Ann Thorac Surg 2002;74:825-829
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Reduction in brain embolization using the aegis aortic cannula during bypass in swine1
David J. Cook, MD*a,
Kenton J. Zehr, MDb,
Thomas A. Orszulak, MDb
a Department of Anesthesiology, Mayo Medical School, Rochester, Minnesota, USA
b Department of Surgery, Mayo Medical School, Rochester, Minnesota, USA
Accepted for publication May 1, 2002.
* Address reprint requests to Dr Cook, Department of Anesthesiology, Mayo Foundation and Mayo Clinic, 200 First St SW, Rochester, MN 55905 USA
e-mail: cook.david{at}mayo.edu
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Abstract
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Background. Cerebral embolization during cardiopulmonary bypass (CPB) is an important cause of neurologic injury. This study determined whether a new aortic cannula (Cardeon Aegis) could substantially reduce brain embolization in a swine CPB model.
Methods. Fourteen 70-kg pigs underwent normothermic CPB, 7 animals with the Aegis device and 7 with a control cannula. Cerebral blood flow was determined using 15-µm fluorescent microspheres before bypass and twice during CPB. After the second bypass CBF measurement, animals were embolized with 120,000 78-µm fluorescent microspheres at normothermia. At the end of the experiment the brain, eyes, kidneys, myocardium, and small bowel were removed and the microspheres isolated.
Results. Cerebral blood flow was equivalent between groups before bypass and during both bypass periods. While the two groups were equivalent with regard to pump flow, temperature, hemoglobin, and PaCO2, use of the Aegis cannula markedly reduced embolization to three of four brain regions. Deployment of the baffle reduced total brain embolization by 91% from a mean of 22 ± 21 emboli per gram in the control animals to 2 ± 6 emboli per gram in animals receiving the Aegis device.
Conclusions. Cerebral blood flow with the Aegis device is equal to or greater than that observed under nonbypass conditions and that seen with conventional aortic cannulas. However, cerebral embolization is profoundly reduced by use of the Aegis device. The application of this cannula may reduce postcardiac surgical neurologic injury.
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Introduction
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Embolization is an important cause of cardiac surgical neurologic morbidity. While air and platelet-fibrin emboli may originate in the bypass circuit, quantitatively the greatest and clinically most important embolization during bypass originates in the heart and ascending aorta [1–3]. The aim of this study is to determine whether use of a new aortic cannula designed to control flow distribution in the aortic arch could reduce brain embolization in a swine model of cardiopulmonary bypass. The tested Aegis cannula (Cardeon Inc, Cupertino, CA) separates flow to the greater and lesser curvatures of the aortic arch by means of a saline-inflatable baffle (Fig 1).
Perfusion ports supplying the arch vessels are cephalad to the baffle and the port supplying the descending aorta is caudad to the baffle or wing. The Aegis cannula is a modification of an earlier device previously reported in this journal [4]. In contrast to the earlier Cobra cannula (Cardeon Inc, Cupertino, CA), the Aegis device has a single lumen and is not designed for independent temperature control of the arch and descending aorta. However, the baffle design is similar so the Aegis should reduce brain embolization in the same way [4].
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Material and methods
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After review and approval by the Institutional Animal Care and Use Committee, 14 pigs weighing 65 to 75 kg, were studied. After pigs were anesthetized with halothane, ketamine, and fentanyl, 4-inch 18-gauge arterial catheters were placed in the femoral and right axillary arteries for mean arterial blood pressure (MAP) measurements and blood sampling. A no.18 single lumen, 20-cm catheter was inserted cephalad to the base of the skull for measurements of internal jugular venous O2 saturation (SjvO2). The right atrium was also catheterized through the internal jugular vein. This catheter served as the injectate port for cardiac output measurements (Oximetrix 3 SO2/CO computer; Abbott Laboratories, Chicago, IL). A 7.5F Baxter/Edwards Thermodilution Paceport catheter (Baxter Healthcare Corporation, Edwards Critical-Care Division, Irvine, CA) was placed for determination of thermodilution cardiac outputs. Cardiac output measurements were made in triplicate before bypass.
For CPB median sternotomy was performed. The bypass circuit was primed with 1,500 mL of crystalloid. Venous drainage to the circuit was through a 40F two-stage cannula placed in the right atrium through the appendage. A hard shell venous reservoir was used. Blood was circulated by a centrifugal pump (Sarns Centrifugal Pump; Sarns, Ann Arbor, MI) through a combined heat exchanger-oxygenator with continuous monitoring of pump flow by a Sarns-Delphin flowmeter (Sarns). Arterial inflow to the animal was by either the 23F Aegis cannula (treatment group) placed through a standard ascending aortotomy or by a 21F Sarns Soft-flow cannula (Terumo Cardiovascular, Ann Arbor, MI) in the control group.
Animals were heparinized before bypass with 450 or more U/kg heparin. During CPB temperature measured in the brain and inferior vena cava by needle and wire thermocouples, respectively, was maintained at 37°C. Hemoglobin concentration was maintained at 8 g · dL-1, PaCO2 at 35 to 40 mm Hg and Pao2 at more than 200 mm Hg. MAP was maintained at 60 to 70 mm Hg by adjusting bypass pump flow rate. The target total bypass flow was 2.2 to 2.5 L · min-1 · m-2. Arterial blood gases were monitored continuously by an "in-line" analyzer (CDI 400, CDI, Irvine, CA).
During the three experimental periods (prebypass and twice during CPB) cerebral blood flow was determined. Blood flow was measured using 15-µm diameter fluorescent-labeled polystyrene microspheres (Molecular Probes, Eugene, OR), according to the blood reference sample method [5, 6]. Orange (excitation/emission wavelengths: 540/560 nm), red (580/605 nm), and blue-green (430/465 nm) microspheres were used. Microspheres were diluted in 6 mL 6% Dextran 70 with 0.025% Tween 80, sonicated, vortexed, and were injected more than 60 seconds into the left atrial appendage (pre-CPB) or into a side port on the aortic inflow line distal to the filter during CPB. Four million 15-µm microspheres were used for blood flow determination before bypass and two million for each of the bypass measurements. Beginning 30 seconds before microsphere injection a reference blood sample was obtained over a period of 4 minutes. Blood was drawn from the femoral artery catheter into a glass syringe by a Harvard withdrawal pump at a rate of 4.9 mL min-1. This was transferred into labeled vials, carefully rinsing syringes and extension lines [6].
After bypass stabilization the first CBF measurement was conducted. In both groups this was done at 30 minutes of bypass; in the Aegis group the baffle remained deflated for this CBF measurement. Thirty minutes later the third CBF measurements were made (60 minutes on bypass in control animals or with the baffle deployed in the Aegis animals). The baffle was filled with saline, complete filling being indicated by inflation of a small external pilot balloon (Fig 1). Immediately after the third CBF measurement, an embolic load of 120,000 78-µm, yellow-green (505/515 nm) fluorescent microspheres (Molecular Probes, Eugene, OR) was given over 2 minutes. In contrast to the 15-µm microspheres used for blood flow determination (which were given into the aortic inflow line), the embolic load was injected into the aortic root proximal to the cannulation site.
After completion of the experiment bypass was terminated, pigs were exsanguinated, and brain, eyes, kidneys, and portions of small bowel were excised. Weighed tissue samples (1 to 2 g) were obtained from the following regions: brain left and right frontal, occipital, and temporal lobes, left and right cerebellar hemispheres, left and right renal cortex and medulla, right and left ventricular myocardium, and three samples from small bowel. All tissue samples were "spiked" with an internal standard of 1,500 crimson (625/645 nm) 15-µm microspheres.
Blood and tissue samples autolyzed in the dark for 2 weeks. Thereafter microspheres were recovered by chemical digestion and repeated steps of sedimentation through centrifugation [6]. The intensity of fluorescence in tissue and blood samples was determined by a spectrofluorometer (SLM 8100; SLM-AMINCO, Rochester, NY). The fluorescence of each sample was measured at its specific excitation/emission wavelength. Organ blood flow (OBF) was calculated from the intensity of fluorescence in blood and tissue samples using the following formula: 
, where R = rate at which the reference blood sample was withdrawn (4.9 mL · min-1), IT = fluorescence intensity of the tissue sample, IR = fluorescence intensity of the blood sample, and Wt = weight of the tissue sample (g). Determination of the number of crimson microspheres (internal standard) at the end of tissue processing allowed determination of microsphere processing loss for each sample in every experiment. The number of microspheres counted in tissues were then corrected for this loss.
To determine the number of the large yellow-green 78-µm emboli per tissue sample, a standard curve with known concentrations of microspheres was constructed by analyzing serial dilutions of microspheres. The relationship between fluorescent intensity and microsphere number is essentially linear in dilute samples [7]. The fluorescence intensity (IT) of the tissue sample was then determined and the concentration of microspheres was determined from a standard curve defined by the following equation: 
, where C = the number of microspheres, b = the Y intercept, and m = the slope of the the line.
Data analysis
Adequate mixing and equal distribution of microspheres was determined by comparing right-sided and left-sided tissue samples. When there was no difference between sides for any paired region, values are presented as a mean of the left and right sides for paired sample. Renal blood flow was determined as follows: under each condition medullary and cortical blood flow were measured and the ratio of flow to the cortex and medulla was calculated. Total renal blood flow was then expressed on the basis of this ratio. For small bowel the mean of the three tissue samples is provided.
All data are expressed as the mean ± SD. A t test was used to compare the Aegis and control groups during each experimental period. Within groups, physiologic variables were compared using repeated measures analysis of variance (ANOVA). When repeated measures ANOVA designated significance, the Bonferroni correction for multiple comparisons was used to identify differences between periods. Values of p less than 0.05 were considered statistically significant.
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Results
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Systemic physiologic data during each study period is presented in Table 1.
The physiologic variables that might have affected cerebral blood flow or embolization, mean arterial pressure (MAP), pump flow, temperature, hemoglobin, or PaCO2, did not differ between groups during any study period with two exceptions. Before bypass the PaCO2 in the Aegis group was higher (42 ± 7 mm Hg) than in the control group (36 ± 2) and during the final CBF measurement and embolization, the MAP in the arch was greater in Aegis than control animals (73 ± 8 and 61 ± 5 mm Hg, respectively; Table 1).
Cerebral blood flow was equivalent between groups in all regions before bypass (Table 2).
Additionally, during the two cardiopulmonary bypass periods cerebral blood flow was equal to or greater than that measured prebypass. During bypass cerebral blood flow was equivalent between Aegis and control groups. Most importantly, there was no difference between groups in cerebral blood flow in any brain region immediately before embolization.
In neither group, for any region, was a left-to-right lateralization of emboli demonstrated, indicating adequate mixing of microspheres in the aortic root. Therefore only the mean embolization values for each region are presented.
Embolization to each of the four brain regions is shown in Table 2. In three of four brain regions embolization was reduced by the Aegis cannula. Only in the temporal lobes could a statistical difference not be demonstrated between groups (control 21 ± 25, Aegis 1 ± 2; p = 0.05). Relative to the control group, embolization to frontal, occipital, and cerebellar lobes were reduced by a mean of 87%, 91%, and 94%, respectively. Across all four-paired brain regions sampled the mean number of emboli per gram was 22 ± 21 emboli per gram in the control animals and 2 ± 6 emboli per gram in Aegis animals (Fig 2).
Embolization to the eyes was reduced in the same way as for brain. Mean eye embolization in Aegis animals was 1 ± 3 emboli per gram while in the control group eye embolization was 11 ± 7 emboli per gram (p = 0.005; Table 2).
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Fig 2. Whole brain embolization in control and Aegis groups. Values are mean ± SD (n = 7 each group). *p < 0.05 by t test.
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Based on the embolization to four paired brain regions and a mean brain weight of 84 ± 5 g the total cerebral embolization in the Aegis group is estimated at 221 emboli or approximately 0.2% of the 120,000 injected into the proximal aorta. Using the same calculation for the control group, the mean number of emboli in the brain was approximately 2216, or 2% of the total embolic load given.
Blood flow and embolization to kidney, myocardium, and small bowel were also determined. As for brain, blood flow to these organs did not differ between control and Aegis animals except for ventricular blood flow in the predicate group exceeding that in the Aegis group during one study period (Table 2). The mean embolization to the kidney, myocardium, and small bowel in the control group was 66 ± 54, 74 ± 50, and 7 ± 11 emboli per gram respectively. Embolization to these organs in the Aegis group did not differ from control with 52 ± 34, 59 ± 37 and 5 ± 5 emboli per gram for kidney and small bowel, respectively; p values were 0.59, 0.55, and 0.65 (Table 2).
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Comment
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The Aegis aortic cannula is a unique innovation. This device represents the third step in evolving cannula-based technologies for reducing cardiac surgery-related brain injury. The first step was development of a dual-lumen cannula that allows independent temperature control of aortic arch and descending aorta by means of an inflatable balloon positioned distal to the left subclavian artery [8]. The second device, the Cobra cannula, also allows dual temperature control [9] but the major change from the earlier device was the placement of an inflatable baffle that has been shown to profoundly reduce brain embolization in a large animal bypass studies [4]. The Aegis device tested here is a simplification of the Cobra device. The Aegis cannula is a single lumen cannula so not designed for dual temperature control. Like the Cobra, however, the positioning of perfusion ports and the effect of the baffle on flow distribution in the arch greatly reduces brain embolization.
This study accomplishes two ends. First, it tests the adequacy of the Aegis device for perfusion in a large animal model by determining blood flow to brain, kidney, and viscera during cardiopulmonary bypass with the Aegis baffle both deflated and inflated. We found that whole body, brain, kidney, and visceral perfusion were equivalent with the Aegis device as under nonbypass conditions. The second purpose of this investigation was to determine if the Aegis device prevented cerebral and ocular embolization. In this study we report a 90% reduction in brain and eye embolization in animals undergoing bypass with the Aegis device.
This marked reduction of brain embolization is very similar to that observed with the Cobra catheter. This is expected as the primary mechanism for reducing embolization is the same in both cannula. Like the Cobra cannula the Aegis device prevents cerebral embolization by means of the baffle and the relative distribution of flow. Fifty percent of the of the total arterial inflow collectively exits the catheter’s three arch ports superior to the inflated wing and 50% exits the distal port of the catheter. As such the arch flow is higher per square meter of BSA than that of the descending aortic flow. The cannula baffle is nonocclusive proximally so excess flow from the greater curvature is shunted proximally around the baffle and into the flow stream along the lesser curvature (Fig 3).
This effectively creates a flow barrier preventing emboli originating in the ascending aorta from traveling to the greater curvature of the arch. This protects the origin of the arch vessels from embolization.
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Fig 3. Schematic of the Aegis catheter in situ demonstrating flow pattern achieved with the device. Fifty percent of the total arterial inflow collectively exits the catheter’s three arch ports (1) superior to the inflated wing and 50% exits the distal port (2) of the catheter. The diagram also illustrates overflow from the superior aspect of the wing around the proximal edge creating a flow barrier.
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This study differs from the previous report for four reasons. First, while functionally and visually similar, the Aegis and Cobra cannulas are different devices. Second, in this study embolization with the Aegis cannula was directly compared with a control cannula used in clinical practice. Third, in contrast to the earlier investigation we determined embolization to organs supplied by the descending aorta as well as to the aortic arch. Finally, cerebral blood flow was measured in this study immediately before embolization as well as before bypass and during CPB with the baffle deflated and inflated. This clearly indicates adequacy of perfusion with Aegis and that the reduction in embolization in the Aegis group was independent of alterations in cerebral blood flow.
A criticism of our investigation is that clinical emboli may differ in composition and size from our 78-µm embolus model. Emboli may consist of air, platelet-thrombin aggregates, fat, or atherosclerotic debris. Our study does not provide specific data as to whether the Aegis device would be equally effective in preventing cerebral embolization of these types of emboli. However, our 78-µm embolus is in the midrange of size of emboli reported during CPB [2] and has a density similar to that of platelet thrombin aggregates. More importantly the arch vessels are protected because of the unique distribution of blood flow achieved with the device. Because the cannula distributes aortic root blood along the lesser curvature and down the descending aorta, we would predict that embolus size or density should not alter the ability of this device to provide cerebral protection. Any embolus carried in the flow stream washing through the aortic root should be carried away from the origins of the arch vessels.
A potential concern with directing emboli away from the arch vessels is redistribution of that embolic material to other organ beds. Although this will occur, it is important to note that emboli shunted away from the arch would be distributed to a much larger body mass, so the concentration effect is predictably quite small. The dilutional influence of the large mass of the body is seen in this investigation where embolization to the kidney and small bowel did not differ significantly in Aegis and control groups. If the Aegis is clinically effective in reducing embolization to the arch by 80% to 90%, based on body mass, we would predict only about a 15% to 20% increase in embolization to the body. Most of that incremental embolization will be delivered to less vital structures, tissues with lower metabolic rates, greater collateralization, and a higher ischemic tolerance than the brain.
The Aegis device appears to be equivalent to the Cobra device in reducing brain embolization in a large animal bypass model. The Aegis cannula was designed for use when there is an indication to reduce embolization to the arch vessels, but dual temperature control is not desired. Because dual temperature control is not a part of the Aegis design it is simple to use. Because the optimal temperature for cardiopulmonary bypass is indeterminate, the potential advantages of the dual-temperature Cobra device over the more simple Aegis cannula have not been defined and will presumably be specific to patient, institution, and surgeon. More importantly, the independent contribution of selective cerebral hypothermia and emboli reduction on neurologic outcomes has not been determined. Outcome results after clinical introduction of the Aegis cannula will further clarify the relative impact of these two mechanisms of neuroprotection.
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Acknowledgments
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This work was supported by a research grant from Cardeon Corporation, Cupertino, California.
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Footnotes
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1 The authors and The Mayo Foundation disclose that they have a financial relationship with Cardeon Corporation. 
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References
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Abstract
Introduction
