Effect of a Nurse-Led Preventive Psychological Intervention on Symptoms of Posttraumatic Stress Disorder Among Critically Ill Patients: A Randomized Clinical Trial.

Importance: A meta-analysis of outcomes during the 6 months after intensive care unit (ICU) discharge indicate a prevalence for clinically important posttraumatic stress disorder (PTSD) symptoms of 25%. Objective: To determine whether a nurse-led preventive, complex psychological intervention, initiated in the ICU, reduces patient-reported PTSD symptom severity at 6 months. Design, Setting, and Participants: A multicenter, parallel-group, cluster-randomized clinical trial with integrated economic and process evaluations conducted in 24 ICUs in the United Kingdom. Participants were critically ill patients who regained mental capacity following receipt of level 3 (intensive) care. A total of 2961 eligible patients were identified from September 2015 to January 2017. A total of 2048 were approached for participation in the ICU, of which 1458 provided informed consent. Follow-up was completed December 2017. Interventions: Twenty four ICUs were randomized 1:1 to the intervention or control group. Intervention ICUs (n = 12; 669 participants) delivered usual care during a baseline period followed by an intervention period. The preventive, complex psychological intervention comprised promotion of a therapeutic ICU environment plus 3 stress support sessions and a relaxation and recovery program delivered by trained ICU nurses to high-risk (acutely stressed) patients. Control ICUs (n = 12; 789 participants) delivered usual care in both baseline and intervention periods. Main Outcomes and Measures: The primary clinical outcome was PTSD symptom severity among survivors at 6 months measured using the PTSD Symptom Scale-Self-Report questionnaire (score range, 0-51, with higher scores indicating greater symptom severity; the minimal clinically important difference was considered to be 4.2 points). Results: Among 1458 enrolled patients (mean [SD] age, 58 [16] years; 599 women [41%]), 1353 (93%) completed the study and were included in the final analysis. At 6 months, the mean PTSD Symptom Scale-Self-Report questionnaire score in intervention ICUs was 11.8 (baseline period) compared with 11.5 (intervention period) (difference, -0.40 [95% CI, -2.46 to 1.67]) and in control ICUs, 10.1 (baseline period) compared with 10.2 (intervention period) (difference, 0.06 [95% CI, -1.74 to 1.85]) between periods. There was no significant difference in PTSD symptom severity at 6 months (treatment effect estimate [difference in differences] of -0.03 [95% CI, -2.58 to 2.52]; P = .98). Conclusions and Relevance: Among critically ill patients in the ICU, a nurse-led preventive, complex psychological intervention did not significantly reduce patient-reported PTSD symptom severity at 6 months. These findings do not support the use of this psychological intervention. Trial Registration: ISRCTN53448131.

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.).

Trial of the route of early nutritional support in critically ill adults.

BACKGROUND: Uncertainty exists about the most effective route for delivery of early nutritional support in critically ill adults. We hypothesized that delivery through the parenteral route is superior to that through the enteral route. METHODS: We conducted a pragmatic, randomized trial involving adults with an unplanned admission to one of 33 English intensive care units. We randomly assigned patients who could be fed through either the parenteral or the enteral route to a delivery route, with nutritional support initiated within 36 hours after admission and continued for up to 5 days. The primary outcome was all-cause mortality at 30 days. RESULTS: We enrolled 2400 patients; 2388 (99.5%) were included in the analysis (1191 in the parenteral group and 1197 in the enteral group). By 30 days, 393 of 1188 patients (33.1%) in the parenteral group and 409 of 1195 patients (34.2%) in the enteral group had died (relative risk in parenteral group, 0.97; 95% confidence interval, 0.86 to 1.08; P=0.57). There were significant reductions in the parenteral group, as compared with the enteral group, in rates of hypoglycemia (44 patients [3.7%] vs. 74 patients [6.2%]; P=0.006) and vomiting (100 patients [8.4%] vs. 194 patients [16.2%]; P<0.001). There were no significant differences between the parenteral group and the enteral group in the mean number of treated infectious complications (0.22 vs. 0.21; P=0.72), 90-day mortality (442 of 1184 patients [37.3%] vs. 464 of 1188 patients [39.1%], P=0.40), in rates of 14 other secondary outcomes, or in rates of adverse events. Caloric intake was similar in the two groups, with the target intake not achieved in most patients. CONCLUSIONS: We found no significant difference in 30-day mortality associated with the route of delivery of early nutritional support in critically ill adults. (Funded by the United Kingdom National Institute for Health Research; CALORIES Current Controlled Trials number, ISRCTN17386141.).

Predicting invasive fungal disease due to Candida species in non-neutropenic, critically ill, adult patients in United Kingdom critical care units.

BACKGROUND: Given the predominance of invasive fungal disease (IFD) amongst the non-immunocompromised adult critically ill population, the potential benefit of antifungal prophylaxis and the lack of generalisable tools to identify high risk patients, the aim of the current study was to describe the epidemiology of IFD in UK critical care units, and to develop and validate a clinical risk prediction tool to identify non-neutropenic, critically ill adult patients at high risk of IFD who would benefit from antifungal prophylaxis. METHODS: Data on risk factors for, and outcomes from, IFD were collected for consecutive admissions to adult, general critical care units in the UK participating in the Fungal Infection Risk Evaluation (FIRE) Study. Three risk prediction models were developed to model the risk of subsequent Candida IFD based on information available at three time points: admission to the critical care unit, at the end of 24 h and at the end of calendar day 3 of the critical care unit stay. The final model at each time point was evaluated in the three external validation samples. RESULTS: Between July 2009 and April 2011, 60,778 admissions from 96 critical care units were recruited. In total, 359 admissions (0.6 %) were admitted with, or developed, Candida IFD (66 % Candida albicans). At the rate of candidaemia of 3.3 per 1000 admissions, blood was the most common Candida IFD infection site. Of the initial 46 potential variables, the final admission model and the 24-h model both contained seven variables while the end of calendar day 3 model contained five variables. The end of calendar day 3 model performed the best with a c index of 0.709 in the full validation sample. CONCLUSIONS: Incidence of Candida IFD in UK critical care units in this study was consistent with reports from other European epidemiological studies, but lower than that suggested by previous hospital-wide surveillance in the UK during the 1990s. Risk modeling using classical statistical methods produced relatively simple risk models, and associated clinical decision rules, that provided acceptable discrimination for identifying patients at 'high risk' of Candida IFD. TRIAL REGISTRATION: The FIRE Study was reviewed and approved by the Bolton NHS Research Ethics Committee (reference: 08/H1009/85), the Scotland A Research Ethics Committee (reference: 09/MRE00/76) and the National Information Governance Board (approval number: PIAG 2-10(f)/2005).

National survey and point prevalence study of sedation practice in UK critical care.

BACKGROUND: The present study was designed to (1) establish current sedation practice in UK critical care to inform evidence synthesis and potential future primary research and (2) to compare practice reported via a survey with actual practice assessed in a point prevalence study (PPS). METHODS: UK adult general critical care units were invited to participate in a survey of current sedation practice, and a representative sample of units was invited to participate in a PPS of sedation practice at the patient level. Survey responses were compared with PPS data where both were available. RESULTS: Survey responses were received from 214 (91 %) of 235 eligible critical care units. Of these respondents, 57 % reported having a written sedation protocol, 94 % having a policy of daily sedation holds and 94 % using a sedation scale to assess depth of sedation. In the PPS, across units reporting a policy of daily sedation holds, a median of 50 % (IQR 33-75 %) of sedated patients were considered for a sedation hold. A median of 88 % (IQR 63-100 %) of patients were assessed using the same sedation scale as reported in the survey. Both the survey and the PPS indicated propofol as the preferred sedative and alfentanil, fentanyl and morphine as the preferred analgesics. In most of the PPS units, all patients had received the unit's reported first-choice sedative (median across units 100 %, IQR 64-100 %), and a median of 80 % (IQR 67-100 %) of patients had received the unit's reported first-choice analgesic. Most units (83 %) reported in the survey that sedatives are usually administered in combination with analgesics. Across units that participated in the PPS, 69 % of patients had received a combination of agents - most frequently propofol combined with either alfentanil or fentanyl. CONCLUSIONS: Clinical practice reported in the national survey did not accurately reflect actual clinical practice at the patient level observed in the PPS. Employing a mixed methods approach provided a more complete picture of sedation practice in terms of breadth and depth of information.

Intravenous immunoglobulin for severe sepsis and septic shock: clinical effectiveness, cost-effectiveness and value of a further randomised controlled trial.

INTRODUCTION: Prior to investing in a large, multicentre randomised controlled trial (RCT), the National Institute for Health Research in the UK called for an evaluation of the feasibility and value for money of undertaking a trial on intravenous immunoglobulin (IVIG) as an adjuvant therapy for severe sepsis/septic shock. METHODS: In response to this call, this study assessed the clinical and cost-effectiveness of IVIG (using a decision model), and evaluated the value of conducting an RCT (using expected value of information (EVI) analysis). The evidence informing such assessments was obtained through a series of systematic reviews and meta-analyses. Further primary data analyses were also undertaken using the Intensive Care National Audit & Research Centre Case Mix Programme Database, and a Scottish Intensive Care Society research study. RESULTS: We found a large degree of statistical heterogeneity in the clinical evidence on treatment effect, and the source of such heterogeneity was unclear. The incremental cost-effectiveness ratio of IVIG is within the borderline region of estimates considered to represent value for money, but results appear highly sensitive to the choice of model used for clinical effectiveness. This was also the case with EVI estimates, with maximum payoffs from conducting a further clinical trial between £ 137 and £ 1,011 million. CONCLUSIONS: Our analyses suggest that there is a need for a further RCT. Results on the value of conducting such research, however, were sensitive to the clinical effectiveness model used, reflecting the high level of heterogeneity in the evidence base.

Post hoc insights from PAC-Man--the U.K. pulmonary artery catheter trial.

OBJECTIVES: To provide descriptive information on patients considered for management with a pulmonary artery catheter (PAC) in U.K. intensive care units and to generate hypotheses to guide future research by examining subsets of patients included in the PAC-Man Study. DESIGN: Randomized controlled trial. SETTING: U.K. general intensive care units. PATIENTS: Adult critically ill patients deemed to require management with a PAC by the treating clinician. INTERVENTIONS: Management with a PAC. MEASUREMENTS AND MAIN RESULTS: A Cox proportional hazards model was used to estimate interactions between treatment effect and time to randomization, age, surgical status, Sequential Organ Failure Score (SOFA) at randomization, organs supported at randomization, and use of flow measurement devices. Type of hospital and size of unit were tested for an interaction with the treatment effect using multilevel logistic regression modeling. There was no effect (or trend) on hospital survival related to the timing of randomization in relation to intensive care unit admission, type of organ support or SOFA score at randomization, age, type of hospital, or size of intensive care unit. No overall difference in acute hospital outcome was seen between use of a PAC and no flow measurement (p = .748) or between use of an alternative flow measurement device and no flow measurement (p = .395). CONCLUSIONS: Post hoc analyses of the PAC-Man Study data set revealed no benefit associated with being managed with a PAC in critically ill patients. However, such analyses are limited, and adequately powered clinical trials are needed of specific population subsets receiving targeted therapies delivered early in the patient's critical illness to optimize the likelihood of reversing or preventing further organ dysfunction. Furthermore, the utility of other flow measurement devices must be investigated as these have already become integrated into critical care management without adequate evaluation.

Informed consent in clinical trials in critical care: experience from the PAC-Man Study.

OBJECTIVES: To identify the proportion of critically ill patients able to consent to participation in a randomised controlled trial (RCT) and to assess to what extent patient consent and relative assent processes could be conducted according to ethics committee permission. DESIGN: Descriptive study nested in an RCT. SETTING: Fifty-six UK intensive care units participating in the PAC-Man trial. PATIENTS AND PARTICIPANTS: First 500 patients consecutively enrolled into PAC-Man. MEASUREMENT AND RESULTS: The outcome measures were patient consent and/or relative assent. Of the 498 patients included, 13 (2.6%) provided consent before randomisation. Of the remaining 485 patients, relative assent was obtained for 394 patients (81.2%), and refused post-randomisation for 3 patients (0.6%). No relatives were available for 15 patients (3.1%), and it was unclear from documentation whether relative assent had been obtained for 73 patients (15.1%). Of the 482 patients who did not provide consent prior to randomisation, 188 (39%) survived. Of these, 175 (93.1%) gave retrospective informed consent, six (3.2%) refused, and seven (3.7%) did not regain mental competency. CONCLUSIONS: A very small proportion of patients were able to give consent before randomisation. Due to the high in-hospital mortality (60.6%), only around one third of the remaining patients could provide consent retrospectively. This study demonstrates difficulties experienced in obtaining consent from critically ill patients to participate in medical research and raises important issues about the ethical basis of the consent process in critical care.

A multicentre, randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of early nutritional support via the parenteral versus the enteral route in critically ill patients (CALORIES).

BACKGROUND: Malnutrition is a common problem in critically ill patients in UK NHS critical care units. Early nutritional support is therefore recommended to address deficiencies in nutritional state and related disorders in metabolism. However, evidence is conflicting regarding the optimum route (parenteral or enteral) of delivery. OBJECTIVES: To estimate the effect of early nutritional support via the parenteral route compared with the enteral route on mortality at 30 days and on incremental cost-effectiveness at 1 year. Secondary objectives were to compare the route of early nutritional support on duration of organ support; infectious and non-infectious complications; critical care unit and acute hospital length of stay; all-cause mortality at critical care unit and acute hospital discharge, at 90 days and 1 year; survival to 90 days and 1 year; nutritional and health-related quality of life, resource use and costs at 90 days and 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Adult general critical care units in 33 NHS hospitals in England. PARTICIPANTS: 2400 eligible patients. INTERVENTIONS: Five days of early nutritional support delivered via the parenteral (n = 1200) and enteral (n = 1200) route. MAIN OUTCOME MEASURES: All-cause mortality at 30 days after randomisation and incremental net benefit (INB) (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: By 30 days, 393 of 1188 (33.1%) patients assigned to receive early nutritional support via the parenteral route and 409 of 1195 (34.2%) assigned to the enteral route had died [p = 0.57; absolute risk reduction 1.15%, 95% confidence interval (CI) -2.65 to 4.94; relative risk 0.97 (0.86 to 1.08)]. At 1 year, INB for the parenteral route compared with the enteral route was negative at -£1320 (95% CI -£3709 to £1069). The probability that early nutritional support via the parenteral route is more cost-effective - given the data - is < 20%. The proportion of patients in the parenteral group who experienced episodes of hypoglycaemia (p = 0.006) and of vomiting (p < 0.001) was significantly lower than in the enteral group. There were no significant differences in the 15 other secondary outcomes and no significant interactions with pre-specified subgroups. LIMITATIONS: Blinding of nutritional support was deemed to be impractical and, although the primary outcome was objective, some secondary outcomes, although defined and objectively assessed, may have been more vulnerable to observer bias. CONCLUSIONS: There was no significant difference in all-cause mortality at 30 days for early nutritional support via the parenteral route compared with the enteral route among adults admitted to critical care units in England. On average, costs were higher for the parenteral route, which, combined with similar survival and quality of life, resulted in negative INBs at 1 year. FUTURE WORK: Nutritional support is a complex combination of timing, dose, duration, delivery and type, all of which may affect outcomes and costs. Conflicting evidence remains regarding optimum provision to critically ill patients. There is a need to utilise rigorous consensus methods to establish future priorities for basic and clinical research in this area. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17386141. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 28. See the NIHR Journals Library website for further project information.

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.

The CALORIES trial: statistical analysis plan.

BACKGROUND: The CALORIES trial is a pragmatic, open, multicentre, randomised controlled trial (RCT) of the clinical effectiveness and cost-effectiveness of early nutritional support via the parenteral route compared with early nutritional support via the enteral route in unplanned admissions to adult general critical care units (CCUs) in the United Kingdom. The trial derives from the need for a large, pragmatic RCT to determine the optimal route of delivery for early nutritional support in the critically ill. OBJECTIVE: To describe the proposed statistical analyses for the evaluation of the clinical effectiveness in the CALORIES trial. METHODS: With the primary and secondary outcomes defined precisely and the approach to safety monitoring and data collection summarised, the planned statistical analyses, including prespecified subgroups and secondary analyses, were developed and are described. RESULTS: The primary outcome is all-cause mortality at 30 days. The primary analysis will be reported as a relative risk and absolute risk reduction and tested with the Fisher exact test. Prespecified subgroup analyses will be based on age, degree of malnutrition, acute severity of illness, mechanical ventilation at admission to the CCU, presence of cancer and time from CCU admission to commencement of early nutritional support. Secondary analyses include adjustment for baseline covariates. CONCLUSION: In keeping with best trial practice, we have developed, described and published a statistical analysis plan for the CALORIES trial and are placing it in the public domain before inspecting data from the trial.

The Protocolised Management in Sepsis (ProMISe) trial statistical analysis plan.

BACKGROUND: The Protocolised Management in Sepsis (ProMISe) trial is an open, multicentre, randomised controlled trial (RCT) of the clinical effectiveness and cost-effectiveness of early, goal directed, protocolised resuscitation compared with usual resuscitation for patients presenting to emergency departments (EDs) in the United Kingdom with early signs of severe sepsis or septic shock. The rationale for the ProMISe trial derives from a single-centre United States RCT that reported a reduction in hospital mortality from 46.5% to 30.5%. OBJECTIVE: To describe the proposed statistical analyses for the evaluation of clinical effectiveness for the ProMISe trial. It is important to complete this plan before inspecting the data, and before completion of two related international studies, so that post-hoc, data-derived decisions are avoided. METHODS: The primary and secondary outcomes were defined precisely, and the approach to safety monitoring and data collection summarised, with a description of the planned statistical analyses including prespecified subgroup and secondary analyses. RESULTS: The primary outcome is all-cause mortality at 90 days. The primary analysis will be reported as a relative risk and absolute risk reduction and tested with the Fisher exact test. Prespecified subgroup analyses will be based on age, baseline Medical Emergency Department Sepsis score, baseline Sequential Organ Failure Assessment score, and time from ED presentation to randomisation. Secondary analyses include adjustment for baseline covariates, estimation of learning curve effects and adjustment for noncompliance. CONCLUSION: In keeping with best practice, we have developed a statistical analysis plan for the ProMISe trial and place it in the public domain before inspecting data from the trial.

Harmonizing international trials of early goal-directed resuscitation for severe sepsis and septic shock: methodology of ProCESS, ARISE, and ProMISe.

PURPOSE: To describe and compare the design of three independent but collaborating multicenter trials of early goal-directed resuscitation for severe sepsis and septic shock. METHODS: We reviewed the three current trials, one each in the USA (ProCESS: protocolized care for early septic shock), Australasia (ARISE: Australasian resuscitation in sepsis evaluation), and the UK (ProMISe: protocolised management in sepsis). We used the 2010 CONSORT (consolidated standards of reporting trials) statement and the 2008 CONSORT extension for trials assessing non-pharmacologic treatments to describe and compare the underlying rationale, commonalities, and differences. RESULTS: All three trials conform to CONSORT guidelines, address the same fundamental questions, and share key design elements. Each trial is a patient-level, equal-randomized, parallel-group superiority trial that seeks to enroll emergency department patients with inclusion criteria that are consistent with the original early goal-directed therapy (EGDT) trial (suspected or confirmed infection, two or more systemic inflammatory response syndrome criteria, and refractory hypotension or elevated lactate), is powered to detect a 6­8 % absolute mortality reduction (hospital or 90-day), and uses trained teams to deliver EGDT. Design differences appear to primarily be driven by between-country variation in health care context. The main difference between the trials is the inclusion of a third, alternative resuscitation strategy arm in ProCESS. CONCLUSIONS: Harmonization of study design and methods between severe sepsis trials is feasible and may facilitate pooling of data on completion of the trials.

The BRACELET Study: surveys of mortality in UK neonatal and paediatric intensive care trials.

BACKGROUND: The subject of death and bereavement in the context of randomised controlled trials in neonatal or paediatric intensive care is under-researched. The objectives of this phase of the Bereavement and RAndomised ControlLEd Trials (BRACELET) Study were to determine trial activity in UK neonatal and paediatric intensive care (2002-06); numbers of deaths before hospital discharge; and variation in mortality across intensive care units and trials and to determine whether bereavement support policies were available within trials. These are essential prerequisites to considering the implications of future policies and practice subsequent to bereavement following a child's enrollment in a trial. METHODS: The units survey involved neonatal units providing level 2 or 3 care, and paediatric units providing level II care or above; the trials survey involved trials where allocation was randomized and interventions were delivered to intensive care patients, or to parents but designed to affect patient outcomes. RESULTS: Information was available from 191/220 (87%) neonatal units (149 level 2 or 3 care); and 28/32 (88%) paediatric units. 90/177 (51%) eligible responding units participated in one or more trial (76 neonatal, 14 paediatric) and 54 neonatal units and 6 paediatric units witnessed at least one death. 50 trials were identified (36 neonatal, 14 paediatric). 3,137 babies were enrolled in neonatal trials, 210 children in paediatric trials. Deaths ranged 0-278 (median [IQR interquartile range] 2 [1, 14.5]) per neonatal trial, 0-4 (median [IQR] 1 [0, 2.5]) per paediatric trial. 534 (16%) participants died post-enrollment: 522 (17%) in neonatal trials, 12 (6%) in paediatric trials. Trial participants ranged 1-236 (median [IQR] 21.5 [8, 39.8]) per neonatal unit, 1-53 (median [IQR] 11.5 [2.3, 33.8]) per paediatric unit. Deaths ranged 0-37 (median [IQR] 3.5 [0.3, 8.8]) per neonatal unit, 0-7 (median [IQR] 0.5 [0, 1.8]) per paediatric unit. Three trials had a formal policy for responding to bereavement. CONCLUSIONS: A substantial number of deaths after trial enrollment were identified, distributed over many trials and units. Few trial teams had responses to bereavement in place. Those with the largest numbers of deaths might be best placed to collaborate in developing and assessing responses to bereavement.