Effect of Sevoflurane Postconditioning on the Incidence of Symptomatic Cerebral Hyperperfusion After Revascularization Surgery in Adult Patients with Moyamoya Disease

Journal Pre-proof Effect of Sevoflurane Postconditioning on the Incidence of Symptomatic Cerebral Hyperperfusion after Revascularization Surgery in Adult Patients with Moyamoya Disease Hyun-Kyu Yoon, Hyongmin Oh, Hyung-Chul Lee, Won-Sang Cho, Jeong Eun Kim, Jae Won Park, Hongyoon Choi, Hee-Pyoung Park PII:

S1878-8750(19)32893-1

DOI:

https://doi.org/10.1016/j.wneu.2019.11.055

Reference:

WNEU 13724

To appear in:

World Neurosurgery

Received Date: 9 August 2019 Accepted Date: 10 November 2019

Please cite this article as: Yoon H-K, Oh H, Lee H-C, Cho W-S, Kim JE, Park JW, Choi H, Park H-P, Effect of Sevoflurane Postconditioning on the Incidence of Symptomatic Cerebral Hyperperfusion after Revascularization Surgery in Adult Patients with Moyamoya Disease, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.11.055. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

Effect of Sevoflurane Postconditioning on the Incidence of Symptomatic Cerebral Hyperperfusion after Revascularization Surgery in Adult Patients with Moyamoya Disease

Hyun-Kyu Yoon1, Hyongmin Oh1, Hyung-Chul Lee1, Won-Sang Cho2, Jeong Eun Kim2, Jae Won Park3, Hongyoon Choi4, Hee-Pyoung Park1

From the Department of 1Anesthesiology and Pain Medicine, 2Neurosurgery, and 4Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea; and 3Department of Neurosurgery, Bucheon St. Mary’s Hospital, The Catholic University of Korea, Bucheon, Korea

To whom correspondence should be addressed: Hee-Pyoung Park M.D., Ph.D Department of Anesthesiology and Pain Medicine, Seoul National University Hospital 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea, 03080 [E-mail: [email protected]] Tel: 82-2-2072-2467; Fax: 82-2-747-5639

Key words: Moyamoya disease, Revascularization, Risk factor, Sevoflurane postconditioning, Symptomatic cerebral hyperperfusion

Running title: SEVOFLURANE POSTCONDITIONING IN MOYAMOYA PATIENTS

1, HYUN-KYU YOON

Effect of Sevoflurane Postconditioning on the Incidence of Symptomatic Cerebral Hyperperfusion after Revascularization Surgery in Adult Patients with Moyamoya Disease

1

2, HYUN-KYU YOON

ABSTRACT OBJECTIVE: Various experimental studies reported neuroprotective effects of sevoflurane postconditioning against cerebral ischemia-reperfusion injury. We thus investigated its neuroprotective effects on hyperperfusionrelated transient neurologic deterioration, called symptomatic cerebral hyperperfusion (SCH) and also identified predictive factors for SCH in moyamoya patients after revascularization surgery. METHODS: 152 adult moyamoya patients undergoing anastomosis of superficial temporal artery to middle cerebral artery were randomly allocated into two groups. Postconditioning group (group S, n=76) inhaled sevoflurane of 1 minimum alveolar concentration for 15 min immediately after reperfusion and then washed it out slowly for 15 min. Control group (group C, n=76) received no intervention. The incidence of SCH was compared between the two groups. RESULTS: The incidence of SCH was not significantly different between groups S and C (53.3 vs 43.4%; P=0.291). The incidence of postoperative complications and the Glasgow Outcome Scale at hospital discharge also did not differ significantly. Predictive factors for SCH included a decreased vascular reserve in preoperative single-photon emission computed tomography (odds ratio [OR], 7.18; 95% confidence interval [95% CI], 1.7829.02; P=0.006), an operation performed on the dominant hemisphere (OR, 3.32; 95% CI, 1.57-6.98; P=0.002), temporal occlusion time (OR, 1.06; 95% CI, 1.01-1.11; P=0.017), and intraoperative minimum partial pressure of carbon dioxide (PaCO2; OR, 0.86; 95% CI, 0.78-0.94; P=0.001). CONCLUSIONS: Sevoflurane postconditioning did not reduce the incidence of SCH after revascularization surgery in moyamoya patients. Rather, a decreased vascular reserve, operation on the dominant hemisphere, increased temporal occlusion time, and decreased intraoperative minimum PaCO2 were associated with SCH in such patients.

2

3, HYUN-KYU YOON

INTRODUCTION Moyamoya disease is a cerebrovascular condition characterized by progressive stenosis of internal carotid arteries and their major branches, which form an abnormal vascular network.1 Among various treatment options, surgical revascularization, connecting the superficial temporal artery (STA) to the middle cerebral artery (MCA), may show favorable results in preventing recurrent stroke and rebleeding.2, 3 However, STA-MCA bypass may carry a risk of postoperative hyperperfusion-related transient neurologic deterioration, called symptomatic cerebral hyperperfusion (SCH),4-7 because the brain may be exposed to ischemia-reperfusion (I/R) injury while restoring the blood and oxygen to the chronically ischemic area. For cerebral I/R injury, oxidative stress, bloodbrain barrier dysfunction, and inflammation play a significant role in exerting deleterious effects on brain.8-10 Although the exact mechanism of postoperative SCH remains unclear in moyamoya patients, oxidative stress and inflammatory responses during revascularization seem to be involved in the development of SCH in these patients.7, 11, 12 Recently, various pharmacologic agents including sevoflurane have been investigated for postconditioninginduced neuroprotection.13 According to previous experimental studies, postconditioning with sevoflurane has exhibited neuroprotective effects against cerebral I/R injury via anti-oxidant, anti-apoptotic, and antiinflammatory mechanisms.14-18 Sevoflurane also showed acceptable profiles regarding hemodynamic stability, brain condition, and emergence in anesthesia for neurosurgery, compared with propofol and desflurane.19 Therefore, it may be reasonable to investigate neuroprotective effects of sevoflurane on postoperative SCH, which was regarded as a kind of I/R injury, in moyamoya patients. Unfortunately, to our knowledge, there is no clinical study to investigate sevoflurane postconditioning-induced neuroprotection against cerebral I/R injury in human brain. In this study, we hypothesized that sevoflurane postconditioning would reduce the incidence of postoperative SCH in moyamoya patients undergoing STA-MCA anastomosis. The beneficial effects of sevoflurane postconditioning were evaluated by comparing the incidences of postoperative SCH and other postoperative complications (i.e., transient ischemic attack, cerebral infarct, hemorrhage, seizure, and wound infection) and the Glasgow Outcome Scale at hospital discharge between patients treated with sevoflurane 3

4, HYUN-KYU YOON

postconditioning and those without. In addition, we identified predictive factors of postoperative SCH in such patients.

4

5, HYUN-KYU YOON

MATERIALS AND METHODS Study Population After the institutional review board of Seoul National University Hospital (1506–069–680) approved this study, the study protocol was registered at ClinicalTrials.gov (identifier: NCT02510586, date of registration: July 29, 2015). Written informed consent was obtained from all patients prior to enrolment. We enrolled patients aged 18–80 years old who were scheduled for revascularization surgery due to moyamoya disease from August 2015 to November 2018. We excluded patients from the study who declined to participate, had uncontrolled hypertension or diabetes mellitus, had a previous history of acute renal failure, had used cyclooxygenase-2 inhibitors, or had any kind of cerebral interventions related to moyamoya disease. Block randomisation was performed using a computer-generated program by an investigator who was blinded to the study. Block sizes were four and six. Patients were randomly assigned to two groups: sevoflurane postconditioning group (group S) or control group (group C). The randomization order was concealed in an opaque envelope that was opened immediately before the completion of STA-MCA anastomosis. The patients and surgeons were blinded to the group assignment. All enrolled patients were evaluated using single-photon emission computed tomography (SPECT) preoperatively. Patients entered the operating room without any premedication. Anesthetic induction was performed using target-controlled infusions of propofol and remifentanil with target effect-site concentrations of 4 µg/mL and 4 ng/mL, respectively. After administering rocuronium at a dose of 0.6–0.8 mg/kg, tracheal intubation was performed. Then the radial artery was cannulated for continuous blood pressure monitoring, and either the subclavian or internal jugular vein was catheterized for drug and fluid administration. During surgery, the settings of mechanical ventilation were as follows: a tidal volume of 8 ml/kg ideal body weight, a fraction of inspired oxygen of 0.35–0.50 with a total gas flow of 1.5–2 L/min, a positive end-expiratory pressure of 5 cmH2O, respiratory rates that were adjusted to maintain partial pressure of carbon dioxide (PaCO2) within 40 ± 5 mmHg. Intraoperative systolic arterial pressure was kept at the level of 10–20 mmHg higher than the preoperative value until the completion of STA-MCA anastomosis. To maintain blood pressure within this range, phenylephrine (30–100 µg) was intermittently administered, and if necessary, a phenylephrine (0.5–1.0 µg/kg/min) or norepinephrine (0.01–0.1 µg/kg/min) continuous infusion was used. After STA-MCA anastomosis, 5

6, HYUN-KYU YOON

the systolic arterial pressure was kept at the level of the preoperative value or 10–20 mmHg lower. The anesthetic depth was assessed using the bispectral index, and this value was maintained at 40–60. In group S, one-cycled sevoflurane postconditioning was performed for 30 min immediately after the completion of the STA–MCA anastomosis. The sevoflurane postconditioning protocol20 was characterized by the following three phases: an induction phase to reach 1.0 minimum alveolar concentration (MAC) of sevoflurane, delivering 1.5 MAC of sevoflurane with a gas flow of 10 L/min for 5 min; a maintenance phase to deliver 1 MAC of sevoflurane with a gas flow of 10 L/min for 10 min; and a washout phase without sevoflurane administration with a gas flow of 2 L/min for 15 min. End-tidal sevoflurane concentrations were recorded at the end of each phase. During the sevoflurane postconditioning period, infusion rates of propofol and remifentanil were adjusted or discontinued at the discretion of the attending anesthesiologist to prevent hypotension and deep anesthesia. In group C, no intervention was implemented at the time of reperfusion. After surgery, all patients were transferred to the intensive care unit (ICU), after taking computed tomography scans of the brain. All surgical procedures were performed by two skilled neurosurgeons. The surgical techniques, such as the size of craniotomy, preparation of the STA, the recipient site (the third or fourth branch of the MCA), and size of STAMCA anastomosis remained unchanged during the study period. In the ICU, after complete recovery from anesthesia, all patients received a full neurological examination by neurosurgeons blinded to the group assignment. During the postoperative period, systolic arterial pressure was strictly controlled within ±20% of the preoperative value for about 3 days. If the patients presented a new neurological deficit that was in accordance with the region of anastomosis (i.e., dysphasia, dysarthria, and hand motor dysfunction), magnetic resonance imaging (MRI) with arterial spin labelling and/or SPECT was performed to assess postoperative cerebral perfusion. Postoperative SCH was defined as meeting all of the following criteria:7 new-onset postoperative neurological deficit that was not observed preoperatively, a delayed neurological deficit that did not develop immediately postoperatively, postoperative neurological symptoms that resolved completely within 15 days of symptom onset, and no definitive hematoma or cerebral infarct on brain imaging during the postoperative period. Finally, the presence of postoperative SCH was reconfirmed by a board-certified neurosurgeon.

6

7, HYUN-KYU YOON

Primary and Secondary Outcomes The primary outcome measure was the incidence of postoperative SCH after revascularization surgery. The secondary outcome measures were the incidence of postoperative complications, such as transient ischemic attack, cerebral infarct, hemorrhage, seizure, and wound infection and the Glasgow Outcome Scale at hospital discharge.

Sample Size Determination In previous studies, the reported incidence of SCH after revascularization surgery for moyamoya disease was 17–50%,4, 6, 7, 21-23 with an average incidence of about 33%. To obtain a 20% decrease in the incidence of postoperative SCH in patients treated with sevoflurane postconditioning, enrolment of 69 patients per group was needed to achieve a two-tailed level of significance of 0.05 with a power of 80%. Considering a possible dropout rate of a 10%, a total of 152 patients were enrolled.

Statistical Analyses Discrete variables, such as the incidence of postoperative SCH and other postoperative complications and the Glasgow Outcome Scale at hospital discharge were evaluated using the chi-square test or Fisher’s exact test. To compare continuous variables, such as temporal occlusion time, fluid balance, preoperative, intraoperative, and postoperative laboratory findings, the amount of anesthetics used during anesthesia, the onset and duration of postoperative SCH, and length of hospital and ICU stay, the Student’s t-test or Mann-Whitney U test was used depending on the results of a Kolmogorov-Smirnov test. All statistical analyses were accomplished using SPSS software (version 25.0; IBM Corp., Armonk, NY). Statistical significance was indicated by a P-value <0.05.

7

8, HYUN-KYU YOON

RESULTS Among the 179 patients who were eligible for this study, 27 patients were excluded because 15 patients refused to participate in the study and 12 patients did not meet the inclusion criteria (Figure 1). The remaining 152 patients were enrolled and randomised. After randomisation, one patient who did not meet the inclusion criteria (age < 18 years) in group S was detected and excluded from data analyses. The incidence of patients with decreased vascular reserve, which was defined as a 10% or more decrease of cerebral vascular reserve in the acetazolamide challenge study compared with baseline study, on preoperative SPECT was significantly higher in group S than in group C (94.7 vs. 82.9%; P = 0.037, Table 1). The preoperative level of C-reactive protein was significantly lower in group S than in group C (0.04 [0.01–0.10] vs. 0.06 [0.03–0.21] mg/dL; P = 0.029). Among intraoperative variables, surgical and anesthesia time were significantly longer in group S than in group C (303.4 ± 48.9 vs. 284.8 ± 41.6 min, P = 0.013; 367.8 ± 53.1 vs. 344.9 ± 41.9 min, P = 0.004, respectively, Table 2). In addition, a greater amount of phenylephrine was used during surgery in group S (8054.0 ± 4851.3 vs. 6320.8 ± 4039.2 µg, P = 0.018). Serum levels of hematocrit and C-reactive protein on postoperative day (POD) 2 were significantly lower in group S than in group C (32.4 ± 3.1 vs. 33.6 ± 3.1%, P = 0.021; 5.4 [3.6–6.8] vs. 6.2 [4.4–8.7] mg/dL, P = 0.024, respectively). The incidence of postoperative SCH was not significantly different between group S and group C (53.3 vs. 43.4%; P = 0.291, Table 3). The onset and duration of postoperative SCH did not differ significantly between the two groups. In addition, the incidence of other postoperative complications and the Glasgow Outcome Scale at hospital discharge were not significantly different between the two groups. Risk factors of postoperative SCH after revascularization surgery in moyamoya patients are presented in Table 4. In multivariate binary logistic regression analyses, decreased vascular reserve on preoperative SPECT (odds ratio [OR], 7.18; 95% confidence interval [CI], 1.78–29.02; P = 0.006), operation on the dominant hemisphere (OR, 3.32; 95% CI, 1.57–6.98; P = 0.002), temporal occlusion time (OR, 1.06; 95% CI, 1.01–1.11; P = 0.017), and intraoperative minimum PaCO2 (OR, 0.86; 95% CI, 0.78–0.94; P = 0.001) were independent risk factors for postoperative SCH. 8

9, HYUN-KYU YOON

DISCUSSION Sevoflurane postconditioning did not reduce the incidence of postoperative SCH and other postoperative complications after STA-MCA anastomosis in moyamoya patients. In addition, sevoflurane postconditioning did not affect the Glasgow Outcome Scale at hospital discharge. In moyamoya patients, pathologic vessels form in response to chronic insufficient perfusion in areas of the brain. These abnormal vessels have impaired cerebral autoregulation and cerebrovascular reactivity and they cannot adapt to an abrupt increase in blood flow after revascularization surgery.5 Although the exact mechanisms of postoperative SCH in moyamoya patients remain unclear, these abnormal vessels may be considered as an important determinant factor for postoperative SCH. An abrupt increase in the arterial blood flow to chronically ischemic areas with poor vascular reserve may induce oxidative stress.24-26 It can increase free radical production and release of matrix metalloproteinase-9 (MMP-9). These substances can weaken the integrity of the blood-brain barrier, leading to vasogenic cerebral oedema.24-27 In addition, the bioactivity of nitric oxide, which plays an important role in maintaining cerebral autoregulation,28 can be decreased in the presence of oxidative stress, leading to endothelial dysfunction and impaired cerebral autoregulation.29, 30 Previous studies have reported that the free radial scavenger and MMP-9 blocking agent successfully reduced the incidence of postoperative SCH in moyamoya patients.11, 12 Meanwhile, cerebral ischemia also triggers the inflammatory cascade by releasing various inflammatory cytokines and chemokines, resulting in breakdown of the blood-brain barrier.31 In particular, increased interleukin-1 may be associated with cerebral vasodilation and hyperemia after vascular reperfusion in moyamoya patients.32, 33 Taken together, these findings indicate that oxidative stress and inflammation may be involved in the development of postoperative SCH after revascularization surgery in moyamoya patients. This is the first study to investigate the neuroprotective effects of sevoflurane postconditioning in the human brain. In previous experimental studies, sevoflurane postconditioning showed neuroprotective effects against cerebral I/R injury via anti-oxidant and anti-inflammatory mechanisms.14,

15, 17, 34

Therefore, sevoflurane

postconditioning after STA-MCA anastomosis was expected to reduce the incidence of postoperative SCH by providing anti-oxidant and anti-inflammatory effects. In contrast to our expectations, sevoflurane postconditioning did not reduce the incidence of postoperative SCH. There are some possible explanations for 9

10, HYUN-KYU YOON

this result. Firstly, to the best of our knowledge, there is no consensus regarding an effective method of sevoflurane postconditioning in clinical practice. In this study, we adopted the postconditioning method, which was implemented successfully in liver resection surgery.20 The timing, frequency, duration, and dose of sevoflurane postconditioning may be crucial factors in determining its therapeutic efficacy.16, 35 In two previous studies showing beneficial effects of sevoflurane postconditioning after cardiac surgery, the duration of exposure to sevoflurane inhalation at the ICU were 4 and 2 h, respectively.35, 36 However, in the present study, the duration of sevoflurane postconditioning was 30 min, shorter than those in the aforementioned studies. This indicates that our method for sevoflurane postconditioning may be insufficient to have clinically significant neuroprotective effects on postoperative SCH. Secondly, propofol is known to abolish organ-protective effects of remote ischemic preconditioning by interfering with the signal transducer and activator of transcription 5 in cardiac surgical patients.37 Similarly, neuroprotective effects of sevoflurane postconditioning may be abrogated in this study as a large amount of propofol was continuously infused during the surgery in both groups. Thirdly, vasodilatory effects of sevoflurane might have influenced on our results. Previous studies have revealed that sevoflurane can induce cerebral vasodilation in a dose-dependent fashion and impair cerebral autoregulation.38, 39

Actually, the incidence of postoperative SCH was likely to be higher in patients treated with sevoflurane

postconditioning, although statistical significance was not indicated between the two groups in this study. The median end-tidal sevoflurane concentration was 1.7%, which might cause changes of regional cerebral blood flow in the affected region in patients with preserved cerebrovascular response. Finally, according to prior investigations, the size of the STA and recipient artery were associated with the development of cerebral hyperperfusion.12, 40 Such anatomical factors rather than sevoflurane postconditioning may contribute more to the development of postoperative SCH. Many studies have reported predictive factors for SCH after revascularization surgery, such as adult-onset and hemorrhagic-onset of the disease, operation on the dominant hemisphere, higher white blood cell count on POD 1, a smaller diameter of the recipient artery, preoperative ischemic presentation, and modified Rankin Score at admission.4, 6, 12, 41 Similarly, a decreased vascular reserve, operation site, temporal occlusion time, and intraoperative minimum PaCO2 are associated with postoperative SCH. Preoperative poor vascular response is a well-known predictor of the development of cerebral hyperperfusion in moyamoya patients.7, 42 The longer the 10

11, HYUN-KYU YOON

ischemic time, the higher the level of induced oxidative stress and free radical production, which may increase the risk for cerebral hyperperfusion.43 Carbon dioxide is a potent vasodilator of cerebral arteries.44 Moyamoya patients have impaired cerebrovascular response to hypercapnic stimuli, because their abnormal vessels are already maximally dilated.45 Hypercapnia can decrease cerebral blood flow in the area perfused by collateral vessels due to intracerebral steal. On the contrary, because cerebrovascular responses to hypocapnic stimuli seem to be intact in collateral vessels of moyamoya disease, hypocapnia can lead to hypoperfusion. Both hypercapnia and hypocapnia can decrease cerebral perfusion in chronic ischemic areas and subsequently make patients vulnerable to SCH after revascularization.1 The present study had several limitations. Firstly, we did not directly measure inflammatory cytokines, MMP-9, or enzymes related to oxidative stress and intracellular signal transduction. Therefore, the exact pathophysiology involved in neuroprotective effects of sevoflurane postconditioning was not evaluated. Secondly, this was a single center study. The incidence of SCH in this study was relatively higher, compared with those in other studies.4,

7, 21, 22

This may be attributed to strict surgical indications for STA-MCA

anastomosis in moyamoya patients. Most patients who underwent cerebral revascularization surgery in our institution presented with progressive and repetitive ischemic symptoms and significant cerebral hemodynamic instability confirmed by preoperative SPECT or perfusion MRI. As indications for surgery and preference of surgical techniques may vary depending on the experiences and training of neurosurgeons,46 care should be taken when interpreting our results. Lastly, in clinical practice, there is no consensus establishing beneficial effects of sevoflurane postconditioning on neuroprotection. To evaluate the neuroprotective effects of sevoflurane postconditioning on postoperative SCH obviously, future studies are needed using different doses, durations, and frequencies of sevoflurane inhalation and different intravenous sedatives for anesthesia induction and maintenance.

11

12, HYUN-KYU YOON

CONCLUSIONS Sevoflurane postconditioning for 30 min did not reduce the incidence of SCH after STA-MCA anastomosis in moyamoya patients. Decreased vascular reserve, operation on the dominant hemisphere, temporal occlusion time, and intraoperative minimum PaCO2, rather than sevoflurane postconditioning, were associated with the development of postoperative SCH.

12

13, HYUN-KYU YOON

ACKNOWLEDGEMENTS None

Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

13

14, HYUN-KYU YOON

REFERENCES 1.

Kim JS. Moyamoya Disease: Epidemiology, Clinical Features, and Diagnosis. J Stroke. 2016;18:2-11.

2.

Kim T, Oh CW, Kwon OK, Hwang G, Kim JE, Kang HS, et al. Stroke prevention by direct revascularization for patients with adult-onset moyamoya disease presenting with ischemia. J Neurosurg. 2016;124:1788-1793.

3.

Miyamoto S, Yoshimoto T, Hashimoto N, Okada Y, Tsuji I, Tominaga T, et al. Effects of extracranialintracranial bypass for patients with hemorrhagic moyamoya disease: results of the Japan Adult Moyamoya Trial. Stroke. 2014;45:1415-1421.

4.

Fujimura M, Mugikura S, Kaneta T, Shimizu H, Tominaga T. Incidence and risk factors for symptomatic cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in patients with moyamoya disease. Surg Neurol. 2009;71:442-447.

5.

Zhao WG, Luo Q, Jia JB, Yu JL. Cerebral hyperperfusion syndrome after revascularization surgery in patients with moyamoya disease. Br J Neurosurg. 2013;27:321-325.

6.

Hwang JW, Yang HM, Lee H, Lee HK, Jeon YT, Kim JE, et al. Predictive factors of symptomatic cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in adult patients with moyamoya disease. Br J Anaesth. 2013;110:773-779.

7.

Kim JE, Oh CW, Kwon OK, Park SQ, Kim SE, Kim YK. Transient hyperperfusion after superficial temporal artery/middle cerebral artery bypass surgery as a possible cause of postoperative transient neurological deterioration. Cerebrovasc Dis. 2008;25:580-586.

8.

Yamato M, Egashira T, Utsumi H. Application of in vivo ESR spectroscopy to measurement of cerebrovascular ROS generation in stroke. Free Radic Biol Med. 2003;35:1619-1631.

9.

Latour LL, Kang DW, Ezzeddine MA, Chalela JA, Warach S. Early blood-brain barrier disruption in human focal brain ischemia. Ann Neurol. 2004;56:468-477.

10.

Kuroda S, Siesjo BK. Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clin Neurosci. 1997;4:199-212.

11.

Uchino H, Nakayama N, Kazumata K, Kuroda S, Houkin K. Edaravone Reduces HyperperfusionRelated Neurological Deficits in Adult Moyamoya Disease: Historical Control Study. Stroke. 2016;47:1930-1932.

12.

Fujimura M, Niizuma K, Inoue T, Sato K, Endo H, Shimizu H, et al. Minocycline prevents focal neurological deterioration due to cerebral hyperperfusion after extracranial-intracranial bypass for moyamoya disease. Neurosurgery. 2014;74:163-170; discussion 170.

13.

Fan YY, Hu WW, Nan F, Chen Z. Postconditioning-induced neuroprotection, mechanisms and applications in cerebral ischemia. Neurochem Int. 2017;107:43-56.

14.

Lee H, Park YH, Jeon YT, Hwang JW, Lim YJ, Kim E, et al. Sevoflurane post-conditioning increases nuclear factor erythroid 2-related factor and haemoxygenase-1 expression via protein kinase C pathway 14

15, HYUN-KYU YOON

in a rat model of transient global cerebral ischaemia. Br J Anaesth. 2015;114:307-318. 15.

Zhang Y, Zhang FG, Meng C, Tian SY, Wang YX, Zhao W, et al. Inhibition of sevoflurane postconditioning against cerebral ischemia reperfusion-induced oxidative injury in rats. Molecules. 2011;17:341-354.

16.

Wang JK, Yu LN, Zhang FJ, Yang MJ, Yu J, Yan M, et al. Postconditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury via PI3K/Akt pathway. Brain Res. 2010;1357:142-151.

17.

Hwang JW, Jeon YT, Lim YJ, Park HP. Sevoflurane Postconditioning-Induced Anti-Inflammation via Inhibition of the Toll-Like Receptor-4/Nuclear Factor Kappa B Pathway Contributes to Neuroprotection against Transient Global Cerebral Ischemia in Rats. Int J Mol Sci. 2017;18.

18.

Seo JH, Park HP, Jeon YT, Lim YJ, Nam K, Hwang JW. Combined treatment with celecoxib and sevoflurane after global cerebral ischaemia has no additive neuroprotective effects in rats. Br J Anaesth. 2013;110:988-995.

19.

Bastola P, Bhagat H, Wig J. Comparative evaluation of propofol, sevoflurane and desflurane for neuroanaesthesia: A prospective randomised study in patients undergoing elective supratentorial craniotomy. Indian J Anaesth. 2015;59:287-294.

20.

Beck-Schimmer B, Breitenstein S, Bonvini JM, Lesurtel M, Ganter M, Weber A, et al. Protection of pharmacological postconditioning in liver surgery: results of a prospective randomized controlled trial. Ann Surg. 2012;256:837-844; discission 844-835.

21.

Fujimura M, Shimizu H, Inoue T, Mugikura S, Saito A, Tominaga T. Significance of focal cerebral hyperperfusion as a cause of transient neurologic deterioration after extracranial-intracranial bypass for moyamoya disease: comparative study with non-moyamoya patients using N-isopropyl-p[(123)I]iodoamphetamine single-photon emission computed tomography. Neurosurgery. 2011;68:957964; discussion 964-955.

22.

Fujimura M, Kaneta T, Mugikura S, Shimizu H, Tominaga T. Temporary neurologic deterioration due to cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in patients with adult-onset moyamoya disease. Surg Neurol. 2007;67:273-282.

23.

Uchino H, Kuroda S, Hirata K, Shiga T, Houkin K, Tamaki N. Predictors and clinical features of postoperative hyperperfusion after surgical revascularization for moyamoya disease: a serial single photon emission CT/positron emission tomography study. Stroke. 2012;43:2610-2616.

24.

del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab. 2003;23:879-894.

25.

Siesjo BK, Agardh CD, Bengtsson F. Free radicals and brain damage. Cerebrovasc Brain Metab Rev. 1989;1:165-211.

26.

Chan PH. Role of oxidants in ischemic brain damage. Stroke. 1996;27:1124-1129.

27.

Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents 15

16, HYUN-KYU YOON

oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:1393-1400. 28.

Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev. 2009;61:62-97.

29.

Forstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010;459:923-939.

30.

White RP, Vallance P, Markus HS. Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans. Clin Sci (Lond). 2000;99:555-560.

31.

Danton GH, Dietrich WD. Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol. 2003;62:127-136.

32.

Fearon WF, Fearon DT. Inflammation and cardiovascular disease: role of the interleukin-1 receptor antagonist. Circulation. 2008;117:2577-2579.

33.

Kang HS, Kim JH, Phi JH, Kim YY, Kim JE, Wang KC, et al. Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry. 2010;81:673678.

34.

Rodriguez-Gonzalez R, Baluja A, Veiras Del Rio S, Rodriguez A, Rodriguez J, Taboada M, et al. Effects of sevoflurane postconditioning on cell death, inflammation and TLR expression in human endothelial cells exposed to LPS. J Transl Med. 2013;11:87.

35.

Steurer MP, Steurer MA, Baulig W, Piegeler T, Schlapfer M, Spahn DR, et al. Late pharmacologic conditioning with volatile anesthetics after cardiac surgery. Crit Care. 2012;16:R191.

36.

Hellstrom J, Owall A, Bergstrom J, Sackey PV. Cardiac outcome after sevoflurane versus propofol sedation following coronary bypass surgery: a pilot study. Acta Anaesthesiol Scand. 2011;55:460-467.

37.

Kottenberg E, Musiolik J, Thielmann M, Jakob H, Peters J, Heusch G. Interference of propofol with signal transducer and activator of transcription 5 activation and cardioprotection by remote ischemic preconditioning during coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2014;147:376-382.

38.

Matta BF, Heath KJ, Tipping K, Summors AC. Direct cerebral vasodilatory effects of sevoflurane and isoflurane. Anesthesiology. 1999;91:677-680.

39.

Conti A, Iacopino DG, Fodale V, Micalizzi S, Penna O, Santamaria LB. Cerebral haemodynamic changes during propofol-remifentanil or sevoflurane anaesthesia: transcranial Doppler study under bispectral index monitoring. Br J Anaesth. 2006;97:333-339.

40.

Uchino H, Kazumata K, Ito M, Nakayama N, Kuroda S, Houkin K. Intraoperative assessment of cortical perfusion by indocyanine green videoangiography in surgical revascularization for moyamoya disease. Acta Neurochir (Wien). 2014;156:1753-1760.

41.

Zhao M, Deng X, Zhang D, Wang S, Zhang Y, Wang R, et al. Risk factors for and outcomes of postoperative complications in adult patients with moyamoya disease. J Neurosurg. 2018:1-12.

42.

Ohue S, Kumon Y, Kohno K, Watanabe H, Iwata S, Ohnishi T. Postoperative temporary neurological deficits in adults with moyamoya disease. Surg Neurol. 2008;69:281-286; discussion 286-287. 16

17, HYUN-KYU YOON

43.

Agardh CD, Zhang H, Smith ML, Siesjo BK. Free radical production and ischemic brain damage: influence of postischemic oxygen tension. Int J Dev Neurosci. 1991;9:127-138.

44.

Battisti-Charbonney A, Fisher J, Duffin J. The cerebrovascular response to carbon dioxide in humans. J Physiol. 2011;589:3039-3048.

45.

Kuwabara Y, Ichiya Y, Sasaki M, Yoshida T, Masuda K, Matsushima T, et al. Response to hypercapnia in moyamoya disease. Cerebrovascular response to hypercapnia in pediatric and adult patients with moyamoya disease. Stroke. 1997;28:701-707.

46.

Kim JE, Jeon JS. An update on the diagnosis and treatment of adult Moyamoya disease taking into consideration controversial issues. Neurol Res. 2014;36:407-416.

17

18, HYUN-KYU YOON

FIGURE LEGENDS Figure 1. CONSORT flowchart

18

1

Table 1. Patient Characteristics and Preoperative Variables Group S

Group C

(n = 75)

(n = 76)

37.0 (26.0–46.0)

38.5 (26.0–50.0)

0.259

Female

49 (65.3)

55 (72.4)

0.449

BMI (kg/m2)

25.3 ± 4.1

25.0 ± 3.8

0.662

1 (1.3)

0 (0.0)

0.497

Hemorrhage

12 (16.0)

20 (26.3)

0.176

Infarct

21 (28.0)

25 (32.9)

0.634

TIA

41 (54.7)

31 (40.8)

0.123

Ⅲ

33 (44.0)

34 (44.7)

1.000

Ⅵ

22 (29.3)

19 (25.0)

0.678

Ⅴ

8 (10.7)

8 (10.5)

1.000

Hypertension

22 (29.3)

23 (30.3)

1.000

Diabetes mellitus

11 (14.7)

10 (13.2)

0.974

Cardiac disease

3 (4.0)

0 (0.0)

0.120

Neurologic disease

9 (12.0)

5 (6.6)

0.386

Hepatic disease

3 (4.0)

1 (1.3)

0.367

Renal disease

0 (0.0)

3 (3.9)

0.245

Thyroid disease

6 (8.0)

7 (9.2)

1.000

Hematologic disease

1 (1.3)

2 (2.6)

1.000

Malignancy

1 (1.3)

1 (1.3)

1.000

Decreased basal perfusion

40 (53.3)

34 (44.7)

0.371

Decreased vascular reserve

71 (94.7)

63 (82.9)

0.037

13.3 ± 1.6

13.1 ± 1.3

0.429

6.7 ± 1.8

6.5 ± 2.0

0.607

261.4 ± 64.0

252.1 ± 66.9

0.387

CRP (mg/dL)

0.04 (0.01–0.10)

0.06 (0.03–0.21)

0.029

Free T4 (ng/dL)

1.05 (0.98–1.12)

1.02 (0.92–1.12)

0.439

98.2 ± 18.3

98.4 ± 21.0

0.971

1.51 (0.85–2.31)

1.31 (0.70–2.16)

0.167

68 (90.7)

67 (88.2)

0.813

4 (5.3)

9 (11.8)

0.245

Variable Age (years)

P value

Initial presentation (%) Seizure

Suzuki grade (%)

Comorbidities (%)

Preoperative SPECT findings (%)

Preoperative laboratory findings Hb (g/dL) 3

WBC (10 /µL) 3

Platelet (10 /µL)

T3 (ng/dL) TSH (uIU/mL) Thyroid function Euthyroid Hyperthyroidism

2

Hypothyroidism

3 (4.0)

0 (0.0)

0.120

Data are presented as median (interquartile range), number (%), or mean ± standard deviation. BMI, body mass index; TIA, transient ischemic attack; SPECT, single-photon emission computed tomography; Hb, hemoglobin; WBC, white blood cell; CRP, C-reactive protein; TSH, thyroid-stimulating hormone. In the group S, sevoflurane postconditioning was performed for 30 min after anastomosis of superficial temporal artery to middle cerebral artery. In the group C, no intervention was performed at the time of reperfusion.

3

Table 2. Intraoperative Variables and Postoperative Laboratory Findings Group S

Group C

Mean Difference

P

(n = 75)

(n = 76)

(95% CI)

value

Surgical time (min)

303.4 ± 48.9

284.8 ± 41.6

18.6 (-33.2 to -4.0)

0.013

Anesthesia time (min)

367.8 ± 53.1

344.9 ± 41.9

22.9 (-38.3 to -7.5)

0.004

35.4 ± 8.0

34.5 ± 7.9

0.9 (-3.5 to 1.7)

0.474

0.8% (-14.7 to 16.3)

1.000

Variable

Temporal occlusion time (min) Operation side (%) Dominant

41 (54.7)

41 (53.9)

Non-dominant

34 (45.3)

35 (46.1)

Fluid balance (ml)

152.7 ± 833.9

46.6 ± 633.2

106.1 (-344.0 to 131.8)

0.388

4 (5.3)

1 (1.3)

4.0% (-2.6 to 11.7)

0.209

75 (100.0)

72 (94.7)

5.3% (-0.5 to 12.8)

0.120

8054.0 ± 4851.3

6320.8 ± 4039.2

3 (4.0)

4 (5.3)

1.3% (-6.5 to 9.3)

1.000

Hct min (%)

31.4 ± 4.3

31.3 ± 4.0

0.1 (-1.4 to 1.2)

0.932

Hct max (%)

35.6 ± 3.9

34.8 ± 4.1

0.8 (-2.1 to 0.5)

0.242

PaCO2 min (mmHg)

37.0 ± 3.7

37.5 ± 4.4

0.5 (-0.8 to 1.8)

0.541

PaCO2 max (mmHg)

42.9 ± 4.3

42.6 ± 4.4

0.3 (-1.7 to 1.1)

0.682

472.0 (376.0–

459.0 (368.4–

513.7)

511.3)

NA

0.563

Propofol dose (µg/kg/hr)

8.2 (7.4–9.2)

8.2 (7.4–9.4)

NA

0.818

Remifentanil dose (ng/kg/hr)

8.0 (6.8–9.2)

8.4 (6.9–10.0)

NA

0.439

1.7 (1.6–1.9)

NA

0.90 (0.87–0.96)

NA

33.9 ± 4.0

33.7 ± 3.7

0.2 (-1.3 to 0.9)

0.780

8.4 (7.0–10.9)

8.2 (6.6–10.1)

NA

0.537

203.9 ± 56.8

196.6 ± 50.7

7.3 (-24.6 to 10.0)

0.406

32.4 ± 3.1

33.6 ± 3.1

1.2 (0.2 to 2.2)

0.021

9.2 (7.4–11.7)

8.8 (7.4–11.5)

NA

0.913

180.7 ± 52.9

178.3 ± 52.7

2.4 (-19.4 to 14.6)

0.774

Intraoperative transfusion (%) Continuous infusion Phenylephrine (%) Phenylephrine dose (µg) Norepinephrine (%)

1733.2 (-3168.0 to 298.4)

0.018

Intraoperative laboratory findings

PaO2/FiO2 min (mmHg)

End-tidal sevoflurane concentration during sevoflurane postconditioning (vol%) Age-adjusted MAC for sevoflurane during sevoflurane postconditioning Postoperative laboratory findings Postoperative day 0 Hct (%) 3

WBC (10 /µL) 3

Platelet (10 /µL) Postoperative day 2 Hct (%) 3

WBC (10 /µL) 3

Platelet (10 /µL)

4

CRP (mg/dL)

5.4 (3.6–6.8)

6.2 (4.4–8.7)

NA

0.024

Data are expressed as mean ± standard deviation, number (%), or median (interquartile range). CI, confidence interval; Hct, hematocrit; min, minimum; max, maximum; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; FiO2, fraction of inspired oxygen; NA, not applicable; MAC, minimum alveolar concentration; WBC, white blood cell; CRP, C-reactive protein. In the group S, sevoflurane postconditioning was performed for 30 min after anastomosis of superficial temporal artery to middle cerebral artery. In the group C, no intervention was performed at the time of reperfusion.

5

Table 3. Postoperative Clinical Outcomes Group S

Group C

Mean Difference

(n = 75)

(n = 76)

(95% CI)

Overall incidence

52 (69.3)

42 (55.3)

14.0% (-1.4 to 28.5)

0.106

SCH

40 (53.3)

33 (43.4)

9.9% (-5.9 to 25.0)

0.291

Onset (day)

2.0 (1.0–4.0)

2.0 (0.0–3.0)

NA

0.270

Duration (day)

3.0 (2.0–5.0)

5.0 (3.0–6.0)

NA

0.114

TIA

8 (10.7)

2 (2.6)

8.1% (-0.2 to 17.3)

0.056

Seizure

6 (8.0)

13 (17.1)

9.1% (-1.7 to 20.0)

0.149

Infarct

6 (8.0)

7 (9.2)

1.2% (-8.4 to 10.8)

1.000

Hemorrhage

2 (2.7)

2 (2.6)

0.1% (-6.6 to 6.9)

1.000

Wound infection

5 (6.7)

2 (2.6)

4.1% (-3.4 to 12.3)

0.276

Length of ICU stay (day)

2.0 (2.0–2.0)

2.0 (2.0–2.0)

NA

0.729

Length of hospital stay (day)

9.0 (7.0–11.0)

8.0 (7.0–11.0)

NA

0.668

3

1 (1.3)

0 (0.0)

1.3% (-3.6 to 7.1)

0.497

4

5 (6.7)

2 (2.6)

4.1% (-3.4 to 12.3)

0.276

5

69 (92.0)

74 (97.4)

5.4% (-2.3 to 14.0)

0.167

70 (100.0)

61 (95.3)

4.7% (-1.3 to 12.9)

0.106

Fair

0 (0.0)

2 (3.1)

3.1% (-2.6 to 10.7)

0.226

Poor

0 (0.0)

1 (1.6)

1.6% (-3.8 to 8.4)

0.478

62 (88.6)

54 (85.7)

2.9% (-8.7 to 14.9)

0.816

Variable

P value

Postoperative complications (%)

Glasgow outcome scale at hospital discharge (%)

Evaluation on the extent of revascularization (%) Postoperative 6-month TFCA* Good

Postoperative 6-month SPECT† Favorable

Data are expressed as number (%) or median (interquartile range). CI, confidence interval; SCH, symptomatic cerebral hyperperfusion; NA, not applicable; TIA, transient ischemic attack; ICU, intensive care unit; TFCA, transfemoral cerebral angiography; SPECT, single-photon emission computed tomography * Postoperative TFCA was performed only in 134 patients (70 patients in the group S and 64 in the group C). † Postoperative SPECT was performed only in 133 patients (70 patients in the group S and 63 in the group C). In the group S, sevoflurane postconditioning was performed for 30 min after anastomosis of superficial temporal artery to middle cerebral artery. In the group C, no intervention was performed at the time of reperfusion.

6 Table 4. Univariate and Multivariate Binary Logistic Analyses for Risk Factors of Symptomatic Cerebral Hyperperfusion after Revascularization Surgery in Adult Moyamoya Patients Postoperative SCH

Univariate Analysis

Yes (n = 73)

No (n = 78)

Odds ratio (95% CI)

P value

Hemorrhagic presentation (%)

12 (16.4)

20 (25.6)

0.57 (0.26–1.27)

0.170

Euthyroid status (%)

62 (84.9)

73 (93.6)

0.39 (0.13–1.17)

0.093

Decreased vascular reserve on previous

69 (94.5)

65 (83.3)

3.45 (1.07–11.12)

48 (65.8)

34 (43.6)

36.0 (28.3–41.0)

Multivariate Analysis* Odds ratio (95% CI)

P-value

0.038

7.18 (1.78–29.02)

0.006

2.49 (1.29–4.80)

0.007

3.32 (1.57–6.98)

0.002

32.0 (28.0–40.0)

1.03 (0.99–1.08)

0.119

1.06 (1.01–1.11)

0.017

468.0 (402.9–516.0)

462.9 (336.0–511.4)

1.00 (1.00–1.01)

0.111

36.1 ± 4.0

38.3 ± 4.0

0.87 (0.80–0.95)

0.001

0.86 (0.78–0.94)

0.001

Preoperative

SPECT (%) Operation on the dominant hemisphere (%) Intraoperative Temporal occlusion time (min) PaO2/FiO2 min (mmHg) PaCO2 min (mmHg)

Data are expressed as number (%), median (interquartile range), or mean ± standard deviation. SCH, symptomatic cerebral hyperperfusion; CI, confidence interval; SPECT, single-photon emission computed tomography; PaO2, partial pressure of oxygen; FiO2, fraction of inspired oxygen; min, minimum; PaCO2, partial pressure of carbon dioxide. *

Adjusted by initial hemorrhagic presentation, preoperative euthyroid status, preserved vascular reserve at preoperative SPECT, operation on the dominant hemisphere,

temporal occlusion time, and intraoperative minimum PaO2/FiO2 and PaCO2, which were variables with a P value less than 0.2 in univariate binary logistic regression analysis. Nagelkerke R2 statistic is 0.250 in step 4. Hosmer and Lemeshow goodness of fit test was not significant at 5% (P = 0.542) in step 4.