579

Does Compounding of Local Anesthetic Agents

Increase Their Toxicity in Humans?

DANIEL C. MOORE, M.D.

L. DONALD BRIDENBAUGH, M.D.
PHILLIP 0.BRIDENBAUGH, M.D.
GALE E. THOMPSON, M.D.
GEOFFREY T. TUCKER, Ph.D.t
Seattle, Washington*

As

YET, the ideal local anesthetic agent

has not been produced. The pharmacologic and physiologic characteristics of
such an agent probably would include: (1)
rapid onset; (2) wide and rapid spread,
with deep penetration of nerves; (3) low
tissue toxicity; (4) low systemic toxicity;
(5) rapid absorption from the site of injection, so as not to cause tumefaction; (6)
rapid detoxification, without accumulation
of the drug or its metabolic byproducts;
(7) stability, permitting heat sterilization;
(8) high solubility in cold physiologic saline solutions; and (9) prolonged duration
of action, so that a single-dose rather than
a continuous-dose technic might be em-

ployed. These characteristics should not depend on the use of a vasoconstrictor drug
in the local anesthetic solution, but should
be maintained if vasoconstrictors are indicated.
To approach these requirements, we and
others have used the technic of compounding (mixing of two local anesthetic agents)
to take advantage of the rapid onset, spread,
and penetration of one agent and the prolonged duration of action of another.1-*
Either dibucaine or tetracaine has been
compounded with chloroprocaine, hexylcaine, lidocaine, mepivacaine, or procaine
in approximately 2098 patients for caudal
and epidural blocks.1-3

*The Mason Clinic, Seattle, Washington 98101.

?University of Washington School of Medicine, Seattle, Washington 98105. Virginia Mason Research
Center, Seattle, Washington 98101.

..

580

ANESTHESIA
AND ANALGESIA. Current Researches VOL.51, NO.4, JULY-AUGUST,
1972

In white rats, white mice, and in dogs,

the compounding of tetracaine with chloroprocaine, lidocaine, mepivacaine, procaine,
and prilocaine has increased the incidence
of systemic toxic reactions and deaths in
comparison with the use of these agents
singly.5--7Additive or synergistic action has
been considered the cause of increased toxicity, with the implication of similar effects
in

TABLE 1
Number of Epidural, Caudal, and Peripheral
Nerve Blocks Performed with Compounded
Solutions for Surgical and Obstetric
Procedures
Number of
epidural ond
coudol blocks

Compounded agents

Number of
peripheral
nerve blocks

Lidocaine + tetracaine
6277
Mepivacaine + tetracaine 2539
Chloroprocaine + tetracaine 638
Propoxycaine + tetracaine
78
Prilocaine + tetracaine
3

This paper presents the results of our

use of compounded solutions in humans, in
partial answer to the question, Is toxicity
increased when compounded solutions of
local anesthetic agents are injected into
humans?

1
986
12
0

4
9535
1003
10,538

Total

METHOD
The following data were abstracted from
the anesthetic records of patients given com- not those inherent in technic, such as hypopounded solutions of local anesthetic tension from sympathetic blockade followagents: (1) types and number of blocks ing epidural block.
administered; (2) dosage of the two local
anesthetic agents; (3) dosage of vasoconRESULTS
strictor drugs; (4) onset and establishment
All blocks were performed as described
of surgical anesthesia; (5) duration of the earlier,4 and compounded solutions were
block; (6) complications. Duration was de- used in single-dose technics only.
termined by noting the time in the postopNUMBER
OF PATIENTS,
LOCALANESTHETerative period when the patient complained
of pain in the operated area, or during the IC AGENTSEMPLOYED, AND BLOCKSPERsurgical procedure when there was evidence FORMED. -From 1952, when we started to
of the block dissipating, indicated by pain use compounded solutions (chloroprocaine,
in the conscious patient, or, in the semicon- lidocaine, mepivacaine, prilocaine, or proscious or unconscious patient, restlessness; poxycaine plus tetracaine) through 1970, a
increased respiration, blood pressure, or total of 10,538 patients received such solupulse rate; return of muscle tone; the need tions for (1) caudal block; (2) epidural
for additional anesthesia to complete the block; (3) brachial plexus block; or (4) scisurgical procedure; or combinations of atic and femoral nerve blocks, with or withthese. Complications included those from out lateral femoral cutaneous nerve block,
the local anesthetic agents themselves, such obturator nerve block, or both (tables 1and
as local tissue toxicity, generalized systemic 2). Compounding of solutions for periphtoxic reactions, or neurologic sequelae, but eral nerve block was not started until 1967.

TABLE 2
Types and Numbers of Peripheral Nerve Blocks Done with
Compounded Solutions for Operative Procedures
Blocks

Lidocaine
tetracoine

Brachial plexus
Axillary

Supraclavicular
Sciatic and femoral nerves, with or
without lateral femoral cutaneous
nerve and obturator nerve

Mepivacoine
tetracaine

141
333

Prilocaine
tetracaine

5
3
4

12

512
1

986

Chloropracaine
tetracaine

Local Anesthetic Toxicity.

. .Moore, et a1

581

Chloroprocaine, lidocaine, or mepivacaine

plus tetracaine were the principal compounds employed. Prilocaine and propoxycaine were used in only 85 cases before
1966; because of the insignificant number,
these will not be considered further. Lidocaine or chloroprocaine plus tetracaine were
the principal agents compounded through
1966. Lidocaine plus tetracaine was used in
only one peripheral nerve block during that
time; therefore this compound for such use
is given no further consideration. Prior to
1967 chloroprocaine was compounded with
tetracaine for 638 epidural blocks but for
only 12 peripheral nerve blocks, and the
peripheral nerve blocks will not be considered further. The use of chloroprocaine was
discontinued when the pharmaceutical company that originally developed the agent
stopped producing it.

rine was 1:200,000,that is, 0.1 ml. (0.1 mg.)

of epinephrine 1:lOOO in 20 ml. of solution,
and the maximum total milligram dose of
epinephrine for any regional block technic
was 0.25 mg. Even when regional block
technics requiring more than 50 ml. of the
local a n e s t h e t i c solution were executed
(block of the sciatic, femoral, lateral femoral cutaneous, and obturator nerves,
which require 100 ml.) , 0.25 mg. of epinephrine was not exceeded since this amount
does not usually cause a severe epinephrine
reaction or initiate arrhythmias even in patients with cardiac disease. Therefore, in
peripheral nerve blocks requiring in excess
of 50 ml. of the local anesthetic solution the
concentration is less than 1:200,000 e.g.,
when 100 ml. is used the concentration of
epinephrine is 1 :400,000.

After 1966, mepivacaine plus tetracaine

was used almost exclusively because the
time of onset, spread, penetration, and establishment of surgical anesthesia of mepivacaine were comparable to those of lidocaine, and the commercial packaging of the
agent was better suited for our method of
compounding.

For lumbar epidural block, used primarily for intra-abdominal surgery, 2 mg. of
tetracaine was added to each milliliter of
either 1.5 percent lidocaine, 1.5 percent mepivacaine, or 2 percent chloroprocaine, and
a maximum of 20 ml. was injected into the
lumbar epidural space.4 In the majority of
cases the dose was 18 ml. or less.

DOSAGE.-Solutions

to be compounded
were mixed immediately before injection.
We incorporated epinephrine in all compounded solutions. For epidural and caudal
block through 1966, the epinephrine concentration varied depending on the volume
of the local anesthetic solution injected,
that is, where 12 to 25 ml. was administered
the concentration was 1:125,000 and when
26 to 50 ml. was used, 1:200,000.From 1967
on the maximum concentration of epineph-

For caudal block, used primarily for

perineal surgery, 2 mg. of tetracaine was
added to each milliliter of 1.5 percent lidomine or 1.5 percent mepivacaine up to a
total volume of 25 to 30 ml. When between
31 and 50 ml. was used, as for vaginal hysterectomy, we selected a solution of 1 percent lidocaine or 1 percent mepivacaine,
rather than 1.5 percent, to avoid exceeding
our approximate maximum dose of lidocaine

*fessor of Anesthesiology
C. MOORE,M.D., is Clinical Associate Proat the University of Washington,
DANIEL

Seattle, and Director, Department of Anesthesiology, the

Mason Clinic and the Virginia Mason Hospital, Seattle,
Washington. Dr. Moore is one of the most active members of the specialty, holding honorary membership in
many organizations and having written four books and
over eighty papers. His principal interests have been
local anesthetic agents and regional technics. In 1944 he
graduated from Northwestern University Medical School,
Evanston, Illinois, and was an intern and a Resident in Anesthesiology a t
Wesley Memorial Hospital, Chicago. He is a Past President (1959) of the
American Society of Anesthesiologists.

582

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ANESTHESIA
AND ANALGESIA. Current Researches VOL.51, No. 4, JULY-AUGUST,
1972

or mepivacaine for a single-dose technic,

and we added 2 mg. of tetracaine to each
milliliter of lidocaine or mepivacaine.

to convulsions-2 had received a solution

of lidocaine plus tetracaine and the other 2,
a solution of mepivacaine plus tetracaine.
All were treated with oxygen by bag and
mask and all recovered.

For peripheral nerve block for extremity

procedures, with a volume of 50 ml. or less
In 1 patient with cancer of the rectum,
of injected solution, 2 mg. of tetracaine was
added to each milliliter of 1percent mepiva- a caudal block for biopsy, using 20 ml. of
caine. If over 50 ml. (60-100 ml.) were to 1.5 percent lidocaine (300mg.) and 40 mg.
be used, tetracaine (1 mg./lb. of body of tetracaine, with epinephrine 1:125,000,
weight, not to exceed 200 mg. or a final tet- was followed by a bilateral paralysis which
racaine concentration of 0.25 percent) was gradually extended from the 10th to the
added to the 0.5 percent mepivacaine solu- 6th thoracic dermatome over a 3-week petion. The weaker solution of mepivacaine riod. This complication resulted from what
was selected when volumes necessary for was diagnosed as an ascending spinal arthe block were more than 50 ml., to avoid tery syndrome.
exceeding our approximate maximum dose
No complications followed peripheral
of this drug.
nerve block.
ONSET, ESTABLISHMENT,AND DURATION
OF SURGICAL
ANESTHESIA.
-For epidural
DISCUSSION
and caudal block, compounded solutions had
OPTIMAL MILLIGRAM
DOSAGE
OF TETRA(1) onset within 5 to 8 minutes; (2) surgical anesthesia within 12 to 25 minutes; and CAINE AS RELATEDTO CHLOROPROCAINE,
- For com(3)a duration of from 2% to 2y4 hours. In LIDOCAINE,OR MEPIVACAINE.
caudal block, solutions containing 1.5 per- pounding local anesthetic agents, our apcent lidocaine or 1.5 percent mepivacaine, proximate maximum doses are (1) 1000 mg.
as compared with 1 percent, usually estab- of chloroprocaine; (2) 500 mg. of lidocaine
lished surgical anesthesia earlier, but dura- or mepivacaine; and (3) 1 mg./lb. (body
tion of anesthesia was approximately the weight) of tetracaine, not to exceed 200
mg.4 These are the same maximum doses
same.
which we would employ if the agents were
For peripheral nerve block, onset and es- not compounded.
tablishment of surgical anesthesia with comFor epidural block, we inject no more
pounded solutions were similar to those for
caudal and epidural block, but duration than 20 ml. of the local anesthetic solution
4 to 51/2 into the epidural space, whether or not the
was significantly longer-from
solution is ~ompounded.~
When the amounts
hours, and occasionally longer.
used for skin wheal, local infiltration, and
COMPLICATIONS.No local tissue toxicity test dose are added to this, however, the
resulted from the use of compounded solu- total of the compounded solution may reach
tions in any block procedure.
26 ml. Thus, maxima may reach 390 mg.
Following lumbar epidural block, 6 pa- of lidocaine, 390 mg. of mepivacaine, 520
tients exhibited systemic toxic reactions. mg. of chloroprocaine, and 52 mg. of tetraAfter receiving lidocaine plus tetracaine, 3 caine, but the total milligram dosage of
patients convulsed and 1 lost consciousness, these agents is markedly less than our maxiprobably from the cerebral effects of the mum dose for any one agent used alone.
lidocaine. Following mepivacaine plus tetFor caudal block, when a volume of soluracaine, one convulsed and one remained
conscious but was disoriented. All recovered tion of 30 ml. or less is to be used, including
uneventfully after treatment with oxygen skin wheal, local infiltration, test dose, and
amount injected into caudal canal, the ratio
by bag and mask.
of compounding is 2 mg. of tetracaine to
One patient, in whom a lumbar epidural each milliliter of 1.5 percent lidocaine or 1.5
block with 18 ml. of a 1.5 percent solution percent mepivacaine. We seldom inject
of lidocaine (270 mg.) and 36 mg. of tetra- more than 30 ml., equaling a maximum of
caine with 1:125,000 epinephrine was ad- 450 mg. of lidocaine or mepivacaine and 60
ministered for an appendectomy, experi- mg. of tetracaine. I n the unusual case, when
enced permanent bilateral weakness of the 31 to 50 ml. of solution (including skin
quadriceps muscle.
wheal, local infiltration, test dose, a n d
Following caudal block, 4 patients ex- amount injected into the caudal canal) is
hibited systemic toxic reactions progressing used and 2 mg. of tetracaine is added to

Local Anesthetic Toxicity.

. . Moore,et a1

each milliliter of 1 percent lidocaine or 1

percent mepivacaine, the maximum amount
injected is 310 to 500 mg. of lidocaine or
of mepivacaine and 62 to 100 mg. of tetracaine. Therefore, in caudal block, the total
dosage of the compounded local anesthetic
agents is usually less than our approximate
maximum dosage of either agent injected
alone.
For peripheral nerve block, as concentrations of lidocaine or mepivacaine in excess
of 1 percent may produce neuritis, we do
not routinely employ them for this technic.4
For brachial plexus block, we use 50 ml.
of solution; for sciatic and femoral nerve
blocks, 50 ml.; and for sciatic and femoral
nerve blocks with either lateral femoral cutaneous nerve block or obturator block, or
both, 70 to 100 ml.4
When volumes of 50 ml. are employed,
2 mg. of tetracaine is added to each milliliter of 1 percent mepivacaine, 500 mg. of
mepivacaine and 100 mg. of tetracaine being
administered. When 70 to 100 ml. of solution is injected, tetracaine (1 mg./lb., not
to exceed 200 mg.) is added to each milliliter of 0.5 percent mepivacaine, 350 to 500
mg. of mepivacaine and varying amounts
of tetracaine, depending on body weight,
being injected. Therefore, in peripheral
nerve blocks, the maximal dose of either
agent is not exceeded.
The reasons for such ratios in compounding in order to produce the long duration of
action of tetracaine are not clearly understood. However, this phenomenon has been
observed in man by us and in dogs by Defalque and Stoelting.9

583
anesthesia lasts for 1%to 3 hours. The addition of tetracaine does not alter the time
of onset or establishment of surgical anesthesia, but duration of anesthesia is lengthened to 4 to 59$ hours and occasionally
longer. For some unexplained reason, tetracaine alone, used for peripheral nerve block,
gives a duration of 6 to 9 hours or longer.

ADVANTAGES
OF COMPOUNDING.
- Most
anesthesiologists prefer single-dose to continuous technics because (1) they are technically less difficult and time-consuming;
(2) the incidence of complications is less
-for example, broken plastic tubing; and
(3) the incidence of unsatisfactory anesthesia is less. For most surgical procedures,
single-dose regional block requires the use
of a local anesthetic agent with a prolonged
duration. While the commonly employed
agents, such as chloroprocaine, lidocaine, or
mepivacaine, do have excellent diffusion
and penetrability as well as rapid onset and
rapid establishment of surgical anesthesia,
they do not produce prolonged sensory and
motor blockade. Therefore, they are not
satisfactory agents for single-dose technics
in the following circumstances: (1) teaching of regional block, which may require 30
to 45 minutes prior to preparation and draping of the patient for surgery; (2) epidural
or caudal block, where the time needed for
establishment of surgical anesthesia and
for the surgical or obstetric procedure exceeds the duration of action of these agents;
(3) peripheral nerve block for surgical procedures requiring anesthesia in excess of 3
hours; or (4) prolonged pain relief, either
during the postoperative period or following
diagnostic and therapeutic blocks.

COMPARISON OF ONSET, ESTABLISHMENT

OF SURGICAL ANESTHESIA,
AND DURATION On the other hand, although tetracaine in
OF SURGICAL ANESTHESIA
WITH LIDOCAINE concentrations of 0.1, 0.15, or 0.25 percent
AND MEPIVACAINE.When only lidocaine, for single-dose peripheral nerve block pro-

mepivacaine, or chloroprocaine is used for vides a duration of anesthesia of 6 to 9

epidural or caudal block, onset occurs in 5 hours, or even 10 to 14 hours when the soluto 8 minutes, surgical anesthesia is estab- tion contains epinephrine, many anesthesilished within 12 to 25 minutes, and duration ologists do not use tetracaine because (1)
of action is from 1 to 1%hours, when such its onset time is 5 to 10 minutes; (2) surgisolutions contain epinephrine. When tetra- cal anesthesia may not be established for 15
caine is added, onset and establishment of to 40 minutes; (3) diffusibility is limited,
surgical anesthesia are not altered, but requiring marked accuracy of placement on
duration of action is extended to 21/4 to 2% or near the nerves; and (4) it has been
(falsely) accused of being too toXi~.4,10J1
hours.
For peripheral nerve block, when only
Even if the time of onset and establishlidocaine or mepivacaine with epinephrine ment of maximum anesthesia were as rapid
is employed, onset is within 5 to 8 minutes, with 0.1, 0.15, or 0.25 percent tetracaine as
surgical anesthesia resulting in 12 to 25 with 1.5 percent lidocaine or 1.5 percent
minutes (depending on accuracy of place- mepivacaine, we would not use these conment of the local anesthetic solution), and centrations of tetracaine for single-dose

584

..

ANESTHESIA
AND ANALGESIA.Current Researches VOL. 51, No. 4, JULY-AUGUST,
1972

caudal or epidural block, as the resulting

sensory and motor anesthesia is more consistently predictable with lidocaine or mepivacaine.
- Local toxicity from
COMPLICATIONS.
compounded solutions-for example, slough
of tissue-did not occur in our experience or
in that of other investigators.'-3 We observed two unexplained neurologic complications following the use of compounded
solutions-one after caudal block and the
other after epidural block. This incidence is
not markedly different from that of neurologic sequelae following epidural block reported by Bonica and associates' (1:3637
patients), by .Lund3 (2:10,OOO patients),
and by Hellmannl2 (2:26,127 patients). I n
our cases, the epinephrine content may have
been too great, but this is debatable. Since
1966, by maintaining the optimal maximum
epinephrine concentration of 1:200,000 for
all regional nerve blocks, no neurologic sequelae or alteration in duration of anesthesia has resulted.

We observed 10 systemic toxic reactions

(eight of which progressed to convulsions)
following injection of compounded solutions
into the epidural space via a lumbar interspace or the sacral hiatus. In these cases,
routine tests were made to avoid intravascular or subarachnoid injection of the dose
of the drug calculated to produce the desired anesthesia. The tests, aspiration for
blood or spinal fluid and injection of 3 to 5
ml. of the local anesthetic solution, followed
by observation of the patient for 5 minutes
to detect either changes in sensorium or
onset of anesthesia, were in all cases negative.
Our incidence of systemic toxic reactions
progressing to convulsions does not differ
significantly from that reported by other
authors. Bonica's group' reported generalized systemic toxic reactions following epidural blocks in 116 of 3637 patients, with
8 convulsing, and LundS in 44 of 10,OOO
patients, with 11 convulsing. Hellmannlz
did not report the number of generalized
systemic reactions, but 17 of his 26,127 patients convulsed.
APPLICABILITY
OF EXTRAPOLATINGRESULTS FROM ANIMALS
TO H u M A N s .
compounding of chloroprocaine, lidocaine,
mepivacaine, prilocaine, or procaine with
one another or with tetracaine was found to
increase the severity of systemic toxic reac-

tions and the incidence of death in certain

strains of white rats and mice and in dogs,
use of these compounds in humans was postulated to be dangerou~.~-T
However, results
of such animal experiments, especially with
ester-type agents, cannot properly be extrapolated to humans, as acute toxicity studies
in animals involve rapid administration of
drug until death, high brain levels being
produced within such a short time that catabolism of the agent is negligible. In contrast, clinical tolerance involves the kinetics
of drug absorption, distribution, and elimination.
Furthermore, the animals used in these
studies catabolize ester derivatives quite
slowly,13-16 while humans metabolize them
rapidly.13~14~16
Using gas chromatography,
we could detect no tetracaine in the blood of
patients 2 to 30 minutes after administering
150 mg. for bilateral intercostal nerve
blocks.
The assay for tetracaine can determine 0.1
mcg./ml. of the drug when added to human
blood in vitro, and significantly less than
this can be detected. The assay is similar
to that for anilide derivatives, except that
arsenite solution is added and the blood is
frozen pending analysis, to prevent hydrolysis of tetracaine during and after sampling." OtherslcJ* have also found difficulty
in measuring tetracaine in vivo in humans
but have confirmed that it can be measured
in vitro.
Therefore, since lidocaine or mepivacaine
injected in humans for caudal, epidural, and
peripheral nerve blocks does not reach peak
blood levels for 10 to 30 minutes, as determined by gas chromatography, and since
tetracaine cannot be measured after normal
clinical doses, presumably because it is
rapidly metabolized, we can hypothesize
that high levels of the drugs do not coincide
and that generalized systemic toxic reactions are not likely to occur in humans as
a result of compounding an anilide with an
ester. This assumes, of course, that metabolites of tetracaine are not significantly toxic.
At present, no methods are available for
determining precisely the levels of esterized
derivatives in human blood
~local
~ ~anesthetic
~ ~
following normal clinical doses. Such methods should be sought, so that uptake and
elimination of the ester derivatives can be
determined in man.

Local Anesthetic Toxicity.

. . Moore, et a1

CONCLUSIONS
In a retrospective study of the records of
over 10,000 patients given local anesthetic
agents for caudal, epidural, brachial plexus,
or peripheral nerve blocks, compounding of
certain parenteral agents was found to give
more satisfactory results than use of the
agents singly.
The primary advantage of compounding
is that it permits the use of single-dose technics by taking advantage of the outstanding
qualities of each local anesthetic agent, that
is, the rapid establishment of surgical anesthesia of chloroprocaine, lidocaine or mepivacaine, and the prolonged duration of tetracaine.
Compounded solutions permit single-dose
technics for epidural or caudal block in
many instances where a continuous technic
would be mandatory with a single agent.
Other advantages are also described.
Compounding as detailed herein is a safe
technic in man. Data indicating systemic
toxic reactions and deaths in animal experiments with such compounded local anesthetic solutions do not appear subject to
extrapolation for clinical purposes.
Finally, when anesthesia is unsatisfactory following a regional block performed
with the approximate maximum dose of
either an anilide or an ester derivative and
it is decided to repeat the block, a local
anesthetic agent of an alternate chemical
derivation should be used. For example, if
an anilide derivative is injected initially
and the resulting anesthesia is unsatsfactory, reinjection should be done with an
ester derivative.

Generic and Trade Names of Drugs

Chloroprocaine-Nesacaine
Dibucaine-Nupercaine
Epinephrine-Adrenalin
Hexylcaine-Cyclaine
Lidocaine-X y locaine
Mepivacaine-Carbocaine
Prilocaine-Citanest
Procaine-Novocain
Propoxycaine-Blockain
Tetracaine-Pontocaine

585

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single injection technic. Anesthesiology 10:473-478,
1949
2. Bonica JJ, Backup PH, Anderson CE, et al:
Peridural block: analysis of 3,637 cases and a review. Anesthesiology 18:723-784,1957
3. Lund PC: Peridural anesthesia. A review of
10,OOO administrations. Acta Anaesth Scand 6:143159, 1962
4. Moore DC: Regional Block. Fourth edition.
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1966
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16. Foldes FF, Davis DL, Shanor G, et al: Hydrolysis of ester-type local anesthetics and their
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17. Tucker GT: Determination of bupivacaine
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