William T. Schmeling

Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane

Following brief periods (5–15 min) of total coronary artery occlusion and subsequent reperfusion, despite an absence of tissue necrosis, a decrement in contractile function of the postischemic myocardium may nevertheless be present for prolonged periods. This has been termed “stunned” myocardium to differentiate the condition from ischemia or infarction. Because the influence of volatile anesthetics on the recovery of postischemic, reperfused myocardium has yet to be studied, the purpose of this investigation was to compare the effects of halothane and isoflurane on systemic and regional hemodynamics following a brief coronary artery occlusion and reperfusion. Nine groups comprising 79 experiments were completed in 42 chronically instrumented dogs. In awake, unsedated dogs a 15-min coronary artery occlusion resulted in paradoxical systolic lengthening in the ischemic zone. Following reperfusion active systolic shortening slowly returned toward control levels but remained approximately 50% depressed from control at 5 h. In contrast, dogs anesthetized with halothane or isoflurane (2% inspired concentration) demonstrated complete recovery of function 3–5 h following reperfusion. Because the anesthetics directly depressed contractile function, additional experiments were conducted in which a 15-minute coronary artery occlusion was produced during volatile anesthesia; however, each animal was allowed to emerge from the anesthetized state at the onset of reperfusion. Similar results were obtained in these experiments, demonstrating total recovery of contractile function within 3–5 h following reperfusion. Thus, despite comparable degrees of contractile dysfunction during coronary artery occlusion in awake and anesthetized dogs, the present results demonstrate that halothane and isoflurane produce marked improvement in the recovery of segment function following a transient ischemic episode. Therefore, volatile anesthetics may attenuate postischemic left ventricular dysfunction occurring intraoperatively and enhance recovery of regional wall motion abnormalities during reperfusion.

Comparison of the Systemic and Coronary Hemodynamic Actions of Desflurane, Isoflurane, Halothane, and Enflurane in the Chronically Instrumented Dog

The systemic and coronary hemodynamic effects of desflurane were compared to those of isoflurane, halothane, and enflurane in chronically instrumented dogs. Since autonomic nervous system function may significantly influence the hemodynamic actions of anesthetics in vivo, a series of experiments also was performed in the presence of pharmacologic blockade of the autonomic nervous system. Eight groups comprising a total of 80 experiments were performed on 10 dogs instrumented for measurement of aortic and left ventricular pressure, the peak rate of increase of left ventricular pressure (dP/dt), subendocardial segment length, coronary blood flow velocity, and cardiac output. Systemic and coronary hemodynamics were recorded in the conscious state and after 30 min equilibration at 1.25 and 1.75 MAC desflurane, isoflurane, halothane, and enflurane. Desflurane (+79 +/- 12% change from control) produced greater increases in heart rate than did halothane (+44 +/- 12% change from control) or enflurane (+44 +/- 9% change from control) at 1.75 MAC. Desflurane preserved mean arterial pressure to a greater degree than did equianesthetic concentrations of isoflurane. This result was attributed to a smaller effect on peripheral vascular resistance as compared to isoflurane and greater preservation of myocardial contractility as evaluated by peak positive left ventricular dP/dt and the rate of increase of ventricular pressure at 50 mmHg (dP/dt50) compared to other volatile anesthetics. Increases in diastolic coronary blood flow velocity (+19 +/- 6 and +35 +/- 12% change from control at 1.75 MAC, respectively) and concomitant decreases in diastolic coronary vascular resistance (-41 +/- 12 and -58 +/- 6% change from control at 1.75 MAC, respectively) were produced by desflurane and isoflurane. In the presence of autonomic nervous system blockade, the actions of desflurane and isoflurane were nearly identical with the exception of coronary vasodilation. After autonomic nervous system blockade, isoflurane increased coronary blood flow velocity, but desflurane did not. Furthermore, both desflurane and isoflurane continued to produce less depression of myocardial contractility than did halothane and enflurane. In summary, at equianesthetic concentrations, desflurane and isoflurane produced similar hemodynamic effects; however, in the absence of drugs that inhibit autonomic reflexes, desflurane had less negative inotropic activity and produced less decrease in arterial pressure. The coronary vasodilator actions of desflurane and isoflurane within the limitations of this model were not similar. When the increase in heart rate and rate-pressure product produced by desflurane were prevented in dogs with autonomic nervous system blockade, desflurane produced no change in coronary blood flow velocity.

Prolongation of the QT interval by enflurane, isoflurane, and halothane in humans.

&NA; Previous investigations in laboratory animals have documented the ability of the volatile anesthetics to prolong the QT interval and the QT interval corrected for level of heart rate, QTc. The purpose of the present investigation was to evaluate the direct electrocardiographic and hemodynamic effects of enflurane, isoflurane, and halothane in healthy, unpremedicated patients using an inhalation induction to avoid the confounding effects of other anesthetic agents. Experiments were conducted in 22 adult male patients, (ASA physical status I or II) divided into three groups given either enflurane (n = 6), isoflurane (n = 8), or halothane (n = 8) anesthesia. Twenty‐four‐hour preoperative, preinduction, and postinduction hemodynamic and electrocardiographic measurements were obtained. Anesthetic blood concentrations, levels of plasma electrolytes, and arterial blood gas tensions were also quantitated. Halothane administration (0.81 ± 0.06 mM) did not significantly alter the PR interval or QRS duration but significantly increased the QT (0.38 ± 0.01 to 0.45 ± 0.01 s) and QTc intervals (0.39 ± 0.01 to 0.44 ± 0.02 s). Isoflurane anesthesia (1.04 ± 0.11 mM) did not significantly change QRS duration or PR and QT intervals but significantly prolonged the QTc interval (0.42 ± 0.01 to 0.47 ± 0.14 s). Similarly, enflurane anesthesia (2.16 ± 0.13 mM) significantly prolonged the QTc (0.40 ± 0.01 to 0.46 ± 0.14 s) without change in QRS duration or PR and QT intervals. Plasma electrolyte levels and arterial gas tensions remained within normal limits in all patients. All patients maintained a normal sinus rhythm during the study despite prolongation of the QTc induced by the volatile anesthetics. These results extend previous observations in experimental animals to humans and suggest that ventricular repolarization is directly altered by the volatile anesthetics. Despite the absence of cardiac arrhythmias in this study, prolongation of the QTc interval by volatile inhalation anesthetics suggests that caution should be used during administration of volatile anesthetics to patients with congenital, acquired, or pharmacologically induced prolongation of the QTc.

Alteration of Left Ventricular Diastolic Function by Desflurane, Isoflurane, and Halothane in the Chronically Instrumented Dog with Autonomie Nervous System Blockade

The effects of the new volatile anesthetic desflurane on three indices of left ventricular diastolic function were examined and compared to those produced by equianesthetic concentrations of isoflurane and halothane. Diastolic function has been shown to significantly influence systolic performance, but the effects of volatile anesthetics on diastolic function have not been extensively examined. Since autonomic nervous system function may significantly influence hemodynamic actions of anesthetics in vivo, experiments were performed in the presence of pharmacologic blockade of the autonomic nervous system. Three groups comprising a total of 23 experiments were performed using 11 dogs instrumented for measurement of aortic and left ventricular pressure, rate of increase of left ventricular pressure (dP/dt), subendocardial segment length, and cardiac output. Systemic hemodynamics were recorded in the conscious state and after 30 min equilibration at 1.0 and 1.5 MAC desflurane, isoflurane, or halothane. Ventricular relaxation was described using invasively derived time constants of isovolumetric relaxation with zero (To) or nonzero (Tn) assumptions of asymptotic decay. Chamber and myocardial stiffness the viscoelastic properties of the ventricle, were described using exponential relationships relating ventricular pressure to segment length and end-diastolic pressure to Lagrangian strain, respectively. Desflurane produced a significant (P less than 0.05) and dose-dependent increase in isovolumetric relaxation as a evaluated by both time constants (To, 22.2 +/- 2.0 during control to 33.9 +/- 3.5 ms at 1.5 MAC; Tn, 33.1 +/- 1.6 during control to 45.1 +/- 4.3 ms at 1.5 MAC). Similar degrees of prolongation of isovolumetric relaxation were produced by isoflurane (Tn, 35.6 +/- 1.5 during control to 47.1 +/- 2.9 ms at 1.5 MAC) and halothane (Tn, 31.7 +/- 2.2 during control to 42.3 +/- 3.9 ms at 1.5 MAC). Halothane also caused an increase in regional passive chamber stiffness (Kp, 0.46 +/- 0.07 during control to 0.88 +/- 0.17 mm-1 at 1.5 MAC) indicating a decrease in ventricular compliance. No changes in chamber stiffness were observed with desflurane or isoflurane. In addition, no significant changes in myocardial stress-strain relationships as evaluated by nonlinear elastic coefficients, alpha (gain) and beta (myocardial stiffness), were observed with any anesthetic. Although the effects of volatile anesthetics on systolic function could not be entirely excluded from the analysis, the results indicated that desflurane, isoflurane, and halothane produce equivalent degrees of prolongation of isovolumetric relaxation. Halothane also caused a decrease in compliance during passive filling as evaluated by chamber stiffness, but no change in compliance was observed at end diastole as assessed by stress-strain relationships.(ABSTRACT TRUNCATED AT 400 WORDS)

The Effects of the Stereoisomers of the α2-adrenergic Agonist Medetomidine on Systemic and Coronary Hemodynamics in Conscious Dogs

The alpha 2-adrenergic agonist medetomidine produces systemic hemodynamic effects that are mediated by both peripheral and central nervous system actions. The current investigation was designed to characterize coronary and systemic hemodynamic effects of the D- and L-stereoisomers of medetomidine in conscious, chronically instrumented dogs with and without autonomic nervous system blockade. Dogs were instrumented for measurement of aortic pressure, coronary blood flow velocity, cardiac output, left ventricular pressure, rate of change in pressure (dP/dt), and subendocardial systolic shortening. Administration of the D-isomer of medetomidine (doses of 1.25, 2.5, and 5.0 micrograms/kg, each administered over 10 min, with 60 min between doses) significantly altered systemic hemodynamics, in a biphasic fashion. A decrease in respiratory rate without change in arterial blood gas tensions occurred. With the 5 micrograms/kg dose of D-medetomidine, an initial pressor response was followed by secondary, significant (P less than 0.05), and dose-related decreases in heart rate (74 +/- 3 to 57 +/- 4 beats per min), mean arterial pressure (109 +/- 2 to 100 +/- 3 mmHg) and the rate-pressure product (10.5 +/- 0.4 to 7.0 +/- 0.5 beats.min-1.mmHg.10(3] accompanied by a reduction in plasma concentrations of norepinephrine. No changes in left ventricular end diastolic pressure or coronary blood flow velocity occurred. In contrast to the D-isomer, the L-isomer (1.25, 2.5 and 5.0 micrograms/kg) produced no changes in hemodynamics or plasma concentrations of norepinephrine. In dogs pretreated with hexamethonium (20 mg/kg), propranolol (2 mg/kg), and atropine methylnitrate (3 mg/kg) to produce autonomic nervous system blockade, D-medetomidine also produced an initial pressor response, but no secondary reduction in heart rate or arterial pressure occurred. The results indicate that the D-isomer of medetomidine is stereospecific for alterations in hemodynamics: the active D-isomer produces decreases in heart rate, arterial pressure, and the rate-pressure product via diminished sympathetic and/or augmented parasympathetic tone. This conclusion is supported by the absence of these changes after pharmacologic blockade of the autonomic nervous system.

Influence of desflurane, isoflurane and halothane on regional tissue perfusion in dogs

The actions of desflurane, isoflurane and halothane on regional tissue perfusion were studied using radioactive microspheres in dogs chronically instrumented for measurement of arterial and left ventricular pressure, global (left ventricular dP/dtmax) and regional (percent segment shortening) contractile function, and diastolic coronary blood flow velocity. Systemic and coronary haemodynamics and regional tissue perfusion were measured in the conscious state and during anaesthesia with equihypotensive concentrations of desflurane, isoflurane, and halothane. All three volatile anaesthetics (P < 0.05) increased heart rate and decreased mean arterial pressure, left ventricular systolic pressure, and left ventricular dP/dtmax Myocardial perfusion was unchanged in subendocardial, midmyocardial, andsubepicardial regions by the administration of either dose of desflurane. No redistribution of intramyocardial blood flow (endo/epi ratio) was observed during desflurane anaesthesia. Although regional myocardial perfusion was reduced (P < 0.05) in a doserelated fashion by halothane and by isoflurane at high concentrations, redistribution of intramyocardial blood flow was not observed during halothane or isoflurane anaesthesia. All three volatile anaesthetics reduced blood flow to the renal cortex, but only desflurane produced a decrease in renal cortical vascular resistance. Hepatic blood flow decreased in response to halothane but not desflurane or isoflurane. Concomitant decreases in hepatic resistance were observed during administration of desflurane and isoflurane. Doserelated decreases in intestinal and skeletal muscle blood flow were observed during halothane and isoflurane but not desflurane anaesthesia. The results suggest that desflurane maintains myocardial, hepatic, intestinal, and skeletal muscle blood flow while halothane and isoflurane decrease regional tissue perfusion in these vascular beds to varying degrees during systemic hypotension in the chronically instrumented dog.RésuméCe travail étudie les effets du desflurane, de l’isoflurane et de l’halothane sur la perfusion régionale à l’aide de microsphères radioactives sur des chiens préparés à demeure pour mesures itératives de la tension artérielle et ventriculaire gauche, de la contractilité globale (dP/dtmax ventriculaire gauche) et régionale (index de raccourcissement segmentaire) ainsi que de la vélocité du débit coronarien diastolique. L’hémodynamique systémique et coronaire et la perfusion régionale ont été mesurées à l’état de conscience et pendant l’anesthésie avec des concentrations hypotensives équivalentes de desflurane, d’isoflurane et d’halothane. Les trois agents (P < 0,05) ont augmenté la fréquence cardiaque et diminué la tension artérielle moyenne et le dP/dtmax ventriculaire gauche. La perfusion myocardique est demeurée inchangée aux régions subendocardique, midendocardique et subépicardique pendant l’administration de desflurane. On n’observe pas de redistribution du débit intramyocardique (rapport endo./épi.) pendant l’anesthésie au desflurane. Bien que la perfusion régionale soit réduite (P < 0,05) de façon proportionnelle pour les concentrations élevées d’isoflurane et d’halothane, la redistribution de débit sanguin myocardique n’est pas observée pendant l’anesthésie avec ces agents. Alors que les trois agents volatils diminuent le débit sanguin au cortex rénal, seul le desflurane en diminue la résistance vasculaire. Le débit sanguin hépatique diminue sous halothane mais non sous isoflurane et desflurane. Une diminution simultanée des résistances hépatiques survient pendant l’administration de desflurane et d’isoflurane. Des baisses de débit sanguin à l’intestin et aux muscles squelettiques proportionnelles à la concentration sont observées pendant l’anesthésie à l’halothane et l’isoflurane mais ne surviennent pas sous desflurane. Ces résultats suggèrent le maintien par le desflurane des débits sanguins myocardique, hépatique, intestinal et musculaire alors que l’halothane et l’isoflurane diminuent la perfusion tissulaire régionale de ces lits vasculaires à différents degrés pendant l’hypotension systémique chez le chien.

INFLUENCE OF VOLATILE ANESTHETICS ON MYOCARDIAL CONTRACTILITY IN VIVO : DESFLURANE VERSUS ISOFLURANE

The direct effects of desflurane on myocardial contractility in vivo have not been characterized. Therefore, the purpose of this investigation was to systematically examine the effects of desflurane on myocardial contractile function and compare these actions to equianesthetic concentrations of isoflurane in chronically instrumented dogs. Contractility was evaluated using an established index of inotropic state, the preload recruitable stroke work (PRSW) versus end-diastolic segment length (EDL) relationship. Since autonomic nervous system tone may influence the hemodynamic effects of the volatile anesthetics in vivo, experiments were performed in the presence of pharmacologic blockade of the autonomic nervous system. Two groups of experiments were performed with seven dogs instrumented for measurement of aortic and left ventricular pressure, the maximum rate of increase of left ventricular pressure (dP/dt), subendocardial segment length, coronary blood flow velocity, and cardiac output. After autonomic nervous system blockade, ventricular pressure-segment length loops were generated using preload reduction via partial inferior vena caval occlusion. The PRSW versus EDL relation was calculated from the pressure-length loops. Dogs were then anesthetized with 1.0 or 1.5 MAC desflurane or isoflurane in a random fashion, and measurements were repeated after 30 min of equilibration at each anesthetic concentration. The PRSW versus EDL slope reflected similar changes in contractile state when desflurane or isoflurane was administered (53 +/- 4 during control to 26 +/- 4 erg.cm-2 x 10(-3).mm-1 at 1.5 MAC desflurane, and 57 +/- 5 during control to 31 +/- 3 erg.cm-2 x 10(-2).mm-1 at 1.5 MAC isoflurane). In conclusion, desflurane and isoflurane produced equivalent direct decreases in myocardial contractility.

Alteration of canine left ventricular diastolic function by intravenous anesthetics in vivo. Ketamine and propofol

Diastolic function has been shown to influence overall cardiac performance significantly, but the effect of intravenous anesthetics on diastolic function has not been previously characterized in vivo. The effects of ketamine and propofol on two indices of left ventricular diastolic function were examined in chronically instrumented dogs. Because autonomic nervous system function may significantly influence the systemic hemodynamic actions produced by intravenous anesthetics in vivo, experiments were performed in the presence of pharmacologic blockade of the autonomic nervous system. Two groups comprising a total of 14 experiments were performed using 7 dogs instrumented for measurement of aortic and left ventricular pressure, the maximum rate of increase of left ventricular pressure (dP/dt), subendocardial segment length, and cardiac output. Systemic hemodynamics and diastolic function were recorded and evaluated in the conscious state and after a 20-min equilibration at 25-, 50-, and 100-mg.kg-1.h-1 infusion doses of ketamine or propofol. Ventricular relaxation was described using the time constant of isovolumetric relaxation (tau) assuming a nonzero asymptote of ventricular pressure decay. Regional chamber stiffness, an index of passive ventricular filling, was described using an exponential equation relating segment length to ventricular pressure between minimum ventricular pressure and the onset of atrial systole.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct coronary and cerebral vascular responses to dexmedetomidine : significance of endogenous nitric oxide synthesis

Dexmedetomidine activates alpha 2-adrenergic receptors in the central nervous system and in the peripheral vasculature. In vivo dexmedetomidine has been found to cause alterations in coronary and cerebral blood flows and arterial pressure by stimulation of vascular smooth muscle alpha 2 receptors. The direct vasoconstrictor effects of alpha 2-adrenergic agonists may be opposed by release of endothelium-derived relaxing factor believed to be nitric oxide. A functional endothelium was demonstrated recently in canine coronary collateral vessels. The objective of the current study was to assess the direct effect of dexmedetomidine on isolated canine proximal and distal coronary arteries, coronary collateral vessels, and middle cerebral arteries. Responses were measured in tissue baths in the presence of indomethacin 10(-5) M and in the absence and presence of NG nitro-l-arginine methyl ester (L-NAME), an inhibitor of vascular nitric oxide synthesis. Dexmedetomidine (3 x 10(-8) to 3 x 10(-3.9) M) caused constriction (3.9, 5.5, 72.8, and 2.3% for proximal and distal coronary arteries, middle cerebral arteries, and coronary collateral vessels, respectively, expressed as a percentage of KCl-induced contraction) in all vessels. This constriction was enhanced by the presence of L-NAME in all vessels except cerebral arteries. The selective alpha 2-adrenergic antagonist atipamezole (10(-4) M) abolished the response to low but not high concentrations of dexmedetomidine in middle cerebral arteries, proximal coronary arteries, and coronary collateral vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of End-Systolic Pressure—Length Relations and Preload Recruitable Stroke Work as Indices of Myocardial Contractility in the Conscious and Anesthetized, Chronically Instrumented Dog

Development of an index of myocardial contractility that is both load independent and easily quantified in vivo has been a difficult task. Recently, three measures of contractile state have been advocated that appear to fulfill these requirements: the end-systolic pressure-length relationship (ESPLR), the ESPLR area, and regional preload recruitable stroke work (PRSW). Because the effects of halothane and isoflurane on these indices of contractility have yet to be studied, the purpose of this investigation was to compare the effects of these volatile anesthetics on contractile function as evaluated via these techniques in chronically instrumented dogs. Because autonomic nervous system tone substantially influences systemic hemodynamics in vivo, experiments were performed in the presence of pharmacologic blockade of the autonomic nervous system. Four groups comprised the 36 experiments that were performed with nine dogs. Following inhalational induction, the dogs were maintained on 1.5 MAC and 2 MAC of halothane or isoflurane. Pressure-length loops were generated after 1 h of equilibration using preload reduction via partial inferior vena caval occlusion or afterload augmentation by a phenylephrine infusion. The PRSW and ESPLR were then calculated, respectively. Slope and length intercept variables obtained from the ESPLR failed to significantly change from control with increasing levels of anesthetic depth despite substantial decreases in other indices of contractility. However, combination of slope and length intercept parameters into the ESPLR area model proved to be a sensitive and easily calculable measure of depressed myocardial function. Similarly, regional PRSW slope precisely reflected changes in contractile state when halothane (62 +/- 10 for control to 30 +/- 6 erg.cm-2.10(-3).mm-1 at 2 MAC) or isoflurane (83 +/- 14 for control to 55 +/- 8 erg.cm-2.10(-3).mm-1 at 2 MAC) were administered. The PRSW slope also demonstrated a significant difference in depressed contractility when equianesthetic concentrations of halothane and isoflurane were compared (63 +/- 7% of control with halothane versus 86 +/- 4% of control with isoflurane at 1.5 MAC; 50 +/- 5% of control with halothane versus 70 +/- 6% of control with isoflurane at 2 MAC). The ESPLR area also accurately demonstrated the differential depression in contractile function suggested by recent in vitro studies when equianesthetic doses of halothane and isoflurane were compared in vivo. Therefore, while ESPLR slope and length intercept variables fail as indices of myocardial contractility, ESPLR area and regional PRSW slope were shown to be useful indicators of contractile state in the conscious and anesthetized dog.