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Is intensified diuretic therapy an effective new treatment strategy in obstructive sleep apnoea patients with uncontrolled hypertension?

Lombardi, Carolinaa; Mariani, Davidea,b; Parati, Gianfrancoa,b,c

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doi: 10.1097/HJH.0000000000000108
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There is evidence of an important mutual interaction between sleep disorders and cardiovascular problems. Patients with cardiovascular diseases often complain of several sleep disturbances such as sleep fragmentation, insomnia and breathing disorders during sleep.

On the contrary, patients with sleep disorders are more frequently affected by cardiovascular problems. Such a reciprocal interaction makes it often difficult to determine which is the cause and which is the effect between these conditions.

Sleep-related breathing disorders, particularly obstructive sleep apnoea syndrome (OSAS), formerly named Pickwickian syndrome, are highly prevalent in the general population, OSAS affecting at least 4% of middle-aged men and 2% of middle-aged women in the developed world, with its prevalence increasing in parallel with the growing prevalence of obesity.

Individuals with OSAS are also characterized by a worsened quality of life and by excessive daytime somnolence, and are at an increased risk of road traffic and workplace accidents when compared with nonapnoeic individuals [1–3].

From a public health viewpoint, also the reported increased risk of cardiovascular morbidity and mortality associated with a diagnosis of obstructive sleep apnoea (OSA) is of particular importance [4,5]. OSA is associated with a higher prevalence of hypertension, in particular resistant hypertension, myocardial infarction, cardiac arrhythmias, congestive heart failure and stroke. Indeed, untreated severe OSA confers a three-fold increased risk of death from cardiovascular causes [1,2,6].

Prevalence of hypertension in OSA patients ranges from 35 to 80% and appears to be influenced by OSA severity. In fact, more than 60% of individuals with respiratory disturbance index greater than 30 were found to be hypertensive. Conversely, approximately 40% of hypertensive patients are diagnosed with OSA. Finally, when focussing on patients with resistant hypertension, OSA prevalence is significantly higher, reaching 83% [7].

Given this background, and the relevant interaction between OSA and cardiovascular disorders, it is evident that strategies for OSA treatment also play a key role in cardiovascular diseases prevention.

The most widely used treatment for OSA is nasal continuous positive airway pressure (CPAP) application, which is reported to be able to reduce blood pressure (BP) values in particular in patients characterized by severe OSA, good compliance to CPAP therapy and hypertension at baseline [1,2]. However, such a support to ventilation is sometimes not well accepted by patients, in particular when they are of young age, affected by milder OSA and not complaining of excessive daytime somnolence. Moreover, its impact on BP reduction, at least based on available meta-analyses, has been reported to be, overall, only of mild entity [1,2].

Other treatment strategies have therefore been proposed, including positional therapies aimed at forcing OSA individuals to sleep on their side, weight loss, use of oral devices, surgery and electrical stimulation of the hypoglossus nerve, all interventions aimed at preventing night-time upper airways occlusion [3,8,9].

All currently available treatment strategies for OSA have been developed based on progress in understanding of OSA pathophysiology, and until now, they have mostly focused on solutions aimed at mechanically or functionally widening upper airways space. More recently, evidence has been provided that nocturnal upper airways occlusion may also be facilitated by fluid accumulation in upper airways walls, either because of increased water and sodium retention at the kidneys levels, owing to an increased aldosterone production and stimulation of mineralcorticoid receptors [10], and/or because of a nocturnal rostral shift of body fluids from peripheral vessels and interstitial spaces of lower limbs [11]. These reports have suggested novel treatment strategies, aimed at antagonizing mineral corticosteroid receptors, for example through spironolactone administration [12]. Also, the possibility to reduce peripheral leg fluid volume, aimed at preventing night-time fluid displacement from the lower extremities to the upper body during sleep and thus at reducing the resulting increased degree of nocturnal upper airways obstruction and the consequent severity of sleep apnoea, could be considered, although no evidence in this regard has been provided yet.

The present article by Kasai et al.[13] in this issue of the Journal of Hypertension reports on the results of an experimental approach aimed at exploring the importance of reducing fluid shift from lower extremities to the upper body in determining OSA severity. In particular, this article was aimed at testing the hypothesis that intensified diuretic therapy (metolazone 2.5 mg and spironolactone 25 mg daily for 7 days after which the daily dose was doubled for 7 additional days) can reduce the apnoea-hypopnoea index and BP of uncontrolled hypertensive patients with OSA. This study thus specifically focused on the hypothesis that the ‘fluid shift theory’ could affect the pathogenesis of OSA in uncontrolled hypertensive patients and might thus open the way to a new treatment strategy.

The theory of ‘fluid shift’ was one of the proposed mechanisms to explain pathophysiology of sleep-related breathing disorders (SRBDs) in particular in heart failure patients. The theory is based on the hypothesis that during the day, fluid is accumulated by gravity in the feet and legs of upright patients. When patients shift to the recumbent position for sleep, leg oedema is reabsorbed into circulating blood volume and contributes to worsen oedema in the lungs, leading to the central sleep apnoeas, but also in the upper airways, increasing the possibility of their collapse at night and thus leading to OSA [14].

The study by Kasai et al.[13] included 16 (11 men and five women) individuals with uncontrolled hypertension and moderate-to severe OSA [defined as an apnoea/hypopnoea index (AHI) ≥20 /h of sleep, of which ≥50% of events were obstructive]. No patient had been previously diagnosed with OSA or treated with CPAP. All patients underwent full polysomnography combined with noninvasive ‘beat-to-beat’ BP measurement during the night (Portapres device; Finapres Medical Systems Inc, Amsterdam, The Netherlands) before and after intensified diuretic treatment. BP evaluations additionally included baseline 24-h ambulatory BP monitoring; clinic BP and pulse rate measured twice after 5 min of rest in seated position at night before polysomnography; and home BP monitoring performed daily twice in the morning (0600–0800 h) and twice in the evening (2100–2300 h). Moreover, body weight, total body fluid, leg fluid volume, neck circumference and calf circumference were measured just before instrumentation for polysomnography, and after awakening the next morning. Finally, plasma levels of aldosterone and renin, serum sodium, potassium and creatinine were obtained in the early morning following polysomnography, both before and after intensified diuretic treatment.

The study by Kasai et al.'s [13] demonstrates that in patients with uncontrolled hypertension and moderate-to severe OSA, a 2-week course of diuretic treatment reduced the volume of fluid accumulating in the legs during the day and also reduced its redistribution to the upper body, including the neck, during sleep. These effects were accompanied by a decrease in total AHI, in particular during non-rapid eye movement sleep. Finally, changes in overnight fluid distribution were significantly correlated to the fall in BP values in the morning.

The study by Kasai et al. [13] represents the first experimental assessment of the hypothesis that reducing body fluids, and thus their rostral nocturnal shift, might reduce severity of OSA and the related BP increase. In spite of the interest of such a topic, however, also a few limitations of this work need to be mentioned. A first important limitation is the lack of a control group (including patients with OSA followed up without intensive diuretic treatment), which underlines the need of additional investigations in this field. A second limitation, also acknowledged by the authors, is the small improvement in OSA severity resulting from the intensified diuretic therapy, whose actual clinical relevance still needs to be clearly understood. Indeed, the difference between AHI values measured before and after treatment was statistically significant but of small size (AHI being reduced from 57.7 ± 33.0 to 48.5 ± 28.2 events per hour). Moreover, oxygen saturation during the night was not different before and after treatment. This may suggest that the contribution of fluid shift to severity of OSA is of modest entity only. Finally, this study included only a small number of individuals (n = 16), which may limit the generalizability of its findings.

In conclusion, the results of this study, although of theoretical interest, should be considered as pilot observations, and additional investigations of larger size and with appropriate experimental design are needed to further explore this intriguing issue. These studies should in particular focus on the effects of an intensified diuretic treatment on 24-h and night-time ambulatory BP values of OSA patients, which may more faithfully reflect the effects of rostral fluid volume shift during sleep.


Conflicts of interest

There are no conflicts of interest.


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