The Different Effects of Intravenous Propofol and Midazolam Sedation on Hemodynamic and Heart Rate Variability

Ni Ni Win, MBBS*, Haruhisa Fukayama, DDS, PhD, JBDA, IJBDA†, Hikaru Kohase, DDS, PhD, JBDA, IJBDA*, and Masahiro Umino, DDS, PhD, JBDA, IJBDA*
*Section of Anesthesiology and Clinical Physiology, Department of Oral Restitution, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University; and †Department of Dental Anesthesiology, School of Dental Medicine, Tsurumi University, Yokohama, Japan

Heart rate (HR) and arterial blood pressure (BP) changes have been reported during conscious sedation with propofol and midazolam. One potential mechanism to explain these changes is that propofol and midazolam affect HR and BP via changes in the cardiac autonomic nervous system. Two specific hypotheses were tested by HR variability analysis: 1) propofol induces predominance of parasympathetic activity, leading to decreased HR and BP, and 2) midazolam induces predominance of sympathetic activity, leading to increased HR and decreased BP. Thirty dental patients were included in a prospective, randomized study. HR, BP, low frequency (LF), high frequency (HF), and entropy were monitored during the awake, sedation, and recovery periods and depth of sedation was assessed using the Observer’s Assessment of Alertness/ Sedation score. Propofol induced a significant decrease in total power (503 209 ms2/Hz versus 162 92 ms2/

Hz) and LF/HF ratio (2.5 1.2 versus 1.0 0.4), despite the absence of any change in HR during the sedation period compared with baseline. Midazolam decreased normalized HF (34 10% versus 10 4%) but did not significantly change LF/HF ratio (2.3 1.1 versus 2.2 1.4) and increased HR in the sedation period. Compared with baseline, propofol was associated with a significant increase in normalized HF in the recovery period (34 11% versus 44 12%) and a significant decrease in HR, whereas midazolam was associated with an increase in LF/HF ratio (2.3 1.1 versus 3.7 1.8) with no change in HR. These results indicated a dominant parasympathetic effect of propofol and a dominant sympathetic effect of midazolam in both periods. These results should be considered during conscious sedation, especially in patients at risk of cardiovascular complications. (Anesth Analg 2005;101:97–102)

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ropofol and midazolam are used extensively for both general anesthesia and sedation, and small-dose propofol and midazolam sedation is used in dental practice. Hemodynamic changes, including changes in heart rate (HR) and arterial blood pressure (BP), have been reported during conscious sedation with propofol (1,2) and midazolam (3). One potential mechanism is that propofol and midazolam affect the HR and BP via changes in the cardiac autonomic nervous system (ANS), an important neural control system for maintaining cardiovascular stability. Previous studies have evaluated the effects of propofol and midazolam on cardiac ANS functions by means of HR variability (HRV)
Accepted for publication December 23, 2004. Address correspondence and reprint requests to Ni Ni Win, MBBS, Anesthesiology and Clinical Physiology, Department of Oral Restitution, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, 1–5– 45, Yushima, Bunkyou-ku, Tokyo, Japan, 113– 8549. Address e-mail to ninianph@tmd.ac.jp. DOI: 10.1213/01.ANE.0000156204.89879.5C
©2005 by the International Anesthesia Research Society 0003-2999/05

analysis, a noninvasive and widely used technique (4,5). HRV analysis can provide important clinical information on the effect of anesthesia on the ANS and central nervous system because cyclical variation in HR is mediated by central neural mechanisms and by baroreceptors and chemoreceptors (6). The sympathetic and parasympathetic components of HRV are active over different frequency ranges. The low-frequency component (LF, 0.05– 0.15 Hz) is influenced by both cardiac sympathetic and parasympathetic activity (5), and the high-frequency component (HF, 0.15 Hz) originates from cardiac parasympathetic activity (7). Therefore, the LF/HF ratio reflects dominance of cardiac sympathetic activity (8,9). In addition, entropy has been reported to reflect parasympathetic modulation of HR (10). There has been controversy as to whether propofol increases sympathetic or parasympathetic activity during general anesthesia (11–13) and there are no reports on the effects of propofol sedation on cardiac ANS activity. It has not been clarified that midazolam activates
Anesth Analg 2005;101:97–102

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ECG electrodes (leads I.. Midazolam was administered at a rate of 0. and the ECG signals were fed to a memory HR monitor (LRR-03™. Responsiveness Scores of the Modified Observer’s Assessment of Alertness/Sedation Score Response Responds readily to name spoken in normal tone Lethargic response to name spoken in normal tone Responds only after name is called loudly or repeatedly Responds only after mild prodding or shaking Does not respond to mild prodding or shaking Does not respond to noxious stimulation Score Level 5 (Alert) 4 3 2 1 0 Methods With the approval of the Tokyo Medical and Dental University Ethics Committee and informed consent. An OAA/S of 3 to 4 was maintained in both groups during the surgery by additional drug titration. and 2) midazolam induces predominance of sympathetic activity. The patients were randomly divided into a propofol group and a midazolam group. No patients received premedication. The impedance of each electrode was maintained below 5 K . Both anesthetics were discontinued when the last suture was completed. Japan). The sedation period data were recorded for 2 min beginning 1 min after reaching OAA/S 3. electrocardiogram (ECG). Tokyo. Propofol (Diprifusor™. within 20% of baseline values). and recovery data were recorded for 2 min. A 22-gauge catheter was inserted into a forearm vein for drug administration. Suwa Trust. The Bispectral Index (BIS) value was monitored with a BIS® monitor (Model A2000.98 AMBULATORY ANESTHESIA WIN ET AL. The surgical procedure was started 5 min after infiltration with local anesthetic. Respiratory rate (RR) and body temperature were measured at baseline and during the recovery period. Aspect Medical Systems. congestive heart failure. it is unknown whether sympathetic or parasympathetic activity is more affected during conscious sedation with propofol and midazolam. age 30 – 62 yr) were recruited for the study.14) and that it increases sympathetic activity during sedation (15). While the patients were left undisturbed. and the R-R interval (RRI) was continuously monitored. HEART RATE VARIABILITY DUE TO SEDATION ANESTH ANALG 2005. The control data or baseline data were recorded for 2 min before sedation with the patient lying quietly and breathing spontaneously. and removes it automatically. and during the recovery period. Each patient was requested to take only liquids and a light soft meal within 2 h before sedation. Patients who had severe ischemic heart disease. leading to increased HR and decreased BP. MA) and BIS Sensor strips. the OAA/S score was determined every minute until achieving the OAA/S 5. during sedation.e. The anesthesiologist was blinded as to the BIS value so that sedation depth would be assessed only by the OAA/S clinically. Data were analyzed and averaged at 2-min intervals at baseline. Five patients were taking an antihistamine for allergy. The . including noise. The fast peaks of R waves on the ECG were detected. Lidocaine (2%) with epinephrine (1:80.075 mg/kg until OAA/S 3 was reached.101:97–102 either sympathetic or parasympathetic activity during general anesthesia (9. the RRI data were obtained at 2-ms sampling intervals and analyzed by the maximum entropy method at high resolution with the “MemCalc” computer program (17–19). provided vital signs were stable (i.5 mg over 30 s each time. Tokyo. and peripheral oxygen saturation (Spo2) by pulse oximetry (BP-608 Evolution. GMS. We defined OAA/S 3 as a conscious sedation state and OAA/S 5 as baseline and recovery period from sedation. UK) was infused at an initial target effect-site concentration of 1 g/mL and increased in increments of 0. “MemCalc” executes a linearized version of the nonlinear least squares method for fitting analysis in the time domain combined with the maximum entropy method or spectral analysis in the frequency domain. For real-time analysis. Colin Medical Technology. Tokyo. Japan) were noninvasively and continuously monitored. During surgery RR was monitored at 5-min intervals by an anesthesiologist. or other disorders known to affect ANS function were excluded. HR. 30 dental implantation patients (ASA physical status I–II. Further.5 g/mL after the OAA/S assessment every minute until OAA/S 3 was reached. The BIS value and HRV data were continuously recorded on separate personal computers by an investigator. Natick. Table 1. diabetes mellitus. It provides reliable analyses of HRV over a minimum interval of 30 s and recognizes the abnormal RRI of premature beats or artifacts. leading to decreased HR and BP. Japan). and V5) were attached for HRV analysis.000 or 1:160. and the dose was increased after the OAA/S assessment every minute to a total bolus of 0. AstraZeneca Pharmaceuticals. II. An anesthesiologist used the modified Observer’s Assessment of Alertness/Sedation Score (OAA/S) (Table 1) to assess sedation depth (16). BP.000) was used as the local anesthetic to suppress pain associated with the dental procedures after the sedation period. Two specific hypotheses were tested by HRV analysis in this study: 1) propofol induces predominance of parasympathetic activity. The patients rested supine on a dental chair for 2 min while standard monitors were applied. The data were transferred to an online computer loaded with HRV analysis software (TARAWA/ WIN.

HRV was expressed as randomness of the pulse interval. the RR (breaths/min) was 16 2 in the propofol group and 16 3 in the midazolam group. Repeated-measures analysis followed by Bonferroni correction was performed for between-group comparison of hemodynamic variables and percentage changes in HRV data and LF/HF ratio. BP returned to baseline with midazolam but remained below baseline with propofol. (13) observed a decrease in HF with no . and required 4 1 min after surgery to reach OAA/S 5 with propofol and 5 2 min with midazolam. entropy. Our findings are consistent with theirs.ANESTH ANALG 2005.15 Hz) and HF (0. Scheffer et al. LF/HF.g. Total spectral power data and entropy were analyzed by a nonparametric method (Mann-Whitney U-test). During the recovery period.15– 0. or body temperature between the baseline and the recovery periods in either group.05. “MemCalc” was also used to calculate entropy from a pulse time series of 4 RRI. midazolam 95% confidence interval. 74 –79). LF. entropy was expressed from 0 (regular interval pulse series. e. and their study failed to demonstrate a clinical conscious level despite BIS monitoring. There were no changes in RR. LF and HF (proportional power) were calculated as percentages of TP (%LF LF/TP 100 and %HF HF/TP 100). no variability) to 100% (maximal randomness. Baseline HR and BP were comparable in the propofol and midazolam groups (Table 3).5) mL in the midazolam group.6 –9.101:97–102 AMBULATORY ANESTHESIA WIN ET AL. The entropy changes in both groups were directionally similar to the changes in HF. To confirm normal distribution. Thus. LF/HF decreased significantly in the propofol group but did not change significantly in the midazolam group. and 15 patients were actually included in each group in the study. Both groups showed comparable decreases in BP during sedation. Table 2. 0. LF. (12) reported that continuous infusion of propofol at a rate of 300 g · kg 1 · min 1 reduced cardiac parasympathetic tone based on a decrease in entropy and HF with no significant changes in LF.05. LF/HF remained below baseline in the propofol group but increased in the midazolam group. even though all patients were consciously sedated at OAA/S 3. During recovery.04 – 0. Kanaya et al.6 –10. Spo2. and HF without any change in HR.5 mg/kg) reduces TP.5 Hz) was obtained by addition of LF and HF. Midazolam (n 15) 6/9 52 11 56 13 158 7 49 17 80 17 5/10 49 10 55 8 157 6 51 19 84 18 TP. and the LF/HF ratio was also assessed. Changes in RR and tidal volume influence HRV. HF. By contrast. and entropy decreased significantly during the sedation period in both groups (Table 4). (11).4 (range.5 Hz) bands was calculated. and HR at BIS values of 80 and 60.. 69 –75. Propofol induced significant decreases in TP. The differences between the groups in both the sedation and recovery period were statistically significant. 0. HRV was measured during spontaneous respiration (RR unknown) and intermittent positive pressure ventilation was performed occasionally. 3. Statistical significance was determined as P 0. BIS values at baseline and during recovery were comparable in both groups (Table 3) but were significantly different during sedation (propofol 95% confidence interval.20) based on our pilot data on the assumption that a 10% difference between groups in percentage change in HRV parameters relative to baseline would be important clinically. The median dose of local anesthetic was 5. noise). However. and LF/HF ratio with no change in HR. but a statistically significant difference in HR was noted during sedation and the recovery period. During the sedation period. and Spo2 was 97 2% in both groups. Total spectral power (TP. The sample size of 12 patients in each group was determined by a power analysis ( 0. 3. indicating predominance of parasympathetic activity during sedation (OAA/S 3). HF and entropy were significantly higher than the baseline values in the propofol group but below the baseline values in the midazolam group (Table 4).04 – 0. HEART RATE VARIABILITY DUE TO SEDATION 99 power of the RRI (ms2) with LF (0. According to Deutschman et al. propofol (2. The data for descriptive (categorical) variables were subjected to the 2 test. During the sedation period. Results There were no significant differences in demographic data or duration of sedation and surgery between the two groups (Table 2). The decreased BP with no change in HR indicates that propofol attenuates the baroreflex reaction (20). Discussion The results of this study demonstrated that IV conscious sedations with propofol and midazolam differed in terms of changes in HR and HRV during the sedation and recovery periods. During the recovery period. LF and HF power. Patient Characteristics and Duration of Surgery and Sedation Propofol (n 15) Gender (male/female) Age (yr) Body weight (kg) Height (cm) Duration of surgery (min) Duration of sedation (min) Values are means sd.4 (range.8) mL in the propofol group and 5. The absolute power of HRV used in their study is inconsistent with the proportional power used in ours. underwent surgery uneventfully.

3 39 209 11 11 1.5 39 504 67 34 2. Although HF is affected by tidal volume and RR.100 AMBULATORY ANESTHESIA WIN ET AL. The decrease in HR without change in BP cannot be interpreted as activation of a baroreflex.05 between propofol and midazolam groups. Galletly et al. Arterial Blood Pressure. HEART RATE VARIABILITY DUE TO SEDATION ANESTH ANALG 2005. with a significant increase in HR and no change in LF/ HF. midazolam caused a significant decrease in TP. they did not discuss their effect. In the recovery period midazolam was associated with a significant increase in LF/HF ratio and significantly decreased HF and entropy. did. It is difficult to explain the absence of any change in HR during the recovery period despite the dominance of sympathetic action. † P Sedation 73 104 63 75 72 82 112 67 75 77 5 10** 8** 7** 6**† 7**† 14** 9* 14* 5** Recovery 65 113 67 82 96 74 119 72 84 95 5**† 11** 8** 8** 1 6 13 12 15 2 75 131 81 99 97 74 126 75 87 96 5 13 10 13 1 5 16 11 15 2 0. During the sedation period. suggesting decreased parasympathetic activity and unchanged sympathetic activity. Increased RR after midazolam could not be excluded as a cause for the change in their HRV data.1 mg/kg) that caused a decrease in HF and BP.4* 9* 80* 6* 4*† 1. thereby resulting in sympathetic depression. In the recovery period (OAA/S 5).4† 7*† Recovery 451 46 44 1. indicating predominant sympathetic action. * P 0. (15) demonstrated a vagolytic effect of midazolam (0.2 11 243 10 10 1. The increase in HR with decrease in BP during sedation means that baroreflex activity is compensated. and Bispectral Index (BIS) changes in Specific Time Periods Baseline Propofol Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean arterial blood pressure (mm Hg) BIS Midazolam Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean arterial blood pressure (mm Hg) BIS Values are presented in mean sd. However.2 22 92* 4* 7* 0. as we and Deutschman et al. relative to baseline value. HRV was analyzed in the unconscious state during spontaneous respiration with assisted artificial ventilation.5 mg/kg of propofol. the Ratio of High Frequency (HF) to Low Frequency (LF) and Entropy (%) Baseline Propofol Total power %Low frequency power (LF) %High frequency power (HF) LF/HF ratio Entropy Midazolam Total power %Low frequency power (LF) %High frequency power (HF) LF/HF ratio Entropy Values are presented in mean sd. Previous reports (9. Komatsu et al. and our findings are consistent with theirs. there has been controversy as to whether midazolam attenuates (21) or compensates (22) the negative feedback mechanism in the regulation of HR by baroreflex activity.05 between propofol and midazolam groups.05. HF and entropy. LF. Power (ms2/Hz) of Heart Rate Variability. It may be attributable to attenuated baroreflex . ** P 0. (14) found that midazolam (0. propofol induced significant increases in HF and entropy and significant decreases in LF and LF/HF.3 mg/kg) decreased normalized unit (nu) LF while increasing the nuHF power component of HRV without affecting HR. The decrease in HR was probably attributable to dominance of parasympathetic action. nor did they maintain patients on propofol infusion before further intervention.4 49 480 79 24 3.1 10 0. In their study. † P Sedation 162 14 17 1. significant change in LF after 2. resulting in parasympathetic activation and sympathetic depression. suggesting predominance of sympathetic action.8*† 6† 503 66 34 2.05 relative to baseline value.14 –15) and our findings suggest that midazolam enhances the dominance of parasympathetic action at very large doses but induces dominance of sympathetic action at small doses. Heart Rate.7 33 212 11* 12* 1* 13* 195 22 8*† 1. Table 4.101:97–102 Table 3.0 30 144 18 10 2.01 and * P 0.

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