The dilution of local anesthetics with normal saline is a common practice. In epidural anesthesia, for example, when requiring 1% lidocaine after previously administering 2% lidocaine, we often do not open a new ampoule of 1% lidocaine but rather prepare 1% lidocaine from the remaining 2% lidocaine by dilution with saline. However, the influence of the dilution on the outcome of the epidural block remains unclear.
Sodium chloride is added to commercially available local anesthetics so as to match the osmotic pressure of local anesthetic to that of the living body. Therefore, the content of sodium chloride is different among various local anesthetics. The drug information sheet reports that the contents of NaCl are 8 mg/mL and 7 mg/mL in 1% and 2% mepivacaine, respectively. Saline, 0.9% of NaCl, contains 9 mg/mL of sodium chloride. Thus, the NaCl content of 1% mepivacaine derived from 2% mepivacaine diluted with the same volume of saline should be equal to that of plain 1% mepivacaine. However, solutions of both 1% and 2% lidocaine include 6 mg/mL of NaCl. Therefore, the NaCl content of 1% lidocaine produced by dilution of 2% lidocaine with the same volume of saline should be larger than that of plain 1% lidocaine.
We hypothesized that there may be a difference in potency of epidural blockade between plain 1% lidocaine and 2% lidocaine diluted with saline to 1% lidocaine because nerve excitability and conduction can be influenced by various factors such as local anesthetics or altered ion concentrations in the extracellular fluid (1).
The study was approved by the Hospital Ethics Committee and informed consent was obtained from all patients. Forty consecutive female patients, ASA physical status I and II, scheduled for gynecological abdominal surgery were enrolled in this prospective, randomized, double-blind trial. Patients were excluded if there was any contraindication to epidural anesthesia or communication difficulties that would influence postoperative assessment. Also excluded were pregnant women and individuals with continuing alcohol or drug abuse or who were taking medications that would interfere with drug metabolism such as vasodilators and hypotensive drugs. Each patient was randomly allocated to one of two groups; those in group P received plain commercially prepared 1% lidocaine and those in group D received 1% lidocaine derived from 2% lidocaine and the same volume of saline.
All patients received lactated Ringer’s solution at a rate of 1 mL/kg for 1 h before arrival in the operating room and at 10 mL · kg−1 · h−1 during the subsequent observation period. Operating room temperature was maintained at 25°C. The epidural puncture was performed at the L1-2 interspace with a 17-gauge Tuohy needle using the midline approach, with patients in the lateral decubitus position. The epidural space was identified using a loss-of-resistance to saline technique. <1 mL of saline was injected after the needle entered the epidural space. A 19-gauge epidural catheter was advanced 4 cm into the epidural space with the bevel directed cephalad. Eight mL of plain 1% lidocaine (group P) or 4 mL of 2% lidocaine diluted with the same volume of saline (group D) was infused epidurally at a rate of 0.5 mL/s through the catheter, 2 min after injecting 2-mL test dose of the same solution to the main dose over 4 s, with the patient in the supine position. Twelve mL of each solution was prepared, and 2 mL of the 12 mL was used as the test dose, 8 mL as the main dose, and the remaining 2 mL was used for measurement of pH and sodium and chloride ion concentrations of the solution. Epinephrine was not added to any of the study solutions. The study solutions were prepared independently by a separate (blinded) study participant.
Sensory and motor blockade, skin temperature at the left big toe, arterial blood pressure, and heart rate were assessed at 5, 10, and 15 min after the end of injection of the main dose of lidocaine. The sensory assessment commenced in the block zone and moved towards no block. Sensory blockade (complete loss of sharpness in pinprick perception) was evaluated bilaterally with a short-beveled needle. The dermatome was considered blocked only if the block could be demonstrated bilaterally. Perineal blockade was assessed at 5, 10, and 15 min. Motor blockade was assessed by recording the motor function of the lower limbs (Modified Bromage Scale) immediately after each evaluation of sensory block: 0 = no paralysis (full flexion of knees and feet); 1 = inability to raise extended legs (just able to move knees); 2 = inability to flex knees (able to flex ankle joints); 3 = inability to flex ankle joints (unable to flex ankle joints and knees). Skin temperature at the left big toe was continuously monitored with the thermometer CTM-303 (TERMO, Japan) throughout the observation. Neurological assessments were performed by a blinded anesthesiologist who was unaware of group assignment.
After the neurological assessments, patients received surgery under general and epidural anesthesia. Epidural analgesia was used for their postoperative pain management.
Changes in blocked dermatomes, skin temperature, arterial blood pressure, and heart rate were tested with analysis of variance with repeated measures for within-group comparisons and non-repeated measures for between-group comparisons. If significant differences were detected by analysis of variance, individual means were compared by using the Student-Newman-Keuls test. The χ2 test was used to compare frequency of patients with perineal sensory blockade and motor blockade (Bromage grade). Unpaired Student’s t-test was used for demographic data, pH levels and sodium and chloride concentrations. Differences were considered statistically significant at P < 0.05.
A total of 40 patients completed the study. All patients successfully underwent epidural puncture and catheter insertion. There were no significant differences in the demographic features of the patients of the two groups (Table 1). Although the pH of the two solutions was similar, sodium and chloride ion concentrations in group D were significantly larger than those of group P (Table 2).
The spread of sensory blockade increased gradually in both groups (Table 3). However, at all assessment times, significantly more dermatomes were blocked in the P group compared with the D group (P < 0.01). At the 5-min assessment time, perineal blockade with bilateral block of the second to fourth sacral dermatomes was noted in 11 patients of group P and 0 patients of group D (P < 0.01, χ2 test). There were also significant differences between the groups at 10 and 15 min.
No difference was found in motor blockade between before and after epidural injection in both groups. All patients had either bilateral grade 0 or 1 block throughout the investigation. Bilateral Bromage grade 1 blockade by 15 min after epidural injection of the main dose of lidocaine was noted in only 8 patients of group P and 4 patients of group D.
Skin temperature over the left big toe gradually increased in the two groups. No differences were found at each assessment time between the two groups. However, the increase of the skin temperature in group P was significantly faster than in group D (Table 4). Mean arterial blood pressure decreased gradually in both groups. There were no significant differences at all assessment times between the two groups. However, the mean arterial blood pressure decreased slightly from baseline at 5 min in group P, whereas it remained unchanged until 15 min in group D. The heart rate did not change during the observation period in both groups.
The present study suggests that 1% lidocaine prepared by diluting 2% lidocaine with the same volume of saline is less potent in epidural sensory blockade compared with commercially prepared plain 1% lidocaine.
When assessing sensory blockade at 5-minute intervals for 15 minutes after the start of epidural infusion, the spread of sensory block was narrower at all assessment times in the patients who received the diluted solution. The spread of sensory blockade is enhanced by an increase in concentration or in the volume of local anesthetic solution (2,3). Furthermore, the speed of onset of sensory blockade is augmented by rapid epidural infusion (4) and use of warm local anesthetic (5). In the present study, the 15-minute interval was too short to evaluate the final spread of sensory blockade, but we controlled temperature and used a constant dose of local anesthetic to eliminate these known influences on the outcome of epidural blockade, and the results showed important differences in the spread of sensory blockade (increase of foot skin temperature and decrease of mean arterial blood pressure) between the two solutions. Although we have demonstrated a difference in onset, the impact on block duration and regression remains unstudied.
In this study, a larger concentration of sodium ion was found in the saline-diluted lidocaine solution. Plain 1% lidocaine contains 6 mg/mL of NaCl, of which sodium ion is 103 mEq/L [6 × 1000/(23 + 35.5)] (the latter represent the atomic weights of sodium and chlorine, respectively). The 3 mEq/L difference between the 106 mEq/L indicated in Table 2 and 103 mEq/L is a result of the added sodium hydroxide. It is probable that 2% lidocaine also includes approximately 106 mEq/L of sodium ions, and this concentration increases with saline dilution.
The role of hypernatriosis should not be overlooked as a factor that could promote nerve excitability and conduction. Local anesthetics act on the nerve membrane by interfering with its ability to undergo the specific changes that result in the altered permeability to sodium ion. Thus local anesthetics increase the threshold for electrical excitation in the nerve. However, nerve excitability is principally determined by the state of membrane sodium channels, which can be enhanced by increasing extracellular sodium ions (6). Furthermore, as established by Schimek et al. (7), exposure to an iso-osmotic hyponatric solution reduces the amplitude and prolongs the latency of axons. The potential of 2% lidocaine prepared by dilution using the same volume of saline may be less than that of plain 1% lidocaine, possibly because the accumulation of sodium ions may increase local nerve excitability, creating the need for a larger dose of local anesthetic or reducing the effect of a given dose (8).
We also demonstrated that 1% lidocaine prepared by diluting 2% lidocaine with the same volume of saline contained a larger concentration of chloride ions compared with plain 1% lidocaine. IV administration of saline could decrease blood pH (9). The decrease in pH associated with saline infusion is attributed to hyperchloremic metabolic acidosis (10). Our result suggests that pH is similar between the two solutions. However, whether epidural administration of chloride ions changes local pH remains unknown. The pH is important in determining the local anesthetic effect. The large concentration of chloride ions in lidocaine solution has not been excluded as a plausible explanation for the reduced epidural blockade.
Commercially available lidocaine and saline are preservative free. Commercial lidocaine includes sodium chloride, sodium hydroxide, and hydrochloric acid besides lidocaine. Therefore, the difference between plain 1% lidocaine and 2% lidocaine diluted with the same volume of saline should be explained by the differences in the concentrations of sodium ion, chloride ion, hydroxide ion, and hydrogen ion. In the present study, there was no difference in pH between the two solutions, although hydroxide ion could neutralize acid.
The influence of epidural saline on epidural anesthesia is controversial. Hore et al. (11) indicated that epidural saline produces segmental sensory changes to pinprick in pain-free patients. However, Tay et al. (12) found that epidural saline has no effect on any measurements of the cutaneous current perception threshold for both large- and small-diameter sensory nerve fiber function and sensation to touch, pinprick, and cold. In addition, a more rapid recovery of motor and sensory block in patients undergoing epidural anesthesia can be achieved with the use of saline epidural washout (13). The additional epidural saline not only dilutes the local anesthetic but also increases volume of the solution injected epidurally, which implies no change in the dose (concentration × volume) of local anesthetic. However, Okutomi and Hoka (14) have shown that a large volume of saline injected in the epidural space to elicit loss-of-resistance reduces the spread of hypesthesia for pinprick. Considered together, these results suggest that epidural saline interrupts the anesthetic effect of local anesthetics, but no detailed information is available concerning the mechanism of the effect of epidural saline on the actions of epidural anesthesia.
The present study emphasizes the need to use lidocaine without dilution with saline to avoid the potential problem of insufficient epidural blockade. Further studies are required to examine the potential effects of epidural saline on the pharmacokinetics of lidocaine and the role of sodium and chloride ion concentrations as determinants of epidural blockade. In addition, extrapolation of our results to other nerve blocks with lidocaine and saline may not be appropriate but warrants examination.
In conclusion, the spread of sensory blockade, foot temperature increase, and rate of arterial blood pressure decrease were decreased after epidural infusion of 2% lidocaine diluted with the same volume of saline compared with those produced by commercially prepared plain 1% lidocaine.
1. Orchardson R, Peacock JM. Factors affecting nerve excitability and conduction as a basis for desensitizing dentine. Arch Oral Biol 1994;39:81S–6.
2. Scott DB, McClure JH, Giasi RM, et al. Effects of concentration of local anaesthetic drugs in extradural block. Br J Anaesth 1980;52:1033–7.
3. Concepcion M, Covino BG. Rational use of local anaesthetics. Drugs 1984;27:256–70.
4. Kanai A, Suzuki A, Hoka S. Rapid injection of epidural mepivacaine speeds the onset of nerve blockade. Can J Anaesth 2005;52:281–4.
5. Clark V, McGrandy E, Sugden C, et al. Speed of onset of sensory block for elective extradural caesarean section: choice of agent and temperature of injectate. Br J Anaesth 1994;72:221–3.
6. Orchardson R. The generation of nerve impulses in mammalian axons by changing the concentrations of the normal constituents of extracellular fluid. J Physiol (London) 1978;275:177–89.
7. Schimec F, Sumi SM, Fink BR. Differential effects of hypoosmotic hyponatric swelling on A and C fibers. Anesthesiology 1984;60:198–204.
8. Mather LE. Tachyphylaxis in regional anesthesia: can we reconcile clinical observations and laboratory measurements? Anaesthesiol Intensive Care Med 1986;176:3–9.
9. Williams EL, Hildebrand KL, McCormick SA, et al. The effect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg 1999;88:999–1003.
10. McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia 1994;49:779–81.
11. Hore PJ, Silbert BS, Cook RJ, et al. A double-blind assessment of segmental sensory changes with epidural fentanyl versus epidural saline in patients undergoing extracorporeal shock-wave lithotripsy. Anesthesiology 1990;72:603–6.
12. Tay B, Wallace MS, Irving G. Quantitative assessment of differential sensory blockade after lumbar epidural lidocaine. Anesth Analg 1997;84:1071–5.
13. Chan VW, Nazarnia S, Kaszas Z, et al. The impact of saline flush of the epidural catheter on resolution of epidural anesthesia in volunteers: a dose-response study. Anesth Analg 1999;89:1006–10.
14. Okutomi T, Hoka S. Epidural saline solution prior to local anaesthetic produces differential nerve block. Can J Anaesth 1998;45:1091–3.