Midazolam and propofol reduce cerebral blood flow (CBF) similarly via a decrease in the cerebral metabolic rate of oxygen.1,2 However, these 2 types of sedatives have different effects on the autonomic nervous system and endothelium-induced relaxation. In the autonomic nervous system, midazolam induces sympathetic dominance, whereas propofol induces parasympathetic dominance.3,4 Although midazolam has no effect on endothelium-dependent relaxation, propofol may suppress the action of nitric oxide in smooth muscle cells.5 Moreover, midazolam shows apparent augmentation of cerebrovascular resistance.6,7 The autonomic nervous system, endothelium-derived factors, and cerebrovascular smooth muscle relate to regulation of not only steady-state but also dynamic changes in CBF.8–11 Therefore, the contrastive effects of midazolam and propofol may lead to different alterations in dynamic cerebral autoregulation.
The ability of cerebral arterioles to buffer changes in CBF induced by rapid changes in arterial blood pressure is referred to as dynamic cerebral autoregulation.9,12 Several studies of cerebral autoregulation have evaluated dynamic cerebral autoregulation in addition to assessing time-average CBF.13,14 Transfer function analysis between arterial blood pressure oscillations and CBF fluctuations reveals a frequency-dependent property of dynamic cerebral autoregulation.9,10 In addition, several studies have shown that alterations in dynamic cerebral autoregulation can occur regardless of changes in time-average CBF velocity.11,15,16 These reports suggest that the evaluation of dynamic cerebral autoregulation by transfer function analysis provides different information from the assessment of time-average CBF velocity.
We evaluated dynamic cerebral autoregulation during midazolam and propofol sedation using spectral and transfer function analysis of arterial blood pressure variability and CBF velocity variability, to investigate whether midazolam and propofol have different effects on dynamic cerebral autoregulation.
The IRB of Nihon University School of Medicine approved this study. All study volunteers provided written informed consent as well as a medical history, and were screened based on a physical examination including electrocardiography, arterial blood pressure, and CBF velocity measurements. Exclusion criteria included failure to obtain CBF velocity signals in the middle cerebral artery by transcranial Doppler ultrasonography. One volunteer was screened out because of inadequate CBF velocity signals and 1 volunteer was screened out because of a food allergy. Ten healthy, normotensive men with a mean age of 22 years (range, 20–24 years), height of 172 cm (range, 163–179 cm), and weight of 67 kg (range, 58–84 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 structure and ear, after the optimal angle of insonation with the highest velocity and best-quality Doppler signal had been identified in screening procedures.17
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 in a comfortable bed, in an environmentally controlled experimental room, at an ambient temperature of 23°C to 25°C. An electrocardiograph (BP-508; Colin, Aichi, Japan), pulse oximeter (NPB-75; Nellcor Puritan Bennett, Inc., Pleasanton, CA), nasal cannula for monitoring end-tidal carbon dioxide (ETCO2) (NPB-75; Nellcor Puritan Bennett, Inc., Pleasanton, CA), and a bispectral index monitor (BIS XP®; Aspect Medical Systems, Inc., Norwood, MA) were used to monitor vital signs. Beat-to-beat arterial blood pressure was measured in the radial artery at heart level using tonometry with a noninvasive arterial blood pressure monitor (JENTOW 7700; Colin). To calibrate continuous (beat-to-beat) arterial blood pressure, intermittent arterial blood pressure was also measured by an 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 passing time. CBF velocity in the middle cerebral artery was continuously measured by transcranial Doppler ultrasonography (WAKI; Atys Medical, St. Genis Laval, 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 structure and ear by an experienced technician.17 Excellent reliability of CBF velocity measured by transcranial Doppler ultrasonography has been reported.18 The waveforms of continuous arterial blood pressure, CBF velocity, and electrocardiography were recorded at a sampling rate of 1 kHz using commercial software (Notocord-hem 3.3; Notocord, Paris, France) throughout the experiment. A 22-gauge catheter was inserted into a forearm vein for drug administration.
The study was a randomized, single-blind, crossover comparison among midazolam, propofol, and a placebo (normal saline). The sequence of drugs and placebo administration in each subject was determined at random, and the subjects were blinded to types of administrations. All subjects received all 3 types of administration, and at least 7 days were allowed between administrations. The modified Observer's Assessment of Alertness/Sedation (OAA/ S) scale was used to assess sedation depth.3,19 An OAA/S scale score of 5 (responds readily to name spoken in normal tone) was defined as the baseline state and an OAA/S scale score of 3 (responds only after name is called loudly and/or repeatedly) was defined as a conscious sedation state. An OAA/S scale score of 3 was the end point for titration of the drug administrations. BIS was used to confirm the stability of sedation depth during data acquisition.
Drugs were administered after recording baseline data for 6 minutes after at least 30 minutes of rest. Midazolam was administered at an initial bolus dose of 0.5 mg, and the additional bolus dose of 0.5 mg was administrated every 2 minutes after OAA/S assessment until OAA/S scale score 3 was reached. Propofol was infused at an initial dose of 2.0 mg/kg/h for 5 minutes and increased in increments of 0.5 mg/kg/h every 5 minutes after OAA/S assessment until OAA/S scale score 3 was reached. Normal saline was administered for approximately 21 minutes as a placebo to evaluate the possible effects of time factors. After reaching OAA/S scale score 3 or 15 minutes after beginning the normal saline administration, drug administration data were recorded for 6 minutes. Infusions of propofol and normal saline continued during data collection.
Six minutes of continuous arterial blood pressure, CBF velocity, and electrocardiographic waveforms were used for spectral and transfer function analyses during spontaneous respiration of room air. Mean values for steady-state mean arterial blood pressure (MAP), CBF velocity, and heart rate were obtained by averaging the 6 minutes of data. Values of respiration rate, ETCO2, and arterial oxygen saturation were manually recorded every minute on one-off measures. The values at 7 time points (0, 1, 2, 3, 4, 5, and 6 minutes) during this period were averaged and used as each subject's individual data.
Beat-to-beat values of MAP and CBF velocity 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,9,10 MAP and CBF velocity beat-to-beat data 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 CBF velocity variability, mean value of transfer function gain, phase and coherence function were calculated in the very-low-frequency (0.02–0.07 Hz), low-frequency (0.07–0.20 Hz), and high-frequency (0.20–0.30 Hz) ranges (Fig. 1). These ranges were specifically selected to reflect different patterns of the dynamic pressure-flow relationship.9,10 A coherence function (strength of association) between 0 and 1 reflects the linear relationship between MAP and CBF velocity. Phase reflects the temporal relationship between the 2 variables. To avoid the occurrence of phase “wrap-round,” we corrected the negative value by adding a constant, 2π, inspecting for each harmonic before the averaging phase in the very-low-frequency range. 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.
Variables were compared using 2-way repeated-measures analysis of variance with Stage (baseline and drug administration) × Drug (midazolam, propofol, and placebo). The interaction effect was considered the most relevant for determining drug effects. To determine where significant differences occurred, a Student-Newman-Keuls post hoc test was used for all pairwise comparisons. A P value <0.05 was considered statistically significant. Analyses were performed using PC-based software (SigmaStat; Systat Software, Inc., Chicago, IL). Data are presented as mean ± SD.
Continuous measurement of respiratory data was not possible in 1 subject because of a water drop in the sampling tube for ETCO2 monitoring during propofol administration. These values were excluded from the group-averaged data for statistical analysis.
Table 1shows the average values of steady-state hemodynamic (n = 10) and respiratory (n = 9) data. Steady-state CBF velocity decreased significantly with midazolam and propofol administration, relative to levels with placebo administration (significant interaction effects, P = 0.024). Steady-state MAP decreased significantly with propofol administration (significant main effect of Time, P = 0.043). Respiration rate with placebo administration was lower than with midazolam and propofol administration (significant main effect of Drug, P = 0.036), whereas arterial oxygen saturation decreased slightly but significantly with midazolam and propofol administration (significant main effect of Time, P = 0.012). BIS decreased significantly with all drug administrations (significant main effect of Time, P = 0.001).
Table 2 shows group-averaged frequency domain data and Figure 1 shows group-averaged transfer function analysis of beat-to-beat changes in MAP and CBF velocity after drug administrations. The low-frequency power of MAP variability did not change at any drug administration, but the low-frequency power of CBF velocity decreased significantly with midazolam and propofol administration (significant main effect of Time, P = 0.014). Coherence in this range decreased significantly with midazolam administration (significant main effect of Time, P = 0.042). The transfer function gain decreased significantly with midazolam administration, in contrast to no measurable change with propofol or placebo administration (significant interaction effects, P = 0.015). Phase, spectral power, and transfer function indices in the very-low-frequency and high-frequency ranges did not change with any drug administration.
The primary finding of this study was that, although the decrease in the steady-state CBF velocity was equivalent for midazolam and propofol administration, change in transfer function gain between MAP variability and CBF velocity variability was significantly different between the 2 drugs. Only midazolam administration resulted in a decrease in transfer function gain in the low-frequency range, suggesting improvement of dynamic cerebral autoregulation.
Cerebral autoregulation maintains steady-state CBF at relatively constant levels despite large sustained changes in perfusion pressures.20 However, CBF velocity responds briskly to rapid changes in arterial blood pressure even under normal conditions.9,12 Continuous measurement of CBF velocity by transcranial Doppler in a large cerebral artery provides data with high temporal resolution, and reveals prominent beat-to-beat fluctuations,12 similar to the oscillations observed in arterial blood pressure.9,10 The regulation of these rapid changes in CBF is recognized as dynamic cerebral autoregulation. Transfer function analysis quantifies the buffering ability of distal cerebral arterioles in response to beat-to-beat fluctuations in arterial blood pressure, and yields insights into dynamic, frequency-dependent properties of cerebral autoregulation.9,10 This buffering ability is dependent on the frequency of arterial blood pressure oscillations, and the dynamic pressure-flow relationship has consistently shown a pattern resembling a high-pass filter. For example, coherence and transfer function gain are generally higher and phase is lower at relatively higher frequencies (>0.1 Hz), indicating that fluctuations in CBF velocity are more dependent on relatively faster oscillations in arterial blood pressure. Using this analysis method to evaluate dynamic cerebral autoregulation regardless of changed or unchanged time-average CBF velocity has provided novel information on cerebral circulation.11,15,16 However, the transfer function approach relies solely on the relationship between spontaneous oscillations in arterial blood pressure and fluctuations in CBF velocity. Therefore, diminution of spontaneous oscillations influences the analysis by this approach. However, the 17 to 20 mm Hg of the range in MAP variations observed during spontaneous respiration in this study is comparable to the approximately 10 to 20 mm Hg variation induced by phenylephrine infusion or the thigh cuff deflation method.12,13 Thus, transfer function analysis would be reasonable for evaluation of autoregulation and the methods with manipulation of arterial blood pressure.
In this study, steady-state CBF velocity decreased with both midazolam and propofol administration, consistent with previous studies.1,2,6,7 This change in CBF velocity may have been induced by a decrease in the cerebral metabolic rate of oxygen.1,2 Also, apparent augmentation of cerebrovascular resistance due to midazolam administration6,7 and the suppressive effects of propofol on endothelium-dependent relaxation5 might reduce the steady-state CBF velocity, respectively.
Despite deceases in steady-state CBF velocity under both types of sedatives, transfer function gain (magnitude of transfer) in the low-frequency range significantly decreased only with midazolam. This change differed significantly from the absence of change in transfer function gain with propofol. These results suggest that the ability of distal cerebral arterioles to respond to rapid spontaneous oscillations in arterial blood pressure is augmented during midazolam sedation, indicating improvement of dynamic cerebral autoregulation. Conversely, the present findings demonstrated no changes in transfer function gain in any frequency range with propofol administration, despite a decrease in steady-state CBF velocity. These findings suggest that dynamic cerebral autoregulation is not altered by propofol sedation, consistent with the results of propofol anesthesia reported in a previous study.13 To our knowledge, this study is the first to demonstrate that midazolam and propofol sedation lead to different alterations in dynamic cerebral autoregulation. That is, dynamic control of cerebral circulation is augmented during midazolam sedation compared with during propofol sedation. This difference in effect on dynamic cerebral autoregulation may result from the different neurological and/or vasoactive functions of midazolam and propofol mentioned in the beginning of the article. Compared with propofol, midazolam causes sympathetic dominance of autonomic balance3 and strong constriction of cerebral arterioles.6,7 These particular effects of midazolam may relate to a decrease in transfer function gain in the low-frequency range. Previous frequency domain studies have indicated that dynamic cerebral autoregulation in the low-frequency range may be partly modulated by autonomic and myogenic mechanisms.10,11 Although we did not attempt to elucidate in this study the specific factors and/or mechanisms behind changing dynamic cerebral autoregulation, we speculate that the improved dynamic cerebral autoregulation during midazolam sedation may be induced by multiple factors, including autonomic and myogenic mechanisms.
We used BIS in the assessment of sedation depth and stability during measurement of the data. Compared with baseline, BIS decreased during data collection for all drug administrations. A previous study showed that light natural sleep occurred at BIS values of 75 to 90.21 In the present study, BIS values with all drug administrations were approximately 75. However, sedative drugs have direct hypnotic effects that placebo lacks. Therefore, “natural sleep” is not necessarily equal to “sedation” by sedative drugs. In the present study, whether depth of “sleep” by placebo was equal to that of “sedation” by sedative drugs is unknown. BIS has several limitations in the assessment of sedation depth.21,22 For example, BIS indicates various and wide values among individuals and effects of age, in addition to drug-specific characteristics.22,23 Also, different sedation depths sometimes show similar BIS values.22 It would be difficult to rigorously define the equivalent depth of sedation between drugs. However, BIS has been widely used for the assessment of sedation depth in clinical practice, and is generally believed to be clinically reliable.22,23 We therefore believe that there was no clinically significant difference in sedation depth between midazolam and propofol and that the stability of the 2 drugs is comparable.
One limitation of the present protocol is the use of transcranial Doppler ultrasonography for measurements of middle cerebral artery blood flow. The validity of using transcranial Doppler ultrasonography to estimate changes in CBF is based on the assumption that the diameter of the middle cerebral artery changes minimally (<4.0%), confirmed during hypocapnia,24,25 hypercapnia,25 hypotension, and hypertension.25,26 Although direct vasoconstrictive effects of midazolam and propofol on the middle cerebral artery are unclear, these sedative drugs do not alter the diameter or tone of large arterioles in pial vessels.27,28 Therefore, the potential change of the middle cerebral artery during midazolam and propofol sedation is likely to be minimal.
There is also the possibility that changes in arterial CO2 concentration may have influenced the present results. Midazolam and propofol have depressive effects on respiration. An increase in arterial CO2 concentration reportedly impairs dynamic cerebral autoregulation.9,29 Thus, if increases in arterial CO2 occurred, we may have underestimated the improvement of dynamic cerebral autoregulation.
The present regime and volume of midazolam and propofol would lead to light or moderate sedation. Therefore, the regime and volume may be appropriate for sedation in clinical settings where a reaction to verbal instructions is required, such as dental treatment, fiberscopic checkup, or operations during local and lumbar anesthesia. To select an optimum sedative for each patient and operative condition, anesthesiologists must also consider sedative characteristics, such as circulatory effect, context-sensitive half-life, and the presence of antagonists. The present findings may contribute new information to assist in sedative selection. However, whether midazolam sedation restores impaired cerebral autoregulation is unknown. To directly reveal the clinical significance of these findings, clinical studies that investigate the effects of midazolam on impaired cerebral autoregulation will be needed.
In this study, we investigated the basic effects of midazolam and propofol sedations on cerebral circulation in healthy volunteers and discovered that midazolam and propofol have different effects on dynamic cerebral autoregulation, despite having equivalent decreases in steady-state CBF velocity. Midazolam leads to a potential improvement of dynamic cerebral autoregulation.
YO helped with study design, conduct of study, data collection and analysis, and manuscript preparation; KI helped with study design, conduct of study, and manuscript preparation; KA, DG, and NH helped with conduct of study and data collection; and JK and SO helped with study design and manuscript preparation.
1. Wolff J. Cerebrovascular and metabolic effects of midazolam and flumazenil. Acta Anaesthesiol Scand Suppl 1990;92:75–7
2. Oshima T, Karasawa F, Satoh T. Effects of propofol on cerebral blood flow and the metabolic rate of oxygen in humans. Acta Anaesthesiol Scand 2002;46:831–5
3. Win NN, Fukayama H, Kohase H, Umino M. The different effects of intravenous propofol and midazolam sedation on hemodynamic and heart rate variability. Anesth Analg 2005;101:97–102
4. Deutschman CS, Harris AS, Fleisher LA. Changes in heart rate variability under propofol anesthesia: a possible explanation for propofol-induced bradycardia. Anesth Analg 1994;79:373–7
5. Miyawaki I, Nakamura K, Terasako K, Toda H, Kakuyama M, Mori K. Modification of endothelium-dependent relaxation by propofol, ketamine, and midazolam. Anesth Analg 1995; 81:474–9
6. Nugent M, Artru AA, Michenfelder JD. Cerebral metabolic, vascular and protective effects of midazolam maleate: comparison to diazepam. Anesthesiology 1982;56:172–6
7. Forster A, Juge O, Morel D. Effects of midazolam on cerebral hemodynamics and cerebral vasomotor responsiveness to carbon dioxide. J Cereb Blood Flow Metab 1983;3:246–9
8. White RP, Vallance P, Markus HS. Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans. Clin Sci (Lond) 2000;99:555–60
9. Giller CA. The frequency-dependent behavior of cerebral autoregulation. Neurosurgery 1990;27:363–8
10. Zhang R, Zuckerman JH, Giller CA, Levine BD. Transfer function analysis of dynamic cerebral autoregulation in humans. Am J Physiol 1998;274:H233–41
11. Zhang R, Zuckerman JH, Iwasaki K, Wilson TE, Crandall CG, Levine BD. Autonomic neural control of dynamic cerebral autoregulation in humans. Circulation 2002;106:1814–20
12. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke 1989;20:45–52
13. Strebel S, Lam AM, Matta B, Mayberg TS, Aaslid R, Newell DW. Dynamic and static cerebral autoregulation during isoflurane, desflurane, and propofol anesthesia. Anesthesiology 1995;83:66–76
14. Ogawa Y, Iwasaki K, Aoki K, Kojima W, Kato J, Ogawa S. Dexmedetomidine weakens dynamic cerebral autoregulation as assessed by transfer function analysis and the thigh cuff method. Anesthesiology 2008;109:642–50
15. Ogawa Y, Iwasaki K, Aoki K, Saitoh T, Kato J, Ogawa S. Central hypervolemia with hemodilution impairs dynamic cerebral autoregulation. Anesth Analg 2007;105:1389–96
16. Low DA, Wingo JE, Keller DM, Davis SL, Cui J, Zhang R, Crandall CG. Dynamic cerebral autoregulation during passive heat stress in humans. Am J Physiol Regul Integr Comp Physiol 2009;296:R1598–605
17. Giller CA, Giller AM. A new method for fixation of probes for transcranial Doppler ultrasound. J Neuroimaging 1997;7:103–5
18. Brodie FG, Atkins ER, Robinson TG, Panerai RB. Reliability of dynamic cerebral autoregulation measurement using spontaneous fluctuations in blood pressure. Clin Sci (Lond) 2009; 116:513–20
19. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244–51
20. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 1990;2:161–92
21. Sleigh JW, Andrzejowski J, Steyn-Ross A, Steyn-Ross M. The bispectral index: a measure of depth of sleep? Anesth Analg 1999;88:659–61
22. Ibrahim AE, Taraday JK, Kharasch ED. Bispectral index monitoring during sedation with sevoflurane, midazolam, and propofol. Anesthesiology 2001;95:1151–9
23. Denman WT, Swanson EL, Rosow D, Ezbicki K, Connors PD, Rosow CE. Pediatric evaluation of the bispectral index (BIS) monitor and correlation of BIS with end-tidal sevoflurane concentration in infants and children. Anesth Analg 2000;90:872–7
24. Serrador JM, Picot PA, Rutt BK, Shoemaker JK, Bondar RL. MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis. Stroke 2000;31:1672–8
25. Giller CA, Bowman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery 1993;32:737–41
26. Larsen FS, Olsen KS, Hansen BA, Paulson OB, Knudsen GM. Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation. Stroke 1994; 25:1985–8
27. Kumano H, Shimomura T, Furuya H, Yomosa H, Okuda T, Sakaki T, Kuro M. Effects of flumazenil during administration of midazolam on pial vessel diameter and regional cerebral blood flow in cats. Acta Anaesthesiol Scand 1993;37:567–70
28. Wallerstedt SM, Reinstrup P, Uski T, Bodelsson M. Effects of propofol on isolated human pial arteries. Acta Anaesthesiol Scand 1999;43:1065–8
29. Panerai RB, Deverson ST, Mahony P, Hayes P, Evans DH. Effects of CO2
on dynamic cerebral autoregulation measurement. Physiol Meas 1999;20:265–75