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Subclinical impairment of lung airways in patients with panic disorder
Subclinical Impairment of Lung Airways in Patients with Panic Disorder Giampaolo Perna, Claudio Marconi, Marco Battaglia, Angelo Bertard, Andrea Panzacchi, and Laura Bellodi
Lung function was assessed in 17 panic patients and 20 heallhy controls. Panic patien~ had abnormal values for some dynamic lung volumes, namely Peak F~'piratory .;:lowRate (PEFR), Expiratory Flow at 75% of Vital Capacity (FEF75) and Maximum Mid-Expiratory Flow Rate (MMEF). Such functional abnormalities might imffcate subclinical obstruction of lung airways, possibly relevant to the mechanisms related to panic disorder (PD). Key Words: Panic, respiration, spirometry, hyperventilation, norepinephrine, a s ~
Introduction Data from clinical and biological studies suggest that respiration and its related mechanisms might be important in panic disorder (PD). The most important biological and psychological theories say that respiration is central in the etiopathogenesis of this disorder. Klein (1993) hypothesized that "deranged suffocation alarm monitor" is the basic abnormality_ in panic patients; Papp et al (1993) suggested that instabifity of autonomic nervous system, expressed by respiratory abnormalities and coupled with cognitive distress, plays a significant role, and Ley (1985, 1989) emphasized the central role of hyperventilation and its cognitive misinterpretation. Smothering sensations and choking are among the most striking symptoms experienced by panic patients during both spontaneous (Klein 1981) and induced panic attacks (Zandbergen et al 1991a, Perna et al 1994) and these sensa-
From the Anxiety Clinical and R ~ h Unit, Department of Neuropsychiatric Sciences, S. Raffae|e Hospital, (GP, MB, AB, LIB); and the i.T.B.A., Section of Physiology, National Research Council of Italy, (CM, AP) Milan, Italy. Address reprint requests to Prof. L. Bellodi, Department of Neuropsychiatric Sciences, S. Raffaele Hospital, 29 via Prinetfi 20127, Milan Italy. Received October 12,1993; revised January 31,1994.
© ! 994 Society of Biological Psychiatry
tions, together with ~ e t y , are often present during episodes of asthma, the clinical (Yellowlees et al 1988; Yellowlees and Kalucy 1990; Shavitt et al 1992) and metabofic characteristics (e.g., hyperventilation) (~bbert and Pilsbury 1988; McFadden and Lyons 1968)of which overlap with those of PD. In addition, recent studies suggest partial overlap between respiratory disease and PD: the prevalence of PD in subjects with Chronic Obstructive ~lmonary D~A~--A
19 l l l ~ t l ~ t ~
Ill tlt~t lattaJt VUttUUt~ ~a'tauataJF~t v t t u
1990) and the lifetime prevalence of r e s p ~ r y disorders in panic patients is higher than in patients with obsessivecompulsive or eating disorders (Zandbergen et al 1991b). Although several studies have focused on investigation of possible impairment of the central nervous system control mechanisms of ventilation (Gorman et al 1988; Papp et al 1993), only a few studies have investigated lung function, mainly during the preliminary evaluation of patients. Cart et al (1992) measured Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 sec (FEV 1) and Expiratory Flow at 50% of Vital Capacity (FEF50) in I0 PD patients and did not find any significant differences from consols. Pain et al (1988) measured Vital Capacity (VC) and lEVI and reported no differences between PD patients and controls, whereas Lousberg et al (1988) found FVC and FEV 1 signif0006-3223/94/$07.00
G.Pemaetal
I I 1 ~ I~YCHIATRY
icantly lower in PD patients and FEV 1 the same. The failure to find abnormalities of lung function of patients with PD is mainly related to the use of insensitive tests (FVC, FEV 1, VC), able to detect only gross abnormalities. In view of the possible relationship of panic to peripheral respiratory disturbance, we have assessed lung function in patients with PD without clinical evidence of lung disease, using more sensitive indices and looking for functional airways impairments.
Methods and Materials
Subjects Seventeen Caucasian patients (10 women and 7 men, aged 31.1 "4- 10.1 years) with PD with/without agoraphobia, but no other .Axis I disorders, volunteered for this stx~dy, and there were 20 healthy Caucasian controls (12 women and 8 men, aged 30.3 +- I0 years) without Axis I diagnoses. Patients were recruited consecutively over 6 months in the Anxiety Disorders Clinical and Research Unit of San Raffaele Hospital in Milan and diagnoses were made by psychiatrists using the Structured Clinical Interview for DSM Ill-R, Upjohn version (Spitzer and Williams 1986). The number of panic attacks during the preceding week was 2.5 +_ 1.9 and mean duration of illness was 6. I +_ 5.9 years (range 1-17). Fourteen patients (82%) were agoraphobics. Controls were recruited from the hospital staff and by advertisements placed around the University. Criteria for exclusion for patients and controls were past or current diagnoses of respiratory disorders (COPD, pneumonia, bronchitis, and allergy), significant concurrent medical problems, competitive sport activities, and personal history of smoking. All the subjects were in good physical condition and had never taken medication chronically, the participants gave their informed consent and had not taken any psychotropic drugs for at least 2 weeks, nor any medication at all for at least 3 days before testing.
Lung Function Assessment Respiratory functions were measured spirometrically, according to recommendation of the American Thoracic Society (1987, 1991), by an experienced exercise physiologist. Lung function was always evaluated at the same hour in the afternoon to avoid circadian effects. Immediately before the whole procedure, fitness was scored on a 3-point scale (1 = poor, 2 = medium, 3 = good), instructions for correct maneuvers were given, and patients were requested to fill-in a self-rating 10-point anxiety scale (ranging from 0 = none to 10 = extreme anxiety), describing their global subjective anxiety. Tests for restrictive and/or obstructive ventilatory abnormalities were used.
The presence of a restrictive ventilatory defect (altered lung or chest motility or anatomy) might be indicated by decreases in static lung volumes, such as the Vital Capacity (VC) (the maximal volume of air exhaled from the point of m a x i ~ inhalation), Expiratory Residual Volume (ERV) (the maximal volume of air exhaled after a regular expiration), Total ~ n g C ~ i t y (TIC) (the maximal volume of air in the lung after a maximal inhalation) and Inspiratory Capacity (IC) ( ~ maximal volume of air inhaled after a regular inhalation). On the other hand, a gross obstructive ventilatory defect might be indicated by an increase of Residual Volume (RV) (the volume of air in the lung after a maximal exhalation), which is another static lung volume, by an i n c ~ in the Motley Index (MI -- 100 RVglLC) (normal values ~ e e n 20 and 35), a reduction of Forced Vital Capacity (FVC) (the maximal volume of air exhaled forcefully with maximal effort) and Forced E~.piratory Volume in I sec (FEV 1) (the maximal volume of air forcefully exhaled within the first sec of the test), all of which are dynamic lung volumes, and by a reduction of the Tiffeneau Index (TI - 100 FEVI/FVC) (normal values between 70 and 85). An obstructive ventilatory defect in the middlesmall airways might be suggested by decreases in Forced Expiratory Flow at 75% vital capacity (FEF75), at50% vital capacity (FEF50) or at 25% vital capacity (FEF25), Maximal Mid-Expiratory Flow Rate (MMEF) (mean forced expiratory flow during the middle half of the FVC) and Peak Expiratory Flow Rate (PEFR), which are also dynamic lung volumes. Tests were done with a Sensor Medics computerized apparatus using the ~ C 4400tc Nitrogen Washout and the MMC 4400tc Advanced Spirometry software programs. Static lung volumes were assessed three times and the largest values reported. Dynamic lung volumes were read off at least three acceptable forced expiratory curves and results from the "best test" curve (American Thoracic Society !987) with the !~,~gestsum of FVC and !:~_V! ~portexi RV was assessed by the nitrogen washout method and two patients were not able to complete the procedure. All the other parameters described were assessed by spirometry. Because observed spirometric values show high between-individual variation with approximately 70% accounted for by differences in gender, age, weight, height (and race, had there been any), all the measures (except MI and TI) were expressed as percentages of the value predicted according to the subject's height, weight, age, gender and race.
Data Analyses Exploratory Analyses of Covariance (ANCOVA) were used to evaluate the influence of baseline anxiety and duration of illness on respiratory measurements. Two different
Impairmentof LungAirwaysin Patients withPD
~psY~T1tY
Multivariate Analyses of Variance (MANOVA) were perfonned, separately for predicted static and dynamic lung volumes: the first was applied to VC, ERV,'H,C and IC and the second to FVC, FEVI, FEF?5, FEF50, FEF25, MMEF ~ d PEFR. MANOVA was also appfied to evaluate observed spirometric values. The two-tailed Student's t-test was used for the MI, TI, RV, age, weight and height and the one-tailed Student's t-test for baseline anxiety.
pauents than in controls 0Figure I). MANOVA applied to "observed" values ~ the s i ~ i ~ ~ ~erences for FEF75 and PEFR ~ the significance for MMEF disappeaced (Observed values: F= 3.90; ~ = 1, 35;
p=0.056).
Discussion Our findings suggest that some dynam~ aspects of lung function may be ~ in PD ~ t s , whereas lung function seems to be ~ . The normality of VC, ERV, IC, TLC, RV, FVC, a ~ FEVI, co~arned ~ normal values of N'fl ~ TI, e x c l ~ overt respijatory abnormalities. The low values for I~.r_F25,which expresses the abnormalities in the smallest airways, in ~ controls and patients might be due to environmental f a c t ~ (e.g., air pollution) as this parameter can reflect the rmnimal alterations to be expected in persons living in large ~ area. The significantly lower predic~ values for PEFT, FEF75, and MMEF in panic pati~ts; ~ reflect altered expiratory flow in lung airways, suggesting the presence of ~ ~bclinical obstngfve abnormah'ties in ~ e n t s with PD. ~ though PEFR and FEF75 are ~ a l l y effort-dependent and might be influenced by the subject's degree of collaboralion, related to both specific cognitive aspects of PD ~ a specific psychological discomfort related to the test, MMEF is effort-independent and is considered to reflect airflow in the small airways (McFadden and Linden 1972).
Results There were no significant differences between patients and controls in age, weight (60.9 +_ 14.8 kg vs 63.7 +_ 10.5 kg), height (167 _+ 10.5 cm vs 169.5 +_ 7 cm), gender, or fitness. Table 1 shows static and dynamic lung volumes for PD patients and controls, both as observed and as percentages of predicted values. According to ANCOVA, neither the duration of illness nor baseline anxiety had any significant relationship to lung function values. Patients had higher baseline anxiety than controls (CTs: 3.3 - 2.9, Pts: 6.5 +2.3; t =-3.67; df= 1, 35:p -< 0.001). Static lung volumes (VC, ERV, IC, TLC) and the MI, TI, and RV were normal and did not differ between panic patients and controls. On the contrary, the dynamic lung volumes FEF75 (Predicted values: F = 9.18; df = 1, 35; p = 0.005), PEFR (Predicted values: F = 12.29; df = 1, 35; p = 0.001) and MMEF (Predicted values: F = 4.15; df= 1, 35; p = 0.05) were significantly lower (MANOVA) in panic
Table i. Staticand DynamicLungVolumesin PD patients and NormalControh PD patients
Normal controls Observed Dynamic volumes FVC FEV 1 FEF75 t-"~-50 FEF25 MMEI PEFR Static volumes VC TLC ERV IC RV o Motley index (n.y. 20-35) Tiffeneau index (n.y.70-85)
Predicted
4.3 ± 0.9 3.6 -+ 0.7 6.0 ± !.8 4.4 __ 1.2 i.9 ± 0.7 3.6 ± 0.9 6.9 +_ 2.0
97.7 104.7 86.2 83.7
4.7 ± 6.3 ± 1.5 ± 3.2 ± 1.6 ±
0.9 1.2 0.4 0.7 0.4
603
± 12.8 ± 14.5 ± 21.3 -" "~ n
Observed
± 0.9 +- 0.8 -- 1.9 + 1.7 ._.
95.2 +- 6.0 95.5 ± 13.5 64.2 -- 22.9 :.o~+ an7
65.9 ± 21.0 93.9 ± 19. I 93.0 ± 27.0
1.8 ± 0.9 2.9 ± 1.2 0.8 ± 1.8
60.2 ± 24.0 77.9 ± 28.2 65.1 ± 20.2
106.9 ± 13.9 103.0 ± 9.0 84.4 ± 21.8
4.2 ± 1.0 5.8 -+ 1.2 1.3 ± 0.5
113.6 ± 21.9
2.9 +- 0.6
102.7 ± 23.8
1.5 ± 0.5
100.3 ± 8.7 I01.9 ± 9.6 78.2 ± 23.4 112.3 ." 21.2 107.4 - 24.1
L~.
U
4.0 3.2 4.4 36
Predicted
.
5.3 ± 4.7
25.1 = 5.9
84.6 ± 9.7
79.5 ± 12.6
vJ.v,..
--
.,~..
Predicted: percentages of the predicted value. Observed: absolute values obtained expressed as Liters for static lung volumes, FVC and FEVI and Liters/sex. for FEF75, FEFS0, FEF25, MMEF, PEFIL "Calculated on 15 patients and 20 controls.
tlOL F~Y~ATI~Y 19Q4~36:60I~i05
% Predtoted
G. [~flul ~ M
Vmluu
140 120 100 80 60 40 20 .
,
.
....
0 FVC
FEV1 FEF75 FEFS0 FEF25 MMEF
PEFR
Dynamic Lung Volumes /
Controla ~ PD Patients
Figure 1. Dynamiclung volumesin PD patients and normal~ s .
The absence of any significant influence of baseline anxiety, which might influence the subject's collaboration and automatic nervous system arousal; suggests that anxiety per se doe,s not interfere significantly with respiratory performance. The duration of illness, which might be ~ expression of the chronicity of the disorder, does not affect the results and therefore cannot be invoked as an important factor in the explanation of our findings. Although the subjects had no important medical problems, and especially respiratory diseases, we cannot exclude that there might have been subclinical medical conditions playing a role. The abnormalities found in expiratory flow parameters could be either an etiologic factor or an effect of PD, or both. Airways smooth-muscle tone is the most important factor in control of the caliber of lung airways, and we could speculate that the presence of airway obstruction might be related to abnormalities in the mechanisms controlling bronchial tone. The tone of the smooth muscles in the small airways is finely regulated by the autonomic nervous system (there are cholinergic, adrenergic and noncholinergic nonadrenergic influences) (Barnes 1986) and the subclinical obstruction of small airways found in panic patients might well be due to an imbalance of such regulatory mechanisms, as a recent study by Papp et al (1993) has suggested that an unstable autonomic nervous sytem is the basic abnormality in PD and several studies have demonstrated significant disregulation of adrenergic activity in PD (Villacres et a11987; Charney et
al 1990), and especially reduced function of peripheral beta-adrenoreceptors (Hess et al 1984; Maddock et al 1993). We found u,,~ u,,.,.,~hocon~ . . . . . e..~__&~d by the dvnamic impairment of lung function might also be a consequence of airway cooling provoked by hyperventilation in predisposed subjects (Deal et al 1979; Lewis et al 1984), as well as it might represent a factor able to induce and sustain hyperventilation per se, which has been suggested to be significant in panic (Hibbert and Pillsbury 1984; Ley 1985; Liebowitz et al 1985; Cowley and Roy-Byme i987; Bass et al 1989). In agreement with the observations of Papp et (i993) and Maddock et ai (1993), the abnormalities we found might also be parts of an adaptive psychobiological process developed in response to abnormal mechanisms in the central nervous system, possibly related to respiration and noradrenergic function. From a cognitive point of view, the presence of subclinical dynamic impairment of lung function might enhance "interoceptive sensations" (Ehlers et al 1988) related tO respiration. These sensations might trigger catastrophic misinterpretation (Clark 1986), linked to the development of panic attacks as a result of cognitive mechanisms. The data were obtained with 14 different tests given to a small group of subjects. Therefore, these results need to be confirmed by studies of larger groups and their specificity to PD compared with changes in other anxiety disorders. If the importance of our data is confirmed in larger case studies,
~
t
of Lung Airways in Patients with PD
~
the nature of the subclinical obstruction might be clarified by evaluating bronchial responsiveness to bronchodilators in panic patients and controls undergoing spirometry and by reassessing patients after successful anfipanic treatment, both pharmacological and cognitive.
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References American Thoracic Society (1987): Standardization of spimmetry --1987 update.Am Rev Respir Dis 136:1285-1298. American Thoracic Society (1991): Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 144:1202-1218. Barnes PJ (1986): Neural control of human airways in health and ~sease. Am Rev Respir Dis 134:1289-13!4.
Bass C, Lelliot P, Marks I (1989): Fear talk versus voluntary hyperventilation in agoraphobics and normals. Psychol Med 19:669-676. Carr RE, Lehrer PM, Hochron SM (1992): Panic symptoms in asthma and panic disorder:, a preliminmy test of the dyspneafear theory. Beha¢ Res ?her 30:251-261. Charney DS, Woods SW, Price LH, Goodman WK, Glazer WM, Heninger GR (1990): Noradrenergic dysregulation in panic disorder. In Ballanger JC (ed), Neurobiology of Panic Disorder. New York: Alan R. Liss, pp 91-105. Clark DM (1986): A cognitive approach to panic. Behav Res ?'her 24:461-470. Cowley DS, Roy-Byrne PP (1987): Hyperventilation and panic disorder. Am J Med 83:929-937. Deal FC, McFadden ER, Ingrain RH, Strauss RH, Jaegger JJ (1979): Roie of respiratory heat exchange in production of exercise induced asthma. J Appl Physio146:467-475. Elders A, Margraf J, Roth WT (1988): Selective information processing, interception, and panic attacks. In Hand I, Wittchen HU (eds), Panic and Phobias 2. Berlin: Springer-Verlag, pp 129-148. Hibbert G, Pilsbury D (1984): Hyperventilation as a cause of panic attacks. Br Med J 288:263-264. Hibbert G, Pilsbury D (1988): HyperventiL'lfion in panic attacks: emll~ll.,~nt t ~ x n i t n r l n o
~s.mu
L b
nf
tt~nwnt2n~nRc
~"~t~rt ~.
Hi,~Tido
Rr
I
Psychiatry 153:76--80. Kz~_jg.~B, Rifkin A, Doddi S, Kolli R (1990): The prevalence of anxie~ ~4~.~rdersin patients with chronic obstructive'~uLmonary dise.ase,t4m J Psychiatry 147:200-201. Klein DF (1~93): False suffocation alarms, Spontaneous Panics. and related conditions. An integrative hypothesis. Arch Gen Psychiatry 50:306-317. Lewis RA, Lewis MN, Tattersfield AE (1984): Asthma induced by suggestion: Is it due to airways cooling? Am Rev Resp Dis 129:691-695. Ley R (1985): Blood, breath and fears: A hyperventilation theory of panic attacks and agoraphobia. Clin Psychol Rev 5:271-285. Ley R (1989): Dyspneic-fear and catastrophic cognitions in hyperventilatory panic attacks. Behav Res Ther 27:549-554. Liebowitz MR, Gorman JM, Fyer AJ, et al (1985): Lactate provo-
cation of penk ~ If: bioctzmi~ ~ p h y o ~ a l findings.Arch Gen Psyckiarry 42:709-719. Lonsberg H, Griez E, van den Hem MA (198~): ~ dioxide c~tivity in ~ disorder. Acta Psychialr Scand 77:214-218. Maddock RJ, ~ CS, Magliozzi JR, ~ DW (1993): Evidence ~ decreased function of l ~ ~ y ~ e Be*_*.adrenmeceptors reflects regulatory and ~ v e ~ in panic d i ~ with agoraphobia. Am J Psychiatry 150:.12191225. McFadden ER, Lyons HA (1968): Arterial gas tension in asthma. N Engl J Med 278:1027-I032. McFadden ER, ~ DA (1972): A ~ in Maximum Mid-Expiratory Flow Rate. A spirogr',ohic manifestation of small airway disease.AmJMed52:725-737. Ness RM, Cameron OG, Curtis C~, McCann DS, Huber-Smith MI (1984): Adrenergic function in ~ t s with panic anxiety. Arch Gen Psychiatry 41:771-776. Pain MCF, Bidd~,eN, Tiller JWG (1988): ~ disorder, the ventilatory response to carbon dioxide and respiratory variables. Psychosom Med 50:541-548. Papp LA, Klein DF, ~ JM (1993): ~ dioxide hypersensitivity, hyperven~afion, ~ panic disorder. Am JPsychiatry 150:1149-I 157. Perna G, Battaglia M, Garberi A, ~ o C, Bertani A, Bellodi L (1994): CO2/O2 c ~ e n g e test in panic disorder. Psychiatry Res. 52:159-171. Shavitt RG, Gentil V, Mandetta R (1992): The association of panic/agoraphobia and asthma. Contributing factors and clinical impfications. Gen Hosp Psychiatry I4:420-423. Villacres EC, Hollified M, Katon WJ, ~Ikinson CW, Veith RC (1987): Sympathetic nervous sytem activity in panic disorder. Psychiatry Res 21:313-321. Yellowlees PM, Kalucy RS (1990): Psychobiological aspects of asthma and the consequent research impfications. Chest 97:628-634. Yellowlees PM, Haynes S, Ports N, Ruffin RE (I 988): P s y c ~ c morbidity in patients with life-threatening asthma: Initial report of a controlled study. Med JAust 149:246-249. Zandbergen J, Pols H, Fernandez I, Griez E (1991a): An analysis of panic symptoms during hypercarbia compared to hypocarbia in patients with panic attacks. J Affective Disord 23:131136. Zandbergen J, Bright M, Po~ H, Fernandez I, de Loof C, Griez E ( 1991b): Increased lifetime prevalence of respiratory disease in panic disorder? Am J Psych/awy 148:1583-1585.
Lung function was assessed in 17 panic patients and 20 heallhy controls. Panic patien~ had abnormal values for some dynamic lung volumes, namely Peak F~'piratory .;:lowRate (PEFR), Expiratory Flow at 75% of Vital Capacity (FEF75) and Maximum Mid-Expiratory Flow Rate (MMEF). Such functional abnormalities might imffcate subclinical obstruction of lung airways, possibly relevant to the mechanisms related to panic disorder (PD). Key Words: Panic, respiration, spirometry, hyperventilation, norepinephrine, a s ~
Introduction Data from clinical and biological studies suggest that respiration and its related mechanisms might be important in panic disorder (PD). The most important biological and psychological theories say that respiration is central in the etiopathogenesis of this disorder. Klein (1993) hypothesized that "deranged suffocation alarm monitor" is the basic abnormality_ in panic patients; Papp et al (1993) suggested that instabifity of autonomic nervous system, expressed by respiratory abnormalities and coupled with cognitive distress, plays a significant role, and Ley (1985, 1989) emphasized the central role of hyperventilation and its cognitive misinterpretation. Smothering sensations and choking are among the most striking symptoms experienced by panic patients during both spontaneous (Klein 1981) and induced panic attacks (Zandbergen et al 1991a, Perna et al 1994) and these sensa-
From the Anxiety Clinical and R ~ h Unit, Department of Neuropsychiatric Sciences, S. Raffae|e Hospital, (GP, MB, AB, LIB); and the i.T.B.A., Section of Physiology, National Research Council of Italy, (CM, AP) Milan, Italy. Address reprint requests to Prof. L. Bellodi, Department of Neuropsychiatric Sciences, S. Raffaele Hospital, 29 via Prinetfi 20127, Milan Italy. Received October 12,1993; revised January 31,1994.
© ! 994 Society of Biological Psychiatry
tions, together with ~ e t y , are often present during episodes of asthma, the clinical (Yellowlees et al 1988; Yellowlees and Kalucy 1990; Shavitt et al 1992) and metabofic characteristics (e.g., hyperventilation) (~bbert and Pilsbury 1988; McFadden and Lyons 1968)of which overlap with those of PD. In addition, recent studies suggest partial overlap between respiratory disease and PD: the prevalence of PD in subjects with Chronic Obstructive ~lmonary D~A~--A
19 l l l ~ t l ~ t ~
Ill tlt~t lattaJt VUttUUt~ ~a'tauataJF~t v t t u
1990) and the lifetime prevalence of r e s p ~ r y disorders in panic patients is higher than in patients with obsessivecompulsive or eating disorders (Zandbergen et al 1991b). Although several studies have focused on investigation of possible impairment of the central nervous system control mechanisms of ventilation (Gorman et al 1988; Papp et al 1993), only a few studies have investigated lung function, mainly during the preliminary evaluation of patients. Cart et al (1992) measured Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 sec (FEV 1) and Expiratory Flow at 50% of Vital Capacity (FEF50) in I0 PD patients and did not find any significant differences from consols. Pain et al (1988) measured Vital Capacity (VC) and lEVI and reported no differences between PD patients and controls, whereas Lousberg et al (1988) found FVC and FEV 1 signif0006-3223/94/$07.00
G.Pemaetal
I I 1 ~ I~YCHIATRY
icantly lower in PD patients and FEV 1 the same. The failure to find abnormalities of lung function of patients with PD is mainly related to the use of insensitive tests (FVC, FEV 1, VC), able to detect only gross abnormalities. In view of the possible relationship of panic to peripheral respiratory disturbance, we have assessed lung function in patients with PD without clinical evidence of lung disease, using more sensitive indices and looking for functional airways impairments.
Methods and Materials
Subjects Seventeen Caucasian patients (10 women and 7 men, aged 31.1 "4- 10.1 years) with PD with/without agoraphobia, but no other .Axis I disorders, volunteered for this stx~dy, and there were 20 healthy Caucasian controls (12 women and 8 men, aged 30.3 +- I0 years) without Axis I diagnoses. Patients were recruited consecutively over 6 months in the Anxiety Disorders Clinical and Research Unit of San Raffaele Hospital in Milan and diagnoses were made by psychiatrists using the Structured Clinical Interview for DSM Ill-R, Upjohn version (Spitzer and Williams 1986). The number of panic attacks during the preceding week was 2.5 +_ 1.9 and mean duration of illness was 6. I +_ 5.9 years (range 1-17). Fourteen patients (82%) were agoraphobics. Controls were recruited from the hospital staff and by advertisements placed around the University. Criteria for exclusion for patients and controls were past or current diagnoses of respiratory disorders (COPD, pneumonia, bronchitis, and allergy), significant concurrent medical problems, competitive sport activities, and personal history of smoking. All the subjects were in good physical condition and had never taken medication chronically, the participants gave their informed consent and had not taken any psychotropic drugs for at least 2 weeks, nor any medication at all for at least 3 days before testing.
Lung Function Assessment Respiratory functions were measured spirometrically, according to recommendation of the American Thoracic Society (1987, 1991), by an experienced exercise physiologist. Lung function was always evaluated at the same hour in the afternoon to avoid circadian effects. Immediately before the whole procedure, fitness was scored on a 3-point scale (1 = poor, 2 = medium, 3 = good), instructions for correct maneuvers were given, and patients were requested to fill-in a self-rating 10-point anxiety scale (ranging from 0 = none to 10 = extreme anxiety), describing their global subjective anxiety. Tests for restrictive and/or obstructive ventilatory abnormalities were used.
The presence of a restrictive ventilatory defect (altered lung or chest motility or anatomy) might be indicated by decreases in static lung volumes, such as the Vital Capacity (VC) (the maximal volume of air exhaled from the point of m a x i ~ inhalation), Expiratory Residual Volume (ERV) (the maximal volume of air exhaled after a regular expiration), Total ~ n g C ~ i t y (TIC) (the maximal volume of air in the lung after a maximal inhalation) and Inspiratory Capacity (IC) ( ~ maximal volume of air inhaled after a regular inhalation). On the other hand, a gross obstructive ventilatory defect might be indicated by an increase of Residual Volume (RV) (the volume of air in the lung after a maximal exhalation), which is another static lung volume, by an i n c ~ in the Motley Index (MI -- 100 RVglLC) (normal values ~ e e n 20 and 35), a reduction of Forced Vital Capacity (FVC) (the maximal volume of air exhaled forcefully with maximal effort) and Forced E~.piratory Volume in I sec (FEV 1) (the maximal volume of air forcefully exhaled within the first sec of the test), all of which are dynamic lung volumes, and by a reduction of the Tiffeneau Index (TI - 100 FEVI/FVC) (normal values between 70 and 85). An obstructive ventilatory defect in the middlesmall airways might be suggested by decreases in Forced Expiratory Flow at 75% vital capacity (FEF75), at50% vital capacity (FEF50) or at 25% vital capacity (FEF25), Maximal Mid-Expiratory Flow Rate (MMEF) (mean forced expiratory flow during the middle half of the FVC) and Peak Expiratory Flow Rate (PEFR), which are also dynamic lung volumes. Tests were done with a Sensor Medics computerized apparatus using the ~ C 4400tc Nitrogen Washout and the MMC 4400tc Advanced Spirometry software programs. Static lung volumes were assessed three times and the largest values reported. Dynamic lung volumes were read off at least three acceptable forced expiratory curves and results from the "best test" curve (American Thoracic Society !987) with the !~,~gestsum of FVC and !:~_V! ~portexi RV was assessed by the nitrogen washout method and two patients were not able to complete the procedure. All the other parameters described were assessed by spirometry. Because observed spirometric values show high between-individual variation with approximately 70% accounted for by differences in gender, age, weight, height (and race, had there been any), all the measures (except MI and TI) were expressed as percentages of the value predicted according to the subject's height, weight, age, gender and race.
Data Analyses Exploratory Analyses of Covariance (ANCOVA) were used to evaluate the influence of baseline anxiety and duration of illness on respiratory measurements. Two different
Impairmentof LungAirwaysin Patients withPD
~psY~T1tY
Multivariate Analyses of Variance (MANOVA) were perfonned, separately for predicted static and dynamic lung volumes: the first was applied to VC, ERV,'H,C and IC and the second to FVC, FEVI, FEF?5, FEF50, FEF25, MMEF ~ d PEFR. MANOVA was also appfied to evaluate observed spirometric values. The two-tailed Student's t-test was used for the MI, TI, RV, age, weight and height and the one-tailed Student's t-test for baseline anxiety.
pauents than in controls 0Figure I). MANOVA applied to "observed" values ~ the s i ~ i ~ ~ ~erences for FEF75 and PEFR ~ the significance for MMEF disappeaced (Observed values: F= 3.90; ~ = 1, 35;
p=0.056).
Discussion Our findings suggest that some dynam~ aspects of lung function may be ~ in PD ~ t s , whereas lung function seems to be ~ . The normality of VC, ERV, IC, TLC, RV, FVC, a ~ FEVI, co~arned ~ normal values of N'fl ~ TI, e x c l ~ overt respijatory abnormalities. The low values for I~.r_F25,which expresses the abnormalities in the smallest airways, in ~ controls and patients might be due to environmental f a c t ~ (e.g., air pollution) as this parameter can reflect the rmnimal alterations to be expected in persons living in large ~ area. The significantly lower predic~ values for PEFT, FEF75, and MMEF in panic pati~ts; ~ reflect altered expiratory flow in lung airways, suggesting the presence of ~ ~bclinical obstngfve abnormah'ties in ~ e n t s with PD. ~ though PEFR and FEF75 are ~ a l l y effort-dependent and might be influenced by the subject's degree of collaboralion, related to both specific cognitive aspects of PD ~ a specific psychological discomfort related to the test, MMEF is effort-independent and is considered to reflect airflow in the small airways (McFadden and Linden 1972).
Results There were no significant differences between patients and controls in age, weight (60.9 +_ 14.8 kg vs 63.7 +_ 10.5 kg), height (167 _+ 10.5 cm vs 169.5 +_ 7 cm), gender, or fitness. Table 1 shows static and dynamic lung volumes for PD patients and controls, both as observed and as percentages of predicted values. According to ANCOVA, neither the duration of illness nor baseline anxiety had any significant relationship to lung function values. Patients had higher baseline anxiety than controls (CTs: 3.3 - 2.9, Pts: 6.5 +2.3; t =-3.67; df= 1, 35:p -< 0.001). Static lung volumes (VC, ERV, IC, TLC) and the MI, TI, and RV were normal and did not differ between panic patients and controls. On the contrary, the dynamic lung volumes FEF75 (Predicted values: F = 9.18; df = 1, 35; p = 0.005), PEFR (Predicted values: F = 12.29; df = 1, 35; p = 0.001) and MMEF (Predicted values: F = 4.15; df= 1, 35; p = 0.05) were significantly lower (MANOVA) in panic
Table i. Staticand DynamicLungVolumesin PD patients and NormalControh PD patients
Normal controls Observed Dynamic volumes FVC FEV 1 FEF75 t-"~-50 FEF25 MMEI PEFR Static volumes VC TLC ERV IC RV o Motley index (n.y. 20-35) Tiffeneau index (n.y.70-85)
Predicted
4.3 ± 0.9 3.6 -+ 0.7 6.0 ± !.8 4.4 __ 1.2 i.9 ± 0.7 3.6 ± 0.9 6.9 +_ 2.0
97.7 104.7 86.2 83.7
4.7 ± 6.3 ± 1.5 ± 3.2 ± 1.6 ±
0.9 1.2 0.4 0.7 0.4
603
± 12.8 ± 14.5 ± 21.3 -" "~ n
Observed
± 0.9 +- 0.8 -- 1.9 + 1.7 ._.
95.2 +- 6.0 95.5 ± 13.5 64.2 -- 22.9 :.o~+ an7
65.9 ± 21.0 93.9 ± 19. I 93.0 ± 27.0
1.8 ± 0.9 2.9 ± 1.2 0.8 ± 1.8
60.2 ± 24.0 77.9 ± 28.2 65.1 ± 20.2
106.9 ± 13.9 103.0 ± 9.0 84.4 ± 21.8
4.2 ± 1.0 5.8 -+ 1.2 1.3 ± 0.5
113.6 ± 21.9
2.9 +- 0.6
102.7 ± 23.8
1.5 ± 0.5
100.3 ± 8.7 I01.9 ± 9.6 78.2 ± 23.4 112.3 ." 21.2 107.4 - 24.1
L~.
U
4.0 3.2 4.4 36
Predicted
.
5.3 ± 4.7
25.1 = 5.9
84.6 ± 9.7
79.5 ± 12.6
vJ.v,..
--
.,~..
Predicted: percentages of the predicted value. Observed: absolute values obtained expressed as Liters for static lung volumes, FVC and FEVI and Liters/sex. for FEF75, FEFS0, FEF25, MMEF, PEFIL "Calculated on 15 patients and 20 controls.
tlOL F~Y~ATI~Y 19Q4~36:60I~i05
% Predtoted
G. [~flul ~ M
Vmluu
140 120 100 80 60 40 20 .
,
.
....
0 FVC
FEV1 FEF75 FEFS0 FEF25 MMEF
PEFR
Dynamic Lung Volumes /
Controla ~ PD Patients
Figure 1. Dynamiclung volumesin PD patients and normal~ s .
The absence of any significant influence of baseline anxiety, which might influence the subject's collaboration and automatic nervous system arousal; suggests that anxiety per se doe,s not interfere significantly with respiratory performance. The duration of illness, which might be ~ expression of the chronicity of the disorder, does not affect the results and therefore cannot be invoked as an important factor in the explanation of our findings. Although the subjects had no important medical problems, and especially respiratory diseases, we cannot exclude that there might have been subclinical medical conditions playing a role. The abnormalities found in expiratory flow parameters could be either an etiologic factor or an effect of PD, or both. Airways smooth-muscle tone is the most important factor in control of the caliber of lung airways, and we could speculate that the presence of airway obstruction might be related to abnormalities in the mechanisms controlling bronchial tone. The tone of the smooth muscles in the small airways is finely regulated by the autonomic nervous system (there are cholinergic, adrenergic and noncholinergic nonadrenergic influences) (Barnes 1986) and the subclinical obstruction of small airways found in panic patients might well be due to an imbalance of such regulatory mechanisms, as a recent study by Papp et al (1993) has suggested that an unstable autonomic nervous sytem is the basic abnormality in PD and several studies have demonstrated significant disregulation of adrenergic activity in PD (Villacres et a11987; Charney et
al 1990), and especially reduced function of peripheral beta-adrenoreceptors (Hess et al 1984; Maddock et al 1993). We found u,,~ u,,.,.,~hocon~ . . . . . e..~__&~d by the dvnamic impairment of lung function might also be a consequence of airway cooling provoked by hyperventilation in predisposed subjects (Deal et al 1979; Lewis et al 1984), as well as it might represent a factor able to induce and sustain hyperventilation per se, which has been suggested to be significant in panic (Hibbert and Pillsbury 1984; Ley 1985; Liebowitz et al 1985; Cowley and Roy-Byme i987; Bass et al 1989). In agreement with the observations of Papp et (i993) and Maddock et ai (1993), the abnormalities we found might also be parts of an adaptive psychobiological process developed in response to abnormal mechanisms in the central nervous system, possibly related to respiration and noradrenergic function. From a cognitive point of view, the presence of subclinical dynamic impairment of lung function might enhance "interoceptive sensations" (Ehlers et al 1988) related tO respiration. These sensations might trigger catastrophic misinterpretation (Clark 1986), linked to the development of panic attacks as a result of cognitive mechanisms. The data were obtained with 14 different tests given to a small group of subjects. Therefore, these results need to be confirmed by studies of larger groups and their specificity to PD compared with changes in other anxiety disorders. If the importance of our data is confirmed in larger case studies,
~
t
of Lung Airways in Patients with PD
~
the nature of the subclinical obstruction might be clarified by evaluating bronchial responsiveness to bronchodilators in panic patients and controls undergoing spirometry and by reassessing patients after successful anfipanic treatment, both pharmacological and cognitive.
Raffa~ ~
Mitaa fer her ~
~
PSYCtUAT~Y
i
a
p ~ y ~ r y and N e = ~ ~ . Umvenity of ~ . reviewingthe manus~'ril~amiC Araaciofor ~ ~
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