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Anesth Analg 2006;102:17-24
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000184818.32635.fd

CARDIOVASCULAR ANESTHESIA

Small-Dose Epoprostenol Decreases Systemic Oxygen Consumption and Splanchnic Oxygen Extraction During Normothermic Cardiopulmonary Bypass

Jan-Peter Braun, MD*, Torsten Schroeder, MD*, Sabine Buehner, Dr (Biology){dagger}, Uday Jain, MD, PhD, FACC, FAHA||, Ulrich Döpfmer, MD, FRCA*, Josephine Schuster, MD*, Selcuk Bas, MD*, Ingolf Schimke, MD§, Pascal M. Dohmen, MD{ddagger}, Herbert Lochs, MD{dagger}, Wolfgang Konertz, MD{ddagger}, and Claudia Spies, MD*

*Departments of Anesthesiology and Intensive Care, {dagger}Gastroenterology, {ddagger}Cardiac Surgery, and §Cardiology, Campus Charité Mitte, Charité University Hospital, Charité–University Medicine Berlin, Germany; and ||St. Mary’s Medical Center, San Francisco, California

Address correspondence and reprint requests to Jan-Peter Braun, MD, Klinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Campus Charité Mitte, Charité Universitätsmedizin Berlin, Schumannstr. 20-21, D-10117 Berlin, Germany. Address e-mail to jan.braun{at}charite.de.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Normothermic, nonpulsatile cardiopulmonary bypass (CPB) impairs systemic and splanchnic oxygen transport and increases gastrointestinal permeability. It is an important therapeutic goal to avoid splanchnic dysoxia during CPB. Small-dose prostacyclin therapy improves splanchnic oxygen transport and microcirculation in septic patients. In this study, we sought to determine if during cardiac surgery, the prostacyclin analog epoprostenol improves the balance of systemic and splanchnic oxygen transport. Eighteen patients undergoing cardiac valve replacement were randomized to receive either epoprostenol (3 ng ·kg–1 ·min–1) or placebo during, and for 1 hour after, surgery. Systemic and splanchnic oxygen delivery, consumption, and extraction and arterial, mixed venous, and hepato-venous lactate concentrations were measured before, during, and after CPB. Gastrointestinal permeability was measured 1 day before and 1 day after surgery using the triple sugar permeability test. During CPB, the epoprostenol group had decreased systemic oxygen consumption and splanchnic oxygen extraction (P = 0.024). These effects were not present 1 hour after the end of epoprostenol infusion. The study was not adequately powered to determine whether epoprostenol altered the trend towards increased lactate metabolism and increased postoperative gastrointestinal permeability, nor could we demonstrate any differences between groups in clinically relevant end-points. In conclusion, these findings suggest that during normothermic CPB, small-dose epoprostenol therapy may reduce systemic oxygen consumption and splanchnic oxygen extraction.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Appendix
 References
 
The incidence of clinically apparent mesenteric ischemia is approximately 0.2%–0.5% of all patients undergoing cardiopulmonary bypass (CPB). The mortality rate of this complication ranges between 70% and 100% (1). Arteriosclerosis, age older than 70 years, hyperosmolaric dehydration, and cardiac ischemia are the main risk factors (1). CPB itself seems to impair mucosal circulation in the gastrointestinal tract (GIT) (2). During normothermic, nonpulsatile CPB, oxygen delivery to the GIT is maintained and oxygen extraction is increased because there is increased oxygen requirement (3). Arterial, mixed-venous and hepato-venous lactate plasma levels increase during and after CPB; however, hepatic lactate metabolism is not affected (3,4). After normothermic CPB, gastrointestinal (GI) barrier function is impaired (3).

Increased splanchnic oxygen extraction and decreasing hepato-venous oxygen saturation (Lvo2) demonstrate the lack of oxygen in the splanchnic circulation. Redistribution of blood flow away from mucosa or an inflammatory response to CPB originating in the gut are possible factors affecting splanchnic oxygen transport during CPB (2,5). Prostacyclin improves microcirculation and has antiinflammatory properties (6,7). In experimental and clinical settings, small-dose prostacyclin therapy improves blood flow to the GIT and mucosal microcirculation (8–13), but its effects on oxygen transport have never been investigated during normothermic CPB. In an experimental setting, prostacyclins enhance recovery of increased gut permeability after an ischemic insult (14,15). The gut-protective effects of endogenous prostacyclins were demonstrated in a clinical trial (16).

We hypothesized that small-dose therapy with epoprostenol, a prostacyclin analog, administered during surgery and during the first hour after admission to the intensive care unit (ICU) reduces splanchnic oxygen extraction. This may lead to an improved GI barrier function after surgery. The normal range of small-dose therapy is from 1 to 5 ng ·kg–1 ·min–1 · We chose a dose of 3 ng ·kg–1 ·min–1 to avoid pronounced hemodynamic effects such as large decreases in vascular resistance, because 16 of our 18 patients were suffering from aortic stenosis. Decreases of systemic vascular resistance were seen with doses of more than 3 ng ·kg–1 ·min–1 in patients with cardiac failure (17). Maintenance of adequate systemic oxygenation during cardiac surgery improves clinical outcome (18). This pilot study investigated the course of systemic and splanchnic oxygen delivery and uptake and lactate metabolism in patients undergoing cardiac valve replacement.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Appendix
 References
 
This clinical study was approved by our institutional ethics committee, and each patient gave written informed consent. Patients were randomized into two groups by drawing lots out of a black bag immediately before the induction of anesthesia. Once a lot was drawn, it was not put back into the bag. The investigator drawing the lots and preparing the randomized medication was not involved in data acquisition and patient enrollment for this study. The list of group allocation was sealed to all other investigators up to the end of data acquisition.

Exclusion criteria were age <18 years, terminal renal or severe hepatic dysfunction, pregnancy, and acute or chronic GI diseases.

Either epoprostenol or normal saline solution was infused via a syringe pump. Patients in the epoprostenol group received epoprostenol at a dose of 3 ng ·kg–1 ·min–1, and the placebo group patients received an equal volume of normal saline. This medication was started after baseline measurements (i.e., 10 min before the start of surgery) and continued until 1 hour after admission to the ICU.

Oral premedication was with 1–2 mg of flunitrazepam the evening before surgery and 0.07–0.1 mg/kg of oral midazolam half an hour before transfer to the operating room. Before the induction of anesthesia, all patients received 7–10 mL/kg of balanced electrolyte solution. Anesthesia was induced with fentanyl 4–7 µg/kg, midazolam 1–4 mg, etomidate 0.15–0.3 mg/kg and pancuronium 0.1–0.15 mg/kg for muscle relaxation. For maintenance of anesthesia, we used fentanyl 0.5–1.0 mg/h and propofol 3–4 mg ·kg–1 ·h–1 and repeat doses of pancuronium, as required. After the induction, a fiberoptic pulmonary artery catheter (Opticath®, Abbott, North Chicago, IL) was inserted into the right hepatic vein via a right femoral vein puncture. Correct placement, i.e., location of the tip at least 5 cm within the right liver vein, was confirmed by radiograph and transesophageal echocardiography. A pulmonary artery catheter with continuous measurement of cardiac index (CI) and mixed venous oxygen saturation (Svo2; Opti-Q®; Abbott,) and a four-lumen central venous catheter were inserted through the right internal jugular vein. Body temperature was measured using a Foley catheter with a thermistor tip (TycoHealthcare, Neustadt, Germany).

Normoventilation was confirmed by hourly blood gas tension measurements and continuous measurement of the end-expiratory carbon dioxide concentration. Perioperative antibiotic prophylaxis was provided with three doses of 1.5 g of cefuroxime: after the induction of anesthesia, after weaning from CPB, and 6 h after admission to the ICU.

Membrane oxygenators (Quadrox®; Jostra, Hirlingen, Germany) and a centrifugal pump (Rotaflow®; Jostra, Hirlingen, Germany) were used for normothermic, nonpulsatile CPB. The pump flow rate was set to more than 2.5 L ·min–1 ·m–2, and the mean arterial blood pressure was kept to more than 50 mm Hg. The pump was primed with 800 mL of balanced electrolyte solution and 500 mL of hydroxyethyl starch solution (10%). During commencement of extracorporeal circulation, all patients received a total of 50,000 KIU/kg of aprotinin. Cardiac arrest was induced and maintained by intermittent anterograde administration of warm-blood cardioplegia-solution enriched with potassium.

According to institutional standards, dopamine and glycerol trinitrate were used as required during weaning from CPB (Table 1). Red blood cell transfusions were given to maintain hematocrit levels to above 22% during CPB. In stable patients, sedation with propofol was discontinued 3 h after admission to the ICU.


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  		Table 1. Demographic Data and Data from the Perioperative Period

 

Blood samples for blood gas analysis and for lactate, electrolyte, and glucose measurements were obtained simultaneously from the arterial, hepatic venous, and pulmonary artery catheters at predefined points in time and analyzed using an ABL 700 system (Radiometer, Copenhagen, Denmark).

Hepato-splanchnic blood flow (HBFI) measurements were performed by means of the constant-infusion-technique of indocyanine-green (ICG) using the Fick principle (ICG-Pulsion, Munich, Germany) (19). After a bolus injection of a 12-mg priming dose of ICG dye into the central venous catheter, ICG was applied for 30 min at a constant infusion rate of 1 mg/min. After 30 min, blood samples were collected simultaneously from the radial artery and liver veins. The ICG concentration in plasma was determined by spectrophotometry at a wave length of 804 nm with a correction for blank density (900 nm) (20).

Blood oxygen content was calculated using a standard formula (see Appendix). To calculate the total and splanchnic oxygen supply per square meter of body surface, the oxygen content was multiplied by the CI or by the hepatic blood flow index, respectively.

The calculation of the hepato-splanchnic lactate uptake (Appendix) was used to determine the metabolic potency of liver regarding lactate (4) (Appendix). The hepato-splanchnic lactate efflux ratio was calculated to quantify the contribution of lactate originating in the splanchnic area (20).

The following variables were obtained after the induction of anesthesia (preCPB), i.e., immediately before the administration of the study medication, 30 min after the beginning of CPB, i.e., during study drug administration, and 2 h after admission to the ICU (ICU + 2), i.e., 1 h after the end of study drug administration: body temperature; arterial, mixed-venous, and hepato-venous blood gas analyses and lactate concentrations; systemic and splanchnic oxygen delivery; systemic and splanchnic oxygen consumption; splanchnic lactate uptake, and the hepatic lactate:efflux ratio.

On the day before surgery, and on the first postoperative day, patients were subjected to a standardized GI permeability triple sugar test. Sucrose served as a marker for gastroduodenal permeability (21), and the lactulose/mannitol-ratio (permeability index) served as a marker for the intestinal permeability (22). After an overnight fast, each patient provided a pre-test urine sample. Thereafter, patients drank a solution containing 20 g of sucrose, 10 g of lactulose, and 5 g of mannitol dissolved in 100 mL of water. The solution was administered via gastric tube in patients still being intubated. Urine was collected over 5 h with sodium azide as a preservative. Subjects fasted except for free intake of water during the test. Total urine volume was recorded on completion of the test. The sugars were quantified by high-power liquid chromatography with pulsed electrochemical detection (Dionex, Idstein, Germany); chromatography module: 250 x 40 mm Carbopac PA-1 column (Dionex); eluent 150 mmol of NaOH; flow: 1 mL/min. Results were expressed as percentage recovery of the ingested dose of the sugars.

Sample size calculation was based on our observational cohort study (3). This study showed a mean increase in splanchnic oxygen extraction of 13% (38% extraction after the induction of anesthesia and 51% during CPB). Using NQuery advisor(TM) we calculated a sample size of 36 patients per group. This calculation was based on the assumption that halving the increase in splanchnic oxygen extraction by administration of epoprostenol is a clinically relevant end-point. In agreement with our local ethics committee, a pilot study was initiated randomizing 10 patients into each group.

Data are presented as medians and interquartile ranges. Adjustment for body surface area was made for all variables based on hemodynamic values. For statistical evaluation, we used SPSS for windows (SPSS IAC, version 11.5, Chicago, IL). For comparison of consecutive observations, Friedman nonparametric analysis of variance for dependent samples was used. For comparison of two dependent samples, Wilcoxon’s test was used. Significance was assessed at P ≤ 0.05. Mann-Whitney U-test was performed to analyze differences between the groups. Delta values for differences between the groups were calculated by subtracting values at CPB or ICU + 2 from preCPB.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Appendix
 References
 
Table 1 shows the demographic and clinical characteristics of the two groups. We originally randomized 10 patients for each group. In one patient in each group, it was not possible to place a liver venous catheter into a stable position. Data of these two patients were excluded from all reported results. The only relevant difference between the groups was a higher proportion of women in the epoprostenol group. After CPB, no patient required dopamine exceeding 6 mcg · kg–1 ·min–1or glyceroltrinitrate exceeding 0.5 mcg · kg–1 ·min–1. At preCPB and during the measurement on CPB, no patient received any vasoactive substance (Table 1). There were no significant differences between groups in the following variables during the measurement on CPB: mean arterial blood pressure, 61 ± 4 mm Hg in the placebo group and 60 ± 3 mm Hg in the epoprostenol group; mean temperature, 36.0°C ± 0.6°C in the placebo group and 36.0°C ± 0.5°C in the epoprostenol group; mean hematocrit, 27.0% ± 3% in the placebo group and 26.6% ± 3% in the epoprostenol group; and mean arterial CO2 partial pressure, 35.4 ± 2.6 mm Hg in the placebo group and 35.5 ± 2.4 mm Hg in the epoprostenol group. Ventilation for more than 12 h was required in one patient in the epoprostenol group and in two patients in the placebo group. Two patients in the epoprostenol group and three in the placebo group stayed in the ICU for longer than 24 h.

In both groups, there was a trend for CI, HBFI, and systemic oxygen delivery to increase during the study period (Table 2). At preCPB, systemic oxygen delivery was larger (P = 0.04) in the placebo group because of the higher hematocrit (median, 39.1 versus 36.5) and CI (Table 2). Systemic oxygen consumption during CPB was smaller (P = 0.024) in the epoprostenol group. There was a trend (P = 0.06) for the systemic O2 extraction during CPB to be lower in the epoprostenol group. Systemic O2 extraction from preCPB to CPB decreased in the epoprostenol group, increased in placebo group, and the change was different between the two groups (P = 0.008). In each group, O2 extraction preCPB was not significantly different from that at ICU + 2.


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  		Table 2. Systemic and Splanchnic Oxygen Transport

 

Svo2 (Fig. 1) during CPB was reduced in the placebo group (P = 0.04). Only in the placebo group was a significant decrease of Svo 2 during CPB compared with preCPB observed (P = 0.008). The Svo 2 measurements at ICU + 2 were not significantly different between the groups and were not significantly different from preCPB in either group.



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  		Figure 1. Mixed venous oxygen saturation in the two groups. Values are medians and interquartile ranges. *P = 0.04. PreCPB = before cardiopulmonary bypass; CPB = 30 min after start of cardiopulmonary bypass; ICU + 2 = 2 h after admission to the intensive care unit; Svo2 = mixed venous oxygen saturation; filled triangles = epoprostenol group; filled circles = placebo group.

 

During CPB, hepato-splanchnic oxygen extraction was significantly reduced in the epoprostenol group (P = 0.024) (Table 2). At ICU+2, the difference between the groups was not significant (P = 0.136).

In the epoprostenol group, Lvo 2 was unchanged throughout the study period (Fig. 2). In the placebo group, Lvo2 decreased at CPB and ICU + 2 compared with preCPB (P = 0.018). During CPB, Lvo2 was increased in the epoprostenol group (P = 0.024). At ICU + 2, there was a trend (P = 0.09) in that direction.



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  		Figure 2. Hepato-venous oxygen saturation in the two groups. Values are medians and interquartile ranges. *P = 0.024. At ICU + 2, P = 0.09 for the difference between the groups. PreCPB = before cardiopulmonary bypass; CPB = 30 min after start of cardiopulmonary bypass; ICU + 2 = 2 h after admission to the intensive care unit; Lvo2 = hepato-venous oxygen saturation; filled triangle = epoprostenol group; filled circle = placebo group.

 

Arterial, mixed-venous and hepato-venous lactate concentrations, the lactate uptake, and the splanchnic lactate efflux ratio did not show any significant difference between groups at any time. A significant increase of arterial, mixed venous, and hepato-venous lactate concentrations was observed in both groups during and after surgery when compared with baseline values (P < 0.001). Hepato-venous lactate concentrations were always less than mixed venous and arterial values (P ≥ 0.006). Splanchnic lactate uptake increased parallel to the lactate concentrations.

In both groups, gastroduodenal permeability (measured by sucrose excretion) (P = 0.033) and intestinal permeability (measured by lactulose-mannitol-ratio; P = 0.005) increased significantly after CPB compared with the baseline values (Fig. 3). The change in differences of the values after and before surgery was not different between the groups (P = 0.95 and 0.54, respectively).



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  		Figure 3. The box plots indicate the median and the interquartile range, and the limits indicate the 95% confidence interval. Left panel: Gastroduodenal permeability determined by the sucrose urine-excretion fraction 1 day before (white box plots) and 1 day after surgery (black box plots), with placebo patients on the left and epoprostenol patients on the right. Right panel: Intestinal permeability determined by the ratio of lactulose urine-excretion divided by mannitol urine-excretion 1 day before (white box plots) and 1 day after surgery (black box plots), with placebo patients on the left and epoprostenol patients on the right.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Appendix
 References
 
Our previous observational study (3) demonstrated that during normothermic CPB, splanchnic blood flow is maintained and splanchnic oxygen extraction is markedly increased. Supposing a positive effect, the influence of epoprostenol on splanchnic oxygen transport was investigated in this pilot study. We detected reduced systemic oxygen consumption in epoprostenol-treated patients during CPB, with maintained oxygen delivery, and reduced splanchnic oxygen extraction. One hour after stopping epoprostenol, these effects were no longer present. Because dopamine and glycerol trinitrate were not administered during CPB, they could not have influenced the results during CPB. This study was not powered sufficiently to detect an effect of epoprostenol on lactate metabolism or GI permeability.

The reason for the increase of splanchnic oxygen consumption during CPB is not clear. Suggested mechanisms are impaired GI microcirculation (13), an inflammatory reaction in the splanchnic region (23), or a combination of the two mechanisms. These mechanisms might be affected by small-dose administration of epoprostenol. All patients were anesthetized by a total IV anesthesia using propofol, fentanyl, and pancuronium. Propofol seems to influence splanchnic circulation less than volatile anesthetics (24,25).

The effects of small-dose prostacyclin therapy on splanchnic circulation and oxygen transport have previously been investigated only in noncardiac surgery patients. Kaisers et al. (11) found that small-dose epoprostenol therapy after liver transplantation increases CI, systemic oxygen delivery, and Lvo2. Significant changes in oxygen uptake were not seen in the aforementioned study. In 1987, Bihari et al. (26) described the effects of 5 ng ·kg–1 ·min–1 of prostacyclin in 27 septic patients with respiratory failure. Oxygen delivery was increased in all patients. Oxygen uptake was increased only in the 13 patients who did not survive. Oxygen consumption decreased in the 14 patients who survived. Radermacher et al. (27) demonstrated an increase in gastric mucosal pHi in 16 patients with sepsis caused by 10 ng ·kg–1 ·min–1 of epoprostenol. Kiefer et al. (12) demonstrated an increase in splanchnic blood flow in septic patients. We did not detect an increase in splanchnic blood flow during normothermic CPB.

Boeken et al. (7) observed an increase in elastase during CPB, which was negated by prostacyclin 10–20 ng ·kg–1 ·min–1. Similarly, in our study, during CPB, splanchnic oxygen consumption in the epoprostenol group was not increased, and hepato-venous oxygen saturation was not reduced, indicating reduced inflammation.

This study was not powered to detect the effect of epoprostenol on lactate metabolism. Epoprostenol did not seem to affect the mildly increased lactate during CPB. The interquartile range of lactate was small (Table 3) and not different from our previous data (3). Uptake of lactate in the liver, a marker of its metabolic activity, did not show any intergroup difference. The splanchnic lactate efflux index indicates that part of circulating lactate originated in the splanchnic area. This part did not increase during the study period in either group. The splanchnic lactate uptake increased with increasing plasma lactate concentration. This indicates a preserved lactate metabolism during and after normothermic CPB (3). Similarly, Kiefer et al. (12) did not observe an effect of epoprostenol on lactate concentration during sepsis.


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  		Table 3. Lactate Metabolism

 

We previously reported that gastroduodenal and intestinal permeability increased after surgery (3). This study was not powered to detect the effect of epoprostenol on GIT permeability. Because the dose of epoprostenol we used may have been inadequate to optimally affect the GIT permeability, we decided not to enroll additional patients at this dose. Blikslager et al. (14) and Little et al. (15) reported prostacyclin improved recovery of small intestine permeability after experimental ischemia/reperfusion in a pig model. During abdominal surgery, Brinkmann et al. (16) observed an increased bacterial translocation after inhibition of endogenous prostacyclin production with ibuprofen. We are not aware of any clinical study of small-dose prostacyclin’s effect on GIT permeability.

In conclusion, small-dose epoprostenol therapy during normothermic CPB reduced systemic oxygen uptake and splanchnic oxygen use. Antiinflammatory and microcirculatory effects of epoprostenol could be responsible for these findings. Further studies are required to determine if clinically apparent mesenteric ischemia is reduced. A dose-ranging study is required to determine if there is a significant effect of epoprostenol on splanchnic organ dysfunction during and after CPB, as measured by lactate metabolism and GI permeability.

We thank Professor Dr. Klaus-Dieter Wernecke, Department of Medical Biometry, Humboldt University Berlin, Germany, for the detailed statistical advice.


   Appendix
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
References
 
Arterial oxygen content =

caO2 = arterial hemoglobin concentration (g/dL) x 1.39 x arterial oxygen saturation + dissolved oxygen.

Mixed-venous oxygen content =

cvO2 = mixed-venous hemoglobin concentration ([Hb]) x 1.39 x mixed-venous oxygen saturation + dissolved oxygen

Hepato-venous oxygen content =

chO2 = hepato-venous hemoglobin concentration ([Hb]) x 1.39 x hepato-venous oxygen saturation + dissolved oxygen

Hepato-splanchnic blood flow index = HBFI

Arterial lactate concentration = calact

Mixed-venous lactate concentration = cvLact

Hepato-venous lactate concentration = chlact

Total oxygen supply =

sys. DO2 = caO2 x CI

Splanchnic oxygen supply =

spl. DO2 = caO2 x HBFI

Total oxygen consumption =

sys. Vo2 = (caO2 – cvO2) x CI

Splanchnic oxygen consumption =

spl. Vo2 = (caO2 – chO2) x HBFI

Total oxygen extraction =

sys O2-ER = (caO2 – cvO2) x caO2–1

Splanchnic oxygen extraction =

spl O2-ER = (caO2 – chO2) x caO2–1

Splanchnic lactate uptake =

>spl. lact-uptake = (calact – chlact) x HBFI

Hepato-splanchnic lactate efflux ratio =

spl. lact:efflux = (chlact x HBFI) x (calact x CI)–1


   Footnotes
 
Accepted for publication August 16, 2005


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press