Is milrinone equivalent to amrinone during enflurane anesthesia in the dog?

Dose-response curves for milrinone during 2.1-2.3% end-tidal enflurane anesthesia were studied in six dogs given three successive boluses and 30-minute infusions of milrinone: 1) 40 microgram/kg plus 3 microgram.kg-1.min-1 (plasma level at 5 and 30 minutes after beginning of infusion: 122 +/- 14 and 136 +/- 14 ng/ml); 2) 60 microgram/kg plus 6 microgram.kg-1.min-1 (285 +/- 31 and 304 +/- 19 ng/ml); 3) 80 microgram/kg plus 12 microgram.kg-1.min-1 (498 +/- 32 and 581 +/- 28 ng/ml), demonstrating a progressive improvement of cardiac performance. Differences between milrinone and amrinone were also studied during enflurane anesthesia in six other dogs given milrinone or amrinone at 3- to 4-week intervals using both a low dose that did not decrease mean arterial pressure significantly and a dose that decreased mean arterial pressure 20-25% below baseline values. There was a dose-related effect with both drugs on the measured hemodynamic variables. Plasma catecholamine levels did not change significantly in either group. The results of our studies show that during enflurane anesthesia 1) there is a correlation between milrinone plasma levels and improvement of cardiac performance and, 2) milrinone, at low and high doses studied without or with a significant decrease in mean arterial pressure, respectively, is similar to amrinone in its activity to improve cardiac performance by similar positive inotropic, chronotropic, and vasodilating effects.

Acute closed-chest canine model for anaesthesia research.

An acute closed-chest canine model may be useful to study a wide variety of hypotheses relevant to cardiovascular physiology and pharmacology in circumstances which are clinically relevant. The absence of anatomical perturbations allows recovery of the subjects for conservation of animal resources and to serve as their own controls. The use of a chronic tracheostomy has facilitated inhalation anaesthesia without the use of other agents and allows easy access to the trachea in awake animals with minimal adverse effects. A thorough understanding of the techniques utilized aids in the interpretation of results obtained with this as with any other model.

Cardiovascular interactions of lidocaine with verapamil or diltiazem in the dog.

Lidocaine in low and high doses was given by sequential infusions to isoflurane-anesthetized dogs (1.75 +/- 0.03% end-tidal concentration) with or without concurrent infusions of diltiazem or verapamil, to assess changes in cardiovascular function. When lidocaine was administered alone, the low plasma levels (approximately 2 micrograms/ml) caused only a modest reduction in left ventricular dP/dt. The higher plasma lidocaine levels (approximately 6 micrograms/ml) reduced both left ventricular dP/dt and cardiac index, and increased pulmonary capillary wedge pressure and systemic vascular resistance. Diltiazem or verapamil, when administered alone at plasma concentrations of approximately 150-200 ng/ml, prolonged atrioventricular conduction, decreased heart rate and cardiac index, and, in the case of verapamil, also decreased left ventricular dP/dt and mean arterial pressure. When lidocaine was added to diltiazem or verapamil, the low plasma levels of lidocaine depressed cardiac function in the presence of either calcium channel blocking drug. In the presence of these levels of verapamil or diltiazem, only one of six verapamil-treated animals and three of six diltiazem-treated animals were able to maintain a mean arterial pressure greater than 50 mmHg with the higher dose of lidocaine. Caution may be advised if the addition of lidocaine, by whatever route, is indicated in subjects who have recently received intravenous verapamil or diltiazem.

Amrinone and verapamil-propranolol induced cardiac depression during isoflurane anesthesia in dogs.

This study was designed to investigate the possibility of whether verapamil diminishes the effects of amrinone, whether amrinone can reverse verapamil-propranolol depression, and also to evaluate whether the order of administering the drugs would have any effect during 1.7-1.8% end-tidal isoflurane anesthesia in dogs. At 3-4-week intervals, each of six conditioned mongrel dogs (23 +/- 1 kg) received amrinone (A) (4 mg/kg plus 100 micrograms X kg-1 X min-1), verapamil (V) (200 micrograms/kg plus 7.5 micrograms X kg-1 X min-1) and propranolol (P) (150 micrograms/kg plus 0.8 microgram X kg-1 X min-1) in four different orders of administration: VAP, AVP, VPA, and PVA. Plasma levels achieved were 15 +/- 1 to 24 +/- 2 micrograms/ml for amrinone, 24 +/- 2 to 59 +/- 10 ng/ml for propranolol, and 81 +/- 10 to 163 +/- 17 ng/ml for verapamil, equivalent to high therapeutic (amrinone) and therapeutic (propranolol, verapamil) levels in humans. The results of this study show that amrinone is able to reverse many of the effects of verapamil (group VAP) and also many of the effects of verapamil-propranolol or propranolol-verapamil (groups VPA, PVA) combinations. Amrinone improved cardiac index, left ventricular dP/dtmax, pulmonary capillary wedge pressure, and central venous pressure without increasing catecholamines. However, mean arterial pressure remained decreased with decreased systemic vascular resistance, which necessitates careful consideration depending upon patient circumstances. The results also show that verapamil-propranolol can reverse the positive inotropic effects of amrinone (group AVP).(ABSTRACT TRUNCATED AT 250 WORDS)

Amrinone blunts cardiac depression caused by enflurane or isoflurane anesthesia in the dog.

The effects of two infusion rates of amrinone, a positive inotrope and vasodilator, were studied during high and low concentrations of either enflurane or isoflurane anesthesia in a canine model. The anesthetic concentrations used were: "low" = 2.1-2.2% enflurane or 1.7-1.8% isoflurane, and "high" = 3.4-3.5% enflurane or 3.0-3.1% isoflurane. The two infusion rates of amrinone were: "low" = 2 mg/kg plus 30 micrograms X kg-1 X min-1 and "high" = 4 mg/kg plus 100 micrograms X kg-1 X min-1. In the present study, amrinone, in sufficient doses, blunted the deleterious effects of enflurane or isoflurane on myocardial function, reduced systemic vascular resistance (SVR) and pulmonary capillary wedge pressure, restored left ventricular dP/dtmax (LVdP/dtmax), and maintained cardiac index, even at the high concentrations of enflurane or isoflurane that caused marked cardiac depression. However, with reduced SVR, mean arterial pressure remained low. With lower enflurane or isoflurane, high concentrations of amrinone elevated LVdP/dtmax and heart rate above baseline, which might be of concern if myocardial oxygen supply were limited. No arrhythmias were observed at any time in this study. Amrinone did not increase plasma catecholamine levels with either anesthetic. Elevated amrinone plasma concentrations persisted for at least 1 hr after cessation of the high amrinone infusion and continued stimulatory effects on the cardiovascular system were observed. These results suggest that in selected patients amrinone may be beneficial in the short-term treatment of perioperative depression of cardiac performance.

The cardiovascular and adrenergic actions of verapamil or diltiazem in combination with propranolol during halothane anesthesia in the dog.

Continuous infusions of verapamil and diltiazem were established in halothane-anesthetized dogs (1.15-1.35% end tidal concentration) with or without a concomitant propranolol infusion to investigate changes: in cardiovascular function, in reflex activation as reflected in circulating catecholamine levels, and in the chronotropic response to the exogenously administered beta agonist, isoproterenol. Verapamil plasma levels of approximately 100 and 250 ng X ml-1, diltiazem plasma levels of approximately 140 and 325 ng X ml-1, and propranolol levels of approximately 70 ng X ml-1 were tolerated individually in the presence of halothane, although atrioventricular conduction was prolonged in the verapamil and diltiazem groups. Catecholamine levels were increased in the high verapamil group. However, when propranolol was combined with the lower levels of verapamil or diltiazem, the result was decreased heart rate, blood pressure, left ventricular maximum rate of tension development (dP/dt), and cardiac index with increased systemic vascular resistance. When the attempt was made to proceed to the increased plasma levels of verapamil or diltiazem in the presence of propranolol, 6/6 animals in the verapamil-propranolol group and 4/6 animals in the diltiazem-propranolol group were unable to maintain a mean arterial blood pressure of greater than 50 mmHg, and many developed 2 degrees or higher heart block.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of beta-adrenergic blockade on the cardiovascular response to diltiazem or verapamil in dogs.

Diltiazem or verapamil were each given at two different infusion rates to pentobarbital-anesthetized dogs with or without a concurrent infusion of propranolol. Changes in cardiovascular function, in reflex activation as reflected by circulating catecholamine levels, and in the chronotropic response to an exogenous beta-adrenergic agonist, isoproterenol, were measured. When administered alone, diltiazem or verapamil, at plasma concentrations of 160 and 370 ng/ml, or 230 and 500 ng/ml, respectively, prolonged atrioventricular conduction and caused systemic vasodilation with a decrease in mean arterial pressure. Cardiac index increased, associated with an increase in arterial norepinephrine level. Heart rate increased with the lower level of verapamil; left ventricular dP/dt increased with both levels of verapamil and at the higher level of diltiazem. Plasma propranolol levels of approximately 35 ng/ml were well tolerated in the absence of diltiazem or verapamil. When added to diltiazem or verapamil, propranolol resulted in an increase in systemic vascular resistance to near control values; a decrease in cardiac index, left ventricular dP/dt, and heart rate; and worsened atrioventricular conduction. Three of nine animals in the high verapamil-propranolol group were unable to maintain a mean arterial pressure greater than 50 mm Hg, and developed a low cardiac index with an elevated systemic vascular resistance, despite very high levels of circulating catecholamines. Compared to the anesthetized state, greater amounts of isoproterenol were needed to effect the same increase in heart rate with the addition of diltiazem, verapamil, or propranolol alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma diltiazem levels, cardiovascular function, and coronary hemodynamics during enflurane anesthesia in the dog.

Diltiazem was administered to dogs by an intravenous infusion protocol, which resulted in plasma levels of 71 +/- 6 (n = 7), 139 +/- 9 (n = 7), 353 +/- 33 (n = 10), and 1064 +/- 143 (n = 6) ng/ml, to evaluate the effects of diltiazem on cardiovascular function and coronary hemodynamics in the presence of anesthetic concentrations of enflurane. An additional group of six dogs received enflurane only. The only changes observed with enflurane alone were a decrease in left ventricular (LV) dP/dt, cardiac index (CI), and coronary blood flow 60 min after the baseline measurements were made. In all of the diltiazem groups, plasma level-related prolongation of the PR interval of the electrocardiogram was observed, with development of second degree heart block and junctional rhythms in animals at the two higher plasma levels. Mean arterial pressure and LV dP/dt decreased at the two higher diltiazem plasma levels after 30 min of infusion, and three of six dogs in the highest group had to be dropped from the study because of severe hypotension. The cardiac index was no different from enflurane alone with the three lower plasma diltiazem levels. No changes were observed in coronary sinus blood flow, coronary vascular resistance, myocardial oxygen uptake, or myocardial lactate extraction. Circulating norepinephrine levels were elevated in the two higher diltiazem groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-related cardiovascular effects of amrinone during enflurane anesthesia in the dog.

The dose-related cardiovascular effects of amrinone, a synthetic cardiotonic and vasodilating drug, were investigated in dogs anesthetized with enflurane (2.2-2.4% end-tidal concentration). Twelve mongrel dogs were divided into two groups of six animals: an enflurane group (E) that received only enflurane, and an amrinone group (A). In the latter group each dog received the following sequential boluses and 30-min infusions: 1) the amrinone solvent alone; 2) amrinone, 1 mg/kg + 5 micrograms X kg-1 X min-1; 3) amrinone, 2 mg/kg + 10 micrograms X kg-1 X min-1; 4) amrinone, 4 mg/kg + 20 micrograms X kg-1 X min-1. Over the course of the experiment, 2.2-2.4% end-tidal enflurane alone resulted in a gradual decrease in cardiac index (CI), stroke volume index (SVI), and the maximum left ventricular dP/dt (LV dP/dtmax), without changes in heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), or pulmonary capillary wedge pressure (PCWP) in group E. Significant differences from group E after 30 min of the lowest dose of amrinone included higher CI and SVI with lower systemic vascular resistance (SVR). The medium dose of amrinone, in addition to the effects already observed with the lowest dose of amrinone, decreased MAP and pulmonary vascular resistance (PVR), and increased LV dP/dtmax, when compared to group E only. Furthermore, the highest dose of amrinone caused lower pulmonary artery mean pressure (PAM), PCWP, and higher HR with shortened PR interval. The differences in MAP, CI, LV dP/dtmax, PCWP, PAM, PR interval, SVR, and PVR compared to E were still significant 30 min after the cessation of the highest dose. This study shows that the myocardial depressant effects of enflurane in an unstimulated canine model with a previously healthy heart can be overcome in a dose-related manner by amrinone. In contrast to other vasodilators, no reflex increase in plasma catecholamines was seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined effects of verapamil and isoflurane on coronary blood flow and myocardial metabolism in the dog.

The effects of three different plasma levels of verapamil on coronary hemodynamics and myocardial metabolism in the presence of 1.61 +/- 0.05% end-tidal concentration of isoflurane (mean +/- SEM) were studied in a canine model, using a thermodilution coronary sinus catheter to measure coronary sinus blood flow and pressure and to provide coronary sinus plasma samples. A control group receiving only isoflurane was also studied (n = 6). Plasma arterial verapamil levels of 55 +/- 7 (n = 6); 134 +/- 7 (n = 10); and 301 +/- 37 ng X ml-1 (n = 5), were achieved by a loading dose followed by a continuous infusion for 30 min. The only changes with time in the isoflurane group were decreases in left ventricular maximum rate of tension development (dP/dt) and left ventricular stroke work index compared with control after 90 min without changes in myocardial oxygen balance. The low plasma verapamil level caused reductions in heart rate, mean and diastolic arterial pressure, and left ventricular dP/dt without changes in myocardial oxygen supply or myocardial metabolism. Intermediate verapamil concentrations produced a transient initial increase in heart rate and a reduction in stroke volume index. With the intermediate and the highest levels of verapamil, mean and diastolic arterial pressure, left ventricular dP/dt, and cardiac index were decreased. An increase in arterial norepinephrine plasma levels was seen in the intermediate and the highest levels of verapamil; however, a transient coronary vasodilation occurred without changes in myocardial oxygen balance. Significant prolongation of the PR interval was observed in all verapamil groups, with second or third degree heart block in some of the higher-dose animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic effects of verapamil administration after large doses of fentanyl in man.

Thirteen patients with good left ventricular function undergoing coronary artery revascularization were studied to determine the cardiovascular effects of verapamil, 75-150 micrograms X kg-1, after a large dose (100 micrograms X kg-1) of fentanyl, with pancuronium for muscle relaxation. The patients were continued on their usual cardiovascular medications until the time of surgery, which included nitrates, beta adrenergic blockers, and nifedipine. Anaesthesia with fentanyl was associated with decreases in mean arterial blood pressure, systemic vascular resistance, left ventricular stroke work index, and circulating catecholamine levels. Mean values were not further changed by verapamil, but individual patients had additional modest decreases in blood pressure and systemic vascular resistance. Cardiac index, however, was well maintained. Plasma catecholamines remained depressed after verapamil under the study condition. Thus, in patients with good left ventricular function, clinically relevant doses of verapamil were well tolerated even in the presence of an anaesthetic that included large doses of fentanyl, with suppression of circulating catecholamine levels.

Influence of diltiazem on cardiovascular function and coronary hemodynamics during isoflurane anesthesia in the dog: correlation with plasma diltiazem levels.

Diltiazem was administered to dogs by intravenous infusion to achieve plasma levels of 47 +/- 3 (n = 7), 148 +/- 12 (n = 8), 263 +/- 10 (n = 8), and 379 +/- 43 (n = 8) ng X ml-1, to evaluate the effects of diltiazem on cardiovascular function and coronary hemodynamics, when given in the presence of anesthetic concentrations of isoflurane. Plasma level related prolongation of the PR interval of the electrocardiogram was the most prominent effect observed, with development of 2 degrees heart block or junctional rhythms in several of the animals at the two higher plasma levels. Mean arterial pressure, transiently decreased after the loading dose in all groups, was no different from control values after 30 min of infusion. Left ventricular dP/dt was mildly decreased at the three highest plasma levels, whereas right and left heart filling pressures were increased at the two highest plasma levels. Cardiac index and systemic vascular resistance were unchanged. No changes were observed in coronary sinus blood flow, coronary vascular resistance, myocardial oxygen uptake, myocardial lactate extraction, or circulating epinephrine or norepinephrine levels in any of the groups. In the presence of anesthetic concentrations of isoflurane, over the range of plasma levels investigated in this study, the vasodilating properties of diltiazem were not observed, yet conduction effects were prominent and decreases in left ventricular performance occurred. No untoward effects on global myocardial metabolism were detected under these conditions.

Effects of verapamil on uterine blood flow and maternal cardiovascular function in the awake pregnant ewe.

Calcium entry blocking drugs may have a role in the treatment of maternal and fetal tachyarrhythmias, as well as for treatment of premature labor. This study was undertaken to assess the hemodynamic effects of verapamil in the awake pregnant ewe. Verapamil, 0.2 mg/kg administered intravenously over 3 min, resulted in the following maternal cardiovascular changes: transient (2 min) but significant decreases in systolic, diastolic, and mean blood pressures, and significant but equally transient increases in central venous pressure and mean pulmonary arterial pressure. Pulmonary capillary wedge pressure increased for 5 min. These results are consistent with the negative inotropic and peripheral vasodilating effects of verapamil. Cardiac output, systemic vascular resistance, and pulmonary vascular resistance were unaffected. Uterine blood flow decreased 25% at 2 min and remained significantly (7-18%) below control levels for 30 min after drug injection. The effects of verapamil on uterine blood flow suggest that it should be used with caution in cases where uteroplacental perfusion is compromised.

Verapamil: placental transfer and effects on maternal and fetal hemodynamics and atrioventricular conduction in the pregnant ewe.

Verapamil may have application in the field of obstetrics for treatment of maternal and fetal tachyarrhythmias. This study was performed to assess the maternal and fetal hemodynamic effects of this drug, as well as to determine its placental transfer and effects on maternal and fetal atrioventricular conduction in the pregnant ewe. Verapamil, 0.2 mg/kg, administered intravenously over 3 min, resulted in a transient decrease in maternal mean and diastolic blood pressures. There was, however, no significant change in fetal systolic, diastolic, and mean blood pressures. Maternal and fetal heart rates also were unchanged throughout the experiment. Atrioventricular conduction, assessed by measurement of PR intervals, was prolonged in both the ewe (41%) and the fetus (78%). Placental transfer of verapamil was limited, as shown by the umbilical vein to uterine artery drug concentration ratios of 0.35-0.45 throughout most of the experiment. Fetal hepatic extraction of the drug appeared to be substantial, since the drug concentration in the fetal carotid artery was less than that of the umbilical vein at 1, 3, and 5 min after drug injection.