Partial Liquid Ventilation in ARDS
Abstract & Commentary
By David J. Pierson, MD, Editor, Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, is Editor for Critical Care Alert.
Synopsis: In this large-scale randomized clinical trial in adult patients with ARDS, partial liquid ventilation using two different strategies for administration resulted in a greater number of serious adverse outcomes and did not improve survival compared to conventional ventilatory support.
Source: Kacmarek RM, et al. Partial liquid ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2006;173:882-889.
Partial Liquid Ventilation (PLV) with Perfluorocarbon (PFC) has been demonstrated in animal models of acute lung injury to recruit dependent lung regions (the so-called "liquid PEEP" effect), to redistribute blood flow to better ventilated regions, to thus improve gas exchange compared with conventional ventilation, and also to facilitate the clearance of retained secretions. Further, preliminary studies demonstrated the clinical feasibility of PLV in humans, and post-hoc analysis of data from a phase II trial1 suggested that mortality might be reduced and other outcomes improved with the use of PLV in patients with ARDS. Accordingly, the authors of this paper designed a large-scale, multi-center clinical trial of PLV—administered according to 2 different dosing strategies—compared to conventional ventilatory support in adult patients with the acute respiratory distress syndrome (ARDS).
At 56 centers throughout the United States and in 6 other countries, investigators recruited patients between the ages of 16 and 65 who had a known ARDS risk factor, bilateral radiographic infiltrates, and a PaO2/FIO2 of 300 mm Hg or less on an FIO2 of 0.5 or more with positive end-expiratory pressure (PEEP) at least 13 cm H2O. A relatively homogeneous population of patients with predominantly single-organ failure was sought via an extensive list of 28 exclusion criteria. The primary outcome was 28-day ventilator-free days; secondary outcomes were mortality, time to unassisted ventilation, percentage of patients alive and off ventilation at day 28 after randomization, and rate of ARDS resolution. Patients were randomized to conventional ventilation, low-dose PFC (10 mL/kg predicted body weight, PBW), or high-dose PFC (20 mL/kg PBW). A carefully controlled protocol governed the instillation and monitoring of PFC administration in the two treatment groups. All patients received PLV for at least 48 hours, and administration of PFC could continue for up to another 72 hours if the FIO2 remained greater than 0.5.
Out of 3,817 patients screened for enrollment in the study, 311 were randomized to the 3 management groups. Ventilator-free days 28 days after randomization were 13.0 ± 9.3 in the conventional ventilation group, 7.4 ± 8.5 in the low-dose PLV group (P < 0.001), and 9.9 ± 9.1 in the high-dose PLV group (P = 0.043). The 28-day mortality in the 3 groups was 15%, 26%, and 19%, respectively (differences not statistically significant). There were more instances of pneumothorax, hypotension, and hypoxia in the PLV patients. The authors conclude that PLV at both the low- and high doses used in this study did not improve outcomes, and was associated with greater numbers of serious adverse outcomes compared to conventional mechanical ventilation, and that this approach to management is not indicated in adults with ARDS.
This was a carefully done study, as very thoroughly documented in this paper. The protocol was complicated, and many aspects of the use of PLV and the assessment of the patients had to be chosen more or less arbitrarily. The patients were enrolled between 1998 and 2000, prior to the publication of the ARDS Net low-tidal-volume study.2 The tidal volumes (mean, 9 mL/kg PBW) and end-inspiratory plateau pressures (mean, 30-32 cm H2O) were higher than used by the ARDS Net, and the levels of PEEP employed were high. However, the 3 treatment groups were very well matched, and it is unlikely that these deviations from what is now standard practice in most centers affected the results.
As in most other negative randomized controlled trials involving interventions with positive effects in preliminary reports, the authors assert that PLV may yet prove useful and postulate a number of reasons why benefit that truly exists could not be demonstrated in the present trial. They cite aspects of the PFC administration and monitoring that might be improved, and ways in which patient selection and ventilator management in this trial could have affected the results. They caution that "it is still unclear how to optimally dose PFCs and adjust ventilator settings in patients receiving PLV. Therefore, the overall role, if any, of PFCs in ventilator management of ARDS remains to be determined despite this negative study."
Low-tidal-volume, low-plateau-pressure ventilation saves lives in patients with ARDS,2,3 but the search continues for another specific intervention that does so. Put another way, although alternative ventilatory approaches such as HFOV, and management adjuncts such as surfactant, nitric oxide, and prone positioning have been the subjects of enthusiastic initial reports and continue to have strong advocates, none has been shown in a randomized controlled trial to improve outcomes in unselected patients with ARDS. We can now add PLV to that list, but with one important difference: its lack of availability to clinicians. Unlike the situation with prone positioning, inhaled nitric oxide, and HFOV, with PLV physicians will not have the dilemma of whether to try an unproven but still-advocated and readily available intervention in managing their patients with severe ARDS.
- Hirschl RB, et al. Prospective, randomized controlled pilot study of partial liquid ventilation in adult acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;165:781-787.
- Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301-1308.
- Amato MB, et al. Effects of protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338:347-354.