role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea

15
J Physiol 591.5 (2013) pp 1179–1193 1179 The Journal of Physiology TOPICAL REVIEW Role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea Laura H. White and T. Douglas Bradley Sleep Research Laboratory and Department of Medicine of the University Health Network Toronto Rehabilitation Institute and Toronto General Hospital, and the Centre for Sleep Medicine and Circadian Biology of the University of Toronto, Toronto, Ontario, Canada Abstract Obstructive sleep apnoea (OSA) is common in the general population and increases the risk of motor vehicle accidents due to hypersomnolence from sleep disruption, and risk of cardiovascular diseases owing to repetitive hypoxia, sympathetic nervous system activation, and systemic inflammation. In contrast, central sleep apnoea (CSA) is rare in the general population. Although their pathogenesis is multifactorial, the prevalence of both OSA and CSA is increased in patients with fluid retaining states, especially heart failure, where they are associated with increased mortality risk. This observation suggests that fluid retention may contribute to the pathogenesis of both OSA and CSA. According to this hypothesis, during the day fluid accumulates in the intra- vascular and interstitial spaces of the legs due to gravity, and upon lying down at night redistributes rostrally, again owing to gravity. Some of this fluid may accumulate in the neck, increasing tissue pressure and causing the upper airway to narrow, thereby increasing its collapsibility and pre- disposing to OSA. In heart failure patients, with increased rostral fluid shift, fluid may additionally accumulate in the lungs, provoking hyperventilation and hypocapnia, driving P CO 2 below the apnoea threshold, leading to CSA. This review article will explore mechanisms by which over- night rostral fluid shift, and its prevention, can contribute to the pathogenesis and therapy of sleep apnoea. (Received 20 September 2012; accepted after revision 6 December 2012; first published online 10 December 2012) Corresponding author T. D. Bradley: University Health Network Toronto General Hospital, 9N-943, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada. Email: [email protected] Abbreviations AHI, apnoea–hypopnoea index; ANP, atrial natriuretic peptide; BMI, body mass index; CAPD, continuous ambulatory peritoneal dialysis; CPAP, continuous positive airway pressure; CSA, central sleep apnoea; ESRD, end-stage renal disease; IJV, internal jugular vein; LBPP, lower body positive pressure; LFV, leg fluid volume; MRI, magnetic resonance imaging; OSA, obstructive sleep apnoea; P aO 2 , arterial partial pressure of oxygen; P CO 2 , partial pressure of carbon dioxide; PCWP, pulmonary capillary wedge pressure; UA, upper airway; UA-XSA, upper airway cross-sectional area; UPPP, uvulopalatopharyngoplasty. Laura White is a Clinical Research Fellow at the University Health Network, Toronto, investigating the role of fluid retention and redistribution in the pathogenesis and treatment of sleep apnoea. She obtained her medical degree at Edinburgh University and is a Specialist Trainee in Respiratory Medicine in the South West of England. T. Douglas Bradley is Professor of Medicine and Director of the Division of Respirology of the University of Toronto and of the Sleep Research Laboratories of the Toronto Rehabilitation Institute and Toronto General Hospital. He obtained his MD degree from the University of Alberta and his specialty and research training at the University of Toronto and McGill University. His research focuses on the causes and consequences of sleep apnoea and of its treatment on cardiovascular diseases, especially heart failure, hypertension and stroke. His work has been supported by the Canadian Institutes of Health Research and other agencies. C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society DOI: 10.1113/jphysiol.2012.245159

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Page 1: Role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea

J Physiol 591.5 (2013) pp 1179–1193 1179

The

Jou

rnal

of

Phys

iolo

gy

TOP ICAL REV IEW

Role of nocturnal rostral fluid shift in the pathogenesisof obstructive and central sleep apnoea

Laura H. White and T. Douglas Bradley

Sleep Research Laboratory and Department of Medicine of the University Health Network Toronto Rehabilitation Institute and Toronto General Hospital,and the Centre for Sleep Medicine and Circadian Biology of the University of Toronto, Toronto, Ontario, Canada

Abstract Obstructive sleep apnoea (OSA) is common in the general population and increasesthe risk of motor vehicle accidents due to hypersomnolence from sleep disruption, and risk ofcardiovascular diseases owing to repetitive hypoxia, sympathetic nervous system activation, andsystemic inflammation. In contrast, central sleep apnoea (CSA) is rare in the general population.Although their pathogenesis is multifactorial, the prevalence of both OSA and CSA is increased inpatients with fluid retaining states, especially heart failure, where they are associated with increasedmortality risk. This observation suggests that fluid retention may contribute to the pathogenesisof both OSA and CSA. According to this hypothesis, during the day fluid accumulates in the intra-vascular and interstitial spaces of the legs due to gravity, and upon lying down at night redistributesrostrally, again owing to gravity. Some of this fluid may accumulate in the neck, increasing tissuepressure and causing the upper airway to narrow, thereby increasing its collapsibility and pre-disposing to OSA. In heart failure patients, with increased rostral fluid shift, fluid may additionallyaccumulate in the lungs, provoking hyperventilation and hypocapnia, driving PCO2 below theapnoea threshold, leading to CSA. This review article will explore mechanisms by which over-night rostral fluid shift, and its prevention, can contribute to the pathogenesis and therapy ofsleep apnoea.

(Received 20 September 2012; accepted after revision 6 December 2012; first published online 10 December 2012)Corresponding author T. D. Bradley: University Health Network Toronto General Hospital, 9N-943, 200 ElizabethStreet, Toronto, Ontario, M5G 2C4, Canada. Email: [email protected]

Abbreviations AHI, apnoea–hypopnoea index; ANP, atrial natriuretic peptide; BMI, body mass index; CAPD,continuous ambulatory peritoneal dialysis; CPAP, continuous positive airway pressure; CSA, central sleep apnoea;ESRD, end-stage renal disease; IJV, internal jugular vein; LBPP, lower body positive pressure; LFV, leg fluid volume;MRI, magnetic resonance imaging; OSA, obstructive sleep apnoea; P aO2 , arterial partial pressure of oxygen; PCO2 ,partial pressure of carbon dioxide; PCWP, pulmonary capillary wedge pressure; UA, upper airway; UA-XSA, upperairway cross-sectional area; UPPP, uvulopalatopharyngoplasty.

Laura White is a Clinical Research Fellow at the University Health Network, Toronto, investigatingthe role of fluid retention and redistribution in the pathogenesis and treatment of sleep apnoea.She obtained her medical degree at Edinburgh University and is a Specialist Trainee in RespiratoryMedicine in the South West of England. T. Douglas Bradley is Professor of Medicine and Directorof the Division of Respirology of the University of Toronto and of the Sleep Research Laboratoriesof the Toronto Rehabilitation Institute and Toronto General Hospital. He obtained his MD degreefrom the University of Alberta and his specialty and research training at the University of Torontoand McGill University. His research focuses on the causes and consequences of sleep apnoea and ofits treatment on cardiovascular diseases, especially heart failure, hypertension and stroke. His workhas been supported by the Canadian Institutes of Health Research and other agencies.

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society DOI: 10.1113/jphysiol.2012.245159

Page 2: Role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea

1180 L. H. White and T. D. Bradley J Physiol 591.5

Obstructive sleep apnoea (OSA) is a commoncondition, characterised by repetitive apnoeas due tocollapse of the pharynx. These occur secondary to thenormal withdrawal of pharyngeal dilator muscle tone atthe onset of sleep, superimposed upon a narrowed orcollapsible pharynx (AAMSTF, 1999). The prevalence ofOSA increases with increasing body mass index and neckgirth, probably due to fat deposition in the soft tissuesurrounding the pharynx, which narrows the lumen andincreases its collapsibility (Horner et al. 1989; Shelton et al.1993). However, only approximately one-third of thevariability in sleep apnoea severity is attributable to thesetwo indices of obesity (Dempsey et al. 2002). Therefore,other factors must be playing a role in the pathogenesis ofOSA.

In contrast to OSA, central sleep apnoea (CSA) ischaracterised by partial or complete cessation of air-flow due to a temporary reduction in, or cessation of,central respiratory drive. Central hypopnoeas and apnoeasusually occur following episodes of hyperventilationwhen PCO2 falls toward or below the apnoea threshold,respectively, during sleep. The tendency to hyperventilateis associated with augmented central and peripheralchemo-responsiveness (Solin et al. 2000). CSA, althoughrare in the general population, is common in patients with

heart failure, where it can co-exist with OSA, raising thepossibility of a common pathogenesis (Bixler et al. 1998;Tkacova et al. 2001; Tkacova et al. 2006; Yumino et al.2009).

The prevalence of sleep apnoea is much higher inpatients with fluid-retaining states such as heart failureand end-stage renal disease (ESRD) than in the generalpopulation (Young et al. 1993; Jurado-Gamez et al. 2007;Yumino et al. 2009). This led to the hypothesis thatfluid retention is involved in the pathogenesis of bothOSA and CSA. According to this hypothesis, during theday, fluid accumulates in the intravascular and inter-stitial spaces of the legs due to gravity, and upon lyingdown at night redistributes rostrally, again due to gravity.Some of this fluid may accumulate in the neck, increasingtissue pressure and causing the upper airway (UA) tonarrow, predisposing to OSA, or in the lungs, whereit may provoke hyperventilation, predisposing to CSA(Fig. 1).

There is now considerable evidence to support thishypothesis. Therefore, the primary objective of this articleis to review this evidence and explore the mechanisms bywhich fluid retention during the day and its nocturnalredistribution might contribute to the pathogenesis ofOSA and CSA.

+ -

DAY

NIGHT

PCWP PCWP

• sitting time/inactivity• Fluid-retaining

conditions

Daytime leg fluid accumulation

• Exercise• Compression stockings• Diuretics• Dialysis

Rostral fluid shift

NECK

UA-XSA

UA collapsibility

UA obstruction

OSA

CHEST

Pulmonary congestion

Pulmonary irritant receptors

Hyperventilation

PCO2

Central apnoea

CSA

PCWP

Heart failure

chemosensitivity

PCO2PCO2PCO2

Figure 1. The role of overnight rostral fluid shift in the pathogenesis of obstructive and central sleepapnoea (OSA and CSA)Overnight fluid shift from the legs to the neck can affect upper airway mechanics and lead to OSA, whereasfluid shift to the lungs can provoke hyperventilation, hypocapnia and CSA. CO, cardiac output; PCO2 , partialpressure of carbon dioxide; PCWP, pulmonary capillary wedge pressure; UA, upper airway; UA-XSA, upper airwaycross-sectional area.

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society

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J Physiol 591.5 Nocturnal rostral fluid shift in apnoea 1181

Table 1. Prevalence of sleep apnoea in different populations

Population Study N AHI OSA prevalence (%) CSA prevalence (%)

Community Young et al. (1993) 602 ≥15 9 (M) 4 (F)Duran et al. (2001) 2148 ≥15 14 (M) 7 (F)Bixler et al. (1998)∗ 741 ≥20 6 0.5

Hypertension Fletcher et al. (1985)∗ 46 ≥10 30Worsnop (1998)† 34 ≥10 23

Drug-resistant hypertension Logan et al. (2001) 41 ≥10 83Pratt-Ubunama (2007) 71 ≥10 65

End-stage renal disease de Oliveira Rodrigues et al. (2005) 45 ≥5 31Jurado-Gamez et al. (2007) 32 ≥10 44

Heart failure Javaheri et al. (2006)∗ 100 ≥15 12 37Yumino et al. (2009) 218 ≥15 26 21

AHI, apnoea–hypopnoea index; F, female; M, male; OSA, obstructive sleep apnoea; CSA, central sleep apnoea. ∗All men; †33/34 men.

Prevalence of sleep apnoea in patients withfluid-retaining states

Sleep apnoea is diagnosed by overnight polysomnography,during which apnoeas and hypopnoeas are detected byan absence or reduction in tidal volume for at least 10 s,respectively (Iber, 2007). During obstructive apnoeas,respiratory drive persists resulting in inspiratory effortsagainst the occluded airway, causing chest wall distortion.In contrast, during central apnoeas, respiratory drive isabsent. The presence and severity of sleep apnoea isdetermined by the apnoea–hypopnoea index (AHI), whichis the number of apnoeas and hypopnoeas per hour ofsleep. A sleep apnoea disorder is present if the AHI is ≥5and mild if the AHI is 5–15, moderate if 15–30 and severeif ≥30 (AAMSTF, 1999).

In the general population, the prevalence of OSA isestimated at 3–14% in men and 4–9% in women, while theprevalence of CSA is <1% (Young et al. 1993; Bixler et al.1998; Duran et al. 2001; Ip et al. 2001). In comparison, theprevalence of OSA is higher in patients with fluid-retainingconditions, and of CSA is higher in patients with heartfailure (Table 1).

In contrast to the general population, severity of OSAis not associated with increasing BMI in heart failurepatients, suggesting that factors other than obesity aremore important in the pathogenesis of OSA in thesepatients (Arzt et al. 2006). In heart failure patients, thosewith sleep apnoea have greater sodium intake, whichpromotes fluid retention, than those without sleep apnoea,and the AHI correlates with sodium intake (Kasai et al.2011).

Mechanisms of fluid shift within the body and its rolein the pathogenesis of OSA and CSA

Starling’s forces. Overnight rostral fluid shift cancontribute to the pathogenesis of OSA and CSA via

Starling’s forces. Isotonic fluid moves passively betweenthe capillaries and the interstitial space according thebalance of opposing forces: capillary hydrostatic versuscolloid osmotic pressure (Starling, 1896). When movingfrom the lying to the upright position, hydrostatic pressurein the capillaries of the legs exceeds that in the interstitialcompartment due to gravitational effects and this causesfiltration of fluid from the capillaries into the interstitialspace. This concept is key to understanding movementof fluid between the intravascular and extravascularspaces of the legs, lungs and neck between day andnight.

Leg fluid changes with posture. Lying down and standingup are associated with significant alterations in body fluiddistribution. (Thompson et al. 1928; Waterfield, 1931b;Youmans et al. 1934). Capillary pressure in the legs onstanding (90–120 cmH2O) greatly exceeds the pressurerequired for movement into the interstitial space (just15–20 cmH2O) and filtration rate is directly proportionalto venous pressure (Krogh et al. 1932; Youmans et al.1934; Levick & Michel, 1978). As a consequence, onstanding, plasma volume decreases by 300–400 ml but legvolume increases by 100–300 ml, due to venous poolingand fluid filtration into the interstitial space, with thereverse occurring on lying down (Table 2).

Intravascular fluid loss on standing is quite rapid:plasma concentration increases over the first 20–40 minafter which it plateaus. The rate of filtration from thecapillaries to the interstitial space decreases over time dueto rising capillary colloid osmotic and increasing tissuepressures, until a balance is achieved and filtration ceases(Krogh et al. 1932; Landis & Gibbon, 1933; Youmans et al.1934). On changing from standing to lying, the reverseoccurs, with most fluid reabsorbed within 30–60 min,with an initial rapid decrease followed by an exponentialdecay in fluid shift (Thompson et al. 1928; Waterfield,1931a; Fawcett & Wynn, 1960; Berg et al. 1993). Therefore

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society

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1182 L. H. White and T. D. Bradley J Physiol 591.5

Table 2. Summary of studies examining postural fluid changes

Outcome Time courseStudy Subjects measured Method Manoeuvre (minutes) Result

Thompson et al.(1928)

Normal Plasma volume Dye dilution Lying to standing 30 −290 ml

Waterfield et al.(1931a)

Normal Plasma volume Carbon monoxidedilution

Lying to standing 40 −425 ml

Waterfield et al.(1931b)

Normal Leg volume Waterdisplacement

Calf musclecontraction

Immediate −75 ml

Lying to standing 40 +83 mlYoumans et al.

(1934)Normal and low

proteinLeg volume Water

displacementLying to standing 60 +250 ml (normal)

+330 ml (lowprotein)

Fawcett & Wynn(1960)

Normal and lowprotein/oedematous

Plasma volume Dye dilution Lying to standing 15 −11% (normal)−11% (low protein)

60 −10% (normal)−16% (low protein)

Plasma volume Dye dilution Standing to lying 15 +8% (normal)+14% (low protein)

60 +14% (normal)+21% (low protein)

Berg et al. (1993) Normal XSA of calf CT Standing to lying 120 −5.5%∗

Calf fluid volume Bioimpedance −8.7%†Baccelli et al. (1995) Normal Leg intravascular

blood volumeBlood-pool

scintigraphyLying to standing 2 +135%

Lung bloodvolume

−16%

∗No further change after 60 min; †exponential decay in reduction in fluid volume; CT, computer tomography; XSA, cross-sectional area.

upon lying in bed at night, fluid rapidly shifts fromthe interstitial to the intravascular compartment of thelegs.

In fluid overloaded patients who have increased venouspressure, the interstitial space can accommodate largeincreases in volume, with oedema formation (Guyton,1965). Hence on lying down, the greater the degree ofleg oedema, the greater the volume of fluid filtered intothe vascular space and the greater the decrease in leg fluidvolume (Yumino et al. 2010). Similarly, in patients who areoedematous due to low protein states, decreased colloidosmotic pressure results in a greater movement of fluidfrom the vasculature to the interstitial space of the legs onstanding, and vice versa (Youmans et al. 1934). Increasesin microvascular permeability, as have been described indiabetic and heart failure patients and in conditions ofacute and chronic inflammation, may increase the volumeof fluid moving between the intravascular and interstitialspaces in response to changes in hydrostatic pressure(Jaap et al. 1993; Mahy et al. 1995; Kvietys & Granger,2012). Theoretically, therefore, hypoalbuminaemia andincreases in microvascular permeability could predisposeto sleep apnoea, but no studies have addressed thesepossibilities.

Rostral fluid shifts from the legs during recumbency.Fluid re-entering the venous system on lying down movesrostrally to both the chest and the neck with the effectsof gravity (Avasthey & Wood, 1974; Terada & Takeuchi,1993). On lying down, leg blood volume decreases rapidlyand fluid is redistributed to the thorax, neck and head(Hildebrandt et al. 1994; Baccelli et al. 1995). Whenfluid is shifted out of the legs during application oflower body positive pressure (LBPP) via inflation ofanti-shock trousers, neck circumference increases within1 min, indicating rapid movement of fluid into the neck(Chiu et al. 2006; Shiota et al. 2007; Su et al. 2008).Therefore, in oedematous patients, the increased volumeof fluid re-entering the intravascular space at night wouldresult in greater movement of fluid into the chest and theneck than in normovolaemic subjects.

Obstructive sleep apnoea

Complex anatomical, physiological and neural factorsare involved in UA collapse in patients with OSA, asoutlined in Fig. 2, and reviewed elsewhere (Ryan &Bradley, 2005). The UA is surrounded by bones and soft

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society

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J Physiol 591.5 Nocturnal rostral fluid shift in apnoea 1183

tissues. Due to mismatch between the space availablewithin the bony cage and amount of soft tissue inside it,upper airway cross-sectional area (UA-XSA) is decreasedin OSA patients (Schwab et al. 1995). Additionally,UA collapsibility is increased in OSA patients. The UAacts like a Starling resistor during sleep: under passiveconditions it collapses when intraluminal pressure fallsbelow extraluminal pressure. The intraluminal pressure atwhich the UA collapses is termed Pcrit. Factors influencingPcrit include pharyngeal wall compliance, intra- andextraluminal pressures and pharyngeal dilator muscleactivity (Fig. 2). In OSA patients, pharyngeal complianceis increased and Pcrit is frequently positive such thatcollapse can occur above atmospheric pressure duringsleep, whereas in normal subjects Pcrit is negative (Brownet al. 1985; Gleadhill et al. 1991).

The pharyngeal dilator muscles maintain UA patencyand their reduced activity during sleep predisposes to UAcollapse. A number of pathways influence the activityof the UA dilator muscles (Fig. 2) (Ryan & Bradley,2005). Compromise of one or more of these pathways,such as reduced UA mechanoreceptor and mucosalsensory sensitivity, can further predispose to UA collapse(Chadwick et al. 1991; Loewen et al. 2011). In addition,overnight fluid shift into the neck veins and pharyngealmucosa may increase tissue pressure around the UA,decrease UA-XSA and increase UA collapsibility, pre-disposing to obstructive apnoeas.

Cross-sectional area and pressure of the internal jugularvein (IJV) increase when moving from upright to supine(Lobato et al. 1998; Cirovic et al. 2003). Expansion ofthe IJVs is, however, limited by the mandible laterallyand cervical spine posteriorly, so that increased pressureis most likely transmitted medially to the pharynx,narrowing its lumen. In addition, increased hydrostatic

pressure is likely to cause transudation of fluid intothe interstitial space surrounding the UA. In animals,increased extrapharyngeal tissue pressure, created byinflation of balloons within the peripharyngeal tissues, wastransmitted to the pharynx and both decreased UA-XSAand increased UA resistance (Winter et al. 1995; Kairaitiset al. 2009).

In histological specimens of patients with OSAobtained from uvulopalatopharyngoplasty (UPPP),mucosal oedema is common (Woodson et al. 1991;Sekosan et al. 1996; Anastassov & Trieger, 1998; Bergeret al. 2002). In some studies, this was associated withinflammation, which could be due to vibratory injury fromsnoring rather than fluid accumulation (Woodson et al.1991; Sekosan et al. 1996; Paulsen et al. 2002). However,inflammatory changes were also found in controls andnon-apnoeic snorers and so were not specific to OSA.Specimens obtained at UPPP are from the uvula andsoft palate and so may not be representative of changesthroughout the pharyngeal walls, especially the tongue.Pharyngeal wall oedema has, however, been reported onMRI of the UA in OSA patients (Fig. 3) and pharyngealmucosal water content decreased after continuous positiveairway pressure (CPAP) therapy (Ryan et al. 1991;Elias et al. 2013). The relative importance of post-ural fluid accumulation and UA inflammation in thecausation of UA mucosal oedema therefore remains to beseen.

Alterations in pharyngeal blood volume can alsoinfluence UA properties. In anaesthetised cats, vaso-dilatation induced by intravenous nitroprusside increasedUA collapsibility in association with a 39% reductionin UA-XSA largely due to increased pharyngeal mucosalwater (Wasicko et al. 1990). Conversely, topical applicationof phenylepinephrine, a vasoconstrictor, to the pharynx

Pharyngeal dilator

muscle activity

at sleep onset

in REM

• Mucosal sensory reflexes• Vagal input

Extraluminal

tissue pressure

Bony cage

Soft tissue volume

Pharyngeal wall

compliance

UA collapsibility

Variable Intraluminal

pressure

FLUID

+

Mucosal oedema

PASSIVEACTIVE

?

+

-

+

at waking

• Chemosensitivity• Central respiratory neurons• Wakefulness drive to breathe

- +

Figure 2. Mechanisms influencing upper airway(UA) collapsibility in the pathogenesis ofobstructive sleep apnoea (OSA)A number of dynamic factors, including fluid shift intothe neck, determine the active (pharyngeal dilatormuscle activity) and passive (intra- and extraluminalpressure and pharyngeal wall compliance) properties ofthe UA which can increase UA collapsibility and lead toUA obstruction and OSA. REM, rapid eye movementsleep.

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society

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1184 L. H. White and T. D. Bradley J Physiol 591.5

increased UA-XSA by 14% in normal human subjects(Wasicko et al. 1991).

Shepard et al. (1996) first studied the possible effectof fluid shifts into and out of the neck on the UAof men with OSA. They used leg tourniquets and legelevation to decrease and increase venous return fromthe legs, respectively, although neither fluid shifts norneck vein distension were measured. At end-inspiration,mean UA-XSA decreased with leg elevation comparedto leg tourniquets, although there was no difference atend-expiration, when UA collapse is most likely to occur.While not definitive, these data did suggest a tendency forUA narrowing in response to increased venous return inmen with OSA.

Application of LBPP, which displaces approximately350 ml of fluid from the legs of healthy subjects, inducesincreases in neck circumference and UA resistance, anda decrease in UA-XSA within 1 min, probably reflectingan increase in IJV volume (Chiu et al. 2006; Shiota et al.2007). However, after 5 min, although neck circumferencedid not increase any further, there was a further increasein UA resistance and decrease in UA-XSA which may havebeen due to transudation of fluid into the pharyngealmucosa. Similarly, LBPP increased UA collapsibility, whichcorrelated with the decrease in leg fluid volume andincrease in neck circumference (Su et al. 2008). Takentogether, these studies indicate that changes in intra-vascular and extravascular pharyngeal mucosal fluidcontent influence UA anatomy and physiology.

Overnight rostral fluid shift from the legs to the neckhas been measured in a number of patient populations.In non-obese men, severity of OSA was strongly related tothe degree of overnight leg fluid volume (LFV) reductionand concomitant increase in neck circumference (Redolfiet al. 2009). Indeed, the reduction in LFV was the strongestcorrelate of the AHI and explained approximately 64%of its variability independently of other factors includingBMI. The overnight increase in neck circumference

correlated strongly with the overnight decrease in LFVsupporting the concept that some leg fluid redistributedto the neck. Similar relationships were observed betweenovernight decrease in LFV and severity of OSA in patientswith hypertension and men with heart failure (Fig. 4A)and ESRD (Friedman et al. 2010; Yumino et al. 2010; Eliaset al. 2012).

Overnight rostral fluid shift might not be a primarycausal factor for OSA, but could be secondary to negativeintrathoracic pressure generated by inspiratory effortsduring obstructive apnoeas, drawing fluid from the legsinto the neck. However, in heart failure patients withOSA, CPAP, while preventing obstructive apnoeas, didnot reduce overnight fluid movement out of the legs,indicating that rostral fluid shift from the legs is a primaryphenomenon (Yumino et al. 2010).

Finally, it is possible that elevated systemic venousand pulmonary arterial pressures could prevent venousdrainage from the head and neck thereby potentiating UAoedema, tissue pressure and collapsibility. As describedearlier, OSA is common in heart failure patients, whohave elevated pulmonary and central venous pressures.In patients with idiopathic or chronic thrombo-embolicpulmonary arterial hypertension, one study reported avery high prevalence of OSA of 89%, although the reasonfor this high prevalence was not determined (Jilwan et al.2013). Additionally, in fluid-overloaded ESRD patients,there was a strong correlation between both IJV volumeand UA mucosal water content, and AHI, although centralvenous pressure was not measured (Elias et al. 2013).

Fluid balance in OSA. Oedema is common in OSApatients, even in those without underlying fluid retainingstates, suggesting that OSA itself may lead to oedema(Whyte & Douglas, 1991; Iftikhar et al. 2008). Aminority of OSA patients may develop pulmonary hyper-tension either secondary to intermittent hypoxia-drivenpulmonary vasoconstriction, or to elevated pulmonary

Figure 3. Magnetic resonance images of the upperairways from end-stage renal failure patients with(A) and without (B) obstructive sleep apnoea (OSA)Significantly more pharyngeal wall oedema (arrows) isobserved in the OSA patient, as indicated by lightershade and as quantified by arbitrary units. Reproducedwith permission from Elias et al. 2013.

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society

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J Physiol 591.5 Nocturnal rostral fluid shift in apnoea 1185

capillary wedge pressure (PCWP) due to left ventriculardiastolic dysfunction, both of which cause oedema dueto raised systemic venous pressure (Bradley et al. 1985;Sajkov & McEvoy, 2009).

The potential role of fluid-regulating hormones inoedema formation in OSA patients is unclear. AlthoughOSA leads to sympathetic activation it remains uncertainwhether this stimulates their rennin–angiotensin–aldosterone system (Somers et al. 1995). For example,studies have shown variable levels of these hormones inOSA patients compared to controls, or before and afterCPAP treatment (Follenius et al. 1991; Rodenstein et al.1992; Maillard et al. 1997; Moller et al. 2003). Atrialnatriuretic peptide (ANP), which promotes diuresis andnatriuresis, may be elevated in OSA patients at night(Genest, 1986; Maillard et al. 1997; Kita et al. 1998). Thisis probably due to the effects of negative intrathoracicpressure generation and intermittent apnoea-relatedhypoxia that lead to increased venous return, pulmonaryvasoconstriction, left ventricular diastolic dysfunction and

right atrial stretch, which stimulates ANP release (Yalkutet al. 1996). Increased ANP levels should counter-act oedema formation. However, treatment of OSAby CPAP decreases ANP levels in association withreduced nocturia and oedema, probably by reducingright atrial stretch (Baruzzi et al. 1991; Kita et al. 1998;Blankfield et al. 2004). Thus the relative roles of therennin–angiotensin–aldosterone system and ANP in fluidregulation in OSA remain uncertain.

Since OSA can contribute to oedema formation, thiscould lead to a vicious cycle of increased overnight rostralfluid shift and more severe OSA. However, as treatmentwith CPAP for one night did not prevent fluid shift fromthe legs, this suggests that nocturnal rostral fluid shift is aprimary mechanism in the pathogenesis of OSA (Yuminoet al. 2010). However, over longer periods of time CPAPmay reduce oedema, but it remains to be determinedwhether this can attenuate OSA via reduction in over-night rostral fluid shift since, on withdrawal of CPAP,AHI immediately increases (Blankfield et al. 2004; Kohler

Figure 4 Relationship between overnight �LFV andAHI in men and women with heart failureA, correlation between overnight decrease in leg fluidvolume (LFV) and apnoea–hypopnea index (AHI) in menwith heart failure and either obstructive or central sleepapnoea. Central sleep apnoea was associated withgreater overnight fluid shift. Reproduced with permissionfrom Yumino et al. 2010. B, in women with heart failure,there is no correlation between overnight decrease in LFVand AHI. �LFV, overnight change in leg fluid volume.Reproduced with permission from Kasai et al. 2012.

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1186 L. H. White and T. D. Bradley J Physiol 591.5

et al. 2011). However, changes in oedema and overnightrostral fluid shift were not measured in relation to CPAPwithdrawal.

Central sleep apnoea

CSA is common in patients with heart failure and is oftenassociated with Cheyne–Stokes respiration, during whichthere is a gradual waxing and waning pattern of tidalvolumes followed by central apnoea (Yumino & Bradley,2008). Although CSA is also seen at high altitude or maybe idiopathic, this review is limited to CSA in heart failure.In heart failure patients, risk factors for CSA include malesex, older age, atrial fibrillation, increased left ventricularfilling pressure and end-diastolic volume, increased peri-pheral and central chemosensitivity to CO2, and hypo-capnia (Yumino & Bradley, 2008). Overnight rostral fluidshifts may also contribute to the pathogenesis of CSA.

During sleep, ventilation is largely dependent uponmetabolic CO2 production and ambient PCO2 . Centralapnoea occurs when PCO2 falls below the thresholdrequired to stimulate respiration (i.e. the apnoeathreshold), which usually increases from wakefulness tosleep. However, heart failure patients with CSA chronicallyhyperventilate, causing hypocapnia with PCO2 closer tothe apnoea threshold than normal. Thus, even slightperturbations that augment ventilation, such as arousalsfrom sleep, can trigger a central apnoea by driving PCO2

below the apnoea threshold. In heart failure patients withCSA, AHI is inversely proportional to PCO2 (Naughtonet al. 1993).

Mechanisms by which hyperventilation occurs inpatients with heart failure include increased peri-pheral and central chemosensitivity, and stimulationof pulmonary vagal irritant receptors by pulmonarycongestion due to elevated PCWP (Roberts et al. 1986;Yu et al. 1998; Javaheri, 1999; Solin et al. 2000). PCWPis, in turn, determined by severity of heart failure anddegree of intravascular fluid volume overload (Schoberet al. 1985; Nawada et al. 1993; Yu et al. 2005). For example,in heart failure patients, PCO2 is inversely proportional toPCWP (Lorenzi-Filho et al. 2002). In addition, patientswith heart failure and CSA have higher PCWP than thosewithout CSA and intensive medical therapy decreases bothPCWP and AHI (Solin et al. 1999).

In fluid overloaded patients with heart failure,particularly those with leg oedema, lying down atnight causes rostral fluid displacement out of the intra-vascular and interstitial compartments of the legs due togravitational effects (Thompson et al. 1928). The resultantincreased venous return to the heart and thorax can leadto increases in PCWP, intrathoracic fluid content andextracellular lung water (Larsen et al. 1986; van Lieshoutet al. 2005; Drazner et al. 2010).

These factors appear to play a role in the pathogenesisof CSA. For example, the AHI in men with heart failureand CSA strongly correlated with the degree of over-night decrease in LFV (Fig. 4A) (Yumino et al. 2010). Inaddition, there was a gradation in the degree of overnightLFV reduction from no or mild sleep apnoea (–98 ml), toOSA (–235 ml), to CSA (–404 ml). As patients with CSAhad similar overnight increases in neck circumference tothose with OSA, the extra fluid from the legs is likely tohave been redistributed to the lungs, since the greater theovernight decrease in LFV, the lower the nocturnal PCO2

and the higher the AHI. Presumably, fluid movement intothe lungs stimulated pulmonary irritant receptors whichprovoked hyperventilation and a fall in PCO2 below theapnoea threshold.

Furthermore, in heart failure patients, severity of CSAis reduced by raising the head of the bed, presumablyby reducing fluid shift into the lungs, thereby reducingpulmonary congestion and ventilation, and allowing PCO2

to rise (Altschule & Iglauer, 1958; Soll et al. 2009).Although in one study thoracic fluid content did notchange with altered sleeping angle, this finding contra-sted with other studies in which thoracic fluid contentincreased from the upright to supine position in subjectswithout heart failure (Larsen et al. 1986; van Lieshoutet al. 2005). Accordingly, further studies are requiredto determine whether fluid accumulation in the lungscontributes to the pathogenesis of CSA in heart failure.

Alterations in sleep apnoea type

Tkacova et al. (2001) observed that in heart failure patientswith both OSA and CSA, sleep apnoea type shifted frompredominantly obstructive to predominantly central fromthe beginning to the end of the night. This was associatedwith increases in periodic breathing cycle duration andcirculation time, and a decrease in PCO2 . Since theformer two measurements are inversely proportion tocardiac output, the shift from obstructive to central eventsoccurred in association with a fall in cardiac output,whereas the reduction in PCO2 suggested an increasein PCWP (Hall et al. 1996; Lorenzi-Filho et al. 2002).Furthermore, amongst heart failure patients who under-went two sleep studies several months apart, conversionfrom predominantly OSA to CSA was associated with adecrease in nocturnal PCO2 and an increase in periodicbreathing cycle duration, and vice versa (Tkacova et al.2006). These findings suggest that in HF patients withleft ventricular systolic dysfunction, the adverse cardio-vascular effects of OSA are potent enough, in some cases,to lower cardiac output and raise PCWP sufficiently tocause a shift to CSA.

In heart failure patients cardiac function can alter withchanges in medication use, sodium and fluid intake and

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cardiac ischaemia. Deterioration in cardiac function isoften accompanied by increased fluid retention and legoedema, and vice versa. Therefore, the above observationssuggest that in some heart failure patients, OSA and CSAare part of a shifting spectrum of sleep-related breathingdisorders whose predominant type is influenced by cardiacfunction and degree of nocturnal rostral fluid shift.

Conversely, however, patients with OSA who do nothave heart failure do not appear to develop central apnoeasover the course of the night. Although left ventriculardiastolic dysfunction has been observed in OSA patients,it is quite mild and insufficient to cause a large enoughincrease in PCWP to give rise to a HF syndrome withpulmonary congestion (Fung et al. 2002; Arias et al. 2005;Shivalkar et al. 2006). Furthermore, in OSA patients bothwith and without heart failure, the maximum fluid shiftfrom the legs is about 300 ml, whereas in heart failurepatients with CSA maximum fluid shift is about 600 ml(Redolfi et al. 2009; Yumino et al. 2010). In OSA patientsthere is no correlation between overnight fluid shift andPCO2 , unlike in those with CSA, where there is an inversecorrelation (Yumino et al. 2010). Thus the magnitude offluid shift associated with OSA appears to be insufficient tocause pulmonary congestion, stimulate pulmonary vagalirritant receptors and provoke hyperventilation and a fallin PCO2 below the apnoea threshold.

Factors influencing overnight rostral fluid shift andsleep apnoea

As described earlier, when standing still or sitting, the calfmuscles are relatively inactive, hydrostatic pressure exceedsosmotic pressure and fluid moves from the capillaries intothe interstitial space, forming leg oedema. Calf musclecontraction compresses the leg veins, whose one-wayvalves only permit blood flow towards the heart, resultingin increased venous return (Arnoldi, 1966). Accordingly,contraction of the calf muscles prevents pooling of fluidin the legs; therefore walking and calf muscle contractionwhile sitting prevent leg oedema (Winkel & Jorgensen,1986a,b; Noddeland & Winkel, 1988; Stick et al. 1992).

Increasingly, modern life is associated with less physicalactivity, owing to an increase in sedentary occupationsand hence greater time spent sitting. In addition, aspeople grow older, they lead an increasingly sedentary life(Murphy et al. 2011). This lack of physical activity increasesfluid accumulation in the legs during the day. Thus,inactive individuals may be predisposed to greater rostralfluid displacement from the legs when lying down at nightand therefore greater fluid movement into the chest andneck. In this way, physical inactivity and sitting could playa role in the pathogenesis of both OSA and CSA. Indeed,in non-obese men the AHI was proportional to overnightdecrease in LFV which was in turn proportional to sitting

time during the day (Redolfi et al. 2009). Similarly, it wasshown that in heart failure patients with OSA or CSA,AHI and overnight decrease in LFV were related directlyto sitting time and degree of leg oedema, and inversely tophysical fitness (Yumino et al. 2010).

Age may also be a factor affecting rostral fluid shifts.In elderly women, there is increased capillary filtrationinto the interstitial tissues of the legs in response to lowerbody negative pressure (which simulates increased venouspressure) as compared to young women, although suchchanges have not been observed in men (Lanne & Olsen,1997; Lindenberger & Lanne, 2007). Similarly, dependentfluid accumulation in the legs is more likely to occurin the elderly due to reduced activity and compromisedfunction of the venous valves of the legs, which allowsgravitational fluid accumulation (Schirger & Kavanaugh,1966). Indeed, in non-obese, otherwise healthy men withOSA, overnight decrease in leg fluid volume correlatedwith age independently of other factors, including sittingtime (Redolfi et al. 2009). These observations support theconcept that older age increases the tendency for fluidshifts into the interstitial tissues of the legs while standingand back into the vascular compartment while recumbentduring sleep.

Epidemiological studies demonstrate that higher levelsof exercise are associated with reduced prevalence andincidence of OSA, independently of BMI (Peppard &Young, 2004; Quan et al. 2007; Awad et al. 2012). Theobservation that supervised exercise reduces the AHImodestly in patients with OSA, without change in bodyweight provides evidence that lack of exercise contributesto OSA causation (Giebelhaus et al. 2000; Sengul et al.2011; Awad et al. 2012). Similarly, in heart failure patients,exercise training reduced severity of OSA or CSA modestly(Yamamoto et al. 2007; Ueno et al. 2009). One possiblereason for this, not tested, was that increased activityreduced daytime leg fluid accumulation, thereby reducingrostral fluid shift into the neck or chest overnight. Regularexercise decreases sympathetic activity in heart failurepatients and, in animal studies, reduces sodium and waterretention, which could reduce fluid retention in the legsduring the daytime (Zanesco & Antunes, 2007; Patel &Zheng, 2012).

Effect of interventions directed at fluid shifts on sleepapnoea

In different patient populations, interventions that reducenocturnal fluid shift consistently attenuate sleep apnoea.For example, wearing compression stockings preventsdaytime fluid accumulation in the legs by reducingfluid filtration from the intravascular to the interstitialspace via an increase in tissue hydrostatic pressure.In otherwise healthy men with OSA, and in patients

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with OSA and chronic venous insufficiency, wearingcompression stockings for 1 day or 1 week, respectively,reduced AHI by a third, in association with attenuationsin the overnight decrease in LFV and increase in neckcircumference (Redolfi et al. 2011a; Redolfi et al. 2011b).

In patients with drug resistant hypertension, treatmentwith the aldosterone antagonist spironolactone for8 weeks, decreased AHI by almost 50%, in associationwith diuresis and reduced blood pressure (Gaddam et al.2010). Similarly, intensive diuretic therapy in patients withdiastolic heart failure and severe OSA increased UA-XSAand decreased the AHI modestly (Bucca et al. 2007).

In patients with ESRD and sleep apnoea, conversionfrom conventional to nightly nocturnal haemodialysissignificantly reduced the AHI (Hanly & Pierratos,2001). However, in another similar study, nocturnalhaemodialysis had no effect on the AHI but did causean increase in UA-XSA in those both with and withoutsleep apnoea (Beecroft et al. 2008). In patients undergoingnocturnal peritoneal dialysis, the AHI was significantlylower than when they converted to continuous ambulatoryperitoneal dialysis (CAPD), in association with greaternocturnal fluid removal, lower total body water, greaterUA-XSA and reduced tongue volume (Tang et al. 2009).Finally, in patients with nephrotic syndrome, leg oedemaand OSA, treatment of the nephrotic syndrome withsteroids resolved oedema, reduced total body water, andreduced the AHI by 50% (Tang et al. 2012). However, innone of these studies on ESRD patients was overnight fluidshift measured.

The commonest treatment for OSA, CPAP, is thoughtto alleviate OSA by acting as a ‘pneumatic splint’ ofthe UA (Sullivan et al. 1981). However, it may haveother mechanisms of action. For example, when patientswith OSA were treated with 4–6 weeks of nasal CPAP,UA-XSA increased proportional to the reduction in UAmucosal water content measured by MRI (Ryan et al.1991). In another study, UA-XSA increased after just1 week of CPAP (Corda et al. 2009). In a study of patientswith heart failure and OSA, CPAP reversed OSA inassociation with attenuation of the overnight increasein neck circumference (Yumino et al. 2010). Togetherthese data provide evidence that one mechanism by whichCPAP alleviates OSA is by counteracting overnight fluidaccumulation in the neck and pharyngeal mucosa byincreasing intraluminal UA pressure, which opposes intra-vascular hydrostatic pressure.

Influence of sex on sleep apnoea

The prevalence of OSA is considerably lower in womenthan in men, although reasons for this have not beenfully elucidated (Young et al. 1993). Compared to men,pharyngeal length in women is shorter and reflex UA

compensatory responses to UA obstruction are stronger,both of which would tend to stabilise the UA of womenduring sleep and protect them from developing OSA(Malhotra et al. 2002; Chin et al. 2012). Differences in UAcollapsibility, genioglossus activity, neck fat distributionand hormonal status have also been investigated aspotential explanations for the difference in prevalenceof OSA between the sexes, but none fully explain thisdifference (Lin et al. 2008).

Differences in overnight rostral fluid shift betweenmen and women may be a mechanism contributing tothe higher male prevalence of OSA. In men with heartfailure, overnight increase in both neck circumference andAHI were proportional to the overnight decrease in LFV(Fig. 4A) (Yumino et al. 2010; Kasai et al. 2012). Inwomen with heart failure, however, despite a similarovernight decrease in LFV, the overnight increase inneck circumference was much smaller than in men, withno relationship between AHI and overnight change inLFV (Fig. 4B). Similarly, in healthy men and women,application of LBPP caused a similar decrease in LFV, butUA collapsibility increased more in men than women (Suet al. 2009). These studies suggest that a greater proportionof the fluid shifting from the legs accumulates in the neckin men than in women, which may therefore result inincreased peripharyngeal pressure, decreased UA-XSA andincreased UA collapsibility, predisposing to OSA.

Reasons for differing patterns of overnight fluidredistribution between men and women are not clear.Anatomical factors may play a role. For example, womenhave large venous plexi around the uterus, ovaries andvagina, with no equivalent in men (Kachlik et al. 2010).These plexi may sequester fluid that has shifted from thelegs overnight, preventing accumulation in the neck. Thispossibility is supported by the observation that womenhad greater pooling of blood in the abdomen duringapplication of lower body negative pressure than men(White & Montgomery, 1996). Further studies of posturalfluid shifts with measurement of fluid in the abdomen andneck may help to determine if abdominal pooling of fluidin women accounts for lower overnight fluid accumulationin the neck than men.

Conclusion and future directions

There is now considerable evidence that sedentary livingand fluid retention in the legs during the daytime andits overnight rostral shift contribute to the pathogenesisof both OSA and CSA, at least in men. Further work isrequired to better characterise patterns of fluid shifts inOSA and CSA. This will require direct measurements offluid volumes of the legs, abdomen, chest and neck. Inparticular, it would be important to determine whethergreater fluid sequestration in the abdomen and pelvis of

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women contributes to their lower prevalence of OSA thanmen.

Although a number of studies have measured fluiddisplacement from the legs, characterisation of the timecourse of these overnight fluid shifts to the chest and neckwould provide further insight into the pathogenesis ofOSA and CSA. For example, overnight conversion fromOSA to CSA in heart failure patients may be related tofluid initially accumulating in the neck, then subsequentlyin the chest in association with decreasing cardiac outputand increasing PCWP.

Finally, treatment of OSA and CSA by various formsof positive airway pressure, such as CPAP, is poorlytolerated by many. Hence, alternative effective therapiesare required. In view of the above, opportunities nowabound to examine prevention of fluid retention inthe legs during the day and its overnight rostral shiftas a novel therapeutic target for sleep apnoea in thesetting of larger, longer-term randomised clinical trials.Potential interventions include diuretics and aldosteroneantagonists, sodium restriction, compression stockings,elevating the head of the bed, exercise interventions andultrafiltration.

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Acknowledgements

This work was supported by Canadian Institutes of HealthResearch operating grant MOP-82731. L. H. White is supportedby an unrestricted fellowship from Sleep Country Canada.

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society