CRCM

Discussion

These, as yet unpublished studies, were conducted prior  to  more recent experiments on CSA at high altitude, which have provided additional insights into the interpretation of the results.

Effects on Cardiac Function

The individually titrated CPAP therapy was associated with normalisation of cardiac function over twelve months:

Cardiac index was abnormally low before therapy, improved at three months, and normalised by 12 months. Pulmonary artery occlusion pressure (PAOP) was abnormally high before CPAP therapy, but fell into the normal range after twelve months CPAP therapy.

Associated with those changes were falls in systemic vascular resistance indexed to body surface area (SVRI), which is an objective measure of left ventricular “afterload”. It progressively fell to normal by 12 months.

Extra vascular lung water (EVLW), measured by the double indicator dilution technique [20], was abnormally high before CPAP therapy despite standard medical therapy for heart failure. It normalised between 3 and 12 months of therapy.

The novel EVLW measurements, show objectively what is seen clinically; that heart failure patients with CSA usually have an element of lung congestion.

The improvement in cardiac function parameters was not surprising: Earlier studies in animal models had shown that increased intrathoracic pressure was associated with increased cardiac output [28]. Naughton et al [29] had previously shown in human’s improvements in CSA and heart function by non-invasive techniques, but EVLW had not previously been measured in this context.

Effects on sleep

All subjects showed severe central sleep apnea on their initial diagnostic sleep studies. The obstructive AHI was normal and the minimum oxygen saturation was moderately low.  After three months therapy there had been a significant fall in the central AHI. By twelve months this value had fallen further to normal, with a slight increase in minimum saturation and clinically important fall in the arousal index.  A fall in the arousal index would explain at least some of the fall in circulating noradrenaline values that was also observed.

The obstructive AHI however had, after three months CPAP therapy, risen from normal to moderate severity obstructive sleep apnea. This reciprocal change in the relationship between central and obstructive events continued over the next nine months, such that after 12 months nasal CPAP therapy, the central events were now normal, but the obstructive events now represented severe obstructive sleep apnea.  Although one subject withdrew after 3 months, his central AHI was close to the group average initially, and by 3 months he had developed some OSA. His absence at 12 months was therefore unlikely to have skewed the results, but did weaken the power of the statistical analysis.  The mean BMI had not changed, to account for the very dramatic increase in obstructive events.

Sleep architecture, (the proportion of sleep time occupied by the different sleep stages), also changed very dramatically with nasal CPAP therapy.  Stage 1 NREM sleep fell by three months and further at twelve months (p < 0.05). Normal is less than 5% so even at twelve months it was still abnormally high (on the nonCPAP test night), but the fall to less than one third of baseline would be regarded clinically as very important.

Stage 2 NREM sleep increased from a low value to a normal value by twelve months (p < 0.01).  Stages 3 and 4, (slow wave sleep), were somewhat reduced for age at baseline and did not change substantially over time.  REM sleep which usually occupies 1525% of sleep time was abnormally low at baseline, then increased into the normal range by three months (p < 0.05).  It remained normal at twelve months.  Overall; there was a dramatic shift from light sleep, (Stages 1 and 2), to deeper sleep, (more Stage 2 and REM sleep), with nasal CPAP therapy.

Sleep state is one of the “classical factors” predisposing to CSA.  The reduction in Stage 1 sleep with nasal CPAP treatment reduced that propensity to CSA.  However Stage 1 sleep remained an abnormally large percentage of sleep time at 13% by twelve months, yet CSA had completely resolved.  The change in sleep architecture with nasal CPAP treatment therefore, whilst possibly contributing to the resolution of CSA, was not the only, nor probably the primary cause of the resolution of CSA. It is more likely that the resolution of CSA caused consolidation of sleep and improved sleep architecture by reducing arousals.

Effects on pattern of breathing

A high ventilator response to CO₂ in patients with CCF and CSA has been shown by others [3,30]. The resolution of CSA in our subjects over time on CPAP therapy, coincided with a pattern of improvement in measured heart failure indices (CI, SVR1, PAOP, Plasma Noradrenaline) and a slight rise in PaCO2, which would fit with current theories about aetiology of CSA in patients with CCF [7].  Briefly; CCF causes hyperventilation [11] resulting in hypocapnia, which in light sleep induces apnea [27]. Apnea allows brain PCO2 to rise again, initiating hyperventilation, which returns the patient to hypocapnia and another apnea.  The documented degree of hypocapnia has been surprisingly minor (4mmHg or less) [10] the mechanism(s) by which CCF causes hyperventilation are uncertain: There are a number of, not mutually exclusive, possible mechanisms:

1. By J receptor stimulation, 2. Due to slow clearance of brain PCO2 due to the low cardiac output, causing an elevated PbCO2.  3. Increased ventilator response to CO2 (the brain produces the CO₂/H+ which provides the tonic central respiratory drive [31] 4. Due to an increase in ventilator drive by other means (eg sympathetic activation).

CSA occurs at high altitude in normal subjects by a similar mechanism: At high altitude hypocapnia is driven by a high ventilatory response to hypoxia rather than pulmonary congestion, nevertheless the same hypocapnia/light sleep mechanism causes CSA. This has been shown to be reversed by increasing cerebral blood flow [5,32]. This may well have been the mechanism of improvement in these patients. One would expect cerebral perfusion to improve with improved cardiac output, the effect of which would be to lower the central CO2/H+ drive to ventilation.

Other factors such as moving eupnia away from the apneic threshold because of the rise in PaCO₂ or reduced J receptor stimulation due to clearance of extravascular lung water may have also been important.

Of particular interest was the previously unreported development of significant OSA during the same time frame.  The reverse effect was previously seen in normal subjects who had mild OSA at sea level, but who then developed severe CSA upon ascent to high altitude [33]. The authors speculated that the high central drive, due to hypoxia, transformed the OSA into CSA by increasing ventilator instability and by stiffening the upper airway. A switch from CSA to OSA has been previously reported in a patient with CCF who changed from severe CSA to OSA after heart transplantation.  The author speculated that the “airway instability” associated with OSA predated the CSA [34]. A similar effect has been described by Gold et al with supplemental oxygen therapy [35].

We advance a similar speculation;  that the subjects had OSA prior to the development of severe CCF and CSA, and that resolution of the CSA for the reasons outlined above, allowed the pattern of breathing during sleep to return to the previous pattern of OSA, much, as shown in the heart transplant patient [34].

All PSGs were scored by the same experienced registered polysomnographer.  Other authors using only chest and abdominal bands to differentiate central from obstructive events found a 0.96 positive predictive value for CSA and 0.98 for OSA [35] compared to scoring using an oesophageal catheter to measure pleural pressure. In our studies, diaphragm surface EMG signals were also used to aid the differentiation of central from obstructive events, so the scoring should have been even more accurate than reported in Gold et al’s study [35].

Effects on quality of life

“Quality of life” was measured by a validated questionnaire [17].  There was both a clinically and statistically significant improvement over three and twelve months that reflected the improvements in sleep quality and walking distance, presumably reflecting improvements in cardiac function.  The questionnaire used a number of elements that assess sleep and dyspnoea, which would be positively influenced by successful nasal CPAP therapy in this group.  Daytime somnolence, (or energy level), should have also been improved with reduced arousals from sleep.

The six-minute walk test results showed a clinically important, but modest, increase, reflecting normalisation of resting cardiac index at twelve months.

Conclusion

We have shown significant normalization of sleep architecture and resolution of severe CSA by CPAP therapy, at individualized pressures, over a twelve-month period in a small group of patients with severe heart failure.  In addition we have observed in the same subjects, the development of severe OSA as the CSA resolved, which has not previously been reported in response to CPAP therapy. This may be clinically important in the management of patients with severe heart failure and CSA.  The literature suggests that chronic heart failure will be the next major cardiovascular epidemic [36].  We are likely therefore to see many more patients with severe CCF and CSA [37].

Prescriptions for the provision of positive airway pressure (PAP) to these patients during sleep assume that the CSA will remain constant.  Our results, and the experience of others [34], suggest that if PAP improves cardiac function over time, then  additional strategies may be required to deal with  recurrent, or unmasked, OSA. The level of PAP required is likely to vary over time (and cardiac function) as the degree of CSA and OSA change.

Acknowledgements: We wish to acknowledge with thanks the assistance of Ms Pamela Johnson who scored all the sleep studies, and the assistance of the ICU nursing staff at Manly Hospital during the haemodynamic studies.

The research was performed in the ICU at Manly Hospital. Manly NSW. Australia 2095, and Peninsula Sleep Clinic.

Both authors have seen and approved the manuscript.

These results were not part of a registered clinical trial.

Conflict of Interest:  Both authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speaker’s bureaus; membership, employment , consultancies, stock ownership, or any other equity interest; and expert testimony or patent licensing arrangements) or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials in this manuscript.

Funding:  Sensormedics/ALF Grant in Aid and Northern Sydney Area Health Service grant provided financial support in the form of funding in 1995. Neither sponsor had any role in the design and conduct of this research.

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