The role of hyperventilation - hypocapnia in the
O papel da hiperventilação - a hipocapnia no
Andras Sikter,1 Ede Frecska,2 Ivan Mario Braun,3
A b s t r a c tObjective: The authors present a profile of panic disorder based on and generalized from the effects of acute and chronichyperventilation that are characteristic of the respiratory panic disorder subtype. The review presented attempts to integrate threepremises: hyperventilation is a physiological response to hypercapnia; hyperventilation can induce panic attacks; chronichyperventilation is a protective mechanism against panic attacks. Method: A selective review of the literature was made using theMedline database. Reports of the interrelationships among panic disorder, hyperventilation, acidosis, and alkalosis, as well ascatecholamine release and sensitivity, were selected. The findings were structured into an integrated model. Discussion: Thepanic attacks experienced by individuals with panic disorder develop on the basis of metabolic acidosis, which is a compensatoryresponse to chronic hyperventilation. The attacks are triggered by a sudden increase in (pCO ) when the latent (metabolic)
acidosis manifests as hypercapnic acidosis. The acidotic condition induces catecholamine release. Sympathicotonia cannot ariseduring the hypercapnic phase, since low pH decreases catecholamine sensitivity. Catecholamines can provoke panic whenhyperventilation causes the hypercapnia to switch to hypocapnic alkalosis (overcompensation) and catecholamine sensitivitybegins to increase. Conclusion: Therapeutic approaches should address long-term regulation of the respiratory pattern andelimination of metabolic acidosis.
Descriptors: Acidosis; Catecholamines; Hyperventilation; Hypocapnia; Panic disorder
R e s u m oObjetivo: Os autores apresentam um modelo de transtorno do pânico que se baseia nos efeitos da hiperventilação aguda ecrônica, característicos do subtipo respiratório de transtorno do pânico. O modelo é generalizado a partir desses efeitos. Eleintegra três características da hiperventilação: a hiperventilação é uma resposta fisiológica à hipercapnia; a hiperventilação podeinduzir ataques de pânico; a hiperventilação crônica representa um mecanismo protetor contra os ataques de pânico. Método:Revisão seletiva da literatura a partir da base de dados Medline. Foram selecionados relatos referentes à inter-relação entretranstorno do pânico, hiperventilação, acidose, alcalose, liberação de catecolaminas e sensibilidade a catecolaminas, sendo osachados estruturados de modo a formar um modelo integrado. Discussão: Os ataques de pânico do transtorno do pânicodesenvolvem-se com base numa acidose metabólica, que é uma resposta compensatória à hiperventilação crônica. Os ataquessão desencadeados por um súbito aumento da pressão parcial de dióxido de carbono (pCO ), quando a acidose (metabólica)
latente se manifesta pela acidose hipercápnica. A condição acidótica induz liberação de catecolaminas. A simpaticotonia nãopode manifestar-se durante a fase de hipercapnia, pois o baixo pH diminui a sensibilidade às catecolaminas. As catecolaminaspodem provocar pânico quando a hipercapnia comuta para uma alcalose hipocápnica devido à supercompensação pelahiperventilação, situação na qual a sensibilidade às catecolaminas liberadas começa a aumentar. Conclusão: As abordagensterapêuticas deveriam voltar-se para a regulação em longo prazo do padrão respiratório e a eliminação da acidose metabólica.
Descritores: Acidose; Catecolaminas; Hiperventilação; Hipocapnia; Transtorno de pânico
St. Rokus Hospital, Department of Internal Medicine, Budapest, Hungary
National Institute for Psychiatry and Neurology, Budapest, Hungary
Institute of Psychiatry, Universidade de São Paulo (USP) School of Medicine, São Paulo (SP), Brazil
CorrespondenceZoltan RihmerHûvösvölgyi út 116, 1021
Conflict of interests: NoneSubmitted: May 17, 2006
investigating the catecholamine sensitivity of brain and other
Although the correlation between the respiratory panic
tissues in relation to pH. We also included 10 articles on
disorder (PD) subtype and hyperventilation is well established
psychiatric topics presenting borderline relationships with PD.
in the literature, the active role of hyperventilation in the
The search of the literature and the article selection were
pathomechanism of PD is less understood. Although Wilhelm
carried out by András Sikter, who has been researching this
et al. provided a thorough review of the three main theories
topic for decades and therefore has profound insight into the
on the role of hyperventilation in PD,1 they identified
issue. The author notes on the articles evaluated have been
contradictions among them and did not offer a synthesis of
arranged into a logical order so that they can be integrated
t h e c u r r e n t c o n c e p t s . T h e i n c r e a s e o f t i s s u e H+ i o n
concentration, which is regulated promptly and effectively byrespiration-induced changes in pCO , is a strong stimulus of
catecholamine release. However, acidotic conditions decrease
Maintaining the homeostasis of intracellular and extracellular
the catecholamine sensitivity of target organs (the inverse of
pH is a crucial regulatory task for the organism. A couple of deep
what occurs in alkalosis). In a panic attack, these events occur
breaths can substantially decrease CO concentration, increasing
in rapid succession. Therefore, understanding the timing and
extracellular pH to 7.4-7.7. Since CO readily passes through
the time constant (how quickly a change develops) of
cell membranes, intracellular pCO decreases to the same
physiological variables is crucial for resolving the apparent
degree. Therefore, altering respiration can produce marked
contradictions and establishing a coherent model.
changes in intracellular pH, the consequences of which are
The role of hypocapnia in the pathomechanism of PD has
outlined below.7 Acute hypocapnia has a progressive effect on
been largely overlooked in the literature.2 During the late
membrane permeability, metabolism, oxygen consumption, and
1930s, hyperventilation played a central role in the diagnostic
cardiac function,8 as well as exciting the nervous system
formulation of hyperventilation syndrome.3-4 Shortly after the
through the hypopolarization of neurons.9-10 In contrast,
conceptualization of PD in the DSM III (1980), it became
hypercapnia results in decreased cell membrane permeability,11
evident that there had been an overlap between symptoms of
metabolic depression,12 reduced muscle contractility13, and
hyperventilation syndrome and PD.5 The article written by Klein
hyperpolarization of neurons. In short, acute hypocapnia elicits
in 1993 represented an important step toward settling the
effects similar to those seen when the sympathetic nervous
long-standing debate on the role of hyperventilation.6 Klein
system is stimulated, whereas acute hypercapnia evokes
denied the importance of acute or chronic hyperventilation in
parasympathetic effects. The latter occurs despite the fact that
the generation of panic attacks. Although he described a
h y p e r c a p n i a c a u s e s i n c r e a s e s i n t h e l e v e l s o f s e r u m
positive correlation between chronic hyperventilation and panic
adrenaline and noradrenaline.14 There are conflicting data
attacks, he used this observation in order to put forth the idea
i n t h e l i t e r a t u r e r e g a r d i n g s e r u m a d r e n a l i n e a n d
that chronic hyperventilation is protective against panic.
noradrenaline levels in acute hypocapnia, some authors
The aim of this study was to review the literature on PD,
r e p o r t i n g n o a l t e r a t i o n s 14 a n d o t h e r s d e m o n s t r a t i n g
with a special focus on the role of hyperventilation and
significant decreases.15 Hypoxia is a disturbing variable in
hypocapnia in the pathomechanism of PD. Special attention
most investigations.16 Catecholamine sensitivity decreases
was paid to studies investigating the interrelationships between
i n h y p e r c a p n i c a c i d o s i s a n d i n c r e a s e s i n h y p o c a p n i c
panic, pH, pCO , tissue catecholamine sensitivity, and
alkalosis.7 These changes in catecholamine level and
c a t e c h o l a m i n e e l i m i n a t i o n , a s w e l l a s t h e i r t e m p o r a l
sensitivity affect target organs. Lower intracellular pH is
t h e t r i g g e r f o r n o r a d r e n a l i n e r e l e a s e f r o m t h e l o c u scoeruleus during panic attacks.17-18
Chronic hypocapnia elicits a cascade of changes due to
We conducted a selective review of the literature in the
compensatory mechanisms for the restoration of intracellular
Medline database, limiting our searches to articles published
and extracellular physiological pH. Renal reabsorption of
between 1937 and 2006. Our approach was to discuss the
chlorine ions and excretion of bicarbonate is increased in
available literature on PD in order to show that it is not only a
s u s t a i n e d h y p o c a p n i a . 19 I n a n e x p e r i m e n t a l m o d e l o f
psychiatric disorder but also a regulatory disorder. Our first
hyperventilation in dogs, it was shown to take five days for the
search included the terms “panic” and “hyperventilation”, and/
kidneys to reestablish the equilibrium.20 In humans, the role
or “hypocapnia” and/or “hypercapnia”. This search strategy
of intracellular buffer mechanisms is more important, and
yielded a total of 317 articles, from which we selected 33 for
adaptation to chronic hyperventilation or hypoventilation is
analysis. In selecting these articles, our principal aim was to
therefore less dependent on renal function.21 The process of
represent all major opinions and trends. Within this context,
adaptation is similarly slow: to regain equilibrium can take
we selected articles written by the most prominent authors.
five to seven days.7 It takes equally as long to reverse the
Therefore, these articles and their main arguments present a
changes after the occurrence of eucapnia. Buffer mechanisms
logical progression. In addition, we reviewed the most
include the release of hydrogen ions, which shifts pH toward
controversial papers. Furthermore, 17 of the articles included
the physiological level, although this process also occurs only
deal with the physiology and pathology of catecholamine
homeostasis in relation to panic. These articles were identified
Various authors have downplayed the role of hyperventilation
by adding the search terms “acid-base disorder”, “acidosis”,
in PD and have recommended that the term ‘hyperventilation
“alkalosis”, “hypocapnia”, “hypercapnia”, “catecholamine”,
syndrome’ no longer be used.21-24 However, in another review
“noradrenaline”, “adrenaline”, and “sympathetic nervous
article, Gardner argues for the preservation of the term.25 Other
system”. In this step of the selection process, we focused on
authors have stated that chronic hyperventilation is a common
articles investigating the relationship between acidosis/alkalosis
cause of both hyperventilation syndrome and PD.5,25-26 Recently,
a n d c a t e c h o l a m i n e p r o d u c t i o n , a s w e l l a s o n t h o s e
Nardi addressed the role of hyperventilation in PD and tried to
clarify it, stating that it is considered to be “.a cause, a correlate,
of PD, and that similar irregularity can be found in
or a consequence of panic attacks.” According to Nardi, acute
generalized anxiety disorder.40 The similarity can explain
hyperventilation might play a role in the pathomechanism of the
the high comorbidity of these two conditions.26 In individuals
with generalized anxiety disorder, the irregularity of breathing
In a study using transcutaneous monitoring, no relationship
is less pronounced than in those with PD.41 Various studies
was found between PD and hyperventilation.28 This method is
have shown that, in individuals with PD, there is a strong
outdated due to its high inertia (slow decay) in monitoring changes
correlation between the degree of respiratory irregularity
in arterial pCO .2 It is widely accepted that the respiratory PD
and the frequency of panic attacks, as well as between
subtype, which accounts for approximately 50% of all PD cases,
such irregularity and CO vulnerability.1,41-42 Irregular
i s c l o s e l y r e l a t e d t o h y p e r v e n t i l a t i o n a n d r e p r e s e n t s a
respiration occasionally causes elevated pCO , which can
hyperventilation syndrome comorbidity.2,5,25-26
There are three views in the literature regarding the role that
The hypothalamic-pituitary-adrenocortical axis model of
hyperventilation plays in the pathomechanism of PD. In the first,
hypercapnia induced panic is generally accepted in the
panic is triggered by elevated CO levels, and hyperventilation
literature,17,43 although it was recently questioned by
follows as a physiological response.1,29 In this model, the
Gorman,44 who discovered inconsistencies and pointed out
hyperventilation is a consequence, an epiphenomenon observed
that, during CO challenge, actual pCO values correlate
during naturally-occurring and drug-induced panic attacks. In
negatively with signs and symptoms of panic. This indicates
the view of other authors30-31 – a view shared by followers of the
that panic develops not during hypercapnia but during the
cognitive-behavioral theory of PD1 – hyperventilation-induced
subsequent hypocapnic phase. The way Gorman puts it:
hypocapnia plays a central role. The opinion of psychotherapists
“.in panic disorder patients, we have found that elevated
can be summarized as follows: individuals with PD can
cortisol, fear and hypocapnia are intercorrelated in the few
misinterpret the bodily sensations caused by hyperventilation as
minutes before actually experiencing an acute attack.”
being indicative of life-threatening danger.32
As previously mentioned, higher pCO leads to increased
However, the most widely accepted view is that detailed by
noradrenaline release.18 However, in human plasma,
Klein6: hyperventilation is a protective mechanism against panic
noradrenaline has a half-life of only a few minutes.45-46 In
reactions. In his thorough study, Klein demonstrated that patients
the rebound phase of hypocapnia, cells present increased
with PD are hypersensitive to increases in pCO , and that panic
s e n s i t i v i t y t o r e s i d u a l c a t e c h o l a m i n e s .7 S t r o n g
attacks are triggered by a relative increase in the level of CO .
catecholamine stimuli are known to induce panic attacks.47
Such individuals present chronic hyperventilation as a means of
Individuals with PD present normal catecholamine levels
avoiding the panic-inducing increase in CO levels.
between panic attacks.48 It is therefore possible that, in
We agree with Klein that chronic hyperventilation has some
a d d i t i o n t o t h e h y p e r c a p n i a - r e l a t e d i n c r e a s e i n
defensive effects against panic attacks in individuals with PD,
c a t e c h o l a m i n e l e v e l s , t h e h y p o c a p n i a - i n d u c e d
since a sudden increase of pCO (e.g. CO challenge) has been
catecholamine sensitivity plays a significant role in the
s h o w n t o p r o v o k e s u c h a t t a c k s . 33 H o w e v e r, c h r o n i c
hyperventilation is always accompanied by compensatory metabolic
Borelli et al. conducted electrophysiological studies in
acidosis. In an individual with chronic hyperventilation, life events
animals50 and concluded that panic attacks represent a
(i.e., relaxation, sleep, premenstrual phase, etc.) can cause pCO
pathological manifestation of ‘freezing behavior’ (low-arousal
to rise to the normal baseline or above.6 The latent metabolic
condition), rather than the high-arousal condition of the
acidosis then appears, and the elevated concentration of H+
‘fight-or-flight’ response.51 ‘Freezing behavior ’ initially
increases CO sensitivity of the respirator y center. It can be
manifests as immobility, bradycardia, and hypoventilation
assumed that the chronic hyperventilation itself is responsible for
but can transform into the flight response, which is
the increased CO sensitivity observed in individuals with PD.
characterized by vigorous locomotion, tachycardia, and
The best supporting evidence is provided by Klein himself, who
hyperventilation.52 The sudden change in the respiratory
found chronic hyperventilation to correlate positively with lactate-
pattern that precedes the flight response indicates the
induced panic and CO sensitivity.6 Hypophosphatemia, which is
similarity with panic attacks. It is quite probable that the
an indicator of chronic hyperventilation, has been found to be
role the brainstem plays in the pathomechanism of PD is
predictive of lactate-induced panic attacks.34 Decreased plasma
more important than previously suggested.
bicarbonate is also a marker of chronic hyperventilation and
We can build a profile of PD that integrates the three
sensitizes to the onset of panic attacks.35 However, chronic
hyperventilation theories. Individuals with the respiratory
hypercapnia accompanied by metabolic alkalosis has been shown
PD subtype present chronic hyperventilation. The chronic
to correlate negatively with the development of panic attacks.6
hyperventilation results in a compensatory decrease in
V a r i o u s r e s e a r c h e r s h a v e b e e n s u c c e s s f u l i n u s i n g
intracellular and extracellular pH due to renal secretion of
hyperventilation to provoke panic attacks.27,36-39 Nardi addressed
bicarbonate and due to the tissue buffer mechanisms. A
the role of hypocapnia and hypercapnia in PD with equal focus
balanced steady-state is established between the hypocapnic
and equal importance in the pathogenesis.27,38-39 However, the
alkalosis and the metabolic acidosis. Multiple factors can
overall effect of hyperventilation on panic was significantly less
lead to a sudden increase in CO levels. In individuals with
than that of CO inhalation. Respiratory challenge tests (CO and
PD and presenting sustained hypoventilation episodes,
breath-holding) can provoke panic attacks in individuals presenting
irregular breathing causes abrupt changes in pCO . In the
t h e r e s p i r a t o r y P D s u b t y p e . 39 C e r e b r a l h y p o x i a , c h r o n i c
prelude to a panic attack, an abrupt increase of pCO occurs,
hyperventilation, and anxiety persist in the interim between panic
w h i c h l e a d s t o u n u s u a l l y h i g h i n t r a c e l l u l a r H +
attacks.26 Although individuals with PD are prone to continue
c o n c e n t r a t i o n s , t h e r e b y t r i g g e r i n g t h e r e l e a s e o f
hyperventiling,1,32 the hyperventilation facilitates panic attacks.
noradrenaline in the locus coeruleus. This sudden increase
Caldirola stated that an irregular breathing pattern is predictive
in intracellular acidosis elicits hypocapnia by compensatory
h y p e r v e n t i l a t i o n . I n a d d i t i o n , i n d i v i d u a l s w i t h P D
the corresponding metabolic acidosis, is a predisposing factor
overcompensate for hypercapnia.53 The consequence is severe
for PD. Therefore, therapeutic approaches should address long-
sympathicotonia, since the higher catecholamine level resulting
term regulation of respiratory patterns60 and elimination of
from the previous hypercapnia overlaps with the increased
catecholamine sensitivity caused by the hypocapnic alkalosis. The adrenergic/noradrenergic tonus results in fear mediatedby the limbic system, and the expectation of threat can createa vicious circle. Long after the chemical component phase ofa panic attack is over, the cortical excitation persists, leavingthe individual with a lingering, subjective feeling of anxiety.
Hyperventilation pushes the individual toward progression of
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J. Paediatr. Child Health (2003) 39 , 372–375 EpiPen epidemic: Suggestions for rational prescribing in childhood food allergy Department of Allergy, Immunology and Infectious Diseases, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia Abstract: There has been a marked increase in community concerns of the risk of food induced anaphylaxis in children