Improving Outcomes After Post-Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation.

This scientific statement presents a conceptual framework for the pathophysiology of post-cardiac arrest brain injury, explores reasons for previous failure to translate preclinical data to clinical practice, and outlines potential paths forward. Post-cardiac arrest brain injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, and recovery and repair. Previous research has been challenging because of the limitations of laboratory models; heterogeneity in the patient populations enrolled; overoptimistic estimation of treatment effects leading to suboptimal sample sizes; timing and route of intervention delivery; limited or absent evidence that the intervention has engaged the mechanistic target; and heterogeneity in postresuscitation care, prognostication, and withdrawal of life-sustaining treatments. Future trials must tailor their interventions to the subset of patients most likely to benefit and deliver this intervention at the appropriate time, through the appropriate route, and at the appropriate dose. The complexity of post-cardiac arrest brain injury suggests that monotherapies are unlikely to be as successful as multimodal neuroprotective therapies. Biomarkers should be developed to identify patients with the targeted mechanism of injury, to quantify its severity, and to measure the response to therapy. Studies need to be adequately powered to detect effect sizes that are realistic and meaningful to patients, their families, and clinicians. Study designs should be optimized to accelerate the evaluation of the most promising interventions. Multidisciplinary and international collaboration will be essential to realize the goal of developing effective therapies for post-cardiac arrest brain injury.

The impact of frailty and rapid response team activation on patients admitted to the intensive care unit: A case-control matched, observational, single-centre cohort study.

BACKGROUND: Frailty is a multi-dimensional syndrome associated with mortality and adverse outcomes in patients admitted to the intensive care unit (ICU). Further investigation is warranted to explore the interplay among factors such as frailty, clinical deterioration triggering a medical emergency team (MET) review, and outcomes following admission to the ICU. METHODS: Single-centre, retrospective observational case-control study of adult patients (>18 years) admitted to a medical-surgical ICU with (cases) or without (controls) a preceding MET review between 4 h and 14 days prior. Matching was performed for age, ICU admission diagnosis, Acute Physiology and Chronic Health Evaluation III (APACHE III) score and the 8-point Clinical Frailty Scale (CFS). Cox proportional hazard regression modelling was performed to determine associations with 30-day mortality after admission to ICU. RESULTS: A total of 2314 matched admissions were analysed. Compared to non-frail patients (CFS 1-4), mortality was higher in all frail patients (CFS 5-8), at 31% vs. 13%, and in frail patients admitted after MET review at 33%. After adjusting for age, APACHE, antecedent MET review and CFS in the Cox regression, mortality hazard ratio increased by 26% per CFS point and by 3% per APACHE III point, while a MET review was not an independent predictor. Limitations of medical treatment occurred in 30% of frail patients, either with or without a MET antecedent, and this was five times higher compared to non-frail patients. CONCLUSION: Frail patients admitted to ICU have a high short-term mortality. An antecedent MET event was associated with increased mortality but did not independently predict short-term survival when adjusting for confounding factors. The intrinsic significance of frailty should be primarily considered during MET review of frail patients. This study suggests that routine frailty assessment of hospitalised patients would be helpful to set goals of care when admission to ICU could be considered.

Progressive changes in pulmonary gas exchange during invasive respiratory support for COVID-19 associated acute respiratory failure: A retrospective study of the association with 90-day mortality.

BACKGROUND: Ratio of arterial pressure of oxygen and fraction of inspired oxygen (P/F ratio) together with the fractional dead space (Vd/Vt) provides a global assessment of pulmonary gas exchange. The aim of this study was to assess the potential value of these variables to prognosticate 90-day survival in patients with COVID-19 associated ARDS admitted to the Intensive Care Unit (ICU) for invasive ventilatory support. METHODS: In this single-center observational, retrospective study, P/F ratios and Vd/Vt were assessed up to 4 weeks after ICU-admission. Measurements from the first 2 weeks were used to evaluate the predictive value of P/F ratio and Vd/Vt for 90-day mortality and reported by the adjusted hazard ratio (HR) and 95% confidence intervals [95%CI] by Cox proportional hazard regression. RESULTS: Almost 20,000 blood gases in 130 patients were analyzed. The overall 90-day mortality was 30% and using the data from the first ICU week, the HR was 0.85 [0.77-0.94] for every 10 mmHg increase in P/F ratio and 1.61 [1.20-2.16] for every 0.1 increase in Vd/Vt. In the second week, the HR for 90-day mortality was 0.82 [0.75-0.89] for every 10 mmHg increase in P/F ratio and 1.97 [1.42-2.73] for every 0.1 increase in Vd/Vt. CONCLUSION: The progressive changes in P/F ratio and Vd/Vt in the first 2 weeks of invasive ventilatory support for COVID-19 ARDS were significant predictors for 90-day mortality.

Frailty in the prediction of delirium in the intensive care unit: A secondary analysis of the Deli study.

BACKGROUND: Delirium is an acute disorder of attention and cognition with an incidence of up to 70% in the adult intensive care setting. Due to the association with significantly increased morbidity and mortality, it is important to identify who is at the greatest risk of an acute episode of delirium while being cared for in the intensive care. The objective of this study was to determine the ability of the cumulative deficit frailty index and clinical frailty scale to predict an acute episode of delirium among adults admitted to the intensive care. METHODS: This study is a secondary analysis of the Deli intervention study, a hybrid stepped-wedge cluster randomized controlled trial to assess the effectiveness of a nurse-led intervention to reduce the incidence and duration of delirium among adults admitted to the four adult intensive care units in the south-west of Sydney, Australia. Important predictors of delirium were identified using a bootstrap approach and the absolute risks, based on the cumulative deficit frailty index and the clinical frailty scale are presented. RESULTS: During the 10-mth data collection period (May 2019 and February 2020) 2566 patients were included in the study. Both the cumulative deficit frailty index and the clinical frailty scale on admission, plus age, sex, and APACHE III (AP III) score were able to discriminate between patients who did and did not experience an acute episode of delirium while in the intensive care, with AUC of 0.701 and 0.703 (moderate discriminatory ability), respectively. The addition of a frailty index to a prediction model based on age, sex, and APACHE III score, resulted in net reclassified of risk. Nomograms to individualize the absolute risk of delirium using these predictors are also presented. CONCLUSION: We have been able to show that both the cumulative deficits frailty index and clinical frailty scale predict an acute episode of delirium among adults admitted to intensive care.

Protracted fibrinolysis resistance following cardiac surgery with cardiopulmonary bypass: A prospective observational study of clinical associations and patient outcomes.

BACKGROUND: Surgery on cardiopulmonary bypass (CPB) elicits a pleiomorphic systemic host response which, when severe, requires prolonged intensive care support. Given the substantial cross-talk between inflammation, coagulation, and fibrinolysis, the aim of this hypothesis-generating observational study was to document the kinetics of fibrinolysis recovery post-CPB using ClotPro® point-of-care viscoelastometry. Tissue plasminogen activator-induced clot lysis time (TPA LT, s) was correlated with surgical risk, disease severity, organ dysfunction and intensive care length of stay (ICU LOS). RESULTS: In 52 patients following CPB, TPA LT measured on the first post-operative day (D1) correlated with surgical risk (EuroScore II, Spearman's rho .39, p < .01), time on CPB (rho = .35, p = .04), disease severity (APACHE II, rho = .52, p < .001) and organ dysfunction (SOFA, rho = .51, p < .001) scores, duration of invasive ventilation (rho = .46, p < .01), and renal function (eGFR, rho = -.65, p < .001). In a generalized linear regression model containing TPA LT, CPB run time and markers of organ function, only TPA LT was independently associated with the ICU LOS (odds ratio 1.03 [95% CI 1.01-1.05], p = .01). In a latent variables analysis, the association between TPA LT and the ICU LOS was not mediated by renal function and thus, by inference, variation in the clearance of intraoperative tranexamic acid. CONCLUSIONS: This observational hypothesis-generating study in patients undergoing cardiac surgery with cardiopulmonary bypass demonstrated an association between the severity of fibrinolysis resistance, measured on the first post-operative day, and the need for extended postoperative ICU level support. Further examination of the role of persistent fibrinolysis resistance on the clinical outcomes in this patient cohort is warranted through large-scale, well-designed clinical studies.

Furosemide versus placebo for fluid overload in intensive care patients-The randomised GODIF trial second version: Statistical analysis plan.

BACKGROUND: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. METHODS: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. CONCLUSION: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. TRIAL REGISTRATIONS: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.

Volume responsiveness revisited: an observational multicenter study of continuous versus binary outcomes combining echocardiography and venous return physiology.

Echocardiography can assess cardiac preload when fluid administration is used to treat acute circulatory failure. Changes in stroke volume (SV) are inherently a continuous phenomenon relating to the pressure gradient for venous return (VRdP). However, most clinical studies have applied a binary definition based on a fractional change in SV. This study tested the hypothesis that calculating the analog mean systemic filling pressure (Pmsa) and VRdP would enhance echocardiography to describe SV responses to a preload challenge. We investigated 540 (379 males) patients during a standardized passive leg raising (PLR) maneuver. Patients were further categorized by the presence of impaired right ventricular function (impRV) or increased intra-abdominal hypertension (IAH). Multivariable linear regression identified VRdP (partial r = -0.26, P < 0.001), ventilatory-induced variations in superior vena cava diameter (partial r = 0.43, P < 0.001), and left ventricular outflow tract maximum-Doppler velocity (partial r = 0.13, P < 0.001) as independent variables associated with SV changes. The model explained 38% (P < 0.001) of the SV change in the whole cohort and 64% (P < 0.001) when excluding patients with impRV or IAH. The correlation between Pmsa or VRdP and SV changes lost statistical significance with increasing impRV or IAH. A binary definition of volume responsiveness (>10% increase in SV) generated an area under the curve of 0.79 (P < 0.001) in logistic regression but failed to identify Pmsa or VRdP as independent variables and overlooked the confounding influence of impRV and IAH. In conclusion, venous return physiology may enhance echocardiographic assessments of volume responsiveness, which should be based on continuous changes in stroke volume.NEW & NOTEWORTHY The analog mean systemic filling pressure and the pressure gradient for venous return combined with echocardiography predict continuous changes in stroke volume following a passive leg raising maneuver. The confounding effects of impaired right ventricular function and increased intra-abdominal pressure can be identified. Using a binary cutoff for the fractional change in stroke volume, common in previous clinical research, fails to identify the importance of variables relevant to venous return physiology and confounding conditions.

Atrial Fibrillation (AFIB) in the ICU: Incidence, Risk Factors, and Outcomes: The International AFIB-ICU Cohort Study.

OBJECTIVES: To assess the incidence, risk factors, and outcomes of atrial fibrillation (AF) in the ICU and to describe current practice in the management of AF. DESIGN: Multicenter, prospective, inception cohort study. SETTING: Forty-four ICUs in 12 countries in four geographical regions. SUBJECTS: Adult, acutely admitted ICU patients without a history of persistent/permanent AF or recent cardiac surgery were enrolled; inception periods were from October 2020 to June 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 1,423 ICU patients and analyzed 1,415 (99.4%), among whom 221 patients had 539 episodes of AF. Most (59%) episodes were diagnosed with continuous electrocardiogram monitoring. The incidence of AF was 15.6% (95% CI, 13.8-17.6), of which newly developed AF was 13.3% (11.5-15.1). A history of arterial hypertension, paroxysmal AF, sepsis, or high disease severity at ICU admission was associated with AF. Used interventions to manage AF were fluid bolus 19% (95% CI 16-23), magnesium 16% (13-20), potassium 15% (12-19), amiodarone 51% (47-55), beta-1 selective blockers 34% (30-38), calcium channel blockers 4% (2-6), digoxin 16% (12-19), and direct current cardioversion in 4% (2-6). Patients with AF had more ischemic, thromboembolic (13.6% vs 7.9%), and severe bleeding events (5.9% vs 2.1%), and higher mortality (41.2% vs 25.2%) than those without AF. The adjusted cause-specific hazard ratio for 90-day mortality by AF was 1.38 (95% CI, 0.95-1.99). CONCLUSIONS: In ICU patients, AF occurred in one of six and was associated with different conditions. AF was associated with worse outcomes while not statistically significantly associated with 90-day mortality in the adjusted analyses. We observed variations in the diagnostic and management strategies for AF.

Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study.

BACKGROUND: Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET). METHODS: In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET. RESULTS: Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion. CONCLUSIONS: ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients. TRIAL REGISTRATION: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834 ; retrospectively registered September 15th 2022).

Mechanical ventilation post-bilateral lung transplantation: A scoping review.

BACKGROUND: Evidence from lung protective ventilation (LPV) in the acute respiratory distress syndrome has commonly been applied to guide periprocedural ventilation in lung transplantation. However, this approach may not adequately consider the distinctive features of respiratory failure and allograft physiology in the lung transplant recipient. This scoping review was conducted to systematically map the research describing ventilation and relevant physiological parameters post-bilateral lung transplantation with the aim to identify any associations with patient outcomes and gaps in the current knowledge base. METHODS: To identify relevant publications, comprehensive literature searches of electronic bibliographic databases were conducted with the guidance of an experienced librarian in MEDLINE, EMBASE, SCOPUS and the Cochrane Library. The search strategies were peer-reviewed using the PRESS (Peer Review of Electronic Search Strategies) checklist. The reference lists of all relevant review articles were surveyed. Publications were included in the review if they described relevant ventilation parameters in the immediate post-operative period, published between 2000 and 2022 and involved human subjects undergoing bilateral lung transplantation. Publications were excluded if they included animal models, only single-lung transplant recipients or only patients managed with extracorporeal membrane oxygenation. RESULTS: A total of 1212 articles were screened, 27 were subject to full-text review and 11 were included in the analysis. The quality of the included studies was assessed to be poor with no prospective multi-centre randomised controlled trials. The frequency of reported retrospective LPV parameters was as follows: tidal volume (82%), tidal volume indexed to both donor and recipient body weight (27%) and plateau pressure (18%). Data suggest that undersized grafts are at risk of unrecognised higher tidal volume ventilation indexed to donor body weight. The most reported patient-centred outcome was graft dysfunction severity in the first 72 h. CONCLUSION: This review has identified a significant knowledge gap that indicates uncertainty regarding the safest ventilation practice in lung transplant recipients. The risk may be greatest in patients with established high-grade primary graft dysfunction and undersized allografts, and these factors may define a sub-group that warrants further investigation.

The effect of ketamine and fentanyl on haemodynamics during intubation in pre-hospital and retrieval medicine.

BACKGROUND: Ketamine use for rapid sequence intubation (RSI) is frequent in pre-hospital and retrieval medicine (PHARM) and is associated with potentially deleterious haemodynamic changes, which may be ameliorated by concurrent use of fentanyl. OBJECTIVES: To describe the frequency with which fentanyl is used in conjunction with ketamine in a system where its use is discretionary, and to explore any observed changes in haemodynamics with its use. METHODS: A retrospective observational study of over 800 patients undergoing RSI with ketamine ± fentanyl in the PHARM setting between 2015 and 2019. The primary outcome was the proportion of patients in each group who had a systolic blood pressure (SBP) outside a pre-specified target range, with adjustment for baseline abnormality, within 10 min of anaesthetic induction. RESULTS: Eight hundred and seventy-six patients were anaesthetised with ketamine, of whom 804 were included in the analysis. 669 (83%, 95% CI 80%-86%) received ketamine alone, and 135 (17%, 95% CI 14%-20%) received both fentanyl and ketamine. Median fentanyl dose was 1.1 mcg/kg (IQR 0.75-1.5 mcg/kg). Systolic blood pressure (SBP) at induction was consistently associated with SBP after intubation in multivariable logistic regression, but fentanyl use was not associated with a change in odds of meeting the primary outcome (OR 1.08; 95% CI 0.72-1.60), becoming hypertensive (OR 1.35; 95% CI 0.88-2.07) or hypotensive (OR 0.76; 95% CI 0.47-1.21). CONCLUSIONS: The addition of fentanyl to ketamine for RSI was not associated with an alteration of the odds of post-induction haemodynamic stability, although the doses used were low. These findings justify further study into the optimal dosing of fentanyl during RSI in pre-hospital and retrieval medicine.

Target temperature management following cardiac arrest: a systematic review and Bayesian meta-analysis.

BACKGROUND: Temperature control with target temperature management (TTM) after cardiac arrest has been endorsed by expert societies and adopted in international clinical practice guidelines but recent evidence challenges the use of hypothermic TTM. METHODS: Systematic review and Bayesian meta-analysis of clinical trials on adult survivors from cardiac arrest undergoing TTM for at least 12 h comparing TTM versus no TTM or with a separation > 2 °C between intervention and control groups using the PubMed/MEDLINE, EMBASE, CENTRAL databases from inception to 1 September 2021 (PROSPERO CRD42021248140). All randomised and quasi-randomised controlled trials were considered. The risk ratio and 95% confidence interval for death (primary outcome) and unfavourable neurological recovery (secondary outcome) were captured using the original study definitions censored up to 180 days after cardiac arrest. Bias was assessed using the updated Cochrane risk-of-bias for randomised trials tool and certainty of evidence assessed using the Grading of Recommendation Assessment, Development and Evaluation methodology. A hierarchical robust Bayesian model-averaged meta-analysis was performed using both minimally informative and data-driven priors and reported by mean risk ratio (RR) and its 95% credible interval (95% CrI). RESULTS: In seven studies (three low bias, three intermediate bias, one high bias, very low to low certainty) recruiting 3792 patients the RR by TTM 32-34 °C was 0.95 [95% CrI 0.78-1.09] for death and RR 0.93 [95% CrI 0.84-1.02] for unfavourable neurological outcome. The posterior probability for no benefit (RR ≥ 1) by TTM 32-34 °C was 24% for death and 12% for unfavourable neurological outcome. The posterior probabilities for favourable treatment effects of TTM 32-34 °C were the highest for an absolute risk reduction of 2-4% for death (28-53% chance) and unfavourable neurological outcome (63-78% chance). Excluding four studies without active avoidance of fever in the control arm reduced the probability to achieve an absolute risk reduction > 2% for death or unfavourable neurological outcome to ≤ 50%. CONCLUSIONS: The posterior probability distributions did not support the use of TTM at 32-34 °C compared to 36 °C also including active control of fever to reduce the risk of death and unfavourable neurological outcome at 90-180 days. Any likely benefit of hypothermic TTM is smaller than targeted in RCTs to date.

Capnodynamic monitoring of lung volume and blood flow in response to increased positive end-expiratory pressure in moderate to severe COVID-19 pneumonia: an observational study.

BACKGROUND: The optimal level of positive end-expiratory pressure (PEEP) during mechanical ventilation for COVID-19 pneumonia remains debated and should ideally be guided by responses in both lung volume and perfusion. Capnodynamic monitoring allows both end-expiratory lung volume ([Formula: see text]) and effective pulmonary blood flow (EPBF) to be determined at the bedside with ongoing ventilation. METHODS: Patients with COVID-19-related moderate to severe respiratory failure underwent capnodynamic monitoring of [Formula: see text] and EPBF during a step increase in PEEP by 50% above the baseline (PEEPlow to PEEPhigh). The primary outcome was a > 20 mm Hg increase in arterial oxygen tension to inspired fraction of oxygen (P/F) ratio to define responders versus non-responders. Secondary outcomes included changes in physiological dead space and correlations with independently determined recruited lung volume and the recruitment-to-inflation ratio at an instantaneous, single breath decrease in PEEP. Mixed factor ANOVA for group mean differences and correlations by Pearson's correlation coefficient are reported including their 95% confidence intervals. RESULTS: Of 27 patients studied, 15 responders increased the P/F ratio by 55 [24-86] mm Hg compared to 12 non-responders (p < 0.01) as PEEPlow (11 ± 2.7 cm H2O) was increased to PEEPhigh (18 ± 3.0 cm H2O). The [Formula: see text] was 461 [82-839] ml less in responders at PEEPlow (p = 0.02) but not statistically different between groups at PEEPhigh. Responders increased both [Formula: see text] and EPBF at PEEPhigh (r = 0.56 [0.18-0.83], p = 0.03). In contrast, non-responders demonstrated a negative correlation (r = - 0.65 [- 0.12 to - 0.89], p = 0.02) with increased lung volume associated with decreased pulmonary perfusion. Decreased (- 0.06 [- 0.02 to - 0.09] %, p < 0.01) dead space was observed in responders. The change in [Formula: see text] correlated with both the recruited lung volume (r = 0.85 [0.69-0.93], p < 0.01) and the recruitment-to-inflation ratio (r = 0.87 [0.74-0.94], p < 0.01). CONCLUSIONS: In mechanically ventilated patients with moderate to severe COVID-19 respiratory failure, improved oxygenation in response to increased PEEP was associated with increased end-expiratory lung volume and pulmonary perfusion. The change in end-expiratory lung volume was positively correlated with the lung volume recruited and the recruitment-to-inflation ratio. This study demonstrates the feasibility of capnodynamic monitoring to assess physiological responses to PEEP at the bedside to facilitate an individualised setting of PEEP. TRIAL REGISTRATION: NCT05082168 (18th October 2021).

Protocol for an individual patient data meta-analysis on blood pressure targets after cardiac arrest.

BACKGROUND: Hypotension is common after cardiac arrest (CA), and current guidelines recommend using vasopressors to target mean arterial blood pressure (MAP) higher than 65 mmHg. Pilot trials have compared higher and lower MAP targets. We will review the evidence on whether higher MAP improves outcome after cardiac arrest. METHODS: This systematic review and meta-analysis will be conducted based on a systematic search of relevant major medical databases from their inception onwards, including MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL), as well as clinical trial registries. We will identify randomised controlled trials published in the English language that compare targeting a MAP higher than 65-70 mmHg in CA patients using vasopressors, inotropes and intravenous fluids. The data extraction will be performed separately by two authors (a third author will be involved in case of disagreement), followed by a bias assessment with the Cochrane Risk of Bias tool using an eight-step procedure for assessing if thresholds for clinical significance are crossed. The outcomes will be all-cause mortality, functional long-term outcomes and serious adverse events. We will contact the authors of the identified trials to request individual anonymised patient data to enable individual patient data meta-analysis, aggregate data meta-analyses, trial sequential analyses and multivariable regression, controlling for baseline characteristics. The certainty of the evidence will be assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. We will register this systematic review with Prospero and aim to redo it when larger trials are published in the near future. CONCLUSIONS: This protocol defines the performance of a systematic review on whether a higher MAP after cardiac arrest improves patient outcome. Repeating this systematic review including more data likely will allow for more certainty regarding the effect of the intervention and possible sub-groups differences.

Management of acute atrial fibrillation in the intensive care unit: An international survey.

BACKGROUND: Atrial fibrillation (AF) is common in intensive care unit (ICU) patients and is associated with poor outcomes. Different management strategies exist, but the evidence is limited and derived from non-ICU patients. This international survey of ICU doctors evaluated the preferred management of acute AF in ICU patients. METHOD: We conducted an international online survey of ICU doctors with 27 questions about the preferred management of acute AF in the ICU, including antiarrhythmic therapy in hemodynamically stable and unstable patients and use of anticoagulant therapy. RESULTS: A total of 910 respondents from 70 ICUs in 14 countries participated in the survey with 24%-100% of doctors from sites responding. Most ICUs (80%) did not have a local guideline for the management of acute AF. The preferred first-line strategy for the management of hemodynamically stable patients with acute AF was observation (95% of respondents), rhythm control (3%), or rate control (2%). For hemodynamically unstable patients, the preferred strategy was observation (48%), rhythm control (48%), or rate control (4%). Overall, preferred antiarrhythmic interventions included amiodarone, direct current cardioversion, beta-blockers other than sotalol, and magnesium in that order. A total of 67% preferred using anticoagulant therapy in ICU patients with AF, among whom 61% preferred therapeutic dose anticoagulants and 39% prophylactic dose anticoagulants. CONCLUSION: This international survey indicated considerable practice variation among ICU doctors in the clinical management of acute AF, including the overall management strategies and the use of antiarrhythmic interventions and anticoagulants.

Association of deranged cerebrovascular reactivity with brain injury following cardiac arrest: a post-hoc analysis of the COMACARE trial.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury. METHODS: A post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TOx) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TOx > 0 indicating impaired reactivity and TOx > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TOx was analysed in the 0-12, 12-24, 24-48 h time-periods and integrated over 0-48 h. The primary outcome was the association between TOx and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3-5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury. RESULTS: In 108 patients with sufficient data to calculate TOx, 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p = 0.002). Integrated TOx for 0-48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [- 1.17 to 2.94] vs. - 2.71 95% CI [- 4.16 to - 1.26], p = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time (p = 0.001), including the high-normal oxygen (p = 0.002), carbon dioxide (p = 0.012) and MAP (p = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups (p < 0.05). NfL concentrations were higher in patients with impaired CVR compared to those with intact CVR (43 IQR [15-650] vs 20 IQR [13-199] pg/ml, p = 0.042). CONCLUSION: Impaired CVR over 48 h was more common in patients with chronic hypertension and associated with poor outcome. Decreased upper MAP bound and a narrower MAP range for maintained CVR were associated with poor outcome and more severe brain injury assessed with NfL. Trial registration ClinicalTrials.gov, NCT02698917 .

Associations between mean systemic filling pressure and acute kidney injury: An observational cohort study following cardiac surgery.

BACKGROUND: Venous congestion has been implied in cardiac surgery-associated acute kidney injury (CSA-AKI). The mean systemic filling pressure may provide a physiologically more accurate estimate of renal venous pressure and renal perfusion pressure but its association with CSA-AKI has not been reported. METHODS: Patients admitted to ICU following cardiac surgery without pre-operative renal dysfunction were included with monitoring of mean arterial pressure (MAP) and central venous pressure (CVP) and cardiac output (CO) to calculate the mean systemic filling pressure analogue (Pmsa ). The AKI-KDIGO guidelines were used to define CSA-AKI. Logistic regression models including CO, heart rate, MAP, CVP and Pmsa were used to ascertain the association with CSA-AKI and reported by odds ratio (OR) with 95% confidence interval (95%CI) and area under the curve (AUROC). RESULTS: One hundred and thirty patients (out of 221 screened) were included of whom 66 (51%) developed CSA-AKI. Patients with CSA-AKI were older, with greater weight and increased stay in ICU while the proportion of comorbidities, type of surgical procedures, APACHE III scores and fluid volumes administered were similar to patients without AKI. The Pmsa , but not CVP, was associated with CSA-AKI (OR 1.2 95%CI [1.16-1.25]). Renal perfusion pressure was associated with CSA-AKI estimated as MAP-Pmsa (OR 0.81 [0.76-0.86]) and MAP-CVP (OR 0.89 [0.85-0.93]) with the former generating a higher AUROC (median difference 0.10 [0.07-0.12], P < .001) in the regression model. CONCLUSIONS: The Pmsa in post-operative cardiac surgery patients was associated with the development of CSA-AKI also when incorporated into estimates of renal perfusion pressure.

Interpreting the results of clinical trials, embracing uncertainty: A Bayesian approach.

Most clinical trials use null hypothesis significance testing with frequentist statistical inference to report P values and confidence intervals for effect estimates. This method leads to a dichotomisation of results as 'significant' or 'non-significant'. A more nuanced interpretation may often be considered and in particular when the majority of the confidence interval for the effect estimate suggests benefit or harm. In contrast to the frequentist dichotomised approach based on a P value, the application of Bayesian statistics allocates credibility to a continuous spectrum of possibilities and for this reason a Bayesian approach to inference is often warranted as it will incorporate uncertainty when updating our current belief with information from a new trial. The use of Bayesian statistics is introduced in this paper for a hypothetical sepsis trial with worked examples in the R language for Statistical Computing environment and the open-source statistical software JASP. It is hoped that this general introduction to Bayesian inference stimulates some interest and confidence among clinicians to consider applying these methods to the interpretation of new evidence for interventions relevant to anaesthesia and intensive care medicine.

Volume status and volume responsiveness in postoperative cardiac surgical patients: An observational, multicentre cohort study.

BACKGROUND: The best strategy to identify patients in whom fluid loading increases cardiac output (CO) following cardiac surgery remains debated. This study examined the utility of a calculated mean systemic filling pressure analogue (Pmsa ) and derived variables to explain the response to a fluid bolus. METHODS: The Pmsa was calculated using retrospective, observational cohort data in the early postoperative period between admission to the intensive care unit and extubation within 6 hours. The venous return pressure gradient (VRdP) was calculated as Pmsa  - central venous pressure. Concurrent changes induced by a fluid bolus in the ratio of the VRdP over Pmsa , the volume efficiency (Evol ), were studied to assess fluid responsiveness. Changes between Pmsa and derived variables and CO were analysed by Wilcoxon rank-sum test, hierarchial clustering and multiple linear regression. RESULTS: Data were analysed for 235 patients who received 489 fluid boluses. The Pmsa increased with consecutive fluid boluses (median difference [range] 1.3 [0.5-2.4] mm Hg, P = .03) with a corresponding increase in VRdP (median difference 0.4 [0.2-0.6] mm Hg, P = .04). Hierarchical cluster analysis only identified Evol and the change in CO within one cluster. The multiple linear regression between Pmsa and its derived variables and the change in CO (overall r2  = .48, P < .001) demonstrated the best partial regression between the continuous change in CO and the concurrent Evol (r = .55, P < .001). CONCLUSION: The mean systemic filling Pmsa enabled a comprehensive interpretation of fluid responsiveness with volume efficiency useful to explain the change in CO as a continuous phenomenon.

New-onset atrial fibrillation in the intensive care unit: Protocol for an international inception cohort study (AFIB-ICU).

INTRODUCTION: New-onset atrial fibrillation (NOAF) is frequently observed in critically ill patients and may be associated with prolonged hospital stay and increased mortality. Considerable variation exists in the reported frequencies of NOAF due to the lack of a standardised definition and detection method. Importantly, there are limited data on NOAF in the intensive care unit (ICU). Thus, we aim to provide contemporary epidemiological data on NOAF in the ICU. METHODS AND ANALYSIS: We have designed an international inception cohort study including at least 1,000 consecutive adult patients acutely admitted to the ICU without prior history of persistent or permanent AF. We will present data on the incidence, risk factors, used management strategies and outcomes of NOAF. We will register data daily during stay in the ICU for a maximum of 90 days after admission. The incidence of NOAF and management strategies used will be presented descriptively, and we will use Cox regression analyses including competing risk analyses to assess risk factors for NOAF and any association with 90-day mortality. CONCLUSION: The outlined international AFIB-ICU inception cohort study will provide contemporary data on the incidence, risk factors, used management strategies and outcomes of NOAF in adult ICU patients. ETHICS AND DISSEMINATION: This observational study poses no risk to the included patients. All participating sites will obtain relevant approvals according to national laws before patient enrollment. Funding sources will have no influence on data handling, analyses or writing of the manuscript. The study report(s) will be submitted to an international peer-reviewed journal.