Cardiac implications of amlodipine-dantrolene combinations.

PURPOSE: Cardiac disorders, cardiac arrest and ventricular fibrillation in the most severe cases, have been observed after the administration of dantrolene to patients treated by verapamil for coronary artery disease. This study was designed to examine the interaction of dantrolene with amlodipine, a dihydropyridine. METHODS: In 12 anaesthetized, open-chest pigs, the effects of the interaction have been studied on heart rate, atrioventricular conduction, monophasic action potential duration, intraventricular conduction time, left ventricular dP/dt max and mean blood pressure. The study was performed with normal coronary circulation and ischaemia of a large area of the left ventricule, obtained by complete occlusion of the left anterior descending coronary artery near its origin, under pacing at a constant high rate, 180 beats.min-1. The drugs were injected iv, amlodipine 0.4 mg.kg-1 first and dantrolene 3.0 mg.kg-1 20 min later in six animals and the order was reversed in the other animals. RESULTS: Sinus rate and atrioventricular conduction were not affected by amlodipine, but were slowed by dantrolene added (145 +/- 9 to 131 +/- 7 beats.min-1, P < 0.01 and 150 +/- 15 to 180 +/- 20 msec, P < 0.01). In contrast, amlodipine or amlodipine plus dantrolene did not change MAP duration or conduction time in the normal heart. Similarly, they did not alter the maximal variations due to ischaemia, but delayed them, while prolonging the time to onset of fibrillation (111 +/- 8 to 343 +/- 33 sec. P < 0.001 with amlodipine alone, 289 +/- 11 to 323 +/- 16 sec, P < 0.05 with dantrolene). Left ventricular dP/dt max was lowered from 1670 +/- 86 to 1532 +/- 50 mmHg.sec-1 (P < 0.001) and mean blood pressure from 79 +/- 4 to 70 +/- 3 mmHg (P < 0.01) by amlodipine, but dantrolene did not enhance and even counteracted these effects. Finally, potassium plasma concentration did not increase above 5.1 +/- 0.2 mmol.L-1 under the dual influence of amlodipine and dantrolene. CONCLUSION: In usual clinical doses, dantrolene may be safely administered concurrently with amlodipine.

Bupivacaine hastens the ischemia-induced decrease of the electrical ventricular fibrillation threshold.

Myocardial ischemia sensitizes the cardiotoxic effects of bupivacaine, especially the propensity to ventricular fibrillation. To investigate this sensitization and to elucidate its mechanism, the influence of bupivacaine alone, or associated with ischemia, was studied on electrical fibrillation threshold in anesthetized, open chest pigs. Determination of fibrillation threshold was performed with impulses of 100 ms duration at the rate of 180 bpm, in the absence of ischemia and at the end of increasing periods of ischemia (30, 60, 120, 180 s) obtained by complete occlusion of the left anterior descending coronary artery close to its origin. The effect of bupivacaine (1.00 mg/kg initial dose plus 0.04 mg.kg-1.min-1 over 25 min) was compared to the control in the same animals. This effect corresponded to 1.4-1.8 micrograms/mL plasma concentrations likely to be observed in humans after regional anesthesia. Bupivacaine significantly increased the fibrillation threshold before coronary occlusion from approximately 7.0 to 9.5 mA. In contrast, during ischemia the fibrillation threshold was shifted to the left and down, with a hastening of spontaneous fibrillation. Recording of monophasic action potentials in the ischemic area revealed that conduction time was prolonged by more than 100% under the combined influence of ischemia and bupivacaine, whereas the major enhancement of excitability due to ischemia was not attenuated by bupivacine. Therefore, bupivacaine should be used with caution in the condition of ischemia, especially if heart rate is rapid. In the present experiments, tachycardia is another factor in the enhancement of bupivacaine effects on conduction.

[Surgery for epidermolysis bullosa in children: value of the association of inhalation anesthesia and locoregional anesthesia]. / Chirurgie de l'épidermolyse bulleuse grave chez l'enfant: intérêt de l'association anesthésie générale par inhalation-anesthésie locorégionale.

Due to the cutaneous and mucosal fragility associated with epidermolysis bullosa, this disease is a source of various practical problems for the anaesthesiologist concerning the surgical posture, the monitoring of vital functions, the airways control and the vascular access, as all these procedures may worsen, sometimes dramatically, the lesions in these young patients, still in a precarious health state. Basing on published studies and their own experience, the authors have used in these patients a combined locoregional and general anaesthesia. The latter was obtained with isoflurane, administered in the non intubated and spontaneously breathing patient through a closed surgical isolation container (Vi-Drape), including the patient's head and ventilated with a ventilator generating a PEEP for long procedures. The results obtained during 9 procedures in 3 children are reported and discussed. For several shorter procedures (for example wound dressing), intramuscular ketamine was used.

Enhancement by ischemia of the risk of cardiac disorders, especially fibrillation, in regional anesthesia with bupivacaine.

The impairment of intraventricular conduction by bupivacaine may result in reentrant arrhythmias including ventricular fibrillation. The concentrations responsible for serious accidents are high (5.0 to 8.0 micrograms/ml), but likely to be lowered by myocardial ischemia which gives rise to similar disorders. Therefore we did an electrophysiological study of bupivacaine's effects in an ischemic area of the myocardium. Monophasic action potential (MAP) of the ventricular myocardium was recorded in 30 anesthetized, open-chest pigs. Conduction time and effective refractory period were also measured. Data were obtained during short periods (10-15 s) of pacing at 180 beats/min, but ventricular beats remained governed by the sinus node in the intervals. Ischemia was produced by occluding the left anterior descending coronary artery completely but transiently (up to 8 min), not far from its origin. Comparison was made between the effects of bupivacaine i.v. (n = 10), ischemia (n = 10) and both factors (n = 10). Two min after injection of bupivacaine 2.0 mg/kg (plasma levels 2.0-3.0 micrograms/ml), the duration of MAP was only slightly (7.5-15%) prolonged and its ischemia-induced shortening only slightly attenuated by bupivacaine. At the same time, conduction time was considerably (75-150%) lengthened and its ischemia-induced lengthening enhanced, so that ventricular fibrillation induced by coronary occlusion occurred sooner (about 100 instead of 300 s) in the presence of bupivacaine. Consequently, bupivacaine should be used only with caution in individuals whose myocardium is ischemic or liable to ischemia episodes.

[Gastroesophageal reflux with combined caudal and halothane anesthesia in children]. / Reflux gastrooesophagien sous anesthésie caudale et halothane au masque chez l'enfant.

Sixteen children, aged 2 to 5 years and ranked ASA 1, were included in this study assessing gastro-oesophageal reflux occurring under halothane anaesthesia, before and during, caudal anaesthesia. They were scheduled for surgery below the umbilicus lasting 1 to 5 h. After premedication with oral hydroxyzine (2 mg.kg-1) and intravenous atropine (10 micrograms.kg-1), induction was carried out with 3% halothane. A gastro-oesophageal pH probe was inserted via the nose after calibration at 37 degrees C. A neutral pH for the oesophageal electrode and an acid pH for the gastric one demonstrated the correct position of the probe. The pH was then registered every 4 s. The probe was left in situ until the patient left the recovery room. The caudal anaesthesia catheter was then inserted with the patient lying on his left side. Caudal anaesthesia was began with 2.5 mg.kg-1 of plain bupivacaine and 5 mg.kg-1 of plain lidocaine. When the patient was lying supine again, narcosis was maintained with 0.5% halothane and 50% nitrous oxide. A dose of 1.5 mg.kg-1 of bupivacaine was injected every 30 to 45 min. None of the children displayed any respiratory signs (coughing, dyspnoea, bronchospasm, cyanosis) during the combined anaesthetic. Two episodes of asymptomatic gastro-oesophageal reflux were revealed by this method, one lasting 7 minutes and occurring during insertion of the caudal catheter, and the other, lasting 4 minutes, during recovery. There were no pulmonary sequels. There was excellent respiratory and haemodynamic stability throughout. The two episodes seemed to have been triggered off by rapid displacement of the patient and too deep an anaesthetic.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse interaction between bupivacaine and halothane on ventricular contractile force and intraventricular conduction in the dog.

Regional anesthesia with bupivacaine in pediatric patients is often accompanied by light levels of halothane general anesthesia. To determine the potential cardiotoxicity of these two drugs when used together, we defined the interaction between moderate plasma bupivacaine concentrations (1270-1760 ng/mL) and halothane (end-tidal concentrations, 0.5%-1.0%) on ventricular contractility and conduction in 22 closed-chest dogs anesthetized with chloralose. Bupivacaine alone (1-mg/kg intravenous bolus plus a 0.1-mg.kg-1.min-1 constant rate infusion) resulted in significant increases in ventricular conduction time (VCT) and effective refractory period (VERP) and nonsignificant decreases in dP/dtmax and blood pressure. The addition of halothane resulted in hypotension and in progressively increasing plasma bupivacaine levels secondary to reduced hepatic clearance, which led to further dose-related significant increases in VCT and VERP and to significant decreases in dP/dtmax and blood pressure. In other dogs given halothane but in which bupivacaine levels were held constant (1400 ng/mL), VCT remained constant and VERP lengthened slightly, whereas dP/dtmax decreased. We conclude that the combination of bupivacaine and halothane can cause adverse effects on ventricular contractility and intraventricular conduction.

Possible role of drug interactions in bupivacaine-induced problems related to intraventricular conduction disorders.

Clinically, bupivacaine has depressant effects on intraventricular conduction that may lead to serious atrioventricular blocks or reentrant arrhythmias at plasma levels below those required to produce these effects experimentally (2-3 micrograms/ml instead of 8-10 micrograms/ml). The difference could be due to drugs present in the blood at the time of regional anesthesia that similarly inhibit conduction. This hypothesis was examined in 30 anesthesized, closed-chest dogs by measuring conduction time in the ventricular contractile fibers as well as effective refractory period under pacing at a constant, relatively high (180 beats/minute) rate. Changes in sinus rate were limited, as well as changes in ventricular effective refractory period and blood pressure regardless of the drug tested. In contrast, cibenzoline, disopyramide, and propranolol increased conduction time and lengthened QRS duration. Clomipramine appeared to prolong conduction time and widen QRS only moderately in therapeutic doses, whereas verapamil did not manifest noticeable effects on conduction. Caution is therefore recommended in regional anesthesia with bupivacaine in subjects being treated with cardiovascular drugs, such as cibenzoline, disopyramide, and propranolol and their congeners, or even by tricyclic antidepressants.

Ventricular and atrial electrophysiological effects of a IC antiarrhythmic drug, cibenzoline, in the innervated dog heart. Role of sodium and calcium channels.

The effects of cibenzoline, rightly known as a sodium channel inhibitor (class IC antiarrhythmic drug), were investigated in anaesthetized, closed-chest dogs, on conduction in the contractile fibres, ventricular and atrial, the His-Purkinje system and the atrioventricular node. In ventricular muscle, conduction time was measured between base and apex by two endocavitary electrodes. The other conduction times were obtained from the recording of the His bundle potentials. In addition, effective refractory period was determined by the extrastimulus method in ventricular and atrial muscle and in the atrioventricular node, and sinus rate monitored in the intervals of pacing periods. In the absence of vagal tone, cibenzoline in 4 mg.kg-1 dose prolonged conduction times in the ventricular contractile tissue, His-Purkinje system and atrial contractile tissue to a large extent, but decreasingly from the former to the latter. This prolongation was antagonized by hypernatremia (174 mmol.l-1). In contrast, conduction time in the atrioventricular node, effective refractory periods and sinus rate were very little influenced. In the presence of vagal tone, the prolongation of conduction times in the ventricular contractile tissue. His-Purkinje system and atrial contractile tissue did not differ substantially from previously. It was the same for ventricular effective refractory period. But atrial effective refractory period was then considerably lengthened, while conduction time and effective refractory period in the atrioventricular node were greatly shortened and sinus rate notably accelerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation by mild hypothermia of ventricular conduction disturbances and reentrant arrhythmias induced by bupivacaine in dogs.

High concentrations of bupivacaine and profound hypothermia individually cause intraventricular conduction disturbances and reentrant arrhythmias. The effects of the combination of relatively low concentrations of bupivacaine and mild hypothermia are unknown and are the subject of this study. Three groups (n = 10-12) of dogs anesthetized with thiopental-chloralose were treated as follows: group 1, bupivacaine + hypothermia; group 2, bupivacaine alone; group 3, hypothermia alone. Bupivacaine was administered as a 4 mg/kg iv bolus followed by an iv infusion of 0.1 mg.kg-1.min-1. Hypothermia, i.e., a 4 degrees C reduction in core temperature, was produced by cooling the blood with an extracorporeal circuit. The peripheral ECG was recorded to determine the duration of QRS complexes and the QT interval. Conduction time and effective refractory period (ERP) of ventricular contractile tissue were measured with right ventricular endocavitary electrodes. Measurements were made with the heart paced at 180 beats/min and without pacing. In group 1 dogs, bupivacaine (plasma level, 2.8 +/- 0.3 microgram/ml) initially caused a prolongation of conduction time and QRS duration, which were further lengthened (approximately doubled) by a temperature decrease of 4 degrees C from baseline. The QT interval and ERP also were increased but to a lesser degree. In dogs in which the effects were most pronounced, rhythm disorders, such as wave burst arrhythmias (most common), premature systoles, ventricular tachycardia, and even ventricular fibrillation, occurred either spontaneously or during pacing. Bupivacaine alone (group 2) increased QRS duration and conduction time significantly, whereas hypothermia alone (Group 3) did not cause changes in any conduction variables. In neither group were dysrhythmias observed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Locoregional anesthesia in pediatrics]. / L'anesthésie locorégionale en pédiatrie.

Local anaesthesia may consist of a sensitive and a motor blockade. It is essentially used in human clinic for the sensitive blockade which is induced. All techniques or nearly are possible in regional anaesthesia for children if they are practised with discernment by a physician accustomed to the same techniques in adults. But caudal anaesthesia remains the most commonly performed and simple. The main advantages consist in abolition of intra- and postoperative pain, calm and comfort but also in a decrease of respiratory complications. There are two leading risks: infectious and especially toxic after an accidental injection of bupivacaine. These techniques should be systematically proposed but carefully carried out in all suffering children.

[Caudal anesthesia in pediatric surgery. Pharmacokinetic study and clinical significance]. / Anesthésie caudale en chirurgie pédiatrique. Etude pharmacocinétique et intérêt clinique.

In 1987, 758 caudal anaesthesia allowed the execution of 41% of all our department's operations. Urological, genital, inguinal and lower limbs surgery were the most frequent. The injection into the extradural space through the hiatus sacralis always included the mixture of lidocaine with bupivacaine to speed up the beginning of the operation. The patients were split up into 2 equal groups and were given 1.25 ou 2.50 mg.kg-1 of bupivacaine (i.e. 0.50 ml.kg-1 of a 2.50 or 0.50% solution). Bupivacaine plasma levels were determined by high performance liquid chromatography in 40 patients from the first group and in 42 patients from the second. They reached their maximum about 500 or 1,000 ng.ml-1 respectively, 30 mn after the injection and always fell back 4 hours after the administration. These concentrations were compared with the levels obtained by infusion to the dog, which cause serious cardiac disorders with 6,000 to 8,000 ng.ml-1 levels, and elicit ventricular fibrillation with 8,000 to 10,000 ng.ml-1. So the safety margin appears greater when overdose and/or intravascular injection are avoided. Caudal anaesthesia is easy, fast acting and allows to relieve post-operative pain. It is suitable for all surgery below the umbilicus and can be used on an outpatient basis.

Effects of isoproterenol and propranolol on pharmacologically induced depression of intraventricular conduction.

The cardiac adrenergic system is known to have practically no influence on conduction velocity in the ventricles under normal conditions. The effects of isoproterenol and propranolol were investigated on depression of intraventricular conduction induced by a class IC antiarrhythmic drug, cibenzoline, in anaesthetized, closed-chest dogs. In addition to electrocardiogram for measurement of QRS duration in sinus rhythm, conduction time was measured in the ventricular contractile tissue between an electrode advanced to the apex and a pacing electrode near the base, at 400- and 200-ms pacing periods. Effective refractory period (ERP) was measured concurrently according to the extrastimulus method. After intraventricular conduction had been slowed down by cibenzoline IV administered (loading dose of 3 mg/kg plus infusion of 0.2 mg/kg/min over 15 min), isoproterenol was infused or propranolol injected by the intravenous route also (0.5 mn/micrograms/kg/min over 5 min and 0.4 mg/kg, respectively). When conduction time has been raised by 75/150% (depending on the pacing rate), isoproterenol appears to attenuate and propranolol to aggravate substantially the impairment of conduction, whereas the reduction undergone by ERP does not differ from usual. Thus, reentrant arrhythmias might be prevented by isoproterenol and triggered by propranolol. Intraventricular conduction, when depressed, therefore, is sensitive to adrenergic drugs, probably because of the enhanced influence of polarization of the fibres in the presence of a sodium conductance impairment.

Haemodynamic effects of high plasma concentrations of bupivacaine in the dog.

The threshold concentrations responsible for circulatory collapse were experimentally investigated by intravenously infusing the drug at high rates (0.2 and 0.3 mg kg-1 min-1 over 20 min, and 0.4 mg kg-1 over 10 min) to 11 anaesthetized and ventilated dogs. Bupivacaine plasma concentrations at the time of haemodynamic measurements were, respectively, 4303 +/- 46, 5829 +/- 615, and 8930 +/- 689 ng ml-1 (means +/- SEM). Cardiac output appeared to be the first and the most affected of the haemodynamic variables studied. Its reduction was already significant with the 0.2 mg kg-1 min-1 bupivacaine infusion, whereas mean systolic blood pressure remained unchanged because of the compensatory increase in vascular resistance. The fall of cardiac output was enhanced by the rise in bupivacaine infusion rate, with simultaneous substantial decreases in left ventricular pressure and LV dP/dt max. At this stage, the increase in systemic vascular resistance was less marked than at low infusion rates, and was not sufficient to prevent hypotension. The variations of mean pulmonary blood pressure and pulmonary capillary wedge pressure did not reach statistical significance, and the absence of significant change in mean pulmonary blood pressure at the time cardiac output was reduced reflected the increase in pulmonary vascular resistance. These results suggest that high plasma concentrations of bupivacaine exert a depressant effect on cardiac contractions earlier than on arteriolar tone.

[Systemic toxicity of local anesthetics. Pharmacokinetic and pharmacodynamic factors]. / Toxicité systémique des anesthésiques locaux. Facteurs pharmacocinétiques et pharmacodynamiques.

Local anaesthetics can have systemic adverse effects, mostly affecting the central nervous system and the heart. The physicochemical characteristics of the different local anaesthetics are recalled, for they determine the relationship between structure, activity and toxicity. The pharmacokinetic factors involved in the toxic effects of local anaesthetics, whether the drug is given in a single extravascular dose or, accidentally, within a blood vessel, are discussed. The toxic effects of repeated administrations of local anaesthetics depend on the metabolism of the drug as well as on pharmacokinetic factors. Possible maximal doses and drug interactions are also discussed. The mechanism of action of local anaesthetics, which block the sodium channel, explains their tissue toxicity and, more specifically, their central nervous and cardiovascular toxicities, which are more pronounced for the more potent local anaesthetic agents (bupivacaine, etidocaine). Systemic maternal effects and transplacental passage probably explain their foetal toxicity. Specific toxic effects are seen with some drugs, such as methaemoglobinaemia and allergic reactions (rarely for amide agents). Overall, local anaesthetic accidents are rare, but they must be prevented.

[Phenoperidine: pharmacology and use in pediatric resuscitation]. / La phénopéridine: pharmacologie et utilisation en réanimation pédiatrique.

Phenoperidine is mainly metabolised in the liver, and has a biliary and urinary elimination. Because its analgesic effects are fast and prolonged, this drug is often used in pediatric intensive care units, due to its interesting pharmacologic properties (mild cardiac and respiratory depression).