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
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Abstract |
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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 kg1 min1 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: 8417
Keywords: circulation, extracorporeal; receptors, adrenergic; pig
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Introduction |
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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 1-mediated vasoconstriction seen during extracorporeal circulation and therefore lead to an improved microvascular perfusion in the splanchnic bed.
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Materials and methods |
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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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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 min1 (which is approximately 50% of the cardiac output), was established for 2 h. In seven animals, group III, dopexamine 3 µg kg1 min1 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 Students t-test for comparison between the groups. Paired Students 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 MannWhitney 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.
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Results |
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Discussion |
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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 levelsthe 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 1020 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 kg1 min1 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 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 s1 and 3.78 (0.61) mm s1 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.
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