IPHIVAP

Is inhaled prophylactic heparin useful for prevention and management of pneumonia in ventilated ICU patients?

Bandeshe. J Crit Care 2016; 34:95-102. doi:10.1016/j.jcrc.2016.04.005

Clinical Question

  • In adult mechanically ventilated patients, does inhaled heparin compared to inhaled saline or usual care reduce the incidence of ventilator acquired pneumonia (VAP)?

Design

  • Feasibility phase 2b study
  • Multi-centre
  • Randomised, controlled trial
  • Double-blind design (treating physicians and patients)
  • concealed allocation by off-site computer randomisation
  • Permuted block stratification according to study centre and surgical/non-surgical patient status
  • Powered at 80% to detect reduction in VAP from expected baseline of 12% to 6%, with statistical significant set at 0.05, if 914 patients recruited
  • Trial terminated due to futility after reviewing baseline VAP incidence and a revised power calculation
  • Intention to treat analysis

Setting

  • Number of centres and location not specified
  • “…the majority of patients were recruited from a single center”
  • April 2011 to December 2013

Population

  • Inclusion: Adult patients over 18 years old; under 24 hours invasive mechanical ventilation; likely to require at least a further 48 hours of mechanical ventilation
  • Exclusion: pregnancy; treatment limitations defined; contraindications to heparin; systemic anticoagulation administration; previous enrolment
    • Routine heparin for thromboembolism prevention and renal replacement therapy was allowed
  • 2103 screened; 214 randomised; none lost to follow-up
  • Baseline characteristics
    • Mean age: 56 years
    • Mean APACHE II score: 18.9
    • Mean SOFA score: 6
    • Gender: 66% male
    • Pneumonia diagnosis on admission: 42%
    • Non-surgical admission: 64%

Intervention

  • Heparin group
    • Nebulised unfractionated heparin 5000 units
    • Made up to 2 ml with 0.9% saline
    • administered every 6 hours

Control

  • Saline group
    • 0.9% sodium chloride 2 ml
    • Administered every 6 hours
  • Usual Care group
    • No nebulised heparin or saline
    • Allocation to this group was not ‘blinded’ to the clinical staff

Management common to all groups

  • Study drug administered regularly until no longer mechanically ventilated for more than 48 hours or discharge from ICU
  • If re-intubated for further mechanical ventilation, the study drug was administered according to the patient’s previous allocation
  • Humidification and all non-saline/heparin nebulised therapies were allowed
  • Pneumonia was treated according to standard recommendations, with at least 5 days antibiotics

Outcome

  • Primary outcome: No difference in the incidence of VAP
    • Clinical diagnosis: heparin group 28% vs saline group 24% vs usual care group 26%; P=0.85
    • Klompas criteria: heparin group 7% vs saline group 6% vs usual care group 7%; P=1.0
  • Secondary outcome: No significant differences found (heparin vs saline vs usual care)
    • Time to VAP: 7 days vs 7.5 days vs 8 days; P=0.35
    • Ventilator associated complications: 29% vs 15% vs 18%; P=0.59
    • Adverse events: 7% vs 6% vs 1%; P=0.27

Authors’ Conclusions

  • Nebulised 5000 units of unfractionated heparin given four times a day is not recommended for the prophylaxis of ventilator associated pneumonia.

Strengths

  • Good study methodology so no significant biases likely and probably good accuracy of results (internal validity)
    • Appropriate randomisation method and concealment
    • Blinded treatment and additional ‘usual care’ group to remove possible influence of nebulised saline
    • No patients lost to follow-up
    • Objective definition for primary outcome
  • Broad inclusion criteria so good external validity and generalisability

Weaknesses

  • Under-powered to firmly conclude that heparin has no effect
    • Point effect of Absolute Risk Reduction (ARR) for heparin group vs all control group is 0.75% (95% CI -6.41% to 7.91%)
    • Authors point out that, if this point effect is accurate and baseline is 6%, a trial with 22,000 patients is required to provide sufficient power for firm conclusion!
    • Although probably clinically negligible, this IPHIVAP trial cannot rule out heparin being beneficial (up to ARR 7.9%) or harmful (up to ARI 6.4%)
  • With 90% excluded after screening and majority recruited from single centre, some may argue that results are not generalisable

The Bottom Line

  • Nebulised heparin is probably ineffective, or the effect is clinically negligible, therefore I shall not be administering this to my patients to prevent ventilator associated pneumonia

External Links

Metadata

Summary author: Duncan Chambler
Summary date: 9 February 2017
Peer-review editor: Steve Mathieu

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