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Effect of Dopamine Infusion on Hemodynamics after Hepatic Denervation
Journal of Surgical Research 96, 23–29 (2001) doi:10.1006/jsre.2000.6064, available online at http://www.idealibrary.com on
Effect of Dopamine Infusion on Hemodynamics after Hepatic Denervation 1 Paul E. Wise, M.D., David H. Wiley, M.S., James G. Drougas, M.D., John Marsh, B.S., Irene D. Feurer, Ph.D., William C. Chapman, M.D., K. Taylor Blair, B.A., J. Kelly Wright, M.D., Virginia A. Eddy, M.D., and C. Wright Pinson, M.D., M.B.A. 2 Division of Hepatobiliary Surgery and Liver Transplantation, Nashville Veterans Affairs Medical Center and Vanderbilt University Medical Center, Nashville, Tennessee 37232-4753 Submitted for publication May 9, 2000; published online January 31, 2001
significantly between the control and denervated animals at baseline, 3, 6, 12 (all P < 0.05), and 30 mcg/kg/ min DA (P ⴝ 0.10). Control vs denervation MAP at baseline was 100 ⴞ 4 vs 98 ⴞ 4 Torr and at 30 mcg/kg/ min it was 110 ⴞ 3 vs 101 ⴞ 5 mm Hg. Conclusions. Hepatic flows tended to be higher after denervation. HAF showed similar increases with DA in both control and denervation groups. Increases in PVF and THBF with DA infusion were not present after denervation. HR was significantly decreased and MAP tended to be lower after denervation. The HR and MAP response to DA was similar in both groups. Therefore, both denervation and DA infusion have an effect on systemic and hepatic hemodynamics. © 2001 Academic Press Key Words: liver transplantation; pig; porcine; hepatic hemodynamics; liver perfusion; dopamine; catecholamine; hepatic blood flow; hepatic denervation.
Background. The effects of dopamine (DA) on systemic hemodynamics are better understood than its effects on hepatic hemodynamics, especially after liver denervation occurring during liver transplantation. Therefore, a porcine model was used to study DA’s effects on hemodynamics after hepatic denervation. Materials and methods. Fifteen pigs underwent laparotomy for catheter and flow probe placement. The experimental group (n ⴝ 7) also underwent hepatic denervation. After 1 week, all pigs underwent DA infusion at increasing doses (3–30 mcg/kg/min) while measuring hepatic parameters [portal vein flow (PVF), hepatic artery flow (HAF), total hepatic blood flow (THBF ⴝ HAF ⴙ PVF), portal and hepatic vein pressures] and systemic parameters [heart rate (HR), mean arterial pressure (MAP)]. Results. There was a significant increase in HAF from baseline to the 30 mcg/kg/min DA infusion rate (within-subjects P < 0.01), but the differences between the two groups were not significant. PVF and THBF showed large effects (increases) with denervation, but the increase in flow with DA infusion was not present after denervation. Perihepatic pressures were unchanged by denervation or DA. Heart rate differed
INTRODUCTION
Hepatic nerve fibers are known to play a role in the regulation of blood flow to the liver. These nerves travel via the hepatoduodenal ligament to enter the liver at the porta hepatis, and they consist primarily of fibers from the celiac plexus, the abdominal vagi, and the right phrenic nerve [1, 2]. In order to perform a donor hepatectomy for liver transplantation, all of these nerves must be transected. A few studies have examined the hepatic and/or systemic hemodynamic impact of acute hepatic denervation in dogs and rats, but they have shown conflicting changes in the hemodynamics after denervation [3–5]. The impact of severing these nerves on hemodynamics therefore remains unclear, especially in a nonacute model. Because the stable, conscious swine model for hepatic studies has
Presented at the 24th Annual Symposium of the Association of Veterans Administration Surgeons Meeting, Seattle, Washington, April 9 –11, 2000. 1 Funded in part by grants from the Department of Veteran Affairs and the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. 2 To whom correspondence and reprint requests should be addressed at Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, 801 Oxford House, Nashville, Tennessee 37232-4753. Fax: (615) 936-0435. E-mail: [email protected].
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0022-4804/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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been refined in our laboratory and been shown to have similarities to humans [6], we chose to examine the effects of hepatic denervation in this model, which has previously received only occasional use in the literature to study hepatic denervation [7]. The hepatic artery and the portal vein provide the blood flow to the liver, approximately 15–30% and 70 – 85%, respectively [8]. The high-pressure, welloxygenated arterial inflow in addition to the lowpressure, less-oxygenated, and nutrient-laden portal inflow, makes the liver a unique organ [8]. Control of this unusual inflow is determined by three main factors: intrinsic and extrinsic regulation of hepatic arterial vascular resistance dictating hepatic artery flow (HAF), extrinsic regulation of portal vein flow (PVF) by intestinal vascular resistance, and intrinsic regulation of PVF through changes in portal vein pressure (PVP) [9]. These factors are known to be susceptible to the administration of exogenous agents systemically or via the hepatic artery or portal vein directly [2]. This is especially true for the administration of intravenous catecholamines, which can have substantial effects on total hepatic blood flow (THBF). One of the more common catecholamines given during or after liver transplantation is dopamine (DA) [10], the direct precursor of norepinephrine. It is believed to have splanchnic and renal vasodilatory effects when administered at lower doses (ⱕ3 mcg/kg/min), inotropic effects at higher doses (3–10 mcg/kg/min), and vasoconstricting effects at the highest doses (⬎10 mcg/kg/min) [11, 12]. We have previously examined the effects of DA infusion on hepatic hemodynamics in the pig model and found that blood flow to the liver is augmented at all doses of DA from 3 to 30 mcg/kg/min [13]. Therefore, in order to further correlate this model to the clinical situation of dopamine administration after liver transplantation, we chose to determine the effect of increasing rates of DA infusion on systemic and hepatic hemodynamics following hepatic denervation in a stable, nonanesthetized swine model. MATERIALS AND METHODS Animals. Healthy, crossbred swine (Yorkshire ⫻ Hampshire ⫻ Duroc) were instrumented and studied following protocols approved by the Vanderbilt University Institutional Animal Care and Use Committee. The pigs were housed individually, kept on a 12-h light/ 12-h dark cycle, fed once a day, and were supplied with water ad libitum. They were placed on a fast 12 h prior to instrumentation. Instrumentation. An intramuscular injection of atropine (0.05 mg/kg), acetylpromazine (0.1 mg/kg), and ketamine (20 mg/kg) was given followed by endotracheal tube placement for the administration of halothane or isoflurane anesthesia. During the instrumentation and denervation procedures, electrocardiogram was continually monitored and blood gases were frequently obtained and analyzed. Using sterile technique, two silastic catheters (inner diameter: 0.158 cm, outer diameter: 0.318 cm, Dow Corning Corp, Midland, MI) were inserted peripherally. The first was inserted into either the right common carotid or a femoral artery and was used to monitor sys-
temic mean arterial pressure (MAP) and to sample arterial blood for pH, pCO 2, and pO 2. The second catheter was inserted into either the internal jugular or the femoral vein and was used to infuse fluids and monitor central venous pressure. After these catheters were placed, they were tunneled subcutaneously to exit between the scapulae for placement in a monitoring “backpack.” Operation. After the instrumentation was complete, a midline laparotomy was performed, again using sterile technique. In the control group (n ⫽ 8), the hepatic artery and portal vein were identified and isolated while using caution not to disturb the hepatic nerves. In the denervated group (n ⫽ 7), these nerves were removed by skeletonization and 90% phenol application. With the central vessels exposed, both groups underwent insertion of a silastic catheter into the portal vein to monitor PVP and insertion of another catheter into a hepatic vein to measure hepatic vein pressure (HVP). In order to obtain accurate measurements of the HAF, the right gastric and gastroduodenal arteries were ligated. Next, ultrasonic flow probes were placed and secured around the portal vein to monitor PVF and the hepatic artery to monitor HAF. The catheters and flow probe lines were passed through the right lateral abdominal wall and tunneled subcutaneously to join the other catheters between the scapulae. With all the catheters externalized in one locale on the back, they were gathered and kept within a small monitoring backpack that was sutured to the skin. The catheters were tested for patency and filled with heparinized saline (100 units/mL) prior to abdominal closure. Our laboratory has previously described this procedure in greater detail [6]. Postoperative care. Postoperatively, the pigs were returned to the animal care facility and given food and water ad libitum once they had fully recovered from anesthesia. Intravenous nalbuphine (0.2 mg/kg) was given up to every 4 h for pain management during the first 2 postoperative days. Also, the catheters were flushed daily with heparinized saline. The pigs were allowed at least 7 days for full recovery. This has been determined in our laboratory to be an appropriate recovery time for the return of baseline preoperative hepatic hemodynamics in the control animals [6]. Experimental setup. For obtaining data, the pig was placed in a metal cage lined with straw and transported to the laboratory, where it remained throughout the study period. All of the pigs appeared healthy, were afebrile, were eating and drinking normally, and had functional catheters and flow probes at the time of the study. Once removed from the backpack, the catheters were connected to electronic pressure transducers (Model P23X2, Viggo-Spectramed, Oxnard, CA), and the two flow probes were connected to a Doppler Flowmeter (Model T208 Transonic Systems, Ithaca, NY). A cardiotachometer was inserted in-line with the peripheral arterial catheter to measure heart rate (HR) in addition to MAP. All of these measurements (flows, pressures, and heart rate) were recorded on an eight-channel physiograph (Gould Electronics, Cleveland, OH). Core body temperature was also recorded using a rectal temperature probe. Measurements. After connecting the pig to the monitoring devices, baseline measurements were collected. Next, dopamine was infused through a systemic vein at rates starting at 3 mcg/kg/min and increasing to 6, 12, 15, and 30 mcg/kg/min sequentially. The pig’s hemodymanics were allowed to equilibrate for 1 h at each infusion rate prior to obtaining readings from each of the catheters and flow probes. Blood was also drawn at this time from the arterial line for blood gas analysis on an Acid–Base Analyzer (Model ABL 30, Radiometer, Copenhagen, Denmark). The variables that were measured at each infusion rate in this study were HAF, PVF, PVP, HVP, systemic MAP, HR, core body temperature, arterial pH, arterial pCO 2, and arterial pO 2. THBF was calculated as the sum of HAF and PVF. Statistical methods. Data were analyzed via univariate and multivariate analysis of variance (ANOVA) methods. Univariate analyses (adjusted for multiple comparisons) tested between-subjects effects at specific points (e.g., control vs denervation at baseline). Effect
WISE ET AL.: HEMODYNAMIC EFFECTS OF DOPAMINE AFTER DENERVATION
TABLE 1 Arterial pH, pCO 2, and pO 2 with Increasing Dopamine Infusion in Control and Denervated Pigs Variable Arterial pH
Arterial pCO 2
Arterial pO 2
DA infusion rate (mcg/kg/min)
Control
Denervated
Baseline 3 6 12 15 30 Baseline 3 6 12 15 30 Baseline 3 6 12 15 30
7.45 ⫾ 0.01 7.45 ⫾ 0.01 7.45 ⫾ 0.01 7.46 ⫾ 0.01 7.46 ⫾ 0.01 7.47 ⫾ 0.01 36.8 ⫾ 1.1 36.7 ⫾ 1.2 37.2 ⫾ 1.0 36.2 ⫾ 1.0 36.3 ⫾ 1.0 34.1 ⫾ 0.9 89.3 ⫾ 3.2 83.7 ⫾ 2.7 79.2 ⫾ 2.4 81.2 ⫾ 3.8 77.6 ⫾ 2.1 81.2 ⫾ 3.8
7.44 ⫾ 0.01 7.44 ⫾ 0.01 7.44 ⫾ 0.01 7.44 ⫾ 0.01 7.44 ⫾ 0.01 7.45 ⫾ 0.01 36.3 ⫾ 1.4 35.8 ⫾ 3.0 36.9 ⫾ 2.5 38.2 ⫾ 2.7 34.3 ⫾ 6.0 34.9 ⫾ 3.8 90.4 ⫾ 4.9 95.6 ⫾ 5.8 101.3 ⫾ 11.7 89.0 ⫾ 5.7 87.7 ⫾ 3.9 85 ⫾ 1.8
sizes, differences expressed in standard normal deviates, were computed and interpreted using standard procedures [14]. Mixed model repeated measures ANOVA was employed to test (1) the withinsubjects effect of DA infusion; (2) the between-subjects effect of group (denervation vs control); and (3) the interaction effect of DA infusion by group. The latter effect represents whether the pattern of the (individual) animal’s responses to DA infusion differs between groups (denervation vs control). Simple (within-subjects) contrasts reflecting the change at each DA infusion rate relative to baseline were also tested. The nonparametric Wilcoxon rank-sum test was used when changes in values after denervation were opposite to changes in control values with increasing DA infusion. Values are expressed as the mean ⫾ standard error of the mean (SEM).
RESULTS
There were a total of 15 pigs studied, n ⫽ 8 in the control group and n ⫽ 7 pigs in the experimental group. The average weight of the pigs was 36.3 ⫾ 2.7 kg and they were studied on 10.6 ⫾ 0.6 days following instrumentation. Temperature, arterial pH, and arterial pCO 2 values for the control and denervated animals are shown in Table 1. Effects of denervation at baseline. Prior to DA infusion, the control and denervated animals were compared to determine the effects of denervation at baseline. HAF, PVF, and THBF were 114 ⫾ 22 vs 169 ⫾ 89, 720 ⫾ 96 vs 1503 ⫾ 550, and 841 ⫾ 100 vs 1671 ⫾ 578 mL/min in the control vs denervated animals, respectively. While these differences did not achieve statistical significance in this sample, they represent large effects for both PVF and THBF (both differences 0.8 standard normal deviates). The finding for HAF represents a small effect (0.3 standard normal deviates) [14].
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HR and MAP were 104 ⫾ 6 vs 83 ⫾ 7 bpm (P ⬍ 0.05) and 100 ⫾ 4 vs 98 ⫾ 4 mm Hg (n.s.) for the control vs denervated pigs, respectively. HAF with DA infusion and denervation. HAF increased to 168 ⫾ 26 mL/min in the control animals vs 258 ⫾ 118 mL/min in the denervated animals with DA infusion at 30 mcg/kg/min, a significant increase from baseline measures in both animal groups (P ⬍ 0.01, within-subjects). This was an increase in HAF in the controls by 47% from baseline to 30 mcg/kg/min of DA and an increase by 53% in the denervated group (see Fig. 1a). The effect of DA infusion on HAF did not statistically differ between the two animal groups based upon the absence of both a between-subjects effect (P ⫽ 0.54) and interaction effect of DA infusion by group (P ⫽ 0.71). PVF with DA infusion and denervation. PVF increased to 866 ⫾ 169 mL/min in the control animals but decreased to 1295 ⫾ 351 mL/min in the denervated animals with DA infusion at 30 mcg/kg/min. This represents a change in PVF of 146 ⫾ 100 mL/min (⫹20%) and ⫺207 ⫾ 214 mL/min (⫺14%), respectively (see Fig. 1b). This difference is significant (P ⬍ 0.05, Wilcoxon rank-sum). THBF with DA infusion and denervation. THBF increased to 1038 ⫾ 169 mL/min (⫹23%) in the control animals but decreased to 1553 ⫾ 414 mL/min (⫺7%) in the denervated pigs at a DA infusion rate of 30 mcg/ kg/min (P ⫽ 0.06, Wilcoxon rank-sum) (see Fig. 1c). PVP and HVP with DA infusion and denervation. There were no significant differences in the hepatic or portal venous pressures between the control and denervated animals at different infusion rates of DA (see Table 2). MAP with DA infusion and denervation. MAP increased to 110 ⫾ 3 mm Hg in the controls and to 101 ⫾ 5 mm Hg in the denervated animals at 30 mcg/kg/min of DA. This was an increase in MAP for the control group of 10% (within-subject, P ⫽ 0.09) from baseline to 30 mcg/kg/min of DA and no change in the denervated group (within-subjects effect, P ⫽ 0.16) (see Fig. 2a). HR with DA infusion and denervation. The effect of denervation on HR was statistically significant between-subjects with pairwise effects not only at baseline but also at 3, 6, 12 (all P ⬍ 0.05), and 30 mcg/kg/min DA (P ⫽ 0.10). Thus the between-subjects effect of denervation on heart rate (P ⬍ 0.05) was evident across levels of DA infusion, but these changes are not significant. HR increased to 120 ⫾ 12 bpm (⫹15%) in the control animals and increased to 91 ⫾ 8 bpm (⫹10%) in the denervated animals at 30 mcg/kg/ min of DA infusion (see Fig. 2b).
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FIG. 1. (a) Hepatic artery flow (HAF) with increasing dopamine infusion in control and denervated pigs (P ⬍ 0.01, within-subjects effect across dopamine infusion rates). (b) Portal vein flow (PVF) with increasing dopamine infusion in control and denervated pigs. The difference between baseline PVF values represents a large effect (0.8 standard normal deviates). The increases in PVF with DA infusion in control animals are not seen after denervation. (c) Total hepatic blood flow (THBF) flow with increasing dopamine infusion in control and denervated pigs. The difference between baseline THBF values represents a large effect (0.8 standard normal deviates). The increases in THBF with DA infusion are not seen after denervation.
DISCUSSION
There are few studies examining the effects of liver denervation and systemic DA administration on hepatic and systemic hemodynamics. Kato et al. studied the hemodynamic effects of DA on denervated livers in a nonacute, conscious dog model [15]. He found that denervation limited the effects of DA on the portal system, causing a blunting of the increase in PVF with
systemic DA administration when compared to controls. This finding was confirmed in our experiments. There was, however, no difference in the baseline measurements of PVF between denervated and control animals, which is in opposition to our findings of a large baseline effect of denervation. There was also no significant difference in the HAF after denervation or with dopamine infusion. This is consistent with our
WISE ET AL.: HEMODYNAMIC EFFECTS OF DOPAMINE AFTER DENERVATION
TABLE 2 Portal and Hepatic Venous Pressures with Increasing Dopamine Infusion in Control and Denervated Pigs Variable Portal vein pressure (PVP)
Hepatic vein pressure (HVP)
DA infusion rate (mcg/kg/min)
Control
Denervated
Baseline
7.0 ⫾ 1.0
4.7 ⫾ 1.7
3 6 12 15 30 Baseline
7.4 ⫾ 0.9 7.1 ⫾ 1.6 6.4 ⫾ 0.9 5.8 ⫾ 1.0 5.6 ⫾ 1.3 3.8 ⫾ 0.8
7.3 ⫾ 2.5 6.7 ⫾ 2.3 5.7 ⫾ 2.1 5.3 ⫾ 2.0 5.5 ⫾ 1.9 6.0 ⫾ 2.7
3 6 12 15 30
4.5 ⫾ 0.7 5.3 ⫾ 0.8 3.3 ⫾ 0.7 3.6 ⫾ 0.7 3.0 ⫾ 0.8
6.6 ⫾ 2.3 6.2 ⫾ 2.3 5.2 ⫾ 2.7 4.8 ⫾ 2.9 5.0 ⫾ 2.4
findings of no difference after denervation but counter to our findings of increasing HAF with increasing DA infusion. Thus, it seems that the hepatic nerves are important in the hepatic hemodynamic effects of DA in the dog model, primarily on the portal venous system. Currently, few studies of this nature have been performed on swine. We chose to study the effects of hepatic denervation and DA administration on the hemodynamics of a conscious, stable pig model. This allowed for obtaining measurements from the swine in their normal, physiologic resting state without interference from anesthesia, intraoperative humoral mediator release, or volume or temperature fluxes that might alter the data being collected [6]. In addition, it has been established that the pig model is an excellent model for hepatic studies, providing possible insight into human physiology and pathophysiology [16 –18]. Our experiments showed that both PVF and HAF tended to be higher after denervation prior to DA infusion. Subsequent DA infusion in the control animals increased both PVF and HAF, but this effect was not present in denervated animals. The large baseline effect on PVF after denervation is unusual in that none of the hepatic denervation literature shows any change in PVF after denervation in dogs, rats, or swine [3, 7, 19]. Based on the known mechanisms determining PVF, either there is a significant decrease in portal outflow resistance in these animals or their splanchnic blood flow is significantly increased [2, 8, 9, 20, 21]. Given that we measured PVP and saw no significant difference between the two groups at baseline, this does not explain the increase in PVF. The probability of a decrease in the portal vein resistance of our denervated animals leading to an increase in PVF is un-
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likely, given the extensive hepatic physiologic studies performed in the past showing that this is not a factor in determining PVF [9]. The more likely possibility is that there is an efferent humoral (or nervous) factor from the liver that is released (or no longer present) due to the lack of hepatic innervation that induces increased splanchnic flow and thus increased portal vein flow. This could not be substantiated by our study design and would be worthy of further study.
FIG. 2. (a) Systemic mean arterial pressure (MAP) with increasing dopamine infusion in control and denervated pigs. Within-, between-subjects, and interaction effects were not statistically significant. (b) Heart rate (HR) with increasing dopamine infusion in control and denervated pigs. The between-subjects effect of denervation was statistically significant (*P ⬍ 0.05, †P ⫽ 0.10 control versus denervated animals).
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HAF increased significantly over baseline in both our control and denervated animals with the systemic infusion of DA at 30 mcg/kg/min. At the lower doses of DA, increased HAF is likely explained by stimulation of the dopaminergic receptors on the hepatic artery, leading to decreased resistance and increased flow. At the higher, vasoconstricting doses of DA, the hepatic arterial resistance should increase with ␣-adrenergic receptor stimulation, causing vasoconstriction and decreased flow, but this may be counteracted by an increase in cardiac output (not measured in our study). An increase in HAF with high doses of DA has been previously noted in both swine and human studies [13, 22, 23]. PVF and THBF did not show a statistically significant variation over the course of DA infusions in the denervated animals despite the increase in HAF, but the control animals did show a 20% increase in PVF and a 23% increase in THBF at the highest DA infusion rates. This is consistent with the literature reporting an increase in liver blood flow with dopamine infusion [12, 15, 22, 24]. Based on our results and those of Kato et al. [15], it appears that denervation blunts the increase in PVF and THBF with DA administration. The most interesting finding in our study was that HR was significantly decreased by denervation. In addition, the expected HR response to DA (via myocardial  1-adrenergic receptor stimulation) was blunted after denervation but remained intact in control animals. These systemic effects of denervation have not been reported before. MAP tended to be lower after denervation (not significantly), but the response to DA was similar in both groups with an expected decrease at lower doses (peripheral -adrenergic vasodilation) and an increase at higher doses (peripheral ␣-adrenergic vasoconstriction) [11]. These findings might also be explained by the presence (or absence) of an efferent factor after denervation that leads to splanchnic vasodilation and increased PVF. The blood sequestration in the mesenteric and hepatic beds with the splanchnic vasodilation would likely explain the decreased MAP we observed. In the face of adequate flows and low MAP, an increase in HR might not be necessary in order to provide adequate tissue perfusion. This does not explain why the expected -adrenergic effects of DA on the heart were nonexistent after denervation. In summary, we were attempting to gain insight into the effects of hepatic denervation in order to determine the hepatic and systemic hemodynamic changes that occur with the administration of dopamine. This has potential implications for the use of dopamine after liver transplantation as well as providing avenues for future study to identify the mechanisms for hemodynamic changes after hepatic denervation.
ACKNOWLEDGMENTS This work was supported in part by grants from the Department of Veterans Affairs and the National Institutes of Health (Individual National Research Service Award 1 F32 DK09959-01).
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Effect of Dopamine Infusion on Hemodynamics after Hepatic Denervation 1 Paul E. Wise, M.D., David H. Wiley, M.S., James G. Drougas, M.D., John Marsh, B.S., Irene D. Feurer, Ph.D., William C. Chapman, M.D., K. Taylor Blair, B.A., J. Kelly Wright, M.D., Virginia A. Eddy, M.D., and C. Wright Pinson, M.D., M.B.A. 2 Division of Hepatobiliary Surgery and Liver Transplantation, Nashville Veterans Affairs Medical Center and Vanderbilt University Medical Center, Nashville, Tennessee 37232-4753 Submitted for publication May 9, 2000; published online January 31, 2001
significantly between the control and denervated animals at baseline, 3, 6, 12 (all P < 0.05), and 30 mcg/kg/ min DA (P ⴝ 0.10). Control vs denervation MAP at baseline was 100 ⴞ 4 vs 98 ⴞ 4 Torr and at 30 mcg/kg/ min it was 110 ⴞ 3 vs 101 ⴞ 5 mm Hg. Conclusions. Hepatic flows tended to be higher after denervation. HAF showed similar increases with DA in both control and denervation groups. Increases in PVF and THBF with DA infusion were not present after denervation. HR was significantly decreased and MAP tended to be lower after denervation. The HR and MAP response to DA was similar in both groups. Therefore, both denervation and DA infusion have an effect on systemic and hepatic hemodynamics. © 2001 Academic Press Key Words: liver transplantation; pig; porcine; hepatic hemodynamics; liver perfusion; dopamine; catecholamine; hepatic blood flow; hepatic denervation.
Background. The effects of dopamine (DA) on systemic hemodynamics are better understood than its effects on hepatic hemodynamics, especially after liver denervation occurring during liver transplantation. Therefore, a porcine model was used to study DA’s effects on hemodynamics after hepatic denervation. Materials and methods. Fifteen pigs underwent laparotomy for catheter and flow probe placement. The experimental group (n ⴝ 7) also underwent hepatic denervation. After 1 week, all pigs underwent DA infusion at increasing doses (3–30 mcg/kg/min) while measuring hepatic parameters [portal vein flow (PVF), hepatic artery flow (HAF), total hepatic blood flow (THBF ⴝ HAF ⴙ PVF), portal and hepatic vein pressures] and systemic parameters [heart rate (HR), mean arterial pressure (MAP)]. Results. There was a significant increase in HAF from baseline to the 30 mcg/kg/min DA infusion rate (within-subjects P < 0.01), but the differences between the two groups were not significant. PVF and THBF showed large effects (increases) with denervation, but the increase in flow with DA infusion was not present after denervation. Perihepatic pressures were unchanged by denervation or DA. Heart rate differed
INTRODUCTION
Hepatic nerve fibers are known to play a role in the regulation of blood flow to the liver. These nerves travel via the hepatoduodenal ligament to enter the liver at the porta hepatis, and they consist primarily of fibers from the celiac plexus, the abdominal vagi, and the right phrenic nerve [1, 2]. In order to perform a donor hepatectomy for liver transplantation, all of these nerves must be transected. A few studies have examined the hepatic and/or systemic hemodynamic impact of acute hepatic denervation in dogs and rats, but they have shown conflicting changes in the hemodynamics after denervation [3–5]. The impact of severing these nerves on hemodynamics therefore remains unclear, especially in a nonacute model. Because the stable, conscious swine model for hepatic studies has
Presented at the 24th Annual Symposium of the Association of Veterans Administration Surgeons Meeting, Seattle, Washington, April 9 –11, 2000. 1 Funded in part by grants from the Department of Veteran Affairs and the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. 2 To whom correspondence and reprint requests should be addressed at Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, 801 Oxford House, Nashville, Tennessee 37232-4753. Fax: (615) 936-0435. E-mail: [email protected].
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0022-4804/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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been refined in our laboratory and been shown to have similarities to humans [6], we chose to examine the effects of hepatic denervation in this model, which has previously received only occasional use in the literature to study hepatic denervation [7]. The hepatic artery and the portal vein provide the blood flow to the liver, approximately 15–30% and 70 – 85%, respectively [8]. The high-pressure, welloxygenated arterial inflow in addition to the lowpressure, less-oxygenated, and nutrient-laden portal inflow, makes the liver a unique organ [8]. Control of this unusual inflow is determined by three main factors: intrinsic and extrinsic regulation of hepatic arterial vascular resistance dictating hepatic artery flow (HAF), extrinsic regulation of portal vein flow (PVF) by intestinal vascular resistance, and intrinsic regulation of PVF through changes in portal vein pressure (PVP) [9]. These factors are known to be susceptible to the administration of exogenous agents systemically or via the hepatic artery or portal vein directly [2]. This is especially true for the administration of intravenous catecholamines, which can have substantial effects on total hepatic blood flow (THBF). One of the more common catecholamines given during or after liver transplantation is dopamine (DA) [10], the direct precursor of norepinephrine. It is believed to have splanchnic and renal vasodilatory effects when administered at lower doses (ⱕ3 mcg/kg/min), inotropic effects at higher doses (3–10 mcg/kg/min), and vasoconstricting effects at the highest doses (⬎10 mcg/kg/min) [11, 12]. We have previously examined the effects of DA infusion on hepatic hemodynamics in the pig model and found that blood flow to the liver is augmented at all doses of DA from 3 to 30 mcg/kg/min [13]. Therefore, in order to further correlate this model to the clinical situation of dopamine administration after liver transplantation, we chose to determine the effect of increasing rates of DA infusion on systemic and hepatic hemodynamics following hepatic denervation in a stable, nonanesthetized swine model. MATERIALS AND METHODS Animals. Healthy, crossbred swine (Yorkshire ⫻ Hampshire ⫻ Duroc) were instrumented and studied following protocols approved by the Vanderbilt University Institutional Animal Care and Use Committee. The pigs were housed individually, kept on a 12-h light/ 12-h dark cycle, fed once a day, and were supplied with water ad libitum. They were placed on a fast 12 h prior to instrumentation. Instrumentation. An intramuscular injection of atropine (0.05 mg/kg), acetylpromazine (0.1 mg/kg), and ketamine (20 mg/kg) was given followed by endotracheal tube placement for the administration of halothane or isoflurane anesthesia. During the instrumentation and denervation procedures, electrocardiogram was continually monitored and blood gases were frequently obtained and analyzed. Using sterile technique, two silastic catheters (inner diameter: 0.158 cm, outer diameter: 0.318 cm, Dow Corning Corp, Midland, MI) were inserted peripherally. The first was inserted into either the right common carotid or a femoral artery and was used to monitor sys-
temic mean arterial pressure (MAP) and to sample arterial blood for pH, pCO 2, and pO 2. The second catheter was inserted into either the internal jugular or the femoral vein and was used to infuse fluids and monitor central venous pressure. After these catheters were placed, they were tunneled subcutaneously to exit between the scapulae for placement in a monitoring “backpack.” Operation. After the instrumentation was complete, a midline laparotomy was performed, again using sterile technique. In the control group (n ⫽ 8), the hepatic artery and portal vein were identified and isolated while using caution not to disturb the hepatic nerves. In the denervated group (n ⫽ 7), these nerves were removed by skeletonization and 90% phenol application. With the central vessels exposed, both groups underwent insertion of a silastic catheter into the portal vein to monitor PVP and insertion of another catheter into a hepatic vein to measure hepatic vein pressure (HVP). In order to obtain accurate measurements of the HAF, the right gastric and gastroduodenal arteries were ligated. Next, ultrasonic flow probes were placed and secured around the portal vein to monitor PVF and the hepatic artery to monitor HAF. The catheters and flow probe lines were passed through the right lateral abdominal wall and tunneled subcutaneously to join the other catheters between the scapulae. With all the catheters externalized in one locale on the back, they were gathered and kept within a small monitoring backpack that was sutured to the skin. The catheters were tested for patency and filled with heparinized saline (100 units/mL) prior to abdominal closure. Our laboratory has previously described this procedure in greater detail [6]. Postoperative care. Postoperatively, the pigs were returned to the animal care facility and given food and water ad libitum once they had fully recovered from anesthesia. Intravenous nalbuphine (0.2 mg/kg) was given up to every 4 h for pain management during the first 2 postoperative days. Also, the catheters were flushed daily with heparinized saline. The pigs were allowed at least 7 days for full recovery. This has been determined in our laboratory to be an appropriate recovery time for the return of baseline preoperative hepatic hemodynamics in the control animals [6]. Experimental setup. For obtaining data, the pig was placed in a metal cage lined with straw and transported to the laboratory, where it remained throughout the study period. All of the pigs appeared healthy, were afebrile, were eating and drinking normally, and had functional catheters and flow probes at the time of the study. Once removed from the backpack, the catheters were connected to electronic pressure transducers (Model P23X2, Viggo-Spectramed, Oxnard, CA), and the two flow probes were connected to a Doppler Flowmeter (Model T208 Transonic Systems, Ithaca, NY). A cardiotachometer was inserted in-line with the peripheral arterial catheter to measure heart rate (HR) in addition to MAP. All of these measurements (flows, pressures, and heart rate) were recorded on an eight-channel physiograph (Gould Electronics, Cleveland, OH). Core body temperature was also recorded using a rectal temperature probe. Measurements. After connecting the pig to the monitoring devices, baseline measurements were collected. Next, dopamine was infused through a systemic vein at rates starting at 3 mcg/kg/min and increasing to 6, 12, 15, and 30 mcg/kg/min sequentially. The pig’s hemodymanics were allowed to equilibrate for 1 h at each infusion rate prior to obtaining readings from each of the catheters and flow probes. Blood was also drawn at this time from the arterial line for blood gas analysis on an Acid–Base Analyzer (Model ABL 30, Radiometer, Copenhagen, Denmark). The variables that were measured at each infusion rate in this study were HAF, PVF, PVP, HVP, systemic MAP, HR, core body temperature, arterial pH, arterial pCO 2, and arterial pO 2. THBF was calculated as the sum of HAF and PVF. Statistical methods. Data were analyzed via univariate and multivariate analysis of variance (ANOVA) methods. Univariate analyses (adjusted for multiple comparisons) tested between-subjects effects at specific points (e.g., control vs denervation at baseline). Effect
WISE ET AL.: HEMODYNAMIC EFFECTS OF DOPAMINE AFTER DENERVATION
TABLE 1 Arterial pH, pCO 2, and pO 2 with Increasing Dopamine Infusion in Control and Denervated Pigs Variable Arterial pH
Arterial pCO 2
Arterial pO 2
DA infusion rate (mcg/kg/min)
Control
Denervated
Baseline 3 6 12 15 30 Baseline 3 6 12 15 30 Baseline 3 6 12 15 30
7.45 ⫾ 0.01 7.45 ⫾ 0.01 7.45 ⫾ 0.01 7.46 ⫾ 0.01 7.46 ⫾ 0.01 7.47 ⫾ 0.01 36.8 ⫾ 1.1 36.7 ⫾ 1.2 37.2 ⫾ 1.0 36.2 ⫾ 1.0 36.3 ⫾ 1.0 34.1 ⫾ 0.9 89.3 ⫾ 3.2 83.7 ⫾ 2.7 79.2 ⫾ 2.4 81.2 ⫾ 3.8 77.6 ⫾ 2.1 81.2 ⫾ 3.8
7.44 ⫾ 0.01 7.44 ⫾ 0.01 7.44 ⫾ 0.01 7.44 ⫾ 0.01 7.44 ⫾ 0.01 7.45 ⫾ 0.01 36.3 ⫾ 1.4 35.8 ⫾ 3.0 36.9 ⫾ 2.5 38.2 ⫾ 2.7 34.3 ⫾ 6.0 34.9 ⫾ 3.8 90.4 ⫾ 4.9 95.6 ⫾ 5.8 101.3 ⫾ 11.7 89.0 ⫾ 5.7 87.7 ⫾ 3.9 85 ⫾ 1.8
sizes, differences expressed in standard normal deviates, were computed and interpreted using standard procedures [14]. Mixed model repeated measures ANOVA was employed to test (1) the withinsubjects effect of DA infusion; (2) the between-subjects effect of group (denervation vs control); and (3) the interaction effect of DA infusion by group. The latter effect represents whether the pattern of the (individual) animal’s responses to DA infusion differs between groups (denervation vs control). Simple (within-subjects) contrasts reflecting the change at each DA infusion rate relative to baseline were also tested. The nonparametric Wilcoxon rank-sum test was used when changes in values after denervation were opposite to changes in control values with increasing DA infusion. Values are expressed as the mean ⫾ standard error of the mean (SEM).
RESULTS
There were a total of 15 pigs studied, n ⫽ 8 in the control group and n ⫽ 7 pigs in the experimental group. The average weight of the pigs was 36.3 ⫾ 2.7 kg and they were studied on 10.6 ⫾ 0.6 days following instrumentation. Temperature, arterial pH, and arterial pCO 2 values for the control and denervated animals are shown in Table 1. Effects of denervation at baseline. Prior to DA infusion, the control and denervated animals were compared to determine the effects of denervation at baseline. HAF, PVF, and THBF were 114 ⫾ 22 vs 169 ⫾ 89, 720 ⫾ 96 vs 1503 ⫾ 550, and 841 ⫾ 100 vs 1671 ⫾ 578 mL/min in the control vs denervated animals, respectively. While these differences did not achieve statistical significance in this sample, they represent large effects for both PVF and THBF (both differences 0.8 standard normal deviates). The finding for HAF represents a small effect (0.3 standard normal deviates) [14].
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HR and MAP were 104 ⫾ 6 vs 83 ⫾ 7 bpm (P ⬍ 0.05) and 100 ⫾ 4 vs 98 ⫾ 4 mm Hg (n.s.) for the control vs denervated pigs, respectively. HAF with DA infusion and denervation. HAF increased to 168 ⫾ 26 mL/min in the control animals vs 258 ⫾ 118 mL/min in the denervated animals with DA infusion at 30 mcg/kg/min, a significant increase from baseline measures in both animal groups (P ⬍ 0.01, within-subjects). This was an increase in HAF in the controls by 47% from baseline to 30 mcg/kg/min of DA and an increase by 53% in the denervated group (see Fig. 1a). The effect of DA infusion on HAF did not statistically differ between the two animal groups based upon the absence of both a between-subjects effect (P ⫽ 0.54) and interaction effect of DA infusion by group (P ⫽ 0.71). PVF with DA infusion and denervation. PVF increased to 866 ⫾ 169 mL/min in the control animals but decreased to 1295 ⫾ 351 mL/min in the denervated animals with DA infusion at 30 mcg/kg/min. This represents a change in PVF of 146 ⫾ 100 mL/min (⫹20%) and ⫺207 ⫾ 214 mL/min (⫺14%), respectively (see Fig. 1b). This difference is significant (P ⬍ 0.05, Wilcoxon rank-sum). THBF with DA infusion and denervation. THBF increased to 1038 ⫾ 169 mL/min (⫹23%) in the control animals but decreased to 1553 ⫾ 414 mL/min (⫺7%) in the denervated pigs at a DA infusion rate of 30 mcg/ kg/min (P ⫽ 0.06, Wilcoxon rank-sum) (see Fig. 1c). PVP and HVP with DA infusion and denervation. There were no significant differences in the hepatic or portal venous pressures between the control and denervated animals at different infusion rates of DA (see Table 2). MAP with DA infusion and denervation. MAP increased to 110 ⫾ 3 mm Hg in the controls and to 101 ⫾ 5 mm Hg in the denervated animals at 30 mcg/kg/min of DA. This was an increase in MAP for the control group of 10% (within-subject, P ⫽ 0.09) from baseline to 30 mcg/kg/min of DA and no change in the denervated group (within-subjects effect, P ⫽ 0.16) (see Fig. 2a). HR with DA infusion and denervation. The effect of denervation on HR was statistically significant between-subjects with pairwise effects not only at baseline but also at 3, 6, 12 (all P ⬍ 0.05), and 30 mcg/kg/min DA (P ⫽ 0.10). Thus the between-subjects effect of denervation on heart rate (P ⬍ 0.05) was evident across levels of DA infusion, but these changes are not significant. HR increased to 120 ⫾ 12 bpm (⫹15%) in the control animals and increased to 91 ⫾ 8 bpm (⫹10%) in the denervated animals at 30 mcg/kg/ min of DA infusion (see Fig. 2b).
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FIG. 1. (a) Hepatic artery flow (HAF) with increasing dopamine infusion in control and denervated pigs (P ⬍ 0.01, within-subjects effect across dopamine infusion rates). (b) Portal vein flow (PVF) with increasing dopamine infusion in control and denervated pigs. The difference between baseline PVF values represents a large effect (0.8 standard normal deviates). The increases in PVF with DA infusion in control animals are not seen after denervation. (c) Total hepatic blood flow (THBF) flow with increasing dopamine infusion in control and denervated pigs. The difference between baseline THBF values represents a large effect (0.8 standard normal deviates). The increases in THBF with DA infusion are not seen after denervation.
DISCUSSION
There are few studies examining the effects of liver denervation and systemic DA administration on hepatic and systemic hemodynamics. Kato et al. studied the hemodynamic effects of DA on denervated livers in a nonacute, conscious dog model [15]. He found that denervation limited the effects of DA on the portal system, causing a blunting of the increase in PVF with
systemic DA administration when compared to controls. This finding was confirmed in our experiments. There was, however, no difference in the baseline measurements of PVF between denervated and control animals, which is in opposition to our findings of a large baseline effect of denervation. There was also no significant difference in the HAF after denervation or with dopamine infusion. This is consistent with our
WISE ET AL.: HEMODYNAMIC EFFECTS OF DOPAMINE AFTER DENERVATION
TABLE 2 Portal and Hepatic Venous Pressures with Increasing Dopamine Infusion in Control and Denervated Pigs Variable Portal vein pressure (PVP)
Hepatic vein pressure (HVP)
DA infusion rate (mcg/kg/min)
Control
Denervated
Baseline
7.0 ⫾ 1.0
4.7 ⫾ 1.7
3 6 12 15 30 Baseline
7.4 ⫾ 0.9 7.1 ⫾ 1.6 6.4 ⫾ 0.9 5.8 ⫾ 1.0 5.6 ⫾ 1.3 3.8 ⫾ 0.8
7.3 ⫾ 2.5 6.7 ⫾ 2.3 5.7 ⫾ 2.1 5.3 ⫾ 2.0 5.5 ⫾ 1.9 6.0 ⫾ 2.7
3 6 12 15 30
4.5 ⫾ 0.7 5.3 ⫾ 0.8 3.3 ⫾ 0.7 3.6 ⫾ 0.7 3.0 ⫾ 0.8
6.6 ⫾ 2.3 6.2 ⫾ 2.3 5.2 ⫾ 2.7 4.8 ⫾ 2.9 5.0 ⫾ 2.4
findings of no difference after denervation but counter to our findings of increasing HAF with increasing DA infusion. Thus, it seems that the hepatic nerves are important in the hepatic hemodynamic effects of DA in the dog model, primarily on the portal venous system. Currently, few studies of this nature have been performed on swine. We chose to study the effects of hepatic denervation and DA administration on the hemodynamics of a conscious, stable pig model. This allowed for obtaining measurements from the swine in their normal, physiologic resting state without interference from anesthesia, intraoperative humoral mediator release, or volume or temperature fluxes that might alter the data being collected [6]. In addition, it has been established that the pig model is an excellent model for hepatic studies, providing possible insight into human physiology and pathophysiology [16 –18]. Our experiments showed that both PVF and HAF tended to be higher after denervation prior to DA infusion. Subsequent DA infusion in the control animals increased both PVF and HAF, but this effect was not present in denervated animals. The large baseline effect on PVF after denervation is unusual in that none of the hepatic denervation literature shows any change in PVF after denervation in dogs, rats, or swine [3, 7, 19]. Based on the known mechanisms determining PVF, either there is a significant decrease in portal outflow resistance in these animals or their splanchnic blood flow is significantly increased [2, 8, 9, 20, 21]. Given that we measured PVP and saw no significant difference between the two groups at baseline, this does not explain the increase in PVF. The probability of a decrease in the portal vein resistance of our denervated animals leading to an increase in PVF is un-
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likely, given the extensive hepatic physiologic studies performed in the past showing that this is not a factor in determining PVF [9]. The more likely possibility is that there is an efferent humoral (or nervous) factor from the liver that is released (or no longer present) due to the lack of hepatic innervation that induces increased splanchnic flow and thus increased portal vein flow. This could not be substantiated by our study design and would be worthy of further study.
FIG. 2. (a) Systemic mean arterial pressure (MAP) with increasing dopamine infusion in control and denervated pigs. Within-, between-subjects, and interaction effects were not statistically significant. (b) Heart rate (HR) with increasing dopamine infusion in control and denervated pigs. The between-subjects effect of denervation was statistically significant (*P ⬍ 0.05, †P ⫽ 0.10 control versus denervated animals).
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HAF increased significantly over baseline in both our control and denervated animals with the systemic infusion of DA at 30 mcg/kg/min. At the lower doses of DA, increased HAF is likely explained by stimulation of the dopaminergic receptors on the hepatic artery, leading to decreased resistance and increased flow. At the higher, vasoconstricting doses of DA, the hepatic arterial resistance should increase with ␣-adrenergic receptor stimulation, causing vasoconstriction and decreased flow, but this may be counteracted by an increase in cardiac output (not measured in our study). An increase in HAF with high doses of DA has been previously noted in both swine and human studies [13, 22, 23]. PVF and THBF did not show a statistically significant variation over the course of DA infusions in the denervated animals despite the increase in HAF, but the control animals did show a 20% increase in PVF and a 23% increase in THBF at the highest DA infusion rates. This is consistent with the literature reporting an increase in liver blood flow with dopamine infusion [12, 15, 22, 24]. Based on our results and those of Kato et al. [15], it appears that denervation blunts the increase in PVF and THBF with DA administration. The most interesting finding in our study was that HR was significantly decreased by denervation. In addition, the expected HR response to DA (via myocardial  1-adrenergic receptor stimulation) was blunted after denervation but remained intact in control animals. These systemic effects of denervation have not been reported before. MAP tended to be lower after denervation (not significantly), but the response to DA was similar in both groups with an expected decrease at lower doses (peripheral -adrenergic vasodilation) and an increase at higher doses (peripheral ␣-adrenergic vasoconstriction) [11]. These findings might also be explained by the presence (or absence) of an efferent factor after denervation that leads to splanchnic vasodilation and increased PVF. The blood sequestration in the mesenteric and hepatic beds with the splanchnic vasodilation would likely explain the decreased MAP we observed. In the face of adequate flows and low MAP, an increase in HR might not be necessary in order to provide adequate tissue perfusion. This does not explain why the expected -adrenergic effects of DA on the heart were nonexistent after denervation. In summary, we were attempting to gain insight into the effects of hepatic denervation in order to determine the hepatic and systemic hemodynamic changes that occur with the administration of dopamine. This has potential implications for the use of dopamine after liver transplantation as well as providing avenues for future study to identify the mechanisms for hemodynamic changes after hepatic denervation.
ACKNOWLEDGMENTS This work was supported in part by grants from the Department of Veterans Affairs and the National Institutes of Health (Individual National Research Service Award 1 F32 DK09959-01).
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