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Ann Thorac Surg 1997;63:728-735
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Regional Perfusion Abnormalities With Phenylephrine During Normothermic Bypass

Department of Anesthesiology and Office of Biostatistics, The University of Texas Medical Branch, Galveston, Texas

Accepted for publication October 14, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Hypotension and vasopressors during cardiopulmonary bypass may contribute to splanchnic ischemia. The effect of restoring aortic pressure on visceral organ, brain, and femoral muscle perfusion during cardiopulmonary bypass by increasing pump flow or infusing phenylephrine was examined.

Methods. Twelve anesthetized swine were stabilized on normothermic cardiopulmonary bypass. After baseline measurements, including regional blood flow (radioactive microspheres), aortic pressure was reduced to 40 mm Hg by decreasing the pump flow. Next, aortic pressure was restored to 65 mm Hg either by increasing the pump flow or by titrating phenylephrine. The animals had both interventions in random order.

Results. At 40 mm Hg aortic pressure, perfusion to all visceral organs and femoral muscle, but not to the brain, was significantly reduced. Increasing pump flow improved perfusion to the pancreas, colon, and kidneys. In contrast, infusing phenylephrine (2.4 ± 0.6 µg · kg^-1·min^-1) increased aortic pressure but failed to improve splanchnic perfusion, so that significant perfusion differences existed between the pump flow and phenylephrine intervals.

Conclusions. Increasing systemic pressure during cardiopulmonary bypass with phenylephrine causes significantly lower values of splanchnic blood flow than does increasing the pump flow. Administering vasoconstrictors during normothermic cardiopulmonary bypass may mask substantial hypoperfusion of splanchnic organs despite restoration of perfusion pressure.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Despite ongoing improvements in cardiac operative techniques and the management of cardiopulmonary bypass (CPB), splanchnic organ dysfunction in the postoperative period persists, causing substantial morbidity and mortality [1–6]. One factor consistently implicated in the pathogenesis of postoperative visceral dysfunction is hypotension during CPB. Systemic vascular resistance markedly declines during CPB [4] and, with nonpulsatile flow, visceral perfusion is linearly related to perfusion pressure [7]. Consequently, the recommendation is frequently made to elevate and maintain systemic blood pressure either by increasing the pump flow rate or by administering a vasoconstrictor [4, 8–10]. However, no consensus exists as to which technique provides the best regional organ perfusion, and each technique has potential hazards. Increasing the pump flow rate during CPB may require the addition of volume to the venous reservoir and can increase collateral myocardial blood flow, as well as the potential risk of blood trauma and microemboli formation. On the other hand, vasoconstrictors could, by their very nature, compromise and reduce regional perfusion to vital organs [11]. The use of vasopressors in the perioperative period has been implicated as an independent risk factor for the development of postoperative gastrointestinal complications in several [1, 2, 12, 13], but not all [4, 14] studies. It is unclear whether vasopressors or the underlying hypotension prompting the use of vasopressors is responsible for this morbidity.

This study was designed to examine the effects of restoring systemic perfusion pressure either by increasing the pump flow or by infusing a vasoconstrictor (phenylephrine) on regional perfusion of the cerebral cortex, kidneys, splanchnic organs, and skeletal muscle. Normothermic CPB was used because of the recent clinical interest in warm heart operations and the need under these conditions to maintain aortic perfusion pressure by phenylephrine infusions [15, 16]. This experimental model attempts to identify which of these vascular beds are constricted by phenylephrine as perfusion pressure is augmented during CPB.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Animals were handled according to the guidelines approved by the American Physiological Society and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). The institutional Animal Care and Use Committee approved this study.

General anesthesia was induced in 12 fasted, mature, female Yorkshire pigs (weight, 31.9 ± 1.1 kg; range, 27.5 to 32.8 kg) using ketamine (20 mg/kg intramuscularly) followed by sodium thiopental (5 to 10 mg/kg intravenously) for endotracheal intubation. Each animal was ventilated with a tidal volume of 15 mL/kg using a volume-cycled ventilator (model 607; Harvard Apparatus, Natick, MA). The respiratory rate was adjusted to maintain normocarbia, and the inspired oxygen concentration was adjusted to maintain arterial oxygen tension greater than 100 mm Hg. Anesthesia was maintained with a continuous intravenous infusion of diazepam (0.3 mg·kg^-1·h^-1) and fentanyl (30 µg·kg^-1·h^-1). Supplemental boluses of fentanyl (10 µg/kg) and diazepam (0.1 mg/kg) with isoflurane (0.25% to 0.5% inspired concentration) were administered as necessary to maintain a sufficient depth of anesthesia, as indicated by eye reflexes and acute increases in blood pressure and heart rate during spontaneous circulation, or by hypertension and cyclic variability in blood pressure during CPB. Muscle paralysis was provided by pancuronium, 0.1 mg/kg intravenously, and was repeated as required to prevent shivering.

A catheter was inserted into the right femoral artery for microsphere sampling and arterial blood gas analysis. Another catheter was placed in the right femoral vein and was threaded proximally 10 to 12 cm into the inferior vena cava to administer intravenous fluid and to measure intraabdominal venous pressure. The left femoral vein was isolated and cannulated without ligation, with the catheter tip threaded 3 cm distally into the hindquarter to measure femoral venous pressure. Core temperature was recorded by a precalibrated thermistor probe (Yellow Springs Instruments, Yellow Springs, OH) placed in the distal esophagus. The swine was turned prone, and both temporalis muscles were dissected free from the overlying cranium and reflected laterally. Along the midline of the cranium, a 1-cm burr hole was drilled to expose the superior sagittal sinus, which was cannulated directly. The temporalis muscles were reopposed.

Through a median sternotomy incision, transducer-tipped catheters (model MPC 500; Millar Instruments, Houston, TX) were placed in the proximal aorta through the right internal mammary artery and in the superior vena cava through the right internal mammary vein. The pericardium was incised and tented. Heparin, 300 U/kg, was administered before inserting a 20-F infusion cannula in the ascending aortic arch and a 40-F two-stage venous drainage cannula through the right atrium to harvest venous return. Heparin doses were repeated during CPB as necessary to maintain the activated clotting time at greater than 400 seconds. The pump was primed with 1,000 mL of electrolyte solution (Plasmalyte; Baxter Edwards Critical Care, Deerfield, IL) and 500 mL of Hespan 6% hetastarch (Hespan; Dupont Pharmaceuticals, Wilmington, DE). A 40-µm arterial blood filter and bubble trap (model SP3840; Pall Biomedical Products, East Hills, NY) was inserted in the arterial infusion line, and a membrane oxygenator with reservoir unit (model VPCML Plus; Cobe Cardiovascular, Arvada, CO) was used. Nonpulsatile perfusion was provided by a roller pump (model 700; Sarns, Ann Arbor, MI). The arterial oxygen tension was adjusted using an air-oxygen mixture to maintain it above 200 mm Hg, and the gas flow was adjusted to maintain normocarbia. Isoflurane was administered through an inline vaporizer on the gas inflow circuit. Normothermia was maintained throughout the experiment.

Experimental Protocol
After the animals had stabilized on bypass at a pump flow rate of 100 mL·kg^-1·min^-1, baseline measurements were obtained, which included blood flow using radioactive microspheres. Next, the pump flow rate was reduced for a mean aortic pressure (MAP) of 40 mm Hg. Twenty minutes later, we obtained repeat measurements at this low perfusion pressure interval. Each animal was then subjected to the following two conditions: (1) restoration of MAP to 65 mm Hg by increasing the pump flow rate (pump flow interval), and (2) restoration of MAP to 65 mm Hg by infusing dilute phenylephrine (phenylephrine interval). During the latter, the pump flow was maintained at the same rate as during the low perfusion pressure interval while phenylephrine (10 mg in 50 mL 0.9% saline solution) was titrated by syringe pump directly into the venous reservoir. The order of interventions to restore MAP was randomized so that each animal received both treatment modalities. Each condition included 20 minutes of stabilization before repeat measurements were acquired.

Measurements
Central venous and aortic pressures were measured using transducer-tipped catheters connected to a Gould ES2000 electrostatic recorder (Valley View, OH). Arterial blood gases (model 1306; Instrumentation Laboratory, Lexington, MA) and hemoglobin (CO-Oximeter model 482; Instrumentation Laboratory) were measured repeatedly. After the animals had stabilized on bypass, plasma glucose was determined by a glucometer (Lifescan Inc, Milipitas, CA) and plasma osmolality was measured using a vapor pressure osmometer (Wescor, Logan, UT). Regional blood flow was quantified by injecting two to three million radioactive microspheres (15 ± 3 µm in diameter) labeled with strontium 85, cobalt 57, scandium 46, niobium 95, or tin 113. The order of microspheres was randomized, and the dose was selected to ensure that all regional tissue samples contained more than 400 microspheres [17]. Each microsphere dose was sonicated for 30 minutes, mixed with 3 mL of saline solution, vortexed, and injected over 15 seconds through the aortic cannula. This injection technique produces adequate mixing without recirculation [17]. Reference sampling from the femoral artery began 10 seconds before injection of the microspheres, and blood samples were collected in separate tared vials at 6.5 mL/min for 4 minutes.

Tissue Sampling
At the completion of each experiment, the heart was arrested using a saturated potassium solution, CPB was discontinued, and the animal was exsanguinated. Both kidneys were removed, and 5-mm coronal sections were acquired from the center of each. The renal cortex was separated from the medulla by sharp dissection, and the cortex was further divided into outer two-thirds and inner one-third segments. Tissue samples (3 to 5 g) of gastric mucosa and transmural slices of the pancreas, duodenum, jejunum, ileum, and colon were excised. Tissue samples (30 to 40 g) of femoral muscle from the left leg were excised. The brain was removed; total radioactivity from the left and right cerebral hemispheres was counted, as well as from the cerebellum.

Tissue samples were weighed and analyzed for regional blood flow. Radioactivity was counted in each specimen using a Packard gamma counter (Meriden, CT) with a 3-in sodium iodide crystal. Appropriate corrections were made for spillover radioactivity from other isotopes and for tissue sample height. Tissue blood flow (mL/min per 100 g) was calculated as:

(1)

where Q_t = tissue blood flow; Q_r = reference sample blood flow; C_t and C_r = radioactivities in tissue and reference samples, respectively; and W_t = weight of the tissue sample. Systemic vascular resistance (mm Hg · mL^-1·min^-1) was calculated as: [MAP - central venous pressure] ÷ pump flow. Regional vascular resistances (mm Hg·mL^-1·min^-1 per 100 g) in the stomach, pancreas, kidney, femoral muscle, and cerebral hemispheres were calculated as: [MAP - regional venous pressure] ÷ regional blood flow. Venous pressure in the splanchnic bed for all visceral organs was assumed to be that measured in the inferior vena cava.

Statistical Methods
Six animals received phenylephrine as the first treatment and increased pump flow as the second treatment. The other 6 animals received increased pump flow as the initial treatment followed by phenylephrine as the second treatment. The effect of treatment sequence between groups was assessed using analysis of variance for the two-period crossover study. The effect of aortic pressure (baseline; hypotension) and the effect of treatment (phenylephrine; increased pump flow) were assessed using analysis of variance with repeated measures for a two-factor experiment. Fisher's least significant difference procedure with Bonferroni adjustment for the number of comparisons was used for multiple comparisons, with a p value less than 0.05 considered significant. Data are expressed as mean ± standard error of the mean.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The study was completed successfully in all 12 animals, with CPB lasting 158 ± 2 minutes (range, 145 to 165 minutes). Table 1 illustrates the hemodynamic and oxygenation data during CPB. During the study, a linear relation was established between alterations in pump flow and MAP, where aortic pressure = [0.02 x pump flow] + 16 mm Hg (r² = 0.759; p < 0.01). Reducing pump flow at the low perfusion pressure interval significantly reduced aortic pressure by 50%. Subsequent elevation of aortic pressure to 65 mm Hg required increasing the pump flow from 47 ± 2 to 71 ± 3 mL·kg^-1·min^-1 or the titration of phenylephrine at 2.4 ± 0.6 µg·kg^-1·min^-1 (range, 0.5 to 6.2 µg·kg^-1·min^-1). Oxygenation and temperature variables remained relatively stable throughout the experiment, except for a significant increase in serum hemoglobin during the phenylephrine infusion. Baseline plasma glucose was 72 ± 4 mg/dL and plasma osmolality was 297 ± 3 mOsm/L.

Decreasing pump flow at the low perfusion pressure interval caused significant reductions in blood flow to all visceral organs, the kidneys, and femoral muscle. In particular, perfusion to the gastric mucosa and pancreas was halved by hypotension (Table 2). Although systemic vascular resistance did not change as perfusion pressure was reduced (Table 3), renal vascular resistance increased. Accordingly, the ratio of outer to inner renal cortical flow decreased with hypotension (Table 4). Vascular resistances in the stomach and pancreas were not altered at the low perfusion pressure interval. Cerebral, and presumably cerebellar, blood flows were not adversely affected by hypotension (see Table 2) because of a 50% reduction in cerebral vascular resistance with hypotension (see Table 3).

During the infusion of phenylephrine, systemic vascular resistance increased by nearly 100% as MAP was restored to 65 ± 1 mm Hg (see Table 3). Overall, the change in systemic vascular resistance was markedly greater with phenylephrine than with increased pump flow (Fig 1A). Regional blood flows to the kidneys and all visceral organs were significantly lower with phenylephrine than at the pump flow interval despite similar perfusion pressures. Resistances in the gastric, pancreatic, and renal vascular beds were significantly greater with phenylephrine than at the low perfusion pressure interval, as well as when perfusion pressure was elevated by pump flow (see Table 3; Figs 1B, 1C, 1D). Although regional vascular resistance data for the small and large intestines were not analyzed, their responses to increased flow and phenylephrine infusion were similar to that found in the stomach. The change in regional vascular resistance with phenylephrine was greater than the change with increased flow by factors of 2.1 (duodenum and ileum), 2.2 (jejunum), and 3.5 (colon). In contrast, vascular resistance in the femoral muscle and cerebral hemispheres with phenylephrine did not differ from those in the pump flow interval (Figs 1E, 1F), indicating that this dose of phenylephrine had minimal vasoconstrictor effect on perfusion to these regions during normothermic CPB.

View larger version (25K): [in this window] [in a new window]   Fig 1. . Individual changes in vascular resistance from the low perfusion pressure interval are depicted for the systemic circulation (A), stomach (B), pancreas (C), renal cortex (D), femoral muscle (E), and cerebral hemispheres (F). As perfusion pressure was restored to 65 mm Hg with phenylephrine, significant increases in vascular resistance were found in the systemic circulation as well as in the stomach, pancreas, and kidneys. At similar perfusion pressures, femoral muscle and cerebral vascular resistances were not different with phenylephrine and increased pump flow. Solid bars indicate mean values. (*p < 0.05 compared with the pump flow interval.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Hypotension occurs frequently during CPB, with a marked reduction in systemic vascular resistance secondary to hemodilution, reduced blood viscosity, and dilution of circulating catecholamines, with lesser effects from hyperkalemia, complement activation, and a generalized inflammatory response to extracorporeal circulation [12, 18]. Therapy to restore aortic pressure consists of infusing a systemic vasoconstrictor, such as phenylephrine, or increasing pump flow, which is limited by the amount of venous reservoir volume, excessive arterial line pressures, and potential blood trauma. In several studies, the perioperative use of vasopressor drugs has been implicated in the occurrence of gastrointestinal complications [2, 12, 13]. However, more recent studies have found no clear indication that infusing vasopressors during CPB is harmful [4, 14]. Part of the difficulty in determining outcome from perioperative therapy is the large number of patients required to study a problem that has a relatively low incidence.

The present study compared the effects of increasing pump flow and infusing phenylephrine on regional organ perfusion as aortic pressure was restored from 40 mm Hg to 65 mm Hg during CPB. Phenylephrine was examined because it is a selective -adrenergic agonist stimulating vascular smooth muscle receptors [19–22] and is commonly recommended for use during cardiac operations [8, 14–16]. In general, regional vascular resistance is determined directly by perfusion pressure and inversely by regional perfusion. Our experimental model assessed the relative influence of two different therapies on both indices during normothermic CPB. Others who have studied the vascular effects of vasoconstrictors have noted that any influence of a drug on regional vascular resistance could be either a pressure-independent effect by direct, neurohumorally mediated vasoconstriction or a secondary, pressure-dependent effect from autoregulation [20–22].

Hellebrekers and colleagues [20] studied regional autoregulatory responses in the mesenteric, renal, and iliac vascular beds during phenylephrine infusion in conscious dogs. With systemic hypertension, the mesenteric and renal beds, but not the iliac bed, contributed substantially to the overall change in regional vascular resistance by indirect autoregulatory mechanisms in addition to a direct vasoconstrictive effect. In that study, phenylephrine elicited a greater direct vasoconstrictive response in the iliac vasculature than in the mesenteric bed. Similarly, Meininger and Trzeciakowski [22] found little direct vasoconstrictor effect of phenylephrine on the mesenteric circulation in anesthetized rats over a pressure range of 20 to 140 mm Hg. Unlike angiotensin II, phenylephrine failed to shift the intestinal pressure-flow relation downward, indicating a relative sparing of mesenteric vasoconstriction. Based on these animal studies, phenylephrine should be ideal for increasing vascular resistance during CPB by predominantly causing skeletal muscle vasoconstriction.

Although similar doses of phenylephrine were tested [20, 22], the present study showed that phenylephrine had minimal effects on femoral vascular resistance but greater effects on the splanchnic circulation during CPB (see Fig 1). Any discrepancy in our results compared with other studies may be explained by the effects of anesthetic drugs or of nonpulsatile perfusion on regional vascular tone. The other studies quantified the autoregulatory component of the overall change in regional vascular resistance with phenylephrine by controlling MAP using arterial hemorrhage [20] or a vascular occluder [21, 22]. Because of the limited number of measurement intervals using microspheres in the present study, pressure autoregulation of regional blood flow during CPB was not examined. Further, the range of arterial pressure examined in the present study may be below the autoregulatory limits in splanchnic organs during CPB, as has been found in the kidney [7, 23]. Finally, our animals did not have autonomic ganglionic blockade to minimize competitive effects from baroreceptor-mediated reflex decreases in vascular resistance [21]. However, each animal served as its own control so that the individual effects of increased flow and phenylephrine could be contrasted, and the order of treatment modalities did not affect our results. This model allowed the examination of specific vascular beds as perfusion pressure was increased across a physiologic and commonly encountered range during CPB.

Increasing the pump flow caused significant improvements in blood flow to the renal cortex, colon, and pancreas, where vascular resistance appeared passive. In other visceral organs, such as the stomach and small intestine, increasing the pump flow failed to improve perfusion significantly. In a previous study of porcine CPB [7], visceral perfusion to all organs increased with pump flow, but at higher rates than those used in the present study. Administering phenylephrine to restore aortic blood pressure to 65 mm Hg failed to improve perfusion to the stomach and pancreas. This failure was due, in large part, to marked increases in regional vascular resistances (see Fig 1). Other parts of the small and large intestine showed similar responses to phenylephrine: The changes in regional vascular resistance were two to three times greater when phenylephrine was used than when pump flow was increased. Phenylephrine increased systemic vascular resistance, but part of the vasoconstrictor effect was seen predominantly in visceral organs and the renal cortex, more so than in the femoral muscle bed. These findings suggest that a marked disparity in regional perfusion can exist as perfusion pressure is pharmacologically restored, so that the adequacy of visceral organ perfusion cannot be assured by monitoring MAP alone. In contrast, the cerebral circulation appeared relatively independent of perfusion pressure over this range regardless of pump flow or the use of phenylephrine, and was the only organ that demonstrated intact autoregulation during CPB. Although the administration of vasoconstrictors in high concentrations has been implicated as causing inadequate cerebral perfusion [15], data from the present study do not support this contention in this dose range (0.5 to 6.2 µg · kg^-1·min^-1).

Low perfusion pressure during CPB has been reported to decrease renal blood flow and cause cortical flow redistribution [7], a finding that was confirmed by the present study. Renal perfusion, therefore, appears to be related to pump flow rate and to be sensitive to reductions in perfusion pressure. However, restoring perfusion pressure by infusing a vasoactive drug, whether dopamine [7] or phenylephrine (present study), without changing the pump flow failed to improve renal blood flow. Rather, increasing the pump flow and, consequently, the perfusion pressure improved renal perfusion. Similarly, a direct linear relation was established between aortic pressure and gastric mucosal perfusion over the range of 40 to 80 mm Hg when produced by altering the pump flow rate. However, gastric mucosal hypoperfusion persisted during CPB despite maintenance of an adequate perfusion pressure by phenylephrine infusion. These findings are consistent with the general concept that visceral organs have a limited ability to autoregulate with nonpulsatile flow, which may be related to the enhanced level of sympathetic tone [7] or the release of vasoconstrictor substances [24] during CPB. A substantial amount of the increase in systemic vascular resistance with phenylephrine was derived from splanchnic vasoconstriction (see Fig 1). Our results are similar to those found in a swine model of endotoxic shock, in which phenylephrine titration to restore MAP failed to improve visceral blood flow [25]. However, unlike that study, ours showed significant increases in vascular resistances in the stomach and pancreas with phenylephrine during CPB, which may reflect the relatively tight control of pressure and flow permitted during CPB. Consequently, CPB by itself may compromise splanchnic blood flow, with confounding effects from hypotension, which can exacerbate the magnitude of splanchnic hypoperfusion. The subsequent use of vasopressors to treat hypotension during CPB failed to improve visceral perfusion despite restoration of perfusion pressure, indicating a potential hazard of this mode of therapy.

Several potential limitations of the present study should be addressed. First, regional blood flows were not measured before CPB and, consequently, any relative changes with initiation of CPB were not examined. Further, only normothermia was studied; the systemic effects of hypothermia may alter these vascular responses because vascular resistance is markedly influenced by cooling [14]. Finally, MAP was restored to 65 mm Hg, a level of perfusion pressure frequently recommended during CPB [4, 8, 16]. Whether visceral perfusion might increase at higher perfusion pressures, even with phenylephrine, requires further study.

In conclusion, this study illustrates the sensitivity of splanchnic organs to hypoperfusion during normothermic CPB and the linear relation between splanchnic blood flow and pump flow rate. The use of a systemic vasoconstrictor such as phenylephrine to manage hypotension during CPB may not improve splanchnic perfusion as perfusion pressure is increased. Within the gastrointestinal tract, the gastric mucosa and the pancreas were particularly sensitive to alterations in pump flow rate, perfusion pressure, and the infusion of phenylephrine. Renal cortical blood flow correlated directly with perfusion pressure as regulated by pump flow, but not by the infusion of phenylephrine. Cerebral perfusion remained unaffected by alterations in pump flow, perfusion pressure, and administration of phenylephrine, indicating intact cerebral autoregulation. The use of vasoconstrictors during normothermic CPB did not improve splanchnic or renal perfusion abnormalities at low pump flow rates despite restoration of perfusion pressure.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported in part by grant RO1 44944 from the National Institutes of Health. We gratefully acknowledge editorial review by Faith McLellan and secretarial support from Kimberly Button.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Johnston, Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX 77555-0591.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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