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TOXICITY OF LOCAL ANESTHETICS IN THE FETUS AND THE NEWBORN* MIECZYSLAW FINSTER, M.D. Professor, Department of Anesthesiology Columbia University College of Physicians and Surgeons New York, N.Y.
A
with most drugs used in obstetric analgesia and anesthesia, local anesthetics are transferred rapidly across the placenta into the fetus.1-3 This rapid placental transfer is paralleled by rapid uptake into highly perfused fetal organs, especially the heart, the brain, and the liver.3 Relatively high concentrations of lidocaine in the fetal heart could account for its susceptibility to local anesthetics administered to the mother. Our study has shown that the mean myocardial level of lidocaine in the fetus is not significantly different from that in the mother after two minutes.4 Since the myocardial toxicity of local anesthetics is increased by hypoxia and acidosis, drug levels which are tolerated well by the mother might cause severe myocardial depression in a partially asphyxiated fetus.> Accumulation of local anesthetics in the fetal brain may result in respiratory depression at birth. The incidence and onset of fetal depression are related not only to the dose, but also to the rate of absorption from the site of injection. The latter is especially pertinent to paracervical block (PCB), which requires the injection of a local anesthetic into a highly vascular area. PCB frequently results in transiently elevated levels of drug in the fetal blood, associated with fetal bradycardia and acidosis.- At least 50 perinatal deaths have been attributed to the use of paracervical block.6 More recently a new approach to the testing of newborn infants has revealed changes in neurobehavioral responses within the first eight hours of life after the administration of a clinical dose of lidocaine or mepivacaine to the mother.7 One way to obviate these hazards to the fetus and the neonate is to use less toxic drugs. Shnider and Gildea compared the incidence of s
*Presented as part of a Symposium on Local Anesthetics in Obstetrics held by the Section on Anesthesiology and Resuscitation of the New York Academy of Medicine March 5, 1975.
Bull. N. Y. Acad. Med.
TOXICITY TO LOCAL ANESTHETICS
2 2
3
fetal bradycardia and neonatal depression following PCB with lidocaine, mepivacaine, and prilocaine.8 Prilocaine in equianalgesic doses is about half as toxic to the central nervous system and the myocardium as lidocaine. The mean dosage of each drug was approximately i90 mg. PCB with lidocaine and mepivacaine was followed by fetal bradycardia in 22% of cases, whereas with the use of prilocaine fetal bradycardia occurred in only I I %. Thus, injection of a less toxic drug resulted in a decrease of 50% in post-PCB bradycardia. However, because of the risk of maternal and fetal methemoglobinemia which may develop due to accumulation of orthotoluidine, a metabolite of prilocaine, this drug has never become popular with anesthesiologists.' Another solution to the problem of toxicity is to minimize maternal and fetal blood level of the anesthetic by using the smallest dose that will provide adequate analgesia, by using rapidly metabolized drugs like 2-chloroprocaine, or long-acting drugs such as bupivacaine and etidocaine. In contrast to other commonly used anesthetics which contain an amide linkage and are metabolized rather slowly, 2-chloroprocaine (Nesacaine) contains an ester bond and thus is easily broken down by pseudocholinesterase in plasma. In our recent study we determined the rate of in vitro, hydrolysis of chloroprocaine in blood samples obtained from seven mothers at the time of delivery, from mixed umbilical cord blood obtained simultaneously, and from venous blood obtained from six nonpregnant female volunteers and five male volunteers.10 There was a significant difference between the half-life of chloroprocaine in maternal blood and that in umbilical cord blood; the corresponding values were 2i and 43 seconds, respectively. The half-life of the drug was 25 seconds in nonpregnant female volunteers and 2I seconds in males. Neither the difference between values for mothers and nonpregnant females nor the difference between the latter and the values for males was statistically significant. We also used chloroprocaine in 2% concentration for lumbar epidural anesthesia during labor and delivery, with most encouraging results. Thus, 2-chloroprocaine appears to be a safe local anesthetic drug, owing to its extremely rapid inactivation by plasma cholinesterase in persons of both sexes. Even though the half-life of the drug in fetal blood is twice as long as in the mother, rapid hydrolysis in the maternal blood should prevent substantial placental transfer and intoxication of the fetus. Two new local anesthetics have recently been added to our armaVol. 52, No. 2, February 1976
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M. FINSTER .FISE
mentarium: etidocaine, which is related to lidocaine, and bupivacaine, related to mepivacaine. The new drugs have longer duration of action, higher solubility in lipid, and higher protein-binding capacity in plasma than their parent compounds. When they are used for continuous epidural anesthesia, the long duration of action of these new substances reduces the freqency of "refill" dosage, lessening the risk of toxic reactions caused by the accumulation of drug in mother and fetus. Further, it has been noted that the fetal-maternal equilibration ratio (UV/M) of several local anesthetics correlates with their protein-binding capacity.1' Prilocaine has the lowest binding capacity, 55%. Lidocaine and mepivacaine hold an intermediate position with capacities of 64% and 77%, while bupivacaine and etidocaine are at the top of the list, with values of 94% and 95%, respectively. The highest UV/M ratio occurs with the use of prilocaine, umbilical vein levels and maternal levels being equal, while lidocaine and mepivacaine occupy an intermediate position with UV/M ratios of 0.5 to 0.7. The use of bupivacaine and etidocaine resulted in the lowest UV/M ratios, namely, 0.14 to o.44. These were interpreted to indicate that only a limited proportion of the amount of bupivacaine or etidocaine administered to the mother is transferred across the placenta to the fetus. This hypothesis is contradicted by preliminary results derived from a study now being conducted in our laboratory to determine the placental transfer and tissue distribution of several local anesthetics.'2 Thirty-one guinea pigs were used in the study of etidocaine. Animals were stunned and immersed in liquid nitrogen at varying intervals after a single intravenous injection of etidocaine, 2.5 mg./kg. Drug concentrations in maternal and fetal blood, brain, heart, liver, and kidneys, as well as in the carcass and in the placenta, were measured by means of a gas chromatographic technique. In 27 additional animals the proportion of the injected dose transferred across the placenta was determined on the basis of drug concentrations in fetal homogenates following an intravenous injection of lidocaine, IO mg./kg., to the mother. The ratio of etidocaine concentration between the fetal and maternal blood was substantially lower than that found for lidocaine in a previous study.3 Between two and io minutes after injection the ratios were 0.17 and o.s6, respectively. However, the proportion of the injected dose recovered from fetuses was remarkably similar for etidocaine and lidocaine, amounting to 1.5 to 3% per fetus. In contrast, the Bull. N. Y. Acad. Med.
TOXICITY TO LOCAL ANESTHETICS
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uptake of etidocaine in fetal tissues was much higher. Mean tissue-blood ratios of drug concentrations in the fetal myocardium and brain were twice as high for etidocaine as for lidocaine. High tissue affinity of etidocaine was demonstrated even more dramatically in the fetal liver, where the relative concentrations of etidocaine were about 20 times greater than those of lidocaine. These data indicate that lower concentrations of etidocaine in the fetal blood are due to a more substantial uptake by fetal tissues, as both etidocaine and lidocaine cross the placenta in similar proportions. In conclusion, long-acting local anesthetics such as bupivacaine and etidocaine have the advantage of requiring less frequent reinjection, lessening the risk of accumulation. Their high protein-binding capacity in plasma, however, does not appear to limit their placental transfer. REFERENCES 1973, p. 281. 1. Morishima, H. O., Daniels, S. S., Fin7. Scanlon, J. W., Brown, W. V., Weiss, ster, M., Poppers, P. J., and James, J. B., and Alper, M. H.: NeurobeL. S.: Transmission of mepivacaine havioral responses of newborn infants hydrochloride (Carbocaine) across the after maternal anesthesia. Anesthesihuman placenta. Anesthesiology 27:147, ology 40:121, 1974. 1966. 8. Shnider, S. M. and Gildea, J.: Para2. Shnider, S. M. and Way, E. L.: The cervical block anesthesia in obstetrics. kinetics of transfer of lidocaine (XyloAmer. J. Obstet. Gynzec. 116:320, 1973. caine) across the human placenta. An9. Poppers, P. J. and Finster, M.: The esthesiology 299:944, 1968. use of prilocaine hydrochloride (Cita3. Finster, M., Morishima, H. O., Boyes, nest) for epidural analgesia in obstetR. N., and Covino, B. G.: The placenrics. Anesthesiology 29:1124, 1968. tal transfer of lidocaine and its uptake by fetal tissues. Anesthesiology 36:159, 10. Finster, M., Perel, J. M., Hinsvark, 1972. 0. N., and O'Brien, J. E.: Pharmacodynamics of 2-chloroprocaine (Nesa4. Morishima, H. O., Heymann, M. A., caine), an ester-type local anesthetic. Rudolph, A. M., and Barrett, C. T.: Fourth Europ. Congr. Anesth. AmsterToxicity of lidocaine in the fetal and dam, Excerpta Medica, 1974, No. 330, newborn lamb and its relationship to p. 189. asphyxia. Amer. J. Obstet. Gynec. 112: 11. Covino, B. G.: Comparative clini72, 1972. cal pharmacology of local anesthetic 5. Teramo, K. and Widholm, 0.: Studies of the effect of anesthetics on foetus. 1. agents. Anesthesiology 35:158, 1971. The effect of paracervical block with 12. Morishima, H. O., Finster, M., Pedersen, H., Boyes, R. N., and Covino, mepivacaine upon foetal acid-base values. Acta Obstet. Gynec. Scand. B. G.: Placental transfer and tissue distribution of etidocaine and lidocaine (Suppl.) 46:1, 1967. 6. Teramo, K.: Perinatal Risks of Parain guinea pigs. Annual Meeting, Amer. Soc. Anesth. Chicago, 1975, p. 83. cervical Block. In: Fetal Pharmacology, Boreus, L., editor. New York, Raven,
Vol. 52, No. 2, February 1976
TOXICITY OF LOCAL ANESTHETICS IN THE FETUS AND THE NEWBORN* MIECZYSLAW FINSTER, M.D. Professor, Department of Anesthesiology Columbia University College of Physicians and Surgeons New York, N.Y.
A
with most drugs used in obstetric analgesia and anesthesia, local anesthetics are transferred rapidly across the placenta into the fetus.1-3 This rapid placental transfer is paralleled by rapid uptake into highly perfused fetal organs, especially the heart, the brain, and the liver.3 Relatively high concentrations of lidocaine in the fetal heart could account for its susceptibility to local anesthetics administered to the mother. Our study has shown that the mean myocardial level of lidocaine in the fetus is not significantly different from that in the mother after two minutes.4 Since the myocardial toxicity of local anesthetics is increased by hypoxia and acidosis, drug levels which are tolerated well by the mother might cause severe myocardial depression in a partially asphyxiated fetus.> Accumulation of local anesthetics in the fetal brain may result in respiratory depression at birth. The incidence and onset of fetal depression are related not only to the dose, but also to the rate of absorption from the site of injection. The latter is especially pertinent to paracervical block (PCB), which requires the injection of a local anesthetic into a highly vascular area. PCB frequently results in transiently elevated levels of drug in the fetal blood, associated with fetal bradycardia and acidosis.- At least 50 perinatal deaths have been attributed to the use of paracervical block.6 More recently a new approach to the testing of newborn infants has revealed changes in neurobehavioral responses within the first eight hours of life after the administration of a clinical dose of lidocaine or mepivacaine to the mother.7 One way to obviate these hazards to the fetus and the neonate is to use less toxic drugs. Shnider and Gildea compared the incidence of s
*Presented as part of a Symposium on Local Anesthetics in Obstetrics held by the Section on Anesthesiology and Resuscitation of the New York Academy of Medicine March 5, 1975.
Bull. N. Y. Acad. Med.
TOXICITY TO LOCAL ANESTHETICS
2 2
3
fetal bradycardia and neonatal depression following PCB with lidocaine, mepivacaine, and prilocaine.8 Prilocaine in equianalgesic doses is about half as toxic to the central nervous system and the myocardium as lidocaine. The mean dosage of each drug was approximately i90 mg. PCB with lidocaine and mepivacaine was followed by fetal bradycardia in 22% of cases, whereas with the use of prilocaine fetal bradycardia occurred in only I I %. Thus, injection of a less toxic drug resulted in a decrease of 50% in post-PCB bradycardia. However, because of the risk of maternal and fetal methemoglobinemia which may develop due to accumulation of orthotoluidine, a metabolite of prilocaine, this drug has never become popular with anesthesiologists.' Another solution to the problem of toxicity is to minimize maternal and fetal blood level of the anesthetic by using the smallest dose that will provide adequate analgesia, by using rapidly metabolized drugs like 2-chloroprocaine, or long-acting drugs such as bupivacaine and etidocaine. In contrast to other commonly used anesthetics which contain an amide linkage and are metabolized rather slowly, 2-chloroprocaine (Nesacaine) contains an ester bond and thus is easily broken down by pseudocholinesterase in plasma. In our recent study we determined the rate of in vitro, hydrolysis of chloroprocaine in blood samples obtained from seven mothers at the time of delivery, from mixed umbilical cord blood obtained simultaneously, and from venous blood obtained from six nonpregnant female volunteers and five male volunteers.10 There was a significant difference between the half-life of chloroprocaine in maternal blood and that in umbilical cord blood; the corresponding values were 2i and 43 seconds, respectively. The half-life of the drug was 25 seconds in nonpregnant female volunteers and 2I seconds in males. Neither the difference between values for mothers and nonpregnant females nor the difference between the latter and the values for males was statistically significant. We also used chloroprocaine in 2% concentration for lumbar epidural anesthesia during labor and delivery, with most encouraging results. Thus, 2-chloroprocaine appears to be a safe local anesthetic drug, owing to its extremely rapid inactivation by plasma cholinesterase in persons of both sexes. Even though the half-life of the drug in fetal blood is twice as long as in the mother, rapid hydrolysis in the maternal blood should prevent substantial placental transfer and intoxication of the fetus. Two new local anesthetics have recently been added to our armaVol. 52, No. 2, February 1976
222 24
M. FINSTER .FISE
mentarium: etidocaine, which is related to lidocaine, and bupivacaine, related to mepivacaine. The new drugs have longer duration of action, higher solubility in lipid, and higher protein-binding capacity in plasma than their parent compounds. When they are used for continuous epidural anesthesia, the long duration of action of these new substances reduces the freqency of "refill" dosage, lessening the risk of toxic reactions caused by the accumulation of drug in mother and fetus. Further, it has been noted that the fetal-maternal equilibration ratio (UV/M) of several local anesthetics correlates with their protein-binding capacity.1' Prilocaine has the lowest binding capacity, 55%. Lidocaine and mepivacaine hold an intermediate position with capacities of 64% and 77%, while bupivacaine and etidocaine are at the top of the list, with values of 94% and 95%, respectively. The highest UV/M ratio occurs with the use of prilocaine, umbilical vein levels and maternal levels being equal, while lidocaine and mepivacaine occupy an intermediate position with UV/M ratios of 0.5 to 0.7. The use of bupivacaine and etidocaine resulted in the lowest UV/M ratios, namely, 0.14 to o.44. These were interpreted to indicate that only a limited proportion of the amount of bupivacaine or etidocaine administered to the mother is transferred across the placenta to the fetus. This hypothesis is contradicted by preliminary results derived from a study now being conducted in our laboratory to determine the placental transfer and tissue distribution of several local anesthetics.'2 Thirty-one guinea pigs were used in the study of etidocaine. Animals were stunned and immersed in liquid nitrogen at varying intervals after a single intravenous injection of etidocaine, 2.5 mg./kg. Drug concentrations in maternal and fetal blood, brain, heart, liver, and kidneys, as well as in the carcass and in the placenta, were measured by means of a gas chromatographic technique. In 27 additional animals the proportion of the injected dose transferred across the placenta was determined on the basis of drug concentrations in fetal homogenates following an intravenous injection of lidocaine, IO mg./kg., to the mother. The ratio of etidocaine concentration between the fetal and maternal blood was substantially lower than that found for lidocaine in a previous study.3 Between two and io minutes after injection the ratios were 0.17 and o.s6, respectively. However, the proportion of the injected dose recovered from fetuses was remarkably similar for etidocaine and lidocaine, amounting to 1.5 to 3% per fetus. In contrast, the Bull. N. Y. Acad. Med.
TOXICITY TO LOCAL ANESTHETICS
2 2 5
uptake of etidocaine in fetal tissues was much higher. Mean tissue-blood ratios of drug concentrations in the fetal myocardium and brain were twice as high for etidocaine as for lidocaine. High tissue affinity of etidocaine was demonstrated even more dramatically in the fetal liver, where the relative concentrations of etidocaine were about 20 times greater than those of lidocaine. These data indicate that lower concentrations of etidocaine in the fetal blood are due to a more substantial uptake by fetal tissues, as both etidocaine and lidocaine cross the placenta in similar proportions. In conclusion, long-acting local anesthetics such as bupivacaine and etidocaine have the advantage of requiring less frequent reinjection, lessening the risk of accumulation. Their high protein-binding capacity in plasma, however, does not appear to limit their placental transfer. REFERENCES 1973, p. 281. 1. Morishima, H. O., Daniels, S. S., Fin7. Scanlon, J. W., Brown, W. V., Weiss, ster, M., Poppers, P. J., and James, J. B., and Alper, M. H.: NeurobeL. S.: Transmission of mepivacaine havioral responses of newborn infants hydrochloride (Carbocaine) across the after maternal anesthesia. Anesthesihuman placenta. Anesthesiology 27:147, ology 40:121, 1974. 1966. 8. Shnider, S. M. and Gildea, J.: Para2. Shnider, S. M. and Way, E. L.: The cervical block anesthesia in obstetrics. kinetics of transfer of lidocaine (XyloAmer. J. Obstet. Gynzec. 116:320, 1973. caine) across the human placenta. An9. Poppers, P. J. and Finster, M.: The esthesiology 299:944, 1968. use of prilocaine hydrochloride (Cita3. Finster, M., Morishima, H. O., Boyes, nest) for epidural analgesia in obstetR. N., and Covino, B. G.: The placenrics. Anesthesiology 29:1124, 1968. tal transfer of lidocaine and its uptake by fetal tissues. Anesthesiology 36:159, 10. Finster, M., Perel, J. M., Hinsvark, 1972. 0. N., and O'Brien, J. E.: Pharmacodynamics of 2-chloroprocaine (Nesa4. Morishima, H. O., Heymann, M. A., caine), an ester-type local anesthetic. Rudolph, A. M., and Barrett, C. T.: Fourth Europ. Congr. Anesth. AmsterToxicity of lidocaine in the fetal and dam, Excerpta Medica, 1974, No. 330, newborn lamb and its relationship to p. 189. asphyxia. Amer. J. Obstet. Gynec. 112: 11. Covino, B. G.: Comparative clini72, 1972. cal pharmacology of local anesthetic 5. Teramo, K. and Widholm, 0.: Studies of the effect of anesthetics on foetus. 1. agents. Anesthesiology 35:158, 1971. The effect of paracervical block with 12. Morishima, H. O., Finster, M., Pedersen, H., Boyes, R. N., and Covino, mepivacaine upon foetal acid-base values. Acta Obstet. Gynec. Scand. B. G.: Placental transfer and tissue distribution of etidocaine and lidocaine (Suppl.) 46:1, 1967. 6. Teramo, K.: Perinatal Risks of Parain guinea pigs. Annual Meeting, Amer. Soc. Anesth. Chicago, 1975, p. 83. cervical Block. In: Fetal Pharmacology, Boreus, L., editor. New York, Raven,
Vol. 52, No. 2, February 1976
![[Acute toxicity due to local anesthetics].](/assets/img/hold.png)
