Effects of amrinone on ischaemia–reperfusion injury in cirrhotic patients undergoing hepatectomy: a comparative study with prostaglandin E1

R. Orii1, Y. Sugawara2, M. Hayashida1, Y. Yamada1, K. Chang1, T. Takayama2, M. Makuuchi2 and K. Hanaoka1

1Department of Anaesthesiology and Hepatobiliary Panceatic Surgery Division and 2Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan*Corresponding author

Accepted for publication: April 28, 2000


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The effects of amrinone, a selective phosphodiesterase III inhibitor, on liver ischaemia reperfusion injury have not yet been clarified. Forty-five patients with hepatocellular carcinoma who underwent partial liver resection using Pringle’s manoeuvre were studied. Patients were divided into three groups: those given amrinone, those given prostaglandin E1 (PGE1) and those not treated (controls). An indocyanine green (ICG) clearance test was performed before the operation and three times during surgery: just before induction of liver ischaemia, just after liver resection and 60 min after reperfusion. Blood lactate and base excess were measured at the same times. Systolic and diastolic arterial pressure, heart rate, cardiac index and oesophageal temperature were monitored. Aminotransferase levels were recorded the day before surgery, 1 h after operation and on the first and third postoperative days. These data were compared between groups. The ICG elimination rate, lactate and base excess in the amrinone group differed significantly from those in controls during the observation period (P=0.03, P=0.04 and P=0.03, respectively). The differences between the PGE1 and control groups were not significant. There were no significant differences between the groups in perioperative vital signs, cardiac index or postoperative aminotransferase. Amrinone enhanced intraoperative ICG elimination in cirrhotic patients who underwent liver resection.

Br J Anaesth 2000; 85: 389–95

Keywords: pharmacology, amrinone; pharmacology, phosphodiesterase inhibitors; liver


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Amrinone is a non-catecholamine, non-glycoside drug with combined positive inotropic and vasodilating properties. Its mechanism of action is mediated by selective phosphodiesterase III enzyme inhibition, which increases cyclic adenosine 5'-monophosphate (cAMP) in both vascular smooth muscle and myocardium by preventing the degradation of cAMP. Increased cAMP increases muscle contraction by increasing myocardial intracellular calcium available from the sarcoplasmic reticulum. In contrast, in vascular smooth muscle cells, increased cAMP decreases intracellular calcium through an increase in calcium resequestration into the sarcoplasmic reticulum, producing relaxation and vasodilation. Since amrinone not only augments cardiac contractility but also reduces preload and afterload, it has been used to treat heart failure.1

In addition to its therapeutic effects in heart failure, amrinone appears to be ideal for treating peripheral circulatory disorders and improving viability of ischaemic tissues,1 so we thought that it might also be useful for treating ischaemic liver. This study was designed to evaluate the effects of amrinone on the function of liver damaged by ischaemia–reperfusion injury. To evaluate liver function during hepatectomy involving liver ischaemia, indocyanine green (ICG) clearance and blood lactate concentrations were measured. ICG clearance2 3 is an indicator of the metabolic function of the liver and of liver blood flow. The effects of amrinone on intraoperative liver function were compared with those of prostaglandin E1 (PGE1), which has been reported to improve liver dysfunction after ischaemia–reperfusion injury.4


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The study protocol was approved by the ethics committee of our local authority. Informed consent was obtained from each patient.

Patients
From April 1998 to October 1999, 142 patients underwent hepatectomy at the Hepatobiliary Pancreatic Division, Department of Surgery, Tokyo University Hospital. Resectability was assessed and the surgical procedure was selected by following an algorithm based on three parameters: the presence or absence of ascites, total serum bilirubin concentration and ICG clearance.5 Patients with no ascites, a serum total bilirubin concentration of <2.0 mg dl–1 (34 mmol litre–1) and an ICG elimination rate (ICG-K) of >0.06 units min–1 were selected for surgery. ICG-K is a rate constant defined as the plasma ICG elimination rate.6

Forty-five patients (37 males and eight females, aged 48–76 yr) were included in this study. All patients were classified as ASA physical status II. To lessen the heterogeneity of the patient population and to exclude patients with severe cirrhosis, the inclusion criteria were defined as follows: (i) subjects were cirrhotic with hepatocellular carcinoma; (ii) tumours were limited to one segment according to Couinaud’s nomenclature for liver segmentation;7 (iii) either subsegmentectomy8 or limited resection of the tumour was scheduled; (iv) Pringle’s manoeuvre was used to induce liver ischaemia. In our institution, Pringle’s manoeuvre is usually applied during hepatectomy to reduce blood loss. Briefly, the hepatoduodenal ligament was clamped using Fogarty forceps for 15 min to interrupt portal and hepatic arterial blood supply. This was followed by a 5 min release period. This schedule was repeated until liver resection was accomplished.9

Limited resection requires non-anatomical resection of the tumour(s) with an adequate margin of surrounding non-tumourous liver tissue. Subsegmentectomy requires complete anatomical resection of that subsegment of liver which is fed by the same portal branches. The method used by our surgical team to identify the subsegment in question has been described in detail elsewhere.10 Patients were excluded if intraoperative ultrasound revealed tumour extension beyond one segment or if a procedure other than Pringle’s manoeuvre was applied to induce ischaemia.

The patients who fulfilled these criteria were divided randomly into three groups. The randomization, which was done after the initial laparotomy and intraoperative ultrasound, was done by a permuted block design without stratification. The patients in the amrinone (n=15) and PGE1 groups (n=15) received an intravenous infusion of amrinone (Amcoral; Meiji Pharmaceutical Co. Ltd, Tokyo, Japan) or PGE1 (Prostandin; Ono Pharmaceutical Co. Ltd, Osaka, Japan), respectively, through a central venous catheter at a rate of 4.0 or 0.02 µg kg–1 min–1, respectively. The amrinone or PGE1 infusion was initiated at the start and terminated at the end of surgery. The 15 patients in the control group received neither drug. No placebo was administered to the control group as it was difficult to prepare one, because of the yellowish colouring agent contained in Amcoral.

Preoperative risk factors included hypertension in one patient in the amrinone group, one patient with diabetes mellitus and one with hypertension in the PGE1 group, and one case each of hypertension and arrhythmia in the control group. Clinical and surgical details of the patients are given in Tables 1 and 2, respectively.


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Table 1 Clinical details (number, range (median) or mean (SD))
 
Anaesthesia
Anaesthesia was induced with midazolam 0.05–0.1 mg kg–1, thiopental sodium 2–4 mg kg–1 and fentanyl 2 µg kg–1 and maintained with 0.8–1.5% end-tidal isoflurane, 50% nitrous oxide in oxygen, and fentanyl 1–2 µg kg–1 h–1. Muscle relaxation was maintained with pancuronium bromide 0.08 mg kg–1 h–1. Mechanical ventilation was set at a respiratory frequency of 10–15 min–1 and an inspiratory/expiratory duration ratio of 1:2. The respiratory tidal volume was reduced to about 60% just before starting liver resection to reduce the thoracic and right atrial pressure and, consequently, back-bleeding from the hepatic veins and their tributaries.5 The concentration of inspired oxygen was set to give an arterial oxygen tension of >120 mm Hg. The arterial carbon dioxide tension was maintained at 35–45 mm Hg. Invasive arterial pressure, heart rate and electrocardiogram (five leads and two channels: II and V5), pulse oximetry, end-tidal carbon dioxide tension and oesophageal temperature were monitored routinely.

Crystalloid infusion was kept to a minimum (4–4.5 ml kg–1 h–1) to avoid sodium retention. Fresh frozen plasma was transfused when necessary to maintain stable haemodynamics. Packed red cells or fresh whole blood was transfused as required.

Data collection
One of the authors (M.H.) determined grouping and loaded an infusion pump with a blank, amrinone or PGE1 syringe. Each syringe was covered with a black sheet so that it could not be seen by the surgeon or the anaesthetist. M.H. supervised the anaesthetist in charge of anaesthetic and exerted discretion in the event of complications resulting from the study drugs.

The following variables were recorded by the anaesthetist in charge of the anaesthetic. An ICG (Diagnogreen; Daiichi Pharmaceutical Co., Tokyo, Japan) test was performed before surgery, as a baseline (t0), and three times during surgery, just before the induction of liver ischaemia by Pringle’s manoeuvre (t1), just after reperfusion of the liver, i.e. the completion of liver resection (t2) and 60 min after reperfusion (t3). Preoperative ICG-K was measured conventionally; ICG 0.5 mg kg–1 was injected intravenously, blood was sampled 5, 10 and 15 min after injection and the plasma concentration of ICG was measured using the method of Nielsen.11 The blood concentration of ICG (in µg ml–1) decreases exponentially with time (in minutes). The logarithm of the slope of the ICG versus time plot gives the elimination constant for ICG. During surgery, as it was not always possible for the anaesthetist in charge of the anaesthetic to take a blood sample exactly 5, 10 and 15 min after injection, pulse dye densitometry was used for ICG-K measurement. The blood concentration of ICG obtained by the conventional method correlates well with that obtained by pulse dye densitometry. According to a previous report,12 in 27 patients with liver disease following ICG injection, blood ICG concentration was measured by the conventional method and pulse dye densitometry simultaneously. The blood dye concentration correlated well with the value obtained by pulse dye densitometry (correlation coefficient=0.953). The optical sensor of an ICG clearance meter (DDG-2001; Nihon Kohden Industry Co. Ltd, Tokyo, Japan) was applied to the right second finger. ICG-K was determined by measuring light transmission through the finger at 810 and 940 nm.13 The cardiac index was measured using a dye dilution method by calculating the area under the very initial phase of the ICG concentration–time curve with a computer. Systolic and diastolic arterial pressure (SAP and DAP), heart rate and oesophageal temperature were also recorded at t0, t1, t2 and t3. The lactate concentration and base excess of arterial blood were measured with an ABL 625 analyser (Radiometer, Copenhagen, Denmark) at the same times.

The observation period was divided into three phases: the pre-ischaemic phase (from t0 to t1), the ischaemic phase (from t1 to t2) and the post-ischaemic phase (from t2 to t3). The rate of lactate accumulation in the pre-ischaemic phase was calculated as the difference between blood lactate concentrations at t1 and t0, divided by the duration of this phase. The rate of lactate accumulation in the ischaemic phase or elimination rate in the post-ischaemic phase was calculated similarly.

Blood aspartate and alanine aminotransferase (AST and ALT) concentrations were measured before surgery (day –1), one hour after surgery (day 0) and on the first and third postoperative days (days 1 and 3, respectively).

Statistical analysis
The statistical software package Stat View (SAS Institute Inc., Cary, NC, USA), version 5.0 for Windows, was used throughout the analysis. Ages are given as range (median) and all other data as means (SD). The physical and surgical characteristics of the groups were compared by the {chi}2 test or an analysis of variance (ANOVA), as appropriate. Calculated variables such as the lactate accumulation rate in the groups were compared by ANOVA. Evaluated retrospectively, 15 patients in each group ensured a 75% chance of detecting a relevant difference (d=1.00) with a significance level of {alpha}=0.05 for a two-tailed test. The difference d is given by the difference between the means of two groups divided by the variance, {sigma}.14

The variables measured during and after anaesthesia in each group were compared with the corresponding baseline levels using ANOVA with Bonferroni’s correction. The variables measured during and after anaesthesia were analysed with a two-way ANOVA for repeated measures to examine differences among the groups. Differences were considered significant at P<0.008 in ANOVA with Bonferroni’s correction and at P<0.05 in the other analyses.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Surgical results
Surgery lasted for 410 (137) min (95% confidence interval (CI) 357–465 min). The pre-ischaemic and ischaemic phases lasted 165 (95) min (95% CI 131–198 min) and 70 (46) min (95% CI 57–85 min), respectively. Blood loss was 601 (390) ml kg–1 (95% CI 443–756 ml kg–1) or 13.6 (9.1) ml kg–1 (95% CI 9.5–16.5 ml kg–1). The resected liver weighed 157 (186) g (95% CI 95–238 g). There were no significant differences among the groups with regard to these surgical characteristics (Table 2).


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Table 2 Surgical details (mean (SD))
 
Complications after hepatectomy were observed in one, two and two patients in the control, amrinone and PGE1 groups, respectively. These included bile leakage from a dissection plane of the liver in two patients and pleural effusion in three patients. No patients died during the first 30 days after the operation.

Changes in haemodynamics
SAP and DAP did not change significantly between t0 and t2 in any group, but increased significantly at t3 in the control and PGE1 groups (P<0.0001 in each comparison, Figure 1A and B). Heart rate did not change significantly between t0 and t2 in any group, but was significantly higher at t3 than at t0 in the amrinone and PGE1 groups (P=0.007 and P=0.001 in each comparison, Figure 1C). Cardiac index and oesophageal temperature remained unchanged throughout the observation period in all three groups (Figures 1D and E).



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Fig 1 Changes in (A) systolic arterial pressure, (B) diastolic arterial pressure, (C) heart rate, (D) cardiac index and (E) oesophageal temperature. Data are expressed as means ± SD. Bold solid line, amrinone group (n=15); thin solid line, PGE1 group (n=15); broken line, control group (n=15). *P<0.008 compared with the mean preoperative level; t0, before laparotomy; t0, just before induction of liver ischaemia; t2, just after liver resection; t3, 60 min after reperfusion.

 
Changes in ICG-K
After drug treatment, ICG-K was significantly higher at t1 than at t0 (P=0.006) in the amrinone group, but not in the PGE1 or control group (Figure 2A). Just after reperfusion, ICG-K was significantly lower at t2 than at baseline in the control group (P=0.006), but not in the amrinone or PGE1 groups. The ICG-K concentration at t3 did not differ from baseline in any of the groups.



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Fig 2 Changes in (A) the indocyanine green elimination rate, (B) arterial blood lactate concentration, (C) base excess, (D) plasma aspartate aminotransferase and (E) alanine aminotransferase. Data are expressed as means ± SD. Bold solid line, amrinone group (n=15); thin solid line, PGE1 group (n=15); broken line, control group (n=15). *P<0.008 compared with the mean preoperative level; **P<0.05 by two-way repeated-measures ANOVA to examine the effect of PGE1 or amrinone on each factor compared with controls; t0, before laparotomy; t1, just before induction of liver ischaemia; t2, just after liver resection; t3, 60 min after reperfusion; D-1, day –1 (the day before the operation); D0, day 0, 1 h after the operation; D1 and D3, the first and third postoperative days, respectively.

 
Changes in lactate and base excess
The lactate concentration tended to increase during the pre-ischaemic phase, increased markedly during the ischaemic phase and tended to decrease during the post-ischaemic phase (Figure 2B). The lactate concentration at t2 was significantly higher than baseline in each group (P<0.0001 in each comparison). The rate of lactate accumulation or elimination during each phase is shown in Table 3.


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Table 3 Rate of lactate accumulation or elimination rate (µmol l–1 min–1) (mean (SD)). Positive numbers indicate accumulation and negative numbers elimination. aCompared with controls
 
Base excess continued to decline until t2 in each group (Figure 2C). Base excess at t2 was significantly lower than at t0 in the PGE1 and control groups (P=0.007 and P=0.003, respectively).

Changes in AST and ALT
AST concentrations in all groups reached their maximum (216 (239), 231 (152) and 246 (125) IU litre–1 in the amrinone, PGE1 and control groups, respectively) on the first postoperative day (Figure 2D). ALT concentrations showed similar changes (Figure 2E).

Comparison among the groups
Two-way repeated-measures ANOVA revealed that SAP, DAP, heart rate, cardiac index, oesophageal temperature, AST and ALT did not differ significantly among the groups at any time in the observation period.

In contrast, ICG-K in the amrinone group differed significantly from that in the control group (P=0.03). ICG-K in the PGE1 group tended to differ from those in the control and amrinone groups, but these differences were not statistically significant (P=0.1 for each comparison).

Lactate concentration and base excess in the amrinone and control groups also differed significantly throughout the observation period (P=0.04 and P=0.03, respectively). Lactate concentration and base excess in the PGE1 and control groups differed, but these differences were not statistically significant (P=0.09 and P=0.25, respectively).

The lactate accumulation rate during the pre-ischaemic phase in the amrinone group was significantly lower than that in the control group (P=0.03, Table 3). In contrast, the lactate accumulation rates during the ischaemic phase were comparable in the three groups. During the post-ischaemic phase, the lactate elimination rate in the amrinone and PGE1 groups tended to be lower than that in the control (P=0.09).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
To our knowledge, there have been no previous reports on the effects of amrinone on the function of liver subjected to ischaemia–reperfusion injury. This randomized, blinded study demonstrated that continuous intravenous administration of low-dose amrinone resulted in enhanced ICG-K elimination during hepatectomy. Such treatment also resulted in a reduced blood lactate concentration. With amrinone, lactate accumulation was reduced before ischaemia and its elimination tended to be greater after ischaemia. ICG elimination is a reliable indicator of hepatic blood flow and of hepatocellular function.15 16 In addition, as we and other authors have demonstrated in previous studies,17 18 blood lactate profiles, especially lactate accumulation and elimination rates, are some of the most sensitive indicators of hepatic function during liver surgery. The results obtained in this study indicate that low-dose amrinone augments intraoperative liver function during hepatectomy involving liver ischaemia.

How does low-dose amrinone keep ICG-K concentrations higher intraoperatively? One possible explanation is increased hepatic blood flow either through augmented cardiac function or through dilated hepatic vascular beds, although the cardiac index in the amrinone group was comparable to that in the control group. Total hepatic flow is usually regulated by hepatic arterial flow. This unique intrinsic regulation system is called the hepatic arterial buffer response.19 The arterial buffer maintains intrahepatic pressures and liver volume.19 However, it is possible that amrinone and isoflurane significantly attenuate this response after ischaemia–reperfusion injury.

Another possibility is that amrinone might minimize the effects of intracellular calcium overload and its harmful sequelae. Liver ischaemia–reperfusion injury is mediated, at least in part, through an elevation in intracellular calcium.20 Amrinone is known to inhibit cytoplasmic calcium mobilization, increasing the cAMP concentration.21

During the pre-ischaemic phase, lactate concentration tended to increase in all three groups. This might be a result of decreased uptake of lactate resulting from decreased hepatic blood flow during compression and mobilization of the liver for hepatectomy, which caused lactate accumulation even before the liver was subjected to ischaemia.18 22 Anaesthetic agents might also impair hepatic function. Although isoflurane does not appear to depress hepatic function, as measured by the ICG test in patients with normal hepatic function,18 a dose-dependent decrease in hepatic blood flow induced by isoflurane might depress liver function significantly in cirrhotic patients, and thus enhance lactate accumulation.23–26 In this pre-ischaemic phase, lactate accumulation was prevented to a considerable extent with amrinone. This result, coupled with enhanced ICG-K, indicated that amrinone augments intraoperative hepatic function during this phase.

During the ischaemic phase, lactate accumulation progressed at similar rates in all three groups. Increases in lactate concentrations during this phase result primarily from increased lactate production by tissue ischaemia and secondarily from the abolition of lactate uptake by the liver.17 18 The similar lactate profiles in the three groups during this phase were not surprising, since hepatic blood flow is abolished completely during Pringle’s manoeuvre, regardless of the drugs used. Postoperative AST and ALT concentrations were similar among the groups. This might also suggest that the magnitude of liver damage caused by ischaemia was similar irrespective of the drugs. In this respect, amrinone might not provide significant organ protection against ischaemia during this phase. Immediately after the end of ischaemia, however, ICG-K was well maintained with amrinone, while it was reduced in the control group. The lactate concentration in the amrinone group immediately after ischaemia remained lower than that in the control group. In addition, after ischaemia, lactate elimination tended to be enhanced with amrinone. These results suggest that liver function was maintained better in the amrinone group during the immediate post-ischaemic period. Thus, the possibility that amrinone provides some organ protection against ischaemia could not be excluded.

Clearance of amrinone in cirrhotic patients is not known, but is likely to be significantly reduced in these circumstances. Although 26–40% of amrinone given intravenously is excreted in the urine unchanged, a substantial fraction of the remaining dose undergoes hepatic metabolism.27 The rate of amrinone administered by continuous infusion in the present study was fixed at 4.0 µg kg–1 min–1, which is much less than that used for the treatment of heart failure (10–20 µg kg–1 min–1).28 Furthermore, in the present protocol, a loading dose was not given, which is usually a bolus of 1–2 mg kg–1.28 The effects of amrinone on ICG metabolism might differ if a different amrinone administration protocol was used, and this might throw further light on this subject.29

In the PGE1 group, ICG-K concentrations tended to remain higher during surgery. This suggests that PGE1 may have some beneficial effects on intraoperative liver function. However, this effect was no greater than that of amrinone. Our results with PGE1 were comparable to those of Tsukada and colleagues,30 who demonstrated that ICG elimination was enhanced by PGE1 dose-dependently in doses ranging from 0.01 to 0.05 µg kg–1 min–1 in cirrhotic patients undergoing partial liver resection. Another study29 revealed that continuous intravenous administration of low-dose PGE1 (0.02 µg kg–1 min–1) had favourable pharmacological effects on the liver during the postoperative period in cirrhotic patients who had undergone subsegmentectomy of the liver.

In conclusion, low-dose amrinone enhanced ICG elimination and lactate metabolism during hepatic resection in cirrhotic patients; its detailed mechanism of action remains unclear.


    Acknowledgements
 
This work was supported in part by a Grand-in-aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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17 Koller J, Wieser C, Furtwangler W, Kornberger R, Konigsrainer A, Margreiter R. Orthotopic liver transplantation and perioperative lactate metabolism. Transplant Proc 1991; 23: 1989–90[ISI][Medline]

18 Orii R, Sugawara Y, Hayashida M et al. Peri-operative blood lactate levels in recipients of living-related liver transplantation. Transplantation (in press)

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