Br. J. Amesth. (1975), 47,56
EVALUATION OF THE TOXIOTY OF LOCAL ANAESTHETIC AGENTS IN MAN D. B. SCOTT SUMMARY
Etidocaine is a new long-acting local anaesthetic agent, similar in many respects to bupivacaine (Adams, Kronberg and Takman, 1972). Both drugs possess an intrinsic anaesthetic potency which is four times greater than that of lignocaine and a duration of local anaesthetic action which is two to four times longer than that of lignocaine. Etidocaine and bupivacaine are also four times more toxic than lignocaine when administered by rapid intravenous injection in animals. However, bupivacaine appears to be twice as toxic as etidocaine following subcutaneous administration in rats. Pharmacokinetic studies involving the intravenous administration of 25-50 mg of both agents revealed a more rapid rate of disappearance of etidocaine from the blood, which suggests a larger volume of distribution (Scott, Jebson and Boyes, 1973), and a significantly smaller venous plasma concentration of etidocaine as compared with bupivacaine following the extradural administration of equal doses of both drugs has been reported (Lund, Cwik and Pagdanganan, 1973). On the other hand, preliminary clinical results indicate that etidocaine must be given in doses 1.5-2.0 times greater than bupivacaine to achieve similar anaesthetic effects for extradural procedures (Lund, Cwik and Pagdanganan, 1973; Bridenbaugh et al., 1973). On the basis of these data, it appeared important to D. B. SCOTT, MJJ., M.R.C.P.E., F.F.AJI.C.S., Department of
Anaesthetics, Royal Infirmary, Edinburgh.
determine the relative toxicity of these two agents in man in order to compare their therapeutic ratios. METHODS
Five medically qualified subjects volunteered to participate in three separate series of experiments involving the intravenous infusion of various local anaesthetic agents. The subjects were monitored continuously using an electrocardiograph and an electroencephalograph. Frequent determinations of arterial pressure and pulse rate were made and venous blood samples from the arm opposite to the one being infused were taken at predetermined intervals during and following the drug infusion. Venous plasma drug concentrations were determined by gas chromatography. Subjective and objective evidence of toxicity were noted by the subject and/or the observer. The subjective symptoms consisted of circumoral numbness and numbness of the tongue, light-headedness and disorientation. Objective signs of toxicity were muscular twitching, slurred speech and nystagmus. The subjective toxic symptoms were graded on a 0, 1 + , 2 + , 3 + basis by the subject himself, while the objective signs were graded in a similar fashion by the observer. In the initial study, bupivacaine and etidocaine were administered intravenously at a rate of 10 mg/min until such time as a maximum dose of 125 mg had been given or until symptoms or signs
Downloaded from http://bja.oxfordjournals.org/ at Frankfurt Univesity Library on September 9, 2014
Etidocaine given by intravenous infusion has been compared, using a double-blind technique, with bupivacaine and lignocaine in respect of toxic symptoms and signs. The degree of toxicity is affected considerably by the rate of drug infusion. At 10 mg/min subjects could tolerate twice the dose of etidocaine as bupivacaine. Tolerance to etidocaine was less at 20 mg/min but still compared favourably with bupivacaine at 10 mg/min. Considering the difference in potency of the two agents it was considered that the therapeutic ratios would not be substantially different. Lignocaine at 20 mg/min was better tolerated than etidocaine. Venous plasma concentration during these experiments showed a more rapid decrease in the case of etidocaine compared with bupivacaine, but the concentrations were unhelpful in predicting the toxic effects. Similarly electroencephalography revealed no abnormalities in spite of marked subjective and objective signs of toxicity.
57
TOXICTTY OF LOCAL ANAESTHETIC AGENTS
RESULTS
Administration of bupivacaine and etidocaine (10 mg/min). In two subjects the infusion of bupivacaine was terminated before the administration of the predetermined maximum dose of 125 mg because of the appearance of severe objective signs of toxicity. The infusion was stopped after the administration of 80 mg in one subject and after 105 mg in the second subject. The average total dose for the bupivacaine group was 112 mg. All five individuals tolerated the infusion of 125 mg of etidocaine. A comparison of the severity of signs and symptoms of toxicity is presented in table I. The major difference between the two agents concerned the frequency and severity of lightheadedness and muscular twitching. Four of the five sub-
jects receiving bupivacaine showed signs of muscle twitching and reported a moderate to marked feeling of lightheadedness. In two subjects muscle twitching was considered sufficiendy severe to terminate the infusion. No objective signs of toxicity occurred in the etidocaine group. Lightheadedness of mild to moderate degree occurred in three subjects. Numbness of the tongue and perioral tissues was observed during nine of the ten infusion periods. This probably is a reflection of the vascularity of these tissues resulting in a sufficiently high concentration of local anaesthetic agents being deposited at the nerve endings to cause localized numbness. Intravenous infusion of etidocaine and lignocaine (20 mg/min). The infusion of etidocaine was terminated following the administration of 135 to 220 mg (mean dose = 161 mg). However, all subjects tolerated 250 mg of lignocaine. Table II shows the frequency and severity of toxic symptoms and signs in the two groups. Treatment with etidocaine resulted in moderate to marked signs of muscular twitching and symptoms of lightheadedness in all subjects. Disorientation and slurred speech were observed commonly. Lightheadedness also occurred in all subjects treated with lignocaine. However, the severity of this symptom was less marked than during the etidocaine infusion. Circumoral numbness was again a common occurrence in both groups. Intravenous infusion of etidocaine (10 mg/min). In the final study, etidocaine alone was administered intravenously at a rate of 10 mg/min to a total dose of 250 mg or until severe signs of toxicity were observed. Two subjects tolerated the entire 250-mg dose. The infusion was terminated at 245 mg in two subjects and at 190 mg in the fifth
TABLE I. Frequency and severity of subjective and objective symptoms of c.n.s. toxicity following intravenous administration of etidocaine and bupivacaine {10 mglmin). Bupivacaine Subject number
Etidocaine Subject number 1
2
3
4
5
1
2
3
4
5
Dose received (mg) 125 T .ighthffld^n
EVALUATION OF THE TOXIOTY OF LOCAL ANAESTHETIC AGENTS IN MAN D. B. SCOTT SUMMARY
Etidocaine is a new long-acting local anaesthetic agent, similar in many respects to bupivacaine (Adams, Kronberg and Takman, 1972). Both drugs possess an intrinsic anaesthetic potency which is four times greater than that of lignocaine and a duration of local anaesthetic action which is two to four times longer than that of lignocaine. Etidocaine and bupivacaine are also four times more toxic than lignocaine when administered by rapid intravenous injection in animals. However, bupivacaine appears to be twice as toxic as etidocaine following subcutaneous administration in rats. Pharmacokinetic studies involving the intravenous administration of 25-50 mg of both agents revealed a more rapid rate of disappearance of etidocaine from the blood, which suggests a larger volume of distribution (Scott, Jebson and Boyes, 1973), and a significantly smaller venous plasma concentration of etidocaine as compared with bupivacaine following the extradural administration of equal doses of both drugs has been reported (Lund, Cwik and Pagdanganan, 1973). On the other hand, preliminary clinical results indicate that etidocaine must be given in doses 1.5-2.0 times greater than bupivacaine to achieve similar anaesthetic effects for extradural procedures (Lund, Cwik and Pagdanganan, 1973; Bridenbaugh et al., 1973). On the basis of these data, it appeared important to D. B. SCOTT, MJJ., M.R.C.P.E., F.F.AJI.C.S., Department of
Anaesthetics, Royal Infirmary, Edinburgh.
determine the relative toxicity of these two agents in man in order to compare their therapeutic ratios. METHODS
Five medically qualified subjects volunteered to participate in three separate series of experiments involving the intravenous infusion of various local anaesthetic agents. The subjects were monitored continuously using an electrocardiograph and an electroencephalograph. Frequent determinations of arterial pressure and pulse rate were made and venous blood samples from the arm opposite to the one being infused were taken at predetermined intervals during and following the drug infusion. Venous plasma drug concentrations were determined by gas chromatography. Subjective and objective evidence of toxicity were noted by the subject and/or the observer. The subjective symptoms consisted of circumoral numbness and numbness of the tongue, light-headedness and disorientation. Objective signs of toxicity were muscular twitching, slurred speech and nystagmus. The subjective toxic symptoms were graded on a 0, 1 + , 2 + , 3 + basis by the subject himself, while the objective signs were graded in a similar fashion by the observer. In the initial study, bupivacaine and etidocaine were administered intravenously at a rate of 10 mg/min until such time as a maximum dose of 125 mg had been given or until symptoms or signs
Downloaded from http://bja.oxfordjournals.org/ at Frankfurt Univesity Library on September 9, 2014
Etidocaine given by intravenous infusion has been compared, using a double-blind technique, with bupivacaine and lignocaine in respect of toxic symptoms and signs. The degree of toxicity is affected considerably by the rate of drug infusion. At 10 mg/min subjects could tolerate twice the dose of etidocaine as bupivacaine. Tolerance to etidocaine was less at 20 mg/min but still compared favourably with bupivacaine at 10 mg/min. Considering the difference in potency of the two agents it was considered that the therapeutic ratios would not be substantially different. Lignocaine at 20 mg/min was better tolerated than etidocaine. Venous plasma concentration during these experiments showed a more rapid decrease in the case of etidocaine compared with bupivacaine, but the concentrations were unhelpful in predicting the toxic effects. Similarly electroencephalography revealed no abnormalities in spite of marked subjective and objective signs of toxicity.
57
TOXICTTY OF LOCAL ANAESTHETIC AGENTS
RESULTS
Administration of bupivacaine and etidocaine (10 mg/min). In two subjects the infusion of bupivacaine was terminated before the administration of the predetermined maximum dose of 125 mg because of the appearance of severe objective signs of toxicity. The infusion was stopped after the administration of 80 mg in one subject and after 105 mg in the second subject. The average total dose for the bupivacaine group was 112 mg. All five individuals tolerated the infusion of 125 mg of etidocaine. A comparison of the severity of signs and symptoms of toxicity is presented in table I. The major difference between the two agents concerned the frequency and severity of lightheadedness and muscular twitching. Four of the five sub-
jects receiving bupivacaine showed signs of muscle twitching and reported a moderate to marked feeling of lightheadedness. In two subjects muscle twitching was considered sufficiendy severe to terminate the infusion. No objective signs of toxicity occurred in the etidocaine group. Lightheadedness of mild to moderate degree occurred in three subjects. Numbness of the tongue and perioral tissues was observed during nine of the ten infusion periods. This probably is a reflection of the vascularity of these tissues resulting in a sufficiently high concentration of local anaesthetic agents being deposited at the nerve endings to cause localized numbness. Intravenous infusion of etidocaine and lignocaine (20 mg/min). The infusion of etidocaine was terminated following the administration of 135 to 220 mg (mean dose = 161 mg). However, all subjects tolerated 250 mg of lignocaine. Table II shows the frequency and severity of toxic symptoms and signs in the two groups. Treatment with etidocaine resulted in moderate to marked signs of muscular twitching and symptoms of lightheadedness in all subjects. Disorientation and slurred speech were observed commonly. Lightheadedness also occurred in all subjects treated with lignocaine. However, the severity of this symptom was less marked than during the etidocaine infusion. Circumoral numbness was again a common occurrence in both groups. Intravenous infusion of etidocaine (10 mg/min). In the final study, etidocaine alone was administered intravenously at a rate of 10 mg/min to a total dose of 250 mg or until severe signs of toxicity were observed. Two subjects tolerated the entire 250-mg dose. The infusion was terminated at 245 mg in two subjects and at 190 mg in the fifth
TABLE I. Frequency and severity of subjective and objective symptoms of c.n.s. toxicity following intravenous administration of etidocaine and bupivacaine {10 mglmin). Bupivacaine Subject number
Etidocaine Subject number 1
2
3
4
5
1
2
3
4
5
Dose received (mg) 125 T .ighthffld^n
