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.

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.

Changes of endothelial nitric oxide synthase level and activity during endothelial cell proliferation.

The goal of this study was to investigate the effect of endothelial cell proliferation on the expression and activity of endothelial nitric oxide synthase (eNOS). Bovine atrial endothelial cells (BAtEC) were studied between day 1 and 6 after seeding. During this period the number of cells in S-phase decreased progressively, while cell number and protein content increased, reaching a maximum at confluence (day 4). Expression of eNOS (determined by ELISA) and eNOS activity (determined by L-arginine to L-citrulline conversion) increased with culture duration with a maximum at confluence. Nitric oxide (*NO) release from BAtEC was determined after stimulation with Ca2+ ionophore A23187 (10 microM, 30 min) by .NO chemiluminescence in the absence of a chemical reduction system. Total *NO release (measured in the presence of 100 U/ml superoxide dismutase) did not change with state of cell proliferation/growth, whereas "bioavailable" *NO (measured in the absence of superoxide dismutase) was low in highly proliferating BAtEC. Relative eNOS activity (.NO and L-citrulline production per eNOS protein) was highest in proliferating BAtEC. The novel finding of this study is that the specific eNOS activity is upregulated in proliferating BAtEC and downregulated in quiescent BAtEC. The amount of "bioavailable" *NO is determined by eNOS activity and *NO inactivation (probably by superoxide), both high in proliferating BAtEC.

The snRNP E protein multigene family contains five pseudogenes with common mutations.

Sequence data from three previously-uncharacterized members of the snRNP E protein multigene family suggest that each is a non-transcribed processed pseudogene, even though one clone has the potential to code for a full-length protein with greater than 90% similarity to previously-characterized E protein cDNAs. Each of the newly-analyzed family members is without introns, contains a tract of polyadenylic acid residues, and is flanked by short direct repeats. In addition, the three sequences all contain point mutations that distinguish them from the E protein coding sequence. Seven point mutations are common to the three sequences described here and to two previously-described E protein pseudogenes. Although all of these mutations are transitions, only 5 of 7 could have been generated by deamination of methylated cytosines in inactive genes. Thus, the common mutations in the pseudogenes suggest an origin other than the expressed gene that we have described. Allelic variants for two of the pseudogenes were detected and repetitive elements are located near four of the five E protein pseudogenes that have been characterized.

The complete primary structure of the human snRNP E protein.

The snRNP E protein is one of four "core" proteins associated with the snRNAs of the U family (U1,U2,U4,U5, and U6). Screening of a human teratoma cDNA library with a partial cDNA for a human autoimmune antigen resulted in the isolation of a cDNA clone containing the entire coding region of this snRNP core protein. Comparison of the 5' end of this cDNA with the sequences of two processed pseudogenes and primer extension data suggest that the cDNA is nearly full length. The longest open reading frame in this clone codes for a basic 92 amino acid protein which is in perfect agreement with amino acid sequence data obtained from purified E protein. The predicted sequence of this protein reveals no extensive similarity to other snRNP proteins, but contains regions of similarity to a eukaryotic ribosomal protein.

Protein O-carboxylmethyltransferase in spermatozoa from normal and infertile men.

In confirmation of several reports, suspensions of normal washed human spermatozoa exposed to a nonionic detergent exhibited considerable activity of the enzyme protein O-carboxylmethyltransferase (PCM), which catalyzes the methyl esterification of carboxyl groups of dicarboxylic amino acid residues in proteins. Various methods for assay of human spermatozoal PCM levels were evaluated, and some properties of the enzyme were studied. Normal human spermatozoa appear to be devoid of other types of protein methyltransferases that catalyze N-methylations of arginyl or lysyl residues in proteins. Spermatozoal PCM levels in infertile patients with motile sperm cells tended to be somewhat higher than those of normal control subjects, especially in those instances where the spermatozoal populations contained abnormally high proportions of immature forms of spermatozoa. Although totally immotile spermatozoa obtained from certain patients exhibited very low PCM activities (as recently reported by other investigators), in this study no invariant relationship between zero motility indexes and spermatozoal PCM was observed. These results are discussed in light of various current hypotheses regarding the functions of PCM in animal cells.

Protein O-carboxylmethylation in relation to male gamete production and function.

Protein O-carboxylmethyltransferase (PCM) activity of differentiating male germ cells in the testis and of spermatozoa is strikingly high. PCM catalyzes the methylesterification by S-adenosylmethionine of dicarboxylic amino acid residues in proteins. PCM appears to be the only type of protein methyltransferase present in mature spermatozoa. Mammalian sperms contain considerable amounts of S-adenosylmethionine and can apparently synthesize this nucleoside from L-methionine and ATP. Spermatozoa are rich in S-adenosylhomocysteine hydrolase. The characteristics of this enzyme in testicular germ cells and in sperms are very similar to those in other mammalian tissues; the very sub-stoichiometric extent of methylation of various pure protein substrates, and the rapid spontaneous hydrolysis of the protein methyl ester products at physiological and especially higher pH values, are particularly remarkable. From studies on processes related to protein O-carboxylmethylation in rat spermatozoa from different regions of the epididymis, and in ejaculated spermatozoa from normal and infertile men, unequivocal evidence could not be obtained for hypotheses of other investigators that PCM-catalyzed reactions are of regulatory importance for the acquisition of a potentiality for motility in sperms during their transit and maturation in the epididymis, or for the locomotion of ejaculated sperms. The findings are discussed in the light of the recent hypothesis of S. Clarke that PCM catalyzes methylesterification of D-aspartyl residues that accumulate in certain proteins as a result of slow spontaneous racemization of L-aspartyl residues, and that the methyl esterification of D-aspartyl residues may be related to disposal or repair of proteins damaged in this fashion.