Acyclic Boryl Complexes of Copper(I).

Reaction of (6-Dipp)CuOtBu (6-Dipp=C{NDippCH2 }2 CH2 , Dipp=2,6-iPr2 C6 H3 ) with B2 (OMe)4 provided access to (6-Dipp)CuB(OMe)2 via σ-bond metathesis. (6-Dipp)CuB(OMe)2 was characterised by NMR spectroscopy and X-ray crystallography and shown to be a monomeric acyclic boryl of copper. (6-Dipp)CuB(OMe)2 reacted with ethylene and diphenylacetylene to provide insertion compounds into the Cu-B bond which were characterised by NMR spectroscopy in both cases and X-ray crystallography in the latter. It was also competent in the rapid catalytic deoxygenation of CO2 in the presence of excess B2 (OMe)4 . Alongside π-insertion, (6-Dipp)CuB(OMe)2 reacted with LiNMe2 to provide a salt metathesis reaction at boron, giving (6-Dipp)CuB(OMe)NMe2 , a second monomeric acyclic boryl, which also cuproborated diphenylacetylene. Computational interrogation validated these acyclic boryl species to be electronically similar to (6-Dipp)CuBpin.

The effect of anterior quadratus lumborum block on morphine consumption in minimally invasive colorectal surgery: a multicentre, double-blind, prospective randomised placebo-controlled trial.

We investigated the efficacy and safety of a bilateral anterior quadratus lumborum block in patients undergoing minimally invasive colorectal surgery. This was a two-centre, double-blind, prospective, randomised, placebo-controlled trial including 150 patients undergoing laparoscopic colorectal surgery (left- or right hemicolectomy, sigmoidectomy) who were enrolled in the institutional abdominal enhanced recovery programme. Before induction of anaesthesia, patients received a bilateral anterior quadratus lumborum block in the left and right lateral decubitus position under ultrasound guidance and were allocated randomly to receive 30 ml of ropivacaine 0.375% (n = 75) or placebo (saline 0.9%) (n = 75) bilaterally. Postoperatively, all patients received multimodal intravenous analgesia including paracetamol, ketorolac and patient-controlled analgesia with morphine. The primary outcome was morphine consumption during the first 24 h after tracheal extubation. Secondary outcomes included severity of pain; presence and extent of sensory block; incidence of postoperative nausea and vomiting; and hospital duration of stay. We also investigated the need for, and dose of, rescue analgesia. Safety outcomes included the incidence of adverse events. Mean (SD) 24-hour morphine consumption was no different between patients allocated to ropivacaine and placebo (28.6 (22.3) mg vs. 28.4 (22.5) mg, p = 0.966, respectively). While a sensory block could be detected in significantly more patients allocated to the ropivacaine group, no differences were detected in pain scores or other secondary or safety endpoints. Patient satisfaction scores were high in both groups. In laparoscopic colorectal surgery, adding a bilateral anterior quadratus lumborum block to a standard multimodal analgesia regimen did not reduce opioid consumption or improve pain scores.

Anaesthetic efficacy and postinduction hypotension with remimazolam compared with propofol: a multicentre randomised controlled trial.

Remimazolam, a short-acting benzodiazepine, may be used for induction and maintenance of total intravenous anaesthesia, but its role in the management of patients with multiple comorbidities remains unclear. In this phase 3 randomised controlled trial, we compared the anaesthetic efficacy and the incidence of postinduction hypotension during total intravenous anaesthesia with remimazolam vs. propofol. A total of 365 patients (ASA physical status 3 or 4) scheduled for elective surgery were assigned randomly to receive total intravenous anaesthesia with remimazolam (n = 270) or propofol (n = 95). Primary outcome was anaesthetic effect, quantified as the percentage of time with Narcotrend® Index values ≤ 60, during surgery (skin incision to last skin suture), with a non-inferiority margin of -10%. Secondary outcome was the incidence of postinduction hypotensive events. Mean (SD) percentage of time with Narcotrend Index values ≤ 60 during surgery across all patients receiving remimazolam (93% (20.7)) was non-inferior to propofol (99% (4.2)), mean difference (97.5%CI) -6.28% (-8.89-infinite); p = 0.003. Mean (SD) number of postinduction hypotension events was 62 (38.1) and 71 (41.1) for patients allocated to the remimazolam and propofol groups, respectively; p = 0.015. Noradrenaline administration events (requirement for a bolus and/or infusion) were also lower in patients allocated to remimazolam compared with propofol (14 (13.5) vs. 20 (14.6), respectively; p < 0.001). In conclusion, in patients who were ASA physical status 3 or 4, the anaesthetic effect of remimazolam was non-inferior to propofol.

Neurodevelopmental outcomes after prenatal exposure to anaesthesia for maternal surgery: a propensity-score weighted bidirectional cohort study.

Up to 1% of pregnant women undergo anaesthesia for non-obstetric surgery. This study investigated neurodevelopmental outcomes after prenatal anaesthesia for maternal surgery. A bidirectional cohort study of children born between 2001 and 2018 was performed: neurodevelopmental outcomes of children who had received prenatal anaesthesia for maternal surgery were prospectively compared with unexposed children, with exposure status being assessed retrospectively. Children exposed to anaesthesia for obstetric and fetal surgery were excluded. The primary outcome was the global executive composite of the behaviour rating inventory of executive function score. Our secondary outcomes were: total problems; internalising problems and externalising problems derived from the child behaviour checklist; psychiatric diagnoses; and learning disorders. In 90% of exposed children, there was a single mean (SD) antenatal anaesthesia exposure lasting 91(94) min. There was a broad spectrum of indications, with abdominal surgery being most frequent. Parents of 129 exposed (response rate 68%) and 453 unexposed (response rate 63%) children participated. There were no arguments for non-response bias. After propensity weighting, there were no statistically significant differences in primary outcome, with a weighted mean difference (95%CI) of exposed minus unexposed children of 1.9 (-0.4-4.2), p = 0.10; or any of the secondary outcomes. Sensitivity analyses confirmed the robustness. Exploratory analyses, however, showed significant differences in certain subgroups for the primary outcome, (e.g. for intra-abdominal surgery, exposure duration > 1 h) and some cognitive subdomains (e.g. working memory and attention). This bidirectional cohort study, the largest investigation on the subject to date, has found no evidence in the general population for an association between prenatal exposure to anaesthesia and impaired neurodevelopmental outcomes.

High-volume patient-controlled epidural vs. programmed intermittent epidural bolus for labour analgesia: a randomised controlled study.

The aim of neuraxial analgesia is to achieve excellent pain relief with the fewest adverse effects. The most recently introduced technique for epidural analgesia maintenance is the programmed intermittent epidural bolus. In a recent study, we compared this with patient-controlled epidural analgesia without a background infusion and found that a programmed intermittent epidural bolus was associated with less breakthrough pain, lower pain scores, higher local anaesthetic consumption and comparable motor block. However, we had compared 10 ml programmed intermittent epidural boluses with 5 ml patient-controlled epidural analgesia boluses. To overcome this potential limitation, we designed a randomised, multicentre non-inferiority trial using 10 ml boluses in each group. The primary outcome was the incidence of breakthrough pain and total analgesic intake. Secondary outcomes included motor block; pain scores; patient satisfaction; and obstetric and neonatal outcomes. The trial was considered positive if two endpoints were met: non-inferiority of patient-controlled epidural analgesia with respect to breakthrough pain; and superiority of patient-controlled epidural analgesia with respect to local anaesthetic consumption. A total of 360 nulliparous women were allocated randomly to patient-controlled epidural analgesia-only or programmed intermittent epidural bolus groups. The patient-controlled group received 10 ml boluses of ropivacaine 0.12% with sufentanil 0.75 µg.ml-1 ; the programmed intermittent group received 10 ml boluses supplemented by 5 ml patient-controlled boluses. The lockout period was 30 min in each group and the maximum allowed hourly local anaesthetic/opioid consumption was identical between the groups. Breakthrough pain was similar between groups (11.2% patient controlled vs. 10.8% programmed intermittent, p = 0.003 for non-inferiority). Total ropivacaine consumption was lower in the PCEA-group (mean difference 15.3 mg, p < 0.001). Motor block, patient satisfaction scores and maternal and neonatal outcomes were similar across both groups. In conclusion, patient-controlled epidural analgesia is non-inferior to programmed intermittent epidural bolus if equal volumes of patient-controlled epidural analgesia are used to maintain labour analgesia and superior with respect to local anaesthetic consumption.

Comparison of predicted and real propofol and remifentanil concentrations in plasma and brain tissue during target-controlled infusion: a prospective observational study.

Target-controlled infusion systems are increasingly used to administer intravenous anaesthetic drugs to achieve a user-specified plasma or effect-site target concentration. While several studies have investigated the ability of the underlying pharmacokinetic-dynamic models to predict plasma concentrations, there are no data on their performance in predicting drug concentrations in the human brain. We assessed the predictive performance of the Marsh propofol model and Minto remifentanil model for plasma and brain tissue concentrations. Plasma samples were obtained during neurosurgery from 38 patients, and brain tissue samples from nine patients. Propofol and remifentanil concentrations were measured using gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry. Data were analysed from the nine patients in whom both plasma and brain samples were simultaneously obtained. For the Minto model (five patients), the median performance error was 72% for plasma and -14% for brain tissue concentration predictions. The model tended to underestimate plasma remifentanil concentrations, and to overestimate brain tissue remifentanil concentrations. For the Marsh model (five patients), the median prediction errors for plasma and brain tissue concentrations were 12% and 81%, respectively. However, when the data from all blood propofol assays (36 patients) were analysed, the median prediction error was 11%, with overprediction in 15 (42%) patients and underprediction in 21 (58%). These findings confirm earlier reports demonstrating inaccuracy for commonly used pharmacokinetic-dynamic models for plasma concentrations and extend these findings to the prediction of effect-site concentrations.

Programmed intermittent epidural bolus vs. patient-controlled epidural analgesia for maintenance of labour analgesia: a two-centre, double-blind, randomised study†.

The programmed intermittent epidural bolus technique has shown superiority to continuous epidural infusion techniques, with or without patient-controlled epidural analgesia for pain relief, reduced motor block and patient satisfaction. Many institutions still use patient-controlled epidural analgesia without a background infusion, and a comparative study between programmed intermittent epidural bolus and patient-controlled epidural analgesia without a background infusion has not yet been performed. We performed a randomised, two-centre, double-blind, controlled trial of these two techniques. The primary outcome was the incidence of breakthrough pain requiring a top-up dose by an anaesthetist. Secondary outcomes included: motor block; pain scores; patient satisfaction; local anaesthetic consumption; and obstetric and neonatal outcomes. We recruited 130 nulliparous women who received initial spinal analgesia, and then epidural analgesia was initiated and maintained with either programmed intermittent epidural bolus or patient-controlled epidural analgesia using ropivacaine 0.12% with sufentanil 0.75 µg·ml-1 . The programmed intermittent epidural bolus group had a programmed bolus of 10 ml every hour, with on-demand patient-controlled epidural analgesia boluses of 5 ml with a 20 min lockout, and the patient-controlled epidural analgesia group had a 5 ml bolus with a 12 min lockout interval; the potential maximum volume per hour was the same in both groups. The patients in the programmed intermittent epidural bolus group had less frequent breakthrough pain compared with the patient-controlled epidural analgesia group, 7 (10.9%) vs. 38 (62.3%; p < 0.0001), respectively. There was a significant difference in motor block (modified Bromage score ≤ 4) frequency between groups, programmed intermittent epidural bolus group 1 (1.6%) vs. patient-controlled epidural analgesia group 8 (13.1%); p = 0.015. The programmed intermittent epidural bolus group had greater local anaesthetic consumption with fewer patient-controlled epidural analgesia boluses. Patient satisfaction scores and obstetric or neonatal outcomes were not different between groups. In conclusion, we found that a programmed intermittent epidural bolus technique using 10 ml programmed boluses and 5 ml patient-controlled epidural analgesia boluses was superior to a patient-controlled epidural analgesia technique using 5 ml boluses and no background infusion.

Postconditioning effects of argon or xenon on early graft function in a porcine model of kidney autotransplantation.

BACKGROUND: Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Preconditioning, reconditioning and postconditioning with argon and xenon protects against renal ischaemia-reperfusion injury in rodent models. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function in a porcine renal autotransplant model was tested. METHODS: Pigs (n = 6 per group) underwent left nephrectomy after 60 min of warm ischaemia (renal artery and vein clamping). The procured kidney was autotransplanted in a separate procedure after 18 h of cold storage, immediately after a right nephrectomy. Upon reperfusion, pigs were randomized to inhalation of control gas (70 per cent nitrogen and 30 per cent oxygen), argon (70 per cent and 30 per cent oxygen) or xenon (70 per cent and 30 per cent oxygen) for 2 h. The primary outcome parameter was peak plasma creatinine; secondary outcome parameters included further markers of graft function (creatinine course, urine output), graft injury (aspartate aminotransferase, heart-type fatty acid-binding protein, histology), apoptosis and autophagy (western blot, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining), inflammatory mediators and markers of cell survival/growth (mRNA and tissue protein quantification), and animal survival. Results are presented as median (i.q.r.). ANOVA and Kruskal-Wallis tests were used where indicated. RESULTS: Peak plasma creatinine levels were similar between the groups: control 20·8 (16·4-23·1) mg/dl, argon 21·4 (17·1-24·9) mg/dl and xenon 19·4 (17·5-21·0) mg/dl (P = 0·607). Xenon was associated with an increase in autophagy and proapoptotic markers. Creatinine course, urine output, injury markers, histology, survival and inflammatory mediators were not affected by the intervention. CONCLUSION: Postconditioning with argon or xenon did not improve kidney graft function in this experimental model. Surgical relevance Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Based on mainly small animal experiments, noble gases (argon and xenon) have been proposed to minimize this ischaemia-reperfusion injury and improve outcomes after transplantation. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function was tested in a porcine kidney autotransplantation model. The peak plasma creatinine concentration was similar in the control, argon and xenon groups. No other secondary outcome parameters, including animal survival, were affected by the intervention. Xenon was associated with an increase in autophagy and proapoptotic markers. Despite promising results in small animal models, postconditioning with argon or xenon in a translational model of kidney autotransplantation was not beneficial. Clinical trials would require better results.

Simplified algorithm for the prevention of postoperative nausea and vomiting: a before-and-after study.

BACKGROUND: Poor adherence to guidelines aimed at reducing the incidence of postoperative nausea and vomiting (PONV) is well known. In a before-and-after study, we tested the effectiveness of a simplified algorithm for PONV prophylaxis on the incidence of PONV. METHODS: In the first audit, we examined the adherence to our institutional guidelines for PONV prevention. In response to the results of this audit, we introduced a simplified algorithm for PONV prevention [female patients receiving triple prophylaxis (dexamethasone and ondansetron plus either a target-controlled infusion with propofol or droperidol) and male patients receiving double prophylaxis, dexamethasone, and ondansetron]. The impact of the simplification of the PONV algorithm was evaluated in a second audit. In both audits, we reviewed the medical records of all adult patients undergoing elective non-cardiac non-day-case surgery under general anaesthesia and being admitted to our post-anaesthesia care unit during two arbitrarily chosen weeks. We assessed the incidence of nausea, vomiting, and PONV after 1 and 24 h, and the compliance with the departmental algorithm for PONV prophylaxis. RESULTS: After simplification of the PONV algorithm, the overall incidence of PONV within 24 h after surgery was significantly lower than before the implementation of the simplified PONV algorithm (22% vs 33%, P=0.02). The PONV incidence within 1 h was comparable between the audits (11% vs 14%, P=0.45). The adherence to departmental guidelines for PONV prophylaxis was significantly higher after the implementation of the simplified PONV algorithm (46% vs 18%, P=0.0001). CONCLUSIONS: A simplified algorithm for PONV prophylaxis resulted in a significant reduction in the PONV incidence and better compliance with the PONV algorithm.

The hip fracture surgery in elderly patients (HIPELD) study to evaluate xenon anaesthesia for the prevention of postoperative delirium: a multicentre, randomized clinical trial.

BACKGROUND: Postoperative delirium occurs frequently in elderly hip fracture surgery patients and is associated with poorer overall outcomes. Because xenon anaesthesia has neuroprotective properties, we evaluated its effect on the incidence of delirium and other outcomes after hip fracture surgery. METHODS: This was a phase II, multicentre, randomized, double-blind, parallel-group, controlled clinical trial conducted in hospitals in six European countries (September 2010 to October 2014). Elderly (≥75yr-old) and mentally functional hip fracture patients were randomly assigned 1:1 to receive either xenon- or sevoflurane-based general anaesthesia during surgery. The primary outcome was postoperative delirium diagnosed through postoperative day 4. Secondary outcomes were delirium diagnosed anytime after surgery, postoperative sequential organ failure assessment (SOFA) scores, and adverse events (AEs). RESULTS: Of 256 enrolled patients, 124 were treated with xenon and 132 with sevoflurane. The incidence of delirium with xenon (9.7% [95% CI: 4.5 -14.9]) or with sevoflurane (13.6% [95% CI: 7.8 -19.5]) were not significantly different (P=0.33). Overall SOFA scores were significantly lower with xenon (least-squares mean difference: -0.33 [95% CI: -0.60 to -0.06]; P=0.017). For xenon and sevoflurane, the incidence of serious AEs and fatal AEs was 8.0% vs 15.9% (P=0.05) and 0% vs 3.8% (P=0.06), respectively. CONCLUSIONS: Xenon anaesthesia did not significantly reduce the incidence of postoperative delirium after hip fracture surgery. Nevertheless, exploratory observations concerning postoperative SOFA-scores, serious AEs, and deaths warrant further study of the potential benefits of xenon anaesthesia in elderly hip fracture surgery patients. CLINICAL TRIAL REGISTRATION: EudraCT 2009-017153-35; ClinicalTrials.gov NCT01199276.

Systemic lidocaine fails to improve postoperative morphine consumption, postoperative recovery and quality of life in patients undergoing posterior spinal arthrodesis. A double-blind, randomized, placebo-controlled trial.

BACKGROUND.: It is inconclusive whether the perioperative administration of systemic lidocaine provides effective postoperative analgesia and enhances recovery in major orthopaedic surgery. We hypothesised that in adolescent and adult patients undergoing posterior spinal arthrodesis, a perioperative lidocaine infusion would reduce opioid requirements during the first 24 postoperative h. METHODS.: 70 patients undergoing posterior arthrodesis were enrolled in this prospective, randomised, double-blind, placebo-controlled clinical trial. Patients received total i.v. anaesthesia with propofol and remifentanil and were randomized to an adjuvant therapy with either lidocaine [i.v.-bolus injection of 1.5 mg kg -1 at induction of anaesthesia, followed by an infusion of 1.5 mg kg -1 h -1 which was continued until six h after arrival at the post-anaesthesia care unit] or placebo (equal volumes of saline). Postoperative pain was treated with patient-controlled i.v. morphine. Primary endpoints of this study were morphine requirements in the first postoperative 24 h. RESULTS.: Systemic lidocaine did not decrease morphine requirements in the first 24 postoperative h [lidocaine-group: 48 (23) mg (mean( sd )) vs placebo-group: 51(19) mg, P = 0.22]. Likewise, groups were not different with respect to the severity of postoperative pain, morphine consumption after 48 and 72 h, incidence of postoperative nausea and vomiting, perioperative inflammation, time to recovery of intestinal function, hospital length of stay, and quality of life (assessed preoperatively and one month postoperatively using the SF-12 physical and mental composite scores). CONCLUSIONS.: In our study, systemic lidocaine had no analgesic benefits in posterior arthrodesis when added to an opioid-based anaesthetic regimen. CLINICAL TRIAL REGISTRATION.: Eudra CT 2012-005264-98.

Intraoperative administered tramadol reduces the need for piritramide in the immediate postoperative period in children undergoing adenotonsillectomy: A retrospective observational study.

PURPOSE: Adenotonsillectomy is a frequently performed procedure in pediatric day-case surgery causing significant pain for which adequate analgesia is required. Our aim was to investigate if the intraoperative administration of IV tramadol decreases the need for postoperative pain medication in children. Because tramadol has well-known pro-emetic effects, we also assessed the incidence of postoperative nausea and vomiting (PONV). METHODS: We performed a retrospective observational study in 314 children aged 1-13 years undergoing elective adenotonsillectomy. We identified 160 children who had received standard pain medication consisting of IV paracetamol and ketorolac and compared them with a group of 154 children who had received in addition a perioperative infusion of tramadol. RESULTS: 32.5% of the patients in the tramadol group versus 83.8% of the patients in the standard group required postoperative administration of piritramide (p < 0.0001). Groups did not differ with respect to the postoperative need for anti-emetics but in the tramadol group more patients had received prophylactic therapy with odansetron or dexamethasone (P < 0.0001). CONCLUSION: The results of this retrospective study indicate that intraoperative tramadol administration in combination with prophylactic antiemetic therapy decreases the need for piritramide in the immediate postoperative period without increasing the incidence of PONV after tonsillectomy in children.

Xenon anaesthesia for patients undergoing off-pump coronary artery bypass graft surgery: a prospective randomized controlled pilot trial.

BACKGROUND: Off-pump coronary artery bypass (OPCAB) surgery carries a high risk for haemodynamic instability and perioperative organ injury. Favourable haemodynamic effects and organ-protective properties could render xenon an attractive anaesthetic for OPCAB surgery. The primary aim of this study was to assess whether xenon anaesthesia for OPCAB surgery is non-inferior to sevoflurane anaesthesia with regard to intraoperative vasopressor requirements. METHODS: Forty-two patients undergoing elective OPCAB surgery were enrolled in this prospective, single-blind, randomized controlled pilot trial. Patients were randomized to either xenon (50-60 vol%) or sevoflurane (1.1-1.4 vol%) anaesthesia. Primary outcome was intraoperative noradrenaline requirements necessary to achieve predefined haemodynamic goals. Secondary outcomes included safety variables such as the occurrence of adverse events (intraoperatively and during a 6-month follow-up after surgery) and the perioperative cardiorespiratory and inflammatory profile. RESULTS: Baseline and intraoperative data did not differ between groups. Xenon was non-inferior to sevoflurane, as xenon patients required significantly less noradrenaline intraoperatively to achieve the predefined haemodynamic goals {geometric mean 428 [95% confidence interval (CI) 312, 588] vs 1702 [1267, 2285] µg, P<0.0001}. No differences were found for safety. Significantly more sevoflurane patients developed postoperative delirium (POD) (hazard ratio 4.2, P=0.044). The average arterial pressure was lower in the sevoflurane group {median75 [interquartile range (IQR) 6] vs 72 [4] mmHg, P=0.002}. No differences were found for other haemodynamic parameters, the respiratory profile and the perioperative release of inflammatory cytokines, troponin T, serum protein S-100ß and erythropoietin. CONCLUSIONS: Compared with sevoflurane, xenon anaesthesia allows a significant reduction in vasopressor administration in OPCAB surgery. Moreover, xenon anaesthesia was associated with a lower risk for POD, a finding that has to be confirmed in larger studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01757106) and EudraCT (2012-002316-12).