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CARDIOVASCULAR ANESTHESIA

PentaLyte® Does Not Decrease Heparinoid Release but Does Decrease Circulating Thrombotic Mediator Activity Associated with Aortic Occlusion-Reperfusion in Rabbits

Vance G. Nielsen, MD^*, Valerie E. Armstead, MD, Brian T. Geary, BS^*, and Irina L. Opentanova, MS

*Department of Anesthesiology, Division of Cardiothoracic Anesthesia, The University of Alabama at Birmingham, Birmingham Alabama; and Department of Anesthesiology, Thomas Jefferson University, Philadelphia, Pennsylvania

Address correspondence and reprint requests to Vance G. Nielsen, MD, Department of Anesthesiology, The University of Alabama at Birmingham, 619 S. 19th St., Birmingham, AL 35249. Address e-mail to vance.nielsen{at}ccc.uab.edu

	Abstract

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Hemorrhage and thrombosis are associated with major vascular and trauma surgery. Release of heparinoids and thrombotic mediators may contribute to these complications and have been described in rabbits after aortic occlusion-reperfusion. We hypothesized that the resuscitative fluid used could reduce heparinoid and thrombotic mediator release after aortic occlusion-reperfusion in rabbits as assessed by thromboelastographic variables (R, reaction time; , angle; and G, a measure of clot strength). Anesthetized rabbits were administered lactated Ringer’s solution (n = 8) or PentaLyte® (n = 8) at reperfusion after 30 min of ischemia. Blood was obtained before ischemia and after 30 min of reperfusion for thromboelastography under four conditions: 1) unmodified sample, 2) platelet inhibition, 3) heparinase, and 4) platelet inhibition and heparinase. During reperfusion, unmodified samples demonstrated a significant increase in R and decrease in and G that was not affected by PentaLyte®. In the presence of heparinase, no significant fluid-specific thromboelastographic differences were noted. However, thrombotic mediator release (discerned by a decrease in R and an increase in ) during reperfusion in samples with platelet inhibition and heparinase was significantly attenuated by PentaLyte®. PentaLyte® administration does not decrease heparinoid release but does decrease thrombotic mediator release after aortic occlusion-reperfusion.

Implications: PentaLyte® administration does not decrease the heparinoid release associated with aortic occlusion-reperfusion but does decrease the elaboration of a thrombotic mediator. This study serves as a rational basis to determine whether coadministration of PentaLyte® with a heparin antagonist (e.g., protamine or heparinase) may maintain hemostasis after aortic occlusion-reperfusion.

	Introduction

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Among the many functions of blood, hemostasis is of great clinical interest after major vascular and trauma surgery because immediate, poorly controllable or uncontrollable hemorrhage, subsequent visceral organ thrombosis, or both are major sources of morbidity and mortality (1–6). Thoracic aortic occlusion-reperfusion adversely affects hemostasis in the rabbit, as assessed by thromboelastography (7). During reperfusion, blood samples took twice as long to begin clotting and clotted less than half as quickly, and clots were less than half as strong as the values of baseline samples (7). These hemostatic changes observed after aortic occlusion-reperfusion occurred while circulating platelet concentrations did not differ from sham-operated animals (7). In a subsequent study, an increase in circulating heparinoid activity was determined to be the primary mechanism by which the speed of clot formation and clot strength decreased in rabbits after hepatoenteric ischemia-reperfusion (8). Another finding of this study was that a thrombotic mediator or mediators was concurrently released with heparinoids during reperfusion, on the basis of observations in blood samples without platelet function (8). Although facile interventions may decrease the heparinoid-mediated hemostatic effects during reperfusion (e.g., heparinase or protamine administration), an undesirable, unopposed thrombotic effect could predominate. From a therapeutic standpoint, an intervention that attenuates tissue injury associated with hepatoenteric ischemia-reperfusion could potentially decrease both heparinoid and thrombotic-mediated hemostatic derangements.

One such intervention could be the administration of hydroxyethyl starch solutions during reperfusion. We previously demonstrated that both Hextend and PentaLyte® (BioTime, Inc., Berkeley, CA) (hetastarch and pentastarch solutions, respectively) significantly decrease lung, liver, and gastrointestinal injury after thoracic aortic occlusion-reperfusion in rabbits (9,10). One of the mechanisms by which these colloid solutions decreased injury likely included a reduction in the release of the hepatocellular oxidant-generating enzyme xanthine oxidase (9,10). Of interest, inhibition of xanthine oxidase activity decreased mast cell-mediated intestinal reperfusion injury (11)—and mast cells are a putative source of heparinoids. Thus, the purpose of this study was to test the hypothesis that PentaLyte® administration could reduce the heparinoid and thrombotic mediator release associated with thoracic aorta occlusion-reperfusion as compared with lactated Ringer’s solution administration in rabbits.

	Methods

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The study was approved by our animal review committee. New Zealand White rabbits (2–3 kg) were anesthetized with 10 mg/kg IV ketamine via a marginal ear vein and subsequently administered inhaled 1% isoflurane carried in 99% oxygen. Isoflurane administration (inspired concentration) was monitored with an anesthetic specific monitor (model 8100; BCI International, Waukesha, WI). After tracheotomy and placement of a 3.5-mm-outer-diameter endotracheal tube, mechanical ventilation with a Harvard Apparatus ventilator (Harvard Apparatus, Holliston, MA) was performed with PaCO₂ maintained at 32–45 mm Hg. Pancuronium was administered 0.3 mg · kg^-1 · hr^-1 IV to facilitate mechanical ventilation. Arterial pressure was monitored by placement of a 22-gauge central ear artery catheter and a right femoral arterial catheter for blood sampling. Central venous access was obtained via the right internal jugular vein for pressure monitoring and fluid administration. All pressures were recorded on a Grass Model 7D polygraph (Grass Instruments, Quincy, MA). All rabbits received a maintenance infusion of lactated Ringer’s at 4 mL · kg^-1 · hr^-1, and esophageal temperatures were maintained at 38°C–39°C with a heating pad. A 30-min equilibration period followed completion of the surgical preparation.

After equilibration, rabbits were randomized to either the group administered lactated Ringer’s solution (n = 8) or PentaLyte® (n = 8). PentaLyte® is a 6% pentastarch solution containing balanced electrolytes (Na⁺ = 143 mmol/L, Cl^- = 124 mmol/L, Ca⁺² = 2.5 mmol/l, Mg⁺² = 0.45 mmol/L, and K⁺ = 3 mmol/L), glucose (5 mmol/L), and lactate buffer (28 mmol/L). The administration of each fluid is described in greater detail subsequently. Aortic occlusion groups underwent a left femoral cutdown, with insertion of a 4F Fogarty embolectomy catheter into the thoracic aorta with the balloon placed 1–2 cm above the diaphragm, as confirmed by postmortem examination. Aortic occlusion was achieved by inflation of the catheter balloon with saline. A femoral arterial pressure of 0–10 torr confirmed subdiaphragmatic ischemia. After 30 min of occlusion, the balloon was deflated and the catheter removed. Reperfusion was verified by return of pulsatile flow to the femoral arterial line and transient hypotension as measured by the ear arterial line. Postocclusion shock was treated as previously described (9,10), according to the following algorithm. At the beginning of reperfusion, an IV bolus of lactated Ringer’s solution or PentaLyte® (20 mL/kg) was administered over 2 min, followed by an infusion bolus of lactated Ringer’s solution adjusted to maintain central venous pressure (CVP) at the 30-min equilibration value ± 2 mm Hg. Next, phenylephrine administration began at reperfusion and was adjusted as follows: if the CVP = 30-min equilibration value ± 2 mm Hg and the mean arterial blood pressure was <80% of the 30-min equilibration value, phenylephrine was administered. Last, sodium bicarbonate 8.4% was infused IV to maintain the arterial base deficit near zero.

Arterial blood samples were obtained after 30 min of equilibration and after 30 min of reperfusion for blood gas analysis (Model 1640; Instrumentation Laboratory, Lexington, MA) with K⁺, Ca⁺², and hematocrit determination. Platelet concentrations were concurrently determined with a Sysmex K-800 (TOA Medical Electronics Co., Ltd., Kobe, Japan). Modified thromboelastographic analyses were performed after 30 min of equilibration and after 30 min of reperfusion with two computer-controlled Thrombelastographs® (Model 5000; Haemoscope Corp., Skokie, IL), each with two channels, for a total of four thromboelastograms generated per time point. All blood samples destined for thrombelastographic analysis were placed in disposable plastic cups in the Thrombelastograph. The four thrombelastographic conditions were as follows: 1) 350 µL of blood with 10 µL of 0.9% NaCl, 2) 350 µL of blood with 10 µL of cytochalasin D (final concentration 10µM), 3) 350 µL of blood with 10 µL of 0.9% NaCl in the presence of heparinase I (from Flavobacterium heparinum, 2.0 IU per cup), and 4) 350 µL of blood with 10 µL of cytochalasin D in the presence of heparinase I. Cytochalasin D inhibits microtubule formation (and glycoprotein IIb/IIIa activation) in platelets, resulting in a thromboelastographic signature caused only by coagulation proteins in whole blood (12,13). Cups containing 2 IU of heparinase will digest up to 6 IU/mL of heparin activity. The proper functioning of the Thrombelastograph was confirmed daily with quality control standards purchased from Haemoscope. The following thromboelastographic variables were measured for each sample for a 1-h period at 39°C (the normal temperature of the rabbit): reaction time (R [min]), angle ( [degrees]), maximum amplitude (MA [mm]), and shear elastic modulus (G [dyne/cm²]). A detailed description of the methodology of thromboelastography has been presented in great detail elsewhere (12,14). In brief, R is defined as the time from when the blood sample is placed into the thromboelastograph cup until initial fibrin formation occurs as noted by a signal of 2-mm amplitude, and is the angle formed from R to the inflection point of the thromboelastographic signal as clot strength stabilizes; it is a measure of the kinetics of clot formation. MA is the largest amplitude of the thrombelastographic signal and is a measure of clot strength. Finally, G is a measure of clot strength (14) calculated from MA as follows: G = (5000 x MA)/(100 - MA). The relationship between MA and G is curvilinear. As MA varies from 0 to 100, G concordantly varies from 0 to infinity. Given this relationship, it is conceptually and statistically important to express clot strength as G (14). Consequently, while MA was determined, G was reported. The contribution of platelets to G (G_P) was defined by the total G of whole blood not exposed to cytochalasin D (G_T) minus the G of blood exposed to cytochalasin D, which is attributable to the soluble components of the coagulation pathway (G_SC) (7,8,13).

In an effort to identify the thrombotic mediator released after hepatoenteric ischemia, plasma tissue factor activity (TF) was determined after 30 min of equilibration and after 30 min of reperfusion, as previously described (15). We chose to measure TF because it has been implicated as an important pathophysiologic mediator after trauma in a murine model (15) and significantly enhances G in the rabbit (13). In brief, heparinized blood samples were centrifuged at 25°C for 5 min, with plasma immediately stored at -85°C until TF assay. A TF activity assay kit (America Diagnostica, Greenwich, CT) that detects sample TF by activation of a chromogenic enzyme cleaved from de novo factor VIIa/TF was used to spectrophotometrically determine rabbit plasma TF activity (15).

All variables are expressed as mean ± SD. With regard to thromboelastography, it was decided a priori that blood samples that did not clot were to be assigned an R value of 60 min, an value of 0°, an MA value of 0 mm, and a G value of 0 dyne/cm². Parametric data were analyzed with one-way analysis of variance with repeated measures as appropriate. Nonparametric data were analyzed with Wilcoxon’s signed rank test or the Mann-Whitney U-test as appropriate. Specifically, to analyze the effects of the resuscitative fluid administered on hemostasis over time, the differences between the 30-min equilibration and 30-min reperfusion values for all thromboelastographic variables were compared with the Mann-Whitney U-test. Post hoc analyses were conducted with the Student-Newman-Keuls test. An error of <0.05 was considered significant.

	Results

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Aortic occlusion-reperfusion significantly increased R in the group administered lactated Ringer’s solution and significantly decreased , G_T, and G_SC values in both groups in the absence of heparinase and in the presence or absence of platelet inactivation, as depicted in Table 1. Further, G_P (as a percentage of G_T) significantly increased during reperfusion, regardless of the fluid used. In contrast, in the presence of heparinase without platelet inactivation, R and did not significantly change after ischemia-reperfusion; however, although G_T did not change in the group administered lactated Ringer’s solution, G_T values decreased in the group administered PentaLyte®. Next, in the presence of both heparinase and platelet inactivation, rabbits administered lactated Ringer’s were noted to have a significantly decreased R, increased , and unchanged G_SC after ischemia-reperfusion. In contrast, in the presence of heparinase and cytochalasin D, rabbits administered PentaLyte® had no significant changes in R or but had a significant decrease in G_SC after ischemia-reperfusion. Similarly, in the presence of heparinase and cytochalasin D, rabbits administered lactated Ringer’s solution had a significantly larger increase in and a significantly smaller decrease in G_SC compared with animals administered PentaLyte®. Last, in the presence of heparinase, G_P (as a percentage of G_T) did not significantly increase after ischemia-reperfusion in the group administered lactated Ringer’s solution but did significantly increase in animals administered PentaLyte®.

View this table: [in this window] [in a new window]   Table 1. Thromboelastographic Variables R (min), (degrees), and G (dyne/cm2)

Hemodynamics, platelet concentration and hematocrit, and arterial blood gas analysis data are depicted in Tables 2 and 3. Although there were no significant differences in mean arterial blood pressure or CVP values between the groups, both groups had a significantly decreased heart rate at 30 min of reperfusion compared with 30 min of equilibration values. Further, the PentaLyte® group had a significantly increased heart rate at 30 min of reperfusion compared with the group administered lactated Ringer’s solution. Although there were no differences between the groups, aortic occlusion-reperfusion resulted in significantly smaller arterial pH and Ca⁺² values. PaO₂ values were significantly more in both groups after aortic occlusion-reperfusion. Hematocrit values were not significantly changed by either aortic occlusion-reperfusion or the fluid administered. However, animals administered PentaLyte® had a significantly smaller circulating platelet concentration compared with rabbits administered lactated Ringer’s solution. The group administered lactated Ringer’s solution required 2.6 ± 0.8 mg/kg per 30 min of phenylephrine and 43 ± 8 mL/kg per 30 min of lactated Ringer’s solution. In contrast, animals administered PentaLyte® required significantly less phenylephrine (1.3 ± 0.9 mg/kg per 30 min) and lactated Ringer’s solution (8 ± 2 mL/kg per 30 min).

	Discussion

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The inability to attenuate heparinoid release with PentaLyte® administration may be explained in part by the possibility that mast cell degranulation occurs primarily during ischemia in this model. First, in terms of histology and intramucosal pH, gastric mucosa is well preserved by PentaLyte® administration after aortic occlusion-reperfusion, whereas the administration of lactated Ringer’s solution is associated with significantly more injury (10). Because the gastrointestinal tract is resplendent with mucosal mast cells, one would posit that the rapid restoration of adequate blood flow and maintenance of histologic architecture with PentaLyte® resuscitation could decrease mast cell degranulation. However, if the ischemic insult alone is sufficient to elicit heparinoid release, then no mast cell inhibiting or stabilizing intervention administered at reperfusion could decrease the release of heparinoids from reperfusing tissues. Another possible reason why PentaLyte® administration did not decrease heparinoid release could be that the stimuli affecting the mast cell in the interstitial space (e.g., xanthine oxidase-generated radical formation) might be inaccessible to any beneficial effects exerted by intravascular pentastarch. Last, although PentaLyte® may decrease continuing heparinoid release by attenuating mucosal injury and mast cell degranulation, the heparinoids released by ischemia may require more than 30 minutes of reperfusion to be cleared from the circulation. Future studies involving pretreatment with mast cell inhibitors before ischemia and treatment during reperfusion are planned to determine the course of heparinoid release after hepatoenteric ischemia-reperfusion.

In contrast to heparinoid release, the release of the thrombotic mediators associated with aortic occlusion-reperfusion is modulated during reperfusion. Given that trauma (and associated systemic ischemia) increased plasma TF activity in a murine model (15), we had posited that TF could be released during reperfusion, exerting the increase in thrombotic activity observed in our rabbit model. Instead, aortic occlusion-reperfusion is associated with an acute decrease (30%–36%) in plasma TF activity. Further, there was no significant fluid-specific effect on plasma TF activity after ischemia-reperfusion. A possible explanation of this decrease in TF may be heparinoid-stimulated TF pathway inhibitor (TFPI) release. TFPI is a potent, competitive inhibitor of TF and is elaborated by mainly vascular endothelial cells, smooth muscle cells, and macrophages (16,17). Furthermore, TFPI expression is increased in vitroand in vivo by heparin (18,19). The exact mechanisms by which TF activity decreases after aortic occlusion-reperfusion, therefore, deserve further investigation. Although we could not implicate TF as the circulating thrombotic mediator, the attenuation of the release of the thrombotic mediators by PentaLyte® suggests that formation occurs during reperfusion. The identification, localization, and regulation of the thrombotic mediators will be the focus of future investigations.

As mentioned previously, one approach to attenuating heparinoid-mediated coagulopathy in a clinical setting may be to administer protamine or heparinase. Before advocating this intervention, we suggest determining whether or not an acute decrease in circulating heparinoid activity may exacerbate injury in reperfusing organs such as the intestine. Indeed, if reperfusion injury were increased by microcirculatory thrombi in the hepatoenteric vasculature, a reduction in hepatic procoagulant release or decrease in tissue plasminogen activator clearance could paradoxically worsen hemostatic function. We envision that a multifaceted approach with pharmacological interventions designed to concurrently decrease the elaboration of both heparinoid and thrombotic mediator release will ultimately be successful in providing acceptable hemostasis without increasing reperfusion injury.

In conclusion, PentaLyte® administration does not decrease heparinoid release but does decrease thrombotic mediator release associated with aortic occlusion-reperfusion in rabbits. The roles of TF and TFPI in this model are unclear. Future investigations will determine whether pretreatment with mast cell stabilizers or inhibitors or treatment with heparin antagonists coupled with a hydroxyethyl starch solution, such as PentaLyte®, may provide adequate hemostasis without increasing reperfusion injury. Last, the present study serves as a rational basis for future clinical investigations to determine the role of heparinoid release and the resuscitative fluid administered in the maintenance of hemostasis in shock states.

	Acknowledgments

 
Supported in part by a grant from BioTime, Inc., Berkeley, CA (Dr. Nielsen), by the National Institutes of Health Grant KO8-GM00686 (Dr. Armstead), and by the Departments of Anesthesiology.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999