Peter C. Duke

A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery

BACKGROUND Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences. METHODS In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days. RESULTS The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22). CONCLUSIONS Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).

Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery

OBJECTIVE Inhibition of cyclooxygenase 2 provides analgesia in ambulatory patients. We prospectively evaluated the safety and efficacy of a newly introduced cyclooxygenase 2 inhibitor in patients undergoing coronary artery bypass grafting surgery through a median sternotomy in a randomized clinical trial. METHODS A total of 462 patients with New York Heart Association classes I to III who were less than 77 years of age and were from 58 institutions in the United States, Canada, Germany, and the United Kingdom participated in this multicenter, phase III, placebo-controlled, double-blind, randomized, parallel-group trial. Patients were allocated at a ratio of 2:1 to parecoxib/valdecoxib or standard care (control) groups, respectively. Intravenous study drug (40 mg) was administered within 30 minutes after extubation and every 12 hours for a minimum of 3 days. Subsequently, oral treatment at a dose of 40 mg every 12 hours was initiated and administered for a combined total of 14 days. Patient-controlled analgesia with morphine, oral opioids, or acetaminophen was available as required. Assessment of the analgesic efficacy of the study drug was primarily based on morphine and morphine equivalent use. Additional efficacy evaluations included daily pain intensity, patient and physician global evaluation of study medication, and pain effect on quality of life. Clinical adverse events were assessed by the principal investigator at each site from the time of the first dose through the 30-day postdosing period. RESULTS Patients in the parecoxib/valdecoxib group received significantly less morphine or morphine equivalents than patients in the control group during the 0- to 24-hour (P =.009), 24- to 48-hour (P =.017), 72- to 96-hour (P =.002), 96- to 120-hour (P =.004), and 120- to 144-hour (P =.037) periods. Both patients (P <.001) and physicians (P <.001) evaluated the study medication as significantly better than control therapy. The modified Brief Pain Inventory questionnaire used in the oral dosing period detected significant improvements in the parecoxib/valdecoxib treatment group in 6 of 8 domains tested (eg, current pain, worst pain, and mood) beginning on day 4 and continuing for at least 4 days. Although there were no differences between the groups in overall adverse events, serious adverse events occurred twice as frequently in parecoxib/valdecoxib-treated patients (19.0%, 59/311 patients) than in control patients (9.9%, 15/151 patients; P =.015). Regarding individual serious adverse events, a greater incidence in sternal wound infection was found in the parecoxib/valdecoxib patients (10 [3.2%]) versus control patients (0 [0%]) (P =.035). The incidences of other individual serious adverse events, including cerebrovascular complications, myocardial infarction, and renal dysfunction, were proportionally greater but not significantly different between the groups. CONCLUSIONS In patients undergoing coronary artery bypass grafting surgery, the cyclooxygenase 2 inhibitor combination, parecoxib/valdecoxib, was effective for postoperative analgesia. However, the 14-day treatment regimen also was associated with an increased incidence of serious adverse events overall and sternal wound infections in particular. Therefore our study raises important concerns requiring their comprehensive evaluation in a large-scale trial before these cyclooxygenase 2 inhibitors are used in patients undergoing coronary artery bypass grafting surgery.

Age-related morphine kinetics

The kinetic disposition of morphine was compared in 13 young and 7 older healthy subjects after a single intravenous dose of 10 mg/70 kg morphine. The apparent volume of distribution at steady state in elderly subjects was only half of that in young subjects. This difference was derived from reductions in both central and peripheral kinetic compartment volumes in the older subjects. The β elimination phase for morphine was more rapid, but its plasma clearance was reduced in older subjects. Calculation of the peripheral compartment morphine concentration for these subjects indicated that drug concentration in this kinetic space was higher in older subjects for 1.5 hr after dosing.

Halothane Depresses Baroreflex Control of Heart Rate in Man

Baroreflex control of heart rate was determined during three awake control situations and during two depths of halothane anesthesia in man. Baroreflex function was quantiated by calculating the pressor test slope from the R-R interval change on the ECG produced by a pharmacologically induced pressor response. During the three awake control situations the subjects breathed room air or 100 per cent O2 spontaneously or 100 per cent O2 with ventilation controlled. Mean (+/- SD) slopes obtained were 15.1 +/- 4.5, 15.6 +/- 6.8 and 18.4 +/- 9.9, respectively. No significant difference in baroreflex function slope was observed. During light halothane anesthesia (0.7 per cent endtidal) baroreflex function was significantly depressed (mean slope = 2.5 +/- 1.5), and it was abolished at 1.1 per cent end-tidal halothane (mean slope = 0.03 +/- 0.04). It is concluded that halothane anesthesia produces depression of baroreflex control of heart rate in man.

The efficacy and resource utilization of remifentanil and fentanyl in fast-track coronary artery bypass graft surgery : A prospective randomized, double-blinded controlled, multi-center trial

We compared (a) the perioperative complications; (b) times to eligibility for, and actual time of the following: extubation, less intense monitoring, intensive care unit (ICU), and hospital discharge; and (c) resource utilization of nursing ratio for patients receiving either a typical fentanyl/isoflurane/propofol regimen or a remifentanil/isoflurane/propofol regimen for fast-track cardiac anesthesia in 304 adults by using a prospective randomized, double-blinded, double-dummy trial. There were no differences in demographic data, or perioperative mortality and morbidity between the two study groups. The mini-mental status examination at postoperative Days 1 to 3 were similar between the two groups. The eligible and actual times for extubation, less intense monitoring, ICU discharge, and hospital discharge were not significantly different. Further analyses revealed no differences in times for extubation and resource utilization after stratification by preoperative risk scores, age, and country. The nurse/patient ratio was similar between the remifentanil/isoflurane/propofol and fentanyl/isoflu-rane/propofol groups during the initial ICU phase and less intense monitoring phase. Increasing preoperative risk scores and older age (>70 yr) were associated with longer times until extubation (eligible), ICU discharge (eligible and actual), and hospital discharge (eligible and actual). Times until extubation (eligible and actual) and less intense monitoring (eligible) were significantly shorter in Canadian patients than United States’ patients. However, there was no difference in hospital length of stay in Canadian and United States’ patients. We conclude that both anesthesia techniques permit early and similar times until tracheal extubation, less intense monitoring, ICU and hospital discharge, and reduced resource utilization after coronary artery bypass graft surgery.

The effects of age on baroreceptor reflex function in man

SummaryThe relationship of age to baroreceptor reflex activity was determined in 35 healthy volunteers ranging in age from 19 to 65 years. Intra-arterial catheters were placed and blood pressure and pulse rate responses of each subject were observed during a Valsalva maneuver (31 subjects) and during the Pressor Test (33 subjects). The Valsalva maneuver consisted of a forced expiration sufficient to raise a column of mercury 40 torr for 10 seconds. This resulted in a reduction in pulse pressure (Baroreceptor stimulus) during the maneuver followed by a transient overshoot in diastolic pressure (response) following its termination. In comparison to younger subjects, older subjects had a greater reduction in pulse pressure but similar overshoot in diastolic pressure. The pressor test consisted of observing the effect of increasing systolic blood pressure (stimulus) on pulse duration (response) following the intravenous administration of phenylephrine. By relating each systolic pressure to the immediately succeeding R-R interval, a linear relationship was found. Its slope expressed in milliseconds of R-R interval change per torr increase in systolic pressure is an index of baroreflex function. Older subjects have less cardiac slowing compared to younger subjects and a hyperbolic relationship exists between age and slope ( r = 0.84, p < 0.05 ). These tests indicate that baroreceptor reflex function decreases with aging.RésuméNotre étude sur l’activité réflexe baroréceptrice en fonction de l’âge a porté sur 35 volontaires en bonne santé et âgés de 19 à 65 ans.Après mise en place de canules artérielles, l’on a enregistré la pression et la fréquence cardiaque au cours d’une manœ uvre de Valsalva, chez 31 sujets et durant un test d’hypertension chez 33 sujets.La manœ uvre de Valsalva consistait pour fins de cette étude en une expiration forcée suffisante pour élever une colonne de mercure de 40 torr durant 10 secondes. L’on observait dans ces circonstances une chute de la pression différentielle (stimulus) suivie d’une élévation passagère de la pression diastolique survenant à la fin de la manœ uvre (réponse). Par comparaison aux plus jeunes, les plus vieux sujets montraient une plus grande diminution de la pression différentielle, mais leur élévation de la diastolique ( réponse ) était comparable.Le test d’hypertension consistait à élever les effets de l’élévation de la pression systolique (stimulus) consécutive à l’administration intraveineuse de Phenylephrine, sur la fréquence cardiaque. Les modifications de l’espace RR (en millisecondes) inscrites en fonction de l’élévation de la pression (torr) permettaient d’établir une relation linéaire témoin de la fonction baroréflexe. Les sujets plus âgés ont montré moins de ralentissement de la fréquence en fonction de l’élévation de la pression. Ces tests indiquent que l’activité baroréflexe diminue avec l’âge.

Thoracic epidural analgesia improves pulmonary function in patients undergoing cardiac surgery

Purpose: Pulmonary dysfunction commonly occurs following coronary artery bypass graft (CABG) surgery, increasing morbidity and mortality. We hypothesized that thoracic epidural anesthesia (TEA) would improve pulmonary function and would decrease complications in patients undergoing CABG surgery.Methods: This prospective, randomized, controlled trial was conducted with Ethics Board approval. Fifty patients, undergoing CABG surgery, were randomized to the epidural group or to the patient-controlled analgesia morphine group. Patients in the epidural group received a high, thoracic epidural, preoperatively. Intraoperatively, 0.75% ropivacaine was infused, followed postoperatively, by 0.2% ropivacaine for 48 hr. Outcome measurements included: visual analogue pain scores; spirometry; atelectasis scores on chest radiographs; and the incidence of atrial fibrillation.Results: Twenty-five patients were enrolled in each group. Patients in the epidural group had significantly less pain on the operative day, and for the subsequent two days. Compared to baseline, the forced expiratory volume in one second was significantly higher in the epidural group, on the first and second postoperative days (43.7±12.2%vs 36.4±12.0%,p<0.002, and 43.3±12.5%vs 38.4±11.0%,p<0.05). There was significantly more atelectasis in the control group, four hours postoperatively (p<0.04); however, on the third, postoperative day, the groups were similar with regards to this outcome. The incidence of atrial fibrillation was similar in both groups, and there were no complications related to the epidural.Conclusions: High TEA decreases postoperative pain and atelectasis and improves pulmonary function in patients undergoing CABG surgery. Our results support the use of TEA in this group of patients.RésuméObjectif: Des troubles pulmonaires surviennent fréquemment à la suite d’une chirurgie de pontage aortocoronarien (pAC), ce qui augmente la morbidité et la mortalité. Nous avons émis l’hypothèse que l’anesthésie péridurale thoracique (ApT) améliorerait la fonction pulmonaire et réduirait les complications chez les patients subissant une chirurgie de pAC.Méthode: Après avoir obtenu l’accord du Comité d’éthique, nous avons mené cette étude prospective, randomisée et contrôlée. Cinquante patients subissant une chirurgie pAC ont été randomisés dans deux groupes, péridurale ou analgésie contrôlée par le patient avec de la morphine. Les patients du groupe péridurale ont reçu une péridurale thoracique haute avant l’opération. pendant l’opération, ils ont reçu une perfusion de ropivacaïne 0,75 %, puis de la ropivacaïne 0,2 % pendant 48 h après l’opération. Les résultats mesurés étaient les scores de douleur sur l’échelle visuelle analogue, la spirométrie, les scores d’atélectasie sur les radiographies pulmonaires et l’incidence de fibrillation auriculaire.Résultats: Chaque groupe comprenait 25 patients. La douleur chez les patients du groupe péridurale était considérablement moins élevée le jour de l’opération et les deux jours suivants. par rapport aux données de base, le volume expiratoire maximal en une seconde était significativement plus élevé dans le groupe péridurale le premier et le deuxième jour postopératoire (43,7±12,2 % vs 36,4±12,0 %, p<0,002, et 43,3±12,5 % vs 38,4±11,0 %, p<0,05). L’atélectasie a été significativement plus élevée dans le groupe témoin quatre heures après l’opération (p<0,04) ; toutefois, le troisième jour postopératoire, les groupes ont montré des résultats d’atélectasie similaires. L’incidence de fibrillation auriculaire était semblable dans les deux groupes, et il n’y a pas eu de complication associée à la péridurale.Conclusion: L’analgésie péridurale thoracique haute réduit la douleur postopératoire et l’atélectasie et améliore la fonction pulmonaire chez les patients subissant un pAC. Nos résultats appuient l’utilisation de l’ApT chez ce groupe de patients.

The effect of halothane with nitrous oxide on baroreflex control of heart rate in man

To assess the effect of halothane with 70 percent nitrous oxide on the human baroreflex, we observed the heart rate response to pharmacological elevation of blood pressure in subjects anaesthetized to the 1 MAC and 1.25 MAC levels. We observed, in comparison to the awake control, that at I MAC halothane with 70 per cent nitrous oxide and oxygen, the baroreflex was depressed and this became more significant at 1.25 MAC anaesthesia. In comparison to previous similar studies on the effect of halothane-oxygen anaesthesia, there was significantly less baroreflex depression at equianaesthetic doses with halothane with 70 per cent nitrous oxide.Ré SUMéPour é valuer l’ action de 1’ halothane sur le systè me barorecepteur ré flexe de l’ humain, on a é tudié le comportement de la fré quence cardiaque aprè s l’ é lé vation de la tension arté rielle induite pharmacologiquement chez des sujets anesthé sies aux niveaux MAC 1 et MAC 1. 25. Lorsqu’ on a comparé avec les contrô les obtenus au pré alable chez les sujets é veillé s, on a observé une dé pression du systè me baroré cepteur ré flexe à MAC 1 par 1’ halothane dans un mé lange protoxyde d’ azote (70 pour cent) oxygè ne dé pression qui s’ accentuait lorsque le MAC atteignait 1.25. Cette dé pression du systè me ré flexe a é té moindre à des concentrations é quivalentes d’ halothane dans le mvlange protoxyde à 70 pour cent que celle rapporté e lors d’ é tudes similaires anté rieures.

Aging and alfentanil disposition in healthy volunteers and surgical patients

We studied the pharmacokinetic disposition of alfentanil in 20 volunteers and in 15 surgical patients 20-72 years old. Pharmacokinetic disposition was first order and was well described by a two-compartment open model. Centralcompartment volume of distribution was 0.131 ± 0.087 L · kg-1 (mean ± SD) in young healthy volunteers and decreased modestly with increasing age (r = - 0.32, P < 0.05). However, apparent volume of distribution at steady-state, 0.404 ± 0.205 L · kg-1 for the whole study cohort, was not age-related. Plasma clearance of alfentanil in young healthy subjects, 9.3 ± 6.3 ml · kg-1min-1, also showed an inverse relationship with age (r = -0.54, P < 0.001), and was not affected by surgical stress in subjects older than 60 years. Cigarette smoking and sex of the subjects did not contribute to interindividual differences in the kinetic disposition of this drug. Our finding that interindividual differences in disposition of alfentanil were the least in older subjects suggests that its pharmacological effects related to pharmacokinetic disposition should be most predictable in the elderly.RésuméOn a étudié la disposition pharmacocinétique de ľalfentanil chez 20 volontaires en bonne santé et chez 15 patients chirurgicaux âgés de 20 à 72 ans. La disposition pharmacocinétique était du premier ordre et était bien décrite par le modèle ouvert à deux compartiments. Le volume du compartiment central de distribution était de 0.131 ± 0.028 L ·kg-1 (moyenne ± SM) chez des patients volontaires en bonne santé et diminuant légèrement avec ľaugmentation de ľâge (r = -0.32, P < 0.05). Cependant, le volume apparent de distribution après équilibration était de 0.404 ± 0.035 L ·kg-1 pour tous les patients de ľétude et n’était pas en relation avec ľâge. La clearance plasmatique de ľalfentanil chez des sujets jeunes en bonne santé était de 9.3 ± 2.0 ml·kg-1 -min-1, a aussi démontré une relation inverse avec ľâge (r = 0.54, P < 0.001), et n’était pas affectée par le stress chirurgical chez les sujets plus âgés que 60 ans. Le tabagisme et le sexe des sujets n’a pas contribué à des différences dans la disposition de cette drogue. On a trouvé que les différences entre les individus dans la disposition de ľalfentanil étaient moindres chez les sujets âgés suggérant que ses effets pharmacologiques reliés à la disposition pharmacocinétique doivent être plus prévisibles chez les gens âgés.

Canadian guidelines for training in adult perioperative transesophageal echocardiography : Recommendations of the cardiovascular section of the canadian Anesthesiologists' society and the canadian society of echocardiography

PurposeTo establish Canadian guidelines for training in adult perioperative transesophageal echocardiography (TEE).MethodsGuidelines were established by the Canadian Perioperative Echocardiography Group with the support of the cardiovascular section of the Canadian Anesthesiologists’ Society (CAS) in conjunction with the Canadian Society of Echocardiography.Guidelines for training in echocardiography by the American Society of Echocardiography, the American College of Cardiology and the Society of Cardiovascular Anesthesiologists were reviewed, modified and expanded to produce the 2003 Quebec expert consensus for training in perioperative echocardiography. The Quebec expert consensus and the 2005 Guidelines for the provision of echocardiography in Canada formed the basis of the Canadian training guidelines in adult perioperative TEE.ResultsBasic, advanced and director levels of expertise were identified. The total number of echocardiographic examinations to achieve each level of expertise remains unchanged from the 2002 American Society of Echocardiography-Society of Cardiovascular Anesthesiologists guidelines. The increased proportion of examinations personally performed at basic and advanced levels, and the level of autonomy at the basic level suggested by the Quebec expert consensus are retained. These examinations can be performed in a perioperative setting and are not limited to intraoperative TEE. Training “on the job”, the role of the perioperative transesophageal echocardiography examination, requirements for maintenance of competence, and duration of training are also discussed for each level of training. The components of a TEE report and comprehensive TEE examination are also outlined.ConclusionThe Canadian guidelines for training in adult perioperative TEE reflect the unique Canadian practice profile in perioperative TEE and address the training requirements to obtain expertise in this field.RésuméObjectifÉtablir des lignes directrices canadiennes pour la formation à l’échocardiographie transœsophagienne (ETO) chez l’adulte.MéthodeLes lignes directrices ont été établies par le Groupe canadien sur l’échocardiographie périopératoire, appuyé par la section cardiovasculaire de la Société canadienne des anesthésio-logistes (SCA) conjointement avec la Société canadienne d’écho-cardiographie. Nous avons passé en revue, modifié et développé les lignes directrices de l’American Society of Echocardiography, l’American College of Cardiology et la Society of Cardiovascular Anesthesiologists pour en arriver au consensus d’experts du Québec en 2003 sur la formation en échocardiographie périopératoire. Le consensus d’experts du Québec et les lignes directrices de 2005 sur l’utilisation de l’échocardiographie au Canada ont formé la base des lignes directrices de la formation canadiennes en ETO périopératoire chez l’adulte.RésultatsLes niveaux de compétence élémentaire, avancé et supérieur ont été déterminés. Le nombre total d’examens d’échocardiographie nécessaires pour atteindre chaque niveau de compétence est demeuré inchangé depuis les lignes directrices de 2002 de l’American Society of Echocardiography-Society of Cardiovascular Anesthesiologists. Nous avons conservé le nombre croissant d’examens réalisés personnellement aux niveaux élémentaire et avancé et le degré d’autonomie au niveau élémentaire suggérés par le consensus d’experts québécois. Ces examens peuvent être réalisés dans un contexte périopératoire et ne sont pas limités à l’ETO peropératoire. La formation «en milieu de travail», le rôle de l’examen d’échocardiographie transœsophagienne périopératoire, les exigences du maintien de la compétence et la durée de la formation sont aussi discutées pour chaque niveau de formation. La composante d’un rapport d’ETO et l’examen d’ETO détaillé sont décris des Guidelines for the Provision of Echocardiography in Canada.ConclusionLes lignes directrices canadiennes pour la formation à l’ETO périopératoire chez l’adulte représentent le profil particulier de la pratique canadienne en ETO périopératoire et traitent des exigences nécessaires pour acquérir des compétences dans le domaine.