Midazolam Sedation Induces Upper Limb Coordination Deficits That Are Reversed by Flumazenil in Patients with Eloquent Area Gliomas

• Published in: Anesthesiology (Philadelphia) Vol. 131; no. 1; pp. 36 - 45
• Main Authors: Lin, Nan, Han, Ruquan, Hui, Xuan, Zhang, Kaiying, Gelb, Adrian W.
• Format: Journal Article
• Language: English
• Published: United States Copyright by , the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc 01.07.2019
• Subjects: Adult; Brain Neoplasms - complications; Brain Neoplasms - physiopathology; Female; Flumazenil - pharmacology; GABA Modulators - pharmacology; Glioma - complications; Glioma - physiopathology; Humans; Hypnotics and Sedatives - pharmacology; Male; Midazolam - pharmacology; Middle Aged; Motor Disorders - chemically induced; Motor Disorders - drug therapy; Motor Disorders - physiopathology; Upper Extremity - physiopathology
• ISSN: 0003-3022; 1528-1175; 1528-1175
• DOI: 10.1097/ALN.0000000000002726

WHAT WE ALREADY KNOW ABOUT THIS TOPICSedation is known to unmask focal neurologic deficits in patients with supratentorial brain tumors but the mechanism is unclear WHAT THIS ARTICLE TELLS US THAT IS NEWWhen induced with midazolam, these deficits can be reversed by flumazenil, suggesting a γ-aminobutyric acid–mediated mechanism BACKGROUND:Midazolam has been found to exacerbate or unmask limb motor dysfunction in patients with brain tumors. This study aimed to determine whether the exacerbated upper limb motor-sensory deficits are mediated through benzodiazepine sites by demonstrating reversibility by flumazenil in patients with gliomas in eloquent areas. METHODS:This was an interventional, parallel assignment, nonrandomized trial. Study subjects were admitted in the operating room. Patients with supratentorial eloquent area gliomas and volunteers of similar age without neurologic disease were sedated with midazolam, but still responsive and cooperative. Motor and sensory functions for upper extremities were evaluated by the Nine-Hole Peg Test before and after midazolam, as well as after flumazenil reversal. RESULTS:Thirty-two cases were included15 in the glioma group and 17 in the control group. The total dose of midazolam and flumazenil were comparable between the groups. In the glioma group, the times to task completion after midazolam in the contralateral hand (P = 0.001) and ipsilateral hand (P = 0.002) were 26.5 (95% CI, 11.3 to 41.7) and 13.7 (95% CI, 5.0 to 22.4) seconds slower than baseline, respectively. After flumazenil reversal, the contralateral hand (P = 0.99) and ipsilateral hand (P = 0.187) performed 1.2 (95% CI, −3.3 to 5.8) and 1.5 (95% CI, −0.5 to 3.5) seconds slower than baseline, respectively. In the control group, the dominant (P < 0.001) and nondominant hand (P = 0.006) were 2.9 (95% CI, 1.4 to 4.3) and 1.7 (95% CI, 0.5 to 2.9) seconds slower than baseline, respectively. After flumazenil, the dominant hand (P = 0.99) and nondominant hand (P = 0.019) performed 0.2 (95% CI, −0.7 to 1.0) and 1.3 (95% CI, −0.2 to 2.4) seconds faster than baseline, respectively. CONCLUSIONS:In patients with eloquent area gliomas, mild sedation with midazolam induced motor coordination deficits in upper limbs. This deficit was almost completely reversed by the benzodiazepine antagonist flumazenil, suggesting that this is a reversible abnormality linked to occupation of the receptor by midazolam.