Dopexamine reverses colonic but not gastric mucosal perfusion defects in lethal endotoxin shock

J. J. Tenhunen*, T. J. Martikainen, A. Uusaro and E. Ruokonen

Department of Anesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland

*Corresponding author: Department of Critical Care Medicine, Room 1055, Scaife Hall, 3550 Terrace Street, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. E-mail: tenhjj@anes.upmc.edu

Accepted for publication: July 16, 2003


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Whilst dopexamine appears to increase overall splanchnic blood flow in postoperative and septic patients, the effects on gastric mucosal perfusion are controversial and based on concomitantly increasing mucosal to arterial PCO2 gradients (PdCO2). We hypothesized that dopexamine alters splanchnic blood flow distribution and metabolism during experimental endotoxin shock and modifies the inflammatory response induced by endotoxin.

Methods. In an experiment with anaesthetized normovolaemic, normoventilated pigs, 21 animals were randomized into: (i) subacute lethal endotoxin shock for 14 h (n=7 at baseline); (ii) endotoxin shock with dopexamine infusion (aiming to exceed baseline cardiac output, n=7); or (iii) controls (n=7). Regional blood flow and metabolism were monitored.

Results. Endotoxin produced a hypodynamic phase followed by a normo/hyperdynamic, hypotensive phase. Despite increasing systemic blood flow in response to dopexamine, proportional splanchnic blood flow decreased during the hypodynamic phase. Dopexamine gradually decreased fractional coeliac trunk flow, while fractional superior mesenteric arterial flow increased. Dopexamine induced early arterial hyperlactataemia and augmented the gastric PdCO2 gradient while colonic luminal lactate release and colonic PdCO2 gradient were reversed. Dopexamine did not modify the inflammatory response as evaluated by arterial IL-1ß and IL-6 concentrations.

Conclusions. Dopexamine protects colonic, but not gastric mucosal epithelium in experimental endotoxin shock. This may be related to redistribution of blood flow within the splanchnic circulation.

Br J Anaesth 2003; 91: 878–85

Keywords: blood, flow, splanchnic; complications, shock; measurement techniques, microdialysis; metabolism, lactate


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Inotropic drugs are frequently required in sepsis to increase systemic blood flow and oxygen delivery. Poor splanchnic perfusion may accompany sepsis, and therefore inotropes with preferential splanchnic vasodilation may be of use. Dopexamine is a widely used inotrope in the UK.1 It may improve splanchnic perfusion although controversial results exist in the literature.24 In addition to its circulatory effects, dopexamine may also attenuate inflammatory responses in sepsis.5

Subacute experimental endotoxaemia is a well-accepted model of sepsis.68 The primary response to endotoxin infusion is an abrupt increase in pulmonary vascular resistance followed by a decrease in cardiac function.6 8 During the progression of endotoxin shock a hyperdynamic, hypotensive circulation with a systemic inflammatory response develops.

Based on our preliminary results,9 we hypothesized that dopexamine alters blood flow distribution and metabolism within the splanchnic region during experimental endotoxin shock and modifies the inflammatory response to endotoxin. We aimed to study the haemodynamic and metabolic effects of dopexamine in an experimental model of subacute (prolonged to 14 h) endotoxaemia. In particular, we focused on the effects of dopexamine on systemic and regional blood flow and metabolism at the onset of endotoxic shock, which is associated with poor cardiac performance. We also studied the effects of dopexamine on blood flow distribution and metabolism later during the progression of sepsis. Finally, we investigated the effects of dopexamine on markers of inflammation.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The institutional animal use and care committee of the University of Kuopio approved this study procedure.

Anaesthesia
Twenty-one Finnish landrace pigs (24–35 kg) were fasted for 48 h with access to water. The gastrointestinal tract was emptied with an osmotic laxative (Colonsteril®, Orion, Espoo, Finland) 2 days before the experiment. Thirty minutes before preparation, the animals were premedicated with atropine 0.05 mg kg–1 of body weight and azaperone 8 mg kg–1 i.m. An ear vein was cannulated and anaesthesia was induced with i.v. ketamine (250 mg) and sodium thiopental 5–15 mg kg–1. Anaesthesia was maintained with sodium thiopental (5–10 mg kg–1 h–1) and fentanyl (5 µg kg–1 h–1) infusions. Animals were weighed and moved to the operating table. We used tracheotomy to ensure secure airway access. The lungs were ventilated with volume-controlled mode ventilator (Servo 900E, Siemens Elema, Sweden). The partial pressure of arterial blood oxygen was maintained above 13.3 kPa by adjusting the fraction of oxygen in the inspiratory gas (FIO2). Tidal volume was maintained within 10–15 ml kg–1 and minute volume adjusted to maintain normocapnoea 4.5–5.5 kPa (34–41 mm Hg). Positive end-expiratory pressure of 5 cm H2O was used throughout the experiment. We measured pulmonary artery occlusion pressure (PAOP) every hour during the experiment and maintained this between 5–7 mm Hg aiming to normovolaemia. Core temperature was measured using the thermistor at the tip of the pulmonary artery catheter and was maintained between 38 and 39°C by regulating the temperature of the table, i.v. fluids and using a heat lamp. We used 2–4 mg i.v. injections of pancuronium (Pavulon® NV Organon, Oss, Netherlands) for neuromuscular block.

Fluid management
For maintenance fluid therapy, saline 5 ml kg–1 h–1, 0.9% was infused throughout the experiment. Fluid resuscitation with Ringer’s acetate and hydroxyethyl starch 1:1 was given to achieve PAOP 5–7 mm Hg at baseline. During the different phases of endotoxaemia, volume challenges (20–50 ml) were given if cardiac output or systemic arterial pressure decreased abruptly or systemic arterial pressure in response to the respiratory cycle occurred.10 However, PAOP was maintained <10–12 and CVP <16 mm Hg, because fluid resuscitation was limited by right ventricular function. Glucose 50% infusion was used to maintain blood glucose at 5–7 mmol litre–1.

Animal preparation
Full sterility was maintained throughout the surgery. We cannulated the right femoral artery to measure systemic arterial blood pressure and to collect arterial blood samples. Right jugular and subclavian veins were prepared. The hepatic vein was cannulated through the jugular vein and the location of the catheter was ensured with manual palpation and ultrasound as required. A pulmonary artery catheter was directed to the pulmonary artery through the right subclavian vein. A full midline laparotomy was performed. The urinary bladder was drained, a nasogastric tube was inserted, and the stomach emptied. We used calibrated perivascular ultrasonic transit time flow probes (Transonic Systems Inc., Ithaca, NY, USA). The descending aorta was visualized through the diaphragm and flow probe inserted (14 mm) around the aorta. We inserted a left pleural drain and closed the diaphragm. Portal, coeliac trunk, superior mesenteric artery and hepatic arteries were visualized and correct sized probes inserted (12, 6, 6, and 4 mm, respectively). Care was taken to visualize all (1–3) branches of the hepatic artery.

Colonic, mesenteric, gastric and portal veins were cannulated to collect regional blood samples. The vessels were cannulated using Seldinger’s technique and fixed only to the entry site of the cannula in the vessel wall and therefore the cannulae did not occlude the vessels. The vein draining the great curve of stomach is a ‘double’ vein with abundant anastomoses between the two so that the venous outflow from the great curve was not occluded by cannulating one of the vessels. Tonometers (Tonometrics, Datex/instrumentarium, Helsinki, Finland) with microdialysis capillaries were inserted into the colon and jejunum. We guided the tip of the tonometer 10–15 cm inside the lumen of the gut through a small anti-mesenteric incision, which was then carefully sutured. The gastric tonometer was guided into the stomach orally and its position was verified by manual palpation. We closed the laparotomy in two layers and finally inserted a right pleural drain. At the end of the experiment the animals were killed with i.v. injection of magnesium sulphate while still anaesthetized.

Experimental procedure
All animals were allowed to stabilize for 8–10 h. A block randomization in three clusters was applied using closed opaque envelopes. We randomly allocated the animals into three groups: ETX (n=7) with Escherichia coli endotoxin infusion, DOPE (n=7) with E. coli endotoxin and dopexamine infusion and controls (n=7). Initially we collected the baseline samples, and if randomized into a group 1–2, started the E. coli endotoxin infusion (20 µg ml–1 in glucose 5%) at a rate of 0.5 µg kg–1 h–1. After 2–4 h, the infusion rate was increased stepwise (doubled every 45–60 min) to induce systemic hypotension. Incremental dosage of endotoxin was limited by not allowing the mean pulmonary arterial pressure to exceed 40 mm Hg. Dopexamine infusion was started after the pulmonary hypertension occurred and was followed by an abrupt decrease in cardiac output. We aimed to increase cardiac output to baseline or higher and adjusted dopexamine infusion accordingly. When cardiac output exceeded baseline, dopexamine infusion was continued at a fixed rate until the end of the experiment.

Tonometry
Gastric, jejunal and colonic mucosal partial pressure of carbon dioxide was measured with a semiautomatic gas analyser (Tonocap®, Datex-Ohmeda, Helsinki, Finland) every 10 min throughout the experiment. Tonometric-arterial PCO2 gradients were calculated at baseline and hourly thereafter. H2-blockers were not used.

Indirect calorimetry
Whole body carbon dioxide production (V·CO2) was measured using continuous indirect calorimetry (Deltatrac, Datex, Helsinki, Finland).

Microdialysis
The microdialysis capillaries used were manufactured in our laboratory. The method has been previously validated for intestinal luminal lactate measurement.11 The capillary membrane was semipermeable polysulfone with pore size of 60 000 Da. The inner diameter of the capillary lumen was 200 µm and the length of the semipermeable portion was 2.0 cm. The outflow tubing was 100 cm long with an inner diameter of 0.134 mm. The in- and outflow tubing were inserted inside the tonometer catheter and the microdialysis catheter was fixed on the surface of the tonometer balloon. The microdialysis catheter was gently compressed to the gut mucosa by filling the balloon on the tonometer. The flow of the microdialysate (Ringer’s acetate) was adjusted to 2 µl min–1, and therefore the delay from the tissue to the collecting tubes was 7 min. Tubes were kept on ice during collection. Samples were collected in 30 min fractions throughout the experiment and microdialysate lactate was analysed within 5 min of fraction collection.

Blood flow measurement
Flowmeter signals (T206 and T106, Transonic) were recorded (30 Hz) on a computer program for further analysis (Dataq instruments Windaq 1.60, Dataq instruments Inc., Akron, OH, USA). In vivo zero-flow was also noted at the end of the experiment (the no-flow signal from each vessel after euthanizing the animal) in order to evaluate a possible calibration error developed during the experiment.

Blood samples
Regional blood samples were taken at baseline and at 4, 8, 10, 12 and 14 h. These samples were analysed for haemoglobin (Hemoxymeter OSM3, Radiometer, Copenhagen, Denmark), blood gases (Radiometer, Copenhagen, Denmark), lactate and pyruvate. In addition, samples for IL-1ß and IL-6 were taken from the femoral artery. Arterial samples for endotoxin concentration measurements were taken at baseline and after the experiment.

Endotoxin, IL-1ß and IL-6 concentrations
Plasma endotoxin concentrations were determined using the Limulus Amebocyte Lysate assay (LAL, Charles RiverEndosafe, Charleston, SC, USA) with chromogenic quantitation (Coatest endotoxin, Chromogenix AB, Mölndal, Sweden). Arterial serum cytokine concentrations (IL-1ß and IL-6) were determined with porcine immunoassay for IL-1ß and IL-6 (Quantikine P, R&D Systems Inc., Minneapolis, MN, USA).

Lactate and pyruvate measurements
Enzymatic lactate oxidase method with polarographic detection was used for both microdialysate and plasma lactate measurements (YSI 2300 Stat Plus, Yellow Springs Instruments Co. Inc., Yellow Springs, OH, USA). Whole blood pyruvate was measured enzymatically (Sigmas UV-706 kit, Sigma Diagnostics, St Louis, MO, USA) with spectrophotometric detection (Shimadzu CL-750, Shimadzu Corporation, Kyoto, Japan). Pyruvate measurements were performed daily.

Calculations and statistical analysis
Total splanchnic blood flow (Q·spl) was calculated as the sum of portal venous and hepatic arterial blood flows. Statistical analysis was via SPSS 9.0.1 (SPSS Inc., Chicago, IL, USA). The data are presented as median (interquartile range) at baseline, 4 and 14 h or during the hyperdynamic phase before the death of the animal (all animals reached a hyperdynamic hypotensive circulatory state and therefore n=7 at the hyperdynamic phase despite three deaths before 14 h). Accordingly, Friedman’s nonparametric analysis of variance for repeated measurements was used for within group comparison. Differences between the groups at baseline were tested using a nonparametric test for independent samples (Kruskal–Wallis test). Post hoc location of a significant difference within group was performed using Wilcoxon’s signed rank test. P<0.05 indicated a statistical significance.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Control and dopexamine-treated animals survived the experiment, while three animals died in the ETX group after 8, 10 and 12 h. Arterial endotoxin concentrations increased in both ETX and DOPE groups while blood endotoxin remained low during control conditions (Table 1). Dopexamine infusion was started at a dose of 1 µg kg–1 min–1 and increased to maximal infusion rates ranging from 9 to 17 µg kg–1 min–1. Systemic haemodynamic and respiratory data are shown in Figure 1. At baseline the groups were comparable except for V·CO2 (P=0.049, Fig. 1) and absolute coeliac trunk blood flow (which had a tendency towards significant difference between the groups, P=0.08).


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Table 1 Arterial endotoxin, interleukin-1ß and -6 concentrations. Data are median (interquartile range). *Significant change within group (Wilcoxon’s signed rank test). #Significant difference between the groups (Kruskal-Wallis test)
 


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Fig 1 (A) Cardiac index (CI), (B) mean systemic arterial pressure (SAPm), (C) mean pulmonary arterial pressure (PAPm), (D) pulmonary arterial occlusion pressure (PAOP), (E) systemic carbon dioxide production (V·CO2), (F) arterial partial pressure of carbon dioxide (PaCO2), (G) central temperature (Tc), and (H) central venous pressure (CVP) in endotoxin shock (light grey columns), dopexamine treated (white columns), and control animals (dark grey columns). *Statistical significance within group over time (Friedman’s nonparametric test for repeated measurements); §significant within group difference (Wilcoxon nonparametric test for two dependent variables); #significant difference between the groups at the baseline (Kruskal–Wallis test).

 
Hypodynamic phase
Regional blood flows
Endotoxin induced a characteristic biphasic shock with a primary hypodynamic phase (after 4 h). Absolute splanchnic blood flow decreased (Q·spl) in proportion to the systemic blood flow reduction (Table 2). Endotoxin decreased absolute coeliac trunk (Q·trunk) and superior mesenteric artery (Q·sma) blood flows during the hypodynamic phase in proportion to cardiac output.


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Table 2 Absolute and proportional regional blood flows in endotoxin shock (ETX, n=7), in endotoxin shock treated with dopexamine (DOPE, n=7) and controls (n=7). Q·splanchnic/CO, fraction of total splanchnic blood flow from cardiac output; SMA/CO, fraction of superior mesenteric blood flow from cardiac output; trunk/CO, proportion of coeliac trunk blood flow from cardiac output. Data are median (interquartile range)
 
Dopexamine reversed the primary low cardiac output observed in the hypodynamic phase (Fig. 1). Dopexamine prevented the reduction in absolute Q·spl while the proportion of splanchnic blood flow from cardiac output decreased (Table 2). Dopexamine appeared to maintain absolute Q·trunk, however trunk blood flow decreased in four of the seven animals while an increase was observed in three. The proportion of Q·trunk from cardiac output decreased. Dopexamine reversed the reduction of absolute Q·sma with a minor reduction in proportion to cardiac output (Table 2).

Regional metabolism
Endotoxin was associated with increasing mucosal to arterial PCO2 gradient only in the colon during the hypodynamic phase and there was no luminal lactate release during the hypodynamic phase at any of the three locations monitored (Table 3). Arterial hyperlactataemia with moderately elevated arterial lactate–pyruvate ratio (L/P) developed during endotoxin infusion. Veno-arterial lactate gradients became negative and regional venous L/P ratios increased over the stomach and jejunum. Hepatic lactate turnover remained constant.


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Table 3 Mucosal to arterial PCO2-gradients and intestinal luminal microdialysate lactate concentrations in endotoxin shock (ETX, n=7), dopexamine (DOPE, n=7) and control (n=7) groups. (t-a)PCO2 gap, tonometric arterial carbon dioxide partial tension gradient. Data are median (interquartile range). *Friedman’s non-parametric test for repeated measurements (within group analysis); §comparison with baseline (Wilcoxon); {dagger}significant difference between the groups (Kruskal-Wallis test)
 
Dopexamine infusion was associated with marked arterial hyperlactataemia with increasing systemic L/P ratio (Table 4) and decreasing mucosal to arterial PCO2 gradient in the jejunum (Table 3). Negative veno-arterial lactate gradients occurred over the stomach, jejunum and colon with increased L/P ratios in the stomach and jejunum, but not the colon. Hepatic lactate turnover remained constant.


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Table 4 Lactate gradients and L/P ratios in endotoxin shock (ETX, n=7), dopexamin treated (DOPE, n=7) and control (n=7) groups. Data are median (interquartile range)
 
Normo/hyperdynamic, hypotensive phase
Regional blood flows
Prolonged endotoxaemia was associated with cardiac output exceeding the baseline level during the hypotensive phase of shock (Fig. 1). Q·spl was maintained at baseline in proportion to cardiac output. The absolute Q·sma in addition to its proportion from cardiac output increased. Q·trunk and its proportion from cardiac output remained constant during prolonged endotoxaemia (Table 2).

Dopexamine did not affect absolute or proportional splanchnic blood flow compared with baseline. Dopexamine increased the absolute Q·sma and its proportion from cardiac output, while the absolute Q·trunk was maintained at baseline and its proportion from cardiac output decreased (Table 2).

Regional metabolism
Prolonged endotoxaemia was associated with increasing mucosal to arterial PCO2 gradients and luminal lactate release in the stomach and colon. Persistent arterial hyperlactataemia with high L/P ratio was observed during prolonged endotoxaemia. Gastric and mesenteric veno-arterial lactate gradients became positive. Gastric and mesenteric venous L/P ratios continued to increase.

Dopexamine reversed high colonic mucosal to arterial PCO2 gradient and luminal lactate release while it augmented the PCO2 gradient in stomach. No effect on gastric luminal lactate release was observed. Dopexamine did not reverse arterial hyperlactataemia or high arterial L/P ratio. Gastric veno-arterial lactate gradient and L/P ratio exceeded baseline in dopexamine treated animals while veno-arterial lactate gradients over the jejunum and colon remained at baseline (Table 4).

Systemic arterial blood IL-1 and IL-6 concentrations increased after endotoxin challenge and dopexamine did not modify this cytokine response (Table 1).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
One of the main findings of the present study was that despite increasing cardiac output at the onset of hypodynamic endotoxin shock, dopexamine decreased the proportional splanchnic blood flow. Second, during prolonged endotoxaemia, dopexamine decreased proportional coeliac trunk blood flow while it gradually increased the proportional superior mesenteric arterial blood flow. Third, during prolonged endotoxaemia both colonic and gastric mucosal to arterial PCO2 gradients increased and intestinal luminal lactate release occurred suggesting probable mucosal dysoxia. Dopexamine reversed mucosal carbon dioxide stagnation and luminal lactate release in the colon while mucosal to arterial PCO2 gradient increased further and luminal lactate release persisted in the stomach. Understandably, as this was an experimental porcine model of endotoxin shock with a comparably low number of animals, interpretation of the findings and extrapolation of the data to clinical setting must be made with caution. However, the controlled randomized design with stable control conditions (except for gradually increasing coeliac trunk blood flow in control animals) suggest that these findings may be of significance. Moreover they offer further explanation for earlier controversial findings regarding splanchnic perfusion and metabolism during endotoxaemia especially if dopexamine is used as an inotrope.

Dopexamine is widely used in critical illness. One of the main indications for its use is to increase gut perfusion (81% of the intensive care units in UK1). Indeed, dopexamine was primarily considered to selectively increase splanchnic perfusion but controversial results were reported by us in postoperative2 and by Meier-Hellmann and colleagues3 in septic patients. In these studies increasing overall splanchnic blood flow was associated with decreasing gastric mucosal pH or increasing mucosal to arterial PCO2 gradient. In addition, if septic patients are treated with norepinephrine, dopexamine does not necessarily increase total splanchnic blood flow as reported by Kiefer and colleagues.4 At least two reasons may explain the controversy. First, the effect of dopexamine on overall splanchnic blood flow may vary with the phase of shock. This was apparent in the present study, where at the onset of the hypodynamic phase the proportion of total splanchnic blood flow decreases during dopexamine infusion. After prolonged endotoxaemia, total splanchnic blood flow returns to baseline during dopexamine infusion. Second, the effect of dopexamine on resistance vessels downstream of each arterial branch supplying the viscera may vary. Indeed, during prolonged endotoxaemia dopexamine maintained overall splanchnic blood flow at baseline levels while there was a redistribution of blood flow within the splanchnic bed. Coeliac trunk blood flow decreased but superior mesenteric blood flow increased. Clearly, endotoxin infusion per se induced gradual redistribution of blood flow within the splanchnic region and this was augmented by dopexamine. This is in accordance with a previous study on endotoxaemic sheep by Schiffer and colleagues.6 In addition, Schwieger and colleagues12 showed that endotoxaemia abolishes the vasodilatory effects of two other dopamine-1 receptor agonists, fenoldopam and dopamine in the coeliac trunk. Finally, in other models of systemic inflammation such as after extracorporeal circulation in rabbits13 or pigs,14 dopexamine appears to have selective vasodilatory effects on vasculature downstream to the superior mesenteric artery as opposed to the coeliac trunk.

We suggest that high metabolic rate during inflammation (as indicated by increasing systemic V·CO2) was met by increasing oxygen delivery to tissues supplied by the superior mesenteric artery but not the tissues supplied by the coeliac trunk. Thereby, the blood flow reduction (relative to metabolic demand) to the gastric mucosa during prolonged endotoxaemia was severe enough to induce not only increasing mucosal to arterial PCO2 gradient but also luminal lactate release. Dopexamine reversed the increase of mucosal to arterial PCO2 gradient and luminal lactate release in the colon, while in the stomach dopexamine eventually induced further widening of the mucosal arterial PCO2 gradient and did not reverse luminal lactate release. We15 16 and others17 have described intestinal luminal lactate release in experimental endotoxin shock and in septic patients, respectively. In addition, gastric venous to arterial lactate gradient became positive indicating lactate production, while mesenteric and colonic venous to arterial gradients remained negative or low. Collectively, these data may indicate that gastric mucosal epithelial cells undergo anaerobic metabolism during dopexamine infusion while the metabolic derangement was reversed in the colonic mucosa. Alternatively, intestinal luminal lactate release and regional venous lactate production may be related to inactivation of pyruvate dehydrogenase (PDH) by endotoxin,18 increased pyruvate production,19 increased Na-K-ATPase activity20 or altered pyruvate delivery to tricarboxylic acid cycle in mitochondria as in poly(ADP-ribose)polymerase (PARP-1) induced cell injury.21 PARP-1 is activated by lipopolysaccharide.22 Since in the present experiment none of these were specifically tested, the mechanism underlying the increase in luminal lactate release remains speculative. However, it is reasonable to conclude that, to some extent, the metabolic state of the intestinal mucosal epithelial cells was altered during prolonged endotoxaemia. In support of anaerobic metabolism and dysoxia is the concomitant increase in gastric mucosal to arterial PCO2 gradient.

The systemic inflammatory response during endotoxin shock was confirmed by high arterial IL-1ß and IL-6. This was, by and large, the main purpose for measuring cytokines. Conversely, one aspect of the stability of the model was verified by stable cytokine concentrations in the control group. Additionally, we report here that dopexamine did not modify the inflammatory response induced by endotoxin. This is in contrast with the results described by Berendes and colleagues.23 They found that dopexamine inhibited IL-6 release in CABG patients. Moreover, Dhingra and colleagues5 previously reported inhibition of lung inflammation by dopexamine. One possible explanation for the discrepancy is the high degree of inflammatory stimulus by endotoxin infusion in the present experiment when compared with the two other studies.

In conclusion and considering that this was a porcine model for endotoxin shock where extrapolation to humans may be limited, we suggest that dopexamine is not associated with selective overall splanchnic vasodilation in the hypodynamic phase of endotoxin shock. In contrast, dopexamine induces a superselective mucosal perfusion defect in the stomach while colonic mucosal perfusion/metabolism is ameliorated by dopexamine during prolonged endotoxaemia. In other words, dopexamine induces blood flow redistribution within the splanchnic area, which may not be considered as a homogeneous entity in different disease states or with various drug interventions.


    Acknowledgements
 
This study was supported in part by a grant from Kuopio University Hospital, and a grant from the Finnish Medical Society.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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23 Berendes E, Mollhoff T, Van Aken H, et al. Effects of dopexamine on creatinine clearance, systemic inflammation, and splanchnic oxygenation in patients undergoing coronary artery bypass grafting. Anesth Analg 1997; 84: 950–7[Abstract]