University Medical Centre Groningen

The Netherlands

Oxygen / ventilatory support in COPD

MEDICATION

OXYGEN

LTX

LVRS

REHABILITATION

VENTILATORY SUPPORT

Severe COPD

MEDICATION

OXYGEN

LTX

LVRS

REHABILITATION

VENTILATORY SUPPORT

Severe COPD

Cu

mu

lati

ve S

urv

ival %

Cu

mu

lati

ve S

urv

ival %

100100

00

Time (months)Time (months)

9090

8080

7070

6060

5050

4040

3030

2020

1010

00

1010 2020 3030 4040 5050 6060 7070 8080

NOTTNOTT

MRCMRC

19 hrs19 hrs

12 hrs12 hrs 15 hrs15 hrs

No OxygenNo Oxygen

Composite slide NOTT and MRC studiesComposite slide NOTT and MRC studies

203 subjects randomized to continuous or 12 203 subjects randomized to continuous or 12 hours of oxygen for at least 12 monthshours of oxygen for at least 12 months

87 subjects randomized to oxygen 87 subjects randomized to oxygen 15 hours/day or none15 hours/day or none

Dynamic Hyperinflation in COPDDynamic Hyperinflation in COPD

• Increases work of breathing from added elastic Increases work of breathing from added elastic loadsloads

• Respiratory muscles at a mechanical disadvantageRespiratory muscles at a mechanical disadvantage

• Contributes to the sensation of dyspnea with Contributes to the sensation of dyspnea with increasing increasing inspiratory pressuresinspiratory pressures

Modified fromModified from Somfay A, ERJ 2001;18:77 Somfay A, ERJ 2001;18:77

3232

1818

2020

2222

2424

2626

2828

3030

0.20.2 0.30.3 0.50.5 0.750.75 1.01.0

FiOFiO22

Resp

irato

ry r

ate

R

esp

irato

ry r

ate

(b

reath

/min

)(b

reath

/min

)

33

0.50.5

11

1.51.5

22

2.52.5

0.20.2 0.30.3 0.50.5 0.750.75 1.01.0

FiOFiO22

Insp

irato

ry c

ap

acit

y (

L)

Insp

irato

ry c

ap

acit

y (

L)

Effect of Oxygen in 10 Non-hypoxemic Patients with Severe COPD, During

Constant Work

22

44

66

88

1010

1212

1414

0.20.2 0.30.3 0.50.5 0.750.75 1.01.0

FiOFiO22

En

du

ran

ce t

ime (

min

)En

du

ran

ce t

ime (

min

)

Improves health-related quality of lifeImproves health-related quality of life

Increases exerciseIncreases exercise

Relieves dyspneaRelieves dyspnea

Reduces air trappingReduces air trapping

Reduces hyperinflationReduces hyperinflation

Reduces ventilationReduces ventilation

Medical Volume Reduction with OxygenMedical Volume Reduction with Oxygen

Exercise capacity – Endurance distance

StudyOxygen

N

Placebo

N

Meters

95% CIWeight

%Meters

95% CI

Davidson 1988 17 17 1.32 52.00 (1.96, 102.04)

Fujimoto 2002c 34 34 3.35 32.00 (0.58, 63.42)

Woodcock 1981 10 10 3.56 35.00 (4.54, 65.46)

Kurihara 1989 14 14 5.82 25.00 (1.17, 48.83)

Fujimoto 2002b 25 25 6.35 24.00 (1.19, 46.81)

McDonald 1995 26 26 7.88 21.00 (0.52, 41.48)

Eaton 2002 41 41 9.01 40.00 (20.85, 59.15)

Knebel 2000 33 33 16.35 5.49 (-8.73, 19.71)

Ishimine 1995 22 22 19.33 18.00 (4.93, 31.07)

Fujimoto 2002a 16 16 27.04 12.00 (0.95, 23.05)

Total (95% CI) 238 238 100.00 18.86 (13.11, 24.61)

-50-50 00 5050Favours placeboFavours placebo Favours Favours oxygenoxygen

Systematic Review of RCT’s of Short Term Benefit of Ambulatory Oxygen in COPD

Supplementary Oxygen and Exercise

• Strong laboratory support for oxygen improving exercise, by decreasing ventilation

• Funding criteria vary among jurisdictions

• Few controlled trials of oxygen during exercise training

Supplemental Oxygen in hypoxemic COPD

Rooyackers J, ERJ 1997;10:1278

AirAir OxygenOxygen

707000

606000

505000

404000

303000

202000

101000

00

6M

WD

(m

)6M

WD

(m

)

Supplemental Oxygen in hypoxemic COPD

0

5

10

15

20

25

30

35

40

45

CRQ SWT

airoxygen

Garrod et al Thorax 2000;55:543

Emtner M, AJRCCM 2003;168Emtner M, AJRCCM 2003;168

Supplemental Oxygen in Non-hypoxemic COPDSupplemental Oxygen in Non-hypoxemic COPD

7700

6600

5500

4400

3300

2200 00 55 11

001155

2200Training Sessions

Work

Rate

(W

att

)

AA

BB

Supplemental Oxygen in Non-hypoxemic COPDSupplemental Oxygen in Non-hypoxemic COPD

Emnter. AJRCCM 2003;168:1034

Oxygen

room air

Emnter. AJRCCM 2003;168:1034

Supplemental Oxygen in Non-hypoxemic COPDSupplemental Oxygen in Non-hypoxemic COPD

Conclusion

1. LTOT is life saving for those with resting hypoxaemia

2. Ambulatory oxygen should increase mobility for those who require LTOT, but the evidence to support this is incomplete

3. Oxygen for exercise training reduces ventilation and may enable training at a higher load.

MEDICATION

OXYGEN

LTX

LVRS

REHABILITATION

VENTILATORY SUPPORT

Severe COPD

• Why should we start NIPPV in COPD ?

• What is the evidence ?

• New studies

Chronic ventilatory support in COPD

Sleep hypothesis

Run-in O2 O2 + NIPPV

TST, min 203 260* 339*#

Efficiency, %

Awake, %

51

38

69*

30

81#

20*#

Meecham Jones et al.1995:152:538-544

Diaz et al. ERJ 2002;20:1490

Hyperinflation hypothesis

Short term randomised controlled trials

Psych.Dysp.

12/4510.85Casanova2000

=10/2550.68Gay 1996

QOLGasex. Sleep

18/2560.86Meecham Jones 1995

Psych. 15/2490.54Strumpf 1991

EffectsBIpapPaCO2FEV1Study

Outcome Sample Treatment effect

Mean

Treatment effect

95 % CI

FVC, L 33/33 -0.01 -0.14 , 0.13

Pimax, cm H2O 24/24 6.2 0.2 , 12.2

Pemax, cm H2O 24/24 18.4 -11.8 , 48.6

PaO2, mmHg 33/33 0.0 -3.8 , 3.9

PaCO2, mmHg 33/33 -1.5 -4.5 , 1.5

6-MWD, m 12/11 27.5 -26.8 , 81.8

Sleep eff., % 13/11 -4.0% -14.7 , 6.7

Wijkstra et al. Chest 2003 ;124:337

Randomised controlled trials

No12/46.70.85Casanova2000

no10/27.30.68Gay 1996

ETCO218/27.40.86Meecham Jones 1995

no15/26.50.54Strumpf 1991

MonitoringBIpapPaCO2FEV1Study

• Why should we start NIPPV in COPD ?

• What is the evidence ?

• New studies

Chronic ventilatory support in COPD

NUTRITION

OXYGEN

LTX

LVRS

REHABILITATION

NIPPV

COPD

+

Ventilatory support during exercise Ventilatory support during exercise

Oxygen Oxygen Ventilation Ventilation Dreher ERJ 2007;29:930

Dreher ERJ 2007;29:930

Ventilatory support during exerciseVentilatory support during exercise

NUTRITION

OXYGEN

LTX

LVRS

REHABILITATION

NIPPV

COPD

+

Nocturnal NIPPV in stable COPD

Measurements

Measurements

Measurements

12 weeks 12 weeks

NIPPV + PR

PR

Randomisation NIPPV

Baseline

3 months

Duiverman ATS 2008 abstract

Not meeting inclusion

criteria (n= 15)

Allocated to NIPPV + rehabilitation(n= 37)

Baseline measurements(n = 35)

Assessed for eligibility(n= 87)

Baseline

3 months

Analysed(n= 32)

Analysed(n = 24)

Drop-outs (n=3)noncompliant

Allocated to rehabilitation (n=35)

Baseline measurements(n = 31)

Randomised(n =72)

Early drop-outs (n=6)- 2 died- 2 withdrew - 2 other diseases

Drop-outs (n=7) - 5 intolerance to NIPPV- 1 noncompliant rehab- 1 died

Run in

NIPPV+rehabilitation Rehabilitation

Subjects, n 31 35

Age, yrs 63 ± 10 61 ± 7.4

BMI, kg/m2 27.1 ± 6.4 27.5 ± 6.3

FEV1, L 0.83 ± 0.37 0.77 ± 0.29

RV, % predicted 212 ± 43 223 ± 62

PaO2, kPa 7.89 ± 1.12 8.42 ± 1.25

PaCO2, kPa 6.81 ± 0.64 6.81 ± 0.76

Patient characteristics

Daytime blood gases Baseline After 3

months

Effect 95% CI

PaCO2, kPa N+R 6.9±0.7 6.4±0.7* -0.32 -0.6 to -0.1

R 6.8±0.8 6.7±0.6

PaO2, kPa N+R 7.8±1.0 8.3±1.2* 0.25 -0.2 - 0.7

R 8.3±1.3 8.3±0.9

HCO3 ,mmol/L N+R 29.2 ±2.3 28.4 ±2.4 -0.90 -1.8 to 0.4

R 29.4±2.7 29.1±1.8

BE, mmol/L N+R 4.6±2.0 3.6 ±1.9* -0.66 -1.4 to 0.3

R 4.±2.1 4.1±1.4

pH N+R 7.39±0.03 7.40±0.02 0.01 -0.01 to -0.02

R 7.40±0.03 7.40±0.03

Health related quality of lifeCRQ

Health related quality of lifeCRQ

dyspnoea fatigue emotion mastery total 0.0

0.5

1.0

1.5

2.0

*

*

*

* *

* *

†

MCID

Ch

ang

e in

CR

Q s

core

(av

erag

e p

er q

ues

tio

n)

Health related quality of life MRF-28

Health related quality of life MRF-28

daily cog inv total

-30

-20

-10

0

10

*

**

† †C

han

ges

in

MR

F-2

8 sc

ore

s (%

)

Activities in daily livingSteps/day

Baseline After 3 months0

2500

5000

7500

10000

12500

15000

*

NIPPV + Rehabilitation

Rehabilitation

Dai

ly s

tep

co

un

t (s

tep

s/d

ay)

Chronic ventilatory support in COPD

• No strong evidence to provide ventilatory to patients with COPD routinely.

• Ventilatory support during exercise might improve its effects, although more studies are needed

• Nocturnal ventilatory support improves the effects of rehabilitation in hypercapnic COPD patients.

Nocturnal blood gases

* *

Muscle resting hypothesis

Sham NIPPV

baseline - 3 wk

NIPPV

baseline - 3wk

PaCO2, kPa 7.4 - 7.3 7.6 – 6.5

Ttot, s 3.4 - 3.3 2.9 - 3.6#

RV, % pred. 201 - 209 201 - 165#

TTdi 0.04 - 0.04 0.05 - 0.04

PEEPi, cm H2O 2.6 - 2.7 2.6 - 1.7#

Diaz et al. ERJ 2002;20:1490

Nocturnal NIPPV and daytime exercise training

Garrod et al.AJRCCM 2000:162:1335

<-------- P <0.009 -------- >

< P<0.01>

Noninvasive ventilation in stable COPD

Lung function Baseline After

Rehab

Effect 95% CI

FEV1, L N+R 0.90±0.38 0.89± 0.39 -0.04 -0.1 - 0.1

R 0.78±0.30 0.81±0.29

VC, L N+R 2.89±0.82 2.98±0.89 -0.07 -0.3 - 0.2

R 2.47±0.73 2.62±0.86

RV%TLC N+R 62±8 62±10 1 -3 - 5

R 66±10 64±9

PImax, kPa N+R 5.6±2.3 6.9±2.2* 0.8 -0.2 – 1.8

R 5.3±2.2 5.9±2.3

Noninvasive ventilation in stable COPD

Breathing pattern Baseline After

Rehab

Effect 95% CI

change

VE, ml/ min N+R 9.8 ± 3.0 10.6 ± 3.1 1.4 0.3 to 2.4

R 9.0 ± 1.9 8.6 ± 2.3

VT, ml N+R 506 ± 144 560 ±135* 50 -9 to 116

R 525 ± 129 519 ± 147

BF, breaths/ min N+R 20 ± 5 19 ±5 0.5 -1.4 to 2.3

R 18 ± 4 17 ± 5

Shuttle walk test

Garrod et al.AJRCCM 2000:162:1335

<-------- P <0.009 -------- >< P<0.01>

NUTRITION

OXYGEN

LTX

LVRS

REHABILITATION

NIPPV

COPD

and hypercapnia

+

Inclusion criteria

• COPD

• FEV1< 50% pred.

• symptoms : dyspnoea on exertion / impaired exercise tolerance

• Age < 75 years

• PaCO2> 45 mmHg

Exclusion criteria• Any diagnosis interfering with a successfull

rehabilitation

• OSAS : AHI > 10

• Currently on NIPPV

• Within last 2 years started a rehabilitation programma

Design (1)

• Randomised open trial

• 2 arms : NIPPV + rehabilitation (A)rehabilitation alone (B)

• Duration : 24 months

Design (2)

0 inclusion / randomisation

3 m control period

3 m A : start NIPPV and after 2 weeks rehab B : start rehabilitation

6 m end of clinical / outpatient rehab 6m start follow-up rehabilitation community

Effect-parameters

• Primary health related quality of life

• Secundary dyspnoeaADL activities PSG gasexchange EMG respiratory musclesfreq./duur opnamesexacerbations freq.

exercise tolerance

0 3 6 12 24

HRQL dyspneuADL

BGAEMG SWTLF

HRQL dyspneuADL PSG

BGAEMG SWTLF

HRQL dyspneuADL PSG BGAEMG SWTLF

HRQL dyspneuADL PSG BGAEMG SWTLF

HRQL dyspneuADL

BGAEMG SWTLF

MEASUREMENTS

CONTROL CLINICAL COMMUNITY

Discussion

• No clear evidence for rationale of NIPPV

• Effect of NIPPV still controversial

• What did we learn ?– Level of hypercapnia– Adequate ventilatory support / monitoring

• What kind of research is needed in COPD ?

Conclusions

• Patients with neuromuscular diseases and thoracic restriction have a good survival after starting NIPPV/TIPPV

• The effects of NIPPV in COPD are still controversial

• Combination of NIPPV and rehabilitation and chronic NIPPV after NIPPV in the acute setting are interesting areas for further research

Chronic NIPPV in COPD

should be done in studies only

Effect of oxygen during endurance test

0

2

4

6

8

10

12

14

16

18

Emtner Rooyackers

Room airOxygen

*

HELIOX

Laude AJRCCM 2006;173:865

Laude AJRCCM 2006;173:865

HELIOX

Heliox

Medication

NM stimulation

ventilatory support

Oxygen

Rehabilitation

in severe COPD

IMT

Van ‘t Hul ERJ 2006;27:65

NIPPV during exercise

Van ‘t Hul ERJ 2006;27:65

NIPPV during exercise

REsearch in COpd

the additional value of VEntilatory support on Rehabilitation

RECOVER

Study design 2004-2008

Inclusion criteria

• COPD (GOLD 3 & 4)• Symptoms : dyspnoea / exercise capacity • PaCO2> 45 mmHg

Randomised open study • REHAB versus Rehab + night-time NIPPV

Primary outcome• Health related QOL

RECOVER

Future Research

• Which patient is a good candidate for what type of intervention

• Combination of strength training and NEMS

• Daytime NIPPV next to exercise

• Combining heliox and rehabilitation

• Life style studies to maintain initial effects

Baseline measurements72 patients

Included60 patients

3 patients OSAS

8 patientsPCO2<6.0 kPa/

>50%pred FEV1

Excluded after baseline 12 patients

1patient heart failureControl period: 6

patients

Rehabilitation: 42 patients

Rehabilitation: 22 patients

Rehabilitation+ NIPPV: 20 patients

Lost:7 patients refused to continue the study5 patients died

Baseline measurements72 patients

Included60 patients

3 patients OSAS

8 patientsPCO2<6.0 kPa/

>50%pred FEV1

Excluded after baseline 12 patients

1patient heart failureControl period: 6

patients

Rehabilitation: 42 patients

Rehabilitation: 22 patients

Rehabilitation+ NIPPV: 20 patients

Lost:7 patients refused to continue the study5 patients died

Bronchodilation and hyperoxia

Peters Thorax 2006;61:559

Diaz et al. ERJ 2002;20:1490

Reduction in Hyperinflation

Interval training (2)

Coppoolse ERJ 1999;14:258

FEV1 37% pred.

30 min/ dag

5 dag/week, 8 wk,

interval versus duur

Interval training (2)

Coppoolse ERJ 1999;14:258

Casaburi et al. ARRD 1991;143:9

Ventilatoire adaptatie

FEV1 1.9 L (56% pred)

5 dg/wk gedurende 8 wk

High = 80% AT

Low = 50% AT

45 min.

Casaburi et al. ARRD 1991;143:9

Ventilatoire adaptatie

Ventilatory support

and

Exercise training

Hakins Thorax 2002;57:853

Peripheral muscle weakness

Bernard et al. AJRCCM 1998;158:629

Training with oxygen

0

5

10

15

20

25

30

35

40

45

CRQ SWT

airoxygen

Garrod et al Thorax 2000;55:543

Exclusion criteria

• Any diagnosis interfering with a successfull rehabilitation

• OSAS : AHI > 10

• Currently on NIPPV

• Within last 2 years started a rehabilitation programma

RECOVER

Design (2)

0 inclusion / randomisation

3 m control period

3 m A : start NIPPV and thereafter rehabilitation B : start rehabilitation

6 m end of clinical / outpatient rehab 6 m start follow-up rehabilitation community

Design (1)

• Randomised open trial

• 2 arms : NIPPV + rehabilitation (A)rehabilitation alone (B)

• Duration : 18 months

RECOVER

Effect-parameters

• Primary health related quality of life

• Secundary dyspnoeaADL activities PSG gasexchange EMG respiratory musclesfreq./duur opnamesexacerbations freq.

exercise tolerance

Exercise

Medication

NM stimulation

ventilatory support

Oxygen

Rehabilitation

in severe COPD

IMT

+

Exercise

Medication

NM stimulation

ventilatory support

Oxygen

Rehabilitation

in severe COPD

IMT

Cross sectional area of thigh muscle

COPDHealthy

Bernard et al. AJRCCM 1998;158:629

Peripheral muscle weakness

Bernard et al. AJRCCM 1999;159:896

Aerobic : 12 wk, 3d/wk

30 min, 80 % PWR

Strength : 12 wk,

60 % 1RM, 2 X 8

80% 1RM, 3 X 8

Neuromuscular electrical stimulation

• COPD (FEV1 0.9 L)

• NMES lower extremity

• 5 days/wk for 6 week (30 sessions)

• Effects : muscle function exercise capacity

dyspnoea Neder Thorax 2002;57:333

Neder et al. Thorax 2002;57:333

Neuromuscular electrical stimulation

Vivodtzev. Chest 2006;129:1540

Rehabilitation and NEMS

Resistance training and testosteron

0

5

10

15

20

25

baseline week 10

placebo/no trainingtestosteron/no trainingplacebo/resistancetestosteron/resistance

Casaburi AJRCCM 2004;170:870

repetitions

leg press fatigue

*

*+

Resistance training and testosteron

0

1

2

3

4

5

6

7

8

9

baseline week 10

placebo/no trainingtestosteron/no trainingplacebo/resistancetestosteron/resistance

Casaburi AJRCCM 2004;170:870

min

constant work rate duration

Rehabilitation and creatine

Loading phase

Rehabilitation and

maintenance

Fuld Thorax 2005;60:531

Upper limb muscle function

0

2

4

6

8

10

12

14

16

loading rehabilitation

creatine

placebo

# *

Fuld Thorax 2005;60:531

repetitions

# *

#

Endurance Shuttle Walk Test

0

50

100

150

200

250

300

350

400

loading rehabilitation

creatine

placebo

Fuld Thorax 2005;60:531

SECONDS

Heliox

Medication

NM stimulation

ventilatory support

Oxygen

Rehabilitation

in severe COPD

IMT

PImax

6 or 12 MWD

Lotters ERJ 2004;20:570

FEV1 : 24% pred.

IMT :

40-50% PImax

30 min /day

5 /wk, 5 week

Ramirez-Sarmiento AJRCCM

2002;166:1491

Exertional Oxygen in COPD• 26 subjects, 73 yrs, FEV1 0.9L, resting PaO2 69

mmHg, PaCO2 41 mmHg

• 12 week cross over of air (6 weeks) versus oxygen (6 weeks) for activities

• 50% of patients preferred the 6 weeks on oxygen and 50% the 6 weeks on air

• No between group benefit to exercise tolerance, quality of life or symptoms after 6 weeks

McDonald CF, AJRCCM 1995;152:1616

Domiciliary Oxygen and Quality of LifeDouble blind randomized cross over of air versus oxygen during exertion, in 6 week blocks. 26 subjects, age 73 6 yr, FEV1 0.9 0.4L, PaO2 69 9 mmHg, PaCO2 41

3 mmHg

Dyspnea Fatigue Emotional Function

Mastery

Baseline 14 ± 5 13 ± 4 33 ± 9 17 ± 6

Home Air 17 ± 6 15 ± 4 35 ± 9 19 ± 5†

Home O2 19 ± 6* 16 ± 4* 36 ± 8* 20 ± 6*

Maximum Score 35 28 49 28

* * Home OHome O22 compared with baseline (p<0.02) compared with baseline (p<0.02)† † Mastery improved with home air compared with baseline (p<0.03). There was no Mastery improved with home air compared with baseline (p<0.03). There was no

significant difference between oxygen and airsignificant difference between oxygen and air

McDonald CF, AJRCCM 1995;152:1616

Phillipson EA, Chest 1984;85:24SPhillipson EA, Chest 1984;85:24S

SleepSleep(REM)(REM)

++ COPDCOPDDeteriorationDeterioration

of gasof gasexchangeexchange

Aggravation ofAggravation ofblood gasblood gas

disturbancesdisturbances

++

++

++

++

++

++

DecreasedDecreasedChemoresponseChemoresponse

ss

HypopneasHypopneasand Apneasand Apneas

Rapid, ShallowRapid, ShallowBreathing Breathing PatternPattern

Loss of PhasicLoss of PhasicIntercostal Intercostal

MuscleMuscleActivityActivity

Loss of Loss of IntercostalIntercostal

Muscle ToneMuscle Tone

FurtherFurther VVAA

FurtherFurther V/QV/Q

PacoPaco22

PaoPao22

SaoSao22

BluntedBluntedChemoresponsesChemoresponses

High PacoHigh Paco22

Low PaoLow Pao22

ImpairedImpairedDiaphragmaticDiaphragmatic

FunctionFunction

High IntrathoracicHigh IntrathoracicAirways ResistanceAirways Resistance

High ClosingHigh ClosingVolumeVolume

High VHigh VD D / V/ VTT

Increased UpperIncreased UpperAirway ResistanceAirway Resistance

Impaired LoadImpaired LoadCompensationCompensation

• NIPPV might improve: sleep, gas exchange, muscle function and mechanics

• Is there adequate evidence of effectiveness for NIPPV in COPD?

• What might be valuable research questions?

Non-invasive Positive Pressure Non-invasive Positive Pressure Ventilation (NIPPV) in COPD Patients Ventilation (NIPPV) in COPD Patients with Chronic Respiratory Failure (CRF)with Chronic Respiratory Failure (CRF)

NIPPV plus Oxygen versus Oxygen alone for Hypercapnic COPD

Run-in O2 O2 + NIPPV

TST, min 203 260* 339*#

Efficiency, % 51 69* 81#

Awake, % 38 30 20*#

14 patients with PaO14 patients with PaO22 45 45 ± ± 6 mmHg and PaCO6 mmHg and PaCO22 56 ± 4 mmHg randomized to 3 56 ± 4 mmHg randomized to 3 months of LTOT versus LTOT + NIPPV. Shown below is taken from Table 3 the months of LTOT versus LTOT + NIPPV. Shown below is taken from Table 3 the effects on sleep, showing improved sleep time, sleep efficiency and reduced effects on sleep, showing improved sleep time, sleep efficiency and reduced wakefulness, with NPPV + LTOT. wakefulness, with NPPV + LTOT.

Meecham-Jones J, 1995;152:538

NIPPV Plus Oxygen versus Oxygen Alone for Hypercapnic COPD

14 patients with PaO2 45 ± 6 mmHg and PaCO2 56 ± 4 mmHg randomized to 3 months of LTOT versus LTOT + NIPPV. Below is Figure 1 showing mean values of daytime arterial PaO2 and PaCO2 at run in and after 3 months of oxygen alone or oxygen plus NIPPV

Meecham-Jones J, 1995;152:538

7575

6060

4545

3030

00Run-Run-

ininOxygeOxyge

n n AloneAlone

Oxygen Oxygen plus plus NPSVNPSV

PaC

OP

aC

O2

2 (m

mH

g)

(mm

Hg

)

7575

6060

4545

3030

00Run-Run-

ininOxygeOxyge

n n AloneAlone

Oxygen Oxygen plus plus NPSVNPSV

PaO

PaO

2

2 (m

mH

g)

(mm

Hg

)

NIPPV in Stable Hypercapnic COPD

Sham NIPPVbaseline - 3 wk

NIPPVbaseline - 3wk

PaCO2, kPa 7.4 - 7.3 7.6 - 6.5

Ttot, s 3.4 - 3.3 2.9 - 3.6#

RV, % pred 201 – 209 201 - 165#

TTdi 0.04 - 0.04 0.05 - 0.04

PEEPi, cm H2O 2.6 - 2.7 2.6 - 1.7#

Diaz O, ERJ 2002;20:1490Diaz O, ERJ 2002;20:1490

36 patients randomized to NIPPV or sham for 3 hours per day, for 5 days a week for 3 weeks. Below is taken from Table 2, showing a reduction in PCO2, lung volume, respiratory frequency and intrinsic PEEP.

NIPPV in Stable Hypercapnic NIPPV in Stable Hypercapnic COPDCOPD36 patients randomized to NIPPV or sham for 3 hours per day, for 5 days a week for 3 weeks. Below is taken from figure 3 showing the relationship between changes in PCO2 and dynamic intrinsic positive end-expiratory pressure in control 0 and MIPPV 0 subjects

Diaz O, ERJ 2002;20:1490Diaz O, ERJ 2002;20:1490

11

00

-1-1

-2-2

-3-3

-4-4 -3-3 -2-2 -1-1 00 11 22 33

PaC

OP

aC

O22 k

Pa

kP

a

PEEPi;PEEPi;dyndyn cmH cmH22OO

Short Term RCT’sStudy FEV1 PaCO2 BiPAP Effects

Strumpf, 1991 0.54 49 15/2 Psych

Meecham-Jones, 1995 0.86 56 18/2HRQL Gases Sleep

Gay, 1996 0.68 55 10/2 -

Casanova, 2000 0.85 51 12/4Psych

Dyspnea

Outcome Sample

Treatment EffectMean

Treatment Effect

95% CI

FVC, L 33/33 -0.01 -0.14 , 0.13

Pimax, cm H2O 24/24 6.2 0.2 , 12.2

Pemax, cm H2O 24/24 18.4 -11.8 , 48.6

PaO2, mmHg 33/33 0.0 -3.8 , 3.9

PaCO2, mmHg 33/33 -1.5 -4.5 , 1.5

6MWD, m 12/11 27.5 -26.8 , 81.8

Sleep Efficiency % 13/11 -4.0% -14.7 , 6.7

Wijkstra P, Chest Wijkstra P, Chest 2003;124:3372003;124:337

Short Term RCT’sStudy FEV1 PaCO2 BiPAP Effects

Strumpf, 1991 0.54 49 15/2 Psych

Meecham-Jones, 1995 0.86 56 18/2HRQL Gases Sleep

Gay, 1996 0.68 55 10/2 -

Casanova, 2000 0.85 51 12/4Psych

Dyspnea

Uncontrolled TrialsStudy FEV1 PaCO2 BiPAP Effects

Elliot 0.53 60 15/2 BGA

Perrin 0.86 58 18/2QoL BGA

Sivasothy 0.70 64 10/2 BGA Jones 0.90 61 12/4 BGA

Short Term RCT’sStudy FEV1 PaCO2 BiPAP Monitoring

Strumpf, 1991 0.54 6.5 15/2 No

Meecham-Jones, 1995 0.86 7.4 18/2 PETCO2

Gay, 1996 0.68 7.3 10/2 No

Casanova, 2000 0.85 6.7 12/4 No

NIPPV Plus Oxygen versus Oxygen Alone for Hypercapnic COPD

Meecham-Jones P, 1995;152:538

14 patients with PaO14 patients with PaO22 45 45 ±± 6 mmHg and PaCO 6 mmHg and PaCO22 56 ± 4 mmHg randomized to 3 months of 56 ± 4 mmHg randomized to 3 months of LTOT versus LTOT + NIPPV. Shown below is taken from Figure 2 the correlation between LTOT versus LTOT + NIPPV. Shown below is taken from Figure 2 the correlation between change in daytime PaCOchange in daytime PaCO22 and change in night PtCO and change in night PtCO22

1010

88

66

44

22

00

-2-200 55 1010 1515 2020 2525 3030

Nocturnal PtCONocturnal PtCO22 (mmHg) (mmHg)

Dayti

me P

aC

OD

ayti

me P

aC

O22 (

mm

Hg

) (

mm

Hg

)

Discussion • No clear evidence for rationale of NIPPV

• Effect of NIPPV still controversial

• What did we learn?– Level of hypercapnia– Adequate ventilatory support– Adequate monitoring

• Where does NIPPV fit in COPD management?

RCT of NIPPV Plus Physical Training RCT of NIPPV Plus Physical Training in Severe COPD in Severe COPD

Garrod R, et al. AJRCCM 2000;162:1335

45 COPD patients (PaCO2 46mmHg) received 8 weeks of exercise training alone or with nightly NIPPV. Below is taken from figure 2 showing changes in the shuttle walk test in both groups at each assessment. Changes were manifested in the A3-A4 representing the 4 weeks from mid rehabilitation to post rehabilitation.

340340

320320

300300

280280

260260

240240

220220

200200

180180

160160

140140A1A1 A2A2 A3A3 A4A4

SW

TS

WT NPPV + ETNPPV + ET

ETET

NutritionNutritionOxygen

LTX

LVRS

Rehabilitation

NIPPV

COPDCOPDwith with

hypercapniahypercapnia+

Enrollment

Exclusion

• Co-morbidities influencing rehabilitation

• Obstructive Sleep Apnea: AHI >10

• Currently receiving NIPPV

• Rehabilitation within the last 2 years

Inclusion

• COPD aged <75 years

• FEV1 <50% predicted

• Dyspnea on exertion and reduced exercise tolerance

• PaCO2 >45 mmHg

Design• Randomised 24 month open trial

• 3 months control

• 3 months NIPPV with facility supervised PR + 21 months community supervised PR (A)

• 3 months facility supervised PR + 21 months community supervised PR (B)

• Primary Outcome: Health related quality of life

• Secondary Outcomes: dyspnoea, activities of daily living, gas exchange, exercise tolerance, exacerbation frequency

Rehabilitation and NIPPV

0 3 6 9 15 21 27

QoL * * * * * * *

Cycle Endurance

* * *Homevisit

6MW * * * * * *

PFT * * * * * * *

Night Study

** * *

50

Control Hospital

Supervised

RehabilitationPeriod

50 Community Based Rehabilitation

Chu C, et al. Thorax 2004;59:1020

COPD Survivors Treated with NIPPV for COPD Survivors Treated with NIPPV for Acute Hypercapnic Respiratory FailureAcute Hypercapnic Respiratory Failure110 patients survived NIPPV. After 1 year, 80% had been readmitted, 63% had a life 110 patients survived NIPPV. After 1 year, 80% had been readmitted, 63% had a life threatening event and 49% had died. Taken from figure 3 showing the probability of survival threatening event and 49% had died. Taken from figure 3 showing the probability of survival for patients who survived a single episode of respiratory failure treated with NIPPVfor patients who survived a single episode of respiratory failure treated with NIPPV

1.00.90.80.70.60.50.40.30.20.10.00 1 2 3 4 5 6 7 8 9 10 11 12

Time (months)Time (months)

Pro

bab

ilit

y o

f S

urv

ival

Criteria • COPD patients who required ventilation for

respiratory failure from AECOPD

• Ventilator free for at least 48 hours

• PaCO2 >45 mmHg at rest 55 mmHg

• Exclude: sleep apnea, heart failure, non-obstructive respiratory conditions

Design • 24 month, randomised trial with 2 arms:

NIPPV and medication (A),Medication only (B)

• Primary outcome - Survival

• Secondary outcome - health related quality of life, hospital admission frequency, exacerbation frequency, activities of daily living, gas exchange, exercise tolerance

Conclusions• The impact of NIPPV in COPD with chronic

respiratory failure remain controversial

• Two interesting areas are:- Combination of NIPPV and PR versus PR alone

- Continued NIPPV after NIPPV used for AECOPD

• Wider use of NIPPV in COPD should await evidence of effectiveness

Beademing tijdens inspanning Beademing tijdens inspanning

ZuurstofZuurstof BeademingBeademing Dreher ERJ 2007;29:930

Swinburn, ARRD 1991;143:913

Zuurstof en dyspneu

Beademing en dyspneu

Dreher ERJ 2007;29:930

Duration of cycle endurance test

Dyspnoea end cycle endurance test

Chronic NIPPV in COPD

What is the rationale ?

• Sleep hypothesis

• Muscle resting hypothesis

• Hyperinflation hypothesis

Short term randomised controlled trials

Psych.Dysp.

12/4510.85Casanova2000

=10/2550.68Gay 1996

QOLGasex. Sleep

18/2560.86Meecham Jones 1995

Psych. 15/2490.54Strumpf 1991

EffectsBIpapPaCO2FEV1Study

Uncontrolled trials

BGA 12/48.10.90Jones

BGA 10/28.60.70Sivasothy

QOLBGA

18/27.80.86Perrin

BGA 15/280.53Elliot

EffectsBIpapPaCO2FEV1Study

Nocturnal hypoventilation

Meecham Jones et al.1995:152:538-544

Oxygen and dyspnoea

Dean ARRD 1992;146:941