MATERNAL AND FOETAL PLASMA CONCENTRATIONS OF BUPIVACAINE AFTER EPIDURAL BLOCK

Transcription

1 Brit. J. Anaesth. (1973), 45,49 MATERNAL AND FOETAL PLASMA CONCENTRATIONS OF BUPIVACAINE AFTER EPIDURAL BLOCK FELICITY REYNOLDS, R. L. HARGROVE AND J. B. WYMAN SUMMARY Plasma bupivacaine concentrations were measured in 70 mothers and babies (UV) at delivery, after continuous epidural block using bupivacaine 0.5 % alone in half the cases and bupivacaine 0.5% with adrenaline (5 /ig/ml) in the remainder. Patients received a total dose of mg of bupivacaine in 1- doses. The mean individual dose was about 47 mg and the mean duration of block 6 hours in both groups. The mean maternal plasma concentration was 0.54 ± 0.05 /xg/ml (SE) after bupivacaine alone and 0.36 ± 0.03 ^g/ml after bupivacaine with adrenaline. This difference is significant (P<0.01). The mean UV concentration was also reduced significantly in the presence of adrenaline, but in no instance even approached a dangerous level. The data suggest that bupivacaine 0.5 % plain used at such a dose rate may produce systemic toxicity in 5 % of mothers when the total dose exceeds 320 mg. Bupivacaine 0.5% without adrenaline is the most popular agent in Great Britain for continuous epidural analgesia in labour. A survey carried out by one of us (F.R.) recently for the Obstetric Anaesthetists' Association has shown that it is used in about 40% of epidural blocks. This popularity alone suggests that it provides satisfactory analgesia, but when large and numerous doses are necessary it may be more inclined to produce systemic toxicity dian bupivacaine with adrenaline. Hyman and Shnider (1971) measured maternal and neonatal blood concentrations of bupivacaine after lumbar epidural blocks with and without adrenaline, but doses given in the different groups were dissimilar, so the effect of adrenaline could not be extracted from the mean figures published. Reynolds and Taylor (1971) found that in continuous epidural analgesia bupivacaine 0.5% widi adrenaline 1:200,000 (5 /^g/ml) yielded lower maternal, and slightly but insignificantly higher neonatal, plasma concentrations than did bupivacaine alone in a series of 18 patients. Both these papers reported umbilical venous to maternal venous (UV: maternal) concentration ratios higher for bupivacaine with adrenaline than for bupivacaine alone. This phenomenon, if genuine, cannot readily be explained. This work set out to explore the effect of adrenaline on UV:maternal ratios in a bigger series, and the extent to which bupivacaine alone might be more toxic than bupivacaine with adrenaline and, most important, to estimate the likely maximum safe dose. METHOD Seventy patients in the Westminster Hospital Maternity Unit were studied and were selected purely upon their willingness to take part in the trial. Half the patients received plain bupivacaine 0.5% and the other hah* bupivacaine 0.5% wida adrenaline 5 /ig/ml. The two groups were matched for age (mean: plain bupivacaine 30 yr, bupivacaine with adrenaline 29 yr) and parity. The local analgesic solution was introduced through a catheter passed 3 cm into the epidural space in the L3-4 region either at induction of labour or during the first stage. The majority of patients were induced under the epidural block. Following induction, labour was accelerated by buccal oxytocin (Syntocinon) in graded doses and the second dose of bupivacaine was administered when the contractions were causing discomfort. Further doses were given whenever the patient felt the return of pain. The initial dose of bupivacaine was 50 mg in most cases and was given with the patient in the sitting position for induction. Subsequent doses were given with the patient either semi-recumbent or at about 45 to die horizontal. For a summary of dosage see table I. The difference between the doses in the two groups is not significant. Venous blood samples were taken from the mother FELICITY REYNOLDS, MJJ., FJ.A.R.CS., Department of Pharmacology, St Thomas's Hospital Medical School, London S.E.I; R. L. HARGROVE, M., B.S., FJ.A.R.C.S., J. B. WYMAN, MJ.E., F.F.A.R.CS., Magill Department of Anaesthetics, Westminster Hospital, London S.W.I.

2 50 BRITISH JOURNAL OF ANAESTHESIA TABLE I. Summary of epidural doses of bupivacaine. Bupivacaine alone Bupivacaine with adrenaline Mean±SE Range Mean±SE Range Total dose (mg) ± ± ^40 No. of doses 3.09 ± ± Individual dose(mg) 47.7 ± ± and from the umbilical cord at delivery, heparinized and centrifuged, and the plasma was stored at 4 C pending analysis. The bupivacaine concentrations in the plasma samples were estimated by the method of Reynolds and Beckett (1968), with minor modifications. RESULTS The duration of epidural blockade is shown in table II. The overall duration is similar in the two groups. The difference between the duration of action of bupivacaine (measured as the interval between two doses) in the two groups is not significant (using Student's (-test, t=\.52; 0.2>P>0.1), because of wide variability in dosage interval determined in part by the progress of labour. The figures suggest, however, that adrenaline might slightly prolong the duration of bupivacaine in this situation. Delivery was spontaneous in over half the cases in both groups (table HI). There were no signs of local analgesic toxicity in mothers or babies; Apgar scores were similar in the two groups, the lowest being 6 at 1 min in a single case in each group; all babies did well subsequently. A summary of plasma concentrations of bupivacaine is given in table IV. In this series adrenaline significantly reduced the bupivacaine concentrations in both mother and baby. In no case was the baby's concentration high, nor was it associated with depression. UV: maternal ratios were similar in the two groups, and were unrelated to the interval between the last dose of bupivacaine and delivery (LDI). Multiple regression analysis relating maternal plasma concentrations of bupivacaine to the total dose, the last dose, the LDI, the overall duration of block and the interval between the last two doses showed a significant correlation with total dose (P<0.001) and LDI (P<0.01) only, in the group given bupivacaine alone. In the group given bupivacaine with adrenaline maternal concentration was significantly related to total dose only (P<0.001). In TABLE II. Duration of epidural blockade. Bupivacaine alone Bupivacaine -+- adrenaline Mean±SE Mean ± SB (min) Range (min) Range Total duration from first dose to delivery 366± ± Interval between final dose and delivery (IX) I) 78.3 ± ± Duration of action (interval between 2 doses) 139± ±11.0 Spontaneous Forceps Caesarean section TABLE III. Type of delivery. Bupivacaine Bupivacaine alone +adrenaline TABLE IV. Plasma concentrations of bupivacaine at delivery. Maternal concentrations Bupivacaine Bupivacaine alone +adrenaline P 35 3! Mean±SE 0.54 ± ±0.03 <0.01 Range Baby's concentration (UV) dig/ml) Mean±SE 0.14± ±0.009 <0.01 Range Mean LTV: maternal ratio both cases the LDI was more significandy related to the logarithm of die maternal concentration, as would be expected. Separate linear regressions were merefore used to define these relationships. Figure 1 relates plasma concentration to total dose of bupivacaine, the correlation being higher after bupivacaine widi adrenaline, but the regression line being higher and the slope steeper after bupivacaine alone. Figure 2 relates plasma concentration, on a logarithmic scale, to LDI, showing a more significant correlation after bupivacaine alone (P<0.001) than after bupivacaine with adrenaline (P<0.02).

3 CONCENTRATIONS OF BUPIVACAINE AFTER EPIDURAL BLOCK c;.o Ic: o c: total dose, mq a total dose, mq. FIG. 1. Maternal plasma concentrations of bupivacaine at delivery, related to total epidural doses (a) in patients given bupivacaine alone and (b) in patients given bupivacaine with adrenaline. Dotted lines represent 95% confidence limits. 500 DISCUSSION So far as the baby is concerned, bupivacaine is confirmed as far safer than other local analgesic drugs that have been investigated for continuous epidural analgesia (Shnider and Way, 1968; Morishima et al., 1966). The highest recorded UV concentration in the series, 0.48 /*g/ml, was found in the baby of a mother who had received 500 mg of bupivacaine without adrenaline. Such a concentration has never been found dangerous. The addition of adrenaline in this series affected the UV concentration of bupivacaine only so far as it affected maternal concentration; contrary to earlier findings (Reynolds and Taylor, 1971; Hyman and Shnider, 1971), the UV: maternal ratio was similar in the two groups, as would be expected, and was not influenced by the interval between dosage and delivery, suggesting that there was sufficient time for equilibration of bupivacaine across the placenta. The effect of adrenaline on maternal plasma concentrations of bupivacaine during continuous epidural blockade will depend both upon the dosage of bupivacaine and on whether adrenaline prolongs its action and so necessitates less frequent dosage. That the effect of adrenaline is dependent upon the dose of bupivacaine is borne out by comparison of figures la and lb. It will be seen that the two regression lines diverge from one another, and whereas adrenaline appears to reduce plasma level only slightly at low dosage, it makes a more marked difference at high doses. In any circumstances the peak plasma level will be less marked after adrenaline (Reynolds and Taylor, 1971) and hence time of sampling will be less important. In the circumstances of the present trial, adrenaline reduced plasma concentrations to a degree not solely accounted for by a reduction in total dosage, since the regression lines in figures la and lb are not coincident. The overall effect is less than in the more vascular area of paracervical block (Hollme'n, Ojala and Korhonen, 1969; Hollmdn, Korhonen and Ojala, 1969; Beazley, Taylor and Reynolds, 1972). In the present series, in patients given solutions containing adrenaline, plasma bupivacaine levels were more dependent on total dosage

4 52 BRITISH JOURNAL OF ANAESTHESIA I I! j-o KM time after last dose of bupivocaine, minutes. FIG. 2. Maternal plasma concentrations of bupivacaine at delivery, related to the rinv interval from the last epidural dose, (a) in patients given bupivacaine alone and (b) in patients given bupivacaine with adrenaline. Dotted lines represent 95% confidence limits. Plasma concentration is shown on a logarithmic scale. and less on sampling Hmp than in the group not given adrenaline. From the data it seems likely that tbe maternal concentration (MC) increases approximately linearly with total dose (x), and that during the time (t) after the last dose it decreases exponentially. This sort of dual relationship can be represented by the mathematical model MC=(a+bx)e- ct +an error due to residual variation A model of this form implies that for a given value of t the maternal concentration is related linearly with total dose, supposing a constant dose rate. In fact, most of the dose rates for the bupivacaine-alone group were between 0.20 and 0.73 mg/min, although two values were considerably higher (1.22 and 2.23 mg/min respectively). The median dose rate was 0.45 mg/min. The dose rate for the bupivacaine with adrenaline group tended to be lower, varying between 0.14 and 0.75 mg/min, with a median dose rate of 0.35 mg/min. Over this range maternal plasma concentration did not appear to be dependent on dose rate in either group. The model was fitted separately to the data from the two groups (excluding the one patient in group (b) whose LDI was 345 min see figure 2b), by choosing the values of the constants a, b and c using the Method of Least Squares. This assumes a constant value for c, the rate of change of plasma concentration with time, whereas individuals are known to vary in this respect. Thus predictions made from the model are only approximate, but may provide useful clinical guidelines. To assess whether a particular procedure is safe, it is useful to estimate the mayi'muro maternal concentration which may occur. Assuming that this mayimiim concentration occurs min after nhministradon of the last dose, as suggested by Hyman and Shnider (1971), we can use the fitted model, widi t fixed at min, to estimate this hypothetical mnyjmiim. At a plasma level of 1.6 y"g/ml it is likely that mild symptoms of systemic toxicity may occur (Reynolds, 1971). The model predicts that for patients receiving bupivacaine alone the maternal concentration will, on average, reach such a level when the total dose reaches 440 mg. (At a constant dose rate of 0.4 mg/min this implies a block duration of about 18 hours.) However, some maternal concentrations will exceed die average considerably, and after a total dose of 320 mg (or a duration of about 13 hours) in about 5% of individuals the concentration will exceed 1.6 /ig/ml (i.e. a 5% risk for each individual). For patients receiving bupivacaine widi adrenaline the fined model suggests that the average concentration (at t= min) will reach 1.6 ^g/ml when the total dose reaches about 650 mg (implying a block duration of about 27 hours at 0.4 mg/min), while 5% of individuals will exceed 1.6 /ig/ml when the total dose reaches 505 mg (a duration of about 21 hours). These total doses are considerably greater than any in our sample, so diey must be regarded with some caution. Larger doses than 505 mg have been given widi impunity, but spread over more than 20 hours (Reynolds and Taylor, 1970). This work dierefore suggests that when bupivacaine 0.5% is given by intermittent epidural injections of doses of about 50 mg to relieve pain during labour, bupivacaine without adrenaline may safely

5 CONCENTRATIONS OF BUPIVACAINE AFTER EPIDURAL BLOCK 53 be given in a total dose of about 320 mg. Moreover, it is normally possible to keep well within this limit for plain bupivacaine if 0.25% is used, thereby avoiding the added risk of adrenaline. ACKNOWLEDGEMENTS We are most grateful to Miss Joyce Carter and Mr A. Swan of the Department of P.lininil Epidemiology and Social Medicine of St Thomas's Hospital for statistical help. REFERENCES Beazley, J. M., Taylor, G., and Reynolds, F. (1972). Placenta] transfer of bupivacaine after paracervical block. Obstet. and Gynec, 39, 2. Hollmen, A., Korhonen, M., and Ojala, A. (1969). Bupivacaine in paracervical block: plasma levels and changes in maternal and foetal acid-base balance. Brit. J. Anaesth., 41, 603. Ojala, A., and Korhonen, M. (1969). Paracervical blockade with Marcaine/adrenaline: plasma concentration of Marcaine and foetal acid-base balance. Acta anaesth. scand., 13, 1. Hyman, M. D., and Shnider, S. M. (1971). Maternal and neonatal blood concentrations of bupivacaine associated with obstetrical conduction anesthesia. Anesthesiology, 33, 81. Morishima, H. O., Daniel, S. S., Finster, M., Poppers, P. J., and James, L. S. (1966). Transmission of mepivacaine hydrochloride (Carbocaine) across the human placenta. Anesthesiology, 27, 147. Reynolds, F. (1971). A comparison of the potential toxicity of bupivacaine, lignocaine and mepivacaine during epidural blockade for surgery. Brit. J. Anaefth., 43, 567. Beckett, A. H. (1968). The determination of bupivacaine, lignocaine and mepivacaine in human blood. J. Pharm. Pharmacol, 20, 704. Taylor, G. (1970). Maternal and neonatal concentrations of bupivacaine: a comparison with lignocaine during continuous extradural analgesia. Anaesthesia, 25, 14. (1971). Plasma concentration of bupivacaine during continuous epidural analgesia in labour: the effect of adrenaline. Brit. J. Anaesth., 43, 436. Shnider, S. M., and Way, E. L. (1968). Plasma levels of lidocaine (Xylocaine) in mother and newborn following obstetrical conduction anesthesia. Anesthesiology, 29, 951. CORRESPONDENCE FLUORIDE NUMBERS Sir, During the past decade, I have offered to provide a service of plasmacholinesterase determinations and dibucaine and fluoride number determinations in the United States. Therefore, I read the article of Whittaker and Vickers (Brit J. Anaesth. (1970), 42, 16) with great interest. In many regards, we share their experience with the cholinesterase laboratories reported in this interesting article but with one exception. Among 113 patients referred to the laboratory for study of the cause of prolonged apnoea, we were unable to identify beyond any doubt, any fluoride-resistant heterozygote or homozygote while we observed the expected incidence of dibucaine - resistant, silent and usual genotypes. Initially we utilized the technique of Harris and Whittaker (Nature (1961), 191, 496), which employs sodium fluoride in a concentration of 50 /JM at 25 *C, with the modification that we used 37 C as utilized in Kalow's ultraviolet method for the determination of dibucaine number in our laboratory. We observed that this temperature change markedly shifted the fluoride numbers but altered the dibucaine numbers very little. This created difficulty in the identification of the exact genotype of the individual. Therefore, currently we use 37*C temperature and a concentration of 2.6X ' molar concentration of sodium fluoride which gives 75% inhibition jn normal plasma for the differentiatioa of fluoride-resistant phenotypes. In this way, we feel, that we increase the sensitivity of the method by extending the range of measurements and thereby facilitating the recognition of abnormal values. The overlap in FN values between various phenotypes is great. E,uE,u=58-68,E 1 u Eif=5O-55, E,u E,d=42-55, E,d Eif=31-39, E,f E,f=34-35, E,d Eid= According to the original recommendation a normal dibucaine number in combination with a low FN is the evidence for the existence of another phenotype. Unfortunately, we were unable to demonstrate by enzyme inhibition studies the existence of an individual with an abnormal fluoride inhibition curve in the presence of a normal dibucaine inhibition curve which would be de facto evidence for the existence of atypical fluorideresistant gene. As shown in table I, even dibucaineresistanc heterozygotes and homozygotes have an abnormal fluoride inhibition which in 113 patients showed a very close correlation as shown in the equation in table I. TABLE I. Correlation at DN with FN in 56 individuals with various plasma cholinesterase genotypes. Apnoeic patients (25) Relatives (31) Genotypes DN FN» DN FN E,u E,u Eiu Eid E,d Eid 76.2** *« FN was determined at 37 *C with 260 /<M concentration. Mean values. FN=0.5 (DN)+37 In order to eliminate further erroneous identification of fluoride-resistant phenotypes, we recommend the use of 260 /im concentrations of NaF at 37 C, which gives 75% inhibition in normal homozygous plasma, 65% inhibition in atypical-normal dibucaine-resistant heterozygous plasma, and 46% inhibition in the plasma of atypical dibucaineresistant homozygotes. Values which are lower by two standard deviations for FN in the presence of DN in the normal range surely indicate the presence of a fluorideresistant gene. In difficult cases, we also recommend determining the pi-inhibitory curve in each suspected fluoride-resistant plasma sample and to determine the Iio or Ire values for NaF inhibition in place of % inhibition caused by a single concentration of the inhibitor. Dr Whittaker was kind enough to offer to send us plasma samples of some known fluoride-resistant homozygotes and heterozygotes for further enzyme kinetic studies. We would also like to respectfully ask other investigators who have access to individuals with fluorideresistant type of phenotype to contact us and kindly arrange for sending samples to our facilities for further studies. In this way we will be able to setde this controversy. We invite the unbiased comments of all investigators working in the field of pharmacogenetics and biochemistry to express their opinion on this topic. ELEMER K. ZSIGMOND Arm Arbor