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Ann Thorac Surg 2003;75:1558-1564
© 2003 The Society of Thoracic Surgeons

Original article: cardiovascular

Influence of prolonged cardiopulmonary bypass times on splanchnic perfusion and markers of splanchnic organ function

Bernhard Kumle, MDa, Joachim Boldt, MDa*, Stefan W. Suttner, MDa, Swen N. Piper, MDa, Andreas Lehmann, MDa, Markus Blome, MDb

a Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany
b Cardiac Surgery, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany

Accepted for publication November 25, 2002.

* Address reprint requests to Dr Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr 79, D-67063 Ludwigshafen, Germany.
e-mail: boldtj{at}gmx.net


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
BACKGROUND: Cardiopulmonary bypass (CPB) is known to have considerable negative impact on perfusion and organ function. The effects of the duration of CPB on markers of splanchnic organ function was studied.

METHODS: Consecutive patients undergoing elective aorto-coronary bypass grafting with CPB times (CPBT) of either less than 70 minutes (n = 15) or more than 80 minutes (n = 15) were prospectively studied. Splanchnic perfusion was assessed by measuring arterial and gastric mucosal PCO2and calculating PCO2gap. Hepatic function was evaluated by monoethylglycinexylidide (MEGX) test and by measuring {alpha}-glutathione S-transferase ({alpha}-GST). Concentration of pancreatitis-associated protein was measured to assess pancreatic integrity. Measurements were performed after induction of anesthesia, at the end of surgery, 4 hours after arrival in the intensive care unit, and on postoperative day 1.

RESULTS: The mean (± standard deviation) CPBT were 54 ± 12 minutes and 99 ± 16 minutes, respectively. PCO2gap increased significantly more in the group with CPBT of more than 80 minutes than in that with CPBT of less than 70 minutes, at +15 ± 4 mm Hg versus +8 ± 3 mm Hg, respectively, indicating reduction in splanchnic perfusion by longer CPBTs. Postoperative MEGX concentrations were significantly lower and postoperative {alpha}-GST concentrations were significantly higher in the group with CPBT of more than 80 minutes than in that with CPBT of less than 70 minutes. Plasma levels of pancreatitis-associated protein remained similar in both groups throughout the study period.

CONCLUSIONS: In our patients with CPBT of more than 80 minutes, splanchnic perfusion and hepatocelluar integrity were moderately affected, whereas pancreatic function remained almost unchanged. Studies including a larger patient population are necessary to assess whether protective approaches would be helpful in patients undergoing complex cardiac surgery with very long CPBT.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
The number of patients undergoing cardiac surgery with cardiopulmonary bypass (CBP) has rapidly increased. Perfusion deficits are a possible risk in the development of postbypass organ dysfunction. Postoperative complications such as hematologic, renal, cardiac, neurologic, and pulmonary complications have been widely discussed [1]. Although gastrointestinal complications may have a low incidence (0.3% to 3%), they are associated with a high mortality (13% to 63%) [2, 3]. Several risk factors (eg, use of vasopressors, preexisting comorbidities, perioperative hypotensive episodes, and valve surgery) have been evaluated for the development of alterations in gastrointestinal organ function. Whether prolonged CBP time is a trigger for changes in the gastrointestinal function is controversial [4, 5]. Conventional liver function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), {gamma}-glutamyltransferase, and bilirubin are nonspecific and assess hepatobiliary injury rather than liver dysfunction [6]. In addition, these enzymes are not distributed uniformly throughout the liver. The highest concentrations were found in periportal areas of the liver; however centrilobular areas, which are relatively deficient in ALT and AST levels, are most susceptible to damage from hypoxia [7]. The cytosolic liver enzyme {alpha}-glutathione S-transferase ({alpha}-GST) is a more sensitive marker of hepatocellular damage and has been used as an indicator to identify rapid changes in hepatocellular integrity [8]. The monoethylglycinexylidide (MEGX) test is a test for quantitative assessment of liver function [9]. This test has been shown as a suitable tool for clinical evaluation of liver function after hypovolemic shock and as a predictor of multiple organ failure in intensive care patients [10]. Gastric mucosal tonometry has been used for assessing splanchnic perfusion in various clinical settings [11]. Measurement of the regional gastric carbon dioxide tension (PrCO2) as well as calculation of the difference between intramucosal and arterial PCO2 [P(r-a)CO2] may provide additional information about blood flow in the splanchnic area [12]. Pancreatitis associated protein (PAP) is a nonenzymatic secretory protein that is normally almost undetectable but is overexpressed by the pancreas during acute phase of pancreatitis in rats and humans [13, 14]. It might therefore serve as a sensitive marker of impaired pancreatic function.

The combination of {alpha}-GST concentrations, MEGX test, gastric tonometry, and PAP concentrations might provide valuable information about organ function and blood flow in the splanchnic area. The aim of the present study was to quantify changes in markers of splanchnic organ function in patients undergoing cardiac surgery with regard to CPB time (CPBT).


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Patient recruitment
After approval of the study by the local ethics committee and after obtaining informed consent, consecutive patients undergoing elective aorto-coronary artery bypass grafting with expected CPBT of less than 70 minutes, as well as those with CPBT of more than 80 minutes, were prospectively studied. A patient with CPBT of 70 to 80 minutes was dropped from the study and replaced by another patient. After 15 patients were included in each group the study was finished. Exclusion criteria were renal insufficiency (serum creatinine >1.5 mg/dL), New York Heart Association class III to IV, valve disease, unstable angina pectoris, history of known liver disease or preexisting liver dysfunction (ALT/AST >20 IU/L), insulin-dependent diabetes mellitus, and alcohol or drug abuse. In addition, patients who were undergoing reoperation were excluded. No corticosteroids or nonsteroidal antiinflammatory drugs were given throughout the investigation period.

Anesthesia and CPB
All patients were premedicated with flunitrazepam (1 to 2 mg/70 kg) 1 hour before induction of anesthesia. Anesthesia was induced with midazolam (0.07 mg/kg), sufentanil (1.5 µg/kg), and pancuronium bromide (0.1 mg/kg). Sufentanil infusion was continued with 1.5 µg · kg-1 · h-1 throughout the surgical procedure, and anesthesia was maintained with isoflurane, midazolam, and pancuronium. Ventilation was adjusted to keep SaO2 greater than 95% (continuous oximetry) and to maintain partial pressure of carbon dioxide (PaCO2) in the physiologic range. Routine intraoperative monitoring included continuous invasive measurement of mean arterial pressure, central venous pressure, and pulmonary artery pressure. Cardiopulmonary bypass was carried out using a nonpulsatile pump and membrane oxygenator. The circuit was primed with 1,500 mL of Ringer’s lactate solution. A standard "high dose" (Hammersmith) aprotinin regimen was used in all patients. Temperature was kept at mild hypothermia (esophageal temperature 32° to 34°C), a flow rate of 2 L · min-1 · m-2 was maintained, and perfusion pressure during CPB was kept between 50 and 70 mm Hg using norepinephrine infusion when necessary. When hemoglobin was less than 7 g/dL, packed red blood cells were given. During weaning from bypass, as much pump blood as necessary was infused to keep pulmonary capillary wedge pressure between 12 and 14 mm Hg. After termination of CPB, the residual blood remaining in the extracorporeal circuit was concentrated using a cell-saving device and the autologous blood was retransfused. Shed mediastinal blood was not retransfused in the postoperative period. Dobutamine was administered when mean arterial pressure was less than 60 mm Hg and cardiac index was less than 2.0 L · min-1 · m-2 despite sufficient volume infusion. The target for cardiac index was 2.5 to 3.0 L · min-1 · m-2. Norepinephrine was administered when systemic vascular resistance was less than 600 dynes · s-1 · cm-5 and mean arterial pressure was less than 60 mm Hg (target for systemic vascular resistance 600 to 1,000 dynes · s-1 · cm-5).

Postoperative treatment
All patients were transferred to the intensive care unit. Mechanical ventilation was continued for the following 4 hours at least. When hemodynamics were stable for 0.5 hour, temperature was more than 36°C, and the patient breathed spontaneously reaching adequate blood gases (PaO2 >70 mm Hg, PaCO2<50 mm Hg, and SaO2>95%), tracheal extubation was performed. Targets for use of vasopressors and inotropes in the intensive care unit were the same as perioperatively. Packed red blood cells and fresh frozen plasma were given to compensate if hemoglobin was less than 8 g/dL and to maintain sufficient hemostasis.

Measurements
Splanchnic perfusion
A nasogastric tube (tonometer TRIP-catheter, Tonometrics Datex/Instrumentarium, Helsinki, Finland) was inserted in all patients. The correct positioning of the tube was confirmed by aspiration of gastric fluid and auscultation over the gastric area after injection of approximately 30 mL of air. The PrCO2 was measured semicontinuously using the Tonocap monitor (Tonometrics Datex/Instrumentarium). The P(r-a)CO2(PCO2 gap) was calculated from systemic PaCO2 and PrCO2.

Liver function
To assess liver function, monoethylglycinexylidide (MEGX) formation test and serum levels of {alpha}-glutathione s-transferase ({alpha}-GST) were measured. The MEGX test was carried out by injection of 1 mg/kg lidocaine intravenously over 1 minute. Blood samples were obtained both before and 15 minutes after lidocaine administration. The MEGX concentration was determined using a fluorescence polarization immunoassay (TDx; Abbot, Wiesbaden, Germany). The concentration after 15 minutes was subtracted from the preinjection concentration to calculate the amount of MEGX produced in 15 minutes. Values of MEGX that are greater than 90 ng/mL are considered as normal, whereas values less than 50 ng/mL are considered to reflect impaired liver function [10]. Serum {alpha}-GST concentration was measured using the Enzyme Immunoassay Hepkit-Alpha Human GST-Alpha (Biotrin, Dublin, Ireland). This quantitative enzyme immunoassay is based on the sequential addition of sample, enzyme conjugate, and substrate to microtiter wells coated with anti–{alpha}-GST immunoglobulin G. The resulting color is proportional to the amount of {alpha}-GST in the sample. The reference range of {alpha}-GST is 0 to 7.5 µg/L. The intraassay coefficient of variation is less than 7%. In addition, activity of aminotransferases (ALT reference range 5 to 24 IU/L]), AST [reference range 5 to 19 IU/L]), and cholinesterase [reference range 3,000 to 9,000 IU/L] were measured by routine laboratory tests.

Pancreatic function
Pancreatic function was assessed by measuring PAP concentrations. Serum PAP concentrations (normal values in volunteers <50 µg/L) were determined using an enzyme-linked immunoassay (PancrePAP, Immundiagnostik, Bensheim, Germany). The intraassay variability of the procedure is 5% to 10%. Amylase (reference range 0 to 40 IU/L) and lipase (reference range 0 to 60 IU/L) were measured using routine laboratory methods.

Data points
All measurements were performed after induction of anesthesia (baseline), at the end of surgery, 4 hours postoperatively in the intensive care unit, and on postoperative day (POD) 1.

Statistical analysis
A formal sample size calculation was performed before the start of the study. The minimum clinically important difference was assumed to be a 25% decrease in MEGX formation. Assuming a standard deviation for MEGX values of up to 20 ng/mL from previous work, and using an {alpha} error of 0.05 (two-sided) and a type II error of 0.2, a minimum number of 14 patients per group was calculated. Data are given as mean ± standard deviation. Statistical analysis was performed with software package SPSS/PC+ (version 4.0; SPSS Inc, Chicago, IL). We used {chi}2 analyses with Fisher’s exact tests for categorical data if appropriate. A nonparametric test (Wilcoxon rank sum) was used for variables that were not normally distributed (Kolmogorov-Smirnov test). Continuous, normally distributed data were compared using paired and unpaired Student t tests or analysis of variance for repeated measures, followed by the Scheffé test). The Bonferroni correction was applied when multiple comparisons were made. Continuous, nonnormally distributed data were compared using the Wilcoxon test. Correlation analysis was used to evaluate correlation between changes in markers of splanchnic organ function and therapeutic interventions (eg, use of catecholamines) A p value of less than 0.05 was considered to be significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
A total of 42 consecutive patients with expected CPBT between less than 70 minutes and more than 80 minutes were screened. Of the 42 patients, 12 were not included because the CPBT were between 70 and 80 minutes. The mean (± standard deviation) CPBTs were 54 ± 12 minutes and 99 ± 16 minutes, respectively. Patients in the two CPBT groups were comparable with regard to biometric data, preoperative left ventricular ejection fraction, postoperative ventilation time, and outcome (Table 1). There were no significant differences in blood loss, urine output, or the use of crystalloids and colloids (gelatin). Use of allogeneic blood, blood products, and catecholamines was also comparable between the two groups (Table 2) and did not show a correlation with changes in markers of splanchnic organ function. One patient in the group with less than 80 minutes of CPBT died 10 days after surgery secondary to myocardial infarction.


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  		Table 1. Demographic Data and Data From Perioperative Period

 

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  		Table 2. Cumulative Peri- and Postoperative Fluid Management and Use of Catecholamines

 
The PCO2gap was normal at baseline (Table 3). However, the PCO2gap increased in both groups with the significantly higher increase in the group with CPBT of more than 80 minutes (+15 ± 4 mm Hg vs +8 ± 3 mm Hg in the patients with CPBT of less than 70 minutes).


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  		Table 3. Hemodynamics and Tonometric Data

 
Aspartate/aminotransferase showed a similar increase from baseline to POD 1 in both groups (Table 4). Cholinesterase decreased significantly in both groups from baseline to POD 2 (Table 4). Both {alpha}-amylase and lipase values were also not different between the two groups (Table 4).


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  		Table 4. Conventional Laboratory Data For Assessing Liver and Pancreas Function

 
The MEGX test was within normal range in both groups at baseline (Fig 1). The MEGX concentration was significantly lower in the group with CPBT of less than 80 minutes in the intensive care unit and on POD 1 than in the group with CPBT of less than 70 minutes. Postoperative {alpha}-GST concentrations were significantly higher in the group with CPBT of more than 80 minutes than in that with CPBT of less than 70 minutes (Fig 1). On POD 1, {alpha}-GST concentrations were still slightly elevated from baseline data only in the group with CPBT of more than 80 minutes (9.3 ±3.4 µU/L vs 1.8 ± 1.8 µU/L in the group with CPBT of less than 70 minutes; p < 0.05) (Fig 2).



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  		Fig 1. Changes in monoethylglycinexylidide (MEGX; normal value >90 ng/mL) levels in the two study groups, expressed as box and whisker plots. Horizontal lines in boxes denote 25th, 50th, and 75th percentile values. Bars denote 5th and 95th percentile values. X with horizontal line denotes the 0th and 1st percentile values and the 99th and 100th percentile values, respectively. Open squares in boxes denotes mean values. (#p < 0.05, significantly different between groups.) (CPBT = cardiopulmonary bypass time; 4 hrs ICU = 4 hours postoperatively in intensive care unit; 1st POD = postoperative day 1.)

 


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  		Fig 2. Changes in {alpha}-glutathione S-transferase ({alpha}-GST; normal value 0 to 7.5 µg/L) in the two study groups, expressed as box and whisker plots. Horizontal lines in boxes denote 25th, 50th, and 75th percentile values. Bars denote 5th and 95th percentile values. X with horizontal line denotes the 0th and 1st percentile values and the 99th and 100th percentile values, respectively. Open squares in boxes denotes mean values. (#p < 0.05, significantly different between groups.) (CPBT = cardiopulmonary bypass time; 4 hrs ICU = 4 hours postoperatively in intensive care unit; 1st POD = postoperative day 1.)

 
Plasma levels of PAP were normal and were similar in both groups throughout the study period (Fig 3).



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  		Fig 3. Changes in pancreatitis-associated protein (PAP; reference range <50 µg/L) levels in two groups, expressed as box and whisker plots. Horizontal lines in boxes denote 25th, 50th, and 75th percentile values. Bars denote 5th and 95th percentile values. X with horizontal line denotes the 0th and 1st percentile values and the 99th and 100th percentile values, respectively. Open squares in boxes denotes mean values. (#p < 0.05, significantly different between groups.) (CPBT = cardiopulmonary bypass time; 4 hrs ICU = 4 hours postoperatively in intensive care unit; 1st POD = postoperative day 1.)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Several investigations provided evidence that intestinal organ function is altered during CPB. In a study by Ohri and colleagues [15], a 49% reduction in perfusion of gastric mucosa during hypothermic nonpulsatile CPB was reported. Altered splanchnic perfusion may initiate bacterial translocation and inflammatory mediator release [16] and promote multiorgan dysfunction [17]. Several authors have reported that a prolonged CPBT might be a significant risk factor for the development of postoperative gastrointestinal complications [5, 18]. In a prospective study of patients with CPBT of more than 100 minutes, a greater rise in gut permeability was demonstrated [15]. We decided to distinguish patients with CPBT of less than 70 minutes from those with CPBT of more than 80 minutes because it has been shown that inflammatory response was relatively small in CPBT of less than 70 minutes and increases significantly beyond 80 minutes of CPBT [19]. As the degree of inflammation appears to be correlated with alterations in organ function, CPBT of more than 80 minutes may affect splanchnic organ function more pronouncedly than CPBT of less than 70 minutes.

During CPB, total blood flow has been shown to decrease by approximately 20%, and hepatic arterial blood flow by 20% to 45% [20]. Gastric PCO2 tonometry has been promoted as a noninvasive measurement for assessing splanchnic perfusion in cardiac surgery [21]. Gastric mucosal hypoperfusion was detected with this method for at least 8 hours after cardiac surgery [22]. The gradient of PCO2 and PrCO2 (CO2gap) has been widely proposed as a marker of splanchnic perfusion [23]. Although the threshold for anaerobic metabolism has not been clearly defined, the upper limit of a normal PrCO2 gradient was set at approximately 8 mm Hg [24]. Postoperatively, the CO2gap was significantly higher in our patients with CPBT of more than 80 minutes than in the other group, indicating considerably reduced splanchnic perfusion by longer CPBT. On POD 1, no more differences in this marker of splanchnic perfusion were found.

Liver function is currently assessed by measurement of conventional liver enzymes that are released into the circulation secondary to hepatocellular damage. The most commonly used markers for altered liver function are AST, ALT, and cholinesterase. However, measurement of these enzymes lacks specificity, as a variety of other organs contain aminotransferases. The formation of the lidocaine metabolite MEGX has been proposed as a dynamic and flow-dependent assessment of liver function [10]. Lidocaine is rapidly metabolized by the liver through a first-pass, mixed-function oxidative process to form the metabolites MEGX and glycinexylidide. Formation of MEGX is mainly dependent on mixed-function oxidase capacity (cytochrome P450 system) within liver microsomes and hepatic blood flow. A MEGX value of more than 90 ng/mL was assumed to be an indicator of normal liver function [10]. We have found significantly faster metabolism of lidocaine in our group with CPBT of less than 70 minutes than in our patients with longer CPBT. The significantly lower MEGX concentrations in the intensive care unit and on POD 1 in the patients with CPBT of more than 80 minutes may indicate moderate alterations in hepatic organ function when CPBT is enhanced.

Another tool to assess liver function is {alpha}-GST. Advantages of using {alpha}-GST are a high cytosolic concentration (4% to 5% of total hepatocellular protein) and a short circulatory half-life (<90 minutes). Increased levels of {alpha}-GST may indicate disturbed hepatocellular integrity [8]. In our study the {alpha}-GST was significantly higher in the patients with CPBT of more than 80 minutes than in the patients with shorter CPBT, also indicating moderate alterations in hepatocellular integrity.

Fernandez-del Castillo and colleagues [25] found a 27% incidence of pancreatic cellular damage in a prospective study of 300 patients undergoing CPB. We measured PAP concentration because in the early phase of acute pancreatitis a strong correlation between PAP concentrations and pancreatitis severity has been described [26]. The PAP is synthesized on the rough endoplasmatic reticulum, then follows the normal secretory pathway through zymogen granules and is finally secreted in the acinar lumen [13, 14]. The PAP is present 6 hours after the onset of pancreatitis and the maximum level of PAP is expected after 24 hours. In our study, PAP concentration remained almost unchanged within the normal range in both groups. The {alpha}-amylase and lipase values were also not different between the groups. Thus it appears that either the mean bypass times of approximately 100 minutes did not affect pancreatic integrity or PAP is not sensitive enough to detect moderate alterations in pancreatic organ function.

The present study was not designed to detect a correlation between CPBT and outcome. The study population was also much too small to find correlations between CPBT and gross dysfunction of splanchnic organs such as mesenteric infarction, jaundice, or manifest pancreatitis. It would require a much larger patient population to conclude definitively that prolonged CPBT is associated with clinically relevant disturbances of splanchnic organ function. The true incidence of gastrointestinal complications might be underestimated in retrospective studies using conventional markers of splanchnic organ dysfunction. The markers that we used to detect alterations in splanchnic perfusion as well as hepatic and pancreatic function may by helpful to elucidate the importance of the duration of CPB with regard to its effects on the splanchnic system.

In all of our patients aprotinin was used according to the standard approach at our institution; thus any differences between the groups are unlikely due to aprotinin. However, because it is well established that aprotinin may beneficially affect inflammation, alterations in markers of splanchnic organ function after CPB may have been more pronounced in patients who were not treated with aprotinin.

In conclusion, we found moderate reductions in splanchnic perfusion associated with moderate disturbances of hepatocellular integrity in the patients with CPBT of more than 80 minutes as compared to patients with CPBT of less than 70 minutes. Further studies with a much larger patient population are required to confirm whether these findings might have an impact on the incidence of gastrointestinal complications and whether protective approaches exist, especially in patients undergoing complex cardiac surgery procedures with significantly prolonged CPBT.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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S. Hasan, C. Ratnatunga, C.T. Lewis, and R. Pillai
Gut ischaemia following cardiac surgery
Interactive CardioVascular and Thoracic Surgery, September 1, 2004; 3(3): 475 - 478.
[Abstract] [Full Text] [PDF]

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