Background
• Commissioned call NIHR HTA
• Objective: To determine if invasive ventilation
using protocolised weaning that includes noninvasive ventilation (NIV) as an intermediate
step is clinically and cost effective compared
to protocolised weaning without NIV
Study summary
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Design: Pragmatic, open label, RCT
Population: Adults, ventilated > 48 hr, fail SBT
Intervention: Weaning using NIV
Comparator: Protocolised invasive weaning
Outcome: Time to liberation from ventilation
Sample size: 920 over 30 months
Study Timeline
2013
Timeline 1 2 3 4 5 6 7
2014
2015
2016
8 9 10 11 12 13 14 15 16 23 24 25 26 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr Nov Dec Jan Feb Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
NOTES:
48 Months (4 years)
TASK:
Trial Set Up
Site Set Up
Patient Recruitment
3 Month Follow-up
6 Month Follow-Up
Data Analysis
Reporting
Recruitment Plan
Target for sites 1.5 patients per month
Outcomes
Primary clinical outcome:
Time from randomisation to liberation from
ventilation
Secondary clinical outcomes
• 30, 90 and 180 day all cause mortality
• Duration of invasive mechanical ventilation and total
ventilator days
• Time to meeting ICU discharge criteria
• Hospital length of stay
• Antibiotic use
• Re-intubation, tracheostomy; adverse events
• Health related quality of life
Inclusion criteria
• Is the patient age 16 years or older?
• Has the patient received invasive mechanical
ventilation for respiratory failure for greater than 48
hours?
• Is the patient ready for weaning?
Exclusion criteria
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Patient known to be pregnant
Presence of tracheostomy
Profound neurological deficit
Any absolute contraindication to NIV
Home ventilation prior to ICU admission
Decision not to re-intubate / withdrawal
Further surgery / procedure requiring sedation planned in
next 48 hours
• Previous participation in the Breathe study
Daily Screening
All ventilated patients will be assessed each morning for eligibility by ICU
nursing / medical staff. Patients will be identified as potentially eligible if
they fulfil the following criteria:
• anticipated or actual requirement for invasive ventilation for > 24
hours
• at least partial reversal of the condition precipitating invasive
ventilation
• stabilisation of "other" organ system failures (i.e. no worsening)
• arterial oxygen saturation measured using pulse oximetry (SpO2) ≥
90% with fractional concentration inspired oxygen (FiO2) ≤ 0.70
• PEEP ≤ 10 cmH2O
• the absence of trial exclusion criteria (above)
A screening log will be maintained at each site which will include the
reasons for non-enrolment.
Daily screening for eligibility and
assess for readiness to wean
Obtain
consent
Record baseline characteristics
Spontaneous Breathing Trial
PASS
Excluded
FAIL
RANDOMISE
Protocolised
NIV
weaning arm
Protocolised
Invasive
weaning arm
CONSENT PROCESS
Approach patient
Patient agrees OR
unable to indicate
preference
Personal Consultee /
NOK
If unavailable
Retrospective
consent
Registered Medical
Practitioner*
* England, Wales, NI
Readiness to wean
Cooperative and pain free
Good cough
PaO2 : FiO2 ratio >24 kPa
PEEP <10 cmH2O
Hb >7 g dL-1
Temperature 36 - 38.5°C
Vasoactive drugs stable
Spont respiratory rate >6 min-1
Walsh BJA 2004
Record baseline characteristics
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Exhaled minute volume
Total respiratory rate
PEEP
Plateau pressure
Heart rate
Systolic blood pressure
Arterial blood gases
SBT
To be performed in accordance with local unit practices
30 mins duration
• T-piece
• Psupp 5cm H2O
• CPAP
Pass – Extubate
Fail - Randomise
Ely N Engl J Med 1996
Standardised protocols
• Ventilator care bundle
– head up position; oral decontamination;
sedation hold; peptic ulcer prophylaxis
• Tracheostomy
– More than 7 days IMV; inability to protect
airway; persistent inability to remove
respiratory secretions
• Re-intubation
– Protocolised and clinical endpoints
Data collection
Baseline variables
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Patient identifiers
Inclusion and exclusion criteria
APACHE II (at admission)
Admission diagnosis
Presence of COPD
Height and weight
Duration of ventilation prior to randomisation
CAM-ICU
Daily data
• Ventilation status
• Adverse events
(IMV, NIV, self• Sedation usage
ventilating)
• Weaning and
• Organ support
ventilator bundle
requirements
compliance
• Level of critical care
• Antibiotic use for
respiratory and nonrespiratory infection
Study endpoints
Endpoints
• Liberation from ventilation
– Add definition from CRF
• Death
• Tracheostomy
• Re-intubation
– Actual
– Protocolised
• ICU discharge data
Discontinuation of intervention
• NIV arm – re-intubation
• IPPV arm – tracheostomy
• Withdrawal of consent
• Need to continue data
collection after
discontinuation of
intervention until ICU /
hospital discharge
After discharge
Before hospital discharge
After hospital discharge
(on site)
(WCTU)
• Consent
• Antibiotic use if
started within ICU
• Acute hospital
discharge date and
status
• HRQoL
• Survival to 180 days
• EQ-5D and SF-12
• Healthcare resource
use questionnaire
Serious Adverse Events
A serious adverse event is an AE that fulfils one or more of the
following criteria:
• Results in death
• Is immediately life-threatening
• Requires hospitalisation or prolongation of existing
hospitalisation
• Results in persistent or significant disability or incapacity
• Is a congenital abnormality or birth defect
• Is an important medical condition.
The causality of SAEs (i.e. relationship to trial treatment) will be
assessed by the investigator(s) and recorded on the SAE form.
**Do not report death, pneumonia, organ failure as SAE**
Safety Reporting
All suspected SAE’s report to Warwick Clinical
Trials Unit within 24 hours
(Tel: 02476 575849 Fax: 02476 150549)
Patient Follow-up
Health-related quality of life: EQ-5D, SF12 at
baseline (estimated)
Patient follow-up: 3 and 6 months EQ-5D and
SF12
Study team
Chief Investigator:
Project Manager:
Trial Coordinator:
Trainee Trial Coordinator:
Research Facilitator:
Research Nurse:
Prof Gavin Perkins
Sarah Duggan
Bev Hoddell
Jess Smith
Laura Blair
Vikki Gordon
Pilot Study Sites
Hospital
HEFT – Heartlands
UHCW
Guys & St Thomas’
QEHB
Bristol RI
RVH Belfast
JR Oxford
PI
Prof Fang Gao-Smith
Chris Bassford
Nick Hart & Luigi Camporota
Catherine Snelson
Tim Gould & Sanjoy Shah
Danny McAuley
Duncan Young
Research Nurse
Peter Sutton
Marie McCauley
Katie Lei/John Smith
Arlo Whitehouse
Katie Sweet
Questions?
Contact: Bev Hoddell, Trial Coordinator. Tel No: 02476-575849 Email: b.hoddell@warwick.ac.uk
Address: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL