content analysis. CONCLUSION: This survey could be of importance in understanding the multiple factors leading to the substantial variation in survival found following OHCA. Furthermore, the interpretation of future studies on OHCA from different settings may be improved to further increase survival following OHCA.

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 a core outcome set for general intensive care unit patients-A protocol.

INTRODUCTION: Different outcomes are reported in randomised clinical trials (RCTs) in intensive care unit (ICU) patients, and no core outcome set (COS) is available for ICU patients in general. Accordingly, we aim to develop a COS for ICU patients in general. METHODS: The COS will be developed in accordance with the Core Outcome Measures in Effectiveness Trials (COMET) Handbook, using a modified Delphi consensus process and semi-structured interviews involving adults who have survived acute admission to an ICU, family members, clinicians, researchers and other stakeholders. The modified Delphi process will include two steps. Step 1: conduction of a modified Delphi survey, developed and informed by combining the outputs of a literature search of outcomes in previous COSs and semi-structured interviews with key stakeholders. We plan at least two survey rounds to obtain consensus and refine the COS. Step 2: a consensus process regarding instruments or definitions to be recommended for the measurements of the outcomes selected in Step 1. A 'patient and public involvement panel' consisting of a smaller group of patients, family members, clinicians and researchers will be included in the development, analysis and interpretation of the COS. DISCUSSION: The outlined multiple method studies will establish a COS for ICU patients in general, which may be used to increase the standardisation and comparability of results of RCTs conducted in patients in the ICU setting.

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.

Considerations of organ donation among prehospital physicians.

INTRODUCTION: Moderate to severe respiratory distress among patients with COVID-19 is associated with a high mortality. This study evaluated ventilator support and mortality by Do Intubate (DI) or Do Not Intubate (DNI) orders. METHODS: This was a retrospective study of patients with COVID-19 and a supplemental oxygen requirement of ≥ 15 l/min. The patients were divided into two groups corresponding to the first and second wave of COVID-19 and were subsequently further divided according to DI and DNI orders and analysed regarding need of ventilator support and mortality. RESULTS: The study included 178 patients. The mortality was 24% for patients with DI orders (n = 115) and 81% for patients with DNI orders (n = 63) increasing to 98% (n = 46) for patients with DNI orders and very high flow oxygen requirements (≥ 30 l/min.). From the first to the second wave of COVID-19, the use of constant continuous positive airway pressure (cCPAP) increased from 71% to 91% (p less-than 0.001), whereas the use of mechanical ventilation decreased from 54% to 28% (odds ratio = 0.38 (95% confidence interval: 0.17-0.85)). CONCLUSION: The mortality was high for patients with DNI orders and respiratory distress with very high levels in supplemental oxygen in both the first and second wave of COVID-19 despite an increase in use of cCPAP and treatment with dexamethasone and remdesivir during the second wave. Hence, careful evaluation on transition to palliative care must be considered for these patients. FUNDING: none. TRIAL REGISTRATION: The study was approved by the Danish Patient Safety Authority (record no. 31-1521-309) and the Regional Data Protection Centre (record no. P-2020-492).

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.

Characteristics, interventions, and longer term outcomes of COVID-19 ICU patients in Denmark-A nationwide, observational study.

BACKGROUND: Most data on intensive care unit (ICU) patients with COVID-19 originate in selected populations from stressed healthcare systems with shorter term follow-up. We present characteristics, interventions and longer term outcomes of the entire, unselected cohort of all ICU patients with COVID-19 in Denmark where the ICU capacity was not exceeded. METHODS: We identified all patients with SARS-CoV-2 admitted to any Danish ICU from 10 March to 19 May 2020 and registered demographics, chronic comorbidities, use of organ support, length of stay, and vital status from patient files. Risk factors for death were analyzed using adjusted Cox regression analysis. RESULTS: There were 323 ICU patients with confirmed COVID-19. Median age was 68 years, 74% were men, 50% had hypertension, 21% diabetes, and 20% chronic pulmonary disease; 29% had no chronic comorbidity. Invasive mechanical ventilation was used in 82%, vasopressors in 83%, renal replacement therapy in 26%, and extra corporeal membrane oxygenation in 8%. ICU stay was median 13 days (IQR 6-22) and hospital stay 19 days (11-30). Median follow-up was 79 days. At end of follow-up, 118 had died (37%), 15 (4%) were still in hospital hereof 4 in ICU as of 16 June 2020. Risk factors for mortality included male gender, age, chronic pulmonary disease, active cancer, and number of co-morbidities. CONCLUSIONS: In this nationwide, population-based cohort of ICU patients with COVID-19, longer term survival was high despite high age and substantial use of organ support. Male gender, age, and chronic co-morbidities, in particular chronic pulmonary disease, were associated with increased risk of death.

[Treatment of out-of-hospital cardiac arrest with mechanical cardiopulmonary resuscitation].

This review provides a summary of treatment of cardiac arrest with mechanical cardiopulmonary resuscitation (CPR). CPR provides chest compressions according to guidelines in the treatment of out-of-hospital cardiac arrest. This is useful in situations where CPR cannot be safely delivered (e.g. during transportation and prolonged CPR). Randomized controlled trials have not shown improved patient outcomes after treatment with mechanical CPR compared to manual CPR. Mechanical CPR can, like manual CPR, cause injuries, and some may be life-threatening. Mechanical CPR is therefore recommended as an adjunct to manual CPR in special circumstances but not used routinely.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists. METHODS: The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals. DISCUSSION: The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

Ketamine as an Anesthetic for Patients with Acute Brain Injury: A Systematic Review.

For years, the use of ketamine as an anesthetic to patients suffering from acute brain injury has been debated because of its possible deleterious effects on the cerebral circulation and thus on the cerebral perfusion. Early studies suggested that ketamine could increase the intracranial pressure thus lowering the cerebral perfusion and hence reduce the oxygen supply to the injured brain. However, more recent studies are less conclusive and might even indicate that patients with acute brain injury could benefit from ketamine sedation. This systematic review summarizes the evidence regarding the use of ketamine in patients suffering from traumatic brain injury. Databases were searched for studies using ketamine in acute brain injury. Outcomes of interest were mortality, intracranial pressure, cerebral perfusion pressure, blood pressure, heart rate, spreading depolarizations, and neurological function. In total 11 studies were included. The overall level of evidence concerning the use of ketamine in brain injury is low. Only two studies found a small increase in intracranial pressure, while two small studies found decreased levels of intracranial pressure following ketamine administration. We found no evidence of harm during ketamine use in patients suffering from acute brain injury.

Does the "Morning Morality Effect" Apply to Prehospital Anaesthesiologists? An Investigation into Diurnal Changes in Ethical Behaviour.

The "morning morality effect"-the alleged phenomenon that people are more likely to act in unethical ways in the afternoon when they are tired and have less self-control than in the morning-may well be expected to influence prehospital anaesthesiologist manning mobile emergency care units (MECUs). The working conditions of these units routinely entail fatigue, hunger, sleep deprivation and other physical or emotional conditions that might make prehospital units predisposed to exhibit the "morning morality effect". We investigated whether this is in fact the case by looking at the distribution of patient transports to hospital with and without physician escort late at night at the end of the shift as a surrogate marker for changing thresholds in ethical behaviour. All missions over a period of 11 years in the MECU in Odense were reviewed. Physician-escorted transports to hospital were compared with non-physician-escorted transports during daytime, evening, and night-time (which correlates with time on the 24 h shifts). In total, 26,883 patients were transported to hospital following treatment by the MECU. Of these, 27.4% (26.9%-27.9%) were escorted to the hospital. The ratio of patient transports to hospital with and without physician escort during the three periods of the day did not differ (p = 1.00). We found no evidence of changes in admission patterns over the day. Thus, no evidence of the expected "morning morality effect" could be found in a prehospital physician-manned emergency care unit.

Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan.

INTRODUCTION: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. METHODS: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. DISCUSSION: The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding the IV fluid therapy in adults with septic shock.

The immune response is affected for at least three weeks after extensive surgery for ovarian cancer.

INTRODUCTION: The treatment of women with ovarian cancer in advanced stages consists of extensive surgery followed by chemotherapy initiated three weeks after surgery. In this study, selected immune parameters were investigated to elucidate when the immune system is normalised following the operation. METHODS: Ten women undergoing extensive surgery for ovarian cancer were compared with a control group of ten women undergoing abdominal hysterectomy for a benign diagnosis. Blood samples were collected over a period of 21 days post-operatively. The levels of interleukin-6, interleukin-8, interleukin-10 and the activity and total frequency of natural killer cells were measured. RESULTS: Interleukin-6 and interleukin-10 were significantly elevated immediately after the operation and also after 21 days. The total population of natural killercells and the total activity were reduced. The total activity of natural killer-cells did not normalise within 21 days. CONCLUSIONS: The level of the cytokines interleukin-6 and interleukin-10 is increased 21 days after the operation, and the function of natural killer cells is not normalised at 21 days after surgery. FUNDING: The study received funding from Odense University Hospital Free Research Fund. TRIAL REGISTRATION: not relevant.