Benjamin G. Covino

Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog.

This study evaluated the systemic toxicity, arrhythmogenicity, and mode of death of convulsant and supraconvulsant doses of lidocaine, bupivacaine, and ropivacaine. Experiments in awake dogs were designed to mimic the clinical situation of an accidental intravenous (IV) injection of local anesthetics.On the first experimental day, lidocaine (8 mg·kg−1 · min−1), bupivacaine (2 mg·kg−1·min−1), and ropivacaine (2 mg·kg−1·min−1) were infused intravenously until seizures occurred (n = 6 for each group). The average dose and arterial plasma concentration at seizure onset was 20.8 ± 4.0 mg/kg and 47.2 ± 5.4 μg/ml for lidocaine, 4.31 ± 0.36 mg/kg and 18.0 ± 2.7 μg/mL for bupivacaine, and 4.88 ± 0.47 mg/kg and 21.4 ± 0.9 μg/mL for ropivacaine.The margin of safety between the convulsive and lethal doses was determined by administering two times the convulsive dose 24 h later. Two dogs given lidocaine died because of progressive hypotension, respiratory arrest, and finally cardiovascular collapse with an average peak plasma concentration (Cmax) of 469 μg/mL. No ventricular arrhythmias were observed in this group. Ventricular arrhythmias occurred in five of six dogs receiving bupivacaine. Four animals died because of hypotension, respiratory arrest, and cardiovascular collapse. One additional animal died because of ventricular fibrillation. The Cmax for bupivacaine was 70.1 ± 14.6 μg/mL in nonsurvivors. In the ropivacaine group one animal died because of hypotension, respiratory arrest, and cardiovascular collapse (Cmax 72.4 μg/mL). A surviving dog had transient premature ventricular contractions.Twenty-four hours later three times the convulsive dose was administered to the survivors. Death occurred in three animals in the lidocaine group, the remaining dog in the bupivacaine group, and four dogs in the ropivacaine group. All deaths were due to hypotension, respiratory arrest, and subsequent cardiovascular collapse. Ventricular arrhythmias were observed in two dogs in the ropivacaine group and the single dog receiving bupivacaine. The results suggest that the convulsive doses for ropivacaine and bupivacaine are similar. However, ropivacaine may possess a greater margin of safety and be less arrhythrnogenic than bupivacaine after an accidental rapid IV injection. Only lidocaine was devoid of arrhythmogenic activity.

Acute cardiovascular toxicity of intravenous amide local anesthetics in anesthetized ventilated dogs.

The acute intravenous cardiovascular toxicity of five amide local anesthetic agents was studied in intact, ventilated dogs anesthetized with pentobarbital. Minimal changes in various cardiovascular functions were seen at doses of 0.3 to 3.0 mg/kg. At 10 mg/kg profound hypotension accompanied by significant decreases in cardiac output and stroke volume were observed with etidocaine and bupivacaine. At this dose lidocaine, mepivacaine, and prilocaine produced moderate signs of cardiovascular depression. Myocardial depression appeared to be primarily responsible for the profound hypotension, as minimal changes in peripheral vascular resistance occurred except as a terminal event. Pulmonary vascular resistance tended to increase before myocardial depression, suggesting a pulmonary vasoconstrictor action of the anesthetics. The cumulative lethal dose varied from appproximately 80 mg/kg for lidocaine and mepivacaine to 40 mg/kg for etidocaine and 20 mg/kg for bupivacaine. The acute cardiovascular toxicity of these agents is proportional to their comparative in vivo anesthetic potency which indicates little difference in therapeutic ratio between the various amide local anesthetics.

Differential Sensitivities of Mammalian Nerve Fibers to Local Anesthetic Agents

The differential sensitivities of mammalian nerve fibers to various local anesthetic agents were investigated. Lidocaine, tetracaine, etidocaine, and bupivacaine demonstrated a consistent pattern of conduction blockade in which the large fast-conducting A fibers were blocked at the lowest drug concentration, the intermediate B fibers were blocked at a higher drug concentration, and the smallest, slowest-conducting C fibers required the highest drug concentration for conduction blockade. A comparison of procaine, chloroprocaine, cocaine, tetrodotoxin and saxitoxin on B and C fibers showed similar effects. These findings indicate that local anesthetic agents are similar to other biological stress modalities in terms of their differential effects on nerve fibers of various sizes and conduction velocities, i.e., the large fast-conducting fibers are more susceptible to conduction blockade than are the smaller, slower-conducting fibers. Discrepancies between results of this study and previous reports in the literature are discussed.

Comparison of bupivacaine- and ropivacaine-induced conduction blockade in the isolated rabbit vagus nerve

Ropivacaine (LEA-103) is a new amino-amide local anesthetic agent the chemical structure and anesthetic properties of which are similar to bupivacaine. Preliminary studies in animals indicate that the CNS toxicities of ropivacaine and bupivacaine are similar, but that ropivacaine may have less arrhythmogenic effects than bupivacaine. The current study was designed to compare the in vitro potency, onset and recovery from block of ropivacaine and bupivacaine using an isolated rabbit vagus nerve model. The effect of varying concentrations of ropivacaine and bupivacaine on the compound action potential of A and C nerve fibers was assessed to determine whether motor and sensory fibers have different sensitivities to the two agents. The results showed that the depressant effect of bupivacaine was 16% greater than that of ropivacaine on motor fibers, but only 3% greater on sensory fibers. An analysis of variance indicated that this was a statistically significant difference (P=0.028). Thus, at the concentrations tested, ropivacaine appears to produce relatively less blockade of motor fibers than does bupivacaine but with similar sensory blockade. The onset of this difference became significant as early as five minutes after the drug exposure was begun. No significant differences in recovery times were observed.

Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog

Two groups of six beagle dogs received rapid intravenous (IV) injections of ropivacaine or bupivacaine on two occasions in a blinded random fashion. Initially, a dose sufficient to cause convulsions (CD) was given followed by twice the CD (2 x CD), which was administered 48 h later. The CD of bupivacaine (4.3 mg/kg) and ropivacaine (4.9 mg/kg) caused significant (P less than 0.05) increases in heart rate and mean arterial blood pressure. There was no difference between drug groups. Seizures were abolished by 10 mg/kg of intravenous thiamylal. Endotracheal intubation and controlled respiration with O2-enriched air with no other treatment resulted in rapid and complete recovery in all dogs. All dogs receiving 2 x CD of bupivacaine (8.6 mg/kg) or ropivacaine (9.8 mg/kg) were initially treated with thiamylal and mechanical ventilation. Two dogs in the bupivacaine group developed hypotension, respiratory arrest, ventricular tachycardia, and ventricular fibrillation, which were resistant to closed chest cardiac massage, treatment with epinephrine, bretylium, and atropine, and direct current cardioversion. The four remaining dogs in the infusion group were successfully resuscitated. All of the animals in the ropivacaine-treated group survived the administration of the 2 x CD dose. Mild hypotension developed in one dog and was treated with intravenous epinephrine (0.75 mg). This resulted in nodal tachycardia, which was abolished after treatment with bretylium. Another dog had two 1-s bursts of premature ventricular contractions requiring no treatment. The rapid treatment of convulsions and cardiovascular toxicity resulted in a decreased number of deaths in both groups when compared with dogs from a previously published study in which no therapy was instituted. Thus, early aggressive treatment of central nervous system and cardiovascular system toxicity is capable of reducing the incidence of mortality associated with the rapid intravenous administration of excessive doses of local anesthetics.

Effects of fentanyl and sufentanil on peripheral mammalian nerves.

The effects of fentanyl and sufentanil on peripheral nerves were evaluated in isolated sheathed and desheathed rabbit vagus nerves. The action potential amplitudes of A and C fibers were recorded before and after a 30-min exposure to 50 and 100 μg/ml of fentanyl and sufentanil. A reversible decrease in the action potential amplitude of A fibers in desheathed nerves was observed after exposure to 100 μg/ml of each drug. The action potential amplitude of C fibers was also decreased but not to the same degree as was the A fiber action potential. Pretreatment with naloxone failed to block the reduction in action potential amplitude produced by the two opiates. No evidence of irreversible conduction blockade indicative of local neural toxicity was seen in these studies. The results suggest that high concentrations of fentanyl and sufentanil may exert a weak local anesthetic-type action on peripheral nerves.

Comparative CNS toxicity of lidocaine, etidocaine, bupivacaine, and tetracaine in awake dogs following rapid intravenous administration

The comparative central nervous system (CNS) toxicity of serially administered intravenous doses of lidocaine, bupivacaine, etidocaine, and tetracaine was investigated in awake dogs. The mean cumulative dose required for convulsive activity was 4.0 mg/kg tetracaine, 5.0 mg/kg bupivacaine, 8.0 mg/kg etidocaine, and 22.0 mg/kg lidocaine. The cumulative convulsive dose of lidocaine was significantly greater than that of the other three agents (P < 0.01). A comparison of the in vivo anesthetic potency and the acute CNS toxicity of these various agents suggests little difference in the therapeutic ratio between less potent anesthetics such as lidocaine and more potent drugs, i.e., tetracaine, bupivacaine, and etidocaine. The relative CNS toxicity of the different agents as determined in awake dogs in this study was compared with their relative cardiovascular toxicity previously evaluated in a series of ventilated dogs anesthetized with pentobarbital. The dose of lidocaine, etidocaine, tetracaine, and bupivacaine required to produce irreversible cardiovascular depression was 3.5–6.7 times greater than that which produced convulsions. These results suggest that the CNS is the primary target organ for the toxic effects of both highly lipid-soluble and highly protein-bound local anesthetics (i.e., bupivacaine, etidocaine, and tetracaine) and less lipid-soluble and less protein-bound drugs (i.e., lidocaine) following rapid intravenous administration.

A Dose-response Study of Bupivacaine for Spinal Anesthesia

A randomized double-blind study was performed to elucidate the interrelationships among volume, concentration, and dosage of bupivacaine adminstered intrathecally. Sixty male patients between the ages of 40 and 80 years having transurethral surgery in the lithotomy position were studied using 10-, 15-, and 20-mg doses of glucose-free bupivacaine as either a 0.5 or a 0.75% solution. Success rate, time of onset and duration of anaglesia and motor block, and cardiovascular responses were assessed. It was found that both 15 and 20 mg of either concentration of bupivacaine provide satisfactory spinal anesthesia for transurethral urologic procedures. However, three of 20 patients receiving the 10-mg dose required supplementation with general anesthesia. Comparison of various volumes and concentrations of bupivacaine indicates that total dosage of bupivacaine is more important than volume or concentration. In several patients with sensory block involving cervical dermatomes, there was no significant hypotension or bradycardia, which suggests that cardiac output and venous return were maintained, perhaps because of the use of lithotomy position.

Bupivacaine Toxicity in Pregnant and Nonpregnant Ewes

The relative central nervous system and cardiovascular toxicity of bupivacaine was compared in pregnant and nonpregnant ewes during continuous infusion of bupivacaine into the jugular vein at the rate of 0.5 mg. kg-1. min-1. In all animals, identical symptoms of toxicity occurred in the following order: convulsions, hypotension, respiratory arrest, and circulatory collapse. The dose of bupivacaine required to produce central nervous system (CNS) toxicity in the pregnant ewe tended to be lower than in the nonpregnant animal, although the difference was not statistically significant (P < 0.1). However, the mean dose of bupivacaine resulting in cardiovascular collapse was significantly lower in pregnant ewes (5.1 ± 0.7 mg/kg) than in nonpregnant animals (8.9 ± 0.9 mg/kg). Similarly, bupivacaine blood concentrations at the onset of respiratory arrest and circulatory collapse were lower in the pregnant group, being 5.2 ± 0.7 μg/ml and 5.5 ± 0.8 μg/ml, respectively, versus 7.5 ± 1.0 μg/ml and 8.0 ± 0.9 μg/ml, respectively, in the nonpregnant group (P < 0.05). The concentration of bupivacaine in the brain of pregnant ewes at the time of cardiovascular collapse was significantly lower (P < 0.01) than in the nonpregnant group (7.5 ± 1.5 vs. 16.3 ± 1.7 μg/g). The myocardial tissue concentration of bupivacaine also tended to be lower in the pregnant group, although the differences were not statistically significant (P < 0.1). Comparisons of bupivacaine doses and blood concentrations associated with the onset of convulsions and circulatory collapse (CC/CNS ratio) with those of lidocaine, reported previously, indicate that a narrower margin of safety exists following administration of bupivacaine in nonpregnant sheep. These ratios were 3.7 ± 0.5 and 1.6 ± 0.1, respectively, for bupivacaine and 7.1 ± 1.1 and 3.6 ± 0.3, respectively, for lidocaine. In addition, the data indicate that the pregnant sheep may be more sensitive to the cardiotoxic effects of bupivacaine than the nonpregnant animal.

Differential Sensitivities of Mammalian Nerve Fibers during Pregnancy

: The onset of conduction blockade in the vagus nerve of pregnant and nonpregnant rabbits was studied utilizing an in vitro sheath nerve preparation. The time required for 50% depression of the action potential (AP) of A, B, and C vagal fibers from five pregnant and six nonpregnant animals was determined after the application of bupivacaine (0.35 mM). The onset of conduction block occurred in 6.7-12.1 min in the A, B, and C fibers from pregnant animals compared to onset times of 17.9-31.6 min in nerves taken from nonpregnant rabbits. The difference in onset time for each type of nerve fiber from pregnant and nonpregnant animals was highly significant. The results suggest either an increased sensitivity of nerve fibers from pregnant animals to bupivacaine or an enhanced diffusion of the bupivacaine to the membrane receptor site. Mechanical factors are clearly not responsible for the observed results. Hormonal factors may play a role in the decreased anesthetic latency, because progesterone levels were significantly higher in the pregnant animals.