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Ann Thorac Surg 2005;79:666-671
© 2005 The Society of Thoracic Surgeons
a Department of Cardiovascular Surgery, School of Medicine, Gazi University, Ankara, Turkey
b Department of Cardiovascular Surgery, School of Medicine, Ondokuz Mayis University, Samsun, Turkey
c Department of Cardiovascular Surgery, State Hospital of Samsun, Samsun, Turkey
d Department of Biochemistry, School of Medicine, Fatih University, Ankara, Turkey
Accepted for publication August 4, 2004.
* Address reprint requests to Dr Iriz, Gazi University Tip Fakültesi Kalp ve Damar Cerrahisi AD Besevler, Ankara 06500, Turkey
(E-mail: erkaniriz{at}hotmail.com).
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Abstract |
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METHODS: Patients were randomized into two groups. Open heart surgery was performed by using hydroxyethyl starch solution in group 1 (n = 15) and Ringer lactate solution in group 2 (n = 15). Preoperative, perioperative, and postoperative S-100ß protein levels and informative cognitive test scores, clinical and operational characteristics of the patients were compared.
RESULTS: A significant difference was found only between preoperative and postoperative results of verbal accuracy (human) test in group 1, whereas differences between preoperative and postoperative scores of continuous skill, verbal accuracy (human), verbal accuracy (animal), verbal accuracy (human–animal), go-no-go paradigm, calculation, and abstract thinking tests were significant in group 2 (p 
0.05). The S-100ß protein levels were not significantly different between the groups (group p = 0.97).
CONCLUSIONS: Because hydroxyethyl starch prime solution used in extracorporeal circulation had significant positive effects with informative–cognitive tests when compared to Ringer lactate solution, it seems to be a better prime solution to prevent cerebral dysfunction in these patients.
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Introduction |
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Hydroxyethyl starch solution is an artificial colloidal solution, and it causes transport of water into intravascular space through hyperosmolarity. It was demonstrated that hydroxyethyl starch (HES) inhibited leukocyte adhesion and chemotaxis and decreased vascular permeability in endothelial tissue [5].
Cerebral ischemia due to microemboli or macroemboli, systemic inflammatory response, and cerebral hypoperfusion during cardiopulmonary bypass (CPB) causes impairment in the blood brain barrier. Therefore, S-100ß protein formed due to cerebral injury leaks through the blood brain barrier into the cerebrospinal fluid and blood circulation. Serum level of S-100ß protein is used as a marker to determine the degree of cerebral injury that may occur during CPB [6, 7].
During CPB, edema can develop in all tissues including the brain. We believe that the solution used as prime solution must have a high oncotic pressure (HES, albumin, and so forth). These kinds of solutions prevent the capillary leakage that causes fluid loss into third space and formation of tissue edema due to low oncotic pressure developed during CPB. Solutions like HES, which prevent the leukocyte adhesion and chemotaxis, and decrease the vascular permeability in the brain tissue [8], can prevent the activation of inflammatory process during CPB as well as the following leukocyte activation and tissue edema.
Hydroxyethyl starch (a colloidal and hyperosmotic) and Ringer lactate (RL) (a crystalloid and isotonic solution) were used as prime solutions in the present study. We aimed to compare the cerebral protective effects of HES and RL solutions in CPB using serum S-100ß protein levels and informative cognitive tests.
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Material and Methods |
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Preoperative and postoperative neurologic examinations were performed by the same neurologist. The neurologic tester was a single individual who was double blinded to both the prime solution used and to the group of patients. The patients were divided into two groups according to numbers selected randomly by a computer (n = 15; 11 men, 4 women in each group, respectively). Group 1 was the HES group and group 2 was the RL group. The mean ages of the patients in group 1 and 2 were 62.4 ± 3.01 years and 60.2 ± 1. 96 years, respectively.
Patient exclusion criteria of the study were as follows: illiterates, anxiety and depression symptoms, inability to establish sufficient cooperation, clinical neurologic defect, previous syncope and transient ischemic attack history, and renal function deficiency because it may affect S-100ß protein levels.
Informative cognitive tests used were attention and concentration, memory, spatial vision skills, psychomotor speed and performance, and high informative function tests that were as follows.
For attention and concentration, a continuous skill test was used [9]. The minimum score was 0 and the maximum score was 25 points.
For frontal lobe functions, verbal accuracy tests (human, animal, human–animal), word list generation, and go-no-go paradigm were used [10, 11]. The test aimed to measure the total number of the names spelled in 1 minute; there was not a constant value.
For memory, a 3-shapes, 3-words test [9] was performed. Minimum score was 0 and maximum score was 2 points for each test.
For high informative functions, calculating ability (minimum score, 0 and maximum score, 4 points) and abstract thinking (minimum score, 0 and maximum score, 3 points) were evaluated [12, 13].
For spatial vision skills and construction, a 3-dimensional cube (minimum score, 0 and maximum score, 1 point) and 11:20 o'clock drawing tests were used (minimum score, 0 and maximum score, 1 point) [14].
Operation
Anesthesia was induced with 0.50 µg/kg remiphentanile, 0.10 mg/kg midazolam, 3.00 mg/kg thiopental, and 0.90 mg/kg rocuronium, and was maintained with 0.25 to 0.50 µg/kg/h remiphentanile and 3.00 to 6.00 mg/kg/h propofol infusion. After standard sternotomy, ascending aorta cannula, and two-stage venous cannula were placed, extracorporeal oxygenation was maintained by a membrane oxygenator (Jostra VKMO 4200; Quadrox + VHK 4200). Hydroxyethyl starch (1,500 mL, 6%; 450/07, Varihes-Eczacibasi, Istanbul, Turkey), and RL (1,500 mL) was used as the prime solution in groups 1 and 2, respectively. Anticoagulation was maintained with heparin (3.0 mg/kg) and activated clotting time was monitored to be kept between 300 and 400 seconds. Body temperature was reduced to 28°C to 32°C to achieve mild hypothermia. At the early stage after the operation, respiration was maintained with a volume-controlled respirator (T-Bird AVS-3, Model 15586-C; Bird Products Corp, Palm Springs, CA), then the patients were extubated after they recovered from general anesthesia and started to breath normally.
Tests
Informative and cognitive tests were applied twice 2 days before the operation and 6 to 7 days after the operation. All neurologic tests were done blindly by one neurologist to maintain consistency of results.
Blood samples were taken preoperatively (stage 1), after aortic cannulation just before CPB was started (stage II), at the time of exit from CPB (stage III), at postoperative hour 5 (stage IV), and at postoperative hour 24 (stage V). The blood samples were centrifuged after 30 minutes and serum samples were transferred into appropriate tubes with a micropipette, and were stored at –20°C until being analyzed. S-100ß protein levels were measured chemiluminometrically with Liaison apparatus using monoclonal two-site immunoradiometric assay (BYK/Sangtec 100 kit [Sangtec Medical AB, Bromma, Sweden]). Analytic sensitivity of the method was 0.02 µg/L, and levels greater than 0.25 µg/L were accepted as pathologic. Intrastudy coefficient of variance was found to be 4.7%.
Statistical Package for Social Sciences 9.00 statistics software was used for statistical analyses. For S-100ß protein levels a two-way analysis of variance with repeated measures on one factor and Bonferonni corrected posthoc test were used. The preoperative and postoperative neuropsychological test scores were compared using the Wilcoxon signed rank test. The other variables (age, CPB duration, postoperative intubation period) of the groups were compared using the Mann Whitney U test.
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Results |
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Diabetes mellitus was present in 4 patients (27%) in group 1 and 5 patients (33%) in group 2. Their blood glucose levels were regulated with appropriate diet and preoperative oral anti-diabetics or insulin.
Preoperative mean ejection fraction percentage measured with transthoracic echocardiography was found to be 57.4 ± 3.21% in group 1 and 57.2 ± 2.92% in group 2.
None of the patients had a cerebrovascular disease such as ischemic cerebrovascular event or syncope. Physical and neurologic examinations were normal in both groups. No murmur was reported on carotid artery auscultation.
The mean age, cross-clamp time, duration of CPB, duration of postoperative intubation, duration of stay in the intensive care unit, discharge time, duration of the operation, preoperative ejection fraction percentage, number of coronary artery bypass grafts, and amount of postoperative drainage of the patients are shown in Table 1. These measurements were not significantly different between the groups (p > 0.05).
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Postperfusion syndrome with cooperation and orientation disorder, agitation, and confusion was observed in 3 patients in group 1 on postoperative day 1. S-100ß protein levels of these patients at postoperative 24-hour levels were 2 to 3 times higher than in the corresponding postoperative 5-hour levels.
Only 4 patients in group 1 and 12 patients in group 2 had higher S-100ß protein levels at postoperative hour 24 than postoperative hour 5. In none of these 4 patients in group 1, the S-100ß increase was up to 2 times, whereas in 9 patients in group 2 postoperative 24-hour levels were >2 times that of postoperative 24-hour values. We expect these results may indicate that almost all patients in the RL group had cerebral injury associated with increased S-100ß levels at postoperative hour 5 and postoperative hour 24, but there was no statistically significant difference between the groups.
A total of 12 informative cognitive tests in five main groups were applied to all patients in both groups. Between two groups, preoperative neurocognitive test scores was not found statistically difference for each of the tests (p > 0.05). Preoperative and postoperative results of these tests (mean values and statistical analyses) are shown in Table 3. The differences were analyzed with the Wilcoxon signed rank test. Accordingly, no significant difference was found between the preoperative and postoperative cognitive test scores in group 1 (p > 0.05), except for the verbal accuracy (human) test. The preoperative verbal accuracy (human) test score of 17.3 ± 1.6 increased to 18.6 ± 1.8 on postoperative assessment. The difference between these two scores was statistically significant (p = 0.02).
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When postoperative informative cognitive test scores of group 1 and 2 were compared, there was a statistically significant difference (p < 0.05). Although there was no statistically significant difference between the S-100ß levels of the groups when compared with the RL group, these results indicate that HES (as a prime solution in extracorporeal circulation) had significant protective effects on cerebral functions in terms of informative-cognitive test scores.
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Comment |
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Hydroxyethyl starch can also influence coagulation directly by factor VIII inhibition, and indirectly by hemodilution [17]. It was reported in clinical studies that HES increased prothrombin time, activated partial thromboplastin time, coagulation time, and bleeding time within the first hour after the operation compared with control groups [17, 18], but all measurements returned to normal levels afterward. Thrombin formation during CPB was claimed to be related to cerebral dysfunction and S-100ß protein [6]. It may be suggested that effects of HES on coagulation mechanisms could prevent development of microemboli and cerebral dysfunction during CPB. However in many clinical studies it was shown that HES did not significantly increase bleeding during surgery compared with other solutions [18, 19]. Similarly the difference between the amounts of postoperative bleeding (drainage) was not significant between the two groups. (p > 0.05)
Many clinical studies have shown that HES reduced cerebral edema and infarcts due to stroke or transient ischemic attack [20, 21]. The lungs, heart, and gastrointestinal system are also known to be affected due to microemboli and increased systemic inflammatory response during CPB [2, 7, 22–24].
After intravenous administration, only 33% of HES is eliminated from the kidney in 24 hours [17]. Therefore it is likely that HES may have preventive effects against late complications, such as tissue injury by regulating microcirculation to tissues and organs within the first 24 hours after CPB.
Although S-100ß protein does not exist in the serum normally, it can be detected after CPB, head trauma, subarachnoid hemorrhage, and stroke [6, 25]. It is a thermostable protein that is not affected by heparin, protamine, and hemolysis [6]. Serum levels increase in case of hypoxia and cellular injury (astroglia and Schwann cells) in the central nervous system [6]. Therefore it is used as a marker to observe cerebral damage during heart surgery.
S-100ß protein secretion is associated with cerebral neuronal or blood-brain barrier damage during CPB [25, 26]. Abdul-Khaliq and colleagues [27] have suggested that as a consequence of astrocyte damage, blood brain barrier is impaired, and S-100ß protein may be secreted in response to blood diffusion into the injured area. When this probable mechanism is considered together with the above discussed effects of HES on cerebral circulation (decrease in vascular permeability and leukocyte adhesion), the mechanisms of protective effect of HES against cerebral damage compared to RL may be explained.
S-100ß protein has early and late secretion phases in CPB patients. Early secretion that is observed just after CPB is associated with subclinical preoperative cerebral damage [6]. In the present study the early secretion phase was found to be similar in both HES and RL groups. This finding, together with the S-100ß protein levels indicate that there was not a marked preoperative pathology regarding cerebral circulation in both groups. The late secretion phase of S-100ß is observed between postoperative hours 15 and 48 and is a sign of perioperative cerebral complication [6]. Although HES could be related to the inhibition of reperfusion injury and brain edema, S-100ß levels were not significant between HES and RL groups in the study.
The postoperative informative cognitive test scores in the RL group were also lower than the HES group in parallel to changes in S-100ß protein levels. Kanbak and colleagues [28] and Kilminster and colleagues [29] have also claimed that neurocognitive disorders are associated with an S-100ß increase after cardiac surgery with CPB. Our results of the present study did not support the idea that there may be a correlation between cerebral dysfunction, increase in S-100ß protein levels, and impairment in cognition.
Methods of diagnosis of cognitive disorders are complex, mostly specific for individuals and independent from CPB, and test results may be affected by surgical stress, anesthesia, sleep disorders, and environmental changes. The results of cognitive function tests in CPB patients are controversial in different studies in CPB patients. However, the general belief is that a postoperative cerebral dysfunction develops, but there is no objective and sensitive cognitive test to diagnose that mild dysfunction.
Cerebral dysfunction is mostly transient, and was shown in many studies performed at 3 months to 5 years after CPB [30]. Klonoff and colleagues [31] examined the patients with neuropsychological dysfunction at 3, 12, and 14 months after coronary artery bypass grafting and reported that dysfunction gradually decreased.
Previous cerebrovascular disease is a risk factor for postoperative early cognitive dysfunction. Redmond and colleagues [32] reported that patients with previous cerebrovascular disease took longer to recover from general anesthesia and to be extubated, and had a greater incidence of reintubation and postoperative confusion. Therefore such patients were not included in the present study.
S-100ß protein increases to maximum levels at the end of CPB and then decreases to normal levels at postoperative hour 24 in 11% to 87% of patients without any neurologic deficit [6, 33]. Interestingly, early mild cognitive dysfunction and accompanying S-100ß increase may be observed in 70% of the patients after CPB [4, 28, 29]. In these patients who were clinically uncomplicated, S-100ß increase may be an evidence of subclinical injury due to diffuse microemboli, cerebral edema, and an increase in blood brain barrier permeability, but irreversible cerebral damage such as neuronal injury was not observed [25, 26].
The main goal of measuring S-100ß protein serum levels and performing informative cognitive tests were to assess the patients who had subclinical findings that could be diagnosed with imaging techniques (ie, computed tomography and magnetic resonance imaging), thereby increasing the sensitivity and specificity of the study. In a magnetic resonance imaging study it was reported that cerebral pathologies could only be observed with this method in only 30% of patients who had no clinical symptoms after CPB [34]. Although there was not a significant difference in this study, predicting subclinical cerebral damage by monitoring S-100ß protein levels may be proved with further studies.
In conclusion, although there was no statistically significant difference between the S-100ß levels of the groups, the patients in the HES group had lower S-100ß levels, better informative cognitive test scores, and better general clinical condition than the RL group during the postoperative follow-up period. Therefore it may be suggested that HES (as a prime solution) is superior to RL. Hydroxyethyl starch solution may cause a reduction in the incidence of cerebral and systemic complications in patients who undergo CPB.
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Acknowledgments |
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