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Intraperitoneal lignocaine for analgesia after laparoscopic cholecystectomy
Original Article
Intraperitoneal lignocaine for analgesia after laparoscopic cholecystectomy Kolsi K (1), Ghozzi H (2) Masmoudi A (1) Mzali R (3) Sahnoun Z (2) Zeghal K (2) Beyrouti MI(3) Karoui A(1)
Abstract Background: The aims of this prospective, placebo-controlled, randomised study were to assess the analgesic effect of the intraperitoneal administration of 40 ml lignocaine in patients undergoing laparoscopic cholecystectomy and to carry out a pharmacokinetic study oflignocaine following instillation. Methods: 42 women undergoing elective cholecystectomy under general anaesthesia were included. At the end of the operation patients were randomised in two groups. Group 1(G 1) received 400 mg 1% lignocaine injected under direct vision into the hepato-diaphragmatic space (200 mg), near and above the hepatoduodenal ligament (200 mg). Group 2 (G2:placebo) received 40 ml 0.9% saline. Postoperative pain was assessed using a visual analogue scale 01AS 100 mm) at 15, 30, 45, 60, 90, 120 minutes, 6 and 24 hours after extubation. No analgesic agent was used at any time throughout the hospital course. Plasma concentrations of lignocaine and venous blood samples were obtained from the patients at 2, 5, 15, 30, 45, 60, 90, and 120 minute intervals after intraperitoneal administration of lignocaine by using high pressure liquid chromatography. Statistics included Student T test and X2 test p<0.05 was considered significant. Results: Mean pain scores were significantly lower in the local anaesthetic group (G1) than in placebo group (G2) from 15 to <)0 minutes and at 6 to 24 hours after surgery. Mean pain scores at rest were significantly lower in the lignocaine group (G 1) than in placebo group (G2) at 15, 45, 60, 90 minutes, 6 and 24 hours after surgery. Patients in the control group had significantly more severe pain with VAS scores more or equal to 50 n1l11 (17120) at every time point after surgery vs. lignocaine group (9120). The duration of action cannot be explained by either systemic effects or the classic local action. Plasma lignocaine concentrations reached the peak at five minutes (Cmax) : 2.95 flg ml'. Individual results from the 20 patients did not show any toxic level of lignocaine at any time during the study. Conclusion: We have shown that intraperitoneal local anaesthetic is a very effective method of pain relief after laparoscopic cholecystectomy. This technique is safe with no apparent side effects. However the dose of lignocaine should not exceed 400 mg as we have found that administration of lignocaine 400 mg is associated with serum concentrations approching toxic levels. Keywords: peritoneal injection; lignocaine; laparoscopic cholecystectomy
Introduction: / Dept 4 AI/csthcsiology 2 Dept 4 Pharmatology; 3 Dept (~r Ttic Habib Bourouiba National Unioersitv Hospital, ,~/;'x, Tunisia. Addressjar correspondence; Dr Kolsi K; Dept, (~rAneslhesio!<~I!Y; 'I7,C Habib Bourcuiba National Univcrsit» Hospital; J029 S/;/x; Tunisia. Tel: 216 4 242248/2/64244223, f':ax : 216 4 243427 Sl/~I!cry:
200
Laparoscopic cholecystectomy has become a technique of choice for gall bladder surgery. Postoperative pulmonary function is better preserved than after an open procedure 1 and the duration of the hospitalisation is short-. However, patients often sutTer from considerable pain during the first 24
Volume 3 (4) December 2000
Acute Pain
Intraperitoneal lignocaine after laparoscopic cholecystectomy Kolsi et al
postoperative hours. Although there are plans to perform laparoscopic cholecystectomy as ambulatory procedure in ASA I patients in the future, patients' postoperative discomfort can make this impossible. Therefore it is imperative that we improve the treatment of pain after laparoscopic cholecystectomy. The peritoneal administration of lignocaine or bupivacaine in the right subdiaphragmatic area has been found to significantly reduce the intensity of postoperative scapular pain with no adverse effects after diagnostic laparoscopy or for yoon ring laparoscopy3.4.5. The reported controversies may be due to the variability of total dose of local anaesthetic, or even lack of control in patient positioning after the localised intraperitoneal instillation of the local anaesthetic. The following study addresses the question of the effects and the safety of intraperitoneal administration of 400 mg 1% lignocaine on pain after laparoscopic cholecystectomy. In parallel, we have carried out a pharrnacokinetic study of lignocaine over the 120 minutes following the instillation.
Patients and methods 42 women (ASA physical status I or II; age 20-60 ears) undergoing elective cholecystectomy under Yeneral anaesthesia were studied.The study protocol ~as approved by the Ethics Committee of the hospital and informed consent was obtained from the patients. All operations were performed by a senior surgeon. The criteria for exclusion from the study were ASA physical status III or greater, history of chronic pain, regular intake of analgesic drugs (NSAIDs), allergy to local anaesthetic agents or a history of psychiatric disease. Premedication was hydroxyzine 1 mg kg-I, 1-2 hours before operation. Monitoring included electrocardiography, pulse oximetry, and automated blood pressure measurement. Standard general anaesthesia was induced with thiopental (6 mg kg-I), fentanyl (3 ug kg-I) and vecuronium (0.08 mg kg-I) and was maintained with 0.5-1 %, halothane in 40% n and 60'X, nitrous oxide and intermittent oxy ge doses of vecuronium and fentanyl (1.5J.lg kg-! every 40 minutes). End-expiratory pC02 was monitored d maintained at approximately 35-40 mmHg ahn yhout the procedure. Intra-abdominal pressure t roug .' 'ntained by insufflation of CO, gas at 12-14 ~snlal mmHg. At the end of surgery, after haemostasis had been secured, residual CO 2 pneumoperitoneum was
evacuated by suction and manual compression of the abdomen in the declive position in all patients. Following surgery patients were randomly allocated to one of two groups, in a double-blind manner: lignocaine group 1 (G 1, n=20) received 400 mg 1% lignocaine instilled under direct vision into the right subdiaphragmatic area (200 mg), directly to the gall bladder bed on the liver, near and above the hepatoduodenal ligament (200 mg), with the patient in the head-down position for 10 minutes. The controlgroup (G2:placebo, n=20) received 40 ml 0.9% saline serum in the same way. After surgery, the neuromuscular blockade was reversed with neostigmine 2.5 mg and atropine 0.5 mg. Patients were transferred to a post anaesthesia care unit where they were monitored and questioned about their postoperative pain at rest by an independent observer who was not involved in patient randomisation or anaesthesia administration. The degree of pain was assessed using a 100 mm visual analogue scale (VAS O=no pain, 100 = maximal pain) at 15,30,45,60,90, 120 minutes, 6 and 24 hours after extubation. In the immediate recovery period of the study (first 24 hours), no analgesics were given to the patients. All patients were discharged the day after surgery. In the lignocaine group 10 ml, samples of venous blood were obtained before and at 2, 5, 10, 15, 30, 60, 90, and 120 minutes after instillation of local anaesthetic into the peritoneal cavity. Data analysis: The results are expressed as mean±SEM. Data was analysed using: Student's T test and X2 test. The appearance of severe pain (EVA>50mm) was analysed with comparison of survival curves using LOGRANK test. P
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201
Intraperitoneal lignocaine after laparoscopic c holecystectomy Kolsi et al
G1: Lignocaine
G2 : Placebo
20
20
Age (years)
43 .5 (10 .9)
42 .1 (9.3)
Weight (kg)
74 .7 (12.5)
72 .9 (11.5)
n
Height (em)
165.5 (5.2)
165 .2 (4 .8)
16/4
17/3
ASA (112)
24hr
20
22
0-50
0-50
12.5 0-50
0-75
36 0-75
23.5 0-75
0.06
0.01
0.04"
90
120
22
22
0-75
0-75
19 0-54
39 0-100
38 0-75
36
34
().85
0.04" 0.04"
0.02"
0.02"
30
45
o-so
22
23.5 0-75
Median Range
42 0-100
().85
0.01"
G1: M ed ian Range
6hr
60
15
G2: 40
Duration of Surgery min
87 .8 (33 .2)
85 .9 (42 .4)
p:
Total fen tanyl meg
471.7 (104)
461.5 (89)
01 =lime of extubation: 15, 30. 45, 60. 00. 120minutes, 6 wid 24 holJ's after extltJalion.
Values are mean (SE) where appropria te
Table 2. Median IlI1d {
'Table I . Patient rliaraacristics
( VA S) at Each TiIllI Poill t I!{trr SII ~l!rry G 1: Lignocaine G2: Placebo
50
Time(T)
0
15
30
45
60
90
120
6h 24h
G1
20
16
14
14
14
13
11
11
11
G2
20
12
10
8
6
5
5
3
3
E
V 40
% Survival P r ob a bility
A 30
m m 0.8 30
45
60
90
120
6hr
I I I
24hr
0 _ -.
0.6
T im e after surgery
I
0 - ., I
Fi.!! . L.Pain
S(( II'/ 'S ,IS
0 - .,
0.4
dctrnninrd by Vi sII 1/1 AliI/ill.!!//(' Scale
I I
(median] ill patients r('(ri!'ill.!! i" l mpf'ri t(l"ca l l(l!" (lrail j(' (G I) (If
saline ((;2) . Fi.!!.2 , Kaplan-Meier sIIn1il'I/I p lots. AppetlmllCC
group (G2) at 15, 45, 60, l)O m inutes, 6 and at 24
(I: VA > 5011I11I) ill 1(I!II(1railll' and (()tltrol ,l!mllp s at cacl: time
ho ur s after sur gery (Table 2). Patie n ts in t he co n t ro l gro up h ad sig n ifica n tly m ore seven:' pain with VAS scores, ~5() 111111 (1712()) at e ver y ti m c point after s u rge ry ve rs us the lignocaine g ro up (l)/ 2()) (Fig 2). N o sid e effe ct s related to ligno cain e occ u r re d. Blo od pressure and heart rat e were sta ble with no differen ce between the g ro ups. The frequen cy of nau sea and vo m iting wa s n ot statist ica lly different betwe en th e lign o cain e g ro u p (six pati ents) and saline group (e ight pati ents). Li gn o cain e wa s a bso r b e d rapidl y from th e peritoneal cav ity. Plasm a lignocaine co nc ent ratio ns rea ched the peak at five minutes referred to pe ak co nc c n rrnt io n (C max): 2 .9 5 p g 1111 . 1 • In d ivid u a l result s from th e 2() patients did not sho w an y to xic levels of lign ocaine at any tim e durin g the study. T he highe st co nc e n tratio n observed at an y time in any patient was 4.H pg m l-1 w hic h is near the to xic level
point q{ter SIl ~l!l'ry. (X2 = 5. 5 62 0 .0 1< p
202
Time (mins) 2 5 Serum Concentration Mean 2.00 1 2.95 Min 0.19 0.6 4.8 Max 5
10
15
30
45
90
60
1.72 1.46 1.22 0.6 0.61 0.53 3.3 2.41 2.4 1
2.15 2.4 2.25 1.87 0.18 0.7 1.23 1.01 4.1 4.58 4.2 2.61
y
9 0
4
C
3
a
2
i
T - Y
5
Y
e
Y
• • • • -• .... • • •.... •.... .... -... .... Y
Y
/
I ,
n 0
Y
Max Mean Min
•....
6
n
120
0
Y
Y
90
120
~
2
5
10
15
30
45
60
Fi,!!.3. Serum (Oll( l'lI lml iollS 4 /(l!l/o(aill l' ,!{ter instillation 4 a dose (! f 400 II/.I! into pC/itol/l'lll cavitv , Data shown cIS 11/1'111/ values with minima IIl1d maxima (11 =20)
Vo lume 3 (4) D e cemb er 2000
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Intraperitoneal lignocaine after laparoscopic cholecystectomy Kolsi et al
under anaesthesia ( 6 ug ml-') .
Discussion: There is a marked interindividual variability of pain after laparoscopic eholecystectomy'>. The reasons for this significant variability are not clear". In fact, laparoscopic cholecystectomy is not a highly invasive operation with minimal tissue damage. The postoperative pain induced by this type of surgery has a considerable visceral component (owing to surgical handling and diaphragmatic irritation by dissolved carbon dioxide) and a lesser parietal component (owing to the holes made in the abdominal wall for the trocars)", In addition, the visceral component at times results in shoulder tip pain, similar in location and type to the pain that occurs with biliary co lic.v' Carbon dioxide is insufflated into the abdominal cavity in order to create the surgical view. It can become entrapped between the liver and the right diaphragm causing irritation of the diaphragm since the patients have to be operated in the reverse Trendelenburg position and CO 2 , moves upwardsv!''-!'. Intraperitoneal instillation of local anaesthetic is our analgesic technique of choice, as it is noninvasive and easy to practice. The choice of the local anaesthetic and its concentration was made on the basis of several considerations: First, given the size of the area involved in surgery, a volume of 20 ml was the minimum required for coverage on all levels". Second, the 1% concentration of the local anaesthetic was chosen after a comparison of the experience listed in previous literature 3 ,4.5 . Lignocaine was chosen because of its low toxicity'>; intraperitoneal administration of doses of 100-150 rng of bupivacaine may result in toxic plasma .
13
concentrations . Analysis of our data indicates that intraperitoneal lignocaine infiltration is a very efficient method of pain relief after laparoscopic cholecystectomy. This data confirms the results of previous studies that reported effective pain relief after laparoscopic procedures with intraperitoneal instillati?n of local anaestheticH.7,14, In contrast, other studies suggests that intraperitoneal bupivacaine or lignocaine does not reduce pain after laparoscopic cholecystectomy 1.,13,15.16.17. Our analysis of the literature has identified ma ny d ifferent factors influencing the outcome: total dosage of local anaesthetic, the site of instillation (right or both right and left subdiaphragmatic areas),
Acute Pain
the moment of administration of local anaesthetic and the position of the patient during and just after instillation. These factors provide multiple explanations for the lack of analgesic effect in some studies: First, the total dosages are IOW6 •15, IH. Second, the increased efficacy of intraperitoneal local anaesthetics may be due to the fact that the solution was applied to both hemidiaphragms and not just to the right subdiaphragmatic area, while the solution was left it! situ7•14• Pasqualucci et al19 emphasise the importance of the timing of anaesthetic administration in postoperative pain preemption. They found that visual analogue pain scores and the consumption of analgesics were significantly lower in patients receiving intraperitoneal bupivacaine immediately after the creation of pneumoperitoneum than at the end of surgery'v-v, Another important factor is the evacuation of the residual CO2 pneumoperitoneum by suction and manual compression of the abdomen in the declive position-l-". In the present study, instillation of lignocaine is performed in the headdown position. Instillation oflocal anaesthetic in this position may improve analgesia, because the drugs are expected to flow towards the coeliac plexus and the phrenic nerve endings. In contrast, some studies have reported no effective pain relief, when local anaesthetics were instilled in the supine position. It is conceivable that in this position the local anaesthetics flow with gravity away from the coeliac plexus and the phrenic nerve endings". In our study no analgesics were used in postoperative period study. This may be the reason that more patients had severe pain (VAS more than 50 mrn): H5'XI in the control group vs 45% in the lignocaine group; twice or much more the rate of previously reported cases, where one-third to one-half of patients had severe pain!o.
Finally, many questions have been asked by our Ethics Committee about the lack of analgesic protocol in the postoperative period before permitting the study. We attempted to simplify the study model as much as possible by using only topical peritoneal local anaesthesia. Furthermore there is currently a lack of evaluation and treatment of postoperative pain in our hospital, which meant that study patients were not disadvantaged. We found that lignocaine was absorbed relatively rapidly from the peritoneal cavity. Plasma lignocaine concentrations reached a peak at five minutes
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Intraperitoneal lignocaine after laparoscopic cholecystectomy Kolsi et al
referred to as peak concentration (Cmax: 2.95 Ilg mI'). The time to the peak (Tmax) was five minutes. Narchif found that, after gynaecological laparoscopy, the rate of absorption of lignocaine from the peritoneal cavity was relatively slow, the time to maximum concentration (tC pmax) was reached at 29 minutes with plain lignocaine 400 mg. In fact, lignocaine was absorbed more rapidly after laparoscopic cholecystectomy than after diagnostic laparoscopy. Lignocaine was probably absorbed through the damaged micro vessels of the gall bladder bed. In Williamson's study> using 200 mg of lignocaine after total abdominal hysterectomy and Narchi's study", the maximum concentration of lignocaine attained (C pmax) was relatively low. Narchif found a Cpmax value of 4.3 Ilg ml- I with plain lignocaine 400 mg, 2.3 Ilg ml- I with lignocaine 400 mg and adrenaline 1:320 000, and 1.89 ug ml- I using lignocaine 400 mg with adrenaline 1:800 000. We used lignocaine without adrenaline because in all cases anaesthesia was conducted with halothane which might produce cardiac dysrhythmias in the presence of increased plasma concentrations of adrenaline and also during laparoscopic procedure with high frequency of hypercapnia. The serum concentration of lignocaine which cerebral toxic symptoms begin to occur is approximately 3 Ill,' ml- I in the unmedicated subject but the threshold increases in patients during anaesthesia-', Thus, our data suggests that a dose of lignocaine 400 mg would be extremely unlikely to result in toxicity when given into subdiaphragmatic area and to the gall bladder bed.
Pain Research in Istanbul, October 1999. References 1. Joris J, Cigarini I, Legrand M, et al.Metabolic and respiratory changes after cholecystectomy performed via laparotomy or laparoscopy.Br J Anaesth 1992: 69:341-345. 2. Berggren U, Gordh T, Grama D, et al. .Laparoscopic versus open cholecystectomy, Hospitalisation, sick leave, analgesia and trauma responses. Sutg 1994:H1:1362-1365. 3 Narchi P,Benhamou D, Fernandez H. Intraperitoneal local anaesthetic pain after day case laparoscopy. The LAncet, 1991,338:1569-1570 4. Narchi P,Benhamou D,Aubrin F. et al. Analgesia using mesosalpinx infiltration combined with intraperitoneal lignocaine for yoon ring Iaparoscopy. Anaesthesiology, 1992,77:3A-17 5. Narchi P ,Benhamou D,Bouaziz H.et al.-Serum concentrations of local anaesthetics following intraperitoneal administration during laparoscopy. Hur. J .cu« Pharmacal, 1992, 42: 223-225. 6. Joris J, Thiry E, Paris P, et al. Pain after laparoscopic cholecystectomy: Characteristic and effect of intraperitoneal bupivacaine. Anesth Ana(~ 1995: 81: 379-384. 7. Mraovic B, Jurisic T, Kogler-Majeric V. et al. Intraperitoneal bupivacaine for analgesia after laparoscopic cholecystectomy. Acta Anaesthesiol Scand 1997; 41: 193-196 H. Alberto P,Verena D, Riccardo C. et al. Pre-emptive Analgesia: Intraperitoneal Local Anaesthetic in Laparoscopic Cholecystectomy, Anesthesiology 1996; 85: 11-20. Lindgren L. Editorial : Pain after laparoscopic cholecystectomy . 1)0 we do our best? Acta Anaesthesiol Scand 1997; 41: 191-192. 10. Fredmann B, Jedeikin R, Olsfanger D. et al. Residual pneumoperitoneum: A cause of postoperative pain after laparoscopic cholecystectomy.Anesth Ana(~ 1994, 79, 1, 152. II. Jackson SA, Laurence A, Hill J.Is post-Iaparoscopy pain related to residual carbon dioxide volume? Br. J of Anaesthesia 1995, 74, 4, 477. 12. Ki.ihlman.G - Pcritoneal block, In: Bonnet F Eledjam (eds) Actualitics in Regional Anaesthesia. First Ed. Arnette 1Y95 . 319 -324. 13. Fuhrcr Y, Charpentier C, Boulanger G, et al, Analgesia after laparoscopic cholecystectomy using intraperitoncal bupivacaine. AIIII Fr Anacsth Rca 1996; 15: 12H-134. 14. Geraldinc C, Olivier J, Manzoor A. ct al. A prospectivc randomised trial of intraoperative
Y.
Conclusion Intraperitoneal 1'X, lignocaine (400 mg) infiltration is shown to be a very efficient method of pain relief after Iaparoscopic cholecystectomy. This technique is safe since we did not see any side effects and serum concentrations. The duration of action cannot be explained by either systemic effects or the classic local action. This treatment could subsequently shorten the duration of the hospital stay and, further reduce the cost of lnparoscopic cholecystectomy performed as day-case surgery.
Acknowledgements We arc grateful to Mr Habib Feki for statistical analysis and to Moufida Bouyahia for English review. Results of this study have been presented as posters
204
at 41 st International Congress of SFAR in Paris, September 1999 and 7th European Conference on
Volume 3 (4) December 2000
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Intraperitoneal lignocaine after laparoscopic cholecystectomy Kolsi et al
15.
16.
17.
18.
bupivacaine irrigation for management of shouldertip pain following laparoscopy. Am] of Surg, 1998, 176 : 258-261. Rademaker B, Kalkman C, Odoom J, et al. Intraperitoneal local anaesthetics after laparoscopic cholecystectomy: Effects on postoperative pain, metabolic responses and lung function. Br. J. Anaestli 1994: 72:263-266. Scheinin B, Kellokumpu I, Lindgren L, et al. Effect of intraperitoneal bupivacaine on pain after laparoscopic cholecystectomy. Acta Anaesthesiol Scand 1995; 39: 195-198. Raetzell M, Maier C, Schroder D, et al. Intraperitoneal application of bupivacaine during laparoscopic cholecystectomy: Risk or benefit? Anesth Ana{g, 1995,81,5,967. Schulte-Steinberg H,Weninger E, Jorkisch D, et al. Intraperitoneal versus interpleural morphine or bupivacaine for pain after laparoscopic cholecystectomy. Anesthesiology 1995:82:634-640.
Acute Pain
19. Pasqualucci A, De Angelis V, Contardo R, et al. Preemptive analgesia: intraperitoneal local anaesthetic in laparoscopic cholecystectomy. Anesthesiology 1996; 85: 11-20. 20. Christina M, Frances C, Sharad S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. A nesth Analg 1996; 82:44-51. 21. Tsimoyiannis EC, Glantzounis G, Lekkas ET, et al. Intraperitoneal normal saline and bupivacaine infusion for reduction of postoperative pain after laparoscopic cholecystectomy. Surg Laparosc Endosc 1998; 8(6): 416-20. 22. Duchene.Analgesia after laparoscopy: Effect of intraperitoneal flushing using saline solution. Ann Fr Anaestn Rea, 1994; 13: 435-440 23. Williamson KM, Cotton BR, Smith G. Intraperitoneal lignocaine for pain after total abdominal hysterectomy.Br.] tif Anaesth 1997; 78:675-677.
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205
Intraperitoneal lignocaine for analgesia after laparoscopic cholecystectomy Kolsi K (1), Ghozzi H (2) Masmoudi A (1) Mzali R (3) Sahnoun Z (2) Zeghal K (2) Beyrouti MI(3) Karoui A(1)
Abstract Background: The aims of this prospective, placebo-controlled, randomised study were to assess the analgesic effect of the intraperitoneal administration of 40 ml lignocaine in patients undergoing laparoscopic cholecystectomy and to carry out a pharmacokinetic study oflignocaine following instillation. Methods: 42 women undergoing elective cholecystectomy under general anaesthesia were included. At the end of the operation patients were randomised in two groups. Group 1(G 1) received 400 mg 1% lignocaine injected under direct vision into the hepato-diaphragmatic space (200 mg), near and above the hepatoduodenal ligament (200 mg). Group 2 (G2:placebo) received 40 ml 0.9% saline. Postoperative pain was assessed using a visual analogue scale 01AS 100 mm) at 15, 30, 45, 60, 90, 120 minutes, 6 and 24 hours after extubation. No analgesic agent was used at any time throughout the hospital course. Plasma concentrations of lignocaine and venous blood samples were obtained from the patients at 2, 5, 15, 30, 45, 60, 90, and 120 minute intervals after intraperitoneal administration of lignocaine by using high pressure liquid chromatography. Statistics included Student T test and X2 test p<0.05 was considered significant. Results: Mean pain scores were significantly lower in the local anaesthetic group (G1) than in placebo group (G2) from 15 to <)0 minutes and at 6 to 24 hours after surgery. Mean pain scores at rest were significantly lower in the lignocaine group (G 1) than in placebo group (G2) at 15, 45, 60, 90 minutes, 6 and 24 hours after surgery. Patients in the control group had significantly more severe pain with VAS scores more or equal to 50 n1l11 (17120) at every time point after surgery vs. lignocaine group (9120). The duration of action cannot be explained by either systemic effects or the classic local action. Plasma lignocaine concentrations reached the peak at five minutes (Cmax) : 2.95 flg ml'. Individual results from the 20 patients did not show any toxic level of lignocaine at any time during the study. Conclusion: We have shown that intraperitoneal local anaesthetic is a very effective method of pain relief after laparoscopic cholecystectomy. This technique is safe with no apparent side effects. However the dose of lignocaine should not exceed 400 mg as we have found that administration of lignocaine 400 mg is associated with serum concentrations approching toxic levels. Keywords: peritoneal injection; lignocaine; laparoscopic cholecystectomy
Introduction: / Dept 4 AI/csthcsiology 2 Dept 4 Pharmatology; 3 Dept (~r Ttic Habib Bourouiba National Unioersitv Hospital, ,~/;'x, Tunisia. Addressjar correspondence; Dr Kolsi K; Dept, (~rAneslhesio!<~I!Y; 'I7,C Habib Bourcuiba National Univcrsit» Hospital; J029 S/;/x; Tunisia. Tel: 216 4 242248/2/64244223, f':ax : 216 4 243427 Sl/~I!cry:
200
Laparoscopic cholecystectomy has become a technique of choice for gall bladder surgery. Postoperative pulmonary function is better preserved than after an open procedure 1 and the duration of the hospitalisation is short-. However, patients often sutTer from considerable pain during the first 24
Volume 3 (4) December 2000
Acute Pain
Intraperitoneal lignocaine after laparoscopic cholecystectomy Kolsi et al
postoperative hours. Although there are plans to perform laparoscopic cholecystectomy as ambulatory procedure in ASA I patients in the future, patients' postoperative discomfort can make this impossible. Therefore it is imperative that we improve the treatment of pain after laparoscopic cholecystectomy. The peritoneal administration of lignocaine or bupivacaine in the right subdiaphragmatic area has been found to significantly reduce the intensity of postoperative scapular pain with no adverse effects after diagnostic laparoscopy or for yoon ring laparoscopy3.4.5. The reported controversies may be due to the variability of total dose of local anaesthetic, or even lack of control in patient positioning after the localised intraperitoneal instillation of the local anaesthetic. The following study addresses the question of the effects and the safety of intraperitoneal administration of 400 mg 1% lignocaine on pain after laparoscopic cholecystectomy. In parallel, we have carried out a pharrnacokinetic study of lignocaine over the 120 minutes following the instillation.
Patients and methods 42 women (ASA physical status I or II; age 20-60 ears) undergoing elective cholecystectomy under Yeneral anaesthesia were studied.The study protocol ~as approved by the Ethics Committee of the hospital and informed consent was obtained from the patients. All operations were performed by a senior surgeon. The criteria for exclusion from the study were ASA physical status III or greater, history of chronic pain, regular intake of analgesic drugs (NSAIDs), allergy to local anaesthetic agents or a history of psychiatric disease. Premedication was hydroxyzine 1 mg kg-I, 1-2 hours before operation. Monitoring included electrocardiography, pulse oximetry, and automated blood pressure measurement. Standard general anaesthesia was induced with thiopental (6 mg kg-I), fentanyl (3 ug kg-I) and vecuronium (0.08 mg kg-I) and was maintained with 0.5-1 %, halothane in 40% n and 60'X, nitrous oxide and intermittent oxy ge doses of vecuronium and fentanyl (1.5J.lg kg-! every 40 minutes). End-expiratory pC02 was monitored d maintained at approximately 35-40 mmHg ahn yhout the procedure. Intra-abdominal pressure t roug .' 'ntained by insufflation of CO, gas at 12-14 ~snlal mmHg. At the end of surgery, after haemostasis had been secured, residual CO 2 pneumoperitoneum was
evacuated by suction and manual compression of the abdomen in the declive position in all patients. Following surgery patients were randomly allocated to one of two groups, in a double-blind manner: lignocaine group 1 (G 1, n=20) received 400 mg 1% lignocaine instilled under direct vision into the right subdiaphragmatic area (200 mg), directly to the gall bladder bed on the liver, near and above the hepatoduodenal ligament (200 mg), with the patient in the head-down position for 10 minutes. The controlgroup (G2:placebo, n=20) received 40 ml 0.9% saline serum in the same way. After surgery, the neuromuscular blockade was reversed with neostigmine 2.5 mg and atropine 0.5 mg. Patients were transferred to a post anaesthesia care unit where they were monitored and questioned about their postoperative pain at rest by an independent observer who was not involved in patient randomisation or anaesthesia administration. The degree of pain was assessed using a 100 mm visual analogue scale (VAS O=no pain, 100 = maximal pain) at 15,30,45,60,90, 120 minutes, 6 and 24 hours after extubation. In the immediate recovery period of the study (first 24 hours), no analgesics were given to the patients. All patients were discharged the day after surgery. In the lignocaine group 10 ml, samples of venous blood were obtained before and at 2, 5, 10, 15, 30, 60, 90, and 120 minutes after instillation of local anaesthetic into the peritoneal cavity. Data analysis: The results are expressed as mean±SEM. Data was analysed using: Student's T test and X2 test. The appearance of severe pain (EVA>50mm) was analysed with comparison of survival curves using LOGRANK test. P
-------------------------------Acute Pain
Volume 3 (4) December 2000
201
Intraperitoneal lignocaine after laparoscopic c holecystectomy Kolsi et al
G1: Lignocaine
G2 : Placebo
20
20
Age (years)
43 .5 (10 .9)
42 .1 (9.3)
Weight (kg)
74 .7 (12.5)
72 .9 (11.5)
n
Height (em)
165.5 (5.2)
165 .2 (4 .8)
16/4
17/3
ASA (112)
24hr
20
22
0-50
0-50
12.5 0-50
0-75
36 0-75
23.5 0-75
0.06
0.01
0.04"
90
120
22
22
0-75
0-75
19 0-54
39 0-100
38 0-75
36
34
().85
0.04" 0.04"
0.02"
0.02"
30
45
o-so
22
23.5 0-75
Median Range
42 0-100
().85
0.01"
G1: M ed ian Range
6hr
60
15
G2: 40
Duration of Surgery min
87 .8 (33 .2)
85 .9 (42 .4)
p:
Total fen tanyl meg
471.7 (104)
461.5 (89)
01 =lime of extubation: 15, 30. 45, 60. 00. 120minutes, 6 wid 24 holJ's after extltJalion.
Values are mean (SE) where appropria te
Table 2. Median IlI1d {
'Table I . Patient rliaraacristics
( VA S) at Each TiIllI Poill t I!{trr SII ~l!rry G 1: Lignocaine G2: Placebo
50
Time(T)
0
15
30
45
60
90
120
6h 24h
G1
20
16
14
14
14
13
11
11
11
G2
20
12
10
8
6
5
5
3
3
E
V 40
% Survival P r ob a bility
A 30
m m 0.8 30
45
60
90
120
6hr
I I I
24hr
0 _ -.
0.6
T im e after surgery
I
0 - ., I
Fi.!! . L.Pain
S(( II'/ 'S ,IS
0 - .,
0.4
dctrnninrd by Vi sII 1/1 AliI/ill.!!//(' Scale
I I
(median] ill patients r('(ri!'ill.!! i" l mpf'ri t(l"ca l l(l!" (lrail j(' (G I) (If
saline ((;2) . Fi.!!.2 , Kaplan-Meier sIIn1il'I/I p lots. AppetlmllCC
group (G2) at 15, 45, 60, l)O m inutes, 6 and at 24
(I: VA > 5011I11I) ill 1(I!II(1railll' and (()tltrol ,l!mllp s at cacl: time
ho ur s after sur gery (Table 2). Patie n ts in t he co n t ro l gro up h ad sig n ifica n tly m ore seven:' pain with VAS scores, ~5() 111111 (1712()) at e ver y ti m c point after s u rge ry ve rs us the lignocaine g ro up (l)/ 2()) (Fig 2). N o sid e effe ct s related to ligno cain e occ u r re d. Blo od pressure and heart rat e were sta ble with no differen ce between the g ro ups. The frequen cy of nau sea and vo m iting wa s n ot statist ica lly different betwe en th e lign o cain e g ro u p (six pati ents) and saline group (e ight pati ents). Li gn o cain e wa s a bso r b e d rapidl y from th e peritoneal cav ity. Plasm a lignocaine co nc ent ratio ns rea ched the peak at five minutes referred to pe ak co nc c n rrnt io n (C max): 2 .9 5 p g 1111 . 1 • In d ivid u a l result s from th e 2() patients did not sho w an y to xic levels of lign ocaine at any tim e durin g the study. T he highe st co nc e n tratio n observed at an y time in any patient was 4.H pg m l-1 w hic h is near the to xic level
point q{ter SIl ~l!l'ry. (X2 = 5. 5 62 0 .0 1< p
202
Time (mins) 2 5 Serum Concentration Mean 2.00 1 2.95 Min 0.19 0.6 4.8 Max 5
10
15
30
45
90
60
1.72 1.46 1.22 0.6 0.61 0.53 3.3 2.41 2.4 1
2.15 2.4 2.25 1.87 0.18 0.7 1.23 1.01 4.1 4.58 4.2 2.61
y
9 0
4
C
3
a
2
i
T - Y
5
Y
e
Y
• • • • -• .... • • •.... •.... .... -... .... Y
Y
/
I ,
n 0
Y
Max Mean Min
•....
6
n
120
0
Y
Y
90
120
~
2
5
10
15
30
45
60
Fi,!!.3. Serum (Oll( l'lI lml iollS 4 /(l!l/o(aill l' ,!{ter instillation 4 a dose (! f 400 II/.I! into pC/itol/l'lll cavitv , Data shown cIS 11/1'111/ values with minima IIl1d maxima (11 =20)
Vo lume 3 (4) D e cemb er 2000
A cu te Pain
Intraperitoneal lignocaine after laparoscopic cholecystectomy Kolsi et al
under anaesthesia ( 6 ug ml-') .
Discussion: There is a marked interindividual variability of pain after laparoscopic eholecystectomy'>. The reasons for this significant variability are not clear". In fact, laparoscopic cholecystectomy is not a highly invasive operation with minimal tissue damage. The postoperative pain induced by this type of surgery has a considerable visceral component (owing to surgical handling and diaphragmatic irritation by dissolved carbon dioxide) and a lesser parietal component (owing to the holes made in the abdominal wall for the trocars)", In addition, the visceral component at times results in shoulder tip pain, similar in location and type to the pain that occurs with biliary co lic.v' Carbon dioxide is insufflated into the abdominal cavity in order to create the surgical view. It can become entrapped between the liver and the right diaphragm causing irritation of the diaphragm since the patients have to be operated in the reverse Trendelenburg position and CO 2 , moves upwardsv!''-!'. Intraperitoneal instillation of local anaesthetic is our analgesic technique of choice, as it is noninvasive and easy to practice. The choice of the local anaesthetic and its concentration was made on the basis of several considerations: First, given the size of the area involved in surgery, a volume of 20 ml was the minimum required for coverage on all levels". Second, the 1% concentration of the local anaesthetic was chosen after a comparison of the experience listed in previous literature 3 ,4.5 . Lignocaine was chosen because of its low toxicity'>; intraperitoneal administration of doses of 100-150 rng of bupivacaine may result in toxic plasma .
13
concentrations . Analysis of our data indicates that intraperitoneal lignocaine infiltration is a very efficient method of pain relief after laparoscopic cholecystectomy. This data confirms the results of previous studies that reported effective pain relief after laparoscopic procedures with intraperitoneal instillati?n of local anaestheticH.7,14, In contrast, other studies suggests that intraperitoneal bupivacaine or lignocaine does not reduce pain after laparoscopic cholecystectomy 1.,13,15.16.17. Our analysis of the literature has identified ma ny d ifferent factors influencing the outcome: total dosage of local anaesthetic, the site of instillation (right or both right and left subdiaphragmatic areas),
Acute Pain
the moment of administration of local anaesthetic and the position of the patient during and just after instillation. These factors provide multiple explanations for the lack of analgesic effect in some studies: First, the total dosages are IOW6 •15, IH. Second, the increased efficacy of intraperitoneal local anaesthetics may be due to the fact that the solution was applied to both hemidiaphragms and not just to the right subdiaphragmatic area, while the solution was left it! situ7•14• Pasqualucci et al19 emphasise the importance of the timing of anaesthetic administration in postoperative pain preemption. They found that visual analogue pain scores and the consumption of analgesics were significantly lower in patients receiving intraperitoneal bupivacaine immediately after the creation of pneumoperitoneum than at the end of surgery'v-v, Another important factor is the evacuation of the residual CO2 pneumoperitoneum by suction and manual compression of the abdomen in the declive position-l-". In the present study, instillation of lignocaine is performed in the headdown position. Instillation oflocal anaesthetic in this position may improve analgesia, because the drugs are expected to flow towards the coeliac plexus and the phrenic nerve endings. In contrast, some studies have reported no effective pain relief, when local anaesthetics were instilled in the supine position. It is conceivable that in this position the local anaesthetics flow with gravity away from the coeliac plexus and the phrenic nerve endings". In our study no analgesics were used in postoperative period study. This may be the reason that more patients had severe pain (VAS more than 50 mrn): H5'XI in the control group vs 45% in the lignocaine group; twice or much more the rate of previously reported cases, where one-third to one-half of patients had severe pain!o.
Finally, many questions have been asked by our Ethics Committee about the lack of analgesic protocol in the postoperative period before permitting the study. We attempted to simplify the study model as much as possible by using only topical peritoneal local anaesthesia. Furthermore there is currently a lack of evaluation and treatment of postoperative pain in our hospital, which meant that study patients were not disadvantaged. We found that lignocaine was absorbed relatively rapidly from the peritoneal cavity. Plasma lignocaine concentrations reached a peak at five minutes
Volume 3 (4) December 2000
203
Intraperitoneal lignocaine after laparoscopic cholecystectomy Kolsi et al
referred to as peak concentration (Cmax: 2.95 Ilg mI'). The time to the peak (Tmax) was five minutes. Narchif found that, after gynaecological laparoscopy, the rate of absorption of lignocaine from the peritoneal cavity was relatively slow, the time to maximum concentration (tC pmax) was reached at 29 minutes with plain lignocaine 400 mg. In fact, lignocaine was absorbed more rapidly after laparoscopic cholecystectomy than after diagnostic laparoscopy. Lignocaine was probably absorbed through the damaged micro vessels of the gall bladder bed. In Williamson's study> using 200 mg of lignocaine after total abdominal hysterectomy and Narchi's study", the maximum concentration of lignocaine attained (C pmax) was relatively low. Narchif found a Cpmax value of 4.3 Ilg ml- I with plain lignocaine 400 mg, 2.3 Ilg ml- I with lignocaine 400 mg and adrenaline 1:320 000, and 1.89 ug ml- I using lignocaine 400 mg with adrenaline 1:800 000. We used lignocaine without adrenaline because in all cases anaesthesia was conducted with halothane which might produce cardiac dysrhythmias in the presence of increased plasma concentrations of adrenaline and also during laparoscopic procedure with high frequency of hypercapnia. The serum concentration of lignocaine which cerebral toxic symptoms begin to occur is approximately 3 Ill,' ml- I in the unmedicated subject but the threshold increases in patients during anaesthesia-', Thus, our data suggests that a dose of lignocaine 400 mg would be extremely unlikely to result in toxicity when given into subdiaphragmatic area and to the gall bladder bed.
Pain Research in Istanbul, October 1999. References 1. Joris J, Cigarini I, Legrand M, et al.Metabolic and respiratory changes after cholecystectomy performed via laparotomy or laparoscopy.Br J Anaesth 1992: 69:341-345. 2. Berggren U, Gordh T, Grama D, et al. .Laparoscopic versus open cholecystectomy, Hospitalisation, sick leave, analgesia and trauma responses. Sutg 1994:H1:1362-1365. 3 Narchi P,Benhamou D, Fernandez H. Intraperitoneal local anaesthetic pain after day case laparoscopy. The LAncet, 1991,338:1569-1570 4. Narchi P,Benhamou D,Aubrin F. et al. Analgesia using mesosalpinx infiltration combined with intraperitoneal lignocaine for yoon ring Iaparoscopy. Anaesthesiology, 1992,77:3A-17 5. Narchi P ,Benhamou D,Bouaziz H.et al.-Serum concentrations of local anaesthetics following intraperitoneal administration during laparoscopy. Hur. J .cu« Pharmacal, 1992, 42: 223-225. 6. Joris J, Thiry E, Paris P, et al. Pain after laparoscopic cholecystectomy: Characteristic and effect of intraperitoneal bupivacaine. Anesth Ana(~ 1995: 81: 379-384. 7. Mraovic B, Jurisic T, Kogler-Majeric V. et al. Intraperitoneal bupivacaine for analgesia after laparoscopic cholecystectomy. Acta Anaesthesiol Scand 1997; 41: 193-196 H. Alberto P,Verena D, Riccardo C. et al. Pre-emptive Analgesia: Intraperitoneal Local Anaesthetic in Laparoscopic Cholecystectomy, Anesthesiology 1996; 85: 11-20. Lindgren L. Editorial : Pain after laparoscopic cholecystectomy . 1)0 we do our best? Acta Anaesthesiol Scand 1997; 41: 191-192. 10. Fredmann B, Jedeikin R, Olsfanger D. et al. Residual pneumoperitoneum: A cause of postoperative pain after laparoscopic cholecystectomy.Anesth Ana(~ 1994, 79, 1, 152. II. Jackson SA, Laurence A, Hill J.Is post-Iaparoscopy pain related to residual carbon dioxide volume? Br. J of Anaesthesia 1995, 74, 4, 477. 12. Ki.ihlman.G - Pcritoneal block, In: Bonnet F Eledjam (eds) Actualitics in Regional Anaesthesia. First Ed. Arnette 1Y95 . 319 -324. 13. Fuhrcr Y, Charpentier C, Boulanger G, et al, Analgesia after laparoscopic cholecystectomy using intraperitoncal bupivacaine. AIIII Fr Anacsth Rca 1996; 15: 12H-134. 14. Geraldinc C, Olivier J, Manzoor A. ct al. A prospectivc randomised trial of intraoperative
Y.
Conclusion Intraperitoneal 1'X, lignocaine (400 mg) infiltration is shown to be a very efficient method of pain relief after Iaparoscopic cholecystectomy. This technique is safe since we did not see any side effects and serum concentrations. The duration of action cannot be explained by either systemic effects or the classic local action. This treatment could subsequently shorten the duration of the hospital stay and, further reduce the cost of lnparoscopic cholecystectomy performed as day-case surgery.
Acknowledgements We arc grateful to Mr Habib Feki for statistical analysis and to Moufida Bouyahia for English review. Results of this study have been presented as posters
204
at 41 st International Congress of SFAR in Paris, September 1999 and 7th European Conference on
Volume 3 (4) December 2000
Acute Pain
Intraperitoneal lignocaine after laparoscopic cholecystectomy Kolsi et al
15.
16.
17.
18.
bupivacaine irrigation for management of shouldertip pain following laparoscopy. Am] of Surg, 1998, 176 : 258-261. Rademaker B, Kalkman C, Odoom J, et al. Intraperitoneal local anaesthetics after laparoscopic cholecystectomy: Effects on postoperative pain, metabolic responses and lung function. Br. J. Anaestli 1994: 72:263-266. Scheinin B, Kellokumpu I, Lindgren L, et al. Effect of intraperitoneal bupivacaine on pain after laparoscopic cholecystectomy. Acta Anaesthesiol Scand 1995; 39: 195-198. Raetzell M, Maier C, Schroder D, et al. Intraperitoneal application of bupivacaine during laparoscopic cholecystectomy: Risk or benefit? Anesth Ana{g, 1995,81,5,967. Schulte-Steinberg H,Weninger E, Jorkisch D, et al. Intraperitoneal versus interpleural morphine or bupivacaine for pain after laparoscopic cholecystectomy. Anesthesiology 1995:82:634-640.
Acute Pain
19. Pasqualucci A, De Angelis V, Contardo R, et al. Preemptive analgesia: intraperitoneal local anaesthetic in laparoscopic cholecystectomy. Anesthesiology 1996; 85: 11-20. 20. Christina M, Frances C, Sharad S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. A nesth Analg 1996; 82:44-51. 21. Tsimoyiannis EC, Glantzounis G, Lekkas ET, et al. Intraperitoneal normal saline and bupivacaine infusion for reduction of postoperative pain after laparoscopic cholecystectomy. Surg Laparosc Endosc 1998; 8(6): 416-20. 22. Duchene.Analgesia after laparoscopy: Effect of intraperitoneal flushing using saline solution. Ann Fr Anaestn Rea, 1994; 13: 435-440 23. Williamson KM, Cotton BR, Smith G. Intraperitoneal lignocaine for pain after total abdominal hysterectomy.Br.] tif Anaesth 1997; 78:675-677.
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