Cardiovascular and electrophysiologic interactions between diltiazem and isoflurane in the dog

The effects of the calcium entry blocker diltiazem (iv loading dose 0.4 mg/kg, iv maintenance dose 0.4 mg/min) and subsequent isoflurane-induced hypotension to mean aortic pressures of 70 and 55 mmHg on global and regional right ventricular (RV) and left ventricular (LV) performance (ultrasonic dimension technique), on coronary (electromagnetic flow probes) and systemic hemodynamics, and on electrophysiologic parameters (PR, QRS, QTc intervals) were studied in eight open-chest dogs, anesthetized and paralyzed by continuous infusions of fentanyl and pancuronium. Diltiazem at a plasma concentration of 282 +/- 33 ng/ml (mean +/- SE) caused significant (P less than 0.05) increases in coronary blood flows, and decreases in coronary and systemic vascular resistances with only little effect on global and regional RV and LV function. However, the PR interval increased by 40%, and three animals developed II degrees atrioventricular block type I. At stable diltiazem plasma levels, administration of isoflurane caused dose-dependent decreases in myocardial segment shortening and stroke volume with unchanged LV or increased RV preload, and little changed RV or reduced LV afterload indicating myocardial depression. Coronary and systemic vascular resistances remained unaffected. At the higher concentration of isoflurane (mean inspired 1.3 +/- 0.2%), seven animals developed intermittent sinus node arrests with pauses up to 12 s followed by intermittent junctional escape or sinus rhythms. Similar interactions might develop in patients on diltiazem receiving isoflurane.     

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)     

Prolonged perivascular use of verapamil or lidocaine decreases skin flap necrosis.

During this experiment the authors investigated whether prolonged local use of verapamil or lidocaine prevents vasoconstriction and establishes better blood supply to the rat epigastric skin flap, hence reducing the necrosis that occurs otherwise. Abdominal wall skin flaps of 45 Sprague-Dawley rats, based on a single pedicle of the femoral vessels, were elevated. A subcutaneous pocket for the microport valve was created, and the adjacent catheter tip was sewn next to the femoral vessels. In the control and the two treatment groups, 0.5 ml saline or vasodilator solution respectively was injected through the microport every 12 hours for 5 days. On postoperative day 5 there was no statistical difference between the flap surfaces in all groups. The area of flap necrosis was significantly lower in the verapamil- (p = 0.001) and the lidocaine-treated (p = 0.012) groups vs. the control group as determined by analysis of variance with Bonferroni's post hoc test. In conclusion, topical application of verapamil and lidocaine solutions for 5 postoperative days decreased flap marginal necrosis significantly. Prolonged injection of vasodilators in the vicinity of the vascular pedicle prevents vasospasm and improves blood supply to the flap.     

Conscious state comparisons of the effects of the inhalation anesthetics and diltiazem, nifedipine, or verapamil on specialized atrioventricular conduction times in spontaneously beating dog hearts

The effects of enflurane (ENF), halothane (HAL), and isoflurane (ISO) on specialized atrioventricular (AV) conduction times were contrasted to awake (control) in 22 chronically instrumented dogs. Dogs were studied with and without diltiazem (DIL), nifedipine (NIF), vehicle for NIF (VEH), or verapamil (VER). These calcium channel blockers (CCB) were administered iv to achieve clinically effective steady-state plasma levels in awake dogs. CCB plasma levels in awake dogs, subsequently anesthetized with ENF (N = 10), HAL (N = 10), or ISO (N = 11), were: DIL = 94 +/- 13 to 124 +/- 9 ng/ml, NIF = 4 +/- 1 to 7 +/- 2 ng/ml, VER 108 +/- 23 to 147 +/- 9 ng/ml. Anesthetized dogs had approximate two-fold increases in plasma levels of DIL or VER. There was no anesthetic effect on plasma levels for NIF. In the absence of CCBs, HAL increased AV nodal conduction time (AVN) compared to awake. There was a 4-10% increase in His-Purkinje (HP) and ventricular (VENT) conduction time with each anesthetic. The CCBs did not alter HP or VENT in awake dogs, but AVN was increased 15-23% by DIL and 28-38% by VER. Three of ten dogs with VER developed complete heart block or AV junctional escape rhythm at each level of ENF. One dog with VER developed type I, 2 degrees (Wenckebach) AV block at each level of HAL and ISO. No dogs with DIL had heart block or escape rhythms during anesthesia. In anesthetized dogs without heart block or escape rhythms, the increase in AVN with VER ranged from 46 to 69%, and with DIL from 36 to 55%. The CCB had no added effects on HP or VENT with any anesthetic. Finally, there were no effects of NIF alone or with the anesthetics on specialized conduction that could not be attributed to VEH. The authors conclude that with the inhalation anesthetics, antiarrhythmic plasma levels of DIL or VER prolong AV nodal most compared to infranodal conduction time. Additionally, heart block or escape rhythms appear more likely with VER and any of the potent inhalation anesthetics.     

Cardiovascular responses to scalp infiltration with different concentrations of epinephrine with or without lidocaine during craniotomy

Intraoperative blood pressure changes alter cerebral blood flow in neurosurgical patients with impaired autoregulation. Infiltration of the scalp before craniotomy may cause hemodynamic changes that depend on the composition of the solution used. We investigated cardiovascular responses to infiltration of the scalp with five different combinations of epinephrine and lidocaine in 112 patients: Group A, lidocaine 0.5%; Group B, lidocaine 0.5% with epinephrine 1:200,000; Group C, lidocaine 0.5% with epinephrine 1:100,000; Group D, normal saline with epinephrine 1:200,000; and Group E, normal saline with epinephrine 1:100,000. Episodes of tachycardia occurred more frequently in group E (P = 0.03). Plain lidocaine did not cause any significant change in blood pressure. The incidence of systolic, diastolic, and mean arterial hypertension was significantly increased in group E (P < 0.01). Episodes of diastolic hypertension occurred more frequently in Group D (P < 0.01). A biphasic diastolic and mean arterial hypotension (around Minute 2 and Minutes 9-15) occurred in Groups C and B (P < 0.001). In conclusion, epinephrine 1:100,000 causes significant tachycardia. Epinephrine in concentrations of 1:100,000 and 1:200,000 causes significant hypertension. The combination of lidocaine and epinephrine attenuates the hypertension but results in a biphasic hypotensive response.     

Effects of verapamil and diltiazem on acute stroke in cats

To test the effect of verapamil and diltiazem in acute stroke, three groups of mongrel cats of either sex underwent occlusion of the middle cerebral artery (MCA) via a transorbital approach under ketamine anesthesia. The first group served as controls, the second received an intravenous infusion of verapamil (0.1 microgram/kg/min), and the third received an intravenous infusion of diltiazem (0.1 to 1.0 microgram/kg/min). All drug infusions began 2 hours before MCA occlusion and continued for the remainder of the experiment. Before and for up to 24 hours after MCA occlusion, regional cerebral blood flow (rCBF), somatosensory evoked potentials (SSEP's), arterial blood gases, blood pressure, temperature, and hematocrit were measured at least every 2 hours. At the experiment's end, brains were perfused with India ink, removed, sliced, photographed for determination of nonperfused brain area, and weighed, dried, and reweighed for H2O content determination. In these studies, verapamil was associated with worsening of rCBF in ischemic regions and inappropriate increases in rCBF in nonischemic regions, indicating intracerebral steal. Diltiazem increased rCBF in marginally ischemic regions. Changes in SSEP's paralleled blood flow changes, with verapamil decreasing amplitude and conduction velocity while diltiazem slightly improved conduction in the ischemic brain. Verapamil increased the area of nonperfused brain and the content of cerebral H2O. Diltiazem-treated animals had decreased cerebral H2O content, but had a marked increase in the area of nonperfused brain, a finding associated with the high incidence of transtentorial herniation in the diltiazem-treated animals. These findings agree with in vitro studies demonstrating high sensitivity of cerebral blood vessels to calcium channel blockers. These studies further support the notion that calcium channel blockers probably affect several different classes of calcium channels, at different brain sites.     

Cardiovascular effects of xylazine recorded with telemetry in the dog

Cardiovascular effects of xylazine have not been studied with telemetry in dogs. In the present study, the effects on cardiovascular parameters after intramuscular (i.m.) administration of 2.0 mg/kg xylazine were studied via telemetry in unrestrained dogs. Telemetry transmitters were implanted subcutaneously (s.c.) with a pressure catheter in the femoral artery. Cardiovascular effects and body temperature effects were assessed after i.m. administration of xylazine. Heart rate decreased for about 10 min and was continuously depressed during 60 min. Thereafter, heart rate slowly increased but had not fully reached pre‐dose values 4 h after treatment. Both systolic and diastolic blood pressure increased immediately after administration of xylazine. The systolic blood pressure showed a peak increase for about 5–10 min and then decreased below the baseline value not normalizing within 90 min. The diastolic blood pressure peaked 5–10 min after xylazine administration but did not return to baseline level until 50 min after administration. Body temperature decreased continuously for about 90 min and remained low for more than 4 h after treatment. An additional administration of xylazine to the same individuals after a recovery period of 4 weeks induced exactly the same response in systolic and diastolic blood pressure and in heart rate. By using the telemetric recording system it was possible to continuously evaluate xylazine‐induced cardiovascular responses in a way that is not possible with conventional techniques.     

Influence of verapamil and diltiazem on the muscle-relaxing effect of atracurium in vivo]

The interaction between atracurium and the two calcium antagonists verapamil and diltiazem were studied in rabbits. It was observed that intravenous verapamil (0.2 mg/kg) reduced by 25% and 30% respectively, the dose of atracurium required to produce a 50% or 95% of neuromuscular blockade. In contrast, intravenous diltiazem (1 mg/kg) failed to produce significant changes.     

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.     

Lung uptake of lidocaine during hyperoxia and hypoxia in the dog

Background: Lidocaine has been shown to accumulate in the lung following its administration. This study was undertaken to determine effects of dose of lidocaine on lung uptake during hyperoxic and hypoxic ventilation.
Methods: Using cross-circulation consisting of ventilation and constant-flow perfusion of the left lower lobe independently from all other lobes of the dog lung under nitrous oxide and halolhane anesthesia, lidocaine was infused into the inflow system, so that plasma lidocaine concentrations in the inflow blood were maintained at 5, 10, 20, 40 and 70 μg/ml respectively during ventilation with 50% O₂ or 3% O₂. During 20 μg/ml lidocaine infusion, indocyanine green (ICG), an intravascular marker, was mixed with the lidocaine solution, in such a fashion that plasma ICG concentration in the inflow blood was maintained at 20 μg/ml. Actual plasma lidocaine and ICG concentrations in blood drawn from the inflow ([Lid]pa, |ICG]pa)and the outflow ([Lid]pv, [ICG]pv) systems were measured 1, 3, 5, 7 and 10 minutes after the beginning of lidocaine infusion. Percent lung uptake of perfused lidocaine was calculated as (1-([Lid]pv/[Lid]pa)/([ICG]pv/[ICG]pa)| x100.
Results: During ventilation hyperoxia, mean percent lung uptakes of lidocaine were 41–52% 1 minute after the beginning of lidocaine infusion, and decreased in time-dependent fashion to 7–12% 10 minutes later. Curves of percent lung uptake of lidocaine over time were similar for the 5 predetermined lidocaine concentration groups (5–70 μg/ml). There were no significant differences in percent lung uptakes of lidocaine between the ventilation hyperoxia and hypoxia conditions.
Conclusions: These findings suggest that percent lung uptake of lidocaine is unaffected by hypoxic ventilation and by varying the concentration of lidocaine in the perfusion through the recipient dog lung lobe.     

Cardiovascular function during controlled hypotension induced by adenosine triphosphate or sodium nitroprusside in the anesthetized dog

The present study was undertaken to compare the hemodynamic effects of adenosine triphosphate (ATP) and sodium nitroprusside (NP) given in equieffective doses to induce hypotension during halothane anesthesia. Eight dogs, instrumented with pressure and ultrasonic dimension transducers for assessment of left ventricular (LV) performance, were given both NP and ATP. Regional blood flow was measured by radioactive microspheres. After 20 min of infusion, both drugs decreased systemic arterial pressure by 36% with minimal changes in cardiac index (CI), LV end-diastolic pressure, or heart rate. However, hypotension produced by ATP was associated with a greater CI (3.84 +/- 0.32 vs 2.97 +/- 0.35 L X min-1 X m-2) than was NP and also associated with a further decrease in systemic vascular resistance (14.4 +/- 1.4 vs 17.7 +/- 2.2 mm Hg X L-1 X min X m2). Left ventricular global function, measured by the slope of the linear regression line of the LV end-systolic pressure-diameter relation (Ees), did not change significantly after either drug. Blood flow to the coronary bed was significantly greater with ATP than with NP (231.6 +/- 30.6 vs 81.7 +/- 6.1 ml X min-1 X 100 g-1). Except for an increase in hepatic arterial blood flow with NP, neither ATP nor NP significantly altered blood flow to the brain, spinal cord, spleen, kidney, jejunum, muscle, and skin. Controlled hypotension by ATP was stable and rapidly reversible without rebound hypertension. The results of this study indicate that ATP is a rapidly acting, effective hypotensive agent that compares favorably with NP.     

Cardiovascular responses and lidocaine absorption in fiberoptic-assisted awake intubation

Local anesthetic toxicity and cardiovascular stress during fiberoptic-assisted awake tracheal intubation were assessed prospectively in 20 patients with airway management problems. Cardiovascular responses, dose of lidocaine, its systemic absorption, and patient comfort were measured. A standardized topical anesthesia protocol of 4% lidocaine aerosol, topical 2% lidocaine viscous gel, and direct perbronchoscopic laryngeal application was used. Awake intubation produced no significant elevation of blood pressure or pulse rate either during the topical application or after the intubation. Despite a large total dose of topical lidocaine (5.3 +/- 2.1 mg/kg), the mean peak arterial plasma lidocaine concentration was low (0.6 +/- 2.1 micrograms/ml). Patient comfort assessment showed that nine patients had no discomfort, whereas 11 had minimal discomfort. Supplementary sedation used was minimal (fentanyl, 1.4 +/- 0.6 micrograms/kg, and diazepam, 1.9 +/- 1.8 mg). This method of producing topical anesthesia for awake tracheal intubation is recommended as a safe, easy, and comfortable method of managing patients with airway difficulties.     

Comparison of intravenous metoprolol, verapamil and diltiazem on the attenuation of haemodynamic changes associated with tracheal extubation.

Changes in heart rate, systolic, diastolic and mean blood pressure were measured after extubation in 60 ASA Grade I and II patients to assess the effects of diltiazem (0.2 mg kg-1), verapamil (0.05 mg kg-1) and metoprolol (0.02 mg kg-1) given as a bolus 2 min before tracheal extubation. All the haemodynamic variables measured increased significantly after extubation in the control and diltiazem groups when compared with the base-line recordings (P < 0.05). Metoprolol effectively blocked the increases in heart rate after extubation and the increase in blood pressure in this group was less when compared with the control group (P < 0.05). Verapamil alleviated the increase in both heart rate and blood pressure. However, profound hypotension and bradycardia requiring therapy, occurred in the verapamil group. For this reason, careful observation is necessary when using verapamil and the routine use of this drug in patients with coronary artery disease requires further studies.     

Comparison of nicardipine, diltiazem and verapamil for controlling the cardiovascular responses to tracheal intubation

We have compared the efficacy of three calcium channel blockers, nicardipine, diltiazem and verapamil, in attenuating the cardiovascular responses to laryngoscopy and intubation in 60 normotensive patients (ASA I) undergoing rapid sequence induction of anaesthesia with thiopentone and fentanyl. We also examined whether or not these blockers inhibited catecholamine release induced by intubation. The patients were allocated to one of four groups (n = 15 for each): saline (control), nicardipine 30 micrograms kg-1, diltiazem 0.2 mg kg-1 or verapamil 0.1 mg kg-1. Verapamil and the three other drugs were administered 45 s and 60 s before the start of direct laryngoscopy, respectively, in a double-dummy design. Anaesthesia was induced with thiopentone 4 mg kg-1 i.v. and fentanyl 2 micrograms kg-1 i.v. Tracheal intubation was facilitated with vecuronium 0.2 mg kg-1. During anaesthesia, ventilation was assisted or controlled with 1% isoflurane and 50% nitrous oxide in oxygen. Laryngoscopy lasting 30 s was attempted 2 min after administration of thiopentone and vecuronium. Patients receiving saline exhibited significant increases in systolic and diastolic arterial pressures (AP), heart rate (HR) and plasma concentrations of catecholamines associated with tracheal intubation. The increase in AP was attenuated in patients treated with any calcium channel blocker. The greatest effect was elicited by verapamil, which attenuated the increase in HR, although nicardipine seemed to enhance tachycardia. All three drugs failed to suppress the increase in plasma catecholamine concentrations in response to tracheal intubation. These findings suggest that bolus injection of verapamil 0.1 mg kg-1 was a more effective method of controlling hypertension and tachycardia associated with intubation than diltiazem 0.2 mg kg-1 or nicardipine 30 micrograms kg-1, and that these prophylactic effects were not caused by inhibition of the catecholamine response.      

Effects of lidocaine and verapamil on early afterdepolarizations in isolated rabbit sinoatrial node

The effects of local anaesthetic anti-arrhythmic agents (lidocaine) and Ca antagonists (Verapamil) have been examined on the early afterdepolarizations (EADs) in isolated rabbit sinoatrial (SA) node. In a nominally calcium free and magnesium free solution, strontium (0.5–4.5mM) produced an EAD in small pieces isolated from the SA node. The additional presence of 0.02–0.6mM lidocaine did not abolish the strontium (0.5mM)-induced EAD. 0.6mM lidocaine produced an increase in EAD amplitude and then abolished a prolonged action potential (AP) associated with repetitive EADs. On the other hand, the addition of 4µM verapamil abolished the strontium (0.5mM)-induced EAD but did not abolish the AP.It is concluded that under conditions when the AP is not abolished, EAD blockade by lidocaine is less effective than that by verapamil.(Miyamae S, Matsuda T, Goto K, et al.: Effects of lidocaine and verapamil on early afterdepolarizations in isolated rabbit sinoatrial node. J Anesth 5: 213–220, 1991)     

Comparative cardiovascular effects of verapamil, nifedipine, and diltiazem during halothane anesthesia in swine

Controversy persists about the cardiac toxicity of bupivacaine if accidentally administered intravenously during regional anesthesia. Using awake, unanesthetized sheep, we evaluated the cardiac effects of low and high equivalent doses of lidocaine and bupivacaine given intravenously over 10 s. All animals convulsed within 30 s of injections. Although both drugs significantly increased heart rate and systemic and pulmonary arterial blood pressure for up to 10 min, cardiac output was affected variably. The magnitude of hemodynamic changes that each drug produced did not differ significantly from each other at either dose level. However, of the sheep receiving intravenous lidocaine, none developed arrhythmias other than mild sinus tachycardia and minimal ST-T wave changes (which occurred in 25% of the animals). After intravenous bupivacaine injection, all sheep had transient changes on the EKG and/or arrhythmias (e.g., supraventricular tachycardia; atrioventricular condition blocks; ventricular tachycardia; multiform premature ventricular contractions; wide QRS complexes; ST-T wave changes; and in one animal, fatal ventricular fibrillation). Normal sinus rhythm usually returned within 8-10 min. Arterial blood gas and acid-base values stayed within the normal range during the studies, and serum potassium did not change significantly from control. In conclusion, in conscious adult sheep, equivalent doses of lidocaine or bupivacaine produced similar central nervous system (CNS) toxicity when rapidly injected intravenously. In the absence of marked hypoxia, respiratory or metabolic acidosis, hyperkalemia, or hypotension, serious cardiac arrhythmias occurred after bupivacaine but not lidocaine.