While reviewing a CPET I noticed the patient had a low PETCO2 throughout exercise and an elevated Ve-VCO2 slope. In addition the patient’s minute ventilation was on the high side (75% of predicted) at peak exercise. This is something you might expect to see in association with pulmonary vascular disease but the subject had a normal DLCO; normal spirometry; their oxygen saturation was normal at all times; and they had a normal maximum VO2 and a normal VO2 at anaerobic threshold. Since there didn’t seem to be any clinical reason for the low PETCO2 I had to wonder whether it was due to hyperventilation syndrome (HVS).
Hyperventilation syndrome is something that everybody “knows” about but is still somewhat ill-defined and this is at least partly because it is most often diagnosed solely by patient-reported symptoms. My lab does not have any diagnostic criteria for hyperventilation syndrome and for this reason I decided to review the literature on the subject.
Hyperventilation syndrome is usually suspected when a patient has rapid, shallow breathing with an irregular breathing frequency and with frequent sigh breaths. Common complaints are dizziness, dry mouth, tingling sensations in the hands and feet and often in combination with chest pain. These symptoms may raise the suspicion that a patient has hyperventilation syndrome and the classic way to diagnose HVS is has to have the patient perform a Hyperventilation Provocation Test (HVPT). During this test a patient voluntarily hyperventilates for three minutes and is then asked whether they felt the symptoms they had been complaining of occurred while they were hyperventilating.
The causes of HVS are considered to be primarily psychosomatic and the majority of articles written on the subject primarily explore this aspect. There are surprisingly few articles on the physiology of HVS and for this reason the physiological causes and consequences of HVS are poorly understood. Of note, I reviewed a couple dozen textbooks on pulmonary function testing and pulmonary diseases that I have on hand and found hyperventilation syndrome to be mentioned in only one (Cotes) where it merited one relatively small paragraph.
A starting point has to be that hyperventilation is ventilation in excess of metabolic requirements. More specifically carbon dioxide is eliminated at a faster rate than it is produced and when this occurs both PaCO2 and PETCO2 are reduced. Inclusion criteria for a number of HVS studies were a PaCO2 that was 30 or less with metabolic compensation (normal pH) or a PETCO2 that was 30 or less over a prolonged period of quiet breathing. This cannot be the sole criteria however, since a reduced PaCO2 is seen in some patients with asthma and a reduced PETCO2 can occur whenever there is significant ventilation-perfusion mismatching (high Vd/Vt) which can occur in emphysema, IPF and heart disease. Patients with HVS usually have normal spirometry, lung volume and DLCO test results however, so this fact could be used to rule out patients with other causes of a reduced PaCO2 or PETCO2.
Interestingly, although HVS could be considered to be caused by a reduced PaCO2 set point which would imply an increased sensitivity of to CO2 several studies have shown that subjects with HVS have a normal response to CO2. The evidence about the response to hypoxia in subjects with HVS is somewhat equivocal with one study indicating that it was normal and another stating that it was depressed except that when the hypoxic test gas mixture contained an elevated CO2 concentration that maintained PETCO2 at 40 mm Hg the hypoxic response was elevated.
Because ventilation is elevated relative to CO2 production in subjects with HVS both the Ve-VCO2 and Ve-VO2 slope tend to be elevated during a CPET. One study showed that a group of subjects with HVS had a Ve/VCO2 of 39.3 at AT versus 29.6 for a matched group of normal subjects. Interestingly, subjects with HVS had a higher incidence of sinus tachycardia and their ECG tended to show downward shifts in the ST-segment, T-wave flattening and these changes were not provoked or worsened by exercise.
Another test that shows a difference between normal subjects and those with HVS is the maximum volitional breath-hold time. This is pretty much what it sounds like; a subject takes a deep breath and the length of time it can be held is measured. Normal subjects tend to have a significantly longer breath-hold time when a breath of 100% oxygen is taken when compared to a breath of room air. Subjects with HVS tend to show no difference in breath-hold times when 100% oxygen is compared to room air, and their breath-holding times tended to be much less than normal subjects (mean 21 seconds versus mean 58 seconds). Although this is an interesting finding, volitional breath-holding is not a standardized test; there are no normal values I am aware of, and most importantly results would appear to depend greatly on patient motivation.
To summarize, the physiological diagnostic criteria for the hyperventilation syndrome would appear to be:
- PaCO2 <= 30 mm Hg
- PETCO2 <= 30 mm Hg
- Elevated Ve-VCO2 slope
- Elevated Ve-VO2 slope
- Elevated Ve/VCO2 at AT.
And in addition, individuals with HVS appear to have a:
- Normal CO2 response
- Reduced volitional breath-holding time
But since these findings can be found in many pulmonary and cardiovascular disorders they have to occur in the absence of any reason to suspect other lung diseases, so at the very least normal PFTs (spirometry, lung volumes and DLCO) and a normal SaO2 need to be present at the same time.
One problem with attempting to study HVS is that the measurement process itself seems to affect results. Specifically, studies have shown that just having a subject breath through a mouthpiece causes them to increase their respiratory rate and minute volume. Along these lines one study noted that when HVS subjects performed a CPET they tended to have a transient increase in Rq well above 1.0 either just before or at the onset of exercise.
Another problem with studying HVS is selecting subjects and there appears to be a wide range of differing inclusion criteria. For some studies a PaCO2 or PETCO2 of 30 or less had to be present at the time of the study, whereas for other studies the subjects only needed to have demonstrated a low PETCO2 at least once during the study period, and other studies only required that the subjects have the correct symptoms and a positive hyperventilation provocation test.
I’m not particularly qualified to criticize but I think that the general belief that HVS is a psychosomatic disorder has limited the physiological research of HVS. Reading what research is available it’s not clear that the categorization of HVS is completely correct since more than one researcher had subjects with chronic hyperventilation without any apparent psychosomatic disorders. It’s also not overly clear to me whether HVS is the same entity when hyperventilation is transitory (rare episodes), episodic (occurs somewhat often) or chronic (constant). I think that despite a clear association of HVS with anxiety and panic disorders there are a number of questions that remain to be answered.
Hyperventilation syndrome should be suspected when a patient complains of shortness of breath, palpitations, dizziness and chest pain; makes frequent sigh breaths; and is associated with anxiety. The classical approach of using symptoms and a hyperventilation provocation test has been criticized by numerous investigators because the rate of false positives is relatively high. Objective physiological factors would appear to include a PaCO2 or PETCO2 that is 30 mm Hg or less and an elevated Ve-VCO2 slope with normal pulmonary function tests and SaO2. HVS can be episodic however, and not all of these factors may be present at the time of testing. When hyperventilation syndrome is already suspected the presence of these factors can be used as an additional confirmation.
There are however, very few physiological studies on HVS and there are numerous discrepancies between them in terms of subject selection and methodology. For these reasons a definitive physiological diagnosis of HVS does not seem possible and at best these factors can only provide a possible confirmation of an existing suspicion.
Notably, the patient whose CPET results got me interested in reviewing the literature on HVS had all of these factors (as well as the elevated Rq during the baseline period and beginning of testing). The physician who ordered the CPET already suspected a pyschosomatic cause for the patient’s shortness of breath and I am able to say that the overall pattern of the results are consistent with that suspicion.
References:
Bass C, Gardner WN. Respiratory and psychiatric abnormalities in chronic symptomatic hyperventilation. Brit Med J 1985; 290: 1387-1390.
Chin K, Hirai M, Kuriyama T, Kita H, Nakamura T, Shimizu K, Kuno K, Ohi M. Hopoxaemia in patients with hyperventilation syndrome. Q J Med 1997; 90: 477-485.
Cotes JE. Chinn DJ, Miller MR. Lung function. Physiology, measurement and application in medicine. Sixth edition, Blackwell Publishing, 2006.
Gardner WN. The pathophysiology of hyperventilation disorders. Chest 1996; 109: 516-534.
Han JN, Stegen K, Simkens K, Cauberghs M, Schepers R, Van den Bergh O, Clement J, Van de Woestijne KP. Unsteadiness of breathing in patients with hyperventilation syndrome and anxiety disorders. Eur Respir J 1997; 10: 167-176.
Hormbrey J, Jacobi MS, Patil CP, Saunders KB. CO2 response and pattern of breathing in patients with symptomatic hyperventilation, compared to asthmatic and normal subjects. Eur Respir J 1988; 1: 846-852.
Hornsveld H, Garssen B. Hyperventilation syndrome: an elegant but scientifically untenable concept. Netherlands J Med 1997; 50: 13-20.
Howell JBL. The hyperventilation syndrome: a syndrome under threat? Thorax 1997; 52: S30-S34.
Jack S, Rossiter HB, Person MG, Ward SA, Warburton CJ, Whipp BJ. Ventilatory responses to inhaled carbon dioxide, hypoxia and exercise in idiopathic hyperventilation. Amer J Respir Crit Care Med 2004; 170: 118-125.
Kinnula VL, Sovijarvi ARA. Hyperventilation during exercise: independence on exercise-induced bronchoconstriction in mild asthma. Resp Med 1996; 90: 145-151.
Vansteenkiste J, Rochette F, Demedts M. Diagnostic tests of hyperventilation syndrome. Eur Respir J 1991; 4: 393-399.
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