Joan W. Flacke

Reduced narcotic requirement by clonidine with improved hemodynamic and adrenergic stability in patients undergoing coronary bypass surgery.

The authors examined the effect of clonidine, a preferential alpha2-adrenergic agonist, upon narcotic requirements, hemodynamics, and adrenergic responses during the perioperative period in patients undergoing CABG surgery. Anesthesia was provided by sufentanil supplemented with isoflurane; sodium n

Effects of dexmedetomidine on systemic and coronary hemodynamics in the anesthetized dog

In addition to central effects, which are the basis of their use in anesthesiology, alpha 2-adrenergic agonists have direct peripheral cardiovascular effects. Dexmedetomidine (DM) has been found to depress cardiac function in dogs, even after autonomic denervation. The present experiments evaluated the effects of DM on coronary flow, myocardial oxygen extraction, and cardiac function in intact, open chest dogs under enflurane anesthesia. Heart rate (HR), mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP), the first derivative of systolic left ventricular pressure (dP/dtmax), and flow in the left anterior descending coronary artery (CBF) were measured and continuously recorded. Cardiac output (CO), plasma catecholamines (CA), hemoglobin and oxygen saturation in arterial, mixed venous, and coronary sinus blood were measured at intervals. Cardiac index (CI), systemic vascular resistance index (SVRI), regional coronary vascular resistance (CVR), and oxygen concentration differences across the systemic [C(a-v)O2], and coronary [C(a-cs)O2] circulations were calculated. DM doses of 0.25, 0.5, 1.0, 2.0, and 4.0 micrograms/kg were given IV at 20-minute intervals. Measurements and samples were taken at peak drug effects and just prior to the next dose. The alpha 2-antagonist atipamezole, 0.5 mg/kg, was given after the last dose of DM. DM caused immediate dose-dependent increases in SVRI, CVR, LVEDP, C(a-v)O2, and C(a-cs)O2, and decreases in HR, and CI, with recovery between doses. DP/dtmax declined after the first two doses and stabilized thereafter, as plasma CA fell to minimal levels. Atipamezole completely reversed all changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of dexmedetomidine, an alpha 2-adrenergic agonist, in autonomically denervated dogs.

Summary The hemodynamic effects of the α2-adrenergic agonist, dexmedetomidine (DM), were studied in eight anesthetized, autonomically denervated dogs. Autonomic block decreased mean arterial pressure (MAP) and cardiac index (CI) by 20% to 95 ± 8 mm Hg and 4.1 ± 0.1 L/min/m2, respectively (mean ± SEM), and reduced nor-epinephrine (NE) and epinephrine plasma levels to almost undetectable levels. DM, administered intravenously (i.v.) either by bolus injection or by slow (20 min) infusion in doses between 1 and 30 (μg/kg, had no effect on heart rate (HR), increased MAP significantly by 98%, decreased CI by 59%, and increased calculated systemic vascular resistance index (SVRI) significantly by 376%, maximally. The effect of the lowest dose was mediated mainly by arteriolar vasoconstriction, and that of higher doses was mediated by vasoconstriction and decreased CI. Left ventricular end-diastolic pressure (LVEDP) increased significantly from 6 ± 2 to > 30 mm Hg, maximally. The effects were cumulative, and the first dose caused near maximal pressor effect; the resistance increase was as great with slow infusion as with bolus injection. Prazosin (1 mg/kg) did not affect the changes, but 0.3 mg/kg atipamezole, a selective α2-antagonist, completely antagonized them. These observations demonstrate potent constriction of both arteriolar resistance and venous capacitance vasculature in dogs. The combination of decreased CI and increased filling pressure implies marked decrease in cardiac function which was, however, fully reversible by atipamezole.

Effects of fentanyl, naloxone, and clonidine on hemodynamics and plasma catecholamine levels in dogs.

A 50-μ/kg dose of fentanyl, given intravenously in divided doses to dogs under enflurane-nitrous oxide anesthesia caused sharp decreases in heart rate (HR), arterial blood pressure (AP), left ventricular dP/dt, and plasma levels of catecholamines. Naloxone, 20 μg/kg given 65--70 min later, completely and rapidly reversed these changes. Because the cardiovascular effects of fentanyl and naloxone occurred in unparalyzed animals under surgical anesthesia without eliciting any motor responses, it seems unlikely that they can be ascribed to changes in awareness and surgical stimulation, especially pain. The brief duration of exposure to the narcotic makes it improbable that the naloxone respone is due to acute dependence and precipitated withdrawal. Pretreatment with 20 μg/kg of atropine only attenuated the decrease in HR, indicating a minor role of vagal mechanisms under these conditions. Administration of 20 μg/kg of clonidine by slow infusion after fentanyl further reduced sympathetic activity and greatly attenuated the naloxone response. Injection of 5 mg/kg of tolazoline after administration of clonidine produced massive cardiovascular stimulation by antagonizing clonidine and unmasking the naloxone reversal of fentanyl. Thus, in fully anesthetized dogs, fentanyl decreased the level of cardiovascular function mainly by reducing sympathetic activity. This effect does not seem to be secondary to analgesia or other sensory depressant effects of the narcotic, but rather to an action on central opioid-sensitive mechanisms regulating cardiovascular function.

Effect of dexmedetomidine, an α2-adrenergic agonist, in the isolated heart

Abstract Dexmedetomidine (DM) was studied in the isolated dog heart in the form of a Starling heart-lung preparation, (HLP). Hearts were subjected to increased loading by (a) increasing cardiac output, and (b) increasing systemic resistance. Results are depicted by cardiac function curves, prepared by plotting left atrial pressure against either systemic cardiac output or mean arterial pressure. DM, given in divided doses up to 44 μg, had no effect on heart rate or cardiac function, nor did injection of 0.5 mg of atipamezole, a selective alpha2-antagonist. Additional injections of very large doses of DM, up to 4,444 μg, caused an increase in heart rate and a leftward shift of the function curves, ie, positive chronotropic and inotropic effects. Plasma catecholamine levels increased markedly between the 444 μg and the 4,444 μg cumulative doses of DM. Administration of 1 mg of prazosin had no effect, but 1 mg of propranolol returned the rate to baseline and markedly shifted function curves to the right and depressed their slopes. Thus, whereas low doses (corresponding to between 1 and 30 wg / kg in intact animals) of DM, given acutely IV, have been shown to depress cardiac function in intact and denervated dogs, this effect is not due to a direct effect on the myocardium. High doses, far beyond doses maximally effective in intact animals and man, release catecholamines from cardiac stores. Plasma DM levels after low doses in the HLP were between 1 to 10 times those seen in intact animals and human volunteers after the usual doses given clinically for their central effects. Because DM caused no myocardial depressant effect in the isolated, blood-perfused canine HLP, decreases in cardiac function seen after this drug is given to intact and autonomically denervated dogs must be due to factor(s) other than a direct action on the myocardium.

Narcotic reversal in hypercapnic dogs: comparison of naloxone and nalbuphine

Reversal of opioid effects by naloxone (NX) can lead to significant cardiovascular problems. We have reported previously that hypercapnic dogs develop greater increases in blood pressure and plasma catecholamine (CA) levels than hypocapnic ones when reversed with naloxone. We have also demonstrated differences between NX and nalbuphine (NBPH) in producing excitatory adrenergic responses when administered during normocapnia. The present study was designed to investigate possible dissimilarities in cardiovascular and sympathetic events after administration of either NX or NBPH in dogs made hypercapnic following fentanyl administration. After induction of anaesthesia with thiopentone and intubation, two groups of dogs were maintained with controlled ventilation on enflurane in oxygen anaesthesia and given 50 μg · kg-1 fentanyl IV. This caused a significant decrease in heart rate (HR) (P < 0.001), mean arterial blood pressure (MAP) (P < 0.001), and plasma concentrations of norepinephrine (NE) (P < 0.002). Then, ventilation was decreased to produce a PaCO2 of 60 mmHg; this was accompanied by a significant elevation in plasma level of both epinephrine (EP1) (P < 0.02) and NE (P < 0.001). Administration of 20 μg · kg-1 NX to six dogs resulted in immediate increases in HR (P < 0.01) and MAP (P < 0.01), and a further rise in CA levels to greater than prefentanyl baseline values. In six other dogs, NBPH (0.3 mg · kg-1) caused increases in HR (P < 0.001) and MAP (P < 0.001) only, and the MAP rise was significantly less than that seen in the NX group (P < 0.01). Neither NE nor EPI levels increased after NBPH. Absolute levels of EPI one minute after reversal with NBPH were not greater than baseline and were significantly less than after NX (P < 0.05). Addition of NX after NBPH caused a further significant increase in EPI to levels greater than baseline (P < 0.002). This study suggests that the abrupt, significant, and sustained increases in MAP and plasma levels of CA which accompany narcotic reversal with NX during hypercapnia are blunted if nalbuphine rather than naloxone is used.RésuméL’antagonisme des effets des opiacés par le naloxone (NX) peut amener des problèmes cardiovasculaires significatifs. On a rapporté dans le passé que des chiens hypercapniques développaient une plus grande augmentation de la pression artérielle et des catécholamines plasmatiques (CA) que ceux qui sont hypocapniques lors de l’antagonisme avec le naloxone. On a aussi démontré des différences entre le naloxone et la nalbuphine (NBPH) dans la production de réponses adrénergiques lorsqu’administrés en normocapnie. Cette étude a été conçue afin d’investiguer les différences possibles dans les réponses sympathiques et cardiovasculaires après administration de soit NX ou NBPH chez des chiens rendus hypercapniques après administration de fentanyl. Après l’induction de l’anesthésie avec du thiopentone et intubation, deux groupes de chiens ont été maintenus avec une ventilation contrôlée sous enflurane et oxygène et ont reçu 50 μg · kg-1 de fentanl par voie intraveineuse. Ceci amena une diminution significative de la fréquence cardiaque (HR) (P < 0,001), pression artérielle moyenne (MAP) (P < 0,001), et des concentrations plasmatiques de norépinéphrine (NE) (P < 0,002). Par la suite, la ventilation fut diminuée afin de produire une PaCO2 de 60 mmHg; ceci fut accompagné par une augmentation significative des niveaux plasmatiques d’épinéphrine (EPI) (P < 0,02) et de norépi-néphrine (P < 0,001).L’administration de20μg · kg-1 de NX à six chiens a occasionne une augmentation immédiate de la fréquence cardiaque HR(P < 0,01) et de la MAP (P < 0,01), et une augmentation de la CA à un niveau supérieur aux valeurs de contrôle avant-fentanyl. Chez les six autres chiens, du NBPH (0,3 mg · kg-1)a occasionné une augmentation de HR et de la MAP (P < 0,001) uniquement, et l’augmentation de la MAP était significativement moindre que celle observée dans le groupe NX (P < 0,01). Ni les niveaux de NE ou EPI augmentèrent après le NBPH. Les niveaux absolus de EPI une minute après antagonisme avec le NBPH ne furent pas supé-rieurs à ceux de la valeur de contrôle et étaient significativement moindres qu’aprés NX (P < 0,005). L’addition de NX après NBPH a occasionné une augmentation significative des niveaux de EPI supérieurs à celui du contrôle (P < 0,002). Cette étude suggère qu’une augmentation brusque, significative, et soutenue de la MAP et des niveaux plasmatiques de CA qui accompagnent l’antagonisme des narcotiques avec le NX durant l’hypercapnie sont amoindris si le nalbuphine plutôt que le naloxone est utilisé.

Cardiovascular effects of fentanyl reversal by naloxone at varying arterial carbon dioxide tensions in dogs.

Clinical reports, as well as animal studies, have described cardiovascular and sympathetic stimulation after the administration of naloxone (NX) to reverse opioid-induced respiratory depression. This investigation examines the effect of Paco2 on hemodynamic and adrenergic responses to NX, by means of 24 experiments carried out in six dogs. Each dog underwent NX reversal of fentanyl (FEN) at three different Paco2 levels: 20, 35, and 60 mm Hg. In a final series of six experiments, the dogs were exposed to increasing Paco2 after autonomic block by total spinal anesthesia and vagotomy. During enflurane anesthesia, 50 μg/kg FEN decreased mean arterial blood pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and epinephrine (EPI) significantly. NX 0.4 mg promptly returned HR and MAP to baseline or above in all experiments; catecholamine (CA) levels increased only in hypercapnic dogs. Increases in HR were the same in all series. MAP, EPI, and NE levels were significantly greater than pre-FEN baseline values only in hypercapnic dogs 1 minute after NX and were also significantly higher in hypercapnic than in hypocapnic dogs at this time. NE levels were greater in hypercapnic dogs at all time periods after NX. In blocked dogs, neither F nor NX had any effects on hemodynamic functions or plasma CA levels; the institution of hypercapnia caused significant decreases in HR, MAP, and systemic vascular resistance. This direct circulatory depressant action of an elevated Pco2 may have attenuated the indirectly mediated excitatory hemodynamic effects of NX in intact dogs, thus explaining the relatively greater effect of hypercapnia on adrenergic than on hemodynamic responses to reversal. This study suggests that abrupt increases in blood pressure and plasma CA levels after naloxone can be blunted if normocapnia or hypocapnia is established before naloxone administration.

Reflex responses to sodium nitroprusside and their control by cryptenamine.

In chloralose-anesthetized dogs the hypotensive and reflex cardiovascular responses to infusions of sodium nitroprusside were studied before and during halothane and enflurane, and before and after divided doses of cryptenamine. The latter drug, a mixture of hypotensive veratrum alkaloids, lowers blood pressure reflexly by acting on afferent receptors (baroreceptors). Control infusions of nitroprusside, which caused 10% to 15% decreases in mean arterial blood pressure, markedly increased heart rate, myocardial contractility, cardiac output, rate-pressure product, and left ventricular minute work in spite of decreases in peripheral vascular resistance. Except for increases in contractility, these reflexly mediated effects were not blocked by the addition of 1% halothane or 2% enflurane. Cryptenamine, on the other hand, potentiated nitroprusside-induced hypotension, markedly diminished increases in heart rate, and eliminated increases in myocardial contractility, rate-pressure product, and left ventricular work. Measurements of cardiovascular function returned promptly to preinfusion values when the nitroprusside was stopped. We conclude that under conditions when a high degree of central vasomotor tone is present, homeostatic reflexes may counteract the direct vasodilator effect of nitroprusside, resulting in the need for a greater dose of nitroprusside and obviating the expected beneficial effects on myocardial oxygen supply/demand ratio. Combining cryptenamine with nitroprusside eliminates these problems and at the same time allows retention of the evanescent action of nitroprusside.