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Neuroprotection during Carotid and Cardiac Surgery

Clinical Focus

The text below is extracted from the multi-institutional academic research projected entitled "NEUROPROTECTION DURING CARDIAC AND CAROTID SURGERY" that has been submitted in 1999 and granted with CHF 850'000. The project has been carried out 2000-2002 and has spun off ABMI. It has been co-signed by:

  • Prof. J. Bogousslavsky, Prof. P.A. Despland, and Dr. G. Devuyst from the Neurology Department of CHUV, Lausanne,
  • Prof. L. von Segesser and Dr P. Ruchat from the Department of Cardiac Surgery, CHUV, Lausanne,
  • Prof. B. Faidutti and Dr. A. Kalangos from the Department of Cardiac Surgery, HUG, Geneva,
  • Prof. M. Kunt, Dr J.-M. Vesin, and Dr. J.-Ph. Thiran from the Signal Processing Laboratory (LTS) of EPFL, Lausanne,
  • Prof. G. Dietler from the Department of Physics, UNIL, Lausanne.

We would like here to honor the memory of our friend and colleague Dr Gérald Devuyst, the respected and renowned neurologist who has been the main force behing this research project, and who very sadly passed away at age 40 in early 2007, leaving behind a wonderful wife, Christine, and a young son, Romain. Gérald is the main sauthor of the text below.

1 An Overview of Neurological Complications in Cardiac and Carotid Surgery

Cerebral complications - stroke and neuropsychological disorders - after both cardiac and carotid surgery are now recognized as a serious and costly healthcare problem, mandating immediate attention for the estimated 1.5 million patients undergoing such surgery through the world annually [1,2]. Major advancements have been made in cardiac and carotid surgery since the 1980s to decrease mortality and major morbidity. Concomitant with protection of the heart, protection of other major organs, and particularly the brain, is increasing, so that new strategies in preoperative embolic risk assessment and in neuroprotection for perioperative management are now required.

The evaluation of the incidence of neurological complications after cardiac and carotid surgery depends from the type of surgery, the neurological and neuropsychological parameters taken into consideration, and the prospective or retrospective character of the studies. A review of Brillman [3] devoted to neurological complications of coronary artery bypass graft (CABG) surgery found a rate of neurological complications ranging from 3 % for the retrospective studies limited to the detection of patients presenting a massive stroke or a post-anoxic encephalopathy to 33 % - 75 % for prospective studies taking into account these major neurological complications as well as disorders of cognitive functions. In the most recent prospective study of Roach et al. [4] devoted to the incidence of adverse cerebral events after CABG surgery, the results from 24 US medical centers indicate that 6 of every 100 patients (6 %) studied suffered significant neurological effects, including death, stroke, or substantial deterioration of intellectual function. In some subgroups of operated patients, the rate of neurological complications can even increase : 1 in 6 patients will develop cerebral complications that are frequently devastating and costly after a valve replacement combined with coronary revascularization [1]. The overall incidence of cognitive decline after cardiac surgery is variable, ranging from 40-50 % of patients to 79 % in the early postoperative period [5-15], whereas the incidence of cognitive disorders at 6 months ranges from 19 % to 57 % [9, 11, 16-17].

Another way to estimate the socioeconomic impact of neurological complications of cardiac surgery consists in evaluating the capability of patients to reintegrate their socioprofessional activities. For instance, the study of Sotiament [18] has shown that 25 % of patients who have undergone a valvular replacement had abandoned their professional activities for neurological reasons 5 years after surgery. Carotid endarterectomy (CE) which is performed approximately in 400,000 patients through the world yearly, is also associated with a combined mortality and morbidity rate of 5 % to 11 % [19]. The 30-day mortality rate linked to CE is 1-2 % [2, 20-21] and is explained by myocardial infarction, stroke, brain hemorrhage, cranial nerve injury and hemorrhage at the surgical site [22-23]. The reported perioperative stroke rate associated with CE ranges from 5 % to 8 % as demonstrated by two recent trials [24-25] and is higher in patients examined postoperatively by a neurologist rather than by a vascular surgeon [21]. Moreover, MRI brain studies revealed 5-10 mm diameter subcortical infarcts occurring after CE in approximately 10 % of patients [26-28]. Cognitive disorders associated with CE is still a matter of debate. With the recent publication of NASCET trialists recommending CE for symptomatic moderate internal carotid artery stenosis - between 50 and 69 % of lumen reduction - the number of CE is likely to increase in the future, requiring new neuroprotection strategies because the benefit / complication ratio of CE will be narrower in these patients.

Neurological - particularly stroke which represents the first cause of permanent physical/intellectual disability in Western countries - and neuropsychological deficits resulting from cardiac surgery as well as carotid surgery are most likely attributed to brain embolism of air or particulate matter [4, 29-37] with risk increasing due to ageing of this population [33, 38-40]. The preponderance of evidence suggests that brain macroemboli (> 200 µm in diameter) - associated with atherosclerotic plaque disruption - are believed to provoke focal neurological deficits such as stroke, whereas particulate microemboli (< 40 µm in diameter) - consisting of white cells and platelet aggregates, fat or air - may be implicated in more subtle diffuse cerebral dysfunction [29] such as cognitive disorders [4, 30-37, 41]. Regarding solid emboli, risk appears to increase with age due to associated increase prevalence and complexity of atherosclerotic plaques in elderly patients [33, 38-40]. Gaseous emboli are believed to be infrequently associated with cerebral ischemia, although little substantial evidence exists to support this contention, whereas solid or particulate microemboli are considered significantly responsible of neurological / neuropsychological complications of both cardiac and carotid surgery. Transcranial Doppler (TCD) remains to date the sole technique that allows monitoring of perioperative brain embolism (macro- or microembolism). The detection of gaseous emboli by using ultrasound was reported in the 60s, while the depiction of solid, or formed emboli such as platelet aggregates, thrombus and atheroma has been demonstrated possible and feasible by ultrasound in animal models, in vitro models and in humans since 1990 [41]. The brain emboli (air or solid) are characterized by a high and transient signal on the Doppler background, called microembolic signals (MES) or high intensity transient signals (HITS) [42]. Innovative signal processing methods will be investigated in this project to perform a more robust and reliable classification of the emboli. Moreover, because preoperatively the assessment of the embolic risk of carotid atherosclerotic plaques remains poor by the classical methods based on gray-scale imaging, we propose to investigate new ultrasound imaging techniques based on the recent developments in tissue harmonic ultrasonography, in order to better classify carotid atherosclerotic plaques according to their embolic risk. The results from this classification by tissue harmonic imaging will be correlate with neurological complications.

Because neurological as well as neuropsychological disorders represent a crucial medical and socioeconomic problem from cardiac and carotid surgery, new neuroprotection strategies are required in these patients. Taking into account that embolism - particularly solid emboli - into brain circulation are responsible of approximately 85 % of these complications on one hand and that TCD is the sole technique permitting the depiction of emboli in the main brain arteries on the other hand, it seems logical to base new protection strategies on the embolus Doppler detection during surgery as well as on the development of new techniques allowing a better assessment of the embolic risk of an atherosclerotic carotid plaque. In the former domain, very preliminary studies [27, 43-44] have shown that immediate feedback information from TCD monitoring - hemodynamic and embolic information - can prompt the vascular surgeon the planned course of surgery and by this way reduce neurological and neuropsychological complications of cardiovascular surgery. However, despite this reasonable basis in favor of Doppler embolus detection during cardiovascular surgery, its application has not been definitively proved to improve the neurological outcome of patients because of some technical limitations. Indeed, despite of recent progress the rejection of artifacts due to probe and tissue's movements is not yet perfect, whereas there is no commercially available TCD device able to discriminate gaseous from solid emboli with a sufficient high confidence. Finally, information concerning the nature of brain embolism - artifact/gaseous/solid - should be provided on-line to the vascular surgeon as an immediate feedback in order to change the surgical technique in real time. For the later domain, i.e. a better analysis of the embolic risk of an atherosclerotic carotid plaque, new developments in ultrasonic imaging, and specially tissue harmonic, are certainly an interesting research direction.

2 Medical state of the art (2003) --- Four Focused Questions

2.1 Does the number of brain emboli correlate with the occurrence of neurological complications during both cardiac and carotid surgery?

Stump et al. [13] reported that patients with neuropsychological deficits after CABG surgery averaged almost twice the number of emboli as those without deficits. Another study of Pugsley et al. [49] observed that among 94 patients at 8 weeks after cardiac surgery, a postoperative neuropsychological deficit was found in 8.6 % of patients with < 200 microemboli and in 43 % of patients with > 1,000 microemboli detected by TCD. Available data suggest that cerebral ischemia during CE occurs when the microembolic count is high: 672 and 157 MES were recorded in cases 1 and 2 that underwent stroke in the study of Gaunt et al. [50]. Jansen et al. [51] described massive embolization in patients with intraoperative stroke. The notion of threshold in the number of MES has even been proposed in two recent studies: Jansen et al. [27] have shown a correlation between an absolute MES count of greater than 10 during any phase of the surgery and appearance of new small cerebral infarcts by MRA while in the study of Levi et al. [52], perioperative stroke occurred in patients who had more than 50 MES / hour during the dissection phase of CE. However, although relatively high MES counts are predictive of cerebral ischemic events, an absolute MES count or rate above which complications reliably occur has not yet been identified. However, if it seems that the number of brain emboli plays a role in the occurrence of neurological complications, we must keep in mind that with current Doppler techniques the conversion of detected signals into counts depends on software programming variables, and whether an increase in signal amplitude reflects an increase in the number of size of emboli is unclear. Therefore, the number of counts may not always represent the exact number of particles traversing the electronic gate [53-54]. It is thus clear that new technical solutions must be developed to address this issue.

2.2 When do brain emboli occur during the course of both cardiac and carotid surgery ? Does this surgical time of MES occurrence correlate with the appearance of neurological complications ?

Documenting when emboli occur during the course of the cardiac surgery may have important implications for surgical practice [55-56]. Indeed, changes in cannulae, vent placement, de-airing methods and the use of biocompatible surfaces may all help to reduce the number of emboli delivered to the brain as a consequence of cardiopulmonary bypass [57]. In the study of Stump et al. [13] devoted to CABG surgery, more than 60 % of the emboli were detected during a period in which physical manipulation of the heart aorta was in progress. Approximately 10 % were detected during the 2 minutes after removal of the aortic cross clamp. TCD studies indicate that cerebral embolism is ubiquitous during the course of carotid endarterectomy, occurring in more than 80 % of patients [43, 50]. Embolism is observed during the dissection phase of surgery in approximately 20 % of patients and is associated with an ulcerated plaque with an attached thrombus at the ICA origin [50, 58]. Embolism is frequently secondary to pushing, pulling, or other manipulation of the operated artery. Embolism is also observed at clamp release and at the time when the wound is being closed in approximately 65 % and 60-70 % of patients respectively [58]. Some studies have revealed an association between the surgical phase in which microembolic signals were detected and the occurrence of neurological complications. For instance, microembolic signals (MES) detected during the dissection [27] and recovery room [28] phases are correlated significantly with small, subcortical, asymptomatic cerebral infarcts as demonstrated by MRI. MES diagnosed during shunting [58] and during the immediate post-operative period [50] are linked with cognitive deterioration or clinically detected cerebral ischemic events [52, 59]. However, these studies show a less than perfect correlation between time MES occurrence and neurological complications, suggesting that the composition of embolism is another probably crucial factor.

2.3 Which is the nature --- gaseous or solid --- and which is the composition --- platelets, fibrin, fat, and cholesterol --- of brain emboli ?

Two recent studies [60-61] have noticed the absolute number of microembolic signals detected by TCD were not necessarily interrelated with a deterioration of postoperative neuropsychiatric state suggesting that the nature of embolism may play an important role rather than their count alone. Thus, the conclusion of these authors [60-61] is that future TCD studies should focus on the differentiation between gaseous and solid emboli even in the clinical setting, as the later may well play a major role for the development of cerebral dysfunction following cardiac surgery and extracorporeal circulation. Some aspects of the interaction between MES composition and cerebral ischemic events remain poorly understood but are probably crucial. In fact, gaseous emboli are thought to be infrequently associated with cerebral ischemia, although little substantial evidence exist to support this contention, whereas particulate or solid microemboli are considered significant in provoking cerebral ischemic events during CE. It is believed that air emboli were not associated with postoperative stroke while formed element emboli were implicated when postoperative stroke occurred [41]. Laboratory models [62] and clinical studies [63-64] suggest that signals similar to the ones seen during the course of CE correspond to gaseous microbubbles as well as particles composed of platelets, fibrin and cholesterol crystals. However, a considerable degree of overlap is found between ultrasonic characteristics of signals made of various materials and available Doppler device do not permit reliable determination of microemboli corresponding to these signals. Despite the application of new criteria for microemboli established by recent meetings, the nature gaseous vs. solid of MES can still not be classified [42]. On the one hand, because such differentiation between gaseous and solid MES is very important in making critical therapeutic decisions (e.g., anticoagulants vs. hyperbaric oxygen administration) and on the other hand, taking into account the limitation of current available Doppler device to predict the nature of MES, it is necessary to develop new technical approaches. Indeed, at this time discriminating the size and composition of embolic material with ultrasonic methodology is difficult with currently available ultrasonic methods. For this reason, the composition of emboli during the different phases of both cardiac and surgery which is probably essential to know in order to adapt therapeutic decisions, is still a matter of debate.

2.4 Is it possible to reduce the neurological complications of both cardiac and carotid surgery by routine transcranial Doppler embolus detection and characterization ?

As neuroprotective treatments become available [48], information regarding the quantity and composition of emboli detected during surgery may be used to direct the most appropriate interventions [57, 66-67]. Hammon et al. [5] have shown that changes in documentation of aortic atherosclerosis coupled with decreased manipulation of the ascending aorta and increased use of the left ventricular vent significantly decreased emboli and improved neurobehavioral outcome in a large group of patients. Interestingly, very few studies have shown that the finding of high MES counts during a specific phase of CE is useful for the vascular surgeon until now. Because microembolism during the dissection phase is often caused by excessive manipulation of the internal carotid artery (ICA), when it occurs, it can be corrected by changing the surgical technique. Indeed, Spencer et al. [43] have found a benefit for the patients by changing the surgical technique when MES are depicted during the CE. A second study from Jansen et al. [44] after the introduction of transcranial Doppler ultrasound (TCD) monitoring (hemodynamic and embolic data from TCD) during CE observed that their intraoperative stroke rate decreased from 4.8 to 1.5 %. The presence of MES during the postoperative phase has prompted reimaging of the operated ICA with subsequent heparin anticoagulation or surgical reexploration because of thrombus formation at the endarterectomy site [50, 59]. Lennard et al. [68] have monitored patients during the 6 postoperative hours and selected those with more than 25 MES during any 10/period and treated them with dextran/40. Consequently, these authors observed an immediate decline in the rate of MES and no perioperative complications. Arrowsmith et al. have shown that neuroprotection represents really a promising avenue in cardiovascular surgery [69]. Because technical limitations of Doppler devices still remain concerning the rejection of artifacts and mainly in the accuracy to discriminate gaseous from solid emboli, there is a lack of appropriate prospective studies involving this fundamental question despite of promising preliminary results.

In summary, all these considerations clearly show the necessity to further develop innovative technical methods to better assess the embolic risk of a patient prior to a cardiovascular operation as well as the need of a perioperative embolic detection and characterization tools.

3 References

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