Cerebral embolization during cardiac surgery: impact of aortic atheroma burden

G. B. Mackensen1,2, L. K. Ti1, B. G. Phillips-Bute1, J. P. Mathew1, M. F. Newman1, H. P. Grocott*,1 and the Neurologic Outcome Research Group (NORG){dagger}

1 Division of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710, USA 2 Present address: Klinik für Anaesthesiologie, Technische Universität München, München, Germany

Corresponding author. E-mail: h.grocott@duke.edu
{dagger}The members of the Neurologic Outcome Research Group of the Duke Heart Center are listed in the Appendix.

Accepted for publication: July 10, 2003


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Background. Aortic atheromatous disease is known to be associated with an increased risk of perioperative stroke in the setting of cardiac surgery. In this study, we sought to determine the relationship between cerebral microemboli and aortic atheroma burden in patients undergoing cardiac surgery.

Methods. Transoesophageal echocardiographic images of the ascending, arch and descending aorta were evaluated in 128 patients to determine the aortic atheroma burden. Transcranial Doppler (TCD) of the right middle cerebral artery was performed in order to measure cerebral embolic load during surgery. Using multivariate linear regression, the numbers of emboli were compared with the atheroma burden.

Results. After controlling for age, cardiopulmonary bypass time and the number of bypass grafts, cerebral emboli were significantly associated with atheroma in the ascending aorta (R2=0.11, P=0.02) and aortic arch (P=0.013). However, there was no association between emboli and descending aortic atheroma burden (R2=0.05, P=0.20).

Conclusions. We demonstrate a positive relationship between TCD-detected cerebral emboli and the atheromatous burden of the ascending aorta and aortic arch. Previously demonstrated associations between TCD-detectable cerebral emboli and adverse cerebral outcome may be related to the presence of significant aortic atheromatous disease.

Br J Anaesth 2003; 91: 656–61

Keywords: brain, embolism; complications, atherosclerosis; heart, cardiopulmonary bypass; measurement techniques, transcranial Doppler; measurement techniques, transoesophageal echocardiography


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Adverse neurological outcomes are a major source of morbidity and mortality after cardiac surgery. Despite significant advancements in myocardial protection, an increase in the number of elderly patients presenting for cardiac surgery has heightened the importance of identifying the risk factors for adverse neurological outcomes and subsequently reducing their incidence. In a study of 2108 patients undergoing coronary artery bypass grafting (CABG) surgery, Roach and colleagues1 found a 6% incidence of adverse cerebral outcomes and identified several risk factors for adverse outcome, including age, diabetes and aortic atherosclerosis. Indeed, atheromatous disease of the aorta, determined by several modalities, has repeatedly been shown to be associated with increased risk of perioperative stroke in cardiac surgical patients.24

In a similar fashion, emboli (both macro and micro) have been associated with adverse cerebral outcome and overall length of hospital stay.5 6 An independent link between atheroma and transcranial Doppler ultrasonography (TCD)-detectable emboli, however, has not been demonstrated previously, possibly because of methodological limitations. Previous investigations have been limited by their use of semiquantitative atheroma measurement methods, which reduce a three-dimensional structure, such as the aorta, to a one-dimensional (height) ordinal variable by using a somewhat arbitrary grading system to categorize the height of the atheroma.7 8 Categorical assessments of atheroma severity may have had limited sensitivity in detecting relationships between emboli and atheroma that might well be uncovered by using more sensitive linear regression methods to analyse continuous (as opposed to ordinal) data.

The purpose of our investigation was to determine the relationship between TCD emboli and a more quantitative two-dimensional aortic atheroma severity assessment9 in patients undergoing CABG.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Anaesthesia and surgery
After institutional review board approval and written informed consent, 128 patients undergoing elective CABG were studied. Patients were excluded if they had a history of cerebrovascular disease (with residual deficits), but no specific assessment of the carotid arteries was performed. Limited but unrelated results from these study patients have been published previously in brief form.9

Induction and maintenance of anaesthesia were achieved with bolus and continuous infusions of midazolam and fentanyl, with supplementary isoflurane (0.5–1.0%) to maintain heart rate and mean blood pressure within 25% of the preinduction values. Pancuronium was given as needed for neuromuscular paralysis. The cardiopulmonary bypass apparatus included a membrane oxygenator (Cobe Laboratories, Lakewood, CO, USA), Sarns roller pump (3M, Ann Arbor, MI, USA) and a 40 µm arterial line filter (Pall Biomedical Products, Glencove, NY, USA) that allowed non-pulsatile cardiopulmonary bypass with flows of 2–2.4 litre min–1 m2 to be carried out. A haematocrit of >=0.18 was maintained throughout cardiopulmonary bypass by the addition of packed red blood cells as necessary. Arterial PCO2 during cardiopulmonary bypass was 35–40 mm Hg (uncorrected for temperature) and the PaO2 was maintained at 150–250 mm Hg. Mean arterial pressure between 50 and 90 mmHg during cardiopulmonary bypass was achieved using i.v. phenylephrine and/or nitroprusside as required. During cardiopulmonary bypass, hypothermia (32–34° C) was induced and the patient was rewarmed when the last distal coronary anastomosis was being placed. Separation from cardiopulmonary bypass was accomplished when bladder and nasopharyngeal temperatures were both >36° C.

Aortic atheroma assessment
A comprehensive transoesophageal echocardiography examination was performed before cardiopulmonary bypass according to recommended guidelines.10 The ascending aorta was visualized by pulling up slightly on the transoesophageal echocardiography probe from a 120° mid-oesophageal view at the level of the aortic valve, to display the ascending aorta longitudinally. The descending aorta was visualized by withdrawing the transoesophageal echocardiography probe from the gastro-oesophageal junction until the left subclavian artery was seen. Withdrawing and rotating the transoesophageal echocardiography probe from the descending aorta visualized the longitudinal segment of the aortic arch. The entire transoesophageal echocardiography study was recorded on videotape for subsequent off-line analysis. The videotaped transoesophageal echocardiography examination of each segment of the aorta was reviewed frame by frame.

After the frame that displayed the most diseased area in each aortic segment (ascending, arch, descending) had been selected, the frame was digitized and analysed using image analysis software (NIH Image 1.6.2; National Institutes of Health, Bethesda, MD, USA). The area of the visualized aorta in the descending aorta was measured by estimating the angle ({alpha}) subtended by the vessel wall, and calculated as a portion of a circular or complete vessel ({pi}r2{alpha}/360°) (Fig. 1).9 Atheroma burden in each segment was calculated as the percentage of the area of the visualized aorta containing atheroma (atheroma burden (% atheroma)=area of plaque/area of visualized aorta). Mobile or pedunculated lesions were measured in exactly the same manner. All measurements were made by consensus between two investigators accredited in transoesophageal echocardiography by the National Board of Echocardiography (LKT, GBM). These investigators were blinded to the TCD emboli information from the patients.



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Fig 1 The atheroma burden in each aortic segment was determined as the ratio of the atheroma area (A) to the total area of the aortic segment visualized. For the descending aorta, where the entire circumference could not always be visualized, the area of the visualized segment was adjusted according the angle ({alpha}) subtended by that segment. r=aortic radius. Used with permission from Ti et al.9

 
Assessment of cerebral emboli
After induction of anaesthesia and intubation, continuous TCD (Neuroguard; Medasonics, Fremont, CA, USA) of the right middle cerebral artery was performed. A 2 MHz pulsed-wave TCD probe with an 18-mm sample length gated at depths of 45–55 mm was used. Doppler signals were recorded from first placement of the probe until skin closure, and emboli were counted using an automated counting system. Adjustments of TCD probe position were made as necessary to ensure optimal signal quality. The TCD study was recorded on VHS videotape and subsequently reviewed off-line by an investigator blinded to the transoesophageal echocardiography atheroma assessment, to verify the embolus counts using both audio and video methods to identify emboli signatures correctly.

Statistics
The details of the patients are presented as mean (SD). Atheroma data and embolus counts are presented as median (interquartile range (IQR)). Emboli counts were log- transformed before analysis in order to produce a normally distributed variable. Multivariate linear regression, to control for potential confounding factors that may affect the number of emboli or the severity of aortic atheroma (including age, cardiopulmonary bypass time and numbers of bypass grafts), was used to compare the number of TCD-detected emboli with the percentage atheroma in each aortic segment. A P value <0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
One hundred and twenty-eight patients were studied. The patient details are presented in Table 1. The atheroma burden (determined as the percentage atheroma) was greatest in the descending aorta (7.71% (4.38–15.27%)) and least in the ascending aorta (0% (0–1.17%)), and an average of 3.32% (0–8.37%) of the visualized aortic arch contained atherosclerotic plaque. The median (IQR) number of emboli recorded during the case was 333 (23–1974).


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Table 1 Patient details. Values are mean (SD) unless stated otherwise. n=128
 
Controlling for the potential covariates of age, cardiopulmonary bypass time and number of bypass grafts, the number of emboli was significantly, albeit weakly, associated with atheroma burden in both the ascending aorta (R2=0.09, P=0.02) and aortic arch (R2=0.11, P=0.013; Table 2). However, there was no association between TCD-detected emboli and the atheroma burden in the descending aorta (R2=0.05, P=0.20). Figure 2 demonstrates the positive relationship between aortic arch atheroma and cerebral emboli.


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Table 2 Multivariate linear regression analysis of the effect of aortic atheroma burden on transcranial Doppler-detected cerebral emboli
 


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Fig 2 The relationship, defined using univariate linear regression, between transcranial Doppler-detected cerebral emboli and atheroma burden in the aortic arch in patients undergoing coronary artery bypass graft surgery. Multivariate linear regression, controlling for age, cardiopulmonary bypass time and numbers of bypass grafts, confirmed this relationship (R2=0.11; P=0.013).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
In this study of patients undergoing CABG surgery, we found an association between the number of TCD-detected cerebral emboli and the atheromatous burden in the ascending and arch segments of the aorta. Although this was a statistically significant association, its strength was admittedly weak. This suggests that there are probably many other factors that influence the number of cerebral emboli, but does confirm that aortic atheroma is at least one of them.

Patients undergoing cardiopulmonary bypass experience considerable numbers of cerebral (as well as systemic) macroemboli (e.g. atherosclerotic debris or fat particles) or as many as thousands of microemboli (e.g. gaseous bubbles or other smaller particulate matter) during a typical cardiac surgical procedure. Convincing evidence for embolization of material to the brain during cardiopulmonary bypass procedures is based on investigations using retinal angiography, TCD techniques, histological examinations and magnetic resonance imaging.1113 The precise composition and the source of these emboli are not clear; however, it is likely that a combination of gaseous emboli and particulate matter can be detected by TCD equipment. Both particulate and gaseous emboli can cause distal obstruction of end-arterial flow in small cerebral arteries, resulting in cerebral ischaemia and neuronal failure. In addition, it has been shown that cerebral embolization can cause a local inflammatory response.14 These processes are probably responsible for some, if not all, of the functional deficits that can be detected in cardiac surgery patients. These data suggest that some of the cerebral emboli may indeed be derived from atheromatous disease in the thoracic aorta.

Numerous reports in the literature have described a strong association between the degree of aortic atherosclerosis and neurological injury in non-surgical populations.15 16 The severity of aortic atherosclerosis also has particularly important ramifications for the neurological outcome of patients undergoing cardiopulmonary bypass. Roach and colleagues1 reported that moderate to severe proximal aortic atherosclerosis was associated with an incidence of cerebral injury (focal injury, or stupor or coma at discharge) at least four times that seen in patients without significant plaques. Atherosclerosis of the aortic arch has also been correlated with an increased risk of stroke after cardiac surgery; the greater incidence of left-hemispheric (representing a destination for arch-generated emboli to move in the direction of blood flow to the downstream carotid vessel) strokes is indirect evidence of the importance of aortic arch atherosclerosis.17

The mechanism by which aortic atherosclerosis causes an adverse neurological outcome after cardiac surgery is believed to be cerebral embolization of atheromatous debris. This embolization occurs primarily as a result of aortic manipulation during palpation, cannulation, cross-clamping, proximal coronary anastomosis and decannulation, and possibly as a result of a ‘sandblasting’ effect from the high-velocity jet exiting the aortic cannula.1820 The results of the present study further support the potential causal role of atheroma burden in the ascending aorta and the arch in the genesis of cerebral embolization and consequent neurological injury.

The location of the atheromas within the aorta and their relationship to the emboli that were detected is significant. Unlike the ascending aorta and aortic arch, the descending aorta showed no association of atheroma with TCD emboli counts. A possible explanation for this is that the descending atheroma seems an unlikely source for cerebral embolization, as antegrade flow from the ascending aortic cannula would cause any atheroma-generated emboli to flow distal to the aortic arch and to be undetectable in the middle cerebral artery. However, some studies have shown a relationship between descending aortic atherosclerosis and postoperative stroke,4 but it is likely that this association simply reflects a greater severity of ascending aortic or arch atherosclerosis in patients with high degrees of descending aortic disease.

There are several limitations to our study. The atheroma assessment technique we used, although potentially an improvement over previously published one-dimensional categorical measurement techniques, involves a two-dimensional image of a specific segment of the aorta. Ideally, a true reflection of atheroma burden should be based on a three-dimensional image of the entire length of a given aortic segment. When technological improvements permit routine three-dimensional ultrasound imaging, additional valuable data may be obtained. Given the current technological limitations of transoesophageal echocardiography imaging, the percentage atheroma method that we used does at least account for the total plaque area that can be visualized. Other methods assume that the area of the aorta that is not able to be imaged is not diseased. Furthermore, our assessment technique does not account for any plaques that contain mobile components, apart from including these mobile plaques in the area of the plaque itself with no special notation of mobility. Katz and colleagues7 showed that atheromatous disease with mobile components conferred a significant risk of perioperative stroke in a population of elderly cardiac surgical patients.

A further limitation relates to the ability of transoesophageal echocardiography to give an adequate image of the distal portion of the ascending aorta, which, because of the interposition of the trachea and the left main-stem bronchus between the aorta and the oesophagus, is difficult to image adequately with transoesophageal echocardiography.21 Epiaortic imaging is a more sensitive means of assessing plaque in the ascending aorta and it is likely that a greater degree of atherosclerosis might have been detected had epiaortic scanning been used. With respect to the TCD, we may have underestimated the total cerebral embolic load, as we were insonating only a single cerebral vessel (right middle cerebral artery). We make the assumption that the embolic load as measured in the right middle cerebral artery reflects the total cerebral embolic load. This could potentially lead to a somewhat inaccurate assessment of the association between emboli and atheromatous burden. Limitations also exist in the TCD technology that we used; it is unable to discriminate between gaseous emboli and particulate emboli (such as those originating from atheroma). The emboli–atheroma relationship could potentially be better defined if the atheroma burden were compared only with the particulate emboli.

A final limitation relates to the fact that the significance of these findings must be considered in the context of their implications for neurological outcome. No neurological outcomes are available for these patients, yet a valuable piece of information would be to understand whether the relationship between cognitive outcome, for example, which is known to be related to cerebral emboli,5 12 could be made stronger by taking into account the atheroma burden of individual patients.

This finding of a relationship between aortic atheroma and cerebral emboli elucidates the likely mechanism behind the previously described relationship between TCD-detected emboli and cerebral outcome. These findings also complete an evidence gap, thereby closing the loop that relates atheroma to emboli, the relationship of which to major adverse cerebral outcomes after cardiac surgery has already been defined.


    Acknowledgements
 
This work was supported in part by grants from the National Institutes of Health (grant 1R01HL54316), the Clinical Research Centers Program (NIH MO1-RR-30) and the American Heart Association (Grant-In-Aid 95010970).


    Appendix
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Neurologic Outcome Research Group of the Duke Heart Center
Director: J. P. Mathew; Co-Director: J. A. Blumenthal. Anesthesiology: H. P. Grocott, S. E. Hill, M. F. Newman, J. P. Mathew, J. G. Reves, D. A. Schwinn, M. Stafford-Smith, D. Warner, M. Harris, J. L. Kirchner, B. Mickley, M. Barnes, E. Carver, B. L. Funk, E. D. Derilus, J. Hawkins, T. Moore, C. Campbell, A. Cheek, T. Kagarise, T. Latiker, E. Lauff, M. Tirronen, R. DeLacy, W. Hansley, Y. M. Connelly, B. Phillips-Bute and W. D. White.

Behavioral medicine: M. A. Babyak, J. A. Blumenthal and K. A. Welsh-Bohmer.

Cardiology: D. B. Mark and M. H. Sketch,

Neurology: C. Graffagnino, D. T. Laskowitz, J. R. Lynch, A. M. Saunders and W. J. Strittmatter.

Pathology: E. Bennett.

Perfusion services: G. Smigla and I. Shearer.

Surgery: R. W. Anderson, T. A. D’Amico, R. D. Davis, D. D. Glower, R. D. Harpole, J. Jaggers, R. H. Jones, K. Landolfo, J. E. Lowe, R. H. Messier, C. Milano, P. K. Smith, E. M. Toloza and W. G. Wolfe.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
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