Christopher Lysakowski

Does Multimodal Analgesia with Acetaminophen, Nonsteroidal Antiinflammatory Drugs, or Selective Cyclooxygenase-2 Inhibitors and Patient-controlled Analgesia Morphine Offer Advantages over Morphine Alone?Meta-analyses of Randomized Trials

The authors analyzed data from 52 randomized placebo-controlled trials (4,893 adults) testing acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors given in conjunction with morphine after surgery. The median of the average 24-h morphine consumption in controls was 49 mg (range, 15–117 mg); it was significantly decreased with all regimens by 15–55%. There was evidence of a reduction in pain intensity at 24 h (1 cm on the 0- to 10-cm visual analog scale) only with nonsteroidal antiinflammatory drugs. Nonsteroidal antiinflammatory drugs also significantly reduced the incidence of nausea/vomiting from 28.8% to 22.0% (number needed to treat, 15) and of sedation from 15.4% to 12.7% (number needed to treat, 37) but increased the risk of severe bleeding from 0% to 1.7% (number needed to harm, 59). Selective cyclooxygenase-2 inhibitors increased the risk of renal failure in cardiac patients from 0% to 1.4% (number needed to harm, 73). A decrease in morphine consumption is not a good indicator of the usefulness of a supplemental analgesic. There is evidence that the combination of nonsteroidal antiinflammatory drugs with patient-controlled analgesia morphine offers some advantages over morphine alone.

Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials

Background: Systemic &agr;2 agonists are believed to reduce pain and opioid requirements after surgery, thus decreasing the incidence of opioid-related adverse effects, including hyperalgesia. Methods: The authors searched for randomized placebo-controlled trials testing systemic &agr;2 agonists administrated in surgical patients and reporting on postoperative cumulative opioid consumption and/or pain intensity. Meta-analyses were performed when data from 5 or more trials and/or 100 or more patients could be combined. Results: Thirty studies (1,792 patients, 933 received clonidine or dexmedetomidine) were included. There was evidence of postoperative morphine-sparing at 24 h; the weighted mean difference was −4.1 mg (95% confidence interval, −6.0 to −2.2) with clonidine and −14.5 mg (−22.1 to −6.8) with dexmedetomidine. There was also evidence of a decrease in pain intensity at 24 h; the weighted mean difference was −0.7 cm (−1.2 to −0.1) on a 10-cm visual analog scale with clonidine and −0.6 cm (−0.9 to −0.2) with dexmedetomidine. The incidence of early nausea was decreased with both (number needed to treat, approximately nine). Clonidine increased the risk of intraoperative (number needed to harm, approximately nine) and postoperative hypotension (number needed to harm, 20). Dexmedetomidine increased the risk of postoperative bradycardia (number needed to harm, three). Recovery times were not prolonged. No trial reported on chronic pain or hyperalgesia. Conclusions: Perioperative systemic &agr;2 agonists decrease postoperative opioid consumption, pain intensity, and nausea. Recovery times are not prolonged. Common adverse effects are bradycardia and arterial hypotension. The impact of &agr;2 agonists on chronic pain or hyperalgesia remains unclear because valid data are lacking.

Dexamethasone and Risk of Nausea and Vomiting and Postoperative Bleeding After Tonsillectomy in Children: A Randomized Trial

CONTEXT Dexamethasone is widely used to prevent postoperative nausea and vomiting (PONV) in pediatric tonsillectomy. OBJECTIVE To assess whether dexamethasone dose-dependently reduces the risk of PONV at 24 hours after tonsillectomy. DESIGN, SETTING, AND PATIENTS Randomized placebo-controlled trial conducted among 215 children undergoing elective tonsillectomy at a major public teaching hospital in Switzerland from February 2005 to December 2007. INTERVENTIONS Children were randomly assigned to receive dexamethasone (0.05, 0.15, or 0.5 mg/kg) or placebo intravenously after induction of anesthesia. Acetaminophen-codeine and ibuprofen were given as postoperative analgesia. Follow-up continued until the 10th postoperative day. MAIN OUTCOME MEASURES The primary end point was prevention of PONV at 24 hours; secondary end points were decrease in the need for ibuprofen at 24 hours and evaluation of adverse effects. RESULTS At 24 hours, 24 of 54 participants who received placebo (44%; 95% confidence interval [CI], 31%-59%) had experienced PONV compared with 20 of 53 (38%; 95% CI, 25%-52%), 13 of 54 (24%; 95% CI, 13%-38%), and 6 of 52 (12%; 95% CI, 4%-23%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P<.001 for linear trend). Children who received dexamethasone received significantly less ibuprofen. There were 26 postoperative bleeding episodes in 22 children. Two of 53 (4%; 95% CI, 0.5%-13%) children who received placebo had bleeding compared with 6 of 53 (11%; 95% CI, 4%-23%), 2 of 51 (4%; 95% CI, 0.5%-13%), and 12 of 50 (24%; 95% CI, 13%-38%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P = .003). Dexamethasone, 0.5 mg/kg, was associated with the highest bleeding risk (adjusted relative risk, 6.80; 95% CI, 1.77-16.5). Eight children had to undergo emergency reoperation because of bleeding, all of whom had received dexamethasone. The trial was stopped early for safety reasons. CONCLUSION In this study of children undergoing tonsillectomy, dexamethasone decreased the risk of PONV dose dependently but was associated with an increased risk of postoperative bleeding. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00403806.

Magnesium as an Adjuvant to Postoperative Analgesia: A Systematic Review of Randomized Trials

BACKGROUND:Randomized trials have reached different conclusions as to whether magnesium is a useful adjuvant to postoperative analgesia. METHODS:We performed a comprehensive search (electronic databases, bibliographies, all languages, to 4.2006) for randomized comparisons of magnesium and placebo in the surgical setting. Information on postoperative pain intensity and analgesic requirements was extracted from the trials and compared qualitatively. Dichotomous data on adverse effects were combined using classic methods of meta-analysis. RESULTS:Fourteen randomized trials (778 patients, 404 received magnesium) tested magnesium laevulinate, gluconate or sulfate. With magnesium, postoperative pain intensity was significantly decreased in four (29%) trials, was no different from placebo in seven (50%), and was increased in one (7%); two trials (14%) did not report on pain intensity. With magnesium, postoperative analgesic requirements were significantly reduced in eight (57%) trials, were no different from placebo in five (36%), and were increased in one (7%). Magnesium-treated patients had less postoperative shivering (relative risk 0.38, 95% confidence interval 0.17–0.88, number-needed-to-treat 14). Seven trials reported on magnesium serum levels. In all, serum levels were increased in patients who received magnesium; in six, serum levels were decreased in those who received placebo. CONCLUSIONS:These trials do not provide convincing evidence that perioperative magnesium may have favorable effects on postoperative pain intensity and analgesic requirements. Perioperative magnesium supplementation prevents postoperative hypomagnesemia and decreases the incidence of postoperative shivering. It may be worthwhile to further study the role of magnesium as a supplement to postoperative analgesia, since this relatively harmless molecule is inexpensive, and the biological basis for its potential antinociceptive effect is promising.

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.

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.

Effect of intraoperative high inspired oxygen fraction on surgical site infection, postoperative nausea and vomiting, and pulmonary function: systematic review and meta-analysis of randomized controlled trials.

Background:Intraoperative high inspired oxygen fraction (FIO2) is thought to reduce the incidence of surgical site infection (SSI) and postoperative nausea and vomiting, and to promote postoperative atelectasis. Methods:The authors searched for randomized trials (till September 2012) comparing intraoperative high with normal FIO2 in adults undergoing surgery with general anesthesia and reporting on SSI, nausea or vomiting, or pulmonary outcomes. Results:The authors included 22 trials (7,001 patients) published in 26 reports. High FIO2 ranged from 80 to 100% (median, 80%); normal FIO2 ranged from 30 to 40% (median, 30%). In nine trials (5,103 patients, most received prophylactic antibiotics), the incidence of SSI decreased from 14.1% with normal FIO2 to 11.4% with high FIO2; risk ratio, 0.77 (95% CI, 0.59–1.00). After colorectal surgery, the incidence of SSI decreased from 19.3 to 15.2%; risk ratio, 0.78 (95% CI, 0.60–1.02). In 11 trials (2,293 patients), the incidence of nausea decreased from 24.8% with normal FIO2 to 19.5% with high FIO2; risk ratio, 0.79 (95% CI, 0.66–0.93). In patients receiving inhalational anesthetics without prophylactic antiemetics, high FIO2 provided a significant protective effect against both nausea and vomiting. Nine trials (3,698 patients) reported on pulmonary outcomes. The risk of atelectasis was not increased with high FIO2. Conclusions:Intraoperative high FIO2 further decreases the risk of SSI in surgical patients receiving prophylactic antibiotics, has a weak beneficial effect on nausea, and does not increase the risk of postoperative atelectasis.

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.

Prevention of Succinylcholine-induced Fasciculation and Myalgia A Meta-analysis of Randomized Trials

Fifty-two randomized trials (5,318 patients) were included in this meta-analysis. In controls, the incidence of fasciculation was 95%, and the incidence of myalgia at 24 h was 50%. Nondepolarizing muscle relaxants, lidocaine, or magnesium prevented fasciculation (number needed to treat, 1.2–2.5). Best prevention of myalgia was with nonsteroidal antiinflammatory drugs (number needed to treat, 2.5) and with rocuronium or lidocaine (number needed to treat, 3). There was a dose-dependent risk of blurred vision, diplopia, voice disorders, and difficulty in breathing and swallowing (number needed to harm, < 3.5) with muscle relaxants. There was evidence of less myalgia with 1.5 mg/kg succinylcholine (compared with 1 mg/kg). Opioids had no impact. Succinylcholine-induced fasciculation may best be prevented with muscle relaxants, lidocaine, or magnesium. Myalgia may best be prevented with muscle relaxants, lidocaine, or nonsteroidal antiinflammatory drugs. The risk of potentially serious adverse events with muscle relaxants is not negligible. Data that allow for a risk–benefit assessment are lacking for other drugs.

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.