Anesth Analg 2001;92:676-680
© 2001 International Anesthesia Research Society
CRITICAL CARE AND TRAUMA
The Effects of Olprinone (a Phosphodiesterase III Inhibitor) on Hepatic Vascular Bed in a Porcine Model of Endotoxemia
Etsuro Nagata, MD*,
Yasuyuki Kakihana, MD
,
Kazumi Tobo, MD*,
Sumikazu Isowaki, MD*, and
Yuichi Kanmura, MD*
*Department of Anesthesiology and Critical Care Medicine, Kagoshima University School of Medicine; and Division of Intensive Care Medicine, Kagoshima University Hospital, Kagoshima, Japan
Address correspondence and reprint requests to Etsuro Nagata, Department of Anesthesiology and Critical Care Medicine, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
 |
Abstract
|
|---|
Decreased hepatic blood flow, and impaired hepatic oxygen delivery caused by endotoxin, result in hepatic metabolic deterioration followed by liver dysfunction and multiple organ failure. Among phosphodiesterase III inhibitors, only olprinone increases hepatosplanchnic blood flow. We evaluated the effects of olprinone on systemic hemodynamics, hepatic circulation, and hepatic oxygen delivery in a porcine model of endotoxemia. Fifteen pigs received a continuous infusion (1.7 µg · kg-1 · h-1) of endotoxin (lipopolysaccharide [LPS]) via the portal vein for 240 min. Seven of these pigs received olprinone infusion (0.3 µg · kg-1 · min-1) via a central vein from t = 150 min to t = 240 min, whereas the eight remaining pigs served as LPS controls. Continuous infusion of LPS caused significant reductions in hemodynamic variables and a significant increase in arterial lactate. After the administration of olprinone during the LPS infusion, portal venous flow and hepatic oxygen delivery were increased and were higher than in the LPS group. Furthermore, olprinone prevented any further increase in arterial lactate. We conclude that the administration of olprinone halted the disturbances in the hepatic circulation, especially in portal venous flow and hepatic oxygen delivery, in a porcine model of endotoxemia.
Implications: Endotoxin is a causative factor in peripheral vascular failure, resulting in a hemodynamic depression that includes a reduction in liver blood flow. The administration of olprinone (phosphodiesterase III inhibitor) improves the liver blood flow circulation in a porcine model of endotoxemia.
|
Introduction
|
|---|
Bacterial endotoxins have many pathologic effects in patients suffering from severe infection, trauma, or complications after major surgery (1,2). Endotoxin is an important causative factor in peripheral vascular failure, resulting in a hemodynamic depression that includes a reduction in hepatic blood flow (3,4). The decrease in hepatic blood flow and the impaired hepatic oxygen delivery (DO2H) caused by endotoxin result in hepatic metabolic deterioration followed by liver dysfunction, multiple organ dysfunction syndrome (MODS), and associated frequent mortality (5). Unfortunately, we still lack specific drugs for patients with the hepatic dysfunction that may arise as a component of MODS in endotoxemia (4,6).
Some reports have indicated that one possible strategy for the prevention of MODS was to increase both cardiac output (CO) and oxygen delivery to supranormal levels by administering inotropic drugs and vasodilators after effective IV fluid therapy (1,2). However, this strategy was not sufficient to improve the mortality rate in patients with septic shock (7). Alternatively, the gradient between mixed venous and hepatic vein oxygen saturation is often increased in septic patients. This indicates that these patients may have an imbalance between oxygen supply and demand in the hepato-splanchnic area (8). Therefore, treatment for liver dysfunction in endotoxemia should be aimed mainly at increasing not only systemic oxygen delivery, but also regional liver blood flow and DO2H. Interestingly, recent clinical experience has indicated that olprinone, but not amrinone or milrinone, significantly increases hepatosplanchnic perfusion in patients undergoing cardiac surgery (9,10). Moreover, in another study (11), the infusion of milrinone did not increase hepatic blood flow in patients with severe congestive heart failure. Therefore, to obtain more information relating to the possible value of olprinone in endotoxemia, we investigated the effects of this drug on the changes in systemic hemodynamics, hepatic circulation, and DO2H that occur during a continuous infusion of endotoxin in a porcine model.
|
Methods
|
|---|
All procedures were performed in accordance with the guidelines for the care and use of laboratory animals in Kagoshima University research laboratories and were approved by the local ethics committee of Kagoshima University. Fifteen male pigs weighing 23 to 28 kg were used in this study. All animals were fasted overnight but had free access to water. The animals were premedicated IM with ketamine hydrochloride (25 mg/kg) and atropine sulfate (0.5 mg). Anesthesia was induced by IV pentobarbital (20 mg/kg) and maintained with 1.0% isoflurane. After intubation with a cuffed endotracheal tube, the animals were paralyzed with pancuronium (bolus of 0.1 mg/kg IV, followed by a continuous infusion of 0.1 mg · kg-1 · h-1), and mechanically ventilated (fraction of inspired oxygen 50%). The tidal volume was adjusted to keep the arterial carbon dioxide tension within the range 35 to 40 mm Hg. Ringer’s solution at a rate of 10 mL · kg-1 · h-1 was continuously infused throughout the experiment. Catheters were surgically placed under sterile conditions. The left internal carotid artery was cannulated for arterial blood sampling and measurement of systemic arterial pressure. A Swan-Ganz thermodilution catheter was inserted via the left external jugular vein and positioned within the pulmonary artery by using the pressure wave on the monitor for guidance. The catheters were connected to pressure transducers, and the Swan-Ganz catheter was also connected to a CO computer. Through an abdominal midline incision, ultrasound transit-time flow probes (Transonic Systems Inc, Ithaca, NY) were placed around the hepatic artery and the portal vein (PV) for continuous measurement of hepatic arterial blood flow (QHA) and portal venous flow (QPV). A 7F double-lumen catheter (3-cm tip distance) was positioned within the PV via a mesenteric vein for the infusion of endotoxin from the distal lumen and for blood sampling from the proximal lumen. After a 60-min stabilization period, consecutive measurements of systemic hemodynamics, blood gases, and hepatic blood flow were made to evaluate both the progression of the induced shock and the effects of olprinone in endotoxemia. The time points for data collection were as follows: t = 0 (the start of the infusion of endotoxin, initial baseline); t = 150 min (the start of the infusion of olprinone, second baseline); and t = 180, 210, and 240 min. Blood samples obtained from catheters placed within the aorta, the pulmonary artery, and the PV were used for the measurement of blood gases. Blood gas analyses were performed on a blood gas analyzer (ABL 2 ; Radiometer, Copenhagen, Denmark) which automatically calculates PO2, PCO2, HCO3, pH, and base excess. The arterial oxygen saturation (SaO2), portal venous oxygen saturation (SPVO2), and hemoglobin concentration (Hb) were also measured at each time point by blood gas analysis with the machine calibrated for pig blood. DO2H was calculated from the equation DO2H = (SaO2 x QHA + SPVO2 x QPV) x 13.4 x 10-5 x Hb. Rectal temperature was continuously monitored and kept at 37°C to 38°C with the aid of a heating pad on the surgical bed.
After surgical preparation, 15 animals received a continuous infusion (1.7 µg · kg-1 · h-1) of endotoxin (lipopolysaccharide [LPS] Serotype O111: B4; Sigma Chemical, St. Louis, MO) via the PV for 240 min. During the latter part of the infusion of LPS, seven animals received olprinone (0.3 µg · kg-1 · min-1) via a central vein from t = 150 to t = 240 min (LPS/Olprinone group). The remaining eight pigs, who received saline (a continuous infusion of 0.09 mL · kg-1 · h-1 via the central vein), served as an LPS control (LPS group) for the unhindered progression of endotoxemia.
All results are expressed as mean ± SD. In the period from 150 min (as a second baseline) to 240 min, the differences between the two groups were evaluated by applying analysis of variance for repeated measurements. If this procedure revealed a significant difference, it was followed by a one-factor analysis of variance to assess the intergroup differences in each variable at the various time points. A separate analysis of variance was used for each group. This was followed by appropriate corrections for repeated use of the test (Scheffé test). A P value <0.05 was considered significant.
|
Results
|
|---|
In the LPS group, a continuous infusion of endotoxin from t = 150 to t = 240 min caused significant decreases in mean arterial pressure, CO, and systemic oxygen delivery, and it caused a significant increase in systemic vascular resistance. There were no significant intergroup differences in these variables in the period up to t = 150 min ( Table 1).
In the LPS group, QHA and DO2H were all significantly reduced in the period from t = 150 to t = 240 min. The administration of olprinone (LPS/Olprinone group) caused no significant alteration in QHA, whereas from t = 150 min to t = 240 min, QPV and DO2H both showed significant increases (from 181 ± 16 mL/min to 272 ± 29 mL/min, P < 0.0001; and from 33 ± 5 to 44 mL/min ± 6 mL/min, P = 0.0083, respectively). Furthermore, the values obtained at t = 240 min for QPV and DO2H were significantly higher in the LPS/Olprinone group than in the LPS group ( Figs. 1, 2).
In the LPS group, the continuous infusion of endotoxin resulted in a lactic acidosis, with a significant increase in the plasma concentration of lactate. In contrast, in the LPS/Olprinone group, the lactate stabilized at or near the second baseline value ( Fig. 3). At t = 240 min, the concentration of lactate was significantly smaller in the LPS/Olprinone group (3.8 ± 0.6 mmol/L) than in the LPS group (8.6 ± 2.8 mmol/L) (P = 0.025).
|
Discussion
|
|---|
Our data showed that the continuous infusion of endotoxin caused a significant reduction in QHA and an impaired DO2H. In endotoxemia, a major mechanism that may account for the genesis of hepatic insufficiency is the induction of hepatocellular hypoxia resulting both from a disturbance of microflow within the liver and a reduction in the blood supply to the liver as a whole.
The mucosal lining of the gut is an important barrier limiting the systemic absorption of intraluminal microbes and microbial products. There is abundant evidence that the barrier function of the gut can be compromised by a variety of pathologic insults, including endotoxicosis (10–13). Therefore, in this study we chose to infuse LPS into the PV because this mimics the situation in which endotoxemia is caused by bacterial translocation from the gut.
Sepsis is often characterized by a number of metabolic abnormalities, including increased plasma lactate concentration, metabolic acidosis, increased glycolysis, and a pathological dependence of oxygen consumption on oxygen delivery. Oldner et al. (14) analyzed the lactate concentrations in the liver, intestine, and arterial blood in a porcine model of endotoxemia. Their results showed that lactate levels were increased in all three sites during endotoxin infusion, but the increase in lactate was more marked in the liver and intestine than in the arterial blood. Although we did not measure the lactate levels in liver or intestinal tissue, our data do show a significant increase in the lactate concentration of the arterial blood during the endotoxin challenge. Iribe et al. (9) reported that olprinone, but not amrinone or milrinone, increased hepatic venous oxygen saturation, and they suggested that it might increase hepatic blood flow and splanchnic perfusion in patients undergoing cardiac surgery. Our results support the assumption that the administration of olprinone limits the increase in lactate otherwise occurring during continuous infusion of endotoxin. Furthermore, olprinone partially restored hepatic blood flow and DO2H after their initial reduction by the endotoxin challenge.
Phosphodiesterase III inhibitors have positive inotropic and vasodilator actions and characteristically cause an increase in cardiac contractility (8,15,16). However, we did not find significant differences in CO between the LPS group and the LPS/Olprinone group in our study of a porcine model of endotoxemia. We adopted the dose of 0.3 µg · kg-1 · min-1 olprinone because this is the clinical therapeutic dose. So, to determine whether there are differences in sensitivity to olprinone between humans and pigs, we shall need to investigate the dose-response relationship for olprinone in this porcine model with concomitant fluid therapy. In our study, despite the absence of significant differences in CO, QHA and DO2H were both significantly higher in the LPS/Olprinone group than in the LPS group. What might be the mechanism underlying the improvements in QHA and DO2H induced by the administration of olprinone in endotoxemia? The pattern of microflow in the liver is primarily influenced by the activity of the smooth muscle of the hepatic artery and PV, although swelling and shrinkage of endothelial or parenchymal cells (induced by altered membrane permeability or regulation of ion pumps) may play an additional role (17,18). Olprinone relaxes the small mesenteric artery of the rabbit via a direct endothelium-independent action on its smooth muscle (19). Thus, olprinone may be able to regulate the distribution of blood via a direct relaxation of the small arteries in the splanchnic vascular beds. Consequently, an increase is needed of the redistribution of blood flow in other organs that may be induced by olprinone.
In this study, we characterized the effects of olprinone on the QHA and on DO2H during an endotoxin challenge. Our results seem to suggest that olprinone may help to restore QHA and DO2H in endotoxemia. We are considering that the administration of olprinone may be a possible clinical treatment (with assessment of the mixed venous and hepatic vein oxygenation saturation) when it is desired to avoid or improve an imbalance between oxygen supply and demand in the hepatosplanchnic area. However, more work is clearly needed to investigate the mechanisms underlying the olprinone-induced improvement in oxygenation in the liver in comparison with other phosphodiesterase III inhibitors. In addition, the question as to whether olprinone might be clinically effective in the prevention or treatment of acute liver dysfunction in endotoxemia remains to be evaluated in more detail.
In conclusion, we investigated the effects of olprinone on QHA and DO2H in a porcine model of endotoxemia. Our results show that, in fact, olprinone improves the hepatosplanchnic circulation in endotoxemia.
|
Acknowledgments
|
|---|
The authors thank Hiroshi Ishida, MD, Teruko Sameshima, PhD, and Junko Miyao for their contributions in performing some of the experiments used in this study, and Dr. Robert Timms for his helpful advice on this manuscript.
|
References
|
|---|
-
Shoemaker W. Relationship of oxygen transport patterns to the pathophysiology and therapy of shock states. Intensive Care Med 1987; 13: 230–43.[ISI][Medline]
-
Hayes MA, Timminis AC, Yau EHS, et al. Oxygen transport patterns in patients with sepsis syndrome or septic shock: influence of treatment and relationship to outcome. Crit Care Med 1997; 25: 926–36.[ISI][Medline]
-
Fink MP. Adequacy of gut oxygenation in endotoxemia and sepsis. Crit Care Med 1993; 21: S4–8.[ISI][Medline]
-
Lamy M, Deby-Dupont G. Is sepsis a mediator-inhibitor mismatch? Intensive Care Med 1995; 21: S250–7.
-
Eidelman LA, Pizov R, Sprung CL. New therapeutic approaches in sepsis: a critical review. Intensive Care Med 1995; 21: S269–72.
-
Adachi H, Tanaka H. Effects of a new cardiotonic phosphodiesterase III inhibitor, olprinone, on cardiohemodynamics and plasma hormones in conscious pigs with heart failure. J Cardiovasc Pharmacol 1997; 29: 763–71.[ISI][Medline]
-
Andreas MH, Donald LB, Martin S, et al. Dopexamine increases splanchnic blood flow but decreases gastric mucosal pH in severe septic patients treated with dobutamine. Crit Care Med 1999; 27: 2166–71.[ISI][Medline]
-
De Backer D, Creteur J, Noordally O, et al. Does hepato-splanchnic VO2/DO2 dependency exist in critically ill septic patients? Am J Respir Crit Care Med 1998; 157: 1219–25.[Abstract/Free Full Text]
-
Iribe G, Yamada H, Matsunaga A, et al. Effects of the phosphodiesterase III inhibitors olprinone, milrinone, and amrinone on hepatosplanchnic oxygen metabolism. Crit Care Med 2000; 28: 743–8.[ISI][Medline]
-
O’Dwyer ST, Michie HR, Ziegler TR, et al. A single dose of endotoxin increases intestinal permeability in healthy humans. Arch Surg 1988; 123: 1459–64.[Abstract]
-
Fitzpatrick PG, Cinquegrani MP, Vakiener AR, et al. Hemodynamic and regional blood flow response to milrinone in patients with severe congestive heart failure: a dose-ranging study. Am Heart J 1987; 114: 97–105.[ISI][Medline]
-
Fink MP, Antonsson JB, Wang H, et al. Increased intestinal permeability in endotoxic pigs: mesenteric hypoperfusion as an etiologic factor. Arch Surg 1991; 126: 211–8.[Abstract]
-
Deitch EA, Specian RD, Berg RD. Endotoxin-induced bacterial translocation and mucosal permeability: role of xanthine oxidase, complement activation and macrophage products. Crit Care Med 1991; 19: 785–91.[ISI][Medline]
-
Oldner A, Goiny M, Ungerstedt U. Splanchnic homeostasis during endotoxin challenge in the pig as assessed by microdialysis and tonometry. Shock 1996; 6: 188–93.[ISI][Medline]
-
Ohhara H, Ogawa T, Takeda M, et al. Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate: 2nd communication—studies in dogs. Arzneimittelforschung 1989; 39: 38–45.[Medline]
-
Takaoka H, Takeuchi M, Odake M, et al. Comparison of the effects on arterial-ventricular coupling between phosphodiesterase inhibitor and dobutamine in the diseased human heart. J Am Coll Cardiol 1993; 22: 598–606.[Abstract]
-
Rodbard S. Evidence that vascular conductance is regulated at the capillary. Angiology 1966; 17: 539–73.
-
Haylett DG, Jenkinson DH. The receptors concerned in the actions of catecholamines on glucose release, membrane potential and ion movements in guinea-pig liver. J Physiol 1972; 225: 751–72.[Abstract/Free Full Text]
-
Fujimoto S, Ohasi M, Hiramoto A, et al. Vasorelaxant effect of olprinone, an inhibitor of phosphodiesterase 3, on mesenteric small artery and vein of rabbits. Eur J Pharmacol 1998; 353: 239–46.[ISI][Medline]
Accepted for publication November 2, 2000.
Top
Abstract
Introduction
= intraportal endotoxin infusion at 1.7 µg · kg-1 · h-1 for 240 min with intravenous olprinone infusion at 0.3 µg · kg-1 · min-1 from 150 min to 240 min. *P < 0.05 vs second baseline (t = 150 min); 
