Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial

Abstract

Introduction: Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation.

Methods: Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization.

Results: Nebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events.

Conclusions: Nebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings.

Trial registration: The Australian Clinical Trials Registry (ACTR-12608000121369).

Figures

Figure 1

Enrollment and outcomes.

Figure 2

Respiratory values over the first 7 days of the study. There were no significant differences between groups in the average daily levels of the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2), predicted body weight (PBW), peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), partial pressure of arterial carbon dioxide (PaCO2), or minute ventilation over the course of the study period (days on which the patient remained mechanical ventilation to a maximum of 14 days from randomization). The numbers of patients who were mechanically ventilated are as follows: day 0 placebo (25) and heparin (25), day 1 placebo (24) and heparin (25), day 3 placebo (21) and heparin (15), day 5 placebo (19) and heparin (11), and day 7 placebo (13) and heparin (7). Graphs represent mean ± standard error of the mean.

Figure 3

Rate of freedom from mechanical ventilation. Over the first 28 days among surviving patients, the rate of freedom from mechanical ventilation was higher in patients administered heparin. Median times of ventilation were 5 days in the heparin group (n = 20) and 8 days in the placebo group (n = 21) (P = 0.01) (log-rank test).

Figure 4

Forest plot of the treatment effect of nebulized heparin on ventilator-free days among survivors at day 28 by baseline characteristics. The microbiological tests included culture of pulmonary lavage fluid and polymerase chain reaction for H1NI. CI, confidence interval.