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© 1999 International Anesthesia Research Society
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Abstract |
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We assessed the role of vasopressin (VP) for the hemodynamic response to pneumoperitoneum in pigs. Four groups of anesthetized pigs were investigated. Nine pigs were intraabdominally insufflated with CO2 and eight were intraabdominally insufflated with argon; eight pigs received an IV injection of 1 mg/kg SR 49059, a VP antagonist, before CO2 insufflation; and six pigs received SR 49059 alone. Hemodynamics, plasma concentrations of VP and vasoactive hormones, and PaCO2 were measured. Data were analyzed by using analysis of variance, Student’s t-test, and Mann-Whitney U-test. Five minutes after insufflation, changes in systemic vascular resistance (SVR) were significantly correlated with changes in VP (r = 0.72; P = 0.005) but not with changes in epinephrine, norepinephrine, renin activity, or PaCO2. SVR increased during CO2 insufflation but not during argon insufflation or CO2 insufflation with a preceding infusion of SR 49059. The SR 49059 injection itself resulted in increases in heart rate and cardiac output and decreases in blood pressure and SVR. We conclude that, during CO2 pneumoperitoneum in pigs, absorbed CO2 initiates a pathophysiological process that stimulates VP release. Hence, VP most likely plays a key role in the hemodynamic response to a CO2-induced pneumoperitoneum.
Implications: Intraabdominal insufflation of CO2 is associated with hemodynamic and hormonal changes. Investigating CO2 and argon-insufflated pigs and using a vasopressin antagonist, we found that CO2 insufflation released vasopressin, which, in turn, induced hemodynamic perturbances.
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Introduction |
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Conventional CO2 pneumoperitoneum can induce significant hemodynamic changes: an increase in arterial blood pressure and systemic vascular resistance (SVR) and a decrease in cardiac output (1–3). This hemodynamic response leads to an increase in myocardial uptake of oxygen, which is particularly deleterious in patients with disturbances in cardiac function. The increase (20%–80%) in SVR occurs with a pneumoperitoneum for which the mechanism has yet to be clearly defined (4). Although absorbed CO2 from the abdominal cavity could lead to mild hypercapnia, hypercapnia per se causes a decrease in SVR by a direct effect on the vasculature (5). Therefore, the vasopressor response is probably due to the activation of one or several vasoactive hormone systems (4,6–10). However, the relationship between SVR and sympathetic or renin-angiotensin-aldosterone system activation is controversial (7–10). Increased plasma concentrations of vasopressin (VP) recorded during the initial period of insufflation, however, provide evidence that VP could be intimately involved in the hemodynamic response to pneumoperitoneum (6,8,11). VP plays a major role in regulatory water solute excretion by the kidney and blood pressure control (12). However, the pathophysiological role of VP and its mechanism of secretion during pneumoperitoneum are not known. Studies in pigs have shown that when intraperitoneal insufflation was performed with an inert gas such as helium (13) or argon (14), the hemodynamic disturbances initially described for CO2 were not found.
We therefore tested, in a pig model of pneumoperitoneum, the hypothesis that instead of increased abdominal pressure (IAP), the specific biochemical effects of insufflated CO2 provoke VP release, which, in turn, induces vasoconstriction and subsequent hemodynamic perturbances. First, we considered the mechanical consequences of IAP and the related effects of CO2 separately, using argon, a control insufflated gas. Second, to differentiate the role of VP from the principal vasopressive hormones, we used a specific antagonist of VP receptors that inhibits VP-induced vasoconstriction.
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Methods |
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This study was approved by our animal care committee. All animals were used in compliance with the Guide for the Care and Use of Laboratory Animals. Thirty-one male pigs (25–30 kg) were anesthetized with IM ketamine (10 mg/kg) and IV pentobarbital (5 mg/kg) injections. Anesthesia was maintained at an end-tidal isoflurane concentration of 1% with intermittent doses of pancuronium (0.1 mg · kg-1 · h-1). After tracheal intubation, ventilation was controlled with 100% oxygen with a tidal volume of 15 mL/kg at a rate adjusted (15–20 breaths/min) to obtain an end-tidal CO2 pressure of 30–35 mm Hg. These ventilation variables were maintained constant for the remainder of the experiment. Peak airway pressures were recorded on the ventilator (Monnal A; CFPO, Paris, France). Continuous monitoring of expired isoflurane and CO2 concentrations was performed using a multigas analyzer (Capnomac Ultima; Datex Corp., Helsinki, Finland). A femoral artery was cannulated to monitor the mean systemic arterial pressure (MAP) and to obtain blood samples to further analyze arterial blood gas and hormone concentrations. A 7F, 110-cm thermistor-tipped flow-directed pulmonary artery catheter was inserted via a femoral vein and positioned by using of a pressure monitor into a branch of the pulmonary artery. Cardiac output (CO) was averaged from triplicate thermodilution measurements at end-expiration using 5 mL of iced saline injectate and a CO computer. Pulmonary capillary wedge and right atrial pressures were measured using transducers set to atmospheric pressure at the level of the right atrium, continuously recorded, and read at end-expiration; SVR was then calculated. Temperature was monitored via the thermistor probe of the pulmonary artery catheter and was maintained at 37.0 ± 0.5°C. Before the experiment, a basal lactated Ringer’s solution was administered to compensate for fasting (5 mL/kg) and was maintained at a rate of 4–6 mL · kg-1 · h-1.
Thereafter, the pigs were divided into four groups. To evaluate the hormonal and hemodynamic responses to pneumoperitoneum, two groups received either CO2 or argon insufflation. To test the effect of a VP blockade on hemodynamics, two groups received an injection of a VP antagonist associated or not associated with a CO2 pneumoperitoneum. At the end of the experiment, the animals were immediately killed by a lethal dose of potassium chloride.
CO2 and Argon Insufflation
After a 90-min period of stabilization, 17 pigs were intraabdominally insufflated in the supine position with CO2 (CO2 group, n = 9) or argon (argon group, n = 8) to a constant IAP of 15 mm Hg. Using a video camera, the peritoneal cavity was systematically inspected for any signs of inadvertent surgical trauma. Cardiorespiratory variables were noted, and blood samples were drawn before (T0); 5 (T1), 20 (T2), and 40 min (T3) after the beginning of insufflation; and 5 (T4) and 30 min (T5) after exsufflation. Plasma concentrations of lysine8 VP, the natural antidiuretic hormone in pigs, were measured by using radioimmunoassay (15); intra- and interassay coefficients of variation were 10%–20%; sensitivity of the assay was 0.5 pg/mL. Plasma concentrations of catecholamine were measured using high-performance liquid chromatography: epinephrine (normal values <80 pg/mL; sensitivity 2 pg/mL) and norepinephrine (normal values <350 pg/mL; sensitivity 2 pg/mL). Plasma renin activity (PRA) was measured as the amount of angiotensin I produced (in ng · mL-1 · h-1) (sensitivity 0.02 ng/mL/h; intra- and interassay coefficients of variation 7% and 8%). Plasma sodium was measured by using flame photometry.
Vasopressin Blockade
The nonpeptide VP antagonist SR 49059 ((2S) 1-[(2R 3S)-(5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxy- benzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide) synthesized by Sanofi Recherche, Montpellier, France (16), was dissolved in dimethyl sulfoxide at a concentration of 10-2 M, then diluted in saline for IV injection. As reported for rats (16), we previously found (data not published) in pigs that IV injection of 1 mg/kg SR 49059 produced complete inhibition of VP-induced hypertension that lasted 4 h. After a 60-min period of stabilization in 14 pigs, hemodynamic variables were noted before (T-2) and 15 (T-1) and 30 min (T0) after the injection of 1 mg/kg SR 49059. At T0, eight pigs were insufflated with CO2 (CO2/SR group), and cardiorespiratory variables were investigated as previously described. Six pigs treated with SR 49059 were not insufflated (SR group). Data are reported as mean ± SD. A two-way analysis of variance for repeated measures was performed to test the effects of time (within-group factor), insufflated gas or SR 49059 treatment (between-group factors), and their interaction (time x group) on investigated variables. For significant F values, within-group comparisons were made at each time interval by using a paired t-test with the Bonferroni correction. The between-group changes were compared by using a Mann-Whitney U-test for unpaired data. Spearman’s correlation was performed to assess the relationship between changes in variables. A P value < 0.05 was considered significant.
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Results |
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Peak airway, right atrial, and pulmonary capillary wedge pressures increased after gas insufflation, then decreased after exsufflation in the argon, CO2, and CO2/SR groups. However, there were no differences among the groups (no significant time x group effect). In contrast, those variables remained stable in the SR group (no significant time effect). In all groups, PaO2 and hematocrit did not change because of the gas insufflation and/or the SR 49059 injection.
CO2 and Argon Insufflation
Preinsufflation (T0) values were comparable between the CO2 and argon groups. There was a significant time effect regarding the gas used in MAP, SVR, VP, and PaCO2 values (Tables 1 and 2). At 5 min of insufflation, increases in MAP, SVR, VP, and PaCO2 were significantly higher in the CO2 group than in the argon group. In addition, changes in SVR at this time were significantly correlated with changes in VP (r = 0.72; P = 0.005) (Fig. 1) but not with changes in epinephrine (r = 0.47), norepinephrine (r = 0.15), PRA (r = 0.26), or PaCO2 (r = 0.23).
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Vasopressin Blockade
Between the CO2/SR and SR groups, the baseline (T-2) values were comparable; the variations in heart rate (HR), MAP, CO, and SVR are reported in Table 3. The SR 49059 injection caused decreases in MAP (36% of baseline) and SVR (47% of baseline) at 15 min and increases in HR (16% of baseline) and CO (19% of baseline) at 30 min after injection. Thereafter, a plateau was reached for all variables. In SR 49059-treated pigs, CO2 insufflation did not result in a significantly different pattern of HR, MAP, CO, and SVR. In contrast, in CO2 insufflated pigs, pretreatment with SR 49059 resulted in a significantly different pattern of MAP, CO, and SVR. After CO2 insufflation, PaCO2 increased in both the CO2 and CO2/SR groups, but there were no significant differences between the two groups (no significant time x group effect). PaCO2 did not change in the SR group (no significant time effect).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our findings support the hypothesis that hemodynamic changes after CO2 pneumoperitoneum are related to the biochemical effects of CO2 and are primarily mediated by an increase in VP plasma concentration. As demonstrated in humans (6,8,11), after the creation of CO2 pneumoperitoneum, we observed that the concentration of VP in plasma markedly increased to values sufficient to powerfully activate vascular myocyte V1a receptors and to provoke intense vasoconstriction (12,17). The diverse results previously obtained could be attributed to the differences in the experimental conditions, because surgical stress situations (18), blood volume, or osmolality variations and the use of medications can have a great influence on VP levels. We therefore took care to avoid these potential problems. First, osmolality remained stable because plasma sodium was unchanged during the experiment in both the argon and the CO2 groups. In addition, although intrathoracic pressures vary during insufflation, the changes in extracardial pressure (evaluated by peak airway pressure) and intracardial pressure (evaluated by right atrial pressure) were similar in the two groups. Therefore, the differences in VP levels between the two groups were not related to alteration in blood volume conditions. Second, catheters requiring an inguinal incision were positioned more than one hour before pneumoperitoneum, and no surgical maneuvers were subsequently performed. Stress was therefore minimal, as confirmed by the low levels of catecholamine during the first 20 minutes of insufflation. Finally, the use of opiates, potential inhibitors of neurohypophysial secretion (19), was avoided. This may explain the high VP baseline values observed in both groups. In contrast, in previous studies (10,20), the use of opiates could explain the moderate VP peak observed during insufflation.
We also evaluated sympathetic and renin-angiotensin-aldosterone system activity to determine whether they were also partly responsible for the observed vasopressive response. The activity of both of these systems increased during pneumoperitoneum in a comparable manner, regardless of which gas was insufflated. However, no correlation was observed between those variations and the increase in SVR. In humans, the results are contradictory (7–10,21), probably because surgery involves the same possible activators as described for VP stimulation.
VP is involved in the control of arterial blood pressure via the vascular smooth muscle cell V1a receptor subtype (12). SR 49059, a potent and specific antagonist of V1a receptor, therefore provides complete inhibition of VP-induced vasoconstrictor effects (16). In the present study, pigs treated with SR 49059 exhibited a transient but marked decrease in both MAP and SVR. SVR then remained low for the duration of the study, corresponding to the period of activity of SR 49059. The evolution of MAP is biphasic: after an initial decrease linked to the decrease in SVR, we observed an upturn at 30 minutes because of the increase in CO, and thereafter a stabilization in values. At baseline, high VP values can no doubt explain the sudden vasodilation during total VP block. In pigs pretreated with SR 49059, CO2 pneumoperitoneum did not modify the hemodynamic profile. Because the VP antagonist SR 49059 exhibited no inhibitory effect on the hypertension induced by angiotensin II and norepinephrine (16), this absence of a vasopressive response to CO2 insufflation therefore confirmed the major pathophysiologic role of VP during laparoscopy.
The absence of change in VP level in the argon-insufflated pigs contrasts with that observed in the CO2-insufflated pigs, which suggests that CO2 per se may be the major stimulus for VP release. This disagrees with previous findings, which support a mechanical explanation of the hormonal response (6,8,11,22). Solis-Herruzo et al. (22) hypothesized that IAP is accompanied by an increase in intrathoracic pressure and, thus, a reduction in atrial transmural pressure, which, in turn, stimulates VP release via intrathoracic volume receptors. To explain how intraabdominal insufflated CO2 can trigger the liberation of VP, the systemic and peritoneal effects of CO2 should be considered. During VP peak, the increase in PaCO2 probably linked to the absorption of gas from the peritoneal cavity remained moderate. Because only severe hypercapnia, not mild hypercapnia, has been shown to cause an increase in plasma VP (23), VP release could probably not be triggered by the systemic changes in acid-base balance. In contrast, a rapid development of a splanchnic hyperemia and acidosis in the peritoneal area has been reported in CO2-insufflated pigs (24,25). Therefore, insufflated CO2, as opposed to an inert gas such as argon, could irritate the peritoneum by modification of the local pH. As suggested by Melville et al. (11), this could activate peritoneal endings which in turn would cause stimulation of neurohypophysial VP via a neurogenic pathway (e.g., vagus).
We conclude that, during CO2 pneumoperitoneum in pigs, CO2 initiates a pathophysiological process that stimulates vasopressin release. Hence, vasopressin most likely plays a key role for the hemodynamic response to a CO2-induced pneumoperitoneum.
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Acknowledgments |
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We thank Dr. S. Lumbroso and Mrs. C. Granat for the hormonal measurements.
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Footnotes |
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Presented in part at the European Society of Anaesthesiology, Barcelona, Spain, April 1998.
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References |
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