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Postoperative Delirium in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting According to the Anesthetic Agent: A Retrospective Study
Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
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Original Article
Postoperative Delirium in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting According to the Anesthetic Agent: A Retrospective Study Chung-Sik Oh, MD, PhDn, Sewon Park, MDn, Seung Wan Hong, MDn, Woon-Seok Kang, MD, PhDn, Tae-Gyoon Yoon, MD, PhDn, Seong-Hyop Kim, MD, PhDn,†,1 *
Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea † Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
Objective: To evaluate the effect of two anesthetic agents (sevoflurane or propofol) on postoperative delirium (POD) in patients undergoing offpump coronary artery bypass grafting (CABG). Design: Retrospective observational design. Setting: University hospital. Participants: Two hundred ninety-two patients undergoing off-pump CABG who were anesthetized with sevoflurane or propofol. Methods: Incidence of POD, laboratory data, and pre-, intra-, and 24-hour postoperative clinical variables were reviewed retrospectively. The independent predictors of POD were evaluated. Measurements and Main Results: The cumulative incidence of POD after off-pump CABG was 10.6% (31 of 292 patients) and the incidence rates of POD were not statistically significant in the sevoflurane and propofol groups (13% [20 of 156 patients] and 8% [11 of 136 patients], respectively; p ¼ 0.137). Other variables, including the laboratory and clinical data also did not differ significantly between the anesthetic groups. Age Z75 years (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.44-16.27; p ¼ 0.011), postoperative pneumonia (OR, 10.84; 95% CI, 3.32-35.34; p o 0.001), 6 or more packed red blood cell units transfusion in the first 24 hours postoperatively (OR, 5.30; 95% CI, 1.32-21.27; p ¼ 0.019), and 24-hour postoperative albumin o3.0 g/dL (OR, 3.38; 95% CI, 1.20-9.31; p ¼ 0.021) were independent predictors of POD after off-pump CABG. Conclusions: The incidence of POD in patients undergoing off pump-CABG did not differ between those receiving sevoflurane versus propofolbased anesthesia. & 2017 Elsevier Inc. All rights reserved.
Key Words: postoperative delirium; sevoflurane; propofol; off-pump coronary artery bypass grafting
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (Grant number: 2015R1A2A2A01006779, 2015). The authors declare that no author has a conflict of interest. 1 Address reprint requests to Seong-Hyop Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, 120-1 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea. E-mail address: [email protected] (S.-H. Kim).
The evolution of anesthetic and surgical techniques has enabled elderly patients to undergo safe cardiac surgery. As cardiac surgery techniques develop for elderly patients, prevention and care for postoperative delirium (POD) are important, as POD is associated with prolonged hospital stay, reduced functional recovery, and increased morbidity and mortality.1 Sevoflurane and propofol are popular anesthetic agents because of their rapid induction and short recovery time.
http://dx.doi.org/10.1053/j.jvca.2017.02.047 1053-0770/& 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Oh C-S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.02.047
C.-S. Oh et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
2
Nonetheless, which of these inhaled and intravenous anesthetic agents is most beneficial for the clinical neurologic outcome remains controversial. According to various preclinical and animal studies, inhaled anesthetics interact with recognized neurodegeneration pathways and increase cellular stress.2–6 In contrast to inhaled anesthetics, propofol had a robust anti-inflammatory effect and resulted in less cognitive impairment.7,8 Therefore, propofol may be a good choice for minimizing the inflammatory response and related neurologic complications. Recent clinical studies have revealed that inhaled anesthetics are beneficial for early postoperative cognitive function in patients who have undergone on-pump coronary artery bypass grafting (CABG).9,10 However, these studies were performed under cardiopulmonary bypass (CPB), which triggers a powerful inflammatory response11 and did not enable clear conclusions to be drawn. Surgical stimulation itself also induces an inflammatory response even without CPB.12 Therefore, a clinical evaluation of the impact of different anesthetic agents (inhaled anesthetics v propofol) on the neurocognitive deficit during off-pump CABG is needed to minimize the confounding effect induced by the CPBinduced inflammatory response. The authors hypothesized that propofol-based anesthesia would result in a reduced inflammatory response and related neurologic complications, such as POD, compared with sevoflurane-based anesthesia during off-pump CABG. This study evaluated the incidence of POD and identified risk factors for developing POD in patients undergoing sevoflurane- or propofol-based anesthesia during off-pump CABG.
in the propofol group. Remifentanil was administered to a fixed target plasma concentration (plasma site, Minto model13) of 10 ng/mL in both groups using a target-controlled infusion device (Orchestras Base Primea; Fresenius Vial, Brézins, France). Anesthesia was maintained according to the standard institutional regimens14 for sevoflurane (sevoflurane group) or propofol (propofol group) with remifentanil at 10 ng/mL. Sevoflurane and propofol were titrated to maintain a bispectral index (BIS) value of 40-50 during the entire anesthetic period. The mean arterial pressure (MAP) was maintained at 460 mmHg during off-pump CABG using volume replacement, inotropes, and vasoconstrictors. Cerebral oxygen saturation was monitored using near-infrared spectroscopy (NIRS) and was maintained within the range of 20% of the initial preinduction value. A decrease in the NIRS value of more than 20% after an abrupt blood pressure decline due to a reversed heart position was managed by increasing the mean systolic arterial pressure or fraction of inspired oxygen, transfusing packed red blood cells (pRBCs), or hypoventilating the patient to improve cerebral blood flow as appropriate. pRBCs were transfused using a guided target hemoglobin level of 10 g/dL considering the patient’s cerebral oxygenation saturation, volume status, and intraoperative blood loss. Patients who showed deterioration in the vital signs or cardiogenic shock due to unstable angina or acute myocardial infarction were treated with an intraaortic balloon pump (IABP) pre- and intraoperatively, which was maintained during the perioperative period.
Methods
Medical treatment and decision-making in the ICU were performed by responsible intensivists. All patients received only remifentanil infusion continuously for sedation and pain control until extubation and an intravenous patient-controlled analgesia pump containing fentanyl (0.2 μg/kg/h, total dosage of 25 µg/kg), ketorolac (0.35 mg/kg/h, total dosage of 2.5 mg/kg), and ramosetron (0.9 mg) was used in all patients after extubation for postoperative pain control as per the institutional strategy.14 Intubation time was defined as the time from arrival in the ICU to extubation in the ICU. The ICU stay duration was defined as the time from arrival in the ICU until the patient satisfied the ICU discharge criteria. Continuous renal replacement therapy (CRRT) was applied after off-pump CABG if the patient showed signs of acute kidney disease, such as elevated serum creatinine level with oliguria, diuretic-resistant fluid overload, and hyperkalemia. Pneumonia was confirmed after off-pump CABG on postoperative follow-up chest radiographs and clinical symptoms and treated with antibiotics. Perioperative new-onset atrial fibrillation (A.fib) was managed by maintaining hemodynamic stability with optimal volume status, using antiarrhythmic medication, and correcting any electrolyte imbalance. Amiodarone was infused based on the decision of responsible doctors referring to relevant guidelines.15
Study Population Ethical approval for this study (approval number: KUH1160073) was provided by the Institutional Review Board of Konkuk University Medical Center, Seoul, South Korea (Chairperson Professor S.H. Lee) on September 4, 2014 and registered at ClinicalTrials.gov (registration number: NCT02374177; http://clin icaltrials.gov). The medical records of the patients undergoing offpump CABG at Konkuk University Medical Center from January 2010 to February 2015 were reviewed retrospectively. The patients received sevoflurane or propofol according to their daily random assignment to two different operating rooms for cardiac surgery, according to an institutional strategy that varied by day of the week, and were managed separately using different anesthetic regimens (one for sevoflurane and the other for propofol) with the same strategy for hemodynamic management. After reviewing the medical records, the patients were divided according to the anesthetic agent that they received (sevoflurane or propofol groups). A patient was excluded if any of the following criteria were met: (1) other concurrent surgery and (2) conversion from off-pump CABG to on-pump CABG.
Intensive Care Unit (ICU) Protocols After Off-Pump CABG
Postoperative Delirium Anesthetic Management During Off-Pump CABG Anesthesia was induced with etomidate or/and low-dose midazolam (1-to-2 mg) in the sevoflurane group and propofol
POD up to postoperative day 7 was evaluated. If the patient’s postoperative cognitive and behavioral functions were abnormal, if attention was disrupted over the short term with
Please cite this article as: Oh C-S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.02.047
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fluctuations over time, disorganized thinking was evident or other associated symptoms were detected by an attending physician, according to the institutional strategy, immediate psychiatric consultation was requested to diagnose POD based on the Diagnostic and Statistical Manual of Mental Disorders criteria.16 The psychiatrist had to evaluate the patients’ abnormal cognitive and behavioral function within 1 hour of requesting the consultation. The authors investigated the incidence of POD by reviewing the medical records. Perioperative Events Up To 1 Week Postoperatively The anesthetic records were reviewed to identify MAP o 60 mmHg, a decrease in the NIRS value 420% of the initial value, and BIS o 40 during the intraoperative period. CRRT, new-onset pneumonia, A.fib occurring for the first time without a history, and POD in the ICU during the first week postoperatively were identified by reviewing the medical records.
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Demographic Data and Known Risk Factors Preoperative characteristics of the patients, including sex, age, height, weight, body mass index, anesthesia duration, intubation duration, ICU stay duration, total numbers of revascularized vessels, and perioperative drug infusion were identified. Known risk factors for POD17,18 were identified: (1) smoking history; (2) underlying diseases including hypertension, diabetes mellitus, dyslipidemia, A.fib, carotid artery stenosis, chronic kidney disease confirmed by nephrologists, and dementia; (3) history of percutaneous coronary intervention, CABG, or cerebrovascular accident; and (4) preoperative status, including left ventricular ejection fraction (LVEF) o 40%, regional wall motion abnormality on echocardiography and in the presence of an IABP. The amount of pRBC transfusion intraoperatively and during the first postoperative 24 hours also was determined from a review of the medical records.
Table 1 Demographic Characteristics
Gender (male/female) Male Female Age Z75 years Height (cm) Weight (kg) BMI Z25 kg/m2 Smoking Z15 pack years Underlying disease Hypertension Diabetes mellitus Dyslipidemia A.fib Carotid artery stenosis Chronic kidney disease Dementia History PCI CABG CVA Preoperative status LVEF o40% RWMA on Echo Preoperative use of IABP Unstable angina Acute MI Intraoperative use of IABP Unstable angina Acute MI
Sevoflurane (n ¼ 156)
Propofol (n ¼ 136)
p Value
114 42 21 163 66 85 69
(73%) (27%) (14%) 7 9 7 12 (55%) (44%)
97 39 13 163 66 78 54
(71%) (29%) (9.6%) 7 9 7 12 (57%) (40%)
0.300 0.924 0.845 0.623 0.435
93 65 8 6 7 12 10
(60%) (42%) (5%) (4%) (5%) (8%) (6%)
86 58 8 7 3 13 5
(63%) (43%) (6%) (5%) (2%) (10%) (4%)
0.526 0.866 0.778 0.591 0.347 0.570 0.291
23 (15%) 2 (1%) 19 (12%)
24 (18%) 2 (2%) 14 (10%)
0.501 1.000 0.612
29 (19%) 69 (46%)
21 (15%) 64 (47%)
0.476 0.772 0.767
5 (3.2%) 7 (4.5%)
4 (2.9%) 9 (6.6%)
2 (1.3%) 2 (1.3%)
1 (0.7%) 2 (1.5%)
0.739
1.000
NOTE. Data are number of patients (%) or mean 7 standard deviation. Intraoperative use of IABP indicates new insertion of IABP during surgery, whereas preoperative use of IAPB indicates new insertion of IABP before surgery. Abbreviations: A.fib, atrial fibrillation; BMI, body mass index; CABG, coronary artery bypass graft; CVA, cerebrovascular accident; Echo, echocardiography; IABP, intra-aortic balloon pump; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RWMA, regional wall motion abnormality.
Please cite this article as: Oh C-S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.02.047
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Laboratory Data Laboratory values, including hemoglobin, hematocrit, albumin, creatinine, high-sensitivity C-reactive protein (HS-CRP), creatine kinase-MB (CK-MB), troponin I and B-type natriuretic peptide (BNP) preoperatively, and 1- and 24-hour postoperatively, were identified from a review of the medical records. Statistical Analysis The primary outcome variable was the incidence of POD occurring within 7 days postoperatively between the different anesthetic agents in patients who underwent off-pump CABG.
Based on a preliminary review of medical records with 30 patients undergoing off-pump CABG under propofol-based anesthesia, the incidence of POD was 13.3% (4 of 30 patients). The sample size of 136 in each group was calculated to detect twice the incidence of POD in the sevoflurane-based group, with a power of 0.80 and an α value of 0.05. Normally distributed continuous data are presented as mean 7 standard deviation. Non-normally distributed continuous data are presented as median (interquartile range). The number of patients (n) and proportions (%) were calculated for categorical variables. The independent twotailed t-test was used to compare normally distributed means of continuous data variables. The Mann–Whitney U-test was used when the data were not distributed normally. The
Table 2 Intra- and Postoperative Variables for the Two Anesthetic Agents Sevoflurane (n ¼ 156) Anesthetic agents for induction Propofol Etomidate Midazolam þ etomidate Anesthesia duration (min) Intubation duration (min) ICU stay duration (min) TNR 1 2 3 4 5 Perioperative drug infusion Dopamine Dobutamine Milrinone Norepinephrine Epinephrine Amiodarone Intraoperative events MAP o60 mmHg NIRS o20% BIS o40 Intraoperative pRBC transfusion r2 U 3-5 U Z6 U Postoperative 1 week events CRRT Pneumonia New-onset A.fib Postoperative 24-h pRBC transfusion r2 U 3-5 U Z6 U
Propofol (n ¼ 136)
p Value o0.001
0 29 127 379 929 2,875
(0%) (18.6%) (81.4%) 7 87 (422) (1,528)
136 0 0 377 987 2,905
(100%) (0%) (0%) 7 84 (385) (1,502)
0.821 0.127 0.997 0.446
29 38 58 30 1
(19%) (24%) (37%) (19%) (1%)
16 39 47 33 1
(12%) (29%) (35%) (24%) (0%)
148 45 23 10 1 29
(95%) (29%) (15%) (6%) (1%) (19%)
132 49 17 4 2 27
(97%) (36%) (13%) (3%) (2%) (20%)
0.348 0.190 0.578 0.166 0.600 0.784
27 (17%) 39 (25%) 79 (51%)
15 (11%) 44 (32%) 72 (53%)
0.127 0.165 0.695 0.449
114 (73%) 36 (23%) 6 (4%)
108 (79%) 24 (18%) 4 (3%)
5 (3%) 16 (10%) 21 (14%)
9 (7%) 13 (10%) 20 (15%)
95 (61%) 49 (31%) 12 (8%)
64 (47%) 55 (40%) 17 (13%)
0.272 0.848 0.866 0.052
NOTE. Data are numbers of patients (%), mean 7 standard deviation, or median (interquartile range). New-onset A.fib indicates that A.fib occurred for the first time without previous atrial fibrillation history. Abbreviations: A.fib, atrial fibrillation; BIS, bispectral index; CRRT, continuous renal replacement therapy; ICU, intensive care unit; MAP, mean arterial pressure; NIRS o20%, less than 20% of initial near-infrared spectroscopic value; pRBC, packed red blood cell; TNR, total number of revascularized vessels.
Please cite this article as: Oh C-S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.02.047
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Age Z 75 years, chronic kidney disease, preoperative use of IABP, preoperative LVEF o 40%, intubation duration 4 3 days, ICU stay 4 1 week, perioperative amiodarone infusion, 3-to-5 pRBC units transfused intraoperatively, postoperative pneumonia, CRRT, 6 or more pRBC units transfused 24 hours postoperatively, albumin o 3.0 g/dL, creatinine Z 1.5 mg/dL and troponin I Z 0.5 ng/mL were included in a binary logistic regression model (Table 4). The model identified age Z 75 years (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.44-16.27; p ¼ 0.011), postoperative pneumonia (OR, 10.84; 95% CI, 3.32-35.34; p o 0.001), 6 or more pRBC units transfused 24 hours postoperatively (OR, 5.30; 95% CI, 1.32-21.27; p ¼ 0.019), and albumin o 3.0 g/dL 24 hours postoperatively (OR, 3.38; 95% CI, 1.20-9.31; p ¼ 0.021) as independent predictors of POD after off-pump CABG.
chi-square test was used to compare categorical variables between the sevoflurane and propofol groups. A univariate analysis of POD for each potential risk factor was performed using logistic regression. Exposures for which the p value was o 0.05 in the univariate analysis were entered into a multivariate conditional logistic regression model to identify independent predictors of POD. All calculations were performed using SPSS ver. 18.0 software (SPSS, Chicago, IL). A p o 0.05 was considered significant.
Results A total of 300 patients underwent off-pump CABG from January 2010 to February 2015, and 292 were eligible for the study (156 for the sevoflurane group v 136 for the propofol group). Eight patients were excluded—2 had concurrent surgery and 6 converted to on-pump CABG. No differences in demographic characteristics were detected between the 2 anesthetic groups (Table 1). No differences in perioperative drug infusion, perioperative events (intraoperative MAP o60 mmHg, a decrease in the NIRS value 4 20% of the initial value, BIS o40; postoperative CRRT, pneumonia, new-onset A.fib), and intra- and 24-hour postoperative pRBC transfusions were detected between the groups (Table 2). Hemoglobin, hematocrit, and albumin decreased 24 hours postoperatively but did not differ significantly between the groups (Table 3). Serum creatinine also did not differ significantly between the groups. HS-CRP, CK-MB, and troponin I levels increased 24 hours postoperatively but did not differ significantly between the groups. BNP also did not differ significantly between the groups during the preoperative period. The cumulative incidence of POD after off-pump CABG up to 7 postoperative days was 10.6% (31 of 292 patients), and 74.2% (23 of 31 patients) developed POD within 3 postoperative days. The incidences of POD in the sevoflurane and propofol groups did not differ significantly (13% [20 of 156 patients] and 8% [11 of 136 patients], respectively, p ¼ 0.137).
Discussion The results of this study indicated that the incidence of POD in patients undergoing off-pump CABG did not differ between those receiving sevoflurane versus propofol-based anesthesia. Advanced age Z75 years, postoperative pneumonia, 6 or more pRBC units transfused 24 hours postoperatively, and albumin o3.0 g/dL 24 hours postoperatively were independent predictors of POD after off-pump CABG in the present study. Inhaled anesthetics have been shown to produce neuroinflammation associated with impaired cognition in various preclinical studies.7,19–21 In contrast to inhaled anesthetics, propofol has not been demonstrated to produce neuroinflammation7 while it improves the neurologic outcome and decreases neuronal damage after cerebral ischemia in animal studies.22 However, the authors found that the antiinflammatory effect of propofol did not provide an advantage in minimizing POD. Although the CPB-related inflammatory response was minimized in the study design, the various inflammatory responses that occurred during the perioperative period12,23 might have mitigated the anti-inflammatory effect of propofol.
Table 3 Pre- and Postoperative Laboratory Values in Relation to the Two Anesthetic Agents Preoperative Sevoflurane (n ¼ 156) Hemoglobin (g/dL) Hematocrit (%) Albumin (g/dL) Creatinine (mg/dL) HS-CRP (mg/dL) CK-MB (ng/mL) Troponin I (ng/mL) BNP (pg/dL)
13.2 39 4.0 0.9 0.2 0.9 0.02 148
7 2.0 (8) (0.6) (0.3) (0.9) (0.8) (0.22) (483)
Postoperative 24 h Propofol (n ¼ 136)
Sevoflurane (n ¼ 156)
Propofol (n ¼ 136)
7 1.9 (8) (0.6) (0.3) (0.8) (0.8) (0.26) (627)
11.2 7 1.1 34 (3) 3.1 7 0.4 0.9 (0.5) 11.7 7 5.4 6.5 (8.9) 1.17 (3.05) –
11.4 7 1.3 34 (5) 3.1 7 0.3 0.8 (0.4) 10.0 (9.7) 8.4 (10.2) 1.58 (3.33) –
13.1 39 3.9 0.9 0.2 1.0 0.03 146
NOTE. Data are mean 7 standard deviation or median (interquartile range). Abbreviations: BNP, B-type natriuretic peptide; CK-MB, creatine kinase-MB; HS-CRP, high-sensitivity C-reactive protein. Please cite this article as: Oh C-S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.02.047
C.-S. Oh et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
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Table 4 Unadjusted and Adjusted Odds Ratios for Postoperative Delirium as a Dependent Variable and Independent Predictors Variables
Incidence
Age Z75 years Chronic kidney disease Preoperative use of IABP Preoperative EF o40% Intubation duration 43 days ICU stay 41 week Perioperative amiodarone infusion Intraoperative pRBC transfusion 3-5 U Postoperative pneumonia Postoperative CRRT apply Postoperative 24-h pRBC transfusion Z6 U Albumin o3.0 g/dL at postoperative 24 h Creatinine Z1.5 mg/dL at postoperative 24 h Troponin I Z0.5 ng/mL at postoperative 24 h
34 25 25 50 11 7 56 60 29 14 29 95 38 210
(12%) (9%) (9%) (17%) (4%) (2%) (19%) (21%) (10%) (5%) (10%) (33%) (13%) (72%)
Unadjusted OR (95% CI) 4.70 3.06 3.94 2.63 12.29 24.90 3.66 2.54 16.5 10.58 10.19 2.46 3.96 4.05
(1.99-11.14) (1.12-8.36) (1.50-10.37) (1.15-6.00) (3.50-43.14) (4.60-134.79) (1.67-8.03) (1.13-5.73) (6.82-40.14) (3.43-32.70) (3.72-27.90) (1.16-5.21) (1.70-9.26) (1.20-13.72)
p Value o0.001 0.029 0.006 0.022 o0.001 o0.001 0.001 0.024 o0.001 o0.001 o0.001 0.019 0.001 0.025
Adjusted OR (95% CI) 4.84 1.03 0.73 2.17 2.13 6.04 1.21 0.80 10.84 0.90 5.30 3.38 1.57 1.42
(1.44-16.27) (0.15-6.96) (0.12-4.27) (0.62-7.67) (0.28-16.07) (0.45-81.65) (0.37-3.97) (0.24-2.68) (3.32-35.34) (0.11-7.56) (1.32-21.27) (1.20-9.31) (0.30-8.25) (0.36-5.70)
p Value 0.011 0.980 0.726 0.229 0.462 0.176 0.749 0.715 o0.001 0.923 0.019 0.021 0.597 0.619
Abbreviations: CRRT, continuous renal replacement therapy; EF, ejection fraction; IABP, intra-aortic balloon pump; ICU, intensive care unit; OR, odds ratio; pRBC, packed red blood cell.
Several studies have revealed inconsistent clinical results. For example, two recent prospective studies by Schoen et al and Royse et al reported better early postoperative cognitive results after cardiac surgery using CPB for inhaled anesthetics compared with those of propofol.9,10 However, Kalimeris et al reported that patients who received propofol showed superior cognitive functioning over those who took sevoflurane for carotid endarterectomy.24 Furthermore, the improved postoperative cognitive function in patients who received inhaled anesthetics in the studies by Schoen et al and Royse et al were no longer present 3 months after the surgery, suggesting that the effects of anesthesia type are not long lasting. According to the present retrospective investigation, POD was not affected by the type of anesthetic agent. Therefore, specific anesthetic agents may not influence the risk of POD. CPB-related systemic inflammation may affect immediate postoperative cerebral function and the incidence of POD.25 The studies of Schoen et al and Royse et al were performed on patients who underwent on-pump CABG, in contrast to offpump CABG in this study, which could have been biased for neuroinflammation. Schoen et al reported that cerebral desaturation during on-pump CABG was related to worse postoperative cognition. However, CPB-related neuroinflammation could be a confounding factor for cognitive dysfunction noted in previous studies.9,10 Furthermore, the reverse heart position during anastomosis of the left circumflex artery or right coronary artery and inotropic or vasoconstrictor use during off-pump CABG could be major contributing factors to hemodynamic instability and cerebral hypoperfusion. Therefore, Baki et al reported that the level of the S100-beta protein, a cerebral injury marker, was lower in patients who received propofol for cardiac surgery with CPB than desflurane.26 However, the levels of interleukin-6 and -8, which are markers of inflammation, were lower in the desflurane group than in the propofol group, indicating that CPB could have various effects
on inflammation and there could be confounders when evaluating neuroinflammation. In this study, the authors focused on delirium and not on postoperative cognitive dysfunction (POCD) during the early postoperative period (within 1 week) for several reasons. POD has an acute onset with more aggressive symptoms, including marked fluctuation in attention and orientation related to postoperative mortality,27 whereas POCD has much more subtle symptoms and is more difficult to define due to the absence of a standard test and the requirement for preoperative baseline psychological testing.28,29 Furthermore, POD and POCD are separate entities and their relationship has yet to be fully elucidated.29 Therefore, further well-designed prospective studies evaluating the effect of anesthetic agents on cognitive function after off-pump CABG to distinguish POD from POCD will be informative. Old age, pneumonia, low albumin, and perioperative transfusion are well-known risk factors for POD,30–32 and they were also independent predictors of POD in this study. However, sevoflurane-based anesthesia was not included in the final independent predictors of POD. This indicated that the effect of the anesthetic agent on POD might be minimal after off-pump CABG. Miyazaki et al revealed that old age, carotid artery stenosis, high creatinine, hypertension, atrial fibrillation, and a history of smoking were independent predictors of POD after off-pump CABG, which was somewhat different from the present study. The authors think that this difference was due to the different factors that were included in the analysis. The final independent predictors could differ in the present study because the authors evaluated the application of IABP and CRRT, a low ejection fraction, and transfusion amount, while Miyazaki et al did not evaluate these factors. Therefore, the authors' predictors and those in Miyazaki et al should be considered simultaneously when performing cardiac anesthesia to reduce POD.
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C.-S. Oh et al. / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
The authors acknowledge some limitations to this study. First, the initial signs or symptoms of POD were detected by the attending physician and a psychiatrist was then consulted. Even when the attending physician precisely observes the symptoms and signs of POD, the hypoactive form of POD is usually more difficult to detect than the hyperactive form. There is thus a chance that the hypoactive form of POD might be missed. The evaluation of POD by using the confusion assessment method for the ICU would have been more suitable in the present study to detect the hypoactive form of POD.33 Second, the potential limitations of this study included the retrospective nature of the data collection and lack of randomization. Assignment of surgical room for cardiac surgery had been decided by the day of the week in the institution and anesthetic agents were decided according to the regimen of blinded attending anesthesiologists who were responsible for the assigned surgical room. The authors thought this assignment could achieve unintentional randomization in the present study. However, even when the choice of anesthetic agents involved unintentional randomization, it could be insufficient to reduce bias. Third, the authors assessed laboratory data up to 1 day postoperatively because they thought that most of the effects of the anesthetic agents on the patients would not last for more than 1 day. Therefore, abnormal laboratory data after postoperative 1 day might have been missed. Finally, the present study might have been somewhat underpowered because of the large gap of expected incidence of POD between the 2 anesthetic agents from the preliminary data. These results suggested that a larger sample size is necessary to conduct advanced statistical analysis. In conclusion, POD presented similarly in patients anesthetized with sevoflurane or propofol during off-pump CABG surgery. Age Z 75 years, 6 or more pRBC units transfused within 24 hours postoperatively, and albumin o 3.0 g/dL 24 hours postoperatively were independent predictors of POD after off-pump CABG. These findings suggested that there were no specific benefits of sevoflurane or propofol in reducing POD after off-pump CABG.
References 1 Koster S, Hensens AG, van der Palen J. The long-term cognitive and functional outcomes of postoperative delirium after cardiac surgery. Ann Thorac Surg 2009;87:1469–74. 2 Zhang G, Dong Y, Zhang B, et al. Isoflurane-induced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by memantine. J Neurosci 2008;28:4551–60. 3 Xie Z, Dong Y, Maeda U, et al. The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels. Anesthesiology 2006;104:988–94. 4 Eckenhoff RG, Johansson JS, Wei H, et al. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology 2004;101:703–9. 5 Wei H, Liang G, Yang H, et al. The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors. Anesthesiology 2008;108:251–60. 6 Yang H, Liang G, Hawkins BJ, et al. Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. Anesthesiology 2008;109:243–50.
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7 Ye X, Lian Q, Eckenhoff MF, et al. Differential general anesthetic effects on microglial cytokine expression. PLoS One 2013;8:e52887. 8 Liu Y, Pan N, Ma Y, et al. Inhaled sevoflurane may promote progression of amnestic mild cognitive impairment: A prospective, randomized parallel-group study. Am J Med Sci 2013;345:355–60. 9 Schoen J, Husemann L, Tiemeyer C, et al. Cognitive function after sevoflurane- vs propofol-based anaesthesia for on-pump cardiac surgery: A randomized controlled trial. Br J Anaesth 2011;106:840–50. 10 Royse CF, Andrews DT, Newman SN, et al. The influence of propofol or desflurane on postoperative cognitive dysfunction in patients undergoing coronary artery bypass surgery. Anaesthesia 2011;66:455–64. 11 Newman MF, Mathew JP, Grocott HP, et al. Central nervous system injury associated with cardiac surgery. Lancet 2006;368:694–703. 12 Cardinale F, Chinellato I, Caimmi S, et al. Perioperative period: Immunological modifications. Int J Immunopathol Pharmacol 2011;24:S3–12. 13 Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997;86:10–23. 14 Kim TY, Kim DK, Yoon TG, et al. Myocardial injury in remifentanilbased anaesthesia for off-pump coronary artery bypass surgery: An equipotent dose of sevoflurane versus propofol. Anaesth Intensive Care 2011;39:418–25. 15 Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854–906. 16 First MB. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Publishing, 1997. 17 Miyazaki S, Yoshitani K, Miura N, et al. Risk factors of stroke and delirium after off-pump coronary artery bypass surgery. Interact Cardiovasc Thorac Surg 2011;12:379–83. 18 Koster S, Hensens AG, Schuurmans MJ, et al. Risk factors of delirium after cardiac surgery: A systematic review. Eur J Cardiovasc Nurs 2011;10: 197–204. 19 Hu Z, Ou Y, Duan K, et al. Inflammation: A bridge between postoperative cognitive dysfunction and Alzheimer’s disease. Med Hypotheses 2010;74: 722–4. 20 Wu X, Lu Y, Dong Y, et al. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-alpha, IL-6, and IL-1beta. Neurobiol Aging 2012;33:1364–78. 21 Yan X-B, Ouyang W, Li G, et al. Involvement of neuronal nitric oxide synthase in cognitive impairment in isoflurane-treated rats. Neuroscience Letters 2012;506:240–4. 22 Kochs E, Hoffman WE, Werner C, et al. The effects of propofol on brain electrical activity, neurologic outcome, and neuronal damage following incomplete ischemia in rats. Anesthesiology 1992;76:245–52. 23 Desborough J. The stress response to trauma and surgery. Br J Anaesth 2000;85:109–17. 24 Kalimeris K, Kouni S, Kostopanagiotou G, et al. Cognitive function and oxidative stress after carotid endarterectomy: Comparison of propofol to sevoflurane anesthesia. J Cardiothorac Vasc Anesth 2013;27:1246–52. 25 Motallebzadeh R, Bland JM, Markus HS, et al. Neurocognitive function and cerebral emboli: Randomized study of on-pump versus off-pump coronary artery bypass surgery. Ann Thorac Surg 2007;83:475–82. 26 Baki ED, Aldemir M, Kokulu S, et al. Comparison of the effects of desflurane and propofol anesthesia on the inflammatory response and s100beta protein during coronary artery bypass grafting. Inflammation 2013;36:1327–33. 27 Martin B-J, Buth KJ, Arora RC, et al. Delirium: A cause for concern beyond the immediate postoperative period. Ann Thorac Surg 2012;93: 1114–20. 28 Funder KS, Steinmetz J. Post-operative cognitive dysfunction—Lessons from the ISPOCD studies. Trends Anaes Crit Care 2012;2:94–7. 29 Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction. Br J Anaesth 2009;103(Suppl 1):i41–6.
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30 Balasundaram B, Holmes J. Delirium in vascular surgery. Eur J Vasc Endovasc Surg 2007;34:131–4. 31 Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: A systematic review. J Am Geriatr Soc 2006;54: 1578–89.
32 Bilotta F, Lauretta MP, Borozdina A, et al. Postoperative delirium: Risk factors, diagnosis and perioperative care. Minerva Anestesiol 2013;79:1066–76. 33 Klugkist M, Sedemund-Adib B, Schmidtke C, et al. Confusion assessment method for the intensive care unit (CAM-ICU): Diagnosis of postoperative delirium in cardiac surgery. Der Anaesthesist 2008;57:464–74.
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Original Article
Postoperative Delirium in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting According to the Anesthetic Agent: A Retrospective Study Chung-Sik Oh, MD, PhDn, Sewon Park, MDn, Seung Wan Hong, MDn, Woon-Seok Kang, MD, PhDn, Tae-Gyoon Yoon, MD, PhDn, Seong-Hyop Kim, MD, PhDn,†,1 *
Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea † Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
Objective: To evaluate the effect of two anesthetic agents (sevoflurane or propofol) on postoperative delirium (POD) in patients undergoing offpump coronary artery bypass grafting (CABG). Design: Retrospective observational design. Setting: University hospital. Participants: Two hundred ninety-two patients undergoing off-pump CABG who were anesthetized with sevoflurane or propofol. Methods: Incidence of POD, laboratory data, and pre-, intra-, and 24-hour postoperative clinical variables were reviewed retrospectively. The independent predictors of POD were evaluated. Measurements and Main Results: The cumulative incidence of POD after off-pump CABG was 10.6% (31 of 292 patients) and the incidence rates of POD were not statistically significant in the sevoflurane and propofol groups (13% [20 of 156 patients] and 8% [11 of 136 patients], respectively; p ¼ 0.137). Other variables, including the laboratory and clinical data also did not differ significantly between the anesthetic groups. Age Z75 years (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.44-16.27; p ¼ 0.011), postoperative pneumonia (OR, 10.84; 95% CI, 3.32-35.34; p o 0.001), 6 or more packed red blood cell units transfusion in the first 24 hours postoperatively (OR, 5.30; 95% CI, 1.32-21.27; p ¼ 0.019), and 24-hour postoperative albumin o3.0 g/dL (OR, 3.38; 95% CI, 1.20-9.31; p ¼ 0.021) were independent predictors of POD after off-pump CABG. Conclusions: The incidence of POD in patients undergoing off pump-CABG did not differ between those receiving sevoflurane versus propofolbased anesthesia. & 2017 Elsevier Inc. All rights reserved.
Key Words: postoperative delirium; sevoflurane; propofol; off-pump coronary artery bypass grafting
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (Grant number: 2015R1A2A2A01006779, 2015). The authors declare that no author has a conflict of interest. 1 Address reprint requests to Seong-Hyop Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Konkuk University Medical Center, 120-1 Neungdong-ro, Gwangjin-gu, Seoul, 05030, Republic of Korea. E-mail address: [email protected] (S.-H. Kim).
The evolution of anesthetic and surgical techniques has enabled elderly patients to undergo safe cardiac surgery. As cardiac surgery techniques develop for elderly patients, prevention and care for postoperative delirium (POD) are important, as POD is associated with prolonged hospital stay, reduced functional recovery, and increased morbidity and mortality.1 Sevoflurane and propofol are popular anesthetic agents because of their rapid induction and short recovery time.
http://dx.doi.org/10.1053/j.jvca.2017.02.047 1053-0770/& 2017 Elsevier Inc. All rights reserved.
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2
Nonetheless, which of these inhaled and intravenous anesthetic agents is most beneficial for the clinical neurologic outcome remains controversial. According to various preclinical and animal studies, inhaled anesthetics interact with recognized neurodegeneration pathways and increase cellular stress.2–6 In contrast to inhaled anesthetics, propofol had a robust anti-inflammatory effect and resulted in less cognitive impairment.7,8 Therefore, propofol may be a good choice for minimizing the inflammatory response and related neurologic complications. Recent clinical studies have revealed that inhaled anesthetics are beneficial for early postoperative cognitive function in patients who have undergone on-pump coronary artery bypass grafting (CABG).9,10 However, these studies were performed under cardiopulmonary bypass (CPB), which triggers a powerful inflammatory response11 and did not enable clear conclusions to be drawn. Surgical stimulation itself also induces an inflammatory response even without CPB.12 Therefore, a clinical evaluation of the impact of different anesthetic agents (inhaled anesthetics v propofol) on the neurocognitive deficit during off-pump CABG is needed to minimize the confounding effect induced by the CPBinduced inflammatory response. The authors hypothesized that propofol-based anesthesia would result in a reduced inflammatory response and related neurologic complications, such as POD, compared with sevoflurane-based anesthesia during off-pump CABG. This study evaluated the incidence of POD and identified risk factors for developing POD in patients undergoing sevoflurane- or propofol-based anesthesia during off-pump CABG.
in the propofol group. Remifentanil was administered to a fixed target plasma concentration (plasma site, Minto model13) of 10 ng/mL in both groups using a target-controlled infusion device (Orchestras Base Primea; Fresenius Vial, Brézins, France). Anesthesia was maintained according to the standard institutional regimens14 for sevoflurane (sevoflurane group) or propofol (propofol group) with remifentanil at 10 ng/mL. Sevoflurane and propofol were titrated to maintain a bispectral index (BIS) value of 40-50 during the entire anesthetic period. The mean arterial pressure (MAP) was maintained at 460 mmHg during off-pump CABG using volume replacement, inotropes, and vasoconstrictors. Cerebral oxygen saturation was monitored using near-infrared spectroscopy (NIRS) and was maintained within the range of 20% of the initial preinduction value. A decrease in the NIRS value of more than 20% after an abrupt blood pressure decline due to a reversed heart position was managed by increasing the mean systolic arterial pressure or fraction of inspired oxygen, transfusing packed red blood cells (pRBCs), or hypoventilating the patient to improve cerebral blood flow as appropriate. pRBCs were transfused using a guided target hemoglobin level of 10 g/dL considering the patient’s cerebral oxygenation saturation, volume status, and intraoperative blood loss. Patients who showed deterioration in the vital signs or cardiogenic shock due to unstable angina or acute myocardial infarction were treated with an intraaortic balloon pump (IABP) pre- and intraoperatively, which was maintained during the perioperative period.
Methods
Medical treatment and decision-making in the ICU were performed by responsible intensivists. All patients received only remifentanil infusion continuously for sedation and pain control until extubation and an intravenous patient-controlled analgesia pump containing fentanyl (0.2 μg/kg/h, total dosage of 25 µg/kg), ketorolac (0.35 mg/kg/h, total dosage of 2.5 mg/kg), and ramosetron (0.9 mg) was used in all patients after extubation for postoperative pain control as per the institutional strategy.14 Intubation time was defined as the time from arrival in the ICU to extubation in the ICU. The ICU stay duration was defined as the time from arrival in the ICU until the patient satisfied the ICU discharge criteria. Continuous renal replacement therapy (CRRT) was applied after off-pump CABG if the patient showed signs of acute kidney disease, such as elevated serum creatinine level with oliguria, diuretic-resistant fluid overload, and hyperkalemia. Pneumonia was confirmed after off-pump CABG on postoperative follow-up chest radiographs and clinical symptoms and treated with antibiotics. Perioperative new-onset atrial fibrillation (A.fib) was managed by maintaining hemodynamic stability with optimal volume status, using antiarrhythmic medication, and correcting any electrolyte imbalance. Amiodarone was infused based on the decision of responsible doctors referring to relevant guidelines.15
Study Population Ethical approval for this study (approval number: KUH1160073) was provided by the Institutional Review Board of Konkuk University Medical Center, Seoul, South Korea (Chairperson Professor S.H. Lee) on September 4, 2014 and registered at ClinicalTrials.gov (registration number: NCT02374177; http://clin icaltrials.gov). The medical records of the patients undergoing offpump CABG at Konkuk University Medical Center from January 2010 to February 2015 were reviewed retrospectively. The patients received sevoflurane or propofol according to their daily random assignment to two different operating rooms for cardiac surgery, according to an institutional strategy that varied by day of the week, and were managed separately using different anesthetic regimens (one for sevoflurane and the other for propofol) with the same strategy for hemodynamic management. After reviewing the medical records, the patients were divided according to the anesthetic agent that they received (sevoflurane or propofol groups). A patient was excluded if any of the following criteria were met: (1) other concurrent surgery and (2) conversion from off-pump CABG to on-pump CABG.
Intensive Care Unit (ICU) Protocols After Off-Pump CABG
Postoperative Delirium Anesthetic Management During Off-Pump CABG Anesthesia was induced with etomidate or/and low-dose midazolam (1-to-2 mg) in the sevoflurane group and propofol
POD up to postoperative day 7 was evaluated. If the patient’s postoperative cognitive and behavioral functions were abnormal, if attention was disrupted over the short term with
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fluctuations over time, disorganized thinking was evident or other associated symptoms were detected by an attending physician, according to the institutional strategy, immediate psychiatric consultation was requested to diagnose POD based on the Diagnostic and Statistical Manual of Mental Disorders criteria.16 The psychiatrist had to evaluate the patients’ abnormal cognitive and behavioral function within 1 hour of requesting the consultation. The authors investigated the incidence of POD by reviewing the medical records. Perioperative Events Up To 1 Week Postoperatively The anesthetic records were reviewed to identify MAP o 60 mmHg, a decrease in the NIRS value 420% of the initial value, and BIS o 40 during the intraoperative period. CRRT, new-onset pneumonia, A.fib occurring for the first time without a history, and POD in the ICU during the first week postoperatively were identified by reviewing the medical records.
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Demographic Data and Known Risk Factors Preoperative characteristics of the patients, including sex, age, height, weight, body mass index, anesthesia duration, intubation duration, ICU stay duration, total numbers of revascularized vessels, and perioperative drug infusion were identified. Known risk factors for POD17,18 were identified: (1) smoking history; (2) underlying diseases including hypertension, diabetes mellitus, dyslipidemia, A.fib, carotid artery stenosis, chronic kidney disease confirmed by nephrologists, and dementia; (3) history of percutaneous coronary intervention, CABG, or cerebrovascular accident; and (4) preoperative status, including left ventricular ejection fraction (LVEF) o 40%, regional wall motion abnormality on echocardiography and in the presence of an IABP. The amount of pRBC transfusion intraoperatively and during the first postoperative 24 hours also was determined from a review of the medical records.
Table 1 Demographic Characteristics
Gender (male/female) Male Female Age Z75 years Height (cm) Weight (kg) BMI Z25 kg/m2 Smoking Z15 pack years Underlying disease Hypertension Diabetes mellitus Dyslipidemia A.fib Carotid artery stenosis Chronic kidney disease Dementia History PCI CABG CVA Preoperative status LVEF o40% RWMA on Echo Preoperative use of IABP Unstable angina Acute MI Intraoperative use of IABP Unstable angina Acute MI
Sevoflurane (n ¼ 156)
Propofol (n ¼ 136)
p Value
114 42 21 163 66 85 69
(73%) (27%) (14%) 7 9 7 12 (55%) (44%)
97 39 13 163 66 78 54
(71%) (29%) (9.6%) 7 9 7 12 (57%) (40%)
0.300 0.924 0.845 0.623 0.435
93 65 8 6 7 12 10
(60%) (42%) (5%) (4%) (5%) (8%) (6%)
86 58 8 7 3 13 5
(63%) (43%) (6%) (5%) (2%) (10%) (4%)
0.526 0.866 0.778 0.591 0.347 0.570 0.291
23 (15%) 2 (1%) 19 (12%)
24 (18%) 2 (2%) 14 (10%)
0.501 1.000 0.612
29 (19%) 69 (46%)
21 (15%) 64 (47%)
0.476 0.772 0.767
5 (3.2%) 7 (4.5%)
4 (2.9%) 9 (6.6%)
2 (1.3%) 2 (1.3%)
1 (0.7%) 2 (1.5%)
0.739
1.000
NOTE. Data are number of patients (%) or mean 7 standard deviation. Intraoperative use of IABP indicates new insertion of IABP during surgery, whereas preoperative use of IAPB indicates new insertion of IABP before surgery. Abbreviations: A.fib, atrial fibrillation; BMI, body mass index; CABG, coronary artery bypass graft; CVA, cerebrovascular accident; Echo, echocardiography; IABP, intra-aortic balloon pump; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RWMA, regional wall motion abnormality.
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Laboratory Data Laboratory values, including hemoglobin, hematocrit, albumin, creatinine, high-sensitivity C-reactive protein (HS-CRP), creatine kinase-MB (CK-MB), troponin I and B-type natriuretic peptide (BNP) preoperatively, and 1- and 24-hour postoperatively, were identified from a review of the medical records. Statistical Analysis The primary outcome variable was the incidence of POD occurring within 7 days postoperatively between the different anesthetic agents in patients who underwent off-pump CABG.
Based on a preliminary review of medical records with 30 patients undergoing off-pump CABG under propofol-based anesthesia, the incidence of POD was 13.3% (4 of 30 patients). The sample size of 136 in each group was calculated to detect twice the incidence of POD in the sevoflurane-based group, with a power of 0.80 and an α value of 0.05. Normally distributed continuous data are presented as mean 7 standard deviation. Non-normally distributed continuous data are presented as median (interquartile range). The number of patients (n) and proportions (%) were calculated for categorical variables. The independent twotailed t-test was used to compare normally distributed means of continuous data variables. The Mann–Whitney U-test was used when the data were not distributed normally. The
Table 2 Intra- and Postoperative Variables for the Two Anesthetic Agents Sevoflurane (n ¼ 156) Anesthetic agents for induction Propofol Etomidate Midazolam þ etomidate Anesthesia duration (min) Intubation duration (min) ICU stay duration (min) TNR 1 2 3 4 5 Perioperative drug infusion Dopamine Dobutamine Milrinone Norepinephrine Epinephrine Amiodarone Intraoperative events MAP o60 mmHg NIRS o20% BIS o40 Intraoperative pRBC transfusion r2 U 3-5 U Z6 U Postoperative 1 week events CRRT Pneumonia New-onset A.fib Postoperative 24-h pRBC transfusion r2 U 3-5 U Z6 U
Propofol (n ¼ 136)
p Value o0.001
0 29 127 379 929 2,875
(0%) (18.6%) (81.4%) 7 87 (422) (1,528)
136 0 0 377 987 2,905
(100%) (0%) (0%) 7 84 (385) (1,502)
0.821 0.127 0.997 0.446
29 38 58 30 1
(19%) (24%) (37%) (19%) (1%)
16 39 47 33 1
(12%) (29%) (35%) (24%) (0%)
148 45 23 10 1 29
(95%) (29%) (15%) (6%) (1%) (19%)
132 49 17 4 2 27
(97%) (36%) (13%) (3%) (2%) (20%)
0.348 0.190 0.578 0.166 0.600 0.784
27 (17%) 39 (25%) 79 (51%)
15 (11%) 44 (32%) 72 (53%)
0.127 0.165 0.695 0.449
114 (73%) 36 (23%) 6 (4%)
108 (79%) 24 (18%) 4 (3%)
5 (3%) 16 (10%) 21 (14%)
9 (7%) 13 (10%) 20 (15%)
95 (61%) 49 (31%) 12 (8%)
64 (47%) 55 (40%) 17 (13%)
0.272 0.848 0.866 0.052
NOTE. Data are numbers of patients (%), mean 7 standard deviation, or median (interquartile range). New-onset A.fib indicates that A.fib occurred for the first time without previous atrial fibrillation history. Abbreviations: A.fib, atrial fibrillation; BIS, bispectral index; CRRT, continuous renal replacement therapy; ICU, intensive care unit; MAP, mean arterial pressure; NIRS o20%, less than 20% of initial near-infrared spectroscopic value; pRBC, packed red blood cell; TNR, total number of revascularized vessels.
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Age Z 75 years, chronic kidney disease, preoperative use of IABP, preoperative LVEF o 40%, intubation duration 4 3 days, ICU stay 4 1 week, perioperative amiodarone infusion, 3-to-5 pRBC units transfused intraoperatively, postoperative pneumonia, CRRT, 6 or more pRBC units transfused 24 hours postoperatively, albumin o 3.0 g/dL, creatinine Z 1.5 mg/dL and troponin I Z 0.5 ng/mL were included in a binary logistic regression model (Table 4). The model identified age Z 75 years (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.44-16.27; p ¼ 0.011), postoperative pneumonia (OR, 10.84; 95% CI, 3.32-35.34; p o 0.001), 6 or more pRBC units transfused 24 hours postoperatively (OR, 5.30; 95% CI, 1.32-21.27; p ¼ 0.019), and albumin o 3.0 g/dL 24 hours postoperatively (OR, 3.38; 95% CI, 1.20-9.31; p ¼ 0.021) as independent predictors of POD after off-pump CABG.
chi-square test was used to compare categorical variables between the sevoflurane and propofol groups. A univariate analysis of POD for each potential risk factor was performed using logistic regression. Exposures for which the p value was o 0.05 in the univariate analysis were entered into a multivariate conditional logistic regression model to identify independent predictors of POD. All calculations were performed using SPSS ver. 18.0 software (SPSS, Chicago, IL). A p o 0.05 was considered significant.
Results A total of 300 patients underwent off-pump CABG from January 2010 to February 2015, and 292 were eligible for the study (156 for the sevoflurane group v 136 for the propofol group). Eight patients were excluded—2 had concurrent surgery and 6 converted to on-pump CABG. No differences in demographic characteristics were detected between the 2 anesthetic groups (Table 1). No differences in perioperative drug infusion, perioperative events (intraoperative MAP o60 mmHg, a decrease in the NIRS value 4 20% of the initial value, BIS o40; postoperative CRRT, pneumonia, new-onset A.fib), and intra- and 24-hour postoperative pRBC transfusions were detected between the groups (Table 2). Hemoglobin, hematocrit, and albumin decreased 24 hours postoperatively but did not differ significantly between the groups (Table 3). Serum creatinine also did not differ significantly between the groups. HS-CRP, CK-MB, and troponin I levels increased 24 hours postoperatively but did not differ significantly between the groups. BNP also did not differ significantly between the groups during the preoperative period. The cumulative incidence of POD after off-pump CABG up to 7 postoperative days was 10.6% (31 of 292 patients), and 74.2% (23 of 31 patients) developed POD within 3 postoperative days. The incidences of POD in the sevoflurane and propofol groups did not differ significantly (13% [20 of 156 patients] and 8% [11 of 136 patients], respectively, p ¼ 0.137).
Discussion The results of this study indicated that the incidence of POD in patients undergoing off-pump CABG did not differ between those receiving sevoflurane versus propofol-based anesthesia. Advanced age Z75 years, postoperative pneumonia, 6 or more pRBC units transfused 24 hours postoperatively, and albumin o3.0 g/dL 24 hours postoperatively were independent predictors of POD after off-pump CABG in the present study. Inhaled anesthetics have been shown to produce neuroinflammation associated with impaired cognition in various preclinical studies.7,19–21 In contrast to inhaled anesthetics, propofol has not been demonstrated to produce neuroinflammation7 while it improves the neurologic outcome and decreases neuronal damage after cerebral ischemia in animal studies.22 However, the authors found that the antiinflammatory effect of propofol did not provide an advantage in minimizing POD. Although the CPB-related inflammatory response was minimized in the study design, the various inflammatory responses that occurred during the perioperative period12,23 might have mitigated the anti-inflammatory effect of propofol.
Table 3 Pre- and Postoperative Laboratory Values in Relation to the Two Anesthetic Agents Preoperative Sevoflurane (n ¼ 156) Hemoglobin (g/dL) Hematocrit (%) Albumin (g/dL) Creatinine (mg/dL) HS-CRP (mg/dL) CK-MB (ng/mL) Troponin I (ng/mL) BNP (pg/dL)
13.2 39 4.0 0.9 0.2 0.9 0.02 148
7 2.0 (8) (0.6) (0.3) (0.9) (0.8) (0.22) (483)
Postoperative 24 h Propofol (n ¼ 136)
Sevoflurane (n ¼ 156)
Propofol (n ¼ 136)
7 1.9 (8) (0.6) (0.3) (0.8) (0.8) (0.26) (627)
11.2 7 1.1 34 (3) 3.1 7 0.4 0.9 (0.5) 11.7 7 5.4 6.5 (8.9) 1.17 (3.05) –
11.4 7 1.3 34 (5) 3.1 7 0.3 0.8 (0.4) 10.0 (9.7) 8.4 (10.2) 1.58 (3.33) –
13.1 39 3.9 0.9 0.2 1.0 0.03 146
NOTE. Data are mean 7 standard deviation or median (interquartile range). Abbreviations: BNP, B-type natriuretic peptide; CK-MB, creatine kinase-MB; HS-CRP, high-sensitivity C-reactive protein. Please cite this article as: Oh C-S, et al. (2017), http://dx.doi.org/10.1053/j.jvca.2017.02.047
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Table 4 Unadjusted and Adjusted Odds Ratios for Postoperative Delirium as a Dependent Variable and Independent Predictors Variables
Incidence
Age Z75 years Chronic kidney disease Preoperative use of IABP Preoperative EF o40% Intubation duration 43 days ICU stay 41 week Perioperative amiodarone infusion Intraoperative pRBC transfusion 3-5 U Postoperative pneumonia Postoperative CRRT apply Postoperative 24-h pRBC transfusion Z6 U Albumin o3.0 g/dL at postoperative 24 h Creatinine Z1.5 mg/dL at postoperative 24 h Troponin I Z0.5 ng/mL at postoperative 24 h
34 25 25 50 11 7 56 60 29 14 29 95 38 210
(12%) (9%) (9%) (17%) (4%) (2%) (19%) (21%) (10%) (5%) (10%) (33%) (13%) (72%)
Unadjusted OR (95% CI) 4.70 3.06 3.94 2.63 12.29 24.90 3.66 2.54 16.5 10.58 10.19 2.46 3.96 4.05
(1.99-11.14) (1.12-8.36) (1.50-10.37) (1.15-6.00) (3.50-43.14) (4.60-134.79) (1.67-8.03) (1.13-5.73) (6.82-40.14) (3.43-32.70) (3.72-27.90) (1.16-5.21) (1.70-9.26) (1.20-13.72)
p Value o0.001 0.029 0.006 0.022 o0.001 o0.001 0.001 0.024 o0.001 o0.001 o0.001 0.019 0.001 0.025
Adjusted OR (95% CI) 4.84 1.03 0.73 2.17 2.13 6.04 1.21 0.80 10.84 0.90 5.30 3.38 1.57 1.42
(1.44-16.27) (0.15-6.96) (0.12-4.27) (0.62-7.67) (0.28-16.07) (0.45-81.65) (0.37-3.97) (0.24-2.68) (3.32-35.34) (0.11-7.56) (1.32-21.27) (1.20-9.31) (0.30-8.25) (0.36-5.70)
p Value 0.011 0.980 0.726 0.229 0.462 0.176 0.749 0.715 o0.001 0.923 0.019 0.021 0.597 0.619
Abbreviations: CRRT, continuous renal replacement therapy; EF, ejection fraction; IABP, intra-aortic balloon pump; ICU, intensive care unit; OR, odds ratio; pRBC, packed red blood cell.
Several studies have revealed inconsistent clinical results. For example, two recent prospective studies by Schoen et al and Royse et al reported better early postoperative cognitive results after cardiac surgery using CPB for inhaled anesthetics compared with those of propofol.9,10 However, Kalimeris et al reported that patients who received propofol showed superior cognitive functioning over those who took sevoflurane for carotid endarterectomy.24 Furthermore, the improved postoperative cognitive function in patients who received inhaled anesthetics in the studies by Schoen et al and Royse et al were no longer present 3 months after the surgery, suggesting that the effects of anesthesia type are not long lasting. According to the present retrospective investigation, POD was not affected by the type of anesthetic agent. Therefore, specific anesthetic agents may not influence the risk of POD. CPB-related systemic inflammation may affect immediate postoperative cerebral function and the incidence of POD.25 The studies of Schoen et al and Royse et al were performed on patients who underwent on-pump CABG, in contrast to offpump CABG in this study, which could have been biased for neuroinflammation. Schoen et al reported that cerebral desaturation during on-pump CABG was related to worse postoperative cognition. However, CPB-related neuroinflammation could be a confounding factor for cognitive dysfunction noted in previous studies.9,10 Furthermore, the reverse heart position during anastomosis of the left circumflex artery or right coronary artery and inotropic or vasoconstrictor use during off-pump CABG could be major contributing factors to hemodynamic instability and cerebral hypoperfusion. Therefore, Baki et al reported that the level of the S100-beta protein, a cerebral injury marker, was lower in patients who received propofol for cardiac surgery with CPB than desflurane.26 However, the levels of interleukin-6 and -8, which are markers of inflammation, were lower in the desflurane group than in the propofol group, indicating that CPB could have various effects
on inflammation and there could be confounders when evaluating neuroinflammation. In this study, the authors focused on delirium and not on postoperative cognitive dysfunction (POCD) during the early postoperative period (within 1 week) for several reasons. POD has an acute onset with more aggressive symptoms, including marked fluctuation in attention and orientation related to postoperative mortality,27 whereas POCD has much more subtle symptoms and is more difficult to define due to the absence of a standard test and the requirement for preoperative baseline psychological testing.28,29 Furthermore, POD and POCD are separate entities and their relationship has yet to be fully elucidated.29 Therefore, further well-designed prospective studies evaluating the effect of anesthetic agents on cognitive function after off-pump CABG to distinguish POD from POCD will be informative. Old age, pneumonia, low albumin, and perioperative transfusion are well-known risk factors for POD,30–32 and they were also independent predictors of POD in this study. However, sevoflurane-based anesthesia was not included in the final independent predictors of POD. This indicated that the effect of the anesthetic agent on POD might be minimal after off-pump CABG. Miyazaki et al revealed that old age, carotid artery stenosis, high creatinine, hypertension, atrial fibrillation, and a history of smoking were independent predictors of POD after off-pump CABG, which was somewhat different from the present study. The authors think that this difference was due to the different factors that were included in the analysis. The final independent predictors could differ in the present study because the authors evaluated the application of IABP and CRRT, a low ejection fraction, and transfusion amount, while Miyazaki et al did not evaluate these factors. Therefore, the authors' predictors and those in Miyazaki et al should be considered simultaneously when performing cardiac anesthesia to reduce POD.
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The authors acknowledge some limitations to this study. First, the initial signs or symptoms of POD were detected by the attending physician and a psychiatrist was then consulted. Even when the attending physician precisely observes the symptoms and signs of POD, the hypoactive form of POD is usually more difficult to detect than the hyperactive form. There is thus a chance that the hypoactive form of POD might be missed. The evaluation of POD by using the confusion assessment method for the ICU would have been more suitable in the present study to detect the hypoactive form of POD.33 Second, the potential limitations of this study included the retrospective nature of the data collection and lack of randomization. Assignment of surgical room for cardiac surgery had been decided by the day of the week in the institution and anesthetic agents were decided according to the regimen of blinded attending anesthesiologists who were responsible for the assigned surgical room. The authors thought this assignment could achieve unintentional randomization in the present study. However, even when the choice of anesthetic agents involved unintentional randomization, it could be insufficient to reduce bias. Third, the authors assessed laboratory data up to 1 day postoperatively because they thought that most of the effects of the anesthetic agents on the patients would not last for more than 1 day. Therefore, abnormal laboratory data after postoperative 1 day might have been missed. Finally, the present study might have been somewhat underpowered because of the large gap of expected incidence of POD between the 2 anesthetic agents from the preliminary data. These results suggested that a larger sample size is necessary to conduct advanced statistical analysis. In conclusion, POD presented similarly in patients anesthetized with sevoflurane or propofol during off-pump CABG surgery. Age Z 75 years, 6 or more pRBC units transfused within 24 hours postoperatively, and albumin o 3.0 g/dL 24 hours postoperatively were independent predictors of POD after off-pump CABG. These findings suggested that there were no specific benefits of sevoflurane or propofol in reducing POD after off-pump CABG.
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