Hyperventilation and panic disorder

Hyperventilation and panic disorder

REVIEW Hyperventilation and Panic Disorder DEBORAH S. COWLEY, M.D. PETER P. ROY-BYRNE, M.D. Seattle, Washington From the Center for Anxiety and De...

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REVIEW

Hyperventilation and Panic Disorder

DEBORAH S. COWLEY, M.D. PETER P. ROY-BYRNE, M.D. Seattle,

Washington

From the Center for Anxiety and Depression, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington. Requests for reprints should be addressed to Dr. Deborah S. Cowley, Department of Psychiatry ZA-99, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 98104. Manuscript submitted March 30, 1987, and accepted May 26, 1987.

Hyperventilation syndrome and panic disorder are both common, serious, and easily treatable disorders. The similarity of their symptoms and physiology, the demonstration of hyperventilation during spontaneous and laboratory-induced panic episodes, provocation of panic-like symptoms in some patients with panic disorder using hyperventilation, the importance of psychologic factors in producing hyperventilation, and successful treatment of panic disorder with breathing retraining all indicate a strong association between these two conditions. About 50 percent of patients in each group show evidence of both disorders. It is suggested that many patients with either diagnosis have the same disorder and share a biologically and often genetically determined hypersensitivity of a central “alarm” system. Panic and hyperventilation provoked by inappropriate activation of this system are postulated to reinforce each other by a positive feedback loop. Treatments directed at any part of this loop are likely to be successful. Clinical implications of the link between these conditions are discussed. Panic episodes were described as a distinct form of anxiety by Freud [I] almost 100 years ago and recently, with the publication of the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III) [2], have been made the basis for the separate diagnostic entity of panic disorder. A panic attack is characterized by the abrupt onset of apprehension or fear accompanied by symptoms such as dyspnea, palpitations, chest pain, dizziness, sweating, feelings of unreality, and fear of dying. Panic disorder, defined as three panic attacks in a three-week period, has a lifetime prevalence of 1 to 2 percent [3], although up to 35 percent of the general population reports having had at least one panic attack [4]. There is strong evidence for a biologic basis for this disorder. Panic disorder is familial [5] and possibly genetic [6], and can be treated successfully with antidepressants [7] and benzodiazepines [8,9]. In these patients, panic episodes can be provoked by pharmacologic challenge with sodium lactate [lo], isoproterenol [ 1 I], yohimbine [12], caffeine [ 131, and carbon dioxide inhalation [ 14- 161. Hyperventilation refers to ventilation in excess of metabolic requirements and is identified most readily when presenting as an acute episode of overbreathing, hypocapnia, and respiratory alkalosis with symptoms of dizziness, paresthesias, tremor, dyspnea, palpitations, and tetany [ 171. However, hyperventilation also occurs in a chronic form known as the chronic hyperventilation syndrome [ 181. This syndrome is characterized by chronic hypocapnia, respiratory alkalosis, a compensatory metabolic acidosis, near-normal pH, and many respiratory, cardiac, neurologic, psychiatric, and gastrointestinal symptoms. The hyperventilation syndrome has been estimated to account for up to IO percent

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TABLE I

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Symptoms of Panic Disorder Hyperventilation Syndrome

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Hyperventilation

Panic Disorder*

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lar symptoms [26,30], hyperventilation has been demonstrated in panic disorder patients [31], and breathing treatment designed to control hyperventilation decreases the frequency of panic attacks [32]. Despite this, numerous reviews of hyperventilation in the medical literature have failed to mention panic disorder, whereas earlier reports of panic disorder rarely alluded to hyperventilation. In this article, we review the evidence for an association between these two conditions, discuss possible causal relationships between them, and outline the clinical implications of recent research in this area.

Syndrome?

Feeling anxiousx Tenseness

of the following: Faster or deeper breathingt Unable to breathe deeply enough Need for air Pounding heartz Rapid heartbeat Irregular heartbeat

Palpitations

Chest pain or discomfort Choking or smothering Dizziness, vertigo, or unsteadiness Feelings of unreality Paresthesias Hot and cold flashes Sweating Faintness Trembling or shaking Fear of dying, going crazy, or doing something uncontrolled

Suffocating Pressure or knot Dizzinesst

Tingling in fingers Head warmth

BACKGROUND in throat

Interestingly, the history of both panic disorder and hyperventilation syndrome dates back to descriptions in the 19th century by Hartshorn [33] and DaCosta [34] of soldiers complaining of multiple symptoms including breathlessness, palpitations, chest pain, nervousness, fatigue, dizziness, sighing, attacks or spells, headache, apprehension, fear of death, trembling, sweating, faintness, and exercise intolerance. This syndrome was known as irritable heart, soldier’s heart, DaCosta’s syndrome, effort syndrome, neurocirculatory asthenia, and anxiety neurosis. In the century since these first descriptions, the symptoms of this syndrome have been attributed to abnormalities of several organ systems. Because many such patients were noted to have a mid-systolic click and heart murmur, their symptoms were attributed to mitral valve prolapse [35]. In 1938, Soley and Shock [36] postulated that all cases of soldier’s heart could be accounted for by involuntary hyperventilation and that symptoms could be relieved by increasing the pC02 of inspired air. In the psychiatric literature, it has been thought that in many cases of neurocirculatory asthenia, symptoms resulted from anxiety, “effort phobia,” or repeated panic attacks [1,371. Although mitral valve prolapse is significantly more prevalent in patients with panic attacks than in those without such episodes, it does not distinguish a subgroup of patients with panic disorder differing in presenting symptoms or response to treatment [38]. Thus, mitral valve prolapse is most likely either an epiphenomenon or an unrelated condition, rather than a cause, of panic disorder. The relationship of hyperventilation syndrome to panic disorder remains unclear, although data regarding symptoms, physiology, response to provocative tests, and treatment indicate that the two conditions are associated in some way.

and face

Blacking out Tremblings Panic2 Feelings of unrest Tiredness Fits of cryingt

DSM-III criteria. 7 Symptoms reported significantly more often in response to a hyperventilation provocation test by patients with hyperventilation syndrome than by patients without the syndrome [33]. The standard used to diagnose hyperventilation syndrome was both reproduction of usual symptoms by hyperventilation and slow recovery of end-tidal pCOp to baseline after the test. The seven most reliable discriminating symptoms are marked with a double dagger. l

of visits to general internists [ 191 and has been attributed to anxiety states [ 18,201 and faulty breathing [21]. Once established, hyperventilation syndrome requires only occasional sighs or deep breaths to maintain the hypocapnia [22], so that patients often do not appear to be overbreathing. However, patients with this condition can be identified by characteristic blood gas abnormalities, reproduction of symptoms with voluntary hyperventilation (the hyperventilation provocation test), and slow recovery of partial carbon dioxide pressure (pCOp) to baseline after hyperventilation [23]. Hyperventilation and panic disorder are commonly seen in general medical settings [ 18,241. Although patients with both disorders frequently present with vague complaints mimicking a variety of diseases, correct diagnosis leads to successful treatment in the majority of cases, thus avoiding long and costly medical workups. Recently, several authors have suggested that panic disorder and hyperventilation are associated [25-291. Panic disorder and hyperventilation syndrome present with simi-

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Presenting symptoms of panic disorder and hyperventilation are strikingly similar, as shown in Table I. The seven most reliable discriminating symptoms of hyperventilation

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syndrome, according to a recent study [39], are marked with a double dagger. Six of these, including both anxiety and feelings of panic, are also among DSM-III criteria for a panic attack. Despite these descriptive similarities, however, there, is a major distinction between the two disorders. The inter-rater reliability for diagnosis of panic disorder is high [40]. On the other hand, the sensitivity and specificity of symptoms in diagnosing hyperventilation syndrome, even using the seven most reliable discriminating symptoms, is poor [39]. This suggests that hyperventilation syndrome is a more heterogeneous condition than panic disorder. The few studies that have examined the co-occurrence and course of these disorders suggest considerable diagnostic overlap between them. In one study of 21 patients with chronic hyperventilation, 10 had psychiatric disorders and nine of these 10 reported panic attacks [41]. More than 70 percent of patients with panic disorder complain of respiratory symptoms such as dyspnea, sighing, and choking during attacks [42]. Most cases of agoraphobia, or avoidance of numerous activities due to fear of sudden incapacitation, have been thought to result from panic episodes [43,44]. However, hyperventilation syndrome has also been reported to lead to phobias and agoraphobia [41]. Furthermore, in one study [45], more than 60 percent of patients with agoraphobia had hyperventilation syndrome diagnosed by results of the hyperventilation provocation test, whereas more than 60 percent of patients with hyperventilation syndrome met the criteria for agoraphobia. In addition, both hyperventilation and panic disorder may begin in childhood. Children of patients with panic disorder show an increased prevalence of anxiety and depression as compared with children of healthy control subjects [46], whereas adults with panic disorder retrospectively report more fears and anxiety as children than do control subjects [47]. Hyperventilation has been noted in children, and follow-up studies show that 40 percent of these children are affected by hyperventilation syndrome as adults [48]. Although panic disorder is significantly more common in first-degree relatives of affected probands than in the general population [5] and may be genetically transmitted [6], there are no family or genetic studies of hyperventilation syndrome. Such studies would be helpful in assessing whether hyperventilation syndrome has a similar familial pattern to panic disorder and whether the two disorders coexist in families of either hyperventilation syndrome or panic disorder probands. PHYSIOLOGY There are many similarities in physiology between hyperventilation and both spontaneous and laboratory-induced panic attacks. Both acute and chronic hyperventilation are associated with characteristic blood gas and acid-base

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changes, hypophosphatemia, and impaired lactate metabolism resulting in increased lactate levels [49,50]. Acute hyperventilation causes vasoconstriction and decreased cerebral and coronary blood flow [51]. Most of our current knowledge regarding the physiology of panic comes from provocative testing with intravenous sodium lactate, which induces symptoms of panic episodes in 70 to 80 percent of panic disorder patients and about 10 percent of control subjects [38,52]. At baseline before lactate infusion, about 50 percent of panic disorder patients show decreased pCOs and bicarbonate consistent with chronic hyperventilation [53]. During the infusion, pCOa and phosphate decrease in both patients and control subjects [31]. These changes are more marked in patients than in control subjects and in patients who panic with lactate than in those who do not, implying that acute hyperventilation accompanies lactateinduced panic. Lactate-induced panic is associated with cerebral vasoconstriction and a lack of the increase in cerebral blood flow seen in normal control subjects or non-panicking patients (Reiman, personal communication). Hypophosphatemia at baseline before lactate infusion has been suggested as a predictor of lactate-induced panic [54]. Thus, the unique changes during lactate-induced panic episodes are those seen during hyperventilation. It is also interesting that panic disorder patients, like hyperventilation syndrome patients, show possibly impaired lactate metabolism, with higher lactate levels developing than in control subjects during lactate infusions [55]. In nonlaboratory situations, acute hyperventilation has been demonstrated during panic attacks in one patient who panicked during renal dialysis [56] and in some, but not all, patients with panic disorder recently studied using ambulatory transcutaneous pC02 monitoring [57]. Physiologic studies therefore give clear evidence that panic disorder and hyperventilation syndrome are associated, although none of these findings gives information about whether one condition triggers the other. TREATMENT Treatment studies add further evidence of an association between the two disorders, : ”*I traditional treatment for acute hyperventilation has Ii:. ,#ebreathing using a paper bag. However, this rnane~~.::.’z:,ne is frequently ineffective, especially for patier;:; : :‘! chronic hyperventilation [58]. Excellent respons: ;: .: !e been reported using provocation of symptor: ;, ntary hyperventilation, preferably in the press ily members, to convince patients and thei: he diagnosis [49,58]. This is followed by rc ,j a paper bag [58], training in slowed bre alearning breathing patterns to emphas: athing [21,61], or stress reduction tt-$~ 1 rodiazepines [62],

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beta blockers [63], and the tricyclic antidepressant clomipramine [64] have also been used with some success. Patients with anic disorder show a good response to pharmacologic % teatment with tricyclic antidepressants [7], monoamine oxidase inhibitors [65], and alprazolam and other benzodiazepines [8,9]. Interestingly, successful pharmacologic treatment of panic disorder both blocks lactate-induced panic and normalizes pH, pCO*, and bicarbonate levels [53]. Most importantly, however, Bonn et al [6 l] have shown improved long-term treatment results in agoraphobic patients trained in diaphragmatic breathing in addition to standard in vivo exposure therapy, and Salkovskis et al [32] have recently demonstrated reductions in panic attack frequency and correction of hypocapnia in panic disorder patients treated with reattribution of panic symptoms to hyperventilation, followed by training in paced breathing. No control treatment was used in the latter study, and in both cases it is unclear whether patients benefited primarily from the changes in respiratory physiology produced by paced breathing or from reattribution of symptoms to a non-life-threatening cause. However, these results do confirm that hyperventilation and panic disorder are linked.

attacks in agoraphobic patients reported that respiratory symptoms preceded feelings of panic in eight of nine patients [29], retrospective reports of symptom timing are notoriously unreliable. Gorman et al [66] have directly tested the hypothesis that hyperventilation causes panic by asking patients with panic disorder to hyperventilate. About 25 percent (seven of 30) of the patients reported panic-like symptoms with hyperventilation, but these were described as less intense than symptoms accompanying spontaneous or lactateinduced panic. Furthermore, Rainey et al [ 1 I] showed that a similar proportion of panic disorder patients (10 of 39) panicked with a placebo D5W infusion, suggesting some nonspecificity of the response to hyperventilation. However, two studies have demonstrated provocation of typical symptoms with voluntary hyperventilation in 61 percent [45] and 95 percent [61] of agoraphobic patients. The discrepancy between these results and those of Gorman et al [66] may result from the definition of a response to hyperventilation as the experience of some of the symptoms of a panic attack, rather than a typical attack. Alternatively, agoraphobic patients may be a more heterogeneous group of patients, not all of whom have panic episodes as the cause of their avoidance behavior. Inhalation of hypercapnic mixtures has been shown to provoke panic-like symptoms more readily than does hyperventilation [ 15,661. This latter finding seems to contradict the theory that hyperventilation causes panic and at least argues that panic does not depend solely on absolute acid-base status. How could the panic-inducing effect of hypercapnia be reconciled with the theory that hyperventilation causes panic? Gorman et al [66] have suggested that central chemoreceptor hypersensitivity in panic disorder patients could account for both panic with hypercapnia and hyperventilation at normal carbon dioxide levels. However, two studies of “neurotic” [67] and panic disorder patients [ 141 showed no differences between patients and control subjects in ventilatory response to carbon dioxide, making chemoreceptor hypersensitivity less likely. Van den Hout and Griez [68] have postulated that rapid changes in pCO2 and pH may be more important than absolute acid-base status in provoking panic. The hypothesis that hyperventilation causes or perpetuates panic attacks fits well with suggestions that cognitive factors, such as the patient’s sensitivity to and interpretation of bodily sensations, as well as the demand characteristics of the situation, play a role in producing panic. That is, in patients with panic disorder, the fear of having another attack may give rise to a heightened awareness of bodily sensations and a phobia of symptoms similar to those experienced with the original attack, or “fear of fear,” which may in turn predispose them to further panic attacks [69,70]. Thus, both hyperventilation

ETIOLOGY AND CAUSAL RELATIONSHIPS At this point, we have established that panic disorder and hyperventilation syndrome are associated in some way. This raises the question of how they are related. Since about 50 percent of each group, or a greater percentage than one would expect from the prevalence of either disorder in the general population, show evidence of both conditions [4 1,45,53], it seems unlikely that hyperventilation syndrome and panic attacks merely coexist without any causal relationship. Thus, possible relationships between them include that hyperventilation causes panic, panic causes hyperventilation, or that they are caused by a separate common underlying factor. Hyperventilation Causes Panic. As noted earlier [31], 50 percent of patients with panic disorder show evidence of chronic hyperventilation at rest, and acute hyperventilation accompanies lactate-induced and spontaneous panic. Unfortunately, there are no good data available to answer the crucial question of whether overbreathing in excess of metabolic demands and hypocapnia precedes or f,ollows the onset of panic. The one detailed study of blood gas and acid-base changes during lactate-induced panic [31] did not report the relative timing of acute hyperventilation and panic. In the single case report of a renal dialysis patient who hyperventilated, panicked, and became hypocapnic in the last hour of a dialysis session, blood gases were only taken at the point of maximal panic [56]. Finally, although one retrospective study of panic

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and hypercapnia could cause panic as a reaction to the physical symptoms that they induce. Finally, carbon dioxide and hyperventilation could both produce panic by acting at different sites. It has been suggested that panic disorder involves a defect in cellular aerobic metabolism resulting in cellular hypoxia [55]. Hyperventilation could certainly cause or exacerbate cellular hypoxia, since alkalosis displaces the oxyhemoglobin dissociation curve to the left (the Bohr effect) and hypophosphatemia may decrease levels of 2,3-diphosphoglycerate [49]. Carbon dioxide, on the other hand, may act by stimulating central noradrenergic neurons

[711.

Thus, it seems probable that hyperventilation causes or perpetuates panic in some panic disorder patients by means of either biologic or cognitive factors. However, further investigation of the relative timing of panic and hyperventilation during panic episodes, the nature and rate of response of panic disorder patients to hyperventilation, and the role of cognitive factors in these disorders is necessary to assess the relative importance of hyperventilation as a cause of panic. Panic Causes Hyperventilation. The hypothesis that hyperventilation causes panic leaves unanswered the question of what triggers hyperventilation. Hyperventilation is a constellation of symptoms and physiologic changes without known etiology. A minority of cases, usually acute and self-limited, are precipitated by welldefined organic conditions such as metabolic acidosis [72], drug intoxication or withdrawal [73], central nervous system disease [74], pain [72], or cirrhosis [75]. Hyperventilation syndrome has been associated with asthma [76]. The bulk of cases, however, have been attributed to poorly characterized anxiety states [ 18,201 or faulty breathing patterns [2 I]. Following voluntary hyperventilation, fewer symptoms develop in normal control subjects than in hyperventilation syndrome patients, and the number and severity of symptoms is not clearly related to pCO2 or pH levels [22]. Furthermore, in patients with hyperventilation syndrome, affective symptoms of attacks, such as anxiety or unhappiness, are correlated better with “neuroticism” than with acid-base status [77]. This suggests that emotional factors are important in the development and expression of hyperventilation. A variety of stressors have been shown to trigger hyperventilation but not to cause panic attacks [78,79]. Thus, in these cases, hyperventilation does not lead to panic. In fact, it may be more likely that panic is one of the poorly defined anxiety states producing hyperventilation. As mentioned earlier, provocation of panic by inhalation of carbon dioxide also argues against the physiologic changes associated with hyperventilation as the cause of panic, especially since carbon dioxide causes more in-

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tense reactions in a larger proportion of panic disorder patients than does hyperventilation [66]. It has been suggested that both carbon dioxide and lactate cause central hypercapnia, with lactate crossing the blood-brain barrier as carbon dioxide [ 157 11. In rats, hypercapnia increases firing of the locus ceruleus [80], an area of the brain that regulates catecholamine activity and which has been implicated in panic disorder [12]. This increase in locus ceruleus activity may trigger panic and secondarily produce hyperventilation, since hyperventilation can be precipitated by hyperadrenergic states [8 I]. Thus, the importance of anxiety in the development of hyperventilation, the precipitation of hyperventilation by hyperadrenergic states such as may be involved in panic attacks, the ineffectiveness of voluntary hyperventilation relative to other pharmacologic challenges to induce panic, and the provocation of panic by hypercapnia suggest that in many cases hyperventilation may be secondary to, rather than causing, panic attacks. However, this hypothesis has not been tested. No attempts have been made to induce typical symptoms in patients with hyperventilation syndrome by using known panic-inducing pharmacologic challenges. Such provocative testing, together with investigations of the relative timing of panic and hyperventilation during attacks, and prospective longitudinal studies of the development of symptoms of panic and hyperventilation, would help determine whether panic attacks are a significant cause of hyperventilation syndrome. Hyperventilation and Panic Have a Common Etiology. Both hyperventilation syndrome and panic disorder appear to be heterogeneous groups with regard to etiology. However, there is clearly significant overlap between them, with about 50 percent of the patients in each group showing evidence of both disorders. We propose that in the majority of cases, hyperventilation and panic are symptoms of the same underlying process, with the diagnostic focus determined by which symptoms are most prominent in a given person, and by the physician’s or patient’s emphasis on somatic as opposed to psychologic symptoms. The main support for this hypothesis comes from the fact that both hyperventilation syndrome and panic disorder are strikingly similar descriptive syndromes without known cause and that, despite a clear association between the two, there is no clearcut relationship between them. In addition, some of the major etiologies currently proposed for panic disorder also provoke hyperventilation. Panic disorder has been suggested to result from increased beta-adrenergic activity [82,83], or from dysregulation of the locus ceruleus [ 121, producing increased central noradrenergic and sympathetic nervous system activity. Panic disorder patients show increased autonom-

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ic arousal at rest [31]. Since hyperadrenergic states increase ventilatory response to carbon dioxide by about 30 percent and produce hyperventilation [81], increased sympathetic nervous system arousal could produce both panic and hyperventilation. However, significant increases in peripheral catecholamine levels have not been demonstrated consistently in lactate-induced panic [31,84,85]. Rainey et al [55] have suggested that panic results from cellular hypoxia, which would also stimulate ventilation [50,86]. Alternatively, since both hyperventilation and panic episodes often occur after exercise or with relaxation as when falling asleep, decreased parasympathetic tone has also been suggested as an etiology for both conditions [87]. Klein [88] has suggested that panic attacks result from a lowered threshold for activation of a central “alarm” system associated with separation anxiety. We propose that most patients with either panic disorder or hyperventilation syndrome share hypersensitivity of a central alarm system mediating the general response to danger, rather than to separation alone. Activation of this system produces both panic and hyperventilation, which in some cases reinforce each other to establish a chronic condition. According to this hypothesis, an underlying biologic and often inherited vulnerability leads to hypersensitivity of a central nervous system alarm that is usually activated by life-threatening situations, causing the “fight or flight” response. In patients with panic disorder, this alarm is triggered inappropriately, causing a panic response with no or little apparent cause. The central alarm system may include the locus ceruleus and associated areas. Panic disorder patients in whom there is a response to lactate have been shown to have increased blood flow in the resting, non-panic state to the right parahippocampal gyrus, an area that receives abundant projections from the locus ceruleus [89]. Activation of the alarm system probably results from multiple stimuli including cognitions, the learned or pre-wired interpretation of a perceived object or situation as dangerous, direct toxic chemical stimuli, and physiologic stimuli such as acid-base changes, abrupt blood pressure or temperature changes, or cellular hypoxia. Patients with panic disorder may be hypersensitive to all or some of these factors. In a few cases, the cellular hypoxia and hypophosphatemia resulting from acute hyperventilation could trigger this alarm in vulnerable patients. In this model, the alarm system, once triggered, produces a variety of hormonal, psychologic, and compensatory physiologic responses including panic, hyperventilation, and possibly a hyperadrenergic state. These episodes of autonomic arousal and symptoms of hypocapnia, occurring without appropriate environmental stress, are interpreted according to the patient’s past experience and characteristic coping style. Thus, some persons may interpret attacks as due to anxiety, whereas

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others may believe that they are having a heart attack or other life-threatening disease. The attack itself is usually self-limited, perhaps as a result of feedback inhibition of the locus ceruleus and by the patient’s ability to escape to a “safe” setting. However, repeated attacks may lead to hypochondriasis, visits to numerous physicians and emergency rooms, and phobias with avoidance of situations in which attacks have occurred. In many cases, the acute hyperventilation provoked by attacks might become chronic, with chronic hypophosphatemia, hypocapnia, and subjective respiratory distress predisposing the patient to further hyperventilation and panic attacks, which would in turn cause further hyperventilation. Thus, panic and hyperventilation, once established, would reinforce each other by means of a positive feedback loop. A similar mutually reinforcing cycle of hyperventilation and anxiety has been proposed by several authors [ 18,20,26] to account for the development of hyperventilation syndrome. The presence of hyperventilation may act as one factor determining which of the 35 percent of people who experience panic attacks go on to have frequent attacks or panic disorder or which patients with generalized anxiety disorder go on to have panic attacks. Conversely, underlying vulnerability to panic may influence in which persons hyperventilation episodes lead to hyperventilation syndrome. Treatments directed at any part of this loop would be successful in panic disorder and hyperventilation. Antidepressants are known to decrease firing of the locus ceruleus [go], whereas cognitive and breathing treatments might affect triggering of the alarm system or the perpetuation of symptoms by hyperventilation and fear of fear. This theory suggests several lines of future research, including family and genetic studies of hyperventilation syndrome, prospective studies of hyperventilation and startle or alarm responses in children whose parents have panic disorder and who are thus at increased risk for the disorder, clinical studies of the extent to which hyperventilation syndrome and panic disorder patients are similar, studies of the role of cognitive factors in these disorders, and studies of changes in the central nervous system and especially the locus ceruleus in humans and animal models with hyperventilation, panic, hypophosphatemia, and cellular hypoxia. CLINICAL RELEVANCE The demonstration of a strong association between hyperventilation syndrome and panic disorder, even without a clear understanding of the relationship between them, has important clinical implications. Both hyperventilation syndrome and panic disorder should be suspected in patients presenting with symptoms included in Table I. Patients diagnosed as having hyperventilation syndrome should be questioned carefullv

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about sudden episodes of panic. Treatment should consist of provocation of characteristic symptoms with voluntary hyperventilation, preferably in the presence of family members, and a breathing treatment involving slowed, abdominal breathing or rebreathing using a paper bag. In the case of treatment-resistant hyperventilation syndrome or hyperventilation syndrome with frequent panic attacks, treatment with an antidepressant such as imipramine, desipramine, or phenelzine should be considered. Panic attacks may also be complicated by such serious conditions as major depression [9 I], agoraphobia [43,44], and alcohol and substance abuse [92,93]. The clinician seeing a patient with hyperventilation syndrome should thus also search carefully for these problems. In turn, hyperventilation should be suspected in all patients presenting with panic attacks. An attempt should be made to confirm the diagnosis using the hyperventilation provocation test. Hyperventilation syndrome should be suspected even if this test induces only physical symptoms characteristic of hyperventilation, rather than a typical panic attack. Breathing treatments should be considered, especially in panic disorder patients with demonstrable hyperventilation. These treatments offer an

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exciting alternative or adjunct to medication in these patients since they involve imparting a sense of mastery to the patient and since many patients with panic disorder seem particularly sensitive to medication side effects. In addition, treatment studies of patients with both of these conditions underscore the role of cognitive factors in determining the course of illness. Thus, thorough patient education and provocation of typical symptoms when possible are important therapeutic tools in both panic disorder and hyperventilation syndrome. COMMENTS In the past, patients affected by panic disorder and the hyperventilation syndrome, with their presentation of multiple, vague, and alarming symptoms, have been puzzling and often frustrating to clinicians. They have frequently been dismissed as “neurotic” and hypochondriacal or have undergone lengthy, uncomfortable, and costly medical workups. The increasing evidence for a clear association between these disorders opens up exciting possibilities for more accurate diagnosis, a wider variety of treatments, and a better understanding of the biologic and cognitive mechanisms underlying the two conditions.

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