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*Department of Anesthesiology, Saitama Cardiovascular and Pulmonary Center, Saitama, Japan; and Department of Anesthesiology and Reanimatology, Gunma University, School of Medicine, Gunma, Japan
Address correspondence and reprint requests to Nobuhiro Okano, Department of Anesthesiology, Saitama Cardiovascular and Pulmonary Center, 1696 Itai Konan-machi Osato-gun, Saitama 360-0105, Japan. Address e-mail to richard{at}ka2.so-net.ne.jp
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Abstract |
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IMPLICATIONS: Hepatic sinusoidal endothelial cells (SECs) are pivotal in the regulation of sinusoidal blood flow. This study showed that SEC function might be impaired during and after cardiopulmonary bypass, irrespective of the temperature management.
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Introduction |
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The hepatic sinusoidal endothelial cells (SECs) have an important role in regulation of the sinusoidal blood flow (7) and are more sensitive to a variety of stresses (endotoxin, hypoxia, and hypothermia) than the hepatocytes (8,9). We previously found hepatic venous desaturation and increases of serum hyaluronate (HA) during normothermic CPB, without any major abnormalities in the postoperative liver function tests that represent hepatocyte function (10). HA, an extracellular matrix component of mucopolysaccharides, is normally taken up and degraded in SECs by binding to HA receptors, leading to its rapid fractional turnover (11). In acute liver dysfunction, as seen in liver allograft rejection after liver transplantation (12) or by a combination of endotoxin and partial hepatectomy (8), increased serum levels of HA represent a functional impairment of SECs. We hypothesized that although standard liver function tests could not detect functional changes in the hepatocytes, hepatosplanchnic desaturation associated with CPB might impair the SEC function, leading to disturbance of HA scavenging. However, hepatic blood flow was not determined in that study. Whether HA uptake was decreased or whether the degradation of HA was suppressed could not be addressed.
We have also observed that hepatosplanchnic oxygenation is worse during normothermic than hypothermic CPB (13). We assumed that HA concentrations would be more increased during normothermic than mild hypothermic CPB. To test the hypothesis that hepatosplanchnic oxygenation is an important determinant of serum HA concentrations during CPB, we investigated plasma kinetics of endogenous HA and hepatosplanchnic oxygenation during and after normothermic and mild hypothermic CPB.
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Methods |
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After each patient was premedicated with 10 mg of diazepam orally, anesthesia was induced with 0.2 mg/kg of midazolam and 5 µg/kg of fentanyl; tracheal intubation was facilitated with 0.1 mg/kg of vecuronium. Maintenance of anesthesia was performed with 15 µg/kg of fentanyl in divided doses, intermittent vecuronium, 4 mg · kg-1 · h-1 of propofol, and 50% oxygen in air. In addition to radial and pulmonary artery catheters (Vigilance®, Swan-Ganz CCO Thermodilution Catheter; Baxter, Deerfield, IL), a hepatic venous catheter (Harmac Medical Products, Buffalo, NY) was inserted into the right hepatic vein via the right femoral vein under fluoroscopic guidance. The tip of the catheter was positioned 1.5 cm proximal to the wedged position (1,4).
Nonpulsatile CPB, with a membrane oxygenator containing a 40-µm arterial filter line (HILITE®; MEDOS Medizintechnik Co., Stolberg, Germany), was performed after priming with a crystalloid solution, with a pump flow of 2.3–2.5 L · min-1 · m-2, a mean arterial blood pressure of 50–90 mm Hg by phenylephrine infusion, and a hematocrit of >20% by transfusion of packed red blood cells if needed. Cardiotomy and venous suction (Capiox®; Terumo, Tokyo, Japan) was used, and the suction effluent was recirculated through the CPB circuit. After systemic heparinization (300 U/kg), CPB was started, and the activated coagulation time was maintained at longer than 480 s. The target nasopharyngeal temperature was >35°C for the normothermic group and was 32°C for the mild hypothermic group. Arterial carbon dioxide tension, uncorrected for temperature, was adjusted to normocapnic levels by using the alpha-stat strategy. After the CPB was discontinued, the cardiac index was maintained >3.0 L · min-1 · m-2 by administering dopamine, dobutamine, or both. Nitroglycerine (0.5 µg · kg-1 · min-1) and diltiazem (1 µg · kg-1 · min-1) also were used throughout the study period, except during CPB.
The administration of propofol for sedation in the intensive care unit (ICU) was discontinued, and patients were extubated when they were awake and their blood gas values became comparable to what they were before surgery. Lactated Ringer’s solution (2–3 mL · kg-1 · h-1), colloids, and packed red blood cells were administered to maintain a central venous pressure of 8–14 mm Hg, a pulmonary artery occlusion pressure of 5–12 mm Hg, and a hematocrit >30%.
Hemodynamic variables; arterial, mixed venous, and hepatic venous blood gases; and arterial and hepatic venous HA and lactate concentrations were measured 1) after the induction of anesthesia; 2) 10 min and 3) 60 min after the start of CPB; 4) at the unclamping of the aorta; 5) 10 min and 6) 60 min after the cessation of CPB; and 7) 6 h and 8) 24 h after admission to the ICU. The blood gas tensions and lactate concentrations were analyzed with a Stat Profile Ultima (Nova Biochemical, Boston, MA) and a Lactate Pro test strip (Arkray, Inc., Kyoto, Japan), respectively.
Hepatic blood flow was determined by a primed (6 mg) and continuous infusion (1 mg/min) of indocyanine green (ICG) for 40 min into a central venous catheter 1) after the induction of anesthesia, 2) during the steady-state of CPB, and 3) after the separation from CPB (14,15). The time period at the end of each 40-min infusion cycle corresponded with the time 1) after the induction of anesthesia, 2) 60 min after the start of CPB, and 3) 60 min after the cessation of CPB, respectively. At each measurement, plasma ICG concentrations after 20, 30, and 40 min of ICG infusion were measured by photometrical extinction of the centrifuged samples at 800 nm, and arterial and hepatic venous ICG concentrations were in steady-state plateaus. Hepatosplanchnic blood flow index (HBFI) was calculated according to the formula listed in Appendix 1. The coefficients of variation for consecutive blood flow measurements were 7.4% ± 2.9% before CPB, 6.2% ± 2.0% during CPB, and 6.8% ± 2.2% after CPB.
The oxygen use variables were systemic and hepatosplanchnic oxygen delivery index (DO2I), systemic and hepatosplanchnic oxygen consumption index (
O2I), and systemic and hepatosplanchnic extraction ratio (OER). The plasma kinetic variables for HA and lactate were the hepatosplanchnic uptake and extraction ratio. These variables were calculated according to the formulae summarized in Appendix 1.
Serum HA concentrations were measured in duplicate by a sandwich binding protein assay (HA kit; Chugai Pharmaceutical Co., Tokyo, Japan). Blood samples collected in chilled tubes were immediately centrifuged at 4000g, and the resultant plasma was stored at -20°C. The detection limit was 5 ng/mL. The within- and between-assay coefficients of variation were 10% and 15%, respectively. Alanine aminotransferase and total bilirubin were measured before surgery, 6 h after the operation, and on postoperative Days 1, 3, and 7.
All data are expressed as mean ± SD. Patient characteristics were analyzed by unpaired Student’s t-tests or 
2 tests, as appropriate. Other variables were analyzed by two-way repeated-measures analysis of variance followed by Bonferroni’s test for intragroup comparisons and by unpaired Student’s t-tests for intergroup comparisons. To test relationships among changes in HBFI, hepatosplanchnic oxygenation, and HA values, linear regression analyses were performed among HBFI, hepatosplanchnic oxygen-use variables (ShvO2, O2I, and OER), and HA kinetic data (arterial and hepatic venous HA concentrations, uptake, and extraction ratio) before, during, and after CPB. The data for normothermic and mild hypothermic CPB were combined for this purpose. A P value of <0.05 was considered significant.
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Results |
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O2I, and OER are illustrated in Figure 1. No significant differences were found between the groups in these variables. Systemic DO2I decreased during normothermic and mild hypothermic CPB because of hemodilution associated with CPB, leading to a proportional decrease in hepatosplanchnic DO2I in both groups (P < 0.05 compared with the pre-CPB values). After CPB, systemic and hepatosplanchnic DO2I increased in both groups, and this continued during the remainder of the observation periods.
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O2I decreased soon after the start of CPB, followed by a return to the pre-CPB values. This return was seen at 60 min after the start of CPB for normothermic CPB and at the rewarming period for mild hypothermic CPB. In both groups, it increased at 6 and 24 h after admission to the ICU. Hepatosplanchnic O2I, however, was markedly increased from the baseline value during normothermic CPB. During mild hypothermic CPB, hepatosplanchnic O2I remained unchanged, despite a decrease in systemic O2I. After CPB, these changes in hepatosplanchnic O2I were no longer seen.
Systemic OER increased during normothermic CPB (P < 0.05 compared with the pre-CPB values). In case of mild hypothermic CPB, systemic OER decreased slightly throughout the CPB period, except for the rewarming period. After admission to the ICU, systemic OER increased in both groups. Changes in hepatosplanchnic OER closely paralleled those in hepatosplanchnic O2I.
As shown in Figure 2, the mixed venous oxygen saturation decreased early in the normothermic CPB process, whereas it decreased at the time of rewarming during mild hypothermic CPB. ShvO2 also decreased early during CPB in both the temperature-management groups. Gross observations showed that this decrease was more pronounced during normothermic than mild hypothermic CPB, but their difference was not statistically significant (P = 0.114). With mild hypothermic CPB, the ShvO2 returned to the pre-CPB control values soon after the separation from CPB, whereas with normothermic CPB, the ShvO2 remained lower 10 min after the cessation of CPB and 6 h after admission to the ICU compared with the pre-CPB control values (P < 0.05).
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HBFI correlated positively with ShvO2 and inversely with hepatosplanchnic OER. An inverse relationship between HBFI and the HA extraction ratio also was observed during CPB. Relationships were not found between ShvO2 and arterial or hepatic venous HA concentrations or its kinetics. However, a positive correlation was found between hepatosplanchnic O2I and arterial concentrations of HA (Table 4).
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Discussion |
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O2 weakly but significantly correlated with arterial concentrations of HA. These findings suggest that changes in hepatosplanchnic oxygen metabolism during CPB contribute in part to the observed increase of serum HA.
Hepatosplanchnic O2 showed a marked increase during normothermic but not mild hypothermic CPB, probably because of increased regional oxygen demand associated with normothermia (20) and the proinflammatory nature of CPB (1,2). O2 exceeded DO2 in the hepatosplanchnic region, at least during normothermic CPB. Nonetheless, this increased hepatosplanchnic oxygen demand appeared to be fully compensated for by an increase in hepatosplanchnic oxygen extraction. Accordingly, ShvO2 decreased particularly during normothermic CPB. The finding of negative values in the hepatosplanchnic lactate extraction ratio observed after mild hypothermic CPB might be related to more impaired glucose metabolism associated with hypothermia (Table 2). However, no significant differences were observed in lactate concentrations or its kinetics between the groups (Fig. 3). Transient lactate increases in patients recovering from cold CPB have been considered a physiologic phenomenon after cardiac surgery (21). Thus, the increased lactate concentrations in both groups may not always indicate the presence of hepatosplanchnic hypoperfusion.
Increased serum levels of HA are found in conditions such as rheumatoid arthritis (22), with increased breakdown of connective tissues, and in liver diseases of various etiologies (18), with reduced elimination of HA. On the basis of the increased uptake of circulating HA during and after CPB (P < 0.05) and the unchanged extraction ratio, the observed large concentrations of HA are primarily a consequence of stimulated synthesis or, perhaps, outflow from the connective tissues. Increasing the hepatic blood flow should be associated with an increased delivery of endogenous HA to the liver, with a consequence of increasing uptake. This relationship was found before CPB (r = 0.44, P = 0.037; data not shown). Despite the mathematical coupling between HBFI and HA uptake, however, the positive correlation between these variables disappeared during CPB (Table 4). HA uptake became abnormal during CPB. In addition, although normal SECs have the capacity to eliminate 10 times the normal amount of endogenous HA (19), the liver failed to significantly increase the extraction ratio (Fig. 3). An inverse correlation was observed between HBFI and the HA extraction ratio during CPB (Table 4). These findings suggest that the liver could not effectively respond to the increased amount of HA during and after CPB.
As shown in Table 4, hepatosplanchnic O2 is an important determinant of ShvO2 during CPB. In addition, endotoxin that may be released during CPB activates Kupffer cells, resulting in cytokine production and secondarily injuring SECs (8). In hyperbilirubinemia after implantation of a left ventricular assist device, an increase in serum levels of HA positively correlated with an increase in serum interleukin 8 concentrations (23). We considered that functional impairment of SECs also was possibly one of the causative factors for the large concentrations of HA during and after CPB.
The finding of unchanged hepatosplanchnic blood flow during normothermic and mild hypothermic CPB was consistent with reports on CPB in humans (15,16). When the hepatosplanchnic O2 increases, as seen in feeding or sepsis, however, hepatosplanchnic blood flow increases in proportion to the increased regional O2 (5). The unchanged blood flow observed during normothermic CPB might be an inappropriate organ response in the face of increased O2. In addition, despite combined therapy with dobutamine and dopamine (5 µg · kg-1 · min-1 each), increased hepatosplanchnic blood flow after CPB did not reach statistically significant levels. The hepatic venous catheterization is suggested not to interfere with hepatic blood flow (14). We speculate that disturbance of the sinusoidal blood flow associated with the SEC dysfunction might contribute to these abnormal organ responses. In patients recovering from CPB, however, dobutamine or dopamine at doses of >5 µg · kg-1 · min-1 is reported to consistently increase hepatosplanchnic blood flow, although these drugs induce inappropriate distribution in the hepatosplanchnic region (24,25). In addition, the phenylephrine dosage used during CPB was roughly doubled during normothermia compared with mild hypothermia (P = 0.089). Thus, the effects of phenylephrine on HBFI should be considered.
Phenylephrine (an 
agonist) was used to maintain arterial blood pressure during CPB. However, it is reported to compromise visceral and peripheral organ perfusion with conventional pump flow and adequate perfusion pressures (26). Indeed, the HBFI estimated during and after CPB was relatively lower for normothermic than mild hypothermic CPB (Table 2). Thus, the phenylephrine infusion during CPB might also contribute to inappropriate organ responses, such as limited increases in blood flow in response to increased O2 and administered catecholamines, as typically observed for the normothermic group. Furthermore, the liver has a dual blood supply (oxygen-saturated blood via the hepatic artery and less-saturated blood via the portal vein). There is a possibility that phenylephrine given during CPB might have reduced the flow of the hepatic artery relative to the portal vein. This might be more pronounced during normothermic than mild hypothermic CPB, which might contribute to the observed differences in ShvO2 during CPB.
The disproportional use of phenylephrine might also explain the observed differences in HA kinetics between the groups. The phenylephrine infusion and resultant low perfusion might have decreased the delivery of HA to the liver, leading to accumulation of HA in the connective tissues during CPB. On improvement of peripheral and visceral organ perfusion after CPB, accumulated HA might have overflowed to the liver. After CPB, the delivery of HA to the liver could have been larger for the normothermic than the mild hypothermic group. Thus, both the arterial and hepatic venous HA differences and HA uptake were greater at 60 minutes after CPB for normothermic than mild hypothermic CPB.
In conclusion, we showed that hepatic venous desaturation and increases of serum HA levels during and after normothermic and mild hypothermic CPB did not lead to any major consequences in the postoperative standard liver function tests. Possible explanations include a transient decrease in ShvO2, a minor degree of SEC dysfunction, a relatively small risk of the patients enrolled, and fully developed compensation mechanisms in the liver. These observations indicate that the SECs are more sensitive to CPB stress than the hepatocytes, but this needs to be validated against the variables that relate to SEC function. Although lack of randomization and the small and uneven study size might obscure any differences between groups, changes in hepatosplanchnic blood flow, hepatosplanchnic oxygenation, serum levels of HA, and lactate metabolism did not differ between the normothermic and mild hypothermic groups. Changes in hepatic oxygen metabolism appear to be related to some extent to the observed increase of serum HA during CPB. Further study is needed to determine more detailed mechanisms of SEC dysfunction associated with CPB.
Appendix 1
HBFI = ICG-i/[(ICG-a - ICG-hv) x (1 - Hct)] x BSA
DsysO2I = (1.36 x Hb x SaO2 + 0.003 x PaO2) x CI
VsysO2I = [1.36 x Hb x (SaO2 - SvO2) + 0.003 x (PaO2 - PvO2)] x CI
OERsys = VsysO2I/DsysO2I
DsplO2I = (1.36 x Hb x SaO2 + 0.003 x PaO2) x HBFI
VsplO2I = [1.36 x Hb x (SaO2 - ShvO2) + 0.003 x (PaO2– PhvO2)] x HBFI
OERspl = VsplO2I/DsplO2I
HA uptake = (HA-a - HA-hv) x HBFI
HA extraction ratio = (HA-a - HA-hv)/HA-a
Lactate uptake = (Lactate-a - Lactate-hv) x HBFI
Lactate extraction ratio = (Lactate-a - Lactate-hv)/Lactate-a
HBFI = hepatosplanchnic blood flow index; CI = cardiac index; BSA = body-surface area; Hct = hematocrit; Hb = hemoglobin concentration; DsysO2I = systemic oxygen delivery index; VsysO2I = systemic oxygen consumption index; OERsys = systemic oxygen extraction ratio; DsplO2I = hepatosplanchnic oxygen delivery index; VsplO2I = hepatosplanchnic oxygen consumption index; OERspl = hepatosplanchnic oxygen extraction ratio; SaO2, SvO2, and ShvO2 = arterial, mixed venous, and hepatic venous oxygen saturations; PaO2, PvO2, and PhvO2 = arterial, mixed venous, and hepatic venous oxygen tensions; ICG-i = infusion rate of indocyanine green; ICG-a and ICG-hv = arterial and hepatic venous indocyanine green concentrations; HA-a and HA-hv = arterial and hepatic venous HA concentrations; Lactate-a and Lactate-hv = arterial and hepatic venous lactate concentrations.
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Acknowledgments |
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We thank Mr. Kamiyashiki and Mr. Someya for their technical assistance (Division of Medical Engineering in our institute).
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cardiopulmonary bypass (CPB). No significant differences are found between the groups for these variables. However, significant interactions between group and time were seen for hepatosplanchnic 
