Journd of‘ Afyectlc‘L’Di.wr&rs, 23 ( 1YY1) I3 I- 136 K+ 1991 Elsevier Science Publishers B.V. All rights

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An analysis of panic symptoms during hypercarbia compared to hypocarbia in patients with panic attacks Jan Zandbergen,

Henk Pols, Isabella

Fernandez

Depurtment of Clinicul P.cychiut~, State UtGwsity of Limhurg

and Eric Griez

Muustricht, The Nethdudc

(Received I6 April 1901) (Revision received 26 July 190 I) (Accepted IX August 1YYI)

Summary

Twenty panic disorder patients underwent a 35% CO, challenge test and a hyperventilation provocation test. CO,-induced anxiety proved to correlate significantly with respiratory symptoms. These symptoms appeared to be considerably more severe during CO, inhalation than during the hyperventilation provocation test, which induced no significant anxiety.

Key words:

Panic

disorder;

Carbon

dioxide;

Hyperventilation

Introduction

In the last decade carbon dioxide (CO,) inhalation has become a well established experimental method for panic provocation in panic disorder (PD) subjects. The most extensively studied procedures include prolonged administration of 5% CO, (German et al., 1984, 1988; Woods et al., 1988) and one vital capacity inhalation of 35% CO, (Griez et al., 1987a). With both methods PD patients have been demonstrated to be highly

Address for correspondence: Jan Zandbergen. M.D., Department of Clinical Psychiatry, State University of Limburg, P.O. Box 616, 6200 MD Maastricht, The Netherlands.

provocation;

Respiration

vulnerable to experimental hypercarbia, whereas healthy control subjects are hardly affected. There are strong indications that the CO, model is specific for PD subjects, as the 35% CO, challenge technique has been shown to differentiate between PD and obsessive-compulsive disorder (OCD) (Griez et al., 1990aI. Baseline arousal was suggested to play a role in C02-induced anxiety; however, it has been demonstrated that CO,-provoked panic cannot merely be attributed to increased baseline anxiety (Griez et al., 199Ob). CO2 inhalation can produce various physical symptoms, most of which are neurovegetative in nature. Some of these autonomic changes may give indications about the mechanisms behind CO,-induced panic. Therefore, it seemed of interest to identify which specific panic symptoms

correlated best with subjective anxiety during CO,-induced panic. Like CO, inhalation, hyperventilation provocation (HVP) has also been found to product various somatic symptoms resembling those of panic. In the past it had been argued that hypocarbia might play an important role in anxicty induction in naturally occurring panic and/or hyperventilation (Lum, lY75; Beumer and Hardonk, 1980; Hibbert, 1984; Ley, 1985; Folgcring, 1YKh). However, recent reports have demonstrated that hyperventilation provocation is definitely less panicogenic than CO, inhalation in PD patients (German et al., lYX4, 1988; Zandbergen et al., 1990). Since both HVP and CO, inhalation are effective in provoking panic-like symptoms, but clearly differ with respect to the induction of subjective anxiety, it seemed of interest to know which symptoms, or cluster of symptoms, differed between experimental hypercarbia and hypocarbia. These symptoms might be specifically related to the subjective anxiety of panic. The present study dealt with both above-mentioned questions by investigating symptom profiles during the 35% CO, challenge and hyperventilation provocation in PD patients. in order to identify which specific panic symptoms arc of major importance to CO,-induced subjective anxiety. The data were partially taken from two previous studies (Gricz et al., 1988; Zandbcrgen et al., IYYO), which had been designed for a different purpose. namely to explore the anxiogenie capacity of experimental hypercarbia and/or hypocarbia in PD as compared to healthy controls. Methods Subjects The 20 experimental subjects, eight men and 12 women, were outpatients at the Anxiety Clinic of the Academic Mental Hospital Vijverdal. They all met DSM-IIIR criteria for panic disorder with or without avoidance (American Psychiatric Association, 1987) and their mean age was 34.9 years (range 21-55). At the time of the experiment they were not undergoing psychiatric treatment, had been free of psychotropic medication for at least 1 week,

and

were

in

good

physical

condition.

Subjects had to refrain from alcohol for at least 8 h and from tea and coffee for at least 2 h preccding the tests. The experimental data of 12 of the 20 subjects were taken from an earlier study (Zandbergen et al., 1990), as were the hyperventilation data of the other eight subjects (Griez et al., 1988). who had also undergone a 35% CO, challenge.

The procedures of the 3S%, CO, challenge technique and the hyperventilation provocation test used in the present study have been described in detail elsewhere (Griez et al., lYX8. lYY0a; Zandbcrgen et al., lY90). Each subject underwent a 35% CO, challenge and a hypervcntilation provocation test in a random crossover design. In the CO, challenge test subjects inhaled one vital capacity of two different gas mixtures, one consisting of 35% CO1 and 65% 0,. and the other consisting of air. In the HVP test subjects hyperventilated for at least 3 min through an open mask, resulting in a reduction of end-tidal pCOz (PETCO,) of at lcast SO%, (hypocapnic hyperpnea, HHP). In the control condition (normocapnic hyperpnea, NHP) the same procedure was repeated with an open tube connected to the mask, resulting in approximately the same value of PETCO, as in baseline breathing.

Immediately before and after each test. the subjects completed a self-rating form to assess I4 panic criteria, according to the draft of DSM-IIIR (Tables 1 and 2), each item ranging in value from 0 to 4. This yielded a total symptom score (range O-56). In addition, they were asked to express their subjective feeling of anxiety on a scale ranging from 0 (no anxiety at all) to 100 (the worst imaginable experience). During the hyperventilation tests (HHP and NHP), the end-tidal pC0, was continuously monitored by means of a Gould Godart Mk II1 capnograph. Dutm anulysis For the 35% CO, challenge test, a net score for subjective anxiety was calculated with the

133

following formula: (value after CO, minus value before CO,) minus (value after air minus value before air). A similar formula was used for calculation of net scores for symptoms. Net scores for the hypcrvcntilation provocation test were calculated using the formula: (value during HHP minus value before HHP) minus (value during NHP minus value before NHP). For the CO, and the HVP conditions separately, the correlation coefficients between net subjective anxiety on the one hand and the net scores of the total number of symptoms and each individual symptom on the other hand were calculated. The net subjective anxiety scores in both conditions were compared using parametric and non-parametric tests for related samples. The net total number of symptoms was analyzed in a similar way. For all symptoms together the net scores of CO2 and the hyperventilation test were com-

TABLE

pared using MANOVA. If a significant difference was found, pair-wise comparisons were performed (parametric and non-parametric). Results

Table 1 shows the correlation coefficients between the net increase in anxiety and the panic symptoms which subjects experienced during the 35% CO2 challenge. It also shows correlation coefficients for the hyperventilation condition. Table 2 shows the net increases in subjective anxiety, the total number of symptoms and the 14 separate symptoms during the 3.5% CO, challenge and the hyperventilation provocation test. A significant difference was found between experimental hypercarbia and hypocarbia with respect to the increase in subjective anxiety and the total number of symptoms. Analysis by means of MANOVA revealed a significant difference for all DSM-IIIR symptoms

I

CORRELATION 35% COZ AND

COEFFICIENTS HVP

BETWEEN

INDUCED

PANIC

SYMPTOMS

AND EXPERIENCED

Correlation of induced panic symptoms with experienced anxiety during COz

I)

Total symptoms

0.460 (P = 0.04

Symptoms I. shortness of breath or smothering sensations 2. choking 3. palpitations or accelerated heart beat

0.536 (P = 0.015) 0.521 (P = 0.019) 0.352 (NS)

4. 5. 6. 7. 8. 9.

chest pain or discomfort sweating faintness dizziness, lightheadedness or unsteady nausea or abdominal distress depersonalization or derealization

IO. numbness or tingling 11. flushes or chills

feelings

sensations

12. trembling or shaking 13. fear of dying 14. fear of going crazy or of doing something

uncontrolled

0.088 0.167 0.082 0.166 ~0.012 0.394

(NS) (NS) (NS) (NS) (NS) (P = 0.085) ( = trend) 0. I16 (NS) - 0.214 (NS) 0.039 (NS) 0.266 (NS) 0.388 (P = 0.091) ( = trend)

ANXIETY

Correlation of induced panic symptoms with experienced anxiety during HVP 0.245, (NS)

0.539 (P = 0.014) 0.222 (NS) 0.407 (P = 0.075) ( = trend) - 0.005 (NS) 0.103 (NS) 0.205 (NS) -0.112 (NS) 0.101 (NS) - 0.075 (NS) ~ 0.072 (NS) 0.442 (P = 0.05 1) ( = trend) - 0.022 (NS) 0.135 (NS) 0.171 (NS)

DURING

TABLE

7

DIFFERENCE

BETWEEN

THE

35% CO,

CHALLENGE

AND

HVP

Net wlue during (‘0, Subjective

anxiety

Total symptoms Symptoms I. shortness of breath or smothering

Net value

Difference

during 11VP

CO,

between

and HVP

r-test

Wilcoxon

30.0

izx.7

P = O.OOI

P = O.OOlh

I 1.7

+

P = 0.00x

P = 0.0052

P = 0.00 I I

sensations

6.5

0.90

0.40 * O.hO

P = 0.000

I .30If- I .lk

0.40 * 1.os

P = 0.031

P = 0.04’~s

I .os +

0.84

0.35 + O.HX

P = 0.050

P = 0.0507

(trend)

(trend)

I .47

0.x

+ I .40

NS

NS

5. sweating

0.40 i 0.65 *

O.YY

Il.25 t 0.0 I

NS

NS

0. faintnesT

I.lOi

1.12

055 + 1.70

NS

NS

I .45 +

I .05

0.50 f I .3x

I’ = O.OO?

P = 0.005’

distress

0.75 +

0.70

or &realization

0.75 *

I .07

- 0. IO + I.33 (I.50 + I .oo

3. choking

3. palpitations

or accelerated

heart heat

4. chest pain or discomfort

7. dizziness, lightheadedness 8. nausea or abdominal 9, depersonalization

or unsteady feelings

I .ho+

P = 0.007

P = 0.0 I46

NS

NS

IO. numbness or tingling sensations

O.hS f

I.50

0.80 + I. I5

NS

NS

I I. flushes or chills

O.YO*

0.05 + 0.64

P = 0.009

P = 0.00x7

17. trembling

0.65 *

I .07 0.93

o.s5*

NS

0.50 i

I .oo

0.75 *0.6-l

NS NS

0.50 +

O.Y5

0.30 * 0.57

NS

NS

or shaking

13. fear of dying 14, fear of going crazy or of doing something

uncontrolled

together (S = 1, M = 6. N = 2; Pillais, Hotellings, Wilks; P = 0.045). Individual symptoms during hypercarbia and hypocarbia were compared using t-tests (crf= 19) and Wilcoxon tests, as shown in Table 2. No significant order effects were found. Discussion In the present study it was found that during CO? inhalation ‘shortness of breath’ and ‘choking’ correlated significantly with subjective anxiety (Table 1). During hyperventilation provocation, the anxiety induced, although weak, correlated significantly with ‘shortness of breath’. In other words, in both experimental conditions anxiety correlated best with respiratory symptoms. During CO, inhalation, trends for a significant correlation with subjective anxiety were found for ‘depersonalization or derealization’ and ‘fear of going crazy or of doing something uncontrolled’. For the latter symptom this is obviously due to auto-correlation. During HVP, trends for a significant correlation with subjcctivc anxiety were

I.19

NS

found for ‘palpitations or accelerated heart beat’ and ‘flushes or chills’; but as mentioned above. HVP is a very weak anxiogenic. Moreover, since multiple correlations were performed, any conclusions concerning these findings of trends seem rather presumptious. Concerning the comparison of the 35% CO, challenge and HVP it is noteworthy that the absolute (but opposite) pH changes are approximately equal in the two conditions. One vital capacity inhalation of 35% CO, results in a pH decrease of about 0.3 (Griez et al., 1987bI. while hyperventilation as described above results in a pH rise of approximately 0.35 (Stortenbeek, 1979). However, the rate at which these pH changes develop is much higher in the hypercarbic than in the hypocarbic condition. The 35% CO, challenge causes a decrease in pH within seconds, whereas during HVP the pH increase occurs within l-2 min, a rate at least 10 times slower than during 35% CO, inhalation. It was found that a rapid increase in pC0, results in a greater increase in panic symptoms and subjective anxiety than a relatively slow decrcasc in pC0,. Both the

135

direction of pC0, (and pH) changes and the rate at which these changes develop could be an important factor in the induced symptoms and anxiety. When the symptom profiles of these hypercarbit and hypocarbic conditions were compared, it was found that the effect of 35% CO, inhalation was greater than HVP for five symptoms (TabIe 2). Both respiratory symptoms (‘shortness of breath’ and ‘choking’) were included in these 5. The other three symptoms (‘dizziness’, ‘nausea’ and ‘hot or cold flashes’) were not related to CO,-induced anxiety, and therefore are probably of minor importance to the anxiety provoked. Regarding these findings, it could be argued that the rapid increase in pC0, and decrease in pH as a consequence of a 35% CO, inhalation result in an acute stimulus to respiration and the appearance of respiratory symptoms, which in turn induce high anxiety by the principle of ‘fear of symptoms’ (Van den Hout et al., 1987) or ‘catastrophic misinterpretation’ (Clark, 1986). As HVP induces less severe respiratory symptoms, this cognitive mechanism would explain the difference between the hypercarbic and hypocarbic conditions. Furthermore, since CO, directly affects the respiratory system, it would not seem surprising that mainly respiratory symptoms are involved. On the other hand, symptoms such as palpitations, faintness and dizziness, which are well known signs accompanying experimental as well as real-life panic, also clearly occurred during the 35% CO, challenge to a degree comparable to that of respiratory symptoms. According to cognitive theory these symptoms would be expected to be anxiogenic in PD (Van den Hout et al., 1987). However, in the present study palpitations, faintness and dizziness were hardly related to CO,-induced anxiety. This could suggest a specific role of respiratory symptoms in PD, although this speculation should be confirmed, for instance by means of studies which compare anxiety and symptom profiles during CO, inhalation with challenges that have a less direct effect on the occurrence of respiratory symptoms. The apparent importance of respiratory symptoms in CO,-provoked panic seems of particular interest when these results are combined with those of recent research on co-morbidity of PD

and diseases affecting the respiratory system. In a previous study we found that PD patients had a higher lifetime prevalence of respiratory diseases than either obsessive-compulsive disorder patients or eating disorder (Zandbergen et al., 1991). Karajgi et al. (1990) found a higher prevalence of PD in a group of patients with chronic obstructive pulmonary disease than in the general population. Taken together, these findings suggest that respiratory symptoms might play an important role in real-life panic in a substantial subgroup of PD patients. Should this close association of panic and respiration be confirmed, it could point to a strong functional relationship between brain structures responsible for respiration and those involved in panic. The locus coeruleus, for example, has been suggested to be involved in panic (German et al., 1984) and has been demonstrated to be stimulated by CO, (Elam et al., 1981). Nuclei in the dorsal raphe, which produce serotonin, may play a role as well (Lingjaerde, 1985; Pols and Griez, 1988; Kahn et al., 1988). Both structures have been demonstrated to influence respiration (Eldridge and MilIhorn, 1981; Mueller et al., 1982). A third possibility connecting panic and respiratory symptoms might be the existence of hypersensitive central chemoreceptors in PD, as has been suggested by a recent study (Lousberg et al., 1988). In conclusion, the results of the present study indicate that respiratory symptoms are of major importance in CO,-induced panic. Although various other panic symptoms such as palpitations, faintness and dizziness were also clearly provoked by 35% CO,, they did not significantly correlate with the anxiety PD subjects experienced. References American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders, 3rd edn., revised. American Psychiatric Press, Washington, DC. Beumer, H.H. and Hardonk, H.J. (1980) Hyperventilation syndrome. J Drug. Res. 3, 671-675. Clark, D.M. (1986) A cognitive approach to panic. Behav. Res. Ther. 24, 461-470. Elam, M., Yao, T., Thoren, P. and Svensson, T.H. (1981) Hypercapnia and hypoxia: chemoreceptor-mediated con-

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