Authors' objectives:

To synthesize the available knowledge about the clinical applications of inhaled nitric oxide (NO), its administration and monitorization, its therapeutic effects, as well as its diffusion and the legal framework of its utilization, both in Spain and Europe, and in the USA.

Authors' results and conclusions: The discovery of NO as universal messenger in the last decade opened a new era of research both at biological and physiological level. Of the different actions of this messenger (endogenous and exogenous), its selective pulmonary vasodilator effect has produced the largest amount of research, both basic and applied, especially in those processes where the development of pulmonary hypertension, and/or an important mismatch between ventilation and pulmonary perfusion take place. NO is a harmless gas and, therefore, its atmospheric concentrations are regulated. Its toxicity by inhaled route takes place basically through oxidation to nitrogen dioxide (NO2) and through its combination with oxyhemoglobin, forming metahemoglobin. To administer NO by the inhaled route, the concentration of this gas, as well as that of the toxic byproducts it may generate (NO2 and metahemoglobin), should be monitored. This involves an accurate checking and gauging of the monitorization and administration devices. At present there is no unique or settled administration and monitorization system for the medical use of NO. Large variability regarding the concentrations in the cylinders and the administration systems has been observed, while the advantages and disadvantages of the accuracy and cost of the different types of available monitors are debated. So far, there are no regulations, guidelines or standards for the storage, administration and monitorization of NO, although there are recommendations to minimize its potential toxicity. Minimal dosages or optimal durations of the NO therapy are neither established. The safety in the administration of this gas is considered to depend partly on the expertise of the personnel that uses it. Most studies related to the clinical application of NO are case-reports or clinical series of different size and follow-up time. In this studies, the main effectiveness measures are of physiopathological type (oxygenation parameters, hemodynamics, pulmonary spirometry and mechanics), extracorporeal membrane oxygenation (ECMO), and survival. Some of the few randomized controlled clinical trials that have assessed the efficacy and safety of NO refer to it as compared to other pulmonary vasodilators or to different dosages; other trials, clinically more relevant, refer to the effect of NO in newborns with hypoxic respiratory failure and persistent pulmonary hypertension. Two of the tree studies that assessed the effect of NO in this condition showed beneficial effects regarding oxygenation and lower ECMO requirements in the treated patients, although mortality is quite similar in both therapeutic groups. The outcome measures used to describe the beneficial effect of inhaled NO in some patients are physiopathological markers. However, these outcome measures have to be considered as surrogate. Up to now, we ignore if the improvement in the oxygenation and/or hemodynamic parameters imply better outcomes regarding survival/disability for the patients.

Authors' recommendations: Inhaled NO is an increasingly applied therapy, especially in intensive care units (newborns, paediatric, and adult). This diffusion has taken place despite the lack of randomized controlled clinical trials showing a better survival rate with its use compared to other usual or more settled therapies, or despite its authorization as a medicinal gas/drug. In no country has NO been officially registered or acknowledged as medicinal gas or drug for one or more specific indications. However, in some countries there is a restrictive authorization for its utilization in specific circumstances, with the condition of gathering, for each patient, data regarding indication, dose, therapeutic effects and adverse reactions. These two facts, absence of a regulatory framework defined for its distribution, and growing diffusion and utilization in clinical applications, arise precisely from the effectiveness of inhaled NO (selective vasodilator effect), measured by physiopathological indicators, and in extremely severe clinical conditions (with high mortality), and in front of the relative failure of other settled therapeutical alternatives. Hence, NO has been broadly applied as last resort therapy.

Authors' methods: Review

Project Status: Completed

URL for project: http://www.gencat.net/salut/depsan/units/aatrm/html/en/dir393/doc7921.ht ml

Year Published: 1997

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Spain

Organisation Name: Agencia de Qualitat i Avaluacio Sanitries de Catalunya

Contact Address: Antoni Parada, CAHTA, Roc Boronat, 81-95 (2nd floor), 08005 Barcelona, Spain, Tel. +34 935 513 928, Fax: +34 935 517 510

Contact Name: direccio@aatrm.catsalut.net / aparada@aatrm.catsalut.net

Contact Email: direccio@aatrm.catsalut.net / aparada@aatrm.catsalut.net

Copyright: Catalan Agency for Health Technology Assessment and Research