Anesth Analg 1999;89:1131
© 1999 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
The Hemodynamic Effects of Cell-Free Hemoglobin During General and Epidural Anesthesia
Hans G. Bone, MD,
René Waurick, MD,
Hugo Van Aken, PhD, MD,
Uli R. Jahn, MD,
Michael Booke, MD, and
Jörg Meyer, MD
Department of Anaesthesiology and Operative Intensive Care Medicine, Westfälische Wilhelms-Universität, Münster, Germany
Address correspondence and reprint requests to Hans G. Bone, MD, Westfälische Wilhelms-Universität Münster, Klinik und Poliklinkik für Anästhesiologie und Operative Intensivmedizin, Albert-Schweitzer-Str. 33, 48129 Münster, Germany. Address e-mail to bone{at}uni-muenster.de
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Abstract
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Although hemoglobin-based oxygen carriers (HBOC) are now being investigated, the effects of HBOC solutions during regional anesthesia have never been analyzed. Therefore, we investigated the hemodynamic changes after HBOC infusion during general anesthesia and thoracic epidural anesthesia. Sheep were assigned to three different groups: a) a control group with six unanesthetized sheep; b) six sheep with a halothane anesthesia (2.0 vol. % in oxygen); and c) six awake sheep with a thoracic epidural anesthesia with bupivacaine. After a period of stabilization, all 18 animals received 100 mg/kg of the HBOC pyridoxalated hemoglobin polyoxyethylene conjugate. The infusion of the HBOC caused a significant increase in mean arterial pressure and pulmonary artery pressure in both the control and epidural anesthesia groups. Anesthesia with halothane reduced the effects of the HBOC-solution on mean arterial pressure but did not abolish the increase in pulmonary artery pressure. Our results demonstrate that vasoconstriction caused by HBOC solutions is not abolished by epidural anesthesia, but halothane anesthesia may alter the hemodynamic effects of HBOC solutions.
Implications: We evaluated the effects of epidural anesthesia and halothane anesthesia on the vasoconstrictive properties of a cell-free hemoglobin solution. The vasoconstriction caused by a cell-free hemoglobin solution was similar in unanesthetized sheep and sheep with thoracic epidural anesthesia and was reduced in sheep with halothane anesthesia.
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Introduction
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Different hemoglobin-based oxygen carriers (HBOC) are now under clinical investigation. An important side effect of most of these HBOC-solutions is a systemic and pulmonary vasoconstriction (1,2). Until now, only a few studies have investigated the interactions between HBOC solutions, hemodynamic changes, and different anesthetics (3,4). The hemodynamic effects of HBOC solutions during regional anesthesia have never been analyzed. Therefore, we investigated the hemodynamic changes after HBOC infusion in awake sheep with and without thoracic epidural anesthesia and in sheep with halothane anesthesia.
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Methods
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After approval by the State Animal Protection Committee, 18 female sheep with an average weight of 39.3 ± 2.6 kg (SEM, range 27–54 kg) were assigned to three different groups and were instrumented for the study.
Six sheep in the awake group (Awake) were sedated with an IM injection of ketamine (15–20 mg/kg). Thereafter, an introducer was placed into the jugular vein, and after percutaneous puncture of the femoral artery, a catheter was forwarded into the abdominal aorta. After instrumentation, the animals were allowed to wake up and were placed in metabolic cages with free access to food and water for the rest of the experiment. Three days after instrumentation, a flow-directed pulmonary artery catheter was inserted using the jugular introducer. The catheters were connected to pressure transducers and monitors. Cardiac output measurements were performed by thermodilution technique, using the average of three injections of cold (2–5°C) saline solution. Baseline hemodynamic variables and arterial and mixed venous blood gases were obtained 1–2 h after the sheep were connected to the monitors. During the experimental period, lactated Ringer’s solution was infused into all animals with an infusion rate of 2 mL · kg-1 · h-1. After baseline measurements had been performed, the awake sheep received an IV bolus of 100 mg/kg pyridoxalated hemoglobin polyoxyethylene conjugate (PHP; APEX Bioscience, Research Triangle Park, NC). Hemodynamic measurements were made 5, 15, 30, 60, 90, and 120 min after the injection of PHP.
In addition to the instrumentation described above, in six sheep in the epidural group (Epidural) an epidural catheter was placed during the administration of ketamine anesthesia. The epidural space was transcutaneously punctured at the L5/S1-level using the loss of resistance technique. A silastic catheter was then inserted into the epidural space and forwarded into the thoracic part of the spine. Spinal or intravascular position of the catheter was excluded by negative catheter aspiration of blood or cerebrospinal fluid. After a recovery period of 3 days, once again spinal or intravascular position of the catheter was excluded by aspiration; thereafter, the sheep received a pulmonary artery catheter, and baseline measurements were made in the same way as described for the awake group. After baseline measurements, all animals of the epidural group received a bolus injection of 5 mL of bupivacaine 0.25% through the epidural catheter. If the sheep were not quadriplegic after 10 min, additional doses of 1 mL of bupivacaine 0.25% were given every 5 min until all four extremities became paralytic. After adjustment of the pressure transducers for the prostrate sheep, a second baseline hemodynamic measurement was performed 10 min after the final dose of local anesthetic was given. Subsequently, the sheep received an IV bolus of 100 mg/kg PHP. Hemodynamic measurements were made 5, 15, 30, 60, 90, and 120 min after the injection of PHP. During this time, no additional bupivacaine was injected into the epidural space.
In six sheep in the general anesthesia group (General), anesthesia was induced with inhaled halothane in oxygen using an animal anesthesia face mask. Endotracheal intubation was performed. Ventilation was controlled with 2.0 vol. % halothane in oxygen during the rest of the experiment. Respiratory rate was adjusted to maintain PaCO2 levels between 30 and 40 mm Hg. The tidal volume was fixed at 12 mL · kg-1 · min-1, and a positive end-expiratory pressure of 5 cm H2O was applied. After endotracheal intubation, a femoral artery catheter and an introducer with a pulmonary artery catheter were inserted as described above. After a stabilization period of 1 h, the six animals in the general anesthesia group received an IV bolus of 100 mg/kg PHP. Measurements were made at the same time points as the other groups. During the 2-h period after the PHP injection, the animals in the general anesthesia group were continuously ventilated with the halothane/oxygen mixture.
After the end of the experimental protocol, all awake sheep were anesthetized with a large dose of propofol (10 mg/kg), and the sheep of all groups were then killed with a lethal dose of saturated KCI-solution (50 mL).
Derived hemodynamic and oxygenation variables were calculated using standard formulas. All data are presented as mean ± SEM. Differences between the timepoints and the three groups were analyzed for significance using analysis of variance followed by Fisher’s LSD with a correction for the number of comparisons. Comparisons of the hemodynamic variables before and just after epidural anesthesia in the Epidural group were made using a paired Student’s t-test. Significance was accepted with P < 0.05.
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Results
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The effects of epidural anesthesia in the Epidural group were satisfactory, judged by paralysis of the extremities and by lack of response to moderate pain stimuli. The dose of bupivacaine 0.25% required to produce a muscle paralysis of all four extremities was 6.8 ± 0.8 mL (range 5–10 mL). In comparison to baseline measurements before epidural anesthesia heart rate, mean arterial pressure (MAP), central venous pressure, systemic vascular resistance index (SVRI), PaO2 and PaCO2 did not change significantly after epidural anesthesia was established. However, cardiac index (CI) decreased from 8.1 ± 0.6 to 7.0 ± 0.46 L · min-1 · m-1 (P < 0.05), and pulmonary occlusion pressure decreased from 10.3 ± 0.8 to 7.0 ± 0.7 mm ± Hg (P < 0.05).
CI and MAP tended to be lower in the general anesthesia group, and SVRI tended to be higher in the general anesthesia group than in the two other groups. These differences failed to reach statistical significance (Figure 1). At almost all time points, oxygen consumption (VO2), as well as the oxygen extraction ratio, was significantly lower in the general anesthesia group than in the two other groups (Table 1).
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Figure 1. Changes in mean arterial pressure (MAP), cardiac index (CI), and systemic vascular resistance index (SVRI) in awake sheep with and without epidural anesthesia and in sheep with general anesthesia that received a bolus of a hemoglobin based oxygen carriers-solution after the 0-min measurement. * P < 0.05 vs 0 min.
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The amount of PHP solution given to the animals ranged depending on the body weight of the sheep from 31 mL to 61 mL. Bolus infusion of PHP caused a rapid increase in central venous pressure in all three groups (Table 1). A transient rise in pulmonary occlusion pressure was observed in the Awake as well as in the General anesthesia group. Left ventricular stroke work index, right ventricular stroke work index, PaO2, VO2, and oxygen extraction ratio were not significantly effected by PHP infusion. The effects of PHP-infusion on MAP, CI, and SVRI are shown in Figure 1. Effects on pulmonary artery pressure (PAP) and pulmonary vascular resistance index are displayed in Figure 2.
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Figure 2. Changes in mean pulmonary artery pressure (PAP), and pulmonary vascular resistance index (PVRI) in awake sheep with and without epidural anesthesia and in sheep with general anesthesia that received a bolus of a hemoglobin based oxygen carriers-solution after the 0-min measurement. *P < 0.05 vs 0 min.
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Discussion
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In our experiments, we investigated the hemodynamic effects of the cell-free hemoglobin solution PHP in awake sheep with and without epidural anesthesia and in anesthetized sheep, which were mechanically ventilated with halothane in oxygen. The main results of these experiments were: 1) PHP infusion caused an immediate increase in MAP in the awake and epidural groups. The MAP increase after PHP infusion in the general anesthesia group was moderate and delayed and failed to reach significance. 2) In all three groups, PHP infusion was followed by an instantaneous and significant increase in PAP.
Similar hemodynamic effects of different HBOC solutions have been described in a variety of preclinical and clinical studies. HBOC solutions have caused vasoconstriction in isolated blood vessels (3), in different animal species (2,5,6), and in clinical trials (7). This vasopressor response was explained by different possible mechanisms: a) a sensitization of  1 and 2 receptors in the peripheral vascular system (8), b) an endothelin release (5,9), and c) a scavenging of the vasodilator nitric oxide (10). The interactions with nitric oxide were regarded as the main reasons for the vasoconstrictive properties of cell-free hemoglobins (6,11,12). In contrast to hemoglobin in red blood cells, cell-free hemoglobin diffuses through the vascular wall and binds a large amount of nitric oxide yielding methemoglobin and nitrate in an extremely rapid reaction (13). However, a recent publication (1) called into question whether interactions with nitric oxide are responsible for the vasoconstrictive response of hemoglobin solutions.
Increases in PAP, pulmonary vascular resistance index, or SVRI may be harmful to patients receiving modified hemoglobins, regardless the reasons of vasoconstriction (2,7). Although many studies investigated hemodynamic effects of modified hemoglobins, few studies looked for interactions between different anesthetic drugs and these hemoglobins (3,4). The hemodynamic effects of HBOC during regional anesthesia have never been investigated. Therefore, we investigated the effects of PHP in awake sheep and in sheep with halothane anesthesia or epidural anesthesia.
Only the sheep of the general anesthesia group had halothane anesthesia and were mechanically ventilated. Before and after PHP application, this group tended to have a lower CI and a lower MAP than the two other groups. These effects on CI and MAP are commonly observed during halothane anesthesia (14). The general anesthesia group also tended to have a higher SVRI than the other two groups. This cannot be explained by pharmacological actions of halothane (14), but may be related to the mechanical ventilation with positive end-expiratory pressure in this group (15). The lower VO2 in the general anesthesia group is not surprising, because only this group had a general anesthesia and was ventilated and had, therefore, a lower need of oxygen. PHP infusion had no significant effect on MAP, CI, or SVRI in the general anesthesia group. In other studies that gave larger doses of HBOC than we gave, increases in MAP and SVRI were seen after infusion of HBOC in halothane-anesthetized animals (16,17). In contrast to these in vivo experiments that did not specifically investigate interactions between hemoglobin and different anesthetics, Jing et al. (3) analyzed vasoconstrictive properties of a modified hemoglobin in the presence of different anesthetics in vitro. They compared the contraction of isolated blood vessels caused by a HBOC in the presence of halothane and isoflurane. In contrast to isoflurane, halothane inhibited the HBOC-induced contractions in a dose-related manner. This inhibition of HBOC-induced vasoconstriction may be caused by interactions of halothane with the heme-part of the hemoglobin (3), although other interactions between halothane and the nitric oxide system have also been described (18). Similar to the in vitro results of Jing et al. (3), we found, in our in-vivo experiment, an attenuated systemic pressure effect of PHP during halothane anesthesia. In contrast to the MAP, PAP significantly increased when PHP was given during halothane anesthesia. Different reactions of the systemic and pulmonary circulation to HBOC-application have been observed before (19).
In most clinical investigations, HBOC solutions were used during isovolemic hemodilution before elective surgery. None of these investigations was performed in patients with epidural anesthesia. However, epidural anesthesia is commonly used for elective surgery, either as a single anesthesia method or in combination with general anesthesia. Epidural anesthesia causes a partial or complete sympathetic blockade. Multiple different possible interactions between nitric oxide and the sympathetic nerve system have been discussed in the literature (20,21). Therefore, the HBOC-associated vasoconstriction, which is most likely caused by NO-scavenging, could be modified when an epidural anesthesia causes a sympathetic blockade.
In our study, epidural anesthesia did not cause significant hemodynamic changes in sheep before HBOC application. Vincent et al. (22), who investigated hemodynamic effects in pregnant sheep, also saw no significant changes in MAP and CI after epidural anesthesia had been established.
Because HBOC solutions can cause vasoconstriction even in isolated vessel rings (3), the sympathetic system can play only a minor role in the hemodynamic effects of HBOC solutions. In our study, sympathetic blockade during epidural anesthesia had no effect on the vasoconstrictive properties of a hemoglobin solution. Gulati and Rebello (8) studied the hemodynamic effects of a HBOC solution in cervical sectioned rats, as well as in bilateral adrenal demedullated rats. They also observed no effects of sympathetic innervation on HBOC-associated vasoconstriction. Therefore, it is likely that vasoconstriction caused by HBOC solutions is not even influenced by changes in the activity of the sympathetic nerve system.
Although the significance of these results is reduced by the small number of animals observed in each group and the fact that only one inhaled anesthetic was examined, our results indicate that the selection of the anesthetic method may alter hemodynamic side effects of HBOC solutions. During halothane anesthesia, unchanged MAP and heart rate values may be misleading, because isolated increases in PAP after HBOC application could be missed when no pulmonary artery catheter is used. Anesthesiologists who give HBOC solutions to patients with halothane anesthesia should be aware of this potential danger.
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References
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Rohlfs RJ, Bruner E, Chiu A, et al. Arterial blood pressure responses to cell-free hemoglobin solutions and the reaction with nitric oxide. J Biol Chem 1998;273:12128–34.[Abstract/Free Full Text]
-
Hess JR, Macdonald VW, Brinkley WW. Systemic and pulmonary hypertension after resuscitation with cell-free hemoglobin. J Appl Physiol 1993;74:1769–78.[Abstract/Free Full Text]
-
Jing M, Ledvina MA, Bina S, et al. Effects of halogenated and non-halogenated anesthetics on diaspirin cross-linked hemoglobin induced contractions of porcine pulmonary veins. Substit Immobil Biotechnol 1995;23:487–94.
-
Cole DJ, Przybelski RJ, Schell RM, et al. Diaspirin crosslinked hemoglobin (DCLHb) does not affect the anesthetic potency of isoflurane in rats. Artif Cells Blood Substit Immobil Biotechnol 1995;23:89–99.[Web of Science][Medline]
-
Bone HG, Schenarts PJ, Booke M, et al. Pyridoxalated hemoglobin polyoxyethylene conjugate normalizes the hyperdynamic circulation in septic sheep. Crit Care Med 1997;25:1010–18.[Web of Science][Medline]
-
Moisan S, Drapeau G, Burhop KE, et al. Mechanism of the acute pressor effect and bradycardia elicited by diaspirin crosslinked hemoglobin in anesthetized rats. Can J Physiol Pharmacol 1998;76:434–42.[Web of Science][Medline]
-
Kasper SM, Grune F, Walter M, et al. The effects of increased doses of bovine hemoglobin on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. Anesth Analg 1998;87:284–91.[Abstract/Free Full Text]
-
Gulati A, Rebello S. Role of adrenergic mechanisms in the pressor effect of diaspirin cross-linked hemoglobin. J Lab Clin Med 1994;124:125–33.[Web of Science][Medline]
-
Schultz SC, Grady B, Cole F, et al. A role for endothelin and nitric oxide in the pressor response to diaspirin cross-linked hemoglobin. J Lab Clin Med 1993;122:301–8.[Web of Science][Medline]
-
Alayash AI, Cashon RE. Reactions of nitric oxide and hydrogen peroxide with hemoglobin-based blood substitutes. Ann N Y Acad Sci 1994;738:378–81.[Web of Science][Medline]
-
Kida Y, Maeda M, Iwata S, et al. Effects of pyridoxalated hemoglobin polyoxyethylene conjugate and other hemoglobin-related substances on arterial blood pressure in anesthetized and conscious rats. Artif Organs 1995;19:117–28.[Web of Science][Medline]
-
Katsuyama SS, Cole DJ, Drummond JC, et al. Nitric oxide mediates the hypertensive response to a modified hemoglobin solution (DCLHb) in rats. Artif Cells Blood Subst Immobil Biotechnol 1994;22:1–7.[Web of Science][Medline]
-
Alayash AI, Ryan BA, Fratantoni JC, et al. Redox reactivity of modified hemoglobins with hydrogen peroxide and nitric oxide: toxicological implications. Biotechnol 1994;22:373–86.
-
Pavlin EG, Su JY. Inhaled anesthetics: cardiopulmonary pharmacology. In: Miller RM, ed. Anesthesia. New York:Churchill Livingstone, 1994:125–56.
-
Nunn J. Nunn’s applied respiratory physiology. 4th ed. Oxford:Butterworth-Heinemann Ltd, 1993.
-
Waschke K, Krieter H, Albrecht DM, et al. Modified hemoglobin as a blood substitute in a rat model. Anaesthesist 1993;42:90–5.[Web of Science][Medline]
-
Loeb A, McIntosh LJ, Raj NR, et al. Regional vascular effects of rHb1.1, a hemoglobin-based oxygen carrier. Pharmacol 1997;30:703–10.
-
Jing M, Ling GSF, Bina S, et al. Halothane attenuates nitric oxide relaxation of rat aortas by competition for the nitric oxide receptor site on soluble guanylyl cyclase. Eur J Pharmacol 1998;342:217–24.[Web of Science][Medline]
-
Freas W, Llave R, Jing M, et al. Contractile effects of diaspirin cross-linked hemoglobin (DCLHb) on isolated porcine blood vessels. J Lab Clin Med 1995;125:762–7.[Web of Science][Medline]
-
Zanzinger J, Czachurski J, Seller H. Inhibition of sympathetic vasoconstriction is a major principle of vasodilation by nitric oxide in vivo. Circ Res 1994;75:1073–7.[Abstract/Free Full Text]
-
Booke M, Waurick R, Van Aken H, et al. Effects of sympathetic nerve blockade on vasoconstrictive properties of nitric oxide synthase inhibition in sheep. Cardiovasc Res 1997;36:111–7.[Abstract/Free Full Text]
-
Vincent RD, Chestnut DH, Sipes SL, et al. Magnesium sulfate decreases maternal blood pressure but not uterine blood flow during epidural anesthesia in gravid ewes. Anesthesiology 1991;74:77–82.[Web of Science][Medline]
Accepted for publication July 6, 1999.
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Abstract
Introduction
