| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hepatic sinusoidal endothelial cells (SECs) are more vulnerable to hypoxia or hypothermia than hepatocytes. To test the hypothesis that hepatic venous desaturation during cardiopulmonary bypass (CPB) leads to impairment of SEC function, we studied the plasma kinetics of endogenous hyaluronate (HA), a sensitive indicator of SEC function, and hepatosplanchnic oxygenation during and after CPB. Twenty-five consecutive patients scheduled for elective coronary artery bypass graft surgery, who underwent normothermic (>35°C; n = 15) or mild hypothermic (32°C; n = 10) CPB participated in this study. A hepatic venous catheter was inserted into each patient to monitor hepatosplanchnic oxygenation and serum levels of HA concentration. Hepatic venous oxygen saturation decreased essentially to a similar degree during normothermic and mild hypothermic CPB. Hepatosplanchnic oxygen consumption and extraction increased during normothermic (P < 0.05), but not mild hypothermic, CPB. Both arterial and hepatic venous HA concentrations showed threefold increases during and after CPB in both groups. A positive correlation was found between hepatosplanchnic oxygen consumption and arterial HA concentrations during CPB, suggesting a role of changes in hepatosplanchnic oxygen metabolism in the mechanisms of increases in serum HA concentrations. The failure of the liver to increase HA extraction to a great degree suggests that a functional impairment of the SEC may contribute to the observed increase of serum HA. 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.
Cardiopulmonary bypass (CPB), with its associated imbalance between oxygen demand and supply in the hepatosplanchnic region and resultant intestinal mucosal injury, leads to a state of endotoxemia and to the release of proinflammatory cytokines (1,2). Low hepatic venous oxygen saturation (ShvO2) or increased hepatosplanchnic oxygen extraction has also been reported during and after CPB (3,4). However, hepatic dysfunction, manifested by an increase in serum transaminases and bilirubin, does not often occur after cardiac surgery with CPB, with the hepatocytes usually being well protected against at least a short period of hypoxia (5). Nevertheless, patients with preexisting liver disease undergoing CPB are at risk of postoperative liver dysfunction with frequent mortality (6). These observations suggest that CPB may affect the integrity of the liver. 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.
After obtaining approval from the ethics committee and written informed consent from the patients, we allocated 25 consecutive patients undergoing elective coronary artery bypass graft surgery into normothermic (Group 1; n = 15) and mild hypothermic (Group 2; n = 10) groups, according to the given surgeons preference. Exclusion criteria for patients included the presence of rheumatoid arthritis, pulmonary disease, and diabetes mellitus and left ventricular ejection fraction <0.4, serum alanine aminotransferase >50 IU/L, total bilirubin >1.5 mg/dL, and serum creatinine >1.5 mg/dL. Preoperative medications included ß-adrenergic blockers, nitrates, calcium channel blockers, potassium channel openers, and angiotensin-converting enzyme inhibitors, which were discontinued on the night before surgery. 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 2.32.5 L · min-1 · m-2, a mean arterial blood pressure of 5090 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 Ringers solution (23 mL · kg-1 · h-1), colloids, and packed red blood cells were administered to maintain a central venous pressure of 814 mm Hg, a pulmonary artery occlusion pressure of 512 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 ( 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 Students t-tests or
Patients with a history of cerebral infarction were equally distributed between the groups (n = 3 in each group), as were those with myocardial infarction (n = 3 for the normothermic group; n = 2 for the mild hypothermic group). As shown in Table 1, other patient characteristics were also compatible between the groups. However, the phenylephrine dosage used during CPB tended to be larger during normothermic than mild hypothermic CPB (P = 0.089). All patients had a normal clinical course and were discharged from the ICU within 3 days after admission. The liver function tests performed on postoperative Days 1, 3, and 7 showed no major abnormalities in either group of patients.
HBFI measured by a constant ICG infusion technique before CPB was 600700 mL · min-1 · m-2 (Table 2), which was similar to the available data (15,16). HBFI did not change during or after CPB in either group. However, HBFI tended to be higher for mild hypothermic than normothermic CPB, particularly in the post-CPB period (P = 0.575).
Changes in systemic versus hepatosplanchnic DO2I, 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.
In both groups, systemic 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 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).
Both hepatic venous and arterial HA concentrations at the pre-CPB period were similar to the values reported previously by Bentsen et al. (17) and Engström-Laurent et al. (18), with the hepatic venous HA concentrations being approximately two thirds of the arterial levels (Table 3). Both hepatic venous and arterial HA concentrations showed an approximately threefold increase at 60 min after the start of CPB (P < 0.05) in both groups. These increases were followed by steady-state plateaus until 10 min after the separation from CPB. Both arterial and hepatic venous HA concentrations returned to the pre-CPB levels 6 h after ICU admission. However, 1 day after admission to the ICU, irrespective of the temperature management, arterial HA concentrations were slightly but significantly larger compared with the pre-CPB control values (P < 0.05). On the same day, hepatic venous HA concentrations also were higher for normothermic CPB compared with the pre-CPB control values (P < 0.05). In addition, the difference between arterial and hepatic venous HA concentrations increased during the course of the observation period and was larger for normothermic than for mild hypothermic CPB (P = 0.040). This difference was significant at 60 min after separation from CPB (P < 0.05).
During the pre-CPB period, the estimated hepatosplanchnic uptake of HA was similar to that reported for the isolated, perfused rat liver (19) and also the extraction ratio for the human liver (17). The hepatosplanchnic uptake of HA was increased approximately twofold during CPB in both groups and was higher for normothermia than mild hypothermia (P = 0.041). This was significant after CPB (P < 0.05). The HA extraction ratio, however, remained unchanged in both groups (Fig. 3).
Arterial blood glucose concentrations were larger with mild hypothermic than normothermic CPB during the course of the observation periods (P = 0.044; Table 2). Both arterial and hepatic venous lactate concentrations also tended to be larger with mild hypothermic CPB. However, the hepatosplanchnic lactate uptake did not change for normothermic and mild hypothermic CPB. Although with mild hypothermic CPB the hepatosplanchnic lactate extraction ratios experienced negative values in the range of -5% to -10%, 10 min and 60 min after the cessation of CPB and 6 h after admission to the ICU (Fig. 3), they did not differ between the groups (P = 0.166).
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
We hypothesized that CPB in humans, with its associated hepatosplanchnic desaturation, results in SEC dysfunction, even in the absence of any clinical abnormalities in hepatocyte function. We showed that hepatosplanchnic desaturation and increases of serum HA, a sensitive indicator of SEC function, occurred during normothermic and mild hypothermic CPB without any major abnormalities in postoperative liver function tests. In addition, we presented data suggesting that SEC function might be impaired during and after normothermic and mild hypothermic CPB. However, we could not document the effect of CPB temperature on changes in ShvO2 or serum HA levels. Of more importance, a direct link between hepatosplanchnic desaturation and increases of serum HA concentrations could not be detected. However, hepatosplanchnic 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 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
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
Phenylephrine (an 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 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.
This work was supported by the institutional research fund of Saitama Cardiovascular and Pulmonary Center. We thank Mr. Kamiyashiki and Mr. Someya for their technical assistance (Division of Medical Engineering in our institute).
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|