Catherine.Osborne, John. Varley* and William.Gardner

Dept of Respiratory Medicine & Allergy, Guy's, King's & St. Thomas's School of Medicine,
Denmark Hill campus, Bessemer Rd, London SE5 9PJ.
*Dept Physiology, Worsley Medical & Dental Building, Leeds University LS2 9JT

The range of arterial PCO2 (PaCO2) is generally quoted as 35-45 mmHg for normal subjects. This range has been determined from measurements recorded under controlled conditions at rest in the laboratory and should therefore only be used as a reference for these situations.

Most previous measurements of PaCO2 or equivalents involved either arterial puncture or use of uncomfortable apparatus such as mouthpiece or masks which may influence the breathing being measured. End-tidal PCO2 (PETCO2 ) recorded from expired air is regarded as equivalent to PaCO2 in resting subjects with normal lungs.

We measured PETCO2 by mass spectrometer sampling relatively uninvasively via a fine nasal catheter (1) and reported that the lower limit of the normal range in the laboratory should be 31 -32 mmHg (4.13 - 4.27 kPa).

We have consistently argued that the lower limit of the normal range should be revised downward for patients during activities of daily living outside the laboratory (3). This is of relevance in the study of patients with hyperventilation related disorders.

We previously showed that the outside range of PETCO2 within which symptoms of hypocapnia can occur in normal subjects was 14-29 mmHg (2). It could therefore be argued that if normal subjects during activities of daily living routinely reduced their PaCO2 below 29 mmHg for periods of time during the day, they may be prone to hypocapnic symptoms, which, if misinterpreted as more serious disease, could lead to a vicious spiral of increasing anxiety, hyperventilation and invalidism(3). It is conceivable therefore, that subjects who naturally keep their PaCO2 at the lower end of the normal range may be the subjects who are particularly vulnerable to hyperventilation disorders, but this need to be established.

Hyperventilation is well recognized as a concomitant of acute asthma, and studies in which PaCO2 was related to the severity of acute asthma showed clear evidence of significant hyperventilation with only modest reductions of FEV1(4). We have also argued that a major aetiological factor in symptomatic hyperventilation is very mild and often previously undiagnosed asthma, which can lead to a vicious cycle of panic and disability(3, 5, 6, 7).

For example, we described a patient who presented with severe hyperventilation and tetany who was subsequently found to have asthma as the sole underlying aetiological factor for hyperventilation (6).

In another study(7), we investigated a group of patients presenting to our accident and emergency department with a primary diagnosis of hyperventilation. Approximately 80% had good evidence of underlying asthma, which had been previously unrecognized in a half. The association between symptomatic hyperventilation and asthma has been emphasized by others. It would therefore be reasonable to propose that mild chronic asthma may be associated with even more marked hyperventilation and hypocapnia than has been described in severe acute asthma.

However, we recently showed that mild asthma was associated with only a small (but significant) reduction of both arterial and end-tidal PCO2 which correlated with airway hyperreactivity and not with measures of lung function or airway inflammation(8), but this study was not able to confirm that mild asthma is invariably associated with more marked and clinically significant hyperventilation.

In the present study we wished to determine whether some normal subjects demonstrated levels of PETCO2 below the accepted normal lower limit during activities of daily living, and whether more dramatic hypocapnia may occur under some circumstances in mild asthmatics under these conditions.

We used our new ambulatory capnograph sampling from a fine nostril catheter with data collected by either on-line by telemetry or off-line by a data logger to study PETCO2 in 23 normal subjects and 11 mild asthmatics over 4 hours during activities of daily living within the workplace and at home (n=8).

For the normal subjects, the mean PETCO2 was 37.3 (SD 2.8) mmHg and the lowest limit of the range (mean minus 2SD) was between 30 and 35 mmHg in 15 subjects and below 30mmHg in 4 (1 male, 3 females). There was no correlation between PETCO2 and lung function, psychological scores, gender or between work place and home. The responses of the asthmatics were not significantly different from those of the normal subjects.

This study therefore confirmed that the majority of both normal subjects and mild asthmatics when measured uninvasively during activities of daily living had end-tidal PCO2 values well below the accepted lower limit of 35mmHg and within the range at which symptoms of hypocapnia could occur.

The subjects with the more extreme reductions of PETCO2 may well be more vulnerable to developing clinically significant hyperventilation, but this requires further study. We were not able to confirm that mild asthmatics have more dramatic hyperventilation during activities of daily living that normal subjects. The hyperventilation in our previously studied patients with mild asthma may have had an additional or alternate etiology.

References:
1. Gardner WN, Meah MS, Bass C. Controlled study of respiratory responses during prolonged measurement in patients with chronic hyperventilation. Lancet 1986;ii:826-830.

2. Rafferty GF, Saisch SGN, Gardner WN. Relation of hypocapnic symptoms to rate of fall of end-tidal PCO2 in normal subjects. Respir Med 1992;86:335-340.

3. Gardner WN. Review: The pathophysiology of hyperventilation disorders. Chest 1996;109:516-534.

4. McFadden ER, Lyons HA. Arterial blood gas tension in asthma. N Engl J Med 1968;278(19):1027-1032.

5. 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. 633-660.

6. Gardner WN, Bass C, Moxham J. Recurrent hyperventilation tetany due to mild asthma. Respir Med 1992;86:349-351.

7. Saisch SGN, Wessely S, Gardner WN. Patients with acute hyperventilation presenting to an inner-city emergency department. Chest 1996;110(4):952-957.

8. Osborne CA, O'Connor BA, Lewis A, Kanabar V, Gardner, W.N. Hyperventilation and asymptomatic chronic asthma. Thorax 2000;55:in press.