Panic, hyperventilation and perpetuation of anxiety

Bog_ Ifeuro-Psychopharmacol.

&Ed.

Psychiat. 2000, Vol. 24, pp. 1069-1089 Copyright Printed

8 2000 Elsevier

in the USA.

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front matter

PII:SO278-5846(00)00130-5

PANIC, HYPERVENTILATION

AND PERPETUATION

OF ANXIETY

LUIZ DRATCU Guy’s Hospital, Division of Psychiatry, Guy’s, King’s and St Thomas’ School of Medical Sciences, London, United Kingdom

(Final form, September

2000)

Qntents

1.

2. 3. 4. 5. 6. 7. 8. 9. 10.

Abstract Introduction Provocation of Panic and the Neurochemistry of Anxiety Sodium Lactate and Chemoreceptors Hyperventilation and Carbon Dioxide Klein’s Suffocation Alarm EEG of Panic Patients in the Non-Panic State: Hyperventilation and Cerebral Hypoxia? COPD, Cerebral Hypoxia and Anxiety Panic Patients in the Non-Panic State: Brain Imaging Studies Hyperventilation and Chronic Anxiety Conclusions Ackowledgement References

Abstract Dratcu, Luiz: Panic, Hyperventilation and the Perpetuation of Anxiety. Prog. Psychopharmacol. & Biol. Psychiat 2000, a, pp. 1069-1089. 02000 Elsevier Science Inc.

Neuro-

1. Studies on the pathogenesis of panic disorder (PD) have concentrated on panic attacks. However, PD runs a chronic or episodic course and panic patients remain clinically unwell between attacks. Panic patients chronically hyperventilate, but the implications of this are unclear. 2. Provocation of panic experimentally has indicated that several biological mechanisms may be involved in the onset of panic symptoms. Evidence from provocation studies using lactate, but particularly carbon dioxide (COl) mixtures, suggests that panic patients may have hypersensitive CO2 chemoreceptors. Klein proposed that PD may be due to a dysfunctional brain’s suffocation alarm and that panic patients hyperventilate to keep pCO;! low. 3. Studies of panic patients in the non-panic state have shown EEG abnormalities in this patient group, as well as abnormalities in cerebral blood flow and cerebral glucose metabolism. These abnormalities can be interpreted as signs of cerebral hypoxia that may have resulted from hyperventilation.

L. Dratcu

1070

4. Cerebral hypoxia is probably involved in the causation of symptoms of anxiety in sufferers of chronic obstructive pulmonary diseases. By chronically hyperventilating, panic patients may likewise be at risk of exposure to prolonged periods of cerebra1 hypoxia which, in turn, may contribute to the chronicity of their panic and anxiety symptoms. 5. Chronic hyperventilation may engender a self-perpetuating mechanism within the pathophysiology of PD, a hypothesis which warrants further studies of panic patients in the non-panic state. Kevwords: anxiety; cerebra1 hypoxia; chronic obstructive pulmonary hyperventilation; panic disorder; positron emmission tomography.

disease; electroencephalogram;

Abbreviations: benzodiazepines (BDZs), carbon dioxide (CO?), cerebra1 blood flow (CBF), chronic obstructive pulmonary disease (COPD), electroencephalogram (EEG), generalised anxiety disorder (GAD), hypothalmic-pituitary-adrenal axis (HPA axis), obsessive compulsive disorder (OCD), panic disorder (PD), partial pressure of CO2 (pCOs), positron emission tomography (PET), selective serotonin reuptake inhibitors (SSRIs).

PD is an anxiety disorder where panic attacks are frequent. PD has a prevalence of over 2% and a high comorbidity

with other psychiatric

syndromes,

particularly

other anxiety disorders

and depression

(Wittchen et al., 1991). Like other anxiety disorders, PD follows a chronic or episodic course (Angst and Vollrath, 1991). Without treatment, many patients report having the disorder for over 20 years (Wittchen and Essau, 1993). A significant progress in understanding biochemical

the pathogenesis

of PD has been made with the introduction of

methods to induce panic attacks in the laboratory (Kahn and Van Praag, 1992). While the

vast majority of studies on PD that followed have been concerned with panic attacks, the abnormalities that these patients may present in the non-panic state have attracted little attention. Unfortunately,

most

panic patients remain unwell between panic attacks. Comorbidity of PD with depression or agoraphobia is the rule rather than the exception

(American

Psychiatric

Association,

1994), but these can be

understood as secondary to the illness. However, there are other changes that occur in the non-panic state that may play a part in the pathogenesis

and course of the illness itself. In addition to persistent anxiety

symptoms, panic patients in the non-panic state have a distorted cognitive perception of their bodily and mental functioning and they also hyperventilate Neurochemical

(Dratcu and Bond, 1998).

models for panic attacks are unlikely to account fully for symptoms that panic patients

experience in the non-panic state. Yet, panic patients experience anticipatory or background

anxiety in

addition to panic attacks, and most still report residual symptoms after they have received treatment with antipanic agents (Roy-Byrne and Cowley, 1994/1995). Probably because this background anxiety can be severe, comorbidity ofPD with GAD can be as high as 60-80% (Breier et al., 1986; Cassano et al., 1990). Moreover, despite the different interpretations

that the association of panic attacks with hyperventilation

Panic, hyperventilation has received

and the perpetuation

1071

of anxiety

(Gorman et al., 1984; Lum, 1987; Klein, 1993) the clinical implications

hyperventilation This article

that chronic

may have for patients, particularly in the long term, are not known. reviews

chemoreceptors

the experimental

evidence

that led to the theory

in PD, followed by a discussion of how hyperventilation

light of this theory

Physiological

of hypersensitive

in panic patients is seen in the

abnormalities that panic patients were found to have in the non-panic

state are described, including results of EEG and brain PET scan studies. These abnormalities possibility

that patients who chronically hyperventilate

hypoxia secondary to hyperventilation anxiety symptoms,

a hypothesis

CO?

raise the

may be exposed to cerebral hypoxia. Cerebral

may be a contributing

factor to the pathogenesis

of panic and

supported by the clinical features that panic patients share in common

with sufferers of COPD.

2. Provocation of Panic and the Neurochemistrv Research on the neurochemistry

of anxiety has adopted studies of the effects of substances

reduce or induce anxiety as its main strategy. It is understood mechanisms

of Anxiety

that information

that can

about the biological

of anxiety can be obtained by examining the association of the psychophysiological

of these agents with their pharmacological

mode of action (Haefely,

model of panic attacks, a variety of panic-provoking

agents have been investigated.

putative mode of action of these agents, different dysfunctions exacerbated

response

effects

1991). In search of a biological On the basis of the

have been hypothesised

to explain the

found in PD patients when compared to healthy subjects or patients with other

psychiatric disorders (Kahn and Van Praag, 1992; Nutt and Lawson, 1992). Following the pioneer study of Pitts and McClure (1967) using sodium lactate, agents subsequently include bicarbonate,

carbon dioxide, noradrenergic

caffeine, hypoglycaemia,

cholecystokinin

compounds,

employed in provocation

drugs with affinity for BDZ-receptors,

and serotonergic agonists (Fig 1).

Guttmacher et al. (1983) and Gorman et al. (1987) set out the criteria for an ideal panicogenic laboratory

studies, namely: safety i.e. the agent, in the panicogenic

administration

agent for

dose, should be safe for routine

to human subjects; symptom convergence i.e. patients should judge the induced attack to

be symptomatically provocation

studies

identical or very similar to their spontaneously

stimulus

should

exhibit

either

absolute

occurring attacks; specificity i.e. the

or threshold

specificity

for panic

patients;

replicubility i.e. the effects of the agent should be consistent in a given patient. If a desensitisation occurs this should be predictable; and clinical validation i.e. drugs that block spontaneous such as antidepressants agents

that

or BDZs, should also block the pharmacologically-induced

do not block

pharmacologically

clinical

panic

attacks,

such

as propranolol,

effect

panic attacks,

attacks. Conversely, should

not

block

the

induced attacks. Criticisms of chemical models of panic have been made in the light

Fig

caffeine d

/

PANIC/ANXIETY

4

dysfunctlonel bnrodiazeplns-

hypqlycaemla

neuropeptldes (CC&

drugs wllh affinity for

1: Neurochemical mechanisms involved In provocation of panic attacks by different agents.

blockade of adenoslne receptors

control oi noradrenerglc activity

catechdamlnes

Panic, hyperventilation

and the perpetuation

of these criteria, as well as in terms of mechanism methodological

1073

of anxiety

of action, construct validity of panic attacks and

design (Uhde and Tancer, 1989).

Firstly, the actual pharmacological

mechanisms

involved in the mode of action of many of the agents

used to induce panic are obscure. This seems especially true when substances which do not cross the blood-brain

barrier, such as lactate and isoprenaline,

are used. Lactate infusions,

motion a series of metabolic changes with little agreement among investigators

for example,

set in

about which ultimately

provoke the panic attacks (Lader, 1991). Moreover, as these agents are unlikely to exert any direct action on the CNS,

any explanation

pharmacological

anxiogenic

effects

has to take the influence

of non-

are known to exert different actions and to interact at different

levels in

factors into account.

Secondly, neurotransmitters the brain. Therefore, panicogenic

of their

it is possible that there are several mechanisms,

and not just one, involved in the

action of a given agent (Gorman et al., 1987). Also, the mode of action of a given agent

may not always have a direct connection

with the defect causing patients to have panic attacks. It

seems plausible that a given agent may precipitate panic by activating a biological mechanism is not directly related to its primary, immediate secondarily

activated

by it (Dratcu and Lader,

pharmacological

their panicogenic

effect fail to explain the panicogenic

affect the same neurochemical

mode of action, but which can be

1993). Finally,

specific modes of action, and which cross the blood-brain

even when agents with putatively

barrier, are used, the theories derived from

effect of all other agents that apparently

CO2 mixtures and the finding that panic patients are particularly susceptible CO* challenge has proved to meet the criteria for a good panicogenic

bringing

to CO1 may have elements

about the prospect

do not

system (Gorman et al., 1987).

An important advance in this area has followed the advent of provocation

the panic response

which

in common

of a single mechanism

studies using inhalation

to increases in pCOz. The

(see below).

More interestingly,

with the panic response

underlying

of

to lactate, thus

the panic response

to two different

agents.

3. Sodium Lactate and Chemoreceptors The theory behind the lactate infusion procedure stems t?om the observation that patients with anxiety disorders have a less efficient exercise response than normal controls, with greater rises in blood lactate. From this, Pitts and McClure (1967) suggested that anxiety attacks might be produced in susceptible individuals intravenously precipitated

by the rise in blood lactate, a hypothesis into 14 patients symptoms

suffering

in 13 patients

which they tested by infusing

from anxiety

neurosis

(and two control subjects)

and 10 nonnal

sodium lactate

controls.

which ‘were markedly

Lactate

similar or

L. Dratcu

1074 identical to those experienced had anxiety symptoms

in their ‘worst anxiety attacks’. None of the patients or control subjects

in response to the saline-glucose

control infusion. Pitts and McClure’s

(1967)

finding has been replicated in a number of studies which showed that infusion of 0.5 to 1 M sodium lactate consistently

induced panic attacks in 26-100% of panic patients in contrast to O-30% of normal

controls (Kahn and Van Praag, 1992).

Pitts and McClure (1967) originally suggested that the effect of lactate was due to hypocalcaemia,

but

Grosz and Farmer (1969) pointed out that the rise in lactate produced by the infusion would cause only a minor change in the ionised calcium concentration

in the blood. Maddock and Mateo-Bermudez

(1990)

claimed to have ruled out the possibility that panic patients were simply less fit than healthy subjects. They observed that patients produced more lactate than controls not only during exercise, but also in response to metabolic challenges such as ventilatory hyperventilation Carr and Sheehan chemoreceptors vasoconstriction,

(1984) proposed

by two mechanisms.

that infusions

during iatrogenic hyperglycaemia.

of lactate lower intracellular

pH in medullary

The systemic alkalosis produced by sodium lactate causes cerebral

ischaemia and consequently

an elevation in the intracellular

1actate:piruvate ratio. At

the same time, the infusions directly increase the 1actate:piruvate ratio in brain regions outside the bloodbrain barrier, such as the chemoreceptors

area. Panic patients could be hypersensitive

so that lowering of pH following lactate administration

to changes in pH

would precipitate panic attacks in patients but

not in normal controls, This theory, however, has not been corroborated. Finally, Liebowitz

et al. (1984, 1985) argued that lactate precipitated

alkalosis and stimulating

the respiratory

peripheral pH and is the penultimate both lactate and bicarbonate that bicarbonate alkalosis

hypoventilation,

in which bicarbonate

than lactate suggests that panic could not be due to metabolic

metabolic

alkalosis

is further metabolised

due to bicarbonate

usually

leads to compensatory

during a panic attack. into CO?. Carbon dioxide crosses the blood-brain

and increases the ventilatory rate by stimulating ventral medullary chemoreceptors. light on the mode of action of lactate, the panicogenic related

to activation

chemoreceptors

(which increases

metabolite of lactate) would also be involved. However, although

whereas patients hyperventilate

However, bicarbonate

a process

provoke panic attacks in panic patients (Gorman et al., 1989), the finding

is less anxiogenic

alone, Moreover,

centres,

panic by inducing metabolic

of CO* chemoreceptors.

barrier

This may shed some

effect of which could also be at least in part

A link between

panic

attacks

and altered

could also provide a rationale to explain why panic patients hyperventilate.

CO2

In fact,

elevation in pC02 has also been shown to provoke panic attacks in susceptible individuals, as discussed next.

Panic, hyperventilation

and the perpetuation

4. mervedation

Hyperventilation

1075

of anxiety

and Carbon Dioxide

is observed during naturally occurring or pharmacologically

induced panic attacks,

and also in panic patients between attacks (Gorman et al., 1984). There are three main views concerning the relationship between hyperventilation attacks

because

hyperventilation

it lowers

pCOz.

and panic. First, hyperventilation

Second,

follows as a physiological

panic

attacks

is the primary cause of panic

are caused

by

response. Finally, hyperventilation

increased

pC02,

and

occurs as a mechanism

to

protect against panic attacks. Hyperventilation

itself has been considered a means of provoking panic attacks, an effect thought to be

due to lowering of pCO2 and the respiratory alkalosis that ensues (Lum, 1987). Indeed, re-breathing

air

enriched with CO2 from a “brown bag” has been used as a technique to curtail panic attacks, as it would reinstate pC02 to normal levels. However, this was disproved by Garssen et al. (1996), who used a fearprovoking situation to induce hyperventilation

in a group of 28 panic patients. From a total of 24 panic

attacks observed in the study, only one was associated with a fall in pCO2. The view that panic attacks result from respiratory

alkalosis following

hyperventilation

has been

superseded by the finding that a single inhalation of 35% CO2 i 65% 02 given to 12 panic patients and 11 normal subjects instantaneously

elicited panic-like symptoms in three and high levels of anxiety in

nine of the patients (Griez et al., 1987). The control subjects rarely rated their symptoms fear. This was further demonstrated

as anxiety or

by Gorman et al., 1988, who found a 5% COz air mixture inhaled

for 20 minutes provoked panic attacks in seven of 12 panic patients but did not in any of four normal controls. Griez et al. (1990) extended their observations

by administering

35% CO2 or compressed

air

(as a placebo control) to groups of panic patients, OCD patients and normal controls. Increases in score for panic symptoms

were significant in all groups. However, while the OCD patients and the control

subjects did not differ from each other, ratings for panic symptoms were significantly

higher for panic

patients as compared to both. Gorman et al. (1988) speculated that CO2 may cause panic through activation of the locus coeruleus and that PD patients

have abnormally

which normally induce increased

sensitive

ventilation

medullary

chemoreceptors.

when pCO2 rises (hypercapnia),

These chemoreceptors, would be activated

at

lower levels of CO2 in panic patients. Bass (1987) and Gelder (1987) however, have argued that, rather than differences

in physiological

sensitivity to CO2 per se, panic attacks in response to either a decrease

or increase of pC0~ could actually be a result of ‘catastrophic’ cognitive interpretations

that PD patients

make of the peripheral changes induced by manipulation of CO* either way. Papp et al. (1993b) attempted to address this issue by testing the hypothesis that it is CO:! specifically, and not the physiological

distress of breathlessness,

which causes panic attacks in PD patients. They

1076

L. Dratcu

compared the responses of panic patients, patients with social phobia and normal controls to inhalation of a mixture of 35% CO2 I 65% 02 for 30 seconds to their responses to a procedure in which subjects had to breathe for 30 seconds through a valve reducing the diameter of the airway. Carbon dioxide inhalation was significantly

more potent than increased

airway resistance

anxiety disorder patients. Moreover, panic patients were significantly

in provoking

panic in the

more sensitive to CO? than were

the patients with social phobia or normal subjects. It was concluded that CO2 inhalation appears to have a specific panicogenic

effect in panic patients that goes beyond simple breathlessness.

The CO1 challenge has proved to meet the criteria for a good panicogenic.

COz-induced

attacks: are a

safe research procedure (Harrington et al., 1996); can be blocked by treatment with SSRIs, which also block naturally occurring panic (Pols et al., 1996); have good test-retest reliability (Verburg et al., 1998); are not influenced

by the experimental

setting (Welkowitz

et al., 1999); and have been successfully

replicated in different groups of panic patients (Biber and Alkin, 1999).

5. Klein’s Suffocation Alarm Papp et al. (1993a) also considered cognitive factors to be relevant in COz-induced panic attacks. After reviewing the relationship between hyperventilation

and PD linking CO1 hypersensitivity,

cognitive and

behavioural factors, and the respiratory effects of antipanic treatments, they concluded that PD might be due to an unstable

autonomic

abnormalities

such

as hyperventilation

hypersensitive

brain stem autonomic control mechanism. Challenges that trigger this control mechanism

result in acute hyperventilation. derealisation,

nervous

system

coupled

with cognitive

and CO;! hypersensitivity

Secondary hyperventilatory

may frighten some psychologically

may

distress.

Thus respiratory

be manifestations

of a

symptoms, such as chest pain, dizziness and

vulnerable patients into catastrophic

thinking,

thus

intensifying the panic experience. In line with these findings, Klein (1993, 1996) suggested that CO* chemoreceptors specific alarm and escape mechanism patients. Thus spontaneous

sensitive to asphyxiation

that is erroneously

panic may be a specific false alarm due to a misfiring

According to this theory, chronic hyperventilation

are linked to a triggered suffocation

in panic alarm.

is protective against panic by keeping pC02 below the

suffocation release threshold. Klein (1993) also differentiates

panic induced by yohimbine, caffeine, m-CPP, flumazenil and inverse

BDZ agonists from panic induced by lactate, bicarbonate and carbon dioxide. He claims that, as in acute fear and uncontrollable

stress, the former is associated with HPA activation and increased cortisolaemia,

but not with respiratory symptoms. Only the latter, which is associated with dyspnoea and lack of HPA activation, Klein states, is truly similar to naturally occurring panic, where the spontaneous

suffocation

Panic, hyperventilation alarm’ concept is valid.

and the perpetuation

1077

of anxiety

Consistent with this view, Biber and Alkin (1999) reported an experiment

which panic patients with prominent respiratory symptoms were found to be significantly to the CO2 challenge than panic patients with the nomespiratory

in

more sensitive

subtype of attacks.

However, there seems to be no empirical evidence that only induced panic with respiratory symptoms, and without HPA activation, is truly similar to naturally occurring panic attacks. Moreover,

the 35%

carbon dioxide challenge, one of the cornerstones of the suffocation alarm theory (Klein, 1993) does not necessarily

discriminate

PD from GAD. Verburg et al. (1995) compared

the responses

of 9 panic

patients with those of 9 GAD patients to inhalation of a 35% CO* / 65% 02 mixture. Panic patients experienced

a significantly

stronger increase in subjective anxiety than GAD patients but increases in

panic symptoms were high in both groups. It was concluded that a large increase in subjective anxiety due to the CO2 challenge is specific for panic patients, but an increase in panic symptoms is not. Later, Cardirola et al. (1997) compared the effects of the 35% CO2 inhalation in a group of panic patients and a group of patients with social phobia. Both groups had a similar anxiogenic response to the challenge. Still, it now seems well established that sensitivity to CO2 and hyperventilation pathogenesis

of PD, but perhaps of other anxiety disorders

dysfunctional

suffocation alarm for PD is correct, hyperventilation

as well. If Klein’s (1993) theory of a represents a physiological

that patients adopt in the attempt to keep pCOz low. This protects patients suffocation

are key elements in the

adjustment

from a hypersensitive

alarm that can misfire in response to fluctuations in pCO2. As a corollary to this theory,

panic patients would tend to become chronic hyperventilators, Nonetheless,

it remains

uncertain

whether

vulnerability

as seems to be the case. to panic

induced

by CO2 also implies

vulnerability to panic induced by lactate. Although in theory the ultimate panic-provoking both procedures may be the same, i.e. stimulation of COz-sensitive chemoreceptors,

mechanism

of

the two procedures

should be compared in the same group of patients before any definite conclusion can be drawn.

6. EEG of Panic Patients in the Non-Panic State: Hyperventilation

and Cerebral Hynoxia?

Compared with the large number of studies on panic attacks, only a few studies have focused on the physiological

changes that panic patients may present between panic attacks. This is puzzling,

first

because many of these patients remain clinically unwell even when they are not panicking, and second, because panic patients do spend most of the time in the non-panic state, however frequent or severe their panic attacks might be. In a study comparing unmedicated

panic patients in the non-panic state with healthy control subjects,

self-ratings of both bodily and psychological as were measurements

of physiological

symptoms of anxiety were significantly

indices of anxiety, such as skin conductance

higher in patients, (Dratcu and Bond,

L. Dratcu

1078

1998). However, patients were also found to have significantly The likeliest explanation hyperventilating.

more slow wave activity on the EEG.

for this was thought to be that patients, unlike the controls, were probably

Further scrutiny

of the data confirmed

that patients

rated themselves

as feeling

significantly more breathless than the control subjects (Dratcu, 1999) (Tablel).

Table 1 EEG of Panic Patients and Healthy Subjects in the Non Panic Statea EEG wavebands

panic patients (n = 14)

(uV2)

healthy subjects (n = 7)

2-4H.z 4.5 - 7.5 Hz 8-13Hz 13.5-26Hz

3.6 +_1.3 3.2 & 1.9 5.4 + 3.7 2.3 f 1.6

2.1 + 1.3 3.8 + 3.9 7.0 * 6.6 2.2 * 2.2

breathlessnessb

22.5 + 23.9

2.6 k 3.7

P<

0.05 n.s. ns. ns. 0.05

a Based on Dratcu, 1999; Dratcu and Bond, 1998. b Bodily symptom scale (lOOnun analogue scale, varying from 0 = absent to 100 = severe) These results are similar to those previously anxious patients with unilateral

diagnosed somatic

hyperventilation

as suffering

symptoms,

reported by O’Sullivan

from hyperventilation

et al. (1992) in a study of nine

syndrome

only two of which had a diagnosis

syndrome was confirmed

and who were presenting of PD. The diagnosis

of

by an end-tidal pCOr of less than 30 mmHg at rest. Six of

the nine patients were found to have abnormal EEGs in the resting state, involving wave activity in one or both cerebral hemispheres.

Voluntary overbreathing

an excess of slow

not only exacerbated

the

slow waves in most patients who already had an excessive EEG slow wave activity in the resting state, but also produced slow wave activity in two of the three patients whose EEG was normal at baseline.

In normal adults, increase of EEG slow wave activity is associated with hyperventilation

and a fall in

pCOr (Kiloh et al., 1981). Van der Warp et al. (1991) used quantitative EEG to assess hyperventilationinduced EEG changes in healthy subjects and confirmed

that hyperventilation

caused an exponential

increase in slow wave activity. The underlying basis of this association is thought to lie in the systemic alkalosis that results from hyperventilation, anoxia (Lishman,

which may lead to cerebral vasoconstriction

1998). Adler (1991) used controlled

hyperventilation

transient ischaemic hypoxia of the brain in healthy subjects. Hyperventilation reduce the P2 amplitude

of the cortical auditory evoked response,

experimentally

and cerebral to induce

was found to significantly

an effect thought to reflect

impairment of synaptic function produced by cerebral hypoxia. In a study using dogs, Kennealy

an

et al.

Panic, hyperventilation (1980) were in fact able to demonstrate

between

1079

of anxiety

directly that acute respiratory alkalosis decreased cerebral blood

flow, increased the affinity of haemoglobin The association

and the perpetuation

for oxygen, and induced cerebral hypoxia.

hyperventilation

and EEG slow wave activity,

an indicator

of cerebral

hypoxia, may be of clinical significance to PD. As anxiety disorders tend to have onset early in life and follow a chronic or episodic course (Angst and Vollrath, 1991; Oakley-Browne,

1991), panic patients

are potentially exposed to long periods of EEG slow wave activity by chronically

hyperventilating.

hyperventilation

will cause cerebral

can cause cerebral hypoxia, presumably

hypoxia for prolonged

chronic hyperventilation

If

periods. If this is true, cerebral hypoxia secondary to chronic hyperventilation

may represent a fiuther factor to be considered in the pathophysiology

7. COPD. Cerebral Hpoxia

of PD.

and Anxiety

There is at least evidence that panic patients who hyperventilate

are more susceptible to lactate-induced

attacks. Coplan et al. (1998) compared baseline pre-lactate infusion measures of a large group of panic patients who panicked following the lactate challenge with those of panic patients who did not panic and healthy subjects. Patients who panicked hyperventilation

and self-reported

in response to lactate were found to have higher levels of

fear and dyspnoea

at baseline,

as well as lower levels of pCOz.

Baseline scores of fear correlated inversely with pCO2 levels and hence positively with hyperventilation. These results are consistent with previous research showing that the three most predictive symptoms of lactate-induced

panic are feelings of fear, dyspnoea and desire to flee (Goetz et al., 1996).

In the light of the evidence for a relationship between PD and a dysfunctional

respiratory system, it is

revealing, albeit well known, that patients with COPD tend to be chronically anxious and depressed by the time that hypoxia has become chronic (Vachon, 1989). There has indeed been a growing interest in the interface between

anxiety disorders,

panic attacks and pulmonary

particularly PD, and COPD, not Ieast because symptoms

disease overlap (Smoller et al., 1996). Asmundson

of

and Stein (1994), for

example, observed that panic patients with a lower level of pulmonary function are the subgroup most likely to experience respiratory and fear symptoms during panic attacks. Lending

support to the view that hyperventilation

argued that further research association

between

is a consequence

in this field would have much to gain by looking at the nature of the

anxiety disorders

and obstructive

lung disease.

hypoxia might occur as a result of chronic hyperventilation, have more in common patients develop

than respiratory

is implicated

of panic attacks, Bass (1997)

symptoms

Yet, if it is true that cerebral

perhaps panic and COPD patients may

alone, particularly

in the anxiety symptoms

patterns seem to emerge Tom studies of anxiety in COPD.

if the hypoxia

that COPD

from which they suffer. Three main broad

1080

L. Dratcu

First, patients suffering from COPD do have a high rate of anxiety and panic symptoms and also a high prevalence of PD. For instance, the great majority of the 48 COPD patients examined by Borak et al. (1991) had a high degree

of anxiety

and depression,

as measured

by a range of psychometric

instruments. Kellner et al. (1992) used a symptom checklist and a symptom questionnaire

to compare a

group of 50 COPD patients with a group of matched family practice patients. Patients in the COPD group were significantly

more anxious and depressed than those in the control group. In another group

of 50 COPD patients consecutively high rate of psychiatric

morbidity

prevalent. This is consistent

admitted to a respiratory unit, Yellowlees

et al. (1987) detected a

(58%), panic and other anxiety disorders (34%) being particularly

with the study of Porzelius et al. (1992) where 18 (37%) of 48 COPD

patients reported experiencing

a panic attack. Finally, Karajgi et al. (1990) adopted DSM diagnostic

criteria to assess 50 outpatients with stable COPD. They found a lifetime prevalence

of 8% for PD in

this group of patients, about three times higher than in the general population,

Second, although most COPD patients may be chronically anxious, their levels of anxiety seem to be closely associated with the severity of their dyspnoea.

In a study of a group of elderly patients with

COPD, periods of greater anxiety coincided with periods of highest levels of dyspnoea (Gift and Cahill, 1990). Conversely,

dyspnoea and anxiety in a group of COPD patients abated concomitantly

an exercise treatment programme

(Carrieri-Kohlman

et al., 1996). This was investigated

in a study of the response of COPD patients to a programme of progressive

following

in more detail

muscle relaxation (Remroe,

1988). Not only was dyspnoea found to correlate positively with levels of anxiety, but the correlation also remained consistently

significant throughout the treatment sessions, at the end of which both had

significantly diminished. Third, there is evidence that pharmacological can reduce symptoms dyspnoea

following

agents that are commonly

used for the treatment of PD

of both anxiety and dyspnoea in COPD patients. Intriguingly, treatment with these drugs may not necessarily

amelioration

be related to anxiolytic

of

effects,

Greene et al. (1989) reported one anxious patient with COPD whose symptoms of dyspnoea and anxiety both improved conducted

following

by Shivaram

placebo for two weeks.

treatment with low doses of alpmzolam.

In a double blind crossover

et al. (1989), 12 patients with COPD received Alprazolam

proved effective

in relieving

alprazolam

Further, in a 12-week randomised

controlled

patients with comorbid

depression.

not only of their depression,

whereas

four

of their dyspnoea.

trial, Borson et al. (1992) compared

therapeutic doses of nortriptyline (a tricyclic antidepressant)

0.25 mg tds or

anxiety symptoms,

patients dropped out of the study while receiving placebo because of worsening

study

treatment

using

with placebo treatment in a group of COPD

Patients receiving nortriptyline

showed a significant

but also of their anxiety and respiratory symptoms.

improvement

Finally, Smoller et al.

(1998) reported that adding sertraline 25-100 mg daily (an SSRI) to the medication regime of 7 COPD

Panic, hyperventilation

and the perpetuation

1081

of anxiety

patients substantially improved symptoms of dyspnoea, an effect that seemed independent

of anxiolytic

effects as most of the patients (four) did not meet diagnostic criteria for either a mood or an anxiety disorder. In a comprehensive Smoller

review of the relationship

et al, (1996) concluded

between

panic, dyspnoea

and respiratory

that panic anxiety can reflect cardiopulmonary

disease,

disease, whereas

dyspnoea can reflect an underlying anxiety disorder. On the one hand, pulmonary disease could be seen as a risk factor for PD as a consequence exacerbation

of pulmonary

episodes of hypercapnia

dysfunction

that these patients

or hyperventilation.

to respiratory physiology by mechanisms misinterpretations

of the repeated episodes of dyspnoea

of respiratory

experience,

and life threatening

coupled

On the other hand, the pathogenesis

with the repeated

of panic may be related

such as the anxiogenic effects of hyperventilation,

symptoms,

and neurobiological

sensitivity

catastrophic

to COz, lactate, or other

signs of suffocation. However, there is yet another side to the connection between dyspnoea and anxiety in COPD patients that should not be overlooked.

Respiratory dysfunction

may well induce changes on pCO2, but it may

also reduce the supply of oxygen to the brain, as is the case in COPD (Lisbman, oxygenation

symptoms

COPD patients not be reflecting mitigate patients’ anxiety? intervals is implicated

symptoms

Enhanced

is likely to play a part in the therapeutic effect that exercise has been shown to have on

anxiety and dyspnoea

cerebral

1998).

function

of COPD patients. Thus, could the anxiety symptoms the effects of cerebral hypoxia,

the amelioration

observed

in

of which could

If the answer is yes, presumably exposure to cerebral hypoxia for extended

in the causation of anxiety in COPD patients. Moreover, persistent

that might follow chronic hypoxia could contribute

to the chronicity

changes in of anxiety

in this patient group. The same principle may in theory also apply to panic patients. Panic

patients in the non-panic state have been shown to have abnormalities in cerebral function that may lend some supportto this claim.

8. Panic Patients in the Non-Panic State: Brain Imaeing Studies Brain imaging studies of panic patients in the non-panic state indicate the presence of abnormalities involving both CBF and cerebral glucose metabolism.

In the pioneer PET study of PD, Reiman et al.

(1984) found that panic patients who had had a panic response to lactate infusion showed an abnormal asymmetry of CBF (left less than right) in the parahippocampal further reported that, compared

gyms. The same group of researchers

with panic patients who did not panic following

lactate infusion or

normal controls, patients who were vulnerable to lactate had an abnormal hemispheric parahippocampal

flow, blood volume and oxygen metabolism (Reiman et al., 1986).

asymmetry

of

1082

L. Dratcu

Nordahl et al. (1990) used PET scanning to compare cerebral glucose metabolism

in panic patients in

the non-panic state and healthy subjects. Consistent with Reiman et al. (1986), they detected asymmetry in the hippocampal

region in patients, but no evidence of global metabolic differences

Patients showed metabolic

decreases

in grey matter.

in the left parietal lobule and anterior cyngulate,

and increased

metabolic rates in the medial orbital frontal cortex. In a similar study, Bisaga et al. (1998) observed that panic patients had abnormal brain metabolism

of glucose in the hippocampal

and parahippocampal

areas. Further, in an attempt to assess the effect of antipanic treatment on the brain’s glucose metabolism of panic patients, Nordahl et al. (1998) compared regional cerebral glucose metabolic rates (rCMRglc) in a group of unmedicated patients with a group receiving imipramine. Both groups were similarly found to have abnormally

low left-right hippocampal

rCMRglc ratios, a feature that seemed unaffected

by

imipramine treatment.

The alterations in cerebral blood flow and glucose metabolism that panic patients were found to have in these studies cannot be ascribed to panic attacks, as patients were all examined in the non-panic Rather, these findings seem to be pointing to persistent abnormalities that would appear not to change even in response

state.

associated with the non-panic state

to antipanic medication,

to the extent of being

regarded by Nordahl et al. (1998) as possibly a ‘trait’ of PD. Brain PET studies performed during panic attacks seem to produce a different type of results. For example, Reiman et al. (1989) observed that CBF increased bilaterally in several areas of the brain during lactate-induced may be related to the finding that lactate-induced

attacks in panic patients. This

panic may facilitate the release of atria1 natriuretic

hormone, a vasodilator and inhibitor of sympathetic activity (Seier et al., 1997).

Could the abnormal effects

CBF and cerebral

glucose metabolism

on the brain of chronic hyperventilation?

available

in brain PET studies.

be associated

To be sure, no direct evidence

There is however that patients

in panic patients

evidence

with a diagnosis

that hyperventilation

Mountz

et al. (1989) reported

of simple phobia

decrease

in global and regional CBF during state anxiety (induced by exposure

caffeine

to this effect is can alter CBF. had a significant

to a fear-provoking

stimulus). The decrease in CBF was identified as being an effect of hyperventilation hypocapnia.

and the ensuing

In another study, Cameron et al. (1990) assessed the effect of a 250 mg mean dose of

(an anxiogenic

agent) on CBF of healthy

subjects.

Although

the dose of caffeine

followed by a 30% decrease of CBF in the whole brain, as compared with baseline measures, had induced presumably

with

a significant hyperventilated

of hypocapnia

reduction

in paC02 in subjects

before they were scanned.

was

caffeine

As subjects

after receiving caffeine, the decrease of CBF was most probably an effect

rather than a direct effect of the dose of caffeine.

Panic, hyperventilation Yet again, if hyperventilation

and the perpetuation

1083

of anxiety

can cause cerebral hypoxia, presumably

chronic hyperventilation

will

cause cerebral hypoxia for prolonged periods. This, in turn, may lead to further cellular and metabolic changes in the brain (Eckenhoff

and Longnecker,

in CBF and cerebral glucose metabolism result of the more immediate that might develop

1996). It could be speculated that the abnormalities

that panic patients have in the non-panic state may be the end

effects on the brain of hyperventilation

following

prolonged

periods of cerebral hypoxia.

Reiman et al. (1986), panic patients who were vulnerable abnormal hemispheric susceptible

asymmetry

combined with long-term

in the non-panic

Interestingly,

effects

in the study of

to lactate, and who were found to have

state, were also described

as being abnormally

to episodic hyperventilation.

9. m

Chronic Anxiety

Panic attacks are the main feature of PD, but panic patients also present a range of other symptoms between syndrome.

their attacks. In particular, Provocation

hyperventilation

as part of the panic

studies, initially using sodium lactate and later the CO2 challenge, demonstrated

that panic patients are likely to have hypersensitive panic patients

has long been recognised

have a brain’s asphyxiation

CO1 chemoreceptors.

Klein (1993) postulated

alann that is hypersensitive

to increases

that

in pCO*, the

activation of which culminates in panic attacks. Thus panic patients chronically hyperventilate

in order

to keep pCOz low. However, hyperventilation

by itself is likely to be involved in at least some aspects of clinical anxiety.

In healthy individuals,

hyperventilation

impairs consciousness

and awareness

of the environment

tests,

are common

features

all of

hyperventilation

which

increases

of

suggestibility,

and also reduces performance

anxiety

leads to systemic alkalosis, vasoconstriction

cerebral hypoxia may also be implicated in the pathogenesis

facilitates the induction of hypnosis,

disorders

(Lishman,

in cognitive

1998).

Moreover,

and cerebral hypoxia. It is possible that of anxiety. Cerebral hypoxia may be one of

the reasons why sufferers of COPD are susceptible to chronic symptoms of anxiety. Similarly, cerebral hypoxia secondary to hyperventilation

could facilitate anxiety and panic symptoms in panic patients.

There is evidence that, by hyperventilating

in the non-panic state, panic patients are exposed to EEG

slow wave activity, a sign of cerebral hypoxia. By chronically hyperventilating,

panic patients could thus

be at risk of sustaining cerebral hypoxia for extended periods. Brain imaging studies of panic patients in the non-panic state have shown abnormalities the clinical significance

in both CBF and cerebral glucose metabolism.

Although

of these findings is unclear, they might be indicating effects of hyperventilation,

hypoxia and other changes in brain function that may unfold.

L. Dratcu

1084

This raises the possibility that, by chronically hyperventilating, functional

abnormality

in central activity. It could be speculated

functional changes which perpetuates further studies of panic patients pathophysiology

panic patients may develop a persistent that this may cause irreversible

patients’ anxiety. This, however,

in the non-panic

state, without which a full understanding

of PD is unlikely to be achieved. The hypothesis

might exist within the pathophysiology

could only be ascertained

that a self-perpetuating

by

of the

mechanism

of PD seems to be plausible enough to warrant such studies.

Finally, panic attacks are paroxysmal

episodes of anxiety. Accordingly,

if a dimensional

approach of

anxiety is adopted, the concept of PD seems to encompass those anxious patients at the clinical end of the spectrum, where anxiety states are most distinct and intense. Whether the neurophannacological

basis of

anxiety is the same at all points upon this spectrum is still unclear. However, another important reason why experimental

studies of panic have attracted scientific interest is that, in theory, knowledge

gained

from studies of PD can be extrapolated to anxiety in general (Nutt and Lawson, 1992). Further studies of panic patients in the non-panic state are most likely to also add to current knowledge of anxiety disorders other than PD alone.

10. Conclusions Panic patients chronically hyperventilate However,

hyperventilation

in the attempt to keep pCOz low and prevent panic attacks.

can induce cerebral hypoxia.

Panic patients in the non-panic

state have

abnormal EEG, CBF and cerebral glucose metabolism, which may be indicating effects on the brain of cerebral hypoxia secondary to hyperventilation.

Enduring effects of cerebral hypoxia could in theory

contribute to perpetuate anxiety symptoms in this patient group, as seems to be the case in patients who suffer from COPD. Further research is needed to determine whether a self-perpetuating exist within the pathophysiology

mechanism might

of PD.

Acknowledgement The author gratefully acknowledges

the help and patience of Ms. Chris Thomas with the typing of this

review.

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Panic, hyperventilation

and the perpetuation

Inquiries and reprint requests should be addressed to: Dr. Luiz Dratcu York Clinic, Thomas Guy House Guy’s Hospital 47 Weston Street London SE1 3RR United Kingdom

of anxiety

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