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Lactate is an important energy intermediate and metabolic buffer, and may be ergogenic. We investigated if lactate supplementation is an effective approach to enhance the exercise performance and acid-base balance of trained cyclists during exercise devised to simulate the demands of endurance road race cycling. Sixteen endurance-trained male cyclists (V·O 2max 59 ± 7 mL·kg -1 ·min -1 ) consumed 120 mg·kg -1 body mass of lactate or a placebo 70 min prior to performing an exercise performance test, comprising five repeated blocks consisting of 1 km and 4 km time trials interspersed with 10 min of moderate-intensity exercise. Blood acid-base balance (including [H + ] and [HCO 3 - ]), heart rate, perceived exertion, and gastro-intestinal tolerance were assessed. There was no effect of lactate supplementation on exercise performance ( p = 0.320), despite a reduction in RPE ( p = 0.012) and increases in [SID] ( p = 0.026) and [HCO 3 - ] ( p = 0.041). In addition, gastro-intestinal side effects were observed, but there was no effect on heart rate. Lactate supplementation did not improve exercise performance, despite positive changes in acid-base balance and RPE. This suggests that the alkalising effects of the supplement can reduce perceived effort, but these benefits do not translate into performance improvements.

Introduction: Historically, university students demonstrate poor movement behaviours that could negatively impact current and future health. Recent literature has focused on identifying determinants of physical activity (PA) and sedentary behaviour (SB) in this population to inform the development of intervention strategies. However, the COVID-19 pandemic substantially restricted movement behaviours in this population, meaning findings of previous research may no longer be applicable within the current societal context. The present study explored the longitudinal relationships between pre-pandemic psychological, behavioural and anthropometric factors, and the movement behaviours of UK university students nine months following the outbreak of COVID-19., Methods: Mental wellbeing (MWB), perceived stress (PS), body mass index (BMI), SB, and PA were assessed using an online self-report survey in 255 students prior to (October 2019) and nine months following (October 2020) the first confirmed case of COVID-19 in the UK. Path analysis was utilised to test relationships between pre-COVID mental wellbeing, perceived stress and BMI, and movement behaviours during the pandemic., Results: The fit of the path analysis model was good (χ2 = 0.01; CMIN = 0.10, CFI = 1.00, RMSEA = 0.00). Pre-covid MWB and PS positively influenced PA (β = 0.29; β = 0.24; P < 0.01) but not SB (β = -0.10; β = 0.00; P = 0.79) during the pandemic. Additionally, pre-pandemic SB and PA positively influenced SB and PA during the pandemic respectively (SB: β = 0.26; P < 0.01) (PA: β = 0.55; P < 0.01). Pre-pandemic BMI did not influence any measured variable during the pandemic (PA: β = 0.03 and P = 0.29; SB: β = 0.06 and P = 0.56), and there was no mediating effect of PA on SB during the pandemic (β = -0.26; P = 0.14)., Conclusion: These findings indicate that pre-covid mental health and movement behaviours had a direct positive influence on PA during the pandemic, but not SB. This longitudinal study demonstrates the influence that prior psychological and behavioural factors have in determining university students' response to periods of elevated stress and uncertainty, furthering our understanding of determinants of health-related behaviours in students., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Savage et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Football match-play causes muscle damage and provokes an inflammatory response. Rapid recovery is paramount to optimising subsequent performance and reducing injury risk. Turmeric contains high concentrations of curcumin, a polyphenol that has been shown to reduce muscle damage and soreness post-exercise in recreational exercisers. However, it is unknown whether a curcumin-containing supplement can support elite footballers recovery between matches. This applied study explored whether a turmeric supplement could improve performance, subjective and physiological markers of recovery, in elite male footballers. Twenty-four elite male footballers divided into a turmeric group, who consumed 60 mL of a turmeric drink twice per day, or a control group who did not. After 96 h of rest, baseline measurements of subjective soreness (leg and whole-body), plasma creatine kinase ([CK]), plasma C-reactive protein ([CRP]), isometric mid-thigh pull (IMTP) and counter movement jump (CMJ), were collected. Following eight competitive matches, subjective leg and whole-body soreness and plasma concentrations of inflammation markers ([CK] and [CRP]) were assessed immediately (0 h), 40 and 64 h post-match. Performance markers (IMTP and CMJ) were also assessed at 40 and 64 h post-match. Percentage change from baseline showed a main effect of group ( p  = 0.035, p  = 0.005) and time ( p  = 0.002, p = 0.002) for both leg and whole-body soreness, respectively. There was a group by time interaction effect ( p  = 0.049) for [CRP]. There were no effects of turmeric on [CK], CMJ or IMTP. This applied study is the first in elite footballers to show that a curcumin-containing supplementation may attenuate a biomarker of inflammation [CRP] and soreness post-match play., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Clayton, Burbeary, Hennis, James, Saward, Colledge, Scott, Gilpin, McMahon and Varley.)

Introduction: Nitrate supplementation in the form of beetroot juice (BRJ) ingestion has been shown to improve exercise tolerance during acute hypoxia, but its effect on exercise physiology remains unstudied during sustained terrestrial high altitude exposure. We hypothesized that performing exercise at high altitude would lower circulating nitrate and nitrite levels and that BRJ ingestion would reverse this phenomenon while concomitantly improving key determinants of aerobic exercise performance., Methods: Twenty seven healthy volunteers (21 male) underwent a series of exercise tests at sea level (SL, London, 75 m) and again after 5-8 days at high altitude (HA, Capanna Regina Margherita or "Margherita Hut," 4,559 m). Using a double-blind protocol, participants were randomized to consume a beetroot/fruit juice beverage (three doses per day) with high levels of nitrate (∼0.18 mmol/kg/day) or a nitrate-depleted placebo (∼11.5 μmoles/kg/day) control drink, from 3 days prior to the exercise trials until completion. Submaximal constant work rate cycle tests were performed to determine exercise efficiency and a maximal incremental ramp exercise test was undertaken to measure aerobic capacity, using breath-by-breath pulmonary gas exchange measurements throughout. Concentrations of nitrate, nitrite and nitrosation products were quantified in plasma samples collected at 5 timepoints during the constant work rate tests. Linear mixed modeling was used to analyze data., Results: At both SL and HA, plasma nitrate concentrations were elevated in the nitrate supplementation group compared to placebo ( P < 0.001) but did not change throughout increasing exercise work rate. Delta exercise efficiency was not altered by altitude exposure ( P = 0.072) or nitrate supplementation ( P = 0.836). V̇O 2 peak decreased by 24% at high altitude ( P < 0.001) and was lower in the nitrate-supplemented group at both sea level and high altitude compared to placebo ( P = 0.041). Dietary nitrate supplementation did not alter other peak exercise variables or oxygen consumption at anaerobic threshold. Circulating nitrite and S-nitrosothiol levels unexpectedly rose in a few individuals right after cessation of exercise at high altitude., Conclusion: Whilst regularly consumed during an 8 days expedition to terrestrial high altitude, nitrate supplementation did not alter exercise efficiency and other exercise physiological variables, except decreasing V̇O 2 peak. These results and those of others question the practical utility of BRJ consumption during prolonged altitude exposure., Competing Interests: MG serves on the medical advisory board of Sphere Medical Ltd. and is a director of Oxygen Control Systems Ltd., received honoraria for speaking for and/or travel expenses from BOC Medical (Linde Group), Edwards Lifesciences, and Cortex GmBH, leads the Xtreme-Everest Oxygen Research Consortium and the Fit-4-Surgery research collaboration, and serves as the UK NIHR CRN national specialty group lead for Anaesthesia, Perioperative Medicine and Pain and is an elected council member of the Royal College of Anaesthetists. DM has received lecture and consultancy fees from Siemens Healthineers and Edwards Lifesciences. MM is a paid Consultant for Edwards Lifesciences, his University Chair was sponsored by Smiths Medical, founding Editor of the Journal of Perioperative Medicine and sits on the Editorial Board of the British Journal of Anaesthesia, and Editor-in-Chief of TopMedTalk. HP was employed by the company AURAPA Würzungen GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hennis, Cumpstey, O’Doherty, Fernandez, Gilbert-Kawai, Mitchell, Moyses, Cobb, Meale, Pöhnl, Mythen, Grocott, Levett, Martin, Feelisch and The Xtreme Alps Research Group.)

Background: Individuals with glycogen storage disease IIIa (GSD IIIa) (OMIM #232400) experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capacity, such as strength and cardiovascular fitness, are limited. Furthermore, the impact of the disease on muscle size and quality is unstudied in weight bearing skeletal muscle, a key predictor of physical function. We aim to produce normative reference values of aerobic capacity and strength in individuals with GSD IIIa, and to investigate the role of muscle size and quality on exercise impairment., Results: Peak oxygen uptake (V̇O 2 peak) was lower in the individuals with GSD IIIa than predicted based on demographic data (17.0 (9.0) ml/kg/min, 53 (24)% of predicted, p = 0.001). Knee extension maximum voluntary contraction (MVC) was also substantially lower than age matched predicted values (MVC: 146 (116) Nm, 57% predicted, p = 0.045), though no difference was found in MVC relative to body mass (1.88 (2.74) Nm/kg, 61% of predicted, p = 0.263). There was a strong association between aerobic capacity and maximal leg strength (r = 0.920; p = 0.003). Substantial inter-individual variation was present, with a high physical capacity group that had normal leg strength (MVC), and relatively high V̇O 2 peak, and a low physical capacity that display impaired strength and substantially lower V̇O 2 peak. The higher physical capacity sub-group were younger, had larger Vastus Lateralis (VL) muscles, greater muscle quality, undertook more physical activity (PA), and reported higher health-related quality of life., Conclusions: V̇O 2 peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data. Patients with higher physical capacity have superior muscle size and structure characteristics and higher health-related quality of life, than those with lower physical capacity. This study provides normative values of these important markers of physical capacity., (© 2022. The Author(s).)

Acute mountain sickness (AMS) occurs when there is failure of acclimatisation to high altitude. The aim of this study was to describe the relationship between physiological variables and the incidence of AMS during ascent to 5300 m. A total of 332 lowland-dwelling volunteers followed an identical ascent profile on staggered treks. Self-reported symptoms of AMS were recorded daily using the Lake Louise score (mild 3-4; moderate-severe ≥5), alongside measurements of physiological variables (heart rate, respiratory rate (RR), peripheral oxygen saturation (SpO 2 ) and blood pressure) before and after a standardised Xtreme Everest Step-Test (XEST). The overall occurrence of AMS among participants was 73.5% (23.2% mild, 50.3% moderate-severe). There was no difference in gender, age, previous AMS, weight or body mass index between participants who developed AMS and those who did not. Participants who had not previously ascended >5000 m were more likely to get moderate-to-severe AMS. Participants who suffered moderate-to-severe AMS had a lower resting SpO 2 at 3500 m (88.5 vs. 89.6%, p = 0.02), while participants who suffered mild or moderate-to-severe AMS had a lower end-exercise SpO 2 at 3500 m (82.2 vs. 83.8%, p = 0.027; 81.5 vs. 83.8%, p < 0.001 respectively). Participants who experienced mild AMS had lower end-exercise RR at 3500 m (19.2 vs. 21.3, p = 0.017). In a multi-variable regression model, only lower end-exercise SpO 2 (OR 0.870, p < 0.001) and no previous exposure to altitude >5000 m (OR 2.740, p-value 0.003) predicted the development of moderate-to-severe AMS. The Xtreme Everest Step-Test offers a simple, reproducible field test to help predict AMS, albeit with relatively limited predictive precision., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The purpose of the study was to investigate the current use of genetic testing in UK elite sport and assess how genetic testing might be received by those employed in elite sport. Seventy-two elite athletes and 95 support staff at UK sports clubs and governing bodies completed an online survey of 11 questions concerning their experience of genetic testing and beliefs regarding the use of genetic testing in sport. Genetic testing related to sports performance and injury susceptibility is conducted in UK elite sport, albeit by a relatively small proportion of athletes (≤17%) and support staff (≤8%). Athletes and their support staff agree that genetics are important in determining elite status (≥79%) and appear willing to engage in genetic testing for individualising training to improve sport performance and reduce injury risk. Opinion was divided on whether genetic information should be used to identify talented athletes and influence selection, eligibility or employment status. Genetic testing for sports performance and injury susceptibility occurs in UK elite sport, however it is not commonly conducted. There is a belief that genetics is an important factor in determining an athlete and there is a willingness to engage in genetic testing for sports performance and injury susceptibility.

The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A ( PPARA ) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature., Competing Interests: Conflict of interest statement: E.G. is Chief Executive Officer and V.L. is Chief Operating Officer of Oroboros Instruments.

Background: Preoperative anaemia and low exertional oxygen uptake are both associated with greater postoperative morbidity and mortality. This study reports the association among haemoglobin concentration ([Hb]), peak oxygen uptake (V˙O2 peak) and anaerobic threshold (AT) in elective surgical patients., Methods: Between 1999 and 2011, preoperative [Hb] and cardiopulmonary exercise tests were recorded in 1,777 preoperative patients in four hospitals. The associations between [Hb], V˙O2 peak and AT were analysed by linear regression and covariance., Results: In 436 (24.5%) patients, [Hb] was <12 g dl-1 and, in 83 of these, <10 g dl-1. Both AT and V˙O2 peak rose modestly with increasing [Hb] (r2 = 0.24, P <0.0001 and r2 = 0.30, P <0.0001, respectively). After covariate adjustment, an increase in [Hb] of one standard deviation was associated with a 6.7 to 9.7% increase in V˙O2 peak, and a rise of 4.4 to 6.0% in AT. Haemoglobin concentration accounted for 9% and 6% of the variation in V˙O2 peak and AT respectively., Conclusions: To a modest extent, lower haemoglobin concentrations are independently associated with lower oxygen uptake during preoperative cardiopulmonary exercise testing. It is unknown whether this association is causative.

Background: For several types of non-cardiac surgery, the cardiopulmonary exercise testing (CPET)-derived variables anaerobic threshold (AT), peak oxygen consumption (VO2 peak), and ventilatory equivalent for CO(2) (VE/VCO2 ) are predictive of increased postoperative risk: less physically fit patients having a greater risk of adverse outcome. We investigated this relationship in patients undergoing gastric bypass surgery., Methods: All patients (<190 kg) who were referred for CPET and underwent elective gastric bypass surgery at the Whittington Hospital NHS Trust between September 1, 2009, and February 25, 2011, were included in the study (n=121). Fifteen patients did not complete CPET. CPET variables (VO2 peak, AT, and VE/VCO2 ) were derived for 106 patients. The primary outcome variables were day 5 morbidity and hospital length of stay (LOS). The independent t-test and Fisher's exact test were used to test for differences between surgical outcome groups. The predictive capacity of CPET markers was determined using receiver operating characteristic (ROC) curves., Results: The AT was lower in patients with postoperative complications than in those without [9.9 (1.5) vs 11.1 (1.7) ml kg(-1) min(-1), P=0.049] and in patients with a LOS>3 days compared with LOS ≤ 3 days [10.4 (1.4) vs 11.3 (1.8) ml kg(-1) min(-1), P=0.023]. ROC curve analysis identified AT as a significant predictor of LOS>3 days (AUC 0.640, P=0.030). The VO2 peak and VE/VCO2 were not associated with postoperative outcome., Conclusions: AT, determined using CPET, predicts LOS after gastric bypass surgery.

Objective: The aim of this study was to investigate the associations between alleles of the hypoxia-inducible factor 1A (HIF1A) C1772T polymorphism and several physiological responses to hypoxia, including the hypoxic ventilatory response (HVR), and serum erythropoietin (EPO), arterial oxygen saturation (Sao2), and acute mountain sickness (AMS) responses during 8 hours of exposure to normobaric hypoxia., Methods: A total of 76 males participated in the study; 52 participants completed an 8-hour exposure to 12.7% oxygen, during which time Sao2, EPO concentrations, and AMS scores were measured, while 62 individuals took part in an HVR trial (in total 38 individuals completed both protocols). DNA was obtained from leukocytes, and a 346-bp fragment of the HIF1A gene containing the C1772T polymorphism was amplified using polymerase chain reaction. Fragments were sequenced to reveal individual genotypes, and the associations between HIF1A genotype and EPO, Sao2, AMS responses to hypoxia and HVR were examined., Results: The magnitude of the hypoxic responses was highly variable between individuals. The increase in participants' EPO responses ranged from 89% to 388% of baseline values following hypoxia, while Sao2 values during the exposure ranged from 71% to 89%. The HVR ranged from -0.04 to +2.18 L x min(-1) x Sao2 %(-1) among participants. No significant differences in EPO, Sao2, AMS, or HVR results were observed between the HIF1A CC genotype and the combined CT/TT genotype group., Conclusion: In this study, the HIF1A C1772T polymorphism does not appear to influence EPO, Sao2, or AMS responses during acute hypoxic exposure, or the magnitude of the HVR., (Copyright 2010 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: We assessed the efficacy and side effects of postoperative analgesia with three different pain regimens in 90 patients undergoing major abdominal surgery. The patients were randomly assigned to one of three groups: epidural morphine (EM) or sufentanil (ES), both combined with bupivacaine, or IM morphine (IM) at fixed intervals. Before incision, patients in the epidural groups received sufentanil or morphine in bupivacaine via a thoracic catheter, followed by a continuous infusion 1 h later. General anesthesia consisted of N2O/O2 and isoflurane for all groups. Patients in all groups received IV sufentanil as part of their anesthetic management. Patients in the IM group received IV sufentanil 1 microg/kg before incision, and patients in all groups received sufentanil 10 microg for inadequate analgesia. Postoperatively, the epidural or IM treatment was continued for > or =5 days. Postoperative analgesia at rest and during coughing and movement was significantly better in the epidural groups than in the IM group during the 5 consecutive days. There were no significant differences between the epidural groups. The incidence of most side effects was similar in all groups. We conclude that epidural analgesia provided better pain relief than IM analgesia, even if the latter was optimized by fixed-dose administration at fixed intervals and included adjustments on demand. Epidural sufentanil and morphine, both combined with bupivacaine, seemed to be equally effective with similar side effects., Implications: Postoperative analgesia with epidural sufentanil or morphine and bupivacaine after major abdominal surgery seemed to be better than the conventional method of IM morphine treatment, despite optimal administration, i.e., fixed doses at fixed intervals with regular adjustments. Analgesic efficacy and side effects of epidural sufentanil and morphine were similar.

We studied effects on the EEG of propofol infused at a rate of 0.5 mg kg-1 min-1 for 10 min in 10 healthy male surgical patients under extradural analgesia. The EEG amplitude in six frequency bands was related to arterial blood propofol concentrations and responsiveness to verbal commands. The EEG amplitude showed a characteristic biphasic response to increasing blood propofol concentrations in all frequency bands. During the infusion, patients lost responsiveness when EEG amplitudes in the high frequency bands were decreasing after having reached a maximum. EEG changes were different during infusion and emergence. Pharmacodynamic modelling, using two effect compartments with dissimilar equilibration constants, resulted in satisfactory fits. We conclude that propofol exerts a biphasic effect on the EEG amplitude in all frequency bands. The dissimilarity of EEG changes during infusion and during emergence suggests that two effect compartments with different equilibration constants exert opposing effects on the EEG.

To assess the efficacy and safety of postoperative analgesia with continuous epidural sufentanil and bupivacaine, we performed a prospective study in 614 patients undergoing major surgery. Before surgical incision, all patients received an initial dose of 50 micrograms sufentanil in 6-10 mL bupivacaine 0.125% via a lumbar or thoracic catheter. After 1 h, a continuous infusion was started with 50 micrograms sufentanil in 50 mL bupivacaine 0.125% at a rate of 6-10 mL/h. The infusion was continued postoperatively for 1-5 days or longer, depending on the type of operation and the patient's analgesic need. In the majority of patients, adequate pain relief was obtained at rest and during movement. Late respiratory depression was observed in three patients; in most patients only minor side effects were seen. Technical complications during epidural puncture or insertion of the catheter were 4% and 3%, respectively. We conclude that continuous epidural sufentanil and bupivacaine is safe and effective.

Background: Cardiovascular instability after intravenous induction of anesthesia may be explained partly by direct negative inotropic effects. The direct inotropic influence of etomidate, ketamine, midazolam, propofol, and thiopental on the contractility of isolated human atrial tissue was determined. Effective concentrations were compared with those reported clinically., Methods: Atrial tissue was obtained from 16 patients undergoing coronary bypass surgery. Each fragment was divided into three strips, and one anesthetic was tested per strip in increasing concentrations (10(-6) to 10(-2) M). Strips were stimulated at 0.5 Hz, and maximum isometric force was measured. Induction agents were studied in two groups, group 1 (n = 7) containing thiopental, midazolam, and propofol, and group 2 (n = 9) consisting of etomidate, ketamine, and propofol., Results: The tested anesthetics caused a concentration-dependent depression of contractility resulting in complete cessation of contractions at the highest concentrations. The IC50s (mean +/- SEM; microM) for inhibition of the contractility were: thiopental 43 +/- 7.6, propofol 235 +/- 48 (group 1), and 246 +/- 42 (group 2), midazolam 145 +/- 54, etomidate 133 +/- 13, and ketamine 303 +/- 54., Conclusions: This is the first study demonstrating a concentration-dependent negative inotropic effect of intravenous anesthetics in isolated human atrial muscle. No inhibition of myocardial contractility was found in the clinical concentration ranges of propofol, midazolam, and etomidate. In contrast, thiopental showed strong and ketamine showed slight negative inotropic properties. Thus, negative inotropic effects may explain in part the cardiovascular depression on induction of anesthesia with thiopental but not with propofol, midazolam, and etomidate. Improvement of hemodynamics after induction of anesthesia with ketamine cannot be explained by intrinsic cardiac stimulation.

In a randomized study, we evaluated lag time (time from the end of injection of muscle relaxant until the first depression of the train-of-four response [TOF]), onset time (time from the end of injection of muscle relaxant until the maximum depression of the first twitch of the TOF [T1]), neuromuscular block, and endotracheal intubating conditions at 1 min after 1 mg/kg succinylcholine (n = 15) and 1.5 mg/kg Org 9487 (n = 30). Two minutes after administration of Org 9487, 15 of the 30 patients received neostigmine for reversal. Recovery of neuromuscular block after succinylcholine, Org 9487 without and Org 9487 with neostigmine were compared using the time until T1 was 90% for the succinylcholine group, and the time until TOF was 70% for the Org 9487 groups. Neuromuscular transmission was monitored mechanomyographically. Onset time was similar (67 [20] and 83 [38] s for succinylcholine and Org 9487, respectively) and endotracheal intubating conditions were also similar after both muscle relaxants. Times until clinically sufficient recovery of neuromuscular block induced by succinylcholine (time until T1 = 90%: 10.6 [3.3] min) and Org 9487 with neostigmine (time until TOF = 70%: 11.6 [1.4] min) were not different. In contrast, in the Org 9487 without neostigmine group, more time was required until complete recovery (24.1 [6.2] min) (P < 0.05). In conclusion, ORg 9487 is a muscle relaxant suitable for endotracheal intubation and short-lasting interventions.

The role of protein binding in relation to the pharmacodynamics of alfentanil was investigated in 15 female and 13 male patients, aged 21-85 yr, ASA physical status 1 or 2, undergoing upper abdominal surgery. All patients had normal cardiac, hepatic, renal, and pulmonary function. None was receiving medication or had a history of alcohol or other drug abuse. Anesthesia was induced and maintained with 66% nitrous oxide in oxygen and alfentanil. Alfentanil was administered by a computer-controlled infusion pump. If, during surgery, the patient exhibited signs of inadequate anesthesia (i.e., response), the target alfentanil plasma concentration was increased by 50-100 ng/ml. If there was no response during a 15-min period, the target concentration was decreased by 50-100 ng/ml. Arterial blood samples were taken before any change of the target concentration and 4 min after the computer had indicated that the new target concentration had been reached. In addition, blood samples were taken before intubation, skin incision, and in the patients in whom ventilation recovered spontaneously before extubation. In the remaining patients a blood sample was taken before the administration of naloxone. Plasma alfentanil concentrations were determined by capillary gas chromatography. Alfentanil protein binding was determined by equilibrium dialysis in an arterial blood sample taken before induction of anesthesia. Alfentanil concentration-effect data were evaluated by logistic regression, where effect was either response or no response to perioperative stimuli. The average free fraction of alfentanil was 9.3 +/- 3.9% (range 3.7-19.1%). For intubation, skin incision, and postanesthesia ventilation, it was not possible to characterize the concentration-effect curves based on total plasma concentrations with logistic regression.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic function during induction of anesthesia, the alfentanil and naloxone requirements, and the speed of recovery from total intravenous anesthesia with alfentanil/midazolam (group M, n = 10) or alfentanil/propofol (group P, n = 10) were compared in patients undergoing lower limb surgery. Twenty patients were randomly assigned to receive either 2 mg/kg propofol in 5 min followed by 9 mg.kg-1.h-1 for 30 min and 4.5 mg.kg-1.h-1 until skin closure, or 0.42 mg/kg midazolam in 5 min followed by 0.125 mg.kg-1.h-1 until skin closure. Simultaneously, a variable-rate infusion of alfentanil was given. Patients were ventilated with 30% oxygen in air. In both groups blood pressure and heart rate decreased significantly (P less than 0.02) and to a similar extent during induction. The total dose of alfentanil was similar in both groups. No patient in group P and nine patients in group M needed naloxone (average dose 130 +/- 70 micrograms, P less than 0.001). Recovery, as judged by psychomotor tests (90% score was reached at 1 h in the P group and at about 4 h in the M group, P less than 0.001), sedative scores, and orientation in time and place, was shorter in group P than in group M. The conclusion is reached that propofol is superior to midazolam in total intravenous anesthesia with alfentanil.

Hepatic uptake and distribution of nondepolarizing muscle relaxants in pigs was investigated. A portocaval shunt preparation enabled the determination of the pharmacodynamics of nondepolarizing muscle relaxants both during temporary liver exclusion and intraportal injection in the same animal. To demonstrate the validity of the model in pigs, in a pilot study the influence of hepatic uptake on neuromuscular blockade by pancuronium (n = 3) and its congener Org 6368 (n = 3) was determined. Thereafter, the influence of hepatic uptake on neuromuscular blockade by gallamine (3.4 mg/kg, n = 5), Org 6368 (0.3 mg/kg, n = 5), and vecuronium (0.1 mg/kg, n = 4 and 0.15 mg/kg, n = 5) was studied in pigs anesthetized with pentobarbital. Each pig received one relaxant, which was injected four consecutive times under different conditions. The first injection was into the jugular vein (iv) the second into the portal vein, the third was iv while the liver was excluded for 10 min and the fourth was iv (control). After each injection the onset time, intensity, recovery rate, and total duration of neuromuscular blockade were measured. These variables were compared between the four injections for each relaxant. In the pilot study the influence of hepatic uptake on neuromuscular blockade was similar for pancuronium and Org 6368. For gallamine the onset time, intensity, recovery rate, and duration of action were similar after all four injections. For Org 6368 the variables of neuromuscular blockade were similar after iv and intraportal injection, but exclusion of the liver prolonged the neuromuscular block.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacodynamics of alfentanil given as a supplement to nitrous oxide anaesthesia were studied in 10 elderly patients undergoing lower abdominal surgery. Plasma alfentanil concentration-effect curves for perioperative stimuli and for the probability of needing naloxone at the end of surgery were fitted by logistic regression. The concentration at which the probability of no response was 0.5 (Cp50) for laryngoscopy was 356 ng ml-1, for opening the peritoneum 295 ng ml-1 and for closing the peritoneum 254 ng ml-1. The average Cp50 for the intra-abdominal part of the operation was 268 +/- 97 ng ml-1. The Cp50 for needing naloxone was 174 ng ml-1. These findings are similar to published values for young healthy females undergoing lower abdominal surgery. Our findings suggest that the pharmacodynamics of alfentanil in the elderly are similar to those in younger adults.

Patients with renal failure and undergoing a cadaver renal transplant were found to have plasma concentrations of laudanosine, following the administration of a single bolus dose of atracurium 0.5 mg kg-1, higher than those found in patients without renal failure. Since laudanosine is a known central nervous system stimulant in a variety of animal species, its actions should be investigated further in man, and particularly in patients with renal failure.

Two groups of women, ASA physical status 1, undergoing surgery for primary breast cancer, were studied to assess the effect of alcohol intake on alfentanil pharmacodynamics. Patients in group 1 (n = 6) had an average daily consumption of 20-40 g alcohol. Patients in group 2 (n = 8) were life-long abstainers or drank only occasionally (less than 60 g per year). Anesthesia was induced and maintained with 66% N2O in O2 and alfentanil. Alfentanil was administered by a computer-controlled infusion pump. If during surgery the patient exhibited somatic, hemodynamic, or other autonomic signs of inadequate anesthesia (response), the target alfentanil plasma concentration was increased by 50-100 ng/ml. If there was no response during a 15-min period, the target concentration was decreased by 50-100 ng/ml. Arterial blood samples were taken before any change of the target concentration, 4 min after a new predicted target concentration was achieved, and at extubation. Plasma concentrations were determined by capillary gas chromatography. Alfentanil protein binding was measured by equilibrium dialysis. Plasma alfentanil concentration-effect data were analyzed by nonlinear regression, where effect was either response or no response to surgical stimuli. The average total alfentanil requirement was significantly (P less than 0.005) higher in group 1 (3.7 +/- 1.2 micrograms.kg-1.min-1) than in group 2 (1.9 +/- 0.4 micrograms.kg-1.min-1). The average Cp50 (the plasma concentration for which the probability of no response during surgery is 50%) was significantly (P less than 0.001) higher in group 1 (522 +/- 104 ng/ml) than in group 2 (208 +/- 26 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

The authors sought to determine whether the metabolites of neostigmine and pyridostigmine contribute to antagonism of neuromuscular blockade. Accordingly, the dose-response relationship, onset and duration of action (n = 60), and pharmacokinetics (n = 22) of neostigmine, pyridostigmine, their metabolites 3-hydroxyphenyltrimethylammonium (PTMA) and 3-hydroxy-N-methylpyridinium (MP), and edrophonium were determined in dogs anesthetized with sodium pentobarbital. The force of contraction of the anterior tibialis muscle was maintained at constant 90% depression by infusing pancuronium. Then, a single iv bolus dose of one of the drugs under study was injected while the pancuronium infusion was continued. Venous blood, urine, and bile were sampled for four hours. Concentrations were determined by liquid chromatographic techniques; a three-compartment pharmacokinetic model was fitted to the serum concentration data. The doses producing 50% antagonism were 6.5, 52, 69, and 40 micrograms/kg for neostigmine, pyridostigmine, edrophonium, and PTMA, respectively. MP was inactive as an antagonist. By comparing approximately equipotent doses, time to peak antagonism (onset) and until 30% of peak antagonism remained (duration) were shorter for both edrophonium and PTMA than for neostigmine and pyridostigmine. Slow distribution and elimination half-lives, volume of distribution at steady state (VDss), and total plasma clearance (Cl) were similar for the drugs except for a smaller Vdss and lower Cl for MP. More than 60% of the dose of each drug was recovered unchanged from urine; less than 1% was recovered from bile. Less than 10% of the dose of neostigmine was recovered as PTMA.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of age on the pharmacodynamics of alfentanil, as a supplement to nitrous oxide anesthesia, were studied in younger (31-52 years; n = 14) and older (56-86 years; n = 14) women undergoing curative surgery for primary breast cancer. Plasma alfentanil concentration-effect curves for perioperative stimuli and for the probability of needing naloxone at the end of the operation were fitted by logistic regression. Effects of age on the plasma concentration-effect relation of alfentanil could not be demonstrated. However, the dose requirement in the older patient group was significantly lower than in the younger patient group.

The influence of growth of an aorta-coronary anastomosis, comparable to the coronary translocation anastomosis during the arterial switch operation, was studied in pigs. The anastomosis between the right coronary artery and the aorta did not grow, and this lack of growth may result in stenosis. With another technique, by which the coronary artery was excised with a cuff of aortic wall, the effects caused by absence of growth were circumvented and a normal-sized coronary ostium was present after growth. However, when no cuff was used, stenosis occurred at the suture line and caused growth retardation of the animal as well as histologic damage to the right ventricle.

To determine the influence of renal function on the pharmacology of atracurium, 10 patients with normal renal function and 10 with renal failure (scheduled for cadaver kidney transplant) were anesthetized with nitrous oxide and halothane. Atracurium besylate, 0.5 mg . kg-1, was given as an iv bolus and plasma samples were collected over a 4-h period. These samples were assayed for atracurium (all patients) and laudanosine, one of the principal metabolites (eight of the normal group), using an ion-exchange liquid chromatographic assay. The plasma concentrations of atracurium for each patient were fitted to a two-compartment pharmacokinetic model. The onset time, duration of action, and recovery time of atracurium neuromuscular blockade were measured. There were no differences found in the pharmacokinetics or pharmaco-dynamics of atracurium between patients with normal renal function and those with renal failure. There were measurable levels of laudanosine following atracurium administration with peak levels of 199 +/- 31 ng . ml-1 at 2 min. The authors conclude that the pharmacokinetics and pharmacodynamics of atracurium are not altered by renal failure.

The authors determined the pharmacokinetics (including transfer into cerebrospinal fluid [CSF]) and the cardiovascular and central nervous system (CNS) effects of laudanosine, a metabolite of atracurium. Eight dogs were anesthetized with halothane; blood pressure and a fronto-occipital electroencephalographic lead were monitored. Laudanosine (1 mg . kg-1 iv) was administered as a bolus, and its concentrations in plasma, CSF, urine, and bile were determined by liquid chromatography. Three-compartment modeling of plasma laudanosine concentrations yielded an elimination half-life for laudanosine of 113 +/- 24 min (mean +/- SD) and a clearance of 25 +/- 8 ml . kg-1 . min-1. CSF concentrations of laudanosine were highest 5-10 min after iv injection of laudanosine and ranged in concentration from 208 to 572 ng . ml-1 (i.e., 36-87% of the corresponding plasma concentrations). Unchanged laudanosine was found in urine (0.5-12% of injected dose) and bile (less than 0.1%); metabolites of laudanosine were found in both fluids. After a 6-h sampling period, dogs were hyperventilated with halothane (FIO2 = 0.2) to a PaCO2 of 26-28 mmHg. Laudanosine was then administered 2 mg . kg-1 iv every 5 min. With cumulative doses of 2-8 mg . kg-1, all dogs showed signs of "awakening" from anesthesia. Cumulative doses of 14-22 mg . kg-1 produced seizure activity in all animals. Mean arterial blood pressure decreased significantly to 86% of control levels at 1 min following administration of laudanosine (1 mg . kg-1 iv) and returned to control levels 4 min later.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of aging after epidural administration of 0.5% bupivacaine without epinephrine were studied in two groups of patients, between 20 and 55 yr old and older than 55 yr, respectively. All patients received 95 mg bupivacaine HCl. The onset of analgesia in caudad segments decreased with age and the upper level of analgesia increased with age. Effects of age on duration of anesthesia could not be demonstrated. The total plasma clearance of bupivacaine decreased and the terminal half-life increased with age. Age had no effect on the peak plasma concentrations and time to peak concentrations.

Effects of age on spinal anesthesia using glucose-free 0.5% bupivacaine without epinephrine were studied in two groups of patients, one between 20 and 55 yr old, the other older than 55 yr. All patients received 15 mg bupivacaine. The time to onset of analgesia in caudad segments and the time to maximal motor blockade decreased with age. The upper level of analgesia did not change significantly with increasing age. The times to recovery from analgesia at T12 and for the total disappearance of analgesia were longer in the older patient group. Effects of age on duration of motor blockade could not be demonstrated. Peak plasma concentrations of bupivacaine were significantly greater and the total plasma clearance significantly decreased in older patients. Age had no effect on time to peak concentration or the terminal half-life.