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Division of Pulmonary & Critical Care Medicine, Dept of Internal Medicine, Justus-Liebig-University, Gießen, Germany
CORRESPONDENCE: R. Schulz, Division of Pulmonary & Critical Care Medicine, Dept of Internal MedicineJustus-Liebig-University, Klinikstr. 36, 35392, Gießen, Germany. Fax: 49 6419942529. E-mail: Richard.Schulz@innere.med.uni-giessen.de
Keywords: primary pulmonary hypertension, sleep disordered breathing
Received: March 14, 2001
Accepted October 27, 2001
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Abstract |
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A total of 20 consecutive patients with PPH who had been admitted for pharmacological investigation of pulmonary vasoreactivity were investigated by lung function testing, right heart catheterization and full-night attended polysomnography.
PB was detected in six patients (30%) (mean±SEM: apnoea/hypopnoea index 37±5 h–1; arterial oxygen saturation was <90% during 56±6.5% of total sleep time). The patients with PB had more severe haemodynamic impairment than those without. They also had a more marked reduction in the pulmonary diffusion capacity and greater arterial hypoxia. PB was markedly improved or even eradicated by nasal oxygen during the night.
Periodic breathing occurs in patients with advanced primary pulmonary hypertension and can be reversed by nocturnal nasal oxygen. The clinical and prognostic significance of periodic breathing in primary pulmonary hypertension needs to be determined by further studies.
Primary pulmonary hypertension (PPH) is a rare disorder of the pulmonary arteries which predominantly affects young and middle-aged females and carries a very poor prognosis 1. By definition the aetiology of PPH is unknown and its diagnosis thus relies on exclusion criteria 2. Treatment of PPH is based on vasodilator therapy, oral anticoagulation and supplemental oxygen (O2) 3. Further therapeutic options are atrial septostomy and lung transplantation 4, 5.
Cheyne-Stokes respiration (CSR) is a specific form of periodic breathing (PB) which can be observed in the setting of congestive heart failure (CHF) 6. It occurs in 
50% of patients with a left ventricular ejection fraction of <40% 7, 8. The pathophysiology of CSR has not yet been fully clarified 9. However, it is assumed that reduction of cardiac output resulting in a prolonged circulation time from the lung to the chemoreceptors plays an important role 10, 11. Decreased blood oxygen tension stimulates the discharge of peripheral chemoreceptors and gives rise to the characteristic crescendo-decrescendo hyperventilation pattern of CSR 12. Conversely, hyperventilation-induced hypocapnia sets the stage for recurrent apnoeas by shifting the hypercapnic ventilatory response to the apnoea threshold for carbon dioxide (CO2) 13, 14. Finally, increased respiratory drive to hypercapnia and decreased body stores of O2 and CO2 are presumed to contribute to the development of CSR in CHF 15, 16.
In advanced PPH profound abnormalities in the haemodynamics and gas exchange parameters may be found. Due to the increased pulmonary artery pressure and pulmonary vascular resistance, cardiac output is likely to be depressed. Together with ventilation-perfusion mismatching this low output syndrome leads to hypoxaemia.
Finally, to compensate for hypoxaemia, hyperventilation and consequent hypocapnia develops. Thus, the same basic mechanisms presumed to underlie CSR in CHF might apply in PPH. However, the characteristics of sleep and breathing in PPH have not previously been reported. Therefore, the aim of the present study was to determine if sleep-disordered breathing is also seen in PPH.
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Patients and methods |
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TOPAbstractPatients and methodsResultsDiscussionReferences |
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Lung function tests
The forced expiratory volume in one second and vital capacity (% predicted, normal values: >80%) were measured, together with the pulmonary carbon monoxide diffusing capacity (DL,CO) by the single breath-holding method (% pred, normal value: >80%) and awake arterial blood gases.
Right heart catheterization
In all patients a Swan-Ganz triple-lumen thermodynamic catheter was inserted via a transjugular or transfemoral venous approach as described previously 17–19. The following haemodynamic parameters were determined with the normal range indicated in brackets: mean pulmonary artery pressure (<20 mmHg at rest); pulmonary capillary wedge pressure (5–10 mmHg); pulmonary vascular resistance (<250 dyn·s–1·cm–5); cardiac output (CO, 5.0–8.0 L·min–1); cardiac index (CI, 2.5–4.0 L·min–1·m–2); right ventricular ejection fraction (60–70%).
Sleep studies
Prior to polysomnography, all patients were interviewed about their sleep pattern and the Epworth Sleepiness Scale (ESS) was used to evaluate daytime sleepiness 20. At night, the electroencephalogram (electrodes at positions C3–A2 and C4–A1 of the international 10–20 system), electrooculogram and electromyogram of the submental and pretibial muscles; airflow at the nose and mouth by thermistors; thoracoabdominal movements by inductance plethysmography; the arterial oxygen saturation (Sa,O2) with pulse oximetry at the finger; and an electrocardiogram were obtained.
All data were recorded on a computerized polysomnograph with the capacity for analogue registration (Sidas GS, Institut für Medizintechnik, GmbH, Wettenberg, Germany). An obstructive apnoea was diagnosed if complete cessation of oronasal flow occurred in the presence of thoracoabdominal breathing movements. If neither oronasal flow nor breathing efforts of the chest and abdomen could be detected the apnoea was scored as central. Hypopnoea was defined as a reduction in the respiratory amplitude of >50% compared to the preceding signals. All apnoeas and hypopnoeas were required to have a duration of at least 10 s. The apnoea/hypopnoea index (AHI) was obtained by dividing the total number of apnoeas and hypopnoeas through the total sleep time (TST). An AHI of >10 h–1 of sleep was considered to be diagnostic of sleep-disordered breathing.
PB was required to show a crescendo-decrescendo pattern of hyperventilatory phases between central apnoeas or hypopnoeas (at least three consecutive cycles). In addition to the AHI, the duration of PB was expressed as per cent of TST. Lung-to-finger circulation time (LFCT) was measured from the first breath after a central apnoea to the subsequent nadir of Sa,O2. An average of 10 randomly selected apnoeas, during nonrapid eye movement (NREM) sleep when Sa,O2 fell sufficiently to allow determination of the Sa,O2 nadir, was taken. Cycle length was measured as the time from the first breath following a central apnoea to the first breath after the following apnoea on the same cycle used to determine LFCT. Cycle length was calculated as the sum of the duration of hyperpnoea and apnoea.
Sleep was staged manually in 30-s intervals according to the criteria of Rechtschaffen and Kales 21. Arousals were scored following the American Sleep Disorders Association criteria 22.
At the time of the investigation, 10 of the 20 patients were receiving long-term oxygen therapy (LTOT). The indication for LTOT in the PPH patients was a daytime oxygen tension in arterial blood (Pa,O2) <8 kPa. Because oxygen administration has been reported to suppress CSR in CHF 23, 24, polysomnography was performed while breathing room air in all patients.
Statistical analysis
If not otherwise indicated, all data are presented as mean±sem. Patients with and without PB were compared by analysis of variance (ANOVA). This was performed for several parameters (i.e. blood gases, lung function, haemodynamics and polysomnographical variables). Treatment effects were evaluated by a paired t-test. A p-value <0.05 was considered as statistically significant.
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Results |
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TOPAbstractPatients and methodsResultsDiscussionReferences |
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and 2. The majority of the patients in this study were young females. Almost all were on oral anticoagulation and more than one-half had already received vasodilator therapy, i.e. calcium-channel blockers or inhalative prostanoids (iloprost (ilomedin®, Fa.; Schering, Berlin, Germany) at a daily cumulative dose of 50–100 µg). On average, arterial blood gas analysis showed pronounced hypocapnia and moderate hypoxia. The pulmonary diffusing capacity was markedly diminished, whereas ventilatory parameters were normal. The patients suffered from severe precapillary pulmonary hypertension with increased pulmonary vascular resistance but normal capillary-wedge pressures. As a result of right-ventricular dysfunction CO and CI were markedly reduced.
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. PB occurred predominantly during phases of NREM 1+2 sleep and was characterized by more hypopnoeas than apnoeas. The patients with PB had severe nocturnal O2 desaturation. On average, the distribution of sleep stages was normal and the number of arousals was moderately increased. Consequently, only two patients complained of sleep-related symptoms including difficulty in falling asleep, nocturnal awakening with dyspnoea and daytime fatigue. An example of a polysomnographical recording of PB observed in a patient with PPH is shown in figure 1.
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. All three male patients investigated suffered from PB. The mean age was similar in the patients with and without PB. The carbon dioxide tension in arterial blood (Pa,CO2) values were not significantly different between the two patient groups but those with PB had more pronounced hypoxaemia than those with a normal breathing pattern. Patients with nocturnal PB had a lower DL,CO than those without. Patients showing PB had a higher pulmonary artery pressure and pulmonary vascular resistance and also more severely depressed right ventricular function.
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, four of these five patients responded with almost complete resolution of the PB, i.e. a decrease of the AHI to <10 h–1. In one patient, O2 had no beneficial effect on nocturnal PB. The sleep architecture was not significantly changed by O2 therapy in these subjects (data not shown).
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Discussion |
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Pathogenetic mechanisms of periodic breathing in primary pulmonary hypertension
PB in PPH may result from similar pathophysiological mechanisms as CSR in CHF. First, prolonged circulation time due to low CO might lead to PB in PPH because only patients with severe reduction of cardiac performance showed sleep-disordered breathing. Second, it is probable that hypoxia plays a role in the development of PB in PPH by stimulating peripheral chemoreceptors as suggested by the more severe arterial hypoxaemia in the patients with PB and by the efficacy of nocturnal nasal O2 supplementation. Marked hypocapnia was present in the patients studied, although, no significant difference in the Pa,CO2 levels between patients with and without PB was found. Nevertheless, hypocapnia as a pathogenetic factor in PB associated with PPH cannot be excluded since the number of patients studied was relatively small.
Changes in chemosensitivity might also contribute to the emergence of PB in PPH. As the patients with PB had a similar degree of hypocapnia at a lower level of Pa,O2, one might speculate that they had a lower hypoxic drive than those patients without PB. Theoretically, a decreased hypoxic drive could promote and/or prolong apnoeas by delaying the onset of hyperventilatory phases in PB. However, it would have been impossible to perform tests of hypoxic sensitivity in these severely hypoxic subjects.
A final point for consideration is the individual level of pulmonary vasoreactivity to alveolar hypoxia, i.e. the strength of the Euler-Liljestrand reflex. It is possible that those patients with more severe hypoxic pulmonary vasoconstriction and ventilation-perfusion mismatching are more prone to developing sleep-disordered breathing. The authors suggest that the lower Pa,O2 in the patients with PB was primarily the consequence of more severely depressed right ventricular function. However, hypoxia by itself could have led to more pronounced pulmonary hypertension and thereby to a prolonged circulation time. Thus, a self-perpetuating vicious circle might be established in PPH which finally leads to the development of PB.
Therapy of periodic breathing in primary pulmonary hypertension
Administration of nasal O2 significantly reduced or even abolished PB in PPH. This finding parallels the observation that CSR in CHF can be successfully treated by the breathing of O2 23, 24. The beneficial effect of O2 was most probably related to the correction of arterial hypoxaemia in patients with PB.
Clinical significance of periodic breathing in primary pulmonary hypertension
The clinical significance of PB in PPH remains to be defined. Only two of the six patients with nocturnal PB complained of sleep-related symptoms. Correspondingly, a relatively low overall number of apnoea-related arousals and almost normal ESS scores were found in the subjects. To reach a firm conclusion concerning this question, a larger number of patients need to be studied.
However, apart from disrupting normal sleep it might well be possible that PB contributes to worsening of pulmonary hypertension as the apnoea-associated hypoxia could trigger further vasoconstriction of the pulmonary vessels. Thus, PB in PPH might not only constitute an adverse prognostic sign, as is known for CSR in CHF 25–27, but it may also contribute to the further progression of the disease.
Limitations of the study
As already stated, a major limitation of the present study was the relatively small number of subjects studied. Furthermore, there was no control group. However, given the low prevalence of significant PB in a younger population, the finding that 30% of patients with PPH showed PB cannot be explained by chance. A final point of criticism concerns the method of measuring ventilatory flow. To monitor flow, oronasal thermistors were employed. It is well known, that other methods are more accurate at detecting apnoeas or hypopnoeas and in differentiating between central and obstructive events. These include recordings from oesophageal balloons, nasal prongs or the measurement of the pulse transit time 28, 29. Unfortunately, this methodology was either not applicable in the patients studied (oesophageal probes) or not yet available in the sleep laboratory at the time of the investigation (nasal prongs, pulse transit time). However, the authors believe that the use of thermistors did not lead to extensive misclassification of sleep-disordered breathing in the patients, as they showed typical waxing and waning of ventilation between hypopnoeas/apnoeas.
To conclude, the occurrence of periodic breathing in patients with severe primary pulmonary hypertension and its reversal by nocturnal nasal oxygen, was described for the first time. The clinical and prognostic implications of periodic breathing in primary pulmonary hypertension remain to be determined by future studies enrolling larger numbers of patients.
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This article has been cited by other articles:
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  S. Ulrich, M. Fischler, R. Speich, and K. E. Bloch Sleep-Related Breathing Disorders in Patients With Pulmonary Hypertension Chest, June 1, 2008; 133(6): 1375 - 1380. [Abstract] [Full Text] [PDF]
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R. Schulz, C. Fegbeutel, H. Olschewski, F. Rose, H.-J. Schafers, and W. Seeger Reversal of Nocturnal Periodic Breathing in Primary Pulmonary Hypertension After Lung Transplantation Chest, January 1, 2004; 125(1): 344 - 347. [Abstract] [Full Text] [PDF]
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