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On-line version ISSN 1678-4642
J. Pneumologia vol.29 no.5 São Paulo Sept./Oct. 2003
Inhaled nitric oxide: clinical application considerations*
Gisele Limongeli GurgueiraI; Werther Brunow de CarvalhoII
IAssistant Physician, Pediatric Intensive
Care Unit, Hospital São Paulo, Hospital Santa Catarina, and Hospital
do Servidor Público Municipal
IIAssociate Professor, Pediatrics Department, Universidade Federal de São Paulo/Escola Paulista de Medicina. Head of the Pediatric Intensive Care Units, Hospital São Paulo, Hospital Santa Catarina and Hospital Beneficiência Portuguesa
The objective of this paper is to report some clinical and therapeutic aspects of inhaled nitric oxide in pediatrics. Some references were obtained from Medline® using the keywords: inhaled nitric oxide and pediatrics, and critical care. Other sources were the University library and personal files. Along the last decade, clinical trials with inhaled nitric oxide demonstrated only a few specific areas of proven efficacy and a variety of possible adverse events. Toxicity related to inhaled nitric oxide included metahemoglobinemia, cytotoxic pulmonary effects, excess production of nitrogen dioxide and peroxynitrite, and injury to the pulmonary surfactant system. The administration of inhaled nitric oxide to patients with severe left ventricular dysfunction and pulmonary hypertension should be cautious, since vasodilatation may increase pulmonary blood flow and lead to excessive preload. Some studies showed the clinical effects related to abrupt nitric oxide withdrawal, including rebound pulmonary hypertension. Current literature supports the therapeutic use of inhaled nitric oxide in persistent pulmonary hypertension of the newborn (gestational age > 34 weeks) to improve oxygenation and avoid extracorporeal oxygenation; and in congenital cardiopathy accompanied by pulmonary hypertension, especially in the immediate postoperative period. To date, research in pediatrics and multicentre trials in adults with inhaled nitric oxide therapy have failed to show mortality reduction or decrease the amount of time under mechanical ventilation for acute respiratory distress syndrome and acute lung injury. This indication needs further investigations. Persistent pulmonary hypertension is the most important indication for inhaled nitric oxide. The Food and Drug Administration has not approved inhaled nitric oxide in acute respiratory distress syndrome for adults and children.
Key words: Nitric oxide/therapeutic use. Pediatrics. Pulmonary hypertension. Critical care.
Abbreviations used in this article
ECC Extracorporeal circulation
CINRGI Clinical Inhaled Nitric Oxide Research Group Initiative
DNA Deoxyribonucleic acid
COPD Chronic obstructive pulmonary disease
FDA Food and Drug Administration
FIO2 Inspired oxygen fraction
PH Pulmonary hypertension
PPH Primary pulmonary hypertension
PPHN Persistent pulmonary hypertension of the newborn
NADH Nicotinamide adenine dinucleotide
NINOS Neonatal Inhaled Nitric Oxide Study
NO Nitric oxide
NO2 Nitrogen dioxide
ECMO Extracorporeal membrane oxygenation
PaO2 Arterial oxygen tension
PAP Pulmonary artery pressure
SAP Systemic arterial pressure
PVR Pulmonary vascular resistance
ARDS Acute respiratory distress syndrome
MV Mechanical ventilation
About 20 years ago, nitric oxide (NO) was considered a noxious, extremely toxic gas that had a natural existence of only some seconds. Due to its high reactivity (it is a free radical with an extra electron), it is rapidly converted to nitrate and nitrite through the reaction of oxygen with water.
Between 1984 and 1987, several studies showed that NO is produced by various cells within our bodies and is essential in a number of organic functions.(1-5) Inside blood vessels, its continual production by endothelial cells promotes relaxation of the underlying smooth muscle, causing vasodilatation.(6-8) In the immune system, macrophages, when stimulated, produce a high amount of NO, which works as a killer molecule, destroying target (cancerous) cells and microorganisms.(2,3) NO also acts in other systems, such as the central nervous system, gastrointestinal, respiratory, cardiac and urinary systems.(2,3) These findings have led to extensive scientific production related to NO.(1)
The use of inhaled NO in diseases that lead to pulmonary hypertension (PH) might, therefore, be very promising, because of its selective pulmonary vasodilator effect, which might improve the ventilation/perfusion ratio and cardiac performance. Most of the pediatric studies performed until now consisted of small samples and assessed only the hemodynamic effects and the effects on oxygenation of inhaled NO.(1,9-11) Only two prospective studies in newborn babies with a larger study sample clearly showed the beneficial effects of inhaled NO on the persistent pulmonary hypertension of the newborn (PPHN),(12,13) which resulted in the approval of NO for use in full-term and near-term (> 34 weeks) newborns by the Food and Drug Administration (FDA). Studies of other diseases, such as acute respiratory distress syndrome (ARDS), failed to show consistent beneficial effects. Therefore, NO use remains restricted, with a number of unanswered questions.(15-21)
A number of noxious substances may be produced by NO. In the presence of oxygen (O2) it is oxidized into nitrogen dioxide (NO2), a highly cytotoxic gas, which, in aqueous solutions, is converted to nitric and nitrous acid. The United States National Institute for Occupational Safety and Health (NIOSH) set the NO2 workplace exposure limit at 5 parts per million (ppm).(22) It has been observed that the greater part of NO toxicity is due to NO2 production resulting from its reaction with O2.
During the use of inhaled NO on patients with PH, it is possible to avoid inhalation of NO2. This can be achieved through the interposition of a soda whitewash system in the mechanical ventilation (MV) apparatus. Alternately, concentrations of NO and O2 that have been determined to cause less conversion to NO2 (the oxidization rate is dependent on O2 concentrations and on the square of NO concentration) can be used. When NO is stored in cylinders together with pure nitrogen (N2), NO2 is not produced. (1)
In aqueous solution, NO reacts with superoxide radicals, producing superoxide-nitrite, a cytotoxic substance. Additionally, it may produce complexes with some metals, as when it binds with hemoglobin, which produces nitrosyl Fe (II)-hemoglobin and then methemoglobin.(1)
Methemoglobinemia occurs due to the increased production of methemoglobin, or when its reduction by diaphorase-NADH (methemoglobin-reductase) is decreased. According to some studies, methemoglobin levels do not increase significantly after exposition to low concentrations of NO2.(3,24) However, subjects that have reduced diaphorase-NADH activity may develop methemoglobinemia. It is known that diaphorase-NADH activity is usually reduced in newborns.(1)
In addition to its noxious effect when reacting with other substances, NO itself may cause direct cell injury, especially through mutation of deoxyribonucleic acid (DNA) at the cell nucleus. (25)
Main adverse effects
Some adverse effects related to the toxicity of NO are methemoglobin production,(26) pulmonary cytotoxic effects due to the production of free radicals by excessive nitrogen dioxide (NO2), production of peroxynitrite and changes in the pulmonary surfactant system.(14) Additionally, carcinogens or teratogens may be produced and unknown effects on immature lungs and changes on hemostasis, such as changes in platelet aggregation, may also occur.(27) Despite the fact that it would be advisable to consider the risk of coagulation disorders associated with the use of inhaled NO, increased incidence of such disorders was not observed in other prospective randomized studies.(28-30)
In patients with severe left-ventricular dysfunction plus PH, sudden dilation of pulmonary vessels may cause increased blood flow, resulting in a damagingly higher preload on a previously injured ventricle.(26)
A number of studies have shown undesirable effects after sudden NO withdrawal, and a rebound effect has also been observed.(31-36) The reasons for this rebound effect are not clear but may be related to inhibition of nitric oxide synthase activity. Various techniques may be employed in order to avoid this effect during withdrawal of inhaled NO. The method most commonly used is that of increasing the inspired oxygen fraction (FIO2) before NO reduction.(37) Other researchers have used a phosphodiesterase inhibitor, dipyridamole, to lessen the rebound effect during inhaled NO withdrawal.(38,39)
Potential uses of inhaled NO
Acute respiratory failure remains one of the most significant factors in the morbidity and mortality of the critically ill. Worsening hypoxemia and contributing to right-ventricular overload, PH is also associated with high mortality rates in a number of diseases, such as persistent pulmonary hypertension of the newborn (PPHN), acute respiratory distress syndrome (ARDS), congenital PH-related cardiopathies, chronic obstructive pulmonary disease (COPD), primary pulmonary hypertension (PPH), and others. A study of adult patients with ARDS showed that increased pulmonary vascular resistance (PVR) correlates directly with the severity of changes in gas exchange.(1) These findings led to a number of researches trying to identify a selective pulmonary vasodilator. Treatment with intravenous vasodilators is limited, as they cannot reduce PVR without causing serious side effects, such as systemic hypotension, which reduces coronary perfusion and consequently worsens right-ventricular function.
The term macroselectivity has been used to differentiate the effects of a vasodilator drug on pulmonary vessels from its effect on systemic circulation. Macroselectivity is determined by the ratio between pulmonary artery pressure (PAP) and systemic arterial pressure (SAP) or by the ratio between the respective resistances. A macroselective pulmonary vasodilator should be able to reduce PVR and improve right-ventricular function. At the moment, there is no intravenous agent that acts only on the pulmonary vasculature.(1)
The term microselectivity has been used to differentiate the effects of a vasodilator drug on the distribution of pulmonary blood flow (perfusion) from its effect on systemic circulation. A number of intravenous agents that have been used, such as nitroprusside, reduce gas exchange by leading to nonselective vasodilation of the pulmonary arteries with perfusion of nonventilated areas, resulting in a lower ventilation/perfusion ratio.(1)
Inhaled NO has two selectivity properties. In contrast to systemic vasodilators, it acts only on ventilated alveoli, thereby causing selective pulmonary vasodilation. By redirecting the flow to these areas, it improves oxygenation and intrapulmonary shunt. There is a pronounced reaction between NO and hemoglobin, and this reaction produces the inactive compounds, nitrite and nitrate. Therefore, NO does not cause systemic vasodilation and does not change coronary perfusion.(1)
Despite the fact that the use of inhaled NO seems to be beneficial for patients with PH of various etiologies, lack of a response was seen in some, that is, no increase in arterial oxygen tension (PaO2) and no reduction in PVR.(27)
To date, the FDA has approved the use of inhaled NO only for the treatment of full-term newborns or pre-term newborns with a gestational age equal to or greater than 34 weeks who have hypoxemic respiratory failure and clinical or echocardiographic evidence of PH, or for the pre- and post-surgical management of children with congenital PH-related cardiopathies.(40) Only two clinical trials showed benefits from inhaled NO: the Inhaled Neonatal Nitric Oxide Study (NINOS) and the Clinical Inhaled Nitric Oxide Research Group Initiative (CINRGI).(12,13) In both studies, there was a significant reduction in extracorporeal membrane oxygenation (ECMO).
Patients with congenital cardiopathy may develop PH due to the pulmonary disease or due to pulmonary vasculature hyperresponsiveness. Children with intra-uterine obstruction of pulmonary blood flow may develop hypoplasia of the alveolar-capillary units. In such patients, the venous hypoxemia that accompanies arterial hypoxemia may help maintain an elevated PVR. Otherwise, a common dilemma in clinical practice is how to keep the PVR elevated in order to balance pulmonary and systemic circulations, trying to maintain adequate tissue oxygenation in cases of truncus arteriosus, hypoplastic left heart syndrome, or other single-ventricle variants. In these patients, lowering pulmonary vascular resistance by using inhaled NO might be fatal. Because of this, NO use in congenital cardiopathies, especially in the neonatal period, should only be considered after careful evaluation of the patient anatomy and physiology.
Congenital cardiopathies with increased pulmonary blood flow or obstruction of pulmonary vein drainage may present with hypertrophy and hyperplasia of the vascular muscles with attendant vasoconstriction. In children submitted to surgical correction of cardiopathies, PH remains an important cause of morbidity and mortality in the immediate post-surgical period. Inhaled NO may be used in the assessment of pulmonary vascular reactivity during catheterization, facilitating the choice of surgical treatment. Two groups of patients may benefit from this assessment: those with single-ventricle function, for whom a cavopulmonary shunt is indicated (when surgical success depends on maintaining low PVR); and those who have increased pulmonary blood flow due to a left-right shunt, in whom a hyperplasia of the muscle layer of the pulmonary capillaries tends to occur, making them less responsive to pharmacological agents.
In children who have had a number of cardiopathies and who can breathe spontaneously, the use of inhaled NO (up to 80 ppm) during catheterization has been shown to reduce PVR significantly, without systemic hypotension or significant elevation on methemoglobin levels.(41) A similar result was observed in the pre-surgical PH evaluation with inhaled NO at 10-ppm and 20-ppm doses in patients with congenital cardiopathy and PH.(42)
Increased PVR frequently occurs in patients with cardiopathy and may be exacerbated by the use of extracorporeal circulation (ECC). Concurrent to the actual pathological status, right-ventricular dysfunction may occur after ECC due to inadequate right-ventricle preservation during surgery, production of pulmonary vascular constrictors such as thromboxane A2 (which results from platelet and leukocyte aggregation) or reduction in endogenous vasodilators such as nitric oxide (NO). Hypoxemia and right-ventricle overload are worsened in the presence of PH. Conventional post-surgical treatment consists of hyperventilation, alkalinization, increased FIO2, and use of inotropics and vasodilators. The use of inhaled NO has proven beneficial and efficient in such patients.(43-45)
Miller et al. obtained a significant reduction in PAP in 10 infants at high risk for PH by using a low concentration of inhaled NO (2, 10 and 20 ppm) in the post-surgical period following cardiac surgery.(46)
A study of post-surgical pediatric patients that compared the effects of hyperventilation with those of inhaled NO after correction of PH-related cardiopathy showed that both techniques are effective in lowering PVR and PAP. The use of inhaled NO, however, was found to have advantages in that there was none of the cardiac output reduction or increased systemic vascular resistance (SVR) typically seen when hyperventilation is employed.(47)
Currently, the FDA approves the use of inhaled NO in pediatric patients submitted to cardiac surgery and in the post-surgical management of PH-related cardiopathy.
Acute pulmonary injury / acute respiratory distress syndrome
Hypoxemia and PH are both present in ARDS and the severity of each of them is closely related to mortality. (16-19) The PH seen in ARDS is caused by active vasoconstriction. This vasoconstriction may be due to alveolar hypoxia, circulating mediators, greater release of vasoconstriction mediators such as thromboxane, or reduction of vasodilator mediators such as endogenous NO, as well as to mechanical factors such as thromboembolism, edema-related vascular compression or increased alveolar pressure. Hypoxemia is caused by a change in the ventilation/perfusion ratio, intrapulmonary shunts or anatomical shunts (patent oval foramen). The use of intravenous vasodilators, such as nitroglycerin or prostaglandin I2, results in a slightly reduced PAP, but with much lower SAP and arterial oxygenation.(48)
Adult and pediatric studies have shown that inhaled NO improves oxygenation in patients with acute pulmonary injury.(31-33) Since it allows reduction of MV parameters, the potential beneficial effects of NO in ARDS include reduced PVR, reduced intrapulmonary shunt, improved right- and left-ventricle function, fewer barometric traumas and lower oxygen toxicity. Nevertheless, multicenter studies of adult patients failed to show any improvement on duration of MV or survival.(15,17) In such studies, patients had increased oxygenation after starting inhaling NO, but that was a transitory response, which failed to reduce MV or FIO2. As can be seen in Table 1, similar findings have been reported in other studies, including pediatric studies.(49)
The use of inhaled NO in patients with ARDS should not be indiscriminate. However, it can be justified in patients in whom improved oxygenation may help maintain clinical stability during the acute phase of hypoxemic respiratory dysfunction (rescue therapy). It can also be used as adjuvant therapy to lower PVR when permissive hypercapnia is used.(50)
So far, the FDA has not approved the use of inhaled NO for ARDS patients. In terms of efficacy, it may be considered as potentially effective but should be used with extremely caution.
The use of inhaled NO has been assessed in other diseases, but the results were not very promising. In patients with COPD, no significant improvement in oxygenation was observed.(49) In pediatric patients with diaphragmatic hernia, the use of NO did not reduce mortality or the need for ECMO.(49)
Patients with heart diseases that cause pulmonary hypertension may also obtain some benefit with the use of inhaled NO. A study of the hemodynamic effects of inhaled NO in patients with PH after mitral valve prolapse showed reduced PAP and PVR, as well as improved mixed venous oxygen saturation, without undesirable hemodynamic effects.(52) Patients with right heart failure may obtain benefits from the use of inhaled NO, since PVR reduction improves cardiac performance. It can also be used for diagnostic evaluation of patients that are candidates for transplant, through the observation of the pulmonary vessel response to inhaled NO.
Other possible indications, which are very little studied, are: pulmonary edema at high altitudes, pulmonary hemorrhage, pulmonary embolism and others.
The use of NO is contraindicated in newborns with right-left shunt dependent cardiopathy, as well as in cases of congenital or acquired methemoglobin reductase deficiency.
Inhaled NO should be used with caution: in cases of anemia, thrombocytopenia, leucopenia or coagulation disorders; in cases of pulmonary edema or acute pulmonary infection; and in patients with severe left-ventricular dysfunction, who may only receive inhaled NO in combination with other agents that improve the left-ventricle performance.
Based on current clinical evidence, the indication and usage of inhaled NO are restricted to two conditions: PPHN and PH combined with hypoxemia and right-ventricular dysfunction in cases of congenital cardiopathy, especially immediately after surgery. In Brazil, there is no governmental authorization for the use of inhaled NO and its use is therefore limited to clinical trial protocols.
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Submitted: 14/01/2003. Accepted, after revision: 11/06/2003.
* Research performed at the Universidade Federal de São Paulo Escola Paulista de Medicina