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Anesth Analg 2003;96:28-32
© 2003 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Hemodilution Does Not Alter Arterial Baroreflex Control of Heart Rate in Anesthetized Dogs

Makoto Tanaka, MD, and Toshiaki Nishikawa, MD

Department of Anesthesia, Akita University School of Medicine, Japan

Address correspondence and reprint requests to Makoto Tanaka, MD, Department of Anesthesia, Akita University School of Medicine, Hondo 1–1-1, Akita-City, 010–8543, Japan. Address e-mail to mtanaka{at}med.akita-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The cardiovascular effects of acute normovolemic hemodilution (ANH) are characterized by increased cardiac output and decreased systemic vascular resistance. However, whether arterial baroreflex function is altered by ANH remains undetermined. We assigned 23 anesthetized, mechanically ventilated dogs to mild ANH (hemoglobin, 7–8 g/dL; n = 11) or profound ANH (hemoglobin, 4–5 g/dL; n = 12) achieved by phlebotomy and simultaneous exchange with lactated Ringer’s solution at 1:3 ratio to maintain constant central venous pressure and pulmonary artery occluded pressure. Baroreflex sensitivity was assessed by measurements of RR intervals of the electrocardiogram and mean arterial blood pressure (MAP) through a femoral artery catheter. Baroreflex responses were triggered by bolus IV injections of phenylephrine (25–75 µg) and nitroprusside (50–100 µg). The linear portion of the baroreflex curves relating RR intervals and MAP were used to determine baroreflex sensitivities. Compared with the predilution period, both ANH groups had significant increases in cardiac output and decreases in systemic vascular resistance (P < 0.01), whereas MAP and heart rate (HR) remained unchanged. However, no significant difference was detected between pre-ANH and post-ANH baroreflex sensitivities in either group. Our results indicate that arterial baroreflex control of HR is preserved during ANH to a hemoglobin concentration of 4–5 g/dL in anesthetized dogs.

IMPLICATIONS: Acute normovolemic hemodilution may be preoperatively used to minimize the requirement of allogeneic blood products during major surgery. We found that baroreflex function is preserved during mild (hemoglobin concentration, 7–8 g/dL) and profound hemodilution (hemoglobin concentration, 4–5 g/dL) in pentobarbital-anesthetized dogs.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Acute normovolemic hemodilution (ANH) is a widely accepted technique during major surgery because it effectively reduces exposure to allogeneic blood products and is less costly than preoperative autologous blood donation in certain types of surgeries (1–3). Cardiovascular and metabolic effects of ANH have been extensively studied in both humans (4–7) and animals (8–10) and were characterized by increased cardiac output (CO) because of decreased blood viscosity, left ventricular ejection impedance (11,12), and peripheral vascular dilation (13), with or without changes in arterial blood pressure and heart rate (HR). Calculated systemic vascular resistance (SVR) is concomitantly decreased. In addition, altered responsiveness to {alpha}- and ß-adrenergic agonists and to certain vasoactive drugs has been documented during ANH in animals (14–16). However, compensatory mechanisms to hemodynamic perturbations (17), including arterial baroreflex responses, have not been well evaluated during ANH.

Accordingly, this study was designed in an in vivo canine preparation to assess changes in arterial baroreflex control of HR during mild and profound normovolemic hemodilution acutely instituted in anesthetized dogs.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study protocol was approved by our institutional Animal Care Committee. We studied 23 adult mongrel dogs of either sex that weighed 9–13 kg. General anesthesia was induced with pentobarbital 30 mg/kg IV and was maintained by a continuous IV infusion of pentobarbital 2.5 mg · kg-1 · h-1 throughout the experiment. The trachea was intubated in all dogs. The lungs were mechanically ventilated with room air supplemented with oxygen via a cuffed tracheal tube using a volume-cycled animal ventilator (model R-60, Aika Co, Ltd, Tokyo, Japan). By serial arterial blood gas analyses, PaCO2 and PaO2 were maintained at 36–42 mm Hg and more than 100 mm Hg, respectively. During all hemodynamic measurements, pulmonary arterial blood temperature was maintained at 37.0°C–38.0°C. Lactated Ringer’s solution was administered at a constant rate of 5 mL · kg-1 · h-1 during the surgical preparation and at 10 mL · kg-1 · h-1 during the hemodynamic measurements including baroreflex sensitivities of the pressor and depressor tests.

An IV catheter was inserted into a forelimb vein for administration of lactated Ringer’s solution and for bolus IV injections of phenylephrine and nitroprusside. Lead II of the electrocardiogram (model 2236A, NEC San-ei Instruments Co, Ltd, Tokyo, Japan) was monitored continuously using subcutaneous electrodes. Measurement of HR was made on a beat-to-beat basis by a cardiotachometer (model 1321, NEC San-ei Instruments) triggered by lead II of the electrocardiogram. Measurement of arterial blood pressure and blood sampling for blood gas tension analysis and measurements of electrolytes and hemoglobin concentration (288 Blood Gas System, Ciba-Corning, Medfield, MA) were performed via the femoral arterial catheter. Mean arterial blood pressure (MAP) was electronically determined. A flow-directed, balloon-tipped pulmonary arterial catheter (5 F Thermodilution Catheter, Arrow, Reading, PA) was inserted via the femoral vein to permit continuous monitoring of pulmonary artery pressure. Measurement of CO was made during the end-expiratory phase by the thermodilution technique in triplicate with 5 mL of iced 5% dextrose solution, and the average value was taken as a representative. Another catheter was positioned in the right atrium from the contralateral femoral vein for monitoring central venous pressure (CVP).

Dogs were sequentially assigned to either the mild ANH group (target hemoglobin concentration of 7–8 g/dL; n = 11) or the profound ANH group (hemoglobin concentration of 4–5 g/dL; n = 12). After a stabilization period of at least 1 h after the surgical procedure, normovolemic hemodilution was instituted in both groups in 30-min periods by phlebotomy and simultaneous exchange with lactated Ringer’s solution at 37°C in a ratio approximately 1:3 to maintain a stable CVP and pulmonary artery occluded pressure. In both groups, pressor and depressor tests were performed immediately before hemodilution and within 10 min after the completion of each hemodilution using IV bolus injections of phenylephrine (25–75 µg) and nitroprusside (50–100 µg) to increase and decrease MAP by 20–30 mm Hg, respectively. These doses were chosen based on our pilot study under the same protocol. The pressor test was always performed first. Typically, a 5-min stabilization period between the pressor and depressor tests allowed MAP and HR to return to the pretest values ± 5%. Thus, determinations of baroreflex sensitivities and hemodynamic measurements typically required <10 min.

Power analysis based on our pilot study revealed that at least 10 dogs would provide a power >0.8 (P = 0.05) for detecting a 40% difference for temporal baroscope changes. The pressor and depressor tests data were analyzed using least-square linear regression on the linear portion of the sigmoid relation between MAP and RR interval when each RR interval was plotted as a function of the preceding MAP during expiration. We used 8–12 pairs of corresponding MAP and RR intervals to analyze each test results. All R2 values were >0.8. Data are presented as mean ± SD throughout the article. Comparisons of hemodynamic variables and baroreflex sensitivities before and after hemodilution and between groups were first analyzed by two-way analysis of variance for repeated measurements. When statistical significance was detected, post hoc testing was accomplished by paired (predilution versus postdilution) or unpaired (mild ANH versus profound ANH groups) t-test. A P value <0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All 23 dogs completed the study protocol without developing ventricular or supraventricular arrhythmia, congestive heart failure, metabolic acidosis, electrolyte disturbances, or significant ST-T alterations on the electrocardiogram. In the mild ANH group, 271 ± 96 mL of whole blood was removed and replaced with 818 ± 295 mL of lactated Ringer’s solution. In the profound ANH group, 662 ± 70 mL of blood was removed and replaced with 2028 ± 184 mL of Ringer’s solution. No significant differences were detected between groups in the average weight of the dogs or predilution values of arterial blood gas tensions, hemoglobin concentrations, and arterial oxygen contents (Table 1). As a result of ANH, hemoglobin concentrations and oxygen contents decreased significantly as compared with the predilution values (P < 0.01), whereas ANH produced no significant changes in arterial pHa, PaCO2, PaO2, or base excess in either group. Plasma sodium, potassium, and ionized calcium concentrations also remained unchanged by ANH and were within normal ranges in both groups. Hemoglobin concentration and oxygen content of the profound ANH group were significantly less than those of the mild ANH group (P < 0.05; Table 1). However, oxygen saturation was more than 98% in all dogs during the study period.


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  		Table 1. Arterial Blood Gas Tensions, Hemoglobin Concentrations, Arterial Blood Oxygen Contents, and Hemodynamic Variables Before (Predilution) and After (Postdilution) Acute Normovolemic Hemodilution (ANH) in Anesthetized Dogs
 
There were no significant differences in predilution hemodynamic variables between groups (Table 1). Whereas MAP, HR, CVP, mean pulmonary artery pressure, and pulmonary artery occluded pressure remained unchanged in both ANH groups, CO and stroke volume significantly increased, and SVR and pulmonary vascular resistance significantly decreased by mild and profound ANH (P < 0.01). Thus, an increase in CO associated with hemodilution is primarily caused by an increase in stroke volume in both groups. Postdilution values of CO and stroke volume in the profound ANH group were significantly more, and SVR was significantly less, than those of the mild ANH group (P < 0.05; Table 1).

There were no significant differences in predilution baroreflex sensitivities between groups (Fig. 1). In contrast to hemodynamic alterations, baroreflex sensitivities of the pressor and depressor tests in the mild ANH group (2.13 ± 0.66 and 1.96 ± 0.60 ms/mm Hg, respectively) remained unchanged after ANH (1.94 ± 0.87 and 1.74 ± 0.66 ms/mm Hg, respectively; Fig. 1). Similarly, predilution values of the pressor and depressor test sensitivities of the profound ANH group (2.26 ± 0.71 and 2.04 ± 0.69 ms/mm Hg, respectively) did not change significantly after ANH (2.18 ± 0.85 and 1.97 ± 0.75 ms/mm Hg, respectively). Moreover, no significant difference was detected in the postdilution values of the baroreflex sensitivity between the mild and profound ANH groups.



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  		Figure 1. Pressor (phenylephrine, top panel) and depressor (nitroprusside, bottom panel) test sensitivities before (predilution) and after (postdilution) acute normovolemic hemodilution (ANH) established by phlebotomy and simultaneous exchange with lactated Ringer’s solution at approximately 1:3 ratio in pentobarbital-anesthetized dogs. Mild (n = 11) and profound (n = 12) ANH groups represent hemoglobin concentrations of 7–8 and 4–5 g/dL, respectively. Values are mean ± SD. No significant difference was detected between the predilution and postdilution values of the pressor and depressor tests in both ANH groups.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
A major finding of the present study is that arterial baroreflex control of HR is not altered during profound ANH to a hemoglobin concentration of 4–5 g/dL in pentobarbital-anesthetized dogs. The effects of ANH on arterial baroreflex function have never been described in either humans or animals.

Arterial baroreflex function is an important, short-term neural control system for maintaining blood flow to vital organs in the face of hemodynamic perturbations. Blood pressure changes induce reflex changes in the cardiac interval, HR, and CO, mediated through the reflex arc including the baroreceptors, afferent nerve pathways, central nervous system (CNS), pre- and postganglionic efferent pathways, peripheral ganglia, and the heart (18). Functional performance of the baroreflex feedback system can be assessed by responses to hypertensive and hypotensive challenges (19) using the classical technique known as the phenylephrine pressor test and nitroprusside depressor test, respectively. Baroreflex sensitivity is defined as the slope of the relationship between arterial blood pressure and RR interval. Therefore, intact baroreflex responsiveness requires preservations of tissue perfusion and oxygenation of each site along the reflex arc including afferent and efferent nerves, CNS, and the heart. In awake, healthy humans, ANH to a hemoglobin concentration of 5 g/dL is generally well tolerated at rest with maintenance of systemic oxygenation and normal plasma lactate concentrations (4). Cerebral metabolic rate of oxygen decreases progressively as hematocrit is reduced from 40% to 5%, but frequencies and amplitudes of electroencephalogram are not affected within the range of cerebral autoregulation in pentobarbital-anesthetized dogs, suggesting intact CNS function at this level of hemodilution (20). In addition, there was no evidence of myocardial isch-emia, such as changes in ST-T morphology or development of congestive heart failure, in our experiment, although subtle myocardial damage or endocardial ischemia could not be excluded. Further study is warranted to determine the critical hemoglobin concentration at which inadequate cardiovascular compensation or suppressed arterial baroreflex function become evident in humans and animals.

Extrapolation of our results suggests that even extreme hemodilution does not disrupt baroreceptor responsiveness to hemodynamic perturbations, such as sudden bleeding or postural change. However, Schou et al. (17) showed in anesthetized pigs that a significantly larger decrease in blood pressure and an increase in arterial lactate concentration resulted from a blood loss of 10 mL/kg in extremely hemodiluted pigs (average hematocrit, 10.8%) as compared with control animals (hematocrit, 34.6%), suggesting limited cardiovascular compensation because of ANH. There are two main effector limbs by which arterial baroreflex maintains blood pressure: the cardiac limb, by which reflex change in primarily vagal activity alters HR and CO; and the vascular limb, by which reflex change in sympathetic activity alters peripheral vascular tone (21). The relationship between the two effector limbs has not been elucidated in either humans or animals. More importantly, whether ANH alters arterial baroreflex control of sympathetic nervous system activity, and thereby vascular tone, remains to be determined.

In pentobarbital-anesthetized rabbits, significant attenuation of reflex-mediated decrease in HR during left aortic nerve stimulation has been reported after an increase of right atrial pressure by volume loading (22). Similarly, arterial baroreflex control of HR is reduced progressively as the right atrial pressure is increased by volume loading in conscious dogs (23). These results indicate apparent interaction between arterial baroreflex function and low-pressure cardiopulmonary reflex system, possibly via the intact vagal afferent pathway and the CNS. Based on these previous findings, our study protocol was designed to maintain cardiac filling pressures of both sides constant at the time of hemodynamic and baroreflex measurements. However, because preload of the heart is more accurately defined as a volume rather than a pressure, and because atrial stretch may not have been reflected as an increase in filling pressure, we cannot exclude a possibility of the interaction between the low-pressure cardiopulmonary reflex system and arterial baroreflex system in our study.

The results of our study also suggest that autonomic nervous system integrity may be maintained during profound ANH to a hemoglobin level of 4–5 g/dL, as seen in uninhibited arterial baroreflex function compared with the pre-ANH condition. This is in contrast with the typical circulatory responses associated with this extent of hemodilution, characterized by increased CO and decreased SVR with little change in blood pressure. Indeed, reflex neural mechanisms were not a prerequisite in modulating the systemic vasodilator and CO responses to hemodilution in rats (9). However, the HR response to hemodilution depends on experimental conditions, anesthetics used, and animal species (4,5,10,24). Anesthetics significantly attenuate circulatory responses to hemodilution by modifying the autonomic and the cardiovascular system (5). Because HR changes associated with an abrupt increase and decrease in blood pressures are considered to better reflect the dynamic component of cardiac vagal control than sympathetic nervous system activity (25), our results on baroreflex sensitivities suggest preserved vagal activity, even in the profound ANH condition.

A possible limitation of the present study would be that normovolemia may not have been maintained during the mild and profound ANH conditions in our experiment. A recent study by Tølløfsrud et al. (26) demonstrated that the volume expansion efficacy of lactated Ringer’s solution was 27% immediately after the infusion of 25 mL/kg given over the period of 30 minutes, rapidly decreasing to <10% within 60 minutes after the infusion in conscious sheep. However, volume expansion efficacy seems somewhat larger after phlebotomy followed by volume infusion than simple volume expansion using a crystalloid solution (27). In addition, we determined baroreflex sensitivities within 10 minutes of established hemodilution while maintaining cardiac filling pressures comparable to that of the predilution levels. One may also argue that ANH may have diluted the plasma pentobarbital concentration and lightened the level of anesthesia when postdilution variables were mea-sured. Whereas both pentobarbital and volatile anesthetics may similarly depress arterial baroreflex responses (28,29), a volatile anesthetic would have produced a more stable level of anesthesia because ANH would not have affected its partial pressure.

In conclusion, our results indicate that arterial baroreflex control of HR is preserved during profound ANH (hemoglobin concentration of 4–5 g/dL) induced by phlebotomy and simultaneous exchange with lactated Ringer’s solution in pentobarbital-anesthetized dogs.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 10, 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 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press