Brit. J. Anaesth.

(1966), 38, 596

DOSAGE OF LIGNOCAINE IN EPIDURAL BLOCK IN RELATION TO

TOXICITY
BY
D. P. BRAID AND D. B. SCOTT
Department of Anaesthetics, Royal Infirmary of Edinburgh

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SUMMARY

The plasma concentrations reached following the epidural injection of 200, 400, 500,
600 and 700 mg of lignocaine have been determined. From these results, a linear
relationship between dosage and plasma concentration was established. Plasma con-
centrations following rapid injection (400 mg in 15 seconds) were determined and
found to be slightly higher than slower (60 seconds) injection. Statistical analysis of
data has allowed a preliminary evaluation of the effects of weight and age upon the
plasma concentrations of lignocaine. Recommendations on the dosage of lignocaine
in epidural block in regard to toxicity are made, and the effects of the various factors
affecting the absorption and elimination of local anaesthetic agents are assessed.

Epidural block often requires a relatively large
quantity of local analgesic drug and, with ligno-
caine, the amount may exceed the maximum dose
generally recommended. The Scandinavian
Pharmacopoeia Council (1957) laid down that
the maximum dose for lignocaine should be 200
mg plain or 500 mg with adrenaline, and these
figures have been widely accepted (Deacock and
Simpson, 1964). Recommendations of this type,
however, are only meaningful if the conditions
applying to the administration are closely defined.
Thus, in some circumstances, 200 mg of plain
lignocaine could be quite inadequate, while in
others, 500 mg with adrenaline might well be
dangerous.
The systemic toxicity of a local analgesic
depends upon the level of the drug reached in
the blood following absorption from the site of
injection. Measurement of the plasma concentra-
tion is, therefore, of great value in determining
the relative importance of the various factors
which may affect toxicity. Among such factors
the most important are:
(a) dose of local analgesic;
(b) site of injection;
(c) drug used;
(d) concentration of solution;
(e) addition of adrenaline;
(f) speed of injection;
(g) body weight and age of patient;
(h) rate of elimination.
In addition, the effect of a concomitant general
anaesthetic must be considered as this will raise
the threshold of plasma concentration at which
toxic manifestations become apparent (Bromage
and Robson, 1961).
Previous work has shown that epidural block
gives significantly lower plasma levels than inter-
costal block. In addition, the effects of adding
adrenaline, altering the concentration of solution,
and changing the drug injected have been des-
cribed (Braid and Scott, 1965). Those studies
were carried out using the same dose of local
analgesic (400 mg). Before the results can be
extrapolated to other dosages, it is necessary to
establish that a linear relationship between dosage
and plasma level exists. Considering the complex
way in which local analgesics are absorbed and
eliminated, it cannot be assumed, for example,
that doubling the dose will double the plasma
concentrations. The present work was undertaken
to determine the effect of various doses upon the
plasma levels found during epidural block. In
addition, the effect of rapid injection was ob-
served and, from all the data so far obtained, an
attempt has been made to assess the importance
of body weight and age.
Thus, in relation to epidural block with ligno-
caine, all the factors (with the exception of rate
of elimination) which the administrator can either
control or make allowances for, have been investi-
gated and their relative importance assessed.
DOSAGE OF LIGNOCAINE IN EPIDURAL BLOCK 597

METHOD TABLE I
Number of patients in each group, the corresponding
Patients. Sixty-five patients were investigated. dose of lignocaine and period of injection. The series
All were adult females undergoing major gynae- of 15 patients receiving 400 mg lignocaine over 60
cological surgery and all received a light general seconds has been reported before (Braid and Scott,
1965).
anaesthetic in addition to an epidural block. No
form of selection was used in allocating patients Vol. of Period of
to the various dosage groups, with the exception No. of Dose 2% sol. injection
panents (mg) (ml) (sec)
that the very old and infirm were not included

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11 200 10 30
in the highest dosage group. 15 400 20 60
Drug. The analgesic solution employed in 12 400 20 15
every patient was 2 per cent plain lignocaine. 3 500 25 75
10 600 30 90
Epidural block. The epidural blocks were per- 9 700 35 105
formed in the second or third lumbar inter-
vertebral space using the loss-of-resistance lowed by nitrous oxide/oxygen, was given to all
technique, a syringe being filled with sterile patients. In most cases this was given subsequent
saline to identify the space. The space identified, to the epidural block, but in the series receiving
the chosen solution was injected. rapid injection, it preceded the block to avoid
Rate of injection. In the majority of cases the any discomfort arising from the fast instillation
injection was made at a rate of 20 ml/min, but of local anaesthetic into the epidural space.
in one group of 12 patients receiving 20 ml of Sampling and estimations. The method of
solution (400 mg), the injection was made over sampling, the analytic technique and its accuracy
15 seconds. have been described in a previous paper (Braid
Dosage. The dose of lignocaine was varied and Scott, 1965).
from 200 mg to 700 mg, i.e. from 10 ml of solu-
tion to 35 ml. TREATMENT OF RESULTS
The number of patients in each group, the By taking six samples from each patient it is
dose of lignocaine and the period of injection are possible to plot a curve of the rise and fall of
given in table I. the plasma concentration following injection of
General anaesthesia. A light general anaes- the drug. To obtain a representative curve for a
thetic, consisting of thiopentone (400 mg) fol- group of subjects it is desirable to calculate mean

TABLE II
Plasma concentrations of lignocaine following epidural injection of 200, 500, 600 and 700 mg.
The results for 400 mg have been reported previously (Braid and Scott, 1965) and are given
for comparison.
EPIDURAL BLOCK
2 per cent plain lignocaine
Dose (mg) Plasma concentration in /<g/ml with standard deviation of mean
patients Mean max.
(n) 5 min 10 min 15 min 20 min 30 min 60 min value
200 2.21 2.49 2.76 2.59 2.13 1.73 3.30
(n = ll) ±0.18 ±0.23 ±0.18 ±0.17 ±0.19 ±0.13 ±0.07
400 2.62 3.31 3.48 3.75 3.46 2.75 4.09
(n=15) ±0.32 ±0.36 ±0.27 ±0.27 ±0.20 ±0.09 ±0.33
500 4.44 5.33 5.34 5.75 4.99 3.85 6.24
(n = 8) ±0.43 ±0.45 ±0.47 ±0.41 ±0.34 ±0.27 ±0.42
600 4.35 5.74 6.69 6.11 5.44 4.48 7.34
(n = 10 ±0.40 ±0.46 + 0.31 ±0.45 ±0.36 ±0.27 ±0.37
700 4.20 6.30 6.80 7.28 6.28 4.80 7.43
(n = 9) ±0.29 ±0.46 ±0.37 ±0.24 ±0.32 ±0.35 ±0.23
598 BRITISH JOURNAL OF ANAESTHESIA

values. The standard deviations are also given for

each mean concentration. It is also of value in
the comparison of the various series to compare
the maYimum mean concentrations with no res-
pect to time of sampling. Such values are also
given in the results.

RESULTS

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Alteration of dose. The results from the five 7OOmg
groups in which the d6se of lignocaine was in- 6OOmg
creased from 200 mg to 700 mg are given in
table II and presented graphically in figure 1. In
figure 2, the maximum values have been plotted
against the dose of lignocaine and the regression
line shown. These results indicate that a linear
relationship between dosage and plasma concen-
trations exists.
Rate of injection. In a series of 12 patients, the
epidural injection of 20 ml of 2 per cent plain
solution (400 mg) was made in 15 seconds. The
relevant results are given in table HI and pre-
sented graphically in figure 3. For comparison, IO 2O 3O 4O SO 6O MIN
the results of epidural injection of the same solu- FIG. 1
tion in another series of patients over a period Curves of the mean plasma concentrations of ligno-
of 60 seconds are given. caine at the various dose levels following epidural
block.
It will be seen that rapid injection does give
slightly higher levels than slow injection, although of body weight and age upon the plasma con-
the difference is only statistically significant at centration. The largest group receiving the same
two of the time intervals. dosage was that receiving 400 mg of plain ligno-
Body weight and age. From our accumulated caine. Scatter diagrams of patients receiving this
data, we have attempted to assess the importance dosage (figs. 4 and 5) show that, in spite of wide
TABLE III
Comparison of plasma concentrations following epidural injection of 400 mg of lignocaine
given over 60 seconds and over 15 seconds. The statistical analysis was based on the Student
"t" test.
EPmURAL BLOCK
20 ml of 2 per cent plain lignocaine
Speed of
injection Plasma concentration in ^g/ml with standard deviation of mean
patients Mean max.
(n) 5 min 10 min 15 min 20 min 30 min 60 min value
60 sec 2.62 3.31 3.48 3.75 3.46 2.75 4.09
(n=15) ±0.32 ±0.36 ±0.27 ±0.27 ±0.20 ±0.09 ±0.33
15 sec 2.23 3.86 4.25 4.77 4.33 2.95 5.11
(n=12) ±0.47 ±0.40 ±0.26 ±0.26 ±0.32 ±0.38 ±0.23
"t" value 0.71 1.01 1.99 2.71 2.36 0.51 2.49
Level of
signifi- NS NS NS 0.05>P>0.01 0.05>P>0.01 NS 0.05>P>0.01
cance (P)
NS = Not significant.
DOSAGE OF UGNOCAINE IN EPIDURAL BLOCK 599

variation in both weight and age, neither factor MAX. PLASMA

seemed to have more than a slight effect upon CONC. jiqfrti
the plasma concentration. Analysis of all groups 8-
indicates that the maximum plasma concentration
has an inverse relationship with body weight and
a direct relationship with age, but both relation-
Max, cone.

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Mglm\
lOl

4O 5O 6O 7O 8O 9OKG
WEIGHT
FIG. 4
Scatter diagram relating maximum plasma concentra-
Regression Line: tion in all patients receiving 400 mg of lignocaine and
body weight.
y=l-O2+O-OO95X

ships are of a minor order compared with that

between plasma concentration and dosage.
Further work is required before this problem is
2OO 4OO 6OO 8OOmg finally resolved, but from this preliminary exam-
FIG. 2 ination of our results, it would appear that body
Maximum plasma concentrations of lignocaine in all weight and age have only slight effects upon the
patients plotted against dosage. The regression line plasma concentrations of lignocaine in adult
and its formula are shown. The correlation coefficient females.
r=0.84 is highly significant (t = 13.1, P<0.001).

Injection Tine 15 second*

D •• 6O •

IO 2O 3O 4O 5O
.J5i*c injection

oOtec injection

UOmin.

FIG. 3
I
MEAN MAX.
CONC

Plasma concentrations of lignocaine following rapid epidural injection (15 sec) of 400 mg
compared with injection over 60 sec.
600
•dAX. PLASMA
CONC. yqfmT
a
2
4O
FIG.
Scatter diagram relating TTmvimiim plasma concentration in all
patients receiving 400 mg of lignocaine and age.
DISCUSSION
Dosage in lumber epidural block is usually
determined by the extent of the required area of
analgesia. If a high spread is required (for
example, for induced hypotension), then doses of
lignocaine up to 600 mg may be required. It is
important, therefore, that the possibility of
generalized toxicity be borne in mind.
Foldes and colleagues (1960) found that, in
conscious patients, systemic toxicity occurred
with lignocaine when the plasma level reached
5 (j.g/ml. This was confirmed by Englesson and
associates (1962) who also found a similar result
with prilocaine. Considerably higher plasma con-
centrations than this may be necessary for toxic
effects to become serious.
Bromage and Robson (1961) found that, when
lignocaine was given to anaesthetized patients,
overt toxicity was not seen until the plasma level
reached 10 [Ag/ml and then it usually took the
form of cardiovascular depression. Whether this
is a true elevation of the toxic threshold, or is
due to suppression of the central nervous excita-
tion, it is not possible to say, but there is little
doubt that the dosage of lignocaine can be in-
creased without apparent harm to the patient if
general anaesthesia is used. From our results, it
would appear that a dosage of 400 mg would be
unlikely to give rise to more than slight symptoms
of toxicity in conscious patients, and we would
BRITISH JOURNAL OF ANAESTHESIA
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6O ~5b YEARS
5
consider this to be the mayimnm dose in these
circumstances. This is borne out by the experi-
ence of Bonica and associates (1957), who
reported 3,637 epidural blocks in conscious
patients. They found a low incidence of toxic
effects, which were mild in 212 (6 per cent) and
severe (with convulsions) in only 8 (0.2 per cent)
using lignocaine with adrenaline in doses of up
to 500 mg. In spite of the rarity of serious toxicity
in this dose range, the anaesthetist must still be
aware of the possibility and be able to deal with
it efficiently and expeditiously.
The administration of concomitant general
anaesthesia will allow a further increase in
dosage, plasma levels of 10 [ig/ml being unlikely
to occur with dosage less than 600 mg of plain
lignocaine. In our experience of over 2,000 epi-
dural blocks, combined with general anaesthesia,
overt toxicity has never been seen although the
dosage has been in the range of 400-600 mg of
plain lignocaine. The use of larger doses than
600 mg we would consider to be quite unneces-
sary in clinical practice.
That we were unable to show a much closer
relationship between body weight and plasma
concentrations may be due to the fact that all
cur patients were adult females. Such patients
differ from each other in body weight more in
regard to the degree of obesity than in lean body
mass. As far as the absorption, distribution and
elimination of these drugs are concerned, the lean
DOSAGE OF LIGNOCAINE IN EPIDURAL BLOCK 601

body mass is probably of much greater import- Adrenaline does increase the intensity of block
ance than total body weight, for it is unlikely that and lengthens its duration (Bromage et al., 1964),
the acquisition of several kilograms of fat would and it is of value on these grounds alone, although
appreciably reduce the likelihood of toxicity from some authors have incriminated it as an aetio-
local analgesics. Indeed, it could well be that die logical factor in the production of anterior spinal
thin, nervous woman, widi a higher metabolic artery thrombosis (Davies, Solomon and Levene,
rate, could attain lower plasma levels than her 1958; Catterberg and Insausti, 1964).
slow, obese sister. It would seem important to Speed of injection. This appears to be of some

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differentiate between large patients and obese importance in relation to toxicity, but in any case,
ones. This, of course, is much easier in children injection should not be too rapid, otherwise the
than in adults, and dosage on a mg/kg basis is cerebrospinal fluid pressure may increase and
probably only valid in the former. give rise to discomfort in conscious patients. One
Because the dose/plasma concentration rela- ml of solution every 2-3 seconds is well tolerated
tionship is linear it is possible to extrapolate the by most patients.
results of earlier work on other factors affecting Body weight and age. In adult patients our
the absorption of lignocaine. Thus, all the main work suggests that litde account should be taken
factors which can be controlled by the adminis- of body weight in calculating dosage. More
trator in epidural block have now been assessed elderly people are less likely to tolerate high
and may be summarized as follows: plasma levels which may occur, and as it is well
Dosage. Using plain lignocaine, a dose of established that the spread of analgesic solution
400 mg should not be exceeded in conscious in the epidural space is enhanced with increasing
patients, but if general anaesthesia is given diis age (Bromage, 1962), high dosage is both un-
may be increased to 600 mg. necessary and undesirable.
Drug used. Plain lignocaine gives plasma levels
46-54 per cent above those of prilocaine (Braid ACKNOWLEDGEMENTS
and Scott, 1965) and if the latter drug is used, We wish to thank Astra Ltd. for their invaluable help
dosage may be increased to 600 mg for the in the preparation of this paper. We are particularly
conscious patient. grateful to Dr. Ortengren for the lignocaine analyses,
and to Dr. P. Frisch for the statistical evaluation.
Concentration of solution. In con^ntrations of
up to 2 per cent, this factor is of no importance
in epidural block (Braid and Scott, 1965). REFERENCES
Addition of adrenaline. Adrenaline lowers the Bonica, J. J., Backup, P. H., Andersen, C E., Had-
plasma level of lignocaine by 25 per cent if used field, D., Crepps, W. F., and Monk, B. F. (1957).
Peridural block: analysis of 3,637 cases and a
in a 1-in-80,000 concentration, and by 18 per review. Anesthesiology, 18, 723.
cent with a l-in-200,000 concentration (Braid Braid, D. P., and Scott, D. B. (1965). The systemic
absorption of local analgesic drugs. Brit. J.
and Scott, 1965). Adrenaline is therefore much Anaesth., 37, 394.
less effective in reducing toxicity in epidural Bromage, P. R. (1962). Spread of analgesic solutions
block than could be assumed from the official in the epidural space and their site of action: a
statistical study. Brit. J. Anaesth., 34, 161.
recommendation, which states that a 250 per cent Robson, J. G. (1961). Concentrations of ligno-
increase in dosage of lignocaine is possible if caine in the blood after intravenous, intramuscular,
adrenaline is added. Assuming that 400 mg of epidural and endotracheal administration. Anaes-
thesia, 16, 461.
plain solution is the maximum dose in conscious Burfoot, M. F., Crowell, D. E., and Pettigrew,
patients, then 500 mg would be the mayi'mnm if R. T. (1964). Quality of epidural blockade. I :
Influence of physical factors. Brit. J. Anaesth.,
1:200,000 adrenaline were added. 36, 342.
Apart from the rather disappointing effect of Catterberg, J., and Insausti, T. (1964). Paraplegia
adrenaline in this respect, the toxic effects of following peridural anaesthesia: a clinical and
experimental study. Rev. Asoc. mid. argent., 78, 1.
adrenaline itself must be considered, especially Davies, A., Solomon, B., and Levene, A. (1958).
if accidental intravenous injection is a possibility. Paraplegia following epidural anaesthesia. Brit,
med. J., 2, 654.
This is a rare complication of continuous epidural Deacock, A. R. de C , and Simpson, W. T. (1964).
block (Foldes and Duncalf, 1964). Fatal reactions to lignocaine. Anaesthesia, 19, 217.
602 BRITISH JOURNAL OF ANAESTHESIA

Englesson, S., Eriksson, E., Wahlqvist, S., and Orten-
gren, B. (1962). Differences in tolerance to intra-
venous xylocaine and citanest (L.67), a new local
anaesthetic. Proc. First European Congress of
Anaesthesiology, Proc. 2, 206.
Foldes, F. F., and Duncalf, D. (1964). Confirmation
of accidental intravascular insertion of epidural
catheters with radio-iodinated serum albumin.
3rd World Congress of Anaesthesiology, Proc. 1,
399.
Molloy, R., McNall, P. G., and Koukal, L. R.
L'analyse statistique des donnfes a permis une evalua-
tion preliminaire des effets du poids et de l'flge sur
les concentrations plasmatiques de la lignocaine. On
fait des recommandations sur le dosage de la ligno-
caine dans l'anesthesie ipidurale en ce qui concerne
la toxiciti, et on itudie les effets de divers facteurs
affectant l'absorption et 1'elimination des anesthesiques
locaux.
LIGNOCAIN-DOSIERUNG BEIM EPIDURAL-

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(1960). Comparison of toiicity of intravenously BLOCK IN BEZUG AUF DIE TOXIZITAT
given local anaesthetic agents in man. J. Amer.
med. Ass., 172, 1493. ZUSAMMEKFASSUNG
Scandinavian Pharmacopoeia Council (Nordiske Es wurden die durch epidurale Injektion von 200,
Farmakopenaevn) 1957. Monograf A56/57. 400, 500, 600 und 700 mg Lignocain erreichten Plas-
makonzentrationen bestimmt. Die Ergebnisse dieser
Untersuchung lassen eine lineare Beziehung zwischen
DOSAGE DE LA LIGNOCAINE DANS Dosierung und Plasmakonzentration erkennen. Die
L'ANESTHESIE EPIDURALE EN RELATION Plasmakonzentrationen nach rascher Injektion (400
AVEC LA TOXICITE mg in 15 Sekunden) wurden bestimmt, und es wurde
festgestellt, dafi diese etwas h6her lagen als bei
SOMMAIRE langsamer (60 Sekunden) Injektion. Die statistische
On a 6tudi£ la concentration plasmatique obtenue a Analyse der Mefiwene gestattete eine vorlaufige
la suite de l'injection epidurale de 200, 400, 500, 600, Aussage der Auswirkungen von Gewicht und Alter
et 700 mg de lignocaine. A partir de ces r&ultats il a auf die Lignocain-Plasmakonzentrationen. Es werden
6te dtabli une relation lineaire entre la dose et la Empfehlungen fiir die Lignocain-Dosierung beim
concentration plasmatique. La concentration plasma- Epiduralblock mit Hinblick auf die Toxizitat gegeben.
tique apres une injection rapide (400 mg en 15 Der Einflufl der verschiedenen Faktoren auf die
secondes) a 6t6 itudife et trouvee legerement plus Absorption und Elimination von LokalanSsthetika
elevee qu'apres une injection plus lente (60 secondes). wird beurteilL

POSTGRADUATE COURSE IN ANAESTHESIA

The Glasgow Postgraduate Medical Board has organized a full-time course of post-
graduate lectures entitled "Current Concepts in Anaesthesia", which will be held in
Glasgow from Monday, September 26 to Saturday, October 1, 1966. The course has
been designed for senior anaesthetists wishing to keep abreast of important advances
in anaesthesia and related fields, including intensive care, acid-base measurement, and
metabolic care. The course would also be of value to those sitting the Final part of
the F.F.A.R.QS.
The provisional programme and application forms can be obtained from the
Director of Postgraduate Medical Education, The University, Glasgow, W.2.