Editorials

Hyperventilation
The paper by Jack and coworkers in the current issue of the
Journal (pp. 118125) describes aspects of control of breathing in a group of patients with idiopathic hyperventilation (1).
Hyperventilation involves medicine, physiology, psychology, and
psychiatry, although it has failed to attain legitimacy in any of
these specialties. The subject has been recently reviewed (24).
There is still widespread misunderstanding about the implications of the finding of a low arterial (PaCO2) or end-tidal (PetCO2)
carbon dioxide tension, and most physicians still use it as a
euphemism for an anxiety state or psychosomatic disorder. This
is not necessarily correct and unfairly labels patients as psychiatric. Most literature on this subject is very old and good papers
using modern technology are sparse. The difficulty with this
subject is clarifying the issues that need to be addressed, and
there has in the past been little consensus. All working in this
field have their own set of beliefs and this editorial will be no
exception.
The first issue in the study of Jack and coworkers (1) concerns
the etiology of the excessive respiratory drive causing the hyperventilation. Are we dealing with a unified group of patients? Is
hyperventilation a disorder per se or is it a clinical finding equivalent to a low potassium for which a cause should be sought?
Unfortunately, in the present study few details are given as to
how individual patients presented, although they were recruited
from chest clinics and thus must have been symptomatic. There
are a number of possibilities.
Although only described anecdotally (3), there are patients
well known to every chest clinic who present with breathlessness
and air hunger of unknown etiology in whom hyperventilation
is probably an epiphenomenon secondary to the breathlessness
or the cause of the breathlessness. Hyperventilation is not necessarily associated with breathlessness and PetCO2 can be halved
with only a 10% increase in ventilation (5). In these patients,
breathlessness and not hyperventilation is the problem and until
the cause of the breathlessness can be elucidated caution should
be used in regarding these patients as having primary hyperventilation. Unfortunately, the basic mechanisms of breathlessness
are still poorly understood.
Asthma, especially when mild and atypical, is a potent cause
of hyperventilation (6). We previously found that 80% of patients presenting to an emergency department with apparent
pure acute hyperventilation had good evidence of asthma that
was previously undiagnosed in half (7). Chest tightness is not a
symptom of hyperventilation per se. The suggestion in the study
of Jack and coworkers that some patients had chest tightness
suggests that some may have been asthmatic. By definition, lung
function is normal in asthma after treatment and in my view
additional investigations such as bronchial challenge tests, ambulatory peak flow recordings, or a trial of inhaled steroids are
desirable to ensure exclusion of atypical asthma.
A third possibility is that some of these patients fall into a
group, which we described in 1986, where intractable chronic
hyperventilation is associated with a range of vague symptoms

but especially chest pain (5, 8). These patients had persistent
hyperventilation at rest and during exercise, but PetCO2 slowly
returned back to normal during sleep. All had air hunger, some
were phobic, but anxiety was not common.
A fourth possibility is that these patients in fact have no
abnormalities at all but are at one end of the spectrum of the
normal range of resting PaCO2. That this is possible was shown
in a very carefully controlled and validated study (9, 10) in which
we measured PetCO2 by an ambulatory capnograph in a group
of normal subjects during four hours of activities of daily living
including eating, talking, and mild exercise. The upper limit of
normal for induction of hypocapnic symptoms in normal subjects
is 28 mm Hg (11), and a significant percentage of our normal
subjects had PetCO2 levels near or below this value for at least
part of the time studied.
Does the etiology of the hyperventilation matter in respect
to the study of Jack and coworkers? I believe it does. Lung
function tests were all normal in this study but are fairly crude
measures of lung mechanics. Control of breathing, especially in
the hypocapnic range, may be influenced by subtle factors that
are very different in each of the above conditions and the etiology
of hyperventilation is almost certainly multifactorial in many
patients. Despite these uncertainties about etiology, it is gratifying that the authors have accepted the growing consensus that
the old nomenclature of hyperventilation syndrome should be
abandoned because there has been complete failure of agreement as to how this syndrome should be defined or whether it
even exists.
The present study contains carefully documented and standardized data showing that carbon dioxide and hypoxic sensitivities are near normal in these patients. This is not surprising.
Hyperventilation probably induces a small shift of the CO2 response curve leftward to lower levels of PaCO2 (12) (this requires
further study in patients with hyperventilation). The PaCO2 levels
in the patients in the present study are almost certainly well
down in the dogleg region of the CO2 response curve, where
the central and probably peripheral chemoreceptors are inactivated and where all respiratory drives are feedforeward drives
from the cortex and other sites (13). It is difficult to see how
increase or decrease in chemoreceptor sensitivity could have any
impact on the resting PaCO2 level in these patients. The presence
of persistent hyperventilation and increased breathlessness during exercise makes a convincing case that the additional respiratory drive in these patients is not of cortical origin, and the
emphasis in the future must be in elucidating the basis of this
additional drive.
Whatever the deficiencies of the study, it is gratifying to see
a serious attempt to study this difficult subject that is a bane of
the life of most chest physicians.
William N. Gardner, M.B.B.S., D.Phil
Respiratory Medicine and Allergy
Guys, Kings and St Thomass School of Medicine
London, United Kingdom
References

Am J Respir Crit Care Med Vol 170. pp 105108, 2004

Internet address: www.atsjournals.org

1. Jack S, Rossiter HB, Pearson MG, Ward SA, Warburton CJ, Whipp BJ.
Ventilatory responses to inhaled carbon dioxide, hypoxia and exercise

106

2.

3.
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5.

6.

7.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 170 2004

in idiopathic hyperventilation. Am J Respir Crit Care Med 2004;170:

118125.
Folgering H. The hyperventilation syndrome. In: Altose MD, Kawakami
Y, editors. Control of Breathing in Health and Disease. New York &
Basel: Marcel Dekker Inc.; 1999. p. 633660.
Gardner WN. The pathophysiology of hyperventilation disorders. Chest
1996;109:516534.
Lum LC. Hyperventilation syndromes in medicine and psychiatry: a review. J R Soc Med 1987;80:229231.
Gardner WN, Meah MS, Bass C. Controlled study of respiratory responses during prolonged measurement in patients with chronic hyperventilation. Lancet 1986;ii:826830.
Osborne CA, OConnor BA, Lewis A, Kanabar V, Gardner WN. Hyperventilation and asymptomatic chronic asthma. Thorax 2000;55:1016
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Saisch SGN, Wessely S, Gardner WN. Patients with acute hyperventilation presenting to an inner-city emergency department. Chest 1996;110:
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8. Bass C, Gardner WN. Respiratory and psychiatric abnormalities in

chronic symptomatic hyperventilation. BMJ 1985;290:13871390.
9. Osborne CA, Varley JS, Gardner WN. Computerized editing of endtidal PCO2 for ambulatory capnography [abstract]. Am J Respir Crit
Care Med 2001;153:A919.
10. Osborne CA, Varley JS, Gardner WN. The true range of end-tidal PCO2
in normal humans measured uninvasively over 4 hr during activities
of daily living. J Physiol 2001;531:44P.
11. Rafferty GF, Saisch SGN, Gardner WN. Relation of hypocapnic symptoms to rate of fall of end-tidal Pco2 in normal subjects. Respir Med
1992;86:335340.
12. Cunningham DJC. Integrative aspects of the regulation of breathing. In:
Guyton, Widdicombe JG, editors. Respiratory Physiology. London:
Butterworths; 1974. p. 303370.
13. Meah MS, Gardner WN. Post-hyperventilation apnoea in conscious
humans. J Physiol 1994;477:527538.
DOI: 10.1164/rccm.2405003

Flies, Mice, and Surprises in Dissecting Environmental

Lung Injury
We are now at an unprecedented time in our ability to unravel
the complex biology underlying many respiratory diseases. A
generation ago, the main tools employed were largely based
upon physiology and lung mechanics. These disciplines remain
central to understanding lung biology, but here, as in virtually
all of biomedical research, advances in molecular biology, genetics, and immunology are now assuming critical roles in our
field.
The challenge for investigators today is to be integrative,
taking new approaches through old familiar terrains. Information coming from the genomes of yeast, flies, and fish are being
applied toward understanding the human disease. The workhorse for analyzing new genomic information is the mouse.
Genes may be added, deleted, turned on and off selectively, and
the impact of these genetic manipulations may then be assessed
in vivo. The study by Hollingsworth and colleagues in this
issue of the Journal (pp. 126132) is a prime example of this
process (1).
In 1985, Drosophila geneticists first identified a gene in fly
larvae that regulated body axis development, which they named
Toll (2). Subsequent research in the fly led to the discovery that
after playing a critical role in development, the Toll gene was
essential in adult flies for inducing innate immune responses to
fly pathogens. Comparative analyses of vertebrate genomes led
to the realization that the Toll gene is ancestrally related to the
Interleukin-1 receptor gene family. We now know that the Toll
gene family recognizes non-self products of bacteria, fungi, and
foreign DNA (3). Activation of the Toll-like receptor (TLR)
gene family leads to the unleashing of a powerful cascade of
cytokines. In the past several years, studies based on mouse
genetics has taught us that septic shock induced by endotoxin
or lipopolysaccharide is the result of activation of the Toll 4
gene (4).
Given this background, Hollingsworth and colleagues investigated four models of environmental lung injury using mice genetically deficient in TLR4, or their identical littermates. The four
inhalational toxicants were lipopolysaccharide, residual oil fly
ash, and acute and subacute ozone exposure. Each of these

stimuli are known to exacerbate lung inflammation. The data

clearly show, as expected, that lipopolysaccharide injury is almost entirely due to activation of TLR4. On the other hand, the
complex microparticulate of residual oil fly ash appears not to
interact with the TLR4, although this does not exclude other of
the nine Toll-like receptors.
The most interesting and surprising finding in the study concerned the role of the TLR4 receptor in ozone-induced lung
injury. Two different ozone exposures were examined. An acute
model challenged mice with 2 ppm ozone for 3 hours (acute
model). The second exposure challenged with 0.3 ppm for 72
hours. In each case, lung lavage protein, leukocytes, and airway
responsiveness to methacholine challenge were scored.
In the acute model, there were no phenotypic differences between TLR4-sufficient and -deficient mice on a pure C57Black/6
background. In contrast, after subacute exposure, although there
were no changes in inflammation or lavage protein levels, there
was a highly significant blunting of the airways hyperresponsiveness to methacholine.
There are several points to consider in analyzing these results.
First, for unclear reasons, the airways responsiveness was assessed
in two different ways in the acute and chronic models. The acute
model used a plethysmographic technique (Buxco Electronics,
Sharon, CT), which is an indirect measure of resistance and compliance. The subacute model used the more direct measurement
of airways pressure/time index. Note that the method of administration and the dose response to methacholine is also different
with the two techniques. Second, the dissociation between inflammation and permeability from airways responsiveness in the
models is interesting. The protection from increased airways responsiveness to methacholine was recently shown in this model
to be complement-dependant and neutrophil-independent (5).
The real surprise in the results in the subacute model comes
when the work of Hollingsworth and colleagues is compared
with the work of Kleeberger and colleagues (6, 7). The latter
group used a technique called quantitative trait locus analyses.
In this powerful technique, two inbred lines of mice, which have
a phenotypic variance in a physiologic response, are crossed,
and the recombinant progeny are screened for the traits. Klee-