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From the *Department of Anesthesiology, Duke University Medical Center; and Division of Perioperative Care and Emergency Medicine, University Medical Center, Utrecht, the Netherlands.
Address correspondence and reprint requests to G. Burkhard Mackensen, MD, Department of Anesthesiology, Duke University Medical Center, DMUC Box 3094, Durham, NC 27710. Address e-mail to b.mackensen{at}duke.edu.
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Abstract |
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METHODS: Male Sprague-Dawley rats undergoing 60 min of normothermic nonpulsatile CPB were randomized to one of the three groups. The PFC group (n = 10) received 60% O2/36% N2/4% CO2 via the membrane oxygenator and 2.7 g/kg (4.5 mL/kg) of PFC into the venous reservoir; the control group (n = 10) received the same gas mixture and 4.5 mL/kg of saline; the N2O group (n = 6) was exposed to 36% N2O/60% O2/4% CO2 and received 4.5 mL/kg of saline. After 10 min and 35 min of CPB, 400 µL of air was injected into a bubble chamber in the CPB circuit. After 20 min, the bubble was removed for volumetric analysis.
RESULTS: Compared with baseline, the bubble decreased 13% ± 5% in size in the PFC group and increased 46% ± 9% in the nitrous oxide group, both of these changes significantly different from the control group (P < 0.0001).
CONCLUSION: The results suggest that PFC administration may be useful in reducing the volume of gaseous bubbles present during CPB.
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Introduction |
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Perfluorocarbon (PFC) emulsions are artificial oxygen-carrying substances that have been clinically investigated as blood substitutes. The rationale for using PFCs during CPB relates primarily to the solubility of PFC emulsions for gases (e.g., oxygen, carbon dioxide, and nitrogen) that is 100,000 times greater than that of plasma (12). Thus, PFC emulsions do absorb air introduced into the circulation. However, the ability of these emulsions to affect gas bubbles during CPB has not been determined. Therefore, we conducted a study to test the hypothesis that PFC emulsions reduce the volume of a gaseous bubble within the CPB circuit.
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METHODS |
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Experimental Procedures
Fasted male Sprague-Dawley rats (13–15-wk old; weight, 400–450 g; Charles River Labs, Wilmington, MA) were anesthetized with 5% isoflurane in oxygen in a plastic induction box. After induction of anesthesia, the trachea was intubated and the lungs mechanically ventilated (Harvard Rodent Respirator; Boston, MA) with a tidal volume of 10 mL/kg and respiratory rate of 55–65 bpm maintaining arterial Paco2 between 36–42 mm Hg. Anesthesia was maintained with 1.5%–2.0% inspired isoflurane.
Pericranial temperature was monitored with CSC 32 (OMEGA Engineering, Stamford, CT) and servo-regulated to a target temperature of 37.0°C during CPB, using a heating blanket and a convective forced-air heating system. A polyethylene catheter (PE-10) was placed in the superficial caudal epigastric artery for measurement of mean arterial blood pressure. The ventral tail artery was cannulated with a 20-G, 28-mm IV catheter, which later served as the arterial inflow from the CPB circuit. A 4.5-F multiorifice dual stage venous cannula (modified from a 4.5 French Desilets-Hoffman Pediatric Introducer; Cook, Bloomington, IN) was advanced via the right external jugular vein for venous return. Heparin 150 IU was administered after placement of the first arterial cannula with an additional 150 IU added just before placement of the jugular venous cannula. All cannulae were secured in situ with silk ties to eliminate the entrainment of extraneous air.
Upon initiation of CPB, the rats were randomized to one of the three groups. The PFC group (n = 10) received a gas mixture of 60% O2, 36% N2, and 4% CO2 via the membrane oxygenator and 2.7 g/kg (4.5 mL/kg) of PFC (Oxycyte®, Synthetic Blood International, San Diego, CA) into the venous reservoir. The dose for PFC was selected based on a phase II study in cardiac surgery (13). The control group (n = 10) received the same gas mixture but 4.5 mL/kg of 0.9% saline. The nitrous oxide group (serving as a positive control; n = 6) received 60% O2, 36% N2O, and 4% CO2 and 4.5 mL/kg of 0.9% saline, during CPB. Isoflurane (1.0%) was administered via the gas inflow of the membrane oxygenator throughout CPB. The lungs of the animals were disconnected from the ventilator during CPB.
Cardiopulmonary Bypass
To avoid excessive hemodilution, the bypass circuit was primed with approximately 15 mL whole blood obtained from a heparinized (100 IU IV heparin per rat) donor rat. In addition, 6% hetastarch (10 mL) was added to the circuit, as needed. The CPB circuit consisted of a specifically designed 8 mL Plexiglas® venous reservoir, a roller pump (Masterflex®; Cole-Parmer Instrument, Vernon Hills, IL) and a custom-designed small-volume oxygenator. The 4 mL priming volume oxygenator was built of 2 Plexiglas shells (12.8 cm x 12.8 cm x 2.7 cm) that carry a sterile, disposable three-layer artificial diffusion membrane, made with hollow polypropylene fibers (Jostra AG, Hirrlingen, Germany) glued together in a crosswise fashion (14). The surface area available for gas exchange was 558 cm2. To prevent excessive heat loss, one of the shells had an integrated heat exchanger.
The CPB flow was 160–180 mL/kg/min. Ten minutes after the start of CPB, using a calibrated glass microliter syringe (total volume 1000 µL), 400 µL of air was injected into a blood-filled glass bubble chamber on the venous side of the circuit as previously reported (15) (Fig. 1). After 20 min of equilibration, the entire bubble was withdrawn into the calibrated syringe, and its volume was determined by reading its 10-µL-precise scale markings. After 10 min, another 400 µL of air was injected into the bubble chamber, allowed to equilibrate, and then similarly withdrawn for measurement. The two consecutive measurements from each animal were treated equally and both were included for analysis of the group's bubble change.
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To evaluate the effect of PFC on the systemic oxygen balance, arterial blood samples from the arterial inflow of the membrane oxygenator and venous blood samples from venous reservoir in CPB circuit were analyzed with IL GEM Premier 3000 (blood gas analyzer; Global Medical Instrumentation, Ramsey, MI), at the following points: 1) before CPB, 2) 10 min after the start of CPB, 3) 30 min after the start of CPB, 4) end of CPB, and 5) 60 min after the end of CPB.
Data Analysis
Physiological data were first compared within each randomized group using one-way analysis of variance (ANOVA) with repeated measurements. Differences among groups were compared using two-way ANOVA with repeated measurements. Changes in bubble size were compared using one-way ANOVA and Bonferroni t-test as a post hoc comparison. Statistical significance was considered when P < 0.05.
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RESULTS |
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The PFC group demonstrated a significant reduction in the bubble volume compared with the control and nitrous oxide groups. The nitrous oxide group showed a significant expansion of the bubble volume compared with the other groups (Fig. 2). Compared with the control group, PFC emulsions reduced the bubble volume by 13% ± 5% (P < 0.0001) and nitrous oxide increased the bubble volume by 46% ± 9% (P < 0.0001). Bubble volume remained basically unchanged in the control group (–2% ± 2%).
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DISCUSSION |
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PFC emulsions have three unique and important properties. First, the solubility of gases such as oxygen, carbon dioxide, and nitrogen in PFC emulsions is 100,000 times greater than in plasma (12). Second, the oxygen transport characteristics for PFC emulsions are fundamentally different from that of blood. In contrast to the sigmoid oxygen dissociation curve for hemoglobin, PFC emulsions are characterized by a linear relationship between the partial pressure of oxygen and oxygen content. Further, oxygen carried by PFC is in the dissolved state, providing a reservoir of oxygen resulting in a higher oxygen partial pressure in the microcirculation, thereby enhancing the driving pressure for the diffusion of dissolved oxygen into the tissue. Finally, PFC particles are significantly smaller than red blood cells (RBCs), which might allow oxygen to be transported through microvessels that are otherwise obstructed by emboli debris preventing the transit of RBCs. Therefore, PFC emulsions have theoretical properties that may allow the scavenging of air emboli that would otherwise contribute to end-organ injury during cardiac surgery, and as well as the delivery of oxygen to distal tissues where gaseous emboli might have disturbed conventional oxygen delivery by RBCs (16). Although PFC solutions have undergone considerable safety testing, they may cause certain side effects such as a reversible delayed febrile reaction with flu-like symptoms or a transient reduction in platelet count (17,18).
Patients undergoing CPB are exposed to many microemboli (e.g., gaseous bubbles or other particulate matter) during cardiac surgery (19,20). Gaseous emboli have been implicated as a potential contributing factor in the development of cerebral (and other organ) injury after cardiac surgery (2,21). Further, CPB without allogenic blood transfusion can result in significant hemodilution and, as a consequence, may potentially reduce oxygen delivery. Theoretically, the administration of PFC during cardiac surgery could accomplish both a significant reduction in gaseous cerebral microemboli and also increase oxygen delivery (perhaps with a decreased need for allogenic blood transfusion).
In addition to potentially reducing the volume of gaseous bubbles that are entrained into the CPB circuit, PFC might also be useful for treatment of air embolism reaching the cerebral circulation. The effectiveness of PFC emulsions to protect against cerebral injury related to air emboli has been evaluated since the 1980s. Menasche et al. (16) and Spiess et al. (22,23) demonstrated that PFC emulsions improve functional recovery from transient neurological deficits caused by cerebral air emboli, and facilitate survival in experimental settings of cerebral air embolism. More recently, PFC emulsions have been introduced as potentially therapeutic for the prevention and treatment of the consequences of cerebral embolism during CPB. Cochran et al. (24) demonstrated that priming the CPB circuit with PFC emulsions resulted in a significant reduction in the severity of neurologic sequelae associated with air embolism after experimental CPB. Further, PFC emulsions have been shown to improve the microvascular circulation during CPB (25,26) and reduce the area of nonperfusion capillary beds in the retinal microcirculation after a massive air insult during CPB.
In addition to the unique properties of PFC emulsions, they also have the potential to decrease the surface tension of gaseous bubbles. Eckmann and Lomivorotov (27) showed, for example, that PFC emulsions enhanced the clearance of microvascular gas embolization in the rat cremaster circulation. However, there has been no study measuring the bubble volume reduction ratio of PFC emulsions directly within the CPB circuit. Our results show that PFC emulsions reduce the volume of an air bubble entrained in the CPB circuit by more than 10%. Although the absolute magnitude of this reduction appears somewhat small, we speculate that this reduction might, at least in part, be responsible for the beneficial effects of PFC emulsions in the context of CPB and cerebral air embolism.
In this study, PFC emulsions also resulted in a small, but significant, increase in systemic oxygenation during CPB. Although this result is not relevant to our hypothesis, it is supported by previous reports demonstrating that PFC emulsions may augment Pvo2 during CPB or hemodilution (28–31). While all prior studies used a Fio2 of 100%, we were able to show beneficial effects on oxygenation despite a lower inspired oxygen concentration (60%) that was chosen to keep the Fio2 comparable to the nitrous oxide group.
There were some limitations to the present study. First, the bubbles in the bubble chamber were not exposed to a vascular bed. Therefore, this study did not replicate any bubble-tissue endothelium interface that would typically be seen clinically. Second, the bubble that we injected did not assume a completely spherical shape. The air bubble had a dome shape with a flat surface at one end that represented the blood-gas interface (Fig. 1). This may have affected the interaction at the blood-gaseous interface by reducing the surface area of the bubble compared with a more spherical bubble. If the entire surface of the bubble had been exposed to blood containing PFC emulsions or nitrous oxide, then the gas diffusion in and out of the bubble may have been even more than what our results have demonstrated. Given the significant bubble expansion in the nitrous oxide group, this study reemphasizes the potential hazards of nitrous oxide use immediately before or after CPB. A final limitation relates to the size of the bubble used. The overall size would have an effect on the bubble surface area to volume ratio, thus affecting the rate of gas diffusion. It is not known however, what size of bubbles are experienced clinically, thus making the significance of this limitation uncertain.
In summary, we demonstrated that PFC administration results in a decrease in gaseous bubble volume during experimental CPB and might also contribute to an improved systemic oxygenation. We speculate that these effects may be useful during CPB, and may partly explain the beneficial effects of PFC emulsions previously demonstrated in the context of experimental cerebral air embolism during CPB.
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Footnotes |
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Supported in part by Synthetic Blood International, San Diego, CA.
Presented at the 28th Annual Meeting of the Society of Cardiovascular Anesthesiologists, April 29–May 3, 2006, San Diego, CA.
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  F. de Lange, K. Yoshitani, A. D. Proia, G. B. Mackensen, and H. P. Grocott Perfluorocarbon Administration During Cardiopulmonary Bypass in Rats: An Inflammatory Link to Adverse Outcome? Anesth. Analg., January 1, 2008; 106(1): 24 - 31. [Abstract] [Full Text] [PDF]
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