Sleep apnoea in End Stage Renal Disease; Impact on mortality and the potential role of CPAP

Transcription

1 Chakravorty Page 1 Sleep apnoea in End Stage Renal Disease; Impact on mortality and the potential role of CPAP Indranil Chakravorty PhD MRCP Visiting Fellow, Beds & Herts Postgraduate Medical School, University of Hertfordshire, College Lane, Hatfield, Herts UK i.chakravorty@herts.ac.uk

2 Chakravorty Page 2 Background Patients with End Stage Renal Disease (ESRD) on renal replacement therapy have a high prevalence of disorders of mood, sleep i and experience poor health related quality of life (HRQL) ii and a high mortality iii. Sleep disorders appear even in the early stages of chronic kidney disease. These disturbances are complex, including difficulties in falling asleep and awakening, interrupted sleep, nightmares, restless legs syndrome (RLS), and Periodic limb movement disorder (PLMS) and sleep apnoea (SA). Major etiological factors of sleep disorders in the uremic patients include older age, long dialysis, alcohol and tobacco abuse and, particularly, the presence of significant comorbidities. The usual contributors to this high mortality are concurrent diseases which include Diabetes mellitus, hypertension, hypercholesterolaemia and coronary artery disease iv. Sleep apnoea is an independent risk factor associated with hypertension, heart disease and poor quality of life in the general population. While the prevalence of SA in general population is 2-4%, the prevalence reported in ESRD patients may be up to 50%. Hence the

3 Chakravorty Page 3 concurrent presence of SA in ESRD patients may pose a substantial additional risk. SLEEP APNOEA SA is a common condition which is characterised by the presence of nocturnal apnoeas or hypopnoeas due to complete or partial closure of the upper airway in combination with daytime symptoms of fatigue and hypersomnolence. The prevalence of SA increases with age and may contribute to increased cardiovascular risk. SA also leads to significant reduction in HRQL and increased risk of road traffic accidents. SA leads to repetitive episodes of hypoxemia, hypercapnoea, sleep disruption, and activation of the sympathetic nervous system. This in turn leads to endothelial dysfunction, oxidative stress, and inflammation v. Because SA has been shown to be widespread in the conventional dialysis population, it may be that it contributes substantially to the sleepiness, reduced muscle performance vi, poor HRQL, and cardiovascular disease found in this population. The causal links between conventional dialysis and SA remains speculative, but there are likely multiple factors related to volume status and azotemia that contribute to the high rate of severe SA in dialysis

4 Chakravorty Page 4 patients. Both nocturnal automated peritoneal dialysis and nocturnal haemodialysis have been associated with reduced severity of SA vii. Hence the combination of SA and ESRD may be multiplying the risks of increased mortality and potentially provide a modifiable risk factor viii ; ix. Currently this concurrence of is poorly recognised and the benefit from treatment yet to be demonstrated in clinical trials. TYPES OF SLEEP APNOEA SA may be obstructive or central. Obstructive SA is caused by repetitive complete or partial closure of the upper airway as a result of relaxation of the pharyngeal muscles during sleep x. Central sleep apnoea usually accompanies cardiovascular or cerebrovascular disorders and is characterised by cessation of breathing accompanied by an open airway. Aetiology may be linked to a reduction in baroreceptor reflex sensitivity xi, however, when present, it is associated with increased arrhythmic risk and higher cardiac mortality. OSA is associated with increased sympathomimetic activity which is reflected in increased risk of hypertension, cardiovascular and cerebrovascular morbidity xii and mortality xiii. Multivariate analysis,

5 Chakravorty Page 5 adjusted for potential confounders, in OSA patients demonstrates that untreated severe obstructive sleep apnoea-hypopnoea significantly increased the risk of fatal and non-fatal cardiovascular events xiv. MECHANISMS OF INCREASED MORTALITY (1) Nocturnal hypoxaemia may be contributing significantly to the increased cardiovascular mortality xv in patients with. Even a 1% decline in nocturnal arterial oxygen saturation below a 95% threshold is likely to increase cardiovascular events by 33% xvi. (2) Left ventricular hypertrophy (LVH) and dysautonomia appear to be most likely intermediate mechanisms mediating the adverse cardiovascular effects of SA in ESRD xvii. As in the non-renal failure population, ESRD patients with LVH have a 2- to 3-fold increased risk of death from cardiovascular diseases, and all cause mortality. In contrast to non-renal failure patients, normotensive ESRD patients may show an increase of left ventricular mass over time. Although LVH can be reversed with good blood pressure control, patients are often undertreated. Even if clinic systolic blood

6 Chakravorty Page 6 pressure levels are optimal, chronic dialysis patients may still have unacceptably high ambulatory blood pressure levels due to a rise in nocturnal blood pressure with SA xviii. (3) Metabolic Syndrome; Subjects with OSA are generally obese, have higher BP and fasting insulin, are more insulin resistant, have lower HDL cholesterol, and an increased incidence of metabolic syndrome, which is an independent risk for cardiovascular mortality xix. (4) They also have bradyarrhythmias and increased ventricular ectopy in association with apnoeas when oxyhemoglobin desaturations become severe xx. Autonomic abnormalities seen in patients with OSA include increased resting heart rate, decreased R-R interval variability, and increased blood pressure variability. (5) Respiratory disturbance index has a positive correlation with aortic stiffness and negative correlation with distensibility. Aortic elastic parameters have an extremely high association with cardiovascular disease. Increased aortic stiffness might be responsible for the LV systolic and diastolic deterioration in OSA

7 Chakravorty Page 7 syndrome xxi. Treatment of OSA is associated with a decrease in diastolic blood pressure and mean arterial pressure with a decrease in Left Atrial Volume. Treatment of OSA may prevent adverse left atrial remodeling xxii. (6) There is evidence that OSA is associated with a group of pro-inflammatory and pro-thrombotic factors that have been identified to be important in the development of atherosclerosis. OSA is associated with increased daytime and nocturnal sympathetic activity. Both atherosclerosis and OSA are associated with endothelial dysfunction, increased C-reactive protein xxiii, interleukin 6, fibrinogen, and plasminogen activator inhibitor, and reduced fibrinolytic activity and related to nocturnal hypoxia xxiv. (7) Serum levels of Vascular endothelial growth factor (VEGF) are elevated in severely hypoxic patients with OSA and are related to the degree of nocturnal oxygen desaturation xxv. OSA has been associated with enhanced platelet activity and aggregation. Leukocyte adhesion and accumulation on endothelial cells are common in both OSA and atherosclerosis xxvi. The formation of plaques was

8 Chakravorty Page 8 more pronounced and extracranial vessel stenosis was more common in the OSA patients xxvii. Chronic exposure to intermittent hypoxia and reoxygenation is a major pathologic factor causing cardiovascular inflammation by activating the NF-kappaB pathway xxviii. (8) Hyperhomocysteinemia and diminished NO production may be causal factors in endothelial dysfunction seen in OSAHS and may explain the association between OSAHS and cardiovascular diseases xxix. TREATMENT POTENTIAL There are three treatment modalities currently available for the treatment of SA. Laser uvulopalatoplasty is usually reserved for patients with tonsillar enlargement, crowded oro-pharynx with demonstrable collapsibility of the upper airway during sleep nasoendoscopy xxx. Mandibular advancement splints are effective in improving snoring and moderate sleep apnoea in suitable individuals with a success rate upto 50-70%. However the mainstay of treatment of moderate to severe OSA remains the modality of delivering continuous positive airway pressure (CPAP) through the nares, a method initially developed by Colin Sullivan in Australia in 1981.

9 Chakravorty Page 9 CPAP therapy has been extensively studied and it remains the mainstay of treatment in OSA, as it is still the most consistently efficacious xxxi and safe option. However, its major disadvantage is that it does not confer a cure to this disorder and hence therapy is generally lifelong with its usual treatment compliance problems. Some studies suggest that nasal CPAP might have a substantial blood pressure lowering effect in hypertensive patients with OSA. This effect could decrease the morbidity and mortality related to cardiovascular complications in patients with OSA xxxii. In long term follow up studies, CPAP has been shown to demonstrate a protective effect on mortality risk xxxiii ; xxxiv. Although long-term controlled trials of the effect of treatment of SA on mortality in patients with heart failure are still pending, treatment of SA, both obstructive and central, does result in a decrease in sympathetic activity and an improvement in systolic function, which are known surrogates of mortality xxxv. The 24-h urinary excretion of norepinephrine was significantly reduced and the plasma Nitric oxide

10 Chakravorty Page 10 concentration was significantly increased after one night of CPAP xxxvi. The role of CPAP therapy in central sleep apnoea is more limited. There has been increasing data on the beneficial effect of CPAP on central sleep apnoea/cheyne-stokes respiration in congestive heart failure xxxvii ; xxxviii. CPAP appears to benefit the failing heart by increasing intrathoracic pressure, which is believed to cause an increase in cardiac output by decreasing the pressure gradient across the heart wall and allowing the left-ventricular end diastolic volume to decrease, thereby reducing the afterload. This beneficial "resting" of the heart has been documented to increase left-ventricular ejection fraction, increase cardiac index, improve inspiratory muscle strength, lower blood pressure and heart rate, decrease plasma and overnight urinary levels of norepinephrine, lower levels of atrial natriuretic peptide and endothelin-1, and increase heart rate variability xxxix. Treatment with CPAP reverses the increased membrane permeability and urine excretion, allowing the peripheral oedema to resolve and the haematocrit to decrease. Increased atrial natriuretic peptide (ANP)

11 Chakravorty Page 11 release and decreased renin-angiotensin-aldosterone activity could be the mechanisms of the observed alterations in fluid distribution in obstructive sleep apnoea xl. Application of CPAP decreased pro-brain Natriuretic Peptide levels significantly in normotensive and, in particular, hypertensive OSA and thus suggests the potential for CPAP to improve cardiovascular comorbidity and co-mortality in OSA xli. The natriuresis and diuresis of OSA patients due to the decrease in proximal and distal tubular sodium reabsorption and in tubular concentration ability during their nocturnal sleep and is returned to normal by CPAP therapy xlii. OSA is linked with a "priming" of neutrophils for enhanced respiratory burst. The increased superoxide generation, which might have major impact on the development of cardiovascular disorders, is virtually fully reversed by effective CPAP therapy xliii. In Central SA, adaptive servo-ventilation has been shown to reduce nocturnal events and lead to improvement in daytime symptoms xliv. Nocturnal dialysis and renal transplantation xlv have also been shown to improve the presence of SA in patients with ESRD. Respiratory correction of chronic metabolic acidosis,

12 Chakravorty Page 12 "uremic toxins," "middle molecules," and hemodialysis are all evoked as etiologic factors xlvi. PERIODIC LIMB MOVEMENT DISORDER Periodic limb movement disorder (PLMS) and restless legs syndrome (RLS) are associated with arousals from sleep and have been shown to cause daytime fatigue, somnolence. Amongst ESRD patients, PLMS has been associated with an increased mortality xlvii. Conclusions Patients with ESRD experience a very high mortality in spite of renal replacement therapy. The concurrent presence of SA (obstructive or central) is likely to multiply the risk of cardiovascular mortality in these patients. Treatment of concurrent OSA with CPAP, provides an easily modifiable risk factor which may reduce the cardiovascular mortality risk substantially. However, further research to answer these vital questions is needed before widespread screening and treatment of ESRD patients with concurrent SA can be strongly recommended.

13 Chakravorty Page 13 Competing interests None References

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