John P. Kampine

Sympathetic Responses to Induction of Anesthesia in Humans with Propofol or Etomidate

Anesthetic induction with propofol commonly results in hypotension. This study explored potential mechanisms contributing to hypotension by recording cardiovascular responses including sympathetic neural activity from patients during induction of anesthesia with propofol (2.5 mg.kg-1 plus 200 micrograms.kg-1.min-1) or, for comparison, etomidate (0.3 mg.kg-1 plus 15 micrograms.kg-1.min-1). Twenty-five consenting, nonpremedicated, ASA physical status 1 and 2, surgical patients were evaluated. Measurements of R-R intervals (ECG), blood pressure (radial artery), forearm vascular resistance (plethysmography), and efferent muscle sympathetic nerve activity ([MSNA] microneurography: peroneal nerve) were obtained at rest and during induction of anesthesia. In addition, a sequential bolus of nitroprusside (100 micrograms) followed by phenylephrine (150 micrograms) was used to obtain data to quantitate the baroreflex regulation of cardiac function (R-R interval) and sympathetic outflow (MSNA) in the awake and anesthetized states. Etomidate induction preserved MSNA, forearm vascular resistance, and blood pressure, whereas propofol reduced MSNA by 76 +/- 5% (mean +/- SEM), leading to a reduction in forearm vascular resistance and a significant hypotension. Both cardiac and sympathetic baroslopes were maintained with etomidate but were significantly reduced with propofol, especially in response to hypotension. These findings suggest that propofol-induced hypotension is mediated by an inhibition of the sympathetic nervous system and impairment of baroreflex regulatory mechanisms. Etomidate, conversely, maintains hemodynamic stability through preservation of both sympathetic outflow and autonomic reflexes.

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.

sevoflurane Mimics Ischemic Preconditioning Effects on Coronary Flow and Nitric Oxide Release in Isolated Hearts

BACKGROUND Like ischemic preconditioning, certain volatile anesthetics have been shown to reduce the magnitude of ischemia/ reperfusion injury via activation of K+ adenosine triphosphate (ATP)-sensitive (K(ATP)) channels. The purpose of this study was (1) to determine if ischemic preconditioning (IPC) and sevoflurane preconditioning (SPC) increase nitric oxide release and improve coronary vascular function, as well as mechanical and electrical function, if given for only brief intervals before global ischemia of isolated hearts; and (2) to determine if K(ATP) channel antagonism by glibenclamide (GLB) blunts the cardioprotective effects of IPC and SPC. METHODS Guinea pig hearts were isolated and perfused with Krebs-Ringers solution at 55 mm Hg and randomly assigned to one of seven groups: (1) two 2-min total coronary occlusions (preconditioning, IPC) interspersed with 5 min of normal perfusion; (2) two 2-min occlusions interspersed with 5 min of perfusion while perfusing with GLB (IPC+GLB); (3) SPC (3.5%) for two 2-min periods; (4) SPC+GLB for two 2-min periods; (5) no treatment before ischemia (control [CON]); (6) CON+GLB; and (7) no ischemia (time control). Six minutes after ending IPC or SPC, hearts of ischemic groups were subjected to 30 min of global ischemia and 75 min of reperfusion. Left-ventricular pressure, coronary flow, and effluent NO concentration ([NO]) were measured. Flow and NO responses to bradykinin, and nitroprusside were tested 20-30 min before ischemia or drug treatment and 30-40 min after reperfusion. RESULTS After ischemia, compared with before (percentage change), left-ventricular pressure and coronary flow, respectively, recovered to a greater extent (P<0.05) after IPC (42%, 77%), and treatment with SPC (45%, 76%) than after CON (30%, 65%), IPC+GLB (24%, 64%), SPC+GLB (20%, 65%), and CON+GLB (28%, 64%). Bradykinin and nitroprusside increased [NO] by 30+/-5 (means +/- SEM) and 29+/-4 nM, respectively, averaged for all groups before ischemia. [NO] increased by 26+/-6 and 27+/-7 nM, respectively, in SPC and IPC groups after ischemia, compared with an average [NO] increase of 8+/-5 nM (P<0.01) after ischemia in CON and each of the three GLB groups. Flow increases to bradykinin and nitroprusside were also greater after SPC and IPC. CONCLUSIONS Preconditioning with sevoflurane, like IPC, improves not only postischemic contractility, but also basal flow, bradykinin and nitroprusside-induced increases in flow, and effluent [NO] in isolated hearts. The protective effects of both SPC and IPC are reversed by K(ATP) channel antagonism.

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.

Venodilation contributes to propofol-mediated hypotension in humans

The present investigation explored the possibility that the commonly observed hypotension that occurs during induction of anesthesia with propofol might be related to its ability to produce venodilation. Thirty-six ASA I and II patients who received no premedication were studied. The first 20 patients were divided into two equal groups. Hemodynamic measurements consisted of heart rate, arterial blood pressure, and forearm venous compliance by occlusive plethysmography. Baseline measurements were made in awake patients while resting in a supine position. Repeat measurements were made during steady-state infusions of propofol (2.5 mg/kg bolus injection, followed by a continuous infusion at 200 μg·kg−1·min−1) or thiopental (4 mg/kg bolus injection, followed by continuous infusion at 200 μg·kg−1·min−1), 10 min after tracheal intubation while patients were artificially ventilated. Both anesthetics resulted in a significant (P <0.05) and similar tachycardia; however, propofol produced significant decreases in systolic (−30 ± 9 mm Hg) and diastolic (−11 ± 4 mm Hg) arterial blood pressure. Forearm venous compliance was significantly increased during propofol administration but unchanged in patients receiving thiopental. In four additional patients receiving smaller consecutive infusions of propofol (50 and 100 μg·kg−1·min−1), significant subtle increases in forearm compliance were also recorded. These increases were not observed in four patients who received placebo infusions. Thus, one mechanism promoting hypotension during propofol anesthesia in humans seems to be related to its direct effects on venous smooth muscle tone and presumably venous return.

Comparison of etomidate, ketamine, midazolam, propofol, and thiopental on function and metabolism of isolated hearts

The authors examined direct myocardial and coronary vascular responses to the anesthetic induction agents etomidate, ketamine, midazolam, propofol, and thiopental and compared their effects on attenuating autoregulation of coronary flow as assessed by changes in oxygen supply/demand relationships. Spontaneous heart rate, atrioventricular conduction time during a trial pacing, left ventricular pressure (LVP), coronary flow (CF), percent oxygen extraction, oxygen delivery, and myocardial oxygen consumption (MVo2) were examined in 55 isolated guinea pig hearts divided into five groups of 11 each. Hearts were perfused at constant pressure with one of the drugs administered at steady-state concentrations increasing from 0.5 μM to 1 mM. Adenosine was given to test maximal CF. At concentrations below 10 μM no significant changes were observed; beyond 50 μM for midazolam, etomidate, and propofol, and 100 μM for thiopental and ketamine, each agent caused progressive but differential decreases in heart rate, atrioventricular conduction time (leading to atrioventricular dissociation), LVP, +dLVP/dtrnax, percent oxygen extraction, and MVo2. The concentrations (μM) at which +dLVP/dtmax was reduced by 50% were as follows: etomidate, 82 ± 2 (mean ± SEM); propofol, 91 ± 4; midazolam, 105 ± 8; thiopental, 156 ± 11; and ketamine, 323 ± 7; the rank order of potency was etomidate = propofol = midazolam > thiopental > ketamine; results were similar for LVP. At the 100 μM concentration, CF was decreased 11% ± 2% by ketamine and 5% ± 3% by thiopental but was increased 17% ± 6% by etomidate, 21% ± 5% by midazolam, and near maximally to 57% ± 10% by propofol; MVo2 was decreased 8% ± 4% by thiopental, 10% ± 5% by ketamine, 19% ± 5% by midazolam, 29% ± 7% by etomidate, and 37% ± 5% by propofol; oxygen delivery/MVo2 was unchanged by thiopental and ketamine but was increased 62% ± 7% by midazolam, 71% ± 9% by etomidate, and 150% ± 15% by propofol. Between 100 μM and 1 mM, thiopental and ketamine did not increase CF but decreased MVo2 and percent oxygen extraction, whereas propofol maximally increased CF and decreased MVo2 and midazolam and etomidate had intermediate effects. These results indicate that on a molar basis, propofol, and less so midazolam and etomidate, depress cardiac function moderately more than thiopental and ketamine, and that propofol markedly attenuates autoregulation by causing coronary vasodilation. With doses used to induce anesthesia, propofol and thiopental appear to depress cardiac function more than ketamine or etomidate.

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.

Effects of Isoflurane on the Baroreceptor Reflex

The baroreceptor reflex has been found to be attenuated during anesthesisa, but the effects of the relatively new anesthetic, isoflurance, on baroreflex function have not been examined throughly. This study was performed to determine the effects of isoflurane on each component of the baroreceptor reflex arc, including the receptors, afferent and efferent nerve pathways, central integratory centers, peripheral ganglia, and the heart. Baroreflex effects on heart rate initiated by systemic pressure changes were examined in conscious and anesthetized dogs (1.3% and 2.6% isoflurane). The effects on individual components of the reflex are were determined by examining carotid sinus baroreceptor afferent activity, sympathetic efferent nerve activity, and heart rate response to direct sympathetic and parasympathetic efferent nerve stimulation in anesthetized dogs. Preganglionic and postganglionic nerve activities were recorded simultaneously during baroreflex activation to determine ganglionic effects of isoflurane. Baroreflex-induced changes in heart rate were not depressed significantly until 2.6% isoflurane if blood pressure changes due to anesthetic administration were prevented. Significant decreases in baseline sympathetic efferent nerve activity were found at 1.3% and 2.6% isoflurane, with depression of postganglionic activity significantly greater than preganglionic activity at 2.6% isoflurane, indicating a ganglionic effect of isoflurance. Cardiac chronotropic responses to direct stimulation of sympathetic and vagal fibers were attenuated significantly by isoflurane, with sympathetic stimulation showing the greater sensitivity to the anesthetic. Carotid baroreceptor afferent activity was increased by isoflurane, and this sensitization of the baroreceptors appeared to contribute to the decreased levels of sympathetic tone. Therefore, although isoflurane was found to alter the baroreceptor reflex through its effects at multiple sites of the baroreflex arc, significant depression of the cardiac chronotropic component of the reflex was seen only at 2.6% isoflurane.

Differential Effects of Etomidate, Propofol, and Midazolam on Calcium and Potassium Channel Currents in Canine Myocardial Cells

Background Intravenous anesthetics etomidate, propofol, and midazolam produce negative inotropic effects of various degrees. The mechanism underlying these differences is largely unknown. Methods The effects of intravenous anesthetics on L-type Calcium sup 2+, transient outward and inward-rectifier Potassium sup + channel currents (ICa, IKto, and IK1) were compared in canine ventricular cells using the whole-cell voltage-clamp technique. ICa and IK were elicited by progressively depolarizing cells from -40 to +40 mV, and from -90 to +60 mV, respectively. The peak amplitude and time-dependent inactivation rate of ICa and IK were measured before, during, and after the administration of equimolar concentrations (5, 30, or 60 micro Meter) of etomidate, propofol, or midazolam. Results Exposure to etomidate, propofol, and midazolam produced a concentration-dependent inhibition of ICa. Midazolam was the most potent intravenous anesthetic; at 60 micro Meter, etomidate, propofol, and midazolam decreased peak ICa by 16 +/- 4% (mean +/- SEM), 33 +/- 5%, and 47 +/- 5%, respectively. Etomidate, propofol, and midazolam given in a 60-micro Meter concentration decreased IKto by 8 +/- 3%, 9 +/- 2%, and 23 +/- 3%, respectively. IK1 was decreased by 60 micro meter etomidate and midazolam by 20 +/- 6% and 14% +/- 5%, respectively. Propofol had no effect on IK1. Conclusions At equimolar concentrations, intravenous anesthetics decreased the peak ICa, IKto, and IK1 with various degrees of potency. Effects of anesthetics on ICa were significantly greater compared with their effects on Potassium sup + currents. These findings suggest that the negative inotropic actions of etomidate, propofol, and midazolam are related, at least in part, to decreased ICa. Some effects, such as IK inhibition, may partially antagonize effects of decreased ICa. Indeed, the final effect of these intravenous anesthetics on myocardium will be the sum of these and other sarcolemmal and intracellular effects.

Nitrous oxide augments sympathetic outflow: direct evidence from human peroneal nerve recordings

Direct evidence for postganglionic sympathetic nerve activation to blood vessels supplying skeletal muscle was sought by recording from the peroneal nerve of 13 volunteers with a 5-μ tipped tungsten needle. Eight subjects breathed through an anesthesia face mask connected to a semiclosed anesthesia circuit for two consecutive 10-min periods while 25% and 40% nitrous oxide (N2O) was administered sequentially. Five subjects served as controls and breathed equivalent concentrations of nitrogen. Blood pressure and central venous pressure were recorded from radial artery and jugular vein catheters. Forearm blood flow was measured by venous occlusion plethysmography. Peroneal nerve recordings were amplified 100,000-fold and integrated for analysis of burst frequency. N2O did not significantly alter respiratory rate, end-tidal CO2 (mass spectrometry), and diastolic or central venous pressures but did produce small but significant increases in heart rate and systolic pressure compared to time—control (P < 0.05). In contrast, N2O was associated with progressive, large increases in muscle sympathetic nerve activity (peak % Δ = 69 ± 22 burst/min [X ± SEM]) and forearm vascular resistance (30 ± 4%) and a nonsignificant increase in plasma norepinephrine levels. Thus, brief exposure to 25% and 40% N2O produces striking increases in sympathetic outflow to skeletal muscle in humans.