Joern Wetterslev

Abstract: Thrombelastography (TEG) and Thrombelastometry (ROTEM) are viscoelastic whole-blood assays evaluating the haemostatic capacity of blood. These devices are used in algorithms to guide transfusion of haemostatic blood components.

Abstract: Objective To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes. Design Systematic review with meta-analyses and trial sequential analyses of randomised trials. Data sources Cochrane Library, Medline, Embase, Science Citation Index Expanded, LILACS, and CINAHL to December 2010; hand search of reference lists and conference proceedings; contacts with authors, relevant pharmaceutical companies, and the US Food and Drug Administration. Study selection Randomised clinical trials comparing targeted intensive glycaemic control with conventional glycaemic control in patients with type 2 diabetes. Published and unpublished trials in all languages were included, irrespective of predefined outcomes. Data extraction Two reviewers independently assessed studies for inclusion and extracted data related to study methods, interventions, outcomes, risk of bias, and adverse events. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models. Results Fourteen clinical trials that randomised 28 614 participants with type 2 diabetes (15 269 to intensive control and 13 345 to conventional control) were included. Intensive glycaemic control did not significantly affect the relative risks of all cause (1.02, 95% confidence interval 0.91 to 1.13; 28 359 participants, 12 trials) or cardiovascular mortality (1.11, 0.92 to 1.35; 28 359 participants, 12 trials). Trial sequential analyses rejected a relative risk reduction above 10% for all cause mortality and showed insufficient data on cardiovascular mortality. The risk of non-fatal myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28 111 participants, 8 trials), but this finding was not confirmed in trial sequential analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25 600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10 793 participants, 7 trials), but trial sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27 769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27 844 participants, 9 trials); trial sequential analysis supported a 30% increased relative risk of severe hypoglycaemia. CONCLUSION: Intensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes. Data available from randomised clinical trials remain insufficient to prove or refute a relative risk reduction for cardiovascular mortality, non-fatal myocardial infarction, composite microvascular complications, or retinopathy at a magnitude of 10%. Intensive glycaemic control increases the relative risk of severe hypoglycaemia by 30%.

Abstract: Patients with type 2 diabetes mellitus (T2D) exhibit an increased risk of cardiovascular disease and mortality compared to the background population. Observational studies report a relationship between reduced blood glucose and reduced risk of both micro- and macrovascular complications in patients with T2D.

Abstract: Meta-analyses including a limited number of patients and events are prone to yield overestimated intervention effect estimates. While many assume bias is the cause of overestimation, theoretical considerations suggest that random error may be an equal or more frequent cause. The independent impact of random error on meta-analyzed intervention effects has not previously been explored. It has been suggested that surpassing the optimal information size (i.e., the required meta-analysis sample size) provides sufficient protection against overestimation due to random error, but this claim has not yet been validated.

Abstract: Systematic reviews with meta-analyses often contain many statistical tests. This multiplicity may increase the risk of type I error. Few attempts have been made to address the problem of statistical multiplicity in systematic reviews. Before the implications are properly considered, the size of the issue deserves clarification. Because of the emphasis on bias evaluation and because of the editorial processes involved, Cochrane reviews may contain more multiplicity than their non-Cochrane counterparts. This study measured the quantity of statistical multiplicity present in a population of systematic reviews and aimed to assess whether this quantity is different in Cochrane and non-Cochrane reviews.

Abstract: In unipolar, and bipolar affective disorders, there is a high risk of relapse that increases as the number of episodes increases. Naturalistic follow-up studies suggest that the progressive development of the diseases is not prevented with the present treatment modalities. It is not known whether centralised and specialised secondary care intervention initiated early after the onset of the diseases can prevent the progression and thereby improve the prognosis.

Abstract: Hepatocellular carcinoma (HCC) results in more than 600,000 deaths per year. Transarterial embolisation (TAE) and transarterial chemoembolisation (TACE) have become standard loco-regional treatments for unresectable HCC.

Abstract: The available evidence on vitamin D and mortality is inconclusive.

Abstract: The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD).

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Abstract: To evaluate the cardiovascular outcomes and other outcomes associated with angiotensin receptor blockers.

Abstract: The risk of cancer from antihypertensive drugs has been much debated, with a recent analysis showing increased risk with angiotensin-receptor blockers (ARBs). We assessed the association between antihypertensive drugs and cancer risk in a comprehensive analysis of data from randomised clinical trials.

Abstract: By tradition colloid solutions have been used to obtain fast circulatory stabilisation in shock, but high molecular weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis. Now lower molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICUs) and 1st choice fluid for patients with severe sepsis. However, HES 130/0.4 is largely unstudied in patients with severe sepsis.

Abstract: The modified Mallampati score is used to predict difficult tracheal intubation. We have conducted a meta-analysis of published studies to evaluate the Mallampati score as a prognostic test. A total of 55 studies involving 177 088 patients were included after comprehensive electronic and manual searches. The pooled estimates from the meta-analyses were calculated based on a random-effects model and a summary receiver operating curve. Meta-regression analyses were performed to explore sources of possible heterogeneity between the studies. The summary receiver operating curve demonstrated an area under the curve of 0.75. The pooled odds ratio for a difficult intubation with a modified Mallampati score of III or IV was 5.89 [95% confidence interval (CI), 4.74-7.32]. The pooled estimates of the specificity and sensitivity were 0.91 (CI, 0.91-0.91) and 0.35 (CI, 0.34-0.36), respectively. The pooled positive and negative likelihood ratios were 4.13 (CI, 3.60-4.66) and 0.70 (CI, 0.65-0.75), respectively. The meta-analyses had statistical and clinical heterogeneity ranging from 87.2% to 99.4%. Meta-regression analyses did not identify any significant explanation of the heterogeneity. We conclude that the prognostic value of the modified Mallampati score was worse than that estimated by previous meta-analyses. Our assessment shows that the modified Mallampati score is inadequate as a stand-alone test of a difficult laryngoscopy or tracheal intubation, but it may well be a part of a multivariate model for the prediction of a difficult tracheal intubation.

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Abstract: Severe bleeding and coagulopathy as a result of massive transfusion are serious clinical conditions that are associated with high mortality. Thromboelastography (TEG) and thromboelastometry (ROTEM) are increasingly used to guide transfusion strategy but their roles remain disputed.

Abstract: Background: Acute hypoxemic respiratory failure, defined as acute lung injury and acute respiratory distress syndrome, are critical conditions associated with frequent mortality and morbidity in all ages. Inhaled nitric oxide (iNO) has been used to improve oxygenation, but its role remains controversial. We performed a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials (RCTs). We searched CENTRAL, Medline, Embase, International Web of Science, LILACS, the Chinese Biomedical Literature Database, and CINHAL (up to January 31, 2010). Additionally, we hand-searched reference lists, contacted authors and experts, and searched registers of ongoing trials. Two reviewers independently selected all parallel group RCTs comparing iNO with placebo or no intervention and extracted data related to study methods, interventions, outcomes, bias risk, and adverse events. All trials, irrespective of blinding or language status were included. Retrieved trials were evaluated with Cochrane methodology. Disagreements were resolved by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effect of iNO in adults and children and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components. We assessed the risk of random error by applying trial sequential analysis. Results: We included 14 RCTs with a total of 1303 participants; 10 of these trials had a high risk of bias. iNO showed no statistically significant effect on overall mortality (40.2% versus 38.6%) (relative risks [RR] 1.06, 95% confidence interval [CI] 0.93 to 1.22; I(2) = 0) and in several subgroup and sensitivity analyses, indicating robust results. Limited data demonstrated a statistically insignificant effect of iNO on duration of ventilation, ventilator-free days, and length of stay in the intensive care unit and hospital. We found a statistically significant but transient improvement in oxygenation in the first 24 hours, expressed as the ratio of Po(2) to fraction of inspired oxygen (mean difference [MD] 15.91, 95% CI 8.25 to 23.56; I(2) = 25%). However, iNO appears to increase the risk of renal impairment among adults (RR 1.59, 95% CI 1.17 to 2.16; I(2) = 0) but not the risk of bleeding or methemoglobin or nitrogen dioxide formation. Conclusion: iNO cannot be recommended for patients with acute hypoxemic respiratory failure. iNO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful.

Abstract: "Good clinical practice" (GCP) is an international guideline on how to conduct clinical trials on medical products involving human participants. Danish statute follows the EU trial directive (2001/20/EF) including the GCP guidelines. This article summarises the practical implementation of reporting adverse events and adverse reactions to the Danish Medicines Agency and the regional ethics committee based on the protocol of the ongoing Copenhagen Insulin and Metformin Therapy (CIMT) trial.

Abstract: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions that are associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far.

Abstract: Clinical evidence continues to expand and is increasingly difficult to overview. We aimed at conceptualizing a visual assessment tool, i.e., a matrix for overviewing studies and their data in order to assess the clinical evidence at a glance.

Abstract: BACKGROUND: The role of carotid artery stenting (CAS) when compared with carotid endarterectomy (CEA) is controversial, with recent trials showing an increased risk of harm with CAS. OBJECTIVE: To evaluate the periprocedural and intermediate to long-term benefits and harms of CAS compared with CEA. Data Sources and STUDY SELECTION: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials searches for randomized clinical trials until June 2010 of CAS compared with CEA for carotid artery disease. Periprocedural (≤30-day) outcomes (death, myocardial infarction [MI], or stroke; death or any stroke; any stroke; and MI) and intermediate to long-term outcomes (outcomes as in the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy [SAPPHIRE] trial: composite of periprocedural death, MI, or stroke plus ipsilateral stroke or death thereafter; periprocedural death or stroke plus ipsilateral stroke thereafter; death or any stroke; and any stroke) were evaluated. DATA EXTRACTION: Two of us independently extracted data in duplicate. Baseline characteristics, inclusion and exclusion criteria, use of an embolic protection device, US vs non-US study, and the earlier-mentioned outcomes of interest were extracted from each trial. DATA SYNTHESIS: We identified 13 randomized clinical trials randomizing 7477 participants. Carotid artery stenting was associated with an increased risk of periprocedural outcomes of death, MI, or stroke (odds ratio = 1.31; 95% confidence interval, 1.08-1.59), 65% and 67% increases in death or stroke and any stroke, respectively, but with 55% and 85% reductions in the risk of MI and cranial nerve injury, respectively, when compared with CEA. The trial sequential monitoring boundary was crossed by the cumulative z curve, suggesting firm evidence for at least a 20% relative risk increase of periprocedural death or stroke and any stroke and at least a 15% reduction in MI with CAS compared with CEA. Similarly, CAS was associated with 19%, 38%, 24%, and 48% increases in the intermediate to long-term outcomes of SAPPHIRE-like outcome, periprocedural death or stroke and ipsilateral stroke thereafter, death or any stroke, and any stroke, respectively. The trial sequential monitoring boundary was crossed by the cumulative z curve, suggesting firm evidence for at least a 20% relative risk increase of any stroke. CONCLUSIONS: In this largest and most comprehensive meta-analysis to date using outcomes that are standard in contemporary studies, CAS was associated with an increased risk of both periprocedural and intermediate to long-term outcomes, but with a reduction in periprocedural MI and cranial nerve injury. Strategies are urgently needed to identify patients who are best served by CAS vs CEA.

Abstract: Conclusions based on meta-analyses of randomized trials carry a status of "truth." Methodological components may identify trials with systematic errors ("bias"). Trial sequential analysis (TSA) evaluates random errors in meta-analysis. We analyzed meta-analyses on laparoscopic vs. small-incision cholecystectomy regarding different outcome measures for the occurrence of type I errors.

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Abstract: Acute hypoxaemic respiratory failure (AHRF), defined as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are critical conditions. AHRF results from a number of systemic conditions and is associated with high mortality and morbidity in all ages. Inhaled nitric oxide (INO) has been used to improve oxygenation but its role remains controversial.

Abstract: General anaesthesia causes atelectasis which can lead to impaired respiratory function. Positive end-expiratory pressure (PEEP) is a mechanical manoeuvre which increases functional residual capacity (FRC) and prevents collapse of the airways thereby reducing atelectasis. It is not known whether intra-operative PEEP alters the risk of postoperative mortality and pulmonary complications.

Abstract: BACKGROUND: Guidelines recommend mild induced hypothermia (MIH) to reduce mortality and neurological impairment after out-of-hospital cardiac arrest. Our objective was to systematically evaluate the evidence for MIH taking into consideration the risks of systematic and random error and to GRADE the evidence. METHODS: Systematic review with meta-analysis and trial sequential analysis of randomised trials evaluating MIH after cardiac arrest in adults. We searched CENTRAL, MEDLINE, and EMBASE databases until May 2009. Retrieved trials were evaluated with Cochrane methodology. Meta-analytic estimates were calculated with random- and fixed-effects models and random errors were evaluated with trial sequential analysis (TSA). RESULTS: Five randomised trials (478 patients) were included. All trials had substantial risk of bias. The relative risk (RR) for death was 0.84 (95% confidence interval (CI) 0.70 to 1.01) and for poor neurological outcome 0.78 (95% CI 0.64 to 0.95). For the two trials with least risk of bias the RR for death was 0.92 (95% CI 0.56 to 1.51) and for poor neurological outcome 0.92 (95% confidence interval 0.56 to 1.50). TSA indicated lack of firm evidence for a beneficial effect. The substantial risk of bias and concerns with directness rated down the quality of the evidence to low. CONCLUSIONS: Evidence regarding MIH after out-of-hospital cardiac arrest is still inconclusive and associated with non-negligible risks of systematic and random errors. Using GRADE-methodology, we conclude that the quality of evidence is low. Our findings demonstrate that clinical equipoise exists and that large well-designed randomised trials with low risk of bias are needed.

Abstract: Surgical site infection (SSI) is a common complication after abdominal surgery and the Centers for Disease Control and Prevention (CDC) criteria are commonly used for diagnosis and surveillance. The aim of this study was to evaluate whether SSI diagnosed according to CDC is clinically relevant (CRSSI) and whether there is agreement between evaluations according to the CDC criteria, the ASEPSIS score (Additional treatment, presence of Serous discharge, Erythema, Purulent exudate, Separation of the deep tissues, Isolation of bacteria and duration of Stay) and CRSSI. We included 54 patients diagnosed with SSI and a matched control group (N=46) without SSI according to the CDC criteria after laparotomy. Two blinded experienced surgeons evaluated the hospital records and determined whether patients had CRSSI, based on the following criteria: antibiotic treatment, surgical intervention, prolonged hospital stay or referral to an intensive care unit for SSI. The rate of CRSSI was 38 of 54 (70%) in patients with CDC-diagnosed SSI and none in patients without a CDC-diagnosed SSI. Sixty-one percent of the CDC-diagnosed SSIs were superficial, of which 48% were considered clinically relevant. There was substantial agreement between the CDC criteria and CRSSI [kappa=0.69; 95% confidence interval (CI): 0.55-0.83] and fair agreement between the ASEPSIS score and the CDC criteria (kappa=0.23; 95% CI: 0-0.49) and between the ASEPSIS score and CRSSI (kappa=0.39; 95% CI: 0.17-0.61). The CDC criteria represent a suitable standard definition for monitoring and identifying SSI, even if some cases of less clinically significant superficial SSI are included.

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Abstract: The pathophysiology of depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis and the use of salivary cortisol measures is increasingly being incorporated into research. The aim of the present study was to investigate whether salivary cortisol differs for patients with depression and control persons. We did a systematic review with sequential meta-analysis and meta-regression according to the PRISMA Statement based on comprehensive database searches for studies of depressed patients compared to control persons in whom salivary cortisol was measured. Twenty case-control studies, including 1354 patients with depression and 1052 control persons were identified. In a random-effects meta-analysis salivary cortisol was increased for depressed patients as compared to control persons on average 2.58 nmol/l (95% C.I.: 0.95-4.21) p=0.002 in the morning and on average 0.27 nmol/l (95% C.I.: 0.03-0.51) p=0.03 in the evening. In a fixed-effects model the mean difference was 0.58 nmol/l (95% C.I.). Study sequential cumulative meta-analyses suggested random error for the finding of this rather small difference between groups. The reference intervals for morning salivary cortisol in depressed patients (0-29 nmol/l) and control persons (1-23 nmol/l) showed substantial overlap suggesting lack of discriminative capacity. These results should be interpreted with caution as the heterogeneity for the morning analysis was large and a funnel plot, suggested presence of bias. Further, in meta-regression analyses higher intra-assay coefficients of variation in cortisol kits (p=0.07) and mean age (p=0.08) were associated with a higher mean difference of morning salivary cortisol between depressed and controls, while gender and depression severity were not. Based on the available studies there is not firm evidence for a difference of salivary cortisol in depressed patients and control persons and salivary cortisol is unable to discriminate between persons with and without depression.

Abstract: This article is a narrative review of the current evidence of the effects on cardiovascular disease (CVD) of oral hypoglycaemic agents that increase insulin sensitivity in patients with type 2 diabetes (T2D). In overweight T2D patients, metformin has been demonstrated to reduce CVD risk, and this beneficial effect may be conserved with the combination of metformin and insulin treatment. However, the effect of glitazones on CVD is uncertain. There is conflicting evidence from large randomized trials to support a protective effect against CVD of lowering blood glucose per se but a systematic review with meta-analysis is lacking. It may be reasonable to aim for an intervention targeting multiple CVD risk factors such as dyslipidaemia, hypertension and albuminuria in T2D patients.

Abstract: AIMS: To investigate clinical and angiographic outcomes after coronary surgery using total arterial revascularization (TAR). METHODS AND RESULTS: We randomized 331 patients with multivessel or isolated left main disease to TAR [internal thoracic (ITA) and radial arteries] vs. conventional revascularization (CR) using left ITA and vein grafts. The primary angiographic outcome was the patency index: number of patent grafts (<50% stenosed) divided by number of constructed grafts. One-year angiography was complete for 83% of patients. Mean patency index (+/-SD) was 87 +/- 22% in the TAR group and 88 +/- 18% in the conventional group (P = 0.52). In 72% of TAR patients and 67% of the conventional group, all grafts were patent (P = 0.45). Multiple imputation of missing angiographic data did not influence on results. Within 1 year, 37 (23%) TAR patients and 43 (25%) conventional group patients suffered cardiac events (HR 1.09, 95% CI 0.70-1.69, P = 0.70). One patient (0.6%) in the TAR group and two (1.2%) in the conventional group died (P = 1.00). CONCLUSION: Within 1 year post-operatively, TAR seems at least as safe and effective as CR. Prolonged follow-up will reveal whether this is sustained or superior results of TAR can justify a more general use.

Abstract: Patients with type 2 diabetes (T2DM) have an increased mortality rate primarily because of macrovascular disease. Where T2DM patients cannot be managed sufficiently through diet, exercise and peroral antidiabetic drugs, that is when haemoglobin A1c (HbA1c) is above 7.0%, it is yet unknown whether a combination of metformin and insulin analogues is superior to insulin analogues alone. Nor is it known which insulin analogue regimen is the optimal.

Abstract: There is increasing awareness that meta-analyses require a sufficiently large information size to detect or reject an anticipated intervention effect. The required information size in a meta-analysis may be calculated from an anticipated a priori intervention effect or from an intervention effect suggested by trials with low-risk of bias.

Abstract: BACKGROUND: Previous studies indicate that avoiding neuromuscular blocking agents (NMBAs) may be a risk factor for difficult tracheal intubation (DTI). We investigated whether avoiding NMBA was associated with DTI. METHODS: A cohort of 103,812 consecutive patients planned for tracheal intubation by direct laryngoscopy was retrieved from the Danish Anaesthesia Database. We used an intubation score based upon the number of attempts, change from direct laryngoscopy to a more advanced technique, or intubation by a different operator. We retrieved data on age, sex, ASA physical status classification, priority of surgery, time of surgery, previous DTI, modified Mallampati score, BMI, and the use of NMBA. Using logistic regression, we assessed whether avoiding NMBA was associated with DTI. RESULTS: The frequency of DTI was 5.1 [95% confidence interval (CI): 5.0-5.3]%. In a univariate analysis, avoiding NMBA was associated with DTI, odds ratio (OR) 1.52 (95% CI: 1.43-1.61)%, P<0.0001. Using multivariate analysis, avoiding NMBA was associated with DTI, OR 1.48 (95% CI: 1.39-1.58), P<0.0001. Among patients intubated using NMBA, a multivariate analysis identified patients anaesthetized with only non-depolarizing NMBA to be more at risk for DTI than those anaesthetized with depolarizing NMBA alone. CONCLUSIONS: Avoiding NMBA may increase the risk of DTI. However, confounding by indication may be a problem in this observational study and systematic reviews with meta-analysis or more randomized clinical trials are needed.

Abstract: OBJECTIVES: Meta-analysis of randomized trials with binary data can use a variety of statistical methods. Zero-event trials may create analytic problems. We explored how different methods may impact inferences from meta-analyses containing zero-event trials. METHODS: Five levels of statistical methods are identified for meta-analysis with zero-event trials, leading to numerous data analyses. We used the binary outcomes from our Cochrane review of randomized trials of laparoscopic vs. small-incision cholecystectomy for patients with symptomatic cholecystolithiasis to illustrate the influence of statistical method on inference. RESULTS: In seven meta-analyses of seven outcomes from 15 trials, there were zero-event trials in 0 to 71.4% of the trials. We found inconsistency in significance in one of seven outcomes (14%; 95% confidence limit 0.4%-57.9%). There was also considerable variability in the confidence limits, the intervention-effect estimates, and heterogeneity for all outcomes. CONCLUSIONS: The statistical method may influence the inference drawn from a meta-analysis that includes zero-event trials. Robustness assessments are needed to reduce bias in meta-analyses that include zero-event trials.

Abstract: BACKGROUND: Endophenotypes are heritable markers, which are more prevalent in patients and their healthy relatives than in the general population. Recent studies point at disturbed regulation of the hypothalamic-pituitary-adrenocortical axis as a possible endophenotype for depression. We hypothesize that potential endophenotypes for depression may be affected by selective serotonin re-uptake inhibitor antidepressants in healthy first-degree relatives of depressed patients. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test from baseline to the end of intervention. METHODS: The AGENDA trial is designed as a participant, investigator, observer, and data-analyst-blinded randomized trial. Participants are 80 healthy first-degree relatives of patients with depression. Participants are randomized to escitalopram 10 mg per day versus placebo for four weeks. Randomization is stratified by gender and age. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test at entry before intervention to after four weeks of intervention. With the inclusion of 80 participants, a 60% power is obtained to detect a clinically relevant difference in the primary outcome between the intervention and the placebo group. Secondary outcome measures are changes from baseline to four weeks in scores of: 1) cognition and 2) neuroticism. Tertiary outcomes measures are changes from baseline to four weeks in scores of: 1) depression and anxiety symptoms; 2) subjective evaluations of depressive symptoms, perceived stress, quality of life, aggression, sleep, and pain; and 3) salivary cortisol at eight different timepoints during an ordinary day. Assessments are undertaken by assessors blinded to the randomization group.

Abstract: SUMMARY: We investigated the diagnostic accuracy of a documented previous difficult tracheal intubation as a stand-alone test for predicting a subsequent difficult intubation. Our assessment included patients from the Danish Anaesthesia Database who were scheduled for tracheal intubation by direct laryngoscopy. We used a four-point scale to grade the tracheal intubation. A previous difficult intubation was defined according to the presence of a record documenting a difficult penultimate tracheal intubation-score for the 15 499 patients anaesthetised more than once. Our assessment demonstrates that a documented history of previous difficult or failed intubation using direct laryngoscopy are strong predictors of a subsequent difficult or failed intubation and may identify 30% of these patients. Although previous investigators have reported predictive values that exceed our findings markedly, a documented previous difficult or failed tracheal intubation appears in everyday anaesthetic practice to be a strong predictor of a subsequent difficult tracheal intubation.

Abstract: Alcoholic hepatitis is a life-threatening disease, with an average mortality of approximately 40%. There is no widely accepted, effective treatment for alcoholic hepatitis. Pentoxifylline is used to treat alcoholic hepatitis, but there has been no systematic review to assess its effects.

Abstract: BACKGROUND: Previous studies have failed to detect high body mass index (BMI) as a risk factor for difficult tracheal intubation (DTI). BMI was investigated as a risk factor for DTI in patients planned for direct laryngoscopy. METHODS: A cohort of 91,332 consecutive patients planned for intubation by direct laryngoscopy was retrieved from the Danish Anesthesia Database. A four-point scale to grade the tracheal intubation was used. Age, sex, American Society of Anesthesiologists physical status classification, priority of surgery, history of previous DTI, modified Mallampati-score, use of neuromuscular blocker, and BMI were retrieved. Logistic regression to assess whether BMI was associated with DTI was performed. RESULTS: The frequency of DTI was 5.2% (95% confidence interval [CI] 5.0-5.3). In multivariate analyses adjusted for other significant covariates, BMI of 35 or more was a risk for DTI with an odds ratio of 1.34 (95% CI 1.19-1.51, P < 0.0001). As a stand alone test, BMI of 35 or more predicted DTI with a sensitivity of 7.5% (95% CI 7.3-7.7%) and with a predictive value of a positive test of 6.4% (95% CI 6.3-6.6%). BMI as a continuous covariate was a risk for failed intubation with an odds ratio of 1.031 (95% CI 1.002-1.061, P < 0.04). CONCLUSIONS: High BMI is a weak but statistically significant predictor of difficult and failed intubation and may be more appropriate than weight in multivariate models of prediction of DTI.

Abstract: BACKGROUND: Random error may cause misleading evidence in meta-analyses. The required number of participants in a meta-analysis (i.e. information size) should be at least as large as an adequately powered single trial. Trial sequential analysis (TSA) may reduce risk of random errors due to repetitive testing of accumulating data by evaluating meta-analyses not reaching the information size with monitoring boundaries. This is analogous to sequential monitoring boundaries in a single trial. METHODS: We selected apparently conclusive (P </= 0.05) Cochrane neonatal meta-analyses. We applied heterogeneity-adjusted and unadjusted TSA on these meta-analyses by calculating the information size, the monitoring boundaries, and the cumulative Z-statistic after each trial. We identified the proportion of meta-analyses that did not reach the required information size and the proportion of these meta-analyses in which the Z-curve did not cross the monitoring boundaries. RESULTS: Of 54 apparently conclusive meta-analyses, 39 (72%) did not reach the heterogeneity-adjusted information size required to accept or reject an intervention effect of 25% relative risk reduction. Of these 39, 19 meta-analyses (49%) were considered inconclusive, because the cumulative Z-curve did not cross the monitoring boundaries. The median number of participants required to reach the required information size was 1591 (range, 339-6149). TSA without heterogeneity adjustment largely confirmed these results. CONCLUSIONS: Many apparently conclusive Cochrane neonatal meta-analyses may become inconclusive when the statistical analyses take into account the risk of random error due to repetitive testing.

Abstract: CONTEXT: Use of 80% oxygen during surgery has been suggested to reduce the risk of surgical wound infections, but this effect has not been consistently identified. The effect of 80% oxygen on pulmonary complications has not been well defined. OBJECTIVE: To assess whether use of 80% oxygen reduces the frequency of surgical site infection without increasing the frequency of pulmonary complications in patients undergoing abdominal surgery. DESIGN, SETTING, AND PATIENTS: The PROXI trial, a patient- and observer-blinded randomized clinical trial conducted in 14 Danish hospitals between October 2006 and October 2008 among 1400 patients undergoing acute or elective laparotomy. INTERVENTIONS: Patients were randomly assigned to receive either 80% or 30% oxygen during and for 2 hours after surgery. MAIN OUTCOME MEASURES: Surgical site infection within 14 days, defined according to the Centers for Disease Control and Prevention. Secondary outcomes included atelectasis, pneumonia, respiratory failure, and mortality. RESULTS: Surgical site infection occurred in 131 of 685 patients (19.1%) assigned to receive 80% oxygen vs 141 of 701 (20.1%) assigned to receive 30% oxygen (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.72-1.22; P = .64). Atelectasis occurred in 54 of 685 patients (7.9%) assigned to receive 80% oxygen vs 50 of 701 (7.1%) assigned to receive 30% oxygen (OR, 1.11; 95% CI, 0.75-1.66; P = .60), pneumonia in 41 (6.0%) vs 44 (6.3%) (OR, 0.95; 95% CI, 0.61-1.48; P = .82), respiratory failure in 38 (5.5%) vs 31 (4.4%) (OR, 1.27; 95% CI, 0.78-2.07; P = .34), and mortality within 30 days in 30 (4.4%) vs 20 (2.9%) (OR, 1.56; 95% CI, 0.88-2.77; P = .13). CONCLUSION: Administration of 80% oxygen compared with 30% oxygen did not result in a difference in risk of surgical site infection after abdominal surgery. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00364741.

Abstract: BACKGROUND: Results from apparently conclusive meta-analyses may be false. A limited number of events from a few small trials and the associated random error may be under-recognized sources of spurious findings. The information size (IS, i.e. number of participants) required for a reliable and conclusive meta-analysis should be no less rigorous than the sample size of a single, optimally powered randomized clinical trial. If a meta-analysis is conducted before a sufficient IS is reached, it should be evaluated in a manner that accounts for the increased risk that the result might represent a chance finding (i.e. applying trial sequential monitoring boundaries). METHODS: We analysed 33 meta-analyses with a sufficient IS to detect a treatment effect of 15% relative risk reduction (RRR). We successively monitored the results of the meta-analyses by generating interim cumulative meta-analyses after each included trial and evaluated their results using a conventional statistical criterion (alpha = 0.05) and two-sided Lan-DeMets monitoring boundaries. We examined the proportion of false positive results and important inaccuracies in estimates of treatment effects that resulted from the two approaches. RESULTS: Using the random-effects model and final data, 12 of the meta-analyses yielded P > alpha = 0.05, and 21 yielded P </= alpha = 0.05. False positive interim results were observed in 3 out of 12 meta-analyses with P > alpha = 0.05. The monitoring boundaries eliminated all false positives. Important inaccuracies in estimates were observed in 6 out of 21 meta-analyses using the conventional P </= alpha = 0.05 and 0 out of 21 using the monitoring boundaries. CONCLUSIONS: Evaluating statistical inference with trial sequential monitoring boundaries when meta-analyses fall short of a required IS may reduce the risk of false positive results and important inaccurate effect estimates.

Abstract: BACKGROUND: Critical illness is associated with uncontrolled inflammation and vascular damage which can result in multiple organ failure and death. Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties but the efficacy and any harmful effects of AT III supplementation in critically ill patients are unknown. OBJECTIVES: To assess the benefits and harms of AT III in critically ill patients. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to November 2006). We contacted authors and manufacturers in the field. SELECTION CRITERIA: We included all randomized clinical trials, irrespective of blinding or language, that compared AT III with no intervention or placebo in critically ill patients. DATA COLLECTION AND ANALYSIS: Our primary outcome measure was mortality. We each independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as relative risks (RR) with 95% confidence intervals (CI). We performed subgroup analyses to assess risk of bias, the effect of AT III in different populations (sepsis, trauma, obstetric, and paediatric patients), and the effect of AT III in patients with or without the use of concomitant heparin. We assessed the adequacy of the available number of participants and performed a trial sequential analysis to establish the implications for further research. MAIN RESULTS: We included 20 randomized trials with a total of 3458 participants; 13 of these trials had high risk of bias. When we combined all trials, AT III did not statistically significantly reduce overall mortality compared with the control group (RR 0.96, 95% CI 0.89 to 1.03; no heterogeneity between trials). A total of 32 subgroup and sensitivity analyses were carried out. Analyses based on risk of bias, different populations, and the role of adjuvant heparin gave insignificant differences. AT III reduced the multiorgan failure score among survivors in an analysis involving very few patients. AT III increased bleeding events (RR 1.52, 95% CI 1.30 to 1.78). AUTHORS' CONCLUSIONS: AT III cannot be recommended for critically ill patients based on the available evidence. A randomized controlled trial of AT III, without adjuvant heparin, with prespecified inclusion criteria and good bias protection is needed.

Abstract: BACKGROUND AND OBJECTIVE: Cumulative meta-analyses are prone to produce spurious P<0.05 because of repeated testing of significance as trial data accumulate. Information size in a meta-analysis should at least equal the sample size of an adequately powered trial. Trial sequential analysis (TSA) corresponds to group sequential analysis of a single trial and may be applied to meta-analysis to evaluate the evidence. STUDY DESIGN AND SETTING: Six randomly selected neonatal meta-analyses with at least five trials reporting a binary outcome were examined. Low-bias heterogeneity-adjusted information size and information size determined from an assumed intervention effect of 15% were calculated. These were used for constructing trial sequential monitoring boundaries. We assessed the cumulative z-curves' crossing of P=0.05 and the boundaries. RESULTS: Five meta-analyses showed early potentially spurious P<0.05 values. In three significant meta-analyses the cumulative z-curves crossed both boundaries, establishing firm evidence of an intervention effect. In two nonsignificant meta-analyses the cumulative z-curves crossed P=0.05, but never the boundaries, demonstrating early potentially spurious P<0.05 values. In one nonsignificant meta-analysis the cumulative z-curves never crossed P=0.05 or the boundaries. CONCLUSION: TSAs may establish when firm evidence is reached in meta-analysis.

Abstract: BACKGROUND: Glucocorticosteroids versus placebo or no intervention for patients with alcoholic hepatitis have been evaluated for more than 35 years. However, the results of randomized trials and meta-analyses differ substantially. AIM: To review all randomized clinical trials of glucocorticosteroids vs. placebo or no intervention for patients with alcoholic hepatitis. METHODS: We searched for randomized trials published before July 2007. The trials were assessed for risk of bias. RESULTS: We included 15 trials with a total of 721 randomized patients. The overall mortality rate was 39.5%. Twelve of the fifteen trials were at risk of bias. Glucocorticosteroids did not statistically reduce mortality compared with placebo or no intervention (relative risk 0.83, 95% CI 0.63-1.11). Glucocorticosteroids significantly reduced mortality in the subgroup of trials with patients with Maddrey's score of at least 32 or hepatic encephalopathy and with low-bias risk. In all analyses, heterogeneity was significant and substantial. Trial sequential analyses using heterogeneity-adjusted information size demonstrated no significant effect of glucocorticosteroids on mortality. Weighted logistic regression analyses taking prognostic factors at randomization into consideration found no significant effect of glucocorticosteroids on mortality. CONCLUSIONS: The current evidence base of mainly heterogeneous with high bias risk trials does not support the use of glucocorticosteroids in alcoholic hepatitis. Large, low-bias risk placebo-controlled randomized trials are needed.

Abstract: AIMS: To assess the clinical outcomes of off- vs. on-pump coronary artery bypass surgery in randomized trials. METHODS AND RESULTS: We searched electronic databases and bibliographies until June 2007. Trials were assessed for risk of bias. Outcome measures were all-cause mortality, myocardial infarction, stroke, atrial fibrillation, and renewed coronary revascularization at maximum follow-up. We applied trial sequential analysis to estimate the strength of evidence. We found 66 randomized trials. There was no statistically significant differences regarding mortality [relative risk (RR) 0.98; 95% confidence interval (CI) 0.66-1.44], myocardial infarction (RR 0.95; 95% CI 0.65-1.37), or renewed coronary revascularization (RR 1.34; 95% CI 0.83-2.18). We found a significant reduced risk of atrial fibrillation (RR 0.69; 95% CI 0.57-0.83) and stroke (RR 0.53; 95% CI 0.31-0.91) in off-pump patients. However, when continuity correction for zero-event trials was included, the reduction in stroke became insignificant (RR 0.62; 95% CI 0.32-1.19). Trial sequential analysis demonstrated overwhelming evidence supporting that off-pump bypass surgery reduces atrial fibrillation. CONCLUSION: Off-pump surgery reduces the risks of postoperative atrial fibrillation compared with on-pump surgery. For death, myocardial infarction, stroke, and renewed coronary revascularization, the evidence is still weak and more low-bias risk trials are needed.

Abstract: OBJECTIVES: To evaluate meta-analyses with trial sequential analysis (TSA). TSA adjusts for random error risk and provides the required number of participants (information size) in a meta-analysis. Meta-analyses not reaching information size are analyzed with trial sequential monitoring boundaries analogous to interim monitoring boundaries in a single trial. STUDY DESIGN AND SETTING: We applied TSA on meta-analyses performed in Cochrane Neonatal reviews. We calculated information sizes and monitoring boundaries with three different anticipated intervention effects of 30% relative risk reduction (TSA(30%)), 15% (TSA(15%)), or a risk reduction suggested by low-bias risk trials of the meta-analysis corrected for heterogeneity (TSA(LBHIS)). RESULTS: A total of 174 meta-analyses were eligible; 79 out of 174 (45%) meta-analyses were statistically significant (P<0.05). In the significant meta-analyses, TSA(30%) showed firm evidence in 61%. TSA(15%) and TSA(LBHIS) found firm evidence in 33% and 73%, respectively. The remaining significant meta-analyses had potentially spurious evidence of effect. In the 95 statistically nonsignificant (P>or=0.05) meta-analyses, TSA(30%) showed absence of evidence in 80% (insufficient information size). TSA(15%) and TSA(LBHIS) found that 95% and 91% had absence of evidence. The remaining nonsignificant meta-analyses had evidence of lack of effect. CONCLUSION: TSA reveals insufficient information size and potentially false positive results in many meta-analyses.

Abstract: BACKGROUND: American College of Cardiology and American Heart Association (ACC/AHA) guidelines on perioperative assessment recommend perioperative beta blockers for non-cardiac surgery, although results of some clinical trials seem not to support this recommendation. We aimed to critically review the evidence to assess the use of perioperative beta blockers in patients having non-cardiac surgery. METHODS: We searched Pubmed and Embase for randomised controlled trials investigating the use of beta blockers in non-cardiac surgery. We extracted data for 30-day all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, heart failure, and myocardial ischaemia, safety outcomes of perioperative bradycardia, hypotension, and bronchospasm. FINDINGS: 33 trials included 12 306 patients. beta blockers were not associated with any significant reduction in the risk of all-cause mortality, cardiovascular mortality, or heart failure, but were associated with a decrease (odds ratio [OR] 0.65, 95% CI 0.54-0.79) in non-fatal myocardial infarction (number needed to treat [NNT] 63) and decrease (OR 0.36, 0.26-0.50) in myocardial ischaemia (NNT 16) at the expense of an increase (OR 2.01, 1.27-3.68) in non-fatal strokes (number needed to harm [NNH] 293). The beneficial effects were driven mainly by trials with high risk of bias. For the safety outcomes, beta blockers were associated with a high risk of perioperative bradycardia requiring treatment (NNH 22), and perioperative hypotension requiring treatment (NNH 17). We recorded no increased risk of bronchospasm. INTERPRETATION: Evidence does not support the use of beta-blocker therapy for the prevention of perioperative clinical outcomes in patients having non-cardiac surgery. The ACC/AHA guidelines committee should soften their advocacy for this intervention until conclusive evidence is available.

Abstract: ABSTRACT: BACKGROUND: A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension. Two trials have shown that a high perioperative inspiratory oxygen fraction (FiO2 = 0.80) significantly reduced risk of surgical site infections after elective colorectal surgery, but a third trial was stopped early because the frequency of surgical site infections was more than doubled in the group receiving FiO2 = 0.80. It has not been settled if a high inspiratory oxygen fraction increases the risk of pulmonary complications, such as atelectasis, pneumonia and respiratory failure. The aim of our trial is to assess the potential benefits and harms of a high perioperative oxygen fraction in patients undergoing abdominal surgery. METHODS AND DESIGN: The PROXI-Trial is a randomized, patient- and assessor blinded trial of perioperative supplemental oxygen in 1400 patients undergoing acute or elective laparotomy in 14 Danish hospitals. Patients are randomized to receive either 80% oxygen (FiO2 = 0.80) or 30% oxygen (FiO2 = 0.30) during surgery and for the first 2 postoperative hours. The primary outcome is surgical site infection within 14 days. The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit. The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power. DISCUSSION: This trial assesses benefits and harms of a high inspiratory oxygen fraction, and the trial may be generalizable to a general surgical population undergoing laparotomy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00364741.

Abstract:

Abstract: Polymorphisms in the MBL2 gene, which affect the structure and influence on the serum concentration of mannose-binding lectin (MBL), are associated with inflammatory and infectious conditions. The importance of MBL2 polymorphisms on outcome in critical ill patients is unclear. Five hundred and thirty-two consecutive critically ill patients admitted to an intensive care unit (ICU) were included over a period of 18 months. Five hundred and thirty-three individuals served as controls. Vital status was obtained 15.5 months after the last patient was included. MBL2 polymorphisms were determined by a PCR-based assay. Homozygosity for MBL2 variant alleles (O/O) causing MBL structural defects was associated with the highest adjusted mortality rate followed by homozygosity for the normal MBL2 allele (A/A) encoding high MBL levels, whereas heterozygous A/O patients had the most favourable outcome (P = 0.015). MBL2 alleles were not associated with death in ICU (n = 166, P = 0.7), but the association appeared soon after discharge from ICU (n = 366): hazard ratio (HR) for O/O using A/A as reference was 1.33 (95% CI: 0.8-2.2) and for A/O it was 0.62 (95% CI: 0.4-0.8) respectively (P = 0.0045) at completion. No difference in MBL2 frequency was observed between patients and controls at baseline, and between patients classified as having sepsis or not. However, patients with the MBL2 O/O genotype had an increased frequency of Gram-positive bacterial infection (P = 0.01). Heterozygosity for MBL2 alleles confers a protective effect whereas homozygosity is associated with the worst outcome soon after discharge from ICU. This may be an example of heterosis.

Abstract: OBJECTIVE: To evaluate the benefits and harms of antithrombin III in critically ill patients. DESIGN: Systematic review and meta-analysis of randomised trials. DATA SOURCES: CENTRAL, Medline, Embase, International Web of Science, LILACS, the Chinese Biomedical Literature Database, and CINHAL (to November 2006); hand search of reference lists, contact with authors and experts, and search of registers of ongoing trials. REVIEW METHODS: Two reviewers independently selected parallel group randomised clinical trials comparing antithrombin with placebo or no intervention and extracted data related to study methods, interventions, outcomes, bias risk, and adverse events. Disagreements were resolved by discussion. Trials in any type of critically ill patients in intensive care were eligible. All trials, irrespective of blinding or language status, that compared any antithrombin III regimen with no intervention or placebo were included. Trials were considered to be at low risk of bias if they had adequate randomisation procedure, blinding, and used intention to treat analysis. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models according to heterogeneity. MAIN OUTCOME MEASURES: Mortality, length of stay in intensive care or hospital, quality of life, severity of sepsis, respiratory failure, duration of mechanical ventilation, incidence of surgical intervention, intervention effect among various populations, and adverse events (such as bleeding). RESULTS: 20 trials randomly assigning 3458 patients met inclusion criteria. Eight trials had low risk of bias. Compared with placebo or no intervention, antithrombin III did not reduce overall mortality (relative risk 0.96, 95% confidence interval 0.89 to 1.03). No subgroup analyses on risk of bias, populations of patients, or with and without adjuvant heparin yielded significant results. Antithrombin III increased the risk of bleeding events (1.52, 1.30 to 1.78). Heterogeneity was observed in only a few analyses. CONCLUSION: Antithrombin III cannot be recommended for critically ill patients based on the available evidence.

Abstract: OBJECTIVES: To evaluate the long term effects of perioperative beta blockade on mortality and cardiac morbidity in patients with diabetes undergoing major non-cardiac surgery. DESIGN: Randomised placebo controlled and blinded multicentre trial. Analyses were by intention to treat. SETTING: University anaesthesia and surgical centres and one coordinating centre. PARTICIPANTS: 921 patients aged > 39 scheduled for major non-cardiac surgery. INTERVENTIONS: 100 mg metoprolol controlled and extended release or placebo administered from the day before surgery to a maximum of eight perioperative days. MAIN OUTCOME MEASURES: The composite primary outcome measure was time to all cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac morbidity. RESULTS: Mean duration of intervention was 4.6 days in the metoprolol group and 4.9 days in the placebo group. Metoprolol significantly reduced the mean heart rate by 11% (95% confidence interval 9% to 13%) and mean blood pressure by 3% (1% to 5%). The primary outcome occurred in 99 of 462 patients in the metoprolol group (21%) and 93 of 459 patients in the placebo group (20%) (hazard ratio 1.06, 0.80 to 1.41) during a median follow-up of 18 months (range 6-30). All cause mortality was 16% (74/462) in the metoprolol group and 16% (72/459) in the placebo group (1.03, 0.74 to 1.42). The difference in risk for the proportion of patients with serious adverse events was 2.4% (- 0.8% to 5.6%). CONCLUSIONS: Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes. Confidence intervals, however, were wide, and the issue needs reassessment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58485613.

Abstract:

Abstract: Cardiac patients lack compensatory capacity during bleeding, pain, and infection with an increased risk of perioperative cardiac complications. The mortality following serious postoperative cardiac events is 1400 patients per year in Denmark. Six months' mortality increases six fold after perioperative myocardial infarction. Information about the patient's heart disease should be available and treatment optimated before surgery and anaesthesia. Evidence-based preoperative risk assessment and perioperative patient care for patients with heart disease and hypertension are summarised.

Abstract:

Abstract: Cardiac events in patients undergoing surgery may have serious consequences for both short- and long-term postoperative prognosis. Recently conducted trials have not demonstrated beneficial effects of perioperative beta-blockade, although originally small trials with methodological flaws did suggest this. We evaluate the evidence for using perioperative beta-blockade in both cardiac and non-cardiac surgery, and conclude that there is no statistically significant effect on mortality and insufficient evidence for a reduction of the incidence of mycocardial infarction in meta-analyses of all randomized trials. However, confidence intervals of the intervention effects in the meta-analyses are wide, leaving room for both benefits and harms. The largest observational study performed suggests that perioperative beta-blockade is associated with higher mortality in patients with low cardiac risk or diabetes, and with lower mortality in patients with high cardiac risk undergoing non-cardiac surgery. Larger randomized trials are needed to determine dosage, optimal duration, and safety of therapy, and to identify populations in whom-and how-perioperative beta-blockade may be beneficial.

Abstract:

Abstract: PURPOSE: To examine the availability and quality of clinical guidelines on perioperative diabetes care in hospital units before and after a randomised clinical trial (RCT) and international accreditation. DESIGN/METHODOLOGY/APPROACH: Interventional "before-after" study in 51 units (38 surgical and 13 anaesthetic) in nine hospitals participating in a RCT in the greater Copenhagen area; 27 of the units also underwent international accreditation. FINDINGS: The proportion of units with guidelines increased from 24/51 (47 percent) units before to 38/51 (75 percent) units after the trial. Among the 27 units without guidelines before the trial, significantly more accredited units compared to non-accredited units had a guideline after the trial (9/10 (90 percent) compared to 5/17 (29 percent). The quality of the systematic development scale and the clinical scales improved significantly after the trial in both accredited units (both p < 0.001) and in non-accredited units (both p < 0.02). The improvement of the systematic development scale was significantly higher in accredited than in non-accredited units (p < 0.01). ORIGINALITY/VALUE: The combination of conducting both the DIPOM Trial and international accreditation led to a significant improvement of both dissemination and quality of guidelines on perioperative diabetic care.

Abstract: BACKGROUND: Recent trials suggest that perioperative beta-blockade reduces the risk of cardiac events in patients with a risk of myocardial ischemia who are undergoing noncardiac surgery. Patients with diabetes mellitus are at a high-risk for postoperative cardiac morbidity and mortality. They may, therefore, benefit from perioperative beta-blockade. METHODS: The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial is an investigator-initiated and -controlled, centrally randomized, double-blind, placebo-controlled, multicenter trial. We compared the effect of metoprolol with placebo on mortality and cardiovascular morbidity rates in patients with diabetes mellitus who were beta-blocker naive, >or=40 years old, and undergoing noncardiac surgery. The study drug was given during hospitalization for a maximum of 7 days beginning the evening before surgery. The primary outcome measure is the composite of all-cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure leading to hospitalization or discovered or aggravated during hospitalization. Follow-up involves re-examination of patients at 6 months and collection of mortality and morbidity data via linkage to public databases. The study was powered on the basis of an estimated 30% 1-year event rate in the placebo arm and a 33% relative risk reduction in the metoprolol arm. The median follow-up period was 18 months. RESULTS: Enrollment started in July 2000 and ended in June 2002. A total of 921 patients were randomized, and 54% of these patients had known cardiac disease, hypertension, or both. CONCLUSION: The results of this study may have implications for reduction of perioperative and postoperative risk in patients with diabetes mellitus who are undergoing major noncardiac surgery.

Abstract: BACKGROUND AND OBJECTIVE: The prognosis of diabetic patients after surgery remains controversial. Some suggest that the rates of death and complications today are almost identical in diabetic and non-diabetic patients within hospital stay or for 30 days postoperatively, whereas others suggest that diabetes still constitutes a major risk factor for both short-term (< or = 30 days) and long-term (> 30 days) patients especially after major cardiac surgery. We examined the long-term postoperative mortality of diabetic patients undergoing major non-cardiac surgery to identify possible perioperative risk factors. METHODS: Data from 179 consecutive diabetic patients, who underwent major non-cardiac surgery at Herlev Hospital, Denmark, during a 12 month period, have been retrospectively analysed. Data were obtained from patient records and from The Danish National Health Register. The main outcome measure was postoperative mortality. Patients were followed for a maximum of 18 months. RESULTS: The median postoperative observation period was 10 months (range 0-18 months). Overall postoperative mortality was 24% (95% confidence interval (CI) 17-31%). One third of the fatalities occurred during the first 30 days. Ischaemic heart disease diagnosed before the operation was associated with an overall postoperative mortality of 44% (95% CI 29-58%), which was significantly (P < 0.03) higher than in diabetic patients without known cardiovascular disease. The major causes of death in 18 out of 39 (46%) patients were diseases of the cardiovascular system. CONCLUSIONS: Diabetic patients undergoing major non-cardiac surgery seem to have a high mortality, often because of cardiovascular death. Future strategies should focus on implementing cardio-protective treatment during the perioperative period.

Abstract: BACKGROUND: Hypoglycemic patients treated by the emergency medical service (EMS) system are commonly left home. The criteria for leaving hypoglycemic patients at home and the appropriateness of the procedure remains, however, unvalidated. The present retrospective article addresses these questions. METHODS: The Copenhagen physician-based mobile intensive care unit (MICU) responds to emergency calls in a two-tier rendezvous system. Its prehospital data from 1995 to 1998 were retrospectively incorporated into a clinical database and cross-referenced with clinical information from three Danish national registries, enabling identification of criteria for transportation of the patients to the hospital, and a detailed 72-h follow up on patients left at home. RESULTS: The MICU treated 1148 hypoglycemic patients within the period, of which 84% were released at home. Treatment or no treatment before arrival of the MICU and level of consciousness following MICU treatment, were found to be strong predictors of a need for transportation to hospital; although other factors were implicated. Within the 72-h following MICU treatment less than 8% of the patients left at home needed secondary MICU or hospital treatment because of glucose regulatory problems, and less than 5% experienced secondary hypoglycemia. Less than 1% was admitted to hospital beds with recurrent hypoglycemia within 24 h. Poor compliance with the diabetic treatment instructions often appeared to be involved in cases of recurrent hypoglycemia. A delay in admission was not to blame for a serious secondary patient course in any of the cases. CONCLUSION: The majority of patients with prehospital hypoglycemia may safely be treated and released at home in a physician-based EMS area.

Abstract: In a double-blind study, we investigated the effects of postoperative epidural local anaesthetic, with or without addition of epidural morphine, on postoperative pain and gastrointestinal function in patients scheduled for radical hysterectomy and pelvic lymphadenectomy. Forty patients were randomized into two study groups: 48-h postoperative epidural 0.2% bupivacaine 8 ml h(-1) (bupi group) or 48-h postoperative epidural 0.2% bupivacaine/morphine 50 microg at 4 ml h(-1) (bupi/morph group). Patients were observed for at least 96 h after surgery. No differences in pain at rest, during cough or mobilization were observed. Patients in the bupi group requested a significant greater amount of supplementary analgesics, but times to first flatus and defaecation were reduced compared with patients in the bupi/morph group. Itching was a significant problem in patients in the bupi/morph group. No differences in postoperative nausea and vomiting, mobilization or time to discharge from hospital were observed between groups. The addition of morphine to postoperative epidural bupivacaine has only limited effect on pain relief and increases time to normalization of gastrointestinal function.

Abstract: In a double blind study we have investigated the effects of epidural local anaesthesia (LA), when added to general anaesthesia (GA) and postoperative paracetamol and NSAID, on postoperative pain and gastrointestinal function in patients undergoing open hysterectomy. Sixty patients were randomized into three study groups: GA, and postoperative paracetamol and NSAID (GA, n=20); GA, paracetamol, NSAID, intraoperative epidural lidocaine and 24-h postoperative epidural saline (Saline, n=20); or GA, paracetamol, NSAID, intraoperative epidural lidocaine and 24-h postoperative epidural bupivacaine (Bupi, n=20). Patients were observed for 72 h postoperatively. Pain at rest, during cough, and mobilization, request for supplementary morphine, and time to first postoperative flatus, was reduced in patients receiving 24-h postoperative epidural anaesthesia, compared with the two other groups. However, these effects of epidural LA, were not sustained beyond the period of infusion, and no differences in PONV, time to first postoperative defecation, mobilization or time to discharge from hospital were observed between groups. A 24 h postoperative epidural infusion with bupivacaine, when added to postoperative paracetamol and NSAID, reduces pain and opioid requirements, but has only limited effects on gastrointestinal function and patient recovery.

Abstract: BACKGROUND AND OBJECTIVE: Late postoperative hypoxaemia after upper abdominal surgery is common even among cardiopulmonary healthy patients. Atelectasis may develop after intubation and persist into or reveal a disposition for atelectasis in the postoperative period. Positive end-expiratory pressure (PEEP) eliminates peroperative atelectasis but the effect on perioperative oxygenation is controversial. This study evaluated the effect of peroperative PEEP optimized pulmonary compliance on perioperative oxygenation and complications. METHODS: Forty patients assessed by electrocardiography, spirometry, functional residual capacity and diffusion capacity were randomly assigned to receive positive end-expiratory pressure (PEEP) or zero end-expiratory pressure (ZEEP) during surgery. PaO2, SPO2 and complications in the postoperative period were evaluated without knowledge of peroperative PEEP or ZEEP application. RESULTS: Peroperative arterial oxygenation improved for all patients receiving PEEP, mean 2.1 kPa (0.7-3.5 kPa). There was no difference in postoperative median PaO2 between the groups. The differences in the incidence of late prolonged postoperative hypoxaemia and complications were 25% (-5% to 55%) and -1% (-31% to 29%) between the ZEEP and the PEEP group, but were not statistically significant.

Abstract: BACKGROUND: The incidence of late postoperative hypoxaemia and complications after upper abdominal surgery is 20-50% among cardiopulmonary healthy patients. Atelectasis development during anaesthesia and surgery is the main hypothesis to explain postoperative hypoxaemia. This study tested the predictive value of PaO2<19 kPa during combined general and thoracic epidural anaesthesia and the preoperative functional residual capacity (FRC) reduction in the 30 degree head tilt-down position for the development of late prolonged postoperative hypoxaemia, PaO2<8.5 kPa for a minimum of 3 out of 4 days, and other complications. Forty patients without cardiopulmonary morbidity, assessed by ECG, spirometry, FRC and diffusion capacity preoperatively, underwent upper abdominal surgery. PaO2 during anaesthesia and preoperative FRC reduction were compared to known risk factors for the development of hypoxaemia and complications: age, pack-years of smoking and duration of operation. The effect of optimizing pulmonary compliance with peroperative positive end-expiratory pressure (PEEP) on postoperative hypoxaemia and complications was evaluated in a blinded and randomized manner. RESULTS: Late prolonged postoperative hypoxaemia and other complications were found in 37% and 38% of the patients, respectively. Patients with PaO2>19 kPa during anaesthesia with F(I)O2=0.33 exhibited a risk, irrespective of PEEP status, of suffering late prolonged hypoxaemia of 0% (0;23) and patients with PaO2<19 kPa a risk of 52% (32;71), P<0.005. Having smoked more than 20 pack-years was associated with a 47% (19;75) higher incidence of postoperative complications than having smoked less than 20 pack-years, P<0.006. CONCLUSIONS: PaO2 during anaesthesia and smoked pack-years provide new tools evaluating patients undergoing upper abdominal surgery in order to predict the patients who develop late postoperative hypoxaemia and complications.

Abstract: In a systematic review, we evaluated randomized controlled trials (RCTs) of peripheral local anesthetics (LA) compared with placebo or no treatment in the control of postoperative pain after laparoscopic surgery. A total of 41 trials with data from 2794 patients were considered appropriate for analysis. Of these 41 RCTs, 13 evaluated intraperitoneal LA after cholecystectomy, four RCTs assessed intraperitoneal LA after other procedures, eight RCTs evaluated port-site infiltration after various procedures, 12 RCTs evaluated mesosalpinx or fallopian tube block after sterilization, and four RCTs considered combined LA regimens. Outcome measures were pain scores, analgesic consumption, and time to first analgesic request. Efficacy was estimated by significant difference (P < 0.05), as reported in the original reports, and by calculation of the weighted mean difference of visual analog scale pain scores between treatment groups. Improved pain relief was observed in seven of the 13 RCTs of intraperitoneal LA after cholecystectomy and in four RCTs of other procedures. A statistically significant weighted mean difference of -13 mm visual analog scale (95% confidence intervals [CI]: -20 to -6) in favor of the treatment groups was observed after cholecystectomy. Three of eight trials of port-site infiltration showed significant differences but questionable clinical importance and validity in two; weighted mean difference was not statistically significant between treatment groups (95% CI -9 to 1). All RCTs of mesosalpinx or fallopian tube block after sterilization showed improved pain relief with a statistically significant weighted mean difference of -19 mm (95% CI -25 to -14) in favor of treatment groups. Data of combined regimens were positive, however, sparse. We conclude that there was evidence for a statistically significant but clinically questionable, important effect of intraperitoneal LA for postoperative pain control. There was evidence for a significant but short-lasting effect of mesosalpinx/fallopian tube block after sterilization, but there was a lack of evidence for any important effect of port-site infiltration. Data from combined regimens were too sparse for conclusions. IMPLICATIONS: A systematic review summarizes, through transparent methodology, available information from randomized, controlled trials to produce the best available evidence-based estimate of a "true" clinical effect of an intervention. This systematic review confirms intraperitoneal and mesosalpinx local anesthetic block, not port-site infiltration, to have some impact on postoperative pain after laparoscopy.

Abstract: We have investigated the effect of 24-h postoperative continuous epidural infusion of 0.2% ropivacaine or 0.2% bupivacaine 8 ml h-1 on pain, request for supplementary analgesics, motor block and gastrointestinal function, in a double-blind, randomized study in 60 patients undergoing open hysterectomy. There were no significant differences between groups in pain, number of patients requesting supplementary analgesics, motor block, ability to walk or time to first flatus or stool. In the subgroup of patients who received supplementary analgesics, patients in the ropivacaine group received significantly more ketorolac than patients in the bupivacaine group. Time to discharge from hospital was similar with ropivacaine and bupivacaine.

Abstract: To determine the incidence, severity and 90-day mortality of acute respiratory failure (ARF), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) we conducted an eight-week prospective cohort study in 48 Danish ICUs, during which all ICU admissions (n = 6647) > 14 years of age were assessed. ARF was defined as intubation and mechanical ventilation > 24 hrs. ALI and ARDS were defined in accordance with the American-European Consensus Conference criteria. Among the 813 patients included, 552 were diagnosed with ARF, 117 with ALI and 95 with ARDS. The incidences (patients per 100.000/yrs) for ARF were 84.8, for ALI 17.8 and for ARDS 14.6. The 90-day mortality was 46.3% for ARF patients without ALI/ARDS, 47.3% for ALI patients and 46.2% for patients with ARDS. Compared to previously reported figures, the ARDS mortality is in the lower range whereas the incidence is slightly higher. This probably reflects a broader selection of patients when using the consensus criteria to define the ARDS population as opposed to definitions previously used.

Abstract: BACKGROUND: Gastrointestinal paralysis, nausea and vomiting, and pain, are major clinical problems following abdominal surgery. Anaesthetic and analgesic techniques that reduce pain and postoperative nausea and vomiting (PONV), and prevent or reduce postoperative ileus, may reduce postoperative morbidity, duration of hospitalisation and hospital costs. OBJECTIVES: To compare effects of postoperative epidural local anaesthetic with regimens based on systemic or epidural opioids, on postoperative gastrointestinal function, postoperative pain, PONV and surgical/anaesthetic complications. SEARCH STRATEGY: Trials were identified by computerised searches of the Cochrane Controlled Trials Register, MEDLINE, EMBASE and by checking the reference lists of trials and review articles. SELECTION CRITERIA: Randomised controlled trials comparing the effects of postoperative epidural local anaesthetic with systemic or epidural opioids. DATA COLLECTION AND ANALYSIS: Collected data included treatment in active (local anaesthetic) and control (opioid based) groups, time to first postoperative stool, time to first postoperative flatus, gastric emptying measured by the paracetamol absorption test, duration of the passage of barium sulphate, pain assessments, use of supplementary analgesics, nausea, vomiting and surgical/anaesthetic complications. MAIN RESULTS: Most studies in this review involved a small number of patients. Furthermore half of the studies indicated a poor level of methodology in particular regarding blinding and report of withdrawals. Heterogeneity of included studies was substantial. Results consistently showed reduced time to return of gastrointestinal function in the epidural local anaesthetic group compared with groups receiving systemic or epidural opioid (37 hours and 24 hours, respectively). Postoperative pain was comparable. Two studies compared the effect of epidural local anaesthetic with a combination of epidural local anaesthetic and opioid on gastrointestinal function. One study favoured epidural local anaesthetic and one study was indifferent. A meta analysis of five of eight studies comparing the effect of epidural local anaesthetic with a combination of epidural local anaesthetic and opioid on postoperative pain, yielded a reduction in VAS pain scores (0-100 mm) on the first postoperative day of 15 mm, in favour of the combination. No significant differences in PONV were observed between epidural local anaesthetic and opioid based regimens. REVIEWER'S CONCLUSIONS: Administration of epidural local anaesthetics to patients undergoing laparotomy reduce gastrointestinal paralysis compared with systemic or epidural opioids, with comparable postoperative pain relief. Addition of opioid to epidural local anaesthetic may provide superior postoperative analgesia compared with epidural local anaesthetics alone. The effect of additional epidural opioid on gastrointestinal function is so far unsettled. Randomized, controlled trials comparing the effect of combinations of epidural local anaesthetic and opioid with epidural local anaesthetic alone on postoperative gastrointestinal function and pain are warranted.

Abstract: A qualitative systematic review of randomized controlled trials (RCT) of incisional local anaesthesia for the control of postoperative pain after open abdominal operations was performed. Twenty-six studies with data from 1211 patients were considered appropriate for analysis. RCT considered inguinal herniotomy, hysterectomy, cholecystectomy and a variety of surgical procedures. Outcome measures were pain scores, supplementary analgesics and time to first analgesic request. Efficacy was estimated by significant difference (p < 0.05) as reported in the original investigation. All trials of herniotomy showed a 2-7 hour lasting, clinically relevant, improved pain relief. Five of eight cholecystectomy trials showed significant differences but in three studies of questionable clinical importance and validity. In other procedures results were inconsistent and in some cases of minor clinical importance. Except for herniotomy there is a lack of evidence for effect of incisional local anaesthesia on postoperative pain and further standardized studies are needed before recommendations can be made.

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Abstract: BACKGROUND AND OBJECTIVES: In a systematic review, we have evaluated double-blind, randomized, controlled trials of intra-articular local anesthesia compared with placebo or no treatment in the control of postoperative pain after arthroscopic knee surgery. METHODS: Outcome measures were pain scores, supplementary analgesics, and time to first analgesic request. Efficacy was estimated by significant difference (P < .05) as reported in the original reports and by calculation of the weighted mean difference of pain scores between treatment groups. RESULTS: Twenty studies with data from 895 patients were considered appropriate for analysis. Twelve of these 20 studies showed improved pain relief after intra-articular local anesthesia in at least one of the considered pain parameters, whereas the eight other studies were without such improvements. In ten of the positive studies, pain scores were significantly lower in the treatment groups compared with the control groups with visual analog scale (VAS) score reductions of between 10 and 35 mm early (1-4 hours) postoperatively. Quantitative analysis with calculation of the weighted mean difference in VAS confirmed a statistically significant but minor clinically important effect on postoperative pain scores. In nine studies, the consumption of supplementary analgesics was reduced 10-50% during observation periods of up to 4 hours; however, in most cases, the analgesic requirements were small to moderate. Only in two of six studies, where time to first analgesic request was evaluated, a significant prolongation of pain relief was observed as lasting between 30 and 50 minutes. CONCLUSIONS: There is a weak evidence for a reduction of postoperative pain after intra-articular local anesthesia in patients undergoing arthroscopic knee surgery, which although being sinall to moderate and of short duration, may be of clinical significance in day-case surgery.

Abstract: In a qualitative systematic review, we have evaluated randomized controlled trials (RCT) of incisional local anaesthesia compared with placebo or no treatment in the control of postoperative pain after open abdominal operations. Twenty-six studies with data from 1211 patients were considered appropriate for analysis. Five RCT considered inguinal herniotomy, four hysterectomy, eight cholecystectomy and nine studies a variety of surgical procedures. Outcome measures were pain scores, supplementary analgesics and time to first analgesic request. Efficacy was estimated by significant difference (P < 0.05), as reported in the original investigation. All studies of herniotomy showed a 2-7-h duration of clinically relevant improved pain relief. Results of hysterectomy studies were inconclusive, with two being negative. Five of the cholecystectomy studies showed significant differences but questionable clinical importance and validity in three. In various other procedures results were inconsistent and in some of minor clinical importance. Except for herniotomy, there was a lack of evidence for effect of incisional local anaesthesia on postoperative pain and further standardized studies are needed before recommendations can be made.

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Abstract: The effects of a split-dose of atropine sulphate versus a single dose of glycopyrrolate given with neostigmine for the reversal of gallamine-induced neuromuscular blockade were studied in 55 patients undergoing gynaecological surgery. The patients were randomized to receive either a single dose of glycopyrrolate (7 micrograms.kg-1) or two doses of atropine (8 micrograms.kg-1 each), given with an interval of 1 min. There were no differences between the two methods with respect to percentage heart rate changes, salivation or arousal time. Four patients demonstrated cardiac arhythmias in the atropine group, whereas none occurred in the glycopyrrolate group (P less than 0.05). It is concluded that a split-dose of atropine has similar chronotropic effects to a single dose of glycopyrrolate for the reversal of gallamine-induced neuromuscular blockade. However, the finding of a higher incidence of cardiac arrhythmias in the atropine group suggests that this reversal regime should be reserved for patients without cardiac disease.

Abstract: The BioLogue International Symposium on Adaptive Clinical Trials was held October 10, 2006, in Copenhagen, Denmark. This symposium brought together clinical trialists and trial experts from academia, industry, and regulatory agencies to initiate a dialogue on opportunities, scope, and challenges regarding adaptive clinical trials.

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