Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B trial): protocol for a mixed-methods process evaluation of a randomised controlled trial.

INTRODUCTION: An association between deep sedation and adverse short-term outcomes has been demonstrated although this evidence has been inconsistent. The A2B (alpha-2 agonists for sedation in critical care) sedation trial is designed to determine whether the alpha-2 agonists clonidine and dexmedetomidine, compared with usual care, are clinically and cost-effective. The A2B intervention is a complex intervention conducted in 39 intensive care units (ICUs) in the UK. Multicentre organisational factors, variable cultures, perceptions and practices and the involvement of multiple members of the healthcare team add to the complexity of the A2B trial. From our pretrial contextual exploration it was apparent that routine practices such as type and frequency of pain, agitation and delirium assessment, as well as the common sedative agents used, varied widely across the UK. Anticipated challenges in implementing A2B focused on the impact of usual practice, perceptions of risk, ICU culture, structure and the presence of equipoise. Given this complexity, a process evaluation has been embedded in the A2B trial to uncover factors that could impact successful delivery and explore their impact on intervention delivery and interpretation of outcomes. METHODS AND ANALYSIS: This is a mixed-methods process evaluation guided by the A2B intervention logic model. It includes two phases of data collection conducted during and at the end of trial. Data will be collected using a combination of questionnaires, stakeholder interviews and routinely collected trial data. A framework approach will be used to analyse qualitative data with synthesis of data within and across the phases. The nature of the relationship between delivery of the A2B intervention and the trial primary and secondary outcomes will be explored. ETHICS AND DISSEMINATION: All elements of the A2B trial, including the process evaluation, are approved by Scotland A Research Ethics Committee (Ref. 18/SS/0085). Dissemination will be via publications, presentations and media engagement. TRIAL REGISTRATION NUMBER: NCT03653832.

Hypothermia vs Normothermia in Patients With Cardiac Arrest and Nonshockable Rhythm: A Meta-Analysis.

Importance: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable. Objective: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm. Data Sources: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis. Study Selection: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score. Data Extraction and Synthesis: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation. Main Outcomes and Measures: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5. Results: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups. Conclusions and Relevance: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK.

INTRODUCTION: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care. METHODS AND ANALYSIS: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs. ETHICS AND DISSEMINATION: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03653832.

COVID-19-associated pulmonary aspergillosis in mechanically ventilated patients: a prospective, multicentre UK study.

BACKGROUND: Invasive pulmonary aspergillosis is a complication of severe COVID-19, with regional variation in reported incidence and mortality. We describe the incidence, risk factors and mortality associated with COVID-19-associated pulmonary aspergillosis (CAPA) in a prospective, multicentre UK cohort. METHODS: From March 2020 to March 2021, 266 mechanically ventilated adults with COVID-19 were enrolled across 5 UK hospital intensive care units (ICUs). CAPA was defined using European Confederation for Medical Mycology and the International Society for Human and Animal Mycology criteria and fungal diagnostics performed on respiratory and serum samples. RESULTS: Twenty-nine of 266 patients (10.9%) had probable CAPA, 14 (5.2%) possible CAPA and none proven CAPA. Probable CAPA was diagnosed a median of 9 (IQR 7-16) days after ICU admission. Factors associated with probable CAPA after multivariable logistic regression were cumulative steroid dose given within 28 days prior to ICU admission (adjusted OR (aOR) 1.16; 95% CI 1.01 to 1.43 per 100 mg prednisolone-equivalent), receipt of an interleukin (IL)-6 inhibitor (aOR 2.79; 95% CI 1.22 to 6.48) and chronic obstructive pulmonary disease (COPD) (aOR 4.78; 95% CI 1.13 to 18.13). Mortality in patients with probable CAPA was 55%, vs 46% in those without. After adjustment for immortal time bias, CAPA was associated with an increased risk of 90-day mortality (HR 1.85; 95% CI 1.07 to 3.19); however, this association did not remain statistically significant after further adjustment for confounders (adjusted HR 1.57; 95% CI 0.88 to 2.80). There was no difference in mortality between patients with CAPA prescribed antifungals (9 of 17; 53%) and those who were not (7 of 12; 58%) (p=0.77). INTERPRETATION: In this first prospective UK study, probable CAPA was associated with corticosteroid use, receipt of IL-6 inhibitors and pre-existing COPD. CAPA did not impact mortality following adjustment for prognostic variables.

Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial.

Importance: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. Objectives: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. Design, Setting, and Participants: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. Interventions: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher). Main outcomes and measures: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. Results: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). Conclusions: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common. Trial Registration: ClinicalTrials.gov Identifier: NCT02908308.

Comparison of four clinical risk scores in comatose patients after out-of-hospital cardiac arrest.

BACKGROUND AND AIMS: Several different scoring systems for early risk stratification after out-of-hospital cardiac arrest have been developed, but few have been validated in large datasets. The aim of the present study was to compare the well-validated Out-of-hospital Cardiac Arrest (OHCA) and Cardiac Arrest Hospital Prognosis (CAHP)-scores to the less complex MIRACLE2- and Target Temperature Management (TTM)-scores. METHODS: This was a post-hoc analysis of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Missing data were handled by multiple imputation. The primary outcome was discriminatory performance assessed as the area under the receiver operating characteristics-curve (AUROC), with the outcome of interest being poor functional outcome or death (modified Rankin Scale 4-6) at 6 months after OHCA. RESULTS: Data on functional outcome at 6 months were available for 1829 cases, which constituted the study population. The pooled AUROC for the MIRACLE2-score was 0.810 (95% CI 0.790-0.828), 0.835 (95% CI 0.816-0.852) for the TTM-score, 0.820 (95% CI 0.800-0.839) for the CAHP-score and 0.770 (95% CI 0.748-0.791) for the OHCA-score. At the cut-offs needed to achieve specificities >95%, sensitivities were <40% for all four scoring systems. CONCLUSIONS: The TTM-, MIRACLE2- and CAHP-scores are all capable of providing objective risk estimates accurate enough to be used as part of a holistic patient assessment after OHCA of a suspected cardiac origin. Due to its simplicity, the MIRACLE2-score could be a practical solution for both clinical application and risk stratification within trials.

Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. METHODS: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2], 50 to 55 mm Hg) or normocapnia (target Paco2, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. RESULTS: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. CONCLUSIONS: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.).

Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest.

Importance: Blood phosphorylated tau (p-tau) and amyloid-ß peptides (Aß) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known. Objective: To evaluate whether the levels and trajectories of blood p-tau, Aß42, and Aß40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest. Design, Setting, and Participants: This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aß42, and Aß40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest. Exposures: Serum p-tau, Aß42, and Aß40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators. Main Outcomes and Measures: Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). Results: This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aß42 and Aß40 concentrations increased over time in most patients but were only weakly associated with neurological outcome. Conclusions and Relevance: In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aß peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

Associations between enteral nutrition and outcomes in the SUP-ICU trial: Protocol for exploratory post hoc analyses.

Critically ill patients are at risk of gastrointestinal (GI) bleeding. Counter measures to minimise this risk include the use of pharmacological stress ulcer prophylaxis (SUP). The effect of enteral nutrition as SUP on GI bleeding event rates is unknown. There are conflicting data describing the effect of co-administration of enteral nutrition with pharmacological SUP, and there is substantial variation in practice. We aim to conduct an exploratory post hoc analysis to evaluate the association of enteral nutrition with clinically important GI bleed rates in ICU patients included in the SUP-ICU trial, and to explore any interactions between enteral nutrition and pharmacologic SUP on patient outcomes. The SUP-ICU trial dataset will be used to assess if enteral nutrition is associated with the outcomes of interest. Extended Cox models will be used considering relevant competing events, including treatment allocation (SUP or placebo) and enteral nutrition as a daily time-varying covariate, with additional adjustment for severity of illness (SAPS II). Results will be presented as adjusted hazard ratios for treatment allocation and enteral nutrition, and for treatment allocation and enteral nutrition considering potential interactions with the other variable, all with 95% confidence intervals and p-values for the tests of interaction. All results will be considered as exploratory only. This post hoc analysis may yield important insights to guide practice and inform the design of future randomised clinical trial investigating the effect of enteral nutrition on GI bleeding.

Dexmedetomidine and Propofol Sedation in Critically Ill Patients and Dose-associated 90-Day Mortality: A Secondary Cohort Analysis of a Randomized Controlled Trial (SPICE III).

Rationale: The SPICE III (Sedation Practice in Intensive Care Evaluation) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation. Objectives: To quantify the association of different infusion rates of dexmedetomidine and propofol, given in combination, with mortality and to determine if this is modified by age. Methods: We included 1,177 patients randomized in SPICE III to receive dexmedetomidine and given supplemental propofol, stratified by age (>65 or ⩽65 yr). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality. Measurements and Main Results: Younger patients (598 of 1,177 [50.8%]) received significantly higher doses of both sedatives compared with older patients to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 µg/kg/h) was associated with reduced adjusted mortality in younger but not older patients. This was consistent with multivariable regression modeling (hazard ratio, 0.59; 95% confidence interval, 0.43-0.78; P < 0.0001) adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients, using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality (hazard ratio, 1.30; 95% confidence interval, 1.03-1.65; P = 0.029). Conclusions: In patients ⩽65 years of age sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registered with www.clinicaltrials.gov (NCT01728558).

Brain injury markers in blood predict signs of hypoxic ischaemic encephalopathy on head computed tomography after cardiac arrest.

BACKGROUND/AIM: Signs of hypoxic ischaemic encephalopathy (HIE) on head computed tomography (CT) predicts poor neurological outcome after cardiac arrest. We explore whether levels of brain injury markers in blood could predict the likelihood of HIE on CT. METHODS: Retrospective analysis of CT performed at 24-168 h post cardiac arrest on clinical indication within the Target Temperature Management after out-of-hospital cardiac arrest-trial. Biomarkers prospectively collected at 24- and 48 h post-arrest were analysed for neuron specific enolase (NSE), neurofilament light (NFL), total-tau and glial fibrillary acidic protein (GFAP). HIE was assessed through visual evaluation and quantitative grey-white-matter ratio (GWR) was retrospectively calculated on Swedish subjects with original images available. RESULTS: In total, 95 patients were included. The performance to predict HIE on CT (performed at IQR 73-116 h) at 48 h was similar for all biomarkers, assessed as area under the receiving operating characteristic curve (AUC) NSE 0.82 (0.71-0.94), NFL 0.79 (0.67-0.91), total-tau 0.84 (0.74-0.95), GFAP 0.79 (0.67-0.90). The predictive performance of biomarker levels at 24 h was AUC 0.72-0.81. At 48 h biomarker levels below Youden Index accurately excluded HIE in 77.3-91.7% (negative predictive value) and levels above Youden Index correctly predicted HIE in 73.3-83.7% (positive predictive value). NSE cut-off at 48 h was 48 ng/ml. Elevated biomarker levels irrespective of timepoint significantly correlated with lower GWR. CONCLUSION: Biomarker levels can assess the likelihood of a patient presenting with HIE on CT and could be used to select suitable patients for CT-examination during neurological prognostication in unconscious cardiac arrest patients.

Mechanical ventilation variables associated with high pulmonary artery pressures in ARDS patients: a post hoc analysis.

BACKGROUND: The relationship between indices of mechanical ventilation and pulmonary artery pressures remains ill-defined in ARDS. As our understanding of mechanical ventilation has progressed, there is now a greater appreciation of the impact of high driving pressures and mechanical power in perpetuating lung injury. However, the relationship between the newer derived indices of mechanical ventilation and pulmonary artery pressure is unclear. We performed a post hoc analysis of the Fluid and Catheters Treatment Trial (FACTT) trial to investigate the associations between mechanical ventilation indices in ARDS patients and the prevalence of pulmonary hypertension. This may help elucidate future clinical targets for more, right ventricular protective, mechanical ventilation strategies. METHODS: We performed a post hoc analysis of the FACTT database to identify ARDS patients who had a pulmonary artery catheter (PAC) inserted and pulmonary artery pressure readings recorded. We excluded any patient with a PAC inserted who was spontaneously breathing, as driving pressure and mechanical power are not validated in this cohort. Three independent analyses were performed: a univariate analysis, to assess for associations between mPAP and mechanical ventilation parameters using Pearson correlation coefficients, a multivariate analysis, to assess for independent associations with mPAP using a multiple regression model according to Akaike's information criteria and finally an analysis for nonlinearity, using the best-fitting model according to the Bayesian information criterion (BIC) from linear, quadratic, fractional polynomial and restricted cubic spline models. RESULTS: All the ventilation parameters demonstrated a significant correlation with mPAP, except tidal volume (once adjusted for respiratory rate) in the univariate analysis. The multivariate analysis demonstrated that the blood pH level, P/F ratio, PaCO2 level, mean airway pressure and the mechanical power indexed to compliance were independently associated with mPAP. In the final nonlinear analysis, associations did not differ from linearity except for 4 variables for which the fractional polynomial was the best-fitting model. These were mechanical power (p = 0.01 compared to the linear model), respiratory rate (p = 0.04), peak pressure (p = 0.03) and mean airway pressure (p = 0.01). Two nonlinear variables associated with mPAP were assessed in more detail, respiratory rate and mechanical power. Inflexion points at a respiratory rate of 16.8 cycles per minute and a mechanical power of 8.8 J/min were demonstrated. CONCLUSIONS: The associations identified between mPAP and mechanical ventilation variables in this analysis would suggest that classical ARDS lung protective strategies, including low tidal volume ventilation and permissive hypercapnia, may negatively impact the management of the subset of ARDS patients with associated right ventricular dysfunction or ACP. Additionally, respiratory rates above 17 cycles per minute show an incremental increase in mPAP. Therefore, increases in tidal volume (within the limitation of driving pressure < 18 cmH20) may represent a more right ventricular protective way to control CO2 and pH.

Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial.

BACKGROUND: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. METHODS: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4-6 on modified Rankin scale). RESULTS: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84-1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80-1.26). CONCLUSIONS: Using a hospital's average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.

Self-reported limitations in physical function are common 6 months after out-of-hospital cardiac arrest.

Title: Self-reported limitations in physical function are common 6 months after out-of-hospital cardiac arrest. Background: Out-of-hospital cardiac arrest (OHCA) survivors generally report good health-related quality of life, but physical aspects of health seem more affected than other domains. Limitations in physical function after surviving OHCA have received little attention. Aims: To describe physical function 6 months after OHCA and compare it with a group of ST elevation myocardial infarction (STEMI) controls, matched for country, age, sex and time of the cardiac event. A second aim was to explore variables potentially associated with self-reported limitations in physical function in OHCA survivors. Methods: A cross-sectional sub-study of the Targeted Temperature Management at 33 °C versus 36 °C (TTM) trial with a follow-up 6 months post-event. Physical function was the main outcome assessed with the self-reported Physical Functioning-10 items scale (PF-10). PF-10 is presented as T-scores (0-100), where 50 represents the norm mean. Scores <47 at a group level, or <45 at an individual level indicate limitations in physical function. Results: 287 OHCA survivors and 119 STEMI controls participated. Self-reported physical function by PF-10 was significantly lower for OHCA survivors compared to STEMI controls (mean 46.0, SD 11.2 vs. 48.8, SD 9.0, p = 0.025). 38% of OHCA survivors compared to 26% of STEMI controls reported limitations in physical function at an individual level (p = 0.022). The most predictive variables for self-reported limitations in physical function in OHCA survivors were older age, female sex, cognitive impairment, and symptoms of anxiety and depression after 6 months. Conclusion: Self-reported limitations in physical function are more common in OHCA survivors compared to STEMI controls. Trial registration: ClinicalTrials.gov Identifier: NCT01946932.

Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial.

BACKGROUND: Targeted temperature management at 33 °C (TTM33) has been employed in effort to mitigate brain injury in unconscious survivors of out-of-hospital cardiac arrest (OHCA). Current guidelines recommend prevention of fever, not excluding TTM33. The main objective of this study was to investigate if TTM33 is associated with mortality in patients with vasopressor support on admission after OHCA. METHODS: We performed a post hoc analysis of patients included in the TTM-2 trial, an international, multicenter trial, investigating outcomes in unconscious adult OHCA patients randomized to TTM33 versus normothermia. Patients were grouped according to level of circulatory support on admission: (1) no-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 mmHg; (2) moderate-vasopressor support MAP < 70 mmHg or any dose of dopamine/dobutamine or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and (3) high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Hazard ratios with TTM33 were calculated for all-cause 180-day mortality in these groups. RESULTS: The TTM-2 trial enrolled 1900 patients. Data on primary outcome were available for 1850 patients, with 662, 896, and 292 patients in the, no-, moderate-, or high-vasopressor support groups, respectively. Hazard ratio for 180-day mortality was 1.04 [98.3% CI 0.78-1.39] in the no-, 1.22 [98.3% CI 0.97-1.53] in the moderate-, and 0.97 [98.3% CI 0.68-1.38] in the high-vasopressor support groups with regard to TTM33. Results were consistent in an imputed, adjusted sensitivity analysis. CONCLUSIONS: In this exploratory analysis, temperature control at 33 °C after OHCA, compared to normothermia, was not associated with higher incidence of death in patients stratified according to vasopressor support on admission. Trial registration Clinical trials identifier NCT02908308 , registered September 20, 2016.

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. There are currently no early biomarkers for prognosis in routine clinical use. Interleukin-6 (IL-6) is a potential biomarker in the context of the established role of neuroinflammation in TBI recovery. Therefore, a systematic review of the literature was performed to assess and summarise the evidence for IL-6 secretion representing a useful biomarker for clinical outcomes. A multi-database literature search between January 1946 and July 2021 was performed. Studies were included if they reported adult TBI patients with IL-6 concentration in serum, cerebrospinal fluid (CSF) and/or brain parenchyma analysed with respect to functional outcome and/or mortality. A synthesis without meta-analysis is reported. Fifteen studies were included, reporting 699 patients. Most patients were male (71.7%), and the pooled mean age was 40.8 years; 78.1% sustained severe TBI. Eleven studies reported IL-6 levels in serum, six in CSF and one in the parenchyma. Five studies on serum demonstrated higher IL-6 concentrations were associated with poorer outcomes, and five showed no signification association. In CSF studies, one found higher IL-6 levels were associated with poorer outcomes, one found them to predict better outcomes and three found no association. Greater parenchymal IL-6 was associated with better outcomes. Despite some inconsistency in findings, it appears that exaggerated IL-6 secretion predicts poor outcomes after TBI. Future efforts require standardisation of IL-6 measurement practices as well as assessment of the importance of IL-6 concentration dynamics with respect to clinical outcomes, ideally within large prospective studies. Prospero registration number: CRD42021271200.

Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators.

Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0-3 vs. 4-6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95-100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.

Mechanically Ventilated Patients Shed High-Titer Live Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) for Extended Periods From Both the Upper and Lower Respiratory Tract.

BACKGROUND: SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome needing intensive care admission and may lead to death. As a virus that transmits by respiratory droplets and aerosols, determining the duration of viable virus shedding from the respiratory tract is critical for patient prognosis, and informs infection-control measures both within healthcare settings and the public domain. METHODS: We prospectively examined upper and lower airway respiratory secretions for both viral RNA and infectious virions in mechanically ventilated patients admitted to the intensive care unit (ICU) of the University Hospital of Wales. Samples were taken from the oral cavity (saliva), oropharynx (subglottic aspirate), or lower respiratory tract (nondirected bronchoalveolar lavage [NBAL] or bronchoalveolar lavage [BAL]) and analyzed by both quantitative PCR (qPCR) and plaque assay. RESULTS: 117 samples were obtained from 25 patients. qPCR showed extremely high rates of positivity across all sample types; however, live virus was far more common in saliva (68%) than in BAL/NBAL (32%). Average titers of live virus were higher in subglottic aspirates (4.5 × 107) than in saliva (2.2 × 106) or BAL/NBAL (8.5 × 106) and reached >108 PFU/mL in some samples. The longest duration of shedding was 98 days, while most patients (14/25) shed live virus for ≥20 days. CONCLUSIONS: ICU patients infected with SARS-CoV-2 can shed high titers of virus both in the upper and lower respiratory tract and tend to be prolonged shedders. This information is important for decision making around cohorting patients, de-escalation of personal protective equipment, and undertaking potential aerosol-generating procedures.

A Clinical Case of COVID-19-Associated Pulmonary Aspergillosis (CAPA), Illustrating the Challenges in Diagnosis (Despite Overwhelming Mycological Evidence).

The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA.

RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic.

BACKGROUND: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. METHODS: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again. RESULTS: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease. CONCLUSION: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.