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* From the Department of Anaesthesia and Intensive Care Medicine, and
the Department of Cardiothoracic Surgery, Cork University Hospital, University College Cork, Cork, Ireland.
Address correspondence to: Dr. Dominic Harmon, Department of Anaesthesia and Intensive Care Medicine, Cork University Hospital, Wilton Road, Cork, Ireland. Phone: 353 21 4546400 ext. 22566; Fax: 353 21 4546434; E-mail: dharmon{at}indigo.ie
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Abstract |
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Methods: Thirty-six ASA III–IV patients undergoing elective CABG were included in a prospective, randomized, single-blinded pilot study. Eighteen patients received aprotinin 2 x 106 KIU (loading dose), 2 x 106 KIU (added to circuit prime) and a continuous infusion of 5 x 105 KIU•hr–1. A battery of cognitive tests was administered to patients and spouses (n = 18) the day before surgery, four days and six weeks postoperatively.
Results: Four days postoperatively new cognitive deficit (defined by a change in one or more cognitive domains using the Reliable Change Index method) was present in ten (58%) patients in the aprotinin group compared to 17 (94%) in the placebo group [95% confidence interval (CI) 0.10–0.62, P = 0.005); (P = 0.01)]. Six weeks postoperatively, four (23%) patients in the aprotinin group had cognitive deficit compared to ten (55%) in the placebo group (95% CI 0.80–0.16, P = 0.005); (P = 0.05).
Conclusion: In this prospective pilot study, the incidence of cognitive deficit after CABG and cardiopulmonary bypass is decreased by the administration of high-dose aprotinin.
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Introduction |
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Aprotinin is a serine protease inhibitor derived from bovine lung, which can decrease blood loss during and after cardiac surgery.7 In a post hoc analysis of 816 CABG patients from a multicentre study,7 aprotinin administration was associated with a significantly (P = 0.04) decreased incidence of stroke (3.1% vs 0.0%). A meta-analysis8 of placebo-controlled, randomized, double-blind studies of CABG patients receiving high-dose aprotinin or placebo has supported the hypothesis of a cerebroprotective effect of aprotinin administration, a reported stroke incidence of 4.2% vs 0%. These data are not definitive as the conclusions are derived from post hoc data analyses.
Although, the mechanism by which aprotinin may confer neuroprotection is not known, an anti-inflammatory effect can be postulated. Another possible neuroprotective mechanism is improved recovery of cerebral metabolism after ischemia.9 By decreasing the volume of shed blood returned to the patient aprotinin administration decreases the risk of stroke.10 Its main site of action may be the microcirculation, where it decreases ischemic injury by decreasing bradykinin generation11 and provides a better microcirculatory environment during early reperfusion.
Using cognitive dysfunction as the primary outcome, we hypothesized that high-dose aprotinin administration would decrease the incidence of cognitive dysfunction following CABG with CPB.
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Methods |
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Anesthesia, surgery and postoperative management
Oral lorazepam 0.02 to 0.03 mg•kg–1 was administered to patients two hours before surgery. General anesthesia was induced with fentanyl 15 to 20 µg•kg–1 and propofol 0.5 to 1.0 mg•kg–1 and maintained using a propofol infusion (2–3 mg•kg–1•hr–1). Muscle relaxation was achieved using pancuronium 0.1 mg•kg–1. Before cannulation of the heart, heparin (at least 350 U•kg–1 iv) was administered to each patient. Additional heparin was administered to achieve and maintain a cephalin kaolin time > 480 sec. CPB was instituted using a hollow fibre oxygenator (Cobe Optima, Sorin Biomedica UK Ltd, Gloucester, UK) and a 40-µm screen arterial filter (Jostra AB, Lund, Sweden) with crystalloid priming and a non-pulsatile flow at 32.0 to 34.0°C. Pump prime consisted of lactated Ringer’s solution 2000 mL, sodium bicarbonate 8.4% 50 mL and mannitol 20% 3 mL•kg–1. The pump flow rate was maintained at 2.4 L•min–1•m–2 during aortic cross clamping. During CPB, pump flows were adjusted to maintain mean arterial pressure at 55 to 70 mmHg and hematocrit was maintained at 20 to 25%. Intermittent use of cardiotomy suction (Adult Sump sucker, Lifestream International, The Woodlands, TX, USA) (0.5–1 L flows) from pericardiotomy to closure of pericardium was used. A cell saver device was not used.
Myocardial protection was by intermittent ante-grade and retrograde blood cardioplegia administered via the aortic root and the coronary sinus respectively. A single aortic cross-clamp was used to complete distal and proximal anastamosis. Aortic venting was used in all patients. At the end of surgery, patients were transferred to the intensive care unit, where mechanical ventilation was continued until local criteria for weaning and tracheal extubation were met.
Administration of study drug
Patients were randomized to a treatment group or placebo. In the treatment group, aprotinin was administered, consisting of 2 x 106 KIU as a loading dose after induction of anesthesia, 2 x 106 KIU added to the CPB circuit prime, and a continuous infusion of 5 x 105 KIU•hr–1 during surgery. The infusion was discontinued at the end of surgery. Patients and the assessor of cognitive function were unaware of the study group to which each patient belonged.
Neuropsychological assessments
Mood was assessed using the hospital anxiety and depression scale.12 The diagnosis of delirium was based on DSM-III-R criteria, and the mini mental state examination. The presence of delirium was assessed on each day of the hospital stay. A detailed neurological examination was also performed on each day of the hospital stay. A battery of cognitive tests including those recommended by the Statement of Consensus 199513 was administered on the day before, and four days and six weeks after surgery. A single clinical psychologist (D.H.), blinded to treatment group allocation, performed all cognitive assessments under standardized conditions.
Domains of cognitive function assessed and the tests used were as follows: verbal memory: Rey Auditory Verbal Learning test (RAVLT). This is a test of immediate memory. Attention: Trail-Making Test parts A and B (TMT A & B). These tests assess speed of visual search, attention, and mental flexibility. Motor speed: the Purdue Pegboard Test. This is a timed test of manual dexterity and fine motor coordination. Executive function/verbal fluency: Controlled Oral Word Association Test (COWAT). This is a test used to assess word fluency. Psychomotor speed: Digit Symbol Test (Dig Symb). This test assesses rapidity of visual-motor responses, attention and concentration. Parallel forms of tests, when available, were used in sequential testing in a randomized manner to minimize practice effects. Having obtained written informed consent, spouses of participating patients were studied as a control group to calculate Reliable Change (RC) indices. The same battery of cognitive tests was administered to spouses at the times described above for patients.
Definition of cognitive deficit
Using the methodology outlined by Jacobson and Truax,14 the Reliable Change Index (RCI) was calculated for each cognitive test using the baseline and follow-up data obtained from control subjects. First, the test-retest reliability coefficient (rxx) was computed for each measure (Pearson correlation coefficient between preoperative and postoperative scores), from which the standard error of measurement (SEm) was calculated using the formula SEm = standard deviation (SD)1(
[1– rxx]), where SD1 is the SD of the preoperative control score. The standard error of the difference (SEdiff) then was calculated using the formula SEdiff = [2(SEm)2]. The standard error of the difference describes the distribution of changes in scores that would be expected if no true change had occurred. To establish a 90% RC confidence interval (two-tailed prediction) the SEdiff was multiplied by ± 1.64 SD1. A correction representing the practice effectb then was added to the two-tailed cut-off points. The practice effect was calculated for each measure as the mean of the difference between each pair of pre- and postoperative control scores. Thus, an RC 90% confidence interval was calculated from this formula for each variable: RC interval = (SEdiff)*( ± 1.64 SD1) + practice effect. The CI limits were rounded to the nearest whole number outside the 90% RC interval. For each neuropsychologic measure, a postoperative minus preoperative difference score was calculated for each patient. When this score fell outside the RC intervals, a significant change in performance on that measure was considered to have occurred.
Statistical analysis
The Sigma Stat 2.0 for Windows (SPSS, Inc., Chicago, IL, USA) software package was used for all statistical analysis. Short-term cognitive decline has been reported in up to 80% of patients after CABG.15 Based on 
= 0.05 and ß= 0.8, a minimum sample size of 17 patients/group was calculated to detect a 40% decrease in the incidence of early postoperative cognitive deficit. Comparison of continuous variables between groups was accomplished using analysis of variance and unpaired two-tailed Student’s t tests for post hoc analysis. Comparison of proportions between groups was accomplished with Chi-square or Fisher’s exact tests as appropriate. A significant level of P < 0.05 was taken to indicate significance. Data are reported as mean (SD or range).
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Results |
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Patient characteristics
Demographic characteristics in the two patient treatment groups and controls were similar with respect to age, height, weight and years of education (Table I
). There was a similar gender ratio in the patient groups but a greater proportion of females in the control group (Table I). The two patient groups were similar in baseline neuropsychological test scores and measures of anxiety and depression (Table I). Depression scores were greater in the placebo group compared to control pre-operatively (Table I). Preoperative medical history variables were similar in the placebo and aprotinin groups (Table II). The duration of CPB and number of coronary grafts were similar in the treatment groups (Table III). Intraoperative temperature was similar in the two groups (placebo: mean = 34.6°C, range = 30–36°C; aprotinin: mean 34.5°C, range 30–34°C).
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. Four patients (11%) developed delirium during hospital stay, three (16%) in the placebo group and one (5%) in the aprotinin group (P = 0.69). No patient had delirium at the time of cognitive assessment. Postoperative cognitive deficit (defined by a change in one or more cognitive domains using the RC method) was present in 10/17 (58%) patients in the aprotinin group compared to 17/18 (94%) in the placebo group (95% CI 0.10–0.62, P = 0.01) four days postoperatively. Six weeks postoperatively, four (23%) patients in the aprotinin group had cognitive dysfunction compared to ten (55%) in the placebo group (95% CI 0.80–0.16, P = 0.05).
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Discussion |
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Patients undergoing cardiac surgery demonstrate a marked generalized inflammatory response.17 Based on animal investigations,18 it is likely that non-specific inflammation exacerbates the injury associated with focal cerebral ischemia following microgaseous or macroatheromatous cerebral embolization, as occurs during CABG and CPB. Therapies aimed at preventing this inflammatory response have demonstrated neuroprotective efficacy in experimental models of cerebral ischemia.19 The use of heparin-coated circuits, which decrease the CPB induced inflammatory response, also produce a better neurological outcome following cardiac surgery.20 An antiinflammatory effect of aprotinin is likely to contribute to its neuroprotective effect.
Aprotinin has both soluble and cell-associated targets within the inflammatory system. It has been shown to significantly decrease neutrophil activation at 15 to 60 min following CPB, as assessed by a diminished expression of Mac-1 (CD11b/CD18).21 It decreases neutrophil azurophilic granule release and blocks secretion of myeloperoxidase and neutrophil elastase induced by neutrophil chemoattractants.22 Aprotinin may therefore exert a potent inhibitory effect on neutrophils. Aprotinin infused at clinically relevant concentrations exerts no effect on either rolling or adhesion of leukocytes, but it significantly inhibits the passage of leukocytes through the endothelial wall.22 Aprotinin can inhibit trypsin-induced increased vascular permeability in the lung, and bronchoalveolar neutrophil accumulation after CPB.23 In vitro, aprotinin acts to inhibit adhesion molecule expression and neutrophil transmigration in endothelial monolayers stimulated with tumour necrosis factor alpha.24 Platelets are one of the key mediators between coagulation and inflammation. Aprotinin can be simultaneously hemostatic and antithrombotic by selectively blocking the proteolytically activated thrombin receptor on platelets, the protease-activated receptor 1, while leaving other mechanisms of platelet aggregation unaffected.25 These antiinflammatory effects may be a neuroprotective mechanism associated with aprotinin administration.
Although several neuroprotective agents are effective in experimental animal models, in the area of clinically effective pharmacological cerebral protection there has been little progress to date.26 This is also true regarding pharmacological protection of adverse cerebral outcomes after cardiac surgery. Pharmacological strategies have included therapies aimed at maintaining the relationship between cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2), with the establishment of the concept of increased cerebral embolic delivery as a function of changeable CBF/CMRO2.27 Thiopental administration, however, did not decrease the incidence of adverse cerebral outcomes and was associated with unwanted side effects.28 Calcium antagonists have been administered in an attempt to limit ischemia-induced neuronal calcium entry and cell death. In a double-blind, randomized clinical trial of patients undergoing cardiac valve replacement,29 the trial was terminated early because of both an increased mortality in the treatment group and a lack of evidence of a beneficial effect of nimodipine. Lidocaine,30 beta-blockers31 and early aspirin therapy32 have recently been demonstrated to have neuroprotective effects associated with CABG. It is noteworthy that theses agents have anti-inflammatory effects.
The most appropriate control group for assessment of cognitive function after CABG has not been defined.13 The "Statement of Consensus on Assessment of Neurobehavioural Outcomes after Cardiac Surgery"13 recommends that measurement error and practice effects are taken into account. Estimation of practice effects and measurement error should match for factors of socio-economic background, educational attainment and mood factors and, probably most importantly, preoperative test scores.33 Patient spouses have previously been used to make calculations of practice effects and measurement error.34 In our study anxiety scores and years of education were similar in the control and patient groups (Table I
). Although the control group had a different male/female ratio to study groups, this was offset by using tests free from sex bias. The "Statement of Consensus on Assessment of Neurobehavioural Outcomes after Cardiac Surgery" recommends that tests used should be free from sex bias,13 which was the case in this study. Thus, differences in male/female ratio were unlikely to have influenced our results.
Although there was a trend towards a decreased incidence of cognitive deficit six weeks postoperatively the study did not have sufficient power to determine a difference at this time. This was because early cognitive deficit (prior to discharge) has been shown to be a critical determinant of long-term cognitive outcome.5 Controversy persists as to the best time point at which to perform postoperative assessments. When cognitive assessment is performed too soon after surgery, residual anesthetic effects and fatigue may artificially decrease performance. Assessment at greater than six months, however, increases the likelihood that deficits are not related to surgery. The small sample size represents a limitation of our study which is thus pilot in nature and results would have to be confirmed in a larger study.
We could not identify the mechanisms responsible for the neuroprotective effect of aprotinin. Mangano and colleagues32 have reported an increased mortality rate as a secondary study outcome associated with antifibrinolytic therapy during CABG. This study32 was not a randomized clinical trial and thus maybe biased by differential prescribing of antifibrinolytic therapy. There was no obvious relation to treatment with aprotinin in the single death that occurred in our study.
The incidence of cognitive deficit after CABG and CPB is decreased by the administration of high-dose aprotinin. Aprotinin administration has been recommended in patients at risk of adverse neurological outcome associated with cardiac surgery.8 This recommendation was based on a retrospective analysis of studies in which the primary outcome was blood loss. The results of this prospective pilot study, specifically designed to assess cognitive outcome, suggests that this recommendation is significant.
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Footnotes |
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Funding source: Department of Anaesthesia and Intensive Care Medicine, Cork University Hospital, University College Cork, Cork, Ireland.
The authors have no commercial or non-commercial affiliations that might represent a conflict of interest.
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References |
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2 Stockard JJ, Bickford RG, Schauble JF. Pressure-dependent cerebral ischemia during cardiopulmonary bypass. Neurology 1973; 23: 521–9.
3 Newman MF, Kramer D, Croughwell ND, et al. Differential age effects of mean arterial pressure and rewarming on cognitive dysfunction after cardiac surgery. Anesth Analg 1995; 81: 236–42.[Abstract]
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5 Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001; 344: 395–402.
6 Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 1996; 335: 1857–63.
7 Alderman EL, Levy JH, Rich JB, et al. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998; 116: 716–30.
8 Murkin JM. Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 2001; 72: S1838–44.
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