Systematic review and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative: patient comfort.

BACKGROUND: Maximising patient comfort during and after surgery is a primary concern of anaesthetists and other perioperative clinicians, but objective measures of what constitutes patient comfort in the perioperative period remain poorly defined. The Standardised Endpoints in Perioperative Medicine initiative was established to derive a set of standardised endpoints for use in perioperative clinical trials. METHODS: We undertook a systematic review to identify measures of patient comfort used in the anaesthetic, surgical, and other perioperative literature. A multi-round Delphi consensus process that included up to 89 clinician researchers was then used to refine a recommended list of outcome measures. RESULTS: We identified 122 studies in a literature search, which were the basis for a preliminary list of 24 outcome measures and their definitions. The response rates for Delphi Rounds 1, 2, and 3 were 100% (n=22), 90% (n=79), and 100% (n=13), respectively. A final list of six defined endpoints was identified: pain intensity (at rest and during movement) at 24 h postoperatively, nausea and vomiting (0-6 h, 6-24 h, and overall), one of two quality-of-recovery (QoR) scales (QoR score or QoR-15), time to gastrointestinal recovery, time to mobilisation, and sleep quality. CONCLUSIONS: As standardised outcomes will support benchmarking and pooling (meta-analysis) of trials, one or more of these recommended endpoints should be considered for inclusion in clinical trials assessing patient comfort and pain after surgery.

Effect of sufentanil on bispectral index in the elderly.

We examined the impact of adding sufentanil during anaesthesia induction with propofol on bispectral index values in elderly patients (≥ 65 years). Patients were randomly assigned to receive a target-controlled sufentanil infusion (effect-site concentration of 0.3 ng.ml-1 ) or matching placebo, followed by a target-controlled propofol induction (initial effect-site concentration of 0.5 µg.ml-1 ; step-wise increase of 0.5 µg.ml-1 ) until loss of consciousness defined as an Observer's Assessment of Alertness/Sedation score < 2. Seventy-one patients (sufentanil 35, placebo 36) completed the study. Mean (SD) age was 72.3 (5.8) years; 41% were women. At loss of consciousness, mean (SD) bispectral index value was 75.0 (8.6) with sufentanil and 70.0 (8.0) with placebo; mean difference -5.0 (95% confidence interval -8.9 to -1.1), p = 0.013. Post-hoc analyses suggest that the difference was significant in men only (mean difference -7.3 (-11.8 to -2.6), p = 0.003). Sufentanil co-induction with propofol results in higher bispectral index values at loss of consciousness in elderly patients.

Alternative intubation techniques vs Macintosh laryngoscopy in patients with cervical spine immobilization: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Immobilization of the cervical spine worsens tracheal intubation conditions. Various intubation devices have been tested in this setting. Their relative usefulness remains unclear. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library for randomized controlled trials comparing any intubation device with the Macintosh laryngoscope in human subjects with cervical spine immobilization. The primary outcome was the risk of tracheal intubation failure at the first attempt. Secondary outcomes were quality of glottis visualization, time until successful intubation, and risk of oropharyngeal complications. RESULTS: Twenty-four trials (1866 patients) met inclusion criteria. With alternative intubation devices, the risk of intubation failure was lower compared with Macintosh laryngoscopy [risk ratio (RR) 0.53; 95% confidence interval (CI) 0.35-0.80]. Meta-analyses could be performed for five intubation devices (Airtraq, Airwayscope, C-Mac, Glidescope, and McGrath). The Airtraq was associated with a statistically significant reduction of the risk of intubation failure at the first attempt (RR 0.14; 95% CI 0.06-0.33), a higher rate of Cormack-Lehane grade 1 (RR 2.98; 95% CI 1.94-4.56), a reduction of time until successful intubation (weighted mean difference -10.1 s; 95% CI -3.2 to -17.0), and a reduction of oropharyngeal complications (RR 0.24; 95% CI 0.06-0.93). Other devices were associated with improved glottis visualization but no statistically significant differences in intubation failure or time to intubation compared with conventional laryngoscopy. CONCLUSIONS: In situations where the spine is immobilized, the Airtraq device reduces the risk of intubation failure. There is a lack of evidence for the usefulness of other intubation devices.

Ventilation strategies in obese patients undergoing surgery: a quantitative systematic review and meta-analysis.

BACKGROUND: Pathophysiological changes due to obesity may complicate mechanical ventilation during general anaesthesia. The ideal ventilation strategy is expected to optimize gas exchange and pulmonary mechanics and to reduce the risk of respiratory complications. METHODS: Systematic search (databases, bibliographies, to March 2012, all languages) was performed for randomized trials testing intraoperative ventilation strategies in obese patients (BMI ≥ 30 kg m(-2)), and reporting on gas exchange, pulmonary mechanics, or pulmonary complications. Meta-analyses were performed when data from at least three studies or 100 patients could be combined. RESULTS: Thirteen studies (505 obese surgical patients) reported on a variety of ventilation strategies: pressure- or volume-controlled ventilation (PCV, VCV), various tidal volumes, and different PEEP or recruitment manoeuvres (RM), and combinations thereof. Definitions and reporting of endpoints were inconsistent. In five trials (182 patients), RM added to PEEP compared with PEEP alone improved intraoperative PaO2/FIO2 ratio [weighted mean difference (WMD), 16.2 kPa; 95% confidence interval (CI), 8.0-24.4] and increased respiratory system compliance (WMD, 14 ml cm H(2)O(-1); 95% CI, 8-20). Arterial pressure remained unchanged. In four trials (100 patients) comparing PCV with VCV, there was no difference in PaO2/FIO2 ratio, tidal volume, or arterial pressure. Comparison of further ventilation strategies or combination of other outcomes was not feasible. Data on postoperative complications were seldom reported. CONCLUSIONS: The ideal intraoperative ventilation strategy in obese patients remains obscure. There is some evidence that RM added to PEEP compared with PEEP alone improves intraoperative oxygenation and compliance without adverse effects. There is no evidence of any difference between PCV and VCV.

Intravenous lidocaine has no impact on rocuronium-induced neuromuscular block. Randomised study.

BACKGROUND: Intravenous lidocaine is increasingly used in surgical patients. As it has neuromuscular blocking effects, we tested the impact of an intravenous lidocaine infusion on the time course of a rocuronium-induced neuromuscular block. METHODS: Fifty-two adults undergoing surgery were randomly allocated to intravenous lidocaine 1.5 mg/kg followed by a continuous infusion of 2 mg/kg/h or physiological saline (control) throughout surgery. Anaesthesia was induced and maintained with a target-controlled propofol infusion and sufentanil. After loss of consciousness, rocuronium 0.6 mg/kg was given. Neuromuscular transmission was measured using train-of-four (TOF)-watch SX (Organon, Swords Co., Dublin, Ireland) acceleromyography. RESULTS: Onset time (to 95% depression of first twitch) was on average 113.9 s (standard deviation 35.3) with lidocaine and 119.5 s (44.9) with saline (P = 0.618). Total recovery time (TOF ratio 0.9) was on average 58.1 min (15.1) with lidocaine and 54.3 min (16.9) with saline (P = 0.394). Clinical duration (until first twitch has recovered to 25%) was on average 33.3 min (7.2) with lidocaine and 30.6 min (8.1) with saline (P = 0.21). Recovery index (time between 25% and 75% recovery of the first twitch) was on average 11.5 min (5.0) with lidocaine and 10.6 min (4.1) with saline (P = 0.458). Recovery time (between 25% recovery of the first twitch and TOF ratio 0.9) was on average 24.8 min (9.3) with lidocaine and 23.2 min (9.2) with saline (P = 0.541). CONCLUSION: A continuous intravenous infusion of lidocaine has no impact on the time course of the neuromuscular blockade induced by a standard intubation dose of rocuronium.

[Evidence-based anesthesiology: knowledge transfer from research into clinical practice]. / Evidenzbasierte Anästhesiologie : Wissenstransfer aus der Forschung in die klinische Praxis.

In the interest of patients evidence-based healthcare should be provided and is increasingly being demanded worldwide. In the daily medical practice however, healthcare based on proven scientific findings has not yet become firmly established. There are several causes for this. Problems occur at the level of knowledge generation, knowledge transfer from research into practice and also at the individual level of the treating healthcare professional. Nowadays, with a rapidly growing amount of knowledge it is almost impossible for the individual to quickly filter out the relevant facts. This article aims to shed light on the various aspects of the process of knowledge transfer from a clinical trial to evidence-based guidelines. It will make the reader aware of potential problems during this process and show some feasible approaches to solving them. Wherever possible, the field of anesthesiology will be used as the reference point. Evidence-based information sources will be presented and advice on how to use them will be given.

Time course of rocuronium-induced neuromuscular block after pre-treatment with magnesium sulphate: a randomised study.

BACKGROUND: A previously published study suggested that pre-treatment with magnesium sulphate (MgSO(4)) had no impact on the speed of onset of rocuronium-induced neuromuscular block. We set out to verify this assumption. METHODS: Eighty patients (18-60 years) were randomly allocated to MgSO(4) 60 mg/kg or placebo (saline). Study drugs were given intravenously for 15 min before induction of anaesthesia with propofol, sufentanil and rocuronium 0.6 mg/kg. Anaesthesia was maintained with a target-controlled propofol infusion. Neuromuscular transmission was measured using train-of-four (TOF)-Watch SX acceleromyography. RESULTS: Onset was analysed in 37 MgSO(4) and 38 saline patients, and recovery in 35 MgSO(4) and 37 saline patients. Onset time (to 95% depression of T1) was on average 77 [SD=18] s with MgSO(4) and 120 [48] s with saline (P<0.001). The total recovery time (DurTOF0.9) was on average 73.2 [22] min with MgSO(4) and 57.8 [14.2] min with saline (P<0.003). The clinical duration (Dur25%) was on average 44.7 [14] min with MgSO(4) and 33.2 [8.1] min with saline (P<0.0002). The recovery index (Dur25-75%) was on average 14.0 [6] min with MgSO(4) and 11.2 [5.2] min with saline (P<0.02). The recovery time (Dur25%TOF0.9) was on average 28.5 [11.7] min with MgSO(4) and 24.7 [8.4] min with saline (P=0.28). CONCLUSION: Magnesium sulphate given 15 min before propofol anaesthesia reduces the onset time of rocuronium by about 35% and prolongs the total recovery time by about 25%.

Benefit and risk of intrathecal morphine without local anaesthetic in patients undergoing major surgery: meta-analysis of randomized trials.

Intrathecal morphine without local anaesthetic is often added to a general anaesthetic to prevent pain after major surgery. Quantification of benefit and harm and assessment of dose-response are needed. We performed a meta-analysis of randomized trials testing intrathecal morphine alone (without local anaesthetic) in adults undergoing major surgery under general anaesthesia. Twenty-seven studies (15 cardiac-thoracic, nine abdominal, and three spine surgery) were included; 645 patients received intrathecal morphine (dose-range, 100-4000 microg). Pain intensity at rest was decreased by 2 cm on the 10 cm visual analogue scale up to 4 h after operation and by about 1 cm at 12 and 24 h. Pain intensity on movement was decreased by 2 cm at 12 and 24 h. Opioid requirement was decreased intraoperatively, and up to 48 h after operation. Morphine-sparing at 24 h was significantly greater after abdominal surgery {weighted mean difference, -24.2 mg [95% confidence interval (CI) -29.5 to -19.0]}, compared with cardiac-thoracic surgery [-9.7 mg (95% CI -17.6 to -1.80)]. The incidence of respiratory depression was increased with intrathecal morphine [odds ratio (OR) 7.86 (95% CI 1.54-40.3)], as was the incidence of pruritus [OR 3.85 (95% CI 2.40-6.15)]. There was no evidence of linear dose-responsiveness for any of the beneficial or harmful outcomes. In conclusion, intrathecal morphine decreases pain intensity at rest and on movement up to 24 h after major surgery. Morphine-sparing is more pronounced after abdominal than after cardiac-thoracic surgery. Respiratory depression remains a major safety concern.

Bispectral and spectral entropy indices at propofol-induced loss of consciousness in young and elderly patients.

BACKGROUND: Bispectral (BIS) and state/response entropy (SE/RE) indices have been widely used to estimate depth of anaesthesia and sedation. In adults, independent of age, adequate and safe depth of anaesthesia for surgery is usually assumed when these indices are between 40 and 60. Since the EEG is changing with increasing age, we investigated the impact of advanced age on BIS, SE, and RE indices during induction. METHODS: BIS and SE/RE indices were recorded continuously in elderly (> or =65 yr) and young (< or =40 yr) surgical patients who received propofol until loss of consciousness (LOC) using stepwise increasing effect-site concentrations. LOC was defined as an observer assessment of alertness/sedation score <2, corresponding to the absence of response to mild prodding or shaking. RESULTS: We analysed 35 elderly [average age, 78 yr (range, 67-96)] and 34 young [35 (19-40)] patients. At LOC, all indices were significantly higher in elderly compared with young patients: BIS(LOC), median 70 (range, 58-91) vs 58 (40-70); SE(LOC), 71 (31-88) vs 55.5 (23-79); and RE(LOC), 79 (35-96) vs 59 (25-80) (P<0.001 for all comparisons). With all three monitors, only a minority of elderly patients lost consciousness within a 40-60 index range: two (5.7%) with BIS and RE each, and seven (20%) with SE. In young patients, the respective numbers were 20 (58.8%) for BIS, 13 (38.2%) for SE, and nine (26.5%) for RE. CONCLUSIONS: In adults undergoing propofol induction, BIS, SE, and RE indices at LOC are significantly affected by age.

Nefopam for the prevention of postoperative pain: quantitative systematic review.

Nefopam, a centrally acting analgesic, has been used in the surgical setting in many countries since the mid-1970s. However, clinical trials provide contflicting results for its analgesic potency. We performed a systematic search (multiple databases, bibliographies, any language, to January 2008) for randomized, placebo-controlled trials of nefopam for the prevention of postoperative pain. Data were combined using classic methods of meta-analyses and were expressed as weighted mean difference (WMD), relative risk (RR), and number needed to treat/harm (NNT/H) with 95% confidence interval (CI). Nine trials (847 adult patients, 359 received nefopam) were included. Nefopam (cumulative doses, 20-160 mg) was given orally or i.v., as single or multiple doses, or as a continuous infusion. Compared with placebo, cumulative 24 h morphine consumption was decreased with nefopam: WMD -13 mg (95% CI -17.9 to -8.15). Pain intensity at 24 h was also decreased: on a 100 mm visual analogue scale, WMD -11.5 mm (95% CI -15.1 to -7.85). The incidence of tachycardia was increased with nefopam (RR 3.12, 95% CI 1.11-8.79; NNH 7), as was the incidence of sweating (RR 4.92, 95% CI 2.0-12.1; NNH 13). There is limited evidence from the published literature that nefopam may be a useful non-opioid analgesic in surgical patients. The analgesic potency seems to be similar to non-steroidal anti-inflammatory drugs. However, dose responsiveness and adverse effect profile remain unclear, and the role of nefopam as part of multimodal analgesia needs to be established. Data in children are lacking.

Transcranial Doppler versus angiography in patients with vasospasm due to a ruptured cerebral aneurysm: A systematic review.

BACKGROUND AND PURPOSE: Transcranial Doppler (TCD) is used for diagnosis of vasospasm in patients with subarachnoid hemorrhage due to a ruptured aneurysm. Our aim was to evaluate both the accuracy of TCD compared with angiography and its usefulness as a screening method in this setting. METHODS: A search (MEDLINE, EMBASE, Cochrane Library, bibliographies, hand searching, any language, through January 31, 2001) was performed for studies comparing TCD with angiography. Data were critically appraised using a modified published 10-point score and were combined using a random-effects model. RESULTS: Twenty-six reports compared TCD with angiography. Median validity score was 4.5 (range 1 to 8). Meta-analyses could be performed with data from 7 trials. For the middle cerebral artery (5 trials, 317 tests), sensitivity was 67% (95% CI 48% to 87%), specificity was 99% (98% to 100%), positive predictive value (PPV) was 97% (95% to 98%), and negative predictive value (NPV) was 78% (65% to 91%). For the anterior cerebral artery (3 trials, 171 tests), sensitivity was 42% (11% to 72%), specificity was 76% (53% to 100%), PPV was 56% (27% to 84%), and NPV was 69% (43% to 95%). Three of these 7 studies reported on the same patients, each on another artery, and for 4, data recycling could not be disproved. Other arteries were tested in only 1 trial each. CONCLUSIONS: For the middle cerebral artery, TCD is not likely to indicate a spasm when angiography does not show one (high specificity), and TCD may be used to identify patients with a spasm (high PPV). For all other situations and arteries, there is either lack of evidence of accuracy or of any usefulness of TCD. Most of these data are of low methodological quality, bias cannot not be ruled out, and data reporting is often uncritical.

Efficacy of 5-HT3 receptor antagonists in radiotherapy-induced nausea and vomiting: a quantitative systematic review.

5-HT3 receptor antagonists are used to treat radiation-induced sickness. The purpose of this study was to define anti-emetic efficacy and potential for harm of these drugs in radiotherapy. A systematic search, critical appraisal and quantitative analysis of relevant data using the number-needed-to-treat or harm (NNT/H) were conducted. Acute (0 to 24h) and delayed (beyond 24 h) anti-emetic efficacy were analysed separately. Data from 1,404 patients were found in 40 trials published in 36 reports. Data from 197 patients receiving ondansetron or granisetron in five randomised trials were regarded as valid according to preset criteria. One placebo-controlled trial had 10 patients per group and in this ondansetron was not significantly different from placebo. In a larger (n = 105) placebo-controlled trial, ondansetron was significantly more efficacious than metoclopramide for complete control of acute vomiting (NNT 2.2, 95% confidence interval (CI) 1.7-3.3) and acute nausea (NNT 3.6, 95% CI 2.2-10.2). Three trials reported delayed outcomes with ondansetron or granisetron: there was no evidence of any difference compared with placebo or other anti-emetics. Two trials reported no acute or delayed but a 'worst day' outcome; in these ondansetron's antivomiting effect was significantly better than placebo (NNT 4.4, 95% CI 2.5-23) or prochlorperazine (NNT 3.8, 95% CI 2.4-10.3), but not its antinausea effect. Constipation and headache were associated significantly with 5-HT3 receptor antagonists compared with other anti-emetics or placebo (NNH 6.4 and 17.1, respectively). Only 14% of published data enabled valid estimation of the anti-emetic efficacy of 5-HT3 receptor antagonists in radiotherapy. There was some evidence that these drugs prevent acute vomiting: 40% of treated patients will benefit (NNT approximately 2.5). The evidence for nausea was less clear. There was no evidence that these drugs are of any benefit beyond 24 h. There was evidence that they produce specific adverse effects.

Pain relief from intra-articular morphine after knee surgery: a qualitative systematic review.

Reduction of postoperative pain by injecting opioid into the knee joint is believed to support the hypothesis of peripheral opioid receptor activation in inflammation. The study design consisted of a systematic review of randomised controlled trials (RCTs). Main outcomes were pain intensity and the use of supplementary analgesics. Efficacy of intra-articular bupivacaine against placebo was used as an index of internal sensitivity. Evidence of efficacy was sought in both early (0-6 h after intra-articular injection) and late (6-24 h) periods. Thirty-six RCTs in knee surgery were found. Six had both a local anaesthetic control and placebo; four showed internal sensitivity. All four sensitive studies had at least one outcome showing efficacy of intra-articular morphine against placebo. Six studies compared intra-articular morphine with intravenous or intramuscular morphine or with intra-articular saline without a bupivacaine control. Four of the six studies showed greater efficacy for intra-articular morphine. There was no dose-response evident. No quantitative analysis of pooled data was done. We conclude that intra-articular morphine may have some effect in reducing postoperative pain intensity and consumption of analgesics. These studies had significant problems in design, data collection, statistical analysis and reporting. Trials of better methodological quality are needed for a conclusive answer that intra-articular morphine is analgesic, and that any analgesia produced is clinically useful.

Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials.

Anaesthetists, using basic scientific concepts of peripheral opioid activity, try to improve regional anaesthesia and postoperative analgesia by injecting opioids, with or without local anaesthetic, close to nerve trunks or nerve endings. To test the evidence that peripherally applied opioids (all except intra-articular) have an analgesic effect outside the knee joint. Systematic search for published reports of randomised controlled trials in the period 1966-1996 (MEDLINE, EMBASE, Oxford Data Base, reference lists) which compared efficacy of peripheral opioids with placebo, local anaesthetic, or systemic opioids in acute pain. Reports of pethidine or intra-articular opioids were not included. Data on intraoperative efficacy (onset, quality, duration of sensory block), and postoperative efficacy (pain intensity, analgesic consumption) were extracted. Statistical significance as indicated in the original reports and clinical relevance of differences between opioids and controls were taken into account to estimate qualitatively overall efficacy. Twenty-six trials with data from 952 patients were analysed. Opioids used were morphine (16 trials), fentanyl (8), alfentanil (1), buprenorphine (1), and butorphanol (1). Of four experimental pain trials, two reported a statistically significant difference in favour of the opioid. In 22 clinical trials efficacy of opioid injections into the brachial plexus (10), Bier's block (4), perineural (3), or other sites (5) was tested. Five of 10 clinical trials measuring intraoperative efficacy reported statistically significant efficacy with opioids compared with control; none of them were judged to be clinically relevant. Five of 17 clinical trials measuring postoperative efficacy reported a significant difference in favour of the opioid; none was judged to be clinical relevant. Trials of lower quality were more likely to report increased efficacy with opioids. Adverse events related to the route of administration were not reported. These trials provide no evidence for a clinically relevant peripheral analgesic efficacy of opioids in acute pain.

Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use.

Randomised controlled trials (RCTs) alone are unlikely to provide reliable estimates of the incidence of rare events because of their limited size. Cohort, case control, and other observational studies have large numbers but are vulnerable to various kinds of bias. Wanting to estimate the risk of death from bleeding or perforated gastroduodenal ulcers with chronic usage of non-steroidal anti-inflammatory drugs (NSAIDs) with greater precision, we developed a model to quantify the frequency of rare adverse events which follow a biological progression. The model combined data from both RCTs and observational studies. We searched systematically for any report of chronic (>/=2 months) use of NSAIDs which gave information on gastroduodenal ulcer, bleed or perforation, death due to these complications, or progression from one level of harm to the next. Fifteen RCTs (19364 patients exposed to NSAIDs for 2-60 months), three cohort studies (215076 patients redeeming a NSAID prescription over a 3-12 month period), six case-control studies (2957 cases) and 20 case series (7406), and case reports (4447) were analysed. In RCTs the incidence of bleeding or perforation in 6822 patients exposed to NSAIDs was 0.69%; two deaths occurred. Of 11040 patients with bleeding or perforation with or without NSAID exposure across all reports, 6-16% (average 12%) died; the risk was lowest in RCTs and highest in case reports. Death from bleeding or perforation in all controls not exposed to NSAIDs occurred in 18 out of 849489 (0.002%). From these numbers we calculated the number-needed-to-treat for one patient to die due to gastroduodenal complications with chronic (>/=2 months) NSAIDs as 1/((0.69x¿6-16%, average 12%¿)-0.002%))=909-2500 (average 1220). On average 1 in 1200 patients taking NSAIDs for at least 2 months will die from gastroduodenal complications who would not have died had they not taken NSAIDs. This extrapolates to about 2000 deaths each year in the UK.

Cerebrospinal fluid passage of intravenous magnesium sulfate in neurosurgical patients.

Increasing evidence suggests a neuroprotective potential of magnesium sulfate (MgSO4). Only limited information about the passage of MgSO4 to the cerebrospinal fluid (CSF) is available in neurosurgical patients. However, with regard to the clinical relevance of magnesium's neuroprotective properties, quantitative data about its CSF passage are needed. The present study aims to assess the amount and the time course of magnesium's CSF passage in neurosurgical patients. To this end, 20 patients undergoing general anesthesia for neurosurgery and needing CSF drainage were included. Patients received an i.v. bolus of 60 mg/kg MgSO4. The increase in plasma and CSF magnesium concentration were measured 30, 90, and 240 min after the end of the MgSO4 infusion. These values were compared with the baseline levels taken before the start of the MgSO4 infusion. Thus, each patient served as his or her own control. Values are expressed as means +/- SD. The plasma magnesium levels were measured as follows: baseline, 0.74 +/- 0.12 mM; at 30 min, 1.24 +/- 0.1 mM (p < 0.01); at 90 min, 0.95 +/- 0.15 mM (p < 0.01), and at 240 min, 0.82 +/- 0.14 mM (p < 0.05). The CSF magnesium levels were measured as follows: baseline, 0.95 +/- 0.11 mM; at 30 min, 1.00 +/- 0.15 mM (NS); at 90 min, 1.10 +/- 0.17 mM (p < 0.01); and at 240 min, 1.13 +/- 0.19 mM (p < 0.001). We concluded that a bolus of 60 mg/kg of MgSO4 leads at least after 90 min to a significant increase in the CSF magnesium concentration. Moreover, the increase in plasma and CSF magnesium concentration is not parallel. Thus, plasma magnesium concentration cannot be used to predict the changes in CSF concentrations.

Propofol [correction of propfol] versus methohexital for electroconvulsive therapy: a meta-analysis.

A systematic search (Medline, Cochrane library, Embase, bibliographies, to 5.2000, no language restriction) was performed for published reports of randomized comparisons of propofol and methohexital for anesthesia during electroconvulsive therapy. We analyzed 15 trials with data on 706 patients. The duration of motor seizure was shorter with propofol (range, 18-39 seconds) than with methohexital (range, 26-48 seconds, weighted mean difference 8.4 seconds [95% CI, 6.6-10.0]). With both propofol and methohexital, there was little evidence of an association between dose and duration of motor seizure (for propofol: r2 = 0.25, P = .08; for methohexital: r2 = 0.11, P = .27). Two small trials investigated clinical outcome; results were inconclusive. Data on adverse effects were sparse. Duration of seizure was not proven to be a useful measure of treatment success in the study of electroconvulsive therapy with propofol or methohexital. The impact of the technique of anesthesia on the underlying disease needs to be established.

Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review.

OBJECTIVE: To quantify efficacy and harm of pharmacological prevention of acute mountain sickness. DATA SOURCES: Systematic search (Medline, Embase, Cochrane Library, internet, bibliographies, authors) in any language, up to October 1999. STUDY SELECTION: Randomised placebo controlled trials. DATA EXTRACTION: Dichotomous data on efficacy and harm from 33 trials (523 subjects received 13 different interventions, 519 a placebo). DATA SYNTHESIS: At above 4000 m the mean incidence of acute mountain sickness with placebo was 67% (range 25% to 100%); incidence depended on the rate of ascent, but not on the altitude or the mode of ascent. Across all ascent rates, dexamethasone 8-16 mg prevented acute mountain sickness (relative risk 2.50 (95% confidence interval 1.71 to 3.66); number needed to treat (NNT) 2.8 (2.0 to 4.6)), without evidence of dose responsiveness. Acetazolamide 750 mg was also efficacious (2.18 (1.52 to 3.15); NNT 2.9 (2.0 to 5.2)), but 500 mg was not. In two trials, adverse reaction (including depression) occurred after dexamethasone was stopped abruptly (4.45 (1.08 to 18); NNT 3.7 (2.5 to 6.9)). With acetazolamide, paraesthesia (4.02 (1.71 to 9.43); NNT 3.0 (2.0 to 6.0)) and polyuria (4.24 (1.92 to 9.37); NNT 3.6 (2.5 to 6.2)) were reported. Data were sparse on nifedipine, frusemide (furosemide), dihydroxyaluminium-sodium, spironolactone, phenytoin, codeine, phenformin, antidiuretic hormone, and ginkgo biloba. CONCLUSIONS: At above 4000 m, with a high ascent rate, fewer than three subjects need to be treated with prophylactic dexamethasone 8-16 mg or acetazolamide 750 mg for one subject not to experience acute mountain sickness who would have done so had they all received a placebo. Acetazolamide 500 mg does not work.

A quantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting.

OBJECTIVES: To test the evidence for a dose-response with ondansetron for treatment of postoperative nausea and vomiting and to establish whether differences in efficacy between doses are of clinical relevance. DESIGN: Quantitative systematic review of published randomised controlled trials. DATA SOURCES: Seven trials from 1991 to January 1996 retrieved from a systematic literature search (Medline, reference lists, hand searching of anaesthetic journals, manufacturer's database); no restriction on language. MAIN OUTCOME MEASURES: Estimation of efficacy (incidence of complete control of further nausea and vomiting) by using odds ratios and the "number needed to treat" method for early (within 6 hours of administration) and late (within 24 hours) periods. RESULTS: Four placebo controlled trials with 1043 patients studied intravenous ondansetron 1 mg, 4 mg, or 8 mg. All doses were more efficacious than placebo in preventing further episodes of nausea or vomiting. For combined data, the point estimates for the number needed to treat were between 3.1 (8 mg) and 3.8 (1 mg) for early efficacy and between 4.1 (8 mg) and 4.8 (1 mg) for late efficacy, without significant differences between doses. No difference was found between ondansetron and droperidol in two trials with 129 patients or between ondansetron and metoclopramide in one trial with 80 patients. CONCLUSIONS: Further nausea and vomiting could be prevented with ondansetron compared with placebo in 25% of patients who had nausea or vomiting (number needed to treat, about 4). There was no evidence of a clinically relevant dose-response between 1 mg and 8 mg or a difference between ondansetron and either droperidol or metoclopramide in a limited dataset. A false impression of ondansetron's efficacy may arise because a quarter of all relevant published reports are duplicates, and reporting of study results is uncritical.

Impact of covert duplicate publication on meta-analysis: a case study.

OBJECTIVE: To quantify the impact of duplicate data on estimates of efficacy. DESIGN: Systematic search for published full reports of randomised controlled trials investigating ondansetron's effect on postoperative emesis. Abstracts were not considered. DATA SOURCES: Eighty four trials (11,980 patients receiving ondansetron) published between 1991 and September 1996. MAIN OUTCOME MEASURES: Percentage of duplicated trials and patient data. Estimation of antiemetic efficacy (prevention of emesis) of the most duplicated ondansetron regimen. Comparison between the efficacy of non-duplicated and duplicated data. RESULTS: Data from nine trials had been published in 14 further reports, duplicating data from 3335 patients receiving ondansetron; none used a clear cross reference. Intravenous ondansetron 4 mg versus placebo was investigated in 16 reports not subject to duplicate publication, three reports subject to duplicate publication, and six duplicates of those three reports. The number needed to treat to prevent vomiting within 24 hours was 9.5 (95% confidence interval 6.9 to 15) in the 16 non-duplicated reports and 3.9 (3.3 to 4.8) in the three reports which were duplicated (P < 0.00001). When these 19 were combined the number needed to treat was 6.4 (5.3 to 7.9). When all original and duplicate reports were combined (n = 25) the apparent number needed to treat improved to 4.9 (4.4 to 5.6). CONCLUSIONS: By searching systematically we found 17% of published full reports of randomised trials and 28% of the patient data were duplicated. Trials reporting greater treatment effect were significantly more likely to be duplicated. Inclusion of duplicated data in meta-analysis led to a 23% overestimation of ondansetron's antiemetic efficacy.