CLINICAL INVESTIGATION
The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males Yojiro Ogawa, DDS, PhD,* Ken-ichi Iwasaki, MD, PhD,* Ken Aoki, PhD,* Ryo Yanagida, MD,* Kaname Ueda, MD,w Jitsu Kato, MD, PhD,w and Setsuro Ogawa, MD, PhDw
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.
Received for publication March 27, 2014; accepted November 26, 2014. From the Departments of *Social Medicine, Division of Hygiene; and wAnesthesiology, 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: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Neurosurg Anesthesiol
Key Words: intravenous sedation, cerebral circulation, benzodiazepine, antagonistic drug, transfer function analysis (J Neurosurg Anesthesiol 2015;27:275–281)
F
lumazenil is frequently administered to antagonize the effects of midazolam after sedation and/or anesthesia. As midazolam reduces cerebral blood flow (CBF),1,2 flumazenil should theoretically antagonize the midazolaminduced reductions in CBF. However, the antagonistic effects of flumazenil administered after midazolam on CBF are controversial.3,4 A previous study reported that flumazenil administration following midazolam anesthesia with fentanyl and nitrous oxide did not antagonize reductions in CBF,4 whereas another report states that simultaneous administration of flumazenil and midazolam antagonized the midazolam-induced reductions in CBF.3 Several factors, such as the level of awareness, subsequent resedation due to midazolam, influence of other drugs, and/or the sequence of midazolam and flumazenil administrations, could have led to these discrepancies in the changes in CBF.3,4 Moreover, our previous study showed that midazolam sedation alters dynamic cerebral autoregulation, which reflects responses of CBF to rapid changes in cerebral perfusion pressure.5 However, it remains unclear whether flumazenil antagonizes the alteration in dynamic cerebral autoregulation induced by midazolam. Clarifying this issue is important for safe and complete recovery from midazolam sedation, especially for evaluating awareness after treatment (eg, following neuroendovascular surgery or surgery under local anesthesia) or deciding readiness for discharge after outpatient examinations under midazolam sedation. We, therefore, investigated the effects of flumazenil administered after midazolam on cerebral circulation, to test our main hypothesis that flumazenil antagonizes the alterations in cerebral circulation induced by midazolam with complete reversal of sedation. Besides, it is important to know the effects on cerebral circulation of flumazenil administered alone at the same dose as is used to completely antagonize midazolam sedation. Therefore, in a second experiment, the effect of flumazenil alone, without midazolam sedation, on cerebral circulation was studied to test the subhypothesis that cerebral circulation
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remains unchanged after administration of flumazenil alone at the same dose as in the first experiment. For evaluation of cerebral circulation, steady-state mean CBF velocity (MCBFV) was measured by transcranial Doppler (TCD) ultrasonography. In addition, dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between mean arterial pressure (MAP) variability and MCBFV variability.
MATERIALS AND METHODS The institutional review board of Nihon University School of Medicine (Itabashi-ku, Tokyo, Japan) approved this study (No. 23-6, June 24, 2011), which was registered in the trial registry of Japan (University hospital Medical Information Network [UMIN], ID: UMIN000012777). All study volunteers provided written informed consent as well as a medical history, and were screened based on a physical examination, including electrocardiography (ECG), arterial blood pressure, and CBF velocity measurements. Exclusion criteria comprised failure to obtain CBF velocity signals in the middle cerebral artery by TCD ultrasonography. A total of 16 healthy, normotensive males with a mean age of 23 years (range, 20 to 26 y), height of 171 cm (range, 163 to 186 cm), and weight of 67 kg (range, 54 to 89 kg) were enrolled. All subjects were familiarized with the measurement techniques and experimental conditions before starting the study. A customized Doppler probe holder was made for each subject, using a polymer mold to fit individual facial bone structures and ears, to allow for repeated studies, after the optimal angle of insonation with the highest velocity and best-quality Doppler signal had been identified in screening procedures.6 Before the experiments, all subjects fasted for at least 2 hours, and refrained from heavy exercise and consuming caffeinated or alcoholic beverages for at least 24 hours. Subjects lay supine on a comfortable bed in an environmentally controlled experimental room at an ambient temperature of 23 to 251C. An ECG, pulse oximeter, nasal cannula for monitoring respiratory rate and end-tidal carbon dioxide (ETCO2) (Life Scope BSM5132; Nihon Koden, Tokyo, Japan), and bispectral index monitor (BIS XP; Aspect Medical Systems Inc., Norwood, MA) were used to monitor vital signs. The waveform of arterial blood pressure was continuously measured in the radial artery at the heart level using tonometry with a noninvasive arterial blood pressure monitor (JENTOW 7700; Colin, Aichi, Japan). The accuracy of this device during anesthesia was confirmed by comparisons with an intra-arterial pressure monitor.7 To calibrate the waveform of arterial blood pressure, intermittent arterial blood pressure was also measured by the oscillometric method with a sphygmomanometer cuff placed over the brachial artery. The calibration was performed just before every data acquisition trial, to avoid potential changes in the sensitivity of the tonometric sensor by movement of subjects and the passage of time. The waveform of CBF velocity in the right middle cere-
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bral artery was continuously measured by TCD ultrasonography (WAKI; Atys Medical, St Genislaval, France). A 2 MHz probe was placed over the temporal window and fixed at a constant angle with the customized probe holder made to fit individual facial bone structures and ears by an experienced technician.6 Excellent reliability of CBF velocity measured by TCD ultrasonography has been reported.8 The curve of peak envelop of Doppler signal was used as the waveforms of CBF velocity. The waveforms of arterial blood pressure, CBF velocity, and ECG were continuously recorded at a sampling rate of 1 kHz using commercial software (Notocord-hem 3.3; Notocord, Paris, France) throughout the experiment. After application of these instruments, a 22 G catheter was inserted into a forearm vein for drug administration. The modified Observer’s Assessment of Alertness/ Sedation (OAA/S) scale was used to assess sedation/ awareness levels.9,10 OAA/S scores at baseline and after flumazenil administration were 5 (responds readily to name spoken in a normal tone), and an OAA/S score of 3 (responds only after name is called loudly and/or repeatedly) was defined as the state of conscious sedation. Bispectral index (BIS) was used to confirm the stability of sedation/awareness levels during data acquisition.
Flumazenil After Midazolam Protocol Baseline data for 6 minutes was measured after at least 30 minutes of quiet rest. Thereafter, midazolam was administered at an initial bolus dose of 0.5 mg, and an additional bolus dose of 0.5 mg was administered every 2 minutes after OAA/S assessment until an OAA/S score of 3 was reached. As an adequate sedative effect is maintained for at least 30 minutes after midazolam administration,11 flumazenil was administered at an initial bolus dose of 0.2 mg 30 minutes after final administration of midazolam, and additional bolus doses of 0.1 mg were administered every 2 minutes until an OAA/S score of 5 was reached. After reaching the OAA/S scores of 3 or 5, data for each stage (during midazolam sedation and after flumazenil administration, respectively) were recorded for 6 minutes.
Flumazenil-alone Protocol At a minimum of 7 days after performing the “flumazenil after midazolam protocol,” flumazenil alone without midazolam sedation was administered to 11 of the 16 original subjects, to study the effects of flumazenil alone on cerebral circulation. Baseline data for 6 minutes was measured after at least 30 minutes of quiet rest. The same amounts of flumazenil at the same time intervals as in the “flumazenil after midazolam protocol” were administered. After confirming OAA/S scores of 5, “flumazenil-alone data” was recorded for 6 minutes. Mean values of steady-state MAP, steady-state MCBFV, and heart rate (HR) were obtained by averaging the 6-minute data of each waveform. Values of BIS, respiratory rate, ETCO2, and arterial oxygen saturation (SpO2) were manually recorded every minute and were Copyright
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Effects of Flumazenil After Midazolam Sedation
averaged as each subject’s individual data. In addition, cerebrovascular resistance was expressed as the cerebral vascular resistance index (CVRi), where CVRi = steadystate MAP/steady-state MCBFV. The 6-minute data of arterial blood pressure and CBF velocity waveforms were used for estimation of dynamic cerebral autoregulation during spontaneous respiration of room air. The values of beat-to-beat MAP and beat-to-beat MCBFV were obtained by integrating signals within each cardiac cycle using PC-based Notocord-hem 3.3 software (Notocord) for spectral and transfer function analyses. Using previously validated algorithms,12,13 the data of beat-to-beat MAP and beatto-beat MCBFV were then linearly interpolated and resampled at 2 Hz. The time series of the data were first detrended with third-order polynomial fitting. Fast Fourier transform and transfer function analyses were performed using a Hanning window on 256-point segments with 50% overlap. This process resulted in 5 segments over the 6 minutes of data. These data were then analyzed using DADiSP software (DSP Development, Cambridge, MA). The spectral power of MAP variability and MCBFV variability, mean value of transfer function gain, phase and coherence function were calculated in the very low-frequency (0.02 to 0.07 Hz), low-frequency (0.07 to 0.20 Hz), and high-frequency (0.20 to 0.35 Hz) ranges. These ranges were specifically selected to reflect different patterns of the dynamic pressure-flow relationship.12,13 A value of coherence function (strength of association) between 0 and 1 reflects a linear relationship between MAP variability and MCBFV variability. Phase reflects the temporal relationship between the 2 variables. Transfer function gain (magnitude of transfer) reflects the ability of the distal cerebral arterioles to buffer changes in CBF velocity induced by transient changes in arterial blood pressure at different frequencies. A small gain indicates that any given change in pressure leads to a small change in flow, implying improved autoregulation. In the “flumazenil after midazolam protocol,” variables were compared using 1-way repeated-measures ANOVA (baseline, during midazolam sedation, and after flumazenil administration). To determine whether significant differences occurred, a Student-Newman-Keuls post hoc test was used for all pair-wise comparisons. In the “flumazenil-alone protocol,” statistical analysis was performed using the paired t test (baseline and flumazenil alone). A P-value of 0.07 Hz), reflecting that fluctuations in flow are more dependent on relatively faster oscillations in pressure.12,13 In addition, transfer function gain (magnitude of transfer) is generally higher at a relatively higher frequency range, indicating that any given oscillation in pressure leads to greater fluctuations in flow.13 In the present study, the frequency-dependent property of dynamic cerebral autoregulation seen in baseline data (Fig. 1) was consistent with that of numerous previous reports.12,13,18 Moreover, dynamic cerebral autoregulation can be evaluated over a wide time range (from about 3 s to about 1 min) by assessing changes in arterial pressure using spectral and transfer function analysis.19 The other methods that induce MAP changes (eg, leg cuff deflation method) calculate autoregulation indices only from “a momentary (a few seconds)” reduction in arterial pressure. During midazolam sedation, transfer function gain in the low-frequency range decreased significantly. This decreased transfer function gain indicates that the ability of distal cerebral arterioles to respond to spontaneous oscillations in arterial blood pressure (within 5 to 14 s) is improved during midazolam sedation. This result was consistent with our previous study.5 However, the decreased transfer function gain persisted after administration of flumazenil, suggesting that flumazenil does not restore the alterations in dynamic cerebral autoregulation induced by midazolam. We speculate that these alterations may be induced through multiple mechanisms and factors, although this study did not attempt to elucidate the specific mechanisms and/or factors behind the alterations in dynamic cerebral autoregulation. First, the augmented cerebrovascular resistance, as mentioned above, may lead to decreases in transfer function gain, because there is an inverse relationship between cerebrovascular resistance and transfer function gain.20 Second, the reduced HR due to flumazenil, which is consistent with that observed in previous studies,3,21 may imply alteration of the autonomic nerve system. Changes in both myogenic and autonomic mechanisms reportedly relate to alterations in dynamic cerebral autoregulation.13,16,22 In addition, previous frequency domain studies have indicated that dynamic cerebral autoregulation in the low-frequency range may be mainly modulated by autonomic and myogenic mechanisms.13,22 Third, slight decreases in ETCO2 may lead to changes in cerebral circulation, implying potential effects of changes in arterial CO2. Fourth, transfer function gain in the high-frequency range changed only in the “flumazenil after midazolam protocol.” This suggests that there may be an interactive and/or additive effect of midazolam and flumazenil. In addition, the additional decreases in steady-state MCBFV may be related to a direct constrictive effect in cerebral arterioles, as CVRi increased significantly after administration of flumazenil. However, direct effects of flumazenil on cerebral arterioles remain unclear. Therefore, we hypothesized that the further reduction in steady-state
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MCBFV might be related not only to this direct constrictive effect of flumazenil, but to changes in the autonomic nerve system, slight decreases in arterial CO2, and interactive and/or additive effects between midazolam and flumazenil. Thus, flumazenil is unlikely to antagonize the changes in steady-state CBF induced by midazolam. However, the present observation of a further reduction in MCBFV after flumazenil administration was inconsistent with previous studies that reported restoration or no changes in steady-state CBF after flumazenil administration.3,4 The present results suggest for the first time that, despite complete antagonism of the sedative effects of midazolam, flumazenil administration does not antagonize both the decreases in steady-state CBF and alterations in dynamic cerebral autoregulation induced by midazolam. The present study also attempted to reveal the effects on cerebral circulation of flumazenil alone without midazolam sedation. Our findings, that flumazenil alone reduces steady-state MCBFV and transfer function gain in the low-frequency range, are consistent with those observed with the “flumazenil after midazolam protocol.” Contrary to our hypothesis, the present study suggests that flumazenil alone leads to slight decreases in steady-state CBF and alterations in dynamic cerebral autoregulation. The primary limitation of the present study is that arterial blood pressure was not measured invasively. Although its reliability has been demonstrated by numerous studies in the time and frequency domain,7,23 noninvasive arterial pressure waveforms have several limitations. For example, discrepancies between intra-arterial and noninvasive arterial pressure waveforms have been found under rapid and large transient changes in arterial pressure.23 Another limitation is the possibility that potential changes in arterial CO2 concentration and the cerebral metabolic rate of oxygen (CMRO2) may have influenced the present results, because we did not measure CMRO2 and arterial CO2. However, our previous study reported that the slight change in ETCO2 (75) has little effects on CBFV and dynamic cerebral autoregulation.5 We investigated the effects of flumazenil after midazolam sedation on cerebral circulation in healthy young males, and discovered that despite complete antagonism of the sedative effects of midazolam, flumazenil would not restore the alterations in cerebral circulation induced by midazolam. This observation may be of importance for procedures performed under light sedation in patients scheduled for discharge after operations under local anesthesia and for outpatient examinations. Further, routine administration of flumazenil must be cautioned against even in young patients. REFERENCES 1. Nugent M, Artru AA, Michenfelder JD. Cerebral metabolic, vascular and protective effects of midazolam maleate: comparison to diazepam. Anesthesiology. 1982;56:172–176. 2. Wolff J. Cerebrovascular and metabolic effects of midazolam and flumazenil. Acta Anaesthesiol Scand Suppl. 1990;92:75–77. 3. Forster A, Juge O, Louis M, et al. Effects of a specific benzodiazepine antagonist (RO 15-1788) on cerebral blood flow. Anesth Analg. 1987;66:309–313. 4. Knudsen L, Cold GE, Holdga˚rd HO, et al. Effects of flumazenil on cerebral blood flow and oxygen consumption after midazolam anaesthesia for craniotomy. Br J Anaesth. 1991;67:277–280. 5. Ogawa Y, Iwasaki K, Aoki K, et al. The different effects of midazolam and propofol sedation on dynamic cerebral autoregulation. Anesth Analg. 2010;111:1279–1284. 6. Giller CA, Giller AM. A new method for fixation of probes for transcranial Doppler ultrasound. J Neuroimaging. 1997;7:103–105. 7. Kemmotsu O, Ueda M, Otsuka H, et al. Arterial tonometry for noninvasive, continuous blood pressure monitoring during anesthesia. Anesthesiology. 1991;75:333–340.
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8. Brodie FG, Atkins ER, Robinson TG, et al. Reliability of dynamic cerebral autoregulation measurement using spontaneous fluctuations in blood pressure. Clin Sci (Lond). 2009;116:513–520. 9. Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990;10: 244–251. 10. Win NN, Fukayama H, Kohase H, et al. The different effects of intravenous propofol and midazolam sedation on hemodynamic and heart rate variability. Anesth Analg. 2005;101:97–102. 11. Dale O, Nilsen T, Loftsson T, et al. Intranasal midazolam: a comparison of two delivery devices in human volunteers. J Pharm Pharmacol. 2006;58:1311–1318. 12. Giller CA. The frequency-dependent behavior of cerebral autoregulation. Neurosurgery. 1990;27:363–368. 13. Zhang R, Zuckerman JH, Giller CA, et al. Transfer function analysis of dynamic cerebral autoregulation in humans. Am J Physiol. 1998;274:H233–H241. 14. Whitwam JG, Amrein R. Pharmacology of flumazenil. Acta Anaesthsiol Scand Suppl. 1995;108:3–14. 15. Fleischer JE, Milde JH, Moyer TP, et al. Cerebral effects of highdose midazolam and subsequent reversal with Ro 15-1788 in dogs. Anesthesiology. 1988;68:234–242. 16. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev. 1990;2:161–192. 17. Aaslid R, Lindegaard KF, Sorteberg W, et al. Cerebral autoregulation dynamics in humans. Stroke. 1989;20:45–52. 18. Iwasaki K, Ogawa Y, Shibata S, et al. Acute exposure to normobaric mild hypoxia alters dynamic relationships between blood pressure and cerebral blood flow at very-low frequency. J Cereb Blood Flow Metab. 2007;27:776–784. 19. Meel-van den Abeelen AS, Simpson DM, Wang LJ, et al. Betweencentre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure-flow relation: the CARNet study. Med Eng Phys. 2014;36:620–627. 20. Serrador JM, Sorond FA, Vyas M, et al. Cerebral pressure-flow relations in hypertensive elderly humans: transfer gain in different frequency domains. J Appl Physiol. 2005;98:151–159. 21. Galletly DC, Williams TB, Robinson BJ. Periodic cardiovascular and ventilatory activity during midazolam sedation. Br J Anaesth. 1996;76:503–507. 22. Zhang R, Zuckerman JH, Iwasaki K, et al. Autonomic neural control of dynamic cerebral autoregulation in humans. Circulation. 2002;106:1814–1820. 23. Sato T, Nishinaga M, Kawamoto A, et al. Accuracy of a continuous blood pressure monitor based on arterial tonometry. Hypertension. 1993;21:866–874. 24. Ogawa Y, Aoki K, Kato J, et al. Differential effects of mild central hypovolemia with furosemide administration vs. lower body suction on dynamic cerebral autoregulation. J Appl Physiol. 2013;114: 211–216. 25. Sleigh JW, Andrzejowski J, Steyn-Ross A, et al. The bispectral index: a measure of depth of sleep? Anesth Analg. 1999;88:659–661.
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The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males Yojiro Ogawa, DDS, PhD,* Ken-ichi Iwasaki, MD, PhD,* Ken Aoki, PhD,* Ryo Yanagida, MD,* Kaname Ueda, MD,w Jitsu Kato, MD, PhD,w and Setsuro Ogawa, MD, PhDw
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.
Received for publication March 27, 2014; accepted November 26, 2014. From the Departments of *Social Medicine, Division of Hygiene; and wAnesthesiology, 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: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Neurosurg Anesthesiol
Key Words: intravenous sedation, cerebral circulation, benzodiazepine, antagonistic drug, transfer function analysis (J Neurosurg Anesthesiol 2015;27:275–281)
F
lumazenil is frequently administered to antagonize the effects of midazolam after sedation and/or anesthesia. As midazolam reduces cerebral blood flow (CBF),1,2 flumazenil should theoretically antagonize the midazolaminduced reductions in CBF. However, the antagonistic effects of flumazenil administered after midazolam on CBF are controversial.3,4 A previous study reported that flumazenil administration following midazolam anesthesia with fentanyl and nitrous oxide did not antagonize reductions in CBF,4 whereas another report states that simultaneous administration of flumazenil and midazolam antagonized the midazolam-induced reductions in CBF.3 Several factors, such as the level of awareness, subsequent resedation due to midazolam, influence of other drugs, and/or the sequence of midazolam and flumazenil administrations, could have led to these discrepancies in the changes in CBF.3,4 Moreover, our previous study showed that midazolam sedation alters dynamic cerebral autoregulation, which reflects responses of CBF to rapid changes in cerebral perfusion pressure.5 However, it remains unclear whether flumazenil antagonizes the alteration in dynamic cerebral autoregulation induced by midazolam. Clarifying this issue is important for safe and complete recovery from midazolam sedation, especially for evaluating awareness after treatment (eg, following neuroendovascular surgery or surgery under local anesthesia) or deciding readiness for discharge after outpatient examinations under midazolam sedation. We, therefore, investigated the effects of flumazenil administered after midazolam on cerebral circulation, to test our main hypothesis that flumazenil antagonizes the alterations in cerebral circulation induced by midazolam with complete reversal of sedation. Besides, it is important to know the effects on cerebral circulation of flumazenil administered alone at the same dose as is used to completely antagonize midazolam sedation. Therefore, in a second experiment, the effect of flumazenil alone, without midazolam sedation, on cerebral circulation was studied to test the subhypothesis that cerebral circulation
Volume 27, Number 4, October 2015
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www.jnsa.com |
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remains unchanged after administration of flumazenil alone at the same dose as in the first experiment. For evaluation of cerebral circulation, steady-state mean CBF velocity (MCBFV) was measured by transcranial Doppler (TCD) ultrasonography. In addition, dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between mean arterial pressure (MAP) variability and MCBFV variability.
MATERIALS AND METHODS The institutional review board of Nihon University School of Medicine (Itabashi-ku, Tokyo, Japan) approved this study (No. 23-6, June 24, 2011), which was registered in the trial registry of Japan (University hospital Medical Information Network [UMIN], ID: UMIN000012777). All study volunteers provided written informed consent as well as a medical history, and were screened based on a physical examination, including electrocardiography (ECG), arterial blood pressure, and CBF velocity measurements. Exclusion criteria comprised failure to obtain CBF velocity signals in the middle cerebral artery by TCD ultrasonography. A total of 16 healthy, normotensive males with a mean age of 23 years (range, 20 to 26 y), height of 171 cm (range, 163 to 186 cm), and weight of 67 kg (range, 54 to 89 kg) were enrolled. All subjects were familiarized with the measurement techniques and experimental conditions before starting the study. A customized Doppler probe holder was made for each subject, using a polymer mold to fit individual facial bone structures and ears, to allow for repeated studies, after the optimal angle of insonation with the highest velocity and best-quality Doppler signal had been identified in screening procedures.6 Before the experiments, all subjects fasted for at least 2 hours, and refrained from heavy exercise and consuming caffeinated or alcoholic beverages for at least 24 hours. Subjects lay supine on a comfortable bed in an environmentally controlled experimental room at an ambient temperature of 23 to 251C. An ECG, pulse oximeter, nasal cannula for monitoring respiratory rate and end-tidal carbon dioxide (ETCO2) (Life Scope BSM5132; Nihon Koden, Tokyo, Japan), and bispectral index monitor (BIS XP; Aspect Medical Systems Inc., Norwood, MA) were used to monitor vital signs. The waveform of arterial blood pressure was continuously measured in the radial artery at the heart level using tonometry with a noninvasive arterial blood pressure monitor (JENTOW 7700; Colin, Aichi, Japan). The accuracy of this device during anesthesia was confirmed by comparisons with an intra-arterial pressure monitor.7 To calibrate the waveform of arterial blood pressure, intermittent arterial blood pressure was also measured by the oscillometric method with a sphygmomanometer cuff placed over the brachial artery. The calibration was performed just before every data acquisition trial, to avoid potential changes in the sensitivity of the tonometric sensor by movement of subjects and the passage of time. The waveform of CBF velocity in the right middle cere-
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bral artery was continuously measured by TCD ultrasonography (WAKI; Atys Medical, St Genislaval, France). A 2 MHz probe was placed over the temporal window and fixed at a constant angle with the customized probe holder made to fit individual facial bone structures and ears by an experienced technician.6 Excellent reliability of CBF velocity measured by TCD ultrasonography has been reported.8 The curve of peak envelop of Doppler signal was used as the waveforms of CBF velocity. The waveforms of arterial blood pressure, CBF velocity, and ECG were continuously recorded at a sampling rate of 1 kHz using commercial software (Notocord-hem 3.3; Notocord, Paris, France) throughout the experiment. After application of these instruments, a 22 G catheter was inserted into a forearm vein for drug administration. The modified Observer’s Assessment of Alertness/ Sedation (OAA/S) scale was used to assess sedation/ awareness levels.9,10 OAA/S scores at baseline and after flumazenil administration were 5 (responds readily to name spoken in a normal tone), and an OAA/S score of 3 (responds only after name is called loudly and/or repeatedly) was defined as the state of conscious sedation. Bispectral index (BIS) was used to confirm the stability of sedation/awareness levels during data acquisition.
Flumazenil After Midazolam Protocol Baseline data for 6 minutes was measured after at least 30 minutes of quiet rest. Thereafter, midazolam was administered at an initial bolus dose of 0.5 mg, and an additional bolus dose of 0.5 mg was administered every 2 minutes after OAA/S assessment until an OAA/S score of 3 was reached. As an adequate sedative effect is maintained for at least 30 minutes after midazolam administration,11 flumazenil was administered at an initial bolus dose of 0.2 mg 30 minutes after final administration of midazolam, and additional bolus doses of 0.1 mg were administered every 2 minutes until an OAA/S score of 5 was reached. After reaching the OAA/S scores of 3 or 5, data for each stage (during midazolam sedation and after flumazenil administration, respectively) were recorded for 6 minutes.
Flumazenil-alone Protocol At a minimum of 7 days after performing the “flumazenil after midazolam protocol,” flumazenil alone without midazolam sedation was administered to 11 of the 16 original subjects, to study the effects of flumazenil alone on cerebral circulation. Baseline data for 6 minutes was measured after at least 30 minutes of quiet rest. The same amounts of flumazenil at the same time intervals as in the “flumazenil after midazolam protocol” were administered. After confirming OAA/S scores of 5, “flumazenil-alone data” was recorded for 6 minutes. Mean values of steady-state MAP, steady-state MCBFV, and heart rate (HR) were obtained by averaging the 6-minute data of each waveform. Values of BIS, respiratory rate, ETCO2, and arterial oxygen saturation (SpO2) were manually recorded every minute and were Copyright
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Effects of Flumazenil After Midazolam Sedation
averaged as each subject’s individual data. In addition, cerebrovascular resistance was expressed as the cerebral vascular resistance index (CVRi), where CVRi = steadystate MAP/steady-state MCBFV. The 6-minute data of arterial blood pressure and CBF velocity waveforms were used for estimation of dynamic cerebral autoregulation during spontaneous respiration of room air. The values of beat-to-beat MAP and beat-to-beat MCBFV were obtained by integrating signals within each cardiac cycle using PC-based Notocord-hem 3.3 software (Notocord) for spectral and transfer function analyses. Using previously validated algorithms,12,13 the data of beat-to-beat MAP and beatto-beat MCBFV were then linearly interpolated and resampled at 2 Hz. The time series of the data were first detrended with third-order polynomial fitting. Fast Fourier transform and transfer function analyses were performed using a Hanning window on 256-point segments with 50% overlap. This process resulted in 5 segments over the 6 minutes of data. These data were then analyzed using DADiSP software (DSP Development, Cambridge, MA). The spectral power of MAP variability and MCBFV variability, mean value of transfer function gain, phase and coherence function were calculated in the very low-frequency (0.02 to 0.07 Hz), low-frequency (0.07 to 0.20 Hz), and high-frequency (0.20 to 0.35 Hz) ranges. These ranges were specifically selected to reflect different patterns of the dynamic pressure-flow relationship.12,13 A value of coherence function (strength of association) between 0 and 1 reflects a linear relationship between MAP variability and MCBFV variability. Phase reflects the temporal relationship between the 2 variables. Transfer function gain (magnitude of transfer) reflects the ability of the distal cerebral arterioles to buffer changes in CBF velocity induced by transient changes in arterial blood pressure at different frequencies. A small gain indicates that any given change in pressure leads to a small change in flow, implying improved autoregulation. In the “flumazenil after midazolam protocol,” variables were compared using 1-way repeated-measures ANOVA (baseline, during midazolam sedation, and after flumazenil administration). To determine whether significant differences occurred, a Student-Newman-Keuls post hoc test was used for all pair-wise comparisons. In the “flumazenil-alone protocol,” statistical analysis was performed using the paired t test (baseline and flumazenil alone). A P-value of 0.07 Hz), reflecting that fluctuations in flow are more dependent on relatively faster oscillations in pressure.12,13 In addition, transfer function gain (magnitude of transfer) is generally higher at a relatively higher frequency range, indicating that any given oscillation in pressure leads to greater fluctuations in flow.13 In the present study, the frequency-dependent property of dynamic cerebral autoregulation seen in baseline data (Fig. 1) was consistent with that of numerous previous reports.12,13,18 Moreover, dynamic cerebral autoregulation can be evaluated over a wide time range (from about 3 s to about 1 min) by assessing changes in arterial pressure using spectral and transfer function analysis.19 The other methods that induce MAP changes (eg, leg cuff deflation method) calculate autoregulation indices only from “a momentary (a few seconds)” reduction in arterial pressure. During midazolam sedation, transfer function gain in the low-frequency range decreased significantly. This decreased transfer function gain indicates that the ability of distal cerebral arterioles to respond to spontaneous oscillations in arterial blood pressure (within 5 to 14 s) is improved during midazolam sedation. This result was consistent with our previous study.5 However, the decreased transfer function gain persisted after administration of flumazenil, suggesting that flumazenil does not restore the alterations in dynamic cerebral autoregulation induced by midazolam. We speculate that these alterations may be induced through multiple mechanisms and factors, although this study did not attempt to elucidate the specific mechanisms and/or factors behind the alterations in dynamic cerebral autoregulation. First, the augmented cerebrovascular resistance, as mentioned above, may lead to decreases in transfer function gain, because there is an inverse relationship between cerebrovascular resistance and transfer function gain.20 Second, the reduced HR due to flumazenil, which is consistent with that observed in previous studies,3,21 may imply alteration of the autonomic nerve system. Changes in both myogenic and autonomic mechanisms reportedly relate to alterations in dynamic cerebral autoregulation.13,16,22 In addition, previous frequency domain studies have indicated that dynamic cerebral autoregulation in the low-frequency range may be mainly modulated by autonomic and myogenic mechanisms.13,22 Third, slight decreases in ETCO2 may lead to changes in cerebral circulation, implying potential effects of changes in arterial CO2. Fourth, transfer function gain in the high-frequency range changed only in the “flumazenil after midazolam protocol.” This suggests that there may be an interactive and/or additive effect of midazolam and flumazenil. In addition, the additional decreases in steady-state MCBFV may be related to a direct constrictive effect in cerebral arterioles, as CVRi increased significantly after administration of flumazenil. However, direct effects of flumazenil on cerebral arterioles remain unclear. Therefore, we hypothesized that the further reduction in steady-state
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MCBFV might be related not only to this direct constrictive effect of flumazenil, but to changes in the autonomic nerve system, slight decreases in arterial CO2, and interactive and/or additive effects between midazolam and flumazenil. Thus, flumazenil is unlikely to antagonize the changes in steady-state CBF induced by midazolam. However, the present observation of a further reduction in MCBFV after flumazenil administration was inconsistent with previous studies that reported restoration or no changes in steady-state CBF after flumazenil administration.3,4 The present results suggest for the first time that, despite complete antagonism of the sedative effects of midazolam, flumazenil administration does not antagonize both the decreases in steady-state CBF and alterations in dynamic cerebral autoregulation induced by midazolam. The present study also attempted to reveal the effects on cerebral circulation of flumazenil alone without midazolam sedation. Our findings, that flumazenil alone reduces steady-state MCBFV and transfer function gain in the low-frequency range, are consistent with those observed with the “flumazenil after midazolam protocol.” Contrary to our hypothesis, the present study suggests that flumazenil alone leads to slight decreases in steady-state CBF and alterations in dynamic cerebral autoregulation. The primary limitation of the present study is that arterial blood pressure was not measured invasively. Although its reliability has been demonstrated by numerous studies in the time and frequency domain,7,23 noninvasive arterial pressure waveforms have several limitations. For example, discrepancies between intra-arterial and noninvasive arterial pressure waveforms have been found under rapid and large transient changes in arterial pressure.23 Another limitation is the possibility that potential changes in arterial CO2 concentration and the cerebral metabolic rate of oxygen (CMRO2) may have influenced the present results, because we did not measure CMRO2 and arterial CO2. However, our previous study reported that the slight change in ETCO2 (75) has little effects on CBFV and dynamic cerebral autoregulation.5 We investigated the effects of flumazenil after midazolam sedation on cerebral circulation in healthy young males, and discovered that despite complete antagonism of the sedative effects of midazolam, flumazenil would not restore the alterations in cerebral circulation induced by midazolam. This observation may be of importance for procedures performed under light sedation in patients scheduled for discharge after operations under local anesthesia and for outpatient examinations. Further, routine administration of flumazenil must be cautioned against even in young patients. REFERENCES 1. Nugent M, Artru AA, Michenfelder JD. Cerebral metabolic, vascular and protective effects of midazolam maleate: comparison to diazepam. Anesthesiology. 1982;56:172–176. 2. Wolff J. Cerebrovascular and metabolic effects of midazolam and flumazenil. Acta Anaesthesiol Scand Suppl. 1990;92:75–77. 3. Forster A, Juge O, Louis M, et al. Effects of a specific benzodiazepine antagonist (RO 15-1788) on cerebral blood flow. Anesth Analg. 1987;66:309–313. 4. Knudsen L, Cold GE, Holdga˚rd HO, et al. Effects of flumazenil on cerebral blood flow and oxygen consumption after midazolam anaesthesia for craniotomy. Br J Anaesth. 1991;67:277–280. 5. Ogawa Y, Iwasaki K, Aoki K, et al. The different effects of midazolam and propofol sedation on dynamic cerebral autoregulation. Anesth Analg. 2010;111:1279–1284. 6. Giller CA, Giller AM. A new method for fixation of probes for transcranial Doppler ultrasound. J Neuroimaging. 1997;7:103–105. 7. Kemmotsu O, Ueda M, Otsuka H, et al. Arterial tonometry for noninvasive, continuous blood pressure monitoring during anesthesia. Anesthesiology. 1991;75:333–340.
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