690
BIOL PSYCHIATRY 1992;31:690-697
Changes in Cerebral Blood Velocity after Intravenous Diazepam Roy J. Mathew, William H. Wilson, Diane F. Humphreys, Joe V. Lowe, and Kathryn E. Wiethe
Cerebral blood velocity (CBV) was measured with transcranial Doppler in 6 normal right-handed male volunteers before and for 50 min after an intravenous injection of O.l mg/kg of diazepam and normal saline during 2 separate visits to the laboratory. Blood pressure, pulse rate, end tidal levels of carbon dioxide and mood changes were quantified before and after the injections. Diazepam injection was associated with significant increases in fatigue and sleepiness. There were no significant changes in end tidal carbon dioxide, respiration, pulse rate, and blood pressure after the injection. Postdiazepam CBV was significantly lower following diazepam compared to CBV foUowing placebo.
Introduction In the normal brain, cerebral blood flow (capillary perfusion) and metabolism are closely coupled with brain function (Raichle et al 1976). The effects of drugs on the central nervous system probably depend on alterations in brain function. Studies utilizing cerebral blood flow (CBF) and metabolism (CMR) as indices of brain function have consistently shown significant changes in regional and global brain function after the administration of psychopharmacological agents (Mathew and Wilson 1991). A number of investigators studied CBF changes after administration of benzodiazepines and barbiturates (Mathew and Wilson 1991). Earlier studies with the nitrous=oxide inhalation technique found global decrease in CBF and CMR after the administration of barbiturates (Betz 1972). More recent studies that utilized the 133Xenon-inhalation tech= nique also found reduction in flow to both right and left hemispheres after intravenous benzodiazepines (Forster et al 1982, 198"~).Concomitant administration of benzodiazepine antagonists blocked this CBF decrease (Wolff 1990). We found a significant decrease in right and left hemispheric CBF (Mathew et al 1985) after nonsedating doses (0. I mg/kg given intravenously over 5 min) of diazepam. More recently in a similar study conducted with Oi5 and positron emission tomography (PET) using the autoradiographic technique, we found significant decrease in CBF to both hemispheres and several brain regions after intravenous administration of O. I mg/kg of diazepam given over 2 min (unpublished results). CBF is regulated by changes in precapillary resistance vessels. Increase and decrease
From the Department of Psychiatry, Duke University Medical Center, Durham, North Carolina. Address reprim requests to Roy J. Mathew, MD, Box 3972, DukeUniversity Medical Center, Durham, NC 27710. Received April 20, 1991, revised December 18, 1991. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
Brain Blood Flow after Diazepam
BIOLPSYCHIATRY 1992;31:690-697
691
in precapillary resistance vessels should also be associated with parallel changes in the cerebral blood velocity (CBV) through the artery supplying those vessels. With the advent of transcranial Doppler (TCD) (Aaslid et al 1982), it became possible to measure blood velocity in major intracranial arteries noninvasively and accurately. A number, f investigators reported significant correlations between changes in CBF and middle cerebral artery flow velocity (Lindegaard et al 1987; Padayachee et ai 1986; Markwalder et al 1984; Kirkham et al 1986; Bishop et al 1986). For example, activation of the occipital cortex (with concomitant increase in local CBF) via visual stimulation was associated with increased flow in posterior cerebral artery (Gomez et al 1990). Because diazepam decreased cerebral capillary perfusion in the entire brain consistently and significantly, it seemed highly likely that it should reduce blood velocity thro, gh major intracranial arteries. We used TCD to examine changes in middle cerebral artery blood velocity after IV administration of diazepam. The present study was undertaken for the following reasons: to the best of our knowledge, measurement of CBV with TCD has not been previously used in psychopharmacologic~l resP~rch. We wanted to investigate the usefulness of the technique. As mentioned above, diazepam is likely to affect CBV because of its known effect on cerebral capillary perfusion but this has not been demonstrated. The shift in frequency of a wave when either the transmitter or receiver is moving with respect to the propagating medium was originally described by Doppler (Eden 1986). In TCD, which is a pulsed ultrasound instrument, the same transducer is used for transmitting and receiving wave energy. The effect detected by this configuration is that of a frequency shift caused by the moving reflector, namely blood. Bursts of ultrasonic energy are transmitted at regular intervals with a burst of pulse repetition. Some of the energy reflected travels back and is detected by the receiver. The Doppler shift is filtered for artifacts and fast Fourier analysis is used to display the spectral content of the Doppler signal. The technique provides quantitative information on flow velocity through various intracranial arteries (Aaslid 1986; Arnolds and yon Reutern 1988). The technique is totally noninvasive and not associated with any known side effects. Six normal right-handed male volunt~rs (age 30.3 _+ 11.3 years) were recruited through local advertising. The participants were interviewed by the senior author to exclude psychiatric disorders. A physical examination was conducted to make sure that the participants were in good physical health. They were required to be free of all medicines for a minimum of 2 weeks before this study. Special care was taken to exclude individuals with a history of alcohol and/or drug abuse. The research project was explained to the selected individuals and their written consent obtained. The subjects reported to the laboratory two times with a minimum interval of i week between the two visits. They were required to avoid alcohol for 24 hr and caffeine and nicotine (which are known to influence CBF) for 4 hr before ~oming to the labor~,tory (Mathew and Wilson 1985; Skinhoj et al 1973). The volunteers rested on a couch during the entire measurement period (1 hr). The laboratory was well lit and quiet. Blood pressure and pulse rate were recorded from the right arm at l-min intervals. End tidal levels of carbon dioxide were also continually monitored during this period. Changes in CO2 are accompanied by parallel changes in CBF and cerebral blood velocity (Bishop et al 1986; Seiler 1990). TCD (TC2-64 manufactured by Eden Medical Electronics) was used to measure middle cerebral artery (right side) blood velocity through a temporal window with a 2 mHz ultrasonic probe. CBV was computed on line by averaging the systolic and diastolic
692
etOLPSYCHIATRY 1992;31:690-697
R.J. Mathew et al
components at l-min intervals and expressed as centimeters per sec. Usually it is easy to obtain good signals through the temporal window in young adults (Halsey 1990). The middle cerebral artery runs laterally and slightly anteriorly as a continuation of the intracarotid artery. The middle cerebral artery has the highest volume flow of all of the branches from the circle of Willis. It carries about 80% of the flow to the hemisphere. First, ultrasonic gel was placed between the probe and the patient's skin in the temporal region. The probe was moved over the skin surface at differer~t angles until a good signal was received. This was associated with a CBV reading of more than 50 cm/sec. The depth setting used was 50 mm. Once a good probe position and angle were found it was immobilized and held in that position by a headband during the rest of the study. A fiat TCD probe was used in this project. After the CBV readings stabilized, baseline recording was conducted over 10 min, then an intravenous injection was given over a 2-rain period. During one visit, the injection was a placebo (normal saline) and during another visit it was 0.1 mg/kg of diazepam. Subjects and the CBV laboratory staff were kept blind to the content of the injections. Recording continued for another 50 min. Changes in mental status before and after the injections were quantified with the Profile of Mood States (POMS) (McNair et al 1971), State Anxiety scale of the State Trait Anxiety Inventory (STAb (Spielberger et al 1970), ar.d an analogue scale for levels of sleepiness. Data Analysis and Results Because of the limited number of subjects, we only used paired t-tests for analyses to compar~ ~ffects of diazepam and placebo on CBV at each of the following selected time points (before infusion, end of infusion, and then at 5-rain intervals to 50 rain). Analyses of blood pressure, pulse rate, and respiration rate followed the same procedure. For the rating scales, which were completed before and after the CBV recordings, change scores were calculated (after-before) and paired t-tests were utilized.
CBV The results of the analyses are summarized in Figure 1. There was a statistically significant decrease in CBV following diazepam compared to CBV following placebo.
Rating Scales Analysis of the POMS, Analogue Sleep Scale, and State Anxiety Scale are presented in Table 1. The POMS factor, fatigue, showed a significant increase following diazepam compared to placebo (p ~< 0.03), the Analogue Sleep Scale also showed a significant increase in sleepiness following diazepam when compared to placebo (p ~< 0.014). There were no other changes in ratings.
Physiological Measures Analyses of systolic and diastolic blood pressure (Figure 2), respiration and pulse rate (Figure 3), and end tidal carbon dioxide (Figure 4) failed to indicate any differences between diazepam and placebo.
Brain Blood Flow after Diazepam
e[OLPSYCHIATRY
693
1992;31:690-697
PERCENT OF BASELINE VELOCITY 10
Figure 1. Effects of diazepam and placebo on mean o5 SIGNIFICANT P¢.05('), P~.01(")
-10 -15 -20 -28 NFUalON -ao 8TART END
6
10
20
80
40
60
MINUTES FROM START OF INFUSION m
PLACEBO
- + - DIAZEPAM
•
t-teat
J]
cerebral blood velocity. Because there is not enough space in the figureto include standard deviations of each data point, standard deviations were averaged after placebo (9.6) and after diazepam (10.5). Standarddeviations for each data point will be supplied upon request.
Discussion CBV decreased significantly immediately after intravenous diazepam and the decrease was sustained for up to 50 min after the injection. Placebo administration was not associated with any significant changes in CBV. Diazepam did not induce any significant changes in pulse, blood pressure, respiration, or end tidal carbon dioxide. Middle cerebral artery velocity was examined with TCD (Aaslid et al 1982). CBV measurements obtained with TCD may show variations between subjects and in the same subject during different visits. However, readings obtained from the same subject with no changes in the recording procedure give stable values over a period of time (Halsey If~0; Aaslid 1986; Arnolds and yon Reutem 1986). A number of factors are responsible for this. The angle between the flow vector (blood) and the observation direction of the probe influences the calculation of flow velocity. Its effect is minimal at low angles of incidence (up to 30°). However, if the angle of incidence is kept constant, the flow values should also remain steady over a period of time. In the present experiment, the angle of mea-
Table !. Analysis of Rating Scale Change Scores after Diazepam and Placebo Placebo
Diazepam
Scales: POMS Factor
Tension Depression Anger Vigor Fatigue Confusion Analogue Sleep scale State anxiety
Mean
SD
Mean
SD
t
1.5 0.2 0.2 2.2 0.5 - 0.5
4.4 0.4 0.4 4.4 ! .8 ! .0
- 2.3 - 0.7 0.2 - 5.2 2.0 2.0
3.8 1.2 0.4 4.4 3.4 3.0
1.05 < 1.0 1.58 2.32 2.95 2.18
NS NS NS 0.07 0.03 0.08
- 15.0 - 4.0
62.8 2.8
57.0 - 3.5
48.8 5.5
3.68 < 1.0
0.014 NS
-
p ~
BIOL PSYCHIATRY 1992;31:690-697
Changes in Cerebral Blood Velocity after Intravenous Diazepam Roy J. Mathew, William H. Wilson, Diane F. Humphreys, Joe V. Lowe, and Kathryn E. Wiethe
Cerebral blood velocity (CBV) was measured with transcranial Doppler in 6 normal right-handed male volunteers before and for 50 min after an intravenous injection of O.l mg/kg of diazepam and normal saline during 2 separate visits to the laboratory. Blood pressure, pulse rate, end tidal levels of carbon dioxide and mood changes were quantified before and after the injections. Diazepam injection was associated with significant increases in fatigue and sleepiness. There were no significant changes in end tidal carbon dioxide, respiration, pulse rate, and blood pressure after the injection. Postdiazepam CBV was significantly lower following diazepam compared to CBV foUowing placebo.
Introduction In the normal brain, cerebral blood flow (capillary perfusion) and metabolism are closely coupled with brain function (Raichle et al 1976). The effects of drugs on the central nervous system probably depend on alterations in brain function. Studies utilizing cerebral blood flow (CBF) and metabolism (CMR) as indices of brain function have consistently shown significant changes in regional and global brain function after the administration of psychopharmacological agents (Mathew and Wilson 1991). A number of investigators studied CBF changes after administration of benzodiazepines and barbiturates (Mathew and Wilson 1991). Earlier studies with the nitrous=oxide inhalation technique found global decrease in CBF and CMR after the administration of barbiturates (Betz 1972). More recent studies that utilized the 133Xenon-inhalation tech= nique also found reduction in flow to both right and left hemispheres after intravenous benzodiazepines (Forster et al 1982, 198"~).Concomitant administration of benzodiazepine antagonists blocked this CBF decrease (Wolff 1990). We found a significant decrease in right and left hemispheric CBF (Mathew et al 1985) after nonsedating doses (0. I mg/kg given intravenously over 5 min) of diazepam. More recently in a similar study conducted with Oi5 and positron emission tomography (PET) using the autoradiographic technique, we found significant decrease in CBF to both hemispheres and several brain regions after intravenous administration of O. I mg/kg of diazepam given over 2 min (unpublished results). CBF is regulated by changes in precapillary resistance vessels. Increase and decrease
From the Department of Psychiatry, Duke University Medical Center, Durham, North Carolina. Address reprim requests to Roy J. Mathew, MD, Box 3972, DukeUniversity Medical Center, Durham, NC 27710. Received April 20, 1991, revised December 18, 1991. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
Brain Blood Flow after Diazepam
BIOLPSYCHIATRY 1992;31:690-697
691
in precapillary resistance vessels should also be associated with parallel changes in the cerebral blood velocity (CBV) through the artery supplying those vessels. With the advent of transcranial Doppler (TCD) (Aaslid et al 1982), it became possible to measure blood velocity in major intracranial arteries noninvasively and accurately. A number, f investigators reported significant correlations between changes in CBF and middle cerebral artery flow velocity (Lindegaard et al 1987; Padayachee et ai 1986; Markwalder et al 1984; Kirkham et al 1986; Bishop et al 1986). For example, activation of the occipital cortex (with concomitant increase in local CBF) via visual stimulation was associated with increased flow in posterior cerebral artery (Gomez et al 1990). Because diazepam decreased cerebral capillary perfusion in the entire brain consistently and significantly, it seemed highly likely that it should reduce blood velocity thro, gh major intracranial arteries. We used TCD to examine changes in middle cerebral artery blood velocity after IV administration of diazepam. The present study was undertaken for the following reasons: to the best of our knowledge, measurement of CBV with TCD has not been previously used in psychopharmacologic~l resP~rch. We wanted to investigate the usefulness of the technique. As mentioned above, diazepam is likely to affect CBV because of its known effect on cerebral capillary perfusion but this has not been demonstrated. The shift in frequency of a wave when either the transmitter or receiver is moving with respect to the propagating medium was originally described by Doppler (Eden 1986). In TCD, which is a pulsed ultrasound instrument, the same transducer is used for transmitting and receiving wave energy. The effect detected by this configuration is that of a frequency shift caused by the moving reflector, namely blood. Bursts of ultrasonic energy are transmitted at regular intervals with a burst of pulse repetition. Some of the energy reflected travels back and is detected by the receiver. The Doppler shift is filtered for artifacts and fast Fourier analysis is used to display the spectral content of the Doppler signal. The technique provides quantitative information on flow velocity through various intracranial arteries (Aaslid 1986; Arnolds and yon Reutern 1988). The technique is totally noninvasive and not associated with any known side effects. Six normal right-handed male volunt~rs (age 30.3 _+ 11.3 years) were recruited through local advertising. The participants were interviewed by the senior author to exclude psychiatric disorders. A physical examination was conducted to make sure that the participants were in good physical health. They were required to be free of all medicines for a minimum of 2 weeks before this study. Special care was taken to exclude individuals with a history of alcohol and/or drug abuse. The research project was explained to the selected individuals and their written consent obtained. The subjects reported to the laboratory two times with a minimum interval of i week between the two visits. They were required to avoid alcohol for 24 hr and caffeine and nicotine (which are known to influence CBF) for 4 hr before ~oming to the labor~,tory (Mathew and Wilson 1985; Skinhoj et al 1973). The volunteers rested on a couch during the entire measurement period (1 hr). The laboratory was well lit and quiet. Blood pressure and pulse rate were recorded from the right arm at l-min intervals. End tidal levels of carbon dioxide were also continually monitored during this period. Changes in CO2 are accompanied by parallel changes in CBF and cerebral blood velocity (Bishop et al 1986; Seiler 1990). TCD (TC2-64 manufactured by Eden Medical Electronics) was used to measure middle cerebral artery (right side) blood velocity through a temporal window with a 2 mHz ultrasonic probe. CBV was computed on line by averaging the systolic and diastolic
692
etOLPSYCHIATRY 1992;31:690-697
R.J. Mathew et al
components at l-min intervals and expressed as centimeters per sec. Usually it is easy to obtain good signals through the temporal window in young adults (Halsey 1990). The middle cerebral artery runs laterally and slightly anteriorly as a continuation of the intracarotid artery. The middle cerebral artery has the highest volume flow of all of the branches from the circle of Willis. It carries about 80% of the flow to the hemisphere. First, ultrasonic gel was placed between the probe and the patient's skin in the temporal region. The probe was moved over the skin surface at differer~t angles until a good signal was received. This was associated with a CBV reading of more than 50 cm/sec. The depth setting used was 50 mm. Once a good probe position and angle were found it was immobilized and held in that position by a headband during the rest of the study. A fiat TCD probe was used in this project. After the CBV readings stabilized, baseline recording was conducted over 10 min, then an intravenous injection was given over a 2-rain period. During one visit, the injection was a placebo (normal saline) and during another visit it was 0.1 mg/kg of diazepam. Subjects and the CBV laboratory staff were kept blind to the content of the injections. Recording continued for another 50 min. Changes in mental status before and after the injections were quantified with the Profile of Mood States (POMS) (McNair et al 1971), State Anxiety scale of the State Trait Anxiety Inventory (STAb (Spielberger et al 1970), ar.d an analogue scale for levels of sleepiness. Data Analysis and Results Because of the limited number of subjects, we only used paired t-tests for analyses to compar~ ~ffects of diazepam and placebo on CBV at each of the following selected time points (before infusion, end of infusion, and then at 5-rain intervals to 50 rain). Analyses of blood pressure, pulse rate, and respiration rate followed the same procedure. For the rating scales, which were completed before and after the CBV recordings, change scores were calculated (after-before) and paired t-tests were utilized.
CBV The results of the analyses are summarized in Figure 1. There was a statistically significant decrease in CBV following diazepam compared to CBV following placebo.
Rating Scales Analysis of the POMS, Analogue Sleep Scale, and State Anxiety Scale are presented in Table 1. The POMS factor, fatigue, showed a significant increase following diazepam compared to placebo (p ~< 0.03), the Analogue Sleep Scale also showed a significant increase in sleepiness following diazepam when compared to placebo (p ~< 0.014). There were no other changes in ratings.
Physiological Measures Analyses of systolic and diastolic blood pressure (Figure 2), respiration and pulse rate (Figure 3), and end tidal carbon dioxide (Figure 4) failed to indicate any differences between diazepam and placebo.
Brain Blood Flow after Diazepam
e[OLPSYCHIATRY
693
1992;31:690-697
PERCENT OF BASELINE VELOCITY 10
Figure 1. Effects of diazepam and placebo on mean o5 SIGNIFICANT P¢.05('), P~.01(")
-10 -15 -20 -28 NFUalON -ao 8TART END
6
10
20
80
40
60
MINUTES FROM START OF INFUSION m
PLACEBO
- + - DIAZEPAM
•
t-teat
J]
cerebral blood velocity. Because there is not enough space in the figureto include standard deviations of each data point, standard deviations were averaged after placebo (9.6) and after diazepam (10.5). Standarddeviations for each data point will be supplied upon request.
Discussion CBV decreased significantly immediately after intravenous diazepam and the decrease was sustained for up to 50 min after the injection. Placebo administration was not associated with any significant changes in CBV. Diazepam did not induce any significant changes in pulse, blood pressure, respiration, or end tidal carbon dioxide. Middle cerebral artery velocity was examined with TCD (Aaslid et al 1982). CBV measurements obtained with TCD may show variations between subjects and in the same subject during different visits. However, readings obtained from the same subject with no changes in the recording procedure give stable values over a period of time (Halsey If~0; Aaslid 1986; Arnolds and yon Reutem 1986). A number of factors are responsible for this. The angle between the flow vector (blood) and the observation direction of the probe influences the calculation of flow velocity. Its effect is minimal at low angles of incidence (up to 30°). However, if the angle of incidence is kept constant, the flow values should also remain steady over a period of time. In the present experiment, the angle of mea-
Table !. Analysis of Rating Scale Change Scores after Diazepam and Placebo Placebo
Diazepam
Scales: POMS Factor
Tension Depression Anger Vigor Fatigue Confusion Analogue Sleep scale State anxiety
Mean
SD
Mean
SD
t
1.5 0.2 0.2 2.2 0.5 - 0.5
4.4 0.4 0.4 4.4 ! .8 ! .0
- 2.3 - 0.7 0.2 - 5.2 2.0 2.0
3.8 1.2 0.4 4.4 3.4 3.0
1.05 < 1.0 1.58 2.32 2.95 2.18
NS NS NS 0.07 0.03 0.08
- 15.0 - 4.0
62.8 2.8
57.0 - 3.5
48.8 5.5
3.68 < 1.0
0.014 NS
-
p ~
