Sleep-related hypoventilation syndromes

Jean Louis Pépin, Maurice Dematteis, Claire Arnaud,

Sandrine Launois, Renaud Tamisier and Patrick Lévy

Sleep laboratory, HP2 laboratoryEA 3745 ERI 0017 INSERM, Grenoble, France

Content

General mechanisms leading to hypoventilation during sleep

Obesity hypoventilation syndrome

Sleep hypoventilation in other restrictive chronic respiratory failure

Needs for polysomnography in patients receiving NIV

General mechanisms leading to hypoventilation during sleep

In normal subjects during sleep

Upper airway resistance increases

Chemosensitivity is reduced and the wakefulness drive to breathe is lost,

resulting in a fall in ventilation

Functional residual capacity decrease (body position)

Wake

Stage 3-4

REM sleep

PaCO2mmHg

During rapid eye movement (REM) sleep, ribcage and accessory breathing muscles are suppressed, particularly

during bursts of eye movements, and breathing is more irregular, rapid and shallow, with a further fall in ventilation

REM sleep hypoventilation: most frequent abnormality

Bourke et al., ERJ 2002

Gonzalez et al, 2002

DecreasedCompliance of the respiratory system

Diaphragmatic weakness

VA/Q Impairment of

ventilation perfusion mismatch

Upper airway collapse favoured by Vital Capacity

reduction and/or neuromuscular weakness

Inadequate respiratory drive

Depending uponthe underlying condition or disease

All these mechanims can be or not involved

Obesity hypoventilation syndrome

• Severe obesity BMI > 30 kg/m2 and diurnal PaCO2 > 43 mmHg

• In the absence of other known cause of hypoventilation

Olson et al Am J Med 2005

Obesity hypoventilation syndromeDefinition

• 1.2 % hospitalized patients (47/4332)

• Prevalence increase with BMI30% BMI > 35 kg/m2, 49% BMI > 50 kg/m2

Nowbar Am J Med 2004

Obesity hypoventilation syndromePrevalence

Morbid obesity nearly constant associated sleep apnea hypersomnia

Pèrez de Llano Chest 2005

Obesity hypoventilation syndromeClinical presentation

41/69 (59.4%) were initially referred for acute respiratory failure10/69 (14.5%) Deaths

Obesity hypoventilation syndromeClinical presentation

Pèrez de Llano Chest 2005

Berg Chest 2001

Obesity hypoventilation syndrome The Use of Health-Care Resources is increased compared to simple obesity

23%

9%*

Nowbar Am J Med 2004

Obesity hypoventilation syndromeMortality

Obesity hypoventilation syndromeMechanisms of the disease

Why do some obese hypoventilate during daytime and sleep?

Respiratory controlUpper airway collapseIncrease

work of breathing

resistance ofrespiratory system

VO2 and VCO2

work ofbreathing

performance ofrespiratory muscles

OSAHS

Obesity

Leptin resistance orLeptin deficiency

Reduced respiratory drive Ventilatory response to CO2

Daytime hypercapnia

compliance ofrespiratory system

resistance ofrespiratory system

VO2 and VCO2

work ofbreathing

performance ofrespiratory muscles

OSAHS

Obesity

Leptin resistance orLeptin deficiency

Reduced respiratory drive Ventilatory response to CO2

Daytime hypercapnia

compliance ofrespiratory system

Obesity hypoventilation syndromeMechanisms of the disease

Inadequate respiratory drive

All obese have increase in work of breathing but those without OHSIncrease their respiratory drive to compensate

Janssens, Pépin, Guo Eur Respir Mon 2008

Obesity hypoventilation syndromeSleep apnea is associated in 90% of cases

Berger KI JAP 2002; 93:917-24

Obesity hypoventilation syndromeSpecific sleep apnea patterns during the night may explain daytime hypercapnia

Ayappa I AJRCCM 2002; 166:1112-5

Obesity hypoventilation syndromeREM sleep hypoventilation

Reduced ventilatory

Drive

Leptin resistance

Chouri Chest 2007

Obesity hypoventilation syndromeREM sleep hypoventilation

REM

Eveil

REM REM REMS

aO2

(%)

FP

( bpm

)

A1A2

Chouri Chest 2007

Decrease in CO2 ventilatory responses

Obesity hypoventilation syndromeREM sleep hypoventilation

OHS with REM hypoventilationmore sleepy

Chouri Chest 2007

Obesity hypoventilation syndromeREM sleep hypoventilation

obesity

Increased work of breathing

Increased ventilatory drive

Eucapnia

OSASAdequate post apnea

hyperventilation

Leptin insensitivity

Olson Am J Med 2005

Eucapnia

Sim

ple

ob

esit

y

Ob

esit

y +

O

SA

SHypoventilation,

Hypercapnia

Hypercapnia

OH

S-O

SA

S

hyp

erca

pn

ia

Ob

esit

y

Hyp

ove

nti

lati

on

Syn

dro

me

Normal or diminished

ventilatory drive

Severe sleep hypoxemia and

sleep fragmentation

Insufficient post apnea ventilation

C57BL/6J-Lepob obese mouses without circulating leptin

O’Donnell Am J Respir Crit care Med 1999

Obesity hypoventilation syndromeLeptin resistance : lost of central effects of leptin

Fantuzzi JACI 2005

Obesity hypoventilation syndromeObesity-Intermittent hypoxia-hypercapnia-Leptin resistance

Preservation of peripheral actions of leptin such as increased sympathetic outflow and cytokine production

Lau Am J Physiol 2005

Obesity hypoventilation syndromeObesity-Intermattent hypoxia-hypercapnia-Leptin resistance

Preservation of peripheral actions of leptin such as increased sympathetic outflow and cytokine production

Obesity hypoventilation syndromeClinical study

Hypothesis:OHS patients exhibit a specific inflammatory response that may participate to

additional cardiovascular morbidity

Design :

Recruitment

Obese recruited from the general population by announcement

Aim

To compare inflammatory status and endothelial function, in OHS versus obese patients, matched for BMI, age and sex.

MethodsSleep, blood gazes and endothelial function, measured by peripheral arterial tonometry (PAT) were analyzed in all included patients. Inflammatory (TNF, IL-6, IL-8, IL-10, Leptin, MCP-1, RANTES) and anti-inflammatory (adiponectin and IL1-RA) parameters were also determined.

OHS (14) OBESE (22) p-value

Sex ♀ (%) 64% 64% ns

Age (years) 57 12 56 10 ns

BMI (kg/m2) 40.5 5.0 41.7 5.4 ns

Waist / Hip ratio 0.95 0.1 0.95 0.1 ns

SBP (mmHg) 126 12 129 11 ns

DBP (mmHg) 80 8.5 82 10 ns

FVC L; (% pred value) 2.61.0 (8326) 3.10.9 (9120) ns

FEV1/ FVC (%) 80 8 78 10 ns

SNIP (cm H2O) 72 22 76 26 ns

CO2 sensitivity (l/m/mmHg) 1.2 0.8 2.8 1.5 0.002

PaO2 (kPa) 9.8 1.3 10.6 1.6 ns

PaCO2 (kPa) 6.2 0.5 5.1 0.4 < 0.0001

pH 7.39 .02 7.43 .02 <0.0001

HCO3- (mmol/l) 27.8 2.0 24.6 1.3 <0.0001

Hypertension (%) 81 38 0.02

Myocardial infarction (%) 6 4 ns

Stroke (%) 0 0 ns

Diabetes (%) 50 30 ns

Hypercholesterolemia (%) 19 38 ns

Anti-Hypertensive drugs (%) 87 46 0.01

Glucose-lowering medications (%) 40 23 ns

Statin 47 33 ns

Fasting blood glucose level (mmol/l)

6.9 2.7 6.2 2.3 ns

HOMA – IR (G*I/22.5) 7.4 11.0 3.1 2.6 0.03

us-CRP (mg/l) 8.6 10.2 7.2 6.5 ns

TST (min) 292 92 358 59 0.05

%Sleep 1-2 76 9 70 7 0.1

% Sleep 3-4 4 7 6 6 ns

% REM Sleep 18 7 24 5 0.03

AHI (n/h) 48 49 45 26 ns

R µ-arousals(n/h) 39 27 43 17 ns

Mean nocturnal SpO2 89 5 90 5 ns

Nadir nocturnal SpO2 72 11 75 8 ns

Sleep time spent with SpO2<90% 37 34 22 21 0.14

Epworth sleepiness scale 12 4 11 5 ns

Pro-inflammatory status for Obese (ob) versus Obesity hypoventilation syndrome (OHS) patients

0

5

10

15

20

25

ob OHS

Res

isti

n (n

g/m

l)

0

5

10

ob OHS

TN

Fa (p

g/m

l)

0

100

200

300

ob OHS

Lep

tin,

ng/

ml

50

150

250

350

ob OHS

MC

P1, p

g/m

l

1

2

3

4

5

6

7

ob OHS

IL6,

pg/

ml

0

50

100

150

200

250

ob OHS

RA

NT

ES,

ng/

ml

p=0.01

0

100

200

300

ob OHS

IL8,

pg/

ml

0

10

20

30

40

ob OHS

Adi

pone

ctin

, µg/

ml

p=0.05

0

1E3

2E3

3E3

4E3

5E3

6E3

ob OHS

IL1-

RA

, pg/

ml

Anti-inflammatory status for Obese (ob) versus Obesity hypoventilation syndrome (OHS) patients

0

10

20

30

40

4 5 6 7 8

OHS

ob

Adi

pone

ctin

µg/

ml

PaCO2, kPa

0

10

20

30

40

5 6 7 8PaCO2, kPa

Adi

pone

ctin

, µg/

ml

0

50

100

150

200

250

5 6 7 8

RA

NT

ES,

ng/

ml

0

50

100

150

200

250

4 5 6

PaCO2, kPa

RA

NT

ES,

ng/

ml

PaCO2, kPa

0

10

20

30

40

4 5 6PaCO2, kPa

Adi

pone

ctin

, µg/

ml

r=-0.38 p=0.02

r=0.63 p=0.002

(ns)

r=-0.69 p=0.006 (ns)

OHS

r=0.54, p=0.002

0

50

100

150

200

250

4 5 6 7 8

ob

PaCO2, kPa

RA

NT

ES,

ng/

ml

Obesity hypoventilation syndromeTherapeutic strategy

What kind of ventilatory support should be use for treating respiratory failure?

Effects of treatment on blood gazes and survival

Efficacy of treatment on

Ventilatory responses

Sleep structure and hypersomnia

Leptin

Obesity hypoventilation syndromeWhat kind of ventilatory support should be use for treating respiratory failure? OHS with OSA but without REM sleep hypoventilation and moderate hypercapnia: CPAP

Bilevel non invasive ventilation

1) Inspiratory trigger

2) Difference between

inspiratory and expiratory pressure

provide Vt

3) Inspiratory/expiratory

cycling

Obesity hypoventilation syndromeWhat kind of ventilatory support should be use for treating respiratory failure? OHS with REM sleep hypoventilation and moderate hypercapnia: Bi-level NIV

Janssens JP CHEST 2003

Obesity hypoventilation syndrome the leading cause for long term home non invasive ventilation

Storre Chest 2006

Obesity hypoventilation syndromeWhat kind of ventilatory support should be use for treating respiratory failure? OHS with REM sleep hypoventilation and moderate hypercapnia: Bi-level NIV with AVAPS

Average Volume-Assured Pressure Support

Chouri Chest 2007

Obesity hypoventilation syndromeBi-level non invasive ventilationEfficacy on sleep structure

Chouri Chest 2007

Obesity hypoventilation syndromeBi-level non invasive ventilationEfficacy on daytime sleepiness

Perez de Lano CHEST 2005

Obesity hypoventilation syndromeBi-level non invasive ventilationEfficacy on mortality

Janssens et al. CHEST 2003;123:67-79

Obesity hypoventilation syndromeBi-level non invasive ventilationEfficacy on mortality

Brendon Respiration 2004

Obesity hypoventilation syndromeBi-level non invasive ventilationChanges in levels of serum leptin: contradictory results

Pèrez de Llano Chest 2005

Obesity hypoventilation syndromeNeeds to adapt ventilatory support with time course evolution?

Highly prevalent and easy to diagnose

Specific metabolic and cardiovascular morbidity

Polysomnography is needed to differentiate OSA and/or REM sleep hypoventilation

Interest of ventilatory responses to CO2

NIV improves blood gazes, sleep, daytime sleepiness and mortality

Changes in ventilatory support in the time course evolution of the disease

Other treatments of obesity required

Obesity hypoventilation syndromeTake home message

Sleep-related

hypoventilation in other

restrictive diseases

Sleep-disordered breathing usually precedes, and probably contributes to daytime ventilatory failure

Reduced VCwith or whithout

Neuromuscular weakness

Perrin et al., 2005

Neuromusculardisorders

Inadequate respiratory drive

Diaphragmatic weaknessDuchenne muscular dystrophy

ALS

Upper airway dysfunction

Parkinson diseaseALSDMD

Obstructive hypopneas misclassified as central

too weak muscles

Myotonic dystrophy

Hypercapnia more commonthan in others muscular diseases

with a similar degree of muscle weakness

Daytime hypersomnia +++

Cortical defect ?

Kyphoscoliosis

Inadequate respiratory drive

REM sleep hypoventilationLoss of compensation of the

accessory muscles

Upper airway obstruction

Guilleminault, Chest 1981

Kyphoscoliosis caused by poliomyelitis

Acquired blunting of drive

Needs for polysomnography

In patients receiving NIV

Disappearance of all abnormal respiratory events?

Asynchrony between the patient and the ventilator?

Occurrence of mouth leaks which induce sleep fragmentation?

Precisely determine the beneficial effects of NIV

Identification of SDB during NIV

There is a need for appropriate sensors when using PSG Flow Effort Sleep fragmentation

More adequate signals could be provided by the ventilator Flow corrected for leaks Detailed analysis of the triggering events Impact on the resulting tidal volume and sleep structure

Identification of SDB during NIV

Ventil. Pressure

Flow pneumotach

Flow leak-correct.

Pulse Transit Time

O2 Desat.related to leaks

Identification of SDB during NIV

Ventil. Pressure

Flow pneumotach

Flow leak-correct.

Pulse Transit Time

O2 desat.related to

REM hypoVA

Identification of SDB during NIV

Ventil. Pressure

Flow pneumotach

Flow leak-correct.

Pulse Transit Time

O2 desat.related toObstructive Hypopnea

Ventilator cycling 1 2

Ventilator cycling

1 Obstructive Hypopnea

2 Reduction in ventilation (lower PCO2?)

Impact of leaks on NIV efficacy

PtcCO2 Micro-arousals

Teschler H et al. Eur Resp J 1999;14:1251-7

Leaks corrected from 0.35 to 0.06 L/s: PCO2 = 7 mm HgArousals from 35 to 14/h

Sleep and efficacy of NIVSleep and efficacy of NIV

Identification of

Leaks ObstructiveEvents

Hypoventilation

Sleep and efficacy of NIVSleep and efficacy of NIV

NIV settings may favor ventilatory and sleep instability and be inadequate to correct SDB

* Back-up frequency and central events* Sleep fragmentation* Upper airway collapse* Persistent hypoventilation during REM sleep

Overall, sleep and breathing during NIV are far from ideal……

Conclusion

Mechanisms of sleep respiratory disturbances in restrictive lung

diseases : REM sleep hypoventilation

Needs for polysomnography at diagnosis, when using non-

invasive ventilation

Conditions most commonly seen

Obesity hypoventilation syndrome ++++

NIV effective treatment