AMANDA PIPER PHD

DEPT OF RESPIRATORY & SLEEP MEDICINE

ROYAL PRINCE ALFRED HOSPITAL
SLEEP & CIRCADIAN GROUP, WOOLCOCK
INSTITUTE OF MEDICAL RESEARCH, UNIVERSITY
OF SYDNEY
1
MECHANISMS AND MANAGEMENT
OBESITY HYPOVENTILATION
SYNDROME
Disorder characterised by:
Obesity (BMI > 30kg.m
-2
)
Daytime hypercapnia (PaCO2 >45mmHg)
Absence of other disorders explaining
hypoventilation
Sleep disordered breathing

OBESITY HYPOVENTILATION SYNDROME
2
IDENTIFYING OHS
Clinically important to recognise and treat OHS
appropriately

HRQoL (Hida 2003)
Risk of PHT (Kessler, 2001)
Higher rates of cardiometabolic morbidity
(Berg, 20o1; Nowbar, 2004)
use of health care resources (Berg 2001)
High socioecomonic costs (Jennum, 2011)
Increased mortality rate (Nowbar, 2004)
Diagnosis often overlooked therapy delayed or not offered
(Nowbar, 2004; Marik, 2012)
3
Piper, Sleep Med Rev 2011
MECHANISMS
Obesity
Respiratory Drive
Sleep Disordered
breathing
4
1. OBESITY
Excessive load on the respiratory system
Reduces lung volumes and insp mm strength
Imposes an elastic load on breathing
BMI assoc with prevalence of OHS
Wt loss associated with improved lung
volumes and PaCO2
But not the only cause
Only a minority of obese
individuals develop hypercapnia
can hyperventilate to normocapnia
Mokhlesi et al, 2008
5
2. ALTERED VENTILATORY CONTROL
Failure of this mechanism
in OHS
Steier et al, Thorax 2009
Eucapnic obese persons
respiratory drive to
maintain V
E
in face of
load

Reduced ventilatory responsiveness to hypoxia and hypercapnia
Han et al, Chest 2001 6
WHY ARE VENTILATORY RESPONSES
DEPRESSED?
Obesity (El Gamal, Chest 2005)
Genetic predisposition
No evidence of depressed
familial responses (Javaheri,
1992; Jokic, 2000)
Acquired
Sleep disordered breathing
Improvement with therapy
Leptin
De Lucas Ramos, Respir Med 2004
7
OHS > Eucapnic MO > Lean
Phipps et al, Thorax 2002
In eucapnic obesity, leptin cf
lean individuals (Caro, 1996)
Serum leptin levels correlate with
HCVR in eucapnic obese (Makinodan
et al, 2008)
Compensatory mechanism to
maintain VE in face of load
Hyperleptinaemia assoc with
HRF in obesity (Phipps, 2002)
OHS is a leptin resistant state
LEPTIN
hormone produced by adipocytes
suppresses appetite and stimulates ventilation
8
3. SLEEP DISORDERED BREATHING
Frank
obstruction
Prolonged
flow limitation
Sleep
hypoventilation
Normal
breathing
Berger et al 2001
Spectrum of sleep breathing abnormalities (Berger et al, 2001)
9
Acute CO2 accumulation
in sleep
Apnea/interapnea
duration ratio (Ayappa, 2002)
Post event ventilatory
response (Berger, 2006)

Borel et al, Respirology 2012
85-90% will have > moderate obstructive sleep apnea (Kessler, 2001)
But only 10-15% of OSA patients develop hypercapnia

What are the mechanisms leading to awake CO2 retention
in patients with OHS & OSA?
Promoters of acute CO2
accumulation
Reduction in drive (innate or
drugs/O2)
Reduction in ventilatory efficiency in
clearing CO2 (lung disease or CHF)
10
Norman et al, J Appl Physiol 2006
reduced HCO3 renal
excretion alone or blunted
ventilatory response
= small effects on CO
2
and
HCO
3
-
synergistic effect when
occurring together
Respiratory-renal interaction
Acute nocturnal respiratory failure
Chronic awake respiratory failure
Mathematical modeling
11
The higher the plasma bicarb, the more blunted the CO2
response (Raurich, Respir Care 2010)
26-31mmol/L
31-37mmol/L
37-44mmol/L


OHS pts with more blunted HCVR demonstrate more
severe REM hypoventilation (Chouri-Pontarollo, 2007)
Bicarb a sensitive marker for the presence of CO
2

retention in OHS (Mokhlesi et al, Sleep Breath 2007)
12
Consistent with clinical findings:
MECHANISMS
Obesity
Respiratory
Drive
Sleep Disordered Breathing
MANAGEMENT
Weight loss
Pharmacotherapy
Acetozolamide
Medroxyprogesterone
Positive Airway
Pressure
THERAPY FOR OHS
13
One third of OHS pts likely to present acutely (Priou, Chest 2010)
Limited data on best management
BTS guidelines, 2002:


ACUTE RESPIRATORY FAILURE & OHS
Carrillo, AJRCCM 2013
Prospective study of 716 pts with
AHRF by NIV
OHS pts older (74 vs 71yrs)
But similar pH (7.22) and CO2
(84 vs 86mmHg)


12 month survival
14
How effective is PAP therapy?
Borel, Chest 2012
RCT of 1 month NIV vs lifestyle management in 35 pts
with mild OHS (mean age 54-58yrs; CO2 45-48mmHg)
CHRONIC RESPIRATORY FAILURE
NIV reduced CO2,
improved nocturnal SpO2
and improved sleep
architecture cf lifestyle
counselling

No difference in change in
ESS
15
CPAP OR BILEVEL THERAPY?
Majority of patients appear to respond to CPAP
Sullivan et al,
>60-80% can be managed with CPAP (Mohklesi,
2006; Piper, 2008)
Most pts have some element of obstructed
breathing during sleep (Kessler et al 2001)

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CPAP THERAPY FOR OHS
Need to provide sufficient pressure to treat obstructive events
Autotitration in an unattended setting not currently
recommended (Morgenthaler, Sleep 2008)
Lack of long term data re compliance, disease progression or
survival
Piper, Exp Rev Respir Med, 2010
Improved sleep
breathing (Banerjee, 2007)
Reversal of CRF
Improved daytime
vigilance (Piper 2008)
Improved QoL (Hida,
2003)

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BILEVEL THERAPY FOR OHS
Major indication for HMV
Positive outcomes with Spont,
ST and VAPS have been
reported
Most effective mode of
therapy not yet established
CPAP responders vs non-
responders
Garner, ERJ 2013
18
RCT of 36 pts with mild-mod OHS, BMI>50kg.m
-2

and CO2 51mmHg managed with CPAP or BVS
over 3mths
(Excluded severe persisting hypoventilation on CPAP)
CPAP VS BILEVEL S
Piper et al, 2008
19
10 stable OHS pts on home
bilevel support
3 consecutive nights
randomised to
S mode
ST (low BURR: 2 breaths below
nocturnal average 11 [10-12]
ST (high BURR: 95
th
centile of
nocturnal average) 21 [18-22]
Nocturnal PtcCO2 similar
under all 3 conditions
S mode :
significant in respir events
& ODI cf with BURR
SQ perceived as sl better
low cf high BURR

Contal et al, Chest 2013
CAHI/hr Mixed AHI/hr
SPONTANEOUS OR S/T MODE?
Questioned the use of
Spontaneous mode in OHS
20
SPONTANEOUS OR S/T MODE?
Small pt numbers not NIV naive
Settings not titrated overnight nor modified for the
specific mode (set closer to low BURR)

21
Contal et al, Chest 2013
S/T VS VOLUME TARGETED PS
Automatic adjustment of pressure support to provide a set
V
T
proposed to offer advantages over fixed pressure
Several studies have evaluated AVAPS in OHS
(Storre, 2006 ; Janssens, 2009; Ambrogio, 2009)
Murphy et al, 2012
RCT of 50 consecutive
OHS pts for 3 mths
Mean PaCO2 50mmHg
and BMI 50
In contrast to previous studies, no difference in SQ or in
control of nocturnal TcCO2 between the two modes
22
CPAP VS BILEVEL THERAPY
No difference between CPAP or bi-level PAP
regarding change in CO
2
if therapy controls SDB

Adherence to therapy is key
Mokhlesi et al 2006
Murphy, Thorax 2012
Average PAP use > 4.5 h/day
(N=34)
PaCO2 8+5mmHg
PaO2 9+11mmHg
Mokhlesi, 2006
Need for multi-modality approach to management
(Borel, Respirology 2012)
Exercise & Rehab
Life style counselling
Weight loss
24
Approx 25% of individuals may remain hypercapnic
despite adherence to therapy (Mokhlesi, J Clin Sleep Med 2006)
SDB not the primary cause of hypoventilation
Despite improved sleep and
gas exchange, 4 weeks of NIV
did not alter blood markers of
inflammation or glucose
metabolism, or endothelial fn.
Borel et al, Chest 2012
25
Borel, PLoS One, 2013
CV comorbidities the major
determinant of death in Obes-assoc
hypoventilation treated with NIV
Persistence of CV abnormalities
despite NIV
in physical activity and wt loss, along with HRQoL
with NIV would create positive conditions for
introducing rehab which could enhance the benefits of
therapy
26
Enhanced PA in OHS with NIV, which was assoc with wt loss
EXERCISE AND WEIGHT LOSS
Murphy et al, 2012
Jordan et al, Thorax 2009

Identified 96 OHS pts from
database for rehab program
(2 sessions/wk for 8-12 wks)
46 (48%) returned questionnaire
Of these, 20 (43%) not at all
likely to attend
Travel the greatest barrier (55%)
41% still would not attend if
travel arranged
Motivation may be problematic
EXERCISE AND WEIGHT LOSS
27
Titrate CPAP to eliminate obstructive
apneas, hypopneas, and flow limitation
Yes
Prescribe CPAP Prescribe Bilevel
No
Increase EPAP for UAO
Increase IPAP to improve SpO2
Monitor adherence
F/U ABG 2 months
Resolution of
Hypercapnia
Continue
bilevel support
Other therapies
Closely monitor
& F/U 2 months
Resolution of
Hypercapnia
Continue on CPAP
?
Maintains SpO2> 85%
Sleep hypoventilation
alone
Acute
respiratory failure
Exercise
Weight loss
Diet
Pathophysiology related to obesity, respiratory drive and SDB
PAP therapy most widely used and evidence-based approach
PAP therapy more effective in improving daytime CO2 and
normalising nocturnal breathing than lifestyle changes mild OHS
CPAP as effective as bilevel (S) in improving daytime and nocturnal
gas exchange mild to moderate OHS with OSA
No evidence that volume targeted PS offers advantages over fixed
pressure PS in unselected patients with mild to moderate OHS
Unclear what mode and BURR is best
Non-compliance with therapy and longer term consequences of
persisting hypercapnia
Impact of PAP on longer term cardiometabolic parameters needs
further evaluation
Need for specific training and lifestyle modification + PAP to
significantly reduce CV risk


29
29
SUMMARY
OXYGEN THERAPY
Wijesinghe, Chest 2011
Mod assoc btw baseline SpO2
and rise PtCO2
Most hypoxemic pt most likely
to retain CO2, and most likely
to receive excessive O2
As with AE of COPD, maintain
SpO2 88-92%
31
Supplemental O2 only
independent predictor of
mortality in OHS (Priou, 2010)
Degree of daytime hypoxia
prior to NIV better predictor of
LT mortality than baseline
hypercapnia (Budweiser et al 2007)
Priou et al 2010