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* From the Departments of Anesthesiology and Reanimation, and
the Nuclear Medicine, Hacettepe University, Faculty of Medicine, Ankara, Turkey.
Address correspondence to: Dr. Meral Kanbak, Department of Anesthesiology and Reanimation, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey. Phone: 90 312 3051987; Fax: 90 312 3109600; E-mail: orhankan{at}ttnet.net.tr
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Abstract |
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Methods: Twenty patients undergoing CABG, randomly allocated into two groups, were enrolled in this prospective, controlled, preliminary study. Isoflurane was used in group I and propofol in group P. Neurological examination and a neuropsychologic test battery consisting of the mini mental state examination (MMSET) and the visual aural digit span test (VADST) were obtained preoperatively and on the third and sixth postoperative days. Blood samples for analysis of S-100ß protein were collected before anesthesia (T1), after heparinization (T2), 15 min into CPB (T3), after CPB (T4) and at the 24th hr postoperatively (T5).
Results: Postoperative neurological examinations of the patients were normal. VADST performance declined significantly on the third day (P < 0.05) in both groups, and there were no significant differences on VADST and MMSET scores between the two groups. In group P, S-100ß protein levels increased significantly at T3 and T4 compared to preoperative and isoflurane levels (P < 0.05).
Conclusions: Despite reports about the neuroprotective effects of propofol, S-100ß protein levels were significantly elevated in group P. Although there was no deterioration in neuropsychological outcome, propofol appeared to offer no advantage over isoflurane for cerebral protection during CPB in this preliminary study of 20 patients.
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Introduction |
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The diagnosis of cerebral injury currently relies on clinical neurological examination, computed axial tomography or magnetic resonance imaging. However, these methods are not always suitable for the unconscious and artificially ventilated, or hemodynamically unstable and thus unable to cooperate. The identification of a biochemical serum marker to assist in diagnosis of cerebral injury would potentially be useful.2,3
It has been reported that S-100ß protein is an early marker for cerebral injury during cardiac operations. S-100ß subunits are present in glial and Schwann cells and, recently, elevated levels have been detected after cardiac operations complicated by neurological injury.4,5 The appearance of S-100ß in serum indicates both neuronal damage and increased permeability of the blood-brain barrier.6
Neuropsychological testing is one of the best methods currently available for assessing changes in intellectual function after a cerebral insult and has identified persistent mild, moderate or severe deterioration in 19% to 38% of patients who undergo CPB.7
Although proposal of mechanisms by which anesthetics or other drugs may produce cerebral protection are controversial and changing rapidly, isoflurane and propofol have been shown to decrease neuronal injury during ischemia by decreasing cerebral oxygen consumption. Propofol protects the brain from neuronal damage induced by brain ischemia and plays a role in the inhibition of neuronal death. Although various surgical techniques and pharmacological methods of brain protection have been evaluated, the effects of different anesthetic regiments on neurological outcome after cardiac surgery remain unclear. In this preliminary study, we evaluated the effect of propofol and isoflurane anesthesia on neuropsychological test performance and S-100ß protein levels in patients undergoing coronary artery bypass grafting (CABG).
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Methods |
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Patients with unstable angina, hepatic and renal insufficiency, additional valve disease, reoperation, preoperative insertion of an intra-aortic balloon pump (IABP), requiring re-exploration for any reason (hemostasis, tamponade, etc.,) necessitating pharmacological support and/or IABP to wean from CPB were excluded from the study.
Twenty patients were randomly classified into two groups by a concealed envelope method. They were premedicated with diazepam 10 mg po. Induction of anesthesia was performed with etomidate 0.2 mg•kg–1 and fentanyl 0.1 µg•kg–1. Vecuronium bromide 0.1 mg•kg–1 was administered to facilitate endotracheal intubation. Oxygen and nitrous oxide were used (3–3 L•min–1) during the maintenance of anesthesia for all patients. After induction, isoflurane was used in group I and a propofol infusion in group P. Isoflurane was administered at a concentration of 1 to 1.5% until CPB and 0.5 to 1% during CPB. Propofol was infused at a rate of 6 mg•kg–1•hr–1 until CPB and 3 mg•kg–1•hr–1 during CPB. All patients were monitored with the bispectral index (BIS) and the anesthetics titrated in order to keep BIS between 40 and 50.
Heparin sulphate 3 mg•kg–1 was administered prior to CPB and supplemented as needed to maintain an activated clotting time of at least 400 sec. CPB was conducted with a roller pump and membrane oxygenator, a 40-µ arterial line filter and non-pulsatile perfusion (at a flow rate of 2.4 L•min–1•m2 normothermia and above 1.6 L•min–1•m2 during hypothermia). The circuit was primed with 1000 to 1500 mL of Ringer’s lactate and 150 mL 20% mannitol. Antegrade cold St. Thomas crystalloid cardioplegia and topical ice slush were used for myocardial protection. Systematic cooling to approximately 28°C was used. Heparin sulphate was reversed with a corresponding dose of protamine sulphate at decannulation. The mean arterial pressure (MAP) was maintained at a target range of 40 to 60 mmHg.
Hemodynamic management aimed at keeping a heart rate below 90 beats•min–1 and MAP above 60 mmHg with volume replacement, changes in anesthetic concentration or administration of nitroglycerin and ephedrine.
Distal coronary anastomoses were performed during a single period of aortic cross clamping. A tangential occluder replaced the cross clamp during the proximal anastomosis. Maximum care was exercised to remove particulate debris and de-air the aorta before weaning from CPB. A MAP of 65 to 85 mmHg was considered optimal. Left atrial pressure was generally kept below 12 mmHg. If bleeding was not excessive, the patients were weaned from mechanical ventilation and the trachea was extubated after additional rewarming in the intensive care unit.
For all patients, blood samples for analysis of S-100ß protein were collected before anesthesia (T1), after heparinization before CPB (T2), 15 min into CPB (T3), following protamine administration CPB (T4) and 24 hr postoperatively (T5). After centrifugation, the serum was kept at –20°C until analysis. The S-100ß protein was analyzed using a commercially available two-site immunoradiometric assay (Santec-100, IRMA kit, Bromma, Sweden). The ß chain as defined by the three monoclonal antibodies - SMST 12, SMSK 25, and SMSK 28 - is detected. After dilution with a phosphate buffer, the serum samples were incubated on plastic beads coated with monoclonal S-100 antibodies, thereby binding S-100ß protein to the beads. The beads were washed and reincubated with anti-S-100 antibodies labeled with I125. The amount of radioactivity bound to immobilized S-100ß was measured in a gamma counter. Samples were analyzed in duplicate. The sensitivity of the assay was 0.2 µg•L–1. S-100ß protein levels in excess of 0.5 µg•L–1 are considered pathological.
A neurologist examined all patients one day prior to surgery and on the third and sixth postoperative days.
Neuropsychological testing was conducted by the same appropriately trained anesthesiologist blinded to anesthetic management. The neuropsychological tests were administered one day prior to surgery and on the third and sixth postoperative days.
The test battery at pretest and follow-up consisted of the following: 1) Mini mental state examination (MMSET): it includes a diagnostically valuable verbal retention test, tasks that assess basic orientation, short-term memory, ability to calculate and visio-motor ability. The number of correct responses scores the test. 2) Visual aural digit span test (VADST): this test assesses alertness, attention, concentration, and short-term memory. VADST mainly measures intersensory integration, sequencing and recall. It consists of four subtests: aural-oral subtest, visual-oral subtest, aural written subtest, and visual written subtest. With regard to the statement of consensus8 on the assessment of neurobehavioural outcomes after cardiac surgery, the neuropsychiatric test battery should have its sensitivity and reliability confirmed in specific populations. The sensitivity and reliability of the MMSET and VADST have been established in a Turkish population.9
Statistical analysis
Data were analyzed with SPSS 10.0.5 for windows (SPSS Inc., Chicago, IL, USA) software. One sample Kolmogorov Smirnov test was used for testing the distribution of data. Comparisons between groups were done with the Mann-Whitney test. General linear model repeated measures analysis of variance was used for analyzing differences between groups and within time. The Wilcoxon signed ranks test was used for analyzing the differences within groups compared to baseline values. P values less than 0.05 were considered significant and a reduction in P values was used when multiple comparisons were made.
It was not possible to calculate sample size prior to initiating the study since the standard deviation of S-100ß levels after CABG are not well known. We performed a post hoc analysis, which demonstrated a power of 38% when groups were compared, 71% when time was compared, and 39% when time and group interaction were analyzed.
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Results |
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. There were no significant differences in demographic characteristics and peroperative variables between the two groups. There was no significant difference between groups for MAP during CPB.
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The VADST scores showed a statistically significant decline in the total performance on the third postoperative day in both the isoflurane and propofol groups (P < 0.05), and returned to basal levels on the sixth postoperative day (Figure 1). This deterioration was seen in all the subtests of the VADST - aural stimuli, verbal stimuli, intersensory integration score (inter IS), and intrasensory integration score (intra IS; P < 0.003). Although a significant decrement was observed in intra IS and inter IS subgroups in group P, the decrement was seen only in intra IS subgroups in group I, when the groups were examined separately. The MMSET scores were increased in both groups at postoperative day six (P > 0.05; Figure 2). There were no statistically significant differences between the two groups in VADST and MMSET scores.
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). A significant difference was observed between the two groups (P < 0.05).
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Discussion |
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We attempted to determine if the anesthetic management affects serum S-100ß protein levels, neuropsychological tests, and early neurological outcome after CABG. Propofol, is a rapidly acting iv anesthetic that suppresses brain electrical activity, and decreases cerebral oxygen consumption together with cerebral blood flow (CBF).13 Anesthetics were proposed as cerebral protectors because of their ability to reduce cerebral metabolism, but recent studies have indicated that metabolic depression is not the only mechanism at work. Propofol decreases the cerebral metabolic rate for oxygen (CMRO2) and CBF while maintaining reactivity to changes in PaCO2. 14 Newman et al.15 studied the effect of burst suppression doses of propofol on CBF and cerebral metabolism during non-pulsatile hypothermic CPB in patients undergoing cardiac valvular surgery. These authors stated that propofol induces decreases in CBF and CMRO2 but has no effect on cerebral oxygen extraction (COE).
Only a few reports on the effects of propofol on CBF and cerebral metabolism in humans are available. Ederberg et al.16 demonstrated that propofol, at a plasma concentration of approximately 9 µg•mL–1, induces a 35% decrease in CBF velocity over a cerebral perfusion pressure range of 30 to 70 mmHg during moderate, hypothermic non-pulsatile CPB. The indirect vasoconstrictive effect of propofol, due to its effect on cerebral metabolism, is partly counteracted by its direct vasodilator effect, as indicated by a 10% decrease in COE. Furthermore, propofol improves the slightly impaired cerebral auto regulatory response seen during CPB.
Ito et al.17 demonstrated that pharmacological agents that act directly on gamma-aminobutyric acid (GABAA) receptors or that modulate GABAA receptor activity such as propofol, midazolam, muscimol are capable of suppressing the severity of brain injury following ischemia in gerbils. We used neuropsychological tests and neurologic examination besides S-100ß protein levels to examine the effects of anesthetic management on cerebral injury after CPB. It has been shown that neurocognitive dysfunction and S-100ß protein levels are moderately correlated.18
Recently Kilminster and colleagues19 found that less S-100ß protein release was associated with worse neuropsychological test performance. In our study there was a significant decrease of VADST scores at postoperative day three but scores returned to baseline on postoperative day six. The propofol group was expected to have less S-100ß protein levels than the isoflurane group because of the brain protective action of propofol. However unexpectedly, we found that S-100ß protein levels were higher with propofol.
Despite the increase in S-100ß protein levels no difference in deterioration of neuropsychological test scores and neurological examination after the operation was seen between groups. We conclude that, using S-100ß levels as a marker of cerebral injury, propofol appears to offer no advantage over isoflurane for brain protection during CPB in this preliminary study of 20 patients.
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Footnotes |
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Accepted for publication November 6, 2003. Revision accepted April 12, 2004.
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2 Blauth CI. Macroemboli and microemboli during cardiopulmonary bypass. Ann Thorac Surg 1995; 59: 1300–3.
3 van Dijk D, Keizer AM, Diephus JC, Durand C, Vos LJ, Hijman R. Neurocognitive dysfunction after coronary artery bypass surgery: a systematic review. J Thorac Cardiovasc Surg 2000; 120: 632–9.
4 Westaby S, Saatvedt K, White S, et al. Is there a relationship between serum S-100ß protein and neuropsychologic dysfunction after cardiopulmonary bypass? J Thorac Cardiovasc Surg 2000; 119: 132–7.
5 Jonsson H, Johnsson P, Alling C, Westaby S, Blomquist S. Significance of serum S100 release after coronary artery bypass grafting. Ann Thorac Surg 1998; 65: 1639–44.
6 Abdul-Khaliq H, Schubert S, Stoltenburg-Didinger G, et al. Protein S-100ß in brain and serum after deep hypothermic circulatory arrest in rabbits: relationship to perivascular astrocytic swelling. Clin Chem Lab Med 2000; 38: 1169–72.[Medline]
7 Stump DA. Selection and clinical significance of neuropsychological tests. Ann Thorac Surg 1995; 59: 1340–4.
8 Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of concensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg 1995; 59: 1289–95.
9 Gungen C, Ertan T, Eker E, Yasar R, Engin F. Reliability and validity of the standardized mini mental state examination in the diagnosis of mild dementia in Turkish population (Turkish). Turk Psikiyatri Derg 2002; 13: 273–81.[Medline]
10 Shaaban Ali M, Harmer M, Vaughan R. Serum S100 protein as a marker of cerebral damage during cardiac surgery. Br J Anaesth 2000; 85: 287–98.
11 Rasmussen LS, Christiansen M, Eliasen K, Sander-jensen K, Moller JT. Biochemical markers for brain damage after cardiac surgery-time profile and correlation with cognitive dysfunction. Acta Anaesthesiol Scand 2002; 46: 547–51.[Medline]
12 Arrowsmith JE, Harrison MJ, Newman SP, Stygall J, Timberlake N, Pugsley WB. Neuroprotection of the brain during cardiopulmonary bypass. A randomized trial of remacemide during coronary artery bypass in 171 patients. Stroke 1998; 29: 2357–62.
13 Kochs E, Hoffman WE, Werner C, Thomas C, Albrecht RF, Schulte am Esch J. The effect of propofol on brain electrical activity, neurologic outcome, and neuronal damage following incomplete ischemia in rats. Anesthesiology 1992; 76: 245–52.[Medline]
14 Souter MJ, Andrews PJ, Alston RP. Propofol does not ameliorate cerebral venous oxyhemoglobin desaturation during hypothermic cardiopulmonary bypass. Anesth Analg 1998; 86: 926–31.[Abstract]
15 Newman MF, Croughwell ND, White WD, Sanderson I, Spillane W, Reves JG. Pharmacologic electroencephalographic suppression during cardiopulmonary bypass: a comparison of thiopental and isoflurane. Anesth Analg 1998; 86: 246–51.[Abstract]
16 Ederberg S, Westerlind A, Houltz E, Svensson SE, Elam M, Ricksten SE. The effects of propofol on cerebral blood flow velocity and cerebral oxygen extraction during cardiopulmonary bypass. Anesth Analg 1998; 86: 1201–6.[Abstract]
17 Ito H, Watanabe Y, Isshiki k A, Uchino H. Neuroprotective properties of propofol and midazolam, but not pentobarbital, on neuronal damage induced by forebrain ischemia, based on the GABAA receptors. Acta Anaesthesiol Scand 1999; 43: 153–62.[Medline]
18 Kanbak M, Avci A, Yener F, Koramaz I, Aypar U. Cerebral injury assessed by S-100 ß protein and neuropsychologic test after coronary artery bypass surgery. Br J Anaesth 1999; 82(suppl I): A 292 (abstract).
19 Kilminster S, Treasure T, McMillan T, Holt DW. Neuropsychological change and S-100 protein release in 130 unselected patients undergoing cardiac surgery. Stroke 1999; 30: 1869–74.
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