Litre Min Research Articles

Vecuronium Pharmacokinetics in Patients With Major Burns

Abstract Background Burn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns. Methods Twenty adults, aged 23–58 yr, with 27–81% total body surface area (TBSA) burn, were studied at 4–57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg −1 was given i.v. as a single bolus within 10 s. Blood samples ( n =20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration–time profiles for burns and non-burns. Results A three-compartment model best described vecuronium concentration–time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min −1 , P vs 6.6 h, P Conclusions The altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns.

Corrigenda

The Journal of PhysiologyVolume 592, Issue 14 p. 3161-3161 CORRIGENDAFree Access Corrigenda This article corrects the following: Tracking pulmonary gas exchange by breathing control during exercise: role of muscle blood flow Philippe Haouzi, Volume 592Issue 3The Journal of Physiology pages: 453-461 First Published online: December 13, 2013 First published: 15 July 2014 https://doi.org/10.1113/jphysiol.2014.277087AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In the article by Haouzi (2014), on p. 454 left column, line 26 from the bottom of the page should read: …, the rate at which CO2 is transported by the venous system () is more than 10 times its rate of production: There is, in addition to the CO2 produced by all the tissues, more than 2 litres min−1 of CO2 coming for the arterial side which must be transported by the venous system towards the lungs (Dejours, 1981). Reference Haouzi P (2014). Tracking pulmonary gas exchange by breathing control during exercise: role of muscle blood flow. J Physiol 592, 453– 461. Volume592, Issue1415 July 2014Pages 3161-3161 ReferencesRelatedInformation

Bispectral Index Guided Sedation in Congenital Pain Insensitivity Syndrome.

Bispectral Index Guided Sedation in Congenital Pain Insensitivity Syndrome.

Validation of cardiac output monitoring based on uncalibrated pulse contour analysis vs transpulmonary thermodilution during off-pump coronary artery bypass grafting

Cardiac output monitoring, as a part of a goal-directed haemodynamic management, has been shown to improve perioperative outcome in high-risk patients undergoing major surgical interventions. However, thorough validation of cardiac output monitoring devices in different clinical conditions is warranted. The aim of our study was to compare the reliability of a novel system for cardiac index (CI) monitoring based on uncalibrated pulse contour analysis (UPCA) with transpulmonary thermodilution (TPTD) during off-pump coronary artery bypass grafting (OPCAB). Twenty patients undergoing elective OPCAB were enrolled into the study. CI measured by means of UPCA (CIUPCA) was validated against CI determined with TPTD technique (CITPTD). Parallel measurements of CI were performed at nine stages during the surgery and after operation. We assessed the accuracy and the precision of individual values and the agreement of trends of changes in CI. Totally, 180 pairs of data were collected. There was a significant correlation between CIUPCA and CITPTD (ρ=0.836, P<0.01). According to a Bland-Altman analysis, the mean bias between the methods was -0.14 litre min(-1) m(-2) with limits of agreement of ±0.82 litre min(-1) m(-2) and a percentage error of 31%. A polar plot trend analysis revealed acceptable angular bias (-0.54°), increased radial limits of agreement (±52.7°), and decreased polar concordance rate (74%). In OPCAB, UPCA provides accurate and precise CI measurements compared with TPTD. However, the ability of this method to follow trends in cardiac output is poor. NCT01773720 (ClinicalTrials.gov).

Novel continuous capnodynamic method for cardiac output assessment during mechanical ventilation

It is important to be able to accurately monitor cardiac output (CO) during high-risk surgery and in critically ill patients. The invasiveness of the pulmonary artery catheter (PAC) limits its use, and therefore, new minimally invasive methods for CO monitoring are needed. A potential method is estimation of CO from endogenous carbon dioxide measurements, using a differentiated Fick's principle to determine effective pulmonary blood flow (EPBF). In this study, we aimed to validate a novel capnodynamic method (COEPBF) in a wide range of clinically relevant haemodynamic conditions. COEPBF was studied in 10 pigs during changes in preload, afterload, CO increase, and bleeding. An ultrasonic flow probe around the pulmonary artery was used as reference method of CO determination. CO was also measured using a PAC thermodilution technique (COPAC). CO and other haemodynamic data were recorded before and during each intervention. Accuracy and precision and also the ability to track changes in CO were determined using Bland-Altman, four-quadrant plot and polar plot analysis. COEPBF and COPAC showed equally good agreement, with a tendency to overestimate CO (bias 0.2 and 0.3 litre min(-1), respectively). The overall percentage error was 47% for COEPBF and 49% for COPAC. The concordance for tracking CO changes was 97 and 95% for COEPBF and COPAC, respectively, with an exclusion zone of 15% and radial limits of ±30°. COEPBF showed reliable trending abilities, equivalent to COPAC. COEPBF and COPAC also showed low bias but high percentage errors. Further studies in animal models of lung injury and in high-risk surgery patients are warranted.

Determination of cardiac output by ultrasound dilution technique in infants and children: a validation study against direct Fick principle

BackgroundIn critically ill children, monitoring of cardiac output (CO) is essential to guide haemodynamic management and facilitate cardiovascular therapy. The ultrasound dilution technique (UDT), a novel minimally invasive indicator method, was recently introduced to determine CO. We validated UDT against the ‘gold standard’ reference technique, the direct Fick principle, in infants and children. MethodsTwenty-six children (median age: 6 yr 2 months; median weight: 19.2 kg) underwent diagnostic heart catheterization. In each child, CO was determined by the Fick principle using direct measurement of oxygen consumption and invasive oximetry. Consecutively, haemodynamically stable conditions provided; three independent measurements of CO were conducted with UDT. CO values were compared using bias and limits of agreement calculated using the Bland–Altman approach and linear regression analysis for the complete study group and for a subgroup with body weight <20 kg (n=14). ResultsThe mean (standard deviation) CO values were 3.76 (1.73) litre min−1 (range 1.38–6.97) for the direct Fick principle and 3.49 (1.72) litre min−1 (range 1.31–7.00) for UDT. An excellent correlation (r=0.96) was found between both methods (P<0.0001). The Bland–Altman analysis demonstrated good clinical agreement with a mean bias of 0.26 litre min−1, limits of agreement of −0.66 and 1.19 litre min−1, and percentage error of 25.9%. Comparable results were obtained for patients <20 kg (mean bias=0.19 litre min−1, percentage error=25.5%). ConclusionsCO measurements by UDT agree favourably with Fick-derived CO data and both techniques were found to be equivalent and interchangeable. UDT represents a valid and applicable method for repetitive CO determinations in infants and children.

Vecuronium pharmacokinetics in patients with major burns

BackgroundBurn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns. MethodsTwenty adults, aged 23–58 yr, with 27–81% total body surface area (TBSA) burn, were studied at 4–57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg−1 was given i.v. as a single bolus within 10 s. Blood samples (n=20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration–time profiles for burns and non-burns. ResultsA three-compartment model best described vecuronium concentration–time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min−1, P<0.0001), which yielded shorter elimination half-life for vecuronium (5.5 vs 6.6 h, P<0.001). BURN was the single most significant covariate that explained the altered vecuronium disposition in burns. ConclusionsThe altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns.

Open-label, phase II study of routine high-flow nasal oxygen therapy in cardiac surgical patients

Respiratory complications after cardiac surgery increase morbidity, mortality, and length of stay. Studies suggest that routine delivery of positive airway pressure after extubation may be beneficial. We sought to determine whether the routine administration of nasal high-flow oxygen therapy (NHF) improves pulmonary function after cardiac surgery. A pragmatic randomized controlled trial; participants received either NHF (45 litre min(-1)) or usual care from extubation to Day 2 after surgery. The primary outcome was number of patients with / ratio ≥445 on Day 3 after surgery. The secondary outcomes included atelectasis score on chest X-ray; spirometry; intensive care and hospital length of stay; mortality on Day 28; oxygenation indices; escalation of respiratory support; and patient comfort. We randomized 340 patients over 14 months. The number of patients with a / ratio of ≥445 on Day 3 was 78 (46.4%) in the NHF group vs 72 (42.4%) standard care [odds ratio (OR) 1.18, 95% confidence interval (CI) 0.77-1.81, P=0.45]. was reduced at both 4 h post-extubation and at 9 a.m. on Day 1 in the NHF group (5.3 vs 5.4 kPa, P=0.03 and 5.1 vs 5.3 kPa, P=0.03, respectively). Escalation in respiratory support at any time in the study occurred in 47 patients (27.8%) allocated to NHF compared with 77 (45%) standard care (OR 0.47, 95% CI 0.29-0.7, P=0.001). Routine use of NHF did not increase / ratio on Day 3 but did reduce the requirement for escalation of respiratory support. Australia New Zealand Clinical Trials Registry www.anzctr.org.au (ACTRN12610000973011).

Reliability of lithium dilution cardiac output in anaesthetized sheep

Cardiac output (CO) measurement with lithium dilution (COLD) has not been fully validated in sheep using precise ultrasonic flow probe technology (COUFP). Sheep generate important cardiovascular research models and the use of COLD has become more popular in experimental settings. Ultrasonic transit-time perivascular flow probes were surgically implanted on the pulmonary artery of 13 sheep. Paired COLD readings were taken at six time points, before and after implantation of a left ventricular assist device (LVAD) and compared with COUFP recorded just after lithium injection. The mean COLD was 5.7 litre min(-1) (range 3.8-9.6 litre min(-1)) and mean COUFP 5.9 litre min(-1) (range 4.0-9.2 litre min(-1)). The bias (standard deviation) was 0.3 (1.0) litre min(-1) [5.1 (16.9)%] and limits of agreement (LOA) were -1.7 to 2.3 litre min(-1) (-28.8 to 39.0%) with a percentage error (PE) of 34.4%. Data to assess trending [rate (95% confidence intervals)] included a 78 (62-93)% concordance rate in the four-quadrant plot (n=27). In the half moon polar plot (n=19), the mean polar angle was +5°, the radial LOA were -49 to +35° and 68 (47-89)% of data points fell within 22.5° of the mean polar angle. Both tests indicated moderate to poor trending ability. COLD is not precise when evaluated against COUFP in sheep based on the statistical criteria set, but the results are comparable with previously published animal studies.

Determination of Cardiac Output by Ultrasound Dilution Technique in Infants and Children: A Validation Study against Direct Fick Principle

Abstract Background In critically ill children, monitoring of cardiac output (CO) is essential to guide haemodynamic management and facilitate cardiovascular therapy. The ultrasound dilution technique (UDT), a novel minimally invasive indicator method, was recently introduced to determine CO. We validated UDT against the ‘gold standard’ reference technique, the direct Fick principle, in infants and children. Methods Twenty-six children (median age: 6 yr 2 months; median weight: 19.2 kg) underwent diagnostic heart catheterization. In each child, CO was determined by the Fick principle using direct measurement of oxygen consumption and invasive oximetry. Consecutively, haemodynamically stable conditions provided; three independent measurements of CO were conducted with UDT. CO values were compared using bias and limits of agreement calculated using the Bland–Altman approach and linear regression analysis for the complete study group and for a subgroup with body weight n =14). Results The mean (standard deviation) CO values were 3.76 (1.73) litre min −1 (range 1.38–6.97) for the direct Fick principle and 3.49 (1.72) litre min −1 (range 1.31–7.00) for UDT. An excellent correlation ( r =0.96) was found between both methods ( P −1 , limits of agreement of −0.66 and 1.19 litre min −1 , and percentage error of 25.9%. Comparable results were obtained for patients −1 , percentage error=25.5%). Conclusions CO measurements by UDT agree favourably with Fick-derived CO data and both techniques were found to be equivalent and interchangeable. UDT represents a valid and applicable method for repetitive CO determinations in infants and children.

Performance of a new pulse contour method for continuous cardiac output monitoring: validation in critically ill patients

BackgroundA new calibrated pulse wave analysis method (VolumeView™/EV1000™, Edwards Lifesciences, Irvine, CA, USA) has been developed to continuously monitor cardiac output (CO). The aim of this study was to compare the performance of the VolumeView method, and of the PiCCO2™ pulse contour method (Pulsion Medical Systems, Munich, Germany), with reference transpulmonary thermodilution (TPTD) CO measurements. MethodsThis was a prospective, multicentre observational study performed in the surgical and interdisciplinary intensive care units of four tertiary hospitals. Seventy-two critically ill patients were monitored with a central venous catheter, and a thermistor-tipped femoral arterial VolumeView™ catheter connected to the EV1000™ monitor. After initial calibration by TPTD CO was continuously assessed using the VolumeView-CCO software (CCOVolumeView) during a 72 h period. TPTD was performed in order to obtain reference CO values (COREF). TPTD and arterial wave signals were transmitted to a PiCCO2™ monitor in order to obtain CCOPiCCO values. CCOVolumeView and CCOPiCCO were recorded over a 5 min interval before assessment of COTPTD. Bland–Altman analysis, %errors, and concordance (trend analysis) were calculated. ResultsA total of 338 matched sets of data were available for comparison. Bias for CCOVolumeView−COREF was −0.07 litre min−1 and for CCOPiCCO–COREF +0.03 litre min−1. Corresponding limits of agreement were 2.00 and 2.48 litre min−1 (P<0.01), %errors 29 and 37%, respectively. Trending capabilities were comparable for both techniques. ConclusionsThe performance of the new VolumeView™-CCO method is as reliable as the PiCCO2™-CCO pulse wave analysis in critically ill patients. However, an improved precision was observed with the VolumeView™ technique. Clinicaltrials.gov identifierNCT01405040.

Transpulmonary thermodilution cardiac output measurement is not affected by severe pulmonary oedema: a newborn animal study

BackgroundThe transpulmonary thermodilution (TPTD) technique is widely used in clinical practice for measuring cardiac output (CO). This study was designed to investigate the influence of various levels of pulmonary oedema on the reliability of CO measurements by the TPTD method. MethodsIn 11 newborn lambs pulmonary oedema was induced using a surfactant washout technique. Serial CO measurements using TPTD (COTPTD) were performed at various amounts of lung water. Simultaneously, CO was measured by an ultrasound flow probe around the main pulmonary artery (COMPA) and used as the standard reference. CO was divided by the body surface area to calculate cardiac index (CI). Data were analysed using correlational statistics and Bland–Altman analysis. ResultsOne lamb died prematurely. A total of 56 measurements in 10 lambs were analysed with a median CIMPA of 2.95 (IQR 1.04) litre min−1 m−2. Mean percentage increase in extravascular lung water (EVLW) between the start and the end of the study was 126.4% (sd 40.4). Comparison of the two CO methods showed a mean bias CI of −0.16 litre min−1 m−2 (limits of agreement ±0.73 litre min−1 m−2) and a percentage error of 23.8%. Intraclass correlation coefficients were 0.91 (95% CI 0.81–0.95) for absolute agreement and 0.92 (95% CI 0.87–0.95) for consistency. Acceptable agreement was confirmed by a tolerability-agreement ratio of 0.39. The within-subject correlation between the amount of EVLWI and the bias between the two methods was not significant (−0.02; P=0.91). ConclusionsCO measurements by the transpulmonary thermodilution technique over a wide range of CI values are not affected by the presence of high EVLWI. The slight underestimation of the CO is independent of the amount of pulmonary oedema.

Delivery of tidal volume from four anaesthesia ventilators during volume-controlled ventilation: a bench study

Tidal volume (V(T)) must be accurately delivered by anaesthesia ventilators in the volume-controlled ventilation mode in order for lung protective ventilation to be effective. However, the impact of fresh gas flow (FGF) and lung mechanics on delivery of V(T) by the newest anaesthesia ventilators has not been reported. We measured delivered V(T) (V(TI)) from four anaesthesia ventilators (Aisys™, Flow-i™, Primus™, and Zeus™) on a pneumatic test lung set with three combinations of lung compliance (C, ml cm H2O(-1)) and resistance (R, cm H2O litre(-1) s(-2)): C60R5, C30R5, C60R20. For each CR, three FGF rates (0.5, 3, 10 litre min(-1)) were investigated at three set V(T)s (300, 500, 800 ml) and two values of PEEP (0 and 10 cm H2O). The volume error = [(V(TI) - V(Tset))/V(Tset)] ×100 was computed in body temperature and pressure-saturated conditions and compared using analysis of variance. For each CR and each set V(T), the absolute value of the volume error significantly declined from Aisys™ to Flow-i™, Zeus™, and Primus™. For C60R5, these values were 12.5% for Aisys™, 5% for Flow-i™ and Zeus™, and 0% for Primus™. With an increase in FGF, absolute values of the volume error increased only for Aisys™ and Zeus™. However, in C30R5, the volume error was minimal at mid-FGF for Aisys™. The results were similar at PEEP 10 cm H2O. Under experimental conditions, the volume error differed significantly between the four new anaesthesia ventilators tested and was influenced by FGF, although this effect may not be clinically relevant.

Pressure recording analytical method for measuring cardiac output in critically ill children: a validation study

Pressure recording analytical method (PRAM) is a novel, arterial pulse contour-based method for measuring cardiac output (CO). Validation studies of PRAM in children are few, and have not assessed both absolute accuracy and ability to track changes in CO across a broad case mix. We aimed to compare CO as measured by PRAM with that using a transpulmonary dilution method in a cohort of critically ill children. Forty-eight, mechanically ventilated children with a median (inter-quartile) weight of 10.7 (5.5-15) kg with arterial and central venous catheters in situ were studied. CO was measured simultaneously using PRAM and the comparator method, transpulmonary ultrasound dilution (UD). Measurements were repeated before and after therapeutic interventions that were intended to augment CO (e.g. fluid bolus). In total, 210 paired measurements were compared. The mean (sd) CO was 1.9 (1.2) litre min(-1) with UD when compared with 1.92 (0.5) litre min(-1) using PRAM. The mean bias was 0.02 litre min(-1) with wide limits of agreement: ± 2.21 litre min(-1), giving a percentage error of 116%. The concordance between PRAM and UD for measuring changes in CO was also poor, with only 37% of measurements falling within the pre-defined polar plot limits of ±30°. There is an unacceptably poor agreement between UD and PRAM. We do not recommend the use of PRAM for measuring CO in critically ill children with the current algorithm.

Single-breath vital capacity high concentration sevoflurane induction in children: with or without nitrous oxide?

Single-breath vital capacity inhalation induction with high concentration sevoflurane (SBVC-HC) is a rapid and 'needleless' technique, preferred and well tolerated in the cooperative child. The addition of nitrous oxide may speed up induction by its second gas effects. Previous studies done in children looking at the effect of N(2)O on this technique lacked power and showed conflicting results. This study aims to investigate the effect of N(2)O on induction time for SBVC-HC sevoflurane induction in children. Eighty unpremedicated, ASA I and II children, aged 5-15 yr having elective surgical procedures under general anaesthesia, were recruited and randomized to: Group A: 8% sevoflurane in O(2) 6 litre min(-1), and Group B: 8% sevoflurane in N(2)O 4 litre min(-1) and O(2) 2 litre min(-1). The primary outcome was the time to 'loss of eyelash reflex'. The time to return of 'regular respiration' and 'conjugate gaze' were also noted. The difference in the 'time to loss of eyelash reflex' was small but statistically significant. Group B: mean duration 53.6 s, standard deviation (SD) 16.1, compared with Group A: 63.5 s, SD 16.1 (mean difference 9.9, 95% confidence interval 2.5-17.3, P=0.01). Differences in the time to return of 'regular breathing' and 'conjugate gaze' were not statistically significant. Patients receiving N(2)O had less excitatory movements (P=0.007), but incidence of other adverse events was low and did not differ significantly between both groups. More than 94% of children would choose this method of induction again in both groups. We conclude that for SBVC-HC sevoflurane induction in children, the addition of N(2)O resulted in faster loss of consciousness and reduced excitatory movements.

Influence of lung injury on cardiac output measurement using transpulmonary ultrasound dilution: a validation study in neonatal lambs

Transpulmonary ultrasound dilution (TPUD) is a promising method for cardiac output (CO) measurement in severely ill neonates. The incidence of lung injury in this population is high, which might influence CO measurement using TPUD because of altered lung perfusion. We evaluated the influence of lung injury on the accuracy and precision of CO measurement using TPUD in an animal model. In nine neonatal lambs, central venous and arterial catheters were inserted and connected to the TPUD monitor. Repeated lavages with warmed isotonic saline were performed to gradually induce lung injury. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe around the main pulmonary artery (COufp). An increase in oxygenation index was used as an indicator of induced lung injury during the experiment. Post-mortem lung injury was confirmed by histopathological examination. Fifty-five sessions of three paired CO measurements were analysed. The mean COufp was 1.53 litre min(-1) (range 0.66-2.35 litre min(-1)), and the mean COtpud was 1.65 litre min(-1) (range 0.78-2.91 litre min(-1)). The mean bias (standard deviation) between the two methods was 0.13 (0.15) litre min(-1) with limits of agreement of ±0.29 litre min(-1). The overall percentage error was 19.1%. The accuracy and precision did not change significantly during progressive lung injury. Histopathological severity scores were consistent with heterogeneous lung injury. The capability to track changes in CO using TPUD was moderate to good. The accuracy and precision of CO measurement using TPUD is not influenced in the presence of heterogeneous lung injury in an animal model.

Comparison of esCCO and transthoracic echocardiography for non-invasive measurement of cardiac output intensive care

The esCCO monitor (ECG- estimated Continuous Cardiac Output, Nihon Kohden(®)) is a new non-invasive tool for estimating cardiac output (CO). It derives CO from the pulse wave transit time (PWTT) estimated by the ECG and the plethysmographic wave. An initial calibration is needed to refine the relation linking pulse pressure (measured by arterial pressure cuff) to PWTT. To assess the accuracy and reliability of the esCCO system, we performed an analysis of agreement of CO values obtained by transthoracic echocardiography (TTE). Thirty-eight intensive care unit patients were prospectively included. CO was determined simultaneously using esCCO (CO(esCCO)) and TTE (CO(TTE)) as our reference method. A total of 103 paired readings from 38 patients were collected. The correlation coefficient between CO(esCCO) and CO(TTE) was 0.61 (P<0.001). The Bland and Altman analysis corrected for repeated measures showed a bias of -1.6 litre min(-1) and limits of agreement from -4.7 to +1.5 litre min(-1), with a percentage error (2 sd/mean CO) of 49%. The correlation for CO changes was significant (R=0.63, P<0.001), but the concordance rate was poor (73%). Polar plot analysis showed an angular bias of -9° with radial limits of agreement from -54° to +36°. The bias appeared to correlate with systemic vascular resistance (R=-0.45, P<0.001). In critically ill patients, the performance of the esCCO monitor was not clinically acceptable, and this monitor cannot be recommended in this setting. Moreover, the esCCO failed to trend CO data reliably.

Comparative molecular field analysis to derive pharmacophore maps for disposition parameters of intravenous anaesthetic agents

The present study examines the molecular basis of the disposition kinetics for i.v. hypnotic agents using comparative molecular field analysis (CoMFA). The systemic clearance (Cl(s) litre min(-1)) and apparent volume of distribution at steady state (Vd(ss) litres) for 14 i.v. anaesthetics in human subjects were obtained from the literature, or from unpublished data, and used to form CoMFA models for the two aspects of drug disposition. Molecular alignment was achieved by field-fit minimization with the lead structure for all models eltanolone. The resulting pharmacophore maps were also compared with the pharmacophores for cardiovascular depression (expressed in terms of the drug concentration in 50% patients, associated with a 20% decrease in mean arterial pressure during infusion anaesthesia in the absence of other adjuvant drugs or noxious stimulation), which were taken from the literature. The CoMFA model for Cl was based on two latent variables, explained 95.2% of the variance in observed activities, and showed good intrinsic predictability (cross-validated q(2) 0.663). The model for Vd(ss) was also based on two latent variables: r(2) 0.986 and q(2) 0.718. Comparison of the pharmacophores for the two disposition parameters showed poor correlation for both electrostatic and steric regions (r=-0.220 and 0.018; both NS). The relative contributions of electrostatic and steric interactions differed between the models (Cl(s) 1.9:1; Vd(ss) 2.5:1). Comparison with the cardiovascular pharmacophores depression models gave r values of 0.551 (P<0.05) and 0.407 (ns) for Cl(s) (for electrostatic and steric models) and -0.225 and -0.448 for Vd(ss) (both ns). Comparison of CoMFA models for drug disposition show only small elements of commonality, suggesting different molecular features may be responsible are two properties. There was better similarity for both disposition pharmacophores with the pharmacophores for cardiovascular depression.

The hyperaemic response to passive leg movement is dependent on nitric oxide: a new tool to evaluate endothelial nitric oxide function

Passive leg movement is associated with a ∼3-fold increase in blood flow to the leg but the underlying mechanisms remain unknown. The objective of the present study was to examine the role of nitric oxide (NO) for the hyperaemia observed during passive leg movement. Leg haemodynamics and metabolites of NO production (nitrite and nitrate; NOx) were measured in plasma and muscle interstitial fluid at rest and during passive leg movement with and without inhibition of NO formation in healthy young males. The hyperaemic response to passive leg movement and to ACh was also assessed in elderly subjects and patients with peripheral artery disease. Passive leg movement (60 r.p.m.) increased leg blood flow from 0.3 ± 0.1 to 0.9 ± 0.1 litre min(-1) at 20 s and 0.5 ± 0.1 litre min(-1) at 3 min (P < 0.05). Mean arterial pressure remained unchanged during the trial. When passive leg movement was performed during inhibition of NO formation (N(G)-mono-methyl-l-arginine; 29-52 mg min(-1)), leg blood flow and vascular conductance were increased after 20 s (P < 0.05) and then returned to baseline levels, despite an increase in arterial pressure (P < 0.05). Passive leg movement increased the femoral venous NOx levels from 35 ± 5 at baseline to 62 ± 11 μmol l(-1) during passive leg movement (P < 0.05), whereas muscle interstitial NOx levels remained unchanged. The hyperaemic response to passive leg movement were correlated with the vasodilatation induced by ACh (r(2) = 0.704, P < 0.001) and with age (r(2) = 0.612, P < 0.001). Leg blood flow did not increase during passive leg movement in individuals with peripheral arterial disease. These results suggest that the hypaeremia induced by passive leg movement is NO dependent and that the source of NO is likely to be the endothelium. Passive leg movement could therefore be used as a non-invasive tool to evaluate NO dependent endothelial function of the lower limb.

Comparison Between an Uncalibrated Pulse Contour Method and Thermodilution Technique for Cardiac Output Estimation in Septic Patients

Background The purpose of this study was to evaluate the reliability of a new uncalibrated pulse contour method, the MostCare, in determining cardiac output (CO) in septic patients. Methods Thirty patients with septic shock admitted to an intensive care unit, receiving a norepinephrine infusion and requiring haemodynamic monitoring with a pulmonary artery catheter, were prospectively enrolled. Thermodilution measurements of CO (ThD-CO) were considered as the ‘gold standard'. MostCare was connected to the monitoring system of the radial arterial pressure waveform to obtain a continuous CO calculation (MostCare-CO). ThD-CO and MostCare-CO measurements were recorded at three different haemodynamic states: baseline (T1), after raising mean arterial pressure (MAP) to 90 mm Hg by increasing the norepinephrine infusion (T2), and after returning the MAP to baseline value by decreasing vasopressor therapy (T3). A Bland–Altman and linear regression analyses were performed. Results A total of 90 paired ThD-CO and MostCare-CO measures were obtained (range 4.1–13.9 litre min −1 for ThD-CO and 4.5–13.5 litre min −1 for MostCare-CO). A good correlation between ThD-CO and MostCare-CO was observed ( R = 0.93). The mean bias between the two techniques was −0.26 litre min −1 (sd 0.98 litre min −1 ) and the 95% limits of agreement were −2.22 to 1.70 litre min −1 . The percentage of error was 25%. Pearson's R was 0.94, 0.92, and 0.93 at T1, T2, and T3, respectively. Conclusions MostCare-CO and ThD-CO showed a good agreement at each time of the study. The reliability of the MostCare system was not affected by the vascular tone changes produced by a norepinephrine infusion.