Anesthesiology 2000; 93:1045–52
`
`© 2000 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
`
`Addition of Sodium Bicarbonate to Lidocaine
`Decreases the Duration of Peripheral Nerve
`Block in the Rat
`Catherine J. Sinnott, B.A.,* Joseph M. Garfield, M.D.,* Johannes G. Thalhammer, D.V.M.,†
`Gary R. Strichartz, Ph.D.*‡
`
`MANY anesthesiologists believe that adding sodium bi-
`carbonate to plain lidocaine hydrochloride can enhance
`the efficacy of this local anesthetic. This topic has been
`most widely investigated in epidural anesthesia. Studies
`have shown that adding sodium bicarbonate to lidocaine
`hydrochloride without epinephrine improves the quality
`of epidural block, whereas adding sodium bicarbonate to
`lidocaine with epinephrine does not. The addition of
`8.4% sodium bicarbonate to 2% lidocaine hydrochloride
`without epinephrine (1:10, vol:vol) was shown to de-
`crease onset time1,2 and enhance the depth of epidural
`block at L4 –S1.2 When bicarbonate was added to 2%
`lidocaine hydrochloride with epinephrine (1:200,000),
`neither onset time nor depth of epidural block at L4 –S1
`roots was altered.3
`Most clinical investigators addressing this question have
`used epidural anesthesia as their paradigm. Accordingly,
`the clinical literature remains unclear as to whether adding
`sodium bicarbonate to either plain lidocaine or lidocaine
`with epinephrine improves the quality of peripheral
`nerve block. In addition, the effect of bicarbonate on
`lidocaine’s onset of action in peripheral nerve block
`remains controversial. For example, Chow et al.4 found
`that adding 8.4% sodium bicarbonate to 1.5% lidocaine
`hydrochloride (1:10) with epinephrine (1:200,000) did
`not speed the onset of analgesia in axillary brachial
`plexus block. However, adding sodium bicarbonate at
`the same concentration and volume ratio to 2% lido-
`caine, with and without epinephrine (1:100,000), did
`decrease the onset time of peribulbar anesthesia.5 Apart
`from effects on onset, the actions of bicarbonate on the
`depth and duration of peripheral nerve block with lido-
`caine has not been previously described.
`In the present study we used a well-defined laboratory
`model, i.e., sciatic nerve block in the rat,6,7 to address
`the effect of sodium bicarbonate on peripheral nerve
`block performed with lidocaine. We compared onset
`time, degree of impairment of nociception, i.e., depth of
`analgesia, and block duration with different lidocaine solu-
`tions in rats receiving percutaneous sciatic nerve blocks.
`Lidocaine solutions, with and without epinephrine, were
`prepared from either crystalline salt or from a commercially
`available source (Abbott Laboratories, North Chicago, IL).
`These solutions were either not alkalinized (plain lido-
`caine), alkalinized with sodium bicarbonate, or alkalinized
`with sodium hydroxide (NaOH).
`
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`
`Background: Adding sodium bicarbonate to lidocaine to en-
`hance its efficacy during peripheral nerve block is controver-
`sial. The authors studied the effect of adding sodium bicarbon-
`ate to lidocaine with and without epinephrine versus equivalent
`alkalinization by sodium hydroxide (NaOH) on onset, degree,
`and duration of peripheral nerve block.
`Methods: Part I examined alkalinization by sodium bicarbon-
`ate versus NaOH to pH 7.8 on 0.5% lidocaine, with and without
`epinephrine (1:100,000), prepared from crystalline salt. Part II
`examined 0.5% and 1.0% commercial lidocaine solutions, with
`and without epinephrine, either unalkalinized or alkalinized
`with sodium bicarbonate or NaOH. With NaOH, pH was adjusted
`to 7.8, but with sodium bicarbonate, no pH adjustments were
`made to simulate clinical conditions.
`Results: In part I, addition of either NaOH or sodium bicar-
`bonate to 0.5% lidocaine without epinephrine produced a faster
`onset than did unalkalinized lidocaine, without effecting degree
`or duration of block. In solutions with epinephrine there were
`no differences in onset, degree, or duration between lidocaine
`alkalinized with sodium bicarbonate versus NaOH. In part II,
`addition of sodium bicarbonate or NaOH to 1.0% commercial
`lidocaine without epinephrine did not accelerate onset com-
`pared with the unalkalinized solution. However, adding sodium
`bicarbonate decreased the degree and duration of block by 25%
`and more than 50%, respectively, compared with lidocaine un-
`alkalinized and alkalinized with NaOH. With epinephrine, so-
`dium bicarbonate hastened onset without effecting degree and
`duration compared with the unalkalinized solution.
`Conclusions: With 1% commercial lidocaine without epineph-
`rine, sodium bicarbonate decreases the degree and duration of
`block. However, in solutions with epinephrine, sodium bicar-
`bonate hastens onset, without effecting degree or duration.
`(Key words: Adjuvant; epinephrine; local anesthesia.)
`
`e
`
`This article is featured in “This Month in Anesthesiology.”
`Please see this issue of ANESTHESIOLOGY, page 5A.
`
`* Pain Research Center, Department of Anesthesiology, Perioperative and Pain
`Medicine, Brigham and Women’s Hospital; † Klinikvorstand, Medizinische Klinik;
`‡ Department of Biological Chemistry and Molecular Pharmacology, Harvard
`Medical School.
`
`Received from the Pain Research Center, Department of Anesthesiology,
`Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Mas-
`sachusetts; the Department of Biological Chemistry and Molecular Pharmacol-
`ogy, Harvard Medical School, Boston, Massachusetts; and Klinikvorstand, Mediz-
`inische Klinik, Veterinarmedizinische Universitat, Wien, Austria. Submitted for
`publication January 12, 2000. Accepted for publication May 18, 2000. Supported
`by grant No. GM 35647 from the US Public Health Service, National Institutes of
`Health, Bethesda, Maryland (to Dr. Strichartz).
`
`Address correspondence to Dr. Strichartz: Pain Research Center, Department
`of Anesthesia, Brigham and Women’s Hospital, Harvard Medical School, Boston,
`Massachusetts 02115. Address electronic mail to: gstrichz@zeus.bwh.harvard.edu.
`Reprints will not be available from the authors. Individual article reprints may be
`purchased through the Journal Web site, www.anesthesiology.org.
`
`Anesthesiology, V 93, No 4, Oct 2000
`
`1045
`
`Exhibit 1111
`Prollenium v. Allergan
`IPR2019-01505 et al.
`
`

`

`1046
`
`SINNOTT ET AL.
`
`Table 1. Composition of Solutions Injected for Sciatic Nerve Block
`
`Name
`
`n
`
`Symbol
`
`Description
`
`pH 6 0.05
`
`0.5% lidocaine HCl (unalkalinized)
`0.5% lidocaine HCl with NaOH
`0.5% lidocaine with 8.4% sodium
`bicarbonate (10;1)
`0.5% lidocaine with epi. (1;100,000) and
`NaOH
`0.5% lidocaine HCl epi. (1;100,000) and
`8.4% sodium bicarbonate (10;1)
`
`0.5% lidocaine HCl (unalkalinized)
`0.5% lidocaine HCl with NaOH
`0.5% lidocaine with 8.4% sodium
`bicarbonate (10;1)
`0.5% lidocaine HCl with epi. (1;100,000)
`(unalkalinized)
`0.5% lidocaine HCl with epi. (1;100,000)
`and 8.4% sodium bicarbonate (10;1)
`
`1% lidocaine HCl (unalkalinized)
`1% lidocaine HCl with NaOH
`1% lidocaine with 8.4% sodium
`bicarbonate (10;1)
`1% lidocaine HCl with epi. (1;200,000)
`(unalkalinized)
`1% lidocaine HCl with epi. (1;200,000)
`and 8.4% sodium bicarbonate (10;1)
`
`5.13
`7.85
`7.85
`
`7.85
`
`7.85
`
`6.58
`7.85
`7.99
`
`6.46
`
`7.85
`
`6.64
`7.85
`7.75
`
`4.46
`
`7.49
`
`(Sigma Chemical, St. Louis, MO) was dissolved in 10 ml
`sterile water (Abbott Laboratories); (2) LOH: 0.5% lidocaine
`hydrochloride alkalinized with NaOH (pH 5 7.85)—50 mg
`lidocaine hydrochloride powder was dissolved in 10 ml
`sterile water, and the pH was adjusted to 7.85 with 30 ml
`(1:333) of 2N NaOH (Fisher Scientific, Pittsburgh, PA);
`(3) LBC: 0.5% lidocaine hydrochloride with 8.4% sodium
`bicarbonate (10:1; pH 5 7.85)—10 ml of 0.55% lido-
`caine hydrochloride was prepared by dissolving 55 mg
`lidocaine hydrochloride in 10 ml sterile water; 10 ml of
`8.4% sodium bicarbonate was prepared by dissolving
`840 mg of sodium bicarbonate powder (Sigma Chemical)
`in 10 ml sterile water, and 1 ml of this solution was added
`to the 10-ml lidocaine solution to make a resultant contain-
`ing 55 mg lidocaine in 11 ml 5 0.5%; (4) LE: 0.5% lidocaine
`with epinephrine (1:100,000) alkalinized with NaOH
`(pH 5 7.85)—100 mg crystalline epinephrine hydrochlo-
`ride (Sigma Chemical) was dissolved in 10 ml sterile water,
`and 10 ml of this (1:100) solution was added to 10 ml of
`0.5% lidocaine (made as above) to achieve a final epi-
`nephrine concentration of 1:100,000; the pH of this
`solution was adjusted to 7.85 with 40 ml (1:250) of 2N
`NaOH; and (5) LBCE: 0.5% lidocaine with epinephrine
`(1:100,000) alkalinized to pH 7.85 with 8.4% sodium
`bicarbonate (10:1) (pH 5 7.85)—this solution was pre-
`pared according to the combined regimens 3 and 4,
`described above. All pHs were measured at room tem-
`perature (20 –22°C) using a Model 611 pH meter (Orion
`
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`
`Part I. 0.5% Solutions prepared from crystalline lidocaine HCl
`(cid:140)
`L
`10
`E
`LOH
`10
`F
`LBC
`10
`
`LE
`
`LBCE
`
`10
`
`10
`
`h
`
`n
`
`Part II. 0.5% Commercial lidocaine HCl solutions
`(cid:140)
`CL
`10
`E
`CLOH
`10
`F
`CLBC
`10
`
`CLE
`
`CLBCE
`
`*CL
`*CLOH
`*CLBC
`
`*CLE
`
`*CLBCE
`
`10
`
`10
`
`h
`
`n
`
`1.0% Commercial lidocaine HCl solutions
`(cid:140)
`10
`E
`10
`F
`9
`
`9
`
`9
`
`h
`
`n
`
`Materials and Methods
`
`Animals
`Male Sprague-Dawley rats (Taconic Farms, German-
`town, NY) weighing 250 –350 g were housed in the
`Brigham and Women’s Hospital animal facilities with a
`12-h light– dark cycle. All behavioral testing and surgical
`procedures in this study were approved by the Harvard
`Medical Area Committee on Animals. All animals used in
`these experiments were handled for 15 min/day for a
`2-week period before the tests to preclude stress-in-
`duced analgesia in rats during experimentation. Han-
`dling procedures involved persistent tactile contact with
`one experimenter (C.J.S.) and several applications of a
`deep pinch with serrated forceps to the fifth metatarsal.6
`
`Experimental Design
`Percutaneous sciatic nerve blocks were performed
`with five lidocaine solutions prepared from either crys-
`talline lidocaine hydrochloride at a concentration of
`0.5% or commercial lidocaine at a concentration of 0.5%
`and 1.0% (Abbott Laboratories; table 1).
`
`Preparation of 0.5% Solutions from Crystalline
`Lidocaine Hydrochloride
`Five 0.5% lidocaine solutions (all exactly 0.5% with
`pH 5 5.13 or 7.85) were prepared from the crystalline
`salt: (1) L: 0.5% plain lidocaine hydrochloride (pH 5
`5.13 6 0.05)—50 mg lidocaine hydrochloride powder
`
`Anesthesiology, V 93, No 4, Oct 2000
`
`

`

`BICARBONATE SHORTENS PERIPHERAL NERVE BLOCK
`
`1047
`
`7.85 with 15 ml (1:667) of 2N NaOH; (3) *CLBC: 1%
`lidocaine hydrochloride alkalinized with 8.4% sodium
`bicarbonate (10:1; pH 5 7.75)—a solution of 1.5% lido-
`caine hydrochloride injection (Abbott Laboratories) was
`diluted to 1.1% with 0.9% NaCl injection; 1 ml of 8.4%
`sodium bicarbonate injection was then added to 10 ml of
`the 1.1% lidocaine solution; (4) *CLE: unalkalinized 1%
`lidocaine hydrochloride with epinephrine (1:200,000)
`injection (Abbott Laboratories; pH 5 4.46); and (5)
`*CLBCE: 1% lidocaine hydrochloride with epinephrine
`(1:200,000) alkalinized with 8.4% sodium bicarbonate
`(10:1; pH 5 7.49)—a solution of 1.5% lidocaine hydro-
`chloride injection was diluted to 1.1% with 0.9% NaCl
`injection; 1 ml of 8.4% sodium bicarbonate injection was
`then added to 10 ml of the 1.1% lidocaine solution, and
`110 ml of epinephrine hydrochloride injection was then
`added to this solution.
`
`Preparation of Commercial Control Solutions
`Three control solutions were prepared for this com-
`ponent of the study. The first contained only 0.9% NaCl
`injection, the second contained 1 ml of 8.4% sodium
`bicarbonate injection combined with 10 ml of 0.9% NaCl
`injection, and the third contained 100 ml of epinephrine
`hydrochloride injection (1:1000) combined with 10 ml
`of 0.9% NaCl injection to make a resultant concentration
`of 1:100,000.
`
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`
`Injection of Lidocaine Solutions
`The injection technique used in this study was the
`same used by Thalhammer et al.6 and Popitz-Bergez et
`al.7 to produce a motor and sensory block of the sciatic
`nerve in a rat. Fifteen groups of rats, each group with
`n 5 9 or 10, received a percutaneous injection with a
`27-gauge needle of 100 ml of one of the 15 lidocaine
`solutions previously described. An additional six groups
`of rats, each with n 5 4, received a percutaneous injec-
`tion of 100 ml of one of six control solutions.
`
`Evaluation of Sensory Functional Deficit
`Analgesia was measured in the ipsilateral limb every 2
`min after injection for up to 40 min, and every 10 min
`thereafter. The neurologic evaluation was a modification
`of the protocol described by Thalhammer et al.6 Noci-
`ception was quantified by evaluating the rat’s with-
`drawal response to a deep pinch (forceful enough to
`reach bone) by serrated forceps at the fifth metatarsal.
`The withdrawal response was graded on an ordinal scale
`of 0 (no withdrawal response) to 4 (a normal, brisk
`withdrawal response). A score of 4 meant a normal
`reaction characterized by a brisk, strong paw with-
`drawal, vocalization, and an attempt to bite the forceps.
`A score of 3 was characterized by a slower, weaker
`withdrawal response, vocalization, and no attempt to
`bite the forceps. A score of 2 corresponded to an even
`
`Research Inc., Boston, MA) with a combination Ag/AgCl-
`glass electrode (Corning Inc., Acton, MA) in a slowly
`stirred solution to minimize vortex-induced dissolution
`of carbon dioxide.
`
`Preparation of Crystalline Control Solutions
`Three control solutions were prepared. The first con-
`tained only sterile water, the second contained epineph-
`rine dissolved in sterile water to a concentration of
`1:100,000 (according to regimen 4), and the third con-
`tained 8.4% sodium bicarbonate dissolved in sterile water
`(according to regimen 3) and diluted to a ratio of 1:10.
`
`Preparation of Commercial 0.5% Lidocaine
`Solutions
`Five 0.5% lidocaine solutions were prepared from com-
`mercially available solutions. The lidocaine concentra-
`tion in all solutions was exactly 0.5%, and in solutions
`with NaOH, pH was adjusted to 7.85. In solutions with
`epinephrine or sodium bicarbonate, there was no inten-
`tional adjustment of pH, in order to simulate clinical
`conditions: (1) CL: 0.5% unalkalinized lidocaine hydro-
`chloride injection (pH 5 6.58); (2) CLOH: 0.5% lidocaine
`hydrochloride alkalinized with NaOH (pH 5 7.85)—10 ml
`of 0.5% lidocaine hydrochloride injection was alkalinized
`with 10 ml (1:1000) of 2N NaOH; (3) CLBC: 0.5% lido-
`caine hydrochloride alkalinized with 8.4% sodium bicar-
`bonate (10:1; pH 5 7.99)—1% lidocaine hydrochloride
`injection (Abbott Laboratories) was diluted to 0.55%
`solution with 0.9% NaCl injection (Abbott Laboratories);
`1 ml of 8.4% sodium bicarbonate injection (Abbott Lab-
`oratories) was added to 10 ml of the 0.55% lidocaine
`solution; (4) CLE: 0.5% unalkalinized lidocaine hydro-
`chloride containing epinephrine (1:100,000) injection
`(Abbott Laboratories; pH 5 6.46); and (5) CLBCE: 0.5%
`lidocaine hydrochloride with 8.4% sodium bicarbonate
`(10:1) and epinephrine (1:100,000) (pH 5 7.85)—1%
`lidocaine hydrochloride injection was diluted to 0.55%
`with 0.9% NaCl injection; 1 ml of 8.4% sodium bicarbon-
`ate injection was added to 10 ml of the 0.55% lidocaine
`hydrochloride solution, and 110 ml of epinephrine hy-
`drochloride (1:1000) injection (American Regent Labo-
`ratories, Shirley, NY) was added to this solution.
`
`Preparation of Commercial 1.0% Lidocaine
`Solutions
`Five 1.0% lidocaine solutions were prepared from com-
`mercially available solutions. The lidocaine concentra-
`tion in all solutions was exactly 1.0%, and in solutions
`with NaOH, pH was adjusted to 7.85. In solutions with
`epinephrine or sodium bicarbonate there was, again, no
`intentional adjustment of pH, to simulate clinical condi-
`tions: (1) *CL: 1% lidocaine hydrochloride injection
`(pH 5 6.64); (2) *CLOH: 1% lidocaine hydrochloride
`alkalinized with NaOH (pH 5 7.85)—10 ml of 1% lido-
`caine hydrochloride injection was alkalinized to pH 5
`
`Anesthesiology, V 93, No 4, Oct 2000
`
`

`

`1048
`
`SINNOTT ET AL.
`
`slower withdrawal response, no vocalization, and no
`biting of the forceps. A score of 1 was characterized by
`a very weak attempt to withdraw. And a score of 0 was
`given when the rat showed none of these responses.
`Previous reports showed that motor block of the sciatic
`nerve could not account for withdrawal response defi-
`cits, proving that true sensory loss was being tested.6
`Analgesia was reported as the mean withdrawal re-
`sponse to deep pinch 6 SD. The duration of block was
`defined as the time until the response returned to a value
`of 3 (75% of normal) after injection. The time of onset
`was the time it took for the response to reach a value of
`2 (50% of normal), from a normal response of 4, after
`injection. The maximum degree of impairment was con-
`sidered the lowest withdrawal response score achieved
`after injection of local anesthetic.
`
`Statistical Analysis
`The duration of onset, the degree of block, and the
`duration of block achieved with lidocaine solutions were
`compared using the Mann–Whitney U rank sum test
`(SPSS Software, Chicago, IL). Only groups of rats receiv-
`ing injection of lidocaine solutions at the same concen-
`tration (either 0.5% or 1.0%) and prepared from the same
`materials (crystalline or commercial
`lidocaine) were
`compared against each other. Furthermore, only pairwise
`comparisons were made between either two groups (those
`receiving injections of lidocaine solutions without epineph-
`rine) or three groups (those receiving injections of lido-
`caine solutions with epinephrine). Therefore, the criterion
`for significance was adjusted, using a Bonferroni approxi-
`mation, to P 5 0.025 for pairwise comparison between
`two groups and P 5 0.017 for pairwise comparison be-
`tween three groups.
`
`Results
`
`Analgesia with 0.5% Crystalline Lidocaine Solutions
`None of the three control solutions (sterile water, 8.4%
`sodium bicarbonate (1:10), or epinephrine (1:100,000)
`produced any impairment of nocifensive function, i.e., a
`normal withdrawal response of 4 was present for 60 min
`after injection. Furthermore, there were no indications
`of motor deficits, such as foot pronation, toe curling, or
`dragging of the limb.
`Considering onset time, alkalinization of 0.5% lido-
`caine without epinephrine by either NaOH (LOH) or
`sodium bicarbonate (LBC) produced a faster onset than
`did unalkalinized lidocaine (L): 3.2 6 1.3 (P 5 0.006)
`and 2.9 6 1.0 min (P 5 0.0024) versus 6.0 6 2.1 min
`(6 SD), respectively (fig. 1). Furthermore, onset times
`with either alkalinizing agent did not differ significantly
`from each other (P 5 0.678). Considering degree of
`block and duration of block, these parameters did not
`differ significantly among the three solutions. Mean val-
`ues (6 SD) of the lowest withdrawal response score
`achieved with the L, LBC, and LOH solutions were 1.2 6
`1.0, 1.0 6 0.8, and 0.4 6 0.7, respectively (P $ 0.059),
`and those for duration of block were 15.0 6 6.2 min,
`11.4 6 3.0 min, and 17.8 6 7.8 min. Duration of block
`achieved with the LBC solution was less, but insignifi-
`cantly so, than that with both L (P 5 0.054) and LOH
`(P 5 0.085).
`When 0.5% crystalline lidocaine with epinephrine
`(1:100,000) was alkalinized to pH 7.85 with either so-
`dium bicarbonate or sodium hydroxide, there were no
`significant differences (P $ 0.1) between the two in
`onset, degree, or duration of block (fig. 2). Mean onset
`times were 2.8 6 1.0 min for both, mean withdrawal
`response scores were 0.0 6 0.0 for LE and 0.2 6 0.3 for
`
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`
`4 • - • - • ♦ ♦ ♦ ♦ ♦ ♦7♦ •--1---•-•-•-• /~
`
`3
`
`2
`
`1
`
`0
`
`~ /
`
`/
`
`ci
`if.)
`ti
`_c
`()
`C
`0:::
`g-
`Q)
`0
`-8
`3l
`C
`0
`Cl.
`(/)
`
`(1) a:
`
`0
`
`2
`
`4
`
`6
`
`8 1 0 12 14 16 18 20 22 24 26 28 30 32 34 36
`Time (Minutes)
`
`Anesthesiology, V 93, No 4, Oct 2000
`
`Fig. 1. Time course of analgesia (inhibition
`of the response to an intense pinch) after
`injection of 0.5% lidocaine hydrochloride
`solutions prepared from crystalline lido-
`caine hydrochloride: plain lidocaine hy-
`drochloride ((cid:140) L; pH 5 5.1; n 5 10); lido-
`caine hydrochloride
`alkalinized with
`NaOH (V LOH; pH 5 7.8; n 5 10); lidocaine
`hydrochloride alkalinized with sodium bi-
`carbonate (v LBC; pH 5 7.8; n 5 10); con-
`trol (» n 5 4).
`
`

`

`BICARBONATE SHORTENS PERIPHERAL NERVE BLOCK
`
`1049
`
`~ 4 . . . . . . . . . . . . . . . -•-•-.11?1~-•
`;:1/
`J,
`
`"
`
`3
`
`/ }
`
`Fig. 2. Time course of analgesia after in-
`jection of 0.5% lidocaine solutions with
`epinephrine prepared from crystalline li-
`docaine hydrochloride: lidocaine hydro-
`chloride with epinephrine (1:100,000)
`and neutralized with NaOH (M LE; pH 5
`7.9; n 5 10);
`lidocaine hydrochloride
`with 8.4% sodium bicarbonate (10:1) and
`epinephrine (1:100,000; m LBCE; pH 5
`7.8; n 5 10); control (» n 5 4).
`
`(1)
`(/)
`C
`0
`Q.
`(/)
`
`(1) a:
`
`0
`
`0
`
`1 0
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`Time (Minutes)
`
`1 00 110 120 130
`
`Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/93/4/1045/401400/0000542-200010000-00028.pdf by guest on 08 October 2020
`
`LBCE, and the mean durations of block were 72.0 6 16.0
`min for LE and 61.0 6 13.8 min for LBCE.
`
`Analgesia with 0.5% Commercial Lidocaine
`Solutions
`Sciatic nerve injections with the three control solu-
`tions for this component of the study (see Methods)
`produced no analgesia or motor block indications for 60
`min after injection.
`Regarding onset time, with 0.5% commercial lidocaine
`without epinephrine, i.e., CL, CLBC, and CLOH, it was
`not possible to compare this parameter among the solu-
`tions because several animals never achieved a with-
`drawal response score of 2, which was the criterion for
`onset. Assessment of degree of block showed that alka-
`linization with sodium bicarbonate (CLBC) produced no
`significant difference in degree of analgesia (mean with-
`
`drawal response score was 3.0 6 0.6) compared with
`unalkalinized lidocaine (CL, 2.8 6 1.1; fig. 3). However,
`alkalinization with sodium hydroxide CLOH resulted in a
`significantly greater degree of impairment (1.1 6 1.2)
`than that with CL (P 5 0.017) and CLBC (P 5 0.004).
`With regard to block duration, there were no significant
`differences between unalkalinized lidocaine (13.2 6 8.3
`min) versus that alkalinized with sodium bicarbonate
`(4.6 6 4.6, P 5 0.021) or NaOH (12.8 6 5.5). However,
`block duration with CLBC was significantly less than that
`with CLOH (P 5 0.006).
`Compared with unalkalinized solutions of 0.5% com-
`mercial
`lidocaine with epinephrine (1:100,000; CLE),
`solutions alkalinized with sodium bicarbonate (CLBCE)
`produced no significant differences relative to onset
`(4.0 6 1.3 min for CLE and 3.8 6 1.1 min for CLBCE; P 5
`0.72), degree (a score of 0.0 6 0.0 for both), or duration
`
`Fig. 3. Time course of analgesia after in-
`jection of commercial 0.5% lidocaine so-
`lutions: plain lidocaine hydrochloride ((cid:140)
`CL; pH 5 6.6; n 5 10); lidocaine hydro-
`chloride alkalinized with NaOH (V CLOH;
`pH 5 7.8; n 5 10); lidocaine hydrochlo-
`ride alkalinized with 8.4% sodium bicar-
`bonate (10:1; v CLBC; pH 5 8.0; n 5 10);
`control (» n 5 4).
`
`0
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`
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`
`Anesthesiology, V 93, No 4, Oct 2000
`
`0
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`2
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`4
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`6
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`8 1 0 12 14 16 18 20 22 24 26 28 30 32 34 36
`
`Time (Minutes)
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`

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`1050
`
`0
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`0
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`1 0
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`20
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`30
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`40
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`50
`
`60
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`70
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`80
`
`90
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`1 00
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`11 0
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`1 20 1 30
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`Time (Minutes)
`
`SINNOTT ET AL.
`
`Fig. 4. Time course of analgesia after in-
`jection of commercial 0.5% lidocaine so-
`lutions with epinephrine: lidocaine with
`epinephrine (1:100,000; M CLE; pH 5 6.5;
`n 5 10);
`lidocaine with epinephrine
`(1:100,000) and 8.4% sodium bicarbonate
`(10:1; m CLBCE; pH 5 7.9; n 5 10); con-
`trol (» n 5 4).
`
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`
`of block (61.0 6 10.4 min for CLE and 57.0 6 7.8 min for
`CLBCE; P 5 0.3845; fig. 4).
`
`Analgesia with 1.0% Commercial Lidocaine
`Solutions
`With 1% commercial lidocaine without epinephrine,
`there were no significant differences relative to onset
`time among the three solutions (fig. 5): CL was 3.2 6 1.0
`min, CLBC was 2.8 6 1.4 min, and CLOH was 2.4 6 0.8
`min; P $ 0.0752. Relative to degree of block, the addi-
`tion of sodium bicarbonate (*CLBC) significantly (P #
`0.011) decreased the degree of block compared with
`both unalkalinized lidocaine (*CL) and lidocaine with
`NaOH (*CLOH). The mean withdrawal response score
`with *CLBC was 0.8 6 0.9, and with *CL and *CLOH it
`was 0.0 6 0.0. Concerning duration of block, the addi-
`
`tion of sodium bicarbonate significantly (P 5 0.0002)
`shortened the duration of block compared with both
`unalkalinized lidocaine and lidocaine alkalinized with
`NaOH. Mean duration of block with *CLBC was 14.4 6
`5.1 min; with *CL it was 55.0 6 13.6 min, and with
`*CLOH it was 38.0 6 6.0 min. The duration of block with
`unalkalinized lidocaine was significantly (P 5 0.004)
`greater than that with NaOH, a finding for which we
`have no ready explanation.
`Adding sodium bicarbonate to 1% lidocaine with epi-
`nephrine (1:200,000) hastened the onset compared with
`unalkalinized (2.4 6 0.8 for *CLBCE vs. 4.4 6 1.3 min for
`*CLE; P 5 0.004; fig. 6). However, the addition of bicar-
`bonate did not significantly (P $ 0.9281) alter the degree
`(a mean withdrawal response score of 0.0 6 0.0 for
`both) or duration of block (75.6 6 18.9 min for *CLE and
`77.8 6 11.3 min for *CLBCE).
`
`Fig. 5. Time course of analgesia after
`injection of commercial 1% lidocaine
`solutions: plain lidocaine hydrochloride
`((cid:140) CL; pH 5 6.6; n 5 10); lidocaine hy-
`drochloride alkalinized with NaOH (V
`CLOH; pH 5 7.8; n 5 10); lidocaine hy-
`drochloride alkalinized with 8.4% so-
`dium bicarbonate (10:1; v CLBC; pH 5
`7.8; n 5 10); control (» n 5 4).
`
`0
`
`10
`
`20
`
`30
`
`60
`50
`40
`Time (Minutes)
`
`70
`
`80
`
`90
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`100
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`Anesthesiology, V 93, No 4, Oct 2000
`
`

`

`BICARBONATE SHORTENS PERIPHERAL NERVE BLOCK
`
`1051
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`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`Time (Minutes)
`
`1 00 11 0 120 130
`
`out added epinephrine, the reverse occurs, i.e., block
`duration and degree of analgesia are substantially de-
`creased by the addition of sodium bicarbonate without
`effecting onset, compared with that observed with no
`alkalinization or alkalinization with NaOH. In contrast,
`when 1.0% lidocaine is coinjected with epinephrine,
`bicarbonate hastens onset.
`Our finding that adding sodium bicarbonate to 1%
`commercial lidocaine without epinephrine does not af-
`fect onset time has been previously described in clinical
`studies. It was shown that alkalinization with sodium
`bicarbonate of 2% commercial lidocaine without epi-
`nephrine did not affect the onset of epidural anesthesia8,
`nor did it affect the onset of action of 1% lidocaine
`during subcutaneous injection.9 However, other studies
`have reported conflicting results. Two investigations
`have shown that alkalinization with sodium bicarbonate
`does accelerate the onset time of lidocaine. The addition
`of sodium bicarbonate to 2% lidocaine produced a faster
`onset of epidural block in one study2 and of peribulbar
`anesthesia in another.5 Unfortunately, in none of the
`clinical studies was the injectate pH reported, before or
`after adjuvant addition. No clinical studies report the
`results of addition of NaOH to local anesthetic solutions.
`We wish to point out that NaOH is not approved for
`clinical use as an alkalinizing agent for local anesthetics
`and do not advocate its use for this purpose until rigor-
`ous clinical testing of its safety and efficacy is performed.
`Our finding that sodium bicarbonate may shorten the
`block duration of lidocaine when it is not coinjected
`with epinephrine, compared with unalkalinized and al-
`kalinized with NaOH, conflicts with the results of one
`study. Parham and Pasieka9 showed that adding sodium
`bicarbonate to 1% lidocaine without epinephrine did not
`affect its duration of action after subcutaneous injection.
`Precipitation was considered as a possible explanation
`
`Fig. 6. Time course of analgesia after in-
`jection of commercial 1% lidocaine solu-
`tions with epinephrine: lidocaine with
`epinephrine (1:200,000; M CLE; pH 5 4.5;
`n 5 9); lidocaine with epinephrine (1:
`200,000) and 8.4% sodium bicarbonate
`(10:1; m CLBCE; pH 5 7.5; n 5 9); control
`(» n 5 4).
`
`ci
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`
`Discussion
`
`The results of our investigation show that the effects of
`sodium bicarbonate on the onset, degree, and duration
`of peripheral nerve block had two discrete manifesta-
`tions: (1) they differed with respect to the presence or
`absence of epinephrine, and (2) they differed with re-
`spect to crystalline versus commercial lidocaine.
`With 1% commercial lidocaine, bicarbonate decreased
`degree and duration, lacking any effect on onset when
`injected without epinephrine. When coinjected with
`epinephrine, however, the reverse occurred: bicarbon-
`ate hastened onset without effecting degree or duration.
`Sodium bicarbonate hastened the onset of block in-
`duced by 0.5% crystalline lidocaine in solutions without
`epinephrine. But with 0.5% commercial lidocaine with-
`out epinephrine, none of the block parameters were
`affected by bicarbonate. With the other commercial
`non– epinephrine-containing solution, i.e., 1% lidocaine
`without epinephrine, bicarbonate did not affect onset
`time but reduced both degree of block (by 25%) and
`duration of block (by . 50%) compared with lidocaine
`unalkalinized and alkalinized with NaOH. Sodium bicar-
`bonate alkalinized the pH of this solution to 7.75 6 0.05.
`The pH of the unalkalinized solution was 6.64 6 0.05,
`whereas that of the solution alkalinized with NaOH was
`7.85 6 0.05. The fact that the pH of the two alkalinized
`solutions are within each other’s error range indicates
`that the effect of bicarbonate on 1% lidocaine is probably
`independent of pH and, rather, a direct effect of bicar-
`bonate itself.
`These results show that the onset of rat peripheral
`nerve block with lidocaine at a low concentration (0.5%)
`may be accelerated by modest alkalinization, from addi-
`tion of either sodium hydroxide or sodium bicarbonate,
`with no perceptible effect on degree or duration. How-
`ever, at higher concentrations of lidocaine (1.0%) with-
`
`Anesthesiology, V 93, No 4, Oct 2000
`
`

`

`1052
`
`SINNOTT ET AL.
`
`alkalinization with sodium bicarbonate reduces pain on
`injection by increasing pH (acidic solutions per se are
`algogenic), decreases onset time, and perhaps produces
`a more complete block by elevating the pH of the lido-
`caine solutions closer to the pKa of this local anesthetic
`(7.8), thus favoring the proportion of the deprotonated,
`membrane-permeant form of the local anesthetic.11,12
`Furthermore, ion trapping of charged local anesthetic
`inside the nerve axons, resulting from axoplasmic acid-
`ification, has also been posited, although experimental
`evidence for this is weak.13 Our investigation has not
`validated the expectation of enhanced blockade, al-
`though the expected physical chemical changes in the
`drug do occur with alkalinization, and lidocaine block of
`nerve impulses in vitro is potentiated by bicarbon-
`ate.13–15 Sodium bicarbonate alkalinization may reduce
`onset time, but it also decreases the degree and duration
`of analgesia. These observations in rats indicate that
`further clinical investigations are necessary to elucidate
`the role of sodium bicarbonate alkalinization of plain
`lidocaine and lidocaine containing epinephrine on the
`quality of peripheral nerve block.
`
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`
`References
`
`1. Fukuda T, Naito H: The effect of pH adjustment of 1% lidocaine on the onset
`of sensory and motor blockade of epidural anesthesia in nonpregnant gyneco-
`logical patients. J Anesth 1994; 8:293– 6
`2. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Lauber R, Hogstrom H,
`Scaramozzino P, Luginbuhl M, Sieber TJ, Zbinden AM: Adding sodium bicarbon-
`ate to lidocaine enhances the depth of epidural blockade. Anesth Analg 1998;
`86:341–7
`3. Gosteli P, Van Gessel E, Gamulin Z: Effects of pH adjustment and carbon-
`ation of lidocaine during epidural anesthesia for foot and ankle surgery. Anesth
`Analg 199