The effect of inhaled heparin on pulmonary coagulation activation and vascular permeability in mechanically ventilated patients with acute lung injury / acute respiratory disress syndrome

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are
potentially lethal conditions, responsible for a considerable amount of
admissions to the Intensive Care Unit (ICU) and for which, at present, only
supportive care is available.

Pulmonary edema, as a result of increased pulmonary vascular permeability
caused by proinflammatory changes, together with pulmonary coagulopathy,
resulting in alveolar fibrin deposition and disturbed fibrin turnover, are the
hallmarks of ALI/ARDS. The alveolar fibrin deposition is in part comparable to
the intravascular deposition of fibrin in patients with sepsis and disseminated
intravascular coagulation and may be aggravated by mechanical ventilation.
Based on a substantial body of evidence, both in vitro and in vivo, there is
rationale to intervene in the pulmonary coagulopathy with anticoagulants in
general, and with heparin in particular, in order to attenuate lung injury.
Delivering heparin directly into the pulmonary compartment may attenuate fibrin
depositions more effectively than systemic administration of heparin, while
reducing the risk of bleeding as a result of systemic anticoagulant effects. In
sheep, nebulization of heparin has been found to be beneficial. Furthermore,
the nebulization of heparin to the lower respiratory tract is feasible and
safe. In pediatric patients with inhalation injuries, heparin nebulization
significantly reduced mortality.

With a bedside radionuclide method the pulmonary leak index (PLI) can be
obtained as a measure of vascular leakage. The PLI is an ideal instrument to
measure effects of therapy on pulmonary vascular leakage, since serial
measurements can be performed.

Hence, nebulization of heparin may have a beneficial effect on pulmonary
coagulopathy and may subsequently decrease pulmonary vascular permeability.

Objectives
1. to determine whether nebulization of heparin decreases coagulation
activation in the pulmonary compartment (i.e. BAL fluid)
2. to determine whether nebulization of heparin decreases pulmonary vascular
permeability

This study will be an open label, placebo controlled, randomized, clinical
trial in which patients will be treated with either unfractionated heparin, or
placebo (i.e. sodium chloride 0.9%). It will be conducted in the
medical-surgical intensive care units of two academic hospitals.

Patients will receive 4 nebulizations of either 4 mL unfractionated heparin (ie
100,000 IU) or 4 mL placebo (ie 0.9% NaCl) depending on randomisation, in a
timeframe of 24 hours.

Both bronchoscopies will be performed when the patients is sedated. In a well
monitored environment such as an Intensive Care Unit, the risk is considered to
be very low.
The radiation from the isotopes used in the radionuclide-techique to obtain the
PLI is well within all safetylimits.
Bloodsampling will be performed with an intra-arterial catheter that is already
in situ in Intensive Care patients. Venous punctures will not be necessary.