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Competing Interests: JRS acts as consultant and Advisory Board member for Paion and as consultant for Medtronic.

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., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.

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.

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., Trial Registry: UK NIHR CRN 7285, ISRCTN 14680495. http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=7285.

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 (-), 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.

Background: Morbidity and mortality are higher in patients with poor preoperative cardiorespiratory reserve. This study aimed to ascertain fitness and therefore risk in elective patients, comparing three measures: Duke Activity Status Index (DASI) questionnaire, incremental shuttle walk test (ISWT), and cycle cardiopulmonary exercise testing (CPET). We looked for correlation between the measures and for thresholds on the questionnaire or shuttle test which could identify fit patients and render CPET unnecessary., Methods: A prospective cohort trial of 50 patients having intra-abdominal surgery. Each performed DASI, ISWT, and CPET during a single visit to the hospital., Results: There was a significant correlation between measured oxygen consumption and both ISWT and DASI. Receiver operator curve showed both the shuttle walk test and the DASI are sensitive and specific predictors of VO(2)peak >15 ml O(2) kg(-1) min(-1) and anaerobic threshold (AT) >11 ml O(2) kg(-1) min(-1). Thirty-two patients would be considered lower risk, having achieved both VO(2)peak and AT cut-offs. Setting an ISWT threshold of 360 m identified 13 of the lower risk patients [positive predictive value (PPV) 1.0, negative predictive value (NPV) 0.49]. Setting a DASI threshold score of 46 identified nine lower risk patients (PPV 1.0, NPV 0.44)., Conclusions: We found a significant correlation between the tests. However, many patients with poor questionnaire scores or shuttle walks had satisfactory CPET results. Hence, the ability of either simple test to determine risk in a heterogeneous surgical population is poor. CPET provides an objective measurement of cardiopulmonary fitness; however, evidence for this information improving patient outcome is limited and requires further research.

Background: As a result of its very low water solubility, propofol is generally presented as a lipid-based formulation with well-characterized limitations., Methods: Propofol (99.7%) was added directly to an aqueous solution of poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide)copolymers (PVP-PLA) block copolymers and stirred in order to obtain a clear solution. This formulation was filtered sterile and then lyophilized to its solid form Propofol-PM (propofol polymeric micelle) which reconstitutes to a propofol 1%w/v (10 mg ml(-1)) clear aqueous solution of 30-60 nm propofol-containing micelles. Population pharmacokinetic data from whole blood and plasma were obtained by administering reconstituted Propofol-PM formulations and a 1% oil in water formulation, Diprivan to male Sprague-Dawley rats (n = 40) at a dose of 10 mg kg(-1). Preliminary recovery data were obtained from a further small study., Results: The pharmacokinetics were best described using a two-compartment mamillary population model, which incorporated sample matrix (blood or plasma) and propofol formulation (Diprivan) or Propofol-PM) as covariates. Sample matrix was applied to all structural model parameters as a dichotomous covariate. An influence of propofol formulation was observed for all parameters (excluding distributional clearance) but only when plasma was used for propofol quantification. In this preliminary pharmacodynamic study, there was no statistically significant difference in the timing of the recovery endpoints between the Propofol-PM formulation and Diprivan groups., Conclusions: Propofol-PM formulations produce anaesthesia in rats. Whole blood pharmacokinetics of Propofol-PM did not differ from those observed with Diprivan.

Background: Sedation of critically ill children requiring artificial ventilation remains a therapeutic challenge due to large individual variation in drug effects and a paucity of knowledge of pharmacokinetics in this population. This study aimed to determine the pharmacokinetics of remifentanil in children requiring ventilation after cardiac surgery., Methods: Twenty-six ventilated children aged 1 month to 9.25 yr (median 1.77 yr) who had undergone cardiac surgery were sedated with a fixed rate infusion of midazolam 50 microg kg(-1) h(-1) and a remifentanil infusion that was commenced at 0.8 microg kg(-1) min(-1) for a minimum of 60 min and subsequently decreased by 0.1 microg kg(-1) min(-1)every 20 min until the patient awoke. Arterial blood concentrations of remifentanil and midazolam were measured using high-performance liquid chromatography. Mixed-effects population models were fitted to the remifentanil concentration-time data., Results: Satisfactory sedation was achieved in all patients as assessed by Comfort score during the initial maintenance and reduction phase of the remifentanil infusion. One patient was withdrawn from the study due to hypotension. Remifentanil pharmacokinetics were best described using a two-compartment allometric model. For a typical child with a body weight of 10.5 kg, clearance was 68.3 ml kg(-1) min(-1), intercompartmental clearance was 80 ml kg(-1) min(-1), the central compartment volume was 91.7 ml kg(-1), and the peripheral compartment volume was 141 ml kg(-1)., Conclusions: A combination of remifentanil and midazolam provided satisfactory sedation for these patients. Owing to enhanced clearance rates, smaller (younger) children will require higher remifentanil infusion rates than larger (older) children and adults to achieve equivalent blood concentrations.

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.

Background: Propofol and sevoflurane are suitable agents for maintenance of anaesthesia during neurosurgical procedures. We have prospectively compared these agents in combination with the short-acting opioid, remifentanil., Methods: Fifty unpremedicated patients undergoing elective craniotomy received remifentanil 1 microg kg(-1) followed by an infusion commencing at 0.5 microg kg(-1) min(-1) reducing to 0.25 microg kg(-1) min(-1) after craniotomy. Anaesthesia was induced with propofol, and maintained with either a target-controlled infusion of propofol, minimum target 2 microg ml(-1) or sevoflurane, initial concentration 2%(ET). Episodes of mean arterial pressure (MAP) more than 100 mm Hg or less than 60 mm Hg for more than 1 min were defined as hypertensive or hypotensive events, respectively. A surgical assessment of operating conditions and times to spontaneous respiration, extubation, obey commands and eye opening were recorded. Drug acquisition costs were calculated., Results: Twenty-four and twenty-six patients were assigned to propofol (Group P) and sevoflurane anaesthesia (Group S), respectively. The number of hypertensive events was comparable, whilst more hypotensive events were observed in Group S than in Group P (P=0.053, chi-squared test). As rescue therapy, more labetolol [45 (33) vs 76 (58) mg, P=0.073] and ephedrine [4.80 (2.21) vs 9.78 (5.59) mg, P=0.020] were used in Group S. Between group differences in recovery times were small and clinically unimportant. The combined hourly acquisition costs of hypnotic, analgesic, and vasoactive drugs appeared to be lower in patients maintained with sevoflurane than with propofol., Conclusion: Propofol/remifentanil and sevoflurane/remifentanil both provided satisfactory anaesthesia for intracranial surgery.

Efforts to develop new hypnotic compounds continue, although several have recently failed in development. Propofol has been reformulated in various presentations with and without preservatives. Pharmacokinetic and pharmacodynamic differences exist between some of these preparations, and it is currently unclear whether any have substantial advantages over the original presentation. The use of target-controlled infusion (TCI) has been extended to include paediatric anaesthesia and sedation. Application of TCI to remifentanil is now licensed. Linking of electroencephalogram (EEG) monitoring to TCI for closed-loop anaesthesia remains a research tool, although commercial development may follow. The availability of stereoisomer ketamine and improved understanding of its pharmacology have increased non-anaesthetic use of ketamine as an adjunct analgesic. It may be useful in subhypnotic doses for postsurgical patients with pain refractory to morphine administration.

This prospective, randomized study compared postoperative pain scores, morphine consumption and length of stay in 95 adults who underwent elective lumbar spine surgery via a posterior incision. Immediately prior to closure the wound was irrigated with triamcinolone 40, 20 or 0 mg. Visual analogue scale pain scores at 24 h after surgery were median 12 (interquartile range 3-24), 15 (6-34) and 33 (20-59) mm for patients receiving triamcinolone 40, 20 mg or no steroid, respectively (P < 0.0005, Kruskal-Wallis test). Total morphine usage after 24 h was 26 (21-39), 27 (17-43) and 43 (27-73) mg for the same groups (P < 0.001, Kruskal-Wallis test). The proportion of patients discharged from hospital on the first day after surgery was 83.9, 77.4 and 54.8% for patients receiving triamcinolone 40, 20 mg and no steroid, respectively (P < 0.028, chi-squared test). Extra-dural triamcinolone reduces pain after lumbar spine surgery and reduces time to discharge from hospital.

We have compared pain scores, morphine consumption and duration of stay for 50 adults who underwent elective cervical spine surgery via a posterior incision in a prospective, double-blind, placebo-controlled, randomized study. During wound closure, the paravertebral muscles and subcutaneous tissues were infiltrated with 40 ml of saline (control) or 0.25% bupivacaine. There were no significant differences in pain scores, morphine consumption or duration of stay between groups. In view of the potential risks of wound infiltration in the cervical region, we consider that this practice should be abandoned.

It has been suggested that oxygen administration to healthy volunteers could improve their memory. We tested this hypothesis with a twin, double crossover, placebo-controlled study in 20 healthy non-smokers, allocated randomly to one of two groups. Blinded to the nature of the gas, group A breathed air first then oxygen on day 1, and then oxygen first, followed by air on day 2. Group B had all exposures in reverse order. After each gas exposure a written memory test with a list of 20 words was carried out and evaluated by a blinded observer. Recall after oxygen exposure (mean 8.3 words) was not significantly different from that after air exposure (mean 9 words).

We describe a system for monitoring and controlling i.v. anaesthesia in rats using burst suppression ratio (BSR) detection in the extradural EEG. After bolus injection, peak BSR values of 95% were achieved with propofol 8 mg kg-1, etomidate 3.5 mg kg-1 and alphaxalone 4.5 mg kg-1. Thiopental 32 mg kg-1 produced a peak BSR of 70% (larger doses were not tolerated). Recovery was fastest with propofol, followed by etomidate and alphaxalone with equal duration, and slowest with thiopental. In further experiments, a closed-loop infusion system maintained BSR accurately at targets of 30%, 50%, 70% or 90% for 60 min with propofol or etomidate. During these experiments the infusion rates were found to decrease with time, more so with etomidate (approximately 40%) than with propofol (approximately 20%). Recovery times were 2-3 times longer with etomidate than with propofol. This model demonstrated differences between i.v. anaesthetics and may be useful in screening new compounds in preclinical development.

We studied 52 adults undergoing elective craniotomy, allocated randomly to one of three opioid treatments: alfentanil 50 micrograms kg-1 followed by 0.833 microgram kg-1 min-1 until dural closure (group Alf.); alfentanil 50 micrograms kg-1 followed by 0.833 microgram kg-1 min-1 for 2 h, then remifentanil 0.25 microgram kg-1 min-1 (group Alf.-Remi.); or remifentanil 1 microgram kg-1 followed by 0.5 microgram kg-1 min-1 reducing to 0.25 microgram kg-1 min-1 after craniotomy (group Remi.). Anaesthesia was maintained with infusion of propofol and 66% nitrous oxide in oxygen. Infusions of propofol and remifentanil were stopped at head bandaging. Group Remi. had the least intraoperative haemodynamic responses and group Alf. the most (P < 0.05). Times to tracheal extubation and obey commands were similar in all groups. In all patients in group Alf.-Remi. and group Remi., the trachea was extubated 27 min from the end of anaesthesia; three patients in group Alf. were slower to recover. Use of analgesia in the recovery room and time to transfer to the neurosurgical unit were similar in the three groups.

The clinical course and diagnosis of a patient with Cushing's disease complicated by pregnancy is described, and the anaesthetic management of trans-sphenoidal selective adenomectomy performed during the second trimester outlined. Problems included obesity, diabetes, hypertension and a suboptimal airway. Fibreoptic awake intubation and intravenous anaesthesia were used. Insulin requirements decreased substantially after surgery. Early administration of hydrocortisone after surgery avoided the risk of an addisonian crisis but delayed biochemical confirmation of a metabolic cure.

There are few data in the literature that describe the use of remifentanil when administered as a component of an inhalation or total i.v. anaesthetic (TIVA) technique. We studied 251 male and female patients, aged 18-75 years, ASA I-II, undergoing inguinal hernia repair, arthroscopic knee surgery or varicose vein surgery of at least 30 min duration without premedication. Patients were randomized to receive a remifentanil loading dose of 1.0 microgram kg-1 followed by a continuous infusion of 0.5 microgram kg-1 min-1 in combination with isoflurane (end-tidal concentration 0.6%), (Group I, n = 115) or propofol (initial infusion rate 9 mg kg-1 h-1 reduced to 6 mg kg-1 h-1 after 10 min), (Group P, n = 118). The remifentanil infusion rate was reduced by 50%, 5 min after tracheal intubation. Intraoperative stresses were treated with a remifentanil bolus (1 microgram kg-1) followed by an increase in the remifentanil infusion rate. At the insertion of the last suture, the remifentanil infusion and concomitant anaesthetic were switched off simultaneously. Times to spontaneous respiration, adequate respiration and tracheal extubation were significantly shorter in group I compared with group P (6.4 min vs 7.6 min, P < 0.01; 7.6 min vs 9.3, P < 0.003; 7.8 min vs 9.5 min, P < 0.015). Overall mean systolic blood pressures during surgery were greater in group P compared with group I (P < 0.05) but the absolute differences were clinically insignificant (4-5 mm Hg).

Ten male volunteers received a 1-min i.v. infusion of a new water soluble steroid anaesthetic agent, ORG 21465. Individuals received doses ranging from 0.8 to 1.8 mg kg-1. All subjects experienced venous pain at the site of injection; those receiving 1.0 mg kg-1 or more became anaesthetized. There was no evidence of histamine release and apnoea did not occur. Excitatory phenomena were observed in all subjects and were dose related; no spikes were seen on the EEG. Pharmacokinetic analysis supported a three-compartment (non-weight-related) model with compartmental volumes V1, V2 and V3 of 4.31, 14.2 and 89.4 litre, respectively. Clearance from the central compartment V1 was 1.55 litre min-1. Inter-compartmental clearances Q1 and Q2 were 2.54 and 1.79 litre min-1. We found that ORG 21465 was an effective anaesthetic in humans. The relationship between sedation, anaesthesia and excitation requires further exploration.

ORG 21465 has been found to possess anaesthetic properties in humans and its pharmacokinetics are known. We performed this study to confirm the characteristics associated with its administration and to define its pharmacodynamic profile, in particular to explore the relationship between sedation, anaesthesia, excitation and plasma drug concentrations. A water soluble preparation of ORG 21465 was administered to six male volunteers as a series of three 15-min computer-controlled, pharmacokinetic model-driven infusions targeting three exponentially increasing plasma concentrations: 0.5, 1 and 2 micrograms ml-1. The clinical characteristics of the resultant sedation and anaesthesia were observed. Plasma concentrations of ORG 21465 were measured during and for 500 min after the infusions and the EEG recorded. A sigmoid e-max effect compartment pharmacodynamic model was fitted to the plasma concentrations and an EEG derivative (spectral edge frequency (SEF)). Anaesthesia with ORG 21465 was associated with involuntary movements in all subjects. A steady state concentration of 1180 ng ml-1 depressed SEF by 50%, the Hill factor describing the sigmoid nature of the concentration-response curve was 1.42 and the equilibration rate constant of the biophase was 0.112 min-1. Anaesthesia with ORG 21465 was found to be unsatisfactory because of involuntary movements and slow equilibration with the biophase.

Paracetamol and diclofenac have different mechanisms of action, and the combination may be more effective than each drug used alone in treating postoperative pain. In a double-blind, controlled design, we studied 60 patients undergoing elective abdominal gynaecological surgery, who received suppositories of paracetamol 1.5 g, diclofenac 100 mg or a combination of the two before the start of surgery. Patients received morphine in the intraoperative period, and cumulative morphine use from a patient-controlled analgesia system was recorded to measure the analgesic effect of the suppositories. Morphine consumption was greatest in the group that received paracetamol alone and lowest in the group given the combination (P < 0.01). There was no difference in the incidence of morphine-related side effects between the groups. We conclude that a diclofenac-paracetamol combination reduced the amount of morphine used compared with paracetamol alone.

Respiratory sinus arrhythmia (RSA) is a cyclical variation in heart rate during breathing, where the heart rate increases during inspiration and decreases during expiration. RSA and the electroencephalogram (EEG) were monitored in 10 patients undergoing elective surgery with isoflurane and nitrous oxide in oxygen anaesthesia after induction with propofol. All patients were subject to controlled ventilation and recovery from competitive neuromuscular block was facilitated by neostigmine and glycopyrronium (seven patients) or atropine (three patients). Median and spectral edge (95%) frequencies of the raw EEG were derived off-line. RSA and EEG indices were obtained during preinduction (baseline), induction, incision, 0.65 and 1.2 MAC of isoflurane maintenance during surgery and recovery. Significant decreases in the level of RSA, median and spectral edge frequencies were observed during induction and significant increases in all indices were observed at recovery in all patients. Significant decreases in the median and spectral edge EEG frequencies occurred in patients treated with atropine both to counteract bradycardia after propofol induction and at antagonism of neuromuscular block (n = 3), compared with patients treated with glycopyrronium (n = 7). In contrast, the level of RSA did not decrease significantly with atropine. It is concluded that measurements of RSA could form the basis of a useful index of anaesthetic depth during isoflurane anaesthesia, even during the use of pharmacologically appropriate doses of atropine. However, any effects of atropine on the raw EEG and on indices derived from the EEG, should be characterized further so that these effects are not confused with changes in anaesthetic depth.

Propofol (2,6-diisopropylphenol, I.C.I. 35,868) is a rapid-acting, intravenous anesthetic agent recently introduced for the induction and maintenance of general anesthesia. This paper describes a gas chromatographic-mass spectrometric procedure using selected-ion monitoring for the determination of plasma propofol levels. The drug and the internal standard (thymol) were extracted from plasma into diethyl ether-pentane, and derivatized to their trimethylsilyl derivatives before analysis. The reproducibility of the daily standard curves had coefficients of variation ranging from 2.7% to 10.2%. The precision of the assay yielded a coefficient of variation ranging from 4.5% to 5.6%, and the concentration means for the seeded control samples were found to be within -1.6% to +0.6% of the theoretical values for propofol. No interfering peaks have been observed in application of this procedure to either normal volunteer or patient samples. The minimum detectable level under the conditions described was 0.20 ng propofol/ml plasma. This assay and a high-performance liquid chromatographic assay with fluorescence detection were both used to measure plasma propofol concentrations in 89 human plasma samples, and the correlation between the two methods was excellent.

Intrathecal diamorphine (heroin, diacetyl morphine) 2.5 mg in isotonic saline 2.5 ml was given to 13 patients in labour through a 26 gauge Quincke needle. Three patients were given epidural bupivacaine at a mean of 295 min after injection of diamorphine and a further 2 used 50% nitrous oxide during the second stage of labour. Eight patients needed no additional analgesia for labour although 1 received a pudendal nerve block for forceps delivery. No neonatal complications attributable to diamorphine were observed. There was a high incidence of post partum headache (6/13 cases). The use of a Sprotte needle and a fine spinal catheter might overcome the limitations of spinal headache and limited duration of action respectively.

Auditory evoked response (AER) was recorded before, during and after physiotherapy in 11 paralysed (atracurium 0.56 (SD) 0.13 mg kg-1 h-1), sedated (propofol 2.2 (1.0) mg kg-1 h-1; fentanyl 4.4 (2.3) micrograms kg-1 h-1) and critically ill patients undergoing ventilation in the intensive care unit (ICU). The latency of the negative wave, NB, was reduced by physiotherapy (mean 44.8 (SD) 7.9 ms before, 41.0 (6.8) ms during (P less than 0.01, non-parametric Friedman test) and 45.6 (6.3) ms after physiotherapy); NB amplitude showed no consistent change (-0.81 (1.4) microV, -0.81 (1.5) microV and -0.71 (1.3) microV, respectively). NB latency responded to patient arousal at constant levels of sedation and this requires further evaluation as a means of monitoring sedation in paralysed patients in the ICU.

Atracurium was used to provide relaxation for intra-abdominal surgery in 15 patients. The regimen comprised an initial bolus (0.4 mg kg-1) followed by an infusion (0.3 mg kg-1 h-1) from 10 min after induction until closure of the peritoneum. Average duration of infusion was 80 min (range 48-166 min). This regimen provided satisfactory relaxation in 13 patients; two patients required one additional bolus of atracurium. Fourteen patients showed a sustained tetanic response to 50-Hz stimulation at the end of surgery and in these neuromuscular blockade was not antagonized. One patient required antagonism following very rapid closure of the abdomen.