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Ann Thorac Surg 1997;64:460-465
© 1997 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Cardiopulmonary Bypass Alters Vasomotor Regulation of the Skeletal Muscle Microcirculation

Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Accepted for publication February 28, 1997.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Cardiopulmonary bypass (CPB) is associated with alterations in the regulation of organ perfusion and vascular permeability. The purpose of this study was to examine the effects of hypothermic CPB on the regulation of the skeletal muscle microcirculation and the modulating influence of the priming solution.

Methods. Sheep were placed on hypothermic CPB with a prime of either Pentastarch hydroxylethyl starch (HS) solution (n = 7), a solution in which HS is conjugated with deferoxamine (n = 7), or Ringer's lactate solution (n = 7). Sheep were placed on hypothermic CPB (27°C) for 90 minutes while the heart was protected with cold blood cardioplegia. Sheep were then separated from CPB and perfused for an additional 3 hours off CPB. Hemodynamics and total water content were measured.

Results. In vitro relaxation responses of gracilis muscle arterioles (70 to 180 µm) to the endothelium-dependent agent acetylcholine, the endothelium-independent cyclic GMP-mediated vasodilator sodium nitroprusside, the ß-adrenergic agonist isoproterenol, and the adenylate cyclase activator forskolin were studied. No statistically significant hemodynamic differences were observed between groups. However, weight gain was significantly less when the priming solution was HS or HS-deferoxamine compared to when Ringer's lactate was used. Skeletal muscle arteriolar relaxations to the endothelium-dependent vasodilator acetylcholine and the ß-adrenergic agonist isoproterenol were impaired after CPB in the HS and Ringer's lactate groups. Acetylcholine response was preserved in the HS-deferoxamine group, whereas the response to isoproterenol remained impaired. The responses to sodium nitroprusside and forskolin were similar in all groups.

Conclusions. Skeletal muscle microvascular endothelium-dependent relaxation and ß-adrenergic relaxation are reduced after CPB using either a crystalloid or HS prime. Skeletal muscle microvascular endothelial dysfunction may be attributable to oxygen-derived free radical-mediated injury, whereas altered ß-adrenergic regulation is attributable to mechanisms other than the generation of oxygen-derived free radicals during CPB.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Systemic hypotension frequently occurs after cardiac operations involving cardiopulmonary bypass (CPB). This decrease in peripheral vascular tone is attributable to altered vasomotor regulation, which may involve reduced -adrenergic receptor function, reduced activity or translocation of protein kinase C, changes in intracellular calcium mobilization, or other components in the vascular smooth muscle contraction pathway [1]. Frequently, drugs such as phenylephrine are required to increase peripheral vascular tone to maintain adequate organ perfusion. It is well established that the vasomotor regulation of the cerebral [2], pulmonary [3], and coronary [4–6] circulations are altered after extracorporeal circulation and cardioplegia. The generation of oxygen-derived free radicals increases during cardiopulmonary bypass [7, 8] and reperfusion of ischemic tissues [9, 10], and may lead to vascular dysfunction. In addition, exposure of the circulation to activated neutrophils [11] and activated complement [12] may impair vasomotor regulation. However, the various vascular beds are affected differently by the physiologic perturbations associated with cardiac operations. For example, the coronary circulation alone is exposed to a cold hyperkalemic milieu, whereas the pulmonary circulation is subjected to ischemia and the inflammatory effects of CPB, but not to hyperkalemia. The cerebral and skeletal muscle circulations are exposed to similar pathologic insults including increased concentrations of cytokines and to nonpulsatile perfusion. However, the muscular and cerebral circulations have different responses to stress and reduced blood pressure. For example, cerebral blood flow is not significantly affected by ₁-adrenoceptor stimulation, whereas the skeletal muscle circulation is very sensitive to this component of adrenergic tone [13]. This can be rationalized teleologically as preservation of cerebral blood flow during hemorrhage or hypotension at the expense of perfusion of the peripheral muscles may have provided a survival advantage to our primitive ancestors. Other indices of peripheral vascular dysfunction, such as increased permeability to water and proteins are hallmarks of extracorporeal circulation, and these may be major limiting factors in reducing surgical morbidity, organ dysfunction, and postoperative length of hospital stay. The effects of CPB on skeletal muscle vasomotor regulation have not been investigated. The purpose of the present study was to examine the effect of hypothermic CPB on regulation of the skeletal muscle microvasculation with respect to endothelium-dependent relaxation and the ß-adrenoceptor cyclic AMP pathway. In addition, the possible ameliorating effects of the systemic administration of an oxygen-derived free radical scavenger conjugated to the osmotically active macromolecule hydroxyethyl starch on microvascular dysfunction was examined.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Surgical Procedures
Dorset-Rambouillet sheep (n = 21) weighing 26 to 31 kg were anesthetized with 80 mg/kg of intravenous alpha-chloralose and 500 mg/kg of urethane. Sheep were intubated and mechanically ventilated. Arterial blood gas and pH were measured during the experiment (pH blood gas analyzer 1306; Instruments Lab, Lexington, MA). Alpha-stat pH management was used during CPB. Systemic arterial pressure and central venous pressure were monitored continuously after direct cannulation of the femoral artery and right internal jugular vein.

Cardiopulmonary Bypass Preparation
A pericardial well was created through a sternotomy incision and the sheep was heparinized intravenously with 400 U/kg. The heart was cannulated through the distal ascending aorta and right atrium. The extracorporeal circuit was composed of a roller pump (Cardiovascular Instruments, Wakefield, MA) and bubble oxygenator (Bentley Bio-2; Baxter Healthcare, Irvine, CA). An arterial filter (Bentley Bio-1025; Baxter Healthcare) was placed into the circuit distal to the roller pump. The CPB circuit was primed according to the study protocol. Core temperature was continuously measured with a rectal probe.

For myocardial protection, antegrade cold blood cardioplegia at 4°C using a 4:1 ratio of autologous blood to crystalloid cardioplegia (consisting of 60 mmol/L of potassium chloride, 12.5 g of mannitol, 50 mL of citrate-phosphate-dextrose solution, 10 mEq of THAM, 5% dextrose solution, and a sufficient quantity of 0.225% saline solution). Iced slush was used for topical myocardial cooling. After the aortic cross-clamp was applied, 300 mL of cold cardioplegic solution was infused into the aortic root at 60 mm Hg. Cardioplegic solution (150 mL) was again infused every 20 minutes. After initiation of CPB, sheep were systemically cooled to a core temperature of 27°C. After approximately 50 minutes, rewarming was commenced. A core temperature of 37°C was attained before separation from CPB. Blood flow was maintained to keep aortic mean pressure at more than 40 mm Hg. If this pressure was not achieved by increasing the perfusion flow during bypass to 100 mL/kg or by increasing fluid volume such that left atrial pressure was more than 12 mm Hg after cessation of CPB, norepinephrine bitartrate (Sanofi Winthrop Pharmaceuticals, New York, NY) was infused through the central venous pressure line. After a total of 90 minutes) of extracorporeal circulation, sheep were separated from CPB and were decannulated. Perfusion was maintained off CPB for 3 hours. Sheep were weighed before initiation of the experiment and at the end. Fluid requirements during and after CPB were measured and recorded.

Sheep were cared for in accordance with the guidelines established by the Beth Israel-Deaconess Medical Center Committee on Animal Research and those prepared by the Committee on Care and Use of Laboratory Animals of the Institute of Animals Resources, National Research Council (NIH publication 86-23, revised 1985).

In Vitro Skeletal Muscle Microvessels
Gracilis muscle specimens were obtained before (control vessel responses) and after hypothermic CPB and 3 hours of perfusion after CPB under normothermic conditions. Skeletal arterioles (internal diameter, 80 to 170 µm) were isolated, cannulated with dual glass micropipettes, secured with 10-0 nylon monofilament sutures, and placed in a microvessel chamber containing warm (37°C) MOPS buffer solution (pH 7.4). Vessels were pressurized to 50 mm Hg in a no-flow state. An inverted microscope (CK-2, 40–200x; Olympus Optical, Tokyo, Japan) connected to a video camera was used to project the vessel image onto a television monitor. An electronic dimension analyzer (Living System Instrumentation, Burlington, VT) was used to monitor continuously the internal lumen diameter. Measurements were recorded on a stripchart recorder.

After equilibration of the microvessels in the MOPS buffer solution for at least 30 minutes, vessels were precontracted by 30% to 50% of the baseline diameter with phenylephrine (0.1 to 100 µmol/L). After stabilization of the precontracted diameter, acetylcholine (1 nmol/L to 0.1 mmol/L), forskolin (1 nmol/L to 0.1 mmol/L), isoproterenol (1 pmol/L to 100 µmol/L), or sodium nitroprusside (1 nmol/L to 0.1 mmol/L) were applied extraluminally. Measurements were obtained 2 to 3 minutes after the drug was administered when the response had stabilized. Two or three vessels were examined from each animal and one or two drug responses were examined on each vessel. The order of administration of drugs was randomized.

Study Protocol
Sheep were divided into three groups according to their CPB priming solution. All animals received 500 mL of lactated Ringer's solution, with either 500 mL 10% hydroxylethyl starch (HS) (n = 7); 500 mL 10% HS conjugated to deferoxamine (HS-deferoxamine; n = 7), or additional 500 mL of Ringer's lactate solution (RL group; n = 7) in the priming solution.

Drugs
Hydroxyethyl starch (Pentastarch) and its conjugate bound to deferoxamine were obtained from Biomedical Frontiers (Minneapolis, MN). Hydroxyethyl starch-deferoxamine is supplied as a 10% solution in physiologic saline. The material has an average molecular weight of 70 to 100 kilodaltons and the concentration of deferoxamine was 26 mmol/L, corresponding to 17 mg/mL of deferoxamine equivalents. Acetylcholine, sodium nitroprusside, isoproterenol, and phenylephrine were obtained from Sigma Chemical (St Louis, MO). Forskolin was obtain from RBI (Natick, MA).

Statistical Analysis
All values are expressed as mean ± standard error of the mean. Blood pressure was analyzed by one-way and two-way analysis of variance followed by Newman-Keuls post hoc test. Responses of microvessels to each agent are expressed as percent relaxation after phenylephrine-induced precontraction of the vessel diameter. Vascular responses were compared by two-way analysis of variance for repeated measures and Neuman-Keuls test post hoc. Statistical significance was assumed with a p value of less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Hemodynamics and Hematocrit
In all groups, initiation of CPB was associated with a significant reduction in mean blood pressure, followed by a slight increase after discontinuation of CPB (Fig 1). The hematocrit was reduced significantly and similarly from 29% ± 2% in all groups before CPB, to 20% ± 2%, 19% ± 2%, and 19% ± 1% in the RL, HS, and HS-deferoxamine groups, respectively, after 3 hours of perfusion after CPB. After CPB, 0.2 to 0.4 µg · kg^-1 · min^-1 norepinephrine was administered to three animals in each group and the amount administered was similar in each group.

View larger version (22K): [in this window] [in a new window]   Fig 1. . Plot of mean arterial blood pressure. Pressure was decreased after onset of cardiopulmonary bypass (CPB) (p < 0.05 pressure at all times versus baseline within all groups, no difference between groups) (HS = hydroxylethyl starch.)

Microvascular Characteristics
Baseline microvessel diameters were similar in all groups averaging 124 ± 6 µm, 120 ± 9 µm, 126 ± 8 µm, and 116 ± 7 µm in the control, RL, HS, and HS-deferoxamine groups, respectively. Contraction induced by phenylephrine was 40% ± 4%, 34% ± 4%, 39% ± 5%, 37% ± 3% (p = all nonsignificant versus control) in control vessels and vessels in the RL, HS, and HS-deferoxamine groups, respectively. The mean concentrations (log molar) of phenylephrine required to attain these contractions were -5.3 ± 0.2, -4.7 ± 0.3 (p < 0.05 versus control), -4.8 ± 0.3 (p < 0.1 versus control), -4.8 ± 0.2 (p < 0.0.5 versus control) in the control, RL, HS, and HS-deferoxamine groups, respectively. Thus, CPB is associated with a slight but statistically significant reduction in the contractile response of skeletal muscle microvessels to ₁-adrenoceptor stimulation.

Endothelium-Dependent Relaxation
Acetylcholine, an endothelium-dependent vasodilator, elicited a potent dose-dependent relaxation response in control skeletal microvessels. Microvessels subjected to CPB showed a significantly reduced relaxation response to acetylcholine in the HS and RL groups. Responses in the HS-deferoxamine group were similar to those in the control vessels (Fig 2).

View larger version (25K): [in this window] [in a new window]   Fig 2. . Plot of in vitro responses of precontracted skeletal muscle microvessels to the cholinergic agonist acetylcholine. Vessels are from the control (n = 7, before cardiopulmonary bypass), Ringer's lactate (n = 7, RL), hydroxylethyl starch (HS)-deferoxamine (n = 7), and hydroxylethyl starch groups (n = 7). Responses are expressed as percent relaxation of the phenylephrine-induced vascular contraction. (*p < 0.05 versus control; p < 0.05 versus hydroxylethyl starch.)

View larger version (30K): [in this window] [in a new window]   Fig 3. . Plot of in vitro responses of precontracted skeletal muscle microvessels to the ß-adrenergic agonist isoproterenol. Vessels are from the control (n = 7, before cardiopulmonary bypass), Ringer's lactate (n = 7, RL), hydroxylethyl starch (HS)-deferoxamine (n = 7), and hydroxylethyl starch groups (n = 7). Responses are expressed as percent relaxation of the phenylephrine-induced vascular contraction. (*p < 0.05 versus control.)

View larger version (23K): [in this window] [in a new window]   Fig 4. . Plot of in vitro responses of precontracted skeletal muscle microvessels to the guanylate cyclase activator sodium nitroprusside. Vessels are from the control (n = 7, before cardiopulmonary bypass), Ringer's lactate (n = 7, RL), hydroxylethyl starch (HS)-deferoxamine (n = 7), and hydroxylethyl starch groups (n = 7). Responses are expressed as percent relaxation of the phenylephrine-induced vascular contraction.

View larger version (21K): [in this window] [in a new window]   Fig 5. . Plot of in vitro responses of precontracted skeletal muscle microvessels to the adenylate cyclase activator forskolin. Vessels are from the control (n = 7, before cardiopulmonary bypass), Ringer's lactate (n = 7, RL), hydroxylethyl starch (HS)-deferoxamine (n = 7), and hydroxylethyl starch groups (n = 7). Responses are expressed as percent relaxation of the phenylephrine-induced vascular contraction.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

The addition of a priming solution containing HS conjugated with deferoxamine preserved endothelium-dependent relaxation, but had no effect on altered ß-adrenergic vascular regulation. Deferoxamine has been shown to inhibit the formation of hydroxyl free radicals by chelating iron and effectively removing it from the oxidation–reduction cycle (Haber-Weiss or Fenton reactions) [10]. Animal and clinical studies have demonstrated that deferoxamine is protective of cardiac myocytes [19] and vascular tissue [5] during reperfusion after tissue ischemia [20–22]. Despite the potential benefits of deferoxamine in reducing oxidant-induced injury in clinical cardiac operations, the use of the nonconjugated form has been limited by its systemic toxicity [23].

It is of interest that both impaired endothelium-dependent relaxation and increased vascular permeability, which is reflected in increased weight gain, were reduced in the group in which HS-deferoxamine was used to prime the CPB circuit. However, HS even when not conjugated with deferoxamine, decreased the fluid requirement and decreased weight gain after CPB. This suggests that oxygen-derived free radicals may be involved in the endothelial dysfunction after CPB, but that the oncotic effect of HS limits weight gain. Oxygen-derived free radicals may directly injure the endothelium, or they may initiate complement activation [12], which subsequently produces vascular dysfunction. Furthermore, complement activation or neutrophil activation, both of which occur during CPB [24, 25], may lead to increased generation of oxygen-derived free radicals.

ß-Adrenoceptor-mediated relaxation was reduced similarly in all experimental groups, whereas the response to forskolin was unchanged. This suggests that CPB desensitizes ß-adrenoceptors and that the desensitization is not affected by the composition of the CPB priming solution. In addition, the altered response to ß-adrenoceptor stimulation is not attributable to the generation of oxygen-derived free radicals. A recent study [26] showed that the exposure of cerebral microvessels to exogenous catecholamines causes a desensitization of ß-adrenoceptors from adenylate cyclase. Thus, increased concentrations of circulating catecholamines during and after CPB may be the cause of the impairment in ß-adrenergic vascular regulation observed in skeletal muscle arterioles.

The findings of the present study suggest an active effect of deferoxamine conjugated to HS in the prevention of microarterial dysfunction after CPB, and are consistent with a role of the hydroxyl radical in causing CPB-induced vasomotor dysfunction. We have previously reported that the addition of deferoxamine to a crystalloid cardioplegic solution will maintain endothelium-dependent relaxation in the coronary circulation better than a plain crystalloid solution. In addition, it is known that vasomotor regulation of another peripheral vascular bed, namely the cerebral circulation, is altered after either normothermic [2] or hypothermic [27] extracorporeal circulation. However, it has not been known how the peripheral skeletal muscle circulation is affected by CPB, or if the effects are altered by increasing colloidal pressure or by the addition of an iron chelator and hydroxyl radical synthesis inhibitor to the priming solution. A knowledge of alterations in the regulation of peripheral vasomotor tone and the responses to endothelium-dependent vasodilators and neuronal agonists may be important in preventing and treating hypotension after CPB. Understanding the differential vascular responses of various vascular beds and the effects of CPB on their respective reactivities may help prevent selective organ ischemia and dysfunction that may occur when systemic hypotension is treated at the expense of blood flow to a specific beds. A limitation of this study is that only one vascular bed was examined. A large proportion of total peripheral vascular resistance may be determined by the mesenteric and other vascular beds. In addition, vascular responses were examined at only one time point. It is likely that the observed changes in vasomotor regulation recover after days to weeks. Finally, vascular permeability per se was not examined. Only one index of increased vascular permeability (weight gain) was studied. Further studies will be required to assess the mechanisms of increased vascular permeability during CPB, such as increased expression of the inducible isoform of nitric oxide synthase or vascular permeability factor. A better understanding of the changes that occur in the control and permeability of the peripheral circulation during CPB will enable us to better regulate systemic vascular resistance and reduce fluid shifts during cardiac operations.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by grant HL46716 from the National Heart, Lung and Blood Institute.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Sellke, MD, Division of Cardiothoracic Surgery, Beth Israel-Deaconess Medical Center, East Campus, Dana 905, 330 Brookline Ave, Boston, MA 02215.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Alon Stamler Robert G. Johnson Frank W. Sellke Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stamler, A. Articles by Sellke, F. W. Search for Related Content PubMed PubMed Citation Articles by Stamler, A. Articles by Sellke, F. W.