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J Thorac Cardiovasc Surg 2008;135:512-520
© 2008 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Solid and gaseous cerebral microembolization after biologic and mechanical aortic valve replacement: Investigation with multirange and multifrequency transcranial Doppler ultrasound

Lorenzo Guerrieri Wolf, MD, Bikram P. Choudhary, MRCS, Yasir Abu-Omar, MRCS, David P. Taggart, MD (Hons), PhD, FRCS*

Department of Cardiothoracic Surgery, John Radcliffe Hospital, Oxford, United Kingdom

Received for publication March 17, 2007; revisions received July 8, 2007; accepted for publication July 10, 2007.

* Address for reprints: David P. Taggart, MD (Hons), PhD, FRCS, Professor of Cardiovascular Surgery (University of Oxford), Department of Cardiothoracic Surgery, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom. (Email: david.taggart{at}orh.nhs.uk).


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
Objective: Cerebral microembolization is a well-recognized phenomenon after cardiac valve replacement, but the relative proportion of solid and gaseous emboli is uncertain. Particulate microemboli are thought to be the most damaging. With the use of multifrequency transcranial Doppler ultrasound, we compared the number and nature of microemboli in recipients of biologic and mechanical aortic valve prostheses.

Methods: The middle cerebral arteries of 60 patients were monitored bilaterally with a new-generation transcranial Doppler ultrasound (Embo-Dop, DWL Elektronische Systeme GmbH, Singen, Germany) that rejects artefacts online and automatically discriminates between solid and gaseous microemboli. All recordings were performed during a 30-minute period 1 day before and at a mean of 5 days and 3 months after isolated aortic valve replacement with a biologic (30, group B) or mechanical (30, group M) prosthesis.

Results: The patients in group B were older, with a mean age of 70.6 ± 9.7 years versus 55.4 ± 9.4 years (P < .005) in the patients in group M. Biologic prosthesis recipients were all taking aspirin (no warfarin); patients with mechanical valves were well anticoagulated with warfarin both 5 days and 3 months after surgery. None of the patients had solid microemboli preoperatively. Five days postoperatively, the absolute number of cerebral microemboli was 145 and 594 for total microemboli (P = .001) and 41 and 182 for solid microemboli (P = .002) in groups B and M, respectively. At 3 months, the absolute number was 65 and 608 for total microemboli (P < .001) and 10 and 188 for solid microemboli (P < .001) in groups B and M, respectively. Solid microemboli accounted for 16% of the total microembolic load in group B compared with 31% in group M (P = .05) at 3 months.

Conclusions: Solid cerebral microemboli represent approximately one third of the total cerebral microembolic load after mechanical aortic valve replacement and are detectable in the majority of such patients both 5 days and 3 months after surgery. The neurofunctional consequences of this phenomenon should be carefully assessed.

Abbreviations and Acronyms AVR = aortic valve replacement; HITS = high intensity transient signals; MCA = middle cerebral artery; TCD = transcranial Doppler


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
Since the first detection of intracavitary echoes in prosthetic heart valves in 1975,1Go several studies have reported transcranially detected high intensity transient signals (HITS) in patients with a normally functioning heart valve prosthesis, including mechanical,2-9Go bioprosthetic,6,7,10Go homograft,11Go and pulmonary autograft12Go recipients, implying cerebral microembolization.

Intraoperative cerebral microembolization is considered to be an important cause of postoperative neurocognitive decline in cardiac surgery.13-16Go This finding is supported by our own recent demonstration of a correlation between the number of intraoperative cerebral microemboli and the subsequent impairment of verbal memory defined by functional magnetic resonance imaging of the brain in patients undergoing coronary artery bypass grafting.17,18Go Although there is previous2,19Go and more recent9Go evidence that a higher HITS count is associated with worse neuropsychologic outcome, there is also evidence that HITS after valve replacement have no correlation with neuropsychologic outcome.6,20-22Go Consequently, any postulated correlation between neurocognitive damage and ongoing postoperative cerebral microemboli production in heart valve prosthesis recipients must be regarded as controversial.

Microembolization after valve replacement is a multifactorial and complex process. It is thought to be caused mainly by high hemodynamic stresses at the valvular level22Go as a consequence of high energy dissipation at valve closure23Go and extremely low pressure zones on the inflow side of mechanical heart valves.24Go This is exaggerated by turbulent blood flow downstream from prosthetic valves22,24Go leading to the formation of nitrogen and oxygen gas bubbles and/or thrombocyte aggregates, which are subsequently recorded in the cerebral circulation as HITS. Prosthetic valve design6,24-26Go and orientation26Go influence both shear rates and the grade of blood flow turbulence and are thought to have an important impact on the formation of such microemboli. Other factors (patient’s age,22Go myocardial contractility,27Go heart rate,27Go method of valve implantation,28Go valve dysfunction,29Go acetylsalicylate infusion,3,24Go oxygen therapy,5,7,21,24,30Go hyperbaric oxygen8Go) have also been found to influence HITS rate after prosthetic valves replacement.

The composition of cerebral microemboli in recipients of prosthetic valves has previously been suspected from various indirect evidence (O2, hyperbaric O2, antiplatelet agents). Although particulate microemboli are likely to be more damaging than gaseous microemboli, a closer correlation between solid cerebral microembolization and neurocognitive decline might be anticipated. Several articles31,32Go have also dealt with the issue of the potential damaging effects of gaseous microemboli.

In the present study, a new-generation transcranial Doppler (TCD) ultrasound33,34Go that rejects artefacts online and automatically discriminates between solid and gaseous microemboli was used to compare the number and nature of microemboli in patients with biological and mechanical aortic valve prostheses early and late after operation in an attempt to determine the exact proportion of particulate microemboli.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Limitations
 Conclusions
 References
 
A total of 60 patients admitted to the John Radcliffe Hospital for elective isolated aortic valve replacement (AVR) were prospectively recruited for the study. All patients gave informed consent, and full ethical approval was obtained from the local research ethics committee (Oxford Research Ethics Committee number C01.258).

The patients were divided into 2 groups. Thirty patients underwent isolated AVR with biological prostheses (group B), and 30 patients underwent isolated AVR with mechanical prostheses (group M). Patients with symptomatic carotid disease, peripheral vascular disease, preoperative neurologic history, or atrial fibrillation were excluded. Methods of valve implantation included the interrupted suture technique with positioning of subannular pledgets and the continuous suture technique with six 2-0 polypropylene sutures. Methods of myocardial protection, cardiopulmonary bypass, aortotomy, valve excision, and debridement were similar in all of the study patients. Transesophageal echocardiography was used routinely in all study patients to demonstrate normal function and seating of the valve and to confirm adequate deairing. All mechanical valves were implanted in their optimum orientation.35Go All patients had a well-functioning aortic prosthesis as demonstrated by echocardiography at the times when the TCD studies were conducted. By the fourth postoperative day, none of the patients were receiving supplemental oxygen.

Transcranial Doppler Monitoring
Bilateral TCD monitoring of the middle cerebral arteries for a continuous period of 30 minutes was performed in all patients 1 day before the operation and at a mean of 5 days (5 ± 1 days in group B and 5.5 ± 1.3 days in group M) and 3 months (90 ± 14 days in group B and 90 ± 7 days in group M) after surgery.

All recordings of the middle cerebral artery (MCA) were performed bilaterally using a multirange, multifrequency TCD (Embo-Dop; DWL Elektronische Systeme GmbH, Singen, Germany), which rejects artefacts online and automatically discriminates between solid and gaseous microemboli.33,34Go We previously described this new-generation equipment.17Go In brief, we simultaneously insonated the MCAs bilaterally through dual-frequency probes (2.0 and 2.5 MHz) fixed to the transtemporal windows above the right and left zygomatic arches using a specifically designed head brace. An additional 2.0-MHz insonation reference gate was set 15 mm superficially to the MCA insonation gate whose depth was set between 45 and 55 mm with a sample volume of 13 mm. The multifrequency system (2.0 MHz and 2.5 MHz) serves for the automatic microemboli nature discrimination: Gaseous microemboli reflect more ultrasound at lower frequencies than at higher frequencies, contrary to what occurs in the case of solid microemboli. The reference gate serves for the online rejection of artifacts: The latter are identified when HITS are detected in both gates (MCAs and reference gates) simultaneously or with a time delay of less than 4 msec.

Statistical Analysis
Patient characteristics are presented as mean ± standard deviation or percentage of the total. The number of microemboli is presented as the absolute number and the median and 25th to 75th percentiles. Statistical comparison, for normally distributed data, was performed using the Student t test for continuous variables and the chi-square test or Fisher exact test (as appropriate) for categoric variables. Because the data for the number of microemboli were not normally distributed, the nonparametric Mann–Whitney U test was used to compare the difference among the 2 groups. The Wilcoxon test was used to analyze the variation of the number of microemboli over time within each group. A stepwise logistic regression analysis was performed to select predictors of HITS; the model was built using variables that demonstrated a P value less than .10 in the univariate analysis. The significance within the model was evaluated with the Wald statistical test. The Statistical Package for the Social Sciences version 12.0 (SPSS Inc, Chicago, Ill) software was used for statistical calculations.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Limitations
 Conclusions
 References
 
Patients in group B (22 male, 8 female) were older than those in group M (23 male, 7 female), with a mean age of 70.6 ± 9.7 years versus 55.4 ± 9.4 years (P < .005). All other demographic and preoperative patient characteristics were similar in the 2 groups and are summarized in Table 1. Operative and postoperative data are shown in Table 2. Biological prosthesis recipients all received aspirin (no warfarin); patients with mechanical valves all received oral anticoagulants with a mean international normalized ratio in the therapeutic range (2.8 ± 0.6) both 5 days and 3 months after surgery. The types of valve prostheses implanted in the study patients are summarized in Table 3.


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  		Table 1 Demographic and preoperative patient characteristics
 

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  		Table 2 Operative and postoperative data
 

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  		Table 3 Type of valve prosthesis implanted in the study patients
 
Microemboli
Twenty percent of patients in both groups were positive for HITS before the operation, but none were solid microemboli. The relative frequency of patients positive for HITS was significantly higher in mechanical heart valve prosthesis recipients than in biological recipients both 5 days and 3 months after surgery. An even more marked difference between the 2 groups was evident for solid microemboli. The percentage of bioprostheses recipients who were positive for solid microemboli decreased significantly over time (P = .01), but this did not occur in those with mechanical valves (Table 4).


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  		Table 4 Percentage of patients positive for any and solid microemboli, absolute number of any microemboli, and proportion of solid and gaseous microemboli detected 1 day before and 5 days and 3 months after isolated aortic valve replacement
 
A similar small amount of total microemboli were detected in biological and mechanical aortic valve prostheses recipients before the operation. At 5 days and 3 months after surgery the median number (25th–75th percentile) of any microemboli (Figure 1) and solid microemboli (Figure 2) was significantly higher in mechanical recipients than biological recipients. Figures 1 and 2 show that the median number (25th–75th percentile) of any and solid microemboli decreased significantly over time in biological recipients, with a steady production of HITS in patients with mechanical valves. Although a similar proportion of solid microemboli was found between the 2 groups early postoperatively, at 3 months after surgery the proportion of particulate microemboli was significantly higher in group M than in group B (Table 4).


Figure 1
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  		Figure 1. Median number (25th–75th percentile) of total microemboli in biologic (group B) and mechanical (group M) aortic valve prostheses recipients, as detected 1 day before (–1) and 5 days (5) and 3 months (90) after isolated AVR. Comparison of number of total microemboli detected in group B: *1 day before and 5 days after surgery (P = .001); {dagger}1 day before and 3 months after surgery (P = .01); {ddagger}5 days and 3 months after surgery (P = .04). Comparison of number of total microemboli detected in group M: §1 day before and 5 days after surgery (P < .0001); ||1 day before and 3 months after surgery (P < .0002); #5 days and 3 months after surgery (P = .5). NS, Not significant.

 

Figure 2
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  		Figure 2. Median number (25th–75th percentile) of solid microemboli in biologic (group B) and mechanical (group M) aortic valve prostheses recipients, as detected 1 day before (–1) and 5 days (5) and 3 months (90) after isolated AVR. Comparison of number of solid microemboli detected in group B: *1 day before and 5 days after surgery (P = .002); {dagger}1 day before and 3 months after surgery (P = .06); {ddagger}5 days and 3 months after surgery (P = .02). Comparison of number of solid microemboli detected in group M: §1 day before and 5 days after surgery (P < .0002); ||1 day before and 3 months after surgery (P < .0003); #5 days and 3 months after surgery (P = .6). NS Not significant.

 
In the multivariate analysis, increased heart rate and the implantation of mechanical valve prosthesis were significantly associated with an increased number of HITS (P = .02 and P = .003, respectively). We did not find an association with patient age.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Limitations
 Conclusions
 References
 
To our knowledge, this is the first report to use a multifrequency TCD to directly compare the number and nature of cerebral microemboli in such a large cohort of biologic and mechanical aortic valve prostheses recipients. The main finding of this study was that solid microemboli represented approximately one third of the total cerebral microembolic load after mechanical AVR and were detectable in the majority of such patients both 5 days (80%) and 3 months (93%) after surgery. In addition, the present study demonstrated that gaseous but not solid microemboli were detectable in approximately 20% of patients with aortic valvular disease before surgery, presumably because of the turbulence generated by a severely diseased valve, and that microembolic signals occur in most patients after both mechanical and biologic valve replacement in the early postoperative period. However, 3 months after surgery there was a reduction in the number of HITS in bioprosthesis recipients but a constant number in patients with a mechanical prosthesis. Moreover, although a minority of patients with bioprostheses experienced solid cerebral microembolization both 5 days and 3 months after surgery, the proportion of these patients who were positive for solid microemboli decreased over time. Finally, in accordance with previous observations,5,8,36-39Go we found that the majority of microemboli were gaseous in nature, with solid microemboli accounting for a percentage of total microembolic load ranging between 16% (in biological prosthesis recipients, 3 months after surgery) and 31% (in mechanical prosthesis recipients, both 5 days and 3 months after surgery).

Discrimination between solid and gaseous microemboli in patients with prosthetic heart valves may have important pathophysiologic, therapeutic, and prognostic implications. The likely nature of cerebral microemboli in such patients has been investigated in the past with differing methods (Table 5). By performing simultaneous ultrasound monitoring, Georgiadis and colleagues36Go reported a significantly higher number of HITS in the common carotid artery compared with those of the ipsilateral middle and anterior cerebral arteries in patients with artificial heart valves, arguing that as bubbles implode with time, the majority of the HITS were likely to be explained by gaseous emboli, consistent with previous spectral characteristic analysis of HITS.39Go A similar conclusion was reached by Baumgartner and colleagues8Go after demonstrating an increase in HITS in 15 mechanical valve recipients subjected to an increase in their environmental pressure. On the other hand, others3,24,40-42Go have provided plausible evidence about the likely solid nature of at least some microemboli. Geiser and colleagues,41Go using morphologic and functional methods, including flow cytometry and platelet-specific antibodies, reported an increased microembolic load and the presence of platelet microparticles associated with a procoagulant activity in patients with prosthetic heart valves symptomatic for cerebrovascular events. Three years earlier, by monitoring antithrombotic treatments and coagulation markers, the same group42Go showed that microemboli are likely to be composed at least in part of platelets. Several other studies supported this hypothesis by demonstrating a decrease in HITS after oral3Go or intravenous3,24Go administration of antiplatelet drugs. For example, Laas and colleagues24Go found a 16% to 41% reduction with intravenously administered lysine acetylsalicylate. suggesting that particulate microemboli constituted a minority component. However, the most frequent method for demonstrating the likely gaseous nature of the majority of cerebral microemboli in prosthetic valve recipients was the reduction in HITS counts during 100% oxygen inhalation:5,7,21,24,30Go Milano and colleagues7Go found a decrease in the number of HITS per hour from 55 (±79) to 22 (±31) after 100% oxygen; Droste and colleagues30Go found a decrease in HITS in 20 patients with mechanical prosthetic cardiac valves from 144 HITS per hour without oxygen to 63 HITS per hour with oxygen. These studies actually suggested that approximately one third of the microemboli cannot be eliminated by 100% oxygen therapy and thus may be particulate. Our results are in agreement with these findings, and the comparison strengthens the importance of their results.


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  		Table 5 Variation in transcranially detected cerebral microembolic load and microemboli nature discrimination methods among different studies
 
Because only indirect methods have been used in the literature to suggest that the nature of microemboli associated with valve prostheses may have a mixed composition, we believe our study to determine the exact proportion of solid and gaseous microemboli using a sophisticated new-generation TCD is particularly valuable. As summarized in Table 5, it can be seen that our results are broadly in line with the findings of previous studies6,7,10-12Go in terms of the incidence of HITS with mechanical valves. However, an interesting finding is that we also found a far higher incidence of HITS in biological valves. This could be the result of an increased sensitivity or a decreased specificity of the technique used for the microemboli detection. Indeed, the automatic rejection of artifacts achievable with the Embo-Dop system reduces bias in the interpretation of HITS and avoids interobserver variability. The original "in vivo" validation of the current multirange and multifrequency TCD system was carried out by Russell and Brucher34Go in a much smaller cohort of prosthetic heart valve recipients. The authors did not, however, compare mechanical and biological prostheses. More recently, Markus and Punter,43Go while confirming the superior discrimination achievable with this new Embo-Dop TCD system compared with conventional TCD ultrasound, reported it to have a sensitivity of only 50% but a specificity of 96% for detecting solid microemboli in vivo. If confirmed, that finding will only serve to emphasize the already significantly greater solid microembolic load detected with mechanical rather than biological prostheses.43Go The suggestion that embolus detection and differentiation may be unreliable in situations with bursts of microemboli entering the sample volume at the same time44Go is not likely to influence our current observations because the frequency of emboli generation was low. Finally, when all the technical parameters of the system (ie, Doppler signal enhancement) are satisfied, as in the current study, the dual-frequency Doppler can discriminate the nature of microemboli with reliable results.44Go

Although biological recipients were all receiving aspirin, mechanical recipients received warfarin without any antiplatelet agents. This could explain the reduction in the proportion of particulate microemboli over time in the biological valve group but not in the mechanical group. Because the use of aspirin in addition to warfarin after mechanical valve replacement has been convincingly shown to reduce the incidence of thromboembolic events and death (the benefit was greater than the increased risk of bleeding),45,46Go it would be interesting to examine HITS using aspirin as well as warfarin in the mechanical valve recipients.

It is tempting to speculate that the steady production of solid microemboli detected in mechanical prosthesis recipients during a 30-minute period, if extrapolated over many years, could clarify at least in part the pathologic mechanisms causing neurocognitive decline associated with chronic cerebral microembolisation in some studies,2,9,19Go but other studies have found no such relationship.6,20-22Go Zimpfer and colleagues47Go initially reported immediate postoperative impairment of neuropsychologic outcome in patients with mechanical and biologic valves, but by 4 months the younger patients with mechanical valves had returned to normal (demonstrating a lack of a correlation between HITS and neuropsychologic outcome). In their 2006 article48Go the same group compared longer term (3 years) follow-up of mechanical AVR with age-matched nonsurgical controls and found no difference in neuropsychologic outcomes in the valve recipients, although these studies can be criticized for using only auditory-evoked P300 latencies as a neuropsychologic test.


   Limitations
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Limitations
Conclusions
 References
 
Although our study sought to determine the exact proportion of solid and gaseous microemboli, its major limitation is the lack of any associated cerebral outcome measurements (eg, neurocognitive testing or magnetic resonance imaging) and therefore uncertainty regarding the clinical significance of its findings.

Because this was not a randomized trial, it is possible that other differences between the 2 groups may have affected the HITS rate independently of valve type. However, as summarized in Tables 1 and 2, mechanical and biologic valve recipients were well matched for the main factors influencing the HITS rate, including myocardial contractility, heart rate, valve type and size, and method of valve implantation. However, the results could also be affected by the use of aspirin in the biologic valve group, which would explain the reduction of microemboli detected over time in group B but not in group M. Indeed, using aspirin instead of warfarin after a biological aortic valve implantation is the current practice among the majority of cardiac surgeons, and consequently our findings reflect a "real-world" situation.

Finally, because a number of different mechanical and biologic valves were used in each group, we cannot comment as to how prosthetic valve design in terms of bileaflet versus tilting disc for mechanical valves and stented versus stentless for bioprostheses influenced the results.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Limitations
 Conclusions
References
 
Solid cerebral microemboli represent approximately one third of the total cerebral microembolic load after mechanical AVR and are detectable in the majority of such patients both 5 days and 3 months after surgery.


   Acknowledgments
 
The authors acknowledge Mr Ravi Pillai, Mr. Chandi Ratnatunga, and Mr Stephen Westaby for allowing us to study their patients.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 

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