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Cardiovascular response and stress reaction to flumazenil injection in patients under infusion with midazolam

Kamijo, Yoshito MD; Masuda, Takashi MD; Nishikawa, Takashi PhD; Tsuruta, Harukazu PhD; Ohwada, Takashi MD

Clinical Investigations
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Objectives: To evaluate the cardiovascular response and acute stress reaction after arousal induced by a benzodiazepine antagonist, flumazenil, in patients sedated with midazolam.

Design: Prospective study.

Setting: Emergency center in a university hospital.

Patients: A total of 12 patients were ventilated mechanically under sedation with midazolam.

Interventions: We monitored the consciousness level, heart rate, systemic blood pressure, pulmonary artery pressure, and pulmonary artery occlusion pressure before and after a bolus injection of 0.5 mg of flumazenil. The score for the consciousness level represents the sum of the scores for eye opening and best motor response, as determined by the Glasgow Coma Scale. We measured the cardiac output, concentrations of norepinephrine, epinephrine, and 3-methoxy-4-hydroxyphenylethyleneglycol in plasma, and concentration of cortisol in serum. We calculated the left ventricular ejection fraction, cardiac index, systemic vascular resistance index, pressure-rate product, systemic oxygen delivery, and systemic oxygen consumption at 0, 10, 30, and 60 mins after injection of flumazenil.

Measurements and Main Results: The serum benzodiazepine's receptor binding activity in serum was in the range from 50 to 1000 ng/mL before injection of flumazenil. Flumazenil improved the consciousness level from 6.7 ± 2.0 to 8.9 ± 1.6 and induced transient elevations in heart rate, blood pressure, systolic pulmonary artery pressure, and pulmonary artery occlusion pressure. Left ventricular ejection fraction, oxygen delivery index, and pressure-rate product increased significantly, from 61% ± 8%, 640 ± 170 mL/min/m2, and 13,300 ± 2600 mm Hg/min at 0 mins to 67% ± 5%, 710 ± 220 mL/min/m2, and 16,500 ± 4400 mm Hg/min at 10 mins, respectively. Concentrations of norepinephrine and epinephrine in plasma increased significantly, from 890 ± 840 pg/mL and 220 ± 360 pg/mL, respectively, at 0 mins to 990 ± 850 pg/mL and 270 ± 300 pg/mL, respectively, at 10 mins. There were no significant changes in the plasma concentration of 3-methoxy-4-hydroxyphenylethyleneglycol, the serum concentration of cortisol after the administration of flumazenil.

Conclusions: Flumazenil did not result in a significant acute stress reaction in midazolam-sedated patients, but it increased myocardial oxygen consumption by enhancing sympathetic nervous activity or antagonizing cardiovascular depression induced by midazolam.

From the Departments of Emergency and Critical Care Medicine (Drs. Kamijo and Ohwada), Intemal Medicine (Dr. Masuda), Clinical Pathology (Dr. Nishlkawa), and Medical Informatics (Dr. Tsuruta), Kitasato University School of Medicine, Kanagawa, Japan.

Address requests for reprints to: Takashi Masuda, MD, The Department of Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 228 Japan. E-mail: tak9999@med.kitasato-u.ac.jp

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