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Eur J Cardiothorac Surg 2001;19:611-618
© 2001 Elsevier Science NL

Neurological injury after surgery for ischemic heart disease: risk factors, outcome and role of metabolic interventions

Rolf Svedjeholma, Erik Håkansonb, Zoltán Szabób, Farkas Vánkya

a Department of Cardiothoracic Surgery, Linköping Heart Center, University Hospital, Linköping, Sweden
b Department of Cardiothoracic Anesthesia, Linköping Heart Center, University Hospital, Linköping, Sweden

Received 13 October 2000; received in revised form 7 February 2001; accepted 8 March 2001.

Corresponding author. Tel.: +46-13-22-20-00; fax: +46-13-10-02-46
e-mail: rolf.svedjeholm{at}lio.se


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Objectives: Neurological complication remains a feared and increasing problem in association with cardiac surgery. The aim of this study was to analyze risk factors for neurological complications in a cohort of patients in whom inotropes for weaning from cardiopulmonary bypass was gradually replaced by metabolic treatment. Methods: The records of 775 consecutive patients undergoing coronary artery bypass grafting (CABG) or combined CABG+valve procedures were examined. Forward stepwise multiple logistic regression analysis was used for statistical evaluation of independent risk factors. Results: The incidence of neurological injury was 1.8% in patients undergoing isolated CABG and 5.4% after combined CABG+valve procedures. After cross-validation multivariate analysis identified history of cerebrovascular disease, advanced age and aortic cross-clamp time as independent risk factors for postoperative cerebral complications. Chronic obstructive pulmonary disease and number of bypasses also emerged as risk factors in the primary analysis. Conclusions: In general, markers for advanced atherosclerosis, with history of cerebrovascular disease as the most important, emerged as predictors for neurological injury. Although it did not enter the final risk model, the results also suggest that postoperative heart failure deserves further surveillance as a potential risk factor for neurological complications. However, no evidence for untoward neurological effects associated with glutamate or glucose–insulin–potassium treatment was found.

Key Words: Neurological injury • Atherosclerosis • Cerebrovascular disease • Postoperative complications • Glutamate • Glucose • Cardiac surgery


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Neurological complication is a feared and increasing problem in association with cardiac surgery. Several risk factors have been identified with advanced age, history of cerebrovascular disease and combined coronary and valvular operations being the factors most consistently associated with stroke [1–6]. The mechanisms behind postoperative cerebral complications in cardiac surgery are multifactorial and include embolism of atherosclerotic debris in association with manipulation of the aorta or valve surgery, thromboembolic events, microembolism from the cardiopulmonary bypass (CPB) circuit and inadequate perfusion of the brain during CPB [2,6–8]. Also, metabolic aspects deserve consideration. Hyperglycemia has been claimed to aggravate the consequences of cerebral ischemia and should thus be avoided [9,10]. This has to be considered as glucose–insulin–potassium (GIK) is gaining reappraisal for treatment of acute myocardial infarction and for metabolic resuscitation and protection in cardiac surgery. Glutamate is an excitatory neurotransmitter in the brain that has been linked with the development of neurological injury [11,12]. In spite of this, glutamate is often used as an additive in cardioplegic solutions. In our practice, metabolic interventions with intravenous glutamate and high-dose GIK over a 5-year period gradually replaced inotropic drugs as the first line for treatment of postoperative heart failure (Fig. 1) [13]. In light of the concerns expressed, surveillance of this treatment was considered mandatory and, hence, our initial experience was registered in a database. This provided us with the opportunity to analyze a comparatively broad set of data (see Appendix A), including traditional and alternative measures for treatment and prevention of postoperative heart failure, as risk factors for cerebral complications.



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  		Fig. 1. Changing measures for treatment and prevention of postoperative heart failure during the study period. The percentage of patients given respective treatment is given on the Y-axis and the year of treatment is given on the X-axis. Additional details about metabolic interventions are given in Appendix A.

 

   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A
 References
 
2.1. Patients
A total of 775 consecutive patients undergoing coronary artery bypass grafting (CABG) or combined CABG+valve procedures were included in the study. Data were collected from the records and stored in a database. Post-discharge mortality data were retrieved from the Swedish Civil Registry and the outcome in patients with neurological injury records was investigated by retrieving records from referring hospitals. Demographic data are presented in Table 1.


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  		Table 1. Preoperative, intraoperative and postoperative data for the total cohort of patients and those with and without postoperative cerebral complicationsa

 
2.2. Clinical management
After an overnight fast and administration of their beta-blockers and calcium antagonists, the patients were premedicated with 4–10 mg oxicone and 0.2–0.5 mg scopolamine intramuscularly. Anesthesia was induced with thiopentone 1–2 mg/kg body weight (BW) and fentanyl 10 µg/kg BW. Pancuronium bromide was used for neuromuscular blockade. Anesthesia was maintained with fentanyl and isoflurane.

CPB was conducted with a membrane oxygenator and a roller pump generating non-pulsatile flow. Ringer's acetate and mannitol were used for priming the extracorporeal circuit. During the time frame of the study moderate hemodilution (hematocrit 20–25%) and moderate hypothermia (32–35°C) were employed. At normothermia the target CPB flow was 2.4 l/m2 body surface area and the target pressure was 60 mmHg. Antegrade or combined ante- and retrograde delivery of St. Thomas' cold crystalloid cardioplegic solution was used for myocardial protection. Weaning off CPB was started at a rectal temperature of 35–36°C. Heparin was neutralized with protamine chloride. Ringer's acetate was used for volume substitution postoperatively. Shed mediastinal blood was routinely retransfused in the intensive care unit. Postoperative rewarming was facilitated by radiant heat provided by a thermal ceiling. Postoperative anticoagulation routines during the study period are given in Appendix A.

The patients were operated by two surgeons. Perioperative management differed from traditional care by its increasing reliance on metabolic measures for treatment of postoperative heart failure. During the early part of the study period metabolic interventions were reserved for the most severe cases of postoperative heart failure [13]. Due to encouraging experience inotropes for weaning from bypass were gradually replaced by prolongation of CPB and metabolic interventions (Fig. 1 and Appendix A). During the latter part of the study period the following measures were undertaken in order, depending on the severity of heart failure: prolongation of CPB, intravenous glutamate, high-dose GIK, inotropic support and mechanical circulatory support. SvO2 and diuresis served as the main guidelines for assessment of the adequacy of the hemodynamic state, rather than cardiac output measurements [14]. The basic concepts and details regarding the metabolic interventions with intravenous glutamate and high-dose GIK have been reported previously [13,14].

2.3. Definitions
Complications presented refer to in-hospital events occurring at our institution. Neurological injury in this study included the following cerebral complications: (1) stroke; (2) depression of consciousness or confusion if associated with signs of cerebral injury on CT scan or focal neurological deficit; and (3) transient ischemic attacks with focal neurological deficit. The majority of patients with suspected neurological injury were examined by a neurologist and by CT scan. Cognitive dysfunction was not assessed. Perioperative myocardial infarction was diagnosed according to screening routines at our institution [14]. Patients were classified as having had postoperative heart failure if the hemodynamic state had warranted active measures directed at improving myocardial function such as prolonged CPB, metabolic, pharmacological or mechanical circulatory support. In general, this implied difficulty in weaning from CPB or deteriorating hemodynamics (usually decreasing SvO2 below 50–55% associated with either oliguria, decreasing arterial blood pressure or increasing atrial filling pressures) after weaning from CPB. A history of cerebrovascular disease was defined as previous stroke or transient ischemic attack, or prior surgical repair of or documentation of obstructive carotid disease (>=50%) on angiography or duplex ultrasound examination.

2.4. Statistical analysis
Data are presented as mean±standard deviation (SD). Non-parametric tests, the Mann–Whitney U-test and Fisher's exact test, were used for comparison of patients with and without postoperative cerebral complications. For evaluation of independent risk factors for postoperative cerebral complication, univariate logistic regression was first employed. Variables undergoing univariate analysis are given in Appendix A. Variables were tested in a stepwise forward multivariate logistic regression model if the univariate P value was less than 0.25. Due to the limited number of events cross-validation of the final model was undertaken. Statistical significance was defined as P<0.05. Statistical analyses were performed with a computerized statistical package (Statistica 5.5, StatSoft, Inc., Tulsa, OK).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A
 References
 
3.1. Neurological injury
Postoperative cerebral complications were observed in 1.9% of all patients and in 1.8% of the patients undergoing isolated CABG. Pre-, intra- and postoperative data in patients with and without cerebral complications are given in Tables 1 and 2.


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  		Table 2. Presentation of neurological injury and outcomes and their impact on hospital stay in individual patientsa

 
Data on the presentation of neurological injury in individual patients are given in Table 2. A delayed onset of neurological deficit with a free interval from the operative procedure was found in four out of 15 of the patients. One of these patients developed a stroke in close association with conversion of atrial fibrillation to sinus rhythm.

3.2. Outcome in patients with neurological injury (Tables 1 and 2)
Two patients died during primary hospitalization. One further patient died during rehabilitation. One-year mortality was 20.0% compared with 2.0% in patients without cerebral complications. The median duration for hospitalization including recovery stay at the referring hospital was 21 days. Complete or near complete recovery was reported in half of the surviving patients. In the remaining patients various residual symptoms were described in the records as presented in Table 2.

3.3. Risk factors for neurological injury
The patients with cerebral complications were on average 4 years older (69±11 years) compared with those without postoperative cerebral complications. A previous history of cerebrovascular disease was found in one-third and signs of advanced peripheral vascular disease or calcification of the ascending aorta on palpation were found in another third of the patients with cerebral complications (Table 2). The patients with cerebral complications also had more extensive coronary artery disease as indicated by a higher number of bypasses performed. Furthermore, the patients with cerebral complications had longer aortic cross-clamp time and CPB time, and postoperative heart failure and atrial fibrillation were more frequently encountered.

The incidence of cerebral complications was 3.5% in diabetics, 3.5% in patients with postoperative atrial fibrillation, 3.9% in patients aged 70 or older, 5.4% in patients undergoing combined valve and CABG procedures, 6.0% in patients with COPD and 8.2% in patients with a previous history of cerebrovascular disease.

According to forward stepwise multiple logistic regression analysis, a history of cerebrovascular disease was the most important risk factor for postoperative neurological injury. Advanced age, aortic cross-clamp time, the number of bypasses and history of COPD also emerged as independent risk factors (Table 3). Of these variables COPD and the number of bypasses did not resist cross-validation.


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  		Table 3. Multivariate forward stepwise logistic regression analysis of risk factors for cerebral complications after CABG and CABG+valve proceduresa

 
3.4. Neurological complications and treatment for postoperative heart failure
Cerebral complications occurred in 5.5% of all patients with signs of postoperative heart failure, in 12.5% of patients treated with inotropes for weaning from CPB, in 10% of patients treated with mechanical circulatory support, in 3.7% of patients treated with high-dose GIK and in 2.6% of patients treated with intravenous glutamate.

To address the potential role of postoperative heart failure as a risk factor for neurological injury, a model recalculation was undertaken by entering this variable to the final multivariate model. This yielded a risk model with an odds ratio (OR) of 2.7 (95% confidence interval (CI) 0.9–8.6, P=0.08) for postoperative heart failure. Repeated recalculation of this model (including postoperative heart failure) by separately entering each of the measures to treat or prevent postoperative heart failure resulted in the following ORs with respect to neurological injury: use of high-dose GIK, OR 0.3 (95% CI 0.1–1.7, P=0.16); use of intravenous glutamate, OR 0.3 (95% CI 0.1–2.0, P=0.23); inotropes for weaning from CPB, OR 1.8 (95% CI 0.3–11.6, P=0.51); and use of mechanical circulatory support, OR 2.1 (95% CI 0.2–25.3, P=0.56).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A
 References
 
To the individual patient stroke is a devastating complication and to the health care system it has major economic repercussions [15]. The incidence of cerebral complications after cardiac surgery varies depending on criteria, type of surgery and patient selection [1,5,6,8,16]. Due to an increasing number of elderly patients with co-morbidities undergoing cardiac surgery, cerebral complications are emerging as one of the main issues to address in this setting. Preventive strategies necessitate increased understanding of risk factors for stroke and other cerebral complications. Obviously, large-scale prospective studies can be expected to yield the most valid data regarding risk factors; however, in certain instances single institution data can contribute to the understanding if they permit assessment of strategies that are institution- or group-specific. Here risk factors for cerebral complications were analyzed in a unique cohort of patients in whom metabolic interventions over a 5-year period gradually replaced inotropic drugs as the first line for treatment of postoperative heart failure (Fig. 1). The metabolic interventions used were intravenous glutamate infusion and high-dose GIK. As concerns regarding untoward neurological effects of these interventions have been expressed it was considered warranted to evaluate if there was any evidence of such effects in clinical practice employing these therapies.

History of cerebrovascular disease emerged as the most important independent risk factor for postoperative cerebral complications [6,8,15,17,18]. Furthermore, advanced age, prolonged aortic cross-clamp time, COPD and number of bypasses emerged as independent risk factors in the multivariable analysis. COPD and number of bypasses did not resist cross-validation of the final multivariate model and, hence, their role should be interpreted cautiously. However, these findings deserve attention as other studies also suggest that these factors predict neurological injury after cardiac surgery [6,18,19]. Possible mechanisms behind the relationship between COPD and neurological complications include increased hemoglobin levels and carbon dioxide retention with associated changes in cerebral vasoreactivity [18,20]. The extent of coronary artery disease has been identified as a strong predictor for postoperative neurological injury [19]. This could reflect the degree of associated systemic atherosclerotic disease but also a relationship between the extent of coronary disease and postoperative heart failure (the latter being associated with a three-fold increase in the incidence of stroke) has been described [19].

Although it did not enter the final risk model our results also suggest that postoperative heart failure is a potential risk factor for neurological complications. Further support has been provided by more recent data showing the need for inotropes to be a risk factor for neurological injury [6]. Moreover, other investigators have found the combination of atrial fibrillation and low output syndrome to predict delayed strokes [8]. In our study, patients treated with inotropes for weaning or mechanical circulatory support had a higher incidence of neurological complications, which considering the employed strategy suggests that the severity of postoperative heart failure could play a role in the risk of developing neurological injury. No evidence or tendencies suggesting an increased risk for neurological complications associated with the use of intravenous glutamate or high-dose GIK were found.

The concerns regarding the potential neurotoxicity of glutamate have been based on animal experimental data mainly obtained in rodents [11,12]. However, in primates glutamate does not pass the blood brain barrier and exogenous glutamate has therefore not been shown to cause cerebral injury [12]. In cardiac surgery, the possible influence of CPB on the blood brain barrier has to be considered. As the cerebral concentration of glutamate is reported to be 50–100 times higher than in blood it is essential that results are interpreted in relation to the dosages applied [12,13]. The dosages of glutamate employed here were moderate and have been reported to cause two- to three-fold elevations of whole blood levels [12]. The present study supports the safety of such dosages but obviously further surveillance is warranted. The situation regarding GIK is related to the quality of blood glucose management. Both hypoglycemia and hyperglycemia are potentially hazardous to the brain. Our database did not include results of blood glucose measurements and, hence, further studies with respect to blood glucose management are warranted. Furthermore, assessment of the extent of neurological injury would have been desirable as the major concern with hyperglycemia is aggravation of existing injury [9,10]. Currently it seems that GIK can be safely used in cardiac surgery provided that blood glucose management is adequate. In fact, properly managed it can be used to improve blood glucose control, which potentially could have a beneficial effect on the outcome of neurological injury [21].

One further observation related to the treatment of postoperative heart failure is the discrepancy regarding CPB time and aortic cross-clamp time as risk factors for neurological injury. Previous studies have identified CPB time as a risk factor [6,8,17,22]. Potential hazards associated with CPB include hypoperfusion, microembolism and inflammatory response [23]. Furthermore, prolonged CPB can be a marker of a complicated procedure or a more severe state of postoperative heart failure [6]. In our multivariable analysis, aortic cross-clamp time was found to be an independent risk factor for neurological injury. However, CPB time did not emerge as an independent risk factor although CPB time was longer in the group of patients with neurological injury. The diverging results could be explained by the employed strategy, which was adopted due to concerns that premature termination of CPB with the aid of inotropes in postoperative heart failure can delay myocardial recovery and lead to more severe states of heart failure. Consequently, prolonged reperfusion of the heart on CPB (together with metabolic support) was used as the first line of treatment in postoperative heart failure and therefore usually did not reflect a severely compromised hemodynamic state or a complicated procedure. Given the circumstances, an extended aortic cross-clamp time more likely reflected a complicated procedure or advanced atherosclerotic disease. An extended aortic cross-clamp time obviously also prolonged the CPB time and with regard to the potential hazards associated with CPB it can be speculated that extra-corporeal perfusion during cardiac arrest may be less adequate for the brain. In fact, it has recently been suggested that the quality of pulsatile flow may be important for brain perfusion during CPB [24].

In individual patients the cause for neurological injury may occasionally be identified with reasonable certainty. One of the patients with postoperative heart failure and neurological injury had been resuscitated immediately prior to surgery, which illustrates that preoperative hemodynamic state also deserves consideration. One patient with recurrent atrial fibrillation developed a stroke in close association with conversion from atrial fibrillation to sinus rhythm. However, atrial fibrillation did not emerge as an independent risk factor although it was more common in patients with neurological complications. This association can be explained by the age distribution but it is noteworthy that other investigators have identified atrial fibrillation as a risk factor for stroke [7,8]. This issue and the observation that more than one-fourth of the neurological complications presented a few days after surgery suggests that coagulative state could play a role in the development of this complication. Interestingly, two of the surviving 12 patients developed pulmonary emboli (Table 2). It remains to be clarified if improved anticoagulation protocols could help to reduce the risk for late neurological events.

Retrospective studies generally yield a lower incidence of neurological complications as compared to prospective studies [2,4]. Furthermore, the reported complications refer to events during hospitalization at our hospital and events after discharge may have been missed [4,8]. Thus, although the study included 775 procedures it was small considering the incidence of neurological complications. The limited number of events renders multivariate analysis susceptible to misclassification and as false positive diagnosis can be expected to have a more pronounced influence only patients with certain neurological injury were included. These circumstances also explain the wide CIs obtained and, hence, ORs should be interpreted cautiously. Cross-validation of the model supported the validity of the main risk factors and the overall incidence of cerebral complications did not differ markedly from the previous studies. Also, other variables traditionally associated with neurological complications such as combined CABG+valve procedures and diabetes, that did not emerge as independent risk factors, exhibited an incidence of neurological injuries in agreement with recent large-scale studies [4,6]. It is conceivable that history of cerebrovascular disease, advanced age, aortic cross-clamp time and extent of coronary disease all to some extent constitute markers for advanced atherosclerotic disease.

Several measures that have been introduced in recent years to prevent neurological injury appropriately address atheromatous disease of the ascending aorta [25]. Epiaortic scanning of the ascending aorta by ultrasound can identify patients with atherosclerotic aortas and provide guidance in the choice of strategy [8]. Manipulation of the aorta can be reduced by a single-clamp technique or avoided by off-pump surgery on the beating heart [25,26]. Use of intra-aortic filtration to capture particulate emboli in association with CPB is another measure that deserves evaluation [27]. Epiaortic scanning of the ascending aorta was not available at our institution during the study period. Since its introduction measures to reduce or avoid manipulation of the aorta are frequently undertaken. Further studies are warranted to address the impact of these strategies on neurological outcome.

To conclude, our results support previous findings suggesting history of cerebrovascular disease to be the most important risk factor for postoperative cerebral complications and in general identify markers for advanced atherosclerotic disease to be of importance. Use of intravenous glutamate and high-dose GIK did not increase the risk for neurological injury.


   Acknowledgments
 
The authors thank Mats Fredriksson from the Department of Occupational and Environmental Medicine at Linköping University for expert statistical advice. The authors are also grateful to Inger Huljebrant and Ingemar Vanhanen for assistance with the collection of data.


   Appendix A
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
References
 
A.1. Data tested in the univariate analysis
The following data were tested in the univariate analysis: age, sex, 1-2-3 vessel disease, left main stenosis, history of myocardial infarct, number of infarcts, history of recent infarct (<4 weeks), history of previous cardiac surgery, left ventricular ejection fraction, unstable angina, hypertension, diabetes mellitus, chronic obstructive lung disease, history of cerebrovascular disease, peripheral vascular disease, preoperative s-creatinine, number of bypassed vessels, use of left internal thoracic artery, redo-procedure, associated valve procedure, aortic cross-clamp time, duration of CPB, postoperative heart failure, need for inotropes for weaning from CPB, need for mechanical circulatory support, use of glutamate, use of GIK, mixed venous oxygen saturation on arrival to the intensive care unit, perioperative myocardial infarction and postoperative atrial fibrillation.

A.2. Postoperative anticoagulation routines during the study period
CABG patients were given 500 mg acetylsalicylic acid (ASA) rectally 8 h after surgery and thereafter 160 mg ASA orally every day. Heparin (5000 IU) was given subcutaneously three times daily until the patients were fully mobilized. After valve replacements warfarin treatment was started on the first postoperative day. Heparin (7500 IU) was given subcutaneously three times daily (starting 12 h postoperatively) until the prothrombin level had reached the therapeutic level.

A.3. Metabolic interventions during the study period
The changing measures for treatment and prevention of postoperative heart failure are given in Fig. 1. Overall inotropes for weaning from CPB were used in 24 patients (3.1%) and metabolic support was given to 148 patients (19.1%). Glutamate was used in 117 patients (15.1%), in 65 patients (8.4%) as treatment for perioperative heart failure and in the remaining cases prophylactically because of severe myocardial ischemia or for study purposes. High-dose GIK was given to 82 patients (10.6%) mainly because of cardiac failure on weaning from CPB. Seventy of these patients also received glutamate infusion.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 

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Q. Chen, E. Ma, K. L. Behar, T. Xu, and G. G. Haddad
Role of Trehalose Phosphate Synthase in Anoxia Tolerance and Development in Drosophila melanogaster
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