No iNO for ARDS
February 1, 2000 4 minutes read
No iNO for ARDS
Abstract & Commentary
Synopsis: When used as salvage therapy for patients with severe acute respiratory distress syndrome, inhaled nitric oxide had a modest, unpredictable effect on oxygenation and its use did not improve survival.
Source: Dupont H, et al. J Crit Care 1999;14(3): 107-113.
Dupont and associates carried out this study in five university medical or surgical ICUs in France. They examined data from all patients with acute respiratory distress syndrome (ARDS) who had received inhaled nitric oxide (iNO) during a two-year period. ARDS was diagnosed similarly to current internationally accepted definitions, and a lung-protective ventilatory strategy was used in managing the patients who limited end-inspiratory plateau pressure and used permissive hypercapnia. Patients received iNO if they had a ratio of arterial PO2 to inspired O2 fraction (PaO2/FIO2) of less than 150 mm Hg for more than two hours after initial stabilization with positive end-expiratory pressure and other ventilator manipulations. Patients receiving other experimental therapies were excluded.
During the two-year study period, 93 patients (31% of all ARDS patients) met inclusion criteria and were given iNO. Their mean age was 49 years, and two-thirds were men. The SAPS II severity score was 45 ± 15, and the mean PaO2/FIO2 ratio prior to initiation of iNO therapy was 95 ± 53 (SD) mm Hg. Causes of ARDS included diffuse pulmonary infection (51%), extrapulmonary infection (21%), and the systemic inflammatory response syndrome (SIRS) without infection (13%). Overall ICU mortality was 69/93 (74%).
None of the variables examined as potential correlates of improved oxygenation or hemodynamics with iNO predicted response. Eventual survivors tended to have better responses than eventual nonsurvivors (P = 0.01), but this difference disappeared after adjusting for other prognostic factors. Overall mortality was not different between responders and nonresponders to iNO. Mortality also did not correlate with the duration of iNO therapy.
COMMENT BY DAVID J. PIERSON, MD, FACP, FCCP
Inhaled nitric oxide directly mediates the dilation of pulmonary vessels in ventilated areas of the lung. Therefore, it has been hoped that iNO would improve the matching of ventilation and perfusion (V/Q) in the lungs of patients with severe ARDS and right-to-left shunting or very low V/Q areas producing severe, refractory hypoxemia, and in so doing both improve oxygenation and reduce pulmonary arterial (PA) pressure. In fact, iNO has these effects in at least some ARDS patients. However, the clinically important questions have been, first, whether improved arterial PO2 and/or decreased PA pressure resulted in better survival or fewer complications in patients with ARDS, and, second, whether favorable responses could be predicted in individual patients.
The answers to these questions have now been established, at least as firmly as is likely to be the case for a while. A much-heralded and expensive large-scale randomized, controlled trial of iNO in patients with ARDS found that iNO improved arterial PO2 by at least 20% in 60% of patients (Dellinger RP, et al. Crit Care Med 1998;26:15-23). However, the study also found that this effect was statistically significant only in the first 24 hours, and that the administration of iNO did not improve overall survival. This and other studies of iNO in patients with ARDS have been nicely reviewed in a recent article by Gerlach et al (Gerlach M, et al. Respir Care 1999;44:184-192).
The present study by Dupont et al addresses an important adjunctive issue. The administration of iNO may not improve survival when groups of ARDS patients are considered together, but there must be individual patients in whom this therapy is life-saving. This has been the rationale for the "compassionate use" of iNO, which has not otherwise been approved for use in the United States outside the research setting, as rescue therapy for that minority of ARDS patients in whom death may occur because of refractory hypoxemia. The results of the Dupont study make such compassionate use more difficult to justify, at least when patients are selected according to the initial PaO2/FIO2 ratio, since a favorable physiologic response to iNO was modest and unpredictable in such patients and did not affect survival.
Inhaled NO has recently been approved by the FDA for treatment of certain cases of refractory hypoxemia in neonates. The gas, along with its associated storage, administration, and monitoring apparatus, is thus available now to clinicians in this country and could be used in adult patients with ARDS, subject to certain rules and restrictions for compassionate use. However, it is now not so much a lack of access to iNO as its cost that will prevent this from happening.
From the information so far made available to the respiratory care department of which I am medical director, the cost to the patient for the clinical use of iNO (which is available only as a complete package, including gas and administration system) will be $3000 for the first day or any portion thereof, and then less thereafter with a cap of $12,000. This cost is likely to be reimbursed only for its approved (that is, neonatal) indication. For patients with ARDS whose families do not have the economic resources to pay for iNO directly, the cost of a trial of iNO therapy would likely be borne by the treating institution. I suspect that this scheme was intentional in order to limit the overall cost of iNO and to prevent its widespread use for nonapproved indications. In any event, it will surely have the effect of preventing clinicians from trying iNO in most adult patients with ARDS.
Inhaled nitric oxide (iNO) was recently approved by the FDA for administration to:
a. adult patients with refractory ARDS.
b. any patient with acute respiratory failure and a PaO2/FIO2 ratio less than 150 mm Hg.
c. neonates with certain forms of refractory hypoxemia.
d. All of the above
e. None of the above
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