Potential Impact of the 2016 Consensus Definitions of Sepsis and Septic Shock on Future Sepsis Research

V. Pettilä on työryhmän ARISE Investigators jäsen.Study objective: The influence of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) on the conduct of future sepsis research is unknown. We seek to examine the potential effect of the new definitions on the identification and outcomes of patients enrolled in a sepsis trial. Methods: This was a post hoc analysis of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial of early goal-directed therapy that recruited 1,591 adult patients presenting to the emergency department (ED) with early septic shock diagnosed by greater than or equal to 2 systemic inflammatory response syndrome criteria and either refractory hypotension or hyperlactatemia. The proportion of participants who would have met the Sepsis-3 criteria for quick Sequential Organ Failure Assessment (qS0FA) score, sepsis (an increased Sequential Organ Failure Assessment score >= 2 because of infection) and septic shock before randomization, their baseline characteristics, interventions delivered, and mortality were determined. Results: There were 1,139 participants who had a qSOFA score of greater than or equal to 2 at baseline (71.6% [95% confidence interval [Cl) 69.4% to 73.8%]). In contrast, 1,347 participants (84.7% [95% CI 82.9% to 86.4%]) met the Sepsis-3 criteria for sepsis. Only 1,010 participants were both qSOFA positive and met the Sepsis-3 criteria for sepsis (63.5% [95% CI 61.1% to 65.8%]). The Sepsis-3 definition for septic shock was met at baseline by 203 participants (12.8% [95% CI 11.2% to 14.5%]), of whom 175 (86.2% [95% CI 81.5% to 91.0%]) were also qSOFA positive. Ninety-day mortality for participants fulfilling the Sepsis-3 criteria for sepsis and septic shock was 20.4% (95% CI 18.2% to 22.5%) (274/1,344) and 29.6% (95% CI 23.3% to 35.8% [60/203]) versus 9.4% (95% CI 5.8% to 13.1%) (23/244) and 17.1% (95% CI 15.1% to 19.1% [237/1,388]), respectively, for participants not meeting the criteria (risk differences 11.0% [95% CI 6.2% to 14.8%] and 12.5% [95% CI 6.3% to 19.4%], respectively). Conclusion: Most ARISE participants did not meet the Sepsis-3 definition for septic shock at baseline. However, the majority fulfilled the new sepsis definition and mortality was higher than for participants not fulfilling the criteria. A quarter of participants meeting the new sepsis definition did not fulfill the qSOFA screening criteria, potentially limiting its utility as a screening tool for sepsis trials with patients with suspected infection in the ED. The implications of the new definitions for patients not eligible for recruitment into the ARISE trial are unknown.Peer reviewe

Fluids or vasopressors for the initial resuscitation of septic shock

Intravenous fluid resuscitation is recommended first-line treatment for sepsis-associated hypotension and/or hypoperfusion. The rationale is to restore circulating volume and optimize cardiac output in the setting of shock. Nonetheless, there is limited high-level evidence to support this practice. Over the past decade emerging evidence of harm associated with large volume fluid resuscitation among patients with septic shock has led to calls for a more conservative approach. Specifically, clinical trials undertaken in Africa have found harm associated with initial fluid resuscitation in the setting of infection and hypoperfusion. While translating these findings to practice in other settings is problematic, there has been a re-appraisal of current practice with some recommending earlier use of vasopressors rather than repeated fluid boluses as an alternative to restore perfusion in septic shock. There is consequently uncertainty and variation in practice. The question of fluids or vasopressors for initial resuscitation in septic shock is the subject of international multicentre clinical trials

In vivo microdialysis to determine subcutaneous interstitial fluid penetration and pharmacokinetics of fluconazole in intensive care unit patients with sepsis

The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates +/- standard deviation (SD) for microdialysis were 51.4% +/- 16.1% with a mean (+/- SD) fluconazole ISF penetration ratio of 0.52 +/- 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC(0-24)) was significantly higher than the median ISF AUC(0-24) (340.4 versus 141.1 mg . h/liter; P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78; P = 0.106). Both minimum and the maximum concentrations of drug in serum (C-max and C-min) showed a significant correlation with the fluconazole plasma exposure (Cmax, R-2 = 0.86, P < 0.0001; Cmin, R-2 = 0.75, P < 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection

A systematic review and meta-analysis of the safety, feasibility and effect of exercise in women with stage II+ breast cancer

To systematically evaluate the safety, feasibility and effect of exercise among women with stage II+ breast cancer.CINAHL, Cochrane, Ebscohost, MEDLINE, Pubmed, ProQuest Health and Medical Complete, ProQuest Nursing and Allied Health Source, Science Direct and SPORTDiscus were searched for articles published prior to March 1, 2017.Randomised, controlled, exercise trials involving at least 50% of women diagnosed with stage II+ breast cancer were included.Risk of bias was assessed and adverse event severity was classified using the Common Terminology Criteria. Feasibility was evaluated by computing median (range) recruitment, withdrawal and adherence rates. Meta-analyses were performed to evaluate exercise safety and effects on health outcomes only. The influence of intervention characteristics (mode, supervision, duration and timing) on exercise outcomes were also explored.There were no differences in adverse events between exercise and usual care (risk difference

Bench-to-bedside review: The evaluation of complex interventions in critical care

Complex interventions, such as the introduction of medical emergency teams or an early goal-directed therapy protocol, are developed from a number of components that may act both independently and inter-dependently. There is an emerging body of literature advocating the use of integrated complex interventions to optimise the treatment of critically ill patients. As with any other treatment, complex interventions should undergo careful evaluation prior to widespread introduction into clinical practice. During the development of an international collaboration of researchers investigating protocol-based approaches to the resuscitation of patients with severe sepsis, we examined the specific issues related to the evaluation of complex interventions. This review outlines some of these issues. The issues specific to trials of complex interventions that require particular attention include determining an appropriate study population and defining current treatments and outcomes in that population, defining the study intervention and the treatment to be used in the control group, and deploying the intervention in a standardised manner. The context in which the research takes place, including existing staffing levels and existing protocols and procedures, is crucial. We also discuss specific details of trial execution, in particular randomization, blinded outcome adjudication and analysis of the results, which are key to avoiding bias in the design and interpretation of such trials

Sheep Updates 2007 - part 3

This session covers seven papers from different authors: PROFITABILITY 1. Benchmarking demonstrates both the potential and realised productivity gains in the sheep and wool industry, Andrew Ritchie, Edward Riggall and James Hall, ICON Agriculture, Darkan 2. Improving sheep genetics will increase farm profitability, Gus Rose, Johan Greeff Department of Agriculture and Food Western Australia, John Young Farming Systems Analysis Service, WA 3. Meat, Merinos and making money in WA Pastoral Zone, M. Alchin, M. Young and T. Johnson, Department of Agriculture and Food Western Australia, GRAZING 4. Nitrogen - farmers\u27 friend or foe? John Lucy and Martin Staines, Department of Agriculture and Food Western Australia 5. Drought proofing grazing systems - a case study from Binnu 2006/7, Tim Wiley & Rob Grima, Department of Agriculture & Food Western Australia 6. Minimising \u27Esperance Storm\u27 livestock losses, Sandra Prosser and Matt Ryan, Department of Agriculture and Food Western Australia 7. Sub-tropical grasses in WA - what is their potential? Geoff Moore, Tony Albertsen, Department of Agriculture & Food Western Australia, Phil Barrett-Lennard, Evergreen Farming, George Woolston, John Titterington, Department of Agriculture and Food Western Australia, Sarah Knight, Irwin-Mingenew Group, Brianna Peake, Liebe Group, Buntine, W

The Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis, a multicentre observational study (ARISE FLUIDS observational study): Rationale, methods and analysis plan

There is uncertainty about the optimal i.v. fluid volume and timing of vasopressor commencement in the resuscitation of patients with sepsis and hypotension. We aim to study current resuscitation practices in EDs in Australia and New Zealand (the Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In Emergency Department Sepsis [ARISE FLUIDS] observational study).ARISE FLUIDS is a prospective, multicentre observational study in 71 hospitals in Australia and New Zealand. It will include adult patients presenting to the ED during a 30 day period with suspected sepsis and hypotension (systolic blood pressur

Understanding implementability in clinical trials : a pragmatic review and concept map

Background The translation of evidence from clinical trials into practice is complex. One approach to facilitating this translation is to consider the 'implementability' of trials as they are designed and conducted. Implementability of trials refers to characteristics of the design, execution and reporting of a late-phase clinical trial that can influence the capacity for the evidence generated by that trial to be implemented. On behalf of the Australian Clinical Trials Alliance (ACTA), the national peak body representing networks of clinician researchers conducting investigator-initiated clinical trials, we conducted a pragmatic literature review to develop a concept map of implementability. Methods Documents were included in the review if they related to the design, conduct and reporting of late-phase clinical trials; described factors that increased or decreased the capacity of trials to be implemented; and were published after 2009 in English. Eligible documents included systematic reviews, guidance documents, tools or primary studies (if other designs were not available). With an expert reference group, we developed a preliminary concept map and conducted a snowballing search based on known relevant papers and websites of key organisations in May 2019. Results Sixty-five resources were included. A final map of 38 concepts was developed covering the domains of validity, relevance and usability across the design, conduct and reporting of a trial. The concepts drew on literature relating to implementation science, consumer engagement, pragmatic trials, reporting, research waste and other fields. No single resource addressed more than ten of the 38 concepts in the map. Conclusions The concept map provides trialists with a tool to think through a range of areas in which practical action could enhance the implementability of their trials. Future work could validate the strength of the associations between the concepts identified and implementability of trials and investigate the effectiveness of steps to address each concept. ACTA will use this concept map to develop guidance for trialists in Australia