In 1980, it was discovered that stimulating endothelial receptors with acetylcholine triggered the production of a substance which spread to the vascular smooth muscle cells and caused vasodilation, this substance having been termed the endothelium-derived relaxing factor (EDRF). Some years later, in 1987, this molecule was proven to be NO6,7, the authors of said studies having been the 1998 Nobel Prize for their discoveries of this molecule.

Following the promising results of studies on the use of iNO in animals and later in humans with pulmonary hypertension8, its use was broadened to ARDS patients. Rossaint et al9 were the first to study the effects of iNO in ARDS patients, having found there to be a reduction of the pulmonary arterial pressure and an increase of the oxygenation at doses of 18-36 ppm. Despite the limitations of their study, the findings justified the dissemination of numerous studies for evaluating iNO in ARDS, which were burgeoning in the 1990’s, demonstrating that when inhaled in small doses (5-80 ppm), it rapidly caused selective pulmonary vasodilation of the ventilated alveoli, hence entailing an improvement in the pulmonary hypertension and an increase in the arterial oxygenation10-12. These findings provided renewed encouragement to researchers such as Gerlach et al.31, who evaluated the response of severe ARDS patients to iNO by means of dose response curves. The results showed an improvement in the oxygenation and reduction in the use of extracorporeal membrane oxygenation in the iNO group, there however having been no differences in the length of time of the mechanical ventilation. Despite the belief that the improvement in the gas exchange would have a bearing on the prognosis of these patients, this encouraged different randomized clinical trials subsequently being conducted13-22 (Table 1). These studies demonstrated the inhalation of NO in ARDS to tentatively improve the arterial oxygenation, although they failed to confirm an improvement in the survival rate or in the morbidity of critical patients. Different meta-analyzes and systematic reviews have also confirmed the increase in oxygenation but nevertheless have not provided evidence of a reduction in the mortality or in the number of ventilator-free days23-30.

The increase in oxygenation substantiated with the iNO has not meant an improvement in prognosis in clinically-relevant terms such as the survival rate. Some authors assert that these results obtained in small-scale, low-powered clinical trials may have significant limitations, and their results may serve better for giving rise to rather than confirming hypotheses4. In fact, the greatest criticism of these studies is that they do not distinguish between severe and moderate ARDS, in the belief that the greatest benefit is achieved in patients with severe hypoxemia and that this sub-group has been poorly represented in the clinical trials32,33. However, a meta-analysis30 recently examined the effect which iNO has on mortality by sub-groups defined by the degree of severity of the hypoxemia for 9 clinical trials and 1,142 patients, no benefit having been found according to the severity of the group. The analysis of sub-groups showed that the therapy with iNO does not reduce the mortality in patients with baseline PaO2/FiO2 ≤ 100 mm Hg (RR 1.01 [95% CI, 0.78-1.32]; p = 0.93; n = 329; 6 trials) or those with a baseline PaO2/FiO2 > 100 mm Hg (RR 1.12 [95% CI, 0.89-1.42]; p = 0.33; n = 740; 7 trials). Nor was any PaO2/FiO2 threshold (increments of 10 mm Hg within 70-200 mm Hg range) identified in which the mortality of the patients treated with iNO was lower than in the controls. One limitation of this study, according to the authors, is that it included solely 329 patients in the severe ARDS sub-group, which limits the statistical power for detecting actual differences in mortality among sub-groups.

Other limitations of these reviews are due to the lack of homogeneity of the patients included in one trial and another, due in part, up to relatively a few years ago, to there being no universal definition of ARDS to improve the coherence between research and clinical practice. Furthermore, there is a lack of homogeneity in the indication and in the treatment, with different methods for administering iNO and differing doses from one trial to another3, which complicates their comparison for drawing any significant conclusions (Table 1). Furthermore, it is currently known that the ventilating strategy employed for managing a patient with acute respiratory insufficiency has a significant bearing on the evolution of the disease, although this finding was discovered after many of these studies had been conducted, in which the patients were ventilated with a tidal volume above the recommended volume of 6 ml kg-1. The slight improvements in oxygenation due to the iNO may be masked by the deleterious effects of a non-protective ventilating strategy used in most trials, which limits neither the tidal volume nor the airway pressure. A protective ventilation within the context of the use of iNO might perhaps have provided more positive results as far as prognosis-related parameters are concerned4,34.

On the other hand, the mortality of ARDS patients is related more to events such as sepsis or multiple-organ dysfunction than to hypoxemia per se35. The fact that the improvement in oxygenation substantiated with the use of iNO has not meant an improvement in the mortality rate may be influenced for this reason4. Furthermore, most of the treatments researched for ARDS are focused on short-term prognosis parameters, such as mortality. However, the patients who survive ARDS may have long-range pulmonary sequelae, such as obstructive, restrictive disorders and alterations in gas exchange, which may compromise their quality of life. The actual impact which iNO may have on these parameters is unknown36. In 2004, Taylor et al.22 evaluated the efficacy of small doses of iNO (5 ppm) in 385 critical patients with moderate/severe lung damage (PaO2/FiO2 ≤ 250) from 46 hospitals, finding a transient increase in the PaO2 without any benefit on the mortality or ventilator-free days. A later follow-up carried out as part of the original study however showed better values in functional respiratory tests at 6 months among the ARDS patients who had been treated with iNO than those treated with placebo36. Nevertheless, the validity of the study is limited by the loss of follow-up of most of the survivors and the lack of information on smoking. The effects of iNO on long-term pulmonary function of ARDS patients and hence their morbidity and quality of life are still as yet to be determined. Nevertheless, the improvement in oxygenation demonstrated with the use of iNO could suffice in itself to justify iNO being used in some severely hypoxemic ARDS patients34.

Following the burgeoning number of articles published concerning iNO in the mid-1990’s, the use of therapy employing iNO began expanding to different disorders such as persistent neonatal pulmonary hypertension, pediatric and adult heart surgery and ARDS34. In fact, at the end of the 1990’s, a working group on using iNO in the ICU of the European Society of Intensive Care Medicine (ESICM) explored the clinical practice of the use of iNO in the ICU by means of a questionnaire which was answered by 310 physicians from 21 countries37. More than 60% of said physicians reported using iNO therapy (63.2%), the specialists among whom were mainly intensive care specialists, pediatricians and anesthesiologists.

However, in ARDS patients, its clinical and prognosis-related repercussion has not met with the anticipated degree of success. In 2005, a group of experts organized by the EISCM and by the European Society of Cardiothoracic Anesthesiologists set out some recommendations regarding iNO therapy in adults within the perioperative and critical care realm. In the specific case of ARDS, they mention that its routine use cannot be recommended, although its use as a rescue treatment in patients with severe refractory hypoxemia is considered reasonable32. The recent publication of the results of a meta-analysis which seem to reject the belief that the greatest benefit is achieved in patients with severe hypoxemia30 continue fostering the idea of relegating the use of iNO in patients with ARDS to extreme situations1,30.

The treatment indications approved by Spain’s Medicines Agency for the use of iNO are the treatment of newborns born with more than 34 weeks of gestation who have hypoxic respiratory insufficiency associated with clinical or echocardiography evidence of pulmonary hypertension, and the treatment of perioperative and postoperative pulmonary hypertension in heart surgery38. There is currently no indication approved for its use in adult ARDS patients, the use thereof hence requiring informed consent (Fig. 2). Despite the foregoing, it continues to be used extensively (off-label indication) as a rescue therapy against refractory hypoxemia. For example, it was used in over 20% of the patients included in a large-scale clinical trial published in 2010 concerning the use of neuromuscular relaxants in ARDS patients39. Similarly, it was used as a treatment during the 2009 influenza-A (H1N1) virus pandemic in 32% of the patients with refractory hypoxemia prior to the administration of ECMO in Australia and New Zealand40 and as rescue therapy in up to 14% of critical patients in Canada41, although scarcely any use was documented in Spain and some series from Latin America42.

Figura 2.

Proposed informed consent form for compassionate use of inhaled nitric oxide (iNO) in adult patients with acute respiratory distress syndrome (ARDS) with severe refractory hypoxemia.

(0.81MB).

Based on the foregoing, inhaled nitric oxide therapy seems reasonable as a medication for compassionate use as an off-label therapy in ARDS patients who present severe refractory hypoxemia.

iNO improves the ventilation/perfusion ratio in the aerated pulmonary regions, as a result of which the use of recruitment maneuvers to get previously-atelectatic terminal alveoli opened up improves their usefulness with a synergetic effect on the increase of the PaO2(43) These recruitment maneuvers include the use of appropriate PEEP (positive end-expiratory pressure) (making it possible to turn patients not responding to iNO into responding patients)44, ventilation in prone position45 and high-frequency ventilation46. Although the repercussion of this synergism on the prognosis of ARDS patients has not been evaluated, the importance of the maneuvers affording the possibility of preventing atelectasis is relevant to allowing iNO to improve the gas exchange by means of selective pulmonary vasodilation in the largest possible number of aerated alveoli.

As far as the use of catecholamines is concerned, it has been hypothesized that septic patients may have an inadequate response to iNO due to the influence of the endogenous and exogenous catecholamines on the pulmonary vasculature, although some studies have revealed that the sepsis condition does not modify the response to the iNO in PaO2/FiO214, and that the effect of the iNO is not influenced by the administration of vasopressors such as noradrenalin47.

In adults, for the treatment of the pulmonary hypertension associated with heart surgery, the initial dose of iNO recommended on technical data sheet is of 20 ppm of inhaled gas. This dose can be increased up to 40 ppm as a maximum dose if the minimum dose has not caused sufficient clinical effects38. However, in the case of ARDS patients, the dosage is a source of controversy. Within this context, different studies have delved into the response in the oxygenation following the administration of different iNO concentrations. The results differ from one another, such that the response observed (increase in the oxygenation or decrease in the pulmonary arterial pressure) varies widely with different doses and treatment times evaluated11,20,31,48-52.

The maximum benefit on the oxygenation has been documented with doses of 0.1 – 2 ppm48,49, and with doses of under 20 ppm31 or under 40 ppm11,50. On the other hand, a worsening of oxygenation has also been substantiated with doses above 20 ppm52 or even 10 ppm20,31. Nor is the relationship between the dose of iNO and the response in the oxygenation (dose response curve) concordant, in contrast to small-scale trials in which both a dose-dependent effect48,49 and a non-dose-dependent effect has been described with the improvement in the variable oxygenation11,50 or with interpatient differences51,52. Gerlach et al.20 found there to be a progressive shifting of the dose-response curve toward the left in ARDS patients who were given iNO continuously for several days. A small percentage of ARDS patients are non-responders to iNO on not increasing the oxygenation relevantly with doses of up to 20 ppm52.

Furthermore, the parameter which must be taken into consideration as a favorable response is not made clear in literature, ranging from a 15% reduction in the FiO214, a higher than 10% increase3 or 20% increase13 in pO2 or at least a 20% increase in the PaO2/FiO233. Nevertheless, taking into account its fast-acting quality, this clinically-significant improvement in the oxygenation must be noticeable within the first hour of the therapy in order to justify continuing its use33. This lack of concordance in seeking the optimum iNO dosage in ARDS patients is patent in a recently-published meta-analysis evaluating the effect of iNO on in-hospital mortality of severe ARDS patients30. The nine clinical trials analyzed show variability in the doses of iNO used. Four trials used a set dose of 521,22 and 1017,20 ppm, one trial randomized patients to different does (1.25-80 ppm)13, the rest of the studies having used smaller doses, thus achieving a response in the oxygenation (average dose of 5.315, 916, 1314 or 5-1019 ppm).

It is therefore complicated to draw any conclusions regarding the ideal dose of iNO in ARDS patients, which should be adjusted daily in each patient33, the minimum effective dose being administered by means of slow-paced reductions, provide that the systemic arterial oxygenation continues to be appropriate with reach reduction32,53.

Administering therapeutic doses of iNO seems safe in terms of NO2 and toxic methemoglobinemia forming. There is no direct evidence of direct iNO toxicity or severe side-effects at clinically-relevant doses27-29. Nevertheless, some safety precautions must be taken, and the administering technique must minimize the amount of NO2 administered to the patient and the environmental exposure to the healthcare workers32,49.

Rebound phenomenon

Withdrawing iNO suddenly should be avoided32, given that a rebound phenomenon has been found to exist in some patients with acute pulmonary hypertension, hemodynamic collapse and worsening oxygenation58, which is due to a reversible inhibition of the endothelial NOS by the iNO3. Withdrawal must therefore be gradual, at least every 12 hours, once the oxygenation has improved and the patient is stable, with a low dose of iNO (5 ppm). The dose should then be progressively reduced to 1 ppm over a period of 6-12 hours, to then be maintained for 30 minutes, continuously monitoring the arterial tension, heart rate and the O2 sat, to then finally disconnect the system38 (Fig. 1).

Figura 1.

Proposed scheme of recommendation for the use of inhaled nitric oxide (iNO) in adult patients with acute respiratory distress syndrome (ARDS) with severe refractory hypoxemia.

(0.77MB).