Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study.

CONTEXT: Survival rates after severe injury are improving, but complication rates and outcomes are variable. OBJECTIVE: This cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DESIGN: We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15). MAIN OUTCOME MEASURES: We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models. FINDINGS: We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. CONCLUSION: The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.

Protocol for the health economic evaluation of increasing the weekend specialist to patient ratio in hospitals in England.

INTRODUCTION: This protocol concerns the evaluation of increased specialist staffing at weekends in hospitals in England. Seven-day health services are a key policy for the UK government and other health systems trying to improve use of infrastructure and resources. A particular motivation for the 7-day policy has been the observed increase in the risk of death associated with weekend admission, which has been attributed to fewer hospital specialists being available at weekends. However, the causes of the weekend effect have not been adequately characterised; many of the excess deaths associated with the 'weekend effect' may not be preventable, and the presumed benefits of improved specialist cover might be offset by the cost of implementation. METHODS/DESIGN: The Bayesian-founded method we propose will consist of four major steps. First, the development of a qualitative causal model. Specialist presence can affect multiple, interacting causal processes. One or more models will be developed from the results of an expert elicitation workshop and probabilities elicited for each model and relevant model parameters. Second, systematic review of the literature. The model from the first step will provide search limits for a review to identify relevant studies. Third, a statistical model for the effects of specialist presence on care quality and patient outcomes. Fourth, valuation of outcomes. The expected net benefits of different levels of specialist intensity will then be evaluated with respect to the posterior distributions of the parameters. ETHICS AND DISSEMINATION: The study was approved by the Review Subcommittee of the South West Wales REC on 11 November 2013. Informed consent was not required for accessing anonymised patient case records from which patient identifiers had been removed. The findings of this study will be published in peer-reviewed journals; the outputs from this research will also form part of the project report to the HS&DR Programme Board.

Safety and Efficacy of Antiviral Therapy for Prevention of Cytomegalovirus Reactivation in Immunocompetent Critically Ill Patients: A Randomized Clinical Trial.

Importance: Latent cytomegalovirus (CMV) infection is present in more than half the adult population, and a viral reactivation (ie, when the virus becomes measurable in body fluids such as blood) can occur in up to one-third of these individuals during episodes of critical illness. Objective: To determine whether antiviral therapy is safe and effective for preventing CMV reactivation in a general population of critically ill patients. Design, Setting, and Participants: A single-center, open-label, randomized, controlled clinical trial recruited 124 CMV-seropositive patients undergoing mechanical ventilation for at least 24 hours in the intensive care unit between January 1, 2012, and January 31, 2014. The mean baseline Acute Physiology and Chronic Health Evaluation II score of all patients was 17.6. Interventions: Patients were randomized to receive anti-CMV prophylaxis with valacyclovir hydrochloride (n = 34) or low-dose valganciclovir hydrochloride (n = 46) for up to 28 days to suppress viral reactivation, or to a control group with no intervention (n = 44). Main Outcomes and Measures: Time to first CMV reactivation in blood within the 28-day follow-up period following initiation of the study drug. Results: Among the 124 patients in the study (46 women and 78 men; mean [SD] age, 56.9 [16.9] years), viral reactivation in the blood occurred in 12 patients in the control group, compared with 1 patient in the valganciclovir group and 2 patients in the valacyclovir group (combined treatment groups vs control: hazard ratio, 0.14; 95% CI 0.04-0.50). Although this trial was not powered to assess clinical end points, the valacyclovir arm was halted prematurely because of higher mortality; 14 of 34 patients (41.2%) had died by 28 days, compared with 5 of 37 (13.5%) patients in the control arm at the point of the decision to halt this arm. Other safety end points showed similar outcomes between groups. Conclusions and Relevance: Antiviral prophylaxis with valacyclovir or low-dose valganciclovir suppresses CMV reactivation in patients with critical illness. However, given the higher mortality, a large-scale trial would be needed to determine the clinical efficacy and safety of CMV suppression. Trial Registration: clinicaltrials.gov Identifier: NCT01503918.

Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock.

BACKGROUND: Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness. OBJECTIVES: The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Fifty-six NHS hospitals in England. PARTICIPANTS: A total of 1260 patients who presented at EDs with septic shock. INTERVENTIONS: EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1. MAIN OUTCOME MEASURES: All-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at -£725 (95% CI -£3000 to £1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events. LIMITATIONS: Recruitment was lower at weekends and out of hours. The intervention could not be blinded. CONCLUSIONS: There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%. FUTURE WORK: The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN36307479. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information.

Trial of early, goal-directed resuscitation for septic shock.

BACKGROUND: Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. METHODS: We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. RESULTS: We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. CONCLUSIONS: In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).

Introduction of medical emergency teams in Australia and New Zealand: a multicentre study.

The philosophy behind medical emergency teams (METs) or rapid response teams leaving the intensive care unit (ICU) to evaluate and treat patients who are at risk on the wards and to prevent or rationalise admission to the ICU is by now well established in many health care systems. In a previous issue of Critical Care, Jones and colleagues report their analysis of the impact on outcomes of METs in hospitals in Australasia and link this to reports appearing in the world literature.

Undergraduate training in the care of the acutely ill patient: a literature review.

OBJECTIVE: To characterise the problem of teaching acute care skills to undergraduates and to look for potential solutions. DESIGN: Systematic literature review including Medline, EMBASE, CINAHL. Eligible studies described education and training issues focusing on caring for acutely ill patients. Articles were excluded if they did not address either educational or clinical aspects of acute care and resuscitation. MEASUREMENT AND RESULTS: We identified and reviewed 374 articles focusing on training or clinical aspects of caring for the acutely ill patient. Undergraduates and junior physicians lack knowledge, confidence and competence in all aspects of acute care, including the basic task of recognition and management of the acutely ill patient. There is wide variability both between and within countries regarding the amount of teaching in critical care offered to undergraduate medical students. Many centres are starting to use an integrated approach to acute care teaching, with early exposure to basic life support and clinical skills, coupled with later exposure to more complex acute care topics. Clinical attachments remain a popular method for training in acute care. Acute care courses are increasingly being used to standardise delivery of practical skills and patient management training. CONCLUSION: The training of healthcare staff in the care of acutely ill patients is suboptimal, adding to patient risk. Improvements in training should start at undergraduate level for maximal effect, should be integrated with postgraduate education, and are likely to enhance current efforts to improve patient safety in acute care.

The Acute Care Undergraduate TEaching (ACUTE) Initiative: consensus development of core competencies in acute care for undergraduates in the United Kingdom.

BACKGROUND: The care of the acutely ill patient in hospital is often sub-optimal. Poor recognition of critical illness combined with a lack of knowledge, failure to appreciate the clinical urgency of a situation, a lack of supervision, failure to seek advice and poor communication have been identified as contributory factors. At present the training of medical students in these important skills is fragmented. The aim of this study was to use consensus techniques to identify the core competencies in the care of acutely ill or arrested adult patients that medical students should possess at the point of graduation. DESIGN: Healthcare professionals were invited to contribute suggestions for competencies to a website as part of a modified Delphi survey. The competency proposals were grouped into themes and rated by a nominal group comprised of physicians, nurses and students from the UK. The nominal group rated the importance of each competency using a 5-point Likert scale. RESULTS: A total of 359 healthcare professionals contributed 2,629 competency suggestions during the Delphi survey. These were reduced to 88 representative themes covering: airway and oxygenation; breathing and ventilation; circulation; confusion and coma; drugs, therapeutics and protocols; clinical examination; monitoring and investigations; team-working, organisation and communication; patient and societal needs; trauma; equipment; pre-hospital care; infection and inflammation. The nominal group identified 71 essential and 16 optional competencies which students should possess at the point of graduation. CONCLUSIONS: We propose these competencies form a core set for undergraduate training in resuscitation and acute care.

Peer-led resuscitation training for healthcare students: a randomised controlled study.

OBJECTIVE: To determine the efficacy of a peer-led tuition model for training healthcare students in basic life support compared to tuition delivered by clinical tutors. DESIGN AND SETTING: Randomised controlled trial in the Medical School, University of Birmingham, UK. PARTICIPANTS: 122 first-year medical, dental, nursing and physiotherapy students. INTERVENTIONS: Students were randomised to receive basic life support tuition from either second-year student instructors or from experienced clinical staff. MEASUREMENTS AND RESULTS: Students' practical skills, knowledge and satisfaction were tested at the end of the course. Instructor reliability was assessed throughout the course. Students taught by their peers were significantly more likely to be successful in the end-of-course practical CPR test than those taught by clinical staff (56/57 vs. 53/62). The student instructors were also found to be more reliable than clinical staff at attending the training sessions (48/48 vs. 36/48). There was no significant difference in the theoretical test results or the students' assessment of the quality of teaching. CONCLUSIONS: This model of peer-led undergraduate training in basic life support provides a quality of education which is at least as good as that provided by clinical staff, while offering advantages in terms of reliability. The re-deployment of clinical tutors from basic to more advanced training may allow the overall enhancement of undergraduate resuscitation and critical care training.