Sheila Harvey

Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial

BACKGROUND Over the past 30 years the pulmonary artery catheter (PAC) has become a widely used haemodynamic monitoring device in the management of critically ill patients, though doubts exist about its safety. Our aim was, therefore, to ascertain whether hospital mortality is reduced in critically ill patients when they are managed with a PAC. METHODS We did a randomised controlled trial to which we enrolled 1041 patients from 65 UK intensive care units. We assigned individuals to management with (n=519) or without (n=522) a PAC. The timing of insertion and subsequent clinical management were at the discretion of the treating clinician. Intensive care units decided a priori to have the option of using an alternative cardiac output-monitoring device in control patients. FINDINGS 1014 patients were eligible for analysis. We noted no difference in hospital mortality between patients managed with or without a PAC (68% [346 of 506] vs 66% [333 of 507], p=0.39; adjusted hazard ratio 1.09, 95% CI 0.94-1.27). We noted complications associated with insertion of a PAC in 46 of 486 individuals in whom the device was placed, none of which was fatal. INTERPRETATION Our findings indicate no clear evidence of benefit or harm by managing critically ill patients with a PAC. Efficacy studies are needed to ascertain whether management protocols involving PAC use can result in improved outcomes in specific groups if these devices are not to become a redundant technology.

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.).

An Evaluation of the Feasibility, Cost and Value of Information of a Multicentre Randomised Controlled Trial of Intravenous Immunoglobulin for Sepsis (Severe Sepsis and Septic Shock): Incorporating a Systematic Review, Meta-Analysis and Value of Information Analysis

BACKGROUND Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. OBJECTIVES To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. DATA SOURCES Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. REVIEW METHODS Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. RESULTS Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control - as an indicator of proper blinding to treatment as a proxy for study quality - associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis. Although the EVI analyses suggested substantial expected net benefit from a large, multicentre randomised controlled trial (RCT) evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. LIMITATIONS As has been identified in previous meta-analyses, there are issues with the methodological quality of the available evidence. CONCLUSIONS Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research. Our recommendations for future research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Risk factors for invasive fungal disease in critically ill adult patients: a systematic review

IntroductionOver 5,000 cases of invasive Candida species infections occur in the United Kingdom each year, and around 40% of these cases occur in critical care units. Invasive fungal disease (IFD) in critically ill patients is associated with increased morbidity and mortality at a cost to both the individual and the National Health Service. In this paper, we report the results of a systematic review performed to identify and summarise the important risk factors derived from published multivariable analyses, risk prediction models and clinical decision rules for IFD in critically ill adult patients to inform the primary data collection for the Fungal Infection Risk Evaluation Study.MethodsAn internet search was performed to identify articles which investigated risk factors, risk prediction models or clinical decisions rules for IFD in critically ill adult patients. Eligible articles were identified in a staged process and were assessed by two investigators independently. The methodological quality of the reporting of the eligible articles was assessed using a set of questions addressing both general and statistical methodologies.ResultsThirteen articles met the inclusion criteria, of which eight articles examined risk factors, four developed a risk prediction model or clinical decision rule and one evaluated a clinical decision rule. Studies varied in terms of objectives, risk factors, definitions and outcomes. The following risk factors were found in multiple studies to be significantly associated with IFD: surgery, total parenteral nutrition, fungal colonisation, renal replacement therapy, infection and/or sepsis, mechanical ventilation, diabetes, and Acute Physiology and Chronic Health Evaluation II (APACHE II) or APACHE III score. Several other risk factors were also found to be statistically significant in single studies only. Risk factor selection process and modelling strategy also varied across studies, and sample sizes were inadequate for obtaining reliable estimates.ConclusionsThis review shows a number of risk factors to be significantly associated with the development of IFD in critically ill adults. Methodological limitations were identified in the design and conduct of studies in this area, and caution should be used in their interpretation.

Effectiveness of bereavement interventions in neonatal intensive care: a review of the evidence.

The provision of bereavement care is an important part of neonatal intensive care. This systematic review of the effectiveness of interventions to support families and facilitate emotional adjustment following the death of a baby suggests that, while these are largely appreciated by parents who have participated in research, there has been little rigorous evaluation of their effectiveness. This review reflects on possible reasons for this; for example: NICU-led bereavement care is changing, the effectiveness of bereavement care is difficult to measure, concepts of effectiveness are not static, and ethical concerns complicate experimental research. Bereavement interventions are compassion-led and generally considered to be beneficial. New research questions and new methodological challenges are discussed with reference to two examples of evolving practice: bereavement photography and the use of ritual. Future research using innovative and sensitive RCTs and consensus amongst relevant stakeholders is suggested.

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.

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 incremental cost effectiveness of withdrawing pulmonary artery catheters from routine use in critical care

ObjectiveThe objective of this study was to conduct an economic evaluation to identify any differences in the expected costs and outcomes between patients treated with pulmonary artery catheters (PACs) and those without, in order to better inform healthcare decision makers.MethodThe evaluation was carried out alongside a clinical trial investigating the use of PACs in intensive care units (ICUs) in the UK. It was conducted from the perspective of the UK NHS, in which PACs are an established intervention. Treating patients without using a PAC was characterised as the new intervention.The primary outcome measure was QALYs. The secondary outcome measure was hospital mortality. NHS costs per patient were calculated for the financial year 2002/03.The bootstrap method was used to characterise the uncertainty of the results and to construct cost-effectiveness acceptability curves.ResultsThe cost per QALY and per life gained from the withdrawal of PACs were £2892 and £21 164, respectively.ConclusionThe results of this study indicate that withdrawal of PACs from routine clinical use in ICUs within the NHS would be considered cost effective in the current decision-making climate.

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.