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Eur J Cardiothorac Surg 2008;33:560-565. doi:10.1016/j.ejcts.2008.01.012
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Prediction of cognitive dysfunction and patients’ outcome following valvular heart surgery and the role of cerebral oximetry

Seong Wook Honga, Jae Kwang Shima,b, Yong Seon Choia, Dae Hee Kimc, Byung Chul Changd, Young Lan Kwaka,b,*

a Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 134 Shinchon-Dong, Seadaemun-Ku, Seoul 120-752, South Korea
b Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
c Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University of Medicine and Science, Incheon 405-760, South Korea
d Department of Thoracic of Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, South Korea

Received 16 October 2007; received in revised form 29 December 2007; accepted 8 January 2008.

* Corresponding author. Address: Department of Anesthesiology and Pain Medicine and Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Ku, Seoul, 120-752, South Korea. Tel.: +82 2 2228 8513; fax: +82 2 364 2951. (Email: ylkwak{at}yuhs.ac).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Objective: Postoperative cognitive dysfunction (POCD) commonly develops after cardiac surgery affecting patients’ outcome. Cerebral oximetry noninvasively measures regional cerebral oxygen saturation (rSO2) and significant correlation has been reported between intraoperative cerebral desaturation and POCD, as well as patients’ outcome following coronary artery bypass grafting. However, evidence is limited in valvular heart surgery (VHS). We investigated the relationship of intraoperative rSO2 values with POCD and length of postoperative hospitalization in patients undergoing VHS. Methods: One hundred patients undergoing elective VHS were enrolled. Neurocognitive evaluation was performed with Mini-Mental State Examination, Trail-Making Test (Part A), and Grooved Pegboard Test at 1 day before and 7th day after surgery. During surgery, rSO2 was continuously monitored and the incidence and duration of decrease in rSO2 values for five consecutive minutes were recorded as follows; (1) decrease in absolute rSO2 values to less than 50%, (2) 40%, and (3) a 20% decrease compared to baseline value. Results: Twenty-three patients (23%) demonstrated POCD. We could not observe any significant differences in either the incidence or duration of decrease in rSO2 values between patients with and without POCD. Low education level and higher baseline temperature had significant correlation with POCD. Patients with cerebral desaturation required significantly longer postoperative hospitalization. Conclusion: In patients undergoing VHS, POCD could not be predicted with cerebral oximetry. However, patients with intraoperative cerebral desaturation required significantly longer postoperative hospitalization and cerebral oximetry appears to be promising in terms of monitoring the brain as the index organ for systemic perfusion and improving patients’ outcome.

Key Words: Valvular heart surgery • Cognitive dysfunction • Cerebral oximetry


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Despite advances in surgical and anesthetic techniques over the years, postoperative cognitive dysfunction (POCD) and neurologic deficit related to cardiopulmonary bypass (CPB) continues to be a problem affecting patients’ outcome [1]. Those are diverse from permanent, such as stroke, to transient, such as intellectual dysfunction, confusion and/or memory deficits. Among them, neurocognitive decline in the early postoperative period is a commonly occurring phenomenon with an incidence varying from 30% to 60% [2]. The most commonly cited etiologies of POCD are embolization and hypoperfusion of the brain [3]. Other reported risk factors for POCD in patients undergoing coronary artery bypass graft surgery (CABG) are systemic inflammation, advanced age, low education level, diabetes, severity of atherosclerotic disease and type of surgery [4]. Although the type of cardiac surgery has been known to affect the prevalence of POCD [5] , knowledge with regard to POCD in valvular heart surgery (VHS) is limited [6]. In addition to the risk factors for POCD in CABG patients, patients undergoing VHS face the problem of intracardiac air and tissue debris and their potential for systemic embolization, thus are more prone to development of POCD [7].

Transcranial near-infrared spectroscopy (NIRS) provides a continuous and noninvasive monitoring of regional cerebral oxygen saturation (rSO2) [8] and recent studies have shown a significant relationship between cerebral desaturation and development of POCD in patients undergoing CABG [9]. Furthermore, using the brain as the index organ, significant correlation has been demonstrated between cerebral desaturation and major organ dysfunctions as well as length of postoperative hospitalization in patients undergoing CABG [9]. However, evidence is lacking with regard to the association of intraoperative rSO2 with patients’ outcome and POCD using structured cognitive testing, following VHS.

We therefore evaluated the development of POCD using neurocognitive function tests in patients undergoing VHS and its association with rSO2 as measured with bifrontal NIRS. Also, we evaluated the relationship between cerebral desaturation and length of postoperative hospitalization as a parameter of patients’ overall outcome in a prospective trial.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1 Patients
This study was approved by the ethics committee of our institution and written informed consent was obtained from all patients. A total of 103 consecutive patients scheduled for elective VHS between August 2006 and July 2007 were included in this prospective observational study. Patients with a history of stroke or psychiatric illness, alcoholism, and carotid artery stenosis over 60% narrowing by carotid duplex ultrasonography scans and who refused the neurocognitive test were not included.

2.2 Anesthetic and CPB management
All patients received a standardized anesthetic and CPB management. In the operating room, 5-ECG leads were attached and leads II and V5 were continuously monitored. A 20-G radial artery catheter was inserted to measure arterial blood pressure and arterial blood gas. A thermodilutional pulmonary artery catheter (Swan-Ganz CCOmbo CCO/SvO2TM, Edwards Lifesciences LLC, Irvine, CA) for continuous cardiac output (CO) and mixed venous oxygen saturation (SvO2) monitoring was inserted into the right internal jugular vein via a 9.0-Fr introducer (AVA HFTM, Edwards Lifesciences LLC, Irvine, CA). Anesthesia was induced with midazolam 0.04–0.05 mg kg–1, sufentanil 1.0–1.5 µg kg–1, and rocuronium 50 mg. After endotracheal intubation, methylprednisolone 20 mg kg–1 was administered to all patients. For anti-fibrinolysis, either aprotinin 2 mKIU or tranexamic acid 6 g was used at the discretion of the attending physician. Anesthesia was maintained with continuous infusion of sufentanil (2–3 µg kg–1 h–1), rocuronium (20–30 mg h–1) and isoflurane (less than 0.5%) in oxygen (50%) with air. A TEE probe was inserted to monitor myocardial performance; determine the severity of atherosclerosis of aorta [10]. Arterial oxygen saturation, nasopharyngeal and rectal temperatures were monitored during the study. Mechanical ventilation was controlled to maintain normocarbia (PaCO2 4.7–5.0 kPa) throughout surgery except during CPB when a continuous positive airway pressure of 5 cmH2O with 50% oxygen was applied. CPB was instituted with a membrane oxygenator primed with 1.5 l of crystalloid solution, and boluses of sufentanil 1.5 µg kg–1 and midazolam 0.05 mg kg–1 were administered through the venous reservoir. Body temperature was cooled to 33–34 °C. Acid–base management was performed with {alpha}-stat method and target range for PaO2 was 200–300 mmHg. A non-pulsatile pump flow rate was maintained at 2.0–2.5 l min–1 m–2 and blood cardioplegic solution was used. At the beginning of rewarming, additional boluses of sufentanil 1.5 µg kg–1 and midazolam 0.05 mg kg–1 were administered. Rewarming rate was around 1 °C every 5 min and arterial inflow temperatures did not exceed 37 °C. After the completion of the surgical procedure and systemic rewarming (rectal temperature of at least 35 °C), patients were weaned from CPB. Before weaning from CPB as well as opening of cross-clamp, careful de-airing was performed with air-vents in the left heart and the ascending aorta under repeated inflation of the lungs. This was confirmed by TEE. During surgery, a CO2 diffuser was placed 5 cm below the wound-opening adjacent to the diaphragm and the CO2 flow was set at 10 l/min. During CPB, mean arterial pressure (MAP) was maintained between 60 and 80 mmHg using phenylephrine, norepinephrine or sodium nitroprusside. The threshold for transfusion of packed red blood cell was a hematocrit less than 20% during CPB, and 25% after CPB.

2.3 Physiologic variables measurement
Physiologic variables including SvO2, PaCO2, PaO2, glucose, hematocrit, cardiac index, MAP, and nasopharyngeal temperature were measured before (T1, baseline) and 15 min after the start of CPB (T2), 10 min after rewarming (T3), after CPB (T4), and after sternum closure (T5). rSO2 was continuously monitored using the INVOS 5100 (Somanetics, Troy, MI) with bifrontal placement of two sensors before the induction of the anesthesia until the end of operation. Baseline rSO2 was defined as the average saturation value over a 1 min period before induction of general anesthesia beginning approximately 3 min after the sensors were applied. Surgeons, anesthesiologists and perfusionists were blinded to the measurement of rSO2 so that no interventions were made according to rSO2 values. Cerebral oxygen saturation values were evaluated with regard to three cutoff points that should reflect critically low oxygenation. The incidence and duration of decrease in rSO2 values (cerebral desaturation) were recorded as any of the three following values for more than five consecutive minutes; (1) decrease in absolute rSO2 values to less than 50%, (2) decrease in absolute rSO2 values to less than 40%, and (3) a 20% decrease compared to individual baseline value [11].

2.4 Neurologic and neuropsychologic assessment
All patients underwent a battery of neurologic and neuropsychologic tests the day before operation and 7 days after the surgery. Cognitive functioning was assessed with the following test: Mini-Mental State Examination (MMSE); Korean Trail-Making Test (part A, TMT-A); and Grooved Pegboard (GP) test. MMSE tests the neurocognitive function such as orientation, registration, attention and calculation, recall and language. TMT-A and GP test examine attention and complex visual-motor coordination. Since the most frequently reported deficits related to surgery with CPB are those of concentration, memory, and learning, and speed of visual-motor response [12], the above neurocognitive function tests were selected in this study. TMT and GP test are recommended for postoperative cognitive function tests in the 1995 Consensus on Neurobehavioral Assessment [13]. POCD was defined as impairment in one or more of the three tests as; (1) a decrease in MMSE score ≥3 points from baseline, (2) 20% increase in time to complete the TMT-A and GP test, compared to baseline. POCD was defined as impairment in one or more of the three tests. To avoid any influence of biorhythm alteration, all neurocognitive function tests were performed in the evening under comparable conditions by the same physician. Patients were divided into two groups according to the presence or absence of cognitive dysfunction.

2.5 Statistical analysis
Data were analyzed with SPSS (version 11.5, SPSS Inc., Chicago, IL) and expressed as mean (standard deviation) or number of patients. For rSO2 data analysis, the time below the three cutoff points was assessed for each hemisphere, and the mean of both measures was calculated for an individual patient. Analyses between the patients with and without POCD were performed using {chi} 2-test or Fisher's exact test for categorical variables, unpaired t-test or Mann–Whitney U-test for continuous variables. Multivariate analysis of predictors for POCD was assessed with logistic regression. A p value less than 0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
Postoperative neurocognitive function tests could not be performed in three patients, because they were still on ventilatory care. Data from these three patients were excluded for analysis, and thus data from 100 patients were evaluated. Twenty-three patients (23%), 1 at MMSE test and TMT-A test, 10 at TMT-A, 10 at GP test, and 2 at both TMT-A and GP test, demonstrated POCD. There were no differences between patients with and without POCD in age, sex, height, weight, educational level, left ventricular ejection fraction, duration of CPB and aortic cross-clamping, combined disease, and in-hospital stay, except hypertension was more frequent in the patients without POCD (Table 1 ).


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  		Table 1 Patient characteristics
 
Perioperative cognitive function test scores are shown in Table 2 .


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  		Table 2 Perioperative cognitive function test scores according to neurocognitive function
 
PaCO2 was significantly lower in at T3 and T4 and PaO2 was significantly higher at T4 and T5 in the POCD patients than in the normal patients. Mean arterial pressure was significantly higher at T3 in the POCD patients than in the normal patients. Baseline temperature was significantly higher in the POCD patients than in the normal patients. Remaining hemodynamic variables and arterial blood gas analyses showed no differences between patients with and without POCD (Table 3 ).


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  		Table 3 Hemodynamic data are presented as mean ± standard deviation
 
The incidence and duration of decrease in rSO2 values below the predefined three cutoff values for more than five consecutive minutes were similar between patients with and without POCD (Table 4 ). In a multivariate logistic regression analysis, lower education level and higher baseline body temperature were significant preoperative predictors for POCD (Table 5 ). Development of cerebral desaturation was not associated with the development of POCD.


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  		Table 4 Incidence and duration of decrease in rSO2 below critical values
 

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  		Table 5 Analysis of risk factors in relation to postoperative neurocognitive dysfunction
 
There were no differences in cognitive function scores between patients without and with intraoperative reduced rSO2 values below the predefined three cutoff values for more than five consecutive minutes (Table 6 ). In comparisons between patients without and with intraoperative cerebral desaturation, baseline rSO2 value (67 ± 8% vs 61 ± 10%, p = 0.002) and postoperative hematocrit level (27.0 ± 3.1% vs 25.2 ± 2.8%, p = 0.010) were significantly lower in patients with intraoperative cerebral desaturation. Remaining preoperative and intraoperative data were similar between the groups. Hospital stay (13 ± 5 days vs 16 ± 10 days, p = 0.046) was significantly longer in patients with intraoperative cerebral desaturation.


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  		Table 6 Perioperative cognitive function test scores according to rSO2
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
In the current study with patients undergoing isolated VHS, we could observe that cerebral desaturation as assessed with NIRS had no significant correlation with development of early POCD, whereas lower level of education and higher baseline body temperature were significant risk factors for POCD. However, patients with cerebral desaturation required significantly longer postoperative hospitalization.

POCD following cardiac surgery is one of frequently reported complications affecting patients’ postoperative outcome. The etiology of POCD can be multifactorial with the most commonly cited etiologies being embolism and hypoperfusion related to CPB affecting cerebral oxygen supply–demand balance [3]. Of the neurological monitoring techniques available to detect cerebral oxygen supply–demand balance during cardiac surgery, NIRS allows continuous, noninvasive, and bedside monitoring of rSO2 and provides information on the occurrence of cerebral desaturation that is as accurate as information obtained by means of invasive techniques [14]. It is particularly useful during non-pulsatile CPB, since it does not require arterial pulsation. Accordingly, use of NIRS during cardiac surgery has been expanded, and the results of various clinical trials are contradictory. Novitzky has reported that the prevalence of cerebral complications can be reduced by maintaining cerebral oxygen saturation above 80% of baseline value, and maintaining its absolute value 50% or above [15]. Yao et al. showed significant correlation with intraoperative desaturation and POCD and that areas of rSO2 <40% were the only predictor for POCD by multivariate logistic regression analysis [16]. Although the risk of air and/or tissue debris embolism is obviously greater in intracardiac operations and VHS was reported to have higher incidence of POCD than CABG [6,17], currently available evidence with regard to cerebral desaturation and POCD are mostly confined to CABG. As to the results of our study, we could not observe any significant correlation between cerebral desaturation and POCD following VHS. Furthermore, in spite of frequent development of cerebral desaturation, there were no differences in the frequency and duration of cerebral oxygen desaturation between patients with and without POCD. These results are in accordance with the study by Reents et al. They evaluated the ability of cerebral oximetry to predict the incidence of neurological problems or the postoperative cognitive performance of patients using various cutoff values, but did not find significant differences between patients with cerebral oximetry measurements above or below cutoff values [18]. Possible explanations include differences between focal and global brain saturation, as NIRS only measures rSO2 of the watershed zone of the anterior and middle cerebral artery [19]. Also, changes in the ratio between arterial/venous blood might have affected the result. NIRS measures rSO2 upon assumption that 75% of blood flow is composed of venous blood [19]. Although we used tepid hypothermia and {alpha}-stat pH management during CPB, the response of cerebral arterial and venous vasculature to cooling and warming might have been different and resulted in changes in the ratio between arterial/venous blood [20]. Therefore, although some studies found a correlation between low rSO2 and poorer cognitive outcome in cardiac surgery, low specificity and an obscure threshold of rSO2 that is critical with respect to POCD are important limitations of this monitor.

Recently, however, Murkin et al. reported that therapeutic efforts to avoid cerebral desaturation as assessed with rSO2 is associated with significantly fewer incidences of major organ dysfunction, shorter length of stay in the intensive care unit and a trend to fewer patients having prolonged hospitalization, in patients undergoing CABG with CPB [9]. Although we did not make interventions to avoid cerebral desaturation in this study because of concomitant investigation for the relationship between rSO2 and POCD, patients who experienced intraoperative cerebral desaturation required significantly longer postoperative hospitalization. As Murkin et al. discussed, optimal cerebral perfusion monitored by cerebral oximetry might be possible to demonstrate similarly optimal systemic perfusion and result in a beneficial effect on the patients’ outcome. Whether interventions to avoid cerebral desaturation result in improved patients’ outcome in patients undergoing VHS merits further clinical investigations. Upon our result regarding the length of postoperative hospitalization, NIRS monitoring appears to be of clinical benefit in terms of using the brain as the index organ for systemic perfusion.

Disparities in the prevalence and incidence of POCD exist in various studies and are attributable to patients’ characteristics, type of surgery, and how and when deficits are measured [1,5,21]. Compared to the results of previous studies, the incidence of POCD in this study was lower. When considering that history of neurologic disease, advanced age, a higher degree of atherosclerosis and carotid artery stenosis are well known risk factors POCD [1], relatively younger age and lower degree of atherosclerosis of the patients and exclusion of patients with history of neurologic disease and significant carotid artery stenosis may account for the low incidence of POCD observed in this study. In addition, insufflation of CO2 into the thoracic cavity is associated with marked decrease in the incidence of microemboli in patients undergoing VHS [22]. The beneficial effect of confirming complete de-airing with intraoperative TEE before removal of air-vents on the development of POCD is also well known [23]. In the current study, both CO2 insufflation and confirmation of complete de-airing with TEE were done in every patient and these maneuvers may also have significantly reduced the incidence of POCD. Although aprotinin has been used in 50 patients, the dosage used was well below 6 mKIU. Since lower dosage of aprotinin was not associated with improved patients’ neurologic and overall outcome, this should not have any influence on our results [24].

Interestingly, higher baseline body temperature was the strongest risk factor for POCD in this study along with lower level of education on multivariate logistic regression analysis. Whether the patients with higher baseline body temperature were in proinflammatory state and had more pronounced systemic inflammation perioperatively was not assessed in this study. Regarding the relationship between metabolic imbalance caused by systemic inflammatory reaction and psychomotor slowing [25], further evaluation for the effect of perioperative inflammatory state and body temperature on POCD seems to be required.

The limitation of this study is as follows. Although all patients were managed according to standard practice of our institution in the postoperative period by physicians blinded of this study, rSO2 was not monitored in the immediate postoperative period. Cerebral desaturation might have occurred during this period, which may have resulted in POCD.

In conclusion, POCD could not be predicted with intraoperative NIRS monitoring in patients undergoing VHS. Only a lower level of education and higher baseline body temperature had significant correlation with POCD. However, patients with intraoperative cerebral desaturation required significantly longer postoperative hospitalization and NIRS appears to be promising in terms of monitoring the brain as the index organ for systemic perfusion and improving patients’ outcome.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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