Ian R. Thomson

Alfentanil pharmacokinetics in patients undergoing abdominal aortic surgery

The pharmacokinetics of alfentanil, 300 μg · kg−1 IV, were determined in patients undergoing elective abdominal aortic reconstruction. The mean age (± SD) of the patients wax 64.3 ±7.4 yr: their mean weight was 74.7 ± 13.8 kg. Five patients underwent aneurysm repair and six had aortobifemoral grafting. Serum alfentanil concentrations were measured by gas-liquid chromatography in samples drawn at increasing intervals over a 24-hr period. A three-compartment model was fitted to the concentration versus time data. The volume of the central compartment and the volume of distribution at steady state (Vdss) were 0.044 ± 0.022 and 0.63 ± 0.32 L · kg−1, respectively. Total drug clearance was 6.4 = 1.9 ml · min−1 · kg−1. The elimination half-time was 3.7 ± 2.6 hr. Patient age was positively correlated with both Vdss and elimination half-time. There were no significant correlations between the pharmacokinetic variables and the duration of aortic cross-clamping, the duration of surgery, or the rate or total volume of IV fluids infused intraoperatively. In general surgical patients, the elimination half-time of alfentanil has been reported to be 1.2–2.0 hr. Although the elimination half-time of alfentanil was longer in patients undergoing abdominal aortic surgery, alfen-tanil was eliminated much faster than either fentanyl or sufentanil in this patient population.RésuméNous avons tracé le profil pharmacocinétique d’une dose intraveineuse de 300 μg · kg−1 d’alfentanil lors de reconstructions électives de l’aorte. Cinq patients subirent une résection d’anévrysme et six autres, un pontage aortobifémoral. Ils avaient en moyenne 64,3 ± 7,4 ans et pesaient 74,7 ± 13,8 kg. On mesura les concentrations sériques d’alfentanil par chromatographie gaz-liquide sur des échantillons prélevés à intervalles croissants pendant 24 h. L’évolution temporelle des concentrations était celle d’un modèle pharmacocinétique tri-compartimental. Le compartiment central avait un volume de 0,044 ± 0,022 L · kg−1 et le volume de distribution à l’équilibre (Vdss était de 0,63 ± 0,32 L · kg−1: la clairance était de 6.4 ±1,9 ml · min−1 · kg−1 et la demievie d’élimination, 3,7 ± 2,6 h. Il y avait une corrélation positive entre l’âge du patient, le Vdss et la demievie. Les variables pharmacocinétiques étaient toutefois indépendantes de la durée du clampage aortique et de l’intervention, de même que du débit et du volume des liquides perfusés par voie veineuse pendant l’opération. Même si elle s’est avérée plus longue que celle de 1,2 à 2 h observée en chirurgie générale, la demievie d’élimination de l’alfentanil est beaucoup plus courte que celles du fentanyl et du sufentanil lors de chirurgie aortique.

A randomized double- blind comparison of fentanyl and sufentanil anaesthesia for coronary artery surgery

Using a randomized double-blind protocol the authors compared two narcotic anaesthetic regimens in 33 patients with good ventricular function undergoing coronary artery surgery. After premedication with morphine and scopolamine, patients received either fentanyl 100 μg.kg-1 (n = 16), or sufentanil 15 μg.kg-1 (n = 17), intravenously (IV) over 10 min to induce anaesthesia. Metocurine 0.42 mg kg-1 provided muscle relaxation. No further IV anaesthetic agents were given. The haemodynamic response to induction, intubation, and surgery, differed minimally between agents. The degree of rigidity on induction was identical with both agents, as were the intervals following induction at which patients lost consciousness, regained consciousness, or met criteria for extubation. However, the interval until extubation criteria were met did correlate with the duration of cardiopulmonary bypass. Sufentanil 15 μg.kg-1, was clinically indistinguishable from fentanyl 100 μg.kg-1, when used as the primary anaesthetic agent for coronary surgery.RésuméUtilisant un protocole randomisé à double insu les auteurs ont comparé deux régimes ďanesthésie au narcotic chez 33 patients ayant une bonne fonction ventriculaire et devant subir une chirurgie coronarienne. Après prémédication avec de la morphine et scopolamine, les patients ont reçu soit du fentanyl 100 μ.g·kg-1 (n = 16) ou du sufentanil 15 μg·kg-1 (n = 17), par voie intraveineuse en dix minutes afin ďinduire ľanesthésie. La métocurine 0.42 mg·kg-1 fut administrée pour relâchement musculaire. Aucune autre injection intraveineuse ďagent anesthésique ne fut donnée. La réponse hémodynamique à ľinduction, intubation et chirurgie a démontré une différence minime entre les deux agents. Le degré de rigidité à ľinduction était identique avec les deux agents. Il en fut de m ême pour les temps de perte de conscience, regain de conscience ou les critères ďextubation. Cependant ľintervalle pour atteindre les critères requis de ľextubation étaient en corrélation avec la durée de la CEC. Le sufentanil 15 μ,g·kg-1 n’étaient pas cliniquement différent du fentanyl 100 μg·kg-1 lorsqu’utilisé comme seul agent anesthésique pour la chirurgie coronarienne.

Dose-response to anaesthetic induction with sufentanil: haemodynamic and electroencephalographic effects

PurposeTo determine the effect of a five-fold variation in sufentanil dose on the haemodynamic and electroencephalo graphic (EEG) response to anaesthetic induction and tracheal intubation.MethodsThirty-four patients undergoing elective coronary artery bypass grafting (CABG) participated in this randomized double-blind study. Patients in Group L (n= 17) received 3 μg · kg−1 sufentanil and those in Group H (n= 17) 15 μg · kg−1. Premedication was 60 μg · kg−1 lorazepam po. Anaesthesia and neuromuscular blockade were induced by infusing sufentanil and 0.15 mg · kg−1 vecuronium iv over five minutes. Haemodynamic data and the electroencephalographic (EEG) spectral edge were acquired by computer and compared at Control, Induction and Intubation.ResultsSufentanil dose did not affect the haemodynamic or EEG response at end-induction. No bradyarrhythmias occurred, and the incidence of hypotension was 12% in both groups. However, during induction apparent electromyographic artifacts and a transiently greater increase in heart rate were observed in Group H. The serum sufentanil concentration at Induction was 6.1 ± 1.8 ng · ml−1 in Group L and 25.4 ± 8.8 ng · ml−1 in Group H, and did not correlate with haemodynamic changes. No patient recalled any intraoperative event.ConclusionIncreasing sufentanil dose from 3 to 15 μg · kg−1 does not influence the ultimate haemodynamic response to induction. Combined with lorazepam premedication, 3 μg · kg−1 sufentanil produces near-maximal haemodynamic and EEG effects and is adequate for induction and tracheal intubation of patients undergoing CABG. Sufentanil 15 μg · kg−1 is no more efficacious, and causes transient cardiovascular stimulation.RésuméObjectifDéterminer les effets hémodynamiques et électroencéphalographiques (EEG) d’une dose quintuple de sufentanil sur l’induction de l’anesthésie et l’intubation de la trachée.MéthodesTrente-quatre patients subissant une chirurgie de revascularisation myocardique (CRVM) non urgente participaient à cette étude aléatoire conduite à double insu. Les patients du groupe L (n= 17) recevaient sufentanil 3 μg · kg−1 et ceux du groupe H (n = 17) 15 μg · kg−1. Tous étaient prémédiqués au lorazepam 60 μg kg−1 per os. L’anesthésie et la curarisation étaient initiées en perfusant le sufentanil et le vécuronium 0,15 mg kg−1 iv en cinq minutes. Les données hémodynamiques et l’EEG spectral comprimé étaient recueillies sur ordinateur et comparées à la phase de contrôle, à l’induction et au moment de l’intubation.RésultatsLe sufentanil n’a pas eu d’effets hémodynamiques ou EEG à l’induction. On n’a pas observé de bradycardie et l’incidence d’hypotension a été de 12% pour les deux groupes. Cependant, pendant l’induction, des perturbations visibles à l’EEG et une augmentation transitoire plus importante de la fréquence cardiaque étaient observés dans le group H. La concentration sérique de sufentanil à l’induction était de 6, 1 ± 1, 8 ng ml−1 pour le groupe L et de 25, 4±8, 8 ng · ml−1 pour le groupe H et n’était pas en corrélation avec les changements hémodynamiques. Aucun des patients n’a mentionné un rappel d’événements peropératoires.ConclusionLaugmentation de la posologie du sufentanil de 3 à 15 mg kg−1 n’a pas d’unfluence sur la réponse hémodynamique en fin d’induction. Associé à une prémédication de lorazepam, le sufentanil 3 μg kg−1 produit des effets hémodynamiques et EEG presque maximaux et est adéquat pour l’induction et l’intubation de la trachée de patients subissant une CRVM. Le sufentanil 15 μg · kg−1 n’est pas plus efficace et provoque une stimulation cardiovasculaire transitoire.

Fentanyl oxygen anaesthesia for abdominal aortic surgery

Patients who present for abdominal aortic surgery often have significant atherosclerotic disease which may involve the coronary arteries. Haemodynamic responses occurring during fentanyl (100 μ.g.kg-1 ) oxygen anaesthesia for abdominal aortic surgery were studied in 16 patients. Anaesthesia was induced with fentanyl 100 μ.g.kg-1 with no supplemental doses and metocurine-pancuronium mixture (4:1). In 13 of 16 patients hyperdynamic circulatory responses to surgical stimuli required treatment prior to aortic cross-clamping. Interventions instituted were sodium nitroprusside or nitroglycerin (n = 13), propranolol (n = 4), and diazepam (n = 4). The serum fentanyl concentration at time of response to surgical stimulus was 18.5 ± 5.6 ng.min-1 (range 7–27 ng.min-1; time from induction 71 ± 49 min, n = 9). Eleven of the 16 patients required treatment for postoperative hypertension. Five of the 16 patients developed myocardial ischaemia, defined as ST segment depression greater than O.ImV, at some time during the operative procedure. Unsupplementedfentanyl anaesthesia (100 μg.kg-1) was unable to maintain a hypodynamic circulation in patients having abdominal aortic operations.RésuméLes patients se présentant pour chirurgie aortique abdominale présentent souvent une maladie athérosclérotique pouvant atteindre les coronaires. Les réponses hémodynamiques survenant lors de la chirurgie sur l’aorte abdominale et une anesthésie aufentanyl (100 μg.kg-1) — O2 ont été étudiées chez 16 patients. L’anesthésie était induite avec du fentanyl 100 μg.kg-1 sans dose supplémentaire de mélange et métocurinelpancuronium (4:1). Pour 13 des 16patients les réponses hyperdynamiques au stimulus chirurgical ont requis un traitement avant le clampage aortique. Les interventions incluent la nitroprussiate de soude ou nitroglycérine (n = 13), propranolol (n = 4), diazepam (n = 4). La concentration sérique de fentanyl au temps de réaction au stimulus chirurgical était de 18.5 ± 5.6 ng.ml-1 (écart: 7–27 ng.ml-1), le temps à partir de l’induction 71 ± 49 min. (n = 9). Onze des 16 patients ont requis un traitement pour l’hypertension post-opératoire. Cinq des 16 patients ont développé une ischémie myocardique définie comme étant une dépression du segment ST supérieur à 0.1mV, lors de la procédure chirurgicale. L’anesthésie au fentanyl, celle (100 μg.kg-1) était incapable de maintenir un état hypodynamique chez les patients devant subir une chirurgie sur l’aorte abdominale.

A two-center study evaluating the hemodynamic and pharmacodynamic effects of cisatracurium and vecuronium in patients undergoing coronary artery bypass surgery.

OBJECTIVEnTo determine the hemodynamic and pharmacodynamic effects of rapid bolus administration of cisatracurium compared with vecuronium.nnnDESIGNnA randomized, prospective, double-blind study.nnnSETTINGnTertiary-care university hospitals.nnnPARTICIPANTSnSeventy-nine adult patients with diagnosed coronary artery disease (CAD).nnnINTERVENTIONnElective coronary artery bypass graft surgery (CABG).nnnMEASUREMENTS AND MAIN RESULTSnPatients were randomly divided into four groups. Patients received a rapid bolus of two or four times the 95% peak depression of twitch (ED95) of either cisatracurium (groups 1 and 2) or vecuronium (groups 3 and 4). Three minutes after a midazolam induction, all patients received a rapid bolus administration of either study drug. Maintenance of anesthesia was with a standardized propofol-sufentanil-oxygen anesthetic. Patients were monitored with radial and pulmonary artery catheters and electromyography. End points of the study were hemodynamic stability at induction, after bolus administration of study drugs, and after intubation; the quality of intubating conditions; drug interventions to correct hemodynamic instability; the onset, duration, and recovery of neuromuscular function; and drug cost. Mean arterial pressure (MAP) and heart rate (HR) decreased in a similar proportion in all four groups after induction while, following study drug administration, MAP and HR did not change significantly. Both cisatracurium groups required more boluses to maintain neuromuscular block, but spontaneous recovery rates were faster. Both agents, but cisatracurium to a lesser degree, showed increased duration with repeated maintenance doses. Both agents afforded good to excellent intubating conditions, but the cost of cisatracurium was significantly less.nnnCONCLUSIONnThe authors conclude there is no evidence of a hemodynamic difference between the two neuromuscular blocking drugs (NMBDs). There are some clinical and cost advantages in favor of cisatracurium.

Validation of fentanyl pharmacokinetics in patients undergoing coronary artery bypass grafting

PurposeThe current emphasis on more rapid recovery and earlier tracheal extubation after cardiac surgery requires greater precision in administering opioids to reap their benefits while minimizing the duration of postoperative respiratory depression. Therefore, we aimed to define a pharmacokinetic model that accurately predicts fentanyl concentrations before, during, and after cardiopulmonary bypass (CPB) in patients undergoing coronary artery bypass grafting (CABG).MethodsParameters for two-compartment and three-compartment models were estimated by applying population pharmacokinetic modelling to fentanyl concentration vs time data measured in 29 patients undergoing elective, primary CABG. The ability of these models to predict fentanyl concentrations in a second series of ten patients undergoing CABG was then assessed.ResultsA simple, three-compartment model had excellent predictive ability, with a median prediction error (PE = ([Fentanyl]meas- [Fentanyl]pred)/[Fentanyl]pred·100%) of −0.5%, and a median absolute PE (APE = ¦PE¦) of 14.0%. In comparison to the two-compartment models, linear regression of measured:predicted concentration ratios indicated that the three-compartment model was free of systematic and time-related changes in bias (P < 0.05). The parameters of this three-compartment model are: V1 15.0 l, V2 20.0 l, V3 86.11, Cl1 1.08 L·min−1, Cl2 4.90 L·min−1, and Cl3 2.60 L·min−1.ConclusionsOur pharmacokinetic model provides a rational foundation for designing fentanyl dose regimens for patients undergoing CABG. When combined with previously published information regarding intraoperative fentanyl pharmacodynamics, dose regimens that reliably achieve and maintain desired fentanyl concentrations throughout the intraoperative period can be designed to achieve specific therapeutic goals.RésuméObjectifL’accent mis actuellement sur une récupération plus rapide et une extubation endotrachéale précoce en cardiochirurgie exige l’administration plus précise d’opioïdes. Nous pouvons ainsi en retirer les avantages tout en diminuant la durée de la dépression respiratoire postopératoire. Notre but était de définir un modèle pharmacocinétique prédictif précis pour les concentrations de fentanyl utilisées avant, pendant et après la circulation extracorporelle (CEC) chez des patients qui subissent un PAC.MéthodeLes paramètres des modèles à deux et trois compartiments ont été estimés en appliquant une modélisation de population à la concentration de fentanyl en fonction du temps chez 29 patients devant subir une première intervention chirurgicale pour un PAC non urgent. La capacité de ces modèles à prédire les concentrations de fentanyl a été évaluée ensuite auprès d’une seconde série de dix patients subissant un PAC.RésultatsUn modèle à trois compartiments a présenté une excellente valeur prédictive, avec une erreur de prédiction médiane (EP = ([Fentanyl]mesuré - [Fentanyl]prédit)/[Fentanyl]prédit ·100 %) de −0,5 %, et une EP médiane absolue (EPA = ¦EP¦) de 14,0 %. En le comparant aux modèles à deux compartiments, la régression linéaire des ratios de la concentration mesurée:prédite a indiqué que le modèle à trois compartiments était exempt de biais systématiques et reliés au temps (P < 0,05). Les paramètres de ce dernier modèle sont : V1 15,0 1 ; V2 20,01; V3 86,11; Cl1 1,08 L·min−1; Cl2 4,90 L·min−1 et Cl3 2,60 L·min−1.ConclusionNotre modèle pharmacocinétique donne un fondement rationnel à la préparation posologiques du fentanyl pour un PAC. Combinant les informations déjà publiées sur la pharmacodynamie du fentanyl peropératoire, nous pouvons préparer des schémas posologiques aux concentrations de fentanyl désirées et les maintenir fidèlement tout au long d’une opération.

Does sufentanil concentration influence isoflurane requirements during coronary artery bypass grafting

OBJECTIVEnTo search for concentration-related suppression of hemodynamic responsiveness by sufentanil.nnnDESIGNnProspective, randomized, double-blind study.nnnSETTINGnUniversity hospital.nnnPARTICIPANTSnPatients undergoing elective coronary artery bypass grafting (CABG).nnnINTERVENTIONnPatients were assigned to target effect-site sufentanil concentrations of 1.5 ng/mL (group L; n = 14), 3.0 ng/mL (group M; n = 13), or 4.5 ng/mL (group H; n = 12). Sufentanil was administered by computer-assisted continuous infusion. Isoflurane was used to maintain intraoperative hemodynamics near preoperative values.nnnMEASUREMENTS AND MAIN RESULTSnHemodynamics, the electroencephalographic spectral edge (SE95), and end-tidal isoflurane concentration (ET-ISO) were measured every 10 to 30 seconds during the prebypass period. Serum sufentanil concentration was measured at intervals. Prebypass serum sufentanil concentrations were stable, averaging 3.0 +/- 0.7, 5.1 +/- 1.1, and 7.1 +/- 1.3 ng/mL in groups L, M, and H, respectively. The groups did not differ with respect to the speed of induction, intraoperative hemodynamics, incidence of isoflurane use, or isoflurane concentrations required. ET-ISO and serum sufentanil levels were not correlated. Among seven group L patients who did not require isoflurane, the average prebypass serum sufentanil concentration ranged from 1.7 to 3.3 ng/mL.nnnCONCLUSIONnSufentanil does not induce concentration-related suppression of hemodynamic responsiveness over the range studied. A stable serum sufentanil concentration of 3.0 +/- 0.7 ng/mL induces the maximal opioid effect and need not be exceeded in patients undergoing CABG. A sufentanil concentration of 1.7 ng/mL provides clinically adequate anesthesia without supplementation in some premedicated patients undergoing CABG.

Con: intraoperative myocardial ischemia is not benign.

The principal importance of intraoperative ischemia is its consistent association with adverse outcome. In coronary artery surgery the finding of prebypass ischemia is an important predictor, and postbypass ischemia is a critical predictor of adverse outcome. One in three patients with postbypass ischemia will suffer an adverse outcome in CABG. Furthermore, prevention of postbypass ischemia may improve outcome in CABG. Clearly, intraoperative ischemia in CABG surgery is an ominous sign that should be regarded with the utmost concern by anesthesiologists. In noncardiac surgery, intraoperative ischemia also indicates about a one in three chance of adverse outcome. Although it is less sensitive than postoperative ischemia, it may have superior positive predictive power and specificity. Most importantly, intraoperative monitoring for ischemia is currently available to most patients, whereas extended postoperative monitoring is not. The finding of intraoperative ischemia defines a high-risk group of patients who may merit special monitoring and treatment. To regard intraoperative ischemia as benign would be inconsistent with available information.

Catecholamine responses to anesthetic induction with fentanyl and sufentanil

In a randomized study, the authors examined the changes in plasma epinephrine and norepinephrine concentrations associated with induction of anesthesia and surgery in 33 patients with good ventricular function undergoing elective coronary artery surgery. After premedication with morphine and scopolamine, patients received either fentanyl, 100 micrograms/kg (n = 16), or sufentanil, 15 micrograms/kg, (n = 17), intravenously (IV), over 10 minutes to induce anesthesia. Metocurine, 0.42 mg/kg, IV, produced muscle relaxation. Arterial blood for plasma catecholamine determinations was drawn prior to induction, every two minutes throughout induction, one minute following endotracheal intubation, and one minute after sternotomy. Plasma epinephrine concentration was unchanged with either induction agent. Plasma norepinephrine concentration increased significantly after administration of either narcotic, peaked between six and ten minutes into induction, and returned to the preinduction value after intubation. Induction-related changes in arterial pressure and pulmonary capillary wedge pressure were significantly correlated with changes in the logarithm of plasma norepinephrine concentration. Similar degrees of endogenous norepinephrine release appear to accompany induction with equipotent doses of fentanyl and sufentanil in patients premedicated with morphine and scopolamine. Norepinephrine release may influence the hemodynamic response to induction with narcotics.

Cardiovascular physiology: VENOUS RETURN

SummaryCardiac output is not regulated simply by autonomically mediated changes in heart rate and stroke volume. More often, changes in cardiac output predominantly reflect changes in the peripheral circulation which in turn change venous return. Any attempt to analyze circulatory function without considering the peripheral circulation will be incomplete.The principles discussed above can be fruitfully applied to the analysis of many clinically important derangements of circulatory function. This discussion is only intended as an introduction to concepts which have been exhaustively developed and discussed by Guyton et al.2 A careful review of this source material will reward the interested reader.