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Ann Thorac Surg 2001;72:S1838-S1844
© 2001 The Society of Thoracic Surgeons

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Supplement: Mechanisms and attenuation of abnormalities in hemostasis/inflammation and neurologic injury: implications for patient outcomes

Attenuation of neurologic injury during cardiac surgery

^a Department of Anesthesiology and Perioperative Medicine, University Hospital Campus—London Health Sciences Center, University of Western Ontario, London, Ontario, Canada

* Address reprint requests to Dr Murkin, Department of Anesthesiology and Perioperative Medicine, University Hospital Campus—London Health Sciences Center, University of Western Ontario, 339 Windermere Rd, London, Ontario, Canada N6A 5A5
e-mail: jmurkin{at}uwo.ca

Presented at Mechanisms and Attenuation of Abnormalities in Hemostasis/Inflammation and Neurologic Injury: Implications for Patient Outcomes, Vancouver, BC, Canada, May 6, 2001.

	Abstract

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
Neurologic injury after cardiac surgery can be divided into type I, including clinically apparent stroke, seizures stupor, or coma, and much more occurring type II injury, including intellectual deterioration, memory deficit, or seizures. Cerebral embolization is demonstrably etiologic in many such cases, and several new aortic cannulas are being introduced that are aimed at capturing or diverting potential cerebral emboli. No outcome data are yet available. Several potentially cerebroprotective pharmacologic therapies including thiopental, propofol, and nimodipine, have been assessed clinically but, generally, the results have been poor. Meta-analysis of the large North American aprotinin database of prospective, randomized, placebo-controlled clinical trials is suggestive of a cerebroprotective potential associated with high-dose aprotinin administration.

	Introduction

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
Several recent studies have drawn the attention of both clinicians, and the lay public to the issue of central nervous system (CNS) injury after cardiac surgery [1, 2]. Fundamentally, it appears as though two different manifestations of CNS injury are involved—one being various forms of clinical stroke, and the other a more subtle but much more common dysfunction of memory and cognition.

In a landmark study, Roach and colleagues [1] prospectively evaluated CNS outcomes in 2,108 patients undergoing surgery for elective coronary artery bypass grafting (CABG) from 24 United States institutions for two general categories of neurologic outcome: type I (focal injury, or stupor or coma at discharge) and type II (deterioration in intellectual function, memory deficit, or seizures). Adverse cerebral outcomes occurred in 129 patients (6.1%). A total of 3.1% had type I neurologic outcomes (8 died of cerebral injury, 55 had nonfatal strokes, 2 had transient ischemic attacks, and 1 had stupor); and 3.0% had type II outcomes (55 had deterioration of intellectual function and 8 had seizures). Patients with adverse cerebral outcomes had higher in-hospital mortality (21% of patients with type I outcomes died, vs 10% of those with type II and 2% of those with no adverse cerebral outcome), longer hospitalization (25 days with type I outcomes, 21 days with type II, and 10 days with no adverse outcome), and a higher rate of discharge to facilities for intermediate or long-term care (69%, 39%, and 10%, respectively). Predictors of type I outcomes were proximal aortic arteriosclerosis, a history of neurologic disease, and older age.

Newman and colleagues [2] evaluated long-term type II outcomes in 261 patients who underwent CABG using neurocognitive tests performed preoperatively, before discharge, and 6 weeks, 6 months, and 5 years after CABG surgery . They demonstrated that the incidence of cognitive decline was 53% at discharge, 36% at 6 weeks, 24% at 6 months, and a disturbing 42% at 5 years. Cognitive function at discharge was shown to be a significant predictor of long-term cognitive function. Others have made similar observations [3, 4].

In our own series assessing postoperative neurobehavioral sequelae in more than 300 CABG patients, the stroke rate was 2.5%, whereas among all CABG patients 33% demonstrated cognitive dysfunction and another 18% demonstrated abnormal neurologic signs 2 months postoperatively [5]. In a 3-year follow-up in 97 of these same patients, 22% suffered cognitive impairment and another 18% again demonstrated abnormal neurologic signs [3]. Although the genesis of CNS injury after cardiac surgery remains unclear, this is likely multifactorial, and reflects some complex interplay between cerebral embolization, hypoperfusion, and both localized and systemic inflammatory processes [6]. It must be borne in mind, however, that up to 10% of elderly patients undergoing total hip arthroplasty, a group in whom cerebral lipid macroemboli and microemboli have also been incriminated [7], can be demonstrated to have postoperative cognitive dysfunction [8].

	Atheroemboli

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
For a large number of CABG patients, cerebral atheroemboli seem likely to account for the majority of type I outcomes. Advanced age, Type II diabetes mellitus, and vascular disease, conditions repeatedly identified as primary risk factors for perioperative stroke, are also predictors of advanced systemic arteriosclerosis and the development of diffuse systemic atheroemboli [9]. There is a demonstrated relationship between significant arteriosclerosis (eg, intimal thickening of more than 5 mm in the aortic arch) and stroke after CABG [10]. This may be present in up to 20% of CABG patients. In a series of 1,200 patients in whom intraoperative ultrasound scanning of the aorta was performed, moderate (3 to 5 mm thick) or severe (> 5 mm; or ulcerations, circumferential aortic involvement, mobile atheroma) ascending aortic atherosclerotic disease was found in 231 (19.3%) patients [11]. What is the mechanism of perioperative stroke?

Aortic manipulation such as required for CABG has been shown to be associated with cerebral embolization. Ascending aortic cannulation and aortic clamp application and removal are among the most significant sources of embolic activity during CABG surgery [12–14]. Cerebral embolization has been closely linked to subsequent adverse neurologic outcomes [14, 15]. This points to atheroembolization as a primary cause of perioperative stroke and CNS impairment [9, 16]. This is not surprising, however, because even in nonsurgical patients presenting with subcortical stroke, new evidence is indicating a much greater role for aortic atheroemboli than previously considered [17]. As has recently been shown using epiaortic ultrasound scanning (EAS) after aortic cannulation and clamping, the presence of aortic atheromatosis significantly increases the chance of plaque fracture and intimal flap formation after aortic instrumentation [18]. The potential for subsequent embolization of either plaque or secondary thrombus is thus high and, in all likelihood, accounts for many of the otherwise unexplained strokes seen on postoperative days 2 and 3. It has also been consistently demonstrated that, with recognition of significant aortic disease, technical modifications aimed at avoidance or elimination of the atherosclerotic aorta are dramatically effective in decreasing the perioperative stroke rate [19–21].

	Detection of aortic atheromatosis

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
In most centers, aortic cannulation is preceded by manual palpation of the aorta to determine suitable sites for cannulation and for placement of aortic clamps and vascular anastamoses. This is currently the standard of care in many cardiac centers in North America and Europe. However, Konstadt and colleagues [22] and Sylviris and associates [23] have demonstrated the unreliability of both palpation and transesophageal echocardiography (TEE) examination for assessment of the ascending aorta. The use of EAS provides accurate images of the aortic wall and lumen and allows for optimization of cannulation sites. In a recent study of 102 patients in whom EAS was performed directly after conventional aortic assessment by surgical palpation, in 23.5% of these patients aortic scanning resulted in a change in surgical management of aortic instrumentation by relocation of clamp or cannulation sites [24]. This was also associated with a significantly lower incidence of cerebral emboli associated with cannulation and release of aortic cross clamp and partial clamp [25]. Direct EAS is therefore the only reliable way in which the ascending aorta can be assessed intraoperatively.

In a series of 10 patients undergoing CABG surgery, St Amand and colleagues [26] reported that EAS resulted in a change in cannulation site in 2 patients, one after detection of unrecognized atheroma, and the other after ultrasonic identification of a section of disease-free aorta in a patient in whom diffuse aortic arteriosclerosis had been determined by palpation. None of these patients experienced a postoperative stroke. In a much larger series, EAS of the ascending aorta was performed in 500 of a consecutive series of 540 patients aged 50 years or more (mean 68 years) who underwent a variety of cardiac operations [27]. Of the patients, 89% required bypass grafting. Moreover, 68% (13.6% of the total) with a mean age of 72 years (range 55 to 85 years) had significant atheromatous disease in the ascending aorta and were considered to be at increased risk for embolization. Palpation identified atheromatous disease in only 26 (38%) of these patients and underestimated its severity. A total of 168 modifications to the standard techniques for cannulation and clamping of the aorta were implemented in the 68 patients (mean 2.5 per patient) and included alterations in the sites of aortic cannulation (50 patients), aortic clamping (54 patients), attachment of the vein grafts (35 patients), and cannulation for infusion of cardioplegic solution (29 patients). Ten patients with severe diffuse atheromatous disease underwent graft replacement of the ascending aorta with hypothermic circulatory arrest without aortic clamping. Permanent neurologic deficits occurred in 5 (1.0%) patients in the entire group but in none of the 68 patients with significant atheromatous disease in whom modifications in technique were used [26].

	Atheroemboli: capture or diversion

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
Based on the high incidence of aortic atheromatosis in CABG patients and the associated risk of embolization, two new devices have been recently introduced. The Embol-X intraaortic filter (EMBOL-X, Mountain View, CA) is a 150-µm net that is inserted through the side port of a modified aortic cannula. It is deployed before release of the aortic cross-clamp and partial occlusion clamp. To date it has been used successfully in several hundred cardiac surgery patients in Europe [28] and it is currrently undergoing large-scale prospective randomized trials in North America. In a similar fashion, the Cardeon "Cobra" is a modified double-lumen aortic cannula (Cardeon, Cupertino, CA) with a flexible shield that acts to divert emboli away from the great vessels of the aortic arch. One lumen can be used to perfuse the body while the other perfuses the aortic arch vessels. This enables differential perfusion of the head and body to be undertaken, enabling differential cooling of the head while maintaining normothermic perfusion of the body [29]. Clinical outcome trials of this device are also currently underway. Whether either of these devices will prove beneficial to decrease the incidence of type I CNS injury is currently being assessed.

	Microemboli

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
Whether from data obtained using fluoroscein retinal angiography, histology of brain sections, or transcranial Doppler, it is apparent that there is evidence from multiple diverse sources demonstrating variable amounts of cerebral microemboli associated with CPB. Current evidence would seem to favor diffuse cerebral microembolization as a significant contributor to type II cognitive dysfunction after cardiac surgery.

In a study from Pugsley and colleagues, the relationship between the magnitude of the embolic load and postoperative cognitive performance was assessed using preoperative and postoperative neuropsychologic testing [30]. These investigators were able to show that patients with the lowest numbers of emboli as detected using transcranial Doppler evidenced a relatively low (<10%) incidence of neurobehavioral dysfunction on postoperative psychometric testing. However, as the embolic load increased, more than 40% of patients who had more than 1,000 emboli detected intraoperatively demonstrated postoperative cognitive impairment. Accordingly, they showed a direct relationship between embolic load and postoperative outcome. As they were using arterial line filters to reduce the embolic counts, they found that use of an arterial line filter decreased embolic load and therefore resulted in an improved outcome postoperatively. These data help to confirm further the association between intraoperative cerebral embolization and postoperative neurobehavioral outcome, and demonstrate the positive role that judicious equipment modifications can play in postoperative outcome.

Although there is considerable evidence for aortic atheroemboli in the genesis of perioperative stroke [9–11], another hypothesis considers the role of cerebral microvascular inclusions, or small capillary and arteriolar dilatations (SCADs). These have been demonstrated to occur after exposure to CPB in both animal models and on postmortem examination of the brains of patients dying within the first week after cardiac surgery with CPB [31]. Brooker and colleagues [32] have further demonstrated a 10-fold increase in numbers of SCADs in animals undergoing CPB in which cardiotomy suction blood was retransfused during CPB, versus those in which shed blood was not administered. As it has been well shown that cardiotomy blood contains a variety of substances including bone wax, marrow, lipid nacelles, in addition to red blood cells, plasma, and inflammatory mediators such as interleukins and tumor necrosis factor, retransfusion of this blood during CPB, wherein bypass of the pulmonary circulation necessitates retransfusion directly into the aorta, may well result in the delivery of a variety of these embolic particles directly into the ascending aorta and thus the cerebral circulation.

	Systemic inflammatory response

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
Activation of platelets and leukocytes has been demonstrated during CPB as a part of a systemic inflammatory response [33]. That such nonspecific activation may exacerbate the impact of focal cerebral ischemia such as may follow microgaseous or macroatheromatous cerebral emboli can be surmised based on responses seen in animal studies. After 3 hours of middle cerebral artery occlusion and 1 hour of reperfusion in a baboon occlusion/reperfusion model, del Zoppo and colleagues [34] demonstrated capillary-obstructing polymorphonuclear leukocytes in the microvascular bed after middle cerebral artery reperfusion during focal ischemia. In another study, white blood cell involvement in the generation of cerebral infarcts was evaluated following ischemia and reperfusion injury in the rat [35]. Control and rats with vinblastine-induced leukopenia (white blood cell counts < 1500/mm³) were compared in a global forebrain ischemic model after 1 hour of ischemia and 1 hour 15 minutes of reperfusion. They demonstrated that the area infarcted in leukopenic rats was significantly less than infarcts generated in corresponding controls (21 ± 16% versus 70 ± 16%). In addition, electroencephalographic (EEG) activity was preserved in all leukopenic animals when compared to controls, both during ischemia and after reperfusion. Both of these studies indicate a key role for white blood cells in the generation of cerebral damage after a cerebral ischemic insult.

Aprotinin, a nonspecific serine protease enzyme inhibitor with broad-spectrum antiinflammmatory properties, has been shown to decrease significantly such white cell activation and transmigration. In a clinical study of patients undergoing CPB, low-dose aprotinin administration was found to have an antiinflammatory effect similar to that of methylprednisolone in blunting release of systemic tumor necrosis factor- and neutrophil integrin CD11B upregulation, a marker of white cell activation, in comparison to untreated controls [36]. Additionally, in patients after major vascular surgery, activation of neutrophils manifesting as increased superoxide production and impaired chemotaxis has been shown to be significantly suppressed by aprotinin administration [37]. In CPB patients, aprotinin has also been shown to suppress the rise of the inflammatory mediator and leukocyte activator interleukin-6 during CPB in comparison to those in a control group [38]. Using intravital microscopy of rat omentum, suppression of leukocyte capillary transmigration by clinically relevant dosages of aprotinin has recently been demonstrated [39]. As discussed below, whether these factors are etiologic in the apparent decrease in stroke rate seen in cardiac surgery patients treated with full-dose aprotinin currently seems an intriguing, although speculative, hypothesis.

	Pharmacologic cerebroprotection

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
Although there has been a substantial number of different pharmacologic agents demonstrating cerebroprotective efficacy in various animal models, in the area of clinically effective pharmacologic cerebral protection there has been remarkably little progress to date. With the clinical demonstration of the role of CO₂ and pH-management during CPB in preserving or disrupting the relationship between cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO₂), and with the establishment of the concept of increased cerebral embolic delivery being both detrimental to CNS outcomes and variable as a function of changeable CBF/CMRO₂ relationships [40], many subsequent clinical therapeutic strategies can be understood as attempts to manipulate this relationship. Initial clinical approaches attempted to limit brain injury by mechanisms linked to decreases in CBF and CMRO₂.

In a randomized study by Nussmeier and colleagues [41] of 182 patients undergoing open-chamber cardiac surgery, a significant reduction in persistent neuropsychiatric dysfunction was reported after administration of high-dose thiopental titrated intraoperatively to induce EEG burst suppression. In a study of 300 patients undergoing closed-chamber CABG procedures, however, a trend toward an increased number of strokes was seen in similarly high-dose thiopental-treated patients (3.3%; 5 of 149) compared with the placebo group (1.3%; 2 of 151), as well as a significantly greater requirement for inotropic support and a delayed awakening in the treatment group [42]. Other clinical data had suggested that if there were any such thiopental-derived cerebroprotective effect, the mechanism might be due to a metabolically driven decrease in CBF, with a concomitant reduction in the delivery of emboli into the brain, rather than occurring primarily as a result of a decrease in CMRO₂ associated with EEG burst suppression [40, 43].

In an assessment of this hypothesis, 225 patients undergoing valvular heart surgery were randomized to receive either sufentanil or sufentanil plus propofol titrated to EEG burst suppression [44]. Blinded investigators performed neurologic and neuropsychologic testing at base line, on postoperative day (POD) 1 (neurologic testing only), POD 5 to 7, and POD 50 to 70. Electroencephalographic burst suppression was successfully achieved in all 109 propofol patients; however, these patients sustained at least as many adverse neurologic outcomes as the 116 controls: POD 1, 40% versus 25% (p = 0.06); POD 5 to 7, 18% versus 8%, (p = 0.07); POD 50 to 70, 6.2% versus 6.2%, (p = 0.80). No differences in the incidence of neuropsychologic deficits were detected either, with 91% of the propofol patients versus 92% of the control patients being impaired at POD 5 to 7, decreasing to 52 and 47%, respectively, by POD 50 to 70. As well, no significant differences in the severity of neuropsychologic dysfunction, depression, or anxiety were noted. These authors concluded that EEG burst suppression surgery with propofol during cardiac valve replacement did not significantly reduce the incidence or severity of neurologic or neuropsychologic dysfunction, suggesting that neither cerebral metabolic suppression nor reduction in cerebral blood flow reliably provide neuroprotection during open heart surgery.

An alternative approach has assessed the cerebroprotective efficacy of calcium antagonists ostensibly acting to decrease ischemic brain injury by limiting ischemia-induced neuronal calcium entry and cell death. Again, initial results were promising. In a small study of 35 patients undergoing CABG or valvular heart surgery, the ability of nimodipine, a dihydropyridine calcium antagonist, to preserve neuropsychometric function after CPB when administered at a dosage of 0.5 µg · kg^-1 · min^-1, was assessed using a battery of cognitive tests preoperatively and at 5 days and 6 months postoperatively [45]. Significantly better postoperative cognitive functioning on tests of verbal fluency and visual retention was observed at 6-month follow-up in nimodipine-treated patients in comparison with the control group. Unfortunately, in a much larger double-blind, randomized clinical trial in patients undergoing cardiac valve replacement (which was designed to determine whether nimodipine reduced the risk of new neurologic, neuroophthalmologic, or neuropsychologic deficits 1 week, 1 month, and 6 months after surgery), enrollment of the total 400 patients had to be stopped prematurely, with only 150 patients randomized to the study [46]. The trial was terminated early because of both an unexpected disparity in death rates between groups and a lack of evidence of a beneficial effect of nimodipine. New deficits were observed in 72% of the placebo group versus 77% of the nimodipine group (p = 0.55). In the 6-month follow-up period, 8 deaths (10.7%) occurred in the nimodipine group (n = 75), compared with 1 death (1.3) in the placebo group (n = 74) (p = 0.02). Major bleeding occurred in 10 patients in the nimodipine group versus 3 in the placebo group (13.3% versus 4.1%; p = 0.04). Six (46.2%) of the 13 patients with major bleeding died compared with 3 (2.2%) among the 136 patients without major bleeding. The authors concluded that their findings added to the growing evidence that calcium antagonists have a prohemorrhagic effect in some patients, and suggest that nimodipine use be restricted perioperatively in patients scheduled for cardiac valve replacement.

The failures seen in virtually all of the previously mentioned clinical trials make the aprotinin-related data discussed below all the more compelling. In a post hoc analysis of 816 CABG patients from a recent multicenter study assessing aprotinin and graft patency [47], patients were separated into those receiving more than 300 mL of shed blood versus those receiving none, and were analyzed for perioperative CVA [48]. This analysis demonstrated a strong drug effect, with aprotinin administration being associated with a significantly (p = 0.04) lower overall incidence of stroke, not only blood loss and transfusion 1.1% compared with an incidence in placebo-treated patients of 2.6%. Overall, in placebo patients, return of shed blood increased the risk of CVA more than three-fold (3.1% versus 0.0%), whereas aprotinin therapy was not associated with increased risk of CVA independent of whether retransfusion was involved (1.1% versus 1.2%). Furthermore, only 18% of aprotinin-treated patients had more than 300 mL of shed blood returned, compared with 46% of the placebo group. These data further support the premise that the return of shed blood has a negative effect on patient outcome, and that aprotinin both decreases the risk of receiving such shed blood and also appears to ameliorate the CNS effects of such transfusion, possibly related to its antinflammatory properties [49, 50].

Further support for this hypothesis comes from a recent metaanalysis [51] of seven placebo-controlled, randomized, double-blind studies of CABG patients receiving full-dose aprotinin or placebo [52–58]. The rationale for combining these data rests on the low percentage of patients who experience stroke, rendering no single study large enough to detect differences between groups given the low occurrence of such a relatively rare event. Therefore, combining data across studies increases the ability to detect meaningful differences between groups. The metaanalysis contained data from 1,867 placebo and full-dose aprotinin patients.

A significantly lower incidence of stroke was found in aprotinin-treated patients in both this and a previous metaanalysis from this earlier database [51, 59]. In the prior metaanalysis of Smith and Muhlbaier [41], 2.4% of the placebo group experienced stroke compared to only 1.0% in the treatment group [59]. The most recent study showed an incidence of cerebrovascular accident as an adverse event, of 4.2% versus 0% in patients valid for safety analysis [58]. Results from data combined across all studies are shown in Table 1.

One fundamental issue remains to be considered, however: namely, that these results are all derived from post hoc data analyses. In none of these studies was stroke reduction a primary outcome variable. Given the size requirements of such a trial, that is understandable. Still, some unknown bias may have occurred in the classification of these patients. The manner in which this bias would affect these results is not readily apparent, however. So, although compelling, these data cannot as yet be considered definitive. Nevertheless, given the data relating to the antiinflammatory activity of aprotinin, coupled with the demonstrated role of inflammation and white cell activation in ischemic brain injury, a cerebroprotective effect of aprotinin can be seen as an increasingly attractive hypothesis.

	Summary

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
As we gain further insight into the mechanisms of perioperative CNS injury associated with cardiac surgery, it is apparent that we cannot continue to perform these procedures as they were originally developed: for much younger patients, with much less systemic atherosclerotic burden and much lower overall risk acuity. For improvements, the widespread adoptation of EAS and appropriate surgical modifications could be expected to decrease the perioperative stroke rate by up to 50% virtually overnight [16]. Various other recommendations for the management of the high-risk patient can be supported from the literature and are included in Table 2.

	Footnotes

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 
Dr Murkin discloses that he has a financial relationship with Bayer Corporation, Cardeon Corporation, and EMBOL-X.

	References

Top Footnotes Abstract Introduction Atheroemboli Detection of aortic... Atheroemboli: capture or... Microemboli Systemic inflammatory response Pharmacologic cerebroprotection Summary References

 

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