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© 2001 International Anesthesia Research Society
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Abstract |
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We compared the plasma lidocaine concentrations associated with continuous epidural infusion at different insertion sites in patients during surgery using epidural plus general anesthesia. In Study 1, there were 12 patients in each of four surgical groups in whom blood loss was expected to be <400 mL. The four groups were as follows: the lower extremity, the lower abdomen, the upper abdomen, and the lung. Liver surgery was excluded from Study 1. Study 2 comprised patients undergoing radical hysterectomy or radical prostatectomy (a radical operation group, n = 12) and hepatectomy (a hepatectomy group, n = 12) in whom the expected surgical blood loss was more than 1500 mL. All patients initially received 0.1 mL/kg followed by a continuous infusion of 0.1 mL · kg-1 · h-1 of 1.5% lidocaine, and plasma concentrations of lidocaine were measured at 15, 30, 60, 90, and 120 min and every 60 min thereafter to 300 min. The plasma lidocaine concentration during surgery did not change regardless of the infusion site or the surgical site, other than the liver. The plasma concentrations of lidocaine in the hepatectomy group increased significantly at 180 min (2.9 ± 0.6 µg/mL, P < 0.01), 240 min (3.5 ± 0.7 µg/mL, P < 0.01), and 300 min (3.6 ± 0.74 µg/mL, P < 0.01) compared with that at 15 min (2.0 ± 0.3 µg/mL), and these values were significantly larger than those in all other groups.
Implications: The site of infusion and the surgical procedure, with the exception of liver surgery, do not affect plasma lidocaine concentrations under continuous epidural infusion at a rate of 1.5 mg·kg-1 ·h-1. Caution should be used when patients receive epidural infusion of lidocaine during hepatectomy.
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Introduction |
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Continuous epidural infusion of local anesthetics in combination with general anesthesia has become popular. Avoidance of excessively large plasma concentrations of local anesthetics during surgery is important for preventing toxicity of local anesthetics and delay of emergence from general anesthesia. The plasma concentrations of local anesthetics after bolus injection at different epidural sites have been reported (1–3), but there have been no reports comparing plasma concentrations of local anesthetics associated with continuous epidural infusion at different insertion sites during surgery. Therefore, we designed a two-part study for measurement of plasma lidocaine concentrations in surgery patients under general anesthesia with continuous epidural infusion of lidocaine at different sites.
The plasma concentration of lidocaine is influenced by cardiac output and/or hepatic blood flow (4,5), which in turn can be affected by many factors during surgery, including blood loss, fluid administration, administration of anesthetics (6) and vasoactive drugs (7), and body temperature (8). Although it is difficult to control for all such factors, we attempted to exclude those other than the epidural infusion site and surgical procedure in Study 1. The surgical site and procedure can affect plasma concentrations of local anesthetics (9); surgery affects hemodynamics, including hepatic blood flow, and results in changes in the distribution volume, absorption, and clearance of drugs. Thus, we selected patients having surgeries in which the expected blood loss was small, and the period of anesthesia would be relatively long. We defined the criteria for fluid administration in Study 1.
Because the liver is a major site of lidocaine metabolism (4), liver surgery should affect plasma lidocaine concentrations. Liver surgery, however, has many factors that affect local anesthetic concentrations, such as preoperative liver dysfunction, heavy bleeding and transfusion, the disturbance of hepatic blood flow, and the administration of vasoactive drugs and injury of the liver parenchyma. There has been no report comparing plasma lidocaine concentrations during hepatectomy or during other surgeries under continuous epidural infusion. Thus, in Study 2, we measured plasma lidocaine concentrations in patients during liver segmentectomy under continuous epidural infusion, and compared them with concentrations in patients during radical hysterectomy or prostatectomy. We selected radical hysterectomy and radical prostatectomy for comparison because the operation time and total blood loss are similar to those observed in liver segmentectomy in our hospital. We also compared the results of Study 1 with those of Study 2 to investigate the effect of blood loss on plasma lidocaine concentrations.
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Methods |
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After institutional and ethical committee approval and informed consent were obtained, 72 patients (ASA physical status I-II) were included in this study. None of them had liver dysfunction and they had not received any medication that would affect the metabolism of lidocaine such as cimetidine (10) and propranolol (11). Patients were scheduled for epidural plus general anesthesia of more than 5 h. In Study 1, there were 12 patients in each of four surgical groups in whom the blood loss was expected to be <400 mL. The four surgical groups were as follows: the lower extremity, the lower abdomen, the upper abdomen, and the lung. Liver surgery was excluded from Study 1. Study 2 comprised patients undergoing radical hysterectomy or radical prostatectomy (a radical operation group, n = 12) and hepatectomy (a hepatectomy group, n = 12) in whom the expected surgical blood loss was more than 1500 mL. Patients in the hepatectomy group underwent one or two segmentectomy, and hepatic inflow occlusion (the Pringle maneuver) (12) was not performed during liver segmentectomy.
Patients were premedicated IM with 50 mg hydroxyzine and 0.5 mg atropine. An IV cannula was placed for fluid administration and a radial arterial cannula was placed for continuous arterial pressure monitoring and blood sampling. Epidural catheters were placed at L4-5 interspaces for lower extremity surgeries, at T12-L1 for lower abdomen or radical surgeries, at T8-9 for upper abdomen or hepatectomy procedures, and at T4-5 for lung surgeries, and advanced 5 cm. A test dose of 3 mL of 1% lidocaine containing 1:100,000 epinephrine was injected. Three minutes after injection of the test dose, if there was no evidence of subarachnoid or intravascular injection, 0.1 mL/kg of 1.5% lidocaine without epinephrine was administered, and continuous infusion of 1.5% lidocaine without epinephrine at a rate of 0.1 mL · kg-1 · hr-1 was begun via infusion pump. Fifteen minutes after the initial injection, the analgesic levels were evaluated by the pinprick method.
General anesthesia was induced IV with 5 mg/kg thiopental and 50–100 µg fentanyl. Tracheal intubation was performed with the help of 0.1 mg/kg vecuronium. No local anesthetic drug was given intratracheally. Ventilation was controlled mechanically to maintain the partial pressure of expiratory carbon dioxide between 30 and 35 mm Hg, as measured by capnography. General anesthesia was maintained with 50% nitrous oxide in oxygen and <0.8% isoflurane, and intermittent boluses of 50 µg fentanyl were given as necessary. Vecuronium was used for muscle relaxation. After the induction of general anesthesia, a double-lumen central venous catheter was inserted via the right internal jugular vein for continuous central venous pressure monitoring and fluid administration. Monitoring included electrocardiogram, capnogram, arterial blood pressure, central venous pressure, pulse oximetry, and bladder temperature. Lactated Ringer’s solution was infused at 20 mL · kg-1 · h-1 during the induction of anesthesia, and the rate of transfusion was maintained at 10 mL · kg-1 · h-1 thereafter in Study 1.
In Study 2, fluid was infused to maintain a preoperative central venous pressure. Hypotension was noted when systolic blood pressure was <90 mm Hg, and was corrected by increasing the rate of IV fluid infusion and by the administration of ephedrine. Lost blood was replaced as necessary; the hemoglobin was maintained at more than 8.0 g/dL with the transfusion of packed red blood cells, and albumin was maintained at more than 3.0 g/dL with 5% albumin or fresh-frozen plasma. Bladder temperature was maintained between 36 and 37°C using a warming device (Bair HuggerTM; Augustine Medical Inc., Minneapolis, MN). Arterial blood gases, serum electrolytes (Na+, K+, Cl-, Ca2+), and blood glucose were analyzed (Stat Profile MTM; Noba Medical, Waltham, MA) at least every 1 h, and these values were maintained within normal ranges by appropriate treatments.
To measure plasma lidocaine concentrations, arterial blood samples of 1 mL were drawn after the initial injection of lidocaine at 15, 30, 60, 90, and 120 min and every 60 min thereafter to 300 min. Blood samples were also taken at the start of surgery, immediately before liver segmentectomy, during liver segmentectomy, and the end of surgery in the hepatectomy group. Blood samples were centrifuged, and the plasma was frozen at -80°C until analyzed. Plasma lidocaine concentrations were measured using an enzyme immunoassay method (EMIT, Syva/aTM; Syntex Co, Palo Alto, CA) by an automatic analysis system (ACA StarTM; Dade International Inc., Wilmington, DE). This lidocaine assay method has been proven to be accurate with a high degree of specificity and precision (13). In our measurements, the coefficients of variation at 0.5, 1.0, 2.5, and 5.0 µg/mL were <10%.
Data are expressed as mean ± SD. Analysis of variance was used to compare patient characteristics (age, height, weight) and the preoperative aspartate aminotransferase, alanine aminotransferase, total bilirubin, albumin, and hemoglobin levels as well as the surgical duration and the amounts of lidocaine and ephedrine administered and the volumes of fluid infused during surgery between groups. Two-way analysis of variance followed by Duncan’s test was used to compare heart rate, mean arterial pressure, and central venous pressure between groups and within groups at each time point. The total blood loss, transfused blood, and plasma lidocaine concentrations were compared with the Kruskal-Wallis test followed by Dunn’s test between groups and within groups at each time point. Values were considered statistically significant when P was < 0.05.
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Results |
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There were no significant differences among groups in patient characteristics or preoperative liver function, albumin, and hemoglobin values ( Table 1). The values of heart rate, mean arterial pressure, and central venous pressure were similar among and within groups during surgery ( Table 2). Total doses of lidocaine infused until 300 min were similar among all groups ( Table 3). Total doses of fentanyl administered were similar among all groups (200–300 µg). There was no significant difference in surgical duration among groups (Table 3).
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Study 1
The total blood loss, fluid infused, and amounts of ephedrine administered for 300 min were similar in all (lower extremity, lower abdomen, upper abdomen, and lung) groups (Table 3). No patient received a transfusion. The full ranges of sensory analgesia at 15 min were between T10-S2, T6-L3, T3-L1, and C6-T9 in the lower extremity, lower abdomen, upper abdomen, and lung groups, respectively.
Blood samples were taken for 300 min in all cases. The plasma lidocaine concentrations at 15 min were similar in all groups ( Fig. 1). No significant change in the plasma lidocaine concentration was observed in any group during the surgery (Fig. 1). The peak plasma lidocaine concentrations were similar among groups (lower extremity 2.1 ± 0.2 µg/mL, lower abdomen 2.1 ± 0.2 µg/mL, upper abdomen 2.2 ± 0.2 µg/mL, lung 2.1 ± 0.2 µg/mL). The times to reach peak levels were not related to time-course or surgical procedure.
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P < 0.01 vs values in other groups.Study 2
The total blood loss, fluid infused, and blood transfused for 300 min were similar in the two (radical operation and hepatectomy) groups, and these values were significantly more in this study than values in Study 1 (Table 3). There was no significant difference between the two groups in the amount of ephedrine administered for 300 min, and the amounts used in Study 2 were similar to the amounts used in Study 1 (Table 3). The full ranges of sensory analgesia at 15 min in the radical operation group were between T6-L3, which were similar to those in the lower abdomen group, and T3-L1 in the hepatectomy group, which were similar to those in the upper abdomen group. Blood samples were taken for 300 min in all cases. The plasma lidocaine concentrations in the two groups at 15 min were similar to those at 15 min in Study 1 groups (Fig. 1). No significant change in the plasma lidocaine concentration was observed in the radical operation group during surgery, and the plasma lidocaine concentrations were similar to those in Study 1 (Fig. 1). Plasma lidocaine concentrations increased significantly in the hepatectomy group at 180 min (2.9 ± 0.6 µg/mL, P < 0.01) and thereafter to 300 min (3.5 ± 0.7 µg/mL at 240 min, and 3.6 ± 0.7 µg/mL at 300 min, P < 0.01) in comparison with the value at 15 min (2.0 ± 0.3 µg/mL) (Fig. 1). Plasma lidocaine concentrations were significantly larger at 180 min (P < 0.01) and thereafter (P < 0.01) in this group in comparison to concentrations in the radical operation group and in all Study 1 groups. Plasma lidocaine concentrations in the hepatectomy group immediately before segmentectomy (2.7 ± 0.5 µg/mL, P < 0.05) during segmentectomy (3.9 ± 0.8 µg/mL, P < 0.01), and at the end of surgery (3.3 ± 0.8 µg/mL, P < 0.01) were significantly larger than the concentration at the start of surgery (2.0 ± 0.2 µg/mL) ( Fig. 2).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The plasma lidocaine concentrations during continuous epidural infusion were similar during the course of surgery, and these levels did not change between types of surgery except during liver surgery, where the plasma lidocaine concentration increased gradually. Our results indicate that the site of infusion, blood loss and the surgical procedure, with the exception of liver surgery, do not affect plasma lidocaine concentrations using continuous epidural infusion at a rate of 1.5 mg · kg-1 · hr-1.
Plasma drug concentration is affected by absorption, distribution, and/or elimination. Factors that can affect plasma lidocaine concentration include site of bolus injection, dose of infused lidocaine, weight and age of patient, plasma protein level and extracellular fluid volume, liver function, and hepatic blood flow (14). The sites of infusion and surgery were the factors that differed between groups in Study 1. Extracellular fluid volume was likely to be similar in all groups because the fluid infusion rate was kept constant, the total blood loss was small, and central venous pressure was maintained constantly. Hepatic blood flow depends on mean arterial blood pressure and cardiac output (4,5). We did not measure cardiac output or hepatic blood flow, and the surgical procedure could affect hepatic blood flow; upper abdominal surgery, in particular, can decrease hepatic blood flow (9). The lung surgery could have affected systemic blood flow, because one-lung ventilation was performed during surgery, leading to the shift of blood to the dependent lung. This potentially affected the distribution of volume and altered the plasma lidocaine concentration. Our results, however, showed that the surgical procedures other than liver surgery did not affect plasma lidocaine concentrations significantly when hemodynamic values were kept stable.
Differences in volume and vascularity of the epidural space could result in different spreads and different absorptions. In considering plasma concentrations of local anesthetics after bolus injection at different epidural sites, Mazze and Dunbar (1) and Tucker et al. (2) reported that the maximal plasma levels of local anesthetics after caudal epidural injection are larger than those after lumbar epidural injection. Mayumi et al. (3) reported small but not statistically significant differences in plasma lidocaine concentrations between the lumbar and thoracic or cervical epidural blocks. Contrary to their findings, the plasma lidocaine concentrations we observed were similar between the lumbar and thoracic groups after 15 min of continuous infusion. Although we evaluated the spread of epidural block 15 min after the start of infusion, we could not measure the spread of lidocaine during surgery. Our results from Study 1 indicate that continuous epidural infusion at different insertion sites does not affect the plasma lidocaine concentration during surgery with stable hemodynamics, though the spread of epidural block might be different.
As mentioned, the amount of blood lost is an important factor that can affect plasma lidocaine concentration. In our radical operation group, the amount of blood lost was significantly larger than the amount in the Study 1 groups, but the plasma lidocaine concentrations were similar. This indicates that if central venous pressure and hemoglobin and albumin values are maintained within normal ranges, a blood loss of approximately 1500 mL may not affect the plasma lidocaine level under continuous epidural infusion.
The plasma lidocaine concentrations gradually increased over time during liver surgery. In patients in whom liver blood flow is abnormally low, or in whom liver function is poor, breakdown of the local anesthetic is markedly decreased, resulting in significantly larger blood levels (15). Preoperative liver dysfunction can affect the metabolism of lidocaine and increase plasma lidocaine concentrations during surgery (16), but the preoperative liver function values were normal in this study. Plasma lidocaine concentrations reached peaks (3.9 ± 0.8 µg/mL) during liver segmentectomy, so that injury to the liver parenchyma and/or reduction in the hepatic blood flow were most likely to play principal roles in increasing plasma lidocaine concentration during surgery. In one case, the plasma lidocaine concentration increased beyond the value of 5 µg/mL. If the preoperative liver function were impaired, the plasma lidocaine concentration would increase more. The doses of lidocaine infused during hepatectomy should be reduced in patients with liver dysfunction. Direct manipulation around the liver would have already decreased the hepatic blood flow, as our results also showed that the plasma lidocaine concentration increased immediately before segmentectomy, before the liver parenchyma had been damaged. Cardiac output and hepatic blood flow should be maintained during anesthesia.
We conclude that the plasma concentrations of lidocaine using continuous epidural infusion during surgery increase during hepatectomy, a finding not observed in other surgeries. Caution should be used when patients receive epidural infusion of lidocaine during hepatectomy.
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References |
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- Mazze RI, Dunbar RW. Plasma lidocaine concentrations after caudal, lumbar epidural, axillary block, and intravenous regional anesthesia. Anesthesiology 1966; 27: 574–9.[Web of Science][Medline]
- Tucker GT, Moore DC, Bridenbaugh PO, et al. Systemic absorption of mepivacaine in commonly used regional block procedures. Anesthesiology 1972; 37: 277–87.[Web of Science][Medline]
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Mayumi T, Dohi S, Takahashi T. Plasma concentrations of lidocaine associated with cervical, thoracic, and lumbar epidural anesthesia. Anesth Analg 1983; 62: 578–80.
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Stenson RE, Constantino RT, Harrison DC. Interrelationships of hepatic blood flow, cardiac output, and blood levels of lidocaine in man. Circulation 1971; 43; 205–11.
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Lundberg J, Lundberg D, Norgren L, et al. Intestinal hemodynamics during laparotomy: effects of thoracic epidural anesthesia and dopamine in humans. Anesth Analg 1990; 71: 9–15.
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Gelman SI. Disturbances in hepatic blood flow during anesthesia and surgery. Arch Surg 1976; 111: 881–3.
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Aldrete JA, Homatas J, Boyes RN, Starzl TE. Effects of hepatectomy on the disappearance rate of lidocaine from blood in man and dog. Anesth Analg 1970; 49: 687–90.
[Free Full Text] - Miyamoto M, Hayano Y, Noguchi T, et al. Plasma lidocaine concentrations during epidural anesthesia–a comparison between patients with normal liver functions and those with abnormal functions. Masui 1988; 37: 696–700.[Medline]
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