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ANESTHETIC PHARMACOLOGY

A Comparative Evaluation of Inhaled Halothane, Isoflurane, and Sevoflurane During Acute Normovolemic Hemodilution in Dogs

Denise Tabacchi Fantoni, DVM, PhD^*, Denise Aya Otsuki, DVM^*, Aline Magalhães Ambrósio, DVM^*, Eunice Yuriko Tamura^*, and José Otávio Costa Auler, Jr, MD, PhD

*Department of Surgery, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil; and Department of Anesthesiology, School of Medicine, University of São Paulo, São Paulo, Brazil

Address correspondence and reprint requests to Denise Tabacchi Fantoni, DVM, PhD, Department of Surgery, School of Veterinary Medicine, University of São Paulo, Rua Professor Dr. Orlando Marques de Paiva 87, CEP 05508-900, São Paulo, Brazil. Address e-mail to dfantoni{at}fmvz.usp.br.

	Abstract

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The hemodynamic response to acute normovolemic hemodilution (ANH) can be affected by the anesthetics used. We randomized 18 mongrel dogs to undergo ANH with 3 different inhaled anesthetics: halothane, isoflurane, or sevoflurane. Hemodynamics, oxygen transport, and gastric pH were measured before blood withdrawal, at the end of hemodilution, and 30 and 60 min after the end of hemodilution. The baseline measurements of all hemodynamic variables were similar among groups, with the exception of heart rate, which was more rapid in the sevoflurane group. Thirty minutes after hemodilution, the cardiac index increased 88%, 86%, and 157% in the halothane, isoflurane, and sevoflurane groups, respectively, whereas arterial-venous oxygen differences and oxygen consumption were larger in the halothane group compared with the isoflurane and sevoflurane groups. Gastric pH obtained by tonometry did not change and was not different among groups. Because the hemodynamic response to ANH was not blunted, all three anesthetics may be safely used for the maintenance of anesthesia.

	Introduction

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Allogeneic blood transfusion is an important therapeutic tool for a number of conditions, especially those associated with trauma and major blood loss (1). However, it conveys the risk of infections and the possibility of immunosuppression, allergic reactions, and cancer recurrence (2–4).

Acute normovolemic hemodilution (ANH) is an effective technique to avoid or reduce allogeneic blood transfusion requirements during major surgery (1,5,6). ANH consists of the removal of a predetermined amount of blood and simultaneous infusion of plasma expanders, such as crystalloids, colloids, or both (7). The changes in blood flow characteristics due to the decrease in blood viscosity, the consequent increase in cardiac output and heart rate, and the increased oxygen extraction rate account for the hemodynamic stability during the procedure (6).

An additional factor that influences hemodynamic stability during hemodilution is the anesthetic used during the procedure (8,9). The depressant effects of some anesthetics could attenuate the hemodynamic response promoted by hemodilution, impairing the increase in cardiac output and stroke volume necessary to maintain oxygen transport (8–10). The inhaled anesthetics are among the most depressant drugs: they decrease contractility, venous return, and arterial blood pressure (11). We compared the hemodynamic response to ANH in dogs anesthetized with halothane, isoflurane, or sevoflurane to verify whether the anticipated response to ANH is sustained during inhaled anesthesia.

	Methods

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The ethics and animal investigation committee at our institution approved this study, which was performed in 18 adult mongrel dogs weighing between 14 and 20 kg. The dogs were fasted for 12 h with free access to water. Before the experiments, they were sedated with IM meperidine (2 mg/kg). Anesthesia was induced with ketamine (5 mg/kg) and midazolam (0.5 mg/kg) administered IV. After endotracheal intubation, anesthesia was maintained with 1 of the 3 anesthetics used in the study: halothane, isoflurane, or sevoflurane in 50% oxygen. The lungs of the animals were mechanically ventilated, and ventilation was adjusted to obtain an end-tidal CO₂ (ETco₂) concentration of 35–45 mm Hg. Pancuronium (0.06 mg/kg) was given for muscle paralysis. The anesthetic concentrations were maintained at 1 minimum alveolar anesthetic concentration (MAC) for each anesthetic during the procedure. Both femoral arteries were catheterized: one for measuring systemic arterial blood pressure and for arterial blood sampling and the other for blood withdrawal. Three large-bore venous catheters were inserted into both cephalic and jugular veins for fluid infusion. A pulmonary artery catheter (7.5F; Baxter, Irvine, CA) was introduced through the left femoral vein, with the tip positioned in the pulmonary artery, guided by pressure monitoring and wave tracings. The pulmonary artery catheter was used for mixed venous blood sampling and to measure mean pulmonary artery pressure, pulmonary capillary wedge pressure, central venous pressure, and cardiac output. Pressure transducers were connected to a multiparametric data-collection system (Viridia CMS; Hewlett-Packard, Andover, MA) for continuous recording of heart rate, pressures, and wave forms. Arterial and venous blood samples were analyzed with a pH/blood gas analyzer (ABL; Radiometer, Copenhagen, Denmark). The dogs’ temperatures were maintained at approximately 37°C by means of a warm blanket (Medi-therm II; Gaymar Industries, Orchard Park, NY).

Gastric intramucosal pH (pHi) was measured by using air-automated tonometry. Ranitidine (2.0 mg/kg) was administered to the dogs before the insertion of the tube. A tonometer tube with a silicone rubber balloon (Catheter TRIP NGS; Tonometrics, Worcester, MA) was positioned in the stomach. Before catheter insertion, the stomach was cleaned for possible residual contents by lavage with 500 mL of warm normal saline. Satisfactory placement of the tube was confirmed by auscultation over the epigastrium after injection of 50 mL of air into its lumen. The tonometer and the airway sampling line were connected to an automated gas analyzer (Tonocap^TM; Datex, Helsinki, Finland). Arterial blood samples were taken simultaneously with measurement of gastric CO₂ (Prco₂) to calculate the regional-to-arterial Pco₂ difference. The pHi was calculated by the Tonocap with the formula

After instrumentation, animals were allowed to stabilize for 30 min and then were randomized into 1 of 3 groups of 6 dogs each. In Group H, anesthesia was maintained with 1 MAC halothane (0.86% end tidal), in Group I with 1 MAC isoflurane (1.28% end tidal), and in Group S with 1 MAC sevoflurane (2.36% end tidal) (12). A gas analyzer (POET IQ; Criticare, Waukesha, WI) calibrated with the standard gas provided by the manufacturer immediately before the beginning of the study was used continuously to ensure that the desired end-tidal concentration of each anesthetic was being administered.

Blood withdrawal was performed in 30 min; blood was simultaneously replaced with lactated Ringer’s (LR) solution and 6% hydroxyethyl starch (200,000 daltons; 0.5 molar substitution ratio). Half of the estimated replacement volume was with LR at a 3:1 ratio (3 volumes LR/1 volume blood), and the second half was with hydroxyethyl starch (1:1 ratio). The solutions were warmed to 38°C before infusion. The volume of blood removed (V) was calculated with the following formula:

where EBV is the estimated blood volume, H_o is the initial hematocrit, H_t is the target hematocrit, and H_av is the average hematocrit [(H_o + H_t)/2] (13). The total amount of blood withdrawn from each dog was calculated to be removed in 30 min, so approximately 20 mL of blood per minute was removed in a continuous fashion. A graduated cylinder was used to measure the correct amount of blood withdrawn. The target hematocrit was established as 28%, which is considered the lower limit in the clinical setting (14,15). The fluids for replacement were reinfused via infusion pumps (Anne; Abbott, North Chicago, IL) to ensure the correct administration time.

Data were collected before blood withdrawal (baseline), 15 and 30 min after the beginning of hemodilution, and 30 and 60 min after the end of hemodilution. Systemic arterial blood pressure, pulmonary artery and central venous pressures, heart and respiratory rates, ETco₂, Spo₂, and inspired and expired halothane, isoflurane, or sevoflurane concentrations were continuously evaluated. Cardiac output was determined with the thermodilution technique. Cardiac index was calculated according to calculated body surface (k · BW^2/3, where k = 0.09) (BW = body weight) (16). Stroke volume, systemic and pulmonary vascular resistance indexes, blood oxygen content, and oxygen delivery (Do₂) and consumption were calculated with standard formulas and data obtained from arterial and mixed venous blood gas analysis (17).

Data were analyzed using analysis of variance for repeated measures followed by the Tukey test to evaluate differences between time points within the same group and between groups. A P value of <0.05 was considered statistically significant. Values are presented as means ± sd.

	Results

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Body weight, volume of fluids administered, and urinary output did not vary among the study groups (Table 1). The initial baseline measurements of all hemodynamic variables were similar among groups, with the exception of heart rate, which was more rapid in the sevoflurane group (Table 2). Immediately after ANH, cardiac index increased 157% in the sevoflurane group, whereas in animals anesthetized with isoflurane and halothane, the increase was 86% and 88%, respectively (Fig. 1). In the isoflurane and halothane groups, the increase was significant only immediately after blood withdrawal, but in the sevoflurane group, cardiac output increased significantly at the end of ANH and remained more than the control values for a further 30 min. The systemic vascular resistance index decreased significantly in all groups immediately after ANH and remained lower during the entire observation period (Table 2). Arterial oxygen content, venous oxygen content, and arterial-venous oxygen differences decreased significantly in the three groups (Table 3). Do₂ increased in the three groups during ANH; however, the increase was significant only in the sevoflurane group. Although oxygen consumption decreased immediately after the end of ANH in the three groups, it was significantly higher in the halothane group when compared with the isoflurane or sevoflurane groups (Table 3). The pHi did not change during the experiment and was not different among groups (Table 4).

View larger version (18K): [in this window] [in a new window]   Figure 1. Changes in cardiac index in dogs undergoing acute normovolemic hemodilution (ANH) and anesthetized with halothane, isoflurane, or sevoflurane (mean ± sd). *P 0.05 compared with control.

	Discussion

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ANH can be a very useful tool to avoid blood transfusion in the surgical patient. We demonstrated in this study that the administration of halothane, isoflurane, or sevoflurane at an end-expiratory concentration equivalent to 1 MAC did not impair the response to ANH in dogs. We observed maintenance of Do₂ and increases in cardiac output.

During ANH, cardiac output, stroke volume, heart rate, and filling pressures should increase in response to the decrease in blood viscosity (1). These hemodynamic responses are responsible for the maintenance of oxygen transport (Do₂) despite the decrease in hemoglobin and arterial oxygen content (7). However, these responses can be influenced by several factors, including anesthetics (8,9,18), the amount of fluid used for plasma expansion, and concurrent medications.

Cardiac output did not change in response to ANH in ASA status I patients anesthetized with enflurane and fentanyl (8) or enflurane/nitrous oxide (9). The cardiac-depressant effects of enflurane and nitrous oxide and the vagal stimulation associated with fentanyl might explain these findings (12). Halothane significantly depresses cardiac contractility, but despite this, we observed a 57% increase in cardiac output with this anesthetic. The end-tidal concentration of halothane in our study was 0.8%, which corresponds to 1.0 MAC in dogs. With this concentration, myocardial depression is much less intense compared with that administered in larger concentrations (12,19). In our study, isoflurane did not blunt all the hemodynamic responses to ANH. Cardiac output increased, but heart rate remained unchanged, as did Do₂ and the oxygen extraction ratio. The group of dogs anesthetized with sevoflurane also had the same pattern of hemodynamic responses to ANH. The initial value for the heart rate was higher in this group of dogs and during the whole experiment. An increase in heart rate of almost 30% is expected with the use of sevoflurane in dogs (11). Although the oxygen extraction ratio was higher in the sevoflurane group when compared with the isoflurane Group 30 minutes after the end of ANH, the difference was small. This could be explained by the higher heart rates observed in the sevoflurane group. The decrease in oxygen extraction verified in the three groups after ANH may be explained by microcirculatory adjustments that probably met the tissue necessities. At this moment of ANH, the lowest values of hematocrit were observed. According to Vicaut et al. (20), hemodilution is an important rheological factor that promotes a significant increase in mean cell velocity and mean volume flow rate.

The use of ketamine for the induction of anesthesia may have contributed to the observed changes in cardiac output. Traber et al. (21) demonstrated that ketamine can increase cardiac output by 17% when used at the same dosage as was used in this study. However, the effects of ketamine are very short-lived, and after induction, 30 minutes elapsed, during which anesthetic maintenance was stabilized. The combination of ketamine and midazolam, as used in this study for the induction of anesthesia, caused minimal cardiovascular and respiratory effects in greyhounds (22). One possible criticism of this study is that we did not take measurements when the dogs were conscious. Because ANH is a technique performed with the subject already anesthetized, the values we considered as controls were those obtained when anesthesia was stabilized, which is similar to the clinical situation.

Maintenance of arterial blood pressure and an increase in, or at least the preservation of, basal venous pressure is of paramount importance in maintaining cardiac output and Do₂ between normal ranges during ANH. Hypotension and a decreased venous return may, indeed, be more important than a specific anesthetic in influencing the cardiovascular response to ANH. When necessary, additional fluids should be infused to maintain normal levels of arterial and central venous pressure. In this study, we observed that arterial blood pressure and central venous pressure increased slightly or were maintained at basal levels, which probably contributed to minimizing the depressant effects of the inhaled anesthetic and allowing that the hemodynamic compensatory mechanisms to ANH occurred.

We chose a moderate level of hemodilution to an H_t of approximately 28% or a hemoglobin of 9 g/dL, which would be an acceptable level for a healthy surgical patient. Although one study showed that small-volume ANH was minimally effective in avoiding exposure to allogeneic blood (23), some studies demonstrated a decrease in the need for blood-bank transfusions with an H_t of 28% to 30% (5,15). ANH efficacy depends on the initial patient hematocrit, transfusion trigger, and surgical blood loss, which should be 0.7 of the patient’s blood volume (24).

The maintenance of gastric pHi and Prco₂ at normal levels may indicate that even under low levels of hematocrit, Do₂ to the tissues, represented by the gastric mucosa, was normal. Prco₂ and pHi monitoring has been suggested as a useful tool to evaluate tissue perfusion (25). The normal values of pHi obtained in our study may reinforce the hypothesis that potent inhaled anesthetics do not interfere with cardiovascular responses to ANH.

In conclusion, our data demonstrated that 1 MAC of halothane, isoflurane, or sevoflurane does not blunt the hemodynamic response to ANH in dogs and may be used safely during this procedure. The hemodynamic effects of inhaled anesthetics at a larger MAC or of IV anesthetics during ANH are unknown and could be the subject of further study.

	Footnotes

 
Supported by the Fundação de Amparo a Pesquisa de São Paulo (99/07163-3) and the Experimental Laboratory of Anesthesia (LIM08).

Accepted for publication September 16, 2004.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Fantoni, D. T. Articles by Auler, J. O. C. Search for Related Content PubMed PubMed Citation Articles by Fantoni, D. T. Articles by Auler, J. O. C., Jr Related Collections Cardiovascular Blood Pharmacology