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Anesth Analg 2002;95:851-857
© 2002 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

ß-Adrenergic Stimulation Restores Oxygen Extraction Reserve During Acute Normovolemic Hemodilution

George J. Crystal, PhD*{dagger}{ddagger}, and M. Ramez Salem, MD*{dagger}

*Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, Illinois; and Departments of {dagger}Anesthesiology and {ddagger}Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois

Address correspondence and reprint requests to George J. Crystal, PhD, Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 W. Wellington Ave., Chicago, IL 60657-5193. Address e-mail to gcrystal{at}uic.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Compensatory increases in oxygen extraction (EO2) during acute normovolemic hemodilution (ANH) have the effect of decreasing tissue oxygen tension values, thus increasing the threat of tissue hypoxia. We hypothesized that if the ß-adrenergic agonist isoproterenol (ISOP) could augment cardiac output (CO) during ANH, it could reverse the increases in EO2 and restore the margin of safety for tissue oxygenation. Studies were performed in seven anesthetized (isoflurane) dogs. CO was measured by using thermodilution, and regional blood flow (RBF) was measured by using radioactive microspheres. Systemic oxygen delivery (DO2), oxygen consumption ({image}O2), and EO2, as well as regional DO2, were calculated. Measurements were obtained under the following conditions in each dog: 1) baseline-1, 2) ISOP (0.1 µg · kg-1 · min-1 IV), 3) baseline-2, 4) ANH, and 5) ISOP during ANH. Hematocrit was 45% ± 3% under baseline conditions and 18% ± 3% during ANH. Before ANH, ISOP caused parallel increases in CO and systemic DO2, which, in the presence of an unchanged {image}O2, reduced EO2. RBF increased in myocardium and spleen, decreased in pancreas, and did not change in brain, spinal cord, or other tissues. ANH caused increases in CO, which were insufficient to offset the decrease in arterial oxygen content, and thus systemic DO2 declined; systemic {image}O2 was maintained by an increase in EO2. ANH-related increases in RBF maintained DO2 in myocardium, brain, duodenum, and pancreas, whereas DO2 declined in kidney and spleen. ISOP during ANH increased CO and systemic DO2, which returned systemic EO2 to baseline, and it increased RBF in myocardium, kidney, duodenum, and spleen. We conclude that 1) ß-adrenergic stimulation with ISOP restored the systemic EO2 reserve during ANH, without apparent adverse effects in the individual body tissues, and that 2) the use of inotropic drugs, such as ISOP, may extend the limit to which hematocrit can be reduced safely during ANH.

IMPLICATIONS: By restoring the oxygen extraction reserve, isoproterenol and other inotropic drugs can enhance the margin of safety and extend the limit to which hematocrit can be reduced safely during acute normovolemic hemodilution. The use of this approach will depend on the degree of hemodilution, the extent of mixed venous oxygen desaturation, and whether increases in cardiac output are possible or desirable.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Hemodilution refers to a decrease in hematocrit or hemoglobin concentration as a result of dilution of red blood cells (dilutional anemia) (1). Although hemodilution was recognized as early as the late 1800s, it was not until the 1970s that the technique of acute normovolemic hemodilution (ANH) was used clinically as a method to minimize the need for allogenic blood transfusions in a variety of surgical procedures (1). The efficacy of ANH as a blood conservation measure can be markedly enhanced when low hematocrits are targeted (1). ANH is being touted as a replacement for preoperative autologous blood donation on the basis that it is less costly and time consuming and that it avoids the risks associated with blood storage (2). ANH is the only method of blood conservation that can provide autologous and fresh whole blood for transfusion.

Although an increase in cardiac output (CO) is the usual response to the reduction in arterial oxygen content (CaO2) during ANH, it is often insufficient in itself to maintain oxygen consumption ({image}O2) (3–7). Because oxygen delivery (DO2) is normally high relative to {image}O2, the baseline level of oxygen extraction (EO2) is modest (approximately 25%). This provides a reserve for EO2, which can be tapped, along with an increase in CO, to maintain {image}O2 during ANH. However, this compensatory increase in EO2 has the drawback of decreasing the values for tissue oxygen tension (PO2) toward the "critical limit," thus increasing the risk of tissue hypoxia and lactic acidosis should blood loss or an increased {image}O2 be encountered (8). An increase in EO2 to 50% has been advocated as a "transfusion trigger" during ANH on the basis that higher values were associated with myocardial lactate production and hemodynamic instability (9).

We hypothesized that if a drug could augment CO during ANH, it could reverse the increases in EO2 and restore the margin of safety for tissue oxygenation. This possibility was tested in anesthetized dogs by using IV infusions of the combined ß1- and ß2-receptor agonist isoproterenol, which has been demonstrated to have positive chronotropic and inotropic effects during ANH (6,10). The associated changes in regional blood flow (RBF) and regional DO2 during isoproterenol in the presence of ANH were assessed and compared with those in the same animals before ANH.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was conducted in compliance with the Institutional Animal Research Committee. Experiments were performed on seven mongrel, conditioned dogs of either sex (weight range, 21–24 kg). Anesthesia was induced with an IV bolus injection of thiopental in a dose of 30 mg/kg. After tracheal intubation, anesthesia was maintained by ventilation with 1.4% isoflurane in oxygen, which is 1 minimum alveolar concentration dose in the dog (11). The isoflurane was supplemented with an IV infusion of fentanyl (12 µg · kg-1 · h-1), which reduced baseline heart rate (HR) to approximately 100 bpm. The volume and rate of the ventilator were set to maintain arterial CO2 tension at 35–40 mm Hg. PO2, partial pressure of CO2, and pH of arterial and mixed venous blood samples were measured electrometrically. Hematocrit was determined with a microcentrifuge. Core body temperature was monitored and maintained at 38°C with a heating pad, warmed IV fluids, and warming lights. Heparin 400 U/kg was administered postsurgically to prevent blood coagulation.

Polyethylene cannulas were inserted into 1) the thoracic aorta via the left femoral and right brachial arteries for monitoring aortic blood pressure and for obtaining samples of arterial blood for analysis of gas composition and pH, 2) the right femoral vein for IV injections and infusions, and 3) the left femoral vein and right carotid artery for isovolemic exchange of whole blood with dextran solution. A 7F Swan-Ganz catheter, equipped with multiple ports and a thermistor at the tip, was introduced into the right femoral vein and flow-directed into the pulmonary artery by using pressure monitoring for guidance. This catheter was used to obtain samples of mixed venous blood and to measure CO by thermodilution. CO was normalized for body weight in kilograms.

A left thoracotomy was performed in the fourth intercostal space, and the pericardium was incised to expose the heart. A small polyethylene cannula was inserted into the left atrium for injecting radioactive microspheres. Aortic pressure was measured with Statham (Costa Mesa, CA) transducers and averaged electronically. HR was derived from the aortic pressure pulse. A permanent record of monitored hemodynamic variables was obtained with a Gould recorder (model 2800S; Gould, Cleveland, OH).

RBF was measured with 15 ± 3 µm radioactive microspheres as described in detail previously (5). Briefly, 1 x 106 microspheres were injected into the left atrium. Beginning simultaneously with each microsphere injection, duplicate reference blood samples were collected at a rate of 6 mL/min for 3 min through two cannulas of different lengths threaded into the aorta via the right femoral artery. Radioactivities of the duplicate reference samples differed by <10%, indicating satisfactory mixing of the microspheres in the left ventricular output.

After the final injection of microspheres, the heart was stopped by IV injection of potassium chloride, excised, and frozen to facilitate transmural sampling. Full-thickness samples were obtained from the right and left ventricular walls. The right ventricular samples were cut into halves transmurally, and the left ventricular samples were cut into thirds transmurally. Samples were also obtained from the abdominal viscera (kidney cortex, liver, duodenum, and spleen), brain, and spinal cord. The tissue and reference blood samples were weighed and analyzed for radioactivity with a gamma scintillation counter equipped with a multichannel analyzer (model 1282-002; LKB, Turku, Finland). Isotope separation was accomplished by standard techniques of {gamma}-spectroscopy. Values for RBF (in mL · min-1 · 100 g-1) were calculated from the equation

equation


where ABF is the rate of arterial reference sampling (mL/min), MC is microsphere radioactivity (counts · min-1 · g-1) in the tissue samples, and AC is the total microsphere radioactivity (counts/min) in the arterial reference samples. The values for RBF within each ventricular wall were averaged to compute a value for mean transmural blood flow. The value for RBF in the subendocardial sample was divided by that in the subepicardial sample to yield a value for the endocardial/epicardial flow ratio.

Blood samples (1 mL) were collected anaerobically from the aorta and the pulmonary artery and analyzed for oxygen content so that the systemic arteriovenous oxygen difference (a - v O2 diff) could be calculated. Systemic {image}O2 (mL · min-1 · 100 g-1) was calculated from the Fick equation:

equation


Systemic and regional DO2 were calculated by multiplying the values for CaO2 and the respective values for blood flow. The systemic EO2 was determined by dividing a - v O2 diff by CaO2.

The dogs were permitted to stabilize for at least 30 min after surgical preparation before baseline measurements were obtained. Isoproterenol was infused (0.1 µg · kg-1 · min-1 IV), and after attainment of steady-state conditions (5–10 min), measurements were repeated. The infusion rate for isoproterenol was based on previous work demonstrating that it had a substantial positive inotropic effect in dogs (12). After at least 30 min for recovery, a second set of baseline measurements was obtained. Then ANH was produced by removing blood from the carotid artery at a rate of 20 mL/min while replacing it with an equal volume of 5% dextran (molecular weight 40,000; American McGaw, Irvine, CA) pumped into the left femoral vein at the same rate. Measurements were obtained at a hematocrit approximating 20%. A final set of measurements was made during a second infusion of isoproterenol in the presence of ANH.

Statistical analysis was performed with Student’s t-tests for paired samples and an analysis of variance for repeated measurements in conjunction with the Student-Newman-Keuls test (13). P < 0.05 was considered significant throughout this study.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Before ANH, isoproterenol reduced mean aortic pressure and increased HR and CO (Tables 1 and 2). The increases in CO caused parallel increases in systemic DO2 and, in the presence of an unchanged systemic {image}O2, reductions in systemic EO2 (Table 2). These systemic changes were associated with heterogeneous changes in RBF (Table 3); isoproterenol increased RBF in the myocardium and spleen, decreased RBF in the pancreas, and had no effect on RBF in the brain and other abdominal viscera. The effects of isoproterenol were reversible, as indicated by the lack of difference between the baseline-1 and baseline-2 values.


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  		Table 1. Systemic Hemodynamic Variables During Isoproterenol (ISOP) Before and During Acute Normovolemic Hemodilution (ANH)
 

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  		Table 2. Systemic Oxygen Metabolism During Isoproterenol (ISOP) Before and During Acute Normovolemic Hemodilution (ANH)
 

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  		Table 3. Regional Blood Flows During and Isoproterenol (ISOP) Before and During Acute Normovolemic Hemodilution (ANH)
 
ANH caused parallel decreases in hematocrit, hemoglobin concentration, and CaO2 (Table 1). Mean aortic blood pressure remained unchanged. Although ANH caused increases in CO, these changes were far less than proportional to the reductions in CaO2; thus, systemic DO2 decreased markedly (Table 2). However, systemic {image}O2 was maintained by increases in EO2.

ANH caused increases in RBF in the myocardium, brain (including the spinal cord), duodenum, and pancreas, but it did not affect RBF in the kidney, spleen, or liver (Table 3). Regional DO2 was maintained in the myocardium, brain, duodenum, pancreas, and liver, whereas it decreased in the kidney and spleen (Fig. 1).



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  		Figure 1. Effect of acute normovolemic hemodilution (ANH) alone and combined with isoproterenol (ISOP) on oxygen delivery in systemic circulation and regional beds (mL · min-1 · 100 g-1). SYS = systemic circulation (mL · min-1 · kg-1); LV = left ventricle; CC = cerebral cortex, SC = spinal cord (cervical); KI = kidney; LI = liver; DU = duodenum; PA = pancreas; SPL = spleen. *P < 0.05 versus baseline; {dagger}P < 0.05 versus ANH. Data are mean ± SD.

 
Isoproterenol during ANH caused parallel increases in CO and systemic DO2, which, in the presence of an unchanged systemic {image}O2, returned systemic EO2 to the baseline (pre-ANH) value (Table 2; Fig. 1). The changes in RBF caused by isoproterenol during ANH differed from those before ANH in several respects (Table 3): the increases in RBF in the myocardium and spleen were enhanced, and RBF increased in the kidney and duodenum and did not decrease in the pancreas. The isoproterenol-induced increases in RBF during ANH increased regional DO2 to the myocardium to levels above those at baseline and returned regional DO2 to the kidney and spleen to their baseline (pre-ANH) values (Fig. 1).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The main finding from this study was that an IV infusion of isoproterenol improved the relationship between systemic DO2 and {image}O2, i.e., increased systemic EO2, during ANH. This occurred without any apparent adverse changes in blood flow or DO2 to the individual body tissues. The hematocrit we targeted (approximately 20%) was well within the range of that evaluated, and found to be tolerated, in clinical investigations in adults and children (7,14,15).

The increase in CO during ANH has been reported to result from an increase in HR, an increase in stroke volume, or a combination of these factors (16). In anesthetized dogs, the relative importance of increases in HR and stroke volume during ANH seems to be related to the baseline level of HR. Anesthetics with vagolytic effects and producing high baseline HR values, e.g., pentobarbital, are usually associated with increases in stroke volume rather than HR during ANH (6,16). However, anesthetics producing low baseline HR values, e.g., fentanyl (used in this study), favor increases in HR rather than stroke volume during ANH. Because of concurrent changes in HR and the loading conditions of the heart, it cannot be assumed that the constant stroke volume during ANH in this study was an indication of no change in myocardial contractility. Although our data can provide no further insight into the question, a study using load-insensitive indexes for myocardial contractility (end-systolic elastance and preload recruitable stroke work) demonstrated an enhanced inotropic state during ANH in anesthetized dogs (17). The relatively modest increases in CO (+37%) during ANH observed in this study are comparable to those found previously in anesthetized humans (7) and laboratory animals (4–6,17).

These responses were not the result of exhausted inotropic and chronotropic reserves, because isoproterenol was capable of increasing both CO and HR. Rather, they apparently reflected a preference of the body to limit the level of cardiac work, i.e., myocardial oxygen use, at a time when oxygen delivery to the myocardium was potentially in jeopardy and to tap its reserve for augmented EO2 in the tissues. A disadvantage of this adjustment was that it increased EO2 to values that approached the critical level (Fig. 2). The increases in CO caused by isoproterenol during ANH restored the DO2 versus VO2 balance to the systemic circulation, as indicated by a return of EO2 to the pre-ANH baseline value (Fig. 2).



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  		Figure 2. Changes in systemic oxygen extraction during acute normovolemic hemodilution (ANH) and the subsequent infusion of isoproterenol (ISOP). The shaded area represents physiologically relevant oxygen extraction reserve. ANH increased oxygen extraction to values approaching the critical level of 50%. ISOP reversed this effect and restored the oxygen extraction reserve. *P < 0.05 versus baseline; {dagger}P < 0.05 versus ANH. Data are mean ± SD.

 
The present findings indicated that the increases in CO during isoproterenol (both before and during ANH) were proportional to the increases in HR, thus implying no change in stroke volume. The avoidance of a decrease in stroke volume in the face of an increased HR, such as occurs with pacing alone (18), is a reflection of an increased myocardial contractility during isoproterenol.

ß-Adrenergic drugs can increase systemic {image}O2 via multiple mechanisms (19): 1) an increased turnover of both glucose and free fatty acids, 2) thermogenesis, and 3) increased cardiac work secondary to chronotropy and inotropy. In this study, isoproterenol had no effect on systemic {image}O2 either in the absence or presence of ANH, probably because of inadequate plasma concentrations. Thus, the increases in systemic DO2 caused parallel increases in systemic EO2. Although isoproterenol at the current dose has been demonstrated to increase myocardial {image}O2 (7), this effect was apparently not large enough to be reflected in the whole-body measurements.

Increases in RBF maintained regional DO2 in the myocardium, brain, spinal cord, and selected abdominal viscera (duodenum and pancreas) during ANH. In the brain and abdominal viscera, this level of DO2 would likely be adequate because there is no reason to expect a change in the tissue oxygen demands. In the myocardium this cannot be assumed, because of variations in the hemodynamic determinants of cardiac work, e.g., increases in HR. However, several lines of evidence suggest that the prevailing myocardial oxygen demands were satisfied during ANH. First, indices of global cardiac performance, e.g., aortic pressure, were not altered, and CO increased. Second, the increases in myocardial blood flow were transmurally uniform (Table 3), implying a lack of selective subendocardial hypoperfusion. Third, previous findings in a similar canine model indicated well maintained myocardial lactate extraction (6,20,21), which suggests an absence of anaerobic metabolism and of myocardial ischemia.

Whether a reduced regional DO2 limited metabolism, function, or both in the kidney and spleen during ANH cannot be assessed from the available data. The possibility cannot be discounted that increases in regional EO2 occurred, especially in the kidney. Because of a primary function in filtering the blood, renal blood flow (and DO2) is normally well in excess of that required to meet its basal oxidative demands (22). This results in a very modest baseline regional EO2 and a substantial extraction reserve, which can be recruited when necessary to maintain adequate renal oxygenation.

The isoproterenol infusions were apparently well tolerated by the various body tissues, both before and during ANH. With respect to the myocardium, isoproterenol was accompanied by increased RBF in both the left and right ventricular walls. Isoproterenol has been demonstrated to cause coronary vasodilation via local metabolic mechanisms secondary to its ß1-receptor-mediated chronotropic and inotropic effects and via direct stimulation of coronary vascular ß2 receptors (23). However, we have shown previously that the dose of isoproterenol used in this study caused increases in myocardial blood flow that were either proportional or slightly less than proportional to the induced increases in myocardial {image}O2, with the result that myocardial EO2 either remained constant or increased modestly (6). This implied that the coronary vasodilation during the isoproterenol infusions was attributable to metabolic factors and that the ß2-receptor-mediated mechanism played no role. Myocardial lactate extraction was preserved during infusions of isoproterenol in the presence of ANH (6), which suggested that the induced increases in RBF (and regional DO2) were sufficient to satisfy the augmented oxygen demands of the myocardium; i.e., that the myocardium tolerated the ß-adrenergic stimulation despite a decreased CaO2. The wide variation in the isoproterenol-induced increases in myocardial blood flow during ANH (Table 3) likely reflects differences in the existing chronotropic and inotropic reserves of the various cardiac preparations.

Histochemical, histological, and electromicroscopic studies have demonstrated that cerebral vessels are well endowed with sympathetic nerve terminals associated with both {alpha}- and ß-adrenergic receptors (24). Yet we found no change in cerebral blood flow during isoproterenol both in the absence and presence of ANH. These findings are in accord with those obtained previously in humans and animal models using either IV or intraarterial infusions of isoproterenol or other catecholamines (25,26). The lack of effect of blood-borne catecholamines, including isoproterenol, on cerebral blood flow has been attributed to their inability to cross the blood-brain barrier (26).

Previous studies, especially those using intraarterial administrations, have demonstrated that isoproterenol can increase blood flow within the kidney and splanchnic organs (27–30). In this study, IV infusions of isoproterenol before ANH increased RBF only in the spleen; RBF decreased in the pancreas and did not change in the kidney, duodenum, or liver. These heterogeneous effects of isoproterenol likely reflected regional differences in the balance between activity of the ß-adrenergic (dilating) and {alpha}-adrenergic (constricting) receptors in the various vascular beds. Activation of the {alpha}-adrenergic receptors would occur as result of the baroreflex-sympathetic nerve response to isoproterenol-induced systemic hypotension.

An unexpected and noteworthy finding was that isoproterenol’s regional vasodilating effects were enhanced after ANH. For example, ANH converted no changes in RBF in the kidney during isoproterenol into marked increases, and it accentuated the increases in RBF in the spleen during isoproterenol. One possible mechanism for this finding is that an activation of the sympathetic vasoconstrictor nerves during ANH resulted in a reduced reserve for further activation during isoproterenol infusion, thus unmasking ß-adrenergic vasodilation. Another is that ANH decreased the concentration of the plasma proteins in the blood, which resulted in a larger portion of isoproterenol being unbound and available to the vasculature (31,32). Regardless of the mechanism, the enhanced isoproterenol-induced vasodilating effects in the spleen and kidney after ANH were effective because they returned regional DO2 to the pre-ANH baseline level (Fig. 1).

In summary, an infusion of isoproterenol during ANH increased CO and systemic DO2, which, in the absence of an increase in systemic {image}O2, returned systemic EO2 to the baseline level. There was no evidence of adverse changes in the individual body tissues. Myocardial blood flow increased in proportion to the augmented cardiac work, without evidence of myocardial ischemia (6). In no tissue did RBF or regional DO2 decrease during the isoproterenol infusions in the presence of ANH. In fact, in the kidney and spleen, both these variables increased markedly.

This study pertains strictly to the specific conditions of the study—i.e., general anesthesia, artificial ventilation, high fraction of inspired oxygen—and to healthy dogs with normal hearts. There is no reason to expect that the effects of isoproterenol would be qualitatively different in humans, although quantitative differences cannot be excluded. Thus, it is important that care be exercised in extrapolating our findings to the human patient. Because of practical constraints, including the limited number of differently labeled microspheres, one dose of isoproterenol infused for a relatively short duration was evaluated in this study. It is uncertain whether a larger dose of isoproterenol would produce a more favorable or less favorable relationship between systemic DO2 and {image}O2 during ANH. It is conceivable that increases in systemic {image}O2 could negate the beneficial effect of further increases in CO and systemic DO2. It is also uncertain how well the body tissues would tolerate more extended infusions of isoproterenol during ANH. Further studies are required to answer these important questions and to assess the efficacy of other inotropes.

Our findings suggest that the administration of a ß-receptor agonist may have promise as a measure to restore the systemic EO2 reserve during ANH, thus reestablishing a margin of safety against tissue hypoxia. We are not advocating that ß-adrenergic inotropic support be used in all patients undergoing ANH. Its use should depend on the degree of hemodilution, the extent of mixed venous oxygen desaturation, and whether increases in CO are possible or desirable.


   Acknowledgments
 
We appreciate the expert technical assistance of Derrick L. Harris, BS.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 20, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press