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Ann Thorac Surg 2003;75:840-846
© 2003 The Society of Thoracic Surgeons
a Division of Intensive Care Medicine, Gunma, Japan
b Department of Anesthesiology and Reanimatology, Gunma University, School of Medicine, Gunma, Japan
c Department of Anesthesiology, Saitama Cardiovascular and Pulmonary Center, Gunma, Japan
Accepted for publication September 19, 2002.
* Address reprint requests to Dr Kadoi, Division of Intensive Care Medicine, Gunma University, School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
e-mail: kadoi{at}med.gunma-u.ac.jp
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Abstract |
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METHODS: One hundred eighty patients scheduled for elective coronary artery bypass grafting were randomly divided into two groups: propofol group (n = 90) and fentanyl group (n = 90). After induction of anesthesia, a fiberoptic oximetry oxygen saturation catheter was inserted into the right jugular bulb to monitor jugular venous oxygen hemoglobin saturation continuously. Hemodynamic measurements and arterial and jugular venous blood gases were measured at seven time points. All patients underwent a battery of neurologic and neuropsychological tests on the day before the operation and at 6 months after the operation.
RESULTS: Cerebral desaturation (defined as a jugular venous oxygen hemoglobin saturation value less than 50%) during cardiopulmonary bypass was more frequent in the fentanyl group than in the propofol group. Cerebral desaturation time (duration when jugular venous oxygen hemoglobin saturation was less than 50%) and the ratio of cerebral desaturation time to total cardiopulmonary bypass time in the fentanyl group differed significantly from those in the propofol group (fentanyl group: 27 ± 14 minutes, 20% ± 9%; propofol group: 18 ± 11 minutes, 14% ± 7%, respectively, p < 0.05). There was no significant difference in postoperative cognitive dysfunction at 6 months after operation between the two groups (propofol group: 5 of 77, 6%; fentanyl group: 5 of 75, 7%).
CONCLUSIONS: Propofol preserved cerebral oxygenation state estimated by jugular venous oxygenation during cardiopulmonary bypass compared with the fentanyl group. However, propofol did not affect postoperative cognitive dysfunction.
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Introduction |
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Several studies have attempted to identify intraoperative factors of cognitive change after CPB [3, 4]. Two possible mechanisms of postoperative cognitive dysfunction are cerebral ischemia and cerebral desaturation as a result of hypoperfusion during CPB [1]. Croughwell and colleagues [3] reported that lower values for internal jugular venous oxygen hemoglobin saturation (SjvO2) at the end of rewarming were associated with cognitive deficits 4 to 8 days after operation. They suggested the importance of assessing the cerebral oxygenation state estimated by SjvO2 during CPB.
Recently, several studies have attempted to improve cerebral oxygenation during CPB. Hanel and associates [5] reported that mild hypercapnia (arterial carbon dioxide pressure from 43.6 mm Hg to 48.6 mm Hg) during the rewarming period could prevent the cerebral desaturation state. However, they did not examine whether this hypercapnia during the rewarming period could improve postoperative cognitive dysfunction. Roach and coworkers [6] reported that a propofol-induced burst suppression did not lead to better neurologic or neuropsychological outcome than did opiate-based anesthesia in patients undergoing valve operations. Subjects in the study by Roach and associates [6] were undergoing cardiac valve operations, not coronary artery bypass grafting (CABG). It is generally accepted that the incidence of postoperative cognitive dysfunction differs between valve operation patients and CABG patients [1]. Inasmuch as the number of patients undergoing CABG is increasing [1], it would be more important to determine whether an anesthetic regimen could improve cerebral oxygenation during CPB.
There have been two reports describing the comparative effects of propofol anesthesia and opiate-based anesthesia on postoperative cognitive dysfunction during hypothermic CPB [7, 8]. However, there has been no comparative study regarding the effects of propofol anesthesia and opiate-based anesthesia on SjvO2 and postoperative cognitive dysfunction during normothermic CPB, which has been widely used in recent years during cardiac surgical procedures [2].
The purpose of this study was to examine the comparative effects of propofol and fentanyl on cerebral oxygenation during normothermic CPB and postoperative cognitive dysfunction.
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Patients and methods |
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Patients were randomly divided into two groups; a propofol group (n = 90), in which patients received 4 to 6 mg · kg-1 · h-1 propofol infusion using a syringe pump continuously until arriving in the intensive care unit, and a fentanyl group (n = 90), in which patients received 40 to 70 µg/kg (mean average, 58.1 ± 15.2 µg/kg, ± standard deviation) of fentanyl infusion. A bispectral index (BIS) monitoring (Aspect Medical Systems, Natick, MA) electrode was attached to the forehead of the patient as instructed by the manufacturer. The anesthetic dosage for each group was defined as that which did not induce hypotension, but which produced an equivalent anesthetic depth during CPB in each group, as measured by BIS monitoring. We did not induce burst-suppression in the propofol group, because the burst-suppression dosage of propofol induced massive hypotension.
All patients received 10 mg of diazepam by mouth 1 hour before anesthesia. Anesthesia was induced by 0.3 mg/kg midazolam, 10 µg/kg fentanyl, and 0.2 mg/kg vecuronium, and the trachea was intubated. After induction of anesthesia, a pulmonary arterial catheter (Vigilance, Swan-Ganz CCO Thermodilution Catheter, Baxter, Irvine, CA) was inserted through the right internal jugular vein. For continuous monitoring of SjvO2, a 4.0F fiberoptic oximetry oxygen saturation catheter (dual-lumen oximetry catheter, Baxter) was inserted into the right jugular bulb using a modified Seldinger technique. This catheter was connected to an analysis system (Explorer System, Baxter) and calibrated in vivo by drawing a blood sample from the catheter. The position of the jugular bulb catheter was verified by roentgenogram. The correctly positioned catheter tip should be placed cranial to a line extending from the atlantooccipital joint space and caudal to the lower margin of the orbit. Jugular venous oxygen hemoglobin saturation was collected and processed in a monitor–computer interface and displayed and stored every 5 seconds on an Apple Macintosh computer (Apple Computer, Cupertino, CA).
Partial pressures of the arterial and jugular venous blood gases were analyzed using CO-oximeter (OSM3, Hemoximeter, Radiometer Co, Copenhagen). All patients were ventilated with oxygen 50% and nitrogen 50%. End-tidal carbon dioxide was monitored (Ultima, Datex, Helsinki, Finland) and maintained between 35 and 40 mm Hg. Muscular relaxation was maintained by intermittent administration of vecuronium. No volatile anesthetic was administrated. After the onset of CPB, 0.2 mg/kg midazolam was infused into all patients. The tympanic temperature was continuously monitored by Mon-a-Therm (Mallinckrodt Co, St. Louis, MO).
Cardiopulmonary bypass was primed with a crystalloid, nonglucose-containing solution, and a nonpulsatile pump flow rate of 2.2 to 2.5 L · min-1 · m-2 was maintained. A membrane oxygenator and a 40-µm arterial line filter were used, and arterial carbon dioxide tension uncorrected for temperature was adjusted to normocapnic levels (35 to 40 mm Hg) by varying fresh gas flow to the membrane oxygenator (
-stat regulation).
Target nasopharyngeal temperatures during CPB were more than 35°C. The limit on maximal inflow temperature was set at 37.5°C.
Hematocrit was maintained at more than 20% on CPB, with the addition of blood as necessary. Phenylephrine infusions were used during CPB to maintain mean arterial pressure at 50 to 80 mm Hg. Intermittently, antegrade blood cardioplegia was administrated at 37°C. Distal coronary anastomoses and proximal anastomoses were performed during a single aortic cross-clamp.
During the CPB period, BIS scores were measured continuously as a monitor of depth of anesthesia. Hemodynamic measurements and arterial and jugular venous blood gases were measured at the following times: (1) after induction of anesthesia and before the start of the surgical procedure, (2) at the onset of CPB, (3) 20 minutes after the onset of CPB, (4) 40 minutes after the onset of CPB, (5) 60 minutes after the onset of CPB, (6) at the cessation of CPB, and (7) at the end of the operation.
Intraoperative epiaortic ultrasonography confirmed that none of the patients had moderate or severe atherosclerotic lesions in the ascending aorta.
Critically low SjvO2 values (<50%) found in normothermic, awake humans account for cerebral dysfunction and electroencephalographic slowing [9, 10]. In addition, Gopinath and associates [11] showed that an SjvO2 less than 50% for more than 10 minutes during intensive therapy care of patients with severe head injuries was strongly associated with a poor neurologic outcome. Thus, we defined cerebral desaturation as a SjvO2 less than 50%.
Neurologic and neuropsychologic assessments
All patients underwent a battery of neurologic and neuropsychological tests on the day before the operation and at 6 months after the operation, administered by trained specialists. The examiners who administrated the cognitive tests were unaware of the patient’s intraoperative treatment assignment (propofol or fentanyl).
The neuropsychological portion of the study design followed the consensus statements on the assessment of central nervous system disorders after cardiac surgery [12].
Cognitive functioning was assessing using the following tests: (1) Mini-Mental Test, (2) Rey Auditory Verbal Learning Test, (3) Trail-Making Test (part A), (4) Trail-Making Test (part B), (5) digit span forward, and (6) grooved pegboard.
Statistical analysis
All data are expressed as mean ± standard deviation. After confirmation of equal variance among the groups by the Bartlett test, two-way repeated measures analysis of variance was performed for multiple comparisons. With a significant F value, the Bonferroni method was used for multiple comparisons. To eliminate a type II error, each individual p value was adjusted. Cerebral desaturation states in the two groups were analyzed using an unpaired Student’s t test. Difference between the preoperative values and those at 6 months after the operation on neuropsychologic tests was assessed with a paired Student’s t test. To obtain an indicator of outcome overall, significant impairment was defined as a decline from preoperative testing of more than one standard deviation on more than 20% of test measures (at least two of six). A multivariable logistic regression with odds ratio was used to examine the predictive variables of adverse outcome at 6 months. After the study was completed, the sample size was evaluated. Based on our previous report [4, 13], we considered a 20% reduction of cognitive dysfunction to be clinically important. The sample size provides 80% power to detect a 20% difference between groups with a 5% probability of a type I error.
Statistical significance was set at p less than 0.05. All calculations were performed on a Macintosh computer with SPSS (SPSS, Inc, Chicago, IL) and StatView 5.0 software packages (Abacus Concepts, Inc, Berkeley, CA).
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There was no significant difference in BIS between groups during the CPB period (fentanyl group, 50 ± 11; propofol group, 47 ± 9; p = 0.53).
Major neurologic defects (defined as clinical evidence of focal cerebral infarction including hemiparesis, visual or gait disturbance, mental changes, or a combination of these) were observed in 3 patients after the operation (propofol group, 3 of 90 [3.3%]; fentanyl group, 3 of 90 [3.3%]; total 6 of 180 [3.3%]).
Table 4 shows the assessment during the intensive care unit period in two groups. There were significant differences in extubation time after CPB and emergence time from the anesthesia between the two groups. However, there were no significant differences in reintubation for pneumonia, length of intensive care unit stay, postoperative renal dysfunction (creatinine concentration > 3.0 mg/dL), postoperative liver dysfunction (glutamine oxaloacetate transaminase or glutamine pyruvate transaminase > 100 U/dL), or catecholamine dosage between the two groups.
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Comment |
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Comparative effects of propofol and fentanyl on jugular venous oxygen hemoglobin saturation
Several studies have investigated the effects of anesthetic agents on SjvO2 during CPB [6–8, 14]. Nandate and coworkers [14] examined the effects of isoflurane, sevoflurane, and propofol on SjvO2 during CPB in patients undergoing CABG and found that reduced SjvO2 was more often observed in the propofol group than in the isoflurane or sevoflurane groups. This finding is inconsistent with our results, but the discrepancy might be attributable in part to the propofol dosage and anesthetic protocol. Nandate and associates [14] used 15 µg/kg fentanyl as an induction agent. Moreover, they did not measure SjvO2 continuously, nor examine postoperative cognitive dysfunction.
Newman and colleagues [7] reported that SjvO2 values were equivalent between propofol-based (burst-suppression) and opiate (sufentanil)-based anesthesia during both hypothermic and normothermic (rewarming) bypass. Similarly, Souter and coworkers [8] found no SjvO2 differences between propofol-based (burst-suppression) and an opiate-benzodiazepine–based anesthetic during hypothermic or normothermic (rewarming) bypass. In contrast, in the present study, we found SjvO2 to be greater with propofol during steady-state normothermic bypass. Both the studies by Newman and colleagues [7] and Souter and coworkers [8] used a much greater dose of propofol than that used in this study (approximately 250 µg · kg-1 · min-1 [7]; approximately 125 µg · kg-1 · min-1 [8]; approximately 85 µg · kg-1 · min-1 [present study]). Both Newman and colleagues [7] and Souter and coworkers [8] also reported significant hypotension and greater vasoconstrictor use in patients receiving propofol versus control subjects. In contrast, propofol patients in this study did not receive significantly greater doses of vasoconstrictor than control subjects. Hypotension and vasoconstrictors may have altered cerebral blood flow. Johnston and associates [15] reported that phenylephrine did not reduce cerebral blood flow in animal models. However, we recently found that increasing mean arterial pressure has some effect on SjvO2 in patients without diabetes during tepid CPB [16]. Therefore, it is possible that differences in propofol dosage and hemodynamics and vasoconstrictor use between the studies by Newman and colleagues [7] and Souter and coworkers [8] and the present study might explain the different findings regarding the effect of propofol versus opiate on SjvO2. The present study findings did not explain why propofol could prevent the reduction of SjvO2 during normothermic CPB. We speculated that because propofol decreased cerebral blood flow and metabolism in parallel, as demonstrated by Newman and colleagues [7], mismatch of flow or metabolism, which was often observed at the initiation of CPB [17], did not occur in the propofol group.
Comparative effects of propofol and fentanyl on postoperative cognitive dysfunction
Several reports have described the effects of propofol on postoperative cognitive dysfunction [6–8]. Roach and associates [6] reported that a burst-suppression dose of propofol during cardiac valve operation did not reduce the incidence or severity of neurologic or neuropsychologic dysfunction during hypothermic CPB. Souter and coworkers [8] reported that propofol did not attenuate the frequency or extent of reductions of SjvO2 less than 50% during the rewarming period or postoperative cognitive decline. Both studies were conducted under hypothermic conditions. The present study examined the effects of propofol and fentanyl on SjvO2 and postoperative cognitive dysfunction during normothermic CPB and is consistent with the other two reports. Our study confirmed that SjvO2 during hypothermic or normothermic CPB did not appear to affect long-term cognitive outcome.
Clinical implications
Early tracheal extubation and the fast-track clinical care pathways are thought to be an acceptable approach to reduce the cost of CABG and possibly improve the physiologic status of patients [18]. Although we did not assess the costs of CABG in propofol-based anesthesia, propofol-based anesthesia is useful for the fast-track method.
Hanel and coworkers [5] reported that mild hypercapnia prevented reduced SjvO2 during the rewarming period. However, they did not examine the effects of mild hypercapnia during rewarming on postoperative cognitive dysfunction. Grigore and colleagues [19] in a recent study from Duke University reported that slower rewarming rates were better than standard rewarming techniques for improving neurocognitive outcome, possibly because of the amelioration of reduced SjvO2. If we prevent reduced SjvO2 during CPB, as was done in the present study and that by Hanel and coworkers [5], will cognitive outcome be improved? Unfortunately, there have been no clear reports regarding the effect of amelioration of reduced SjvO2 on postoperative cognitive dysfunction in patients undergoing CABG. The present study examined the effect of amelioration of reduced SjvO2 on postoperative cognitive decline in patients undergoing CABG. Our data indicate that prevention of reduced SjvO2 during normothermic CPB cannot improve long-term postoperative cognitive dysfunction.
Study limitations
Because a burst-suppression dose of propofol might induce massive hypotension, which would in turn lead to myocardial ischemia in patients undergoing CABG, we did not use a burst-suppression dose of propofol during the study. Therefore, this dosage of propofol might be not enough for brain protection. However, a recent study found that burst suppression was not necessary for maximal neuroprotection with pentobarbital [20].
It remains controversial whether reduced SjvO2 during the CPB period is a predictor of postoperative cognitive dysfunction. Croughwell and associates [3] reported that lower normothermic SjvO2 (at the end of rewarming) were associated with short-term cognitive deficits (4 to 8 days after operation). Subsequent work by Newman and colleagues [21], which included most of the patients reported in Croughwell and coworkers [3], found that SjvO2 had an extremely small independent association with cognitive impairment 7 to 10 days after operation in hypothermic CPB, when baseline cognitive status, age, and years of education were considered in the analysis. Finally, Robson and associates [22] found averaged SjvO2 during hypothermic bypass, and in the early postoperative phase, had no association with cognitive status 3 months after operation in normothermic CPB. In contrast, Yoshitani and coworkers [23] reported that high SjvO2 were associated with cognitive dysfunction after the operation. Further prospective, randomized studies are necessary to identify the association between low or high SjvO2 during CPB and cognitive dysfunction. In addition, we cannot rule out the potential problem in this study. Jugular venous oxygen hemoglobin saturation differences between the two groups were so small, and of such a short duration, that outcome was not likely to be affected. Therefore, we concluded that cerebral venous desaturation of the magnitude observed in this study was not sufficient to influence cognitive outcome.
Because of the limited time available for neuropsychological testing preoperatively, we could not cover all major cognitive domains. Moreover, there were no specific domains concerning the cognitive tests in this study. Further studies are needed to determine whether any correlation exists between SjvO2 reduction and all major cognitive domains.
Robson and colleagues [22] provided evidence that jugular bulb catheters were not very accurate during bypass, possibly because of increased vessel wall contact. However, in previous [17] and present studies, we assessed the accuracy of our oximetric catheter system and found an excellent correlation between oximetry catheter values for SjvO2 and simultaneous SjvO2 values obtained from samples of jugular venous blood measured in a CO-Oximeter.
Because SjvO2 indicates the global balance of cerebral blood flow and metabolism, it is possible that an SjvO2 monitor could not be sensitive enough to detect the regional cerebral oxygenation. However, in a previous study [17], we found a good correlation (r2 = 0.49) between SjvO2 and regional cerebral oxygenation measured by near infrared spectroscopy.
In the present study, we used BIS score as an indicator of anesthetic depth. There have been some controversial results regarding the use of BIS score to represent anesthetic depth [24]. Thus, we cannot rule out the possibility of a difference in anesthetic depth between the two groups.
In the present study, we selected a dichotomous outcome analysis. Controversy exists regarding which analysis would be more meaningful, a dichotomous outcome or continuous outcome measures [25, 26]. Grigore and colleagues [19] found that the analysis of neurocognitive performance as a continuous measure was more sensitive. Blumenthal and associates [26] reported that although the arbitrariness of categorical boundaries was avoided in continuous outcome measures, it was difficult to ascertain with this type of analysis the clinical significance of changes. Statistical analysis does not mean clinical importance [25]. There is no clear agreement whether linear regression is better than logistic regression analysis as a statistical method for assessing the relationship between risk factors and cognitive dysfunction [25]. We must consider what type of analysis is the most appropriate method for assessing cognitive dysfunction.
In conclusion, the fentanyl group had a reduced SjvO2 compared with the propofol group during normothermic CPB. However, this reduced SjvO2 was not associated with long-term cognitive dysfunction.
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Acknowledgments |
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) had decreased at 20 minutes after cardiopulmonary bypass (CPB) compared with at the induction of anesthesia. Moreover, there was a significant difference in jugular venous oxygen hemoglobin saturation between the two groups. *p < 0.05 compared with period 1; #p < 0.05 compared with the propofol group (•) after induction of anesthesia and before the start of the operation (1), at the onset of CPB (2), 20 minutes after the onset of CPB (3), 40 minutes after the onset of CPB (4), 60 minutes after the onset of CPB (5), at the cessation of CPB (6), and at the end of the operation (7).