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The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males

Ogawa, Yojiro DDS, PhD*; Iwasaki, Ken-ichi MD, PhD*; Aoki, Ken PhD*; Yanagida, Ryo MD*; Ueda, Kaname MD; Kato, Jitsu MD, PhD; Ogawa, Setsuro MD, PhD

Journal of Neurosurgical Anesthesiology: October 2015 - Volume 27 - Issue 4 - p 275–281
doi: 10.1097/ANA.0000000000000156
Clinical Investigations

Background: It is unknown whether flumazenil antagonizes the decrease in cerebral blood flow or the alteration in dynamic cerebral autoregulation induced by midazolam. We, therefore, investigated the effects on cerebral circulation of flumazenil administered after midazolam, to test our hypothesis that, along with complete reversal of sedation, flumazenil antagonizes the alterations in cerebral circulation induced by midazolam.

Methods: Sixteen healthy young male subjects received midazolam followed by flumazenil. The modified Observer’s Assessment of Alertness/Sedation (OAA/S) scale and bispectral index (BIS) were used to assess levels of sedation/awareness. For evaluation of cerebral circulation, steady-state mean cerebral blood flow velocity (MCBFV) was measured by transcranial Doppler ultrasonography. In addition, dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between mean arterial pressure (MAP) variability and MCBFV variability.

Results: During midazolam sedation, defined by an OAA/S score of 3 (responds only after name is called loudly and/or repeatedly), BIS, steady-state MAP, steady-state CBFV, and transfer function gain decreased significantly compared with baseline. After flumazenil administration, an OAA/S score of 5 (responds readily to name spoken in a normal tone) was confirmed. Then, BIS and MAP returned to the same level as baseline. However, steady-state MCBFV showed a further significant decrease compared with that under midazolam sedation, and the decreased transfer function gain persisted.

Conclusions: Contrary to our hypothesis, the present results suggest that despite complete antagonism of the sedative effects of midazolam, flumazenil would not reverse the alterations in cerebral circulation induced by midazolam.

Departments of *Social Medicine, Division of Hygiene

Anesthesiology, Division of Anesthesiology, Nihon University School of Medicine, Tokyo, Japan

Supported by JSPS KAKENHI Grant Number 23792388.

The authors have no conflicts of interest to disclose.

Reprints: Ken-ichi Iwasaki, MD, PhD, Department of Social Medicine, Division of Hygiene, Nihon University School of Medicine, 30-1, Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan (e-mail:

Received March 27, 2014

Accepted November 26, 2014

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