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Effect of alkalinization of lidocaine on median nerve block
British Journal of Anaesthesia 84 (2): 163–8 (2000)
Effect of alkalinization of lidocaine on median nerve block D. G. Ririe1, F. O. Walker2, R. L. James1 and J. Butterworth1* 1Department
of Anesthesiology and 2Department of Neurology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA *Corresponding author Median nerve blocks were performed in 10 volunteers in a randomized, double-blind, crossover study to compare the effects of 1% plain lidocaine with 1% lidocaine in sodium bicarbonate 0.1 mmol litre–1. Sensations of hot, cold, pinprick and light touch, compound motor and sensory nerve action potentials, and skin temperature were assessed at 2-min intervals. pH was 6.4⫾0.1 for plain lidocaine and 7.7⫾0.2 for alkalinized lidocaine (P⬍0.001). Alkalinized lidocaine produced more rapid inhibition of compound motor action potentials than plain lidocaine (median 4 (range 2–6) vs 9 (2–14) min) (P⫽0.039). Alkalinized lidocaine also produced more rapid onset of inhibition of compound motor than sensory nerve action potentials (4 (2– 6) vs 8 (4–12) min) (P⫽0.0039). There was no significant difference in any other sensory modality between alkalinized and plain lidocaine. These data suggest that addition of bicarbonate to lidocaine for median nerve block significantly increased the rate of motor block without changing the onset or extent of sensory block. Br J Anaesth 2000; 84: 163–8 Keywords: anaesthetics local, lidocaine; nerve, block; formulations, lidocaine; formulations, pH Accepted for publication: September 23, 1999
Different sensory modalities, such as sensations of touch, cold, warm and pain, have been known to be inhibited with different delays after application of local anaesthetics to nerves.1 This phenomenon of different susceptibility of nerve modalities to local anaesthetics is known as differential nerve block. During regional anaesthesia, differential block can be observed during onset, at steady-state and during offset, and drug effects at all three times may guide local anaesthetic selection. For surgical anaesthesia, analgesia is paramount, but the extent of motor nerve block and speed of onset often determines the efficiency and success of the block. However, the labouring parturient seeks rapid onset of analgesia with minimal motor block. Patients suffering from myofascial pain disorders may benefit from selective block of motor nerves while maintaining sensory function. Therefore, understanding differential and steady-state block and interpreting findings of block of specific modalities with specific local anaesthetics are critical to achieving greater success with regional anaesthesia and analgesia. Altering pH can modify the properties of local anaesthesia during onset of block or at steady state.2–5 Numerous studies have reported increased potency and more rapid onset of block with alkalinized local anaesthetics.6–13 However, the effect of alkalinization of local anaesthetics on differential nerve block has not been studied using multiple modality testing. In this study, we have assessed inhibition of median
nerve fibre transmission using both objective sensory, motor and multiple modality subjective sensory data as we have done in previous studies.14–16 Here, we measured onset of block of the median nerve with lidocaine to test our hypothesis that addition of bicarbonate uniformly speeds the onset of anaesthesia in all modalities. Our data rejected this hypothesis as we observed a significant reduction in the delay of onset of motor block, without a commensurate change in the onset of sensory block.
Subjects and methods After obtaining approval from the Clinical Research Practices Committee and informed consent, we studied 10 volunteers undergoing bilateral median nerve block. No subject had clinical or electrodiagnostic findings consistent with median nerve dysfunction. Both dominant and nondominant median nerves were studied in random order. Median nerve block was performed after preparation of the skin with isopropyl alcohol. A 22-gauge B-bevel needle was used. The needle was inserted lateral to the palmaris longus tendon on the volar aspect of the wrist and advanced until it was felt to pass through the flexor retinaculum. Paraesthesia was not sought, and if it occurred, the needle was repositioned. Plain lidocaine HCl 1% (5 ml) (Astra Pharmaceuticals, Westboro, MA, USA) mixed with normal saline 0.1 ml ml–1 or sodium bicarbonate 100 mmol litre–1 (8.4% NaHCO3 0.1 ml ml–1) was injected over 30–45 s
© The Board of Management and Trustees of the British Journal of Anaesthesia 2000
Ririe et al.
after negative aspiration. Both subjects and investigators were blinded to the solution injected. Measurement of pH was performed in all solutions using a standard pH probe. Using a Nicolet Viking (Madison, WI, USA), the median nerve was serially stimulated at the wrist, 2 cm proximal to the site of local anaesthetic injection. Compound muscle action potentials (CMAP) were recorded using belly tendon electrodes over the abductor pollicis brevis and sensory nerve action potentials (SNAP) were recorded using ring electrodes at the base and distal end of the third digit (middle finger).14 15 17 All stimuli were supramaximal, as determined by ramping stimulus intensity to 20% above that required to detect any further change in response amplitude. The response amplitudes of SNAP and CMAP represent the function of Aα sensory and motor fibres, respectively. Unmyelinated C fibre function was assessed using measurements of skin temperature at the distal end of the index finger with a thermistor accurate to 0.1°C. Light touch sensibility was assessed using Von Frey hairs.18 Sensation to pinprick, hot and cold was assessed on the proximal aspect of the palmar surface of the third digit compared with the same stimulus delivered on the volar aspect of the forearm, halfway between the wrist and the elbow, and recorded as a percentage of baseline sensation in the forearm. Baseline measurements of all modalities were recorded. After injection of the local anaesthetic, all modalities were assessed at 2-min intervals until no change was observed over 10 min or until 30 min had elapsed. As end-points to assess differences in block, we used (1) time to the first noticeable difference, (2) time to half normal effects and (3) area under the effect vs time curve. We chose to study 10 volunteers, assuming that the variability in measurements would be comparable with that in previous studies, and that the difference which we wished to detect was (at a minimum) comparable with that between saline and 0.25% lidocaine. A power analysis was performed based on a one-sided Fisher’s sign test (we assumed that alkalinization would not increase the delay of onset). Assuming that the latency of one drug would be greater than the other drug 90% of the time, we calculated that a sample size of eight patients should find a significant difference with 81% power. The pH of the local anaesthetic is reported as mean (SEM). A t test was used to determine pH differences. All other values are expressed as median (range). Statistical significance was tested for all objective and subjective motor and sensory modalities using Fisher’s sign test. Confidence intervals for drug differences with respect to each end-point were determined using Thompson’s method.19 Statistical analysis was performed using the SAS (SAS Institute, Cary, NC, USA) program. P⬍0.05 was judged significant.
Results pH was 6.4 (0.1) (n⫽10) for plain lidocaine and 7.7 (0.2) (n⫽10) for alkalinized lidocaine (P⬍0.001).
Table 1 Time delay (min) until first noticeable difference after injection of lidocaine or lidocaine⫹bicarbonate. *Confidence⫽degree of confidence; CI⫽ confidence interval. Lidocaine⫹bicarb⫽Lidocaine plus bicarbonate; CMAP⫽ compound motor action potentials; SNAP⫽sensory nerve action potentials; Difference⫽differences between onset time with lidocaine and with lidocaine⫹bicarb. †One-sided Fisher’s sign test Median (range)
Confidence (CI) (%)*
P†
Cold Lidocaine Lidocaine⫹bicarb Difference
4 (0, 20) 4 (2, 20) 0 (–16, 6)
98 (–16, 2)
0.50
Hot Lidocaine Lidocaine⫹bicarb Difference
2 (2, 20) 3 (2, 8) 0 (–16, 4)
94 (–16, 2)
0.50
Pinprick Lidocaine Lidocaine⫹bicarb Difference
3 (2, 8) 4 (2, 20) 1 (–4, 12)
98 (–4, 4)
0.23
Temperature Lidocaine Lidocaine⫹bicarb Difference
3 (2, 10) 8 (2, 18) 2 (–2, 16)
97 (–2, 14)
0.11
Von Frey hairs Lidocaine Lidocaine⫹bicarb Difference
3 (2, 24) 5 (2, 12) 1 (–22, 8)
99 (–22, 4)
0.36
SNAP Lidocaine Lidocaine⫹bicarb Difference
2 (2, 4) 2 (2, 4) 0 (–2, 2)
97 (–14, 2)
0.50
CMAP Lidocaine Lidocaine⫹bicarb Difference
2 (2, 6) 2 (2, 4) 0 (–4, 2)
94 (–4, –2)
0.19
There were no differences between alkalinized and plain lidocaine in the time delay until a ‘just noticeable’ difference was detected after injection (Table 1). Increasing the pH of the lidocaine solution had a significant effect only on CMAP inhibition (Table 1). Alkalinization had no effect on median time to the first noticeable difference for CMAP, which was 2 (range 2–6) min for plain lidocaine compared with 2 (2– 4) min for alkalinized lidocaine. Similarly, alkalinization had no effect on median time to first noticeable difference in SNAP (2 (2–4) min for plain vs 2 (2–4) min for alkalinized lidocaine). Furthermore, there was no significant difference between motor block (as measured by CMAP) and sensory block (as measured by SNAP) with either plain or alkalinized lidocaine for the time to first noticeable difference. Inhibition of CMAP occurred more rapidly with alkalinized than plain lidocaine (Table 2). Time to half maximal effect was significantly reduced with alkalinized (4 (2–6) min) compared with plain (9 (2–14) min) lidocaine (P⫽0.02). Motor and sensory block were achieved at approximately the same rate with plain lidocaine; thus there was no difference between CMAP and SNAP for time to
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Table 2 Time delay (min) until half of the maximal effect was observed after injection of lidocaine or lidocaine⫹bicarbonate. *Confidence⫽Degree of confidence; CI⫽confidence interval. Lidocaine⫹bicarb⫽Lidocaine plus bicarbonate; CMAP⫽compound motor action potentials; SNAP⫽sensory nerve action potentials; Difference⫽differences between onset times with lidocaine and with lidocaine⫹bicarb. †One-sided Fisher’s sign test; ‡onset of SNAP and CMAP significantly different (P⬍0.02) Median (range)
Cold Lidocaine Lidocaine⫹bicarb Difference Hot Lidocaine Lidocaine⫹bicarb Difference Pinprick Lidocaine Lidocaine⫹bicarb Difference Temperature Lidocaine Lidocaine⫹bicarb Difference Von Frey hairs Lidocaine Lidocaine⫹bicarb Difference SNAP Lidocaine Lidocaine⫹bicarb‡ Difference CMAP Lidocaine Lidocaine⫹bicarb‡ Difference
10 (0, 20) 7 (4, 20) 1 (–16, 8) 5 (2, 20) 6 (2, 12) 0 (–16, 8) 8 (2, 20) 8 (2, 20) 1 (–16, 12) 8 (2, 20) 10 (2, 22) 0 (–2, 20) 8 (2, 24) 10 (2, 20) 0 (–16, 18) 11 (4, 12) 8 (4, 12) –1 (–8, 2) 9 (2, 14) 4 (2, 6) –4 (–10, 2)
Confidence (CI) (%)*
96 (–8, 6)
97 (–16, 8)
96 (–4, 6)
97 (–2, 6)
98 (–16, 8)
97 (–8, –2)
96 (–8, –2)
Table 3 Area under the effects vs time curve after injection of lidocaine or lidocaine⫹bicarbonate. *Confidence⫽Degree of confidence; CI⫽confidence interval. Lidocaine⫹bicarb⫽Lidocaine plus bicarbonate; CMAP⫽compound motor action potentials; SNAP⫽sensory nerve action potentials; Difference⫽ difference between onset times with lidocaine and with lidocaine⫹bicarb. †One-sided Fisher’s sign test; ‡onset of SNAP and CMAP significantly different (P⬍0.02)
P†
Median (range)
Confidence (CI) (%)*
P†
98 (–1300, –86)
0.05
0.36
Cold Lidocaine Lidocaine⫹bicarb Difference
1663 (455, 3300) 1145 (374, 2000) –244 (–1560, 115)
0.38
Hot Lidocaine Lidocaine⫹bicarb Difference
1233 (321, 2800) 1188 (260, 2800) –27 (–1000, 1200) 96 (–785, 184)
0.50
0.30
Pinprick Lidocaine Lidocaine⫹bicarb Difference
1195 (665, 2000) 1381 (357, 2480) –10 (–718, 1220)
93 (–368, 196)
0.36
0.06
Temperature Lidocaine Lidocaine⫹bicarb Difference
2128 (1938, 2252) 2019 (1930, 2262) –41 (–323, 128)
96 (–172, 49)
0.50
0.45
Von Frey hairs Lidocaine Lidocaine⫹bicarb Difference
2149 (1890, 3465) 2175 (1795, 3013) –81 (–1343, 1013) 98 (–313, 317)
0.50
0.08
SNAP Lidocaine Lidocaine⫹bicarb‡ Difference
1322 (523, 1654) 1049 (409, 1453) –211 (–1013, 250)
98 (–526, 96)
0.17
0.008
CMAP Lidocaine Lidocaine⫹bicarb‡ Difference
816 (308, 1682) 387 (245, 1273) –492 (–1438, 842)
98 (–811, –414)
0.01
half maximal effect. Conversely, motor block was achieved more rapidly than sensory block with alkalinized lidocaine; time to half maximum effect for CMAP was 4 (2–6) min compared with 8 (4–12) min for SNAP (P⫽0.0039). These results were mirrored in our comparisons of area under the effect vs time curves (Table 3). After injection of alkalinized lidocaine, inhibition of CMAP (median area 387 (245– 1273)) occurred significantly faster than that of SNAP (area 816 (308–1682)). The difference between plain and alkalinized lidocaine was also significant for CMAP. Nevertheless, at steady state, there was no difference in the degree of inhibition of SNAP and CMAP with either plain or alkalinized lidocaine (Fig. 1). There were no differences between plain and alkalinized lidocaine for time of onset, time to half maximal effect or extent of steady-state inhibition of hot, cold or pinprick sensations (Fig. 2, Tables 1–3). Also, light touch perception, as measured using Von Frey filaments, showed similar onset and extent of inhibition (Tables 1–3). Skin temperature increased significantly after local anaesthesia, but in a similar manner in the two groups (Fig. 3, Tables 1–3).
Discussion In this study, we used a previously established model to systematically test if alkalinization of lidocaine differentially altered multiple sensory nerve modalities or motor nerve function.14–16 Quantitative and semi-quantitative objective and subjective data were collected. The median nerve was used as a simple and reproducible model of nerve block. Although multiple sensory modalities were tested, alkalinization had no significant effect. In contrast, alkalinization increased the speed of onset of motor nerve block, as measured objectively using CMAP. Previous investigators have reported effects of alkalinized local anaesthetics on various types of nerve block.6–13 20–24 Generally, these studies measured only the delay in onset of pinprick analgesia. Alkalinization has been shown to increase onset, potency and duration of block.6–13 However, reports of no effect of alkalinization have also been published.20–23 The effects of bicarbonate varied depending on the local anaesthetic used, other additives (e.g. epinephrine), type of nerve block, and the definitions used for onset and extent of nerve block. In some studies, a bicarbonate effect
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Fig 1 Effects of plain lidocaine and lidocaine with bicarbonate (bicarb) on sensory nerve action potentials (SNAP) and compound motor action potentials (CMAP). Data are percentage of the initial amplitude of the action potential waveform elicited by supramaximal simulation of the median nerve. Lidocaine with bicarbonate produced a significant effect on CMAP (P⫽0.02), as measured by time to half maximum effect. The effect of bicarbonate on CMAP was different than that on SNAP (P⬍0.02). There was no effect of bicarbonate inhibition of SNAP and there was no significant difference between SNAP and CMAP after injection of plain lidocaine. At steady state, inhibition was similar for plain lidocaine and lidocaine with bicarbonate. All data are median values.
Fig 2 Effects of plain lidocaine and lidocaine with bicarbonate (bicarb) on perception of pinprick, hot and cold. Subjects described the intensity of stimulation in anaesthetized skin as a percentage of perceived intensity in a constant region of unanaesthetized skin. Initially, perceived intensity was the same at the two sites, which was recorded as 100%. No difference was found between plain lidocaine or lidocaine with bicarbonate for hot, pinprick and cold sensibility. All data are median values.
Fig 3 Effects of plain lidocaine and lidocaine with bicarbonate (bicarb) on skin temperature. Data are percentage of the initial temperature (°C). There was no difference between plain lidocaine and lidocaine with bicarbonate. Consistent with our previous experience, most subjects demonstrated a decline in skin temperature, presumably from a sympathetic response to the pain of injection, before demonstrating an increase in temperature as a result of C-fibre (or preganglionic B-fibre) inhibition and vasodilatation. Data are median values.
on speed of onset but not affecting the overall extent of block may have been overlooked.21 Similarly, inability to detect differences between alkalinized and plain local anaesthetic may be a result of insensitive, qualitative measures of motor and sensory block.20 Finally, the conflicting results may be attributable partially to the differential effect of the alkalinization on sensory and motor nerve fibres. Repeated testing over time, attention to speed and overall or steady-state block, use of objective data and multiple modality subjective testing puts our results in context with other study designs. In light of our observations, most likely only onset of motor block was significantly hastened by alkalinization with bicarbonate for median nerve block (and probably other peripheral nerve blocks also). Furthermore, the difference detected was transient, occurring only during onset and only with a single modality. In our study, addition of sodium bicarbonate to lidocaine significantly increased the solution pH, which may affect local anaesthetic block in several ways. Increasing extracellular pH with a constant extracellular local anaesthetic concentration results in greater intracellular local anaesthetic concentration and more complete inhibition of sodium currents, whether or not intracellular carbon dioxide or pH changes.25 When extracellular pH is increased by addition of bicarbonate, decreased intracellular pH through diffusion of carbon dioxide (produced from the reaction of H⫹ and HCO3– in extracellular fluid) may also play a role in enhancing local anaesthetic block through protonation of intracellular free-base local anaesthetic (‘ion trapping’) and increasing the concentration gradient for the free-base local anaesthetic across the plasma membrane.4 In addition, bicarbonate ions probably non-specifically reduce the margin of safety for nerve conduction and may have a direct action on local anaesthetic binding to the sodium channel.26
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However, the role of these various effects in producing differential motor vs sensory nerve block is unclear, particularly during regional anaesthesia in humans. Why should bicarbonate influence the onset of motor but not sensory nerve block? It is possible that responses to bicarbonate may differ depending on the local anaesthetic. Etidocaine, an anaesthetic with many structural similarities to lidocaine, seems to preferentially inhibit motor fibres during onset and offset of regional block.27 It is possible that bicarbonate merely accentuates a subtle motor:sensory difference inherent to this ‘family’ of related compounds. In contrast, there may be structural differences between sodium channels in motor and sensory fibres. Perhaps, sodium channels in motor fibres are more heavily glycosylated than those in sensory fibres, partially ‘shielding’ the sodium channel from local anaesthetic. The more membrane-permanent free-base form, favoured over the protonated form by bicarbonate, should have a more rapid onset under such circumstances. Sodium channel isoforms differ between nerve and muscle fibres; they may also differ between motor and sensory nerve fibres.28 29 Local anaesthetic solutions pre-packaged with epinephrine appear to show greater effect from alkalinization than plain local anaesthetic solutions.9 23 As a result, in some studies, alkalinization of local anaesthetic in the absence of epinephrine has had no significant effect on block whereas significant differences were noted with epinephrine–local anaesthetic mixtures.9 23 30 In our study, plain lidocaine was compared with epinephrine-free alkalinized lidocaine, and significant differences were found only for motor block. We recognize that different results may have been obtained had we conducted our study using lidocaine solutions prepackaged with epinephrine. Our results suggest that median nerve motor fibres are more sensitive to the effects of alkalinization of lidocaine than sensory fibres. We observed more rapid onset of motor nerve block, measured objectively using CMAP, after alkalinization of lidocaine, with no significant effect on SNAP or any other sensory modality. These results contrast with epidural studies where both modalities were potentiated equally.11–12 We found an effect of bicarbonate only during onset of block but not at steady state. Our inability to show differences at steady state most likely relates to the relatively concentrated solutions of lidocaine used. We anticipated that 1% plain lidocaine would produce nearly complete block of SNAP and CMAP, thus making it difficult to demonstrate increased block at steady state when bicarbonate was added to the local anaesthetic. Thus we cannot exclude the possibility that addition of bicarbonate may increase the potency of lower concentrations of lidocaine at steady state. Our results suggest that alkalinization of plain lidocaine for median nerve block provides no benefit beyond more rapid and, possibly, more profound motor block. In addition, when alkalinized lidocaine solution is used for block, motor
block may be a reliable and early marker for the sensory block that is ultimately achieved.
References 1 Sinclair DC, Hinshaw JR. Sensory changes in procaine nerve block. Brain 1950; 73: 224–43 2 Catchlove RF. Potentiation of two different local anaesthetics by carbon dioxide. Br J Anaesth 1973; 45: 471–4 3 Bokesch PM, Raymond SA, Strichartz GR. Dependence of lidocaine potency on pH and PCO2. Anesth Analg 1987; 66: 9–17 4 Katsuki H, Ibusuki S, Takasaki M, Nagata K, Hiji Y. Monocarboxylic acids enhance the anesthetic action of procaine by decreasing intracellular pH. Biochim Biophys Acta 1997; 1334: 273–82 5 Ritchie JM, Ritchi BR. Local anesthetics: effect of pH on activity. Science 1968; 162: 1394–5 6 Tetzlaff JE, Yoon HJ, Brems J, Javorsky T. Alkalinization of mepivacaine improves the quality of motor block associated with interscalene brachial plexus anesthesia for shoulder surgery. Reg Anesth 1995; 20: 128–32 7 Tetzlaff JE, Yoon HJ, O’Hara J, Reaney J, Stein D, Grimes-Rice M. Alkalinization of mepivacaine accelerates onset of interscalene block for shoulder surgery. Reg Anesth 1990; 15: 242–4 8 Quinlan JJ, Oleksey K, Murphy FL. Alkalinization of mepivacaine for axillary block. Anesth Analg 1992; 74: 371–4 9 Hilgier M. Alkalinization of bupivacaine for brachial plexus block. Reg Anesth 1985; 10: 59–61 10 Gormley WP, Hill DA, Murray JM, Fee JP. The effect of alkalinisation of lignocaine on axillary brachial plexus anaesthesia. Anaesthesia 1996; 51: 185–8 11 Benzon HT, Toleikis JR, Dixit P, Goodman I, Hill JA. Onset, intensity of blockade and somatosensory evoked potential changes of the lumbosacral dermatomes after epidural anesthesia with alkalinized lidocaine. Anesth Analg 1993; 76: 328–32 12 DiFazio CA, Carron H, Grosslight KR, Moscicki JC, Bolding WR, Johns RA. Comparison of pH-adjusted lidocaine solutions for epidural anesthesia. Anesth Analg 1986; 65: 760–4 13 Capogna G, Celleno D, Costantino P, Muratori F, Sebastiani M, Baldassini M. Alkalinization improves quality of lidocaine–fentanyl epidural anaesthesia for caesarean section. Can J Anaesth 1993; 40: 425–30 14 Butterworth JF IV, Walker FO, Lysak SZ. Pregnancy increases median nerve susceptibility to lidocaine. Anesthesiology 1990; 72: 962–5 15 Butterworth JF IV, Walker FO, Neal JM. Cooling potentiates lidocaine inhibition of median nerve sensory fibers. Anesth Analg 1990; 70: 507–11 16 Butterworth J, Ririe DG, Thompson RB, Walker FO, Jackson D, James RL. Differential onset of median nerve block: a randomised, double-blind comparison of mepivacaine with bupivacaine in healthy volunteers. Br J Anaesth 1998; 81: 515–21 17 Kimura J. Electrodiagnosis in Diseases of Nerve and Muscle. Principles and Practice. Philadelphia: FA Davis, 1983 18 Head H. Methods of Examining Sensation. Studies in Neurology, vol. 1. London: H Frowde, 1920; 12–17 19 Hollander M, Wolfe DA. A distribution-free confidence interval based on the sign test (Thompson, Savur). In: Hollander M, Wolfe DA, eds. Nonparametric Statistical Methods. New York: John Wiley, 1973; 48–50 20 Chow MYH, Sia ATH, Koay CK, Chan YW. Aklalinization of lidocaine does not hasten the onset of axillary brachial plexus block. Anesth Analg 1998; 86: 566–8 21 Darian-Smith I, Johnson KO, Dykes R. ‘Cold’ fiber population
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innervating palmar and digital skin of the monkey: responses to cooling pulses. J Neurophysiol 1973; 36: 325–46 Gaggero G, Meyer O, Van Gessel E, Rifat K. Alkalinization of lidocaine 2% does not influence the quality of epidural anaesthesia for elective caesarean section. Can J Anaesth 1995; 42: 1080–4 Candido KD, Winnie AP, Covino BG, Raza SM, Vasireddy AR, Masters RW. Addition of bicarbonate to plain bupivacaine does not significantly alter the onset or duration of plexus anesthesia. Reg Anesth 1995; 20: 133–8 Capogna G, Celleno D, Laudano D, Giunta F. Alkalinization of local anesthetics. Which block, which local anesthetic? Reg Anesth 1995; 20: 369–77 Ibusuki S, Katsuki H, Takasaki M. The effects of extracellular pH with and without bicarbonate on intracellular procaine concentrations and anesthetic effects in crayfish giant axons. Anesthesiology 1998; 88: 1549–57
26 Wong K, Strichartz GR, Raymond SA. On the mechanisms of potentiation of local anesthetics by bicarbonate buffer: drug structure–activity studies on isolated peripheral nerve. Anesth Analg 1993; 76: 131–43 27 Covino BG, Vassallo HG. Local Anesthetics: Mechanisms of Action and Clinical Use. New York: Grune and Stratton, 1976 28 Wright SN, Wang SY, Kallen RG, Wang GK. Differences in steady-state inactivation between Na channel isoforms affects local anesthetic binding affinity. Biophys J 1997; 73: 779–88 29 Nuss HB, Tomaselli GF, Marban E. Cardiac sodium channels (hH1) are intrinsically more sensitive to block by lidocaine than are skeletal muscle (µ 1) channels. J Gen Physiol 1995; 106: 1193–209 30 Bedder MD, Kozody R, Craig DB. Comparison of bupivacaine and alkalinized bupivacaine in brachial plexus anesthesia. Anesth Analg 1988; 67: 48–52
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Effect of alkalinization of lidocaine on median nerve block D. G. Ririe1, F. O. Walker2, R. L. James1 and J. Butterworth1* 1Department
of Anesthesiology and 2Department of Neurology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA *Corresponding author Median nerve blocks were performed in 10 volunteers in a randomized, double-blind, crossover study to compare the effects of 1% plain lidocaine with 1% lidocaine in sodium bicarbonate 0.1 mmol litre–1. Sensations of hot, cold, pinprick and light touch, compound motor and sensory nerve action potentials, and skin temperature were assessed at 2-min intervals. pH was 6.4⫾0.1 for plain lidocaine and 7.7⫾0.2 for alkalinized lidocaine (P⬍0.001). Alkalinized lidocaine produced more rapid inhibition of compound motor action potentials than plain lidocaine (median 4 (range 2–6) vs 9 (2–14) min) (P⫽0.039). Alkalinized lidocaine also produced more rapid onset of inhibition of compound motor than sensory nerve action potentials (4 (2– 6) vs 8 (4–12) min) (P⫽0.0039). There was no significant difference in any other sensory modality between alkalinized and plain lidocaine. These data suggest that addition of bicarbonate to lidocaine for median nerve block significantly increased the rate of motor block without changing the onset or extent of sensory block. Br J Anaesth 2000; 84: 163–8 Keywords: anaesthetics local, lidocaine; nerve, block; formulations, lidocaine; formulations, pH Accepted for publication: September 23, 1999
Different sensory modalities, such as sensations of touch, cold, warm and pain, have been known to be inhibited with different delays after application of local anaesthetics to nerves.1 This phenomenon of different susceptibility of nerve modalities to local anaesthetics is known as differential nerve block. During regional anaesthesia, differential block can be observed during onset, at steady-state and during offset, and drug effects at all three times may guide local anaesthetic selection. For surgical anaesthesia, analgesia is paramount, but the extent of motor nerve block and speed of onset often determines the efficiency and success of the block. However, the labouring parturient seeks rapid onset of analgesia with minimal motor block. Patients suffering from myofascial pain disorders may benefit from selective block of motor nerves while maintaining sensory function. Therefore, understanding differential and steady-state block and interpreting findings of block of specific modalities with specific local anaesthetics are critical to achieving greater success with regional anaesthesia and analgesia. Altering pH can modify the properties of local anaesthesia during onset of block or at steady state.2–5 Numerous studies have reported increased potency and more rapid onset of block with alkalinized local anaesthetics.6–13 However, the effect of alkalinization of local anaesthetics on differential nerve block has not been studied using multiple modality testing. In this study, we have assessed inhibition of median
nerve fibre transmission using both objective sensory, motor and multiple modality subjective sensory data as we have done in previous studies.14–16 Here, we measured onset of block of the median nerve with lidocaine to test our hypothesis that addition of bicarbonate uniformly speeds the onset of anaesthesia in all modalities. Our data rejected this hypothesis as we observed a significant reduction in the delay of onset of motor block, without a commensurate change in the onset of sensory block.
Subjects and methods After obtaining approval from the Clinical Research Practices Committee and informed consent, we studied 10 volunteers undergoing bilateral median nerve block. No subject had clinical or electrodiagnostic findings consistent with median nerve dysfunction. Both dominant and nondominant median nerves were studied in random order. Median nerve block was performed after preparation of the skin with isopropyl alcohol. A 22-gauge B-bevel needle was used. The needle was inserted lateral to the palmaris longus tendon on the volar aspect of the wrist and advanced until it was felt to pass through the flexor retinaculum. Paraesthesia was not sought, and if it occurred, the needle was repositioned. Plain lidocaine HCl 1% (5 ml) (Astra Pharmaceuticals, Westboro, MA, USA) mixed with normal saline 0.1 ml ml–1 or sodium bicarbonate 100 mmol litre–1 (8.4% NaHCO3 0.1 ml ml–1) was injected over 30–45 s
© The Board of Management and Trustees of the British Journal of Anaesthesia 2000
Ririe et al.
after negative aspiration. Both subjects and investigators were blinded to the solution injected. Measurement of pH was performed in all solutions using a standard pH probe. Using a Nicolet Viking (Madison, WI, USA), the median nerve was serially stimulated at the wrist, 2 cm proximal to the site of local anaesthetic injection. Compound muscle action potentials (CMAP) were recorded using belly tendon electrodes over the abductor pollicis brevis and sensory nerve action potentials (SNAP) were recorded using ring electrodes at the base and distal end of the third digit (middle finger).14 15 17 All stimuli were supramaximal, as determined by ramping stimulus intensity to 20% above that required to detect any further change in response amplitude. The response amplitudes of SNAP and CMAP represent the function of Aα sensory and motor fibres, respectively. Unmyelinated C fibre function was assessed using measurements of skin temperature at the distal end of the index finger with a thermistor accurate to 0.1°C. Light touch sensibility was assessed using Von Frey hairs.18 Sensation to pinprick, hot and cold was assessed on the proximal aspect of the palmar surface of the third digit compared with the same stimulus delivered on the volar aspect of the forearm, halfway between the wrist and the elbow, and recorded as a percentage of baseline sensation in the forearm. Baseline measurements of all modalities were recorded. After injection of the local anaesthetic, all modalities were assessed at 2-min intervals until no change was observed over 10 min or until 30 min had elapsed. As end-points to assess differences in block, we used (1) time to the first noticeable difference, (2) time to half normal effects and (3) area under the effect vs time curve. We chose to study 10 volunteers, assuming that the variability in measurements would be comparable with that in previous studies, and that the difference which we wished to detect was (at a minimum) comparable with that between saline and 0.25% lidocaine. A power analysis was performed based on a one-sided Fisher’s sign test (we assumed that alkalinization would not increase the delay of onset). Assuming that the latency of one drug would be greater than the other drug 90% of the time, we calculated that a sample size of eight patients should find a significant difference with 81% power. The pH of the local anaesthetic is reported as mean (SEM). A t test was used to determine pH differences. All other values are expressed as median (range). Statistical significance was tested for all objective and subjective motor and sensory modalities using Fisher’s sign test. Confidence intervals for drug differences with respect to each end-point were determined using Thompson’s method.19 Statistical analysis was performed using the SAS (SAS Institute, Cary, NC, USA) program. P⬍0.05 was judged significant.
Results pH was 6.4 (0.1) (n⫽10) for plain lidocaine and 7.7 (0.2) (n⫽10) for alkalinized lidocaine (P⬍0.001).
Table 1 Time delay (min) until first noticeable difference after injection of lidocaine or lidocaine⫹bicarbonate. *Confidence⫽degree of confidence; CI⫽ confidence interval. Lidocaine⫹bicarb⫽Lidocaine plus bicarbonate; CMAP⫽ compound motor action potentials; SNAP⫽sensory nerve action potentials; Difference⫽differences between onset time with lidocaine and with lidocaine⫹bicarb. †One-sided Fisher’s sign test Median (range)
Confidence (CI) (%)*
P†
Cold Lidocaine Lidocaine⫹bicarb Difference
4 (0, 20) 4 (2, 20) 0 (–16, 6)
98 (–16, 2)
0.50
Hot Lidocaine Lidocaine⫹bicarb Difference
2 (2, 20) 3 (2, 8) 0 (–16, 4)
94 (–16, 2)
0.50
Pinprick Lidocaine Lidocaine⫹bicarb Difference
3 (2, 8) 4 (2, 20) 1 (–4, 12)
98 (–4, 4)
0.23
Temperature Lidocaine Lidocaine⫹bicarb Difference
3 (2, 10) 8 (2, 18) 2 (–2, 16)
97 (–2, 14)
0.11
Von Frey hairs Lidocaine Lidocaine⫹bicarb Difference
3 (2, 24) 5 (2, 12) 1 (–22, 8)
99 (–22, 4)
0.36
SNAP Lidocaine Lidocaine⫹bicarb Difference
2 (2, 4) 2 (2, 4) 0 (–2, 2)
97 (–14, 2)
0.50
CMAP Lidocaine Lidocaine⫹bicarb Difference
2 (2, 6) 2 (2, 4) 0 (–4, 2)
94 (–4, –2)
0.19
There were no differences between alkalinized and plain lidocaine in the time delay until a ‘just noticeable’ difference was detected after injection (Table 1). Increasing the pH of the lidocaine solution had a significant effect only on CMAP inhibition (Table 1). Alkalinization had no effect on median time to the first noticeable difference for CMAP, which was 2 (range 2–6) min for plain lidocaine compared with 2 (2– 4) min for alkalinized lidocaine. Similarly, alkalinization had no effect on median time to first noticeable difference in SNAP (2 (2–4) min for plain vs 2 (2–4) min for alkalinized lidocaine). Furthermore, there was no significant difference between motor block (as measured by CMAP) and sensory block (as measured by SNAP) with either plain or alkalinized lidocaine for the time to first noticeable difference. Inhibition of CMAP occurred more rapidly with alkalinized than plain lidocaine (Table 2). Time to half maximal effect was significantly reduced with alkalinized (4 (2–6) min) compared with plain (9 (2–14) min) lidocaine (P⫽0.02). Motor and sensory block were achieved at approximately the same rate with plain lidocaine; thus there was no difference between CMAP and SNAP for time to
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Table 2 Time delay (min) until half of the maximal effect was observed after injection of lidocaine or lidocaine⫹bicarbonate. *Confidence⫽Degree of confidence; CI⫽confidence interval. Lidocaine⫹bicarb⫽Lidocaine plus bicarbonate; CMAP⫽compound motor action potentials; SNAP⫽sensory nerve action potentials; Difference⫽differences between onset times with lidocaine and with lidocaine⫹bicarb. †One-sided Fisher’s sign test; ‡onset of SNAP and CMAP significantly different (P⬍0.02) Median (range)
Cold Lidocaine Lidocaine⫹bicarb Difference Hot Lidocaine Lidocaine⫹bicarb Difference Pinprick Lidocaine Lidocaine⫹bicarb Difference Temperature Lidocaine Lidocaine⫹bicarb Difference Von Frey hairs Lidocaine Lidocaine⫹bicarb Difference SNAP Lidocaine Lidocaine⫹bicarb‡ Difference CMAP Lidocaine Lidocaine⫹bicarb‡ Difference
10 (0, 20) 7 (4, 20) 1 (–16, 8) 5 (2, 20) 6 (2, 12) 0 (–16, 8) 8 (2, 20) 8 (2, 20) 1 (–16, 12) 8 (2, 20) 10 (2, 22) 0 (–2, 20) 8 (2, 24) 10 (2, 20) 0 (–16, 18) 11 (4, 12) 8 (4, 12) –1 (–8, 2) 9 (2, 14) 4 (2, 6) –4 (–10, 2)
Confidence (CI) (%)*
96 (–8, 6)
97 (–16, 8)
96 (–4, 6)
97 (–2, 6)
98 (–16, 8)
97 (–8, –2)
96 (–8, –2)
Table 3 Area under the effects vs time curve after injection of lidocaine or lidocaine⫹bicarbonate. *Confidence⫽Degree of confidence; CI⫽confidence interval. Lidocaine⫹bicarb⫽Lidocaine plus bicarbonate; CMAP⫽compound motor action potentials; SNAP⫽sensory nerve action potentials; Difference⫽ difference between onset times with lidocaine and with lidocaine⫹bicarb. †One-sided Fisher’s sign test; ‡onset of SNAP and CMAP significantly different (P⬍0.02)
P†
Median (range)
Confidence (CI) (%)*
P†
98 (–1300, –86)
0.05
0.36
Cold Lidocaine Lidocaine⫹bicarb Difference
1663 (455, 3300) 1145 (374, 2000) –244 (–1560, 115)
0.38
Hot Lidocaine Lidocaine⫹bicarb Difference
1233 (321, 2800) 1188 (260, 2800) –27 (–1000, 1200) 96 (–785, 184)
0.50
0.30
Pinprick Lidocaine Lidocaine⫹bicarb Difference
1195 (665, 2000) 1381 (357, 2480) –10 (–718, 1220)
93 (–368, 196)
0.36
0.06
Temperature Lidocaine Lidocaine⫹bicarb Difference
2128 (1938, 2252) 2019 (1930, 2262) –41 (–323, 128)
96 (–172, 49)
0.50
0.45
Von Frey hairs Lidocaine Lidocaine⫹bicarb Difference
2149 (1890, 3465) 2175 (1795, 3013) –81 (–1343, 1013) 98 (–313, 317)
0.50
0.08
SNAP Lidocaine Lidocaine⫹bicarb‡ Difference
1322 (523, 1654) 1049 (409, 1453) –211 (–1013, 250)
98 (–526, 96)
0.17
0.008
CMAP Lidocaine Lidocaine⫹bicarb‡ Difference
816 (308, 1682) 387 (245, 1273) –492 (–1438, 842)
98 (–811, –414)
0.01
half maximal effect. Conversely, motor block was achieved more rapidly than sensory block with alkalinized lidocaine; time to half maximum effect for CMAP was 4 (2–6) min compared with 8 (4–12) min for SNAP (P⫽0.0039). These results were mirrored in our comparisons of area under the effect vs time curves (Table 3). After injection of alkalinized lidocaine, inhibition of CMAP (median area 387 (245– 1273)) occurred significantly faster than that of SNAP (area 816 (308–1682)). The difference between plain and alkalinized lidocaine was also significant for CMAP. Nevertheless, at steady state, there was no difference in the degree of inhibition of SNAP and CMAP with either plain or alkalinized lidocaine (Fig. 1). There were no differences between plain and alkalinized lidocaine for time of onset, time to half maximal effect or extent of steady-state inhibition of hot, cold or pinprick sensations (Fig. 2, Tables 1–3). Also, light touch perception, as measured using Von Frey filaments, showed similar onset and extent of inhibition (Tables 1–3). Skin temperature increased significantly after local anaesthesia, but in a similar manner in the two groups (Fig. 3, Tables 1–3).
Discussion In this study, we used a previously established model to systematically test if alkalinization of lidocaine differentially altered multiple sensory nerve modalities or motor nerve function.14–16 Quantitative and semi-quantitative objective and subjective data were collected. The median nerve was used as a simple and reproducible model of nerve block. Although multiple sensory modalities were tested, alkalinization had no significant effect. In contrast, alkalinization increased the speed of onset of motor nerve block, as measured objectively using CMAP. Previous investigators have reported effects of alkalinized local anaesthetics on various types of nerve block.6–13 20–24 Generally, these studies measured only the delay in onset of pinprick analgesia. Alkalinization has been shown to increase onset, potency and duration of block.6–13 However, reports of no effect of alkalinization have also been published.20–23 The effects of bicarbonate varied depending on the local anaesthetic used, other additives (e.g. epinephrine), type of nerve block, and the definitions used for onset and extent of nerve block. In some studies, a bicarbonate effect
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Fig 1 Effects of plain lidocaine and lidocaine with bicarbonate (bicarb) on sensory nerve action potentials (SNAP) and compound motor action potentials (CMAP). Data are percentage of the initial amplitude of the action potential waveform elicited by supramaximal simulation of the median nerve. Lidocaine with bicarbonate produced a significant effect on CMAP (P⫽0.02), as measured by time to half maximum effect. The effect of bicarbonate on CMAP was different than that on SNAP (P⬍0.02). There was no effect of bicarbonate inhibition of SNAP and there was no significant difference between SNAP and CMAP after injection of plain lidocaine. At steady state, inhibition was similar for plain lidocaine and lidocaine with bicarbonate. All data are median values.
Fig 2 Effects of plain lidocaine and lidocaine with bicarbonate (bicarb) on perception of pinprick, hot and cold. Subjects described the intensity of stimulation in anaesthetized skin as a percentage of perceived intensity in a constant region of unanaesthetized skin. Initially, perceived intensity was the same at the two sites, which was recorded as 100%. No difference was found between plain lidocaine or lidocaine with bicarbonate for hot, pinprick and cold sensibility. All data are median values.
Fig 3 Effects of plain lidocaine and lidocaine with bicarbonate (bicarb) on skin temperature. Data are percentage of the initial temperature (°C). There was no difference between plain lidocaine and lidocaine with bicarbonate. Consistent with our previous experience, most subjects demonstrated a decline in skin temperature, presumably from a sympathetic response to the pain of injection, before demonstrating an increase in temperature as a result of C-fibre (or preganglionic B-fibre) inhibition and vasodilatation. Data are median values.
on speed of onset but not affecting the overall extent of block may have been overlooked.21 Similarly, inability to detect differences between alkalinized and plain local anaesthetic may be a result of insensitive, qualitative measures of motor and sensory block.20 Finally, the conflicting results may be attributable partially to the differential effect of the alkalinization on sensory and motor nerve fibres. Repeated testing over time, attention to speed and overall or steady-state block, use of objective data and multiple modality subjective testing puts our results in context with other study designs. In light of our observations, most likely only onset of motor block was significantly hastened by alkalinization with bicarbonate for median nerve block (and probably other peripheral nerve blocks also). Furthermore, the difference detected was transient, occurring only during onset and only with a single modality. In our study, addition of sodium bicarbonate to lidocaine significantly increased the solution pH, which may affect local anaesthetic block in several ways. Increasing extracellular pH with a constant extracellular local anaesthetic concentration results in greater intracellular local anaesthetic concentration and more complete inhibition of sodium currents, whether or not intracellular carbon dioxide or pH changes.25 When extracellular pH is increased by addition of bicarbonate, decreased intracellular pH through diffusion of carbon dioxide (produced from the reaction of H⫹ and HCO3– in extracellular fluid) may also play a role in enhancing local anaesthetic block through protonation of intracellular free-base local anaesthetic (‘ion trapping’) and increasing the concentration gradient for the free-base local anaesthetic across the plasma membrane.4 In addition, bicarbonate ions probably non-specifically reduce the margin of safety for nerve conduction and may have a direct action on local anaesthetic binding to the sodium channel.26
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However, the role of these various effects in producing differential motor vs sensory nerve block is unclear, particularly during regional anaesthesia in humans. Why should bicarbonate influence the onset of motor but not sensory nerve block? It is possible that responses to bicarbonate may differ depending on the local anaesthetic. Etidocaine, an anaesthetic with many structural similarities to lidocaine, seems to preferentially inhibit motor fibres during onset and offset of regional block.27 It is possible that bicarbonate merely accentuates a subtle motor:sensory difference inherent to this ‘family’ of related compounds. In contrast, there may be structural differences between sodium channels in motor and sensory fibres. Perhaps, sodium channels in motor fibres are more heavily glycosylated than those in sensory fibres, partially ‘shielding’ the sodium channel from local anaesthetic. The more membrane-permanent free-base form, favoured over the protonated form by bicarbonate, should have a more rapid onset under such circumstances. Sodium channel isoforms differ between nerve and muscle fibres; they may also differ between motor and sensory nerve fibres.28 29 Local anaesthetic solutions pre-packaged with epinephrine appear to show greater effect from alkalinization than plain local anaesthetic solutions.9 23 As a result, in some studies, alkalinization of local anaesthetic in the absence of epinephrine has had no significant effect on block whereas significant differences were noted with epinephrine–local anaesthetic mixtures.9 23 30 In our study, plain lidocaine was compared with epinephrine-free alkalinized lidocaine, and significant differences were found only for motor block. We recognize that different results may have been obtained had we conducted our study using lidocaine solutions prepackaged with epinephrine. Our results suggest that median nerve motor fibres are more sensitive to the effects of alkalinization of lidocaine than sensory fibres. We observed more rapid onset of motor nerve block, measured objectively using CMAP, after alkalinization of lidocaine, with no significant effect on SNAP or any other sensory modality. These results contrast with epidural studies where both modalities were potentiated equally.11–12 We found an effect of bicarbonate only during onset of block but not at steady state. Our inability to show differences at steady state most likely relates to the relatively concentrated solutions of lidocaine used. We anticipated that 1% plain lidocaine would produce nearly complete block of SNAP and CMAP, thus making it difficult to demonstrate increased block at steady state when bicarbonate was added to the local anaesthetic. Thus we cannot exclude the possibility that addition of bicarbonate may increase the potency of lower concentrations of lidocaine at steady state. Our results suggest that alkalinization of plain lidocaine for median nerve block provides no benefit beyond more rapid and, possibly, more profound motor block. In addition, when alkalinized lidocaine solution is used for block, motor
block may be a reliable and early marker for the sensory block that is ultimately achieved.
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