Nitric oxide, which exists in a gaseous state and is composed of two atoms, can be found in the natural environment as well as within parts of the human body. Its administration in the clinical scenario as an inhalant (iNO) for adjunctive rescue therapy and improved oxygenation of persistent pulmonary hypertension of newborns (PPHN) and acute respiratory distress syndrome (ARDS).
The FDA approved a new inhaled nitric oxide product in 1999 and another in 2019 for the treatment of:
The definition of ARDS is acute-onset hypoxemia in the presence of bilateral pulmonary infiltrates of non-cardiac origin. ARDS can lead to the development of life-threatening hypoxemia. Pulmonary hypertension complicates the course of neonatal respiratory failure and is reportedly present in over 10 percent of these cases. However, researchers failed to demonstrate a decrease in mortality, length of hospitalization, or an improved outcome with the use of iNO in ARDS patients; therefore, it is not recommended by the FDA for regular use.
Nitric oxide (NO) is produced through the conversion of L-arginine into NO via NO synthases (NOS) in various parts of the body. Endothelial NOS produces NO that acts explicitly as an endogenous vasodilator that diffuses into vascular cells and mediates smooth muscle relaxation by binding to guanylyl cyclase. Guanylyl cyclase converts GTP into cGMP, which activates cGMP-dependent protein kinases. These protein kinases go on to phosphorylate various ionic channels in the endoplasmic reticulum (ER), which causes calcium sequestration and prevents mobilization of calcium within the cell. As a result, smooth muscle cells relax.
Endogenous Pulmonary Vasodilation
iNO delivery is direct to pulmonary vascular endothelial cells where vasodilation occurs and further reduces intrapulmonary shunting. The belief is that while NO causes a myriad of effects within the body, iNO is primarily limited to the lungs. This belief is in part because NO exposed to the bloodstream binds readily to hemoglobin, thus inactivating it and explaining why iNO causes pulmonary vasodilation only with little chance of hypotension or systemic vasodilation.
Inhibition of Platelet Aggregation
NO additionally affects platelet activity. In vitro studies have revealed that NO can activate guanylate cyclase within platelets to accumulate intracellular cGMP. This cGMP goes on to activate protein kinases that reduce the binding of fibrinogen to GPIIb/IIIa and a subsequent partial reduction of platelet aggregation. Research has shown that patients with ARDS have elevated platelets and increased platelet activation within alveolar tissues. Samaha et al. conducted a study to investigate whether iNO and its anti-platelet aggregation effects would influence the platelets of ARDS patients. Their results found significant improvements in oxygenation, reduction of pulmonary arterial pressure, and a decrease in ex-vivo platelet aggregation without a change in these patients' Ivy bleeding times. They concluded that the improvement in oxygenation and pulmonary circulation were attributable to the reduced platelet aggregation.
Research has observed that NO changes the balance of T helper 1 (TH1) and T helper 2 (TH2) cells. Specifically, NO decreases the proliferation rate of TH1 cells and cytokine IL-2 synthesis but increases the production of IL-4 cytokines from TH2 cells. In this manner, NO may inhibit inflammatory responses to viral and bacterial pathogens. Additionally, the belief is that NO affects leukocyte adhesion and recruitment.
iNO's adverse effects are primarily dose-dependent, and the recommended limit for clinical use is 20 ppm for up to 14 days in the preterm infant. However, even low doses may exert cellular toxicity. Infants that have received iNO and ventilation for PPHN for 1 to 4 days reportedly showed nitrotyrosine residues within their lungs, thus indicating potential long term pulmonary complications. Clinical doses of iNO have also exhibited adverse effects. Infants weaning from nitric oxide, when having it withdrawn rapidly, suffered from severe rebound pulmonary vasospasm, most likely due to the actions of exogenous nitric oxide downregulating activity of nitric oxide synthase.
NO can also rapidly interact with other atoms or anions to facilitate damage. It can combine with oxygen in the lungs to form nitrogen dioxide, a potent pulmonary irritant. Additionally, it can interact with a superoxide anion to form peroxynitrite. Peroxynitrite is cytogenic and can disrupt surfactant functioning within the lungs.
Contraindications of iNO include severe left ventricular dysfunction and congenital heart disease involving a right to left shunt. Echocardiogram findings should rule out congenital cyanotic heart disease prior to the initiation of iNO as this drug can further exacerbate heart failure in systems dependent on ductal systemic blood flow.
Therapeutic effects of nitric oxide
Administration as an inhalant provides a rapid and smooth onset with a predictable duration of effect in hypoxic respiratory failure. With most of its immediate effects confined to the lungs, there is relatively low organ toxicity.
Low dose iNO therapy for PPHN could decrease the need for ECMO therapy, as evidenced by the study performed in 2000 by the Clinical Inhaled Nitric Oxide Research Group (CINRGI). Neonates that received low dose iNO therapy had reduced need (38%) for ECMO therapy and less chronic lung disease compared to the control group (48%). Schreiber et al. further confirmed this finding and revealed that preterm infants treated with iNO for respiratory distress had a decreased incidence of chronic lung disease and death.
Current recommendations are limited to 20 ppm as higher doses may be associated with methemoglobinemia and nitric dioxide formation. The Neonatal Inhaled Nitric Oxide Research Group (NiNOS) observed the peak level of methemoglobin to be 2.4% +/- 1.85% in the iNO-treated group compared to controls. Once initiated, daily methemoglobin and nitrogen dioxide levels require close vigilance. The CINRGI study, the only observed adverse effect between control and iNO treated groups, was hypotension.
In animal primary neuronal cell cultures, excess nitric oxide is partially responsible for glutamate neurotoxicity. These glutamate derangements carry implications in numerous neurodegenerative disorders, including stroke, epilepsy, Alzheimer disease, amyotrophic lateral sclerosis, and Huntington disease. However, it is more likely that these neurotoxic mechanisms are subjet to mediation through peroxynitrite, the product of an NO and superoxide anion reaction. Peroxynitrite and excess oxygen free radicals can be generated from severe cellular damage and can cross the blood-brain barrier as lipid-soluble products to accumulate within neuronal tissue.
FDA approval limits iNO to use for persistent hypoxic respiratory distress in preterm infants. It should be used by experienced staff in tertiary level neonatal intensive care units (NICU) that have additionally advanced modes of ventilatory support. Ideally, diagnostic findings such as an echocardiogram performed by a radiologist should rule of cyanotic heart disease before the initiation of iNO therapy as the drug can exacerbate heart failure in these patients. [Level 3] Clinical and diagnostic findings should confirm PPHN in preterm infants before administration, and SaO2 and pulse oximetry readings should be followed closely by the dedicated nurse to ensure adequate administration and alleviation of symptomatic findings.
Sedation may often be required with the administration to prevent agitation in the infant. Therefore the anesthesiologist must be alert and attentive to any rapid changes that can occur as a result of drug-drug interactions. Once initiated, iNO requires gradual weaning to prevent pulmonary vasospasm, and blood levels of methemoglobin should be kept under 2.5% and closely followed (level 1 evidence). Additionally, while adjunctive use for adult ARDS patients may provide relief, it should be known that iNO failed to reduce mortality, length of hospitalization, or improved outcomes in these patients. [Level 3]
|||Monsalve-Naharro JÁ,Domingo-Chiva E,García Castillo S,Cuesta-Montero P,Jiménez-Vizuete JM, Inhaled nitric oxide in adult patients with acute respiratory distress syndrome. Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria. 2017 Mar 1; [PubMed PMID: 28236803]|
|||Steinhorn RH, Therapeutic approaches using nitric oxide in infants and children. Free radical biology [PubMed PMID: 21237265]|
|||Hunt JL,Bronicki RA,Anas N, Role of Inhaled Nitric Oxide in the Management of Severe Acute Respiratory Distress Syndrome. Frontiers in pediatrics. 2016; [PubMed PMID: 27532031]|
|||Joshi MS,Ferguson TB Jr,Han TH,Hyduke DR,Liao JC,Rassaf T,Bryan N,Feelisch M,Lancaster JR Jr, Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions. Proceedings of the National Academy of Sciences of the United States of America. 2002 Aug 6; [PubMed PMID: 12124398]|
|||Radomski MW,Moncada S, Regulation of vascular homeostasis by nitric oxide. Thrombosis and haemostasis. 1993 Jul 1; [PubMed PMID: 7694388]|
|||Samama CM,Diaby M,Fellahi JL,Mdhafar A,Eyraud D,Arock M,Guillosson JJ,Coriat P,Rouby JJ, Inhibition of platelet aggregation by inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology. 1995 Jul; [PubMed PMID: 7605019]|
|||Bogdan C, Nitric oxide and the immune response. Nature immunology. 2001 Oct; [PubMed PMID: 11577346]|
|||Hess D,Bigatello L,Hurford WE, Toxicity and complications of inhaled nitric oxide. Respiratory care clinics of North America. 1997 Dec; [PubMed PMID: 9443360]|
|||Kinsella JP, Inhaled nitric oxide in the term newborn. Early human development. 2008 Nov; [PubMed PMID: 18930613]|
|||Petit PC,Fine DH,Vásquez GB,Gamero L,Slaughter MS,Dasse KA, The Pathophysiology of Nitrogen Dioxide During Inhaled Nitric Oxide Therapy. ASAIO journal (American Society for Artificial Internal Organs : 1992). 2017 Jan/Feb; [PubMed PMID: 27556146]|
|||Hallman M,Bry K,Turbow R,Waffarn F,Lappalainen U, Pulmonary toxicity associated with nitric oxide in term infants with severe respiratory failure. The Journal of pediatrics. 1998 May; [PubMed PMID: 9602194]|
|||Clark RH,Kueser TJ,Walker MW,Southgate WM,Huckaby JL,Perez JA,Roy BJ,Keszler M,Kinsella JP, Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. The New England journal of medicine. 2000 Feb 17; [PubMed PMID: 10675427]|
|||Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The New England journal of medicine. 1997 Feb 27; [PubMed PMID: 9036320]|
|||Peliowski A, Inhaled nitric oxide use in newborns. Paediatrics [PubMed PMID: 23372402]|
|||Schreiber MD,Gin-Mestan K,Marks JD,Huo D,Lee G,Srisuparp P, Inhaled nitric oxide in premature infants with the respiratory distress syndrome. The New England journal of medicine. 2003 Nov 27; [PubMed PMID: 14645637]|
|||Dawson VL,Dawson TM, Nitric oxide neurotoxicity. Journal of chemical neuroanatomy. 1996 Jun; [PubMed PMID: 8811421]|