A pilot study of a pharmacist-led prescribing program for final-year medical students.

BACKGROUND: Junior doctors undertake a significant amount of prescribing; however, they are not well prepared for this, and report they would like more training in their undergraduate courses. To address this we tested a pharmacist-led prescribing program for final-year medical students. METHODS: Sixteen final-year students took part in the program. The program involved students writing prescriptions and getting feedback from clinical pharmacists, undertaking prescribing and calculation tutorials, and spending time in the pharmacy department. Evaluation included a pre- and post-assessment of their confidence and skills in prescribing, and a feedback session discussing the strengths and weakness of the program, and their perceptions about the role of pharmacists. Changes in the pre- and post-assessment of confidence and skills were examined with permutation and Mann-Whitney U tests. RESULTS: There was a significant improvement in students' confidence in prescribing, and a small but consistent improvement in prescribing skills. Of note, no student prescribed inappropriately and potentially harmfully after the program. Participants were positive about the program, and indicated a better understanding about the pharmacists' role and their ability to support them as junior doctors. CONCLUSIONS: This study has shown the potential effect of a pharmacist-led prescribing program on the skills and confidence in prescribing by medical students. It provided an interprofessional teaching opportunity, preparing students for a team-based approach to patient management.

The risk of coronary thrombosis with cyclo-oxygenase-2 inhibitors does not vary with polymorphisms in two regions of the cyclo-oxygenase-2 gene.

AIMS: To investigate whether polymorphisms of the cyclo-oxygenase-2 (COX-2) gene modify the adverse cardiovascular effects of COX-2 inhibitors. METHODS: A case control study was conducted in the Hunter Region of New South Wales, Australia. Cases (n= 460) were hospitalized with acute coronary syndrome (ACS). Controls (n= 640) were recruited from the electoral rolls. Structured interviews gathered information on variables including recent ingestion of non-steroidal anti-inflammatory drugs (NSAIDs). Targeted genotyping of rs 20417(G > C) and rs5275 (T > C) polymorphisms was performed by real-time polymerase chain reaction using allele-specific probes. RESULTS: Ingestion of any NSAID in the week prior to interview was associated with an elevated risk for ACS: adjusted odds ratio 1.8 (1.2, 2.5). The rs 20417 and rs 5275 polymorphisms were not singly associated with risk for ACS: adjusted odds ratios 1.1 (0.80, 1.5) and 1.2 (0.88, 1.5), respectively. Individually, the polymorphisms did not modify the risk of ACS with the drugs. When analyses were conducted by haplotype, the adjusted odds ratio with celecoxib or rofecoxib in individuals who had one or two copies of the 'low risk' haplotype (no GT) was 1.2 (0.29, 5.0), compared with 2.1 (1.1, 4.0) with the 'high risk' haplotype (one or two copies of GT). CONCLUSIONS: We found little evidence of a gene/drug interaction. We found a statistically non-significant trend toward a lower risk of coronary events with NSAIDs in the presence of the 'low risk' haplotype. Even if confirmed, the clinical utility of the finding would be limited as this haplotype is carried by a minority of the population.

Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery, and previous reviews have found them to be effective in reducing blood loss, the need for transfusion, and the need for re-operation due to continued or recurrent bleeding. In the last few years questions have been raised regarding the comparative performance of the drugs. The safety of the most popular agent, aprotinin, has been challenged, and it was withdrawn from world markets in May 2008 because of concerns that it increased the risk of cardiovascular complications and death. OBJECTIVES: To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood cell (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death. SEARCH STRATEGY: We searched: the Cochrane Injuries Group's Specialised Register (July 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (Ovid SP) 1950 to July 2010, EMBASE (Ovid SP) 1980 to July 2010. References in identified trials and review articles were checked and trial authors were contacted to identify any additional studies. The searches were last updated in July 2010. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-fibrinolytic drugs in adults scheduled for non-urgent surgery. Eligible trials compared anti-fibrinolytic drugs with placebo (or no treatment), or with each other. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: This review summarises data from 252 RCTs that recruited over 25,000 participants. Data from the head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of reducing perioperative blood loss, but the differences were small. Compared to control, aprotinin reduced the probability of requiring RBC transfusion by a relative 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.60 to 0.72). The RR for RBC transfusion with TXA was 0.61 (95% CI 0.53 to 0.70) and was 0.81 (95% CI 0.67 to 0.99) with EACA. When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared to aprotinin alone, aprotinin appeared more effective in reducing the need for RBC transfusion (RR 0.90; 95% CI 0.81 to 0.99).Aprotinin reduced the need for re-operation due to bleeding by a relative 54% (RR 0.46, 95% CI 0.34 to 0.62). This translates into an absolute risk reduction of 2% and a number needed-to-treat (NNT) of 50 (95% CI 33 to 100). A similar trend was seen with EACA (RR 0.32, 95% CI 0.11 to 0.99) but not TXA (RR 0.80, 95% CI 0.55 to 1.17). The blood transfusion data were heterogeneous and funnel plots indicate that trials of aprotinin and the lysine analogues may be subject to publication bias.When compared with no treatment aprotinin did not increase the risk of myocardial infarction (RR 0.87, 95% CI 0.69 to 1.11), stroke (RR 0.82, 95% CI 0.44 to 1.52), renal dysfunction (RR 1.10, 95% CI 0.79 to 1.54) or overall mortality (RR 0.81, 95% CI 0.63 to 1.06). Similar trends were seen with the lysine analogues, but data were sparse. These data conflict with the results of recently published non-randomised studies, which found increased risk of cardiovascular complications and death with aprotinin. There are concerns about the adequacy of reporting of uncommon events in the small clinical trials included in this review.When aprotinin was compared directly with either, or both, of the two lysine analogues it resulted in a significant increase in the risk of death (RR 1.39, 95% CI 1.02, 1.89), and a non-significant increase in the risk of myocardial infarction (RR 1.11 95% CI 0.82, 1.50). Most of the data contributing to this added risk came from a single study - the BART trial (2008). AUTHORS' CONCLUSIONS: Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the receipt of allogeneic red cell transfusion. Aprotinin appears to be slightly more effective than the lysine analogues in reducing blood loss and the receipt of blood transfusion. However, head to head comparisons show a lower risk of death with lysine analogues when compared with aprotinin. The lysine analogues are effective in reducing blood loss during and after surgery, and appear to be free of serious adverse effects.

Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery, and previous reviews have found them to be effective in reducing blood loss, the need for transfusion, and the need for re-operation due to continued or recurrent bleeding. In the last few years questions have been raised regarding the comparative performance of the drugs. The safety of the most popular agent, aprotinin, has been challenged, and it was withdrawn from world markets in May 2008 because of concerns that it increased the risk of cardiovascular complications and death. OBJECTIVES: To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood cell (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death. SEARCH STRATEGY: We searched: the Cochrane Injuries Group's Specialised Register (July 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (Ovid SP) 1950 to July 2010, EMBASE (Ovid SP) 1980 to July 2010. References in identified trials and review articles were checked and trial authors were contacted to identify any additional studies. The searches were last updated in July 2010. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-fibrinolytic drugs in adults scheduled for non-urgent surgery. Eligible trials compared anti-fibrinolytic drugs with placebo (or no treatment), or with each other. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. This version of the review includes a sensitivity analysis excluding trials authored by Prof. Joachim Boldt. MAIN RESULTS: This review summarises data from 252 RCTs that recruited over 25,000 participants. Data from the head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of reducing perioperative blood loss, but the differences were small. Compared to control, aprotinin reduced the probability of requiring RBC transfusion by a relative 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.60 to 0.72). The RR for RBC transfusion with TXA was 0.61 (95% CI 0.53 to 0.70) and was 0.81 (95% CI 0.67 to 0.99) with EACA. When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared to aprotinin alone, aprotinin appeared more effective in reducing the need for RBC transfusion (RR 0.90; 95% CI 0.81 to 0.99).Aprotinin reduced the need for re-operation due to bleeding by a relative 54% (RR 0.46, 95% CI 0.34 to 0.62). This translates into an absolute risk reduction of 2% and a number needed-to-treat (NNT) of 50 (95% CI 33 to 100). A similar trend was seen with EACA (RR 0.32, 95% CI 0.11 to 0.99) but not TXA (RR 0.80, 95% CI 0.55 to 1.17). The blood transfusion data were heterogeneous and funnel plots indicate that trials of aprotinin and the lysine analogues may be subject to publication bias.When compared with no treatment aprotinin did not increase the risk of myocardial infarction (RR 0.87, 95% CI 0.69 to 1.11), stroke (RR 0.82, 95% CI 0.44 to 1.52), renal dysfunction (RR 1.10, 95% CI 0.79 to 1.54) or overall mortality (RR 0.81, 95% CI 0.63 to 1.06). Similar trends were seen with the lysine analogues, but data were sparse. These data conflict with the results of recently published non-randomised studies, which found increased risk of cardiovascular complications and death with aprotinin. There are concerns about the adequacy of reporting of uncommon events in the small clinical trials included in this review.When aprotinin was compared directly with either, or both, of the two lysine analogues it resulted in a significant increase in the risk of death (RR 1.39, 95% CI 1.02, 1.89), and a non-significant increase in the risk of myocardial infarction (RR 1.11 95% CI 0.82, 1.50). Most of the data contributing to this added risk came from a single study - the BART trial (2008). AUTHORS' CONCLUSIONS: Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the receipt of allogeneic red cell transfusion. Aprotinin appears to be slightly more effective than the lysine analogues in reducing blood loss and the receipt of blood transfusion. However, head to head comparisons show a lower risk of death with lysine analogues when compared with aprotinin. The lysine analogues are effective in reducing blood loss during and after surgery, and appear to be free of serious adverse effects.

Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study.

STUDY OBJECTIVE: We determine whether droperidol, midazolam, or the combination is more effective for intramuscular sedation in violent and acute behavioral disturbance in the emergency department (ED). METHODS: We conducted a blinded randomized controlled trial of intramuscular sedation for violent and acute behavioral disturbance, comparing droperidol (10 mg), midazolam (10 mg), and droperidol (5 mg)/midazolam (5 mg). Inclusion criteria were patients requiring physical restraint and parenteral sedation. The primary outcome was the duration of the violent and acute behavioral disturbance, defined as the time security staff were required. Secondary outcomes included time until additional sedation was administered, staff and patient injuries, further episodes of violent and acute behavioral disturbance, and drug-related adverse effects. RESULTS: From 223 ED patients with violent and acute behavioral disturbance, 91 patients were included; 33 received droperidol, 29 received midazolam, and 29 received the combination. There was no difference in the median duration of the violent and acute behavioral disturbance: 20 minutes (interquartile range [IQR] 11 to 37 min) for droperidol, 24 minutes (IQR 13 to 35 minutes) for midazolam, and 25 minutes (IQR 15 to 38 minutes) for the combination. Additional sedation was required in 11 (33%; 95% confidence interval [CI] 19% to 52%) droperidol patients, 18 (62%; 95% CI 42% to 79%) midazolam patients, and 12 (41%; 95% CI 24% to 61%) in the combination group. The hazard ratio for additional sedation in the midazolam versus droperidol group was 2.31 (95% credible interval 1.01 to 4.71); for the combination versus droperidol, 1.18 (95% credible interval 0.46 to 2.50). Patient and staff injuries and number of further episodes of violent and acute behavioral disturbance did not differ between groups. There were two adverse effects for droperidol (6%; 95% CI 1% to 22%), 8 for midazolam (28%; 95% CI 13% to 47%), and 2 for the combination (7%; 95% CI 1% to 24%). An abnormal QT occurred in 2 of 31 (6%; 95% CI 1% to 23%) droperidol patients, which was not different from the other groups. CONCLUSION: Intramuscular droperidol and midazolam resulted in a similar duration of violent and acute behavioral disturbance, but more additional sedation was required with midazolam. Midazolam caused more adverse effects because of oversedation, and there was no evidence of QT prolongation associated with droperidol compared with midazolam.

MODELING COST-EFFECTIVENESS OF HIGH DOSE CHEMOTHERAPY AS TREATMENT FOR RELAPSED AGGRESSIVE NON-HODGKIN'S LYMPHOMA IN AN AUSTRALIAN SETTING.

Background: Since 1995 patients with relapsed aggressive non Hodgkin's lymphoma (NHL) have been treated with high dose chemotherapy (HDC) instead of standard dose chemotherapy (SC) because of superior survival demonstrated in the "Parma study". As HDC involves hospital admission and intensive supportive care, the cost of HDC would be predicted to be higher than for SC. The aim of this study was to calculate the Incremental Cost-Effectiveness Ratio (ICER) for HDC compared to SC using Australian costs. Methods: Cost of treatment was determined on 21 pts receiving HDC with characteristics similar to the Parma study from the HDC database of the Calvary Mater Newcastle Hospital (CMNH). Drug, transfusion, inpatient and outpatient attendance and additional relevant data from start of treatment for relapse and up to 100 days following HDC were obtained and costed. SC costs required modelling as all suitable pts are planned to receive HDC if possible, therefore no concurrent SC arms exist. A lifetime estimate of patient-years gained by HDC versus SC was calculated from the area under survival curves (AUC) of HDC and SC. The ICER was calculated according to formula: Incremental Cost / Incremental Benefit = (Costs(HDC)-Costs(SDC)) / (AUC(HDC)-AUC(SDC)). Results: Cost for HDC and SC were $AU37,490 and $AU33,360 respectively, and the AUC(0-infinity) were 4.09 and 3.5 patient life years respectively giving an ICER of $AU7,070 per discounted life year gained. Conclusion Compared to published studies in multiple myeloma and solid organ transplant these results support HDC as a cost-effective treatment in relapsed aggressive NHL.

Activated charcoal decreases the risk of QT prolongation after citalopram overdose.

STUDY OBJECTIVE: We determine whether single-dose activated charcoal (SDAC) administration after citalopram overdose reduces the proportion of patients developing abnormal QT prolongation. METHODS: Data were collected retrospectively for citalopram overdose patients presenting to 8 emergency departments. Demographics, dose, coingested drugs, SDAC administration, and serial ECGs were extracted from medical records. The primary outcome was the proportion of patients who had an observed QT,RR combination at any time above an abnormal threshold, established as a predictor of torsade de pointes. We compared the proportion of patients with QT prolongation who received or did not receive SDAC. These data were analyzed within a Bayesian framework, using probabilities of abnormal QT,RR combinations with and without derived from a previous single-center study. WinBUGS was used to generate posterior estimates and credible intervals of the relative risk by combining the prior probabilities and the study data. RESULTS: SDAC was administered on average 2.1 hours (range, 0.5 to 6.25 hours) after ingestion in 48 of 254 admissions, and abnormal QT,RR combinations occurred in 2 cases (4.2%), compared with 23 of 206 (11.2%) cases not receiving SDAC. There did not appear to be any clinically important difference in age, sex, dose, and cardiotoxic coingestants between the 2 groups. No cases of torsade de pointes occurred. The estimated relative risk of having an abnormal QT,RR combination for SDAC compared to no SDAC was 0.28 (0.06 to 0.70) (median with 2.5% and 97.5% credible limits). The probability that the relative risk was less than 1.0 was 0.99, which can be interpreted as very strong evidence in favor of a beneficial effect of SDAC. The absolute risk difference was estimated as 7.5% and the median number needed to treat as 13.3. CONCLUSION: SDAC may be effective in reducing the risk of a prolonged QT in patients after citalopram overdose. Current trends toward nonuse of activated charcoal should be evaluated to determine whether patients poisoned by specific agents may benefit from activated charcoal administration.

Route of administration of redback spider bite antivenom: determining clinician beliefs to facilitate Bayesian analysis of a clinical trial.

OBJECTIVE: To determine current beliefs of Australasian emergency physicians, to form the basis of 'stopping rules' for a clinical trial of intravenous (i.v.) versus intramuscular (i.m.) redback spider antivenom. METHODS: An email survey of fellows and trainees of the Australasian College for Emergency Medicine. RESULTS: There were 218 responses; 30% used the i.v. route exclusively, 16% used the i.m route exclusively, 17% used i.m. followed by i.v. if there was a poor initial clinical response, and 38% stated that they had no particular preference. The probability given by respondents that the i.v. route is superior allowed us to differentiate 'i.v. enthusiasts' from 'i.v. sceptics'. Median predicted response rates were 90% versus 80% for the i.v. route and 60% versus 75% for the i.m. route in the enthusiastic and sceptical groups, respectively. The median expected absolute advantage of i.v. compared with i.m. antivenom was 20% versus 5%, respectively. The median number-needed-to-treat threshold that would lead respondents to choose the i.v. route in preference to the i.m. was 5. CONCLUSION: Australasian emergency physicians have polarized views on the optimal route for administering redback spider antivenom. We were therefore able to define both sceptical and enthusiastic priors for a fully Bayesian trial analysis. Our findings support using a number needed to treat of 5 (20% absolute advantage) for powering a clinical study and for determining the point at which it should be stopped.

Measuring effectiveness of dietetic interventions in child obesity: a systematic review of randomized trials.

OBJECTIVES: To assess the effectiveness of dietetic treatment for obese children and to report details of dietary interventions. DATA SOURCES: English-language articles from 1975 to 2003 available from health and medical databases. STUDY SELECTION: Randomized controlled trials with subjects younger than 18 years of age that included a dietary intervention in isolation or in combination with lifestyle modifications and/or psychological therapies. One person searched the databases; 2 people independently critically appraised the articles for methodological quality and then extracted data using standardized tools. DATA EXTRACTION: Thirty-seven randomized controlled trials met the inclusion criteria; 17 contained sufficient information for a Forest plot of the standardized effects. Eight studies had a true control and were included in a meta-analysis. The random effects model was reported if the Q noncombinability chi(2) statistic was significant at the 10% level because it has low power as a strict test of homogeneity. DATA SYNTHESIS: The 2 strongly qualified meta-analyses suggest that interventions that include a dietary treatment do achieve relative weight loss. Details of the dietary intervention or participant food intake are rarely described. CONCLUSIONS: It is not possible to evaluate the effectiveness of dietary treatment for childhood obesity because of the lack of high-quality studies and the heterogeneity of designs, treatment combinations, outcome measures, and follow-up. There is an urgent need to improve the quality of studies in this area because childhood obesity poses major health risks for populations, yet there is limited evidence on which to base treatment strategies.

Hyperbaric oxygen for carbon monoxide poisoning : a systematic review and critical analysis of the evidence.

Poisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce the incidence of neurological sequelae. These observations have led some clinicians to use HBO for selected patients with CO poisoning, although there is considerable variability in clinical practice. This article assesses the effectiveness of HBO compared with normobaric oxygen (NBO) for the prevention of neurological sequelae in patients with acute CO poisoning. The following databases were searched: MEDLINE (1966 to present), EMBASE (1980 to present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognised content experts. All randomised controlled trials involving people acutely poisoned with CO, regardless of severity, were examined. The primary analysis included all trials from which data could be extracted. Sensitivity analysis examined trials with better validity (defined using the validated instrument of Jadad) and those enrolling more severely poisoned patients. Two reviewers independently extracted from each trial, including information on the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurological sequelae at follow-up. A pooled odds ratio (OR) for the presence of neurological symptoms at 1-month follow-up was calculated using a random effects model. Bayesian models were also investigated to illustrate the degree of certainty about clinical effectiveness. Eight randomised controlled trials were identified. Two had no evaluable data and were excluded. The remaining trials were of varying quality and two have been published only as abstracts. The severity of CO poisoning varied among trials. At 1-month follow-up after treatment, sequelae possibly related to CO poisoning were present in 242 of 761 patients (36.1%) treated with NBO, compared with 259 of 718 patients (31.8%) treated with HBO. Restricting the analysis to the trials with the highest quality scores or those that enrolled all patients regardless of severity did not change the lack of statistical significance in the outcome of the pooled analysis. We found empiric evidence of multiple biases that operated to inflate the benefit of HBO in two positive trials. In contrast, the interpretation of negative trials was hampered by low rates of follow-up, unusual interventions for control patients and inclusion of less severely poisoned patients. Collectively, these limitations may have led negative trials to overlook a real and substantial benefit of HBO (type II error). There is conflicting evidence regarding the efficacy of HBO treatment for patients with CO poisoning. Methodological shortcomings are evident in all published trials, with empiric evidence of bias in some, particularly those that suggest a benefit of HBO. Bayesian analysis further illustrates the uncertainty about a meaningful clinical benefit. Consequently, firm guidelines regarding the use of HBO for patients with CO poisoning cannot be established. Further research is needed to better define the role of HBO, if any, in the treatment of CO poisoning. Such research should not exclude patients with severe poisoning, have a primary outcome that is clinically meaningful and have oversight from an independent data monitoring and ethics committee.

Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-head trials.

BACKGROUND: Aprotinin has been shown to be effective in reducing peri-operative blood loss and the need for re-operation due to continued bleeding in cardiac surgery. The lysine analogues tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) are cheaper, but it is not known if they are as effective as aprotinin. METHODS: Studies were identified by searching electronic databases and bibliographies of published articles. Data from head-to-head trials were pooled using a conventional (Cochrane) meta-analytic approach and a Bayesian approach which estimated the posterior probability of TXA and EACA being equivalent to aprotinin; we used as a non-inferiority boundary a 20% increase in the rates of transfusion or re-operation because of bleeding. RESULTS: Peri-operative blood loss was significantly greater with TXA and EACA than with aprotinin: weighted mean differences were 106 mls (95% CI 37 to 227 mls) and 185 mls (95% CI 134 to 235 mls) respectively. The pooled relative risks (RR) of receiving an allogeneic red blood cell (RBC) transfusion with TXA and EACA, compared with aprotinin, were 1.08 (95% CI 0.88 to 1.32) and 1.14 (95% CI 0.84 to 1.55) respectively. The equivalent Bayesian posterior mean relative risks were 1.15 (95% Bayesian Credible Interval [BCI] 0.90 to 1.68) and 1.21 (95% BCI 0.79 to 1.82) respectively. For transfusion, using a 20% non-inferiority boundary, the posterior probabilities of TXA and EACA being non-inferior to aprotinin were 0.82 and 0.76 respectively. For re-operation the Cochrane RR for TXA vs. aprotinin was 0.98 (95% CI 0.51 to 1.88), compared with a posterior mean Bayesian RR of 0.63 (95% BCI 0.16 to 1.46). The posterior probability of TXA being non-inferior to aprotinin was 0.92, but this was sensitive to the inclusion of one small trial. CONCLUSION: The available data are conflicting regarding the equivalence of lysine analogues and aprotinin in reducing peri-operative bleeding, transfusion and the need for re-operation. Decisions are sensitive to the choice of clinical outcome and non-inferiority boundary. The data are an uncertain basis for replacing aprotinin with the cheaper lysine analogues in clinical practice. Progress has been hampered by small trials and failure to study clinically relevant outcomes.

Risk of road traffic accidents in patients discharged following treatment for psychotropic drug overdose: a self-controlled case series study in Australia.

BACKGROUND: Use of psychotropic drugs is known to impair driving and increase the risk of road traffic accidents. They are also the most common drugs taken in overdose in hospital-treated episodes of self-poisoning. Most patients who take psychotropic drug overdoses are discharged within 48 hours, while they still have possible subclinical drug effects. OBJECTIVE: Using a self-controlled case series design, we aimed to determine whether patients with psychotropic drug overdose are at a higher risk of a traffic accident in the period following discharge compared with a control period not associated with hospital-treated drug overdose. METHODOLOGY: Using the New South Wales (NSW) Admitted Patient Data Collection (APDC) as the primary source, we retrieved 40 845 hospital separation records dated between 1 July 2000 and 30 June 2008 (8 years) in patients aged 18-80 years admitted to a hospital in NSW following an intentional self-poisoning with a psychotropic drug (coded X61 or X62 as the International Classification of Diseases, 10th Edition, [ICD-10] external cause of injury). Of these, 33459 hospital separations (i.e. discharges, transfers and deaths) involving 24 284 patients were considered eligible as the patients were discharged directly into the community where they could have driven a motor vehicle. We selected three separate post-admission periods (3 days, 1 week and 4 weeks), subtracted the number of inpatient days from each and calculated three separate post-discharge periods (immediate, intermediate and extended, respectively) for each episode of overdose. The control period was the duration of the study period where the individual was aged 18 years or older, excluding the total person-days in the post-discharge period/s and the index inpatient period/s. The APDC dataset was linked to the NSW Roads and Traffic Authority CrashLink dataset to identify any accidents in which each patient was involved as a motor-vehicle driver during the follow-up period. Incidence rate ratio (IRR) for matched post-discharge and control periods was found using random effects Poisson regression. RESULTS: Seventy-two percent of the subjects were discharged within 2 days following their admission with overdose. Compared with the corresponding control periods the risk of a traffic accident was 3.5 times higher (IRR = 3.49; 95% CI 1.66, 7.33; p = 0.001) during the immediate, 1.9 times higher (IRR = 1.88; 95% CI 1.09, 3.25; p = 0.023) during the intermediate and 1.6 times higher (IRR = 1.65; 95% CI 1.27, 2.15; p = 0.0002) during the extended post-discharge period. CONCLUSIONS: Self-poisoning with psychotropic drugs is associated with a markedly increased risk of a traffic accident during the first few days following discharge. These findings raise clinical and medico-legal implications concerning fitness-to-drive during this period. The risk reduces with time but remains significantly elevated after 4 weeks post-overdose. Further research is necessary to find out the factors contributing to this ongoing risk.

Sedation assessment tool to score acute behavioural disturbance in the emergency department.

OBJECTIVE: The objective of the study was to evaluate the effectiveness of the sedation assessment tool (SAT) in assessing patient response to treatment for acute behavioural disturbance (ABD). METHODS: The SAT is a simplified version of the altered mental status score (AMSS) and is a 7-point scale assessing levels of agitation and sedation using only two descriptors. To assess the SAT we firstly compared plots of the SAT and the AMSS versus time in patients with ABD recruited to a clinical trial. AMSS were converted to the SAT for this comparison. Second, the sensitivity and specificity were calculated for an increase in the SAT to +2 or +3 as a predictor of whether additional sedation was required in a prospective cohort of 138 patients. Third, interrater reliability was assessed using two individuals to score the same patient at two different time points and finally the time to record the score was measured. RESULTS: Plots of AMSS and SAT for 91 patients in the clinical trial illustrated similar trends in agitation/sedation. Seventeen of 138 patients in the second cohort had an increase in the SAT. Fifteen of 17 (88%) received additional sedation. The sensitivity and specificity of the SAT for additional sedation was 100% (95% CI 75-100%) and 98% (95% CI 94-100%), respectively. The median time for staff to assign the SAT was 10 s (range 3-15 s). Interrater reliability was high with a kappa of 0.87. CONCLUSION: The SAT is a simple, rapid and useful measure of the level of agitation/sedation in patients with ABD. Increases in the score reliably indicated the need for further sedation.

The dark side of the moon.

OBJECTIVE: The belief that the full moon and disturbed behaviour are closely linked is alive and well, despite studies to the contrary. We investigated the possibility that there is an association between only extreme behavioural disturbance and the full moon. DESIGN, SETTING AND PARTICIPANTS: We undertook an observational study of patients with violent and acute behavioural disturbance who presented to the emergency department of Calvary Mater Newcastle and patients with less severe behaviour for whom hospital security calls were made. MAIN OUTCOME MEASURE: Proportion of patients for whom presentation or security call occurred in each lunar phase, modelled as a Poisson process. RESULTS: Of 91 patients with violent and acute behavioural disturbance, 21 (23%) presented during the full moon--double the number for other lunar phases (P = 0.002). Sixty (66%) had either alcohol intoxication or psychostimulant toxicity, and five attacked staff (biting [2], spitting [1], kicking [1] and scratching [1]). In contrast, 512 hospital security calls for patients with less severe behaviour were evenly distributed throughout the lunar cycle. CONCLUSION: Violent and acute behavioural disturbance manifested more commonly during the full moon.

Inter-rater reliability of manual QT measurement and prediction of abnormal QT,HR pairs.

OBJECTIVES: To assess interobserver agreement when trained healthcare staff measure the QT interval using a standardized approach across a range of QT lengths. METHODS: A sample of 110 electrocardiograms (ECGs) was taken from general and psychotropic overdose admissions to the emergency department including drugs known to cause QT prolongation and Torsades de Pointes. Four of the authors measured the QT interval in all ECGs using a previously developed approach. Each rater was blinded to the ECG admission details and the measurements of the other raters. The primary outcome was the inter-rater agreement for the median QT and interobserver classification as to whether the QT interval was abnormal or not, based on the QT nomogram. RESULTS: There was good agreement between raters (intraclass correlation coefficient, 0.61; 95% CI = 0.53 to 0.69). When classifying the QT as abnormal there was good agreement between the raters with a Fleiss' kappa of 0.61. There was perfect agreement between all four raters on 86 of 110 ECGs (78.2%), agreement between three raters on 18 of 110 (16.3%), and a split between the four on 6 of 110 (5.5%). Disagreement between the automated QT measurement and the majority of the raters was slightly more than within raters. CONCLUSIONS: The study demonstrates that there is good agreement between trained observers when manually measuring the QT interval using a standardized approach. This provides an inexpensive method for the measurement of QT in clinical studies of drug overdose and a potentially useful approach in the clinical assessment of patients with possible QT prolongation.

Systematic review of interventions in the management of overweight and obese children which include a dietary component.

Background The prevalence of overweight and obesity in children and adolescents is increasing at an alarming rate around the world and prevention has become a key public health objective. Treatment and management of those already overweight and obese must be aligned with the best available evidence on effectiveness, if the risk of obesity-related morbidity and mortality is yet be reduced. Diet plays a pivotal role in successful treatment of obesity but to date, there is limited evidence on which to base practice. Objectives To identify and present the best available evidence on the optimal dietetic treatment and management of children and adolescent who are overweight or obese. Search strategy Published English language literature was searched using the electronic databases CINAHL, MEDLINE, PRE-MEDLINE, DARE, COCHRANE, EMBASE, AUSTROM, Current Concepts and Dissertation Abstracts. The databases were limited to English Language from 1975 until 2003. Government reports from the UK, USA and Australian were also searched and a hand search performed for the Journal of the Dietitians Association of Australia, International Journal of Obesity and the Journal of Human Nutrition and Dietetics and the bibliographies of retrieved articles. Selection criteria (i) Interventions that evaluated the effectiveness of nutrition or dietary interventions to treat or manage overweight and obesity; (ii) Children aged less than 18 years; and (iii) Participants were defined as overweight or obese by relative weight or a measure of body weight status, studies that reported body weight per se were excluded. Data collection and analysis An experienced professional librarian searched the databases, and two trained research assistants independently identified studies for retrieval and assessed each article for inclusion. The included studies were critically appraised for methodological quality by two people independently. Data were extracted from the appropriate articles and when a discrepancy arose, a third party would arbitrate. Main results There were 116 articles that met the inclusion criteria. While 49 articles described randomised controlled trials, they arose from 37 separate studies. There were 67 non-randomised trials. Meta-analyses were performed on eight studies that included both a dietary intervention component and an adequate control group and on four studies that had follow-up data. There was a high degree of heterogeneity between studies and this made comparisons between studies problematic. Interventions that include diet therapy generally result in significant weight loss, at least in the short term. Many studies were poorly designed and had no or only minimal follow up. The details of the dietary intervention were often inadequately described and dietary outcomes rarely reported, making repetition of the studies difficult. Reviewers' conclusions There is an urgent need for high quality studies investigating the optimal dietary approach to management of paediatric overweight and obesity. These studies require adequate follow up to ascertain if weight loss can be sustained in the long term. Details of the dietary prescription, adherence to the dietary intervention and diet-specific outcomes need to be reported in order to inform best practice.

Systematic review of interventions in the management of overweight and obese children which include a dietary component.

BACKGROUND: The prevalence of overweight and obesity in children and adolescents is increasing at an alarming rate around the world and prevention has become a key public health objective. Treatment and management of those already overweight and obese must be aligned with the best available evidence on effectiveness, if the risk of obesity-related morbidity and mortality is yet be reduced. Diet plays a pivotal role in successful treatment of obesity but to date, there is limited evidence on which to base practice. OBJECTIVES: To identify and present the best available evidence on the optimal dietetic treatment and management of children and adolescent who are overweight or obese. SEARCH STRATEGY: Published English language literature was searched using the electronic databases CINAHL, MEDLINE, PRE-MEDLINE, DARE, COCHRANE, EMBASE, AUSTROM, Current Concepts and Dissertation Abstracts. The databases were limited to English Language from 1975 until 2003. Government reports from the UK, USA and Australian were also searched and a hand search performed for the Journal of the Dietitians Association of Australia, International Journal of Obesity and the Journal of Human Nutrition and Dietetics and the bibliographies of retrieved articles. SELECTION CRITERIA: (i) Interventions that evaluated the effectiveness of nutrition or dietary interventions to treat or manage overweight and obesity; (ii) Children aged less than 18 years; and (iii) Participants were defined as overweight or obese by relative weight or a measure of body weight status, studies that reported body weight per se were excluded. DATA COLLECTION AND ANALYSIS: An experienced professional librarian searched the databases, and two trained research assistants independently identified studies for retrieval and assessed each article for inclusion. The included studies were critically appraised for methodological quality by two people independently. Data were extracted from the appropriate articles and when a discrepancy arose, a third party would arbitrate. MAIN RESULTS: There were 116 articles that met the inclusion criteria. While 49 articles described randomised controlled trials, they arose from 37 separate studies. There were 67 non-randomised trials. Meta-analyses were performed on eight studies that included both a dietary intervention component and an adequate control group and on four studies that had follow-up data. There was a high degree of heterogeneity between studies and this made comparisons between studies problematic. Interventions that include diet therapy generally result in significant weight loss, at least in the short term. Many studies were poorly designed and had no or only minimal follow up. The details of the dietary intervention were often inadequately described and dietary outcomes rarely reported, making repetition of the studies difficult. REVIEWERS' CONCLUSIONS: There is an urgent need for high quality studies investigating the optimal dietary approach to management of paediatric overweight and obesity. These studies require adequate follow up to ascertain if weight loss can be sustained in the long term. Details of the dietary prescription, adherence to the dietary intervention and diet-specific outcomes need to be reported in order to inform best practice.

A randomised controlled trial of hot water (45 degrees C) immersion versus ice packs for pain relief in bluebottle stings.

OBJECTIVE: To investigate the effectiveness of hot water immersion for the treatment of Physalia sp. (bluebottle or Portuguese Man-of-War) stings. DESIGN: Open-label, randomised comparison trial. Primary analysis was by intention to treat, with secondary analysis of nematocyst-confirmed stings. One halfway interim analysis was planned. SETTING: Surf lifesaving first aid facilities at two beaches in eastern Australia from 30 December 2003 to 5 March 2005. PARTICIPANTS: 96 subjects presenting after swimming in the ocean for treatment of an apparent sting by a bluebottle. INTERVENTIONS: Hot water immersion (45 degrees C) of the affected part versus ice pack application. MAIN OUTCOME MEASURES: The primary outcome was a clinically important reduction in pain as measured by the visual analogue scale (VAS). Secondary outcomes were the development of regional or radiating pain, frequency of systemic symptoms, and proportion with pruritus or rash on follow-up. RESULTS: 49 patients received hot water immersion and 47 received ice packs. The two groups had similar baseline features, except patients treated with hot water had more severe initial pain (VAS [mean +/- SD]: 54 +/- 22 mm versus 42 +/- 22 mm). After 10 minutes, 53% of the hot water group reported less pain versus 32% treated with ice (21%; 95% CI, 1%-39%; P = 0.039). After 20 minutes, 87% of the hot water group reported less pain versus 33% treated with ice (54%; 95% CI, 35%-69%; P = 0.002). The trial was stopped after the halfway interim analysis because hot water immersion was shown to be effective (P = 0.002). Hot water was more effective at 20 minutes in nematocyst-confirmed stings (95% versus 29%; P = 0.002). Radiating pain occurred less with hot water (10% versus 30%; P = 0.039). Systemic effects were uncommon in both groups. CONCLUSIONS: Immersion in water at 45 degrees C for 20 minutes is an effective and practical treatment for pain from bluebottle stings.

Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis.

BACKGROUND: The duration and cost of cancer clinical trials could be reduced if a surrogate endpoint were used in place of survival. We did a meta-analysis to assess the extent to which two surrogates, tumour response and time to progression, are predictive of mortality in metastatic colorectal cancer and non-small-cell lung cancer. METHODS: Summary data (median time to progression, proportion of patients responding to treatment, and median overall survival) from randomised trials of first-line treatment in colorectal cancer (146 trials) and lung cancer (191 trials) were identified. Data were extracted and analysed by linear regression. We used prediction bands for trials with 250, 500, and 750 patients to identify the surrogate threshold effect that would predict a significant difference in survival. FINDINGS: Response to treatment and time to progression correlated with improvement in survival for both lung cancer (p<0.0001 and p=0.0003, respectively) and colorectal cancer (p<0.0001 for both). To predict a significant survival gain in colorectal cancer trials, an improvement of 20% in the number of patients responding to treatment was required in trials with 750 patients, increasing to 26% in trials with 500 patients and 38% in trials with 250 patients. In lung cancer trials, the same prediction required differences in response of 18% for 750 patients, 21% for 500 patients, and 30% for 250 patients. For time to progression for both cancer types, the incremental gain needed to predict a survival improvement was a median of 1.8 months for trials with 750 patients, 2.2 months for 500 patients, and 3.3 months for 250 patients. INTERPRETATION: Irrespective of trial size, large differences in tumour response rate are needed to predict a significant survival benefit. If surrogates are chosen as the primary endpoint in a clinical trial, time to progression is the preferred measure because more modest and achievable differences are needed for a significant survival benefit. Trials in metastatic lung cancer and colorectal cancer should measure survival as their primary outcome unless the surrogate outcome difference is anticipated to exceed the threshold effect size.