help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on April 1, 2004, doi:10.1164/rccm.200207-720OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200207-720OCv1
170/2/118    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jack, S.
Right arrow Articles by Whipp, B. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jack, S.
Right arrow Articles by Whipp, B. J.
American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 118-125, (2004)
© 2004 American Thoracic Society

Original Article

Ventilatory Responses to Inhaled Carbon Dioxide, Hypoxia, and Exercise in Idiopathic Hyperventilation

Sandy Jack, Harry B. Rossiter, Michael G. Pearson, Susan A. Ward, Christopher J. Warburton and Brian J. Whipp

Aintree Chest Centre, University Hospital Aintree, Liverpool; School of Sport and Exercise Sciences, University of Leeds, Leeds, United Kingdom; Division of Physiology, Department of Medicine University of California, San Diego, La Jolla; and the Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, California

Correspondence and requests for reprints should be addressed to Christopher J. Warburton, M.D., Aintree Chest Centre, University Hospital Aintree, Liverpool L9 7AL, UK. E-mail: cjwarby{at}liverpool.ac.uk


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
Idiopathic hyperventilation (IH) is a poorly understood condition of sustained hypocapnia and controversial etiology. Although behavioral/emotional factors may contribute, it is uncertain whether chemosensitivity is altered, hyperventilation is maintained during exercise, and the associated breathlessness reflects the hyperventilation. In 39 patients with IH and 23 control subjects, we described ventilatory responses to isocapnic–hypoxia, hyperoxic–hypercapnia, and exercise; breath-hold tolerance; breathlessness; and psychologic status. Patients demonstrated hyperventilation at rest, with hypocapnia (28 ± 3.8 mm Hg), a normal (slightly alkaline) arterial pH and [H+]a, and a significant base excess (–4.5 ± 2.7 mEq/L), consistent with compensated respiratory alkalosis. Hyperventilation was sustained during exercise, despite hyperoxic–hypercapnic ventilatory responsiveness being normal and isocapnic–hypoxic ventilatory responsiveness being low relative to control (but exceeding control [2.4 ± 1.0 vs. 1.6 ± 0.5 L/min/%, p < 0.05] with acute restoration to normocapnia). Hyperventilation was maintained during exercise, at the resting CO2 "setpoint." Relative to control, the breath-hold tolerance was attenuated, and dyspnea during exercise was significantly greater and not simply ascribable to the high ventilation. These observations suggest that patients with IH have a sustained hyperventilatory and dyspneic drive that, although not attributable to central chemosensitivity, may possibly have peripheral chemoreflex contributions. The nature and etiology of this chronic hyperventilatory drive remain unclear.

Key Words: peripheral chemoreflex • central chemoreflex • dyspnea • breath holding

Acute hyperventilation is manifest as an increased E, with consequent hypocapnia and respiratory alkalosis (E being in excess of that required to clear metabolically produced CO2). For example, "panic disorder" syndrome is associated with transient hyperventilatory episodes that are often precipitated by feelings of fear and resolve once the "panic attack" has subsided. In contrast, chronic asymptomatic (or "idiopathic") hyperventilation (IH) has been described as a clinical entity with no other underlying pathologies and is not associated with fear. This can be distinguished from acute hyperventilation by (1) the ventilatory-induced depletion of rapidly exchanging body CO2 stores having reached completion (1, 2) and (2) the associated respiratory alkalosis being largely, if not fully, compensated by a reduction in bicarbonate concentration (others therefore prefer to term this a combined respiratory alkalosis and metabolic acidosis). The often profound hyperventilation (with arterial PCO2 commonly being below 30 mm Hg and, on occasion, below 20 mm Hg) is associated with symptoms such as shortness of breath, chest tightness, light headedness, and paresthesia (3–7), the sustained and intense nature of which compromises activities of daily living and quality of life (4, 5, 8).

The etiology of IH is controversial, however (4, 5, 7). Causes of a behavioral and/or psychologic nature that activate voluntary ventilatory control pathways (9) have received much attention, given the relatively high incidence of anxiety reactions, depression, and perfectionist and inferiority traits in patients with IH (4, 5, 10–14). An alternative and largely untested hypothesis is that IH may reflect exaggerated respiratory responsiveness to CO2, hypoxia, and/or increased metabolic rate. There are occasional reports that CO2 inhalation can induce an increase in E in subjects with IH (15), although to our knowledge there has been no formal attempt to determine central or peripheral chemoreflex responsiveness. Furthermore, it is not known whether the chronic hyperventilation is maintained during controlled workrate exercise, although (1) Gardner and colleagues (15) have reported that a subset of patients with IH who were mildly hypocapnic at rest became profoundly hypocapnic during walking and (2) Howell (5) has presented a brief report of some patients with IH who evidenced a progressive increase in E during cycle ergometry. Finally, it is not known to what extent the exacerbated breathlessness in the IH patient at rest and during exercise is simply reflective of the elevated E (16, 17).

We therefore wished to address the following issues in subjects with IH presenting with chronic stable hyperventilation. (1) Is there evidence of increased central and/or peripheral chemoreflex responsiveness at rest? (2) Is the hyperventilatory condition sustained during moderate exercise, with alveolar PCO2 remaining regulated at its resting hypocapnic level? (3) Is the exacerbated breathlessness (dyspnea) reflective of effects beyond those expected from the concurrent level of E? Accordingly, ventilatory and perceptual responses to controlled hypoxic, hypercapnic, and exercise challenges were obtained in subjects with IH and age-matched control subjects. This, coupled with the assessment of psychologic status and symptoms, would, we hoped, provide insight into a poorly understood clinical condition. Some of the results of these studies have been previously reported in the form of an abstract (18).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
Thirty-nine subjects with confirmed IH and 23 age-matched control subjects provided written informed consent (study approved by South Sefton Research Ethics Committee). Patients with symptoms suggestive of hyperventilation (unexplained breathlessness, dizziness, chest tightness) but normal pulmonary function (volume divisions, FEFs, diffusing capacity, airway reactivity), cardiac function (resting and exercise 12-lead ECG, ST segment depression < 1 mm), and endocrine function (blood glucose; thyroid, renal, and liver function) were recruited from respiratory clinics at University Hospital Aintree. The resting PaCO2 IH inclusion criterion was 30 mm Hg or less.

Baseline Measurements
All subjects completed standard spirometry (Vitalograph, Maids Moreton, UK); subjects with IH also completed measurement of lung capacities (helium dilution) and single-breath diffusing capacity (Morgan Benchmark; Morgan Medical, Gillingham, UK). Resting PaO2, PaCO2, arterial pH, and base excess were measured in the group with IH. Both groups completed the Hospital Anxiety and Depression questionnaire (maximal range, 0–21) (19) and the Nijmegen (20) questionnaire (maximal range, 0–64) to assess psychologic status and the incidence of hyperventilatory symptoms, respectively.

Exercise Testing
Subjects performed incremental cycle–ergometry (15–20 W/minute) to the limit of tolerance (Corival 400; Lode, Groningen, Netherlands). Gas exchange was monitored breath by breath (CPX D; Medgraphics Corp., St. Paul, MN), incorporating discrete CO2 and O2 analyzers and Pitot flow sensor.

E, O2, CO2, respiratory exchange ratio, ventilatory equivalents for O2 and CO2 (E/O2, E/CO2), and end-tidal (partial) oxygen pressure (PETO2) and end-tidal (partial) carbon dioxide pressure (PETCO2) were derived (21). Heart rate was determined from the ECG R-R interval (Case 12; Marquette, Milwaukee, WI). SaO2 was estimated by pulse oximetry (Biox 3740; Ohmeda, Helsinki, Finland). Subjects rated "shortness of breath" each minute (modified Borg scale, maximal range, 0–10) (22).

Peak O2 was taken as the highest O2 attained. The lactate threshold ({theta}L) was estimated using a conventional cluster of variables (breakpoint in the CO2–O2 relationship (23), with increases in E/O2 and PETO2 but no increase in E/CO2 or fall in PETCO2 (24) (i.e., hyperventilation relative to O2 but not CO2) (Figures 5 and 6).

Hypoxic Ventilatory Responsiveness
Hypoxic ventilatory responsiveness (the slope of the E–SaO2 relationship) was derived from an isocapnic, hypoxic rebreathing test (25) with PETCO2 maintained at (1) the spontaneous eucapnic level and also, for the group with IH, (2) increased to and maintained at 40 mm Hg (by diverting variable fractions of the gasflow through a CO2 absorber) for 10 minutes before the rebreathing test being initiated (i.e., sufficient for CO2 equilibration between arterial blood and brain and thence to provide a new E steady state) (26).

Hypercapnic Ventilatory Responsiveness
Hypercapnic ventilatory responsiveness (the slope of the linear region of the E–PETCO2 relationship) was derived from a hyperoxic CO2 rebreathing test (initial gas composition = 50% O2, 5% CO2, 45% N2) (27).

Breath-hold Time
Subsequent to familiarization (for reproducibility), subjects performed resting breath holds to the limit of tolerance at total lung capacity, first exhaling to residual volume and then immediately inhaling to total lung capacity from a 6-L bag containing room air or 100% O2 (randomized sequence). The control group completed a further set of breath-holds after 3 minutes of volitional hyperventilation to establish PETCO2 at levels similar to the IH group when breathing spontaneously.

Statistical Analysis
Differences were examined by Student's t test or repeated-measures analysis of variance, where appropriate (Stat View: SAS Institute Inc., Cary, NC). Responses are expressed as mean ± SD. Statistical significance was set at p < 0.05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 Conclusions
 REFERENCES
 
Rest
The subjects with IH demonstrated normal pulmonary function, both with respect to predicted values (28) and the control group, with no evidence of arterial hypoxemia (PaO2 = 119 ± 19 mm Hg) (Table 1) . Chronic hyperventilation at rest was evident in the IH group: that is, E was significantly greater than for the control subjects (15.8 ± 5.3 vs. 10.5 ± 2.9 L/minute, p < 0.05), and arterial PCO2 was substantially lower than normal (i.e., 28 ± 3.8 mm Hg). The respiratory alkalosis was essentially fully compensated, with arterial pH within the normal range, although slightly on the alkaline side (i.e., pHa = 7.42 or [H+]a = 40 ± 4.3 nmol/L) and a base excess of –4.5 ± 2.1 mEq/L (Table 1).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Resting pulmonary function for subjects with idiopathic hyperventilation and normal subjects (control) and resting arterial blood–gas and acid–base status for subjects with idiopathic hyperventilation

 
The IH group scored significantly higher on the hospital anxiety rating of psychologic status (10.4 ± 4.6) compared with the control subjects (7.7 ± 4.0, p < 0.01) and somewhat high on the depression rating of psychologic status (6.7 ± 3.9) compared with control subjects (4.4 ± 3.7; p < 0.05), with clinically significant values being seven or more in each case. The Nijmegen symptoms score was also high for the group with IH (43 ± 11) (the upper limit of normal being 23) compared with 12 ± 9 for the control subjects (p < 0.05). This was reflected in the resting breathlessness assessed by the Borg scale (IH = 1.9 ± 1.4; control subjects = 0.1 ± 0.3, p < 0.05).

Hypoxic Ventilatory Responsiveness
The isocapnic E–SaO2 relationship was typically linear throughout the full SaO2 range, with no evidence of any loss of hypoxic response (i.e., manifest as an essentially flat characteristic), as Corne and colleagues (29) have recently reported. The slope of the isocapnic E–SaO2 relationship provided an index of hypoxic ventilatory responsiveness (25). The eucapnic hypoxic ventilatory responsiveness in the IH group was significantly lower than for the control group (0.9 ± 0.5 vs. 1.6 ± 0.5 L/minute/%; analysis of variance, p < 0.05), despite appreciable intersubject variability (range: IH = 0.2–1.7 L/minute/% and control = 1.0–2.4 L/minute/%) (Figure 1) . Although the reported normal values for this test are known to be highly variable among subjects (e.g., 0.5–3.5 L/minute/%) (30), the eucapnic hypoxic ventilatory responsiveness in our IH group may be considered to range from abnormally low to low–normal. However, when the eucapnic end-tidal PCO2 in the subjects with IH was raised experimentally to, and maintained at, a typically normal (or normocapnic) value (i.e., 40 mm Hg), hypoxic ventilatory responsiveness was significantly increased (2.4 ± 1.0 L/minute/%; analysis of variance, p < 0.05) (Figure 1) to lie within the normal reported range (30). Interestingly, this value was actually greater than the value for our control subjects (p < 0.05).



View larger version (22K):
[in this window]
[in a new window]
  		Figure 1. Hypoxic ventilatory responsiveness in (1) subjects with idiopathic hyperventilation (IH) determined at their eucapnic PETCO2 (~ 30 mm Hg) and on another occasion with PETCO2 acutely elevated to the "normocapnic" level (~ 40 mm Hg) and (2) normal subjects (control) at their eucapnic PETCO2 (approximately 40 mm Hg). Solid circles represent individual responses. Open circles represent mean response ± 1 SD. The asterisk indicates a significant difference from all other groups (analysis of variance, p < 0.05). For further detail, see METHODS.

 
Hypercapnic Ventilatory Responsiveness
The slope of the linear phase of the E–PETCO2 relationship during progressive hyperoxic hypercapnia provided an index of hypercapnic ventilatory responsiveness (27). Hypercapnic ventilatory responsiveness averaged 2.13 ± 1.0 L/minute/mm Hg for patients with IH and 1.59 ± 0.5 L/minute/mm Hg for the control subjects (Figure 2) , which was not significantly different (p > 0.05).



View larger version (13K):
[in this window]
[in a new window]
  		Figure 2. Hypercapnic ventilatory responsiveness in (1) subjects with IH (solid circles) and in (2) normal subjects (control) (open circles). For further detail, see METHODS.

 
Breath-hold Tolerance
The tolerance of the subjects with IH to volitional breath holding was strikingly depressed, compared with the control subjects: that is, breath-hold time averaged just 21 ± 12 seconds compared with 58 ± 23 seconds for the control group (Figure 3) . When our control subjects volitionally hyperventilated to produce alveolar gas concentrations similar to those of the IH group before the breath hold (i.e., PETCO2 = 22.4 ± 2.9 mm Hg), breath-hold time was significantly increased to 100 ± 36 seconds (p < 0.05).



View larger version (26K):
[in this window]
[in a new window]
  		Figure 3. Duration of volitional breath-hold maneuvers (1) during inhalation of atmospheric air (FIO2 = 0.21) and 100% oxygen (FIO2= 1.0) in subjects with IH and normal subjects (control) and (2) after acute hyperventilation (HV) in the control group to a PETCO2 of approximately 22 mm Hg (i.e., equal to the eucapnic value of the IH group).

 
Inhalation of 100% oxygen is known to prolong breath-hold time by approximately 80–100% in normal subjects (31). This proved to be significantly so for our control subjects, in whom breath-hold time was increased by 65 ± 13% (i.e., 93 ± 45 seconds). In contrast, breath-hold time in the subjects with IH was not significantly altered by the hyperoxia: 24 ± 18 seconds compared with 21 seconds in normoxia.

Exercise
Peak O2 at the limit of tolerance averaged 1.50 ± 0.4 L/minute in the IH group, which was slightly lower than in the control group (1.90 ± 0.5 L/minute, p < 0.05). After exercise, all of the subjects with IH reported "shortness of breath" as a reason for terminating the test, with this being exclusively the case in 66%—the remainder reporting leg effort in addition. In contrast, the control subjects predominantly reported "tired legs" as a reason for termination, with only 21% citing "shortness of breath."

The noninvasive criteria for {theta}L estimation (i.e., hyperventilation relative to O2 but not CO2; see METHODS) were met in all control subjects and in 23 of the 39 subjects with IH, with {theta}L occurring at similar percentages of O2 peak (IH = 58 ± 9%, control = 54 ± 7%, p > 0.05). For those subjects with IH in whom {theta}L could not be unequivocally estimated, there was evidence of acute-on-chronic hyperventilation either at rest or in the initial stages of the exercise, a phenomenon that has been reported previously in normal subjects caused to hyperventilate acutely before exercise onset (32). That is, a transient increase in the respiratory exchange ratio was observed either just before (to a value of 1.32 ± 0.17, n = 6) or associated with the onset of exercise (to a value of 1.24 ± 0.15, n = 10) (Figure 4) .



View larger version (26K):
[in this window]
[in a new window]
  		Figure 4. Three representative response profiles of E and respiratory exchange ratio to an incremental cycle–ergometer exercise test (performed to the limit of tolerance), as a function of O2 uptake (O2), in the IH group (n = 39). (Left panel) A subject who acutely hyperventilated (i.e., respiratory exchange ratio > 1.0) before the exercise test (n = 6). (Middle panel) A subject who acutely hyperventilated after the onset of the test (n = 10). (Right panel) A subject with no evidence of acute hyperventilation (n = 23).

 
As acute hyperventilation can influence the response profile and thence interpretation of the ventilatory and gas exchange responses to progressive exercise (32), all subsequent analyses were confined to the 23 patients with IH who did not manifest this additional acute hyperventilation. In this subgroup with IH, respiratory exchange ratio averaged 0.88 ± 0.07 during "unloaded pedaling," which was not significantly different from the control subjects (0.85 ± 0.08).

Representative examples of the ventilatory and gas exchange responses to the ramp–incremental exercise for IH and control subjects are shown in Figures 5 and 6 , respectively. Before ramp onset (i.e., during "unloaded" pedaling), the hypocapnic condition was maintained for the group with IH, with alveolar (end-tidal) PCO2 being significantly (p < 0.05) lower (29 ± 4 mm Hg) than in the control subjects (38 ± 3 mm Hg), that is, consistent with the significantly raised E/CO2 (IH = 42 ± 6.5, control = 37 ± 5.3, p < 0.05).



View larger version (26K):
[in this window]
[in a new window]
  		Figure 5. Responses to an incremental exercise test performed to the limit of tolerance in a typical subject with IH. (Left panel, from top down) CO2 output (O2) versus O2 uptake (O2); ventilatory equivalents for O2 and CO2 (E/O2, open circles, E/CO2, solid circles, respectively) versus O2 and end-tidal PCO2 and PCO2 (PETO2, open circles; PETCO2, solid circles, respectively) versus O2. (Right panel, from top down) E versus CO2, VT versus E, and respiratory exchange ratio versus O2. The vertical line is the estimated lactate threshold ({theta}L).

 


View larger version (29K):
[in this window]
[in a new window]
  		Figure 6. Responses to an incremental exercise test performed to the limit of tolerance in a typical normal subject. See Figure 5 for details.

 
During the moderate-intensity range of the ramp (< {theta}L), while the E–CO2 relationship was linear for both the control subjects and the subgroup of 23 subjects with IH (i.e., without acute hyperventilation), the slope ({Delta}E/{Delta}CO2) was significantly steeper in the IH group (IH = 35.7 ± 6.0, control = 25.5 ± 2.4, p < 0.05) with an associated small but significant reduction in the E intercept (IH = 2.6 ± 1.7 L/minute, control = 4.1 ± 1.5 L/minute, p < 0.05). PETCO2 in the group with IH remained close to resting and baseline values (i.e., at {theta}L, IH = 30 ± 5 mm Hg versus control = 41 ± 3 mm Hg, p < 0.05).

Dyspnea
As was the case for rest (discussed previously here), breathlessness in the IH group was significantly (p < 0.05) higher throughout the exercise than for the control subjects. For example, during "unloaded pedaling," 2.31 ± 1.64 versus 0.26 ± 0.40 and, at 40 W, 4.0 ± 1.70 versus 0.87 ± 1.08, for subjects with IH and control subjects, respectively. The exercise-related dyspneic response normalized with respect to ventilation (e.g., rest to 40 W), {Delta}dyspnea/{Delta}E, averaged 0.138 ± 0.137 Borg units/L/minute in the 23 subjects with IH who did not evidence any acute hyperventilation early in the test, which was significantly greater than for the control subjects (0.060 ± 0.082 Borg units/L/minute, p < 0.05).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
Conclusions
 REFERENCES
 
This study of patients with chronic IH has demonstrated the following: (1) the resting ventilatory responsiveness to CO2 under hyperoxic conditions lay within normal limits (consistent with central CO2 chemosensitivity being unaffected), whereas the resting ventilatory responsiveness to hypoxia (which was low at eucapnic levels of alveolar PCO2) was significantly greater than our control values when measured under "normocapnic" conditions (suggesting that peripheral hypoxic chemosensitivity was, in fact, greater than normal when corrected to normocapnia); (2) The ventilatory response to progressive moderate-intensity exercise was substantially in excess of normal, but with no evidence of any acute further hyperventilation of a sustained nature, such that the resting hypocapnic CO2 setpoint was essentially unaffected; and (3) the heightened perception of breathlessness at rest and during exercise did not appear simply to be a consequence of the associated hyperpnea per se.

Ventilatory Control at Rest
The sustained nature of the hyperventilation in our patients with IH was evident in arterial pH at rest being functionally normal, consistent with a fully compensated respiratory alkalosis. The presence of a sustained hyperventilatory drive in the IH group is also suggested by the findings that despite marked hypocapnia (and modest hyperoxia, PaO2 of approximately 120 mm Hg) at rest, the duration of a volitional breath hold was reduced approximately threefold compared with normal subjects in this (Figure 3) and previous studies (33, 34) and, indeed, coheres with the observations of Gardner and Bass (35). When compared with the tolerance time in the normal subjects who acutely hyperventilated to a PETCO2 equivalent to that of the subjects with IH (i.e., approximately 30 mm Hg), the reduction in breath-hold time was approximately sixfold. Furthermore, hyperoxia had little effect on the breath-hold time in the IH group, whereas it markedly increased that of the control subjects. The recent demonstration, by polysomnography, that the hyperventilation in these subjects is maintained in slow-wave (S4) sleep (36) provides further evidence supporting the persistence of the hyperventilation and seemingly excludes "anxiety" or other behavioral mechanisms as necessary sources of the persistent hyperventilation.

As a group, our patients with IH were, at rest, more "anxious" than normal, at least as reflected as the results of the hospital anxiety and depression score (> 7). However, it is not clear whether the relationship between this and the degree of hyperventilation is that of cause or effect (4). We postulate, however, that anxiety may initiate an exaggerated and abnormal ventilatory response to stress, whether physical or emotional, and also a more sustained hyperventilation. Anxiety has been shown previously to increase E, mediated mainly by increased breathing frequency (37). This abnormal response may therefore become part of the "respiratory make-up" of that person, possibly by alteration of the respiratory pattern generators in the brain stem; this would be consistent with the persistence of hyperventilation during slow-wave sleep.

What seems clear from our results is that the sustained hyperventilatory drive in our patients with IH is not attributable to a hypersensitivity of central chemosensory control mechanisms. That is, the ventilatory response to hyperoxic hypercapnia, reflective of central CO2 responsiveness (27), was normal and not different from our control group. What these observations do not answer is whether, within the spontaneously hypocapnic PCO2 range of our patients, the ventilatory control system was operating within a region of relative CO2 insensitivity represented by the "dog-leg" in the ventilation–PCO2 relationship (38). That is, the linear region of the PCO2 range in the Read rebreathing test does not extrapolate back to the resting PCO2 level. One might speculate, however, that a dog-leg might not be so evident when hypocapnia is chronic, as the restoration of arterial pH would be expected to offset some of the hypocapnic restraint on ventilation.

Furthermore, the demonstration that the peripheral chemosensory component (as measured by isocapnic progressive hypoxia) (25) was markedly low in the IH group when PETCO2 was maintained at its normal eucapnic level would seem unlikely to reflect an abnormality. That is, such an observation is consistent with hypocapnic attenuation of peripheral chemoreceptor hypoxic drive (39) and thence ventilatory hypoxic drive (29, 40, 41). However, it should be emphasized that the extent to which this scenario prevails when the hypocapnia is chronic and arterial pH is no longer high is less clear. Indeed, when the hypoxic ventilatory sensitivity was reassessed with PETCO2 experimentally increased to a "normal" level of 40 mm Hg, it increased into the normal range and, interestingly, was significantly greater than for our age-matched control group. The functional significance of this is presently uncertain. Is there a functionally significant sensitization of the peripheral chemoreflex in IH that is normally "masked" by the prevailing hypocapnia or might we (by chance) have selected control subjects with hypoxic responsiveness that tended toward the lower end of the normal range?

What our experiments also do not allow us to answer is whether in IH temporally related characteristics of the arterial blood–gas tensions and pH (periodic or otherwise) might provide a drive to E in excess of that attributable to their conventional "steady-state" (or quasi–steady-state) values (42–45). Neither can they resolve the issue of whether there is an element of "conditioning" inherent in the ventilatory control process (5), and indeed, both exercise and hypoxia have been demonstrated to condition E in normal subjects (42, 46).

Deserving of comment is the possibility that IH might have some overlap with idiopathic central sleep apnea. That is, patients with idiopathic central sleep apnea hyperventilate chronically, both awake and asleep, and have been reported to have heightened central and peripheral chemoreflex responsiveness (47, 48). However, we have conducted overnight polysomnography in patients with IH (including six in the present cohort) and could find no evidence of central sleep apnea, despite PETCO2 remaining low throughout all sleep stages (36, 49). It thus seems that IH and idiopathic central sleep apnea are discrete conditions.

Ventilatory Control in Exercise
Consistent with the chronic nature of the hyperventilation in our patients, with its associated reduced setpoint for arterial PCO2 regulation, was the demonstration that the "excessive" hyperpneic response to moderate exercise (i.e., below the {theta}L) was, in fact, consistent with the ventilatory requirements for maintaining the low CO2 setpoint also during the exercise (50):

(1)
where VD/VT is the physiologic dead space fraction of the breath. This proved to be the case, with (1) the slope of the corresponding E–CO2 relationship being 35.7 ± 6.0 in the subjects with IH and 24.4 ± 2.0 in the control subjects and (2) the ventilatory equivalent for CO2 (E/CO2) at the {theta}L being 39.3 ± 6.5 and 29.6 ± 3.5 in the IH and control subjects, respectively. Although we were unable to monitor arterial PCO2 directly throughout the exercise, the demonstration of a modest tendency toward an increase in the end-tidal PCO2 with increasing work rate in the moderate-intensity domain is consistent with PaCO2 likely having changed little from resting values. That is, the increase in PETCO2 will be largely reflective of the steepening of the expiratory alveolar phase of the respired PCO2 profile, with little change having occurred in the mean alveolar value (51).

Consequently, whatever the source of the resting hyperventilatory drive, it seems not to recede as the subjects' attention became more focused on the task as the work rate increased. This scenario has an interesting parallel with "Ondine's curse" or congenital central hypoventilation syndrome, for which the E response to exercise has been shown to be reduced, consistent with PaCO2 operating at an elevated setpoint (Equation 1) (52, 53).

It was pointed out earlier that the patients with IH were more anxious than normal at rest. We cannot know, however, whether this "anxiety" was maintained, amplified, or suppressed by the exercise task and, if so, in which subjects. It is important to recognize that in this study we have only included subjects with hyperventilation that is not associated with any known physical condition. Furthermore (in terms of the results pertaining to exercise), we only considered those with no additional transient acute hyperventilation at the start of the exercise (Figure 4). Consequently, this may be considered a "pure" and well characterized group of subjects.

Respiratory Perception
The etiology of the exacerbated breathlessness or dyspnea in patients with IH is also a perplexing issue. Traditionally, the intensity of dyspnea is argued to reflect respiratory–mechanical status and thus to increase with ventilation and also with respiratory–mechanical impedance (16, 17). The latter would seem to be an unlikely contributor in the present situation, given the normalcy of pulmonary function in our patients with IH. Furthermore, the magnitude of dyspneic sensation was still higher than expected when normalized with respect to E, suggesting that additional factors may be involved. For example, anxiety might be expected to heighten the degree of breathlessness. A further contribution might possibly derive from the increased hypoxic ventilatory responsiveness that we report under normocapnic conditions in our patients. That is, it has been argued that the peripheral chemoreceptors may provide a drive to dyspnea in exercise that is above and beyond that accruing from respiratory–mechanical factors (54).


   Conclusions
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 Conclusions
REFERENCES
 
If IH is, in fact, an acquired abnormality, as opposed to a genetically determined one, then this has implications for treatment strategies. As an acquired phenomenon, it may be possible to reverse the changes by instituting appropriate breathing therapy (55, 56), although simple maneuvers to consciously alter breathing pattern when the patient is symptomatic may not always be effective (57). In this case, a more sustained alteration of breathing pattern may be required to reverse the changes within the "respiratory make-up" of that subject—possibly with judicious use of chemical and psychotherapeutic anxiolytic strategies. It is still possible, however, that the ventilatory abnormality may be genetically determined and thus, in some subjects, becoming sustained, much in the same way that some subjects with severe chronic obstructive pulmonary disease will become CO2-retaining hypoxic "blue-bloaters," whereas others will become more normoxic hypocapnic "pink-puffers." Study of the families of subjects with IH may be expected to shed some light on this.


   Acknowledgments
 
The authors acknowledge Mersey Regional Heath, UK.


   FOOTNOTES
 
Supported by the Wellcome Trust, UK (064898) (H.B.R.).

Conflict of Interest Statement: S.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.B.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.G.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.A.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.J.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; B.J.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form July 20, 2002; accepted in final form March 31, 2004


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 

  1. Farhi LE, Rahn H. Dynamics of changes in carbon dioxide stores. Anesthesiology 1960;21:604–614.[Medline]
  2. Cherniack NS, Longobardo GS. Oxygen and carbon dioxide gas stores of the body. Physiol Rev 1970;50:196–243.[Free Full Text]
  3. Folgering H. The pathophysiology of hyperventilation syndrome. Monaldi Arch Chest Dis 1999;54:365–372.[Medline]
  4. Gardner WN. The pathophysiology of hyperventilation disorders. Chest 1996;109:516–534.[Free Full Text]
  5. Howell JBL. The hyperventilation syndrome: a syndrome under threat? Thorax 1997;52:30–34.
  6. Kerr WJ, Dalton JW, Gliebe PA. Some physical phenomena associated with anxiety states and their relation to hyperventilation. Ann Intern Med 1937;11:961–992.
  7. Timmons BH, Ley R. Behavioural and psychological approaches to breathing disorders. New York: Plenum; 1994.
  8. Jack S, Davies L, Pearson MG, Calverley PMA, Warburton CJ. Health status in patients with idiopathic hyperventilation (IH) is comparable with patients with severe COPD [abstract]. Am J Respir Crit Care Med 2001;163:A63.
  9. Orem J, Netick A. Behavioral control of breathing in the cat. Brain Res 1986;366:238–253.[CrossRef][Medline]
  10. Soley M, Shock N. The aetiology of effort syndrome. Am J Med Sci 1938;196:840–851.
  11. Lowry TP. Hyperventilation and hysteria. Springfield, IL: Charles C. Thomas; 1967.
  12. Plum F. Neurological integration of behavioural and metabolic control of breathing. In: Porter R, editor. Breathing: Hering-Breuer Centenary Symposium. London: Churchill; 1970. p. 159–181.
  13. Lum C. The syndrome of habitual chronic hyperventilation. In: Hill OW, editor. Modern trends in psychosomatic medicine. London: Butterworth, 1976;11:196–230.
  14. Brashear RE. Hyperventilation syndrome. Lung 1983;161:257–273.[Medline]
  15. Gardner WN, Meah MS, Bass C. Controlled study of respiratory responses during prolonged measurement in patients with chronic hyperventilation. Lancet 1986;2:826–830.[CrossRef][Medline]
  16. Campbell EJM, Howell JB. The sensation of breathlessness. Br Med Bull 1963;19:36–40.[Free Full Text]
  17. Killian KJ, Campbell EJM. Dyspnea. In: Crystal RG, West JB, editors. The lung: scientific foundations. New York: Raven Press; 1991. p. 1433–1443.
  18. Jack S, Rossiter HB, Warburton CJ, Whipp BJ. Cardiopulmonary and metabolic responses to ramp: incremental exercise in subjects with idiopathic hyperventilation. Eur Respir J 2001;18:356s.[CrossRef]
  19. Barczak P, Kane N, Andrews S, Congdon AM, Clay JC, Betts T. Patterns of psychiatric morbidity in a genito-urinary clinic: validation of the hospital anxiety and depression score (HAD). Br J Psychiatry 1988;152:698–700.[Abstract/Free Full Text]
  20. Vansteenkiste. J Rochette F, Demedts M. Diagnostic tests of hyperventilation syndrome. Eur Respir J 1991;4:393–399.[Abstract]
  21. Beaver WL, Wasserman K, Whipp BJ. On-line computer analysis and breath-by-breath graphical display of exercise function tests. J Appl Physiol 1973;34:128–132.[Free Full Text]
  22. Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377–381.[Medline]
  23. Sue DY, Wasserman K, Moricca RB, Casaburi R. Metabolic acidosis during exercise in patients with chronic obstructive pulmonary disease: use of V-slope method for anaerobic threshold determination. Chest 1988;94:931–938.[Abstract/Free Full Text]
  24. Whipp BJ, Ward SA, Wasserman K. Respiratory markers of the anaerobic threshold. In: Tavazzi L, di Prampero PE, editors. The anaerobic threshold: physiological and clinical significance (advances in cardiology 35). Basel: Karger; 1986. p. 47–64.
  25. Rebuck AS, Campbell EJM. A clinical method for assessing the ventilatory response to hypoxia. Am Rev Respir Dis 1974;109:345–350.[Medline]
  26. Bellville JW, Whipp BJ, Kaufman RD, Swanson GD, Aqleh KA, Wiberg DM. Central and peripheral chemoflex loop gain in normal and carotid body-resected subjects. J Appl Physiol 1979;46:843–853.[Free Full Text]
  27. Read DJC. A clinical method for assessing the ventilatory response to carbon dioxide. Australias Ann Med 1967;16:20–32.
  28. British Thoracic Society and the Association of Respiratory Technicians and Physiologists. Guidelines for the measurement of respiratory function. Respir Med 1994;88:165–194.[Medline]
  29. Corne S, Webster K, Younes M. Hypoxic respiratory response during acute stable hypocapnia. Am J Respir Crit Care Med 2003;167:1193–1199.[Abstract/Free Full Text]
  30. Hirshman CA, McCullough RE, Weil JV. Normal values for hypoxic and hypercapnic ventilatory drives in man. J Appl Physiol 1975;38:1075–1098.
  31. Klocke FJ, Rahn H. Breath holding after breathing oxygen. J Appl Physiol 1959;14:689–693.[Abstract/Free Full Text]
  32. Ozcelik O, Ward SA, Whipp BJ. Effect of altered body CO2 stores on pulmonary gas exchange dynamics during incremental exercise in humans. Exp Physiol 1999;84:999–1011.[Abstract]
  33. Fowler WS. Breaking point of breath-holding. J Appl Physiol 1954;6:539–545.[Free Full Text]
  34. Rigg JRA, Rebuck AS, Campbell EJM. A study of factors influencing relief of discomfort in breath-holding in normal subjects. Clin Sci Mol Med 1974;47:193–199.[Medline]
  35. Gardner WN, Bass C. Hyperventilation in clinical practice. Br J Hosp Med 1989;41:73–81.[Medline]
  36. Lowe S, Jack S, Warburton CJ, Calverley PMA. Idiopathic hyperventilation (IHV) during wakefulness and sleep [abstract]. Am Rev Respir Crit Care Med 2001;163:A179.
  37. Masaoka Y, Homma I. Expiratory time determined by individual anxiety levels in humans. J Appl Physiol 1999;86:1329–1336.[Abstract/Free Full Text]
  38. Cunningham DJC, Robbins PA, Wolff CB. Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH. In: Cherniack NS, Widdecombe JG, editors. Handbook of physiology: the respiratory system, control of breathing, Vol. II. Bethesda: American Physiological Society; 1986. p. 475–528.
  39. Hornbein T, Griffo ZJ, Roos A. Quantitation of chemoreceptor activity: interrelation of hypoxia and hypercapnia. J Neurophysiol 1961;24:561–568.[Free Full Text]
  40. Katsaros B, Loeschcke H. Die Rolle der chemorezeptoren des carotis und aortengebiets der katze für die antwort der atmung auf isolierte änderung der wasserstoffion-konzentration im blut. Pflugers Arch 1962;274:21–27.
  41. Cormack RS, Cunningham DJC, Gee JB. The effect of carbon dioxide on the respiratory response to want of oxygen in man. Q J Exp Physiol 1957;42:303–319.
  42. Eldridge FL, Millhorn DE. Oscillation, gating and memory in the respiratory control system. In: Widdicombe JG, Cherniack N, editors. Handbook of physiology, respiration (control). Washington, DC: American Physiological Society; 1986. p. 93–114.
  43. Cross BA, Stidwell RP, Hughes KR, Peppin R, Semple SJG. A comparative study of aortic pH oscillations in conscious humans and anaesthetised cats and rabbits. Respir Physiol 1995;102:51–62.[CrossRef][Medline]
  44. Black AM, Torrance RW. Respiratory oscillations in chemoreceptor discharge in the control of breathing. Respir Physiol 1971;13:221–237.[CrossRef][Medline]
  45. van den Aardweg JG, Karemaker JM. Influence of chemoreflexes on respiratory variability in healthy subjects. Am J Respir Crit Care Med 2002;165:1041–1047.[Abstract/Free Full Text]
  46. Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 2003;26:239–266.[CrossRef][Medline]
  47. Xie A, Wong B, Phillipson EA, Slutsky AS, Bradley TD. Interaction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea. Am J Respir Crit Care Med 1994;150:489–495.[Abstract]
  48. Xie A, Rutherford R, Rankin F, Wong B, Bradley TD. Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med 1995;152:1950–1955.[Abstract]
  49. Lowe S, Jack S, Warburton CJ, Calverley PMA. Does sleep stage affect respiratory pattern in idiopathic hyperventilation [abstract]? Thorax 2001;56:S150–iii45.
  50. Whipp BJ, Pardy RL. Breathing during exercise. In: Cherniack NS, Widdicombe JG, editors. Handbook of physiology: section 3: the respiratory system. Washington, DC: The American Physiological Society; 1986. p. 605–629.
  51. Whipp BJ, Lamarra N, Ward SA, Davis JA, Wasserman K. Estimating arterial PCO2 from flow-weighted and time-averaged alveolar PCO2 during exercise. In: Swanson GD, Grodins FS, editors. Respiratory control: modeling perspective. New York: Plenum; 1990. p. 91–99.
  52. Paton JY, Swaminathan S, Sargent CW, Hawksworth A, Keens TG. Ventilatory response to exercise in children with congenital central hypoventilation syndrome. Am Rev Respir Dis 1993;147:1185–1191.[Medline]
  53. Shea SA, Andrews LP, Shannon DC, Banzett RB. Ventilatory responses to exercise in humans lacking ventilatory chemosensitivity. J Physiol 1993;469:623–640.
  54. Ward SA, Whipp BJ. Effects of peripheral and central chemoreflex activation on the isopnoeic rating of breathing in exercising humans. J Physiol 1989;411:27–43.[Abstract/Free Full Text]
  55. DeGuire S, Gevirtz R, Hawkinson D, Dixon K. Breathing retraining. Biofeedback Self Regul 1996;21:191–198.[CrossRef][Medline]
  56. Han JN, Stegen K, de Valcke C, Clement J, Van de Woestijne KP. Influence of breathing therapy on complaints, anxiety and breathing pattern in patients with hyperventilation syndrome and anxiety. J Psychosom Res 1996;41:481–493.[CrossRef][Medline]
  57. Ley R. The effect of breathing retraining and the centrality of hyperventilation in panic disorder: a reinterpretation of experimental findings. Behav Res Ther 1991;29:301–304.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200207-720OCv1
170/2/118    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jack, S.
Right arrow Articles by Whipp, B. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jack, S.
Right arrow Articles by Whipp, B. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2004 American Thoracic Society