Werner 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

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.

Comparison of Cardiovascular Responses to Verapamil during Enflurane, Isoflurane, or Halothane Anesthesia in the Dog

The cardiovascular responses to increasing infusion rates of the slow calcium channel inhibitor, verapamil, were studied in three groups of dogs during either enflurane, isoflurane, or halothane anesthesia. Control hemodynamic values and plasma samples were taken after 2 h of anesthesia with the given agent. Increasing infusion rates of verapamil were given to achieve a range of plasma verapamil levels up to approximately 500 ng · ml−1. Each infusion rate was administered for 30 min, at which time repeat measurements and plasma samples for verapamil were taken. Mean arterial blood pressure, cardiac index, and left ventricular dP/dt decreased with increasing plasma verapamil levels in the enflurane and isoflurane groups compared with the control values. The values for the enflurane-verapamil combination were significantly lower than those for the other anesthetics at comparable verapamil levels. Compared with enflurane, higher verapamil levels were required with isoflurane to achieve the equivalent degree of hemodynamic depression. A higher incidence of conduction abnormalities also was noted in the enflurane group. In the halothane group, the only significant change observed at these verapamil levels, achieved by continuous infusion, was a prolongation of the PR interval of the ECG. In this animal model, verapamil was least well tolerated by the cardiovascular system during enflurane anesthesia.

Epinephrine-induced Arrhythmias and Cardiovascular Function after Verapamil during Halothane Anesthesia in the Dog

The antiarrhythmic and cardiovascular effects of the slow channel inhibitor, verapamil, were studied during 1.1 MAC halothane anesthesia in the dog. The control epinephrine arrhythmogenic dose to induce ventricular arrhythmias was 2.58 ± 0.77 μg·kg−1. min−1, (mean ± SEM). Three consecutive doses of 0.2 mg/kg verapamil each elevated the dose of epinephrine required to produce a ventricular arrhythmia to 5.17 ± 1.27, 8.07 ± 1.85, and 12.03 ± 2.76 μg·kg−1·min−1, respectively, all of which were significantly elevated above the control value and the preceding values. A second group of dogs, unperturbed by epinephrine, received the same sequence of verapamil doses at similar time intervals for evaluation of effects on cardiovascular function and atrioventricular conduction. Heart rate remained unchanged. Mean arterial pressure decreased maximally by 37 per cent of control, left ventricular dP/dt by 24 per cent, and systemic vascular resistance by 51 per cent. These effects were transient with recovery times of up to one hour. Central venous pressure increased by 44 per cent and left ventricular end diastolic pressure by 27 per cent, while PR interval was prolonged by 40 per cent. Thus, verapamil raised the dose of epinephrine required to elicit a ventricular arrhythmia during halothane anesthesia promptly and cumulatively. At the same time verapamil produced transient peripheral vasodilation, direct depression of myocardial contractility, and prolongation of atrioventricular conduction time that was not cumulative at the intervals studied.

Influence of Respiratory Acidosis on Circulatory Effect of Epinephrine in Dogs

The circulatory depressant effects of respiratory acidosis and the relation between acidosis and the circulatory effects of epinephrine were studied in anesthetized intact dogs after sympathetic and parasympathetic block. Respiratory acidosis invariably depressed myocardial contractile force, cardiac rate, and mean arterial pressure, but only the fall, in contractile force showed a relation with the degree of acidosis. The effect of epinephrine on myocardial contractile force decreased with decreasing arterial pH, but no correlation was found between pH and the effect of epinephrine on arterial blood pressure and on cardiac rate. During continuous infusion of epinephrine, arterial pressure continued to rise after the contractile force had reached its maximum. With repeated periods of epinephrine infusion in the same animal, the response of the myocardial contractile force declined, while the response of the arterial blood pressure was unchanged. Such “differential tachyphylaxis” may occur under clinical conditions with prolonged infusions of vasopressor agents.

Myocardial Hemodynamics during Induced Hypotension: A Comparison between Sodium Nitroprusside and Adenosine Triphosphate

Adenosine triphosphate (ATP) has been reported to be a hypotensive agent similar in effect to sodium nitroprusside (SNP). The purpose of this study was to examine and compare the effects of both SNP and ATP on general coronary hemodynamics, myocardial O2 consumption, and circulating catecholamines. Twelve dogs were anesthetized with 1.0% halothane and given either SNP or ATP by controlled infusion to reduce their systemic blood pressure by 50% for a 2-h period followed by a (blood pressure) recovery period. The ATP-induced hypotension was rapid, easily controlled, not accompanied by tachyphylaxis over the 120 min studied, and resulted in an increase in coronary sinus blood flow (CSBF), which plateaued at 260% above control. The increase in CSBF was almost immediate and remained at this elevated level for the duration of the induced hypotension. During the ATP-induced hypotension, there was no change in heart rate or circulating catecholamines. A 60% reduction in myocardial O2 uptake was observed, presumably from the cardiac unloading. In contrast, SNP-induced hypotension required a marked increase in dose over time, did not significantly increase CSBF, did increase heart rate, and resulted in large increases in circulating plasma catecholamines. Neither agent affected cardiac output. ATP-induced hypotension resulted in no change in cardiac lactic acid uptake, while SNP caused lactic acid production, indicating possible cardiac ischemia or cyanide toxicity.

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.

The Effects of Halothane on the Responses of Cardiac Sympathetic Ganglia to Various Stimulants

The effects of halothane on the responses of cardiac sympathetic ganglia to intra-arterial injection of ganglion stimulants were studied in spinal dogs using heart rate as the index of ganglionic activation. Halothane alone, in concentrations of 1 and 1.5 per cent, did not affect the response to injected acetylcholine. Only after blockade of muscarinic receptors in the ganglion did halothane depress the response to acetylcholine. In addition, halothane markedly inhibited the response to DMPP, a nicotinic receptor stimulant, while leaving unchanged the response to McN-A-343, a muscarinic receptor stimulant. We conclude that halothane specifically inhibits the response to nicotinic ganglionic receptors only, and does so through an effect on the postsynaptic neuron.

Pharmacological activity of some esters of germine with acetic acid

SummaryFive esters of germine with acetic acid were investigated for their pharmacological activity on the circulation of cats, for their veratrinic effect on the sartorius muscle of the frog, and for their toxicity in mice.The germine tetra-, isotetra- and pentaacetate resembled the naturally occurring esters of germine and other naturally occurring alkaloids of the group of veratrum ester alkaloids in their effect on the circulation and on frog muscle, although their potency was much lower than that of the natural germine esters.The mono- and the diacetate of germine showed a different pattern of activity. In frog muscle they caused an increase in twitch height rather than an aftercontraction. In cats they caused not a hypotension, but rather a moderate hypertension. The hypertension is probably due to stimulation of receptors of unknown nature, possibly pain receptors. The effect was attenuated, but not abolished, after destruction of the medullary centers, but did not occur after destruction of the spinal cord.Sensory stimulation after injection of germine mono- and diacetate was noted in the anesthetized animals and was reported by human volunteers.ZusammenfassungFünf Ester des Veratrum Alkaloids Germin mit Essigsäure wurden auf ihre pharmakologische Wirkung auf den Kreislauf der Katze und auf den Sartorius-Muskel des Frosches geprüft. Außerdem wurde die Toxicität der Alkaloide an der Maus bestimmt.Die Alkaloide Tetra-, Isotetra- und Pentaacetylgermin waren am Kreislauf der Katze und am Skeletmuskel des Frosches in ihrer Wirkung den natürlich vorkommenden Esteralkaloiden des Germins ähnlich; ihre Wirkungsstärke war jedoch erheblich geringer. Mono- und Diacetylgermin verhielten sich anders. Am Sartorius-Muskel des Frosches verursachten sie, ebenso wie Germin selbst, eine Zunahme der Zuckungshöhe aber keine Nachkontraktion. Am Kreislauf der Katze trat eine mäßige Blutdrucksteigerung auf statt der für die natürlich vorkommenden Esteralkaloide charakteristischen Blutdrucksenkung. Die Blutdrucksteigerung beruht wahrscheinlich auf der Erregung von bisher nicht identifizierten Receptoren, möglicherweise handelt es sich um Schmerzreceptoren. Die Wirkung konnte durch Zerstörung der Medulla oblongata abgeschwächt aber nicht beseitigt werden. Nach der Zerstörung des Rückenmarks trat keine Blutdrucksteigerung mehr auf.Die Toxicität (LD50, Maus) der Acetylester (mit Ausnahme des Pentaacetats) war vier- bis achtmal so groß als diejenige des Germins und betrug 1/100 bis 1/300 der Toxicität der natürlich vorkommenden Germinester.