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From the Department of Anesthesiology, Gunma University, Graduate School of Medicine, Japan.
Address correspondence and reprint requests to Yuji Kadoi, MD, Department of Anesthesiology, Gunma University, Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Address e-mail to kadoi{at}med.gunma-u.ac.jp.
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Introduction |
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There have been some published data showing that the use of volatile anesthetics, such as isoflurane or sevoflurane, is related to altered cerebrovascular CO2 reactivity under general anesthesia (4–6). Kitaguchi et al. (4) reported that CO2 reactivity was well maintained under 0.88 minimum alveolar anesthetic concentration (MAC) of sevoflurane anesthesia in patients with ischemic cerebrovascular disease. McPherson et al. (5) showed a difference in cerebrovascular CO2 reactivity between 1.4% and 2.8% isoflurane anesthesia. Nishiyama et al. (6) reported that cerebrovascular CO2 reactivity was more in isoflurane anesthesia than in sevoflurane anesthesia in subjects without diabetes mellitus. This report implies that different volatile anesthetics may have different effects on cerebrovascular CO2 reactivity, as was also reported by Summors et al. (7) who showed that volatile anesthetics each have different effects on cerebral vasculature when administered at the same MAC.
The prevalence of diabetes mellitus has been steadily increasing throughout the world for the past 20–30 years. Inevitably, the number of diabetic patients undergoing surgery is also gradually increasing (8). Although it is important for anesthesiologists to know whether the cerebrovascular CO2 reactivity in diabetic patients is different with sevoflurane versus isoflurane anesthesia, there are no data describing the same. In our previous studies (9,10), we found that diabetic patients had an impaired vasodilatory response to hypercapnia under propofol anesthesia. This led us to hypothesize that diabetic patients could also have an impaired cerebrovascular CO2 reactivity under volatile anesthesia. The purpose of this study was to examine the comparative affects of sevoflurane versus isoflurane on cerebrovascular CO2 reactivity in patients with diabetes mellitus.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Patients were considered to have diabetes mellitus if medical records showed that they were diagnosed as having type 2 diabetes and were being medically treated with antidiabetic therapy, such as diet, oral hypoglycemics, or insulin therapy. Duration of the disease was defined as the time period from the start of antidiabetic treatment to the date of the planned surgical procedure.
Patients with a history of cerebrovascular disease, psychiatric illness, and active liver disease (glutamine oxaloacetate transaminase or glutamine pyruvate transaminase >50 U/dL) were excluded from the study. Patients with hypertension were defined as those taking antihypertensive medication, in the form of angiotensin-converting enzyme inhibitors, ß-adrenergic blockers, or Ca channel blockers.
All patients were preoperatively examined for the presence of carotid artery stenosis by performing ultrasonography and magnetic resonance imaging. The presence of carotid artery stenosis was defined as luminal narrowing of >50% (where insignificant or no disease: luminal narrowing 
50%; moderate disease: narrowing >50% but <80%; severe disease: narrowing 
80% but 99%; defined by the area of the short axis view of the carotid artery (11)). One diabetic patient who had moderate to severe carotid artery stenosis was excluded from the study. All patients were examined for the presence of silent lacunar infarction by preoperative brain computed tomography and magnetic resonance tomography. One diabetic patient who had a silent lacunar infarction was excluded from the study. Forty diabetic patients satisfied all the criteria and were included in the study.
Because glycosylated hemoglobin (HbA1c; normal value, 4.5%–5.8%) is one of the indicators for adequacy of control of blood glucose levels in diabetic patients, all patients had their preoperative HbA1c levels measured.
The 40 patients were randomized into 2 groups: sevoflurane group or isoflurane group. Anesthesia was induced with 2 mg/kg of propofol, 5 µg/kg of fentanyl, and 0.2 mg/kg of vecuronium, followed by endotracheal intubation. Muscular relaxation was achieved by intermittent administration of vecuronium. All patients' lungs were ventilated with 33% oxygen and 67% nitrous oxide while continuous monitoring end-tidal carbon dioxide (PetCO2) (UltimaR; Datex, Helsinki, Finland). Tympanic membrane temperature was continuously monitored by Mon-a-ThermR (Mallinckrodt Co, St. Louis, MO). Anesthesia was maintained with either 1.0 MAC of sevoflurane or 1.0 MAC of isoflurane in 33% oxygen and 67% nitrous oxide (1 MAC = 1.71% for sevoflurane and 1.15% for isoflurane). Bispectral index monitor (ASPECT Medical Systems, Natic, MA) was used to assess the effects of equipotent doses of isoflurane and sevoflurane in each group.
The study was performed after the induction of anesthesia and before the start of surgery during a stable hemodynamic period (approximately 20–30 min after the induction of anesthesia) under 1.0 MAC of sevoflurane or isoflurane anesthesia. A 2.5-MHz pulsed transcranial Doppler probe was attached to the patient's head at the right temporal window, and mean blood flow velocity in the middle cerebral artery (Vmca) was measured continuously (Hewlett Packard SONOS 5500R, 2.5 MHz transducer; Hewlett Packard, Andover, MA). After the signals were identified at a depth of 45–60 mm, the probe was fixed using a probe holder so as not to change the insolating angle. The Vmca value at end-expiration was recorded.
After the measurement of baseline Vmca and cardiovascular hemodynamic values, Petco2 was increased by reducing the ventilatory frequency by 2–5 breaths/min. This resulted in an increase in the Petco2 by approximately 6–9 mm Hg within several minutes. All measurements were repeated when Petco2 increased and remained stable for 5–10 min.
The cerebral vasodilatory response to hypercapnia in each patient was calculated as both the absolute change in Vmca (cm · s–1 · mm Hg–1) and the relative change in Vmca (percentage of baseline Vmca/mm Hg) for each millimeter of mercury change in Paco2 using the following formulae (10,12):
Absolute Co2 reactivity = Vmca/Paco2
Relative CO2 reactivity = (absolute CO2 reactivity/baseline Vmca) x 100, where Vmca is the difference between the flow velocity after Paco2 increase and the baseline flow velocity, and Paco2 is the difference between the final and baseline Paco2.
Pulsatile index (PI) was calculated for all study participants using the following formulae (10,12):
Pi = (systolic velocity – diastolic velocity)/mean velocity
All data are expressed as mean ± sd. Unpaired student t-test was used for analysis between sevoflurane and isoflurane groups. After the confirmation of equal variance between groups by the Bartlett test, one-way factorial measure analysis of variance was performed with multiple comparisons. When the F-value was significant, the Bonferroni method was used to make multiple comparisons. To eliminate a type II error, each individual P value was adjusted. After the study was completed, we evaluated sample size, which was calculated based on the hypothesis that absolute CO2 reactivity in sevoflurane patients would decrease by 0.8 cm · s–1 · mm Hg–1 compared with that in isoflurane patients. The sample size provides 80% power to detect a 20% difference between groups with a 5% probability of an 
-type error. In addition, the sample size calculation was based on the hypothesis that absolute CO2 reactivity in insulin-treated patients with sevoflurane would decrease by 0.8 cm · s–1 · mm Hg–1 compared with that in insulin-treated patients with isoflurane. The sample size provides 70% power to detect a 30% difference between groups with a 5% probability of an -type error.
Statistical significance was set at P < 0.05. All calculations were performed on a Macintosh computer with SPSS (SPSS, Inc, Chicago, IL) and Stat View 5.0 software packages (Abacus Concepts, Inc, Berkeley, CA).
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RESULTS |
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Table 2 shows cerebrovascular CO2 reactivity data in the two groups. Values for bispectral index, baseline mean arterial blood pressure, Petco2, PI, and Vmca were essentially identical between the groups. Values for absolute and relative CO2 reactivity in insulin-dependant patients were less than those in antidiabetic drug or diet groups, irrespective of whether they were receiving sevoflurane or isoflurane. Values for absolute and relative CO2 reactivity in patients receiving diet or antidiabetic drug therapy were less in the sevoflurane group as compared to the isoflurane group. In contrast, in the insulin group, there were no significant differences in absolute and relative CO2 reactivity between sevoflurane and isoflurane.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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There are numerous studies analyzing the effects of volatile anesthetics, such as isoflurane or sevoflurane, on cerebrovascular CO2 reactivity (4–6,13–16). McPherson et al. (5) showed that cerebrovascular responsiveness to Paco2 was retained during both 1 and 2 MAC of isoflurane. In contrast, Olsen et al. (13) reported that CBF autoregulation was disrupted at 2 MAC of isoflurane anesthesia but not during 1 MAC of isoflurane anesthesia. With regard to sevoflurane, Kitaguchi et al. (4) reported that both CO2 reactivity and cerebral autoregulation were well maintained during the inhalation of 33% nitrous oxide, 33% argon, and oxygen with 1.5% sevoflurane (0.88 MAC) in patients without diabetes mellitus. Nishiyama et al. (6) examined the comparative effects of sevoflurane and isoflurane on cerebrovascular CO2 reactivity in patients without known cerebral disease and found that cerebrovascular CO2 reactivity was greater in the isoflurane (0.6–0.7 MAC) anesthesia group than in the sevoflurane (0.6–0.7 MAC) anesthesia group. The differential effects of these two volatile anesthetics is probably because of the fact that sevoflurane is reported to have a less direct vasodilator effect than isoflurane in patients without diabetes mellitus (6,16). Our study, which is the first of its kind to evaluate the differential effects of sevoflurane versus isoflurane on cerebrovascular CO2 reactivity in patients with diabetes mellitus, showed that cerebrovascular CO2 reactivity was greater in the isoflurane (1.0 MAC) anesthesia group than in the sevoflurane (1.0 MAC) anesthesia group in diabetic patients treated with dietary restrictions and antidiabetic drug therapy. These results were consistent with those reported by Nishiyama et al. (6). In contrast, the values for cerebrovascular CO2 reactivity were almost identical in the isoflurane and sevoflurane anesthesia groups in diabetic patients treated with insulin therapy. There are several probable reasons for these findings. Our previous study showed that increasing mean arterial blood pressure had no effect on jugular venous O2 saturation (SjvO2) in insulin-dependent patients (9). In contrast, SjvO2 values in control patients or diabetics treated with diet or glibenclamide, were increased after phenylephrine infusion during tepid cardiopulmonary bypass (9). In addition, we found that cerebrovascular CO2 reactivity in diabetic patients was related to the response of SjvO2 to phenylephrine infusion and that decreased cerebrovascular CO2 reactivity and the mean slope of SjvO2 versus cerebral perfusion pressure with increasing cerebral perfusion pressure were associated with HbA1c (17). Stratton et al. (18) reported that in patients with type 2 diabetes, the risk of diabetic vascular complications was strongly associated with previous hyperglycemia. In addition, Pallas and Larson (19) noted that hyperglycemia leads to impaired vascular function through endothelial cell dysfunction. The pathway that seems most affected by the diabetic state is that of nitric oxide. Loss of this pathway is accompanied by a loss of responsiveness to Paco2 and lack of autoregulation related to flow-pressure relationships. From these reports, we speculated that isoflurane was unable to produce vasodilation of the cerebral circulation because of impaired vascular function resulting from previous prolonged hyperglycemia, as indicated by increased HbA1c levels in diabetic patients treated with insulin therapy.
Brian (3) reviewed the importance and relationship of CO2 and cerebral circulation and reported that the key mechanism of CO2-mediated change in cerebral vascular tone is alteration of extracellular brain pH values. Manipulation of Paco2 is common in clinical situations, with hypocapnia being used to control intracranial pressure, and hypercapnia being used to treat cerebral ischemia. The loss of cerebrovascular reactivity in patients with insulin therapy in this study indicates a diminished capacity of the cerebral vasculature to meet cerebral oxygen demand and supply, especially during conditions of hypotension under anesthesia. Indeed, Matta et al. (20) showed that hypocapnia-induced reduction of cerebrospinal fluid is attenuated during hypotension with isoflurane, but it is preserved during hypotension with other hypotensive drugs. Our findings suggested that under hypotensive conditions, control of Paco2 during isoflurane or sevoflurane anesthesia, in diabetic patients treated with insulin therapy, carries an inherent risk.
We examined CO2 reactivity during anesthesia with isoflurane or sevoflurane used together with nitrous oxide. It is reported that the combination of nitrous oxide and isoflurane has a more potent cerebral vasodilatory effect than an equipotent dose of isoflurane used alone (21). Although the effect of nitrous oxide has been ignored in our study because nitrous oxide was administrated at the same concentration in both groups, it is possible that nitrous oxide may have different effects on cerebral circulation when used in combination with different volatile anesthetics.
In this study, we examined the cerebrovascular response to Paco2 by using hypoventilation to increase Vmca, rather than using hyperventilation to decrease Vmca. Cenic et al. (22) reported that cerebrovascular CO2 reactivity was maintained during hypercapnia but was markedly diminished during hypocapnia under propofol anesthesia. We examined the cerebrovascular vasodilatory response to CO2 in diabetic patients using hypoventilation to exclude the possibility that hyperventilation itself would have some effects on the cerebral vasodilatory response to hypercapnia. In addition, McCulloch et al. (23) showed that, although isoflurane impaired cerebral autoregulation in a dose-related manner, hypocapnia induced by hyperventilation itself could restore this isoflurane-induced impaired cerebral autoregulation in normal subjects. Hence, it is possible that in patients treated with insulin therapy, cerebrovascular CO2 reactivity was less with sevoflurane as compared with isoflurane during hyperventilation, similar to that observed in patients with dietary control or receiving antidiabetic drugs.
Just as hyperventilation-induced hypocapnia is often used to treat increased intracranial pressure in the operating room or intensive care unit, hypercapnia, with its consequent vasodilation and increased blood flow, has been proposed to be beneficial for the treatment of focal ischemia by increasing blood flow to the ischemic areas of the brain. Conversely, hypercapnia may also decrease blood flow to the ischemic brain by vasodilating the normal areas of the brain, hence diverting blood from the ischemic areas of the brain (3).
Another potential criticism of our study is that hypercapnia was induced by changing the respiratory rate instead of adding supplemental CO2 into the inspired gas. The technique of inducing hypercapnia by changing the respiratory rate has also been used to examine cerebrovascular CO2 reactivity in humans (10,12), the validity of this method being widely recognized.
Most of our patients had hypertension which, by itself, affects cerebrovascular CO2 reactivity (24). Thus, the possibility that hypertension had some effects on cerebrovascular CO2 reactivity in this study cannot be eliminated.
In conclusion, cerebrovascular CO2 reactivity in insulin-dependent patients is impaired during both sevoflurane and isoflurane anesthesia.
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ACKNOWLEDGMENTS |
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Footnotes |
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Accepted for publication March 21, 2006.
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  Y. Kadoi, S. Saito, C. Kawauchi, H. Hinohara, and F. Kunimoto Comparative effects of propofol vs dexmedetomidine on cerebrovascular carbon dioxide reactivity in patients with septic shock Br. J. Anaesth., February 1, 2008; 100(2): 224 - 229. [Abstract] [Full Text] [PDF]
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