Martin N. Vicenzi

Thromboelastography for monitoring prolonged hypercoagulability after major abdominal surgery

Despite clinical and laboratory evidence of perioperative hypercoagulability, there are no consistent data evaluating the extent, duration, and specific contribution of platelets and procoagulatory proteins by in vitro testing. We tested the hypothesis that the parallel use of standard and abciximab-cytochalasin D-modified thromboelastography (TEG®) can assess 7 days’ postoperative hypercoagulability and can estimate the independent contribution of procoagulatory proteins and platelets. Thromboelastograms were performed before surgery, at the end of surgery, 6 h after surgery, and on postoperative days 1, 2, 3, and 7; they were analyzed for the reaction time and the maximal amplitude (MA). We calculated the elastic shear modulus of standard MA (Gt) and modified MA (Gc), which reflect total clot strength and procoagulatory protein component, respectively. The difference was an estimate of the platelet component (Gp). There was a 10% perioperative increase of standard MA, corresponding to a 50% increase of Gt (P < 0.0001) and an 86%–90% contribution of the calculated Gp to Gt. We conclude that serial standard and modified thromboelastography may reveal prolonged postoperative hypercoagulability and the independent contribution of platelets and procoagulatory proteins to clot strength.

N-Terminal Pro-brain Natriuretic Peptide Identifies Patients at High Risk for Adverse Cardiac Outcome after Vascular Surgery

Background:Preoperative N-terminal pro-BNP (NT-proBNP) is independently associated with adverse cardiac outcome but does not anticipate the dynamic consequences of anesthesia and surgery. The authors hypothesized that a single postoperative NT-proBNP level provides additional prognostic information for in-hospital and late cardiac events. Methods:Two hundred eighteen patients scheduled to undergo vascular surgery were enrolled and followed up for 24–30 months. Logistic regression and Cox proportional hazards model were performed to evaluate predictors of in-hospital and long-term cardiac outcome. The optimal discriminatory level of preoperative and postoperative NT-proBNP was determined by receiver operating characteristic analysis. Results:During a median follow-up of 826 days, 44 patients (20%) experienced 51 cardiac events. Perioperatively, median NT-proBNP increased from 215 to 557 pg/ml (interquartile range, 83/457 to 221/1178 pg/ml; P < 0.001). The optimum discriminate threshold for preoperative and postoperative NT-proBNP was 280 pg/ml (95% confidence interval, 123–400) and 860 pg/ml (95% confidence interval, 556–1,054), respectively. Adjusted for age, previous myocardial infarction, preoperative fibrinogen, creatinine, high-sensitivity C-reactive protein, type, duration, and surgical complications, only postoperative NT-proBNP remained significantly associated with in-hospital (adjusted hazard ratio, 19.8; 95% confidence interval, 3.4–115) and long-term cardiac outcome (adjusted hazard ratio, 4.88; 95% confidence interval, 2.43–9.81). Conclusion:A single postoperative NT-proBNP determination provides important additional prognostic information to preoperative levels and may support therapeutic decisions to prevent subsequent structural myocardial damage.

Ketamine Has Stereospecific Effects in the Isolated Perfused Guinea Pig Heart

Background S(+)-Ketamine is judged to produce more potent anesthesia than either the racemate or the R(-) ketamine isomer because of differential activation of specific cerebral receptors. Other than central nervous system effects, the most important side effects of ketamine occur in the cardiovascular system. We examined the direct cardiac effects of the isomers and the racemate of ketamine in the isolated perfused guinea pig heart. Methods Twenty-three guinea pig hearts were perfused by the Langendorff technique with modified 37 degrees Celsius Krebs-Ringers solution (97% oxygen and 3% carbon dioxide) at a constant perfusion pressure. Eight animals were pretreated with reserpine to deplete hearts of catecholamines. These pretreated hearts were also perfused with Krebs-Ringers solution containing propranolol, phenoxybenzamine, and atropine to block any remaining effects of catecholamines and of acetylcholine. Five additional hearts were perfused with naloxone to block cardiac opioid receptors. Ten hearts were not treated. All 23 hearts were then exposed to four increasing equimolar concentrations of each isomer and the racemate of ketamine for 10 min. Heart rate, atrioventricular conduction time (AVCT), left ventricular pressure, coronary flow, and inflow and outflow oxygen tensions were measured. Percentage oxygen extraction, oxygen delivery, and oxygen consumption were calculated. Results Both isomers and the racemate caused a concentration-dependent depression of systolic left ventricular pressure and an increase in AVCT. in the untreated hearts, S(+)-ketamine decreased heart rate and left ventricular pressure and, at higher concentrations, oxygen consumption and percentage oxygen extraction significantly less than R(-)-ketamine independent of blocked or unblocked opioid receptors. Racemic ketamine depressed cardiac function to a degree intermediate to that produced by the isomers. Coronary flow and AVCT were equally affected by the isomers and by the racemic mixture. In the catecholamine-depleted hearts both isomers and the racemate caused equipotent depression of all variables. In these hearts cardiac depression was greater, and AVCT, coronary flow, and oxygen delivery were significantly greater than in untreated and opioid receptor-blocked hearts. Conclusions Lesser cardiac depression by the s(+) isomer is attributable to an increased availability of catecholamines, because previous depletion of catecholamine stores and autonomic blockade completely inhibited these differences. The inability of cardiac tissue to reuptake released catecholamines into neuronal or extraneuronal sites during exposure to ketamine is stereoselective and caused predominantly by the S(+) isomer. Cardiac opioid receptors are apparently not involved in this phenomenon.

Anesthetics and Automaticity of Dominant and Latent Pacemakers in Chronically Instrumented Dogs: I. Methodology, Conscious State, and Halothane Anesthesia

BackgroundSupraventricular dysrhythmias are common during anesthesia, but have been Incompletely Investigated. Mechanisms may involve altered automaticity of subsidiary pacemakers and participation of vagal reflexes. The following hypotheses were tested: (1) shifts from the sinoatrial (SA) node to subsidiary pacemakers require intact vagal reflexes and (2) halothane sensitizes the heart to epinephrine-induced atrial pacemaker shifts. MethodsEpicardial electrodes were Implanted in eight dogs on both atrial appendages, the right ventricle, along the sulcus terminalis, and at the His bundle. Weekly testing awake (control), awake with atropine methylnitrate, with 1 and 2 μg epinephrine ± kg−1 ± min−1 (3 min-infusions), and under 1.25 and 2 MAC halothane was performed. Electrograms were analyzed for the site of earliest activation (SEA), which was scored 1–6 depending on the distance from the SA node, and expressed as the SEA value. ResultsIn conscious dogs (control) and at 1.25 MAC halothane, epinephrine Increased the SEA values (shifted activation from SA node) and blood pressure, and decreased heart rate; however, with atropine, SEA values were unaffected by epinephrine, although blood pressure and heart rate were elevated. At 2 MAC, atropine did not affect the epinephrine-induced increase in SEA values. Halothane increased SEA values when combined with 1 μg epinephrine ± kg−1 ± min−1. ConclusionsPacemaker shifts account for atrial dysrhythmias in the conscious state and during 1.25 MAC halothane with epinephrine, and require vagal participation. Halothane sensitizes the heart to epinephrine-induced atrial dysrhythmias. Atropine and halothane facilitate His bundle beats during exposure to epinephrine.

Coronary artery plaque burden and perioperative cardiac risk

Background Electron-beam computed tomography–derived coronary calcium score correlates with the morphologic severity of coronary artery disease, reflecting both global atherosclerotic plaque formation and coronary artery luminal narrowing. The current study examines the impact of coronary atherosclerotic plaque burden, measured by coronary calcium score, on the potential for perioperative myocardial cell injury, as assessed by cardiac troponin T elevations in patients undergoing elective vascular surgery. The authors further investigated whether perioperative myocardial cell injury in those patients adversely affects noninvasive measures of left ventricular systolic function, such as ejection fraction and wall motion score. Methods Fifty-one consecutive patients scheduled for vascular surgery were enrolled in this prospective study. In addition to standard preoperative evaluation, including patient history and physical examination, electron-beam computed tomography scan, 12-lead electrocardiography, and transthoracic echocardiography were performed on the day before surgery. Subsequent evaluations on postoperative days 2 and 7 included transthoracic echocardiography and 12-lead electrocardiography. Cardiac troponin T determinations were performed on the day before surgery, immediately preoperatively, and on postoperative days 1, 2, 3, and 7. Results The median coronary calcium score of the 51 patients was 997.0 (25th percentile, 202.5; 75th percentile, 1,949.5). Cardiac troponin T elevations exclusively occurred in patients with a coronary calcium score greater than 1,000. The six patients (12%) with perioperative cardiac troponin T elevations had a 2.5-fold higher coronary calcium score than those without cardiac troponin T elevation (P = 0.021). In these patients, the ejection fraction decreased from 61 ± 10% to 52 ± 13% (mean ± SD) on postoperative day 2 and was 54 ± 16% on postoperative day 7 (P = 0.022). Conclusion A high electron-beam computed tomography coronary calcium score, reflecting substantial coronary plaque burden, carries an increased risk for myocardial cell injury after vascular surgery. In these patients, myocardial damage may result in deterioration of global systolic left ventricular function.

Anesthetics and automaticity of dominant and latent pacemakers in chronically instrumented dogs. II. Effects of enflurane and isoflurane during exposure to epinephrine with and without muscarinic blockade.

BackgroundAtrial dysrhythmias precede ventricular dysrhythmias during epinephrine-anesthetic sensitization, and may be caused by an altered relationship between automaticity of primary and subsidiary pacemakers. The following hypotheses were tested: (1) epinephrine-induced pacemaker shifts with enflurane or Isoflurane require intact vagal reflexes and (2) these anesthetics sensitize the atrial myocardium to epinephrine-induced dysrhythmias. MethodsEight dogs were instrumented for chronic electro-physiologic investigation, including electrodes at the SA node, atrial appendages, right ventricle, and His bundle, and along the sulcus terminalis. After conscious-state testing, dogs were anesthetized with isoflurane or enflurane and exposed to epinephrine, with or without atropine methylnitrate. Eightchannel ECG recordings were analyzed before and during epinephrine infusions. Atrial pacemakers were assigned values 1–6 with Increasing distance from the SA node, normalized and expressed as the site of earliest activation value (SEA). ResultsEpinephrine increased SEA values during enflurane or isoflurane anesthesia. Atropine enhanced this increase during enflurane anesthesia, but abolished the increase during Isoflurane anesthesia. Enflurane increased SEA values only when combined with atropine. Isoflurane did not increase SEA values under any test conditions. ConclusionsWith enflurane, epinephrine-induced atrial pacemaker shifts in chronically Instrumented dogs are caused by direct depression of SA node automaticity or a relative increase of automaticity in subsidiary atrial pacemakers. With isoflurane, pacemaker shifts are caused by reflex-induced vagal suppression of SA node automaticity and escape of latent pacemakers. Enflurane sensitizes the atrial myocardium to dysrhythmias when combined with muscarinic blockade; Isoflurane does not sensitize the atrium.

The Effects of the New Antiarrhythmic E 047/1 on Postoperative Ischemia-Induced Arrhythmias in Dogs

UNLABELLED Perioperative malignant ventricular tachyarrhythmias pose an imminent clinical danger by potentially precipitating myocardial ischemia and severely compromising hemodynamics. Thus, immediate and effective therapy is required, which is not always provided by currently recommended IV drug regimens, indicating a need for more effective drugs. We examined antiarrhythmic effects of the new benzofurane compound E 047/1 on spontaneous ventricular tachyarrhythmia in a conscious dog model. One day after experimental myocardial infarction, 40 dogs exhibiting tachyarrhythmia randomly received (bolus plus 1-h infusion) E 047/1 6 mg/kg plus 6 mg x kg(-1) x h(-1), lidocaine 1 mg/kg plus 4.8 mg x kg(-1) x h(-1), flecainide 1 mg/kg plus 0.05 mg x kg(-1) x h(-1), amiodarone 10 mg/kg plus 1.8 mg x kg(-1) x h(-1), or bretylium 10 mg/kg plus 20 mg x kg(-1) x h(-1). Electrocardiogram was evaluated for number of premature ventricular contractions (PVC), normally conducted beats originating from the sinoatrial node, and episodes of ventricular tachycardia. Immediately after the bolus, E 047/1 reduced PVCs by 46% and increased sinoatrial beats from 4 to 61 bpm. The ratio of PVCs to total beats decreased from 98% to 58%. Amiodarone and flecainide exhibited antiarrhythmic effects with delayed onset. Lidocaine did not suppress PVCs significantly, and bretylium was proarrhythmic. The antiarrhythmic E 047/1 has desirable features, suppressing ischemia-induced ventricular tachyarrhythmia quickly and efficiently, and may be a useful addition to current therapeutic regimens. IMPLICATIONS Life-threatening arrhythmias of the heart after myocardial infarction or ischemia may be treated quickly and efficiently by the new drug E 047/1.

Anesthetics and automaticity of dominant and latent atrial pacemakers in chronically instrumented dogs. III. Automaticity after sinoatrial node excision.

Background Management of patients with sinus node dysfunction must consider the stability of subsidiary pacemakers during anesthesia and treatment with antimuscarinic or sympathomimetic drugs. Baroreflex regulation of atrial pacemaker function is known to contribute to the interactions between inhalation anesthetics and catecholamines. Sinoatrial (SA) node excision can be a model for intrinsic SA node dysfunction. Subsidiary atrial pacemakers are expected to emerge after SA node excision, but they may respond differently to humoral and neural modulation. Isolated and combined effects of epinephrine and methylatropine should help characterize subsidiary pacemaker function during anesthesia with halothane, isoflurane, and enflurane. Methods In eight dogs, SA nodes were excised and epicardial electrodes implanted at the atrial appendages, the His bundle, and along the sulcus terminalis. Spontaneous pacemaker automaticity and subsidiary atrial pacemaker recovery time were measured in the conscious state, in the presence of methylatropine, with 1 and 2 micro gram *symbol* kg1 *symbol* min sup ‐1 epinephrine and during 1.25 and 2 MAC halothane, isoflurane, and enflurane. Results After SA node excision, a stable and regular subsidiary atrial pacemaker rhythm emerged. Each anesthetic prolonged subsidiary atrial pacemaker recovery times. This prolongation was greater in the presence of methylatropine. Without methylatropine, isoflurane and enflurane, but not halothane, further enhanced the baroreflex‐mediated negative chronotropic effects of epinephrine, whereas with methylatropine, each anesthetic reduced the direct positive chronotropic effects of epinephrine. Conclusions Halothane, isoflurane, and enflurane have significant depressant effects on the spontaneous and epinephrine‐altered automatically of subsidiary atrial pacemakers. Depression of subsidiary atrial pacemaker automatically was most apparent in dogs with muscarinic blockade.

Anesthetics and Automaticity of Dominant and Latent Pacemakers in Chronically Instrumented Dogs: IV. Dysrhythmias after Sinoatrial Node Excision

Background Subsidiary atrial pacemakers assume control after sinoatrial (SA) node excision, and anesthetic-catecholamine interactions can produce severe bradycardia during isoflurane anesthesia. We hypothesized that epinephrine enhances atrial, atrioventricular junctional, and ventricular dysrhythmias after SA node excisions in dogs and that inhalation anesthetics would facilitate such dysrhythmias. Methods In eight dogs, SA nodes were excised and epicardial electrodes implanted at the atrial appendages, at the His bundle, and along the sulcus terminalis. Site of the earliest atrial activation and incidences of nonatrial beats were determined in the conscious state, with methylatropine, with epinephrine, and during halothane, isoflurane, or enflurane anesthesia. Results After SA node excision, a stable, regular subsidiary atrial pacemaker rhythm resulted. Epinephrine and halothane shifted the site of earliest activation to more remote atrial sites. Epinephrine-induced ventricular escape was increased by all anesthetics tested, but atropine prevented ventricular escape. Epinephrine-induced His bundle (atrioventricular junctional) and premature ventricular beats were increased by halothane and enflurane. After SA node excision, ventricular escape occurred as a result of epinephrine-anesthetic interactions, especially during anesthesia with isoflurane. Conclusions In dogs with excised SA nodes, anesthetic-catecholamine interaction facilitates ventricular escape, His bundle dysrhythmias, and premature ventricular beats. In addition, halothane and enflurane, more than isoflurane, facilitate ectopic ventricular tachydysrhythmias with epinephrine. Compared to intact dogs, dogs with excised SA nodes may be more susceptible to epinephrine anesthetic dysrhythmias. If findings can be extrapolated to humans, intrinsic SA node dysfunction may facilitate severe cardiac dysrhythmias with inhalation anesthetics and catecholamines.

Anesthetics, catecholamines, and ouabain on automaticity of primary and secondary pacemakers.

Publisher Summary The elucidation of mechanisms for arrhythmias during anesthesia has been the focus of investigation for a long period of time. Cardiac arrhythmias are usually seen as disturbances of impulse generation, propagation, or both. The potent inhalation anesthetic agents, by direct or indirect effects, can alter automaticity of the sinoatrial (SA) node and latent pacemakers in a manner conducive to the formation of ectopic atrial or atrioventricular (AV) junctional rhythm disturbances. However, volatile anesthetics would oppose a possible effect of digitalis to enhance automaticity of subsidiary or ectopic atrial pacemakers to explain paroxysmal atrial tachycardia (PAT) with toxic digitalis. These hypotheses have been tested in both in vitro and in vivo canine models. Variable depression of the inhalation anesthetics must be considered for anesthetic effects on automaticity of primary and secondary pacemakers. Although halothane (HAL), enflurane (ENF), and isoflurane (ISO) produce equivalent depression of SA node automat city, ENF (not HAL or ISO) enhances automaticity of Purkinje fibers exposed to epinephrine (EPI) compared to HAL or ISO. The relative contribution of baroreflex-mediated suppression varies among inhalation anesthetics, depending on their ability to depress the baroreflex arc. Finally, rate responses to ouabain or catecholamines make it unlikely that enhanced automaticity of subsidiary atrial pacemakers (SAP) can explain paroxysmal atrial tachycardia. The findings to date can have relevance to the management of patients with SA node dysfunction, susceptibility to atrial tachyarrhythmias, or advanced AV heart block, or those receiving digitalis.