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Ann Thorac Surg 2000;69:1130-1134
© 2000 The Society of Thoracic Surgeons

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ORIGINAL ARTICLES: CARDIOVASCULAR

Effect of cerebral embolization on regional autoregulation during cardiopulmonary bypass in dogs

^a Departments of Anesthesiology and Cardiovascular Surgery, Mayo Foundation and Mayo Clinic, Rochester, Minnesota, USA

Address reprint requests to Dr Cook, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905
e-mail: cook.david{at}mayo.edu

	Abstract

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Background. Embolization during cardiopulmonary bypass probably alters cerebral autoregulation. Therefore, using laser Doppler flowmetry we investigated the cerebral blood flow velocity changes in response to changes in arterial pressure, before and after embolization in a canine bypass model.

Methods. After Institutional Animal Care and Use Committee approval, 8 anesthetized dogs had a laser Doppler flow probe positioned over the temporoparietal dura. During 37° C cardiopulmonary bypass, the cerebral blood flow velocity response to changing mean arterial pressure (40 to 85 mm Hg in random order) was assessed before and after systemic embolization of 100 mg of 97-µm latex microspheres.

Results. Before embolization, cerebral blood flow velocity increased 39% as mean arterial pressure increased from 40 to 85 mm Hg. Following embolization, a 94% increase in cerebral blood flow velocity was demonstrated over the same mean arterial pressure range. The slopes of the curves relating cerebral blood flow velocity to mean arterial pressure were 0.21 ± 0.74 and 1.31 ± 0.87, before and after embolization (p = 0.016) respectively.

Conclusions. Regional cerebral blood flow autoregulation may be impaired by microembolization known to occur during cardiopulmonary bypass, increasing the dependence of cerebral blood flow on mean arterial pressure.

	Introduction

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The primary cause of post cardiopulmonary bypass neurologic injury is probably focal ischemia secondary to cerebral microembolization, and in some cases, regional hypoperfusion from the combination of hypotension and cerebral vascular disease. In both contexts, perfusion pressure is of physiologic importance. In regional ischemia, autoregulatory capacity is lost and neuronal viability is a function of the adequacy of collateral flow, which is perfusion pressure-dependent [1, 2]. The degree of autoregulatory impairment appears to parallel the severity of the ischemia [1]. Perfusion pressure may also be relevant in patients with atherosclerotic, hypertensive, or diabetic vascular disease. Vascular disease may increase cerebral perfusion-pressure dependency through hemodynamically significant stenosis, by shifting the autoregulatory curve rightward, or limiting the collateral flow response in regional ischemia [3–5].

Global measures of cerebral blood flow (CBF) may not detect changes in blood flow associated with regional embolic events. Conversely, laser Doppler measures changes in regional microcirculatory blood flow velocity, and is an established tool for assessing regional perfusion in brain ischemia [6, 7]. It has also been used for a variety of applications for regional blood flow measurements during cardiopulmonary bypass (CPB) [8, 9]. Unlike many techniques, laser Doppler is well suited to the assessment of autoregulation because continuous measurement is provided. As the middle cerebral artery supplies the greatest proportion of cerebral cortical blood flow, and emboli greater than 30 µm are preferentially delivered to the cortical circulation [10], laser Doppler flowmetry (LDF) of the temporoparietal cortex can assess regional autoregulation following CPB embolization [11].

The purpose of this study was to determine the effect of CPB embolization on cerebral autoregulation using laser Doppler.

	Material and methods

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After review and approval by the Institutional Animal Care and Use Committee, 8 unmedicated, fasting, adult mongrel dogs (18 to 22 kg) were studied. The dogs were placed in a Plexiglas, (Rohn and Haas, Philadelphia, PA) box and anesthesia was induced with 3% to 4% halothane. Peripheral intravenous access was then secured, muscle relaxation was obtained with pancuronium 0.1 mg · kg^-1, and the trachea was intubated. Ventilation was controlled to maintain arterial carbon dioxide tension (PaCO₂) at 35 to 40 mm Hg and an arterial oxygen tension (PaO₂) greater than 150 mm Hg. Anesthesia was maintained with high dose fentanyl and midazolam (bolus: 250 µg · kg^-1 fentanyl and 350 µg · kg^-1 midazolam, followed by infusion: fentanyl 3.0 µg · kg^-1 · min^-1 and midazolam 9.6 µg · kg^-1 · min^-1). Muscle relaxation was maintained by continuous infusion of pancuronium (0.8 µg · kg^-1 · min^-1). A 4-inch 18-gauge catheter was inserted into a femoral artery for mean arterial pressure (MAP) measurements and blood sampling.

Laser Doppler flowmetry (BLF21 Flowmeter; Transonics, Ithaca, NY) was used for measurement of regional cerebral blood flow velocity (CBFv). A burr hole was drilled in the temporoparietal region. A thin layer of bone was preserved during drilling and was removed carefully without dural disruption. After hemostasis, the burr holes were filled with physiologic saline solution and, an 18-G laser Doppler flow probe (Transonics), designed for CBF measurements, was positioned with a micromanipulator, such that it did not overlie dural vessels.

For CPB, a left-sided thoracotomy was performed. Heparin (350 units.kg^-1 iv) was given for anticoagulation. The bypass machine was primed with 1000 mL Plasmalyte (Baxter Health Care Co, Deerfield, IL). Venous drainage to the extracorporeal circuit was by a 36F cannula placed in the right atrium through the right atrial appendage. The blood was circulated by a centrifugal pump through a combined heat exchanger-hollow fiber oxygenator (Bentley Spiral Gold, Irvine, CA) and returned through a cannula (4.5-mm ID) into the root of the aorta. A 40 µm arterial line filter (Bentley Gold, Irvine, CA) was included in the circuit distal to the oxygenator.

Cardiopulmonary bypass was then undertaken and nasopharyngeal temperature, measured by thermocouple, was maintained at 37° C, hemoglobin at 7.5 to 9.0 g · dL^-1, PaCO₂ at 35 to 40 mm Hg and PaO₂ at 150 to 250 mm Hg. When steady state CPB conditions (as defined above) were reached, control CBFv measurements were made by laser Doppler technique at MAPs of 40, 50, 60, 70, and 85 mm Hg in random order. Mean arterial pressure was varied using a combination of alterations in pump flow and phenylephrine infusion (these interventions were chosen as they do not alter CBF independent of their effect on MAP [12, 13]). A given MAP was maintained for 15 minutes, or until CBF was stable, whichever was longer. Following the initial CBF measurements, an embolic load (100 mg of 97-µm nondyed latex microspheres; Bangs Laboratory, Fishers, IN) was delivered through a side port in the aortic cannula. Delivery of microspheres occurred over 5 minutes in a 20-mL 6% Dextran (Baxter, Deerfield, IL) injection volume with 0.02% Tween 80. The syringe was sonicated and vortexed before injection. Following the embolization, the MAP was maintained at 60 to 65 mm Hg for 30 minutes and then autoregulatory measurements were repeated with MAP exposure in the same order as in the prebypass period.

Systemic physiologic data and CBFv data for the pre and post embolization periods were analyzed using a repeated-measures analysis of variance (ANOVA). When ANOVA was significant, the Student-Newman-Keuls test was applied. Systemic physiologic data were compared by using the Student’s t-test at the same MAP, before and after embolization. The regional CBFv at 60 mm Hg was designated as control for pre and post embolization periods for determination of the change in CBFv over the range of MAPs. The slope of the CBFv-MAP relationship in each animal, before and after embolization, was determined in each animal, and the mean determined. A t-test was also used to compare slopes of MAP-CBFv regression curves in pre and post embolization periods. All data are presented as mean ± standard deviation. A p value less than 0.05 was considered significant.

	Results

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Systemic physiologic data for the study periods are presented in Table 1. The three primary determinants of CBFv: temperature, hemoglobin, and PaCO₂ were kept within narrow ranges throughout the study. PaCO₂ was maintained 34 to 37 mm Hg, dural temperature 36.5 to 37.5 °C, and hemoglobin 7.7 to 9.0 g/dL. Temperature and PaCO₂ did not differ within or between pre and post embolization periods. Hemoglobin did not differ within pre and post embolization periods, but did differ between pre and post embolization periods at a single MAP, 50 mm Hg (p < 0.05) (Table 1).

View larger version (13K): [in this window] [in a new window]   Fig 1. Cerebral blood flow velocity (CBFv)% control- mean arterial pressure (MAP) relationship before (left) and after (right) embolization of 97 µ microspheres (n = 8) for each animal. Cerebral blood flow with MAP of 60 mm Hg was designated as 100% before and after embolization. A single data point in the post embolization period had a value of 350% of control, for reasons of scale, this is identified separately.

View larger version (13K): [in this window] [in a new window]   Fig 2. Cerebral blood flow velocity (CBFv)- mean arterial pressure (MAP) relationship before and after embolization of 97 µ microspheres (n = 8). Slopes were determined for each animal in the pre and post embolization period. The mean slopes for both periods are presented, p = 0.016 by t-test.

	Comment

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We predicted that these findings in nonbypass models would be translatable to the cerebral embolization occurring during CPB. We found a 39% increase in CBFv between MAPs of 40 and 85 mm Hg before embolization, and a 94% increase in CBFv over the same MAP range following embolization. In every animal the slope of the MAP-CBFv relationship was steeper in the post embolization than in the pre embolization period. This indicates an increased perfusion pressure dependence after CPB embolization.

A second finding confirms earlier laboratory and clinical reports. We found that under normothermic conditions the MAP-CBFv relationship has a small positive slope even before embolization. This was described previously in a dog model by Mutch and colleagues [15] and in a clinical report of warm bypass by Newman and colleagues [16]. While an increase in CBFv might be expected between MAPs of 40 and 85 mm Hg, CBFv also increased over the autoregulatory range of 50 to 85 mm Hg.

Our study might be criticized because of our use of a latex microsphere model for embolization during CPB. However, we have shown previously [17] that the model is robust, and that the number and size of microspheres given approximate the cerebral embolization which occurs clinically [18]. In an earlier report, with a similar canine model, we found that the brain received 1% to 3% of the total embolization entering the aortic root [17]. There are 197,000 microspheres in the 100 mg used in this experiment (Bangs Laboratory, Fishers, IN). As such, we estimate the cerebral embolic load in this investigation (2%) to be approximately 4000 emboli or 2 mm³. Clinically, using transesophageal echocardiogram and transcranial Doppler, Barbut and colleagues estimated that 4% to 18% of emboli generated in the aorta enter the cerebral circulation of patients [18]. In that study the mean volume of cerebral emboli was estimated to be 276 mm³. Therefore, even correcting for the smaller size of the dog brain (75 to 80 g), we estimate that the volume and number of emboli given in this study approximates that which occurs during clinical CPB in many patients.

This study would have been strengthened by the provision of a second group of dogs serving as a time control. A separate time-control group would insure that the alteration in the CBFv-MAP relationship we demonstrated was a function of embolization and not simply of CPB time. While a second group would strengthen the study, this additional consumption of animals is difficult to justify. While a decrease in CBF with CPB time has been reported [19], a variety of subsequent investigations, both laboratory [20 to 23] and clinical [24, 25], under normothermic [20, 23–25] and hypothermic [20–24] conditions, have failed to document an alteration in CBF as a function of CPB time when temperature is stable. It might also be suggested that bypass time might alter autoregulation without changing CBF per se. Although we did not test for this, it seems unlikely that bypass time, which does not alter CBF, alters its regulation. Finally, and perhaps most importantly, the results we report are what would be predicted based on focal ischemia studies done in nonbypass models [1, 6].

While outcome studies indicate that patient related factors are the primary determinant of neurologic outcome after cardiac operation [26] this is not equivalent to saying that the physiologic management of the patient is unimportant. Cerebral embolization and the risk factors resulting in atheroembolism are the etiologic factors of brain injury, but an understanding of the physiologic consequences of cerebral embolization should help improve patient care and attenuate the consequences of focal ischemia.

	Acknowledgments

 
Hulya Sungurtekin, MD is the recipient of a research scholarship from The Scientific and Technological Research Council of Turkey (TUBITAK), Ankara, Turkey.

	References

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