Byron C. Bloor

Effects of intravenous dexmedetomidine in humans. II: Hemodynamic changes

Dexmedetomidine (DMED) is a novel clonidine-like compound known to have sedative, analgesic, and cardiovascular stabilizing qualities. DMED is a more highly selective alpha 2-adrenergic agonist than clonidine. This investigation examined the hemodynamic effects of four selected iv doses in consenting healthy male volunteers. In a randomized, double-blind, placebo-controlled trial subjects received 0 (n = 9), 0.25 (n = 6) 0.5 (n = 6), 1.0 (n = 6), or 2.0 (n = 10) micrograms/kg of DMED by infusion (2 min). ECG, heart rate (HR), arterial blood pressure (MABP), bioimpedance cardiac output (CO), and plasma catecholamines concentrations (CA) were monitored from 90 min before to 360 min after infusion. Plasma DMED concentrations were measured. DMED produced a maximum decrease in MABP at 60 min of 14%, 16%, 23%, and 27% for the 0.25, 0.5, 1.0, and 2.0 micrograms/kg groups, respectively (P < .05). At 330 min MABP remained below baseline by 8% and 17% at the two largest doses (P < .05). Both HR and CO decreased maximally by both 17% at 105 min. The two largest doses produced a transient (peak at 3 min lasting < 11 min) increased in MABP (16 +/- 2.5 and 24 +/- 10 mmHg, respectively; P < .05) with a concomitantly reduced CO (41%, 2 micrograms/kg; P < .05) and HR (22%, 2 micrograms/kg; P < .05), whereas systemic vascular resistance doubled. Even the lowest dose decreased CA immediately to values close to 20 pg/ml for 5 h. A 2-min iv infusion of DMED produced a transient increase in MABP and a longer lasting decrease in MABP and CA. These DMED doses were well tolerated in the healthy volunteers.

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 intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate.

Dexmedetomidine (DMED) is a highly selective centrally acting alpha 2-adrenergic agonist thought to provide significant sedation without appreciable ventilatory effects. This double-blind, placebo-controlled experiment evaluated four dose levels of DMED (0.25, 0.5, 1.0, and 2.0 micrograms/kg intravenously over 2 min) in 37 healthy male volunteers. Measurements of sedation, arterial blood gases, resting ventilation, hypercapnic ventilatory response (HVR), and metabolic rate (O2 consumption and CO2 production) were performed at baseline, 10 min after DMED infusion, and thereafter at the end of each subsequent 45-min period. DMED caused sedation resulting in loss of responsiveness in most of the subjects administered 1.0 and 2.0 micrograms/kg; sedation was evident for 195 min following 2.0 micrograms/kg (P < .05). Ten minutes following infusion of 1.0 and 2.0 micrograms/kg, PaCO2 had increased by 5.0 and 4.2 mmHg, respectively (P < .05), and 60 min following 2.0 micrograms/kg, VE had decreased by 28% (P < .05). The placebo group showed a progressive increase in the HVR slope (50% increase by 330 min following the infusion; P < .05). Overall, across all the DMED doses, the slope was decreased (P < .05) at all times after DMED. The calculated ventilation at a PaCO2 of 55 mmHg was decreased (39%; P < .05) 10 min following 1.0 and 2.0 micrograms/kg, returning to control values by 285 min following 2.0 micrograms/kg. O2 consumption increased 16% (P < .05) at 10 min following 2.0 micrograms/kg; CO2 production decreased (22% at 60 min). By 5 h postinfusion, both had returned to normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Clonidine and other alpha2 adrenergic agonists: Strategies for the rational use of these novel anesthetic agents

Clonidine and other clinically available alpha-2 adrenergic agonists reduce inhalational and narcotic anesthetic requirements while providing hemodynamic stability during stressful periods of surgery. Like the opiates, the alpha-2 adrenergic agonists are potent analgesics when given systemically, epidurally, or intrathecally. Their effects are reversed by alpha2 adrenergic antagonists. Newer and more selective alpha2 adrenergic agonists are more potent in their anesthetic action than the clinically available opiates. The important difference is that these agents do not appear to be respiratory depressants and do not have an addiction liability of the opioid type. They have anxiolytic properties and therefore can be potentially useful in the preanesthetic period. This drug class has the potential to provide many of the component effects required for perioperative care. For these reasons, the alpha2 adrenergic class of drugs should be important in the future of anesthesia.

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.

Ventilatory effects of dexmedetomidine, atipamezole, and isoflurane in dogs.

Dexmedetomidine (DMED) is a novel alpha 2 adrenergic agonist that has been shown to have potent analgesic and anesthetic sparing effects. This study was designed to investigate the effects of DMED, both alone and combined with isoflurane, on resting ventilation, the hypercapnic response, and the hypoxic response in dogs. When given alone, 1 microgram/kg decreased resting ventilation by 22% but at larger doses (10, 20, and 100 micrograms/kg) resting ventilation increased, doubling at 100 micrograms/kg. Doses of 10 micrograms/kg and greater caused a maximum depression of 60% in the slope of the hypercapnic response, but no dose had a significant effect on the hypoxic ventilatory response. A dose of 3 micrograms/kg of DMED reduced isoflurane MAC from 1.3% to 0.37%, and the ventilatory effects of this 1 MAC combination were intermediate between the awake values and those of isoflurane-anesthetized (1.3%) dogs. Atipamezole is a specific centrally acting alpha 2 receptor antagonist and when given with DMED in isoflurane-anesthetized dogs prevented the ventilatory depression. However, atipamezole alone also ventilatory stimulating effects, which may indicate tonic alpha 2 adrenergic activity. The ventilatory depression caused by DMED, either alone or combined with isoflurane, at doses that significantly reduce anesthetic requirements are relatively mild.

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.

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.

The effects of captopril on the renin-angiotensin system and the sympathetic nervous system during sodium nitroprusside-induced hypotension in the halothane-anesthetized rabbit.

Three groups of New Zealand white rabbits were used to study the effects of captopril on the renin-angiotensin system and sympathetic nervous system during sodium nitroprusside (SNP)-induced hypotension and halothane anesthesia. Two groups of rabbits (C and CH) were treated with captopril 2 mg/kg i.v. One captopril-treated group (CH) and the third, untreated group (H) received SNP to induce hypotension. In these two groups, the mean arterial blood pressure (MAP) was reduced by 40% for 150 min. Group C did not undergo SNP-induced hypotension and served to document the effects of captopril alone during the 150-min study period. Arterial blood samples for norepinephrine (NE), epinephrine (EPI), and plasma renin activity (PRA) were drawn prior to, during hypotension, and in the recovery period. The SNP dose required to maintain the hypotension was continuously recorded. NE, EPI, and PRA all increased in group H, indicating activation of both the reninangiotensin system and the sympathetic system during hypotension. This was accompanied by a dramatic increase in SNP dose requirement. In the CH group, PRA levels rose sharply and remained elevated. Plasma NE levels increased, while EPI levels remained unchanged with a decline in the SNP dose requirement. The C group demonstrated a rise in PRA levels, accompanied by unchanged NE and EPI levels and MAP during the study period. Captopril administration decreased the SNP dose requirement and significantly decreased the sympathetic response (measured by NE and EPI levels) in group CH as compared to the H group. This decreased sympathetic response to SNP-induced hypotension, as demonstrated by the C and CH groups, implies that captopril may effect the sympathetic nervous system in addition to the reninangiotensin system.