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Smoller JW, Pollack MH, Otto MW, Rosenbaum JF, Kradin RL. Panic anxiety,

dyspnea, and respiratory disease: theoretical and clinical considerations

Article  in  American Journal of Respiratory and Critical Care Medicine · August 1996

DOI: 10.1164/ajrccm.154.1.8680700 · Source: PubMed

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State of the Art

Panic Anxiety, Dyspnea, and Respiratory DiseaseTheoretical and Clinical Considerations

JORDAN W. SMOLLER, MARK H. POLLACK, MICHAEL W. OTTO, JERROLD F. ROSENBAUM,and RICHARD l. KRADIN

McLean Hospital, Belmont, Massachusetts, and the Departments of Psychiatry and Pulmonary and Critical Care Units,Massachusetts General Hospital, Boston, Massachusetts

When intense, acute anxiety is associated with certain physicalsymptoms (e.g., dyspnea, palpitations, chest pain) and cognitivefears (e.g., of dying or going crazy), the experience is describedas a panic attack (Table 1). As defined in the fourth edition ofthe Diagnostic and StatisticalManualofMentalDisorders(DSM­IV) (1), the central feature of panic disorder is the recurrenceof unexpected panic attacks accompanied by persistent fears orworries about the attacks or their consequences. In large com­munity samples, estimates of lifetime prevalence have ranged fromabout 10-15% for panic attacks and 2-4010 for panic disorder(PD) (2-4). Along with panic attacks, sufferers may developagoraphobia and avoidance of situations that might evoke panicattacks. The psychosocial morbidity and costs to society as­sociated with PD are substantial and include substance abuse,depression, suicide attempts, marital dysfunction, unemploy­ment, financial dependency, and increased health services utili­zation (5, 6).

Because the physical symptoms of panic attacks overlap withthose of many medical illnesses, patients with PD frequently pres­ent to primary care and specialty physicians as well as to emer­gency rooms, complaining of cardiopulmonary, neurologic, andgastrointestinal symptoms (7, 8). The cost of excess health careutilization of these patients may be substantial. For example,a third or more of patients undergoing cardiac catheterizationhave no significant coronary stenosis, and of these, a third ormore meet criteria for PD, which may account for their chestpain (9).

Dyspnea, a cardinal symptom of respiratory illness, is alsoa core feature of panic attacks. Indeed, some reports suggest thepresence of dyspnea may discriminate panic from other formsof anxiety (10, 11). Conversely, panic anxiety is often a compo­nent of the dyspnea experienced by patients with respiratory ill­ness. This symptom overlap has raised the question of whetherrespiratory physiology contributes to the pathophysiology ofpanic. In addition, it highlights the need to consider both panicand pulmonary disorders in the differential diagnosis and treat­ment of patients presenting with dyspnea. The following reviewexamines the relationship between respiratory physiology andpanic anxiety and explores the difficulties in the diagnosis andmanagement of panic anxiety in patients with pulmonary disease.

(Received in original form August 8, 1995 and in revised form January 3, 1996)

Correspondence and requests for reprints should be addressed to Jordan W.Smoller, Anxiety Disorders Program, Massachusetts General Hospital, ACC-815,15 Parkman St., Boston, MA 02114.

Am J Respir Crit Care Med Vol 154. pp 6-17, 1996

DYSPNEA, HYPERVENTILATION, AND PANIC:THREE MODELS

Dyspnea, often accompanied by hyperventilation, is a commoncomplaint among individuals suffering from panic disorder. Theinterrelationship of dyspnea, hyperventilation, and panic has beeninterpreted within the context of three conceptual models: (1) thehyperventilation model; (2) the carbon dioxide hypersensitivity/suffocation false alarm model; and (3) the cognitive-behavioralmodel (12-17). Each model emphasizes different aspects of therelationship between respiration and anxiety (Figure).

Hyperventilation Model

Since its initial description in 1937 by Kerr and colleagues(18), the term "hyperventilation syndrome" has been appliedto the clinical presentation of anxiety associated with hyper­ventilation. Symptoms associated with the hyperventilationsyndrome (HVS) include dyspnea, palpitations, chest pain,trembling, and paresthesias (19,20). At least 5-10% of generalmedical outpatients have been reported to suffer from thissyndrome (12, 19). A diagnosis of HVS is made more fre­quently by internists than psychiatrists, who typically describesuch patients as having a panic attack. Whether HVS andPD are distinct entities remains uncertain (20-22). The de­velopment of symptomatic hyperventilation has been ascribedto faulty ventilatory patterns, including rapid, shallow breath­ing (12, 14). Patients with PD, like those with obstructive lungdisease, are prone to accentuated thoracic rather than di­aphragmatic excursions, which may predispose to hyperven­tilation (23).

The hypocapnic alkalosis that results from acute hyperventi­lation may account for certain symptoms reported by patientsduring anxiety attacks (11). For example, hypocapnia-relatedcerebral vasoconstriction can lead to feelings of lightheadedness,dizziness, derealization, and a sense of impending doom. Alkale­mia and coronary vasoconstriction may contribute to chest dis­comfort and palpitations, and hypophosphatemia can provokeparesthesias and dizziness. The Bohr effect exacerbates the isch­emic effects of cerebral and coronary vasoconstriction (12, 24,25). Moreover, the increased work of breathing during hyper­ventilation promotes dyspnea, and hyperventilation may producetachycardia by decreasing parasympathetic tone (26).

Patients with PD appear to be particularly susceptible to theeffects of hyperventilation. For example, in one study (27), sevenof 12 (58%) patients with PD and only one of 12 (8%) controlsubjects had a panic attack after 8 min of hyperventilation suf­ficient to produce an end-tidal Pco, of less than 20 mm Hg. How­ever, in other studies, voluntary hyperventilation produced panicin less than 30% of patients with PD (28-31). Patients who panicshow exaggerated hypocapnia-induced reductions in cerebral

State of the Art 7

3. C02 Hypersensitivity/Suffocation False Alarm Model

Figure. Schematic representation of th ree models of the relationshipbetween dyspnea, hyperventilation (HV), and panic.

Triggering of • D - ---~ HVMedullary Chemoreceptor yspnea ------...--

~ Panic

Panic

Dyspnea

Panic

Autonomic Arousaland ....-------

Hyperventilation

HV~~

Perceived Threat

~Awareness of

~~~'r~:)ue, ----I.~ catast"'IC cognition,

2. Cognitive-Behavioral Model

1. Hyperventilation (HV) Model

potent than voluntary hyperventilation at inducing panic in pa­tients with Po. The sensitivity of patients with PD to CO2com­pared with normal or other psychiatric control subjects has sincebeen demonstrated repeatedly (29, 45-52). COrinduced panicis qualitatively comparable to spontaneous panic and can beprevented by treatment with antipanic medications (53-58). Themost prominent symptoms reported during lactate- or CO2­induced panic and spontaneous panic attacks are respiratory andinclude dyspnea, choking, and smothering sensations (51,59, 60).

Although the mechanisms by which lactate and CO2inducepanic remain unclear, some studies have found that patients whopanic show a distinct ventilatory response to these challenges.Lactate infusion produces hyperventilation in patients with PO,a finding that is counterintuitive because sodium lactate and itsmetabolite bicarbonate should produce a metabolic alkalosis andcompensatory hypoventilation (41). Moreover, several, thoughnot all (61-63), studies have shown that patients with PD developa greater increase in minute ventilation and inspiratory drive withCO2 exposure than do control subjects.

Papp, Klein, Gorman, and colleagues (15, 16, 64) have sug­gested that the ability of lactate and CO2to provoke panic andstimulate ventilation in patients with PD reflects a specific bio­logic vulnerability underlying panic disorder. They propose thatpatients with PD have an abnormally sensitive brainstem respi­ratory control mechanism. When this putative sensor, believedto be the medullary respiratory chemoreceptor area, detects signsof impending suffocation (such as increased Pe02 or lactate lev­els), hyperventilation and autonomic arousal are stimulated. An­imal studies suggest that central chemoreceptors detect hyper­capnia and produce increased firing by the locus coeruleus, whichis believed to be a controlling site for the autonomic storm ac­companying a panic attack (65). There are conflicting data asto whether lactate itself crosses the blood-brain barrier (66, 67),

TABLE 1

DSM-IV CRITERIA FOR A PANIC ATTACK

A discrete period of intense fear or discomfort, in which four (or more) of thefollowing symptoms developed abruptly and reached a peak within 10 min:

1. Palpitations, pounding heart, or accelerated heart rate2. Sweating3. Trembling or shaking4. Sensations of shortness of breath or smothering5. Feeling of choking6. Chest pain or discomfort7. Nausea or abdominal distress8. Feeling dizzy, unsteady, lightheaded, or faint9. Derealization (feelings of unreality) or depersonalization

(being detached from oneself)10. Fear of losing control or going crazy11. Fear of dying12. Paresthesias (numbness or tingling sensations)13. Chills or hot flushes

blood flow (CBF), which could account for their greater suscep­tibility to the effects of hyperventilation (32, 33).

Some reports have found that anxious individuals have evi­dence of chronic hyperventilation, including low serum bicar­bonate, low Pe02 with a relatively normal pH, and hypophos­phatemia (34, 35). Chronic hyperventilators can maintain achronic respiratory alkalosis with only a few additional breathsbeyond their resting respiratory rate (36) and may not appearto be actively hyperventilating. When stressed, they can increasetheir ventilation sufficiently to convert a chronic compensatedrespiratory alkalosis into a symptomatic acute hypocapnic alka­losis. However, some studies havenot detected evidenceof chronichyperventilation in patients with PD (27,37, 38) or a consistentrelationship between the degree of hypocapnia and the severityof symptoms experienced during a panic attack (37, 39). In ad­dition, voluntary hyperventilation may produce distress and phys­ical symptoms related to hypocapnia, but it does not necessarilyproduce the subjective experience of panic (30, 40). Also, it hasnot been established that hyperventilation precedes the onset ofspontaneous panic. Studies in which panic attacks were provokedby inhalation of CO2suggest that panic may precede the onsetof hyperventilation and hypocapnic alkalosis (41).

Nevertheless, some patients presenting with panic and dys­pnea do have symptoms attributable to the physiologic and psy­chologic effects of hyperventilation. This has led to two generaltreatment approaches: paper bag rebreathing (the common emer­gency room procedure in which patients rebreathe expired airto correct hypocapnic alkalosis) and breathing retraining tech­niques. The goal of the latter includes teaching patients slow,abdominal breathing patterns that can be practiced during stress­ful situations and that antagonize hyperventilation (42). Studieshave demonstrated that brief (e.g., 2 wk) courses of such "respi­ratory control" treatments produce sustained remission of panicin some patients (19, 42).

Carbon Dioxide Hypersensitivity/SuffocationFalse Alarm Model

In 1967 Pitts and McClure (43) reported that infusing 0.5 M so­dium lactate produced anxiety attacks in 93% of patients withan anxiety disorder but only 20% of control subjects. The abil­ity of lactate to elicit panic attacks specifically in patients withpanic disorder has since been well established. Overall, lactatechallenges produce panic attacks in approximately two thirds ofpatients with PD but only 10-13070 of normal control subjectsor patients with other psychiatric diagnoses (44). Gorman andcolleagues (28) found that inhalation of an air mixture contain­ing 5% CO2was comparable with lactate infusion and much more

8 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 154 1996

but lactate is peripherally metabolized to bicarbonate and thento CO2by the enzyme carbonic anhydrase. Carbon dioxide freelycrosses the blood-brain barrier, lowers the local pH in the medul­lary respiratory center, and drives ventilation.

According to Klein (15), patients with PD have an abnormallylow suffocation alarm threshold, and panic attacks are the re­sult of "suffocation false alarms." The threshold may be so lowthat the alarm is triggered by relatively trivial stimuli, resultingin apparently spontaneous panic attacks (16). In this model thechronic hyperventilation seen in some panic patients (34, 35) isviewed as an attempt to maintain the Pco, below levels that cantrigger a suffocation alarm.

The hypothesized suffocation alarm system is consistent withthe clinical features of congenital central hypoventilation syn­drome (CCHS or Ondine's curse) (15,64), a rare congenital syn­drome involving a primary failure of autonomic control of ven­tilation. These patients fail to increase ventilation adequately inresponse to hypercapnia (68) and do not experience dyspnea ora sensation of suffocation even when extremely hypercapnic. Ifpanic disorder is the result of an abnormally low suffocationalarm threshold, CCHS may be the result of an abnormally highsuffocation alarm threshold and may represent the physiologicconverse of panic disorder (15). If so, patients with CCHS wouldbe predicted to experience less panic than other groups, despitethe stress of their life-threatening illness. Consistent with this,children with CCHS were found to have fewer anxiety symptomsthan an age-matched community sample that included childrenwith asthma and other chronic medical illnesses (69).

However, some observations do not appear to be consistentwith a CO2 hypersensitivity or suffocation false alarm theory.For example, monkeys infused with sodium lactate showed nosubsequent increase in CSF levels of lactate and Pco., suggest­ing that lactate infusion does not produce panic by increasingcentral lactate or CO2 (66). McNally (70) has pointed out thatthe CO2hypersensitivity theory has grown out of challenge studiesusing concentrations of inspired CO2 (5-35010), which are up to875 times that found in normal air, raising questions of whetherthese studies are relevant to spontaneous panic. Moreover, if pa­tients with PD are so sensitive to CO 2 that presumably minorincreases in Pe02trigger panic attacks in daily life, it is surpris­ing that challenge studies using an F1e02of 5-35% induce panicin only about 60010 of patients with PD. Finally, the theory doesnot account for the clinical observation that anxiety attacks canbe aborted in some patients by paper bag rebreathing; if patientsare hypersensitive to CO2, this technique should exacerbate theirpanic. It has been suggested that paper bag rebreathing func­tions primarily as a distraction or placebo until a self-limitedpanic attack subsides (16), and there is evidence to support thisview (71).

Cognitive Behavioral Model

In the cognitive-behavioral model, it is the individual's fear ofand misinterpretation of the physical sensations associated withdyspnea, hyperventilation, or other symptoms that are thoughtto be crucial in producing panic attacks (13, 72, 73). Individualswho panic appear to be more fearful of anxiety-related physicalsensations (also called "interoceptive cues"), such as dyspnea,chest tightness, or tachycardia. These individuals may then "catas­trophize" about the significance of these sensations; that is, theyinterpret the sensations as being more dangerous than they actu­ally are. This leads to a positive feedback cycleof escalating anxi­ety and physical symptoms as increasing autonomic arousal andhyperventilation produce more bodily sensations about whichthey catastrophize further (Figure). The result is a crescendo in­crease in anxiety, culminating in a full-blown panic attack. Inthis model of dyspnea is one of a variety of interoceptive cuesthat can be misinterpreted and trigger the panic cycle.The model

might also explain why both hypocapnia (after hyperventilation)and hypercapnia (after CO 2 inhalation) can provoke panic be­cause both of these states can produce unpleasant bodily sensa­tions (37, 74). According to a cognitive-behavioral model of PD,it is the fear and catastrophic interpretation of these unexpectedsensations that provoke panic, rather than the stimulation of aspecific aberrant neural pathway or receptor. More specifically,the cognitive-behavioral model predicts that panic will developin individuals with high "anxiety sensitivity," i.e., fears of anxiety­related sensations, when they experience unexpected autonomicsymptoms (75). Consistent with this view, a number of studiessuggest that patients with PD and control subjects have similarphysiologic reactions to provocative agents but are differentiatedby the tendency to catastrophically interpret and respond withpanic to these sensations (17, 76, 77). The role of cognitive fac­tors in exacerbating panic has been substantiated by studies inwhich patients exposed to panicogens, such as sodium lactateor CO2, and given information that reduces their catastrophicthoughts show less tendency to panic (78, 79).

However, some aspects of panic have not been fully explainedby the cognitive model, including the phenomenon of panic at­tacks during sleep (when cognitive misinterpretation may not beoperative), and the finding that certain laboratory challenges,such as hypoglycemia, hypocalcemia, and the cold pressor test,which produce distressing physical sensations, do not reliablyprecipitate panic attacks (80-82). Nevertheless, cognitive-behav­ioral therapy, based on this model, is a first-line treatment forpanic disorder, and panic-free rates of 70-85010 have been reported(83).

Pulmonary Function in Patients with Panic Disorder

Patients with PD experience dyspnea comparable with that ex­perienced by patients with airway obstruction, despite the factthat the patients with PD generally demonstrate normal pulmo­nary function by standard measures (23). Patients with PD havebeen reported to have abnormal proprioception of respiratorystimuli such as inspiratory resistive loads, and unlike nonanx­ious control subjects their perception of dyspnea may be unrelatedto the work of breathing (84).

Studies comparing air flow rates and lung volumes in healthypatients with PD and normal control subjects have generally re­vealed no significant differences (23, 62, 85, 86). However, inone study of presumably healthy patients with PD those withthe lowest FEF50"1. experienced more severe panic symptoms, in­cluding more severe respiratory symptoms (87). Perna and col­leagues (86) compared patients with PD and normal control sub­jects and found no differences in FEVIt FVC, or static lungvolumes, but the FEF50"1., FEF 75"1., and peak expiratory flow ratewere lower in patients with PD. These studies indicate that somepanic patients have small airways dysfunction. If so, cognitivemisinterpretations of the sensation of dyspnea associated withthese changes could trigger their panic attacks (86). However,this hypothesis is not well established, and a recent study of pul­monary function in 38 patients with PD without known pulmo­nary disease failed to find a relationship between FEF50% orFEV l/FVC and the severity of panic symptoms (88).

PANIC AND ANXIETY IN PATIENTS WITHPULMONARY DISEASE

Whereas dyspnea is a characteristic feature of panic attacks, panicanxiety is also a frequent manifestation of pulmonary disease.Many pulmonary disorders, from asthma (89) to pulmonaryhypertension (90), may present with or be complicated by anxi­ety. The differential diagnosis of anxiety and breathlessness in­cludes the pulmonary disorders listed in Table 2.

There appears to be a higher than predicted comorbidity of

State of the Art

TABLE 2

RESPIRATORY CONDITIONS POTENTIALLY PRESENTING AS PANIC

Chronic obstructive pulmonary diseaseAsthmaPneumothoraxPulmonary hypertensionVocal cord or laryngeal dysfunctionPulmonary embolusSleep apneaPulmonary edemaPneumoniaMechanical ventilationHypoxia/hypercapnia of any cause

anxiety disorders, particularly PD, with pulmonary disease (91-95).In one study of psychiatric outpatients (92), the lifetime preva­lence of respiratory disorders was 47% in patients with PD com­pared with 13% in patients with obsessive-complusive disorderor an eating disorder. Conversely, the prevalence of PD amongpulmonary patients appears to be disproportionately high (96,97). Pollack and colleagues (98) found an elevated prevalenceof PD (11070) among all patients referred for pulmonary func­tion testing at a large urban medical center.

The association of anxiety with respiratory disease is not sur­prising given the sensation of dyspnea and impending suffoca­tion that many patients with pulmonary disease often experience.Pulmonary dysfunction with its associated symptoms could trig­ger catastrophic cognitions and panic in anxiety-prone individ­uals. Alternatively, pulmonary disease could unmask panic inpredisposed patients because of recurrent episodes of hypercar­bia and acidosis that trigger a sensitive "suffocation alarm" sys­tem. Panic and respiratory disease are also linked through medi­cations used to treat respiratory disorders that can be anxiogenic,including glucocorticoids, beta-adrenergic agonists, methylxan­thines, and anticholinergics. Thus, pulmonary disease may bea risk factor for the development of PD. In a retrospective case­control study of 150 consecutive anxiety patients (94), 42.7% ofthose with PD had a history of respiratory disease that predatedtheir anxiety disorder, compared with only 16.2% of patients withother anxiety disorders.

Chronic Obstructive Pulmonary Disease

Anxiety is associated with impaired quality of life in patientswith chronic obstructive pulmonary disease (COPD) (99, 100),and greater levels of anxiety have been associated with more in­tense dyspnea in these patients (101-105). Estimates of the prev­alence of anxiety and panic in patients with COPD have rangedfrom 2% to 96% (96, 97, 106, 107). Patients' "fear of dyspnea"may lead to avoidance of otherwise achievable physical activityand cause further deconditioning (106). Anxious patients withCOPD often fear emotional upset or situations that are emo­tionally charged because of their concern that emotional arousalwill trigger breathlessness (106, 108). As a result, they may se­verely restrict their activities and interpersonal relationships. Ina study of 50 consecutive patients with chronic obstructive air­way disease referred to a respiratory unit, 34% met DSM-IIIcriteria for an anxiety disorder and 24% met criteria for PD,which was the single most common psychiatric disorder in thissample (109). This prevalence of PD is roughly lO-fold greaterthan that seen in the general population. Neither pulmonary func­tion testing nor response to bronchodilators differentiate thosepatients with COPD who panic from those who do not (97, 98).However, those patients who panic have more catastrophic cog­nitions and fears about bodily sensations (97).

The degree of dyspnea experienced by patients with COPD

9

appears to be related more to their sensitivity to CO 2 than tothe degree of airway obstruction (110). Klein (15, 64) has hypothe­sized that "blue bloaters," who experience relatively little dys­pnea despite chronic hypercarbia, have a blunted suffocationalarm sensitivity. In contrast, "pink puffers" maintain relativelynormal CO 2 levels by increasing ventilation; they remain COrresponsive and experience marked dyspnea, suggesting a lowersuffocation alarm threshold. The implication that "blue bloaters"should have lower rates of PD has not yet been investigated.

Asthma

Asthma is frequently associated with anxiety and panic (111-115).Approximately 6-30% of patients with asthma have been re­ported to meet criteria for PD (89, 113, 116, 117), with a lowerprevalence in community than in clinical samples (118). The ex­istence of panic in these patients is often underrecognized. Forexample, Shavitt and coworkers (116)found that among 107 con­secutive outpatients with asthma, 6.5 % met criteria for PD and13.1% for agorphobia; none of these patients had previously re­ceived a psychiatric diagnosis or treatment. In some cases panicand hyperventilation may trigger exacerbations of asthma, per­haps by increasing airway exposure to cool, dry air (119, 120).

Patients with panic disorder and asthma are more sensitiveto the experience of dyspnea than are those without pulmonarydisease, and the fear of dyspnea may directly trigger panic at­tacks in some of these patients (23). As with other patients withCOPD, patients with asthma who panic seem to have greater"anxiety sensitivity" (fears about the adverse consequences ofanxiety-related bodily sensations), but pulmonary dysfunctionis not more severe compared with patients with asthma who donot have PD (117).

Patients who have asthma and anxiety disorders may developa cycle of excessive fear and avoidance of activities, resulting insignificant impairments in their quality of life (114). High levelsof anxiety have been associated with asthma exacerbations re­quiring hospitalization (121)and may predict asthma-associatedmortality (122). Kinsman and colleagues (123) have identifieda personality trait called "panic fear" that appears to predictseverity and intractibility of asthma exacerbations. Patients highin panic fear are more fearful, emotionally labile, rejection­sensitive, and less able to persist in the face of difficulty. Amongpatients with asthma, high levels of panic fear and generalizedanxiety correlate with the use of more intensive steroid regimens,overuse of bronchodilators, and more frequent and lengthy hos­pitalizations independent of objective pulmonary function (111,112, 124).

Smoking and Nicotine Dependence

Smoking and nicotine use have been reported to have both anxio­lytic and anxiogenic effects (125-127). Female, but not male, pa­tients with PD are reported to have higher rates of smoking thanage-matched control subjects, and retrospective reports indicatethat smoking often precedes the onset of PD (128). In a largecommunity sample, smokers who met criteria for nicotine de­pendence had elevated lifetime rates of anxiety disorders, al­though nondependent smokers did not (129). These findings sug­gest that nicotine can provoke anxiety or that patients prone toanxiety use nicotine for the sedative effect that it may have dur­ing states of high arousal (130), and there is evidence that bothmay be true (125, 127). Nicotine withdrawal may mimic panicsymptoms, and smoking may have an anxiolytic effect by attenu­ating these symptoms (131). Because patients with a history ofdepressive and anxiety disorders report more severe nicotine with­drawal symptoms (132), they may experience greater difficultyin smoking cessation.

10 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 154 1996

Sleep Apnea

Nocturnal panic attacks may be associated with sleep apnea. Of301 patients diagnosed with sleep apnea, 18 (6%) had nocturnalpanic attacks and four met criteria for PD (133). Notably, allof these patients were middle-aged men, whereas PD is gener­ally more common in women. The occurrence of nocturnal panicattacks in men with daytime sleepiness should prompt consider­ation of a diagnosis of sleep apnea.

Vocal Cord Dysfunction

Laryngeal or vocal cord dysfunction, in which abnormal adduc­tion of the vocal cords produces upper airway obstruction, isassociated with dyspnea, wheezing, and stridor and is often mis­taken for "refractory asthma" (134, 135). A number of clinicalsyndromes present with dyspnea and laryngeal dysfunction, sothat a definitive diagnosis requires laryngoscopic visualizationof the vocal cords and documentation of paradoxical closure (134,135). The relation of vocal cord dysfunction (VCD), if any, topanic disorder has not been defined, although, like PD, mostcases occur in women (136) and patients may experience parox­ysmal attacks of dyspnea associated with extreme anxiety (137).The attacks have been aborted by having the patient pant at theonset of an attack (138). In at least a subset of VCD patients,functional or psychological factors have appeared to playa role,and VCD has been variably characterized as a factitious disor­der, somatization disorder, or conversion disorder (135). In thelargest published series to date, VCD patients were more likelyto have had a history of psychiatric hospitalization than wereasthma patients; 73% had received a diagnosis of major depres­sion, and 37% had been diagnosed with a personality disorder(136). However, it is not clear whether a psychiatric diagnosisis associated with most cases of VCD (135, 137).

Mechanical Ventilation

Panic anxiety can be a significant problem for patients on me­chanical ventilation and may interfere with weaning (139-141).In one study of 158 patients interviewed retrospectively (140),300/0 experienced "agony or panic" during ventilation, and panicwas associated with episodes of intratracheal suctioning and withasynchrony between spontaneous and mechanical ventilation.The inability to communicate was found to be the variable moststrongly related to panic anxiety.

TREATMENT OF PANIC AND ANXIETY INPULMONARY PATIENTS

The goals of treating panic and anxiety in pulmonary patients,as in patients without medical illness, include relief of the anxi­ety, prevention of its complications (including agoraphobia anddepression), and improvement in overall quality of life. With pul­monary patients, however, there may be the additional goals ofalleviating breathlessness, decreasing disability, and improvingfunctional status. In an early study, Burns and Howell (102)foundthat patients with chronic bronchitis and breathlessness dis­proportionate to their degree of pulmonary disease had a highrate of depression and anxiety; treating these emotional distur­bances relieved their dyspnea and improved their exercise toler­ance. Subsequent reports have also found that improvements indepression and anxiety are associated with increased exercisetoler­ance in patients with COPD (142, 143). Patients with respiratorydisease complicated by anxiety perceive themselves to be moredisabled than those without psychiatric diagnoses, despite com­parable objective pulmonary function (113).This self-perceptionof disability and a marked fear of dyspnea can lead patients tolimit their activities inappropriately and are thus important tar­gets of treatment.

For several reasons, the management of panic is more com­plicated in patients with respiratory disease. The first difficultyarises with diagnosis. The symptoms of anxiety and respiratorydisease overlap considerably, and it may be difficult to deter­mine whether a patient who presents with dyspnea and anxietyis suffering an exacerbation of an underlying pulmonary diseaseor a panic attack. Moreover, these alternatives are not mutuallyexclusive: anxiety may heighten the sensation of dyspnea frompulmonary disease, and dyspnea may provoke panic. However,failing to distinguish the contribution of anxiety from that ofrespiratory disease can have important implications. The patientwith asthma whose dyspnea reflects a panic attack may benefitmost from anxiolytics and may worsen if aggressivelytreated witha regimen of anxiogenic pulmonary medications, such as beta­agonists and steroids. Conversely, mistakenly attributing breath­lessness to anxiety could lead to undertreating potentially life­threatening pulmonary disease (114). Unfortunately, in a givenepisode it may be impossible to determine the independent con­tributions of panic and pulmonary disease, and clinicians mayhave to err on the side of caution by treating the pulmonary dis­ease first and foremost. However, over time, patients who dis­play marked anxiety or panic should be assessed for the pres­ence of comorbid PD or other anxiety disorders. A directedhistory may reveal a prior diagnosis of PD or agoraphobic avoid­ance of situations unrelated to physical illness, such as highwaydriving, crowds, or traveling far from home. Psychiatric consul­tation or screening instruments designed for use in medical set­tings (144) may be helpful in establishing a diagnosis.

A second difficulty in treating panic and anxiety in pulmo­nary patients is the risk that anxiolytic medication will adverselyimpact pulmonary function or interact with concomitant medi­cations. Benzodiazepines, a mainstay of the pharmacologic treat­ment of anxiety in many patients, can cause respiratory depres­sion and exacerbate hypercapnia in some patients with pulmonarydisease (133, 145-148). Some have suggested (149) that in patientswith marked COPD, doses of psychotropic medications shouldbe one third or less than doses used in medically healthy patients.

Given the scope of the problem, there is surprisingly littleknown about the optimal management of anxiety and its dis­orders among patients with respiratory disease. Moreover, thosestudies that have examined the effect of treatment interventionson anxiety in pulmonary patients have tended to examine generalmeasures of anxiety states rather than specifically assessing panicor other symptoms of anxiety disorders. Consequently, most ofthe treatment strategies discussed below are derived from studiesof medically healthy patients with PD and generalized anxietydisorder (Table 3).

Benzodiazepines

The high-potency benzodiazepines alprazolam and clonazepamhave been shown to be effective antipanic agents in several con­trolled trials (150, 151), although other benzodiazepines, includ­ing lorazepam and diazepam, have been shown to be compara­bly effective when used in adequate doses (152, 153). As notedpreviously, the use of benzodiazepines in patients with pulmo­nary disease requires caution because they can produce respira­tory depression and worsen hypercapnia, in part by blunting CO 2

sensitivity (I 54-15§). Although there are reports to the contrary(157-160), several reports of patients with COPD treated withalprazolam (148, 161), diazepam (145, 146), chlordiazepoxide(162), and clorazepate (147) indicate that benzodiazepines are noteffective antidyspneic agents and can worsen the pulmonary sta­tus of patients with COPD. Nevertheless, in patients with severeanxiety that interferes with function and is unresponsive to othermeasures, benzodiazepines may be beneficial if carefully moni­tored. Benzodiazepines also may be useful in anxious, mechani-

State of the Art 11

TABLE 3

TREATMENTS FOR PANIC DISORDER: RELATIVE EFFICACY ANDTOLERABILITY IN PATIENTS WITH RESPIRATORY DISEASE

Comments

fffective for generalized anxiety. May be arespiratory stimulant.

Initiate therapy at low doses to avoid[itteriness. Fluvoxamine decreases themetabolism of theophylline threefold andmay raise plasma levels.

May cause bronchoconstriction. Can be usedas required for performance anxiety. Decreasesomatic but not cognitive aspects of panic

Use may be limited by availability of trainedtherapists and by patient acceptance.

May depress respiration and worsen hyper­capnia in dose-dependent fashion. Short half­life agents (e.g., alprazolarn, lorazepam) mayhave less risk of prolonged respiratorydepression. Avoid in sleep apnea. Can beused as required.

All TeAs are likely to be effective for panic.IMI and CMI are best studied; DMI and NTPare often better tolerated. Initiate therapyat low doses to minimize jitteriness. PTPhas been used in sleep apnea.

Contraindicated for patients on bronchodllatorsor other sympathomimetics.

--------_.._- -- _._-------_..-._--..- .-_._".,_..,~. _0' ~ _~__ .,~

Usual Dose Range Safety /Tolerabil ityin Medically Antipanic in Patients with

Healthy Patients" Efficacy Respiratory Diseaset

2-10 mg/d +++++ +++

2-12 mg/d ++++ +++

1-5 mg/d +++++ ++-+++

10-45 mg/d ++++ ++

100-300 mg/d +++++ ++++

100-250 mg/d +++++ ++++

100-300 mg/d +++++ ++++

100-300 mg/d +++++ ++++

50-150 mg/d +++++ ++++

100-300 mg/d +++++ ++++

15-60 mg/d ++++

15-90 rnq/d +++++ +

10-60 rnq/d +++++ +

10-40 mg/d +++++ +++++

25-200 mg/d +++++ +++++

10-40 mg/d +++++ +++++

100-300 mg/d +++++ +++++

15-60 mg/d + +++++

30-120 mg/d ++ ++

50-100 mg/d ++ ++

NA +++++ +++++

Treatment

Beta blockersPropranololAtenolol

BenzodiazepinesAlprazolaml.orazepamClonazeparnDiazepam

---_._-_."----"---------

Cognitive-behavioral therapy

Tricyclic antidepressants (TCAs)Imipramine (IMI)Clomipramine (eMI)DoxepinAmitriptylineNortriptyline (NTP)Desipramine (OM I)Protriptyline (PTP)

Monoamine oxidase inhibitorsPhenelzineTranylcypromine

Selective serotonin reuptake inhibitorsFluoxetineSertralineParoxetineF1uvoxamine

AzapironesBuspirone

* Elderly patients and those with moderate-to-severe pulmonary, hepatic, or renal disease usually require lower doses to minimize toxicity.t Based on clinical experience and limited, controlled data.

cally ventilated patients for whom the risk of hypoventilationis less relevant. There is limited evidence that lorazepam producesless respiratory depression than other benzodiazepines (163, 164).In general, plasma levelsof benzodiazepines with short half-lives(e.g.,alprazolam, oxazepam, lorazepam) are lesslikelyto accumu­late than those with longer half-lives (e.g., diazepam, clonaze­pam, clorazepate) and may be relatively safer in patients withrespiratory disease. Benzodiazepines should be avoided in pa­tients with sleep apnea because their sedative and respiratorydepressant effects can worsen hypoventilation and may even ex­acerbate panic in these patients (133).

Antidepressants

Antidepressants of several classes are effective antipanic andanxiolytic agents. Moreover, they do not carry the risks of respi­ratory suppression or physical dependence associated with thebenzodiazepines. These agents are also useful for the comorbiddepressive symptoms seen in many patients with either anxietydisorders or pulmonary disease.

Tricyclic antidepressants. These agents are effective againstboth panic and generalized anxiety (165). Doses of 100-300 mg/dof imipramine or its equivalent are typically used for patientswith PD, and recent investigations in medically healthy patientssuggest that the optimal imipramine dose may be 2.25 mg/kgper day (166). Patients whose panic attacks are characterized byprominent respiratory symptoms may respond better to imipra­mine than to alprazolam (167).

Although tricyclicantidepressants (TCAs) do not have markedadverse effects on ventilation, patients with severe pulmonarydisease may have difficulty tolerating higher dose ranges (149,154, 168-170). Side effects associated with TCAs include an­ticholinergic (e.g., dry mouth, constipation, urinary hesitancy),antihistaminic (e.g., sedation), and anti-alpha-adrenergic (e.g.,orthostatic hypotension) effects as wellas prolongation of cardiacconduction times. Tertiary amines (e.g., imipramine, amitripty­line, doxepin) tend to have more of these side effects than thesecondary amines (e.g.,desipramine, nortriptyline). The anticho­linergic effects of these agents may have salutory bronchodilat­ing effects in patients with obstructive disease (149, 154, 171),but there is little clinical evidence of this (143, 168, 170).

Some early reports suggested that imipramine and amitripty­line may not only improve mood but also decrease respiratorysymptoms and improve functional status in patients with asthma(114, 154, 172-175). Reports of the use of tricyclics in patientswith COPD have had equivocal results. Doxepin has been recom­mended as the antidepressant of choice for patients with COPDand depression complicated by agitation or panic attacks (176).However in a placebo-controlled study, Light and colleagues (143)found that doxepin (mean dose, 105 mg/d) was not effective inrelievingdepression or anxiety in a group of patients with COPD(FEV l < 1.25 L) and 3 of 12 (25010) of doxepin-treated patientshad intolerable side effects. In case reports and case series, im­ipramine, amitriptyline, and nortriptyline have been effective inimproving anxiety, depression, and dyspnea in patients with

12 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 154 1996

COPD (102, 169, 175). These include a patient with a FEV 1 ofOAL who was able to tolerate imipramine at 250 mg/d withmarked improvement in her PD (175). Nortriptyline was also ef­fective in relieving anxiety, depression, and functional disabilitywithout impairing cardiopulmonary function in patients withmoderate-to-severe COPD under placebo-controlled conditions(177, 178).

Tricyclic antidepressants, including imipramine, clomipra­mine, and protriptyline, have also been reported to improve ven­tilatory drive and oxygenation in some patients with sleep apnea(179-182). However, their sedating properties and potential forcardiac toxicity may complicate use of TCAs in these patients.Protriptyline, the least sedating TCA, has also been reported toproduce short-term improvements in gas exchange in patientswith obstructive and restrictive disease (168, 183), but it has notbeen well studied in PD.

Selective serotonin reuptake inhibitors. The selective seroto­nin reuptake inhibitors SSRls (e.g., fluoxetine, sertraline, parox­etine, fluvoxamine) have become first-line agents in the treat­ment of PD because of their demonstrated efficacy, tolerability,and ease of use. Because patients with PD sometimes experiencejitteriness and increased arousal when starting treatment withSSRls, treatment may be best initiated at low doses (e.g., 5 mg/dof fluoxetine, 25 mg/d of sertraline) and carefully titrated upto therapeutic doses (e.g.,20-40 mg/d of fluoxetine, 50-200 mg/dof sertraline).

Animal studies have suggested that serotonin can act as ei­ther a respiratory depressant (184-188) or respiratory stimulant(188-192), depending on the species, receptor subtypes, and brain­stem areas examined. In brainstem respiratory control centers,serotonin may act in part to decrease CO2 responsivity and limitthe hyperventilatory response to CO2 (185, 187), although evi­dence on this point is conflicting. The serotonergicTeA clomipra­mine decreases CO2 sensitivity in patients with PD (55), and de­creased CO2 responsivity might be one mechanism by whichserotonergic agents block panic attacks (15, 16). If so, SSRls mighthave antidyspneic effects in addition to their anxiolytic effects(15). This hypothesis is supported by a case series of nine pa­tients with intractable dyspnea with and without anxiety or mooddisorders who experienced improvements in dyspnea and exer­cise tolerance after treatment with sertraline (Smoller, Pollack,and Kradin, unpublished observations, 1995).

The SSRls have a relatively favorable side-effect profile andappear to be well tolerated in patients with COPD (193). In anopen trial comparing fluoxetine and protriptyline in the treat­ment of sleep apnea, both medications improved oxygenationand reduced hypoventilation in half the patients, but fluoxetinewas better tolerated (194). As with any psychotropic medication,however, it would be prudent to initiate SSRI therapy at low doseswith gradual upward titration in patients with severe pulmonarydisease.

Monoamine oxidase inhibitors. Although the monoamine ox­idase inhibitors (MAOls) (e.g., phenelzine, tranylcypromine) areeffective antipanic medications, their side effects (e.g.,orthostatichypotension, weight gain) and the risk of hypertensive crises as­sociated with dietary tyramine and sympathomimetic medica­tions have limited their use. In patients with asthma and COPD,these medications should be avoided, because beta-agonists usedto manage exacerbations of their pulmonary disease may pro­voke hypertensive reactions.

Other Agents

The anxiolytic buspirone is a 5HTlA receptor partial agonistthat has been found to be comparable to benzodiazepines in thetreatment of generalized anxiety disorder (195-199), although ithas not been shown to have efficacy in PD (200). Therapy is ini-

tiated at 5 mg three times a day and can be titrated up to 10 to20 mg three times daily if necessary.The onset of action of buspi­rone is generally 2 to 4 wk, and there is no apparent risk of phys­ical dependence (198). In the brainstem, serotonin may producerespiratory stimulation via 5HTl A receptors (188, 189),and buspi­rone appears to stimulate respiration and increase CO2 sensitiv­ity (201, 202). This property of buspirone might account for itspoor anti panic efficacy, because respiratory stimulants are of­ten panicogenic (203, 204). Nevertheless, in some patients withpulmonary disease, buspirone may be an effectiveanxiolytic (205,206); unlike benzodiazepines, it does not impair ventilatory drive(156,206-208). Use of buspirone with concomitant bronchodi­lators has been well tolerated (209). Two double-blind, placebo­controlled studies of buspirone in COPD report conflictingresults. Singh and colleagues (207)reported a 6-wk trial of buspi­rone (30-60 mg/d) in patients with COPD with mild anxiety andfound no significant effect on anxiety, dyspnea, pulmonary func­tion, or exercisetolerance. However,Argyropoulou and coworkers(206), using a lower dose (20 mg/d) of buspirone and shorterduration of treatment (2 wk), found significant improvementsin anxiety, dyspnea, and exercisetolerance in patients with COPDwith FEV l < 1.5 L.

Antihistamines (e.g., diphenhydramine, hydroxyzine) aresometimes used for their anxiolytic and sedative effects in pa­tients with anxiety, although these agents do not appear to havespecificantipanic effects. Hydroxyzine may possess bronchodilat­ing and respiratory stimulant properties (154). In one trial com­paring diazepam, placebo, and the antihistamine promethazinein 18 "pink puffers" (145), promethazine (125 mg/d) was as­sociated with decreased breathlessness and improved exercisetolerance and did not impair lung function. A subsequent study(210)failed to find a benefit of promethazine for dyspnea or ex­ercise tolerance.

Beta-blockers are sometimes used to treat symptoms of auto­nomic arousal associated with anxiety but are relatively contrain­dicated in patients with asthma and obstructive lung disease be­cause they can provoke bronchoconstriction.

Neuroleptics are occasionally used for their anxiolytic effects,particularly in hospitalized patients with agitation, delirium, orpsychosis (211). The high-potency neuroleptic, haloperidol, doesnot have marked respiratory depressant effects and can be givenorally or parenterally (for example, in ventilated patients). How­ever,neuroleptics do not have antipanic effects and are not recom­mended as anxiolytics in outpatients.

Cognitive-Behavioral Therapy

Cognitive-behavioral therapy (CBT) has demonstrated efficacyin PD (212) and generalized anxiety disorder (213). CBT involves"cognitive restructuring," directed at correcting unrealistic think­ing patterns such as catastrophizing and behavioral techniquessuch as breathing retraining and relaxation. A crucial elementof the treatment is exposure, of which there are two types. "In­teroceptive exposure" involves inducing and then desensitizingpatients to feared bodily sensations. For example, the therapistmay have patients hyperventilate to induce numbness and tin-.gling or run in place to induce tachycardia and help patients learnnot to escalate anxiety in response to these symptoms. In "situa­tional exposure.t'patients progressively expose themselves to sit­uations (e.g., shopping in a mall) that they have avoided becauseof their fear of panic attacks. The panic-free rates achieved withCBT in PD are comparable with those achieved with medicationand may be better maintained (83). For patients with pulmonarydisease, these approaches offer effective treatment without therisks of side effects or drug interactions that may be associatedwith pharmacotherapy. Cognitive-behavioral approaches may beparticularly useful and relevant to anxious pulmonary patients

State of the Art

because the presence of catastrophic cognitions and somaticpreoccupation appears to distinguish those pulmonary patientswho panic from those who do not (97, 117). However, the veryreal threat of respiratory decompensation facing patients withsevere lung disease must be integrated within the cognitive­behavioral treatment. When it is difficult to determine whetherthe patients' beliefs about the nature of his symptoms or physi­cal limitations are realistic or distorted, the cognitive-behavioraltherapist should consult with the patient's internist or pulmo­nologist to distinguish cognitive distortions from appropriatefears and restrictions.

Pulmonary Rehabilitation and OtherNonpharmacologic Approaches

Rehabilitation programs that include progressiveexercise, breath­ing retraining, education, and psychosocial support can improveexercise tolerance, dyspnea, and quality of life in patients withCOPD, even when there is no demonstrable change in pulmo­nary function (106, 108, 142,214, 215). Relaxation training mayalso relieve anxiety and dyspnea in patients with COPD (216,217).Agle and colleagues (142)found that desensitizing patientsto their fear of dyspnea was of particular importance to outcome,highlighting the value of cognitive interventions in these patients.The use of relaxation and stress management techniques also hasbeen reported to improve function in patients with asthma (115,218, 219).

Optimizing Treatment of the Underlying Pulmonary Disease

For some anxious patients, successful treatment of their under­lying pulmonary disease may be associated with significant re­lief of anxiety symptoms. Edlund and colleagues (133)reportedon 12patients with sleep apnea who had nocturnal panic attacks.Several had experienced worsening of their panic when treatedin the past with benzodiazepines, which can also worsen sleepapnea. However, all these patients experienced remission of panicwhen treated with continuous positive airway pressure. Recently,several cases have been reported of patients who had panic at­tacks or PD and endstage COPD due to o-l-antitrypsin deficiency(220). After lung transplantation, their anxiety symptoms cleareddespite the stress of the procedure, posttransplantation course,and treatment with potentially anxiogenic medications; they re­mained asymptomatic after being tapered off antipanic medi­cation. From a pathophysiologic viewpoint, remission of panicafter treatment of pulmonary disease could be understood asremoving both the substrate for catastrophic cognitions and thebiologic stimulus to panic.

SUMMARY

There is intriguing evidence suggesting pathophysiologic rela­tionships among dyspnea, hyperventilation, and panic anxiety.The symptoms of panic attacks and pulmonary disease overlap,so that panic anxiety can reflect underlying cardiopulmonarydisease and dyspnea can reflect an underlying anxiety disorder.The pathogenesis of panic may be related to respiratory physiol­ogy by several mechanisms: the anxiogenic effects of hyperven­tilation, the catastrophic misinterpretation of respiratory symp­toms, and/or a neurobiologic sensitivity to CO2 , lactate, or othersignals of suffocation. In a subset of patients with PD, incipientpulmonary dysfunction may also contribute to their anxietysymptoms.

Patients with pulmonary disease, particularly those with ob­structive lung disease, have a high rate of panic symptoms andPD. There is reason to believe that pulmonary disease consti­tutes a risk factor for the development of panic related to repeatedexperiences with dyspnea and life-threatening exacerbations of

13

pulmonary dysfunction, repeated episodes of hypercapnia orhyperventilation, the use of anxiogenic medications, and the stressof coping with chronic disease.

Panic in pulmonary patients may carry significant morbidity,including phobic avoidance of activity, overly aggressive treat­ment with anxiogenic medications, and more prolonged and fre­quent hospitalization. Successful treatment of panic in these pa­tients can improve functional status and quality of life by relievinganxiety and dyspnea.

Nonpharmacologic treatment of panic, including cognitive­behavioral approaches, can be useful in patients with concomi­tant respiratory disease. Sedating medications such as benzodiaz­epines should be used with caution in patients with pulmonarydisease to avoid respiratory depression. Serotonergic antidepres­sants (SSRIs) and anxiolytics (buspirone) may be effective treat­ments for panic or generalized anxiety in pulmonary patientsand have relatively little potential for significant adverse effects.

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