Transcript Dia 1

RESCUE TRIAL
Dept. of Home mechanical ventilation
REspriratory Support in COPD
after acUte Exacerbation
10 december 2007
Marianne Zijnen-Jacqueline Rischen-Andre Kroos
Rationale
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chronic ventilatory support for
patients with neuromuscular
disease and kyphoscoliosis in the
Netherlands is routinely managed
by 4 home mechanical ventilation
(HMV) centres.
 no consensus yet how to treat
patients with COPD with chronic
respiratory failure after an acute
event
Objective
 to investigate if chronic nocturnal ventilatory support at home after
acute respiratory failure treated by ventilatory support either invasively
or non-invasively leads to
 a prolongation in time to readmission to hospital for an acute
exacerbation,
 improves quality of life,
 survival and cost-effectiveness in these patients compared to
medical treatment only.
Study design
 The protocol concerns a multi-centre, prospective, randomized,
controlled study.
Intervention
 It will take 2 years to include all 200 patients from which 100 will
receive non-invasive ventilatory support at night at home as well as
medical treatment,
 and 100 comprise the control group who will receive medical
treatment only, for the duration of 1 year.
Main study parameters/endpoints
 Primary study parameter: time to readmission.
 Secondary parameters; health related quality of life, readmission rate,
survival, medical costs, dyspnoea, ADL, exercise tolerance, blood
gasses, lung function, muscle strength, nutritional status.
Nature and extent of the burden and risks associated with
participation, benefit and group relatedness:
 A few studies, although somewhat limited in design, showed that NIV
reduced readmission rates and improved survival.
 Other important potential benefits that may be realized by study
participants include improved air exchange, a better quality of life, less
dyspnoea and an improved quality of sleep.
 Both patients and non participating subjects can benefit from this
study and its outcome, but it is also possible that subjects will not
receive any benefit from treatment.
 Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading
cause of death in the world, and further increases in its prevalence
and mortality can be predicted in the coming decades.
 A recent study showed that the prevalence of COPD in the
Netherlands from 1994 till 2015 will increase with 59% for men, while
for women the increase will be even higher (123%).3
 The impact of aging and smoking on the future burden of chronic obstructive
pulmonary disease: a model analysis in the Netherlands.
(Feenstra et al 2001)
 The costs of COPD are for over 55% driven by exacerbations, largely
due to hospital admissions.
International guidelines
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patients with COPD who are admitted to the hospital with an acute
respiratory failure due to an exacerbation should receive non invasive
ventilatory support (NIV) next to standard medical therapy.
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These guidelines are based on several randomised controlled trials
including a meta–analysis that showed that NIV improved survival
while it decreases the length of stay and the need for intubation.
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Lightowler JV, Wedzicha JA, Elliott MW et al. Non-invasive positive pressure ventilation to treat respiratory failure
resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and metaanalysis. BMJ 2003; 326: 185.
READMITTANCE AND DEATH
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Usually NIV can be stopped after some days as the clinical condition
of the patient improves.
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However, the literature shows that within 12 months after discharge
80% of the patients will be admitted again due to exacerbations,
while 50% will die in the same period as a result of respiratory failure.
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Chu CM, Chan VL, Lin AWN et al. Readmission rates and life threatening events in COPD survivors treated with
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non-invasive ventilation for acute hypercapnic respiratory failure. Thorax 2004; 59: 1020-1025
Exacerbation frequency and LF
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Percentage change in FEV1 with standard errors over 4 years. Open circles represent infrequent exacerbators; open
circles represent frequent exacerbators
(Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease
Thorax 2002)
Exacerbation frequency and QOL
 Exacerbation frequency close correlate of decreased QOL
Target in management COPD
 Readmittance and death
 Increase in prevalence
 Exacerbation and LF
 Exacerbation and QOL
 High healthcare costs
 TARGET: reducing exacerbations
The Question is
 whether continuation of NIV after acute (N)IV might be a novel
treatment that could possibly decrease the exacerbation frequency
and hospitalisations
NIPPV long term effects
 1) Resting dysfunctional respiratory muscles thereby increasing their
daytime strength and endurance;
 2) Improving peripheral muscle function from a better milieu (pH,
PaO2, PaCO2);
 3) Preventing the repeated nocturnal arousal’s thereby improving the
quality of sleep;
 4) Resetting of respiratory centre (drive).
 There are some theoretical reasons why chronic NIV in COPD might be effective:
 1) Resting dysfunctional respiratory muscles thereby increasing their daytime strength
and endurance;
 2) Improving peripheral muscle function from a better milieu (pH, PaO2, PaCO2);
 3) Preventing the repeated nocturnal arousal’s thereby improving the quality of sleep;
 4) Resetting of respiratory centre (drive).
 A study by Diaz et al13 showed an interesting outcome after NIV. The authors
conducted a randomised, placebo controlled study of the physiological effects of NIV in
COPD patients with stable hypercapnic respiratory failure. They found that after 3 hours
of BiPAP during daytime, NIV decreased the PaCO2 by lowering the level of
hyperinflation and PEEPi (intrinsic positive end-expiratory pressure).
 19 Nevertheless, until now there is no clear evidence that chronic NIV
is effective in COPD patients with stable respiratory failure.
unstable patients who survived acute respiratory
failure treated by ventilatory support
 Two studies are important in this respect. Firstly, an English study
investigated the impact of domiciliary NIV on the need for admission to
hospital and its attendant costs.20 Thirteen patients were identified
with recurrent acidotic exacerbations of COPD who tolerated and
responded well to NIV. Chronic NIV at home resulted in a saving of
11,720 Euro per patient per year. Total days in hospital fell from a
mean 78 days to 25 (p=0.004), and the number of admissions from a
mean of 5 to 2 days (p=0.007). They concluded that domiciliary NIV
for a highly selected group of COPD patients with recurrent
admissions requiring NIV was effective at reducing admissions and
minimises costs.
 The second study showed that NIV after acute respiratory failure could
even improve survival. This prospective randomised controlled trial
was conducted in 162 mechanically ventilated patients who tolerated
a spontaneous breathing trial after extubation.21 They were either
randomised for NIV for 24 hours or conventional management with
oxygen. Overall the 90-days survival did not change significantly
between groups. However, patients who were hypercapnic after the
spontaneous breathing trial showed a significant better survival in the
NIV group compared to medical treatment only. Fifty percent of this
group were patients with COPD.
Who: Patients with COPD who survived a period of acute respiratory failure in hospital
due to an exacerbation treated by ventilatory support both invasively or non-invasively
Inclusion patients + informed consent
When: Between 48 hours after
ending ventilatory support and
discharge
Randomisation
Control group
Treatment group
Standard medical care in hospital
Standard medical care +
Initiation of NIPPV in hospital
Standard medical care at home
NIPPV at home
Questionnaires and tests at baseline, 3, 6 and 12 months
 Multicentre trial
 Prospective, randomized, controlled
 3 home ventilation centres
 Nurse consultants
 200 patients
STUDY POPULATION
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Population (base)
The study will be done in patients with Chronic Obstructive
Pulmonary Disease (COPD) who remain hypercapnic after an
exacerbation with acute respiratory failure treated in hospital by
ventilatory support either invasively or non-invasively.
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Inclusion criteria
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1) Chronic Obstructive pulmonary disease (COPD),
GOLD severity stage 3 and 4.
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2) Minimally 48 hours without ventilatory support after invasive or non
invasive ventilatory support during an acute respiratory failure and
maximally until discharge.
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3) Persistent hypercapnia (PaCO2 > 6.0 kPa) during daytime at rest
without ventilatory support.
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Exclusion criteria
1) Age < 18 or =>75 years;
2) Significant bronchiectasis with recurrent infections;
3) Significant heart failure;
4) Kyphoscoliosis;
5) Neuromuscular disease;
6) Obstructive sleep apnea (Apnea Hypopnea Index: AHI >15 /hr);
7) Current use of Continuous Positive Airway Pressure (CPAP) or
Bilevel Positive Airway Pressure (BiPAP);
8) Insufficient motivation for chronic ventilatory support;
9) Social circumstances making chronic ventilatory support impossible;
10) Other disease factors limiting life expectations
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Main study parameter/endpoint
Time to event is the primary study outcome, for which an event is
defined as a readmission to hospital due to an exacerbation or death.
An exacerbation is defined using a modified version of the definition
of Rodriguez-Roisin, as an event in the natural course of the disease
defined as characterized by a change in the patient’s baseline
dyspnoea, cough, and/or sputum that is beyond day-to-day
variations, is acute in onset, and which is treated with an antibiotics
course and/or prednisolon in patients with underlying COPD. 23, 24
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Secondary study parameters/endpoints
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- Exacerbations
- Health related quality of life
- Total readmission rate
- Total event rate
- Survival
- Medical costs
- Dyspnoea
- Activities of daily living
- Exercise tolerance
- Blood gasses PaO2 and PaCo2
- Lung function
- Inflammation (systemic) markers*
- Muscle strength*
- Nutritional status*
* if possible in specialised centres
 Randomisation for:
 FEV1 ( 0.8 L or > 0.8 L)
 PaCO2 (  7.0 kPa or > 7.0 kPa)
 BMI ( 30 kg/m² or > 30 kg/m²)
 Ventilatory support (invasive or non-invasive)
 Rehabilitation programme (yes/no)
Study procedures
 Exacerbations
 Health related quality of life
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Survival
Medical Costs
Dyspnoea
ADL
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Exercise tolerance
Blood gasses PaO2 and PaCO2
Lung function
BODE-index
MWD
Diary
MRF-28, CRQ, CCQ,
SRI
Cost diary
MRC dyspnoea scale
GARS &
pedometer
6-MWD
Arterial puncture
FEV1 & IVC
BMI, FEV1,
Dyspnoea & 6-