BIOl. I~YCHIATRY I ~ l ;29:843-854
843
Hyperventilation-lnduced Panic Attacks in Panic Disorder With Agoraphobia Richard J. Maddock and Cameron S. Carter
Eight minutes of h)~e,wenti!ation to an end-tidal Pco2 of less than 20 mmHg led ,'.~, a panic attack in 7 of 12 patients with panic disorder with agoraphobia and only 1 of 12 ,normal controls. Patients experienced greater increases in panic s-ympiom~ than comrols during hyperventilation. Patients who reported more distress from somatic symptoms of hyperventilation during the preceding week were more likely io punic during hyperventilation. Patients who panicked during hyperventilation exhibited a delayed recovery of normocapnia follow#zg hyperventilation. Hyperventilation by this protocol is an effective means of inducing panic attacks in the laboratory. A hyperventilation challenge may identify a subgroup of patients for whom hyperventilation symptoms ~re frequently associated with panic. Introduction The relationship of hyperventilation to panic attacks has been the subject of much recent controversy. One view is that hyperventilation-induced respiratory ~alosis is a primary cause of spontaneous attacks in patients with panic disorder (Bonn et al 1984; Salkovskis et al 1986). A contrasting view is that hypercentilation is an important consequence of panic attacks but is not a Frimary cause of spontaneoas attacks (Hibbert and Pilsbury 1989; Gorman and Uy 1987). Some studies have found breathing retraining to be an effective therapy for panic disorder, suggesting a causal relationship between hyperventHation and panic attacks (Bonn et al 1984; Salkovskis et al 1986). However, other studies |~ave found less favorable results of tneathing retraining in panic disorder (Hibbert and Chan 1989; de Ruiter et al 1989b). Studies that employ continuous monitoring of Pco2 have generally found that hypoc~pnia is unlikely to be a primary cause of panic attacks (Hibbert and Pilsbury 1989; Zarcone et al 1987). In general, there is stronger eviden:~e for hyperven~ation being a conseque,ace of panic attacks than a primary cause. Hyperventilation may have its greatest pathophysi.ological significance as part of a positi~'e feedback loop between anxiety and sortiatic symptoms (Cowley and Roy-Byme 1987). There has also been controversy about a related question: Is voluntary hyperventilat-ion an effective means of inducing panic attacks in a laboratory or clinic setting in patients with panic-related diagnoses? Mmw earl;¢ investigators reported routine success in provoldng panic symptoms with hyperventilation (Kerr et al 1937; Lum 1976). However,
From the Department of Psychiatry, University of California, Davis, School of Medicine. Address reprint requests to Richard Maddock, M.D., Department of Psychiatry, University of California, Davis Medical Center, 4430 V Street, Sacran~nto, CA 95817. Received August 2, 1990; revised October 19, 1990. © 1991 Society of Biological Psychiatry 0006-3223/91/$03.50
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R.J. Maddock and C.S. Carter
in an attempt to study this question in a controlled fashion, Gorman et al (1988) reported successful induction of panic attacks with hyperventilation in only 23% of a sample of panic patients. More recently, Griez et al (1988) reported no hyperventilation-induced panic attacks in 11 patients with panic disorder. Nonetheless, reports of hyperventilationinduced panic attacks or panic symptoms in 40%-80% of patients with panic disorder with agoraphobia continue to appear in the literature (Holt and Andrews 1989a; de Ruiter et al 1989a; Garssen et al 1983). Variations in the duration and degree of hypocapnia and in the methods of assessing the occurrence of a panic attack make it difficult to interpret some of these studies. The demonstration that hyperventilation is an effective means of provoking panic in a controlled setting is important to the development of laboratory techniques for biological and psychological studies of panic. In addition it has relevance to the development of successful treatment strategies. Exposure to interoceptive cues associated with panic attacks has been reported to be an effective means of treatment for panic disorder (Klosko et al 1990). Hyperventilation may have value as a technique for providing exposure to panic-associated somatic cues. In a recent study in our laboratory (Maddock and Mateo-Bermudez 1990), patients with panic disorder hyperventilated to maintain a Pco2 of 20 mmHg for 8 min. Although we were primarily interested in the metabolic effects of respiratory alkalosis, we observed panic attacks in 50% of our patients during the hyperventilation condition. We now report the results of a larger study in which we evaluated the effectiveness of hyperventilation as a means of provoldng panic in patients with panic disorder with agoraphobia. In our earlier study, we noted a delay in recovery from hyperventilation as reflected by a lower Pco.~ 10 min following the end of the hyperventilation condition in patients compared to controls. Other investigators have noted a similar persistence of hypocapnia following hyperventilation in panic disorder (Gorman et ai 1988; Hibbert and Pilsbury 1989). Thus, a second purpose of the current study is to extend tht.~e earlier ebservations of a delayed recovery of normocapnia following hyperventilation in panic patients.
Methods
Subjects The subjects were 12 patients who met DSM-III-R criteria for Panic Disorder with Agoraphobia and 12 normal control subjects matched for age and sex. Diagnoses were made using the Structured Clinical Interview for DSM-III-R, Upjohn version (Spi~er and Williams 1986). There were nine women and three men in each group. The average age of patients was 35.8 years (range 21-51), and that of controls was 36.0 years (range 23-52). Six of the patients had mild, five had moderate, and one had severe agoraphobia. No patient had a concurrent diagnosis of major depression or substance abuse. Controls were recruited by newspaper advertisement, were free of psychiatric illness, and had no prior contact with our laboratory. All subjects were in good physical health and had no history of pulmonary disease. Patients had been free of psychoactive medications for a minimum of 2 weeks prior to participation in this study. All patients reported at least weekly panic attacks (by DSM-III-R criteria) for the preceding 4 weeks.
Hyperventilation-lnduced Panic Attacks
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Procedure Subjects came to the lab at 8 AM after an overnight fast. The Mobility Inventory avoidance alone (MAL) and avoidance accompanied scales (MAC) (Chambless et al 1985), the Anxiety Sensitivity Index (ASI) (Reiss et al 1986), and a scale assessing recent somatic symptoms of panic (SSP) were administered. On the SSP subjects rated how much they had bec.~ distressed by each of the 11 somatic symptoms of panic (DSM-IH-R criteria) in the past week on a 0 - 4 scale (not at all, a little, moderately, markedly, and extremely). A heparin~zed catheter was then placed in a forearm vein and after 30 min of rest, baseline measurements were made. They then ingested glucose (1 g/kg body weight) in water as a part of a study of lactate metabolism and hyperventilation in panic disorder, ~ported elsewhere (Maddock and Carter 1989). After patients rested a further 20 min, prehyperventila, io~ measurements were made. Subjects were then asked to "'breaLhe deeply and rapidly" safficient to maintain an end-tidal P¢o2 of 20 mmHg for 8 min. A visual ~ a l o g monitor gave subjects feedback as to their end-tidal Pco2 during hyperventilation and the subjects were instructed to maintain this level at or below 20 mmHg. After 8 ~ n of hyperventilation, subjects were instructed to "breathe normally." Subjects were monitored during a 15-rain recovery period following the end of the hyperventilation coMition. End-tidal Pco2 was monitored continuously from a loose-fitting face mask by a Godard infrared capnograph. Analog output from the capnograph was channeled to a Grass polygraph to provide a record of end-tidal Pco2 and respiratory rate (RR) throughout the experiment. Respiratory rate and Pco2 were scored from the polygraph record at base ;line, and every 2 min during hyperventilation and the 15-rain posthyperventilation recovery period. Anxiety symptoms were assessed by an 1 l-[~oint (0-10) visual analog scfle for overall anxiety rating (AR) and by the Acute Panic Inventory (API) (Dillon et al 1987). API and AR were administered at baseline, immediately prior to hyperventilauon, ~ mediately after nyperventilation, and 15 min posthyperventilation. AR was also a d r ~ istered every 2 min during hyperventilation. Blood samples were obtained at three time points during the procedure, as part of the metabolic study (Maddock and Carter 1989).
Subject Instructions Prior to the procedure• subjects gave informed consent. The consent form for both patients and controls acknowledged the risk that subjects might experience physical discomfort uL~ including dizziness• tingling sensations, disorientation, ury-' . . . .m. U. U t H'- • or anxiety uuL""---m~.k~ vrocedure. The term panic attack was not used. If patients specifically asked whether or not they might panic, this possibility was acknowledged. This occurred only occasionaiiy. The rationale given to the patients was "'this is a study of sugar metabolism in patients with anxiety." Once the apparatus was in place• subjects were given the following instructions. "The experiment begins now with a baseline period. During this period you should just sit quietly and relax. From now until the end of the experiment we will remain behind the room divider most of the time. If you need anytF~ng, just ask for us. Periodically, we will approach you to give you instructions or rating scales, or to draw your blood. We will not carry on other convocations with you. Again, if you need anything, just ask, but please postpone casual questions until the ead of the experiment." The same psychiatrist (CSC) conducted the procedure on each occasion. He related to the patients in an attentive, courteous but formal manner in a further attempt to stabilize the interpersonal demand characteristics of the procedure. Although the consent fo.~n acknowl-
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BIOL PSYCHIATRY 1991;29:t~3-854
R.J. Maddock and C.S. Carter
edged that subjects could discontinue the procedure at any time, we did not draw further attention to that option.
Assessment of Panic Our criteria for a panic attack were an increase in intensity of at least four panic symptoms on the API, accompanied by either an increase of at least 2 points on the AR to a value of 5 or greater or any AR score of 7 or greater, plus the a~ending psychiatrist's assessment that a panic attack occurred. This assessment was based upon a subject's report of a sudden increase in anxiety (similar to usual panic in the patient group) accompanied by physical symptoms, and a sense of dread with an urge to stop the procedure or leave the lab in search of a safer place. Data Analysis The following planned comparisons were made. The numbers of subjects experiencing panic attacks during hyperventilation in the patient versus the control group were compared using the Fisher exact probability test. Group differences in API, ,,~u2,MAL, MAC, ASI, and SSP scores at baseline and change scores for AR and API (maximum score following hyperventilation minus baseline score) were assessed with the Mann-Whitney test. Group comparisons of RR and Pco2 at baseline and during hyperventilation were made by t-tests. Respiratory data during the posthyperventilation recovery period were analyzed by two~way repeated measures analysis of variance (ANOVA) with three groups: patients who panicked, patients who did not panic, and controls. Post hoc comparisons were made with the Tukey test (ct = 0.05). End-tidal Pco2 during the recovery period was quantified as "percent recovery." This was defined as (RC,) - Pco2 (HV) Pco2 (BL) - PCO2 ( a v )
PCO 2
where Pco2 (RC~) is Pco2 daring recovery at time i, Pco2 (HV) is mean Pco2 during hyperventilation, and Pco2 (BL) is baseline Pco2. This calculation yields the percent of return toward baseline PCO2relative to the degree of hypocapnia that developed during hyperventilation. The time at which 50% recovery of Pco2 occurred was determined for each subject and analyzed using a two-way factorial ANOVA for the three groups. Respiratory rate dtwing recovery was Quantified as "change in RR." This was calculated as the recovery value minus the baseline value. All p values are two-tailed. Results All controls and 11 of the 12 patients voluntarily completed all 8 min of the hyperventilation condition. One patient asked to discontinue the procedure after 6 min. However, this patient was unable to reduce her ventilation and continued to hyperventilate into the recovery period. Mean end-tidal Pco2 during the hyperventilation period ranged from 11.2 to ! 3.7 .,~mHg. Seven of 12 patients and 1 of 12 controls had a panic attack during hyperventilation by our criteria. This represents a significantly greater occurrence of panic attacks in the patient group (p < 0.05).
Hyperventilation-lnd~acedPanic Attacks
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Table !. AR and API Ratings Before, During, and After Hypep:entilation~
Minute during WV Bas~!ine Anxiety Rating Patients (n = 12) PAN (n = 7) N P (n = 5) Controls (n = 12) Acute Panic Inventory Patients (n = 12) PAN (n = 7) NP (n = 5) Controls (n = 12)
3.2 b'~ 4.4 ~ 1.4 0.6
2
4
6
5.8 7.1 4.3 3.1
6.0 7.4 4.0 2.8
6.4 7.9 4.4 3.2
Immediately post-HV
5.8s 7.4 / 3.4 1.3
15 rain post-HV
5.8 7.9 3.0 1.8
2.8 3.7 0.6
21.5 27.4 13.2 5.2
8.2 12.4 2.4 I.I
1.6
Maximum change from baseline
3.3~ 3.~ 2.8 3.2 15.Y 19.9" ON
3.7
°PAN = patients w~m panicked during HV; NP -- patients who 0~:-1not panic. q2omparisons made by Mann-Whitney test, two-tailed. cPatients > ccnlrol i, p < 0.001. q~atients versus controls, NS. •PAN > NP, p < 0.025. IPAN versus NP, NS. ~Patients > controls, p < 0.05.
Scores on AR and API ratings are shown in Talkie 1. Patients had significantly higher scores on boOl ratings than controls at baseline. The increase in API from baseline to hyperventilation was significantly greater in patients than controls (U = 9.5, n = 12,12, p < 0.001). Patients who panicked during hyperventilation had higher AR scores at baseline than patients who did not panic (U = 3, n = 7,5, p < 0.02). Scores on MAL, MAC, ASI, and SSP are shown in Table 2. As expected, patients had higher scores than controls on all scales. Pat;,ents who panicked during hyperventilation did not differ significantly from nonpanicking patients on these scales. However, there was a trend toward higher scores on the SSP in patients who panicked (U = 5.5, n = 7,5, p = 0.06). A subscale of the SSP mcludexl six symptoms commonly reported during hyperventilation (dyspnea, choking, dizzy or faint feelings, numbness or tingling, depersonalization or derealization, and tremor). Ratings on the subscale of somatic symptoms of hyperven-
T a b l e 2. C l i n i c a l R a t i n g s at B a s e l i n e in P a t i e n t s a n d C o n t r o l s a
Patients (a = 12) PAN (n = 7) NP (n = 5) Controls (n = 12)
MAL
.MAC
ASI
SSP
SSH
76.2 b'` 73.8 79.6 36.9
50.6 a 51.5 49.5 32.0
49.9" 46.0 54 6 31.0
14.2 c 18.1 8.8 1.0
7.Y 9.7 e 4.0 0.7
°MAL = Mobility Inventory, alone scale; MAC = Mobility Inventory, a:,,co~-npaniedscale; ASI = Anxiety Scus[:ivity Index; SSP = somatic symptoms of panic" SSH = somatic symptoms of hypervent;.lation; PAN = panicking patients; N'P = nonpanicking patients. ~omparisons made by Mann-Whitney test, two-tailed. CPatients > controls, p < 0.001. *Patients > controls, p < 0.02. ePAN > NIP, p = 0.04.
848
R.J. Maddock and C.S. Carter
BIOL PSYCHIATRY i 99 i ;29:843-854
Table 3. End-tidal Pco2 and Respiratory Rate Before and During Hyperventilation ° Minute during HV
Mean
2
4
5
during HV
37. i b'" 35.5 d 39.2 35.6
16.0 15.9 16.0 14.4
14.8 14.6 15.2 14.8
14.7 14.5 14.8 14.2
15.2c 15.tY~ 15.4 i4.4
14.2e 14.3~ 14.0 10.9
33.6 31.0 37.2 33.5
33.6 33.0 34.4 29.8
33.3 33.6 33.0 30.2
33.5c 32.5d 34.9 31.2
Baseline End-ddal Pco: mmHg P~.ticnts (n = 12) P/~N (n = 7) NP {n = 5) Controls (n = 12) Respiratory Rate Patients (n = 12) PAN (n = 7) NP (n = 5) Controls (n = 12)
°PAN = patients who panicked during HV; NP = patients who did not panic. bComparisons made by t-test, two-tailed. CPatients versus controls, NS. aPAN versus NP, NS. "Patients versus controls, p < 0.025.
tilation (SSH) are shown in Table 2. Patients w h o panicked reported significantly more of these symptoms in the preceding week than patients who did not panic ( U = 4.5, n = 7,5, p = 0.04). Respiratory data at baseline and during hyperventilation are shown in Table 3. There was no significant difference between patients and controls in P¢o2, either at baseline or during hyperventilation. Patients had significantly higher R R than controls at baseline, but no difference was observed during hyperventilation. Percent recovery of end-tidal Pco2 during the posthyperventilation recovery period is shown in Figure 1. Two-way A N O V A showed a significant main effect for group ( F = 7.44, df = 2, p < 0.004). Post hoc testing showed that this effect was due to significantly less recovery of Pco2 in the patients who panicked than in control subjects or nonpanicking patients. There was a trivial main effect for time ( F = 194.5, df = 6, p < 0.(.h~31) and no significant group-by-time interaction ( F = 1.46, d f = 12, NS).
i00 ~d 0
c~
80
~I
60
~
40
Figure 1. Percent recove~ of end-tidal Pco2 following hyperventilation. Means and standard errors are shown. Panicking patients (PAN) had significantly lower values than nonpanicking patients (NP) or controis (CON).
T a
PAN
L_
a,i
o
20
N
0
i
~
l
!
|
i
g
2
4
6
8
10
12
14
minutes
p o s t HV
Hyperventilation-lnduced Panic Attacks
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=m '21 10 c
.m l
T
n
PAN
~
NP
c0N
8
Figure 2. Change in respiratory rate from baseline d ~ n g ~ recovery period following h ~ r ventilation. Means and standard errors are shown. Panicking ~ tients (PAN) had significantly higher increases over baseh~ than nonpanic~g ~atients (NP} or controls (CON) (see text).
~p
6 E o
L
4 2 0
~=~
-2
0
e
|
|
s
2
4
6
8
minute~
e
I0
i
12
14
p o s t XV
Two-way ANOVA of time to 50% recovery of Pco2 revealed a significant group effect (F = 12.5, df = 2, p < 0.0003}. Post hoc testing showed that this effect was due to a longer time to 50% recovery in the patients who panicked [8.3 _+ 2.9 min (mean +_ SD)] than in nonpanicking patients (4 _+ 0.0 rain) or normal controls (4.7 _+ l .(3 ~ ) . There was almost complete separation between panicking and nonpanicking patients on this parameter. Only one panicking patient was within the range of the n o n p a n i c ~ g group. Change from baseline RR during the posthyperventilation recovery period is shown in Figure 2. Two-way ANOVA showed a significant main effect for group (F = 3.58, df = 2, p = 0.046) and a group-by-time interaction (F = 2.50, df = 12, p < 0.006). There was no significant effect for time (F = 1.30, df - 6, NS). Post hoc analysis of the group effect showed a greater increase over baseline l~R in the patients who panicked compared to the two other groups. Post ~c,,: analysis of the group-by-time interaction showed that patients who panicked exhibited significantly greater increases over baseline RR at minutes 2, 4, and 6 compared to controls, and at minute 6 compared to nonpanickmg patients.
Discussion Eight minutes of hyperventilation to an end-tidal PCO 2 of less than 20 mmHg led to a panic attack in 7 of 12 patients with panic disorder. Patients were significantly more likely to panic than were control subjects. The 58% incidence of a hyperventilationinduced panic attack in this sample of patients is similar to the 50% incidence reported in an earlier study from our laboratory (Maddock and Mateo-Bennudez 1990) and to the 40% to 80% incidence reported in other studies (Helt and Andrews 1989a; de Ruiter et al 1989a; Garssen et al 1983). It is also in the range of results from other panic-induction methods, including infusion of 5 mmoi,'i~./kg sodium lactate (60% to 80%) (Liebowitz et al 1984), inhalation of 5% CO2 (40% t~:~60%) (Gorman et al 1988; Woods et al 1988), ingestion of 480 mg caffeine (38%) (Uhde and Boulenger 1989), and ingestion of 20 mg yohimbine (54%) (Chamey et al 1987). Howe;er our results contrast with several studies finding a much lower incidence of panic attacks reduced by voluntary hyperventi!ation. Rapee (1986) reported that no panic attacks occurred d~.~ringvoluntary hyperventilation
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BIOL PSYCHIATRY 1991;29:843-854
RJ. Maddock and C.S. Carter
in 20 subjects with panic disorder. However, this study differed from ours in its demand characteristics, the medication status of patients, and the duration of hyperventilation. According to Rapee "all attempts were made to dispel any fears" prior to hyperventilation and subjects were not excluded if they were taking benzodiazepines. In addition, subjects were required to hyperventilate for only 90 sec. The drug-free status of our patients, the longer duration of hyperventilation (8 min), and the more neutral demand characteristics of our protocol (including an intentional avoidance of reassuring subjects) would all be expected to increase the likelihood of panic induction. Nonetheless, in the Rapee (1986) study, th~ panic disorder patients experienced significantly more distressing somatic symptoms of anxiety than a comp-,aison group of patients with generalized anxiety disorder. Gorman et al (1988) reported that only 7 of 30 patients (23%) with panic disorder experienced a panic attack d ~ n g voluntary hyperventilation to an end-tidal Pcoz of approximately 25 mmHg f~r ,~ to 15 min. This milder hypocapnia and an unbalanced order design may have contribute,; to the lower incidence of hyperventilation-induced panic. In the study by Gorman et al (1988), the hyperventilation condition always occurred 15 rain after patients had been chal!enged with 5% CO, inhalation. In an earlier study from our laboratory, we challenged paaic patients with two consecutive hyperventilation conditions 35 rain apart. Fifty percent Cf the patients panicked following the first hyperventiiafion challenge and only 25% panicked following the second. Self-rated anxiety was significantly lower following the second hyperventilation challenge than the first (Maddock and Mateo-Bermadcz 1990). These findings suggest that when two anxiogenic challenges are given in rapid succession, the second one is less powerful. Such an order effect could explain the relatively lower incidence of hyperventilation-induced panic in tlie Gorman et al (1988) study. Griez et al (1988) reported on 11 panic patients and 8 controls subjected to 4 min of voluntary hyperventilation. They found a trend for patients to report a greater increase in somatic symptoms following hyperventilation than control subjects. However, they found only small increases in subjective anxiety-and no panic attacks in the patient group. A difference in subject sample may account for this discrepant result. Our subjects all had panic disorder with agoraphobia and were currently suffering from at least weekly four symptom panic attacks. It is likely that our patients were more clinically ill than those studied by Griez et al (1988), who are described only as "meeting DSM-HI criteria for panic disorder." Two recent studies found that patients with panic disorder plus agoraphobia are more sensitive to the panic-inducing effects of hyperventilation than are patients with panic disorder alone (Holt and Andrews 1989a; de Ruiter et al 1989a). Targum (1990) found that panic patients having weekly attacks were far more sensitive to anxiogenic challenge than were patients having one attack or less per month. In the current study and in our previous investigation (Maddock and Mateo-Bermudez 1990), all subjects received a glucose load prior to hyperventilation. It has been shown that carbohydrate ingestion leads to an increase in sympathetic nervous system activity in humans (Welle et al 1981; Seaton et al 1984). It is possible that this carbohydrateinduced increase in sympathetic tone could have acted synergistically with hypervefitilation to produce greater anxiety and more panic attacks in our subjects. However, no significant change in APl or AR ratings was seen in our subjects following glucose ingestion. It has also been shown that hyperventilation following a glucose load increases serum lactate in animals and humans more than hyperventilation in fasted subjects (Brautbar et al 1983; Maddock and Mateo-Bermudez 1990). However, this increase in lactate
Hyperventilation-lnduced P~,aticAttacks
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851
is small (about 25% of the increase seen with a standard lactate infusion) and delayed (it peaks approximately 15 min following the end of hyperventilation in o,~ subjects). These factors make it unlikely that increased lactate contributed to the anxiogenic effect of hyperventilation. However, a role for sympathetic or metabolic factors in po~ntiaring the anxiogenic effects of hyl~rventilation in this protocol cannot ~ excluded. Further studies using similar conditions for hyperventilation but without glucose ingestion may clarify the role of this metabolic stimulus in hyperventilation-induced panic. Our patients experienced significantly greater increases in somatic symptoms of anxiety (API) but not global anxiety (AR) following hyperventilation as compared with controls. A similar dissociation between hypervenfilation-induced increases in somatic symptoms and global anxiety was noted by Griez et al (1988). Vulnerabiliry to somatic symptoms rather than global anxiety following hyperventilation may be a more distinctive feature of the patient group. However, relatively higher baseline scores on the AR (three patients rated 7 on a 0-10 scale) than the APl (range = 0-18 on a 0-51 scale) suggest that a "ceiling" effect may have limited the sensitivity of the AR but not the APl to further increases in anxiety. The return to normal Pco2 levels following hyperventilation was s i ~ c a m l y delayed iI~ the patients who panicked during hyperventilation. This was manifested by lower endtidal Pc02 throughout the I5-min recovery period and by a significant delay in reaching 50% recovery of baseline PCO2. This result is consistent with earlier studies of panic disorder (Gorman et al 1988; Hibbert and Pilsbury 1989) and "'hyperventilation syndrome," a condition that overlaps extensively with panic disorder and agoraphobia (Folgering Colla 1978; Hardonk and Beumer 1979; Garssen et al 1983). Delayed recovery of normocapnia following hyperventilation has been proposed as a diagnostic marker for the hyperventilation syndrome (Hardonk and Beumer 1979). In our study, as in the study of Gorman et al (1988), delayed recovery of normocapnia was evident only in the patients who had experienced a panic attack during hyperventilation, not in the nonp~cking patients. Thus, delayed recovery of normocapnia following hyperventilation may not be a diagnostic or "trait" marker in panic disorder, but, rather, a specific consequence of an acute panic attack. The initially elevated respiratory rate and the continued hypocapnia in the patients who panicked are both consistent with continued hyperventHation persisting into the recovery period. The mechanism of this excess ventilation under hypocapnlc conditions following hyperventilation is uncertain. Folgering and Durlinger (1983) studied the effect of alveolar PCO2 on posthyperventilation breathing. They found that hyperventilation persisted longest into the recovery period when Pco2 was the lowest. They attributed this effect to the excitatory influence of hypocapnia on the general function of neurons influencing the respiratory center. There is little evidence for central chemoreceptor influence on respiration below a Pco2 of 35-40 mmHg (Gardner et al 1986). Typically, ventilatory drive is decreased during h~ocapnia but is increased during periods of increased vigilance and arousal (Lambertsen 1980). This delayed recovery of normocapnia may result from persistent hyperventilation secondary to the increased, arousal associated with an acute panic attack. This effect might be further amplified by the nonspecific excitatory effects of hypocapnia. Our findings agree with other reports that hyperventilation is one of the physiological changes most consistently observed during laboratory-induced panic attacks (Gorman et al 1986, 1988; Papp et al 1989). Patients who panicked during hyperventilation were characterized by higher overall anxiety prior to hyperventilation and more frequent somatic symptoms of hyperventilation during the preceding week. The importance of baseline anxiety as an indicator of vu!.
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R.J. Maddock and C.S. Carter
nerabil~ty to laboratory-induced panic has been frequently reported (Ehlers et al 1986; Liebowitz et al 1984). The higher incidence of recent somatic symptoms of hyperventilation in patl.ents who panicked during hyperventilation is consistent with the findings of Gorman et al (1988). These observations suggest that a hyperventilation challenge test may identify a subgroup of patients for whom hyperventilation symptoms are frequently associated with panic. These patients might be most likely to benefit from therapeutic exposure to hyperventilation symptoms. In this regard, i~ is of interest that one of the patients who panicked during this experiment later described the event as "very therapeutic" and attributed her subsequent recovery largely to this experience. Patients who panicked during hyperventilation did not differ from nonpanicking patients in the tendency to interpret anxiety symptoms as harmful (ASI) or in ratings of avoidance behavior (MAL and MAC'. This contrasts with earlier t'eports of greater sensitivity to hyperventilation in patients with panic and agoraphobia compared to patients with panic disorder alone (Holt ~nd Andrews 1989a; de Ruiter et al 1989a). Methodological features of our study, such as greater degree and duration of hypocapnia, may have overshadowed an effect of severity of avoidance behavior on sensitivity to hyperventilation in our sample. A relative hypocapnia at rest in panic patients has been reported by some investigators (Gorman et al 1986; Papp et al 1989; Rapee 1986) but not seen by others (Holt and Andrews 1989b). Our patients did not differ from controls in resting Pco:,, but they did exhibit a significm~t!y higher respiratory rate. Such "baseline" differences are difficult to interpret because the intrinsic stress of the laboratory situation is unlikely to permit true basal measurements. In summary, this study demonstrates that hyperventilation to a Pco2 of less than 20 mmHg for 8 min is an effective means of provoking panic attacks in patients with panic disorder with agoraphobia. This technique may be useful in studying biological and psychological aspects of acute panic in a laboratory setting (Maddock and Carter 1989; Holt and Andrews 1989a). It may also prove useful as a means of therapeutic exposure to panic-associated cues in behavioral treatment of a subgroup of patients with panic disorder. Delayed recovery of normocapnia occurs following hyperventilation-induced panic. This may represent continued hyperventilation as a consequence of an acute panic attack. The authors thank Carol Buckinger, Dr. Holly llfeld, Carla Levin R.N.M.S., Gary Summers, and Mark Wahle for invaluable technical assistance and Jane Rachford for manuscript preparation.
References Bonn JA, Readhead CPA, Timmons BH (1984): Enhanced adaptive behavior response in agoraphobic patients pre-treated with breathing retraining. Lancet ii'565-669.
Brautbar N, Leibovici H, Massry SG (1983): On the mechanisms of hypophosphatemia during acute hyperventilation: Evidence for increased muscle glycolysis. Miner Electrolyte Metab 9:4550. Chambless DL, Caputo GC, Jasin SE, Gracel EJ, Williams C (1985): The mobility inventory for agoraphobia. Behav Res Ther 23:35-44. Charney DS, Woods SW, Goodman WK, Heninger GR (1987): Neurobiological mechanisms of panic anxiety: Biochemical and behavioral correlates of yohimbine-induced panic attacks. Am J Psychiatry 144:1030-1036. Cowley DS, Roy-Byrne PP (1987): Hyperventilation and panic disorder. Am J Med 83:929-937.
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de Ruiter C, Garssen B, Rijken H, Kraaimaat F (1989a): The hyperventilation syndrome in ~ c disorder, agoraphobia ~ d generalized anxiety disorder. Behav Res Ther 27:447-452. ae Ruiter C, Rijken H, Garssen B, Kraaimaat F ¢1989b): Breathing retra~nhag, exposure, and a combination of both, in the treatment of panic disorder with agoraphobia. Behav Res Ther 27"637-655. Dillon DJ, Gorman JM, Liebowitz MR, Fyer AJ, Klein DF (1987): Measurement of lactate-induced panic and anxiety. Psychiatry Res 20:97-105. Ehlers A, Margraf J, Roth WT, et al (1986): Lactate infusions and panic attacks. Psychiat~ Res 17:295-308. Folgering H, Colla P (1978): Some anomalies in the control of PaCO2 in patients with a hyperventilation syndrome. Bull Ear Physiopathol Respirat 14:503-512. Folgering H, Durlinger M (1983): Time course of posthyperventilation breathing in humans depends on alveolar CO2 tension. J Appl Physiol Respirat Environ Exerc Physiol 54:809-813. Gardner WN, Meah MS, Bass C (1986): Controlled study of respiratory responses during prolonged measurement in patients with chronic hyperventilation. Lancet ii:826-830. Garssen B, Veenendaal WV, Bloemink R (! 983): Agoraphobia and the hyperventilation syndrome. Behav Res Ther 21:643-649. Gorman JM, Uy J (1987): Respiratory physiology and p:thological anxiety. Get Hosp Psychiatry 9:410--419. Gorman JM, Cohen BS, Leibowitz MR, et al (1986): Blood gas changes and hypophosphatemia in lactate induced panic. Arch Gen Psychiatry 43:1067-1071. Gorman JM, Fyer MR, Goetz R, et al (1988): Ventilatory physiology in patients with panic disorder. Arch Gen Psychiatry 45:31-39. Griez E, Zandbergen J, Lousberg H, van den Hout M (1988): Effects of low pulmonary CO2 on panic anxiety. Compr Psychiatry 29:490-497. Hardonk HJ, Beumer HM (1979): Hyperventilation syndrome. In Vinken PJ, Bruyn GW (eds), Handbook of Clinical Neurology, vol 38. Amsterdam: Elsevier, pp 309-360. Hibbert G, Chan M (1989): Respiratory control: Its contribution to the treatment of panic attacks. A controlled study. Br J Psychiatry 154:232-236. Hibbert G, Pilsbury D (1989): Hyperventilation: Is it a cause of panic attacks? Br J Psychiatry 155:805-809. Holt PE, Andrews G (1989a): Provocation of panic: Three elements of the panic reaction in four anxiety disorders. Behav Res Ther 27:253-261. Holt PE, Andrews G (1989b~: Hyperventilation and anxiety in panic disorder, social phobia, GAD and normal controls. Behav Res Ther 27:453--460. Kerr WJ, Dalton JW, Gliebe PA (1937): oome physical pheno~'nena associated with anxiety, states and their relation to hyperventilation. Ann Intern Med 11:961-992. Klosko JS, Barlow DH, Tassinari R, Cerny JA (1990): A comparison of alprazolam and behavior therapy in treatment of panic disorder. J Consult Clin Psychol 58:77-84. Lambertsen CJ (1980): Chemical control of respiration at rest. In Mountcastle VB (ed), Medical Physiology, 14th ed, vol 2. St. Louis: Mosby, pp 1774-1827. Liebowitz MR, Fyer AJ, Gorm~ JM, et al (1984): Lactate provocation of panic attacks: Clinical and behavioral findings. Arch Gen Psychiatry 41:764-770. Lum LC (1976): The syndrome of habitual chronic hyperventilation. In Hill OW (ed), Modern Trends in Psychosomatic Medicine, vol 3. London: Butterworths. Maddock RJ, Carter CS (1989): Hyperventilation and lactate metabolism in panic disorder. Biol Psychiatry 25:192A. Maddock RJ. Mateo-Bermudez J (1990): Elevated serum lactate following hyperventilation during glucose infusion in panic disorder. Biol Psychiatry 27:411-418.
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Papp LA, Martinez JM, Klein DF, et al (1989): Arterial blood gas changes in panic disorder and lactate induced panic. Psychiatry Res 28:171-180. Rapee R (1986): Differential response to hyperventilation in panic disorder and generalized anxiety disorder. J Abnorm Psychol 95:24--28. Reiss S, Peterson RA, Gursky DM, McNally RJ (1986): Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav Res Ther 24:1-8. Salkovskis PM, Jones DRO, Clark DM (1986): Respiratory control in the treatment of panic attacks: Replication and extension with measures of behavior and pC'O.,. Br J Psychiatry 148:526-532. Seaton TS, Welle S, Alex S, Lilavivat U, Campbell R (1984): The effect of adrenergic blockade on glucose-induced thermogenesis. Metabolism 33:415-419. Spitzer R, Williams J (1986): Structured Cl"nical Interview for DSM-III-R--Upjohn VersionRevised. New York: New York State Psychiatric Institute. Targum SD (1990): Panic acuity affects reactivity to ar,xiof~enic challenge studies. Presented at Psychiatric Research Society Annual Meeting, Park City, March 7-10, 1990. Uhde TW, Boulenger JP (1989): Caffeine model of panic. In Lerer B, Gen'lon S (eds), New Directions in Affective Disorders. New York: Springer-Verlag, pp 410-413. Welle S, Lilavivat U, Campbell RG (1981): Thermic effect of feeding in man: Increased plasma norepinephrine levels following glucose but not protein or fat consumption. Metabolism 30:953958. Woods SW, Chamey DS, Goodman WK, Heninger GR (1988): Carbon dioxide-induced anxiety. Arch Gen Psychiatry 45:43-52. Zarcone VP, Maddock RJ, Siegel D (1987): Atypical polysomnographic features in the sleep of a panic disorder patient. Sleep Res 15:99.
843
Hyperventilation-lnduced Panic Attacks in Panic Disorder With Agoraphobia Richard J. Maddock and Cameron S. Carter
Eight minutes of h)~e,wenti!ation to an end-tidal Pco2 of less than 20 mmHg led ,'.~, a panic attack in 7 of 12 patients with panic disorder with agoraphobia and only 1 of 12 ,normal controls. Patients experienced greater increases in panic s-ympiom~ than comrols during hyperventilation. Patients who reported more distress from somatic symptoms of hyperventilation during the preceding week were more likely io punic during hyperventilation. Patients who panicked during hyperventilation exhibited a delayed recovery of normocapnia follow#zg hyperventilation. Hyperventilation by this protocol is an effective means of inducing panic attacks in the laboratory. A hyperventilation challenge may identify a subgroup of patients for whom hyperventilation symptoms ~re frequently associated with panic. Introduction The relationship of hyperventilation to panic attacks has been the subject of much recent controversy. One view is that hyperventilation-induced respiratory ~alosis is a primary cause of spontaneous attacks in patients with panic disorder (Bonn et al 1984; Salkovskis et al 1986). A contrasting view is that hypercentilation is an important consequence of panic attacks but is not a Frimary cause of spontaneoas attacks (Hibbert and Pilsbury 1989; Gorman and Uy 1987). Some studies have found breathing retraining to be an effective therapy for panic disorder, suggesting a causal relationship between hyperventHation and panic attacks (Bonn et al 1984; Salkovskis et al 1986). However, other studies |~ave found less favorable results of tneathing retraining in panic disorder (Hibbert and Chan 1989; de Ruiter et al 1989b). Studies that employ continuous monitoring of Pco2 have generally found that hypoc~pnia is unlikely to be a primary cause of panic attacks (Hibbert and Pilsbury 1989; Zarcone et al 1987). In general, there is stronger eviden:~e for hyperven~ation being a conseque,ace of panic attacks than a primary cause. Hyperventilation may have its greatest pathophysi.ological significance as part of a positi~'e feedback loop between anxiety and sortiatic symptoms (Cowley and Roy-Byme 1987). There has also been controversy about a related question: Is voluntary hyperventilat-ion an effective means of inducing panic attacks in a laboratory or clinic setting in patients with panic-related diagnoses? Mmw earl;¢ investigators reported routine success in provoldng panic symptoms with hyperventilation (Kerr et al 1937; Lum 1976). However,
From the Department of Psychiatry, University of California, Davis, School of Medicine. Address reprint requests to Richard Maddock, M.D., Department of Psychiatry, University of California, Davis Medical Center, 4430 V Street, Sacran~nto, CA 95817. Received August 2, 1990; revised October 19, 1990. © 1991 Society of Biological Psychiatry 0006-3223/91/$03.50
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in an attempt to study this question in a controlled fashion, Gorman et al (1988) reported successful induction of panic attacks with hyperventilation in only 23% of a sample of panic patients. More recently, Griez et al (1988) reported no hyperventilation-induced panic attacks in 11 patients with panic disorder. Nonetheless, reports of hyperventilationinduced panic attacks or panic symptoms in 40%-80% of patients with panic disorder with agoraphobia continue to appear in the literature (Holt and Andrews 1989a; de Ruiter et al 1989a; Garssen et al 1983). Variations in the duration and degree of hypocapnia and in the methods of assessing the occurrence of a panic attack make it difficult to interpret some of these studies. The demonstration that hyperventilation is an effective means of provoking panic in a controlled setting is important to the development of laboratory techniques for biological and psychological studies of panic. In addition it has relevance to the development of successful treatment strategies. Exposure to interoceptive cues associated with panic attacks has been reported to be an effective means of treatment for panic disorder (Klosko et al 1990). Hyperventilation may have value as a technique for providing exposure to panic-associated somatic cues. In a recent study in our laboratory (Maddock and Mateo-Bermudez 1990), patients with panic disorder hyperventilated to maintain a Pco2 of 20 mmHg for 8 min. Although we were primarily interested in the metabolic effects of respiratory alkalosis, we observed panic attacks in 50% of our patients during the hyperventilation condition. We now report the results of a larger study in which we evaluated the effectiveness of hyperventilation as a means of provoldng panic in patients with panic disorder with agoraphobia. In our earlier study, we noted a delay in recovery from hyperventilation as reflected by a lower Pco.~ 10 min following the end of the hyperventilation condition in patients compared to controls. Other investigators have noted a similar persistence of hypocapnia following hyperventilation in panic disorder (Gorman et ai 1988; Hibbert and Pilsbury 1989). Thus, a second purpose of the current study is to extend tht.~e earlier ebservations of a delayed recovery of normocapnia following hyperventilation in panic patients.
Methods
Subjects The subjects were 12 patients who met DSM-III-R criteria for Panic Disorder with Agoraphobia and 12 normal control subjects matched for age and sex. Diagnoses were made using the Structured Clinical Interview for DSM-III-R, Upjohn version (Spi~er and Williams 1986). There were nine women and three men in each group. The average age of patients was 35.8 years (range 21-51), and that of controls was 36.0 years (range 23-52). Six of the patients had mild, five had moderate, and one had severe agoraphobia. No patient had a concurrent diagnosis of major depression or substance abuse. Controls were recruited by newspaper advertisement, were free of psychiatric illness, and had no prior contact with our laboratory. All subjects were in good physical health and had no history of pulmonary disease. Patients had been free of psychoactive medications for a minimum of 2 weeks prior to participation in this study. All patients reported at least weekly panic attacks (by DSM-III-R criteria) for the preceding 4 weeks.
Hyperventilation-lnduced Panic Attacks
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Procedure Subjects came to the lab at 8 AM after an overnight fast. The Mobility Inventory avoidance alone (MAL) and avoidance accompanied scales (MAC) (Chambless et al 1985), the Anxiety Sensitivity Index (ASI) (Reiss et al 1986), and a scale assessing recent somatic symptoms of panic (SSP) were administered. On the SSP subjects rated how much they had bec.~ distressed by each of the 11 somatic symptoms of panic (DSM-IH-R criteria) in the past week on a 0 - 4 scale (not at all, a little, moderately, markedly, and extremely). A heparin~zed catheter was then placed in a forearm vein and after 30 min of rest, baseline measurements were made. They then ingested glucose (1 g/kg body weight) in water as a part of a study of lactate metabolism and hyperventilation in panic disorder, ~ported elsewhere (Maddock and Carter 1989). After patients rested a further 20 min, prehyperventila, io~ measurements were made. Subjects were then asked to "'breaLhe deeply and rapidly" safficient to maintain an end-tidal P¢o2 of 20 mmHg for 8 min. A visual ~ a l o g monitor gave subjects feedback as to their end-tidal Pco2 during hyperventilation and the subjects were instructed to maintain this level at or below 20 mmHg. After 8 ~ n of hyperventilation, subjects were instructed to "breathe normally." Subjects were monitored during a 15-rain recovery period following the end of the hyperventilation coMition. End-tidal Pco2 was monitored continuously from a loose-fitting face mask by a Godard infrared capnograph. Analog output from the capnograph was channeled to a Grass polygraph to provide a record of end-tidal Pco2 and respiratory rate (RR) throughout the experiment. Respiratory rate and Pco2 were scored from the polygraph record at base ;line, and every 2 min during hyperventilation and the 15-rain posthyperventilation recovery period. Anxiety symptoms were assessed by an 1 l-[~oint (0-10) visual analog scfle for overall anxiety rating (AR) and by the Acute Panic Inventory (API) (Dillon et al 1987). API and AR were administered at baseline, immediately prior to hyperventilauon, ~ mediately after nyperventilation, and 15 min posthyperventilation. AR was also a d r ~ istered every 2 min during hyperventilation. Blood samples were obtained at three time points during the procedure, as part of the metabolic study (Maddock and Carter 1989).
Subject Instructions Prior to the procedure• subjects gave informed consent. The consent form for both patients and controls acknowledged the risk that subjects might experience physical discomfort uL~ including dizziness• tingling sensations, disorientation, ury-' . . . .m. U. U t H'- • or anxiety uuL""---m~.k~ vrocedure. The term panic attack was not used. If patients specifically asked whether or not they might panic, this possibility was acknowledged. This occurred only occasionaiiy. The rationale given to the patients was "'this is a study of sugar metabolism in patients with anxiety." Once the apparatus was in place• subjects were given the following instructions. "The experiment begins now with a baseline period. During this period you should just sit quietly and relax. From now until the end of the experiment we will remain behind the room divider most of the time. If you need anytF~ng, just ask for us. Periodically, we will approach you to give you instructions or rating scales, or to draw your blood. We will not carry on other convocations with you. Again, if you need anything, just ask, but please postpone casual questions until the ead of the experiment." The same psychiatrist (CSC) conducted the procedure on each occasion. He related to the patients in an attentive, courteous but formal manner in a further attempt to stabilize the interpersonal demand characteristics of the procedure. Although the consent fo.~n acknowl-
846
BIOL PSYCHIATRY 1991;29:t~3-854
R.J. Maddock and C.S. Carter
edged that subjects could discontinue the procedure at any time, we did not draw further attention to that option.
Assessment of Panic Our criteria for a panic attack were an increase in intensity of at least four panic symptoms on the API, accompanied by either an increase of at least 2 points on the AR to a value of 5 or greater or any AR score of 7 or greater, plus the a~ending psychiatrist's assessment that a panic attack occurred. This assessment was based upon a subject's report of a sudden increase in anxiety (similar to usual panic in the patient group) accompanied by physical symptoms, and a sense of dread with an urge to stop the procedure or leave the lab in search of a safer place. Data Analysis The following planned comparisons were made. The numbers of subjects experiencing panic attacks during hyperventilation in the patient versus the control group were compared using the Fisher exact probability test. Group differences in API, ,,~u2,MAL, MAC, ASI, and SSP scores at baseline and change scores for AR and API (maximum score following hyperventilation minus baseline score) were assessed with the Mann-Whitney test. Group comparisons of RR and Pco2 at baseline and during hyperventilation were made by t-tests. Respiratory data during the posthyperventilation recovery period were analyzed by two~way repeated measures analysis of variance (ANOVA) with three groups: patients who panicked, patients who did not panic, and controls. Post hoc comparisons were made with the Tukey test (ct = 0.05). End-tidal Pco2 during the recovery period was quantified as "percent recovery." This was defined as (RC,) - Pco2 (HV) Pco2 (BL) - PCO2 ( a v )
PCO 2
where Pco2 (RC~) is Pco2 daring recovery at time i, Pco2 (HV) is mean Pco2 during hyperventilation, and Pco2 (BL) is baseline Pco2. This calculation yields the percent of return toward baseline PCO2relative to the degree of hypocapnia that developed during hyperventilation. The time at which 50% recovery of Pco2 occurred was determined for each subject and analyzed using a two-way factorial ANOVA for the three groups. Respiratory rate dtwing recovery was Quantified as "change in RR." This was calculated as the recovery value minus the baseline value. All p values are two-tailed. Results All controls and 11 of the 12 patients voluntarily completed all 8 min of the hyperventilation condition. One patient asked to discontinue the procedure after 6 min. However, this patient was unable to reduce her ventilation and continued to hyperventilate into the recovery period. Mean end-tidal Pco2 during the hyperventilation period ranged from 11.2 to ! 3.7 .,~mHg. Seven of 12 patients and 1 of 12 controls had a panic attack during hyperventilation by our criteria. This represents a significantly greater occurrence of panic attacks in the patient group (p < 0.05).
Hyperventilation-lnd~acedPanic Attacks
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Table !. AR and API Ratings Before, During, and After Hypep:entilation~
Minute during WV Bas~!ine Anxiety Rating Patients (n = 12) PAN (n = 7) N P (n = 5) Controls (n = 12) Acute Panic Inventory Patients (n = 12) PAN (n = 7) NP (n = 5) Controls (n = 12)
3.2 b'~ 4.4 ~ 1.4 0.6
2
4
6
5.8 7.1 4.3 3.1
6.0 7.4 4.0 2.8
6.4 7.9 4.4 3.2
Immediately post-HV
5.8s 7.4 / 3.4 1.3
15 rain post-HV
5.8 7.9 3.0 1.8
2.8 3.7 0.6
21.5 27.4 13.2 5.2
8.2 12.4 2.4 I.I
1.6
Maximum change from baseline
3.3~ 3.~ 2.8 3.2 15.Y 19.9" ON
3.7
°PAN = patients w~m panicked during HV; NP -- patients who 0~:-1not panic. q2omparisons made by Mann-Whitney test, two-tailed. cPatients > ccnlrol i, p < 0.001. q~atients versus controls, NS. •PAN > NP, p < 0.025. IPAN versus NP, NS. ~Patients > controls, p < 0.05.
Scores on AR and API ratings are shown in Talkie 1. Patients had significantly higher scores on boOl ratings than controls at baseline. The increase in API from baseline to hyperventilation was significantly greater in patients than controls (U = 9.5, n = 12,12, p < 0.001). Patients who panicked during hyperventilation had higher AR scores at baseline than patients who did not panic (U = 3, n = 7,5, p < 0.02). Scores on MAL, MAC, ASI, and SSP are shown in Table 2. As expected, patients had higher scores than controls on all scales. Pat;,ents who panicked during hyperventilation did not differ significantly from nonpanicking patients on these scales. However, there was a trend toward higher scores on the SSP in patients who panicked (U = 5.5, n = 7,5, p = 0.06). A subscale of the SSP mcludexl six symptoms commonly reported during hyperventilation (dyspnea, choking, dizzy or faint feelings, numbness or tingling, depersonalization or derealization, and tremor). Ratings on the subscale of somatic symptoms of hyperven-
T a b l e 2. C l i n i c a l R a t i n g s at B a s e l i n e in P a t i e n t s a n d C o n t r o l s a
Patients (a = 12) PAN (n = 7) NP (n = 5) Controls (n = 12)
MAL
.MAC
ASI
SSP
SSH
76.2 b'` 73.8 79.6 36.9
50.6 a 51.5 49.5 32.0
49.9" 46.0 54 6 31.0
14.2 c 18.1 8.8 1.0
7.Y 9.7 e 4.0 0.7
°MAL = Mobility Inventory, alone scale; MAC = Mobility Inventory, a:,,co~-npaniedscale; ASI = Anxiety Scus[:ivity Index; SSP = somatic symptoms of panic" SSH = somatic symptoms of hypervent;.lation; PAN = panicking patients; N'P = nonpanicking patients. ~omparisons made by Mann-Whitney test, two-tailed. CPatients > controls, p < 0.001. *Patients > controls, p < 0.02. ePAN > NIP, p = 0.04.
848
R.J. Maddock and C.S. Carter
BIOL PSYCHIATRY i 99 i ;29:843-854
Table 3. End-tidal Pco2 and Respiratory Rate Before and During Hyperventilation ° Minute during HV
Mean
2
4
5
during HV
37. i b'" 35.5 d 39.2 35.6
16.0 15.9 16.0 14.4
14.8 14.6 15.2 14.8
14.7 14.5 14.8 14.2
15.2c 15.tY~ 15.4 i4.4
14.2e 14.3~ 14.0 10.9
33.6 31.0 37.2 33.5
33.6 33.0 34.4 29.8
33.3 33.6 33.0 30.2
33.5c 32.5d 34.9 31.2
Baseline End-ddal Pco: mmHg P~.ticnts (n = 12) P/~N (n = 7) NP {n = 5) Controls (n = 12) Respiratory Rate Patients (n = 12) PAN (n = 7) NP (n = 5) Controls (n = 12)
°PAN = patients who panicked during HV; NP = patients who did not panic. bComparisons made by t-test, two-tailed. CPatients versus controls, NS. aPAN versus NP, NS. "Patients versus controls, p < 0.025.
tilation (SSH) are shown in Table 2. Patients w h o panicked reported significantly more of these symptoms in the preceding week than patients who did not panic ( U = 4.5, n = 7,5, p = 0.04). Respiratory data at baseline and during hyperventilation are shown in Table 3. There was no significant difference between patients and controls in P¢o2, either at baseline or during hyperventilation. Patients had significantly higher R R than controls at baseline, but no difference was observed during hyperventilation. Percent recovery of end-tidal Pco2 during the posthyperventilation recovery period is shown in Figure 1. Two-way A N O V A showed a significant main effect for group ( F = 7.44, df = 2, p < 0.004). Post hoc testing showed that this effect was due to significantly less recovery of Pco2 in the patients who panicked than in control subjects or nonpanicking patients. There was a trivial main effect for time ( F = 194.5, df = 6, p < 0.(.h~31) and no significant group-by-time interaction ( F = 1.46, d f = 12, NS).
i00 ~d 0
c~
80
~I
60
~
40
Figure 1. Percent recove~ of end-tidal Pco2 following hyperventilation. Means and standard errors are shown. Panicking patients (PAN) had significantly lower values than nonpanicking patients (NP) or controis (CON).
T a
PAN
L_
a,i
o
20
N
0
i
~
l
!
|
i
g
2
4
6
8
10
12
14
minutes
p o s t HV
Hyperventilation-lnduced Panic Attacks
BIOLPSY(HIA'URY
849
I ~ | ,~:847 -854
=m '21 10 c
.m l
T
n
PAN
~
NP
c0N
8
Figure 2. Change in respiratory rate from baseline d ~ n g ~ recovery period following h ~ r ventilation. Means and standard errors are shown. Panicking ~ tients (PAN) had significantly higher increases over baseh~ than nonpanic~g ~atients (NP} or controls (CON) (see text).
~p
6 E o
L
4 2 0
~=~
-2
0
e
|
|
s
2
4
6
8
minute~
e
I0
i
12
14
p o s t XV
Two-way ANOVA of time to 50% recovery of Pco2 revealed a significant group effect (F = 12.5, df = 2, p < 0.0003}. Post hoc testing showed that this effect was due to a longer time to 50% recovery in the patients who panicked [8.3 _+ 2.9 min (mean +_ SD)] than in nonpanicking patients (4 _+ 0.0 rain) or normal controls (4.7 _+ l .(3 ~ ) . There was almost complete separation between panicking and nonpanicking patients on this parameter. Only one panicking patient was within the range of the n o n p a n i c ~ g group. Change from baseline RR during the posthyperventilation recovery period is shown in Figure 2. Two-way ANOVA showed a significant main effect for group (F = 3.58, df = 2, p = 0.046) and a group-by-time interaction (F = 2.50, df = 12, p < 0.006). There was no significant effect for time (F = 1.30, df - 6, NS). Post hoc analysis of the group effect showed a greater increase over baseline l~R in the patients who panicked compared to the two other groups. Post ~c,,: analysis of the group-by-time interaction showed that patients who panicked exhibited significantly greater increases over baseline RR at minutes 2, 4, and 6 compared to controls, and at minute 6 compared to nonpanickmg patients.
Discussion Eight minutes of hyperventilation to an end-tidal PCO 2 of less than 20 mmHg led to a panic attack in 7 of 12 patients with panic disorder. Patients were significantly more likely to panic than were control subjects. The 58% incidence of a hyperventilationinduced panic attack in this sample of patients is similar to the 50% incidence reported in an earlier study from our laboratory (Maddock and Mateo-Bennudez 1990) and to the 40% to 80% incidence reported in other studies (Helt and Andrews 1989a; de Ruiter et al 1989a; Garssen et al 1983). It is also in the range of results from other panic-induction methods, including infusion of 5 mmoi,'i~./kg sodium lactate (60% to 80%) (Liebowitz et al 1984), inhalation of 5% CO2 (40% t~:~60%) (Gorman et al 1988; Woods et al 1988), ingestion of 480 mg caffeine (38%) (Uhde and Boulenger 1989), and ingestion of 20 mg yohimbine (54%) (Chamey et al 1987). Howe;er our results contrast with several studies finding a much lower incidence of panic attacks reduced by voluntary hyperventi!ation. Rapee (1986) reported that no panic attacks occurred d~.~ringvoluntary hyperventilation
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RJ. Maddock and C.S. Carter
in 20 subjects with panic disorder. However, this study differed from ours in its demand characteristics, the medication status of patients, and the duration of hyperventilation. According to Rapee "all attempts were made to dispel any fears" prior to hyperventilation and subjects were not excluded if they were taking benzodiazepines. In addition, subjects were required to hyperventilate for only 90 sec. The drug-free status of our patients, the longer duration of hyperventilation (8 min), and the more neutral demand characteristics of our protocol (including an intentional avoidance of reassuring subjects) would all be expected to increase the likelihood of panic induction. Nonetheless, in the Rapee (1986) study, th~ panic disorder patients experienced significantly more distressing somatic symptoms of anxiety than a comp-,aison group of patients with generalized anxiety disorder. Gorman et al (1988) reported that only 7 of 30 patients (23%) with panic disorder experienced a panic attack d ~ n g voluntary hyperventilation to an end-tidal Pcoz of approximately 25 mmHg f~r ,~ to 15 min. This milder hypocapnia and an unbalanced order design may have contribute,; to the lower incidence of hyperventilation-induced panic. In the study by Gorman et al (1988), the hyperventilation condition always occurred 15 rain after patients had been chal!enged with 5% CO, inhalation. In an earlier study from our laboratory, we challenged paaic patients with two consecutive hyperventilation conditions 35 rain apart. Fifty percent Cf the patients panicked following the first hyperventiiafion challenge and only 25% panicked following the second. Self-rated anxiety was significantly lower following the second hyperventilation challenge than the first (Maddock and Mateo-Bermadcz 1990). These findings suggest that when two anxiogenic challenges are given in rapid succession, the second one is less powerful. Such an order effect could explain the relatively lower incidence of hyperventilation-induced panic in tlie Gorman et al (1988) study. Griez et al (1988) reported on 11 panic patients and 8 controls subjected to 4 min of voluntary hyperventilation. They found a trend for patients to report a greater increase in somatic symptoms following hyperventilation than control subjects. However, they found only small increases in subjective anxiety-and no panic attacks in the patient group. A difference in subject sample may account for this discrepant result. Our subjects all had panic disorder with agoraphobia and were currently suffering from at least weekly four symptom panic attacks. It is likely that our patients were more clinically ill than those studied by Griez et al (1988), who are described only as "meeting DSM-HI criteria for panic disorder." Two recent studies found that patients with panic disorder plus agoraphobia are more sensitive to the panic-inducing effects of hyperventilation than are patients with panic disorder alone (Holt and Andrews 1989a; de Ruiter et al 1989a). Targum (1990) found that panic patients having weekly attacks were far more sensitive to anxiogenic challenge than were patients having one attack or less per month. In the current study and in our previous investigation (Maddock and Mateo-Bermudez 1990), all subjects received a glucose load prior to hyperventilation. It has been shown that carbohydrate ingestion leads to an increase in sympathetic nervous system activity in humans (Welle et al 1981; Seaton et al 1984). It is possible that this carbohydrateinduced increase in sympathetic tone could have acted synergistically with hypervefitilation to produce greater anxiety and more panic attacks in our subjects. However, no significant change in APl or AR ratings was seen in our subjects following glucose ingestion. It has also been shown that hyperventilation following a glucose load increases serum lactate in animals and humans more than hyperventilation in fasted subjects (Brautbar et al 1983; Maddock and Mateo-Bermudez 1990). However, this increase in lactate
Hyperventilation-lnduced P~,aticAttacks
esYc~v
851
is small (about 25% of the increase seen with a standard lactate infusion) and delayed (it peaks approximately 15 min following the end of hyperventilation in o,~ subjects). These factors make it unlikely that increased lactate contributed to the anxiogenic effect of hyperventilation. However, a role for sympathetic or metabolic factors in po~ntiaring the anxiogenic effects of hyl~rventilation in this protocol cannot ~ excluded. Further studies using similar conditions for hyperventilation but without glucose ingestion may clarify the role of this metabolic stimulus in hyperventilation-induced panic. Our patients experienced significantly greater increases in somatic symptoms of anxiety (API) but not global anxiety (AR) following hyperventilation as compared with controls. A similar dissociation between hypervenfilation-induced increases in somatic symptoms and global anxiety was noted by Griez et al (1988). Vulnerabiliry to somatic symptoms rather than global anxiety following hyperventilation may be a more distinctive feature of the patient group. However, relatively higher baseline scores on the AR (three patients rated 7 on a 0-10 scale) than the APl (range = 0-18 on a 0-51 scale) suggest that a "ceiling" effect may have limited the sensitivity of the AR but not the APl to further increases in anxiety. The return to normal Pco2 levels following hyperventilation was s i ~ c a m l y delayed iI~ the patients who panicked during hyperventilation. This was manifested by lower endtidal Pc02 throughout the I5-min recovery period and by a significant delay in reaching 50% recovery of baseline PCO2. This result is consistent with earlier studies of panic disorder (Gorman et al 1988; Hibbert and Pilsbury 1989) and "'hyperventilation syndrome," a condition that overlaps extensively with panic disorder and agoraphobia (Folgering Colla 1978; Hardonk and Beumer 1979; Garssen et al 1983). Delayed recovery of normocapnia following hyperventilation has been proposed as a diagnostic marker for the hyperventilation syndrome (Hardonk and Beumer 1979). In our study, as in the study of Gorman et al (1988), delayed recovery of normocapnia was evident only in the patients who had experienced a panic attack during hyperventilation, not in the nonp~cking patients. Thus, delayed recovery of normocapnia following hyperventilation may not be a diagnostic or "trait" marker in panic disorder, but, rather, a specific consequence of an acute panic attack. The initially elevated respiratory rate and the continued hypocapnia in the patients who panicked are both consistent with continued hyperventHation persisting into the recovery period. The mechanism of this excess ventilation under hypocapnlc conditions following hyperventilation is uncertain. Folgering and Durlinger (1983) studied the effect of alveolar PCO2 on posthyperventilation breathing. They found that hyperventilation persisted longest into the recovery period when Pco2 was the lowest. They attributed this effect to the excitatory influence of hypocapnia on the general function of neurons influencing the respiratory center. There is little evidence for central chemoreceptor influence on respiration below a Pco2 of 35-40 mmHg (Gardner et al 1986). Typically, ventilatory drive is decreased during h~ocapnia but is increased during periods of increased vigilance and arousal (Lambertsen 1980). This delayed recovery of normocapnia may result from persistent hyperventilation secondary to the increased, arousal associated with an acute panic attack. This effect might be further amplified by the nonspecific excitatory effects of hypocapnia. Our findings agree with other reports that hyperventilation is one of the physiological changes most consistently observed during laboratory-induced panic attacks (Gorman et al 1986, 1988; Papp et al 1989). Patients who panicked during hyperventilation were characterized by higher overall anxiety prior to hyperventilation and more frequent somatic symptoms of hyperventilation during the preceding week. The importance of baseline anxiety as an indicator of vu!.
852
BIOL PSYCH!~',TRY 1991,29:843-854
R.J. Maddock and C.S. Carter
nerabil~ty to laboratory-induced panic has been frequently reported (Ehlers et al 1986; Liebowitz et al 1984). The higher incidence of recent somatic symptoms of hyperventilation in patl.ents who panicked during hyperventilation is consistent with the findings of Gorman et al (1988). These observations suggest that a hyperventilation challenge test may identify a subgroup of patients for whom hyperventilation symptoms are frequently associated with panic. These patients might be most likely to benefit from therapeutic exposure to hyperventilation symptoms. In this regard, i~ is of interest that one of the patients who panicked during this experiment later described the event as "very therapeutic" and attributed her subsequent recovery largely to this experience. Patients who panicked during hyperventilation did not differ from nonpanicking patients in the tendency to interpret anxiety symptoms as harmful (ASI) or in ratings of avoidance behavior (MAL and MAC'. This contrasts with earlier t'eports of greater sensitivity to hyperventilation in patients with panic and agoraphobia compared to patients with panic disorder alone (Holt ~nd Andrews 1989a; de Ruiter et al 1989a). Methodological features of our study, such as greater degree and duration of hypocapnia, may have overshadowed an effect of severity of avoidance behavior on sensitivity to hyperventilation in our sample. A relative hypocapnia at rest in panic patients has been reported by some investigators (Gorman et al 1986; Papp et al 1989; Rapee 1986) but not seen by others (Holt and Andrews 1989b). Our patients did not differ from controls in resting Pco:,, but they did exhibit a significm~t!y higher respiratory rate. Such "baseline" differences are difficult to interpret because the intrinsic stress of the laboratory situation is unlikely to permit true basal measurements. In summary, this study demonstrates that hyperventilation to a Pco2 of less than 20 mmHg for 8 min is an effective means of provoking panic attacks in patients with panic disorder with agoraphobia. This technique may be useful in studying biological and psychological aspects of acute panic in a laboratory setting (Maddock and Carter 1989; Holt and Andrews 1989a). It may also prove useful as a means of therapeutic exposure to panic-associated cues in behavioral treatment of a subgroup of patients with panic disorder. Delayed recovery of normocapnia occurs following hyperventilation-induced panic. This may represent continued hyperventilation as a consequence of an acute panic attack. The authors thank Carol Buckinger, Dr. Holly llfeld, Carla Levin R.N.M.S., Gary Summers, and Mark Wahle for invaluable technical assistance and Jane Rachford for manuscript preparation.
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