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J Thorac Cardiovasc Surg 1995;110:819-0828
© 1995 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Galveston, Tex.
Supported in part by a grant from the American Heart Association (92G-621).
Presented at the Surgical Infection Society Fourteenth Annual Meeting, April 27-31, 1994, Toronto, Ontario, Canada.
Received for publication Sept. 2, 1994. Accepted for publication Dec. 22, 1994. Address for reprints: Joseph B. Zwischenberger, MD, Cardiothoracic Surgery, University of Texas Medical Branch, Galveston, TX 77555-0528.
Abstract
Impaired gut mucosal perfusion has been reported during cardiopulmonary bypass. To better define the adequacy of gut blood flow and oxygenation during cardiopulmonary bypass, we measured overall gut blood flow and ileal mucosal flow and their relationship to mucosal pH, mesenteric oxygen delivery and oxygen consumption in immature pigs (n = 8). Normothermic, noncrossclamped, right atrium–to–aorta cardiopulmonary bypass was maintained at 100 ml/kg per minute for 120 minutes. Animals were instrumented with an ultrasonic Doppler flow probe on the superior mesenteric artery, a mucosal laser Doppler flow probe in the ileum, and pH tonometers in the stomach, ileum, and rectum. Radioactive microspheres were injected before and at 5, 60, and 120 minutes of cardiopulmonary bypass for tissue blood flow measurements. Overall gut blood flow significantly increased during cardiopulmonary bypass as evidenced by increases in superior mesenteric arterial flow to 134.1%±8.0%, 137.1%±7.5%, 130.3%±11.2%, and 130.2%±12.7% of baseline values at 30, 60, 90, and 120 minutes of bypass, respectively. Conversely, ileal mucosal blood flow significantly decreased to 53.6%±6.4%, 49.5%±6.8%, 58.9%±11.6%, and 47.8%±10.0% of baseline values, respectively. Blood flow measured with microspheres was significantly increased to proximal portions of the gut, duodenum and jejunum, during cardiopulmonary bypass, whereas blood flow to distal portions, ileum and colon, was unchanged. Gut mucosal pH decreased progressively during cardiopulmonary bypass and paralleled the decrease in ileal mucosal blood flow. Mesenteric oxygen delivery decreased significantly from 67.0±10.0 ml/min per square meter at baseline to 42.4±4.6, 44.9±3.5, 46.0±3.6, and 42.9±3.9 ml/min per square meter at 30, 60, 90, and 120 minutes of bypass. Despite the decrease in mesenteric oxygen delivery, mesenteric oxygen consumption increased progressively from 10.8±1.4 ml/min per square meter at baseline to 13.4±1.2, 15.9±1.2, 16.7±1.4, and 16.6±1.54 ml/min per square meter, respectively. We conclude that gut mucosal ischemia during normothermic cardiopulmonary bypass results from a combination of redistribution of blood flow away from mucosa and an increased oxygen demand. (J THORACCARDIOVASCSURG1995;110:819-28)
Despite advances in cardiopulmonary bypass (CPB) management, patients undergoing CPB are at risk for the development of postperfusion systemic inflammatory response syndrome and multiorgan dysfunction syndrome. In their most pronounced forms, systemic inflammatory response syndrome and multiorgan dysfunction syndrome may be manifested as pulmonary, renal, and gastrointestinal tract dysfunction and hemodynamic instability in the postoperative period.
1 The initiation of these responses is often attributed to whole-body inflammatory reactions caused by extensive blood-surface interactions, 2 activation of the complementsystem and polymorphonuclear leukocytes, 3,4 oxygen free-radical generation, 5 and release of cytokines. 6,7
Recently, the development of systemic inflammatory response syndrome and multiorgan dysfunction syndrome in critically ill patients has been attributed to pathophysiologic changes in the gut. 8 Gut ischemia can jeopardize the integrity of the mucosal barrier and increase the prevalence of bacterial translocation and endotoxin absorption from the gut. 9,10 Meanwhile, impaired mucosal perfusion has been reported during experimental and clinical CPB with the use of laser Doppler flowmetry. 11-14 Fiddian-Green and Baker, 15 with use of gastrointestinal tract tonometers to show a decrease in gastric mucosal pH, an indicator of gut mucosal ischemia, positively correlated gastric mucosal hypoperfusion with increased infections and gastrointestinal tract complications after cardiac operations. In contrast, early work on regional perfusion during extracorporeal circulation with the venous outflow 16 and microsphere 17 techniques showed an increase in blood flow to the gut in canine and primate models, yet gut oxygen consumption (VO2) was decreased in the canine model, suggesting shunting of blood flow away from the metabolically active gut mucosa.
Changes in gut organ blood flow and VO2 during CPB have not been quantitatively defined. Hypothermic CPB has been shown to cause an initial decrease in gut VO2 followed by a subsequent increase with rewarming. 13 The relationship between total gut or mucosal blood flow and gut metabolism is important in understanding the mechanism of postperfusion systemic inflammatory response syndrome and multiorgan dysfunction syndrome and in seeking efforts to reduce the associated morbidity and mortality. In the present study, we investigated the effects of normothermic CPB on total mesenteric blood flow, fractional blood flow to different regions of the gut, gut mucosal pH, and mucosal blood flow and their relationship to gut VO2.
MATERIALS AND METHODS
The experimental protocol was approved by the Animal Care and Use Committee of the University of Texas Medical Branch, Galveston, Tex. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).
Studies were done in eight female immature Yorkshire pigs weighing 25.6 ± 4.3 kg. After an overnight fast, pigs were sedated with intramuscular ketamine (7.5 mg/kg) and the lungs mechanically ventilated with 2.0% to 2.5% isoflurane after endotracheal intubation. The pigs were then instrumented with femoral arterial and venous catheters and a pulmonary arterial catheter with an on-line O2 saturation probe tip (Opticath, Abbott, Mountain View, Calif.). A left flank incision allowed retroperitoneal exposure of the superior mesenteric artery (SMA) and a transit-time ultrasonic flow probe (Transonic, Ithaca, N.Y.) was placed on the vessel at its origin from the abdominal aorta. Through the same incision, intraperitoneally, a purse-string suture was made on a tributary mesenteric vein through which an infant feeding catheter was placed at a length of 15 to 20 cm to reach the portal vein for retrieval of blood samples. A laser Doppler flow probe (LDF 1000, Transonic) was placed directly on the ileal mucosa via an antimesenteric enterotomy with the laser sensor secured facing the mucosa. An intestinal tonometer (Tonometrics, Bethesda, Md.) was placed into the lumen of the distal ileum through the same enterotomy. Tonometers were also guided into the stomach (per os) and rectum (per rectum). A 30-minute stabilization period was allowed before baseline systemic and splanchnic hemodynamic values and arterial, mixed venous, and portal venous blood gas measurements were recorded.
Beef lung heparin (400 IU/kg, Upjohn, Kalamazoo, Mich.) was given for systemic heparinization, followed by subsequent administrations to maintain the activated clotting time (model 400, Hemochron, Edison, N.J.) greater than 450 seconds. Normothermic, nonpulsatile, noncrossclamped CPB was initiated with two-stage single venous cannulation (34F, Bard, Tewksbury, Mass.) and aortic arch perfusion (21F, Argyle, St. Louis, Mo.). A membrane oxygenator with an integral heat exchanger (Plexus, Irvine, Calif.), a roller pump (model 5000, 3M/Sarns, Ann Arbor, Mich.), and an in-line arterial filter (Pall, Fajardo, Puerto Rico) were used in the perfusion circuit (Tygon, Akron, Ohio). The CPB circuit was primed with 1000 ml Plasmalyte solution (Baxter, Deerfield, Ill.) and 500 ml 6% hetastarch (Du Pont, Wilmington, Del.). CPB flow was maintained at 100 ml/kg per minute to keep the mixed venous oxygen saturation (SvO2) greater than 70% per the protocol. Standard perfusion parameters of SvO2, mean arterial pressure, central venous pressure, and hematocrit were measured at 30, 60, 90, and 120 minutes of CPB. Blood flow and gastrointestinal tract mucosal pH measurements were also recorded at baseline and every 30 minutes during CPB. No vasoactive drugs or blood were used. At the end of the 120-minute bypass period, animals were killed with 10 ml intravenous saturated KCl.
Mean arterial and central venous pressures were measured with the use of transducers (P23, Statham Gould, Oxnard, Calif.) connected to a multichannel pen recorder (model 7758, Hewlett-Packard, Waltham, Mass.). Cardiac output was determined by the thermodilution technique with a cardiac output computer (Oximetrix 3, Abbott, North Chicago, Ill.). Arterial, mixed venous, and mesenteric venous blood gas values were measured with a blood gas analyzer and Co-Oximeter (system 1302 and model 282, Instrumentation Laboratory, Lexington, Mass.) and corrected to the animal's temperature.
Gut oxygen delivery (DO2) and VO2 were determined by the following equations:
where SaO2 and SpO2 are the arterial and portal blood O2 saturation (percentage), PaO2 and PpO2 are the arterial and portal blood O2 partial pressures (millimeters of mercury), Hgb is the hemoglobin concentration (grams per deciliter), Qm is the SMA blood flow (liters per minute), and SA is the body surface area (square meters).
Mucosal pH was calculated on the basis of the measurement of the CO2 tension (PCO2) from samples of saline solution in the silicone balloon catheters positioned in the lumen of the stomach, ileum, and rectum. The silicone balloon, which is permeable to CO2, is filled with saline solution. Because CO2 is a readily diffusible gas, PCO2 of the saline solution in the silicone balloon equilibrates with the intraluminal PCO2 of that intestinal segment, which, in turn, is in equilibrium with the PCO2 of the mucosa. 15 Samples of the saline solution were allowed to equilibrate with the mucosa for 30 minutes, and tonometrically measured PCO2 and the concomitantly measured arterial [HCO3-] concentration were then substituted into the Henderson-Hasselbalch equation to obtain the mucosal pH value at baseline and every 30 minutes during CPB as follows:
where [HCO3-] is the arterial bicarbonate concentration (milliequivalents per liter); PCO2 is that value measured in the aliquot obtained from the tonometer equilibrating balloon.
Blood flow to specific regions of the splanchnic viscera was measured by the radioactive microsphere technique. 18 Four different isotopes were used in each animal to determine fractionated blood flow at different time points. Microspheres (15 ± 3 µm diameter) labeled with 141Ce, 85Sr, 95Nb, and 46Sc were suspended in 10% dextran with polysorbate 80 (Tween 80, DuPont, Boston, Mass.). They were injected into the left atrium (at baseline) and arterial cannula at 5, 60, and 120 minutes of CPB. Calibration of blood flow was done by withdrawing a reference sample of aortic blood at 7.5 ml/min starting just before injection of the microspheres and continuing for 3 minutes. Approximately 4 to 8 x 106 microspheres were injected with each measurement. This ensured that at least 400 microspheres per gram were lodged in most tissue samples or in the arterial reference for a 95% confidence of an error less than 10%. Blood flow to right and left kidneys was commpared to confirm adequate aortic mixing of microspheres during injection.
At autopsy, multiple full-thickness wall tissue samples (2 x 2 cm) were taken from stomach, duodenum, jejunum, ileum, and colon. All the tissue samples were placed into preweighed polypropylene tubes together with the reference blood samples. Individual isotope activities were determined by a gamma counter (model A5550, Packard, Laguna Hills, Calif.). Blood flow was calculated by the following formula and is reported as milliliters per minute per 100 grams of tissue:
where Qt is tissue blood flow (milliliters per minute per 100 grams tissue), Mt is microsphere radioactivity in the tissue sample (counts per minute), Qref is the withdrawal rate of the aortic reference sample (milliliters per minute), Mref is the microsphere radioactivity in reference blood samples (counts per minute), and Wt is the sample weight (grams).
Data are expressed as mean plus or minus the standard error of the mean and were displayed and analyzed by SigmaPlot and SigmaStat programs (Jandel Scientific, San Rafael, Calif.). Comparisons with baseline values were made by one-way analysis of variance with Dunnett's test, with time treated as a repeated measurement factor. Significance was accepted with p < 0.05.
RESULTS
The main physiologic variables during CPB are summarized in Table I. During CPB at a flow rate of 100 ml/kg per minute, mean arterial pressure was maintained higher than 50 mm Hg and SvO2 higher than 70%, as dictated by the experimental protocol. The expected hemodilution occurred and the hematocrit value was maintained higher than 15%.
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Table II. Baseline blood flow to the duodenum, jejunum, ileum, and colon was 40.4 ± 5.9, 47.9 ± 13.3, 42.7 ± 7.9, and 35.4 ± 7.2 ml/min per 100 grams of tissue, respectively. Blood flow significantly increased in the proximal portions of the gut, the duodenum and jejunum, during CPB, whereas it remained unchanged in the distal portions, the ileum and colon.
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An increase in mucosal permeability has been implicated for translocation of bacteria and endotoxins and subsequently for contributing to the systemic inflammatory response syndrome and multiorgan dysfunction syndrome in patients undergoing CPB. 8 The intestinal mucosal barrier consists of mucoid secretions and proliferative epithelial cells with tight intercellular junctions. The barrier is characterized by its relative impermeability to most solutes and active transport mechanisms of selected ones. 19 This barrier, along with other functions, prevents bacteria and their endotoxins from entering the portal and systemic circulation.
Our earlier 11,12 and present studies have shown that normothermic CPB is associated with gut mucosal ischemia despite "adequate" global perfusion: there is normal or even increased overall blood flow through the SMA, but the gut mucosa remains ischemic, as evidenced by mucosal blood hypoperfusion measured by laser flowmetry and mucosal acidosis measured by tonometry. Coinciding with this observation are results of clinical studies that show similar evidence of gut mucosal ischemia during CPB. Fiddian-Green and Baker, 15 using the orogastric tonometer, reported a 50% prevalence of mucosal acidosis as manifested by a decrease in gastric mucosal pH values from 7.52 before CPB to less than 7.32 by the end of CPB in 85 patients. Andersen and associates 20 found that the gastric mucosal pH in 10 patients decreased from 7.45 before CPB to 7.30 at 1 hour after CPB. In a series of eight patients, Niinikoski and Kuttila 21 showed that the gastric pH decreased progressively during cardiac operation and remained low after operation. In 10 patients undergoing coronary artery bypass grafting Ohri and associates 14 measured a 51% decrease in gastric mucosal blood flow with the use of laser Doppler flowmetry, a finding similar to our experimental data. Although gut mucosal ischemia during CPB is demonstrated in immature swine in our studies, the trend to or severity of mucosal ischemia and acidosis in adult patients undergoing cardiac operations in the studies cited is similar.
Our present study demonstrates that mucosal ischemia during normothermic CPB results from the combination of mucosal hypoperfusion and increased gut VO2. With the measured increase in overall gut blood flow, mucosal hypoperfusion is likely to be the result of mucosal vasoconstriction and blood redistribution away from the mucosa. A host of vasoactive substances (hormones, autacoids, and cytokines) are known to be released or altered during CPB that can potentially affect regional blood flow at the macrocirculatory and microcirculatory levels, 22 and these substances can also be candidates for vasoconstriction of gut mucosa. Main vasoconstrictors that have been shown to be released during CPB include vasopressin, 23 catecholamines, 24 andthromboxane A2 and B2. 25,26 In a model of experimental CPB identical to that of the current study, our group found elevated levels of a highly vasoconstrictive thromboxane compound in association with the decrease in mucosal blood flow. 11 CPB in human beings is associated with an increase in circulating tumor necrosis factor formation that can activate other vasoactive substances. 7 Initiation of CPB is alsoassociated with activation of complement (C3a and C5a), 27 which causes vasoconstriction and increased capillary permeability. 28 Loss of pulsatility in the renal arteries and low perfusion can trigger the renin-angiotensin-aldosterone system and lead to increased production of angiotensin II, 29,30 which is also a potent splanchnic vasoconstrictor. Antagonists of such vasoconstrictive mediators and the effect of pulsatile blood flow during CPB on mucosal perfusion, therefore, warrant further studies.
Increased gut VO2 was another contributing factor to mucosal ischemia in our study. During normothermic CPB, gut VO2 progressively increased despite the decrease in gut DO2. Increased total body VO2 and a higher metabolic rate have been shown in patients after cardiac operations. 31-34 Such changes inVO2 may be a result of inflammatory responses initiated during CPB. Hypothermia, however, may diminish this response. Indeed, during experimental hypothermic CPB, 13 gutVO2 initially decreased when the animal was cooled, but surged to 33% higher than the baseline value during rewarming.
Studies on the DO2-VO2 relationship have shown that VO2 is independent of DO2 as long as the DO2/VO2 ratio is higher than a critical value, below which anaerobic metabolism occurs and VO2 decreases concomitantly with DO2. 35,36 Measurements of DO2 and VO2 with instrumentation similar to that used in the present study suggested that the critical value of the DO2/VO2 ratio is approximately 1.3 for the whole body and 1.5 for the gut, and these ratios increased to 1.9 and 2.2, respectively, during experimental sepsis. 37 Sepsis also increases total body and gut VO2 itself. 37,38 During CPB, theabrupt decrease in O2 delivery because of hemodilution coupled with increased oxygen demand could result in pathologic oxygen supply dependency that will limit the increase in VO2. 39 In our model of normothermic bypass, the gut DO2/VO2 ratio remained greater than 2.9 and VO2 increased progressively throughout the course of CPB, suggesting high gut metabolism, probably as a result of an inflammatory response. Such inflammatory responses and their effect on the gut DO2-VO2 relationship during CPB remain to be further defined. In addition, hypothermic CPB, with its effect on reducing the oxygen demand of the gut tissue, may partially protect the gut from mucosal ischemia.
The gut lumen is a rich source of gram-negative bacteria that constantly release lipopolysaccharide from their outer membrane; these endotoxins normally cannot cross the mucosal barrier because of their relatively large molecular size. Even if some small amounts cross, they are efficiently scavenged by the reticuloendothelial system. Mucosal ischemia occurring during CPB may greatly increase mucosal permeability. 14,40 Increased mucosal permeability, along with a known dysfunction of the hepatic reticuloendothelial system 41 and the systemic immunosuppression 42 associated with CPB, may allow bacteria and particularly smaller endotoxins to enter the portal and systemic circulation. In turn, bacteremia or endotoxemia, or both, exacerbate mucosal ischemia and promote translocation 43,44 and further increase themetabolic demand for oxygen in splanchnic organs. 45 This hypothesis is supported by the fact that endotoxin levels during CPB are preferentially higher in the blood of the splanchnic circulation, 20 and the degree of mucosal acidosis during CPB correlates well with the risk for subsequent complications or death. 46
In summary, the present study demonstrates significant gut mucosal ischemia during normothermic CPB despite normal indices of global perfusion. Factors that contribute to mucosal ischemia include redistribution of blood flow away from the mucosa, possibly because of regional vasoconstriction, and increased total gut metabolism. Gut mucosal ischemia during CPB may lead to mucosal barrier malfunction and translocation of bacteria or endotoxins, or both, causing postperfusion systemic inflammatory response syndrome and multiorgan dysfunction syndrome. Strategies to effectively reduce redistribution of intestinal blood flow during CPB may decrease the resultant morbidity and mortality in patients at high risk.
Footnotes
From the Departments of Surgerya and Anesthesiology,b University of Texas Medical Branch, Galveston, Tex. 
References
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G. E. Hill The Inflammatory Response to Cardiopulmonary Bypass-- Should It Be Treated? Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 229 - 235. [Abstract] [PDF]
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M. Tofukuji, G. L. Stahl, C. Metais, M. Tomita, A. Agah, C. Bianchi, M. P. Fink, and F. W. Sellke Mesenteric dysfunction after cardiopulmonary bypass: role of complement C5a Ann. Thorac. Surg., March 1, 2000; 69(3): 799 - 807. [Abstract] [Full Text] [PDF]
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D. J. Cook Changing Temperature Management for Cardiopulmonary Bypass Anesth. Analg., June 1, 1999; 88(6): 1254 - 1254. [Full Text] [PDF]
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R. M. FCPS, A. Samenesco, D. Royston, and A. Rees Cardiopulmonary effects of 7.2% saline solution compared with gelatin infusion in the early postoperative period after coronary artery bypass grafting J. Thorac. Cardiovasc. Surg., January 1, 1998; 115(1): 178 - 189. [Abstract] [Full Text] [PDF]
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C. O'Dwyer, L. C. Woodson, B. P. Conroy, C. Y. Lin, D. J. Deyo, T. Uchida, and W. E. Johnston Regional Perfusion Abnormalities With Phenylephrine During Normothermic Bypass Ann. Thorac. Surg., March 1, 1997; 63(3): 728 - 735. [Abstract] [Full Text]
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