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Trial registered on ANZCTR


Registration number
ACTRN12612000038897
Ethics application status
Approved
Date submitted
22/11/2011
Date registered
9/01/2012
Date last updated
25/01/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
Inhaled Prophylactic Heparin in Ventilator Associated Pneumonia Prevention (IPHIVAP)
Scientific title
Inhaled Prophylactic Heparin in Ventilator Associated Pneumonia Prevention- A randomised controlled trial of nebulised unfractionated heparin versus saline or usual care to prevent the development of VAP in invasively ventilated patients
Secondary ID [1] 273449 0
NIL
Universal Trial Number (UTN)
U1111-1125-9815
Trial acronym
IPHIVAP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ventilator Associated Pneumonia 279221 0
Condition category
Condition code
Respiratory 279424 279424 0 0
Other respiratory disorders / diseases
Infection 279428 279428 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ARM 1:(a) Intervention group - nebulised unfractionated sodium heparin ( 2 mls, 5000 U) every 6 hours
ARM 2:(b) Placebo group 1 (2 mls of Sodium Chloride0.9%) every 6 hours or usual practice of nebulised bronchodilators for clinical indication only
ARM 3:(c) Placebo group 2 Usual care-unblinded– no active nebulized treatment with saline unless deemed clinically necessary by the treating clinician

In both arm 1 and 2 the patients will receive the study drug until the patient has been extubated for more than 48 hrs and the clinician is confident that the patient is pneumonia free and reintubation is unlikely or if the patient is extubated and discharged within the 48hrs.
Intervention code [1] 283766 0
Prevention
Intervention code [2] 283776 0
Treatment: Drugs
Comparator / control treatment
Placebo and standard care
Control group
Active

Outcomes
Primary outcome [1] 285996 0
Nebulised heparin used as a prophylactic agent is associated with an absolute risk reduction of 6 % in the incidence of ventilator associated pneumonia.
VAP and time to VAP

1.Patients will be screened daily using the Modified Centre for Disease Control criteria for VAP after Klompas.

Bronchoscopy and bronchoalveolar lavage will be performed where possible upon the suspicion of VAP and quantitative cultures performed using standard laboratory measures.
Semiquantitative endotracheal aspirate culture or bronchial washing will be performed as the routine microbiological culture method.

2. Clinical Pulmonary Infection Score at time of clinical diagnosis of and for 48 hours prior to the onset of VAP. For the purposes of the study possible VAP will be a CPIS > 6 without modified CDC criteria for VAP.

The final determination of definite or probable VAP will be made by an independent panel not directly associated with patient care.

Polymicrobial episodes of VAP were considered to be due to the microorganisms with the highest yield.
90-100 episodes of VAP are expected during this study in a total of 831 914 enrolled patients. To assess the performance of the modified CDC criteria of Klompas for this study a random selection of 20 patients with VAP will be chosen at the time of clinical diagnosis to have a bronchoscopic BAL performed to assess sensitivity and specificity of the diagnostic algorithm. This proportion is consistent with current unit practices.
Timepoint [1] 285996 0
2 years
Secondary outcome [1] 294918 0
Nebulised heparin used as a prophylactic agent is associated with a absolute risk reduction of 50% in the incidence of airway colonization by Gram negative enteric bacteria

1.Pneumonia Progress

(a)SOFA score at the time of diagnosis
(b)Daily SOFA score until the time of resolution of VAP
(c)Daily maximal and minimal temperature, blood white cell count , PaO2/FiO2 until resolution of pneumonia
(d)Bacterial isolates from endotracheal aspirates /bronchoalveolar lavage
(e)Appropriate antimicrobial therapy

Appropriate antibiotic therapy was defined as the use of least one antibiotic to which the microorganisms thought to be aetiologic for VAP being sensitive on in vitro testing using breakpoints in the local laboratory

2. Resolution of Pneumonia
I Clinical Responses:

1. Clinical resolution of pneumonia breakpoints were defined as the first day after VAP diagnosis when at least two of the following factors returned to within the defined parameters
(a)Highest daily temperature >38oC
(b)Peripheral blood white cell count < 10,000 X 109/l
(c)PaO2/FiO2 > 250 despite the presence or absence of ARDS
(d)Clearance of purulent secretions on endotracheal suctioning as assessed by nursing staff
(e)>1 in 6 infiltrates on CXR

Failure to improve is defined as lack of improvement in at least two of these parameters after 48 hours of appropriate antibiotic therapy
2.Cure
(a)Completion of treatment
(b)Not requiring further bacterial treatment to treat this episode of VAP
(c)Improved or lack of progression on CXR
(d)Recovery from acute infection

3.Failure
(a)Patient did not respond during treatment and required additional antibiotic therapy
(b)Initial recovery but later deterioration requiring additional antibiotic therapy
(c)Died because of pneumonia

4. Indeterminate
(a)Patient failed to have an outcome determination or
(b)Withdrew from treatment less than 48 hours after initiation of therapy
(c)Received concomitant antibiotics for reasons other than failure or
(d)Died during therapy for infectious related reasons

II Microbiological Responses

1.Eradication
(a)No pathogens present in repeat lower respiratory tract culture or
(b)Patient's clinical outcome of cure precluded availability of a specimen for culture

2.Persistence
(a)Baseline pathogen present in repeat lower respiratory culture after course of treatment with appropriate antibiotic completed or
(b)Patient received antibiotics for more than 21 days to treat lung infection

3.Development of pneumonia recurrence

(a)Baseline pathogen was absent from repeat lower respiratory tract culture but reappeared during follow-up along with signs and symptoms of pneumonia (CPIS > 6)

4. Indeterminate
(a)Patient's received other antibiotics for reasons other than failure
(b)Failed to have an outcome determination or
(c)Withdrew from therapy less than 48 hours after commencement of treatment
(d)Died during therapy from infectious related reasons

5. Development of superinfection
(a)New pathogen(s) emerged during treatment requiring additional antibiotic therapy and
(b)Clinical and laboratory evidence showing emergence or exacerbation of infection

From the day of diagnosis of VAP, second daily endotracheal aspirates (Monday, Wednesday, Friday) will be submitted for semiquantitative culture for 10 days or until the patient is not ventilated using an artificial airway.
Timepoint [1] 294918 0
2 years
Secondary outcome [2] 294919 0
Nebulised heparin is associated with faster resolution of VAP
I Clinical Responses:

1. Clinical resolution of pneumonia breakpoints were defined as the first day after VAP diagnosis when at least two of the following factors returned to within the defined parameters
(a)Highest daily temperature > 38oC
(b)Peripheral blood white cell count < 10,000 X 109/l
(c)PaO2/FiO2 > 250 despite the presence or absence of ARDS
(d)Clearance of purulent secretions on endotracheal suctioning as assessed by nursing staff
(e)> 1 in 6 infiltrates on CXR

Failure to improve is defined as lack of improvement in at least two of these parameters after 48 hours of appropriate antibiotic therapy
2.Cure
(a)Completion of treatment
(b)Not requiring further bacterial treatment to treat this episode of VAP
(c)Improved or lack of progression on CXR
(d)Recovery from acute infection

3.Failure
(a)Patient did not respond during treatment and required additional antibiotic therapy
(b)Initial recovery but later deterioration requiring additional antibiotic therapy
(c)Died because of pneumonia

4. Indeterminate
(a)Patient failed to have an outcome determination or
(b)Withdrew from treatment less than 48 hours after initiation of therapy
(c)Received concomitant antibiotics for reasons other than failure or
(d)Died during therapy for infectious related reasons
Timepoint [2] 294919 0
2 years

Eligibility
Key inclusion criteria
Non-invasively mechanically ventilated for < 24hours prior to intubation
No previous mechanical ventilation
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Pregancy
2.Aged less than 18 years of age
3.Patients with previous known sensitivity to heparin (any formulation or route) including heparin induced thrombocytopenia
4.Any contraindication to routine prophylaxis for deep vein thrombosis using subcutaneous heparin
5.Presence of a coagulopathy including platelet dysfunction thought to be of clinical significance of any type on admission considered to be a contraindication to routine prophylaxis for deep vein thrombosis using subcutaneous heparin
6.Patients receiving any other type of systemic full anticoagulation
7.Patients transferred from another intensive care unit with more than 48 hours of mechanical ventilation before entering into the present study.

Patients receiving routine subcutaneous thromboembolism prophylaxis (= 15,000/units day) or heparin as part of continuous dialysis therapy where systemic anticoagulation is not required are suitable for inclusion but enrolled patients must be withdrawn from the study upon the need for systemic full anticoagulation or bleeding considered due to the effects of the inhaled heparin by the treating consultant.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The treatment groups apart from the “standardl care” control group will remain blinded to the treating clinicians. The clinical trial assistant (research pharmacist) in each site will be unblinded for the preparation of the daily treatments.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A permuted block method will be used to define the three treatment groups stratified by study centre. The notification of the randomisation sequence will be controlled by a secure website for allocation to the treatment groups upon patient enrolment
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 4748 0
4029

Funding & Sponsors
Funding source category [1] 284243 0
Charities/Societies/Foundations
Name [1] 284243 0
Royal Brisbane and Women's Hospital Foundation
Address [1] 284243 0
Royal Brisbane and Women's Hospital
Butterfield Street
HERSTON QLD 4029
Country [1] 284243 0
Australia
Funding source category [2] 284253 0
Charities/Societies/Foundations
Name [2] 284253 0
Intensive care foundation
Address [2] 284253 0
Level 2, 10 levers Terrace
Carlton, Victoria, 3053
Country [2] 284253 0
Australia
Primary sponsor type
Individual
Name
A/Prof Robert Boots
Address
ICU Admin Offices
Level 3
Ned Hanlon Building
Royal Brisbane and Women's Hospital
Butterfield Street
HERSTON QLD 4029
Country
Australia
Secondary sponsor category [1] 269198 0
None
Name [1] 269198 0
Address [1] 269198 0
Country [1] 269198 0

Ethics approval
Ethics application status
Approved

Summary
Brief summary
Patients who are in intensive care may need to have their breathing assisted by a ventilator. Although all care is taken,pneumonia develops in 12% of patients on ventilators. This is because tubes connecting patients to the ventilator impair the lungs normal defenses against infection and causes inflammation in the airways. Inhaled heparin may assist to reduce this risk. Heparin has been used in patients with airway burns and has shown to decrease the inlammation and promote healing. This study will attempt to determine if giving inhaled heparin to patients needing mechanical ventilation will reduce their chances of developing pneumonial
Trial website
NIL
Trial related presentations / publications
NIL
Public notes

Contacts
Principal investigator
Name 33421 0
Address 33421 0
Country 33421 0
Phone 33421 0
Fax 33421 0
Email 33421 0
Contact person for public queries
Name 16668 0
A/Prof Robert Boots
Address 16668 0
Department of Intensive Care Medicine Admin offices
Level 3 Ned Hanlon Building
Royal Brisbane and Women's hospital
Butterfield Street
HERSTON QLD 4029
Country 16668 0
Australia
Phone 16668 0
+61 7 36368111
Fax 16668 0
Email 16668 0
Robert_Boots@health.qld.gov.au
Contact person for scientific queries
Name 7596 0
A/Prof Robert Boots
Address 7596 0
Department of Intensive Care Medicine Admin offices
Level 3 Ned Hanlon Building
Royal Brisbane and Women's hospital
Butterfield Street
HERSTON QLD 4029
Country 7596 0
Australia
Phone 7596 0
+61 7 36368111
Fax 7596 0
Email 7596 0
robert_boots@health.qld.gov.au

No information has been provided regarding IPD availability
Summary results
No Results