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Cardiovascular, respiratory, and panic reactions to epinephrine in panic disorder patients
Cardiovascular, Respiratory, and Panic Reactions to Epinephrine in Panic Disorder Patients Gudo A. van Zijderveld, Ben J. TenVoorde, Dirk J. Veltman, Lorenz J.P. van Doornen, Jacob F. Orlebeke, Richard van Dyck, and Fred J.H. Tilders Key Words: Panic disorder, epinephrine, heart rate variability, spectral analysis, hyperventilation BIOL PSYCHIATRY 1997;41:249-251
Introduction Although it is well accepted that the autonomic nervous system is involved in the pathophysiology of anxiety, there is still considerable debate regarding the role of the catecholamines in panic. In normals a tendency to report psychosomatic complaints is associated with an increase in emotional reactions to epinephrine (E) infusions but not with an exaggerated increase in peripheral arousal, suggesting a crucial role of cognitive factors (van Zijderveld et al 1992, 1993). Since the introduction of the DSM-III-R (American Psychiatric Association 1987), administration of E has never been used to test the panicogenic response in panic disorder patients. A number of studies suggest a dysfunction of regulatory autonomic processes in these patients (Yeragani et al 1990a, 1990b; George et al 1989). Spectral analysis of heart rate variability (HRV) and blood pressure variability (BPV) is a noninvasive tool to explore cardiac autonomic balance and may also be useful to study possible sympathetic and parasympathetic dysfunction in panic disorder patients (Friedman et al 1993; Middleton et al 1994). This report presents an analysis of HRV and BPV during acute E-induced panic states. Next to abnormal autonomic function, hyperventilation has also been considered as an important syrup-
From the Department of Psychiatry, Vrije Universiteit, Amsterdam, The Netherlands. Address reprint requests to Gudo A. van Zijderveld, Department of Psychophysiology, Vrije Universiteit, De Boelelaan 1111, 1081 HV Amsterdam, The Netherlands. Received February 21, 1994; revised July 22, 1996.
© 1997 Society of Biological Psychiatry
tom-producing mechanism in panic attacks (Papp et al 1993). To test this suggestion, the ventilatory response to E was directly tested by the measurement of transcutaneous pCO 2.
Methods Twenty-four outpatients, 11 men and 13 women, were studied. All patients met DSM-III-R criteria for panic disorder with agoraphobia. Exclusion criteria were concurrent Axis I disorders, inability to discontinue psychotropic medication at least 2 weeks before the study, or any significant medical condition. Subjects were allocated at random to either E or placebo. After the procedure was explained, all subjects gave informed consent. The procedure has been described in detail elsewhere (Veltman et al 1996). An intravenous catheter was inserted into the left antecubital vein. The sensor for transcutaneous pCO2 (PtcCO2) measurements was attached to the skin of the inside of the lower arm. E was administered at three increasing infusion rates (20, 40, and 80 ng/kg/min) for 15 min at each dose level in the E group, or saline in the placebo group. Subjects were regularly asked to rate their anxiety level on a 100-point scale. In case of a panic attack, administration of E was discontinued. A panic attack was defined as a sudden increase in anxiety, reflected in an increase of at least 30 points above the lowest score of the subject on the 100-point scale [Subjective Unit of Distress Scale (SUDS)], together with four (or more) symptoms of the DSMIII-R definition of a panic attack, with at least one of the psychological symptoms of the DSM-III-R definition (fear of dying, fear of going crazy, or fear of losing control). Both 0006-3223/97/$17.00 PII S0006-3223(96)00421-0
250
BIOLPSYCHIATRY
Brief Reports
1997 ; 4 1 : 2 4 9 - 2 5 1
LF SpeeLral
Power
-O- l e p i n ~ h r l n e
Hlq
SBP
E p l n e p h r l n e .o.. PhteNfl~o
o. P l e . o l b o
~1~
DBP
n
Ii[ 0
1
2
$
0
t
8
3
0
1
2
M~
~
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I
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I........ I f
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.....I....
3
Figure 1. Mean values of logarithmic LF power values of HR, SBP, and DBP before (0) and during infusions at the infusion rates of 20, 40, and 80 ng/kg/min corresponding with 1, 2, and 3 at the horizontal axis, respectively. Data obtained at the last dose were available from only 5 patients receiving epinephrine because of attrition due to panic. subjects and the observing psychiatrist were blind to the experimental condition. PtcCO 2 was measured by a microgas monitor (Kontron microgas 7640, Kontron Instruments). Values of PtcO2 and PtcCO2 are closely related to the arterial blood gas partial pressure (Pilsbury and Hibbert 1987; Garssen et al 1994). The COMBI (PO2/PCO2) sensor (Model 81) was heated to a constant temperature of 43.7°C. Approximately 1 hour before each measurement the sensor was calibrated. PtcCO2 values were sampled every 30 sec. Subjects were freely breathing. Beat-tobeat arterial pressure was recorded by the Ohmeda 2300 FinapresT M finger blood pressure monitor (Settels and Wesseling 1985). Episodes of 5 min were selected at the end of the baseline period, and at the end of each infusion rate. The continuous peripheral blood pressure recordings were used to derive interbeat interval (IBI) and heart rate (HR). Absolute mean successive difference (MSD) in IBis was computed as an index of cardiac vagal tone in the time domain. Spectral power was computed in three frequency bands: a low-frequency band (LF: 0.02-0.06 Hz) has been associated with peripheral vascular tone or reninangiotensin activity (Akselrod et al 1985); a mid-frequency band (MF: 0.06-0.14 Hz) is associated with a mixture of sympathetic and vagal activity (Saul et al 1990); and a high-frequency band (HF: 0.14-0.50 Hz) is associated with vagal activity (Malliani et al 1991). Barorefiex sensitivity (BRS) is computed as the transfer gain within the MF band, estimated from the cross spectrum of systolic blood pressure and interbeat intervals. BRS is expressed as unit interval change per unit pressure change (msec/mmHg). Statistical comparisons are made between placebo and E [multivariate analysis of variance (MANOVA) with repeated measurements with E as the between factor] and of interaction effects between the factors dose and condition. Post hoc comparisons were made between the patients who panicked and those who did not.
Figure 2. Mean values of BRS, MSD, and PtcCO 2 before (0) and during infusions at the infusion rates of 20, 40, and 80 ng/kg/min corresponding with 1, 2, and 3 at the horizontal axis, respectively. Data obtained at the last dose were available from only 5 patients receiving epinephrine because of attrition due to panic. SBP, and DBP (all p values < .05) were significantly higher during E as compared with placebo (Figure 2). Post hoc analysis between panickers and nonpanickers revealed that E was panicogenic in 8 patients (Table 1). A significant increase in SUDS, HR, and a stronger decrease in PtcCO 2 was observed in the panickers as compared with nonpanickers. No significant differences were found in any frequency band between panickers and nonpanickers (not shown).
Conclusions This study demonstrates that 8 out of 12 panic disorder (PD) patients receiving E (66.6%) experienced a panic attack, which is similar to the percentage of panickers during various other pharmacologic challenges. In previous reports, healthy controls experienced an increase in anxiety during epinephrine but they did not panic (van Zijderveld et al 1992, 1993). This suggests that PD patients are sensitive to [3-adrenergic stimulation, as was previously shown by studies using isoproterenol (Pohl et al 1990); however, due to the small number of nonpanicking patients in the present report, our findings should be interpreted with caution. E clearly perturbed peripheral vascular tone, as evidenced by a significant difference between placebo and E with regard to the LF power of HR and SBP. The finding that no differences between placebo and E occurred in the MF range may be unexpected, but has also been reported by others (Tulen et al 1994). The 0.1 Hz component may not be a purely sympathetic marker as is stated by some (e.g., Pagani et al 1986). Table 1. Comparison of Cardiovascular Reactivity and Transcutaneous pCO 2 Response of Epinephrine Panickers and Epinephrine Nonpanickers Epinephrine panickers (n = 8)
Results Comparions between placebo and epinephrine were made and showed an expected increase in HR (p < .001) and systolic blood pressure (SBP) (p < .05) and a decrease in diastolic blood pressure (DBP) (p < .05) during infusion of E. E induced a gradual decrease in BRS (p < .001), MSD (p < .05), and in PtcCO 2 (p < 05), as indicated by significant interactions between the factors dose and condition (Figure 1). The LF powers of HR,
SUDS HR SBP DBP MSD PtcCO2
30.0 14.2 24.6 8.5 -7.1 -3.2
(16.9) (9.2) (22.3) (19.9) (7.8) (2.2)
V a l u e s are c h a n g e scores + SD.
Epinephrine nonpanickers (n = 4) -1.2 3.9 10.8 -2.4 -4.1 -.75
(15.4) (3.8) (4.2) (7.3) (4.1) (1.5)
p values <.01 <.03 ns ns ns <.05
Brief Reports
BIOL PSYCHIATRY
251
1997;41:249-251
Parasympathetic influences in this frequency range may be active as well (Sleight et al 1995). E also did not influence HF fluctuations, indicating unaffected parasympathetic nervous system activity. Reliable HF frequency spectra may require paced breathing (Pomerantz et al 1985). In challenge studies, however, controlled respiration is hard to apply because hyperventilation is a potential symptom of panic. In contrast to the HF frequency spectra, the decrease during E in more robust indexes such as BRS and MSD reflects diminished vagal tone. Time domain and frequency domain-based indexes of cardiac autonomic control may be differentially influenced by the (unpaced) breathing pattern. Therefore, it is generally advisable to calculate both indexes because a) the choice of a particular method may lead to different conclusions on the vagal contribution to heart rate variability; and b) there is no standardization in heart rate variability analysis, which makes it difficult to compare results between studies. Although the drop in PtcCO 2 was too small to
be indicative of clinically significant hyperventilation during acute panic, it is in agreement with the observation that ventilatory indexes are reliable correlates of acute anxiety states (Papp et al 1988; Kollai and Kollai 1992). The mechanism of activation of the central nervous system by E is, however, incompletely understood because sympathomimetics penetrate the bloodbrain barrier poorly or not at all. Treatment studies showed only limited efficacy of ~-blockers (Pohl et al 1990), suggesting that other receptor systems may also be involved in E-induced panic. A possible route by which E and also other substances could precipitate panic in anxiety disorder patients is via a hypersensitive CO 2 chemoreceptor system (Papp et al 1993). Nearly all pharmacologic panicogens stimulate the respiratory system to some extent. Triggering this hypersensitive brain stem respiratory system causes hyperventilation, which may incite panic. The fall in PtcCO 2 during panic we registered indicated a trend towards hyperventilation and is consistent with this hypothesis.
References Akselrod S, Gordon D, Madwed JB, et al (1985): Hemodynamic regulation: Investigation by spectral analysis. Am J Physiol 249:H867-H875. American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Friedman BH, Thayer JF, Borkovec TD, et al (1993): Autonomic characteristics of nonclinical panic and blood phobia. Biol Psychiatry 34:298-310. Garssen B, Buikhuisen M, Homsveld H, et al (1994): The ambulatory measurement of transcutaneous PCO 2 J Psychophysiol 8:231-240. George DT, Nutt DJ, Walker WV, et al (1989): Lactate and hyperventilation substantially attenuate vagal tone in normal volunteers. Arch Gen Psychiatry 46:153-156. Kollai M, Kollai B (1992): Cardial vagal tone in generalised anxiety disorder. Br J Psychiatry 161:831-835. Malliani A, Pagani M, Lombardi F, et al (1991): Cardiovascular neural regulation explored in the frequency domain. Circulation 84:482-492. Middleton HC, Ashby M, Robbins TW (1994): Reduced plasma noradrenaline and abnormal heart rate variability in resting panic disorder patients. Biol Psychiatry 36:847-849. Pagani M, Lombardi F, Guzetti S, et al (1986): Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dogs. Circ Res 59:178-193. Papp LA, Gorman JM, Liebowitz MR, et al (1988): Epinephrine infusions in patients with social phobia. Am J Psychiatry 145:733-736. Papp LA, Klein DF, Gorman JM (1993): Carbon dioxide hypersensitivity, hyperventilation, and panic disorder. Am J Psychiatry 150:1149-1157. Pilsbury D, Hibbert G (1987): An ambulatory system for long-term continuous monitoring of transcutaneous pCO2 Bull Eur Physiopathol Respira 23:9-13. Pohl R, Yeragani VK, Balon R, et al (1990): Isoproterenol-induced
panic: A I~-adrenergic model of panic anxiety. In JC Ballenger (ed), Neurobiology of Panic Disorder. New York: Wiley-Liss v:ppl07-120. Pomeranz B, Macaulay RJB, Caudill MA (1985): Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 248:H151-H153. Saul JP, Rea RF, Eckberg DL, et al (1990): Heart rate and muscle sympathetic nerve variability during reflex changes of autonomic activity. Am J Physiol 258:H713-H721. SelXelsJJ, Wesseling KH (1985): FIN.A.PRES: Non-invasive finger arterial pressure waveform registration. In Orlebeke JF, Mulder G, van Doomen LIP (eds), The Psychophysiology of Cardiovascular Control. New York: Plenum Press, pp 267-283. Sleight P, La Rovere M, Mortara A, et al (1995): Physiology and pathophysiology of heart rate and blood pressure variability in humans: Is power spectral analysis largely an index of baroreflex gain? Clin Sci 88:103-109. Tulen JHM, Man in 't Veld AJ, van Roon AM, et al (1994): Spectral analysis of hemodynamics during infusions of epinephrine and norepinephrine in men. J Appl Physiol 76: 1914-1921. van Zijderveld GA, van Doomen LJP, van Faassen I, et al (1992): The psychophysiological effects of adrenaline infusions as a function of trait anxiety and aerobic fitness. Anxiety Res 4:257-274. van Zijderveld GA, van Doomen LJP, Orlebeke JF, et al (1993): Neurosomatism, adrenaline and mental performance. Biol Psychol 36:157-181. Veltman DJ, van Zijderveld GA, van Dyck R (1996): Epinephrine infusions in panic disorder: A double blind placebocontrolled study. Journal of Affective Disorders 39:133-140. Yeragani VK, Meiri PC, Pohl R, et al (1990a): Heart rate and blood pressure changes during postural change and isometric handgrip exercise in patients with panic disorder and normal controls. Acta Psychiatr Scand 81:9-13. Yeragani VK, Balon R, Pohl R, et al (1990b): Decreased R-R variance in panic disorder patients. Acta Psychiatr Scand 81:554-559.
Introduction Although it is well accepted that the autonomic nervous system is involved in the pathophysiology of anxiety, there is still considerable debate regarding the role of the catecholamines in panic. In normals a tendency to report psychosomatic complaints is associated with an increase in emotional reactions to epinephrine (E) infusions but not with an exaggerated increase in peripheral arousal, suggesting a crucial role of cognitive factors (van Zijderveld et al 1992, 1993). Since the introduction of the DSM-III-R (American Psychiatric Association 1987), administration of E has never been used to test the panicogenic response in panic disorder patients. A number of studies suggest a dysfunction of regulatory autonomic processes in these patients (Yeragani et al 1990a, 1990b; George et al 1989). Spectral analysis of heart rate variability (HRV) and blood pressure variability (BPV) is a noninvasive tool to explore cardiac autonomic balance and may also be useful to study possible sympathetic and parasympathetic dysfunction in panic disorder patients (Friedman et al 1993; Middleton et al 1994). This report presents an analysis of HRV and BPV during acute E-induced panic states. Next to abnormal autonomic function, hyperventilation has also been considered as an important syrup-
From the Department of Psychiatry, Vrije Universiteit, Amsterdam, The Netherlands. Address reprint requests to Gudo A. van Zijderveld, Department of Psychophysiology, Vrije Universiteit, De Boelelaan 1111, 1081 HV Amsterdam, The Netherlands. Received February 21, 1994; revised July 22, 1996.
© 1997 Society of Biological Psychiatry
tom-producing mechanism in panic attacks (Papp et al 1993). To test this suggestion, the ventilatory response to E was directly tested by the measurement of transcutaneous pCO 2.
Methods Twenty-four outpatients, 11 men and 13 women, were studied. All patients met DSM-III-R criteria for panic disorder with agoraphobia. Exclusion criteria were concurrent Axis I disorders, inability to discontinue psychotropic medication at least 2 weeks before the study, or any significant medical condition. Subjects were allocated at random to either E or placebo. After the procedure was explained, all subjects gave informed consent. The procedure has been described in detail elsewhere (Veltman et al 1996). An intravenous catheter was inserted into the left antecubital vein. The sensor for transcutaneous pCO2 (PtcCO2) measurements was attached to the skin of the inside of the lower arm. E was administered at three increasing infusion rates (20, 40, and 80 ng/kg/min) for 15 min at each dose level in the E group, or saline in the placebo group. Subjects were regularly asked to rate their anxiety level on a 100-point scale. In case of a panic attack, administration of E was discontinued. A panic attack was defined as a sudden increase in anxiety, reflected in an increase of at least 30 points above the lowest score of the subject on the 100-point scale [Subjective Unit of Distress Scale (SUDS)], together with four (or more) symptoms of the DSMIII-R definition of a panic attack, with at least one of the psychological symptoms of the DSM-III-R definition (fear of dying, fear of going crazy, or fear of losing control). Both 0006-3223/97/$17.00 PII S0006-3223(96)00421-0
250
BIOLPSYCHIATRY
Brief Reports
1997 ; 4 1 : 2 4 9 - 2 5 1
LF SpeeLral
Power
-O- l e p i n ~ h r l n e
Hlq
SBP
E p l n e p h r l n e .o.. PhteNfl~o
o. P l e . o l b o
~1~
DBP
n
Ii[ 0
1
2
$
0
t
8
3
0
1
2
M~
~
ptceoa
I
m
I........ I f
I
.....I....
3
Figure 1. Mean values of logarithmic LF power values of HR, SBP, and DBP before (0) and during infusions at the infusion rates of 20, 40, and 80 ng/kg/min corresponding with 1, 2, and 3 at the horizontal axis, respectively. Data obtained at the last dose were available from only 5 patients receiving epinephrine because of attrition due to panic. subjects and the observing psychiatrist were blind to the experimental condition. PtcCO 2 was measured by a microgas monitor (Kontron microgas 7640, Kontron Instruments). Values of PtcO2 and PtcCO2 are closely related to the arterial blood gas partial pressure (Pilsbury and Hibbert 1987; Garssen et al 1994). The COMBI (PO2/PCO2) sensor (Model 81) was heated to a constant temperature of 43.7°C. Approximately 1 hour before each measurement the sensor was calibrated. PtcCO2 values were sampled every 30 sec. Subjects were freely breathing. Beat-tobeat arterial pressure was recorded by the Ohmeda 2300 FinapresT M finger blood pressure monitor (Settels and Wesseling 1985). Episodes of 5 min were selected at the end of the baseline period, and at the end of each infusion rate. The continuous peripheral blood pressure recordings were used to derive interbeat interval (IBI) and heart rate (HR). Absolute mean successive difference (MSD) in IBis was computed as an index of cardiac vagal tone in the time domain. Spectral power was computed in three frequency bands: a low-frequency band (LF: 0.02-0.06 Hz) has been associated with peripheral vascular tone or reninangiotensin activity (Akselrod et al 1985); a mid-frequency band (MF: 0.06-0.14 Hz) is associated with a mixture of sympathetic and vagal activity (Saul et al 1990); and a high-frequency band (HF: 0.14-0.50 Hz) is associated with vagal activity (Malliani et al 1991). Barorefiex sensitivity (BRS) is computed as the transfer gain within the MF band, estimated from the cross spectrum of systolic blood pressure and interbeat intervals. BRS is expressed as unit interval change per unit pressure change (msec/mmHg). Statistical comparisons are made between placebo and E [multivariate analysis of variance (MANOVA) with repeated measurements with E as the between factor] and of interaction effects between the factors dose and condition. Post hoc comparisons were made between the patients who panicked and those who did not.
Figure 2. Mean values of BRS, MSD, and PtcCO 2 before (0) and during infusions at the infusion rates of 20, 40, and 80 ng/kg/min corresponding with 1, 2, and 3 at the horizontal axis, respectively. Data obtained at the last dose were available from only 5 patients receiving epinephrine because of attrition due to panic. SBP, and DBP (all p values < .05) were significantly higher during E as compared with placebo (Figure 2). Post hoc analysis between panickers and nonpanickers revealed that E was panicogenic in 8 patients (Table 1). A significant increase in SUDS, HR, and a stronger decrease in PtcCO 2 was observed in the panickers as compared with nonpanickers. No significant differences were found in any frequency band between panickers and nonpanickers (not shown).
Conclusions This study demonstrates that 8 out of 12 panic disorder (PD) patients receiving E (66.6%) experienced a panic attack, which is similar to the percentage of panickers during various other pharmacologic challenges. In previous reports, healthy controls experienced an increase in anxiety during epinephrine but they did not panic (van Zijderveld et al 1992, 1993). This suggests that PD patients are sensitive to [3-adrenergic stimulation, as was previously shown by studies using isoproterenol (Pohl et al 1990); however, due to the small number of nonpanicking patients in the present report, our findings should be interpreted with caution. E clearly perturbed peripheral vascular tone, as evidenced by a significant difference between placebo and E with regard to the LF power of HR and SBP. The finding that no differences between placebo and E occurred in the MF range may be unexpected, but has also been reported by others (Tulen et al 1994). The 0.1 Hz component may not be a purely sympathetic marker as is stated by some (e.g., Pagani et al 1986). Table 1. Comparison of Cardiovascular Reactivity and Transcutaneous pCO 2 Response of Epinephrine Panickers and Epinephrine Nonpanickers Epinephrine panickers (n = 8)
Results Comparions between placebo and epinephrine were made and showed an expected increase in HR (p < .001) and systolic blood pressure (SBP) (p < .05) and a decrease in diastolic blood pressure (DBP) (p < .05) during infusion of E. E induced a gradual decrease in BRS (p < .001), MSD (p < .05), and in PtcCO 2 (p < 05), as indicated by significant interactions between the factors dose and condition (Figure 1). The LF powers of HR,
SUDS HR SBP DBP MSD PtcCO2
30.0 14.2 24.6 8.5 -7.1 -3.2
(16.9) (9.2) (22.3) (19.9) (7.8) (2.2)
V a l u e s are c h a n g e scores + SD.
Epinephrine nonpanickers (n = 4) -1.2 3.9 10.8 -2.4 -4.1 -.75
(15.4) (3.8) (4.2) (7.3) (4.1) (1.5)
p values <.01 <.03 ns ns ns <.05
Brief Reports
BIOL PSYCHIATRY
251
1997;41:249-251
Parasympathetic influences in this frequency range may be active as well (Sleight et al 1995). E also did not influence HF fluctuations, indicating unaffected parasympathetic nervous system activity. Reliable HF frequency spectra may require paced breathing (Pomerantz et al 1985). In challenge studies, however, controlled respiration is hard to apply because hyperventilation is a potential symptom of panic. In contrast to the HF frequency spectra, the decrease during E in more robust indexes such as BRS and MSD reflects diminished vagal tone. Time domain and frequency domain-based indexes of cardiac autonomic control may be differentially influenced by the (unpaced) breathing pattern. Therefore, it is generally advisable to calculate both indexes because a) the choice of a particular method may lead to different conclusions on the vagal contribution to heart rate variability; and b) there is no standardization in heart rate variability analysis, which makes it difficult to compare results between studies. Although the drop in PtcCO 2 was too small to
be indicative of clinically significant hyperventilation during acute panic, it is in agreement with the observation that ventilatory indexes are reliable correlates of acute anxiety states (Papp et al 1988; Kollai and Kollai 1992). The mechanism of activation of the central nervous system by E is, however, incompletely understood because sympathomimetics penetrate the bloodbrain barrier poorly or not at all. Treatment studies showed only limited efficacy of ~-blockers (Pohl et al 1990), suggesting that other receptor systems may also be involved in E-induced panic. A possible route by which E and also other substances could precipitate panic in anxiety disorder patients is via a hypersensitive CO 2 chemoreceptor system (Papp et al 1993). Nearly all pharmacologic panicogens stimulate the respiratory system to some extent. Triggering this hypersensitive brain stem respiratory system causes hyperventilation, which may incite panic. The fall in PtcCO 2 during panic we registered indicated a trend towards hyperventilation and is consistent with this hypothesis.
References Akselrod S, Gordon D, Madwed JB, et al (1985): Hemodynamic regulation: Investigation by spectral analysis. Am J Physiol 249:H867-H875. American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Friedman BH, Thayer JF, Borkovec TD, et al (1993): Autonomic characteristics of nonclinical panic and blood phobia. Biol Psychiatry 34:298-310. Garssen B, Buikhuisen M, Homsveld H, et al (1994): The ambulatory measurement of transcutaneous PCO 2 J Psychophysiol 8:231-240. George DT, Nutt DJ, Walker WV, et al (1989): Lactate and hyperventilation substantially attenuate vagal tone in normal volunteers. Arch Gen Psychiatry 46:153-156. Kollai M, Kollai B (1992): Cardial vagal tone in generalised anxiety disorder. Br J Psychiatry 161:831-835. Malliani A, Pagani M, Lombardi F, et al (1991): Cardiovascular neural regulation explored in the frequency domain. Circulation 84:482-492. Middleton HC, Ashby M, Robbins TW (1994): Reduced plasma noradrenaline and abnormal heart rate variability in resting panic disorder patients. Biol Psychiatry 36:847-849. Pagani M, Lombardi F, Guzetti S, et al (1986): Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dogs. Circ Res 59:178-193. Papp LA, Gorman JM, Liebowitz MR, et al (1988): Epinephrine infusions in patients with social phobia. Am J Psychiatry 145:733-736. Papp LA, Klein DF, Gorman JM (1993): Carbon dioxide hypersensitivity, hyperventilation, and panic disorder. Am J Psychiatry 150:1149-1157. Pilsbury D, Hibbert G (1987): An ambulatory system for long-term continuous monitoring of transcutaneous pCO2 Bull Eur Physiopathol Respira 23:9-13. Pohl R, Yeragani VK, Balon R, et al (1990): Isoproterenol-induced
panic: A I~-adrenergic model of panic anxiety. In JC Ballenger (ed), Neurobiology of Panic Disorder. New York: Wiley-Liss v:ppl07-120. Pomeranz B, Macaulay RJB, Caudill MA (1985): Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 248:H151-H153. Saul JP, Rea RF, Eckberg DL, et al (1990): Heart rate and muscle sympathetic nerve variability during reflex changes of autonomic activity. Am J Physiol 258:H713-H721. SelXelsJJ, Wesseling KH (1985): FIN.A.PRES: Non-invasive finger arterial pressure waveform registration. In Orlebeke JF, Mulder G, van Doomen LIP (eds), The Psychophysiology of Cardiovascular Control. New York: Plenum Press, pp 267-283. Sleight P, La Rovere M, Mortara A, et al (1995): Physiology and pathophysiology of heart rate and blood pressure variability in humans: Is power spectral analysis largely an index of baroreflex gain? Clin Sci 88:103-109. Tulen JHM, Man in 't Veld AJ, van Roon AM, et al (1994): Spectral analysis of hemodynamics during infusions of epinephrine and norepinephrine in men. J Appl Physiol 76: 1914-1921. van Zijderveld GA, van Doomen LJP, van Faassen I, et al (1992): The psychophysiological effects of adrenaline infusions as a function of trait anxiety and aerobic fitness. Anxiety Res 4:257-274. van Zijderveld GA, van Doomen LJP, Orlebeke JF, et al (1993): Neurosomatism, adrenaline and mental performance. Biol Psychol 36:157-181. Veltman DJ, van Zijderveld GA, van Dyck R (1996): Epinephrine infusions in panic disorder: A double blind placebocontrolled study. Journal of Affective Disorders 39:133-140. Yeragani VK, Meiri PC, Pohl R, et al (1990a): Heart rate and blood pressure changes during postural change and isometric handgrip exercise in patients with panic disorder and normal controls. Acta Psychiatr Scand 81:9-13. Yeragani VK, Balon R, Pohl R, et al (1990b): Decreased R-R variance in panic disorder patients. Acta Psychiatr Scand 81:554-559.