Comparative systemic toxicity of ropivacaine and bupivacaine in nonpregnant and pregnant ewes.
BACKGROUND
Ropivacaine is a new amide local anesthetic, having therapeutic properties similar to those of bupivacaine but with a wider margin of safety. Bupivacaine is probably the most commonly used drug in obstetric epidural analgesia, even though laboratory studies have suggested that pregnancy increases the cardiotoxicity of bupivacaine but not of other local anesthetics. The current study was designed to reevaluate, in a random and blinded fashion, the systemic toxicity of bupivacaine and ropivacaine in nonpregnant and pregnant sheep.


METHODS
Chronically prepared nonpregnant and pregnant ewes were randomized to receive an intravenous infusion of ropivacaine or bupivacaine at a constant rate of 0.5 mg.kg-1.min-1 until circulatory collapse. The investigators were blinded to the identity of local anesthetic. Heart rate, arterial blood pressure, and cardiac rhythm were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations, which appeared in the following sequence: convulsions, hypotension, apnea, and circulatory collapse. Serum drug concentrations and protein binding were determined. Blood pH and gas tensions were measured.


RESULTS
There were no significant differences between non-pregnant and pregnant animals in the doses or serum concentrations of either drug required to elicit toxic manifestations. In nonpregnant animals, similar doses and serum concentrations of ropivacaine and bupivacaine were associated with the onset of convulsions and circulatory collapse. In pregnant ewes, greater doses of ropivacaine as compared to bupivacaine were required to produce convulsions (7.5 +/- 0.5 vs. 5.0 +/- 0.6 mg.kg-1) and circulatory collapse (12.9 +/- 0.8 vs. 8.5 +/- 1.2 mg.kg-1). The corresponding serum concentrations of ropivacaine were similar to those of bupivacaine. Pregnancy did not affect the serum protein binding of either drug. The proportion of animals manifesting a malignant ventricular arrhythmia as the terminal event was similar among all groups.


CONCLUSIONS
The systemic toxicity of ropivacaine or bupivacaine is not enhanced by gestation in sheep. This is in contrast to an earlier study in which the cardiotoxicity of bupivacaine was enhanced during ovine pregnancy. Greater doses of ropivacaine, as compared to bupivacaine, are needed to produce toxic manifestations in pregnant animals.
Santos
A C
AC
Obstetrics and Gynecology, School of Medicine, State University of New York at Stony Brook.
Arthur
G R
GR
Wlody
D
D
De Armas
P
P
Morishima
H O
HO
Finster
M
M
D000577:Amides / Q000633:toxicity*; D000818:Animals; D001049:Apnea / Q000139:chemically induced; D001794:Blood Pressure / Q000187:drug effects; D002045:Bupivacaine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007022:Hypotension / Q000139:chemically induced; D011247:Pregnancy / Q000187:drug effects; D000077212:Ropivacaine; D012640:Seizures / Q000139:chemically induced; D012756:Sheep; D014018:Tissue Distribution
D000577:Amides; D000077212:Ropivacaine; D002045:Bupivacaine