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Development targets in anaesthetic pharmacology have evolved from minimizing harm caused by unwanted effects through an era in which rapid onset and offset of drug effect were prioritised. Today's anaesthetists have access to a library of effective drugs whose characteristics offer controllable hypnosis, analgesia and paralysis with manageable off-target effects. The availability of these agents at generic prices inhibits commercial interest and this is reflected in the limited number of current anaesthetic drug development projects. Recently, questions around neonatal neurotoxicity, delirium and postoperative cognitive dysfunction have stimulated research to characterise these phenomena and explain them in mechanistic terms. Emergent basic science from these enquiries together with exploration of possible effects of anaesthetic drug choice on patient outcomes from cancer surgery may yield new targets for drug discovery. [ABSTRACT FROM AUTHOR]

The article focuses on study based on role of nitrous oxide in modern anaesthetic practice. Topics discussed include Nitrous oxide which is an N-methyl-aspartate receptor antagonist that may reduce the incidence of chronic post-surgical pain; Nitrous oxide that oxidizes Vitamin B12 which can be used in patients with folate/B12 deficiency; and Nitrous oxide that expands air spaces and is contraindicated in patients with pneumothorax.

Summary This review considers the current position of nitrous oxide in anaesthetic practice and balances potential beneficial and disadvantageous effects. The classic adverse characteristics of nitrous oxide, such as diffusion hypoxia, expansion of gas-filled spaces, and postoperative nausea and vomiting, are often cited as reasons to avoid this old drug. Recent concerns regarding neurotoxicity, adverse cardiovascular outcomes, and wound complications have further hardened many practitioners against nitrous oxide. New evidence and underpinning mechanistic data, however, suggest potential beneficial effects on the central nervous system, cardiovascular system, and acute and chronic pain. While we await the outcome of large studies including ENIGMA-II, many clinicians have already decided against this agent. The authors argue that this abandonment may be premature. Clinical Trial Registration None required. [ABSTRACT FROM PUBLISHER]

Summary. Although well established in clinical practice, both propofol and midazolam have limitations. New hypnotics with different and potentially superior pharmacokinetics and pharmacodynamics are under development. These include the benzodiazepine receptor agonists CNS7056 and JM-1232 (2), the etomidate-based methoxycarbonyl-etomidate and carboetomidate, the propofol-related structures PF0713 and fospropofol, and THRX- 918661/AZD3043. The basic pharmacology and the initial anaesthesia studies for each of these agents are reviewed. Several of the agents (CNS7056, THRX-918661/AZD3043, and fospropofol) have reached the stage of clinical trials. To be successful, novel compounds need to establish clear clinical advantages over existing agents and where possible the new agents are discussed in this context. Computer-controlled drug administration offers the ability to automatically implement infusion schemes too complex for manual use and the possibility of linking patient monitoring to administration to enhance patient safety. [ABSTRACT FROM AUTHOR]

Background: Adenosine is analgesic in humans, and the selective adenosine A1 receptor agonist GR79236X has significant anti-nociceptive activity in an animal pain model of inflammatory pain.Methods: Seventy-nine patients with moderate pain after third molar extraction under general anaesthesia were randomized to receive a 15 min double-blind infusion containing either GR79236X 4 microg kg-1, GR79236X 10 microg kg-1, diclofenac 50 mg, or saline placebo. Rescue analgesia was promptly available to all patients.Results: Meaningful pain relief (mild or no pain) was attained by 9 (47%) patients in the placebo group, 12 (63%) patients in the GR79236 4 microg kg-1 group, 10 (48%) patients in the 10 microg kg-1 group, and 16 (80%) patients in the diclofenac 50 mg group. Neither dose of GR79236 produced a significant improvement over placebo, but diclofenac was superior to both placebo (P=0.036) and GR79236 10 microg kg-1 (P=0.034). Median times to rescue or additional analgesia were 62, 100, 60, and 363 min for patients receiving placebo, GR79236 4 microg kg-1, 10 microg kg-1, and diclofenac 50 mg, respectively (diclofenac significantly longer than placebo, P=0.002 log-rank test). Pain control was poor in the placebo group and in both GR79236 groups, with between 79 and 86% of patients having good pain control (i.e. mild or no pain) for <20% of the time compared with only 30% of patients who received diclofenac.Conclusion: We found no evidence of efficacy of GR79236 compared with placebo, but the active control diclofenac was effective. It is possible that a higher dose of GR79236 might have been effective or that i.v. administration of this drug does not achieve appropriate concentrations in the brain or peripheral nerves. [ABSTRACT FROM AUTHOR]

The authors comment on an article describing tracheal intubation of children under sevoflurane/alfentanil anaesthesia without any neuromuscular blocking agent. They explore the usefulness of tracheal intubation without neuromuscular blocking agents. They challenge the motivation of clinicians using the technique. The authors also discuss the effect of allergy to neuromuscular blocking agents.

All patients undergoing elective major surgery at our Colorectal Specialist Unit undergo cardiopulmonary exercise (CPX) testing on a stationary bicycle. Anaerobic threshold (AT) is the point during exercise when anaerobic metabolism supplements aerobic with additional CO2 production. In a study of patients having major abdominal surgery, cardiac mortality was concentrated in those who had an AT of <11 ml O2 kg-1 min-1 on preoperative CPX.1 We stratified 73 consecutive patients presenting for elective major colorectal surgery into high risk (AT<11 ml O2 kg-1 min-1), n=24 or standard risk, n=49 groups. All were approached to participate in a double-blind randomized controlled trial of goal-directed vs standard fluid therapy. Ten patients (five high risk) declined; others were randomized 50:50. All accepted follow-up. For selected patients, a postoperative critical care bed was booked. Length of stay was 13.5 (4-71) vs 8 (3-45) median (range) days for high-risk and standard risk patients, respectively, P=0.002 Mann-Whitney test (Fig. 1). Average excess stay of high-risk patients was 5 days, 95% CI 2-7 days. Length of stay was substantially increased in elective major colorectal surgery patients with poor performance (AT<11 ml O2 kg-1 min-1) at preoperative CPX. The effect of fluid therapy may have an influence. Acknowledgement: This work was supported by a Departmental Project Grant, 2008, administered by the National Institute of Academic Anaesthesia on behalf of the AAGBI. [ABSTRACT FROM AUTHOR]

Background: Cumulative sum (CUSUM) analysis has been used for assessing competence of trainees learning new technical skills. One of its disadvantages is the required definition of acceptable and unacceptable success rates. We therefore monitored the development of competence amongst trainees new to obstetric epidural anaesthesia in a large public hospital.Methods: Obstetric epidural data were collected prospectively between January 1996 and December 2011. Success rates for inexperienced trainees were calculated retrospectively for (1) the whole database, (2) for each consecutive attempt and (3) each trainee's individual overall success rate. Acceptable and unacceptable success rates were defined and CUSUM graphs generated for each trainee. Competence was assessed for each trainee and the number of attempts to reach competence recorded.Results: Mean (sd) success rate for all inexperienced trainees was 76.8 (0.1%), range 63-90%. Consecutive attempt success rate produced a learning curve with a mean success rate commencing at 58% on attempt 1. After attempt 10 the attempt number had no effect on subsequent success rates. From these results, the acceptable and unacceptable success rates were set at 65 and 55% respectively. CUSUM graphs demonstrated 76 out of 81 trainees competent after a mean of 46 (22) attempts.Conclusions: CUSUM is useful for assessing trainee epidural competence. Trainees require approximately 50 attempts, as defined by CUSUM, to reach competence. [ABSTRACT FROM AUTHOR]

Background Intraoperative fluid therapy regimens using oesophageal Doppler monitoring (ODM) to optimize stroke volume (SV) (goal-directed fluid therapy, GDT) have been associated with a reduction in length of stay (LOS) and complication rates after major surgery. We hypothesized that intraoperative GDT would reduce the time to surgical readiness for discharge (RfD) of patients having major elective colorectal surgery but that this effect might be less marked in aerobically fit patients. Methods In this double-blinded controlled trial, 179 patients undergoing major open or laparoscopic colorectal surgery were characterized as aerobically ‘fit’ (n=123) or ‘unfit’ (n=56) on the basis of their performance during a cardiopulmonary exercise test. Within these fitness strata, patients were randomized to receive a standard fluid regimen with or without ODM-guided intraoperative GDT. Results GDT patients received an average of 1360 ml of additional intraoperative colloid. The mean cardiac index and SV at skin closure were significantly higher in the GDT group than in controls. Times to RfD and LOS were longer in GDT than control patients but did not reach statistical significance (median 6.8 vs 4.9 days, P=0.09, and median 8.8 vs 6.7 days, P=0.09, respectively). Fit GDT patients had an increased RfD (median 7.0 vs 4.7 days; P=0.01) and LOS (median 8.8 vs 6.0 days; P=0.01) compared with controls. Conclusions Intraoperative SV optimization conferred no additional benefit over standard fluid therapy. In an aerobically fit subgroup of patients, GDT was associated with detrimental effects on the primary outcome. [ABSTRACT FROM PUBLISHER]

Background: The benefits of stroke volume optimization during surgery are unclear, with recent data not replicating the positive effects of earlier studies.Methods: This was a randomized controlled trial of standard fluid therapy with or without supplementary blinded intraoperative stroke volume optimization in 220 patients having major elective rectal resection or cystectomy with ileal conduit. All patients were treated using a contemporary enhanced recovery pathway. Interventional fluid challenges used Gelofusine (B Braun, Germany), guided by stoke volume variability measured by LiDCOrapid (LiDCO, UK). Participants were stratified by aerobic fitness (characterized by preoperative cardiopulmonary exercise test), surgical specialty, and intended surgical approach (open or laparoscopic). The primary outcome was the prevalence of moderate or severe complications on day 5 after surgery, defined using the postoperative morbidity survey (POMS) criteria.Results: Patients received ∼13 ml kg(-1) h(-1) of i.v. fluids during surgery. The intervention group received an additional mean (sd) 956 (896) ml Gelofusine. There were no statistically significant differences between groups in any primary or secondary end point. A positive POMS on postoperative day 5 was noted in 54 of 111 control subjects (48.6%) and 55 of 109 participants in the intervention group [50.5%; adjusted odds ratio 0.90 (95% confidence interval 0.52-1.57), P=0.717]. Mean (sd) hospital length of stay was 9.6 (6.8) days in the control group and 11.8 (11.5) days in the intervention group (adjusted difference -2.1 (-4.6 to 0.3) days, P=0.091). There was no statistical interaction between stroke volume optimization and aerobic fitness in terms of rate of complications or length of stay.Conclusions: Algorithm-driven stroke volume optimization is of no benefit when superimposed on a liberal baseline fluid regimen in patients having elective major abdominal surgery, when stratified to minimize differences in fitness and surgical approach between groups.Clinical Trial Registration: ISRCTN21597243. [ABSTRACT FROM AUTHOR]

Background Surgical patients with poor functional capacity, determined by oxygen consumption at anaerobic threshold (AT) during cardiopulmonary exercise testing (CPET), experience longer hospital stays and worse short- and medium-term survival. However, previous studies excluded patients who were unable to perform a CPET or who failed to demonstrate an AT. We hypothesized that such patients are at risk of inferior outcomes after elective surgery. Methods All patients undergoing major colorectal surgery attempted CPET to assist in the planning of care. Patients were stratified by their test results into Fit (AT ≥ 11.0 ml O2 kg−1 min−1), Unfit (AT < 11.0 ml O2 kg−1 min−1), or Unable to CPET groups (failed to pedal or demonstrate an AT). For each group, we determined hospital stay and mortality. Results Between March 2009 and April 2010, 269 consecutive patients were screened, and proceeded to bowel resection. Median hospital stay was 8 days (IQR 5.1–13.4) and there were 44 deaths (16%) at 2 yr; 26 (9.7%) patients were categorized as Unable to CPET, 69 (25.7%) Unfit and 174 (64.7%) Fit. There were statistically significant differences between the three groups in hospital stay [median (IQR) 14.0 (10.5–23.8) vs 9.9 (5.5–15) vs 7.1 (4.9–10.8) days, P < 0.01] and mortality at 2 yr [11/26 (42%) vs 14/69 (20%) vs 19/174 (11%), respectively (P < 0.01)] although the differences between Unable and Unfit were not statistically different. Conclusions Patients' inability to perform CPET is associated with inferior outcomes after major colorectal surgery. Future studies evaluating CPET in risk assessment for major surgery should report outcomes for this subgroup. [ABSTRACT FROM PUBLISHER]