Acta anaestli. Scandinav. 1965, Supplementum XVI, 55-69.
`
`A C O M P A R I S O N OF T H E H Y D R O C H L O R I D E
`A N D CARBON D I O X I D E SALTS OF
`L I D O C A I N E A N D P R I L O C A I N E I N E P I D U R A L
`ANALGESIA
`
`PHILIP R. BROMACE
`
`In epidural analgesia the quality and extent of blockade varies widely
`with different drugs, and the technique provides a useful means of comparing
`the efficiency of local anaesthetics in man, since the onset and spread of anal-
`gesia is slow, allowing plenty of time for observation and comparative measure-
`ments.
`TRUANT and BROMACE (unpublished data) have shown, both in vivo and
`in vitro, that the carbonic salts of local anaesthetics have a more powerful
`blocking action than the conventional hydrochloride salts in equivalent concen-
`tration.
`This paper presents the effects of the 2 yo and 3 yo hydrochloride salts of
`lidocaine and prilocaine (propitocaine), compared with their carbonated salts
`formed by combining the anaesthetic bases with carbonic acid.
`
`T H E O R Y OF C A R B O N A T E D L O C A L A N A E S T H E T I C
`S O L U T I O N S
`Hydrogen-ion concentration is one of the most important factors influencing
`uptake of local anaesthetic drugs (KRAIIL et al. 1940, ALBERT 1952), and the
`choice of pH is a compromise between the two conflicting interests of water
`solubility on the one hand and solubility in a lipoid medium on the other,
`since an injectable local anaesthetic must dissolve in both media before it
`can reach its site of action.
`Local anaesthetics penetrate the lipoid phase of cell membranes as the
`electrically indifferent undissociated base, but since the base is only poorly
`soluble in water it must be prepared as a water-soluble salt before it can be
`injected in an aqueous medium:
`The equation :
`
`ALL 2044
`PROLLENIUM V. ALLERGAN
`IPR2019-01505 et al.
`
`

`

`56
`
`PHILIP R. BROMAGE
`
`proceeds to the left in an acid pH when ionization is almost complete, and to
`the right in an alkaline medium when ionization is minimal (Fig. 1). Many
`local anaesthetic solutions are dispensed with a low pH in the region of 4.0,
`for purposes of stability and prolonged storage life, and these solutions must
`be buffered in the tissues before sufficient free base is liberated to effect blockade.
`The time taken to buffer these acid salts delays analgesic action, and so potency
`tends to vary inversely with the initial hydrogen ion concentration (LOFGREN
`1948).
`
`IONIZATION OF A BASE DETERMINED BY pH
`
`4
`
`3
`
`2
`
`1
`
`P K ~ - P H o
`
`-1
`
`-2
`
`-3
`
`-4
`
`0
`
`10
`
`20
`
`30
`
`70
`
`80
`
`90
`
`10
`
`'
`
`40
`50
`60
`% IONIZATION
`FIG. I.-Relationship between pH and degree of ionization of local anaesthetics. When
`P+l
`PI
`the pKa = pH of solution, the ratio - = 1.
`The most efficient compromise in this dilemma between aqueous and lipoid
`solubility will be one that promotes rapid conversion of a water-soluble acid
`salt to undissociated free base. Being an acid gas, carbon dioxide can be made
`to combine with local anaesthetic bases, under the right conditions of low
`
`

`

`LIDOCAINE AND PRILOCAINE IN EPIDURAL ANALGESIA
`
`57
`
`temperature and high partial pressure, and the resultant compounds are water
`soluble.
`Solutions of local anaesthetics prepared in this way have two interesting
`features. First, the drug is present in a bicarbonate form, which is very rapidly
`converted to the undissociated base once the partial pressure of carbon dioxide
`falls to that of the tissue. Second, although the pH of the carbonated solution
`is practically the same as that of the equivalent hydrochloride solutions, the
`rapid diffusion of carbon dioxide across cell membranes causes a fall of intra-
`cellular pH in the immediate neighbourhood, and the resulting electro-
`chemical gradient favours a greater uptake of local anaesthetic base by the
`tissues (CALDWELL 1958, HALPERN and BINACHI 1959, KRAHL and CLOWES
`1938, KRAHL et al. 1940).
`Solutions of lidocaine and prilocaine base have been made available in
`sealed ampoules at a pC0, of 700 mm Hg. The concentrations of base in these
`solutions was 1.75% and 1.71 yo respectively, which is equivalent to the amount
`present in 2% solutions of the corresponding hydrochloride salts.
`
`E XPE R I MENTAL M E T H 0 DS
`Observations of the speed of onset and segmental spread of analgesia and
`intensity of motor blockade were made in 659 patients receiving epidural
`analgesia.
`
`Solutions
`1. 2 yo and 3 yo lidocaine and prilocaine hydrochloride with and without
`adrenaline. When adrenaline was employed it was added freshly to the solution
`immediately prior to injection to produce a concentration of 1 : 200,000. The
`pH of these solutions were checked in a Radiometer pH meter and varied only
`between 6.27 and 6.71.
`2. (a) 1.75% lidocaine C0,-base (at a pC0, of 700 mm Hg) with and
`without adrenaline 1 :200,000; (b) 1.71 yo prilocaine C0,-base with adrenaline
`1 :200,000. The pH of these solutions was 6.49-6.51, measured at 28°C before
`any appreciable evolution of CO,. After equilibration with CO, at 35.6 mm
`Hg the pH rises to 7.30.
`The solutions were administered in the distribution shown in Table 1.
`Uncomplicated surgical patients and volunteers were chosen for the main
`part of the investigation. Subjects with occlusive vascular disease were excluded
`from this series, since they have atypical responses to epidural blockade (BRo-
`MACE 1962a, b). A smaller series of patients receiving continuous epidural
`blockade for labour pains and vaginal delivery has been presented, in order
`to compare the total requirements of analgesic base from the hydrochloride
`and C0,-base solutions over a long period.
`
`

`

`58
`
`Solution
`
`I
`
`Surgical patients
`2 yo plain lidocaine HCI.. ..........
`2 yo lidocaine HCI + adrenaline.. ...
`3 yo plain lidocaine HCI.. ..........
`3 yo lidocaine HCI + adrenaline.. . . .
`2 yo plain prilocaine HCI .... <. ....
`2 Yo prilocaine HCI + adrenaline . . .
`3 yo plain prilocaine HCI ..........
`3 % prilocaine HCl + adrenaline . . .
`1.75 Yo lidocaine base.. ...............
`1.75 Yo lidocaine base + adrenaline. . . .
`1.71 yo prilocaine base + adrenaline. . .
`
`Obstetrical patients
`2 yo lidocaine HCI + adrenaline.. ...
`2 % prilocaine HCI + adrenaline . . .
`1.75 Yo lidocaine base + adrenaline.. ...
`1.71 % prilocaine base + adrenaline . . .
`
`PHILIP R. BROMACE
`TABLE 1.
`Distribution of analgesic solutions in a series of 659 patients receiving
`epidural blockade for surgical and obstetrical indications.
`
`I Mean Age
`
`49.1
`48.6
`53.0
`47.0
`48.9
`49.2
`45.4
`48.8
`48.4
`50.0
`48.9
`
`25.9
`25.0
`26.7
`26.8
`
`N
`
`35
`56
`25
`25
`35
`35
`45
`40
`36
`106
`101
`
`20
`20
`40
`40
`
`Epidural blockade was performed in a standardised manner at the second
`lumbar interspace with the patient sitting up, as previously described (BROMAGE
`1962a, b). In the majority of cases, a syringe filled with air was used for the
`loss-of-resistance test, in order to avoid possible errors of dosage from injecting
`an inexact amount of diluent at the moment of piercing the ligamentum
`flavum .
`
`Measurements of Sensory Blockade
`The patients were tested for analgesia to pin prick within two minutes of
`injection, and the upper and lower limits of segmental analgesia were charted
`on graph paper every minute until the spread of analgesia was complete.
`Thereafter, analgesia was tested every 5-1 0 minutes. The following information
`was obtained from plotting such a diagram (Fig. 2).
`1. Latency of Initial Onset: This is the time taken for analgesia to make its
`first objective appearance, usually in the upper lumbar dermatomes.
`2. Latency of Complete Spread: The time taken for analgesia to spread to
`its farthest limits and to become established in all segments between these
`upper and lower limits.
`
`

`

`LIDOCAINE AND PRILOCAINE IN EPIDURAL ANALGESIA
`
`59
`
`DORSAL
`
`v)
`
`LUMBAR
`
`a z
`h
`v)
`
`SACRAL
`
`i
`
`- B y \ ,
`5
`10
`
`,
`,
`, ,
`IS 20 25 3 0
`MINUTES
`FIG. 2.-Dermatome graph of onset and decay of epidural analgesia.
`A = Latency of initial onset.
`B = Latency of complete spread.
`
`3. Extent of Segmental Spread: In terms of the relationship between the dose
`of anaesthetic used and the number of dermatomes rendered analgesic. Else-
`where, it has been shown that the spread of epidural analgesia is dependent
`on (a) age, and (b) the mass of anaesthetic solute injected, rather than on volume
`or concentration alone (BROMAGE 1962a, b, 1963), and so in this paper, spread
`will be expressed as the mass of base required to block one spinal segment.
`For example, supposing an epidural injection of 20 ml of 2 yo lidocaine hydro-
`chloride produced analgesia of all segments up to T,. If we count the spinal
`segments up from S,, this makes a total of 20 segments (5 sacral, 5 lumbar,
`and 10 thoracic). 20 ml of 2% lidocaine hydrochloride contains:
`20 x 17.5 mg of lidocaine base.
`350
`Dose
`- _ -
`- - 17.5 mg base per segment.
`20
`Segments
`By plotting the dose requirements of many individual cases against age
`we can obtain a mean regression line for any particular solution, and so
`compare the spreading effects of different solutions.
`4. Duration of Action: Figures for duration of action are apt to be misleading
`unless the observer states precisely what is meant by “duration”. Sometimes,
`
`Thus,
`
`

`

`60
`
`PHILIP R. BROMAGE
`
`one or two dermatomes will remain anaesthetised long after analgesia has
`disappeared from the rest of the area of blockade; and yet duration of action
`in these residual segments is clearly of no practical importance, for the anaes-
`thetist wants to know how long he can reasonably expect clinical analgesia
`to persist in the main area of the surgical field and in the segments immediately
`around it. For this reason, duration of action has been taken as the interval
`from the time of complete spread of analgesia to the point when analgesia
`has receded two spinal dermatomes. This has been called duration to recession
`of two segments.
`
`Measurement of Motor Blockade
`The pattern of motor blockade is slower to develop and of shorter duration
`than sensory analgesia. Therefore, for purposes of comparison between patients
`it is important that observations of motor blockade should be made at a relatively
`long interval after the induction of epidural analgesia, but before the block
`has begun to recede. An interval of 3 0 4 minutes after induction was chosen
`as the most suitable period for recording and comparing motor paralysis, for
`this is the point at which motor block is most intense after a single epidural
`injection.
`
`Intensity of motor block
`(with sensory block to S,)
`
`I. Complete
`
`11. Almost complete
`
`111. Partial
`
`IV. None
`
`Unable to move
`feet or knees
`
`J ]
`
`Able to move
`feet only
`
`Just able to
`move knrcs
`
`Full flexion of
`knees and fert
`
`FIG. J.--Assessment of motor blockade (see text)
`
`

`

`LIDOCAINE AND PRILOCAINE IN EPIDURAL ANALGESIA
`
`61
`
`Tests for motor paralysis were made in patients with segmental analgesia
`above the 9th thoracic dermatome, and degrees of motor blockade were
`classified simply in terms of ability to move the feet and legs as in Fig. 3. The
`categories of blockade, Complete, Almost Complete, Partial and Nil were
`given arbitrary scores of 100, 66, 33 and 0 per cent respectively, so that the
`average results from each test solution could be expressed as a percentage of
`the maximum possible score of 100.
`
`Total Dose Requirements in Prolonged Obstetrical Administration
`120 obstetrical patients were given continuous epidural blockade for pain
`relief during labour and vaginal delivery, using a technique that has been
`described previously (BROMACE 196 1 ) .
`Briefly, an epidural catheter was inserted at the second lumbar interspace
`when the cervix was between 3 4 cm dilated. Analgesia of the lower thoracic
`and upper lumbar segments was maintained by injecting small volumes of
`analgesic solution up the catheter at intervals of 90-120 minutes until delivery
`was imminent. Then, with the patient sitting up, sacral analgesia was induced
`by injecting a larger volume of the anaesthetic. In this series, the period of
`analgesic administration varied between 1 and 19 hours.
`The 2 % hydrochloride salts with 1 :200,000 adrenaline were used in 40
`patients (20 lidocaine and 20 prilocaine), and a further two groups of 40
`patients each received lidocaine and prilocaine base with adrenaline.
`In each case the total dose of analgesic agent administered during labour
`was plotted against the duration of blockade. Regression lines were drawn
`through the accumulated data points in order to compare the mean dose
`requirements of the four solutions.
`
`R E S U L T S
`
`Ladeny
`The latency of onset and complete spread for the various test solutions
`are shown in Table 2, and the mean latency times are shown graphically in
`Fig. 4.
`Adrenaline shortens the latency of 2 yo and 3 yo prilocaine hydrochloride
`in the same way that it hastens the onset of 2 yo and 3 yo lidocaine hydrochloride
`(BROMAGE et al. 1964). For example, the very slow spreading time of 2%
`plain prilocaine hydrochloride is shortened from 20.2 minutes to 17.3 minutes.
`Latency is dramatically shortened by the C0,-base solutions and spread
`is fastest with 1.75% lidocaine C0,-base plus adrenaline, being complete in
`a mean time of 10.7 minutes.
`
`

`

`62
`
`PHILIP R. BROMAGE
`
`Solution
`
`PH
`
`1
`
`N
`
`Complete Spread
`
`1 $!!$s)
`
`I
`
`S.D.
`
`N
`
`S.D.
`
`2.3
`
`2.6
`2.4
`
`1.7
`2.8
`
`2.4
`2.7
`
`2.2
`
`2.0
`
`1.7
`
`2.2
`
`Onset
`
`I
`
`Mean
`
`$ih;
`
`6.6
`
`6.48
`
`6.46
`6.31
`
`6.27
`6.30
`
`6.70
`6.48
`
`6.49
`
`6.49*
`
`35
`
`51
`25
`
`25
`35
`
`35
`45
`
`45
`
`36
`
`6.49* 106
`
`5.5
`, 5.5
`
`4.9
`8.0
`
`7.3
`7.7
`
`5.2
`
`4.9
`
`3.7
`
`plain lidocaine HCI.. ..
`2
`2 :G lidocaine HCI +
`adrenaline. .............
`3 yo plain lidocaine HCI.. ..
`3 yo lidocaine HCI +
`adrenaline. .............
`2 yo plain prilocaine HCI. . .
`2 yo prilocaine HCI +
`adrenaline. .............
`3 yo plain prilocaine HCI.. .
`3 yo prilocaine HCl +
`adrenaline. .............
`1.75 yo plain lidocaine
`C0,-base. ..............
`1.75 yo lidocaine GO,-base +
`adrenaline. .............
`1.71 Yo prilocaine GO,-base +
`adrenaline. .............
`6.50* 100
`13.2
`98
`1.0
`4.12
`* pH of freshly opened ampoule at 28°C before evolution of carbon dioxide.
`After equilibration with CO, at 35.6 mm Hg, pH rises to 7.30.
`
`1.17
`
`1.2
`1.43
`
`1.2
`1.58
`
`1.81
`1.77
`
`0.83
`
`1.03
`
`35
`
`56
`25
`
`25
`33
`
`33
`42
`
`42
`
`35
`
`0.89
`
`100
`
`18.1
`
`16.3
`15.3
`
`14.0
`20.2
`
`17.3
`17.0
`
`16.2
`
`11.6
`
`10.7
`
`0 5 ONSET
`I
`
`10
`
`0
`
`I = COMPLETE SPREAD
`IS
`20
`
`2s
`
`LlDOCAlNE
`
`PROPITOCAINE
`
`2% PLAIN
`
`1% t ADRENALINE
`
`3% PLAIN
`
`3% t ADRfNALINE
`
`1% PLAIN
`
`1% t ADRENALINf
`
`3% ?LAIN
`
`3% t ADRfNALINf
`
`175% PLAIN
`
`LIDoCAINE
`
`PROPITOCAINE ( 171% + ADRENALINf
`
`175% I ADRENALINE
`
`HYDROCHLORIDE
`
`C 0 2 - BASE
`
`FIG. 4.-Mean
`
`0
`
`I5
`10
`MINUTES
`latencies of onset and complete spread.
`
`5
`
`10
`
`2s
`
`

`

`LIDOCAINE AND PRILOCAINE IN EPIDURAL ANALGESIA
`
`63
`
`Spread of Analgesia
`The spread of analgesia, expressed as the mass of base required per spinal
`segment was plotted against age in every case, and mean regression lines were
`drawn through the data points for each test solution. The results are shown
`in Fig. 5, and are similar to data published previously (BROMACE 1962a, by
`BROMAGE et al. 1964).
`
`’. ’.
`
`’\
`
`----- 3% Plain Propitomine HCI
`1
`.._._. -.. 2% [ ~~~~~&
`[ HCI
`. -
`1.71% Propilocoins Base 1
`
`1.757. Lidocaine Bare
`
`+
`
`?:renoline
`
`‘\\
`
`’*-
`
`I
`20
`
`1
`40
`
`I
`60
`
`I
`80
`
`FIG. 5.-Regression
`
`AGE
`lines of epidural dose requirements per spinal segment in the ages of
`20 to 80 years.
`
`The drug requirements of base per spinal segment are practically identical
`for 2 yo lidocaine and prilocaine hydrochloride with and without adrenaline,
`as well as for 3% prilocaine with adrenaline. However, 3% plain prilocaine
`hydrochloride requires much higher dosage in the younger age groups.
`The C0,-base solutions with adrenaline spread appreciably further, and
`require less mass of base per segment than the hydrochloride salts, the de-
`
`

`

`64
`
`PHILIP R. BROMAGE
`
`crease in dose requirements amounting to a reduction of 15yo at 20 years of
`age to 25% at 80 years.
`
`I n k m i 0 of Motor Blockade
`The various test solutions produced widely differing degrees of motor
`block, from little or none with plain 2% or 3% lidocaine hydrochloride to
`60% of maximum with 1.75% lidocaine C0,-base with adrenaline (see Fig. 6).
`
`HYDROCHLORIDE
`
`LlDOCAlNE
`
`PROPITOCAINE
`
`2% P L A I N
`
`1Y t A D R I N A L I N I
`
`37. P L A I N
`
`37. t A D R I N A L I N I
`
`17. P L A I N
`
`17. t A D 1 I N A L I N I
`
`IT. ?LAIN
`
`37.
`
`A D R l N A L l N t
`
`I
`
`I
`
`I
`
`I
`
`I
`
`t
`
`I
`
`I
`
`C0,- BASE
`
`LIDoCAINE
`
`175% P L A I N
`1757. * A D R I N A L I N I
`PROPITOCAINE (1717. t A D R I N A L I N I
`
`30
`10
`4 0
`PERCENT OF MAXIMUM BLOCKADE
`Frc;. 6.-Average degree of motor blockade of legs expressed as percentage of maximum.
`
`50
`
`b0
`
`0
`
`10
`
`The hydrochloride salt of prilocaine produced slightly more motor block
`than lidocaine hydrochloride. Addition of adrenaline 1 : 200,000 consistently
`improved the quality of motor blockade of all the plain solutions and its effect
`was more marked with lidocaine than with prilocaine. The most intense motor
`paralysis was produced by the C0,-bases with adrenaline, and these solutions
`showed a 6 0 4 5 % improvement over the results with the equivalent hydro-
`chloride salts.
`
`Duration of Blockade
`Duration, in terms of recession of two dermatomes, is summarised in Fig. 7.
`Plain lidocaine, in both hydrochloride and C0,-base forms, has a short
`action of about 45 minutes, whereas plain prilocaine hydrochloride lasts
`about 75-80 minutes.
`All the solutions have their action extended to about the same duration
`of 95-100 minutes when adrenaline 1 :200,000 is added.
`
`

`

`LIDOCAINE AND PRILOCAINE IN EPIDURAL ANALGESIA
`
`65
`
`LlDOCAlNE
`
`I
`I PROPITOCAINE
`
`2% PLAIN
`
`2% t ADRENALINE
`
`13% t ADRENALINE
`
`I
`
`[ 1% PLAIN
`1% + ADlENALlNE
`
`3% PLAIN
`13% t ADRtNALlNl
`
`175% PLAIN
`
`LIDoCAINE
`
`PROPITOCAINE ( 171% + ADRENALINE
`
`175% t ADRENALINE
`
`HYDROCHLORIDC
`
`CO, - BASE
`
`60
`40
`DURATION : MINUTES
`FIG. 7.-Duration of analgesia, from time of complete spread to recession of two spinal
`dermatomes.
`
`80
`
`100
`
`10
`
`Dose Requirements in Prolonged Obstetrical Administration
`The tendency for epidural blockade to spread widely in pregnant women at
`term has been noted elsewhere (BROMAGE 1961, BROMAGE 1962a, b). This
`characteristic is even more pronounced when the C0,-base solutions are em-
`ployed. For example, during the first stage of labour, an initial dose of 3 ml
`of 1.75% C0,-base lidocaine at the second lumbar interspace is usually
`sufficient to provide analgesia from TI,, to L,, whereas 4 or 5 ml of an equivalent
`concentration of the hydrochloride salt is required for the same segmental
`distribution. Moreover, in this dosage, the C0,-base solutions produce a more
`marked sacral hypalgesia, which often deepens to full analgesia after two
`or three repeated injections over a period of three to five hours, so that by
`the time the mother is ready for delivery, little, if any, attention has to be
`paid to providing additional sacral blockade. With the hydrochloride salts,
`on the other hand, a final injection of 10-13 ml of the 2 % solution, given in
`the sitting position, is usually required before painless forceps extraction can
`be effected.
`Thus, the total dose requirements of the C0,-base solutions are considerably
`reduced below those of their hydrochloride counterparts. Fig. 8 shows the mean
`total dose of the two salts of lidocaine and prilocaine expressed as volume of
`solution and as mass of base required for continuous pain relief during labour.
`It can be seen that the total dose is reduced by 25-35% when the C0,-base
`solutions are used.
`
`

`

`66
`
`PHILIP R. BROMACE
`
`PROPITOCAINE
`
`ML
`Solrtion
`
`HOURS OF CONTINUOUS ANALGESIA
`FIG. 8.-Total dose requirements for continuous epidural analgesia during labour and
`delivery. Regression lines for 2 % hydrochloride and equivalent C0,-base salts of lidocaine
`and prilocaine.
`
`This saving is of value in protracted cases extending over 24 hours, when
`the total dosage may be large enough to give rise to cumulative toxicity and
`high concentrations in the maternal and foetal blood (BROMAGE and ROBSON
`1961).
`
`DISCUSSION
`
`The main clinical characteristics of lidocaine and prilocaine are apparent
`from the results of the hydrochloride salts, summarised in figures 4-8. Plain
`2 yo lidocaine hydrochloride has a slow onset and transient action, and produces
`little or no motor blockade. Prilocaine has an even slower latency, but produces
`more motor paresis, and the plain solutions last appreciably longer than plain
`lidocaine, although when adrenaline is added, both compounds have approxi-
`mately the same duration.
`The addition of adrenaline 1 :2OO,OOO produces a much more favourable
`block with both drugs, shortening latency, and increasing the degree of block-
`ade and the duration of analgesia (BROMAGE et al. 1964). This improvement
`
`

`

`LIDOCAINE AND PRILOCAINE IN EPIDURAL ANALGESIA
`
`67
`
`in the quality of blockade is associated with a diminished uptake by the
`circulation, and lower concentrations of the drug in the venous blood (BROMAGE
`and ROBSON 1961).
`Contrary to previously accepted ideas, increasing the concentration of
`drug does not appear to improve the quality of epidural blockade appreciably,
`although latency may be shortened somewhat at certain concentrations
`(BROMAGE 1963, BROMAGE et al. 1964).
`The apparent superiority of 3% plain prilocaine over the 2% solution is
`offset by the large dose requirements of the former solution (see Fig. 5). The
`mean regression lines for the dose requirements of the other hydrochloride
`solutions are practically identical at any given age, but 3% plain prilocaine
`deviates from these, and a much larger mass of drug is required per dermatome
`in the younger age groups. The reason for this deviation is not immediately
`apparent, but its association with youth and its disappearance in old age
`suggests that it may be due to a more rapid uptake and metabolic destruction
`by non-nervous tissue.
`Thus, although prilocaine is less toxic than lidocaine, the 3 yo plain solution
`does not appear to offer any real advantage over the other test solutions and the
`clinical results with 2% plain prilocaine are almost as good as 3y0, if an
`adrenaline-free solution is required.
`The most effective blocks were provided by the C0,-base solutions. These
`produced a very rapid onset and spread of analgesia, and the quality of sensory
`and motor blockade was more intense than with any of the other solutions.
`Although the duration of blockade is not lengthened appreciably by these
`solutions, the tendency to spread over a wider number of segments reduces
`the total dose requirements below those of the hydrochloride solutions, and
`so the dangers of chronic or cumulative toxicity are less, especially during
`prolonged administration.
`The increased spreading tendencies and reduced dosage requirements of
`the C0,-base solutions were particularly noticeable in the obstetrical series,
`where sacral analgesia developed early, and where total dosage was reduced
`about 30% below that of the hydrochloride solutions. Although it can be
`argued that such an early sacral analgesia is theoretically undesirable in the
`first stage of labour (BROMAGE 1961), no undue delay of labour was observed
`in any of these cases.
`The marked effeciency of the C0,-base solutions is due in part to the regional
`intracellular acidosis that they produce from the rapid diffusion of COP
`Naturally, the possible hazards of such a regional hypercarbia must be con-
`sidered if it k to be applied to clinical anaesthesia, for there are theoretical
`dangers associated with the production of an area of low intracellular pH by
`high partial pressures of carbon dioxide.
`Now, each cell carries within itself the seeds of its own destruction in the
`form of lysosomes, and the lysosomal enzymes have a narrow optimal pH in
`
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`

`68
`
`PHILIP R. BROMAGE
`
`the region of 5.0 (WEBS 1963), so that profound intracellular acidosis leads
`to activation of the autolytic enzymes and death of the cell.
`However, in spite of a high pCO,, the actual quantity of carbon dioxide
`present in the C0,-base solutions is small and each millilitre contains about
`0.1 mMole of C02, 0.035 mMole being in solution, plus 0.069 mMole in
`combination as bicarbonate. Thus, the total dose of CO, in an injection of
`20 ml of C0,-base will amount to only 2.0 mMole. The rapid diffusion of
`CO, ensures that this small quantity will be quickly dissipated through the
`tissues, and so it is most improbable that any group of cells will be exposed to
`a high concentration of CO, for long enough to depress intracellular pH to
`dangerous levels.
`Moreover, even direct application of carbon dioxide at one atmosphere to
`a non-myelinated axon has not produced a measured fall of pH below 6.0
`(CALJNELL 1958), and it seems most unlikely that nerves of the intact body,
`surrounded as they are by so many tissue barriers, will suffer such a severe
`acidosis from a comparable but transient partial pressure of COP
`Clinically, the C0,-base solutions appear to be safe and free of undesirable
`side effects. They have been employed in an additional 115 patients who, for
`a number of reasons, could not be categorised in this comparative series. Some
`of these patients were severely arteriosclerotic and some gravely ill from other
`causes. And so a total number of more than 400 patients have received epidural
`blocks with the C0,-base solutions and no untoward effects have been en-
`countered.
`The marked efficiency of the C0,-base solutions in epidural analgesia
`makes them superior in every way to their hydrochloride counterparts, and
`it would seem that they are worthy of wider clinical trial. The advantage to
`be gained is probably greatest in the case of prilocaine. This compound is less
`toxic than lidocaine, but the very slow latency of its hydrochloride solutions
`is an undesirable feature for epidural techniques in a busy operating theatre.
`On the other hand, the C0,-salt combines low toxicity with rapid onset and
`intense sensory and motor blockade.
`
`SUMMARY
`
`Lumbar epidural blockade has been used in a series of 659 patients to
`compare the analgesic properties of lidocaine and prilocaine.
`Solutions of both compounds were compared as hydrochloride salts in 2%
`and 3 % concentration with and without adrenaline 1 : 200,000. Solutions of
`base, made soluble by equilibration with carbon dioxide at a pC0, of 700
`mm Hg were also compared in concentrations of 1.75 yo for lidocaine and 1.7 1 %
`for prilocaine.
`
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`

`LIDOCAINE AND PRILOCAINE IN EPIDURAL ANALGESIA
`
`69
`
`Comparisons were based on measurements of latency, spread of analgesia,
`intensity of motor blockade and duration of analgesia.
`The quality of blockade in all the test solutions was increased by the addition
`of 1 : 200,000 adrenaline. Prilocaine has a slow latency compared with lidocaine,
`but in plain solution its duration is longer than that of lidocaine.
`The 3 % hydrochloride solutions have no practical advantage over the
`2 % solutions for epidural blockade.
`Analgesia resulting from the C0,-base solutions is superior in every respect
`to the blockade produced by equivalent concentrations of the hydrochloride
`salts.
`
`McGil1:University and Royal Victoria Hospital, Montreal, Canada.
`
`R E F E R E N C E S
`
`ALBERT, A.: Ionization, pH and biological activity. Pharmacol. Rev. 1952, 4, 136.
`BROMAQE, P. R.: Continuous lumbar epidural analgesia for obstetrics. Canad. mcd. Ass. 3.
`1961,8!5, 1136.
`BROMAGE, P. R.: Spread of analgesic solutions in the epidural space and their site of action;
`a statistical study. Brit. 3. Anacsth. 1962 (a), 34, 161.
`BROMAQE, P. R. : Exaggerated spread of epidural analgesia in arteriosclerotic subjects.
`Brit. m d . 3. 1962 (b), 2, 1634.
`BROMAGE, P. R. : Regional Anaeshesia, Spinal Anaestesia. International Anesthesiology Clinics.
`Little Brown & Company, Boston, Mass. 1963, 1, 547.
`BROMAGE, P. R., M. F. BURFOOT, D. E. CROWELL and R. T. PEITIGREW: Quality of epidural
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`CALDWELL, P. C.: Studies on the internal pH of large muscle and nerve fibres. 3. Physwl.
`1958, 142,22.
`HALPERN, B. N., and R. BINAQHI: Selective permeability of living membranes to carbonic
`acid. Nature 1959, 183, 1397.
`KRAHL, M. E., and G. H. A. CLOWES: Physiological effects of nitro- and halo-substituted
`phenols in relation to extracellular and intracellular hydrogen ion concentration. 11.
`3. cell. COW. Physiol. 1938, 11, 21-39.
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`holm, 1948, pp. 82 and 104.
`TRUANT, A. P., and P. R. BROMAGE: To be published.
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`1963, No. 22, p. 45, Cambridge University Press, Cambridge, England.
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