1 Department of Anaesthesiology and Critical Care DAR-B, University Hospital of Montpellier, France. 2 Laboratory of Anaesthesiology and Experimental Surgery, Medical School of Montpellier, France
Corresponding author: Département dAnesthésieRéanimation, Groupe Hospitalier Pitié-Salpétrière, 47-83 Bd de lHôpital, F-75651 Paris Cedex 13, France. E-mail: gilles.boccara@psl.ap-hop-paris.fr
Accepted for publication: December 16, 2002
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Abstract |
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Methods. Carbon dioxide pneumoperitoneum (14 mm Hg intra-abdominal pressure) was performed in 32 anaesthetized young pigs and monitored using a pulmonary artery catheter. Animals received lidocaine 0.5% (0.5 mg kg1) i.v. (n=9) or 2 ml kg1 i.p. (n=9) or saline (n=5) 15 min before the pneumoperitoneum and were compared with a control group (n=9).
Results. I.V. and i.p. lidocaine inhibited increases in mean systemic vascular resistance induced by the pneumoperitoneum [2109 (SD 935) and 2282 (895), respectively, vs 3013 (1067) dyne s1 cm5 in the control group]. Cardiac output was increased. Plasma lidocaine concentrations were threefold higher after i.p. administration than after i.v. administration. After pneumoperitoneum insufflation, plasma lysine-vasopressin concentrations increased in all groups (control 74%, saline 65%, i.p. lidocaine 57%, i.v. lidocaine 74%).
Conclusions. I.V. and i.p. lidocaine blunted systemic vascular responses to carbon dioxide pneumoperitoneum in pigs, but without influencing vasopressin release.
Br J Anaesth 2003; 90: 3438
Keywords: anaesthetics local, lidocaine; complications, pneumoperitoneum; hormones, antidiuretic; sympathetic nervous system, sympathomimetic agents
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Introduction |
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In this study, we assessed the effects of local and systemic lidocaine on the reduction of systemic vasoconstriction and vasopressin release after carbon dioxide pneumoperitoneum in pigs.
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Methods |
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After i.m. premedication with ketamine 10 mg kg1 and midazolam 0.2 mg kg1, general anaesthesia was induced with pentobarbital 5 mg.kg1 i.v. via an ear venous catheter. Tracheal intubation was performed to permit mechanical ventilation with oxygen 100%, tidal volume of 15 ml kg1, and ventilatory frequency of 20 bpm, adjusted to obtain a constant end-tidal carbon dioxide partial pressure (EE'CO2) of 3035 mm Hg before i.p. insufflation. General anaesthesia was maintained with 1% expired isoflurane and repetitive infusion of ketamine 1 mg kg1 and vecuronium 0.1 mg kg1 for neuromuscular block. Fluid replacement was with constant infusion of lactate Ringer solution 10 ml kg1 h1.
Using a surgical approach, a catheter was inserted into the carotid artery to continuously monitor mean arterial pressure (MAP). A pulmonary artery catheter was inserted into the internal jugular to monitor mean pulmonary arterial pressure (MPAP), right atrial pressure (RAP), pulmonary arterial occlusion pressure (PAOP), and to measure CO by thermodilution. SVR and PVR were calculated respectively using the formulae SVR=MAPRAP/COx80 and PVR= MPAPPAOP/COx80. Heart rate (HR) was measured by ECG monitoring. Both EE'CO2 and expired isoflurane concentration were measured by gas analysis (Capnomac, Datex). Temperature was recorded via the thermic probe of a pulmonary artery catheter and maintained with a warming cover. Blood samples were obtained via the carotid catheter for measurement of arterial blood gases, haematocrit and plasma sodium concentration. After centrifugation, plasma was extracted and immediately frozen at 20°C for measurement of hormones. Lysine-vasopressin (LVP; the only type of vasopressin in porcine species8) was measured by radioimmunoassay. Plasma norepinephrine and epinephrine concentrations were measured using high-performance liquid chromatography. Plasma lidocaine concentrations were measured using the Aca discrete clinical analyser for the quantitative determination of lidocaine in plasma, and the Acastar device (Dade Behring). This technique is an adaptation of the EMIT homogeneous enzyme immunoassay technique. The limit of precision is for a numerical value <1.0 µg ml1. For instance, the therapeutic lidocaine concentration varies significantly between people; the therapeutic range is 1.55.0 µg ml1. Concentrations greater than 8.0 µg ml1 are associated with toxic symptoms in normal adults.
Pigs were assigned to one of four groups: i.p. saline 2 ml kg1 (n=5); i.v. lidocaine 0.5 mg kg1 (n=9); i.p. lidocaine 0.5%, 2 ml kg1 (n=9); or no administration (control, n=9). The doses of lidocaine were chosen after a local pilot study to determine the lowest dose needed to avoid cardiovascular effects in anaesthetized pigs. The carbon dioxide pneumoperitoneum was performed with a constant 14 mm Hg intra-abdominal pressure, 15 min after dosing.
After a steady-state period of 30 min after catheter insertion, the pneumoperitoneum was established by carbon dioxide insufflation through a Palmer needle with an automated insufflator (AutoEndoflator, Storz). Haemodynamics (CO, MAP, HR, MPAP, RAP, PAOP, SVR and PVR) and respiratory parameters (EE'CO2, PaO2, PaCO2, pH) were measured and blood samples were taken after the 30 min steady-state period (T0). Before pneumoperitoneum insufflation, haemodynamic data were recorded at 5 min (T1) and 15 min (T2) after lidocaine or saline administration. Haemodynamic values were then noted at 5 min (T3) and 30 min (T4) after insufflation of the pneumoperitoneum, and at 5 min after gas release (T5). Blood samples were taken at T0, T3 and T5.
Statistical analysis
Continuous data are presented as mean (SD) or median (2575th percentile) when data were not normally distributed. ANOVA for repeated measures was applied to assess changes according to time (intragroup variation) or between the groups (intergroup variation) and their interaction (times x groups). For a significant value of F, intragroup comparisons were performed at each time according to Students t-test for paired values, with Bonferroni correction. Variation between groups was compared using the MannWhitney test for unpaired samples. Spearman correlation analysis was used to assess the relationship between variables. A P-value <0.05 was considered significant.
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Results |
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Plasma LVP concentrations increased after pneumoperitoneum and decreased after exsufflation in both groups, with no significant intergroup differences (Fig. 2). After pneumoperitoneum, LVP increased by 74%, 65%, 57% and 74% from baseline in the control, saline, lidocaine i.p. and lidocaine i.v. groups, respectively. There was no difference in plasma norepinephrine or epinephrine concentrations after pneumoperitoneum production in all four groups (Fig. 2).
Plasma lidocaine concentrations were high after i.p. administration but threefold lower after i.v. administration (Fig. 3). Plasma lidocaine concentrations after i.p. administration were higher than after i.v. administration at 5 min after pneumoperitoneum insufflation [4.20 (range 0.904.70) vs 0.40 (0.350.65) µg ml1; P=0.05) and after exsufflation [2.15 (0.524.85) vs 0.50 (0.250.6) µg ml1; P=0.02).
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Discussion |
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Haemodynamic changes after carbon dioxide pneumoperitoneum are characterized by a decrease in venous return, and systemic arterial vasoconstriction induced in large part by humoral mechanisms secondary to a pressure effect on the splanchnic vascular bed.9 10 The decrease in venous return and increase in vascular resistance lead to a decrease in CO. In our results, inhibition of the vascular response to carbon dioxide pneumoperitoneum using lidocaine improved the afterload and the cardiac work associated with an increase in CO. A pressure effect has initially been suggested: right auricular receptor activation by transparietal pressure decreases induces the posterior pituitary to release vasopressin.11 12 However, the absence of haemodynamic changes and vasopressin release after pneumoperitoneum with inert gases such as argon6 or helium13 at the same intra-abdominal pressure suggests a gas effect. The pathophysiological mechanisms of these haemodynamic responses to videolaparoscopy may involve a gas effect and not a pressure effect. In 1980, Bonnet and colleagues14 proposed that the cardiovascular effects induced by pneumoperitoneum were secondary to the peritoneal reaction to carbon dioxide. In the same way, Melville and colleagues15 suggested that the peritoneal nerve endings could be activated, thus provoking vasopressin release by the posterior pituitary gland. Furthermore, the vascular response after i.p. insufflation of carbon dioxide could be related to vasopressin release.6 The mechanisms of vasopressin release and vascular effects during carbon dioxide pneumoperitoneum are not yet established. Thus, carbon dioxide could induce vasopressin release either by a regional action via the enteral sympathetic nervous system or systemically by induction of chemoreceptors and subsequent pituitary gland secretion. At the peak of vasopressin release (5 min after gas insufflation), PaCO2 increased progressively but slightly.6 In anaesthetized dogs, hypercapnia above 55 mm Hg is required to induce plasma vasopressin release.16 Volz and colleagues17 reported that acidosis occurs rapidly in the peritoneal cavity, while Blobner and colleagues18 described splanchnic hyperaemia. Carbon dioxide could irritate the peritoneal fascia via a change in local pH and then provoke direct or indirect sensitization of vascular smooth muscle cells to vasopressin. Rimback and colleagues19 found a beneficial effect of local lidocaine 1% in reducing the peritoneal inflammatory response after application of 0.1 M hydrochloric acid to rat peritoneum. Otherwise, local anaesthetics have anti-inflammatory properties in vitro as well as in vivo, and it has recently been proposed that i.v. infusion of local anaesthetics modulates postoperative inflammatory responses.20 Blocking of nerve endings by in situ administration of local anaesthetics is thought to blunt the haemodynamic consequences induced by carbon dioxide pneumoperitoneum. According to our results, i.p. and i.v. lidocaine inhibit arterial vasoconstriction induced by carbon dioxide pneumoperitoneum without any reduction in vasopressin release. Thus, lidocaine decreased or counteracted the vascular effects of vasopressin, and not its release. Moreover, Lentschener and colleagues21 showed the absence of haemodynamic changes and vasopressin release during 1315 mm Hg carbon dioxide pneumoperitoneum in humans with deep remifentanil analgesia and adequate fluid loading. In addition to anti-inflammatory action, lidocaine, via an improvement in intraoperative analgesia, could also aid in control of the haemodynamic consequences of carbon dioxide pneumoperitoneum.
Lidocaine acts as a local anaesthetic by inhibition of nerve sodium channels and it is extensively used in regional anaesthesia. The plasma lidocaine concentration after regional anaesthesia remained below 5 µg ml1, far below the cardiotoxic concentration (>20 µg ml1) in humans.22 Lidocaine 510 mg kg1 i.v. in anaesthetized cats induces a decrease in sympathetic activity but also direct myocardial depression.23 In humans, lidocaine at subclinical plasma concentrations (1 µg ml1 after 1.5 mg kg1 i.v.) does not inhibit the sympathetic response to a cold pressure test.24 In our study, we used subclinical doses to avoid any direct sympathetic or myocardial action. In pigs, doses of i.v. lidocaine that lead to therapeutic plasma levels for antifibrillatoric efficacy25 or anticonvulsant activity26 are in the range 23 mg kg1. Nevertheless, in situ i.p. administration of lidocaine is associated with high plasma concentrations approaching toxic levels.
The release of vasopressin was sustained during carbon dioxide pneumoperitoneum after i.p. lidocaine administration whereas plasma concentrations of lidocaine were sufficient to inhibit sympathetic nerve activity. This result suggests the absence of a sympathetic nerve pathway in vasopressin release. Inhibition of direct vascular effects of vasopressin by lidocaine itself is also suggested. Otherwise, lidocaine has a direct and biphasic action on artery contraction in humans and in animals in vitro: it produces vasoconstriction in low concentrations (105103 M) and vasodilatation in high plasma concentrations (5x103102 M).27 Recently, the presence of sodium channels in human artery smooth muscle cells has been described, and their stimulation results in contraction after an increase in intracellular free calcium.28 29 The authors reported a high affinity for lidocaine (IC50 0.1 µmol litre1), a sodium channel antagonist, which may lead to a relaxant vascular effect.29 This vascular effect of lidocaine could be involved in the inhibition of the vasopressin-induced vasoconstriction after carbon dioxide pneumoperitoneum.
In clinical practice, continuous i.v. lidocaine infusion rate 2 mg min1 (mean plasma concentration 12 µg ml1) is used to provide postoperative analgesia after laparoscopic cholecystectomy.30 Narchi and colleagues7 reported effective postoperative analgesia after i.p. administration of bupivacaine or lidocaine after videolaparoscopy. Intraoperative haemodynamic investigations were not reported.7 These authors showed that lidocaine 0.5%, 400 mg (80 ml) i.p. is not associated with toxic plasma concentrations 6 h after administration.7 Usually, local anaesthetics are used in videolaparoscopy to achieve postoperative analgesia rather than for beneficial intraoperative haemodynamics. The results of our study address this deficit.
In summary, after prophylactic i.v. administration of lidocaine 0.5 mg kg1, the increases in SVR and PVR in response to induction of carbon dioxide pneumoperitoneum were prevented. In contrast, the increase in vasopressin concentration was not affected. I.P. lidocaine had a similar influence on haemodynamic and hormonal changes but was associated with high plasma concentrations.
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Acknowledgements |
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References |
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