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© 2002 International Anesthesia Research Society
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Abstract |
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Low gastric intramucosal pH (pHi) and an increased gastric-arterial PCO2 difference (CO2 gap) are markers of tissue hypoperfusion. Perfluorocarbons (PFCs) have a large oxygen-carrying capacity and release oxygen when encountering low tissue oxygen tension. Nine cardiac surgical patients instrumented for gastric tonometry were enrolled as part of a multicenter, randomized, single-blinded study of a PFC emulsion (perflubron emulsion [OxygentTM]). Patients were randomized to receive PFC (n = 4) or placebo (n = 5) after intraoperative autologous blood harvesting by acute normovolemic hemodilution. At baseline there were no intergroup differences in tonometric-, hemodynamic-, or oxygen delivery-derived variables, e.g., Control group (pHi, 7.37 ± 0.06; CO2 gap, 6.4 ± 1.3 mm Hg) versus PFC group (pHi, 7.38 ± 0.06; CO2 gap, 6.7 ± 1.5 mm Hg). After acute normovolemic hemodilution, pHi was significantly lower (P < 0.01) in the Control group (7.22 ± 0.25) than in the PFC group (7.44 ± 0.25), and CO2 gap was significantly higher (P < 0.001) in the Control group (23.4 ± 5.1 mm Hg) than in the PFC group (1.8 ± 0.8 mm Hg). These differences in tonometric variables persisted during surgery. The PFC group showed a significantly (P < 0.007) shorter time to first bowel movement postoperatively (2.0 ± 0.8 vs 5.4 ± 1.6 days). Time to consumption of solid food was also shorter in the PFC group and almost achieved statistical significance (P = 0.056).
IMPLICATIONS: This study suggests that the administration of perflubron emulsion prevents gastrointestinal tract ischemia in cardiac surgical patients and may preserve postoperative gastrointestinal tract function.
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Introduction |
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Perfluorocarbon (PFC) emulsions are oxygen-carrying solutions now in widespread clinical trials (1). One goal of the current clinical trials of PFCs is to reduce requirements for allogeneic blood transfusions. We believe that a potentially important use of PFCs relates to their theoretical ability to deliver oxygen to tissues with poor microcirculatory blood flow. Preclinical studies have been conducted that demonstrate the efficacy of PFCs for improving overall oxygenation status by increasing the overall oxygen solubility within the plasma compartment (2,3). These studies have shown that the amount of oxygen delivered by 1 dL of the PFC is approximately equivalent to the amount of oxygen delivered by 3 dL of whole blood (2,3). It is possible that the administration of PFCs may improve tissue oxygenation and reduce some types of organ dysfunction in high-risk surgical patients.
The splanchnic circulation contributes to the regulation of circulating blood volume and blood pressure in humans. Splanchnic ischemia/reperfusion in cardiac surgery may lead to an injury of the intestinal mucosa and induce a systemic inflammatory response, which can progress to multiple organ dysfunction syndrome, which is the leading cause of morbidity and mortality in the intensive care unit (4–11). In a prospective cohort study of 122 adults undergoing cardiac surgery with cardiopulmonary bypass (CPB), Grap et al. (12) reported that the incidence of postoperative gastrointestinal (GI) symptoms (i.e., poor appetite, nausea, and constipation) was 57%. The etiology of these symptoms is unknown; however, stress and injury of the GI tract during surgery are possible mechanisms (5,10).
Abnormal gastric tonometric variables are associated with the subsequent development of complications and increased length of stay (6,11,13,14). Gastric tonometry is the only clinically available US Food and Drug Administration-approved method for monitoring the GI system. The tonometer is a modified gastric tube with a balloon on the distal end that is permeable to CO2. After insertion into the stomach via the nose or mouth, air is instilled into the tonometer’s balloon. The balloon’s contents are subsequently withdrawn after a period of equilibration and assayed for the partial pressure of CO2 (PCO2) by using an infrared analyzer (for air tonometry). The PCO2 measured from the catheter balloon contents (PgCO2) is a reflection of the PCO2 of the gastric lumen and mucosa. GI hypoperfusion and mucosal acidosis lead to an increased PgCO2 out of proportion to the arterial PCO2 (PaCO2), thus creating a difference, or "gap" (PgCO2 - PaCO2). A gap >8 mm Hg is indicative of GI hypoperfusion (6,13).
At our institution, a PFC emulsion, OxygentTM (Alliance Pharmaceuticals Corp., San Diego, CA) was evaluated in a phase III multicenter (40 centers) trial for its efficacy as a temporary oxygen carrier in primary coronary artery bypass patients and for the avoidance of allogeneic red blood cell transfusions. For patients enrolled at our center, automated recycling air tonometry (Tonocap®; Datex-Ohmeda, Tewksbury, MA) was used to test the hypothesis that the administration of IV perflubron emulsion during cardiac surgery preserves gastric tonometric variables and therefore gastric motility.
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Methods |
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After IRB approval and informed consent were obtained, patients undergoing isolated primary coronary artery bypass grafting with CPB were enrolled in a prospective, randomized clinical trial. Exclusion criteria included age <18 yr, emergency surgery, renal dysfunction (defined as preoperative serum creatinine
2.0 mg/dL), and a concomitant surgical procedure, e.g., valve surgery. Patients were randomized by use of a closed-envelope technique. Randomization was produced with a fixed block size of four patients to ensure that equal proportions of patients were randomized to the PFC group and the Control group.
All patients underwent general anesthesia, which included the administration of etomidate, fentanyl, midazolam, cisatracurium, 100% oxygen, and isoflurane (0.2%–1.0%). An intraarterial catheter, a pulmonary artery catheter, and transesophageal echocardiography were used. Surgical techniques and CPB included a standard centrifugal pump, nonpulsatile flow, moderate hypothermia (32°C), and flow rates of 1.8–2.4 L · min-1 · m-2. The CPB machine circuit was primed with 1000 mL of crystalloid and 1000 mL of colloid. The transfusion trigger for red blood cells was 7 g/dL for both groups after CPB.
After the induction of general anesthesia and endotracheal intubation, a TRIP NGS Catheter (Datex-Ohmeda) was placed via the mouth into the stomach, its position was confirmed by aspiration of gastric contents, and its placement was secured by taping the apparatus to the patient. Measurements of regional PgCO2 were obtained at the same time as a corresponding arterial blood gas analysis. Measurements were obtained at the following time points: 1) after the induction of general anesthesia and placement of a TRIP NGS Catheter (baseline); 2) after acute normovolemic hemodilution (ANH) and the administration of either perflubron emulsion or lactated Ringer’s solution (LR), i.e., placebo (post-ANH); 3) immediately after the administration of protamine; and 4) 10 min after chest closure. Gastric tonometry is not validated in patients during CPB. All PaCO2 measurements were corrected for esophageal temperature by using an established equation, as described by Andritsch et al. (15) The gastric PgCO2 gap was calculated by subtracting the temperature-corrected PaCO2 from the gastric PgCO2 (PgCO2 - PaCO2). The intramucosal pH (pHi) was calculated according to the manufacturer’s guidelines (i.e., by inserting the values for gastric tonometry, PgCO2, and the arterial bicarbonate levels into a modified Henderson-Hasselbalch equation).
Because of logistical reasons, an individual who was not blinded to the study group assignment collected intraoperative data, including tonometric variables. However, all postoperative assessments (e.g., time to first bowel movement) were collected by an individual blinded to the study group assignment.
During the operative period, patients were randomized to one of two study arms. Both study groups underwent ANH, in which blood was removed from the patient and replaced in a 1:1 ratio with 5% albumin. The volume of blood removed was calculated to achieve a target hemoglobin concentration of 8 g/dL on CPB. The PFC group received IV perflubron emulsion (1.8 g PFC per kilogram) immediately after ANH, whereas the Control group received a placebo infusion of LR in the same volume (3 mL/kg). Of note, at the time point for tonometric measurements immediately after ANH (post-ANH), the only difference between groups was the administration of PFC.
The treated group also underwent additional blood harvesting immediately before the initiation of CPB (replaced in a 1:1 ratio with 5% albumin) to achieve a target hemoglobin concentration of 6 g/dL on CPB, and an additional 0.9 g PFC per kilogram of IV perflubron emulsion was given immediately after this harvest.
Differences between groups were analyzed after adjusting for their baseline measures (analysis of covariance) for all time points. In addition, differences in postoperative variables between groups were assessed with Student’s t-test. All statistical tests were conducted at the 0.05 level and were two tailed.
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Results |
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Nine patients undergoing primary coronary artery bypass grafting with CPB were studied. Five patients were randomized to the Control group, and four patients were randomized to the PFC group. Perioperative characteristics are summarized in Table 1. There were no significant differences between groups in perioperative variables at baseline (pre-CPB).
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At baseline, tonometric-derived variables (PCO2 gap and pHi) were not different between the two groups (Figs. 1 and 2). Immediately after ANH and the administration of PFC or LR, the CO2 gap was significantly larger (P < 0.001) in the Control group (Fig. 1). Consistent with this difference observed in CO2 gap, the pHi was also significantly worse (P < 0.01) in the Control group (Fig. 2). These differences in tonometric variables persisted throughout surgery (including additional blood harvesting by intraoperative autologous donation and 0.9 g/kg dosing in PFC group), as shown in Figures 1 and 2.
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All four patients in the PFC group maintained normal pHi and PCO2 gap throughout the perioperative period, whereas the Control group showed significant deterioration in these variables. Of note, patients in the PFC group showed a significantly (P < 0.007) shorter time to first postoperative bowel movement (Fig. 3). The time from surgery to consumption of solid food was also shorter in the PFC group, although this difference did not achieve statistical significance (PFC, 1.8 ± 1.0 days, versus Control, 4.1 ± 1.9 days; P = 0.056).
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Hemodynamic-, oxygen delivery-, and consumption-related variables are shown in Table 2. Blood pressure and flow rates were similar between groups at all time points. The mixed venous oxygen saturation was higher in the PFC-treated patients, compatible with the additional contribution of PFC to oxygen delivery.
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There were no differences in inotropic therapy between groups. Only one patient in each group received a small-dose epinephrine infusion (total dose, PFC group 0.002 mg, Control group 0.002 mg).
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Discussion |
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Infarcted bowel and major GI bleeding are rare complications after cardiac surgery (11,16,17). However, it is increasingly recognized that less severe GI tract dysfunction is common and has an incidence of approximately 50% after cardiac surgery (11,12). Several studies, using gastric tonometric derived variables as markers of GI perfusion, have reported impaired GI ischemia/hypoperfusion, increased permeability after cardiac surgery, or both (4,6,11,14).
We hypothesized that the administration of a PFC emulsion would preserve gastric tonometric variables and gastric motility in cardiac surgical patients. In this study we have demonstrated that patients undergoing elective coronary artery bypass grafting with intraoperative autologous donation and CPB who were randomized to PFC had significantly better gastric tonometric variables, i.e., less intramucosal hypercarbia, as demonstrated by CO2 gap. It is noteworthy that the CO2 gap was statistically different between groups at multiple time points despite the small number of patients studied. In contrast to calculated pHi, which can reflect metabolic acidosis or GI hypercarbia, an increased CO2 gap is more specific for GI hypoperfusion. This preservation of tonometric variables seemed to translate into a clinically relevant benefit with regard to the secondary end point of GI motility. The administration of PFC was associated with a clinically significant shorter time to first postoperative bowel movement (P < 0.007). In addition, the time to first consumption of solid food was also shorter in the PFC-treated patients and almost achieved statistical significance (P = 0.056).
The abnormal tonometric variables observed in the Control group most likely reflect occult hypovolemia and splanchnic ischemia. In an elegant study conducted in humans more than 30 years ago involving experimental hemorrhage, Price et al. (18) demonstrated that despite a 1-L (17%) decrease in central blood volume, cardiac output and mean arterial blood pressure did not significantly decrease (cardiac output: before, 6.5 L/min; after, 6.5 L/min; mean arterial blood pressure: before, 91 mm Hg; after, 86 mm Hg). In contrast, splanchnic blood volume decreased by 39%, demonstrating the specific effect of hypovolemia on the GI tract. This study was extended by that of Hamilton-Davies et al. (19), in which seven healthy volunteers underwent a controlled hemorrhage of 1.6 L. This 30% reduction in blood volume resulted in a significant acute deterioration of gastric tonometric-derived variables. However, consistent with the Price et al. (18) study, no changes in heart rate or systemic blood pressure were observed in these volunteers.
Gastric tonometry measures gastric CO2 levels and hence can detect gastric hypercarbia. The origin of the CO2 that can arise from the mucosal and serosal layers is less certain (20). It has been hypothesized that low-flow states may not allow for "washout" of the CO2 in these tissues, resulting in a buildup of CO2 (20). In another proposed mechanism for the development of gastric hypercarbia, mucosal ischemia results in a switch to anaerobic metabolism that ultimately results in an increase in the production of CO2. Although the actual mechanism for gastric hypercarbia is unknown, it should be recognized that abnormal perioperative tonometric variables are a reliable predictor of adverse outcome (6,11,21,22).
We can only speculate regarding the potential mechanisms for the preservation of gastric tonometric variables and gastric motility in the patients administered PFCs, because our study was not specifically designed to address this issue. It is possible that despite normal blood flow at the macro level (i.e., arteries and arterioles), endothelial cell injury and microcirculatory pathology might result in the local "sludging" of erythrocytes at the capillary level. PFC emulsions may improve oxygen delivery to the gastric mucosa by a mechanism based on their small size relative to red blood cells (0.2 vs 7 µm). The much smaller size of the PFC emulsion particles may allow for delivery of oxygen to these areas with impaired microcirculatory flow. In the setting of low flow at the macro level, small hemoglobin concentration, low oxygen saturation, or a combination of these, PFCs should allow for a higher degree of oxygen delivery to the tissues. The exact mechanisms by which PFCs might result in increased oxygen delivery to compromised tissues, such as the gut, are unclear and beyond the scope of this study. Finally, it is possible that the PFCs affect the tonometric variables in this study, not through increased oxygen delivery, but instead by an increased scavenging and removal of CO2. We believe that this potential mechanism is unlikely given that we did not merely observe improvements in gastric tonometric variables, but also differences in GI tract motility. Hence, it seems that PFCs protect the tissues as opposed to merely having an effect on CO2 measurements. The observation that venous oxygen saturation was consistently higher in the PFC-treated patients (Table 2) is compatible with the increased oxygen transport in the PFC-treated patients.
It is unlikely that the differences observed in tonometric variables and postoperative GI tract motility were caused by an effect of the PFC on hemodynamic variables, because these variables were not different between groups. In addition, a volume effect directly attributable to the PFC emulsion is unlikely, given that an equal volume of LR was administered and there is no evidence that these two different types of fluid have different effects as plasma volume expanders. The PFC emulsion is isoosmolar and isooncotic and would not be expected to result in a different effective intravascular volume. In addition, the volume of PFC or LR administered was small (300 ± 85 mL), and any different effects of these fluids would be small. It should be recognized that at the post-ANH time point, the two groups were different only in the administration of PFC or placebo. Hence the highly significant difference in tonometric variables at this time point should be attributable to the administration of the PFC emulsion. At the later time points, additional blood had already been harvested from the PFC group. It is reassuring that the tonometric variables were still significantly different at these time points despite the prior removal of additional blood. Indeed, the additional removal of blood would have been expected to minimize any benefit from the PFC, whereas the PFC-treated patients continued to have normal tonometric variables despite this additional harvest.
A potential limitation of this study was our inability to blind the study personnel and clinicians to the study group assignment during the intraoperative period. It is unlikely that this lack of intraoperative blinding could account for our results. The automated version of air tonometry used does not lend itself to significant operator bias. It is more important to note that the large and consistent differences between groups observed intraoperatively make these differences unlikely to be a result of bias. The sample size of our study also merits comment. The sample size was sufficient to detect highly significant differences in tonometric variables at all three time points. Furthermore, these intraoperative differences were consistent with the statistically significant observed differences in GI tract motility observed postoperatively. Our study was not designed or sufficiently powered to test for differences in other clinical outcomes, such as mortality or length of stay.
In conclusion, the administration of PFC emulsion to cardiac surgical patients was associated with a preservation of normal tonometric-derived variables. The PFC patients also exhibited a faster return of GI tract motility postoperatively. The use of PFC emulsion to protect potentially compromised tissues warrants further study.
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Appendix |
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Oxygen delivery:
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Oxygen consumption:
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Oxygen extraction:
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Where Hb = hemoglobin, Sao2 = arterial oxygen saturation, Svo2 = venous oxygen saturation, and Pao2 = partial pressure of arterial oxygen.
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References |
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Scott MG, Kucik DF, Goodnough LT, Monk TG. Blood substitutes: evolution and future applications. Clin Chem 1997; 43: 1724–31.
[Abstract/Free Full Text] - Alliance Pharmaceutical Corporation. A study to determine the optimal nontoxic intravenous infusion rate of emulsified PFOB in normal human volunteers. Internal Report IMBP-003-IRL 1995; September.
- Alliance Pharmaceutical Corporation. A randomized study of the effects of intravenously administered AFO144 on safety and coagulation function in healthy volunteers. Internal Report OXHT-007-USA; 1997.
- Martinez-Pellus AE, Merino P, Bru M, et al. Endogenous endotoxemia of intestinal origin during cardiopulmonary bypass: role of type of flow and protective effect of selective digestive decontamination. Intensive Care Med 1997; 23: 1251–7.[Web of Science][Medline]
- Mythen MG, Webb AR. The role of gut mucosal hypoperfusion in the pathogenesis of post-operative organ dysfunction. Intensive Care Med 1994; 20: 203–9.[Web of Science][Medline]
- Mythen MG, Webb AR. Intra-operative gut mucosal hypoperfusion is associated with increased post-operative complications and cost. Intensive Care Med 1994; 20: 99–104.[Web of Science][Medline]
- Landow L, Andersen LW. Splanchnic ischaemia and its role in multiple organ failure. Acta Anaesthesiol Scand 1994; 38: 626–39.[Web of Science][Medline]
-
Fiddian-Green RG. Haemodynamic and/or tonometric monitoring in cardiac surgery. Br J Anaesth 2000; 84: 128.
[Free Full Text] - Fiddian-Green RG. Associations between intramucosal acidosis in the gut and organ failure. Crit Care Med 1993; 21: S103–7.[Web of Science][Medline]
- Fiddian-Green RG. Splanchnic ischaemia and multiple organ failure in the critically ill. Ann R Coll Surg Engl 1988; 70: 128–34.[Web of Science][Medline]
- Bennett-Guerrero E, Panah MH, Bodian CA, et al. Automated detection of gastric luminal partial pressure of carbon dioxide during cardiovascular surgery using the Tonocap. Anesthesiology 2000; 92: 38–45.[Web of Science][Medline]
- Grap MJ, Savage L, Ball GB. The incidence of gastrointestinal symptoms in cardiac surgery patients through six weeks after discharge. Heart Lung 1996; 25: 444–50.[Web of Science][Medline]
- Chapman MV, Mythen MG, Webb AR, Vincent JL. Report from the meeting: Gastrointestinal Tonometry—State of the Art. 22nd–23rd May 1998, London, UK. Intensive Care Med 2000; 26: 613–22.[Medline]
- Fiddian-Green RG, Baker S. Predictive value of the stomach wall pH for complications after cardiac operations: comparison with other monitoring. Crit Care Med 1987; 15: 153–6.[Web of Science][Medline]
- Andritsch RF, Muravchick S, Gold MI. Temperature correction of arterial blood-gas parameters: a comparative review of methodology. Anesthesiology 1981; 55: 311–6.[Web of Science][Medline]
- Yilmaz AT, Arslan M, Demirkilc U, et al. Gastrointestinal complications after cardiac surgery. Eur J Cardiothorac Surg 1996; 10: 763–7.[Abstract]
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Perugini RA, Orr RK, Porter D, et al. Gastrointestinal complications following cardiac surgery: an analysis of 1477 cardiac surgery patients. Arch Surg 1997; 132: 352–7.
[Abstract/Free Full Text] -
Price HL, Deutsch S, Marshall BE, et al. Hemodynamic and metabolic effects of hemorrhage in man, with particular reference to the splanchnic circulation. Circ Res 1966; 18: 469–74.
[Abstract/Free Full Text] - Hamilton-Davies C, Mythen MG, Salmon JB, et al. Comparison of commonly used clinical indicators of hypovolaemia with gastrointestinal tonometry. Intensive Care Med 1997; 23: 276–81.[Web of Science][Medline]
- Hamilton MA, Mythen MG. Gastric tonometry: where do we stand? Curr Opin Crit Care 2001; 7: 122–7.[Medline]
- Doglio GR, Pusajo JF, Egurrola MA, et al. Gastric mucosal pH as a prognostic index of mortality in critically ill patients. Crit Care Med 1991; 19: 1037–40.[Web of Science][Medline]
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Kirton OC, Windsor J, Wedderburn R, et al. Failure of splanchnic resuscitation in the acutely injured trauma patient correlates with multiple organ system failure and length of stay in the ICU. Chest 1998; 113: 1064–9.
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