Eur J Clin Pharmacol (1992) 42:223-225
5>B@sseceg®9 @ Springer-Verlag 1992
Serum concentrations of local anaesthetics following intraperitoneal administration during laparoscopy* P. Narchi 1, D. Benhamou 1, H. Bouaziz 1, H. Fernandez 2, and J.-X. Mazoit 3 t Ddpartement d'Anesthdsie-Rdanimation and Service de Gyn6cologie-Obstdtrique, H6pital Antoine B4ctere, and 3 Ddpartement d'Anesth6sie-Rdanimation, H6pital Kremlin Bic6tre, Universit6 Paris-Sud, France
Summary. The present study is a comparison of the pharmacokinetics of four local anaesthetics injected double blind in the right subdiaphragmatic area during outpatient laparoscopy p e r f o r m e d under standard general anaesthesia in 28 young women. 80 ml of one of the following solutions was injected: G r o u p A 0.5 % plain lidocaine (n = 7), G r o u p B 0.5% lidocaine with 1/320.000 adrenaline (n =8), G r o u p C 0.5% lidocaine with 1/800.000 adrenaline (n = 7), and G r o u p D 0.125 % bupivacaine with 1/800.000 adrenaline (n = 6). Blood samples were collected over 360 min from an iv catheter and serum concentrations were measured by gas chromatography. No adverse effects occurred in the study period. In G r o u p A (plain lidocaine), Cmaxwas significantly higher and tm~ significantly earlier than in Groups B and C (lidocaine with adrenaline). A toxic level was not found after either solution in any patient. The intraperitoneal use of doses of 400 mg lidocaine or 100 mg bupivacaine for perioperative analgesia was safe and solutions of lidocaine containing adrenaline appeared to pose even less risk than plain solutions. Key words: Local anaesthetics; laparoscopy, lidocaine, bupivacaine, intraperitoneal analgesia, plasma levels
Laparoscopy is one of the commonest outpatient procedures. Fraser et al have recently, shown that postoperative pain is the most frequent complaint responsible for delaying a return to normal daily activities following this procedure [1]. The analgesic effects of local anaesthetics (lidocaine, bupivacaine or etidocaine) given either by infiltration or peritoneal lavage have been demonstrated following Yoon ring laparoscopic sterilization [2, 3] associated with intravenous sedation or general anaesthesia. In addition, the peritoneal administration in the right subdiaphragmatic area of lidocaine or bupivacaine on beginning laparoscopy has been found significantly to reduce the in* Presented in part at the Annual Meeting of the American Society of Anesthesiologists, Las Vegas, October 1990
tensity of postoperative scapular pain, which frequently occurs after laparoscopy, and the i m p r o v e m e n t lasts for 72 h [4]. Whether the absorption of these drugs through this large and well perfused irrigated area might lead to toxic plasma levels is unknown, although a few authors have measured under similar conditions the Cmaxand t .... of local anaesthetics over 2 h [3, 5, 6]. A double blind randomized study has been designed to compare the safety of the intraperitoneal administration of lidocaine (with and without adrenaline) and bupivacaine during diagnostic laparoscopy, by measuring the serum concentrations over the 360 min following the injection.
Materials and methods 28 healthy, women outpatients scheduled for elective diagnostic laparoscopy were studied. All gave their informed consent and the approval of the Local Research Committee was obtained prior to beginning the study. Hydroxyzine 100 mg orally was administered to all women 90 rain before the induction of general anaesthesia. In the operating room, all patients received 100 pg fentanyl and 2 mg midazolam intravenously followed by mask preoxygenation. Induction of general anaesthesia was performed with thiopental 6 mg.kg -~ and vecuronium bromide 0.1 rag-kg -1, followed after 3 rain by orotracheal intubation. Isoflurane 1% in nitrous oxide-oxygen mixture (50 %) was used to maintain the anaesthesia. A separate iv cannula with a stopcock was placed in a vein in the arm contralateral to that used for the infusion line. Patients were then placed in a 30 degree Trendelenburg position and CO2 insufflation was started using an automatic carbon dioxide insufflator. Once insufflation had been accomplished, and before starting the pelvic exploration, under direct vision the surgeon injected into the right subdiaphragmatic area, in a double blind manner, 80 ml of one of the following solutions four: Group A (n = 7) received 0.5 % plain lidocaine, Group B (n = 8) received 0.5% lidocaine with 1/320.000 adrenaline, Group C (n = 7) received 0.5 % lidocaine with 1/800.000 adrenaline, and those in Group D (n = 6) received 0.125 % bupivacaine with 1/800.000 adrenaline. These solutions were given to reduce the intensity of postoperative scapular pain. Heart rate and arterial blood pressure were checked throughout the operative period in order to detect any vascular absorption of the local anaesthetics or adrenaline following the injection.
224 I0
tients did not show any toxic level of either local anaesthetic at any time during the study. The mean serum concentration profiles of each of the four solutions of local anaesthetics are shown in Fig. 1.
d
10] 10]
0.1
0.01
Discussion C
1
E ¢33
0.1
0.01 cO
1
o
cO
0.1 0.01
10
0.1 0.01 i
0
60
i
120
i
180
i
i
240
360
Time (min)
l~g.la--d. S e r u m concentrations of local anaesthetics in the four groups m e a n (SD). a 0.5 % plain lidocaine, b 0.5 % lidocaine with 1/320.000 adrenaline, c 0.5 % lidocaine with 1/800.000 adrenaline. d 0.125 % bupivacaine with 1/800.000 adrenaline
Blood samples were collected before the injection (TO) and 1, 3, 5, 10, 15, 20, 30, 40, 60, 90,120, 180,240 and 360 rain after it. At the end of the laparoscopy, all women received neostigmine sulfate 40 gg. kg z and atropine 15 gg-kg-1 before removal of the tracheal tube. Local anaesthetic concentrations in serum were measured by gas chromatography with a nitrogen specific detector. A non compartmental pharmacokinetic analysis was used to derive the following individual parameters: peak concentration (Cmax)and the time to reach the peak (tm~x).The area under the concentration-time curve (AUC (0-360 min) was calculated by the trapezoidal rule and the terminal half-life (tin_)was calculated by log-linear regression of the observed terminal half-life. Statistical analysis and comparisons between groups were done using ANOVA with Fisher's exact test for demographic data, and nonparametric tests for the pharmacokinetic data.
The low concentrations of local anaesthetics used, as well as the addition of adrenaline, were aimed to decrease the potential risk of any adverse effects on administration of these drugs into a highly irrigated area. Many previous studies have demonstrated the clinical analgesic effect of the intraperitoneal administration of local anaesthetics, such as lidocaine, bupivacaine and etidocaine, in the setting of Yoon ring laparoscopic sterilization [2, 3, 4, 5, 7]. Since the patients were in a day-case surgery unit, late blood samples (after 360 min) could not be obtained. The present study confirms the pharmacological safety of this mode of administration in humans. In fact, no toxic level of either solution was found during the study, which lasted for 360 rain. The tmaxobserved in the plain lidocaine group (29 rain) was comparable to the values obtained with other extravascular routes, e. g, epidural or axillary [8]. Since the peritoneal surface is extensively drained via the portal vein, a first pass effect leading to a lower Cmaxof plain lidocaine was expected. This was not the case because the C~ax observed in the plain lidocaine group (4.32) was comparable to those reported after other routes of administration, suggesting a minimal first pass effect. However, the addition of adrenaline (1/320.000 or 1/800.000) to lidocaine led both to a significant decrease in Cmax (4.32 versus 2.3 and 1.89 ng. ml- 1) and a significant delay in tmax (29 versus 58 and 52 rain). The low ratio of A U C (0360 min/AUC (0.73-0.85) prevented calculation of other parameters, such as clearance, Vz and mean residence time (MRT). The low ratio is probably due to a flip-flop effect and not to the addition of adrenaline to local anesthetics, since this ratio was only 85 % of that in the plain lidocaine group. Moreover, there was a tendancy (albeit not significant) towards a higher A U C (0-360 min) in the plain lidocaine group compared to lidocaine groups containing either 1/320.000 or 1/800.000 adrenaline: /the changes may reflect a delay in the absorption of lidocaine due to the addition of adrenaline. The use of 0.125 % bupivacaine with 1/800.000 adrenaline in Group D was agreed
Table 1. D e m o g r a p h i c and p h a r m a c o k i n e t i c data. a p < 0.05 vs other lignocaine groups, b p < 0.05 vs all o t h e r groups
Results Patients in the four groups were similar with respect to age, weight and height (Table 1). No patient exhibited any neurological or cardiovascular sign of local anaesthetic toxicity, neither in the operating room nor in the recovery room. The pharmacokinetic parameters in the four groups are compared in Table 1. Cm~ was significantly higher in the plain lidocaine group compared to both lidocaine groups containing adrenaline, tmax occurred significantly earlier in that group. Individual results from the 28 pa-
Lido Plain mean (SD)
Lido 1/320 mean (SD)
Lido 1/800 mean (SD)
Bupi 1/800 mean (SD) 35 (6)
Age (y)
28 (3)
33 (6)
34 (3)
Height (m)
1.62 (8)
1.62 (4)
1.64 (7)
1.63 (7)
Weight (kg)
57 (5)
60 (7)
56 (4)
62 (11)
Cm~ (pglml)
4.32 (1.77) ~
2.3 (0.98)
1.89 (0.69)
0.92 (0.33)
tmax(rain)
29 (16) u
58 (22)
72 (21)
52 (24)
tl/2 (rain)
128 (24)
136 (31)
154 (55)
204 (47)
AUC (0-360) (gg*min.ml-)
570 (203)
382 (165)
358 (116)
143 (47)
225 because this drug has of longer duration of action via other extravascular routes, and so it may be m o r e satisfactory for postoperative analgesia. T h e pharmacokinetic results in this group (D) were very close to those from Groups B and C with a delayed T~,a× and the absence of toxic levels throughout the study. In conclusion, the intraperitoneal administration of local anesthetics is a safe method of obtaining analgesia. Use of plain solution of lidocaine led to a relatively high, but safe serum concentration. The addition of adrenaline to lidocaine increases the margin of safety by decreasing C .... and delaying t .... The i m p r o v e m e n t was probably due to a decrease in the systemic absorption of these drugs through this highly vascular surface.
References 1. RA Fraser, SB Hotz, JB Hurtig, SN Hodges, D Moher (1989) The prevalence and impact of pain after day-care tubal ligation surgery. Pain 39:189-201 2. CD Alexander, BV Wetchler, RE Thompson (1987) Bupivacaine infiltration of the mesosalpinx in ambulatory surgical laparoscopic tubal sterilization. Canad J Anesth 34:362-365
3. RJ Deeb, MB Viechnicki (1985) Laparoscopic tubal ligation under peritoneal lavage anesthesia. Regional Anesth 10:24-27 4. P Narchi, G Lecoq, H Fernandez, D Benhamou (1990) Intraperitoneal local anesthetics and scapular pain following daycase laparoscopy. (Abstract) Anesthesio173:A3-A5 5. R McKenzie, P Phitayakorn, NT Lira Uy, J Chalasani, BM Melnick, RL Kennedy, AF Vicinie (1989) Topical bupivacaflle and etidocaine analgesia following fallopian tube banding. Canad J Anesth 36:510-514 6. FJ Spielman, JF Hulka, GW Ostheimer, RA Mueller (1983) Pharmacokinetics and pharmacodynamics of local analgesia for laparoscopic tubal ligations. Am J Obstet Gynecol 146:821-824 7. S Koetsawang, S Srisupandit, SJ Apimas, CB Champion (1984) A comparative study of topical anesthesia for laparoscopic sterilization with the use of the tubal ring. Am J Obstet Gynecol 150: 931-933 8. RI Mazze, RW Dunbar (1966) Plasma lidocaine concentration after caudal, lumbar, epidural, axillary and intravenous regional anesthesia. Anesthesio127:564
Dr. R Narchi Ddpartement d'Anesthdsie-R6animation H6pital Antoine B6cl6re 157 rue de la porte de Trivaux F-92141 Clamart, France
5>B@sseceg®9 @ Springer-Verlag 1992
Serum concentrations of local anaesthetics following intraperitoneal administration during laparoscopy* P. Narchi 1, D. Benhamou 1, H. Bouaziz 1, H. Fernandez 2, and J.-X. Mazoit 3 t Ddpartement d'Anesthdsie-Rdanimation and Service de Gyn6cologie-Obstdtrique, H6pital Antoine B4ctere, and 3 Ddpartement d'Anesth6sie-Rdanimation, H6pital Kremlin Bic6tre, Universit6 Paris-Sud, France
Summary. The present study is a comparison of the pharmacokinetics of four local anaesthetics injected double blind in the right subdiaphragmatic area during outpatient laparoscopy p e r f o r m e d under standard general anaesthesia in 28 young women. 80 ml of one of the following solutions was injected: G r o u p A 0.5 % plain lidocaine (n = 7), G r o u p B 0.5% lidocaine with 1/320.000 adrenaline (n =8), G r o u p C 0.5% lidocaine with 1/800.000 adrenaline (n = 7), and G r o u p D 0.125 % bupivacaine with 1/800.000 adrenaline (n = 6). Blood samples were collected over 360 min from an iv catheter and serum concentrations were measured by gas chromatography. No adverse effects occurred in the study period. In G r o u p A (plain lidocaine), Cmaxwas significantly higher and tm~ significantly earlier than in Groups B and C (lidocaine with adrenaline). A toxic level was not found after either solution in any patient. The intraperitoneal use of doses of 400 mg lidocaine or 100 mg bupivacaine for perioperative analgesia was safe and solutions of lidocaine containing adrenaline appeared to pose even less risk than plain solutions. Key words: Local anaesthetics; laparoscopy, lidocaine, bupivacaine, intraperitoneal analgesia, plasma levels
Laparoscopy is one of the commonest outpatient procedures. Fraser et al have recently, shown that postoperative pain is the most frequent complaint responsible for delaying a return to normal daily activities following this procedure [1]. The analgesic effects of local anaesthetics (lidocaine, bupivacaine or etidocaine) given either by infiltration or peritoneal lavage have been demonstrated following Yoon ring laparoscopic sterilization [2, 3] associated with intravenous sedation or general anaesthesia. In addition, the peritoneal administration in the right subdiaphragmatic area of lidocaine or bupivacaine on beginning laparoscopy has been found significantly to reduce the in* Presented in part at the Annual Meeting of the American Society of Anesthesiologists, Las Vegas, October 1990
tensity of postoperative scapular pain, which frequently occurs after laparoscopy, and the i m p r o v e m e n t lasts for 72 h [4]. Whether the absorption of these drugs through this large and well perfused irrigated area might lead to toxic plasma levels is unknown, although a few authors have measured under similar conditions the Cmaxand t .... of local anaesthetics over 2 h [3, 5, 6]. A double blind randomized study has been designed to compare the safety of the intraperitoneal administration of lidocaine (with and without adrenaline) and bupivacaine during diagnostic laparoscopy, by measuring the serum concentrations over the 360 min following the injection.
Materials and methods 28 healthy, women outpatients scheduled for elective diagnostic laparoscopy were studied. All gave their informed consent and the approval of the Local Research Committee was obtained prior to beginning the study. Hydroxyzine 100 mg orally was administered to all women 90 rain before the induction of general anaesthesia. In the operating room, all patients received 100 pg fentanyl and 2 mg midazolam intravenously followed by mask preoxygenation. Induction of general anaesthesia was performed with thiopental 6 mg.kg -~ and vecuronium bromide 0.1 rag-kg -1, followed after 3 rain by orotracheal intubation. Isoflurane 1% in nitrous oxide-oxygen mixture (50 %) was used to maintain the anaesthesia. A separate iv cannula with a stopcock was placed in a vein in the arm contralateral to that used for the infusion line. Patients were then placed in a 30 degree Trendelenburg position and CO2 insufflation was started using an automatic carbon dioxide insufflator. Once insufflation had been accomplished, and before starting the pelvic exploration, under direct vision the surgeon injected into the right subdiaphragmatic area, in a double blind manner, 80 ml of one of the following solutions four: Group A (n = 7) received 0.5 % plain lidocaine, Group B (n = 8) received 0.5% lidocaine with 1/320.000 adrenaline, Group C (n = 7) received 0.5 % lidocaine with 1/800.000 adrenaline, and those in Group D (n = 6) received 0.125 % bupivacaine with 1/800.000 adrenaline. These solutions were given to reduce the intensity of postoperative scapular pain. Heart rate and arterial blood pressure were checked throughout the operative period in order to detect any vascular absorption of the local anaesthetics or adrenaline following the injection.
224 I0
tients did not show any toxic level of either local anaesthetic at any time during the study. The mean serum concentration profiles of each of the four solutions of local anaesthetics are shown in Fig. 1.
d
10] 10]
0.1
0.01
Discussion C
1
E ¢33
0.1
0.01 cO
1
o
cO
0.1 0.01
10
0.1 0.01 i
0
60
i
120
i
180
i
i
240
360
Time (min)
l~g.la--d. S e r u m concentrations of local anaesthetics in the four groups m e a n (SD). a 0.5 % plain lidocaine, b 0.5 % lidocaine with 1/320.000 adrenaline, c 0.5 % lidocaine with 1/800.000 adrenaline. d 0.125 % bupivacaine with 1/800.000 adrenaline
Blood samples were collected before the injection (TO) and 1, 3, 5, 10, 15, 20, 30, 40, 60, 90,120, 180,240 and 360 rain after it. At the end of the laparoscopy, all women received neostigmine sulfate 40 gg. kg z and atropine 15 gg-kg-1 before removal of the tracheal tube. Local anaesthetic concentrations in serum were measured by gas chromatography with a nitrogen specific detector. A non compartmental pharmacokinetic analysis was used to derive the following individual parameters: peak concentration (Cmax)and the time to reach the peak (tm~x).The area under the concentration-time curve (AUC (0-360 min) was calculated by the trapezoidal rule and the terminal half-life (tin_)was calculated by log-linear regression of the observed terminal half-life. Statistical analysis and comparisons between groups were done using ANOVA with Fisher's exact test for demographic data, and nonparametric tests for the pharmacokinetic data.
The low concentrations of local anaesthetics used, as well as the addition of adrenaline, were aimed to decrease the potential risk of any adverse effects on administration of these drugs into a highly irrigated area. Many previous studies have demonstrated the clinical analgesic effect of the intraperitoneal administration of local anaesthetics, such as lidocaine, bupivacaine and etidocaine, in the setting of Yoon ring laparoscopic sterilization [2, 3, 4, 5, 7]. Since the patients were in a day-case surgery unit, late blood samples (after 360 min) could not be obtained. The present study confirms the pharmacological safety of this mode of administration in humans. In fact, no toxic level of either solution was found during the study, which lasted for 360 rain. The tmaxobserved in the plain lidocaine group (29 rain) was comparable to the values obtained with other extravascular routes, e. g, epidural or axillary [8]. Since the peritoneal surface is extensively drained via the portal vein, a first pass effect leading to a lower Cmaxof plain lidocaine was expected. This was not the case because the C~ax observed in the plain lidocaine group (4.32) was comparable to those reported after other routes of administration, suggesting a minimal first pass effect. However, the addition of adrenaline (1/320.000 or 1/800.000) to lidocaine led both to a significant decrease in Cmax (4.32 versus 2.3 and 1.89 ng. ml- 1) and a significant delay in tmax (29 versus 58 and 52 rain). The low ratio of A U C (0360 min/AUC (0.73-0.85) prevented calculation of other parameters, such as clearance, Vz and mean residence time (MRT). The low ratio is probably due to a flip-flop effect and not to the addition of adrenaline to local anesthetics, since this ratio was only 85 % of that in the plain lidocaine group. Moreover, there was a tendancy (albeit not significant) towards a higher A U C (0-360 min) in the plain lidocaine group compared to lidocaine groups containing either 1/320.000 or 1/800.000 adrenaline: /the changes may reflect a delay in the absorption of lidocaine due to the addition of adrenaline. The use of 0.125 % bupivacaine with 1/800.000 adrenaline in Group D was agreed
Table 1. D e m o g r a p h i c and p h a r m a c o k i n e t i c data. a p < 0.05 vs other lignocaine groups, b p < 0.05 vs all o t h e r groups
Results Patients in the four groups were similar with respect to age, weight and height (Table 1). No patient exhibited any neurological or cardiovascular sign of local anaesthetic toxicity, neither in the operating room nor in the recovery room. The pharmacokinetic parameters in the four groups are compared in Table 1. Cm~ was significantly higher in the plain lidocaine group compared to both lidocaine groups containing adrenaline, tmax occurred significantly earlier in that group. Individual results from the 28 pa-
Lido Plain mean (SD)
Lido 1/320 mean (SD)
Lido 1/800 mean (SD)
Bupi 1/800 mean (SD) 35 (6)
Age (y)
28 (3)
33 (6)
34 (3)
Height (m)
1.62 (8)
1.62 (4)
1.64 (7)
1.63 (7)
Weight (kg)
57 (5)
60 (7)
56 (4)
62 (11)
Cm~ (pglml)
4.32 (1.77) ~
2.3 (0.98)
1.89 (0.69)
0.92 (0.33)
tmax(rain)
29 (16) u
58 (22)
72 (21)
52 (24)
tl/2 (rain)
128 (24)
136 (31)
154 (55)
204 (47)
AUC (0-360) (gg*min.ml-)
570 (203)
382 (165)
358 (116)
143 (47)
225 because this drug has of longer duration of action via other extravascular routes, and so it may be m o r e satisfactory for postoperative analgesia. T h e pharmacokinetic results in this group (D) were very close to those from Groups B and C with a delayed T~,a× and the absence of toxic levels throughout the study. In conclusion, the intraperitoneal administration of local anesthetics is a safe method of obtaining analgesia. Use of plain solution of lidocaine led to a relatively high, but safe serum concentration. The addition of adrenaline to lidocaine increases the margin of safety by decreasing C .... and delaying t .... The i m p r o v e m e n t was probably due to a decrease in the systemic absorption of these drugs through this highly vascular surface.
References 1. RA Fraser, SB Hotz, JB Hurtig, SN Hodges, D Moher (1989) The prevalence and impact of pain after day-care tubal ligation surgery. Pain 39:189-201 2. CD Alexander, BV Wetchler, RE Thompson (1987) Bupivacaine infiltration of the mesosalpinx in ambulatory surgical laparoscopic tubal sterilization. Canad J Anesth 34:362-365
3. RJ Deeb, MB Viechnicki (1985) Laparoscopic tubal ligation under peritoneal lavage anesthesia. Regional Anesth 10:24-27 4. P Narchi, G Lecoq, H Fernandez, D Benhamou (1990) Intraperitoneal local anesthetics and scapular pain following daycase laparoscopy. (Abstract) Anesthesio173:A3-A5 5. R McKenzie, P Phitayakorn, NT Lira Uy, J Chalasani, BM Melnick, RL Kennedy, AF Vicinie (1989) Topical bupivacaflle and etidocaine analgesia following fallopian tube banding. Canad J Anesth 36:510-514 6. FJ Spielman, JF Hulka, GW Ostheimer, RA Mueller (1983) Pharmacokinetics and pharmacodynamics of local analgesia for laparoscopic tubal ligations. Am J Obstet Gynecol 146:821-824 7. S Koetsawang, S Srisupandit, SJ Apimas, CB Champion (1984) A comparative study of topical anesthesia for laparoscopic sterilization with the use of the tubal ring. Am J Obstet Gynecol 150: 931-933 8. RI Mazze, RW Dunbar (1966) Plasma lidocaine concentration after caudal, lumbar, epidural, axillary and intravenous regional anesthesia. Anesthesio127:564
Dr. R Narchi Ddpartement d'Anesthdsie-R6animation H6pital Antoine B6cl6re 157 rue de la porte de Trivaux F-92141 Clamart, France
