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Ann Thorac Surg 2006;81:97-103
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Splanchnic Organ Injury During Coronary Surgery With or Without Cardiopulmonary Bypass: A Randomized, Controlled Trial

Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom

Accepted for publication June 10, 2005.

^_* Address correspondence to Dr Ascione, Bristol Heart Institute, Bristol Royal Infirmary, Bristol, BS2 8HW United Kingdom (Email: r.ascione{at}bristol.ac.uk).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: We investigated the efficacy of coronary surgery with or without cardiopulmonary bypass in protecting the function of the small intestine, liver, and pancreas.

METHODS: Patients were randomized to off-pump coronary artery bypass grafting (OPCAB) or coronary artery bypass grafting with cardiopulmonary bypass (CABG-CPB). Small intestine function was assessed by differential four sugars (O = methyl-D-glucose, D-xylose, L-rhamnose, and lactulose) permeability and absorption tests. Liver function was assessed by monoethylglycinexylidide/lidocaine ratios and by serial measurements of transaminases (aspartate transaminase and alanine-amino transferase), bilirubin, and alkaline phosphatase. Pancreatic function was assessed by serial measurements of insulin/glucagon ratio, amylase, and glucose. Forty patients were recruited (20 per group).

RESULTS: Permeability and absorption were more impaired in the OPCAB group immediately after surgery, but returned to baseline levels in both groups by postoperative day 5 (interaction of surgery type and time; p = 0.05 and p = 0.02, respectively). Monoethylglycinexylidide/lidocaine ratios were not different in the two groups. Aspartate transaminase and alanine-amino transferase levels were higher in the CABG-CPB group for the first postoperative day, but levels converged by day 3 (interaction of surgery type and time; p < 0.0001 and p = 0.04, respectively). The bilirubin level for the OPCAB group overshot the CABG-CPB group at 36 hours before returning to a similar level 60 hours postoperatively. Amylase levels were higher in the CABG-CPB group than in the OPCAB group (1.17 times; p = 0.03); other markers of pancreatic function showed no differences between the groups.

CONCLUSIONS: Early small intestine function is worse with OPCAB; all functions recover to similar levels in both groups by day 5. Conversely, pancreatic function is worse with the CABG-CPB group than with the OPCAB group. Hepatic metabolic function does not differ by type of surgery to the end of the operation. Postoperative hepatocellular injury was worse with the CABG-CPB group.

	Introduction

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The implications of using either off-pump coronary artery bypass grafting (OPCAB) surgery or conventional coronary artery bypass grafting with cardiopulmonary bypass (CABG-CPB) on most subsystem organ function has been widely investigated [1–2]. However, very little is known about the susceptibility of the splanchnic organs such as the small intestine, liver, and pancreas to ischemia and reperfusion injury in patients undergoing coronary surgery. Although the incidence of visceral complications is reported to be low [3], the in-hospital mortality in these patients was high at 15% to 63% [4–11].

Transient gut mucosal ischemia, shown by intramucosal acidosis [7], has been observed in 50% of patients undergoing cardiac operations; this may increase gut mucosal permeability, leading to the permeation of bacteria and endotoxin across the gut mucosal barrier [7]. Due to its location between the intestinal and systemic circulation, the liver should provide a clearing function for gut-derived bacteria and cytokines [8]. Hepatic dysfunction is believed to interfere with this mechanism [9].

Many factors are potentially implicated in the pathogenesis of gut, liver, and pancreas dysfunction when using cardiopulmonary bypass (CPB), including the decline of systemic vascular resistance, nonpulsatile flow, microemboli, and inflammatory activation [10–12]. The aim of this randomized controlled trial was to compare the effects of OPCAB and CABG-CPB on small intestine, liver, and pancreas injury.

	Material and Methods

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Patient Selection
Patients undergoing elective first-time coronary artery bypass grafting under the supervision of two consultants (RA and GDA) were eligible. Exclusion criteria included chronic liver or pancreatic disease, known gastrointestinal disease, left ventricular ejection fraction < 30%, recent myocardial infarction (< 1 week), renal and respiratory impairment, and peripheral vascular disease. Random treatment allocations were generated in advance of starting the study and were concealed in sequentially numbered, sealed, opaque envelopes; a participant was randomized by opening the next numbered envelope. The study was approved by the United Bristol Healthcare Trust Ethics Committee and all participants gave informed consent (reference number: E4717).

Anesthetic and Surgical Management
Anesthetic technique has been previously described [1]. In the CABG-CPB group, heparin was given at a dose of 300 IU/kg to achieve a target activated clotting time of 480 seconds or greater before commencement of CPB. Nonpulsatile flow was used. The flow rate throughout bypass was 2.4 to 2.6 L/m²/min, and systemic temperature varied from 32°C to 34°C. The surgical and perfusion techniques for the CABG-CPB patients were standardized as previously reported [1–2]. Myocardial protection was achieved with intermittent antegrade warm blood cardioplegia [2].

In the OPCAB group, heparin (100 IU/kg) was administered prior to the start of the first anastomosis to achieve an activated clotting time of 250 to 350 seconds. We used an established technique of exposure and stabilization [13].

At the end of surgery, patients were transferred to the intensive care unit (ICU) and managed according to protocols [1]. Patients were extubated when they met the following criteria: hemodynamic stability, no excessive bleeding (< 80 mL/hr), normothermia, and consciousness with pain control. Postoperative colloid or blood was given to maintain normovolemia and hematocrit > 24%.

On postoperative day 1, in accordance with the intensive care unit protocol, ß-blockers and antihypertensive drugs were re-started if clinically indicated (ie, heart rate > 55 bpm, systolic blood pressure > 110 mm Hg). Drinking, eating, and mobilization were also encouraged.

Small Intestine Function
Small intestine function was assessed by differential sugar permeability and absorption tests using a 5-hour urine analysis. These tests have been used in cardiac surgery [14], and have very high sensitivity [15]. A sugar solution (100 mL), containing 3 O = methyl-D-glucose (3 OMG; 0.2 g), D-xylose (0.5 g), L-rhamnose (1.0 g), and lactulose (5.0 g), was administered orally before and immediately after surgery, and 5 days postoperatively. The absorption and excretion characteristics of these sugars have been described [15].

For preoperative and day 5 assay the following steps were followed: starve for 8 hours, empty bladder, administer the sugars solution orally, and collect urine for 5 hours. For the immediate post-surgery assay, the steps were as follows: empty the stomach through the nasogastric tube, empty the urine bag, instil the sugars solution in the stomach through the nasogastric tube, clamp the nasogastric tube for 5 hours, and collect urine for 5 hours.

Analysis of urine was carried out using thin layer chromatography. The amount of each sugar excreted in the urine was measured and expressed as a percentage of the administered dose. Permeability was assessed as the ratio of lactulose to rhamnose excreted, and absorption was assessed as the ratio of rhamnose to 3 OMG excreted [15].

Liver Function
To assess liver function, monoethylglycinexylidide (MEGX) formation was measured at 15 and 30 minutes after intravenous injection of 1 mg/kg bolus of lidocaine (at a subtherapeutic dose), both prior to induction of anesthesia and at closure of the chest. Lidocaine levels were also measured, and the primary measure of liver function was the MEGX/lidocaine ratio. MEGX and lidocaine were determined by liquid-chromatography-tandem mass spectrometry. This test is very sensitive and is being used increasingly for research and routine clinical practice. It is able to detect subclinical impairment of liver function and has been advocated as a predictor of survival in chronic liver disease and of survival and multiple organ failure in surgical intensive care patients [16–17].

Measures of hepatocellular injury included transaminase activity (aspartate-amino transferase [AST] reference range, 5 to 35 IU/L; alanine-amino transferase [ALT] reference range, 5 to 35 IU/L), bilirubin (reference range, 3 to 17 µmol/L) and alkaline phosphatase (reference range, 30 to 300 IU/L). These markers were measured at baseline (0), and at 1, 12, 36, and 60 hours postoperatively.

Pancreas Function
Pancreatic damage was assessed by pancreas-specific amylase level (reference range, 0 to 40 IU/L), a recognized marker of acinar pancreatic cell function [18]. Serial measurements were made at baseline and 1, 4, 12, and 24 hours postoperatively. Pancreatic islet cell function was assessed at the same times by measuring the blood glucose level and plasma levels of immunoreactive insulin and glucagons, which were expressed as insulin/glucagon ratios.

Data Collection and Statistical Analysis
Intraoperative and postoperative data, including complications and adverse events were prospectively collected and recorded as previously reported [1–2]. Without taking into account repeated measures, the sample size (20 patients per group) meant the study had 80% power to detect an increase or decrease of 0.86 standard deviations on measures of small intestine permeability (ie, a large difference between groups) [19]. However, assuming a correlation of 0.7 between repeated measurements, the study had an effective sample size of about 60 per group and hence 80% power to detect an increase or decrease of 0.51 standard deviations.

The preoperative characteristics and clinical outcomes of patients were summarized. To avoid patients being dropped from the analysis, missing data were interpolated based on data for other patients in the same group. Data were then analyzed with mixed models (SAS, version 8; SAS Institute, Cary, NC), fitting the between subject factor of type of surgery (OPCAB vs CABG-CPB), the within subject factor of time (repeated measurements with increasing duration of time after completion of the operation), and the interaction of these two factors. Results are reported as ratios of levels of markers for the two groups, either as a common ratio across time points when there was no interaction or separately for each time point when there was an interaction (p < 0.10). The preoperative level of a marker was included in all models as a covariate, not as a level within the time factor.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Forty patients were recruited between January 2002 and April 2003 and were randomized to either (1) CABG-CPB (n = 20) or (2) OPCAB (n = 20). All patients received their allocated type of surgery, and no patient required conversion from OPCAB to CABG-CPB.

The preoperative characteristics of patients in the two groups are summarized in Table 1. The median numbers of grafts were 2.5 and 3.0 in the OPCAB and CABG-CPB groups, respectively (p = 0.03, Mann Whitney rank sum test). There were no in-hospital deaths, gastrointestinal, hepatic, pancreatic, neurologic, renal, infective, or pulmonary complications in either group. One patient in the OPCAB group suffered a perioperative myocardial infarction as per predefined criteria. There were no differences in the clinical outcomes (eg, complications, postoperative inotropes, and use of blood products) between the groups, but the study was not designed to detect such differences.

View larger version (20K): [in this window] [in a new window]   Fig 1. Small intestine function up to 5 days postoperatively in the coronary artery bypass grafting with cardiopulmonary bypass (CABG-CPB) and off-pump coronary artery bypass grafting (OPCAB) groups: (A) permeability ratios; (B) absorption index. Data are geometric means; error bars represent 95% confidence intervals. (Dotted lines = preoperative level.)

The AST, ALT, alkaline phosphatase, and bilirubin levels increased with hepatocellular injury. Analyses of both AST and ALT found significant interactions between group and time (p < 0.0001 and p = 0.03, respectively). For AST, mean levels for the CABG-CPB were significantly higher than for the OPCAB group at all, but the final time point (Table 2; Fig 2A). The mean ALT level was also significantly higher for the CABG-CPB than for the OPCAB group 1 hour after surgery, but not thereafter (Table 2). The pattern of changes in levels with time for alkaline phosphatase was similar to that observed for ALT. The OPCAB group had lower levels than the CABG-CPB group at 1 and 12 hours after surgery, but higher levels at 36 and 60 hours; the interaction approached significance, although the groups did not differ significantly at any time point (Table 2).

View larger version (20K): [in this window] [in a new window]   Fig 2. Liver injury up to 60 hours postoperatively in the coronary artery bypass grafting with cardiopulmonary bypass (CABG-CPB) and off-pump coronary artery bypass grafting (OPCAB groups): (A) aspartate-amino transferase (AST) levels; (B) bilirubin levels. Data are geometric means; error bars represent 95% confidence intervals. (Dotted lines = preoperative level.)

Pancreas Function
Amylase and glucose levels and the insulin/glucagon ratio increase with impaired pancreatic function. All three markers rose during the first 24 hours after surgery. Overall, amylase levels were slightly higher in the CABG-CPB than the OPCAB group (by 1.17 times; p = 0.03; Table 2). Glucose levels and insulin/glugacon ratios showed similar changes in both groups during the period of observation (Table 2).

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
There are four main findings of this study. First, small intestine function was poorer in the OPCAB than in the CABG-CPB group immediately after surgery, but both groups recovered to preoperative levels. Second, there were no immediate postoperative differences in intracellular liver function between the OPCAB and CABG-CPB groups, as assessed by the MEGX/lidocaine ratio. Third, during the first postoperative days, AST and ALT levels indicated that liver function was better protected in the OPCAB than in the CABG-CPB group. Fourth, amylase levels, but not glucose or glucagon/insulin ratios, suggested pancreatic function was worse for the CABG-CPB than the OPCAB group, and deteriorated in both groups over the first 2 to 3 postoperative days.

We believe the findings are valid. Allocation to surgical technique was randomized, preventing selection bias. The assays were carried out by laboratory staff blind to the surgical technique. The small sample size restricted the power of the study to detect small differences, and it is possible that some potentially important effects could have remained undetected.

Small Intestine Findings
The gut is a rich source of bacteria and endotoxins, which may cross the gut mucosal-barrier when mucosal permeability is increased. Endotoxinemia has been shown to occur during CPB, and its severity has been correlated with the duration of CPB and the cross-clamp time [20] period, potentially affecting the patient's recovery.

Our study showed that gut permeability increased more, and absorption decreased more, in the OPCAB than the CABG-CPB group at the end of the operation. A possible cause of the transient impairment seen in the OPCAB group might be the transient hemodynamic deterioration associated with coronary target exposure and positioning during OPCAB surgery [13]. However this effect does not seem to last, because permeability and absorption fully recovery in the OPCAB group by day 5 postoperatively.

Liver Findings
Hepatic dysfunction is currently believed to interfere with liver clearing function for gut-derived bacteria and cytokines [14, 16–17], leading to a spillover of endotoxins and bacteria, an important risk factor for systemic inflammatory response syndrome and subsequent multiple organ failure [4].

Subclinical impairment of liver function can be assessed using the MEGX test [9, 16–17]. The MEGX is formed by hepatic cytochrome P450 IIIA4 enzymes during first-pass metabolism [21]. We found no differences in the MEGX/lidocaine ratio between groups, suggesting that there was no immediate effect of surgical technique on hepatic function. The dynamic nature of metabolism of lidocaine and subsequent clearance of MEGX from the circulation makes it impossible to interpret the higher levels of the ratio post surgery.

Our study suggests that a larger hepato-cellular injury in the CABG-CPB group within the first 36 hours when assessed by the release of AST and ALT. Although changes in AST activity may also originate from myocardial injury, the magnitude of the difference in AST activity between groups was very large, and its hepatic origin was supported by the statistically significant difference also observed for the more liver-specific ALT activity. Although the results of AST and ALT activities seem to contradict those of MEGX/lidocaine ratio, they represent different time periods; in fact, the results were the same (ie, no difference) immediately after the operation (Table 2).

The changes in the levels of bilirubin we observed between groups were similar to those for AST, but the level for the OPCAB group overshot the CABG-CPB at 36 hours before returning to a similar value 60 hours after the operation. Levels of bilirubin and alkaline phosphatase remained within normal ranges throughout the observation period in both groups. These results contrast with those of Wang and colleagues [8], who demonstrated an incidence of postoperative hyperbilirubinemia in 35.1% of patients after conventional coronary surgery procedures. The different results may be explained by differences in CPB time. Kumle and co-workers [22] have demonstrated that serious liver dysfunction is mainly observed with prolonged CPB times, much greater than 70 minutes; in our CABG-CPB group, the mean CPB time was relatively short (approximately 70 minutes).

Pancreas Findings
Open-heart procedures could reduce metabolic activity in the pancreas as a result of hypothermia [23], reduced pancreatic blood flow [6], or release of stress hormones during and after nonpulsatile CPB [15]. Although pancreatic complications after CPB are infrequent, they are associated with high mortality [24].

In our study, amylase levels deteriorated more for the CABG-CPB than the OPCAB group, whereas no differences were observed for glucose or glucagon/insulin ratios. It has been reported that the insulin/glucagon molar ratio (rather than the absolute concentration of insulin and glucagon) is an important marker of protein anabolism or catabolism in surgical patients [23]. However, this ratio, together with blood glucose levels did not differ between the groups. Overall, pancreatic function worsened during the postoperative day 1, although levels of amylase and glucose always remained within normal ranges. Our results for the CABG-CPB group are in keeping with those reported in the literature. Paajanen and colleagues [18] reported significant hyperamylasemia after hypothermic cardiopulmonary bypass. Similar results have been recently reported by Kumle and associates [22] who also showed a higher release of amylase associated with a prolonged CPB time.

In conclusion, our study suggests that small intestine function shortly after surgery is worse with OPCAB than with CABG-CPB; all functions recover to similar levels in both groups by day 5. Conversely, pancreatic function is worse with CABG-CPB than with OPCAB. Hepatic metabolic function does not differ by type of surgery to the end of the operation. However, postoperative hepato-cellular injury is worse with CABG-CPB. Further studies are warranted to ascertain the effect of conventional and beating heart coronary surgery on splanchnic organ injury in high-risk patients.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The British Heart Foundation supported this project (project grant reference no.: PS/2000136). Mr Raimondo Ascione is supported by a 5-year Senior Lecturer Fellowship Grant by the Garfield Weston Trust. The authors would like to thank Professor M. Oellerich, Georg-August Universitat Gottingen, Germany, for carrying out the MEGX assays.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Raimondo Ascione Sudath Talpahewa Chanaka Rajakaruna Barnaby C. Reeves Gianni D. Angelini Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ascione, R. Articles by Angelini, G. D. Search for Related Content PubMed PubMed Citation Articles by Ascione, R. Articles by Angelini, G. D. Related Collections Minimally invasive surgery