The organisation of critical care for burn patients in the UK: epidemiology and comparison of mortality prediction models.

In the UK, a network of specialist centres has been set up to provide critical care for burn patients. However, some burn patients are admitted to general intensive care units. Little is known about the casemix of these patients and how it compares with patients in specialist burn centres. It is not known whether burn-specific or generic risk prediction models perform better when applied to patients managed in intensive care units. We examined admissions for burns in the Case Mix Programme Database from April 2010 to March 2016. The casemix, activity and outcome in general and specialist burn intensive care units were compared and the fit of two burn-specific risk prediction models (revised Baux and Belgian Outcome in Burn Injury models) and one generic model (Intensive Care National Audit and Research Centre model) were compared. Patients in burn intensive care units had more extensive injuries compared with patients in general intensive care units (median (IQR [range]) burn surface area 16 (7-32 [0-98])% vs. 8 (1-18 [0-100])%, respectively) but in-hospital mortality was similar (22.8% vs. 19.0%, respectively). The discrimination and calibration of the generic Intensive Care National Audit and Research Centre model was superior to the revised Baux and Belgian Outcome in Burn Injury burn-specific models for patients managed on both specialist burn and general intensive care units.

The Assessment of Risk in Cardiothoracic Intensive Care (ARCtIC): prediction of hospital mortality after admission to cardiothoracic critical care.

The models used to predict outcome after adult general critical care may not be applicable to cardiothoracic critical care. Therefore, we analysed data from the Case Mix Programme to identify variables associated with hospital mortality after admission to cardiothoracic critical care units and to develop a risk-prediction model. We derived predictive models for hospital mortality from variables measured in 17,002 patients within 24 h of admission to five cardiothoracic critical care units. The final model included 10 variables: creatinine; white blood count; mean arterial blood pressure; functional dependency; platelet count; arterial pH; age; Glasgow Coma Score; arterial lactate; and route of admission. We included additional interaction terms between creatinine, lactate, platelet count and cardiac surgery as the admitting diagnosis. We validated this model against 10,238 other admissions, for which the c index (95% CI) was 0.904 (0.89-0.92) and the Brier score was 0.055, while the slope and intercept of the calibration plot were 0.961 and -0.183, respectively. The discrimination and calibration of our model suggest that it might be used to predict hospital mortality after admission to cardiothoracic critical care units.

An evaluation of the clinical and cost-effectiveness of alternative care locations for critically ill adult patients with acute traumatic brain injury.

BACKGROUND: For critically ill adult patients with acute traumatic brain injury (TBI), we assessed the clinical and cost-effectiveness of: (a) Management in dedicated neurocritical care units versus combined neuro/general critical care units within neuroscience centres. (b) 'Early' transfer to a neuroscience centre versus 'no or late' transfer for those who present at a non-neuroscience centre. METHODS: The Risk Adjustment In Neurocritical care (RAIN) Study included prospective admissions following acute TBI to 67 UK adult critical care units during 2009-11. Data were collected on baseline case-mix, mortality, resource use, and at six months, Glasgow Outcome Scale Extended (GOSE), and quality of life (QOL) (EuroQol 5D-3L). We report incremental effectiveness, costs and cost per Quality-Adjusted Life Year (QALY) of the alternative care locations, adjusting for baseline differences with validated risk prediction models. We tested the robustness of results in sensitivity analyses. FINDINGS: Dedicated neurocritical care unit patients (N = 1324) had similar six-month mortality, higher QOL (mean gain 0.048, 95% CI -0.002 to 0.099) and increased average costs compared with those managed in combined neuro/general units (N = 1341), with a lifetime cost per QALY gained of £14,000. 'Early' transfer to a neuroscience centre (N = 584) was associated with lower mortality (odds ratio 0.52, 0.34-0.80), higher QOL for survivors (mean gain 0.13, 0.032-0.225), but positive incremental costs (£15,001, £11,123 to £18,880) compared with 'late or no transfer' (N = 263). The lifetime cost per QALY gained for 'early' transfer was £11,000. CONCLUSIONS: For critically ill adult patients with acute TBI, within neuroscience centres management in dedicated neurocritical care units versus combined neuro/general units led to improved QoL and higher costs, on average, but these differences were not statistically significant. This study finds that 'early' transfer to a neuroscience centre is associated with reduced mortality, improvement in QOL and is cost-effective.

Survival after postoperative morbidity: a longitudinal observational cohort study.

BACKGROUND: Previous studies have suggested that there may be long-term harm associated with postoperative complications. Uncertainty exists however, because of the need for risk adjustment and inconsistent definitions of postoperative morbidity. METHODS: We did a longitudinal observational cohort study of patients undergoing major surgery. Case-mix adjustment was applied and morbidity was recorded using a validated outcome measure. Cox proportional hazards modelling using time-dependent covariates was used to measure the independent relationship between prolonged postoperative morbidity and longer term survival. RESULTS: Data were analysed for 1362 patients. The median length of stay was 9 days and the median follow-up time was 6.5 yr. Independent of perioperative risk, postoperative neurological morbidity (prevalence 2.9%) was associated with a relative hazard for long-term mortality of 2.00 [P=0.001; 95% confidence interval (CI) 1.32-3.04]. Prolonged postoperative morbidity (prevalence 15.6%) conferred a relative hazard for death in the first 12 months after surgery of 3.51 (P<0.001; 95% CI 2.28-5.42) and for the next 2 yr of 2.44 (P<0.001; 95% CI 1.62-3.65), returning to baseline thereafter. CONCLUSIONS: Prolonged morbidity after surgery is associated with a risk of premature death for a longer duration than perhaps is commonly thought; however, this risk falls with time. We suggest that prolonged postoperative morbidity measured in this way may be a valid indicator of the quality of surgical healthcare. Our findings reinforce the importance of research and quality improvement initiatives aimed at reducing the duration and severity of postoperative complications.

Observational study of current use of selective decontamination of the digestive tract in UK critical care units.

BACKGROUND: Evidence supporting selective decontamination of the digestive tract (SDD) is reasonably strong. We set out to determine use in UK critical care units and to compare patient outcomes between units that do and those that do not use SDD. METHODS: A total of 250 UK general critical care units were surveyed. Case mix, outcomes, and lengths of stay for admissions to SDD units (with and without an i.v. component) and non-SDD units were compared using data from the Intensive Care National Audit & Research Centre Case Mix Programme database. RESULTS: A response was received from all the 250 critical care units surveyed. Of these, 13 (5.2%) reported using SDD on some or all admissions, and of these, 3 reported using an i.v. component. Data on 284,690 admissions (April 2008-March 2011) from units reporting to the ICNARC Case Mix Programme (CMP) were included in the analyses. Admissions to SDD (n=196) and non-SDD (n=9) units were a similar case mix with similar infection rates and average lengths of stay in the unit and hospital. There was no difference in risk-adjusted unit or hospital mortality. The rate of unit-acquired infections in blood was significantly lower in SDD units using an i.v. component. CONCLUSIONS: Use of SDD in UK critical care is very low. The rate of unit-acquired infections in blood was significantly lower in SDD units using an i.v. component, but did not translate into a difference in acute hospital mortality or length of stay. There is a need to better understand the barriers to adoption of SDD into clinical practice and such work is underway.

An integrated approach to evaluating alternative risk prediction strategies: a case study comparing alternative approaches for preventing invasive fungal disease.

OBJECTIVES: This article proposes an integrated approach to the development, validation, and evaluation of new risk prediction models illustrated with the Fungal Infection Risk Evaluation study, which developed risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive fungal disease (IFD). METHODS: Our decision-analytical model compared alternative strategies for preventing IFD at up to three clinical decision time points (critical care admission, after 24 hours, and end of day 3), followed with antifungal prophylaxis for those judged "high" risk versus "no formal risk assessment." We developed prognostic models to predict the risk of IFD before critical care unit discharge, with data from 35,455 admissions to 70 UK adult, critical care units, and validated the models externally. The decision model was populated with positive predictive values and negative predictive values from the best-fitting risk models. We projected lifetime cost-effectiveness and expected value of partial perfect information for groups of parameters. RESULTS: The risk prediction models performed well in internal and external validation. Risk assessment and prophylaxis at the end of day 3 was the most cost-effective strategy at the 2% and 1% risk threshold. Risk assessment at each time point was the most cost-effective strategy at a 0.5% risk threshold. Expected values of partial perfect information were high for positive predictive values or negative predictive values (£11 million-£13 million) and quality-adjusted life-years (£11 million). CONCLUSIONS: It is cost-effective to formally assess the risk of IFD for non-neutropenic, critically ill adult patients. This integrated approach to developing and evaluating risk models is useful for informing clinical practice and future research investment.

A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators.

PURPOSE: To determine whether early goal-directed therapy (EGDT) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department (ED) with septic shock. METHODS: Using a search strategy of PubMed, EmBase and CENTRAL, we selected all relevant randomised clinical trials published from January 2000 to January 2015. We translated non-English papers and contacted authors as necessary. Our primary analysis generated a pooled odds ratio (OR) from a fixed-effect model. Sensitivity analyses explored the effect of including non-ED studies, adjusting for study quality, and conducting a random-effects model. Secondary outcomes included organ support and hospital and ICU length of stay. RESULTS: From 2395 initially eligible abstracts, five randomised clinical trials (n = 4735 patients) met all criteria and generally scored high for quality except for lack of blinding. There was no effect on the primary mortality outcome (EGDT: 23.2% [495/2134] versus control: 22.4% [582/2601]; pooled OR 1.01 [95% CI 0.88-1.16], P = 0.9, with heterogeneity [I(2) = 57%; P = 0.055]). The pooled estimate of 90-day mortality from the three recent multicentre studies (n = 4063) also showed no difference [pooled OR 0.99 (95% CI 0.86-1.15), P = 0.93] with no heterogeneity (I(2) = 0.0%; P = 0.97). EGDT increased vasopressor use (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and ICU admission [OR 2.19 (95% CI 1.82-2.65); P < 0.001]. Including six non-ED randomised trials increased heterogeneity (I(2) = 71%; P < 0.001) but did not change overall results [pooled OR 0.94 (95% CI 0.82 to 1.07); P = 0.33]. CONCLUSION: EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU resources.

The added value that increasing levels of diagnostic information provide in prognostic models to estimate hospital mortality for adult intensive care patients.

OBJECTIVE: To investigate in a systematic, reproducible way the potential of adding increasing levels of diagnostic information to prognostic models for estimating hospital mortality. DESIGN: Prospective cohort study. SETTING: Thirty UK intensive care units (ICUs) participating in the ICNARC Case Mix Programme. PATIENTS: Eight thousand fifty-seven admissions to UK ICUs. MEASUREMENTS AND RESULTS: Logistic regression analysis incorporating APACHE II score, admission type and increasing levels of diagnostic information was used to develop models to estimate hospital mortality for intensive care patients. The 53 UK APACHE II diagnostic categories were substituted with data from a hierarchical, five-tiered (type of condition required surgery or not, body system, anatomical site, physiological/pathological process, condition) coding method, the ICNARC Coding Method. The inter-rater reliability using the ICNARC Coding Method to code reasons for admission was good (kappa = 0.70). All new models had good discrimination (AUC = 0.79-0.81) and similar or better calibration compared with the UK APACHE II model (Hosmer-Lemeshow goodness-of-fit H = 18.03 to H = 26.77 for new models versus H = 63.51 for UK APACHE II model). CONCLUSION: The UK APACHE II model can be simplified by extending the admission type and substituting the 53 UK APACHE II diagnostic categories with nine body systems, without losing discriminative power or calibration.

Research priorities in critical care medicine in the UK.

OBJECTIVES: To establish priorities for research in critical care medicine in the UK using survey and nominal group (NG) techniques. DESIGN: The senior doctor and nurse from 325 intensive care units (ICUs) in the UK were invited to contribute up to ten research questions relevant to intensive care organisation, practice or outcomes. These were then ranked twice using a Likert scale by a panel (nominal group) consisting of ten doctors (two trainees) and two nurses from university teaching and district general (community) hospitals. The first ratings were performed privately, and the second after group discussion. Thirty questions, ten each with strong, moderate or weak support, were then returned for rating by the originating ICU staff and the results compared with those of the NG. RESULTS: One hundred eighty-five respondents (35.6 % university teaching, 62.1% district general, 2.3 % not stated) provided 811 questions of which 722 were research hypotheses. The most frequently identified topics were the evaluation of high dependency care, ICU characteristics, treatments for acute lung injury and acute renal failure, nurse:patient ratios, pulmonary artery catheterisation, aspects of medical and nursing practice, protocol evaluation, and interhospital transfers. These were condensed into 100 topics for consideration by the NG. Discussion and re-rating by the group resulted in strong support being offered for 37 topics, moderate support for 48, and weak support for 21. Following circulation of ten questions from each category, nine questions achieved strong support from both ICU staff and the NG. These were the effect on outcomes from critical illness of early intervention, high dependency care, nurse:patient ratios, interhospital transfers, early enteral feeding, optimisation of perioperative care, hospital type, regionalisation of paediatric intensive care and the use of pulmonary artery catheters. The absence of any questions relating to interventions targetting mediators of the immuno-inflammatory response could be a consequence of the failure of recent studies in sepsis to demonstrate benefits in outcome. CONCLUSIONS: The intensive care community in the UK appears to prioritise research into organisational aspects of clinical practice and practical aspects of organ-system support. Health services research and the biological sciences need to develop collaborative methods for evaluating interventions and outcomes.

Outcome measures for adult critical care: a systematic review.

OBJECTIVES: 1. To identify generic and disease specific measures of impairment, functional status and health-related quality of life that have been used in adult critical care (intensive and high-dependency care) survivors. 2. To review the validity, reliability and responsiveness of the measures in adult critical care survivors. 3. To consider the implications for future policy and to make recommendations for further methodological research. 4. To review what is currently known of the outcome of adult critical care. DATA SOURCES: Searches of electronic databases (MEDLINE, EMBASE, CINAHL, PsycLIT, The Cochrane Library and SIGLE) from 1970 to August 1998. Manual searches of five journals (1985-98) not indexed in electronic databases and relevant conference proceedings (1993-98). Reference lists of six existing reviews, plus snowballing from reference lists of all relevant articles identified. STUDY SELECTION: Randomised trials, non-randomised trials (cohort studies) and case series that included data on outcomes after discharge from adult (16 years and over) critical care. DATA EXTRACTION AND SYNTHESIS: If reported, the following data were extracted from each paper: patient characteristics (age, gender, severity of illness, diagnostic category) number of patients eligible for study, follow-up period, number of deaths before follow-up, number and proportion of survivors included in follow-up method of presentation of outcome data - proportion normal as defined by reference values, or aggregate value (e.g. mean or median), or aggregate values plus an indication of variance (e.g. standard deviation or inter-quartile range). Evidence for three measurement properties was sought for each outcome measure that had been used in at least two studies - their validity, reliability and responsiveness in adult critical care. If the authors did not report these aspects explicitly, an attempt was made to use the data provided to provide these measurement properties. For measures that were used in at least ten studies, information on actual reported outcomes were also extracted. RESULTS: MEASURES USED IN CRITICAL CARE: Measures of impairment were largely confined to the respiratory system so are almost certainly not appropriate for many critical care survivors. They can be categorised as respiratory volumes (e.g. vital capacity), gas flow within the respiratory system (e.g. forced expiratory volume in 1 second (FEV1)), pulmonary diffusing capacity (e.g. carbon monoxide diffusing capacity) and visualisation of the upper airway (e.g. bronchoscopy). Multiple tests are often performed. Eight measures of physical functional status were used, five generic and three disease-specific. The most frequently used generic measures were multi-item scales. Two single-item global measures attempted to capture a person's overall activity level or functional status. Five multi-item measures of mental functional status were used, four generic and one specific to trauma patients. The generic measures were either confined to assessing depressive symptoms or also encompassed a measure of anxiety. Measures of neuropsychological functioning relate to a person's cognition, attention, ability to process information and memory. Apart from one single-item measure, which focused on communication level, six multi-item measures were used with critical care survivors. Such measures are particularly appropriate for use with survivors of head injury or other neurological insult and, in that sense, they are disease-specific rather than generic measures. Single item measures of recovery were frequently used but researchers often invented their own, so there was little consistency in the wording. These measures had five principal foci - return to work, return to own home, degree of recovery, productivity and chronic health status. One multi-item scale was also used. (ABSTRACT TRUNCATED)

Differences in the effects of mu- and delta-opioid receptor antagonists upon plasma corticosterone levels in stressed mice.

The effects of intraperitoneal injections of two opioid antagonists on plasma corticosterone levels in stressed mice was investigated. The effects of the mu-opioid receptor antagonist naloxone was dependent on the dose used. Low doses (0.5 and 1 mg/kg) potentiated the elevation of plasma corticosterone observed in saline treated or ether stressed mice, whereas a higher dose (10 mg/kg) produced the opposite effect. The delta-opioid receptor antagonist ICI 154,129 had no significant effect on corticosterone levels. The findings suggest that mu- rather than delta-opioid receptors are important in modifying corticosterone responses to stress and raise the question as to specificity of naloxone at doses above 1 mg/kg.

A trial of permethrin-treated bed nets in the prevention of malaria in Gambian children.

A trial was undertaken in a rural area of The Gambia to investigate the impact of permethrin-treated bed nets on malaria. Two groups of children, matched for age, sex, and malaria exposure, were followed through the rainy season of 1985 for illness and febrile episodes. One group of 205 children slept under permethrin-treated bed nets (0.5 g/m2); 184 children who slept under placebo-treated nets formed the control group. At the end of the rains the children were examined for splenomegaly and blood samples were taken for determination of packed cell volume (PCV) and parasitaemia. Permethrin treatment of bed nets was well accepted and was without side-effects. Children who slept under treated nets had significantly fewer episodes of clinical malaria than control children. However, at the end of the rains there was no significant difference in the prevalence of splenomegaly or parasitaemia or in the mean PCV between the groups. It is suggested that permethrin treatment of nets may have a greater effect on the duration of probing by mosquitoes for a blood meal than on the number of bites received.

A trial of bed nets (mosquito nets) as a malaria control strategy in a rural area of The Gambia, West Africa.

An intervention trial was undertaken in a rural area of The Gambia to assess the impact on malaria morbidity of the use of bed nets. Bed nets were allocated at random among a group of 16 Fula hamlets, where they were previously rarely used. The incidence of febrile episodes with associated malaria parasitaemias throughout the rainy season and the prevalence of splenomegaly and parasitaemia at the end of the rainy season were determined in 233 children aged 1-9 years who slept under bed nets and in 163 children who did not. Bed nets were used correctly by the children in the study cohort, but direct observations showed that a significant number of children left their nets for a period during the night. There was no significant difference in the incidence of clinical attacks of malaria or in any other malariometric measurement between the 2 groups. Thus, bed nets were not effective in reducing malaria morbidity in this group of children. The apparent protection from bed nets demonstrated in previous retrospective surveys may have been due to an increased number of infective bites being received by exposed individuals sleeping close to users of bed nets.

Intensive Care Society's APACHE II study in Britain and Ireland--I: Variations in case mix of adult admissions to general intensive care units and impact on outcome.

OBJECTIVES: To describe the extent of variation in the case mix of adult admissions to general intensive care units in Britain and Ireland and investigate the impact of such variation on outcome. DESIGN: Prospective, cohort study of consecutive admissions to intensive care units. SETTING: 26 general intensive care units in Britain and Ireland. SUBJECTS: 9099 admissions to the intensive care units studied. MAIN OUTCOME MEASURE: Death or survival at discharge before and after adjustment of case mix (age, history of chronic conditions, surgical status, diagnosis, and severity of illness) according to the APACHE II method. RESULTS: Important differences in case mix were found, with large variations between the units. Hospital mortality was significantly associated with most of the case mix factors investigated. CONCLUSIONS: Comparing crude death rates in hospital between intensive care units may be misleading indicators of performance. The collection of data on case mix needs to be standardised and differences in case mix adjusted for when comparing outcome between different intensive care units.

Intensive Care Society's APACHE II study in Britain and Ireland--II: Outcome comparisons of intensive care units after adjustment for case mix by the American APACHE II method.

OBJECTIVES: To compare outcome between intensive care units in Britain and Ireland both before and after adjustment for case mix with the American APACHE II method and to validate the American APACHE II method in Britain and Ireland. DESIGN: Prospective, cohort study of consecutive admissions to intensive care units. SETTING: 26 general intensive care units in Britain and Ireland. SUBJECTS: 8796 admissions to the study intensive care units. MAIN OUTCOME MEASURE: Death or survival at discharge from intensive care unit and hospital. RESULTS: At discharge from both intensive care unit and hospital there was a greater than twofold variation in crude mortality between the 26 units. After adjustment for case mix, variations in mortality were still apparent. For four intensive care units the observed numbers of deaths were significantly different from the number predicted by the American APACHE II equation. The overall goodness of fit, or predictive ability, of the APACHE II equation for the British and Irish data was good, being only slightly inferior to that obtained when the equation was tested on the data from which it had been derived. When patients were grouped by various factors such as age and diagnosis, the equation did not adjust across the subgroups in a uniform manner. CONCLUSIONS: The American APACHE II equation did not fit the British and Irish data. Use of the American equation could be of advantage or disadvantage to individual intensive care units, depending on the mix of patients treated.

Is the volume of mechanically ventilated admissions to UK critical care units associated with improved outcomes?

BACKGROUND: It is unknown whether a volume-outcome relationship exists for mechanically ventilated admissions to UK critical care units. This study was conducted to evaluate the volume-outcome relationship for mechanically ventilated admissions to adult, general critical care units in the UK with a view to informing policy, service delivery and organisation of specialist, advanced respiratory care. METHODS: A retrospective cohort study using data from the Case Mix Programme Database was conducted. The primary exposure of interest was annual volume (absolute number) of mechanically ventilated admissions per critical care unit per year. The primary outcome was ultimate acute hospital mortality. A multivariable analysis was performed to assess the relationship between annual volume and outcome while adjusting for a priori selected confounders. Two interaction tests were performed. The first interaction test was between annual volume and admission type and the second between annual volume and initial acute severity of respiratory failure. Sensitivity analysis excluding volume outlier units and using restricted cubic splines to model volume was also performed. RESULTS: After adjusting for confounding, there was a significant relationship between annual volume and ultimate acute hospital mortality (p < 0.02). The first interaction test revealed a strong interaction between annual volume and admission type, with a more pronounced volume-outcome relationship for non-surgical admissions (p < 0.001). The second interaction test between annual volume and initial acute severity of respiratory failure was not statistically significant (p = 0.12). The analysis using restricted cubic splines demonstrated a similar graphical relationship but the results were not statistically significant (p = 0.87). CONCLUSIONS: A volume-outcome relationship was demonstrated for mechanically ventilated admissions to adult, general critical care units in the UK. The relationship is sensitive to the modelling approach used.

Risk Adjustment In Neurocritical care (RAIN)--prospective validation of risk prediction models for adult patients with acute traumatic brain injury to use to evaluate the optimum location and comparative costs of neurocritical care: a cohort study.

OBJECTIVES: To validate risk prediction models for acute traumatic brain injury (TBI) and to use the best model to evaluate the optimum location and comparative costs of neurocritical care in the NHS. DESIGN: Cohort study. SETTING: Sixty-seven adult critical care units. PARTICIPANTS: Adult patients admitted to critical care following actual/suspected TBI with a Glasgow Coma Scale (GCS) score of < 15. INTERVENTIONS: Critical care delivered in a dedicated neurocritical care unit, a combined neuro/general critical care unit within a neuroscience centre or a general critical care unit outside a neuroscience centre. MAIN OUTCOME MEASURES: Mortality, Glasgow Outcome Scale - Extended (GOSE) questionnaire and European Quality of Life-5 Dimensions, 3-level version (EQ-5D-3L) questionnaire at 6 months following TBI. RESULTS: The final Risk Adjustment In Neurocritical care (RAIN) study data set contained 3626 admissions. After exclusions, 3210 patients with acute TBI were included. Overall follow-up rate at 6 months was 81%. Of 3210 patients, 101 (3.1%) had no GCS score recorded and 134 (4.2%) had a last pre-sedation GCS score of 15, resulting in 2975 patients for analysis. The most common causes of TBI were road traffic accidents (RTAs) (33%), falls (47%) and assault (12%). Patients were predominantly young (mean age 45 years overall) and male (76% overall). Six-month mortality was 22% for RTAs, 32% for falls and 17% for assault. Of survivors at 6 months with a known GOSE category, 44% had severe disability, 30% moderate disability and 26% made a good recovery. Overall, 61% of patients with known outcome had an unfavourable outcome (death or severe disability) at 6 months. Between 35% and 70% of survivors reported problems across the five domains of the EQ-5D-3L. Of the 10 risk models selected for validation, the best discrimination overall was from the International Mission for Prognosis and Analysis of Clinical Trials in TBI Lab model (IMPACT) (c-index 0.779 for mortality, 0.713 for unfavourable outcome). The model was well calibrated for 6-month mortality but substantially underpredicted the risk of unfavourable outcome at 6 months. Baseline patient characteristics were similar between dedicated neurocritical care units and combined neuro/general critical care units. In lifetime cost-effectiveness analysis, dedicated neurocritical care units had higher mean lifetime quality-adjusted life-years (QALYs) at small additional mean costs with an incremental cost-effectiveness ratio (ICER) of £14,000 per QALY and incremental net monetary benefit (INB) of £17,000. The cost-effectiveness acceptability curve suggested that the probability that dedicated compared with combined neurocritical care units are cost-effective is around 60%. There were substantial differences in case mix between the 'early' (within 18 hours of presentation) and 'no or late' (after 24 hours) transfer groups. After adjustment, the 'early' transfer group reported higher lifetime QALYs at an additional cost with an ICER of £11,000 and INB of £17,000. CONCLUSIONS: The risk models demonstrated sufficient statistical performance to support their use in research but fell below the level required to guide individual patient decision-making. The results suggest that management in a dedicated neurocritical care unit may be cost-effective compared with a combined neuro/general critical care unit (although there is considerable statistical uncertainty) and support current recommendations that all patients with severe TBI would benefit from transfer to a neurosciences centre, regardless of the need for surgery. We recommend further research to improve risk prediction models; consider alternative approaches for handling unobserved confounding; better understand long-term outcomes and alternative pathways of care; and explore equity of access to postcritical care support for patients following acute TBI. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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.

The Swine Flu Triage (SwiFT) study: development and ongoing refinement of a triage tool to provide regular information to guide immediate policy and practice for the use of critical care services during the H1N1 swine influenza pandemic.

OBJECTIVES: To use, existing critical care and early pandemic, data to inform care during the pandemic influenza A 2009 (H1N1) pandemic (with a possible use for triage - if the demand for critical care seriously exceeded supply). To monitor the impact of the H1N1 pandemic on critical care services, in real time, with regular feedback to critical care clinicians and other relevant jurisdictions to inform ongoing policy and practice. DESIGN: Modelling of data and cohort study. SETTING: Modelling - 148 adult, general critical care units in England, Wales and Northern Ireland in the Intensive Care National Audit & Research Centre Case Mix Programme. Cohort study - 192 acute hospitals in England, Wales, Northern Ireland, Scotland and the Republic of Ireland. PARTICIPANTS: Modelling - 105,397 admissions to adult, general critical care units. Cohort study - 1728 H1N1 pandemic-related admissions referred and assessed as requiring critical care. MAIN OUTCOME MEASURES: Modelling - requirement for organ support and acute hospital mortality. Cohort study - survival to the end of critical care. RESULTS: Modelling - cancelled or postponed, elective or scheduled surgery resulted in savings in calendar days of critical, Level 3 and advanced respiratory care of 17, 11 and 10%, respectively. These savings varied across units. Using routine, physiological variables, the best triage models, for all and for acute respiratory admissions, achieved only satisfactory concordance of 0.79 and 0.75, respectively. Application of the best model on all admissions indicated that approximately 12.5% of calendar days of critical care could be saved. Cohort study - research governance approvals were achieved for 192 acute hospitals, for 91 within 1 day of central research and development approval across the five countries. A total of 1725 cases (562 confirmed) were reported. Confirmed cases were young (mean age of 40 years), had low severity of acute illness on presentation [61% CURB-65 (confusion, urea, respiratory rate, blood pressure, age over 65 years) 0-1], but had long stays in critical care (median 8.5 days) and were likely to be ventilated (77% for median 9 days). Risk factors for acute hospital death were similar to those for general critical care admissions. CONCLUSIONS: SwiFT was rapidly established. Models based on routine physiology suggested limited value for triage. More data and further modelling are warranted. The magnitude of the pandemic did not approach the worst-case scenario modelling, and UK-confirmed H1N1 cases appeared similar to those reported internationally. FUNDING: The National Institute for Health Research Health Technology Assessment programme.