Dopexamine attenuates microvascular perfusion injury of the small bowel in pigs induced by extracorporeal circulation

F.-U. Sack*,1, B. Reidenbach1, A. Schledt1, R. Dollner1, S. Taylor2, M. M. Gebhard3 and S. Hagl1

1Department of Cardiac Surgery, 2Department of Anaesthesiology and 3Department of Experimental Surgery, University of Heidelberg, D-69120 Heidelberg, Germany*Corresponding author

Accepted for publication: January 1, 2002


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Cardio-thoracic surgery with the use of extracorporeal circulation may lead to an impairment of splanchnic perfusion. The aim of this study was to investigate the effect of dopexamine on gastrointestinal microvascular perfusion failure due to extracorporeal circulation.

Methods. Twenty landrace pigs served as laboratory animals. A loop of the terminal ileum was exteriorized for microscopic observation. In 13 animals a partial left-heart bypass (pLHB), with a non-pulsatile pump flow of approximately 50% of the cardiac output, was established for 2 h. Seven animals received a continuous i.v. infusion of 3 µg kg–1 min–1 dopexamine from the beginning of pLHB to the end of the experiment. Seven sham-operated animals served as controls. The microcirculatory network was analysed by means of intra-vital microscopy prior to, during pLHB, and 2 h after bypass.

Results. Despite normal haemodynamics measured by arterial pressure and cardiac output, pLHB led to significant impairment of microvascular perfusion characterized by arteriolar vasoconstriction, reduction of functional capillary density (FCD) to 30% 2 h after weaning off bypass and diminished blood-cell velocities in submucous venules. Dopexamine attenuated this perfusion impairment, preventing arteriolar vasoconstriction. FCD remained normal.

Conclusion. Our data demonstrate that treatment with the vasoactive drug dopexamine leads to a significant reduction of the perfusion injury of the small bowel.

Br J Anaesth 2002; 88: 841–7

Keywords: circulation, extracorporeal; receptors, adrenergic; pig


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Impairment of gastrointestinal perfusion seems to be one of the basic pathophysiological mechanisms for the development of multiorgan failure.1 2 In cardiac surgery, alterations in splanchnic perfusion are often observed during and after cardiopulmonary bypass.3 4 Gastrointestinal complications are reported with an incidence of only 2–3%, but the observed mortality as a consequence of this particular complication is 12–63% and, therefore, dramatically high.57 Following extracorporeal circulation, mucosal ischaemia, altered gut permeability, and endotoxaemia have been described.8 9

These phenomena might serve as a trigger for the development of multiorgan failure.10 Dysfunction of the microcirculation during and after extracorporeal circulation has been reported in several clinical and experimental studies. The use of extracorporeal circulation may lead to vasoconstriction of the small vessels in the splanchnic vascular system, thus leading to impairment of perfusion. In addition, the pro-inflammatory effects of extracorporeal perfusion might aggravate this reaction. However, to our knowledge no experimental model exists allowing direct quantitative analysis of the different functional units of the microcirculatory network by means of intravital microscopy in the setting of extracorporeal circulation. Therefore, the objective of our study was the intravital microscopic assessment of small bowel microcirculation during extracorporeal circulation and the assessment of the potential protective effect of the vasoactive drug dopexamine (a synthethic catecholamine with activity at dopaminergic and ß2-adrenergic receptors) on microvascular perfusion. The aim of this study was to test the hypothesis that the ß2-adrenergic effects of dopexamine on the pre-capillary arterioles may modulate the {alpha}1-mediated vasoconstriction seen during extracorporeal circulation and therefore lead to an improved microvascular perfusion in the splanchnic bed.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Animal preparation
Twenty landrace pigs (22–26 kg) served as laboratory animals. The animals received care according to the German laws of animal protection. The study protocol and all experimental procedures were approved by the Government Animal Protection Committee. All animals were fasted and were allowed free access to water 24 h prior to the experiment. Anaesthesia was induced with metomidate-hydrochloride 10 mg kg–1 i.m. and azaperon 8 mg kg–1 i.m. followed by i.v. injection of ketamine-hydrochloride 7.5 mg kg–1 and atropine-sulphate 12.5 mg kg–1. Mechanical ventilation was applied after tracheostomy and intubation with 40% inspired oxygen. All subsequent procedures were performed under general anaesthesia maintained with a continuous i.v. infusion of piritramide and midazolam (2.25 and 1.8 mg kg–1 h–1, respectively).

Surgical procedures
A polyethylene catheter was inserted into the carotid artery for continuous arterial pressure monitoring and to allow for blood specimens, and a second was placed in the jugular vein for fluid administration. A small left thoracotomy was performed. Depending on the diameter of the main pulmonary artery, a 12 or 14 mm ultrasonic flow probe (Transonic Systems Inc., Ithaca, NY, USA) was placed around the vessels for continuous recording of cardiac output (CO). Following anticoagulation with 300 I.U. of heparin, the aorta and the left atrial appendage were cannulated with a 14 french and an 18 french aortic and venous cannula, respectively. As a model for partial left-heart bypass (pLHB), both cannulae were connected via a silicon tube 3/8 inch in diameter and connected to a roller pump (Stöckert, München, Germany). Following closure of the thoracotomy, the animals were placed in left lateral position on a criss-cross table of a specially designed intravital-microscope for large animals. A loop of the terminal ileum was exteriorized via a small abdominal incision and placed on a pedestal attached to the microscope (Fig. 1). The loop was stabilized by insertion of a soft and flexible silicon tube of about 15 cm in length. The bowel loop was covered with luicide foil, thus preventing dehydration. This technique appears to be superior to superfusion.11 Application of warm air maintained the tissue temperature constant at 37°C.



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Fig 1 Loop of the terminal ileum ready for microscopic observation. Different ‘regions of interest’ are defined.

 
Intravital-microscopy
For in vivo microscopy, the microvessels were visualized following intra-arterial injection of 1 ml of 5% fluorescein isothiocyanate (FITC)-labelled dextran (MW 150 000, Sigma, St Louis, MO, USA). Fluorescent latex microspheres (1 mm) were injected intra-arterially for measurements of blood-cell velocity. A modified Leitz Orthoplan microscope with a 100 W, HBO, mercury lamp, attached to a Ploemo-Pack illuminator with filter blocks for epi-illumination was used. With 6.3x and 10x long-distance objectives, a magnification of approximately 180x and 350x can be achieved. The observations were recorded by means of a charge-coupled device camera (Kappa, Gleichen, Germany) and a video-system for off-line evaluation. In addition to measuring the vessel diameters and blood-cell velocities (BCV) of the small arterioles in the muscular layer (diameter 20–50 µm), the submucosal collecting venules were also evaluated. These venules, with a diameter ranging from 30 to 70 µm, drain blood from the muscular layer as well as blood from the mucosa of the inner surface of the bowel. The muscular capillary network was recorded for quantification of functional capillary density (FCD). FCD was defined as the length of perfused capillaries divided by the size of the observed area. Several ‘regions of interest’ were selected at random and defined for repetitive observations of the same vessel during the experiment (Fig. 1). Quantitative analysis of the microcirculation was performed off-line by means of a computer-controlled image analysis system (Capimage, Zeintl, Germany). BCV, vessel diameters and FCD were measured quantitatively, whereas macromolecular leakage was defined as accumulation of FITC-dextran in the perivascular tissue with the presentation of the vessels as a negative contrast. The determination of macromolecular leakage is, therefore, strictly descriptive.

Experimental protocol
The animals were randomized into three different groups. Group I with seven sham-operated animals (thoracotomy and cannulation) served as control group. In six animals, assigned to group II, a pLHB with a non-pulsatile pump flow of 2000 ml min–1 (which is approximately 50% of the cardiac output), was established for 2 h. In seven animals, group III, dopexamine 3 µg kg–1 min–1 was injected when pLHB was initiated and continued until the end of the experiment. Macrohaemodynamic parameters such as arterial and central-venous arterial pressure, heart rate and cardiac output were recorded prior to pLHB, during pLHB, and from up to 2 h after the end of the 2-h bypass period. Arterial blood samples were used for repetitive blood-gas analyses. Intravital-microscopic observations were recorded on video tape for later off-line evaluation.

Statistical analysis
Statistical analyses included analysis of variance and Student’s t-test for comparison between the groups. Paired Student’s t-test, including Bonferroni-correction for repeated measurements, was performed for analysing differences within each group in case of normal distribution of the values (SPSS for windows 9.0, SPSS Inc. 1998).

In cases of non-normal distribution of the values the Mann–Whitney test was used to analyse significance within the groups. All macrohaemodynamic parameters are reported as mean (SD), and statistical significance was set at P<0.05. Changes in microcirculatory parameters within groups are reported as changes in percent from pre-pLHB values. Values are expressed as mean (SD), and statistical significance was set at P<0.05.


    Results
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 Abstract
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 Materials and methods
 Results
 Discussion
 References
 
In this experimental design using pLHB, the haemodynamic parameters such as heart rate, central venous pressure, systolic arterial pressure and cardiac output (Table 1) remained unchanged in both the control (group I) and pLHB group (group II). In addition, gases did not differ between the animals of all groups and remained within normal range in all animals. Arterial PO2 values were also always within the range 120–160 mm Hg with 40% inspired oxygen. Arterial PCO2 values were constant between 38 and 41 mm Hg. This haemodynamic stability is a mandatory prerequisite for interpretation of the microhaemodynamic data obtained from the observed microcirculation during pLHB. Continuous administration of dopexamine resulted in a significant increase in CO during the 2 h pLHB bypass, whereas the CO measured during the 2-h observation period after weaning off pLHB returned to baseline values as in the other groups. The flow rate during pLHB was identical in both groups because pump flow was adjusted to 50% of the CO measured at baseline.


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Table 1 Systemic variables in animals without pLHB (control), with extracorporeal circulation (pLHB) and with extracorporeal circulation and dopexamine (pLHB+dopexamine). Baseline is t=0 min; time points t=60 min and t=120 min are with extracorporeal circulation in group pLHB and group pLHB+dopexamine; time points t=180 min and t=240 min are without extracorporeal circulation. Values are mean (SD). *P<0.05 vs baseline (paired t-test); AOPmean=mean aortic pressure; CVP=central venous pressure; CO=cardiac output; HR=heart rate
 
Focusing on the microcirculation, pLHB results in significant vasoconstriction of the small arterioles (20–50 µm) (Fig. 2). This effect was observed after 1 h of pLHB and could be seen even 2 h after disconnection from bypass. In contrast, treatment with dopexamine could prevent this negative effect of pLHB completely (Fig. 2). However, a reduction of arterial blood-cell velocity 1 and 2 h after bypass could be observed in both pLHB groups (Fig. 3). At the level of the nutritive capillaries of the muscle layer, pLHB alone resulted in a severe impairment of FCD (Fig. 4). The reduction of FCD was detectable after 1 h of pLHB with continuous progression to 29% 2 h after the bypass period. In the dopexamine group, FCD remained unchanged, despite a small, but not significant decrease at the end of the observation period. Drainage of the capillary bed into the collecting venules is significantly impaired. In this type of collecting venules which also drain the submucous region, pLHB resulted in an increased leakage for macromolecules of the vascular wall, aggregation of corpuscular blood elements with haemoconcentration as a consequence (Fig. 5). This phenomenon is very similar to the findings in postcapillary venules subjected to ischaemia and reperfusion, thus reflecting a reperfusion injury of the microcirculation.12 As a consequence, the measured BCV were significantly reduced (Fig. 6). A reduction of 20% compared to baseline values could be observed after 1 h of pLHB with a maximal flow reduction (–60%) or even stasis in some vessels at 2 h following bypass. In group III, this flow reduction could not be observed during pLHB. However, after the bypass period, even in dopexamine-treated animals, a significant reduction of venular BCV could be detected. Compared to untreated animals, the degree of reduction in BCV was much smaller after treatment with dopexamine. The maximum reduction in BCV was –14% within the dopexamine group compared to –60% without treatment.



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Fig 2 Arteriolar diameter. Asterisks indicate significant changes from baseline. *P<0.05; **P<0.01; ***P<0.001. Differences are expressed as changes in percent from baseline values. Each data point is based upon approximately 200 single measurements. Time points: 0=basline; 1=1 h of pLHB; 2=2 h of pLHB; 3=1 h after weaning off pLHB; 4=2 h after weaning off pLHB.

 


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Fig 3 Blood-cell velocities in arterioles. (Time points: see Fig. 2.) Asterisks indicate significant changes from baseline. *P<0.05; **P<0.01; ***P<0.001. Differences are expressed as changes in percent from baseline values. Each data point is based upon approximately 200 single measurements.

 


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Fig 4 Functional capillary density. (Time points: see Fig. 2.) Asterisks indicate significant changes from baseline. *P<0.05; **P<0.01; ***P<0.001. Each column represents the measurements of approximately 30 capillary fields.

 


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Fig 5 Haemoconcentration and blood cell aggregates within collecting venules following 2 h pLHB and 1 h after weaning off bypass. *The corpuscular blood cells appear as clots within the FITC-dextran stained (bright) plasma.

 


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Fig 6 Blood-cell velocities in submucous venules. (Time points: see Fig. 2.) Asterisks indicate significant changes from baseline. **P<0.01; ***P<0.001. Differences are expressed as changes in percent from baseline values. Each data point is based upon approximately 200 single measurements.

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Impairment of splanchnic perfusion during cardiac surgery with extracorporeal circulation is one of the major mechanisms responsible for the disruption of intestinal integrity.1 The resulting breakdown of the barrier function of the gut may lead to systemic endotoxaemia with the subsequent release of inflammatory mediators which can promote the development of multiorgan failure.1315 However, besides systemic endotoxaemia, the contact of blood with the artificial surfaces of the bypass circuit and the mechanical trauma of the roller-pump mechanism can trigger an activation of leukocytes and the release of pro-inflammatory cytokines and complement. These phenomena can be observed in both experimental and clinical studies.1619 Moreover, in addition to these pathological changes, the risk of hypothermia and low flow or low pressure during extracorporeal circulation may aggravate the impairment of splanchnic perfusion.

Different multiple mechanisms are involved in the development of gastrointestinal complications. In order to understand and to assess the importance of single pathological changes, a model is required which permits different bypass regimens and allows direct access to the tissue or organ of interest. In vivo observation of the microcirculation may reveal possible damage of extracorporeal circulation at one of the most susceptible levels—the microcirculatory network. The major reason for choosing a model of pLHB was to avoid compromise of macrohaemodynamics. With this approach, arterial pressure and CO can be precisely controlled. This is of major importance because the microcirculation of the gut is extremly susceptible to changes in arterial pressure. Even a drop in systolic arterial pressure of 10–20 mm Hg will result in an immediate vasoconstriction of the small arterioles in the bowel. Similar reactions are seen as a consequence of changes in CO. Using our model, haemodynamic stability can be achieved throughout the experiment. This is important for the interpretation of microcirculatory results. I.v. administration of dopexamine at the dosage of 3 µg kg–1 min–1 resulted in a significant increase in cardiac output during pLHB. Due to the observation that arterial pressures remained unchanged, peripheral vasodilatation with reduced systemic vascular resistance is one effect of the dopexamine infusion. The flow rate of the bypass circuit was maintained constant. During the off-pump period, CO returned to baseline values.

Despite haemodynamic stability, pLHB results in significant impairment of the microcirculation of the ileum. The diameter of the small arterioles decrease significantly during pLHB with a further decrease in the off-pump period. This pathological vasoconstriction of the small arterioles could be prevented by the vasoactive drug dopexamine. The underlying mechanisms causing vasoconstriction are either a reaction to reduced systemic blood flow or blood pressure or a result of locally acting vasoconstrictive mediators or substances. The first possibility seems unlikely because blood pressure and CO remain within physiological ranges throughout the experiment. However, despite the fact that arterial pressure and CO remained unchanged, blood flow may be redistributed within the different organ systems, equating to no overall change. The measured macrohaemodynamic parameters only allow the conclusion that the observed changes in microvascular perfusion of the small bowel are not a result of a systemic hypoperfusion or low CO syndrome. A maldistribution of blood flow in an individual organ system with a consequent decrease in flow may lead to release of vasoactive substances.

Potential vasoconstrictors which are released or generated as a consequence of extracorporeal circulation are arachidonic acid metabolites with thromboxane as the most potent vasoconstrictor and oxygen free radicals released from activated leukocytes.2022 The direct effect of extracorporeal circulation on activation of polymorphonuclear leukocytes within the microcirculation was clearly demonstrated by Kamler and colleagues.23 The administration of dopexamine as a ß2 adrenoreceptor agonist might counteract or modulate {alpha}1-mediated vasoconstriction.24 Despite the positive effect of dopexamine in preventing the pLHB-induced vasoconstriction, the reduction of arterial BCV following pLHB could not be prevented. However, the actual arteriolar BCV in the dopexamine group 1 and 2 h after pLHB were mean 3.63 (SD 0.65) mm s–1 and 3.78 (0.61) mm s–1 respectively. These values are still very high, despite a reduction of 10% max. compared to baseline values. These values do not reflect a pathological impairment of arteriolar perfusion. Within the dependent capillary bed, no significant reduction of FCD was detectable in the dopexamine group. In untreated animals, the impairment of capillary perfusion as a consequence of pLHB is very significant. Only approximately 30% of the observed capillaries were found perfused at the end of the experiment. Typical phenomena like sudden flow stops could be observed. The underlying mechanisms are mostly due to swelling of the capillary endothelial cells and plugging with leukocytes.12 As a result of diminished arteriolar and capillary perfusion, the BCV in collecting venules were significantly reduced in the pLHB group. The reduction in blood flow was observed during pLHB and was detectable even after the end of the bypass period. It is important that the observed collecting venules also drain the mucosa of the bowel. Markedly reduced BCV in these vessel segments reflect a reduced mucosal or villous perfusion. The reduction of venous BCV of 60% compared to baseline values in untreated animals signals significantly disturbed mucosal perfusion. Typical phenomena, usually observed in tissues subjected to ischaemia and reperfusion, like intravessel sludge and haemoconcentration could be observed.

In the dopexamine group, the observed flow reduction in this particular vessel type is much smaller, thus reflecting a protective effect. However, the observed phenomena within the microcirculation of the small bowel are a result of both impaired perfusion during extracorporeal circulation and generation of metabolites with the potential effect of induction of microvascular perfusion injury. Despite the observation that the haemodynamic parameters (i.e. heart rate, arterial pressure and cardiac output) remain within the normal range, pLHB induces perfusion injury of the small bowel. Assessment of macrohaemodynamic parameters does not necessarily allow for conclusions on the microvascular perfusion, especially in cases where the macrohaemodynamics appear ‘normal’. Extracorporeal circulation leads to an impairment of splanchnic perfusion. Treatment with dopexamine attenuates the microvascular perfusion injury. However, following removal from bypass, the degree of damage within the microcirculation of the small bowel even increases. Generation and release of pro-inflammatory mediators and complements, as well as an induction of leukocytes, are potential mechanisms.23 25 26 It is unlikely that dopexamine as a vasoactive substance might directly counteract these ‘immunological’ mechanisms. However, the potential effects of dopexamine, in addition to its vasoactive properties, include modulation of pro-inflammatory cytokines27 and leukocyte function.28 It is not possible to evaluate these mechanisms with reference to our results. However, in improving microvascular perfusion by dopexamine, the degree and extent of these reactions can be reduced. It is important to realize that the impairment of the microcirculation reaches its maximum even after discontinuation of the pLHB. At this time, the positive effect of dopexamine cannot be due to the positive inotropic effect during the bypass period only and the haemodynamic values do not differ between the groups. Further studies on the effect of extracorporeal circulation on the microcirculation of the small bowel are necessary for a better understanding of the underlying pathogenic mechanisms in the development of microvascular-perfusion injury. In particular, there is a need to look at the problems induced by hypothermia and low flow perfusion. The expansion of our model towards the application of a complete cardiopulmonary bypass is possible. The direct effects of different perfusion modalities and therapeutic strategies on the microcirculation of the bowel can be assessed. As a consequence of our findings, a prospective clinical trial with dopexamine in patients undergoing cardiac surgery with cardiopulmonary bypass is planned.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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