Should We Use Nitric Oxide with High-Frequency Oscillatory Ventilation in ARDS? 

Abstract & Commentary

The objective of this study was to prospectively evaluate the oxygenation effect of inhaled nitric oxide (iNO) delivered during high-frequency oscillatory ventilation (HFOV) in patients with the acute respiratory distress syndrome (ARDS). It was a prospective observational study that enrolled 23 adult patients with ARDS who required more than 60% oxygen and had mean airway pressures of > 28 cm H2O. Inhaled nitric oxide was initiated at a dose of 5 ppm and subsequently titrated to determine the dose (5, 10, or 20 ppm) resulting in the greatest increase in arterial oxygenation, as measured by PaO2/FIO2 ratio. Arterial blood gas measurements were obtained 10-15 min after initiation or any increase in iNO dosage to assess the effect on PaO2/FIO2. Arterial blood gases and ventilator settings were recorded at 4 time points: conventional ventilation just before initiating HFOV, HFOV just before initiating iNO therapy, 30 min after the optimal dose of iNO, and 8-12 h after starting iNO. Oxygenation index and PaO2/FIO2 were calculated at the same time intervals.

At 30 min after iNO initiation, 19 (83%) of the patients had a significant increase in arterial oxygenation, as defined by > 20% increase in PaO2/FIO2. The mean change in PaO2/FIO2 at 30 min was 38%. In these 19 patients, PaO2/FIO2 was highest at 20 ppm iNO in 4 patients, at 10 ppm in 8 patients, and at 5 ppm in 7 patients. Compared with baseline measurements, PaO2/FIO2 improved significantly at both 30 min (112 ± 59 vs 75 ± 32 mm Hg; P = 0.01) and 8-12 h after initiation of nitric oxide therapy (146 ± 52 vs 75 ± 32 mm Hg; P < 0.0001). In addition, oxygenation index ([FIO2 × mean airway pressure × 100]/PaO2) was reduced at 8-12 h compared with baseline measurements (26 ± 13 vs 40 ± 17; P = 0.08). Mehta and colleagues concluded that iNO delivered at doses of 5-20 ppm during HFOV increases PaO2/FIO2 and may be a safe and effective rescue therapy for patients with severe oxygenation failure (Mehta S, et al. Acute oxygenation response to inhaled nitric oxide when combined with high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care Med. 2003;31:383-389.)

Comment by Dean R. Hess, PhD, RRT

It is well known that iNO produces an improvement in PaO2 (albeit short-lived) in many patients with ARDS.1 It is likewise known that HFOV can similarly improve PaO2 in some patients with ARDS.2-4 Moreover, it has been shown in infants that the combination of iNO and HFOV improves oxygenation more than either therapy used alone.5 Accordingly, the results of this study are not entirely surprising. However, this study falls short of convincing me to adopt this therapy into my practice. I don’t believe that this study provides convincing evidence that every ICU must have available iNO and a high-frequency oscillatory ventilator to treat their patients with severe ARDS.

There are several significant methodologic problems with this study. First of all, the patients were not randomized. Placebo-controlled, randomized-controlled trials of the use of iNO in patients with ARDS have failed to show a survival benefit (despite short-term improvements in oxygenation).6-9 Second, the patients did not have a trial of nitric oxide while receiving conventional ventilation. Perhaps the oxygenation response with iNO during conventional ventilation would have been as good (or perhaps even better) than it was with HFOV. It is of interest to note that Mehta et al found no significant improvement in PaO2/FIO2 or oxygenation index when patients were switched from conventional ventilation to HFOV. This raises the obvious question, why go to the trouble of using high-frequency ventilation in the first place? Third, Mehta et al use a physiologic outcome (oxygenation) to judge success. Short-term physiologic outcomes have increasingly been recognized as poor surrogates for patient-important outcomes such as survival.10 The hospital survival rate in this study was only 30%. Mehta et al might argue that these were very ill patients, but the fact remains that we have no idea what the survival rate would have been without the use of iNO and HFOV.

One concern in this study is the high incidence of pneumothorax (22%). This is much higher than what is typically observed in patients with ARDS. For example, the incidence of barotrauma in the ARDSnet study was only 10%.11 Because barotrauma has not been reported with the use of iNO, I speculate that the high incidence of pneumothorax in this study was related to the high mean airway pressure associated with HFOV.

Mehta et al conclude that the combination of iNO and HFOV may be a safe and effective rescue therapy for patients with severe ARDS. I have always been confused by the meaning of "rescue therapy." What does this mean? Generally, rescue therapy is the use of an unproven therapy for patients who, in the clinical opinion of those providing care, are failing conventional therapy. If the patient improves after the rescue therapy is initiated, this improvement is attributed to the new therapy. As is the case in this study, the survival with the rescue therapy is usually low. Although the majority of patients who receive the rescue therapy do not survive, the survival of the few is attributed to the rescue therapy. This is most curious reasoning. One might argue that the rescue therapy is ineffective because the majority of patients who receive it do not survive! Perhaps those with a good outcome survive in spite of the rescue therapy rather than because of it!

Of concern is that "rescue therapy" is often also "expensive therapy." This is particularly true of iNO and HFOV. In the United States, 4 days of iNO therapy costs $12,000 and a high-frequency oscillatory ventilator costs more than $25,000. This does not include the training costs and additional clinical demands required for the use of these therapies. In these days of cost constraints in health care, it is difficult to justify expensive therapies for which there is a low level of scientific evidence. The benefit of any rescue therapy can only be determined by an appropriately designed randomized controlled trial with patient-important outcomes. All too often, anecdotally supported "rescue therapy" has later been found ineffective (or worse, harmful) when subjected to appropriately designed studies.


1. Manktelow C, et al. Physiologic determinants of the response to inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology. 1997; 87:297-307.

2. Fort P, et al. High-frequency oscillatory ventilation for adult respiratory distress syndrome—A pilot study. Crit Care Med. 1997;25:937-947.

3. Mehta S, et al. Prospective trial of high-frequency oscillation in adults with acute respiratory distress syndrome. Crit Care Med. 2001;29:1360-1369.

4. Derdak S, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: A randomized, controlled trial. Am J Respir Crit Care Med. 2002;166:801-808.

5. Kinsella JP, Abman SH. High-frequency oscillatory ventilation augments the response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn: Nitric Oxide Study Group. Chest. 1998; 114(1 Suppl):100S.

6. Dellinger RP, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: Results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998;26:15-23.

7. Lundin S, et al. Inhalation of nitric oxide in acute lung injury: Results of a European multicentre study. Intensive Care Med. 1999;25:911-919.

8. Michael JR, et al. Inhaled nitric oxide versus conventional therapy: Effect on oxygenation in ARDS. Am J Respir Crit Care Med. 1998;157:(5 pt. 1)1372-1380.

9. Troncy E, et al. Inhaled nitric oxide in acute respiratory distress syndrome: A pilot randomized controlled study. Am J Respir Crit Care Med. 1998;157:(5 pt. 1) 1483-1488.

10. Rubenfeld GD. Surrogate outcome measures in critical are: It’s the mortality, stupid! Critical Care Alert. 2002;9:138-140.

11. The ARDS Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301-1308.

Dr. Hess is Assistant Professor of Anesthesia, Harvard Medical School; Assistant Director of Respiratory Care, Massachusetts General Hospital, Cambridge, MA.