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Purpose To compare the effectiveness of the intravenous (IV) and intraosseous (IO) routes for drug administration in adults with a cardiac arrest enrolled in the Pre-Hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC2) randomised, controlled trial. Methods Patients were recruited from five National Health Service Ambulance Services in England and Wales from December 2014 through October 2017. Patients with an out-of-hospital cardiac arrest who were unresponsive to initial resuscitation attempts were randomly assigned to 1 mg adrenaline or matching placebo. Intravascular access was established as soon as possible, and IO access was considered if IV access was not possible after two attempts. Results Among patients with out-of-hospital cardiac arrest, 3631 received adrenaline and 3686 received placebo. Amongst these, 1116 (30.1%) and 1121 (30.4%) received the study drug via the IO route. The odds ratios were similar in the IV and IO groups for return of spontaneous circulation (ROSC) at hospital handover [adjusted odds ratio (aOR) 4.07 (95% CI 3.42-4.85) and (aOR 3.98 (95% CI 2.86-5.53), P value for interaction 0.90]; survival to 30 days [aOR 1.67 (1.18-2.35) versus 0.9 (0.4-2.05), P = 0.18]; and favourable neurological outcome [aOR 1.39 (0.93-2.06) versus 0.62 (0.23-1.67), P = 0.14]. Conclusion There was no significant difference in treatment effect (adrenaline versus placebo) on ROSC at hospital handover between drugs administered by the intraosseous route or by the intravenous route. We could not detect any difference in the treatment effect between the IV and IO routes on the longer term outcomes of 30-day survival or favourable neurological outcome at discharge (ISRCTN73485024)., Author(s): Jerry P. Nolan [sup.1] [sup.2], Charles D. Deakin [sup.3] [sup.4], Chen Ji [sup.1], Simon Gates [sup.5], Andy Rosser [sup.6], Ranjit Lall [sup.1], Gavin D. Perkins [sup.1] [sup.7] Author Affiliations: [...]

Purpose To examine the time to drug administration in patients with a witnessed cardiac arrest enrolled in the Pre-Hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC2) randomised controlled trial. Methods The PARAMEDIC2 trial was undertaken across 5 NHS ambulance services in England and Wales with randomisation between December 2014 and October 2017. Patients with an out-of-hospital cardiac arrest who were unresponsive to initial resuscitation attempts were randomly assigned to 1 mg intravenous adrenaline or matching placebo according to treatment packs that were identical apart from treatment number. Participants and study staff were masked to treatment allocation. Results 8016 patients were enrolled, 4902 sustained a witnessed cardiac arrest of whom 2437 received placebo and 2465 received adrenaline. The odds of return of spontaneous circulation decreased in both groups over time but at a greater rate in the placebo arm odds ratio (OR) 0.93 (95% CI 0.92-0.95) compared with the adrenaline arm OR 0.96 (95% CI 0.95-0.97); interaction OR: 1.03, 95% CI 1.01-1.05, p = 0.005. By contrast, although the rate of survival and favourable neurological outcome decreased as time to treatment increased, the rates did not differ between the adrenaline and placebo groups. Conclusion The rate of return of spontaneous circulation, survival and favourable neurological outcomes decrease over time. As time to drug treatment increases, adrenaline increases the chances of return of spontaneous circulation. Longer term outcomes were not affected by the time to adrenaline administration. (ISRCTN73485024)., Author(s): Gavin D. Perkins [sup.1] [sup.2], Claire Kenna [sup.1], Chen Ji [sup.1], Charles D. Deakin [sup.3] [sup.4], Jerry P. Nolan [sup.1] [sup.5], Tom Quinn [sup.6], Charlotte Scomparin [sup.1], Rachael Fothergill [...]

Purpose Myocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects. Methods Two cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values. Results Levosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43-2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers. Conclusion Adding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction., Author(s): David B. Antcliffe [sup.1], Shalini Santhakumaran [sup.2], Robert M. L. Orme [sup.3], Josie K. Ward [sup.1], Farah Al-Beidh [sup.1], Kieran O'Dea [sup.1], Gavin D. Perkins [sup.4] [sup.10], Mervyn Singer [...]

Purpose We performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups. Methods Our pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses. Results Four trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86-1.12] or serious adverse events (RR 1.02, 95% CI 0.82-1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%-3.2%] but fewer arrhythmias (ARD - 2.8%, 95% CI - 0.2% to - 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74-0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion). Conclusions Vasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use., Author(s): Myura Nagendran [sup.1], James A. Russell [sup.2], Keith R. Walley [sup.2], Stephen J. Brett [sup.1] [sup.3], Gavin D. Perkins [sup.4], Ludhmila Hajjar [sup.5], Alexina J. Mason [sup.6], Deborah Ashby [...]

Purpose A systematic review and meta-analysis was conducted to answer the question 'In adults with respiratory failure requiring invasive ventilation for more than 24 h, does a weaning strategy with early extubation to non-invasive ventilation (NIV) compared to invasive ventilation weaning reduce all-cause hospital mortality?' Methods We included randomised and quasi-randomised controlled trials that evaluated the use of non-invasive ventilation, compared to invasive ventilation, as a weaning strategy in adults mechanically ventilated for at least 24 h. The EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) bibliographic databases were searched from inception to February 2018. Bayesian hierarchical models were used to perform the meta-analysis. The primary outcome was mortality at hospital discharge. Secondary outcomes included mortality (30, 60, 90 and 180 days), quality of life, duration of invasive ventilation, weaning failure, length of stay [intensive care unit (ICU) and hospital] and adverse events. Results Twenty-five relevant studies involving 1609 patients were included in the quantitative analysis. Studies had moderate to high risk of bias due to risk of performance and detection bias. Mortality at hospital discharge was lower in the NIV weaning group compared to the invasive weaning group [pooled odds ratio (OR) 0.58, 95% highest density interval (HDI) 0.29-0.89]. Subgroup analyses showed lower pooled mortality at hospital discharge rates in NIV weaning than those in the control group in chronic obstructive pulmonary disease (COPD) patients (pooled OR 0.43, 95% HDI 0.13-0.81) and the effect is less certain in the mixed ICU population (pooled OR 0.88, 95% HDI 0.25-1.48). NIV weaning reduced the duration of invasive ventilation in patients [standardised mean difference (SMD) - 1.34, 95% HDI - 1.92 to - 0.77] and ICU length of stay (SMD - 0.70, 95% HDI - 0.94 to - 0.46). Reported rates of ventilator associated pneumonia (VAP) were lower in the NIV group. NIV weaning did not reduce overall hospital length of stay or long-term mortality. There were insufficient data to compare other adverse events and health-related quality of life. Conclusions The use of NIV in weaning from mechanical ventilation decreases hospital mortality, the incidence of VAP and ICU length of stay. NIV as a weaning strategy appears to be most beneficial in patients with COPD., Author(s): Joyce Yeung [sup.1] [sup.2], Keith Couper [sup.1] [sup.2], Elizabeth G. Ryan [sup.1] [sup.3], Simon Gates [sup.3], Nick Hart [sup.4], Gavin D. Perkins [sup.1] [sup.2] Author Affiliations: (1) 0000 0000 [...]

Purpose A rapidly evolving resuscitation science provides more effective treatments to an aging population with multiple comorbidites. Concurrently, emergency care has become patient-centered. This review aims to describe challenges associated with the application of key principles of bioethics in resuscitation and post-resuscitation care; propose actions to address these challenges; and highlight the need for evidence-based ethics and consensus on ethical principles interpretation. Methods Following agreement on the article's outline, subgroups of 2-3 authors provided narrative reviews of ethical issues concerning autonomy and honesty, beneficence/nonmaleficence and dignity, justice, specific practices/circumstances such as family presence during resuscitation, and emergency research. Proposals for addressing ethical challenges were also offered. Results Respect for patient autonomy can be realized through honest provision of information, shared decision-making, and advance directives/care planning. Essential prerequisites comprise public and specific healthcare professionals' education, appropriate regulatory provisions, and allocation of adequate resources. Regarding beneficence/nonmaleficence, resuscitation should benefit patients, while avoiding harm from futile interventions; pertinent practice should be based on neurological prognostication and patient/family-reported outcomes. Regarding dignity, aggressive life-sustaining treatments against patients preferences should be avoided. Contrary to the principle of justice, resuscitation quality may be affected by race/income status, age, ethnicity, comorbidity, and location (urban versus rural or country-specific/region-specific). Current evidence supports family presence during resuscitation. Regarding emergency research, autonomy should be respected without hindering scientific progress; furthermore, transparency of research conduct should be promoted and funding increased. Conclusions Major ethical challenges in resuscitation science need to be addressed through complex/resource-demanding interventions. Such actions require support by ongoing/future research., Author(s): Spyros D. Mentzelopoulos [sup.1], Anne-Marie Slowther [sup.2], Zoe Fritz [sup.3], Claudio Sandroni [sup.4], Theodoros Xanthos [sup.5] [sup.6], Clifton Callaway [sup.7], Gavin D. Perkins [sup.2], Craig Newgard [sup.8], Eleni Ischaki [...]

Purpose The purpose of this review is to describe the epidemiology of out-of-hospital cardiac arrest (OHCA), disparities in organisation and outcome, recent advances in treatment and ongoing controversies. We also outline the standard of care that should be provided by the critical care specialist and propose future directions for cardiac arrest research. Methods Narrative review with contributions from international resuscitation experts. Results Although it is recognised that survival rates from OHCA are increasing there is considerable scope for improvement and many countries have implemented national strategies in an attempt to achieve this goal. More resources are required to enable high-quality randomised trials in resuscitation. Conclusions Increasing international collaboration should facilitate resuscitation research and knowledge translation. The International Liaison Committee on Resuscitation (ILCOR) has adopted a continuous evidence review process, which facilitate the implementation of resuscitation interventions proven to improve patient outcomes., Author(s): Jerry P. Nolan [sup.1] [sup.2], Robert A. Berg [sup.3] [sup.4], Clifton W. Callaway [sup.5], Laurie J. Morrison [sup.6], Vinay Nadkarni [sup.7], Gavin D. Perkins [sup.8], Claudio Sandroni [sup.9], Markus [...]

Purpose There is an urgent need to develop diagnostic tests to improve the detection of pathogens causing life-threatening infection (sepsis). SeptiFast is a CE-marked multi-pathogen real-time PCR system capable of detecting DNA sequences of bacteria and fungi present in blood samples within a few hours. We report here a systematic review and meta-analysis of diagnostic accuracy studies of SeptiFast in the setting of suspected sepsis. Methods A comprehensive search strategy was developed to identify studies that compared SeptiFast with blood culture in suspected sepsis. Methodological quality was assessed using QUADAS. Heterogeneity of studies was investigated using a coupled forest plot of sensitivity and specificity and a scatter plot in receiver operator characteristic space. Bivariate model method was used to estimate summary sensitivity and specificity. Results From 41 phase III diagnostic accuracy studies, summary sensitivity and specificity for SeptiFast compared with blood culture were 0.68 (95 % CI 0.63-0.73) and 0.86 (95 % CI 0.84-0.89) respectively. Study quality was judged to be variable with important deficiencies overall in design and reporting that could impact on derived diagnostic accuracy metrics. Conclusions SeptiFast appears to have higher specificity than sensitivity, but deficiencies in study quality are likely to render this body of work unreliable. Based on the evidence presented here, it remains difficult to make firm recommendations about the likely clinical utility of SeptiFast in the setting of suspected sepsis., Author(s): Paul Dark [sup.1] [sup.2] [sup.3], Bronagh Blackwood [sup.4], Simon Gates [sup.5], Danny McAuley [sup.4], Gavin D. Perkins [sup.5] [sup.6], Ronan McMullan [sup.7], Claire Wilson [sup.1] [sup.3], Daniel Graham [sup.1] [...]

Purpose Intensive care clinicians play a central role in the co-ordination and treatment of patients that develop life-threatening emergencies. This review evaluates the effect of debriefing after life-threatening emergencies and considers the implications for intensive care training and practice. Methods Studies were identified by searching electronic databases, citation tracking, and contact with subject specialists. Studies evaluating the effect of debriefing after life-threatening emergencies on clinician performance (process) and/or patient outcomes were eligible for inclusion. Study quality was assessed and summarised using the GRADE system. Results The search identified 2,720 studies. After detailed review, 27 studies were included of which 20 supported the use of debriefing. Debriefing was viewed positively (n = 3), improved learning (n = 1), enhanced non-technical performance (n = 4) and technical performance (n = 16), and improved patient outcomes (n = 2). Four cardiac arrest studies were suitable for meta-analysis. This found evidence of improved resuscitation process outcomes [compression fraction (mean difference 6.80, 95 % CI 4.19-9.40, p < 0.001)] and short-term patient outcome [return of spontaneous circulation (OR 1.46, 95 % CI 1.01-2.13, p = 0.05)]. There was no effect on survival to hospital discharge (OR 0.80, 95 % CI 0.38-1.67, p = 0.55). Conclusions This review supports the use of structured debriefing as an educational strategy to improve clinician knowledge and skill acquisition and implementation of those skills in practice. However, the effect of debriefing on long-term patient outcomes is uncertain. There remains a need for further high-quality research, which seeks to identify the optimal method for debriefing delivery and effect on patient outcomes., Author(s): Keith Couper [sup.1] [sup.2] , Bilal Salman [sup.3] , Jasmeet Soar [sup.4] , Judith Finn [sup.5] [sup.6] , Gavin D. Perkins [sup.1] [sup.2] Author Affiliations: (1) grid.413964.d, 0000000403997344, Academic [...]