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 lackin

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 µg). 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 concer

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 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 H2O−1; 95% CI, 8-20). Arterial pressure remained unchanged. In four trials (100 patients) comparing PCV with VCV, there was no difference in 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 VC

Treatment of established postoperative nausea and vomiting: a quantitative systematic review

BACKGROUND: The relative efficacy of antiemetics for the treatment of postoperative nausea and vomiting (PONV) is poorly understood. METHODS: Systematic search (MEDLINE, Embase, Cochrane Library, bibliographies, any language, to 8.2000) for randomised comparisons of antiemetics with any comparator for the treatment of established PONV. Dichotomous data on prevention of further nausea and vomiting, and on side effects were combined using a fixed effect model. RESULTS: In seven trials (1,267 patients), 11 different antiemetics were tested without placebos; these data were not further analysed. Eighteen trials (3,809) had placebo controls. Dolasetron 12.5–100 mg, granisetron 0.1–3 mg, tropisetron 0.5–5 mg, and ondansetron 1–8 mg prevented further vomiting with little evidence of dose-responsiveness; with all regimens, absolute risk reductions compared with placebo were 20%–30%. The anti-nausea effect was less pronounced. Headache was dose-dependent. Results on propofol were contradictory. The NK(1) antagonist GR205171, isopropyl alcohol vapor, metoclopramide, domperidone, and midazolam were tested in one trial each with a limited number of patients. CONCLUSIONS: Of 100 vomiting surgical patients receiving a 5-HT(3) receptor antagonist, 20 to 30 will stop vomiting who would not have done so had they received a placebo; less will profit from the anti-nausea effect. There is a lack of evidence for a clinically relevant dose-response; minimal effective doses may be used. There is a discrepancy between the plethora of trials on prevention of PONV and the paucity of trials on treatment of established symptoms. Valid data on the therapeutic efficacy of classic antiemetics, which have been used for decades, are needed

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 (≥65 yr) and young (≤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: BISLOC, median 70 (range, 58-91) vs 58 (40-70); SELOC, 71 (31-88) vs 55.5 (23-79); and RELOC, 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 ag

Rapid Sequence Induction With a Standard Intubation Dose of Rocuronium After Magnesium Pretreatment Compared With Succinylcholine: A Randomized Clinical Trial.

Succinylcholine remains the muscle relaxant of choice for rapid sequence induction (RSI) but has many adverse effects. High-dose rocuronium bromide may be an alternative to succinylcholine for RSI but recovery times are nearly doubled compared with a standard intubating dose of rocuronium. Magnesium sulfate significantly shortens the onset time of a standard intubating dose of rocuronium. We set out to investigate whether intravenous (IV) pretreatment with MgSO4 followed by a standard intubating dose of rocuronium achieved superior intubation conditions compared with succinylcholine. Adults were randomized to receive a 15-minute IV infusion of MgSO4 (60 mg·kg-1) immediately before RSI with propofol 2 mg·kg-1, sufentanil 0.2 μg·kg-1 and rocuronium 0.6 mg·kg-1, or a matching 15-minute IV infusion of saline immediately before an identical RSI, but with succinylcholine 1 mg·kg-1. Primary end point was the rate of excellent intubating conditions 60 seconds after administration of the neuromuscular blocking agent and compared between groups using multivariable log-binomial regression model. Secondary end points were blood pressure and heart rate before induction, before and after intubation, and adverse events up to 24 hours postoperatively. Among 280 randomized patients, intubating conditions could be analyzed in 259 (133 MgSO4-rocuronium and 126 saline-succinylcholine). The rate of excellent intubating conditions was 46% with MgSO4-rocuronium and 45% with saline-succinylcholine. The analysis adjusted for gender and center showed no superiority of MgSO4-rocuronium compared with saline-succinylcholine (relative risk [RR] 1.06, 95% confidence interval [CI], 0.81-1.39, P = .659). The rate of excellent intubating conditions was higher in women (54% [70 of 130]) compared with men (37% [48 of 129]; adjusted RR 1.42, 95% CI, 1.07-1.91, P = .017). No significant difference between groups was observed for systolic and diastolic blood pressures. Mean heart rate was significantly higher in the MgSO4-rocuronium group. The percentage of patients with at least 1 adverse event was lower with MgSO4-rocuronium (11%) compared with saline-succinylcholine (28%) (RR 0.38, 95% CI, 0.22-0.66, P &lt; .001). With saline-succinylcholine, adverse events consisted mainly of postoperative muscle pain (n = 26 [19%]) and signs of histamine release (n = 13 [9%]). With MgSO4-rocuronium, few patients had pain on injection, nausea and vomiting, or skin rash during the MgSO4-infusion (n = 5 [4%]). IV pretreatment with MgSO4 followed by a standard intubating dose of rocuronium did not provide superior intubation conditions to succinylcholine but had fewer adverse effects

Privacy Risks of Securing Machine Learning Models against Adversarial Examples

The arms race between attacks and defenses for machine learning models has come to a forefront in recent years, in both the security community and the privacy community. However, one big limitation of previous research is that the security domain and the privacy domain have typically been considered separately. It is thus unclear whether the defense methods in one domain will have any unexpected impact on the other domain. In this paper, we take a step towards resolving this limitation by combining the two domains. In particular, we measure the success of membership inference attacks against six state-of-the-art defense methods that mitigate the risk of adversarial examples (i.e., evasion attacks). Membership inference attacks determine whether or not an individual data record has been part of a model's training set. The accuracy of such attacks reflects the information leakage of training algorithms about individual members of the training set. Adversarial defense methods against adversarial examples influence the model's decision boundaries such that model predictions remain unchanged for a small area around each input. However, this objective is optimized on training data. Thus, individual data records in the training set have a significant influence on robust models. This makes the models more vulnerable to inference attacks. To perform the membership inference attacks, we leverage the existing inference methods that exploit model predictions. We also propose two new inference methods that exploit structural properties of robust models on adversarially perturbed data. Our experimental evaluation demonstrates that compared with the natural training (undefended) approach, adversarial defense methods can indeed increase the target model's risk against membership inference attacks.Comment: ACM CCS 2019, code is available at https://github.com/inspire-group/privacy-vs-robustnes

Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP)

BACKGROUND: Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen. METHODS/DESIGN: We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course. DISCUSSION: This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk. TRIAL REGISTRATION: EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT0105027

Using haloperidol as an anti-emetic in palliative care: informing practice through evidence from cancer treatment and post-operative contexts

YesNausea and vomiting are common symptoms in palliative care. Haloperidol is often used as an antiemetic in this context, although direct evidence supporting this practice is limited. To evaluate the efficacy and clinical use of haloperidol as an antiemetic in nonpalliative care contexts to inform practice, the authors conducted a rapid review of (i) published evidence to supplement existing systematic reviews, and (ii) practical aspects affecting the use of haloperidol including formulations and doses that are commonly available internationally. In nausea and vomiting related to cancer treatment, haloperidol was superior to control in two small studies. In postoperative nausea and vomiting (PONV), two randomized controlledtrials found treatment with haloperidol comparable to ondansetron. In palliative care, an observational study found a complete response rate of 24% with haloperidol (one in four patients) which would be consistent with a number needed to treat (NNT) of 3 to 5 derived from PONV. There remains insufficient direct evidence to definitively support the use of haloperidol for the management of nausea and vomiting in palliative care. However, generalizing evidence from other clinical contexts may have some validity