Myocardial uptake of bupivacaine: I. Pharmacokinetics and pharmacodynamics of lidocaine and bupivacaine in the isolated perfused rabbit heart.

Bupivacaine, but not lidocaine, may cause severe cardiac dysrrhythmias in case of accidental intravascular injection. In an attempt to discriminate between a pharmacokinetic and a pharmacodynamic (or both) origin to these differences, we used an isolated rabbit heart model with constant coronary inflow to compare the myocardial uptake and disposition kinetics of lidocaine and bupivacaine. Drug concentration in the outflow perfusate was assayed and surface electrocardiogram was recorded. Drug uptake and disposition kinetics were modeled with a two-compartment open model. An Emax model was used to describe the increase in QRS duration in relation with drug concentration in the central compartment. Lidocaine and bupivacaine exhibited similar myocardial pharmacokinetics (i.e., a rapid decrease in the outflow concentration upon drug administration discontinuation). Bupivacaine-induced maximum increase in QRS duration (Emax) was 15 times superior to lidocaine Emax. The steady-state perfusate concentration producing half Emax was the same for both drugs. We conclude that bupivacaine-induced QRS widening decreases almost at the same rate as does lidocaine-induced QRS widening when drug administration is terminated. Therefore, the different cardiac effects of lidocaine and bupivacaine are not due to differences in myocardial uptake and disposition kinetics.

Myocardial uptake of bupivacaine: II. Pharmacokinetics and pharmacodynamics of bupivacaine enantiomers in the isolated perfused rabbit heart.

The enantiomers of a racemic drug generally differ in their pharmacokinetic and/or pharmacodynamic properties. Because bupivacaine is a mixture of two optical isomers known to exert different toxic properties on isolated nerve preparations, we decided to use an isolated rabbit heart model with constant coronary inflow to compare the myocardial uptake kinetics of the R(+)-, S(-)-enantiomers and the racemic mixture of bupivacaine. The increase in QRS duration was also measured, and the inflow concentration-effect relationship was analyzed for the three drugs. The racemic and the two enantiomers of bupivacaine exhibited similar myocardial pharmacokinetics with a two-compartment profile for all hearts except one. All drugs showed a rapid decrease in the outflow concentration when drug administration was discontinued. The tissue/perfusate concentration ratio at steady state was similar for the three drugs. QRS widening, as well as the occurrence of severe arrhythmias, was much less pronounced in the hearts receiving the S(-) isomer than in the hearts receiving the R(+) isomer or the racemic mixture. Despite the occurrence of arrhythmias, QRS widening was adequately modelled with an Emax model. C50, the inflow perfusate concentration producing half Emax (maximal theoretical increase in QRS duration) was the same for all three drugs. The authors conclude that the S(-)-bupivacaine exerts less detrimental effects on the isolated heart of the rabbit perfused at a constant coronary flow with protein-free buffer.

Effects of epinephrine and clonidine on plasma concentrations of spinal bupivacaine.

ASA II-III patients, scheduled for peripheral vascular surgery, were included in a study designed to assess the effect of spinal epinephrine and clonidine on plasma concentrations of spinally administered 0.5% glucose-free bupivacaine. Patients were allocated randomly to three groups to receive via a spinal catheter 22.5 mg (4.5 ml) of bupivacaine alone (Group B, 9 patients) or combined with 0.3 mg epinephrine (Group BE, 10 patients) or 0.15 mg clonidine (Group BC, 10 patients). Sensory blockade was assessed by pin-prick and motor blockade on the Bromage scale. Bupivacaine plasma concentrations were measured by gas chromatography. A trend to prolongation of local anaesthetic blockade was documented in patients receiving bupivacaine plus epinephrine or clonidine. (Time to regression of sensory blockade to L2: 170 +/- 75 min in Group B, 230 +/- 50 min in Group BE, 232 +/- 64 min in Group BC.) The maximum peak concentration (Cmax), the time to reach Cmax (Tmax) and the time-concentration curve from 0-180 min (AUC) were not different for the three groups (Cmax 228 +/- 112 ng.ml-1 in Group B, 215 +/- 103 ng.ml-1 in Group BE, 234 +/- 159 ng.ml-1 in Group BC; Tmax 41 +/- 34 min in Group B, 59 +/- 31 min in Group BE, 68 +/- 32 min in Group BC; AUC 31.0 +/- 1.7 mg.ml-1.min-1 in Group B, 27.3 +/- 1.1 mg.ml-1.min-1 in Group BE, 27.0 +/- 1.1 mg.ml-1.min-1 in Group BC). The results of this study suggest that epinephrine and clonidine do not decrease blood resorption of spinal bupivacaine.

Clonidine-induced analgesia in postoperative patients: epidural versus intramuscular administration.

To compare the analgesic efficacy and plasma concentration of intramuscular (IM) versus epidural (EP) clonidine, 20 patients recovering from orthopedic or perineal surgery were randomly divided into two groups of ten. Clonidine (2 micrograms/kg) was administered epidurally in group 1 and intramuscularly in group 2. Analgesia was assessed using a visual analog scale (VAS) over a period of 6 h following clonidine administration. Venous blood samples were obtained at specific intervals for radioimmunoassay determination of plasma clonidine concentrations. The maximum reduction in VAS pain score was 78.5 +/- 20.6% in the EP group and 68.1 +/- 31.5% in the IM group (NS). Onset of analgesia was similar (within 15 min of injection), but duration tended to be longer after epidural than intramuscular administration (208 +/- 87 min vs. 168 +/- 95 min, mean +/- SD, P greater than 0.05). The peak plasma clonidine concentration after EP injection was 0.82 +/- 0.22 ng/ml and 1.02 +/- 0.76 ng/ml after IM injection. Hypotension, bradycardia, and drowsiness occurred with both methods of administration. None of these effects required treatment. Thus, in postoperative patients clonidine produces similar analgesia and side effects after parenteral or EP administration.

[Comparison between conventional and continuous spinal anesthesia using bupivacaine]. / Comparaison entre rachianesthésie conventionnelle et rachianesthésie continue utilisant la bupivacaïne.

A study was carried out to find out whether dividing the dose of local anaesthetic would give a better control of the spread and duration of sensory blockade due to spinal anaesthesia. It was carried out in 34 patients (mean age 62 years) scheduled for elective limb vascular surgery. All were classed ASA 2 or 3. Sensory blockade was assessed using a fine needle, and the degree of motor blockade with Bromage's scale. This was carried out every 5 min for the first 30 min, and thereafter, every 15 min until recovery from anaesthesia was complete. In the first group of patients (n = 16), spinal anaesthesia was obtained with a 26 gauge needle, the patient lying on his side; 4 ml of 0.5% bupivacaine were injected (1 ml every 10 seconds) before putting the patient supine. In the second group (n = 18), the catheter for continuous spinal anaesthesia was set up with the patient in the same position as for the first group. Once a length of 1 cm had been introduced in the subarachnoid space, the patient was placed supine and 2 ml of 0.5% bupivacaine were injected. If 15 min later sensory blockade did not reach T10, further 0.5 ml aliquots were given every 10 min so as to obtain a level of sensory blockade between T9 and T11. Maximum extension of sensory blockade was 15.1 +/- 2.3 metamers in group 1, with an extension to T3 in 2 patients. In group 2, 12.9 +/- 3.1 mg bupivacaine anaesthetized 14.2 +/- 1.9 metamers.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative analgesia with extradural clonidine.

The analgesic effect of extradural clonidine was evaluated in a double-blind study. In the recovery room, following orthopaedic or perineal surgery 20 ASA I and II patients were allocated randomly to two groups. The extradural clonidine (EC) group received clonidine 2 micrograms kg-1 in isotonic saline solution 15 micrograms ml-1. The extradural saline (ES) group received the equivalent volume of plain isotonic saline solution. Pain was evaluated by a visual analogue scale (VAS) at 15-min intervals for the first 2 h and subsequently at 30-min intervals for the following 4 h. Morphine 5 mg was given s.c. when patients complained of pain after extradural saline or clonidine. In the EC group, the mean (SD) maximum pain relief was 68.2 (24.1)% of the initial VAS score, but it was only 14.7 (25.2)% in the ES group. The mean duration of analgesia, before injection of morphine, was significantly longer in the EC group (210 (87) min) compared with the ES group (45 (27) min) (P less than 0.001). Drowsiness and moderate hypotension were observed in the EC group.

Baroreceptor control after cervical epidural anesthesia in patients undergoing carotid artery surgery.

Baroreceptor (BR) reactivity was studied in 16 patients scheduled for carotid artery surgery performed under cervical epidural anesthesia with 0.375% bupivacaine (15 mL). In the first seven patients, BR reactivity was assessed by measurement of the slopes of the linear relationship between systolic arterial pressure (SAP) and the RR interval on the electrocardiogram. Alterations of blood pressure (BP) were produced using sequential intravenous (IV) doses of nitroglycerin (NTG; 100 to 200 micrograms) or phenylephrine (PHE; 100 to 200 micrograms), before and 30 minutes after epidural anesthesia. The changes in SAP and heart rate (HR) determined during the four phases of a Valsalva maneuver were evaluated in a second set of measurements before and after cervical epidural blockade. In nine additional patients, a third set of measurements studying BR reactivity after carotid clamping and unclamping was performed in order to assess the effect of carotid handling on BP control. Cervical epidural anesthesia induced moderate decreases in BP (SAP, 150 +/- 18 mmHg before cervical block, 143 +/- 27 mmHg after cervical block, P less than 0.05) and HR (RR, 812 +/- 120 ms before cervical block, 938 +/- 130 ms after cervical block, P less than 0.05). Cervical epidural anesthesia depressed BR reactivity during deactivation as assessed by the decrease in the BR slope after PHE injection (6.6 +/- 4.4 ms/mmHg before cervical block v 2.5 +/- 1.8 ms/mmHg after cervical block, P less than 0.01) and activation as assessed by the changes in SAP and HR during phases II and IV of the Valsalva maneuver.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities in myocardial segmental wall motion during lumbar epidural anesthesia.

The effect of lumbar epidural anesthesia on myocardial wall motion was compared in two groups of patients using precordial two-dimensional echocardiography (2DE). All patients were scheduled to undergo lower abdominal or peripheral surgery. Group 1 included five healthy ASA PS 1 subjects and group 2 included 10 patients with coronary artery disease (CAD). In all patients 12.5 ml of 2% lidocaine HCl was injected into the lumbar epidural space, and systolic and diastolic blood pressures, and heart rate were continuously monitored. 2DE evaluation was performed before and at 10, 20, 30, and 60 min (T10-T60) after epidural lidocaine injection. The left ventricular wall was divided into 16 segments for parasternal long-axis, short-axis and apical four-chamber views. The wall motion of each segment was graded on a scale from 1 (dyskinesia) to 6 (hyperkinesia), with 5 representing normal motion. A decrease in segmental wall motion greater than or equal to 2 grades was considered indicative of ischemia. Plasma lidocaine and catecholamine levels were measured before and 10, 20, and 60 min after epidural lidocaine injection. Peak plasma lidocaine levels in groups 1 and 2 were 2.79 +/- 1.06 micrograms/ml (mean +/- SD) and 2.58 +/- 1.48 micrograms/ml at 10 min, respectively (NS). Plasma epinephrine and norepinephrine levels were unchanged from baseline. Systolic pressures decreased significantly in group 2 from T10 to T60. Diastolic pressure decreased significantly in the same group from T20 to T60, and in group 1 only at T10. Mean arterial pressure decreased significantly in both groups at T30, without change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of tourniquet pain by spinal isobaric bupivacaine with clonidine.

In order to assess the effect of spinal clonidine on tourniquet pain, 30 patients scheduled to undergo orthopaedic surgery under spinal anaesthesia were allocated randomly to two groups. Patients in group I (n = 15) received 0.5% isobaric bupivacaine 15 mg plus isotonic saline 1 ml. Patients in group II (n = 15) received 0.5% bupivacaine 15 mg plus clonidine 1 ml (150 micrograms). Sensory block was evaluated by pinprick and motor block with Bromage's scale. The presence of clonidine significantly prolonged the duration of sensory and motor block. Three patients in group I, but none in group II, experienced tourniquet pain. Hypotension and bradycardia were not worsened by spinal clonidine. The use of clonidine may be a useful technique to augment bupivacaine spinal block.

Dose-related prolongation of hyperbaric tetracaine spinal anesthesia by clonidine in humans.

The effect of clonidine, an alpha 2 agonist, on sensory and motor blockade during spinal anesthesia was studied in 44 ASA physical status I II patients scheduled for orthopedic surgery. The patients were randomly allocated into three groups given 15 mg of 0.5% hyperbaric tetracaine (HT), within group I (N = 14) 1 ml isotonic saline, in group II (N = 15) 0.5 ml saline solution and 0.5 ml clonidine (75 micrograms), and in group III (N = 15) 1 ml clonidine (150 micrograms). Sensory blockade (SB) was evaluated by pinprick and motor blockade (MB) according to Bromage's scale. The level of SB was comparable in the three groups but the duration was different. The 75 micrograms clonidine was associated with 25% prolongation of SB at L2 and 29% prolongation of grade 3 MB Clonidine 150 micrograms prolonged the time of SB at L2 by 72% and grade 3 MB by 96%. Colloid infusion and the decrease in diastolic blood pressure were significantly greater in the clonidine 150 micrograms group compared to group I. A dose related prolongation of spinal anesthesia is demonstrated with clonidine.

[Failure of spinal anesthesia. Evaluation of the practice at a university hospital]. / Echecs de la rachianesthésie. Evaluation de la pratique d'un hôpital universitaire.

There is little data concerning failures in spinal anaesthesia. A retrospective analysis of 337 spinal anaesthesias performed in a teaching hospital gave a 9.8% failure rate. A failure was defined as the need to carry out part or all of a surgical act under general anaesthesia when spinal anaesthesia had been carried out. The main causes of failure were insufficiently or excessively extended neural blockade, insufficient duration or a poor quality sensory blockade with the patient feeling surgical or tourniquet pain. The local anaesthetics used were hyperbaric 0.5% tetracaine with and without 0.1 mg metaraminol, hyperbaric 0.5% prilocaine and isobaric 0.5% bupivacaine. The failure rate was 19.4% with plain hyperbaric tetracaine, 7.6% with tetracaine with metaraminol, 5% with prilocaine and 2.9% with isobaric bupivacaine. This rate was related neither to the experience of the anaesthetist, nor to the clinical features of the patients, nor to the position nor to the needle size. Although there were more failures during orthopaedic procedures, probably because of tourniquet pain, this was not significant. These results confirmed that spinal anaesthesia was a reliable technique. Hyperbaric plain tetracaine did not always guarantee a successful anaesthesia and isobaric bupivacaine should be more commonly used.