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.

Low-dose and high-dose synacthen tests and the hemodynamic response to hydrocortisone in acute traumatic brain injury.

INTRODUCTION: In order to identify whether low-dose (1 microg) tetracosactide (Synacthen) testing may be preferable to high-dose (250 microg) testing in the diagnosis of adrenal insufficiency in traumatic brain injury (TBI), as suggested by studies in other forms of critical illness. METHODS: We retrospectively reviewed the results of modified tetracosactide tests (involving administration of both low-dose and high-dose tetracosactide) conducted for clinical indications in patients in a neurocritical care unit within 10 days of TBI. Sixty-three modified tests were included and cortisol concentrations before and after administration of tetracosactide were extracted from the hospital records. Data were also extracted regarding hemodynamic response to empirical corticosteroid therapy, based on rapid weaning from vasoactive drugs. RESULTS: Cortisol increments at 30 and 60 min following tetracosactide correlated well in the low-dose test (r(2) = 0.875, P < 0.0001). The mean cortisol concentration was 581 nmol/l at 30 min and 556 nmol/l at 60 min in the low-dose test. Cortisol increments following low-dose and high-dose testing correlated well overall (r(2) = 0.839, P < 0.0001), but results were discordant in 27 of 63 cases (43%) when the same diagnostic threshold was used. ROC curve analysis showed that both tests performed poorly in identifying hemodynamic steroid responsiveness (AUC 0.553 and 0.502, respectively). CONCLUSIONS: In the low-dose tetracosactide test, it is sufficient to determine cortisol concentrations at baseline and at 30 min. Low-dose and high-dose tests give discordant results in a significant proportion of cases when using the same diagnostic threshold. Neither test can be used to guide the initiation of corticosteroid therapy in acute TBI.

Awake insertion of the laryngeal mask airway using topical lidocaine and intravenous remifentanil.

We assessed the use of intravenous remifentanil for the insertion of the laryngeal mask airway in 10 healthy awake volunteers, a technique primarily developed to facilitate functional magnetic resonance imaging studies of anaesthesia. Each volunteer received 200 microg glycopyrronium intravenously. Topical airway anaesthesia was effected by 4 ml nebulised lidocaine 4%, followed by 12 sprays of lidocaine 10%. Remifentanil was subsequently infused to achieve an initial target effect-site concentration of 2 ng.ml(-1); increments of 1 ng.ml(-1) were allowed with the maximum effect-site concentration limited to 6 ng.ml(-1). Insertion of the laryngeal mask airway was successful on the first attempt in all cases. The median (IQR [range]) target effect-site remifentanil concentration at insertion was 2.5 (2-3 [2-4]) ng.ml(-1). All volunteers were co-operative during the procedure and only one reported discomfort. Sore throat was a complication in all volunteers. We conclude that the technique allows successful insertion of the laryngeal mask airway in healthy awake volunteers under conditions that were safe and reproducible.

In vivo hepatic 31P magnetic resonance spectroscopy in chronic alcohol abusers.

BACKGROUND/AIMS: In vivo hepatic 31P magnetic resonance spectroscopy (MRS) can provide information on hepatic energy metabolism, phospholipid substrates, and hepatocyte lipid bilayers. The aim of this study was to ascertain the effects of alcohol ingestion on hepatic 31P spectral variables. METHODS: Twenty-six chronic alcohol abusers underwent hepatic 31P MRS 6-12 hours after their last alcoholic drink; studies were repeated in 17 individuals following abstinence from alcohol. The reference population comprised 16 healthy volunteers. Ratios of phosphomonoesters (PME), inorganic phosphate, and phosphodiesters (PDE) relative to beta-adenosine triphosphate (ATP) were measured. RESULTS: In patients with minimal liver injury, recent drinking was associated with a significant elevation in the mean PDE/ATP ratio (P < 0.0001) and an increase in mean PME/ATP, which was not significant; abstinence was associated with reductions in both metabolite ratios. In patients with alcoholic cirrhosis, recent drinking was associated with an elevation in mean PME/ATP (P < 0.05) and an increase in mean PDE/ATP, which was not significant; abstinence was associated with no significant change in PME/ATP but with a reduction in PDE/ATP. CONCLUSIONS: In the absence of significant liver injury, chronic alcohol abuse is associated with the elevation of PME/ATP, possibly reflecting changes in hepatic redox potential, and of PDE/ATP, most likely reflecting the induction of hepatocyte endoplasmic reticulum. In the presence of cirrhosis, these changes are attenuated and modified.

Effects of fish oil on phospholipid metabolism in human and rat liver studied by 31P NMR spectroscopy in vivo and in vitro.

The effect of omega 3 fatty acids on the metabolism of the normal liver was studied using 31P NMR spectroscopy. Human subjects were examined before and after 1, 3 and 7 days of supplementation with 50 mL fish oil per day (12 g omega 3 fatty acids). 31P NMR spectra (1.6 T) revealed a significant increase in phosphodiester (PDE) to ATP ratios after 1 and 3 days of fish oil. After 7 days, [PDE]/[ATP] ratios at a TR of 1 s had returned to baseline levels, but [PDE]/[ATP] at a TR of 5 s appeared to remain high. Rats were fed diets containing 50% of the energy from fish oil or normal rat chow (controls) for 14 days. 31P NMR liver spectra in vivo (4.7 T) confirmed increased [PDE]/[ATP] in rats fed fish oil compared to controls, although the difference was only statistically significant at a TR of 1.5 s but not at a TR of 8 s. 31P NMR spectra of rat liver extracts (8.7 T) suggested that increased concentrations of glycerophosphocholine and possibly glycerophosphoethanolamine were responsible for rising PDE levels in vivo. Phosphocholine (PC) concentrations were markedly reduced in rat liver after fish oil. The combined rise in glycerophosphocholine and reduction in PC would be consistent with a shift from the phospholipase C to the phospholipase A1/A2 pathway of phosphatidylcholine breakdown after fish oil consumption.

Effect of L-alanine infusion on 31P nuclear magnetic resonance spectra of normal human liver: towards biochemical pathology in vivo.

1. 31P n.m.r. spectroscopy in vivo was used to study the effect of L-alanine infusion on the concentrations of gluconeogenic intermediates in normal human liver. Studies were performed in six healthy male subjects (34-44 years, fasted overnight) using a chemical shift imaging pulse sequence on a whole-body n.m.r. system operating at 1.6T. Hepatic 31P n.m.r. spectra were obtained from 10 min before to 70 min after intravenous administration of 0.70 (n = 2), 1.40 (n = 3) or 2.80 (n = 5) nmol of L-alanine/kg body weight over 4.5 min. Concentrations of phosphomonoesters, Pi and phosphodiesters relative to ATP were calculated from peak areas in the n.m.r. spectra, using the beta-ATP peak as a reference. 2. Dose-dependent spectral changes were observed for [phosphomonoesters]/[ATP] and [Pi]/[ATP]. At the highest dose given, maximal changes in [phosphomonoesters]/[ATP] (mean +/- SEM: 98 +/- 12%, P < 0.005) and [Pi]/[ATP] (-33 +/- 3%, P < 0.001) were observed approximately 45 min after the L-alanine infusion. [Phosphodiesters]/[ATP] showed a maximal increase of 24 +/- 6% (P < 0.05), which was independent of the L-alanine dose. Hepatic ATP levels and pH did not change. 3. To identify the metabolites responsible for the changes observed in vivo, male Wistar rats were infused with 11.2 mmol of L-alanine/kg body weight. After 15 min, livers were freeze-clamped and were extracted according to standard procedures. In vitro, 31P n.m.r. spectra obtained at 8.4 or 11.7 T revealed sharp increases in the concentrations of 3-phosphoglycerate and phosphoenolpyruvate after L-alanine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphorus-31 magnetic resonance spectroscopy of the human liver using chemical shift imaging techniques.

Phosphorus-31 magnetic resonance spectroscopy of the human liver was undertaken in 28 healthy adult individuals and in 49 patients with liver disease of varying aetiology. Data localised to the liver were obtained using chemical shift imaging techniques. The mean (+/- 1 S.D.) of the peak area ratio phosphomonoesters (PME)/phosphodiesters (PDE) in healthy adult individuals, from spectra obtained with pulse angle 45 degrees and repetition time 1 s, was 0.24 +/- 0.07. The intra-examination variability of this ratio was 20%, the intra-subject variability 27% and the inter-subject variability 32%. An increase in the PME/PDE was observed in the 31P hepatic MR spectrum from primary or secondary tumours in all 17 patients studied, which invariably represented an increase in PME/ATP and, in some cases, a reduction in PDE/ATP. The spectra did not show aetiological characteristics. A non-specific elevation in PME/PDE was also observed in the 31P hepatic MR spectra of 10 (40%) of 25 patients studied who had diffuse liver diseases, such as cirrhosis and infiltrating malignancies. The spectral pattern did not distinguish between diseases of varying aetiologies, but there was a linear correlation between increasing PME/PDE and a reduction in plasma albumin concentrations (p = 0.03). In three patients with hepatic malignancy and abnormal hepatic 31P-MRS, marked spectral changes were observed after successful treatment to debulk the tumour. Only minor changes were observed in the abnormal spectrum of a fourth patient in whom treatment was unsuccessful. Hepatic 31P-MR spectroscopy may prove useful for monitoring disease processes and treatment effects in well characterised patient populations.

Proton MR spectroscopy of the brain in infants.

Proton magnetic resonance spectroscopy (MRS) was used to study the brain of 2 normal and 15 abnormal infants aged from 33 weeks postmenstrual age (PMA) to 14 months postnatal age. Eleven of the infants were examined on at least two occasions. The principal clinical diagnoses in the abnormal infants were perinatal ischemic and hemorrhagic brain injury. All proton spectra demonstrated peaks that were assigned to N-acetylaspartate (NAA), choline containing compounds (Cho), and creatine plus phosphocreatine (Cr). The NAA/Cho and NAA/Cr ratios increased with age, while the Cho/Cr ratio decreased with age in the majority of infants. The NAA/Cho ratio was generally lower in abnormal infants, but the difference was not apparent before 40 weeks (PMA). This ratio was lowest in infants with the severest degree of neurological abnormality. Proton and phosphorus MRS was compared in seven infants. In those with severe brain lesions, early phosphorus spectra were abnormal. On follow-up the phosphorus spectra became normal, but the proton spectra showed persistently low NAA/Cho and NAA/Cr ratios. Proton MRS provides new information that may be complementary to phosphorus MRS in the diagnosis and monitoring of brain development in normal and neurologically damaged infants.