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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).)

Purpose: Inter-individual variability in bone mineral density (BMD) exists within and between endurance runners and non-athletes, probably in part due to differing genetic profiles. Certainty is lacking, however, regarding which genetic variants may contribute to BMD in endurance runners and if specific genotypes are sensitive to environmental factors, such as mechanical loading via training., Method: Ten single-nucleotide polymorphisms (SNPs) were identified from previous genome-wide and/or candidate gene association studies that have a functional effect on bone physiology. The aims of this study were to investigate (1) associations between genotype at those 10 SNPs and bone phenotypes in high-level endurance runners, and (2) interactions between genotype and athlete status on bone phenotypes., Results: Female runners with P2RX7 rs3751143 AA genotype had 4% higher total-body BMD and 5% higher leg BMD than AC + CC genotypes. Male runners with WNT16 rs3801387 AA genotype had 14% lower lumbar spine BMD than AA genotype non-athletes, whilst AG + GG genotype runners also had 5% higher leg BMD than AG + GG genotype non-athletes., Conclusion: We report novel associations between P2RX7 rs3751143 genotype and BMD in female runners, whilst differences in BMD between male runners and non-athletes with the same WNT16 rs3801387 genotype existed, highlighting a potential genetic interaction with factors common in endurance runners, such as high levels of mechanical loading. These findings contribute to our knowledge of the genetic associations with BMD and improve our understanding of why some runners have lower BMD than others., (© 2021. The Author(s).)

Purpose: Physical activity, particularly mechanical loading that results in high-peak force and is multi-directional in nature, increases bone mineral density (BMD). In athletes such as endurance runners, this association is more complex due to other factors such as low energy availability and menstrual dysfunction. Moreover, many studies of athletes have used small sample sizes and/or athletes of varying abilities, making it difficult to compare BMD phenotypes between studies., Method: The primary aim of this study was to compare dual-energy X-ray absorptiometry (DXA) derived bone phenotypes of high-level endurance runners (58 women and 45 men) to non-athletes (60 women and 52 men). Our secondary aim was to examine the influence of menstrual irregularities and sporting activity completed during childhood on these bone phenotypes., Results: Female runners had higher leg (4%) but not total body or lumbar spine BMD than female non-athletes. Male runners had lower lumbar spine (9%) but similar total and leg BMD compared to male non-athletes, suggesting that high levels of site-specific mechanical loading was advantageous for BMD in females only and a potential presence of reduced energy availability in males. Menstrual status in females and the number of sports completed in childhood in males and females had no influence on bone phenotypes within the runners., Conclusion: Given the large variability in BMD in runners and non-athletes, other factors such as variation in genetic make-up alongside mechanical loading probably influence BMD across the adult lifespan., (© 2021. 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.)

Initial studies indicated that student mental health was impaired during the early stages of the pandemic and that maintaining/improving physical activity gave some protection from mental illness. However, as the pandemic persists, these data may not reflect current circumstances and may have been confounded by exam stress., Methods: This study used an online survey to assess the changes in, and associations between, mental health and movement behaviours in 255 UK university students from before the COVID-19 pandemic (October 2019) to 9 months following the UK's first confirmed case (October 2020). Changes in and associations between mental wellbeing, perceived stress, physical activity, and sedentary behaviour were assessed using a mixed model ANOVA; a multiple linear regression model determined the predictive value of variables associated with Δ mental wellbeing., Results: Mental wellbeing and physical activity decreased (45.2 to 42.3 ( p < 0.001); 223 to 173 min/week ( p < 0.001)), whereas perceived stress and time spent sedentary increased (19.8 to 22.8 ( p < 0.001); 66.0 to 71.2 h/week ( p = 0.036)). Δ perceived stress, Δ sedentary behaviour and university year accounted for 64.7%, 12.9%, and 10.1% of the variance in Δ mental wellbeing ( p < 0.001; p = 0.006; p = 0.035)., Conclusion: The COVID-19 pandemic is having a sustained negative impact on student mental health and movement behaviour.

Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate 'placebo'. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 μM) and at day 5 (D5) of high altitude (22.9 vs 84.3 μM, p < 0.001). Dietary nitrate supplementation also significantly increased both plasma nitrite (0.78 vs. 0.86 μM SL, 0.31 vs. 0.41 μM D5, p = 0.03) and total nitroso product (11.3 vs. 19.7 nM SL, 9.7 vs. 12.3 nM D5, p < 0.001) levels both at sea level and at 4559 m. However, plasma nitrite concentrations were more than 50% lower at 4559 m compared to sea level in both treatment groups. Despite these significant changes, dietary nitrate supplementation had no effect on any measured read-outs of sublingual or forearm blood flow, even when environmental hypoxia was experimentally reversed using supplemental oxygen. In conclusion, dietary nitrate supplementation does not improve microcirculatory function at 4559 m., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Low bone mineral density (BMD) is established as a primary predictor of osteoporotic risk and can also have substantial implications for athlete health and injury risk in the elite sporting environment. BMD is a highly multi-factorial phenotype influenced by diet, hormonal characteristics and physical activity. The interrelationships between such factors, and a strong genetic component, suggested to be around 50-85% at various anatomical sites, determine skeletal health throughout life. Genome-wide association studies and case-control designs have revealed many loci associated with variation in BMD. However, a number of the candidate genes identified at these loci have no known associated biological function or have yet to be replicated in subsequent investigations. Furthermore, few investigations have considered gene-environment interactions-in particular, whether specific genes may be sensitive to mechanical loading from physical activity and the outcome of such an interaction for BMD and potential injury risk. Therefore, this review considers the importance of physical activity on BMD, genetic associations with BMD and how subsequent investigation requires consideration of the interaction between these determinants. Future research using well-defined independent cohorts such as elite athletes, who experience much greater mechanical stress than most, to study such phenotypes, can provide a greater understanding of these factors as well as the biological underpinnings of such a physiologically "extreme" population. Subsequently, modification of training, exercise or rehabilitation programmes based on genetic characteristics could have substantial implications in both the sporting and public health domains once the fundamental research has been conducted successfully.

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.

Nitric oxide (NO) production plays a central role in conferring tolerance to hypoxia. Tibetan highlanders, successful high-altitude dwellers for millennia, have higher circulating nitrate and exhaled NO (E NO ) levels than native lowlanders. Since nitrate itself can reduce the oxygen cost of exercise in normoxia it may confer additional benefits at high altitude. Xtreme Alps was a double-blinded randomised placebo-controlled trial to investigate how dietary nitrate supplementation affects physiological responses to hypoxia in 28 healthy adult volunteers resident at 4559 m for 1 week; 14 receiving a beetroot-based high-nitrate supplement and 14 receiving a low-nitrate 'placebo' of matching appearance/taste. E NO , vital signs and acute mountain sickness (AMS) severity were recorded at sea level (SL) and daily at altitude. Moreover, standard spirometric values were recorded, and saliva and exhaled breath condensate (EBC) collected. There was no significant difference in resting cardiorespiratory variables, peripheral oxygen saturation or AMS score with nitrate supplementation at SL or altitude. Median E NO levels increased from 1.5/3.0  mPa at SL, to 3.5/7.4 mPa after 5 days at altitude (D5) in the low and high-nitrate groups, respectively (p = 0.02). EBC nitrite also rose significantly with dietary nitrate (p = 0.004), 1.7-5.1  μM at SL and 1.6-6.3 μM at D5, and this rise appeared to be associated with increased levels of E NO . However, no significant changes occurred to levels of EBC nitrate or nitrosation products (RXNO). Median salivary nitrite/nitrate concentrations increased from 56.5/786 μM to 333/5,194  μM  with nitrate supplementation at SL, and changed to 85.6/641 μM and 341/4,553 μM on D5. Salivary RXNO rose markedly with treatment at SL from 0.55 μM to 5.70 μM. At D5 placebo salivary RXNO had increased to 1.90 μM whilst treatment RXNO decreased to 3.26 μM. There was no association with changes in any observation variables or AMS score. In conclusion, dietary nitrate supplementation is well tolerated at altitude and significantly increases pulmonary NO availability and both salivary and EBC NO metabolite concentrations. Surprisingly, this is not associated with changes in hemodynamics, oxygen saturation or AMS development., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

The purpose of this study was to investigate the effects of dietary nitrate supplementation, in the form of beetroot juice, on acute mountain sickness (AMS) symptoms and physiological responses, in a group of young males trekking to Mount Everest Base Camp (EBC). Forty healthy male students (mean age (SD): 16 (1) yrs) trekked to EBC over 11 days. Following an overnight fast, each morning participants completed the Lake Louise AMS questionnaire and underwent a series of physiological tests: resting blood pressure as well as resting and exercising heart rate, respiratory rate, and peripheral oxygen saturation. The exercise test consisted of a standardised 2-min stepping protocol and measurements were taken in the last 10 s. Participants in the intervention arm of the study consumed 140 ml of concentrated beetroot juice daily, containing approximately 10 mmol of nitrate, while those in the control arm consumed 140 ml of concentrated blackcurrant cordial with negligible nitrate content. Drinks were taken for the first seven days at high altitude (days 2-8), in two equal doses; one with breakfast, and one with the evening meal. Mixed modelling revealed no significant between-groups difference in the incidence of AMS (Odds Ratio - nitrate vs., Control: 1.16 (95% CI: 0.59; 2.29)). Physiological changes occurring during ascent to high altitude generally were not significantly different between the two groups (Model Coef (95% CI) - average difference nitrate vs., Control: systolic blood pressure, 0.16 (-4.47; 4.79); peripheral oxygen saturation, 0.28 (-0.85; 1.41); heart rate, -0.48 (-8.47; 7.50) (Model Coef (95% CI) - relative difference nitrate vs., Control: ventilatory rate, 0.95 (0.82; 1.08)). Modelling revealed that diastolic blood pressure was 3.37 mmHg (0.24; 6.49) higher for participants in the beetroot juice, however this difference was no larger than that found at baseline and no interaction effect was observed. Supplementation with dietary nitrate did not significantly change symptoms of AMS or alter key physiological variables, in a group of adolescent males during a high altitude trekking expedition. There was no evidence of harm from dietary nitrate supplementation in this context. Given the wide confidence intervals in all models, a larger sample size would be required to exclude a false negative result. Our data suggest that prolonged oral nitrate supplementation is safe and feasible at altitude but has little physiological or clinical effect., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Objective: 'Natural selection' has been shown to have enriched the genomes of high-altitude native populations with genetic variants of advantage in this hostile hypoxic environment. In lowlanders who ascend to altitude, genetic factors may also contribute to the substantial interindividual variation in exercise performance noted at altitude. We performed a systematic literature review to identify genetic variants of possible influence on human hypoxic exercise performance, commenting on the strength of any identified associations., Criteria for Considering Studies for This Review: All studies of the association of genetic factors with human hypoxic exercise performance, whether at sea level using 'nitrogen dilution of oxygen' (normobaric hypoxia), or at altitude or in low-pressure chambers (field or chamber hypobaric hypoxia, respectively) were sought for review., Search Strategy for Identification of Studies: Two electronic databases were searched (Ovid MEDLINE, Embase) up to 31 January 2014. We also searched the reference lists of relevant articles for eligible studies. All studies published in English were included, as were studies in any language for which the abstract was available in English., Data Collection and Analysis: Studies were selected and data extracted independently by two reviewers. Differences regarding study inclusion were resolved through discussion. The quality of each study was assessed using a scoring system based on published guidelines for conducting and reporting genetic association studies., Results: A total of 11 studies met all inclusion criteria and were included in the review. Subject numbers ranged from 20 to 1,931 and consisted of healthy individuals in all cases. The maximum altitude of exposure ranged from 2,690 to 8,848 m. The exercise performance phenotypes assessed were mountaineering performance (n = 5), running performance (n = 2), and maximum oxygen consumption ([Formula: see text]O2max) (n = 4). In total, 13 genetic polymorphisms were studied, four of which were associated with hypoxic exercise performance. The adenosine monophosphate deaminase (AMPD1) C34T (rs17602729), beta2-adrenergic receptor (ADRB2) Gly16Arg single nucleotide polymorphism (SNP) (rs1042713), and androgen receptor CAG repeat polymorphisms were associated with altitude performance in one study, and the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) (rs4646994) polymorphism was associated with performance in three studies. The median score achieved in the study quality analysis was 6 out of 10 for case-control studies, 8 out of 10 for cohort studies with a discrete outcome, 6 out of 9 for cohort studies with a continuous outcome, and 4.5 out of 8 for genetic admixture studies., Conclusion: The small number of articles identified in the current review and the limited number of polymorphisms studied in total highlights that the influence of genetic factors on exercise performance in hypoxia has not been studied in depth, which precludes firm conclusions being drawn. Support for the association between the ACE-I allele and improved high-altitude performance was the strongest, with three studies identifying a relationship. Analysis of study quality highlights the need for future studies in this field to improve the conduct and reporting of genetic association studies.

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 and Aims: Aerobic exercise capacity appears impaired in children with inflammatory bowel disease (IBD). Whether this holds true in adults with IBD is not known. Using cardiopulmonary exercise testing (CPET), we assessed anaerobic threshold (AT) in such patients comparing data with reference values and other elective surgical patients. We also sought to confirm whether the presence of a fistula further reduced AT., Methods: CPET was performed between November 2007 and December 2010 on patients awaiting abdominopelvic surgery. Gender-specific normal reference values were used for comparison. Unadjusted comparison between two groups was made using Mann-Whitney U test and by unpaired t test. Data were adjusted by analysis of covariance, using age and sex as covariates. Differences between patients' observed values and reference values were tested using paired t tests., Results: Four hundred and fourteen patients (234 male) were studied (mean ± SD age, 56.6 ± 16.4 years; weight, 74.2 ± 15.6 kg). Adjusted AT values in Crohn's disease (CD) were lower than colorectal cancer (11.4 ± 3.4 vs 13.2 ± 3.5 ml.kg(-1).min(-1), p = 0.03) and for all other colorectal disease groups combined (12.6 ± 3.5 ml.kg(-1).min(-1), p = 0.03). AT of Ulcerative colitis (UC) and CD patients together were reduced compared to population reference values (p < 0.05)., Conclusion: After adjusting for age and sex, CD patients had a reduced AT compared to patients with colorectal cancer and other colorectal disease groups combined. The pathogenesis of this low AT remains to be defined and warrants further investigation.

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.

The use of cardiopulmonary exercise testing (CPET) as a preoperative risk stratification tool for a range of non-cardiopulmonary surgery is increasing. The utility of CPET in this role is dependent on the technology being able to identify accurately and reliably those patients at increased risk of perioperative events when compared with existing risk stratification tools. This article identifies and reviews systematically the current literature regarding the use of CPET as a preoperative tool for stratifying risk in major non-cardiopulmonary surgery. Specifically, it focuses on evaluating the capacity of CPET variables to predict the risk of postoperative complications and mortality in comparison to other methods of risk assessment. Furthermore, the potential for combining results from CPET and non-CPET methods of risk prediction to enhance the capacity to identify high risk patients is considered. The review indicates that CPET can identify patients at increased risk of adverse perioperative outcomes. However, the selection of variables and threshold values to indicate high risk differ for different surgical procedures and underlying conditions. Furthermore, the available data suggest that CPET variables outperform alternative methods of preoperative risk stratification. Several studies also identify that CPET variables may be used in combination with non-CPET variables to increase perioperative risk prediction accuracy. These findings illustrate that CPET has the capacity to identify patients at increased risk of adverse outcome before a range of non-cardiopulmonary surgical procedures. Further research is required to optimise its use, potentially by combining CPET results with alternative methods of risk stratification.

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.)

Background: Spinal anesthesia for knee arthroscopy can be produced with a low dose of bupivacaine, but additional intrathecal drugs are often required to lower the risk of failed blocks. We investigated the effect of the addition of clonidine (0, 15 or 30 microg) to 5 mg hyperbaric bupivacaine on the duration of the motor block, analgesic quality and ability to void after the surgery in a randomized controlled trial., Methods: Seventy-five patients received spinal anesthesia using either 5 mg hyperbaric bupivacaine (B5C0), 5 mg hyperbaric bupivacaine with 15 microg clonidine (B5C15) or 5 mg hyperbaric bupivacaine with 30 microg clonidine (B5C30). The primary outcome was the duration of the motor block. Secondary outcomes included the time until spontaneous voiding, and the need for additional analgesia or general anesthesia., Results: The mean time to complete regression of motor block was 70 (+/-43) min in group B5C0. Adding 15 and 30 microg of clonidine increased the motor block duration by 25 [95% confidence interval (CI): 2-48] and 34 (95% CI: 11-57) min, respectively, but resulted in better analgesic quality. The mean time until spontaneous voiding was 177 min in the B5C0 group. This time increased with 18 (95% CI -13 to 49) and 44 (95% CI 15-74) min in group B5C15 and group B5C30, respectively., Conclusion: The addition of 15 microg clonidine to 5 mg of intrathecal hyperbaric bupivacaine prolongs the duration of motor block and improves the quality of the block.

We quantified the accuracy of trained nurses to correctly assess the pre-operative health status of surgical patients as compared to anaesthetists. The study included 4540 adult surgical patients. Patients' health status was first assessed by the nurse and subsequently by the anaesthetist. Both needed to answer the question: 'is this patient ready for surgery without additional work-up, Yes/No?' (primary outcome). The secondary outcome was the time required to complete the assessment. Anaesthetists and nurses were blinded for each other's results. The anaesthetists' result was the reference standard. In 87% of the patients, the classifications by nurses and anaesthetists were similar. The sensitivity of the nurses' assessment was 83% (95% CI: 79-87%) and the specificity 87% (95% CI: 86-88%). In 1.3% (95% CI: 1.0-1.6%) of patients, nurses classified patients as 'ready' whereas anaesthetists did not. Nurses required 1.85 (95% CI: 1.80-1.90) times longer than anaesthetists. By allowing nurses to serve as a diagnostic filter to identify the subgroup of patients who may safely undergo surgery without further diagnostic workup or optimisation, anaesthetists can focus on patients who require additional attention before surgery.

Background: The effects of hyperthermia on the human brain are incompletely understood. This study assessed the effects of whole body hyperthermia on cerebral oxygen extraction and autoregulation in humans., Methods: Nineteen patients with chronic hepatitis C virus infection, not responding to interferon treatment, were subjected to experimental therapy with extracorporeal whole body hyperthermia at 41.8 degrees C for 120 min under propofol anesthesia (23 sessions total). During treatment series A (13 sessions), end-tidal carbon dioxide was allowed to increase during heating. During series B (10 sessions), end-tidal carbon dioxide was maintained approximately constant. Cerebral oxygen extraction (arterial to jugular venous difference of oxygen content) and middle cerebral artery blood flow velocity were continuously measured. Cerebral pressure-flow autoregulation was assessed by static tests using phenylephrine infusion and by assessing the transient hyperemic response to carotid compression and release., Results: For treatment series A, cerebral oxygen extraction decreased 2.2-fold and cerebral blood flow velocity increased 2.0-fold during heating. For series B, oxygen extraction decreased 1.6-fold and flow velocity increased 1.5-fold. Jugular venous oxygen saturation and lactate measurements did not indicate cerebral ischemia at any temperature. Static autoregulation test results indicated loss of cerebrovascular reactivity during hyperthermia for both series A and series B. The transient hyperemic response ratio did not decrease until the temperature reached approximately 40 degrees C. Per degree Celsius temperature increase, the transient hyperemic response ratio decreased 0.07 (95% confidence interval, 0.05-0.09; P = 0.000). This association remained after adjustment for variations in arterial partial pressure of carbon dioxide, mean arterial pressure, and propofol blood concentration., Conclusion: Profound hyperthermia during propofol anesthesia is associated with decreased cerebral oxygen extraction, increased cerebral blood flow velocity, and impaired pressure-flow autoregulation, indicating transient partial vasoparalysis.

Background and Objective: Since reports have shown that outpatient preoperative evaluation increases the quality of care and cost-effectiveness, an increasing number of patients are being evaluated purely on an outpatient basis. To improve cost-effectiveness, it would be appealing if those patients who are healthy and ready for surgery without additional testing could be easily distinguished from those who require more extensive evaluation. This paper examines whether published studies provide sufficient data to determine how detailed preoperative history taking and physical examination need to be in order to assess the health of surgical patients and to meet the objective of easy and early distinction., Methods: A MEDLINE search was conducted from 1991 to 2000 with respect to preoperative patient history and physical examination. Altogether, 213 articles were found, of which 29 were selected. Additionally, 38 cross-references, 7 articles on additional testing and 4 recently published papers were used., Results: It is questionable to what extent an extensive history is relevant for anaesthesia and long-term prognosis. With respect to physical examination, it seems unreasonable to diagnose valvular heart disease based on cardiac auscultation only, and it is unclear which method should be used to predict the difficulty of endotracheal intubation. The benefits of routine testing for all surgical patients before operation are extremely limited and are not advocated., Conclusions: The amount of detail of preoperative patient history and the value of physical examination to obtain a reasonable estimate of perioperative risk remains unclear. Although not evidence based, a thorough history taking and physical examination of all patients before surgery seems important until more evidence-based guidelines become available. Diagnostic and prognostic prediction studies may provide this necessary evidence.

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.

Objective: To investigate the influence of recommendations on the quality of postoperative pain management in children., Design: Prospective., Setting: University Hospital Groningen, the Netherlands., Method: After interdisciplinary recommendations on postoperative pain were developed, the quality of postoperative pain management was investigated before implementation (phase I; n = 50 children aged 0-14 who underwent elective surgery), three months after the implementation (phase II; n = 51), and nine months later (phase III; n = 50). Quality was defined by a pain score (for ages 0 to 4 with the 'Children's Hospital of Eastern Ontario pain scale' (CHEOPS) and for ages 4-14 with the Oucher scale) and the prescription of analgetics: kind, dose, frequency, prescription by anaesthetist and doctor on the ward. Pain was scored every 2 hours during the first 24 hours after surgery. A CHEOPS score < or = 6 an Oucher score < or = 50 was defined as adequate; higher scores were defined as inadequate., Results: Pain measurement showed a statistically significant improvement of pain scores in time (phase II and III compared with phase I: odds ratio: 2.5; 95% confidence interval: 1.03-6.00; p < 0.01). Searching for factors that could be responsible for this improvement, like medication, we found no statistically significant differences in everyday practice in phase II and III compared with phase I. However, children who could score their pain by self-report (Oucher) showed the best results in all 3 phases of the study. The youngest children, i.e. less than 6 months old, showed inadequate results during the whole study. The greatest improvement in time during the first 12 hours was seen in the group of children older than 6 months. The recommendations were followed more strictly in younger children, and when continuous morphine was given., Conclusion: Pain scores in children improved after the introduction of recommendations on postoperative pain. However, the improvement could not be attributed to factors like medication. Factors like a change in attitude towards pain could be responsible for this change.

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.

Objectives: In this study, the hemodynamics and sufentanil requirement were compared at two midazolam target plasma concentrations in patients undergoing coronary artery bypass grafting (CABG)., Design: Prospective, randomized study., Setting: University hospital, single institution., Participants: Patients undergoing CABG., Interventions: Patients were randomly assigned to receive midazolam at a target plasma concentration of 150 ng/mL (group 1; n = 10) or 300 ng/mL (group 2; n = 10). Sufentanil infusion was titrated to maintain hemodynamic stability, defined as mean arterial pressure within 15% of baseline values. All patients received preoperative beta-blocking agents. Arterial blood samples of midazolam and sufentanil were analyzed by high-performance liquid chromatography and radioimmunoassay, respectively., Measurements and Main Results: The mean dose of sufentanil (7.5 +/- 1.7 microgram/kg in group 1 v 7.2 +/- 2.5 micrograms/kg in group 2) did not differ. There were no significant differences in hemodynamics between the groups in the period before or after cardiopulmonary bypass (CPB). Before CPB, in two patients in each group, hypertension was controlled with sufentanil only. One patient in group 1 required a vasodilator in addition to sufentanil. No ischemic events occurred before CPB. After CPB, one patient in group 2 required a vasodilator to control hypertension. Two patients in group 2 required treatment with nitroglycerin for myocardial ischemia. Stable plasma concentrations of sufentanil and midazolam were obtained during and after CPB. The midazolam infusion was continued in both groups at a rate of 1.25 micrograms/kg/min during the first 4 postoperative hours. The time to awakening did not differ between the groups (100 +/- 58 minutes in group 1 v 173 +/- 147 minutes in group 2) nor did the plasma concentrations of midazolam (96 +/- 28 ng/mL v 108 +/- 42 ng/mL) at the time of awakening. Intraoperative awareness was not reported., Conclusion: In patients undergoing CABG, good hemodynamic control with a similar incidence of hemodynamic interventions was observed at midazolam target plasma concentrations of 150 and 300 ng/mL when coadministered with sufentanil. The sufentanil requirement was identical in both groups. This study suggests that a midazolam plasma concentration of 150 ng/mL is sufficient to provide satisfactory hemodynamic control and to avoid intraoperative awareness.

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.

To assess the efficacy of epidural sufentanil in providing per- and postoperative analgesia, 40 patients undergoing elective abdominal aortic surgery received either 50 mu g sufentanil in 10 ml normal saline solution (n = 20, ES group) or 10 ml normal saline (n = 20, control group) via a thoracic epidural catheter. The study solution was given (double-blind and at random) after the patients had been anaesthetized with i.v. midazolam, sufentanil and vecuronium. Anaesthesia was maintained with 60% nitrous oxide in oxygen and halothane at a 1% inspiratory concentration. When patients showed signs of inadequate analgesia, supplementary doses of 25 mu g sufentanil were given i.v. The number of patients requiring additional i.v. sufentanil differed significantly between the two groups: 5 out of 20 patients in the ES group vs 13 out of 20 patients in the control group required additional sufentanil (P<0.05). The mean dose administered i.v. did not differ significantly between the two groups: 105 +/- 109.5 mu g vs 138.5 +/- 126.9 mu g (mean +/- SD) in 5 and 13 patients, respectively. No cardiovascular changes were observed after the epidural bolus dose. Postoperative analgesia, consisting of a continuous epidural infusion of 50 mu g sufentanil in 50 ml bupivacaine 0.125% at a rate of 6-10 ml/h after a bolus dose of 10 ml of this solution, was adequate in the majority of patients, as determined by VAS-scores assessed during the epidural treatment (4.3 +/- 1.5 days).

Objective: To study the influence of hypothermic cardiopulmonary bypass (CPB) on the pharmacodynamics and pharmacokinetics of rocuronium., Design: Prospective, descriptive study., Setting: Operating room at a university hospital., Participants: Ten ASA class III and IV patients, ranging in age from 35 to 75 years, scheduled for elective coronary artery bypass grafting., Interventions: Neuromuscular transmission was monitored mechanomyographically. The time course of action of maintenance doses and plasma concentration-response relationships were determined before, during, and after CPB. The plasma concentration decay and renal elimination were studied simultaneously. Plasma and urine concentration of rocuronium were determined by high-performance liquid chromatography., Measurements and Main Results: Hypothermic CPB prolonged the duration of action of maintenance doses and coincided with a lower plasma concentration at a twitch response of 5% of control. The duration of action of maintenance doses returned to prehypothermic CPB level after rewarming to a nasopharyngeal temperature of 37 degrees C. The plasma concentration-response relationship did not return to precooling control value, probably owing to persisting peripheral hypothermia. Both the renal elimination of rocuronium and the plasma concentration decay after the last maintenance dose under normothermic conditions resembled values obtained in patients not undergoing hypothermic CPB., Conclusions: Hypothermic CPB prolongs the duration of action of maintenance doses and alters the plasma concentration-response relationship of rocuronium. These changes may be the result of, on the one hand, an increased sensitivity of the neuromuscular transmission and/or decreased muscle contractility and, on the other hand, the result of a reduced plasma clearance during hypothermia.

In 10 patients scheduled for elective coronary artery bypass grafting under midazolam-sufentanil anaesthesia, the influence of hypothermia on the plasma concentration-response and biodisposition of rocuronium were investigated. Neuromuscular function was monitored mechanomyographically. Plasma and urine concentrations of rocuronium were determined by high performance liquid chromatography. Hypothermic cardiopulmonary bypass prolonged the duration of action of maintenance doses and altered the plasma concentration-response relationship. The elimination and distribution half-lives, following the last maintenance dose after rewarming, and the urinary excretion of rocuronium were similar to values obtained during normothermia. A diminished hepatic uptake and storage in the liver of rocuronium during hypothermia may explain the more pronounced prolongation of the duration compared to that of other steroidal neuromuscular blocking agents.

The neuromuscular and cardiovascular effects of neostigmine, 40 micrograms kg-1, and methyl-atropine, 7 micrograms kg-1, administered at different degrees of rocuronium-induced (600 micrograms kg-1) neuromuscular block were evaluated. In one group of patients spontaneous recovery was awaited (Group A; n = 20). Neostigmine and methyl-atropine were administered 2 minutes after rocuronium (Group B; n = 20) or at 25% twitch recovery (Group C; n = 20). Neuromuscular transmission was monitored mechanomyographically. Data are presented as mean (SD) [95%-CI]. The initial rate of recovery (time until a TOF ratio of 0.2) in group B, i.e. 14.2 (4.5) [12.1-16.3] min, was significantly faster than in group C, i.e. 28.7 (5.3) [26.3-31.1] min. However, the time until clinically sufficient recovery (time until a TOF ratio of 0.7) was similar for groups B, i.e. 29.3 (9.5) [24.9-33.7] min and group C, i.e. 31.8 (5.6) [29.2-34.4] min, both significantly different from that of group A, i.e. 53.2 (14.5) [46.5-59.9] min. The increase in heart rate following neostigmine/methyl-atropine was more pronounced in the group reversed at 2 min after rocuronium (P < 0.01).

Study Objective: To evaluate the time course of action, dose requirement, reversibility, and pharmacokinetics of rocuronium (Org 9426) under 3 anesthetic techniques (nitrous oxide-fentanyl supplemented with propofol, halothane, or isoflurane)., Design: Prospective, randomized study., Setting: Operating suite at a university hospital., Patients: 36 ASA physical status I-III patients aged 18 to 65 years who were scheduled for elective surgery., Interventions: The time course of action of an intubation dose of rocuronium 600 micrograms/kg was investigated in 36 patients. In 18 of these patients, the maintenance dose requirement of rocuronium and reversibility by neostigmine were evaluated. In the remaining 18 patients, the pharmacokinetics of rocuronium after the intubating dose were studied. Neuromuscular transmission was monitored by mechanomyography. Venous blood samples and urine were analyzed by high-performance liquid chromatography., Measurements and Main Results: With the exception of a longer clinical duration of rocuronium-induced neuromuscular block in the isoflurane group compared with the propofol group (p = 0.03), time course of action variables were similar in the 3 groups. In patients receiving maintenance doses of rocuronium, the dose requirement until reversal was 636 +/- 191 micrograms/kg/hr, 496 +/- 107 micrograms/kg/hr, and 384 +/- 127 micrograms/kg/hr for the propofol, halothane, and isoflurane groups, respectively (p = 0.02 for the isoflurane group vs. the propofol group). With respect to the reversal of a rocuronium-induced neuromuscular block, there were no differences in the percentage recovery or rate of recovery among the 3 groups. Pharmacokinetic analysis showed no significant differences for rocuronium during the 3 anesthetic techniques., Conclusion: Isoflurane potentiates the rocuronium-induced neuromuscular block, resulting in a longer clinical duration and lower maintenance dose requirement. This difference is not explained by differences in pharmacokinetics but is probably due to increased sensitivity of the neuromuscular junction to rocuronium during isoflurane anesthesia.

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 intubating conditions and neuromuscular blocking profile following 600 micrograms.kg-1 rocuronium (Org 9426) have been investigated in patients under various experimental conditions. They were compared with conditions following 1.5 mg.kg-1 suxamethonium, preceded by a precurarising dose (10 mg) of gallamine, and with those in a control group in the absence of a muscle relaxant. Rocuronium produced good to excellent intubating conditions at 60 as well as at 90 s after administration, even though there was only a partial blockade of the adductor pollicis muscle. Intubating conditions following suxamethonium were comparable with those after rocuronium. Half of the control patients could be intubated. The clinical duration and the recovery time of 600 micrograms.kg-1 of rocuronium were 24(4) and 9(3) min (mean(s.d.)), respectively. Rocuronium may have a major advantage over existing non-depolarising muscle relaxants due to the early presence of excellent intubating conditions. The results indicate that rocuronium may replace suxamethonium in procedures in which rapid sequence induction is required.

Changes induced by cardiopulmonary bypass (CPB) may markedly affect the pharmacokinetics of drugs. Therefore, the pharmacokinetics of alfentanil before and after CPB were compared in infants and children undergoing cardiac surgery, who had been anesthetized with nitrous oxide in oxygen and low inspiratory concentrations of halothane. Six infants and six children were investigated. Before CPB, alfentanil, 200 micrograms/kg, and after CPB, alfentanil, 80 micrograms/kg, was infused in 10 minutes. Arterial blood samples were obtained before and after CPB for determination of plasma alfentanil concentrations. Bi-exponential functions were fitted to the plasma concentration-time data using weighted least-squares nonlinear regression analysis. A correction was made to account for the contribution of the first infusion to the plasma concentrations measured during and after the second infusion. Total sampling time before CPB (45 to 75 minutes) was too short to allow full characterization of the pharmacokinetics of alfentanil, but allowed estimation of the initial volume of distribution. The initial volume of distribution before CPB was smaller (68 +/- 37 mL/kg in infants and 80 +/- 32 mL/kg in children) than after CPB (235 +/- 58 mL/kg in infants and 179 +/- 99 mL/kg in children; P less than 0.001). The normalized area under the plasma concentration-time curve from 0 to 45 minutes was larger before CPB (17.9 +/- 2.9 mg.min/L in infants and 18.3 +/- 5.4 mg.min/L in children) than after CPB (11.1 +/- 2.9 mg.min/L in infants and 12.9 +/- 3.4 mg.min/L in children; P less than 0.001). Despite intravenous administration of atropine, arterial blood pressure and heart rate decreased significantly after alfentanil was given.

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)

An acute episode of a malignant hyperthermia-like syndrome is described which occurred after suxamethonium and isoflurane anaesthesia in a 41-year-old healthy male patient undergoing a minor elective hand operation. Dantrolene therapy rapidly reversed the life-threatening signs. Laboratory results appeared to confirm the suspicion of malignant hyperthermia. However, the in vitro contracture test, which was carried out according to the standards of the European Malignant Hyperthermia Group, was equivocal.

The dose-response relationship of Org 9426, its time course of action and the reversibility of the residual block by neostigmine have been investigated in 100 patients undergoing various anaesthetic techniques. The dose-response was measured immediately following induction of anaesthesia. Doses of Org 9426, required for 50% and 90% depression of the twitch height, were 202 and 328 micrograms.kg-1, respectively. The clinical duration of the maintenance doses, 150 micrograms.kg-1, ranged from 9.5 to 13.4 min and from 12.8 to 18.9 min for the first and fifth maintenance doses, respectively. Spontaneous recovery indices (25%-75%) were between 9.5 and 16.7 min; neostigmine methylsulphate administered at 25% recovery of the twitch height promptly reversed the residual block. No side effects were observed. The extent of the influence of the anaesthetic on the time course of Org 9426 appears to be fractional considering the variation of the time course within the separate groups.

The CNS effects resulting from the combined administration of midazolam and flumazenil were studied in 8 healthy volunteers to develop a model of the pharmacokinetic-pharmacodynamic interaction. Electroencephalograms (EEG) were recorded between Fp1-M1 and Fp2-M2. The EEG parameter total number of waves between 12 and 30 Hz (TNW12-30) derived by aperiodic analysis was used to quantify the effect. Following a 15 min baseline EEG recording, infusion of placebo or flumazenil was started. Infusion regimens for flumazenil were designed so that 'steady-state' concentrations of 10 and 20 micrograms/L were obtained. Doses of midazolam 15, 30 and 60 mg over 5 min were given 30 min after the start of placebo infusion (session A) or flumazenil infusion to 10 micrograms/L (session B) or 20 micrograms/L (session C), respectively. Venous blood samples were taken until 8 h after the start of the flumazenil or placebo infusion. A sigmoid maximum effect (Emax) model was used to characterise the relationship between the plasma concentration of midazolam which is in equilibrium with the effect compartment concentration (Cem) [Cem/Kp] and TNW12-30. Within 2 to 5 min of starting the midazolam infusion all subjects fell asleep, with loss of eyelid reflex. They awoke between 25 and 82 min later in all 3 sessions. The mean (+/- SD) plasma drug concentrations of midazolam corresponding to half the maximum increase in TNW12-30 (EC50) were 276 +/- 64, 624 +/- 187 and 1086 +/- 379 micrograms/L in sessions A, B and C, respectively. The half-lives reflecting equilibration between plasma concentration and effect (t1/2ke0), estimated by a nonparametric method, were 2.2 +/- 1.2, 3.3 +/- 3.3 and 2.9 +/- 1.2 min for the 3 different sessions. Emax and N were not affected by flumazenil. In each subject the plot of the average measured steady-state plasma flumazenil concentration versus the EC50 of midazolam showed a linear relationship. The plasma concentration of flumazenil that doubled the EC50 of midazolam (Cf,2) was 6.5 +/- 1.0 micrograms/L. The observed interaction is consistent with the competitive nature of the antagonism of midazolam by flumazenil.

The effect of intravenous flumazenil 10 mg on the electroencephalogram (EEG) was investigated in 7 volunteers in a placebo-controlled, randomised, double-blind, crossover study. The EEG was recorded between Fp1-M1 and Fp2-M2 and analysed using an aperiodic analysis technique. Two volunteers were excluded from the study because of significant asymmetry between baseline EEG recordings of the left and right hemisphere, in the remainder there were no changes in the beta-frequency range (12 to 30 Hz) or in other ranges of the EEG during or after flumazenil or placebo administration, with regard to the parameters total number of waves per second or total amplitude per second. There were no changes in heart rate, respiratory rate or blood pressure after administration of flumazenil or placebo. Three volunteers reported feelings of 'pressure to move' during the initial 2 min of the flumazenil infusion. The pharmacokinetics of flumazenil were investigated in the same volunteers. Flumazenil 10 mg was administered intravenously over 10 min; the data from 1 volunteer were excluded from this analysis because of blood sampling problems. The plasma concentration-time data of the remaining 6 volunteers were characterised by a biexponential function. The pharmacokinetic parameters were (mean +/- SD): initial volume of distribution, 16 +/- 5.7L; volume of distribution at steady-state, 64.8 +/- 12.5L; total body clearance, 53.8 +/- 1.2 L/h; distribution half-life, 4.1 +/- 1.3 min; and elimination half-life, 70.2 +/- 9.9 min. The authors conclude that flumazenil has no significant EEG effects. The rapid distribution and elimination of flumazenil may explain its previously reported short duration of action after intravenous anaesthesia with high doses of midazolam.

A patient is presented where routine venepuncture associated with anaesthetic induction resulted in bradycardia and asystole. The case highlights the need for special caution with, and ECG monitoring throughout induction for, patients with a history of syncope. It also demonstrates the need for caution when attributing cardiovascular events during induction to the effect of the induction agents used.

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.