Cor pulmonale in asthma

Br.

J. Dis.

Chest

(1983)

77, 303

COR PULMONALE IN ASTHMA P.M. A. CALVERLEY*, Departments

of Medicine,

J. R. CATTERALL, Respiratory

Medicine

C. SHAPIRO and

Psychiatry,

AND N. J. DOUGLAS University

of Edinburgh

Summary The development of right ventricular failure due to pulmonary hypertension is a common complication of severe chronic bronchitis and emphysema (Renzetti et al. 1976) but is rare in bronchial asthma (Clark 1977). We report a ZO-year-old extrinsic asthmatic with persistent hypoxaemia and carbon dioxide retention, secondary polycythaemia and car pulmonale and describe his further investigation. Case History A ZO-year-old man was referred in 1980 to assess his suitability for domiciliary oxygen therapy. In early childhood he had developed intermittent wheeze and nocturnal cough and had severe flexural eczema. He lost schooling each year due to his eczema and exercise-induced wheeze and when aged 13 his FEVi was 0.8 litres and FVC 1.8 litres (predicted values 2.5 and 3.5 litres respectively). He obtained considerable symptomatic relief from regular sodium cromoglycate but 2 years later inhaled beclomethasone and salbutamol were added, and his FEVi increased to 1 .O litre . In August 1979 he was admitted to hospital with a 3-week history of cough, yellow sputum, increasing breathlessness, wheeze and bilateral ankle swelling. He was centrally cyanosed while breathing air, had a 5 cm elevation of jugular venous pressure, bilateral pitting oedema to both knees, a hyperinflated chest and numerous expiratory rhonchi. His arterial PO2 breathing 24% oxygen was 8.9 kPa with a PC02 of 7.8 kPa and a normal hydrogen ion concentration. His chest radiograph showed hyperinflation with mild cardiomegaly but no evidence of pulmonary venous congestion or bronchiectasis and an ECG showed changes of right ventricular hypertrophy. He was treated with digoxin and diuretics with good effect but 2 months later was readmitted for a further exacerbation of asthma without peripheral oedema. After physiotherapy and bronchodilators his FEVr increased to 1.9 litres but subsequently declined as an outpatient to 1 .O litres despite a trial of 30 mg of prednisolone orally for 7 days. When assessed in 1980 his symptoms were stable, there was no family history of respiratory illness and he denied ever smoking or having had pneumonia. On examination he had a hyperinflated chest, scattered expiratory rhonchi and no clinical evidence of cardiac failure or ventricular hypertrophy. Investigations

To characterize the type formed in January 1980:

and severity

of this patient’s

asthma

the following

tests were per-

Haemoglobin 19.3 g/dl; white blood count 8.7 x lO’/litre; 11% eosinophils; red cell mass 34.6 ml/kg (normal 22-28 ml/kg). Chest radiograph was unchanged and ECG showed incomplete right bundle branch block. * Requests for reprints to: Dr P. M. A. Calverley, Hospital, Greenbank Drive, Edinburgh EHlO 5SB

Department

of Respiratory

Medicine,

City

304

P. M. A. Calverley, J. R. Catterall,

C. Shapiro and N. J. Douglas

Skin tests to six allergens including house dust, Aspergillus and cat fur were strongly positive. Tests for Aspergillus precipitins were negative. The sweat test for cystic fibrosis was normal (sodium 2 6.9 mmol/l, potassium 10 8 mmol/l). Spirometry and lung volume (helium dilution) revealed an FEVr of 2.5 litres, FVC 3.05 litres, a normal total lung capacity but an increased residual volume at 2.7 litres (predicted 1.5 litres) and TLC0 was low normal at 8.4 mmol/litre/kPa. FEVr rose by 20% after inhaled salbutamol and had varied spontaneously by 8% in one year. When breathing air arterial PO2 was 7.3 kPa, PC02 7.0 kPa, H+ 44mmol. The arterial PO2 rose to 9.4 kPa, with a PC02 of 7.4 kPa, when breathing 30% oxygen. Alveolar-arterial oxygen gradient was 4.13 kPa. Pulmonary artery pressure (PAP) was 40/15 mmHg, mean 21.5,mmHg (normal mean PAP 1218 mmHg). The arterial blood gas tensions have been substantially unchanged over 18 months of follow-up with persistent hypoxaemia and carbon dioxide retention.

Table

I.

Oxygenation, nocturnal medroxyprogesterone

Pre-progesterone (air night) Pre-progesterone (Oa night) After 4 weeks progesterone (air night) After 8 months progesterone

sleep, and ventilatory acetate in an asthmatic

control with car

measurements pulmonale

before

Stable SaOz awake

Stable SaOz asleep

Lowest SaOz asleep

‘Dips’

TST (min)

%REM

92.0

90.0

76.0

3

410

20.1

0.07

97.0

97.0

91.5

0

423

17.6

-

91.0

89.5

77.0

1

375

20.2

90.0

88.6

75.2

4

343

21.2

Vel Sa02 (litres/ mm/kPa)

-0.10

and

after

Vel PE TCO,? (litres/ mm/kPa)

3.67

7.62

SaOz, ear oxygen saturation (X); dips, a fall in SaOa of more than 10% from preceding stable sleep SaO,; TST, total sleep time (time from sleep onset to final awakening); REM, rapid eye movement sleep; Ve/SaO*, change in ventilation per unit % fall in SaOa; Ve/PETCOz, change in ventilation per kPa rise in end-tidal COz.

Studies

of oxygenation

duringsleep

and

of ventilatory

control

when

awake

Methods. The patient slept in a quiet darkened room for three consecutive nights, the first serving to acclimatize him to the monitoring equipment. This comprised an electroencephalogram (EEG), electro-oculogram, electromyogram, a Hewlett-Packard HP47201A ear oximeter, a Hellige transcutaneous oxygen electrode, oronasal thermisters and an inductance stethogram to monitor chest wall movement. After acclimatization he received either air or oxygen on consecutive nights in a random fashion, the order being reversed on the subsequent night’s study. On the morning before the first night’s sleep study the ventilatory response to progressive isocapnic hypoxia was measured in duplicate at his resting end-tidal carbon dioxide tension as described by Hudgel and Weil (1974). The steady-state carbon dioxide response was measured in a background of hyperoxia (end-tidal oxygen> 25 kPa) with an inspired CO2 of 2% and subsequently 5%. The results are expressed as instantaneous minute ventilation (Vt x f = Ve inst) per % fall in ear oxygen saturation (SaOz) (Ve/SaOz), or rise in end-tidal CO2 (Ve/PETCOa). Both the studies of ventilatory control and sleep were repeated after 4 weeks of treatment with medroxyprogesterone acetate (MPA) 20 mg t.d.s. and the sleep studies were repeated once more after a total of 8 months’ treatment with MPA.

Cor Pulmonale

305

in Asthma

Results The results of these investigations

are shown in Table I and Fig. 1.

Sleep studies In all the studies the patient slept well with a relatively normal percentage of REM stage sleep. Sa02 fell significantly when breathing air both before and after MPA therapy but these 10% falls in SaOz (dips) were abolished when breathing oxygen. There were no central or obstructive apnoeic periods either before or after therapy, and all the hypoxaemic episodes occurred during periods of

D.McC: ASLEEP BREATHING AIR

REM 8

I Midnight

lam

2am

3am

Lam

5am

6am

IO 7om

TIME

Fig. 1. Oxygen progesterone

27

saturation,

EEG

and

transcutaneous

PO2

during

sleep

breathing

air

prior

to

306

P. M. A. Calverley, J. R. Catterall,

C. Shapiro and N. J. Douglas

recurrent hypoventilation when the amplitude of chest wall movement fell to less than 50% of the stable value during the night. These periods of hypoventilation were as frequent during the oxygen treatment nights as in the air studies.

Ventilatory

control

studies

The ventilatory response to hypoxia was absent initially and the small improvement noted after MPA therapy lies within the error of this measurement. The response to carbon dioxide was blunted before progesterone and although it increased after 1 month of treatment, the patient’s CO2 sensitivity was still subnormal. Discussion A number of asthmatic patients, usually of late onset type develop fixed airways obstruction with relatively little improvement after bronchodilators (Clark 1977), but car pulmonale in any asthmatic is rare (Hudgel & Weil 1974). The long history of asthma and attacks of wheezing together with eosinophilia, positive skin tests, negative Aspergillus precipitins, normal sweat test and spontaneous variation in the severity of air flow obstruction together with the absence of any smoking history or a.lpha,antitrypsin deficiency suggests that this patient is an ‘extrinsic asthmatic’. However, since many similarly affected patients do not develop CO2 retention despite equivalent degrees of airways resistance an additional factor appears to be present in his case. Serial measurements of the CO2 response in patients recovering from acute asthma have shown a progressive increase in CO2 sensitivity in all patients except those who had CO2 retention initially (Rebuck & Read 1971). The CO2 response in our patient was reduced even when he was clinically stable and was similar to those in patients with chronic bronchitis and emphysema with CO2 retention (Clark 1968; Bradley et al. 1979). Likewise our patient’s hypoxic drive to breathing (Ve/Sa02) was similar to that seen in patients with chronic CO2 retention (Fleetham et al. 1980). Th e occurrence of recurrent episodes of nocturnal oxygen desaturation is also similar to the findings in patients with severe chronic bronchitis and emphysema (Douglas et al. 1979) and demonstrates that such changes are not specific for those conditions. Thus although our patient had a clinical history of extrinsic asthma he had developed the physiological abnormalities of ventilatory control and nocturnal oxygenation normally found only in older patients with severe chronic bronchitis and emphysema. Medroxyprogesterone stimulates ventilation and alleviates the nocturnal oxygen desaturation in high altitude polycythaemia (Kryger et al. 1978). Our patient showed no significant improvement in Ve/SaO* after 4 weeks of MPA therapy 1 increase significantly. This relative preservation of although the Ve/PETC02 d’d CO2 responsiveness with a blunted hypoxic drive has been described in another asthmatic with car pulmonale who was not treated with MPA (Hudgel & Weil 1974). MPA did not affect the frequency or duration of nocturnal hypoxaemia after either 4 weeks or 8 months of treatment. On the other hand nocturnal

Cor Pulmonaie

307

in Asthma

oxygen was effective in abolishing the hypoxaemic tinued with this treatment with no ill effects.

episodes and the patient

con-

Acknowledgements We wish to thank Dr W. G. Middleton and Professor D. C. Flenley for permission to report this patient and also to thank Professor Flenley for his advice and the use of his laboratory facilities.

References Bradley,

C. A., Fleetham, J. A. & Anthonisen, N. R. (1979) Ventilatory control in patients with hypoxaemia due to obstructive lung disease. Am. Rev. resp. Dis. 120, 2 1. Clark, T. J. H. (1968) The ventilatory response to CO2 in chronic airways obstruction measured by rebreathing method. Clin. Sci. 34, 559. Clark, T. J. H. (1977) Adult asthma. In: Asthma, eds. T. J. H. Clark & S. Godfrey. London: Chapman and Hall. Douglas, N. J., Calverley, P. M. A., Leggett, R. J. E., Brash, H. M., Flenley, D. C. & Brezinova, V. (1979) Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1, 1. Fleetham, J. A., Mezon, B., West, P., Bradley, C. A., Anthonisen, N. R. & Kryger, M. H. (1980) Chemical control of ventilation and sleep oxygen desaturation in patients with COPD. Am. Rev. resp. Dis. 122, 583. Hudgel, D. W. & We&J. V. (1974) Asthma associated with decreased hypoxic ventilatory drive. Ann. intern. Med. 80, 622. Kryger, M. H., Glas, R., Jackson, D., McCullough, R. E., Scoggin, C., Grover, R. F. 8c Weil,J. V. (1978) Impaired oxygenation during sleep in excessive polycythaemia of high altitude: improvement with respiratory stimulation. Sleep 1, 3. Rebuck, A. F. & Read, J. (1971) Patterns of ventilatory response to carbon dioxide during recovery from severe asthma. Clin. Sci. 41, 13. Renzetti, A. D., McClement, J. H. & Litt, B. D. (1966) Mortality in relation to respiratory function in chronic obstructive pulmonary disease. Am. J. Med. 41, 115.