Use of Nitric Oxide in Infants - Research Paper Example

?Use of Nitric Oxide in Infants Introduction Pediatrics and neonatology are constantly evolving fields and several recent advances have improved outcomes in various clinical conditions, especially in the newborn. One such condition is hypoxemic respiratory failure. Until a decade ago, newborns with this condition were managed with oxygen therapy and ventilation. The advent of new treatment modality, inhaled nitric oxide therapy, has changed the outcome of infants suffering from hypoxemic respiratory failure (1) and there is enormous research going on in this field. When I worked in neonatal intensive care units I was amazed at the potential benefits this therapy could deliver to sick patients with respiratory failure. Thereafter, I developed an interest in nitric oxide therapy. In this essay, uses of nitric oxide in infants will be discussed through review of appropriate literature. Literature review Nitric oxide Nitric oxide is an endogenous messenger molecule and is basically involved in the regulation of various tissues of our body physiologically (2). The molecule is shown to be useful as a therapeutic drug. Major use of this drug has been found to be in the inhaled form (2). Inhaled nitric oxide is one of the recent advances in neonatology. It provides scope for advanced treatment of hypoxic respiratory failure. Hypoxic respiratory failure is a common condition in newborn babies and can result due to various conditions like primary persistent pulmonary hypertension, aspiration pneumonia, respiratory distress syndrome, congenital pneumonia, meconium aspiration syndrome and congenital diaphragmatic hernia (2). Patients with these conditions receive various treatment including oxygen therapy, hyperventilation, high frequency ventilation, alkalosis induction, sedation and neuromuscular blockade. Despite aggressive treatments, significant proportion of the patients develops mortality and morbidity and may even need extracorporeal membrane oxygenation. Inhaled nitric oxide causes selective vasodilatation of the pulmonary vessels. Nitric oxide activates guanylyl cyclase activation leading to production of cyclic guanosine monophosphate and relaxation of smooth muscle. Inhaled nitric oxide not only improves oxygenation but also improves treatment outcomes (1). In infants with increased pulmonary vascular resistance secondary to right ventricular failure or in cases of primary persistent pulmonary hypertension doses between 2- 40ppm are effective in decreasing pulmonary vascular pressures (2). Other than primary persistent pulmonary hypertension, nitric oxide therapy is also useful in acute respiratory distress syndrome, interstitial pulmonary fibrosis and cardiac surgery. Mode of action Nitric oxide is naturally generated in the endothelium of the lung. It is derived from L-arginine after activation of the enzyme nitric oxide synthetase. Thereafter, nitric oxide diffuses into the muscle cells of the blood vessels and causes activation of the guanylate cyclase. This leads to increased production of cyclic guanosine monophosphate which leads to pulmonary vasodilation and improved ventilation-perfusion matching. Inhaled form of nitric oxide for treatment of severe hypoxemic respiratory failure in term infants with persistent primary pulmonary hypertension was used in 1992 (1) and since then several trials have been conducted to ascertain the role of inhaled nitric oxide therapy in both preterm and term infants. Inhaled form of nitric oxide causes selective vasodilatation of pulmonary blood vessels without interfering with systemic and coronary blood pressures. Uses of nitric oxide Nitric oxide is produced endogenously in our body and has a major role to play in regulating the muscle tone of blood vessels. Administration of exogenous nitric oxide, in the form of inhaled therapy, is a new emerging treatment modality for infants with hypoxaemic respiratory failure associated with persistent high pulmonary vascular pressure resulting in right to left shunting across ductus arteriosus, foramen ovale and intrapulmonary channels. Current evidence supports that inhaled nitric oxide therapy is useful for treatment of infants more than or equal to 35 weeks of gestation with hypoxemic respiratory failure who are not responding to conventional respiratory management (3). It is mandatory that all infants scheduled for inhaled nitric oxide therapy must undergo cardiac evaluation in the form of echocardiography to rule of cyanotic heart disease and also to assess pulmonary hypertension and myocardial function. According to Finer and Barrington (3) "inhaled nitric oxide is usually started in infants with an OI >20 to 25, or when the PaO2 remains less than 100 mmHg, despite optimal ventilation with 100% oxygen." In persistent primary pulmonary hypertension of the newborn, there is decreased pulmonary blood flow secondary to persistent fetal circulation. Inhaled nitric oxide has been proven to reduce pressures in the pulmonary vasculature, thereby improving blood supply and oxygenation. Various studies have demonstrated effective decrease of pressures in pulmonary vasculature thereby improving oxygenation with doses of 20ppm (2). Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation (3). However, it is unclear as to whether nitric oxide therapy reduces mortality (3). Another condition in which nitric oxide therapy is useful is respiratory distress syndrome which occurs in premature infants, mostly born before 30 weeks of gestation (4). Pulmonary hypertension is one of the complications of this condition leading to intrapulmonary shunting, severe hypoxemia and dysfunction of the myocardium. In this condition, nitric oxide causes decrease in pulmonary vascular resistance, improves ventilation-perfusion matching and thereby improves gas exchange (2). The effect is dose dependent (4). Inhaled nitric oxide has been found to be useful even in pediatric surgery cases. The drug has been used to assess reactivity of pulmonary vascular resistance in the preoperative phase, to diagnose various anatomic obstructions leading to pulmonary hypertension, to treat pulmonary hypertension when weaning from cardiopulmonary bypass and in the postoperative phase. A dose of 50ppm has been found to be useful in the postoperative period of patients who have undergone surgical correction of atrioventricular septal defects and ventricular septal defects (2). Studies have shown that in such cases, the pulmonary vascular resistance decreases by 43 percent and cardiac index increases to 30 percent (2). In children undergoing Fontan-type procedures, the drug improves hemodynamics by decreasing pulmonary vascular resistance which determines systemic cardiac output in Fontan-type anatomy cases where there is passive pulmonary blood flow exists (2). Nitric oxide has also been found to be useful in patients with sickle cell disease. Sickle cell disease is a condition in which the cell sickles during certain situations and lead to hemolysis and painful crises situations. Nitric oxide binds to hemoglobin and causes vasodilatation, preventing blocking of blood vessels by the red blood cells that are sickled. Thus oxygen delivery goes uninterrupted and resolution of painful crises occurs. The nitric oxide attached to hemoglobin alters the sickle shape of the blood cells and help in movement (2). Previously, neonatologists were of the opinion that in infants less than 35 weeks of gestation, inhaled nitric oxide therapy was useful in preventing bronchopulmonary dysplasia. However, the cochrane collaboration review opined that such early rescue therapy has no positive effect on the mortality or morbidity of infants (4). It does not decrease the risk of bronchopulmonary dysplasia either. Also, one major disadvantage in this scenario is increased risk of complications like intraventricular hemorrhage and periventricular leukomalacia (6). In view of conflicting evidence, routine use of inhaled nitric oxide in very sick preterm infants is guarded. However, there is vague evidence that treatment with inhaled nitric oxide in preterm babies with history of oligohydramnios and prolonged rupture of membranes, lowered mortality and bronchopulmonary dysplasia (4). Overall, it can be said that inhaled nitric oxide therapy is not useful as rescue therapy or as routine treatment in preterm infants who need assisted ventilation (2). It may however be considered in defined clinical situations like preterm babies who are critically ill and hence respiratory failure and history of oligohydramnios. Significance for respiratory care Side effects of nitric oxide therapy Inhaled nitric oxide is a drug and it has potential adverse effects like any other drugs. Even workers associated with the drug have potential side effects. Nitric oxide, in the presence of oxygen, gets converted to nitrogen dioxide which increases airway reactivity and also causes pulmonary parenchymal damage (2). High levels of nitric oxide can lead to methemoglobinemia which can interfere in tissue oxygenation and ultimately lead to tissue hypoxia and associated complications. Intraventricular hemorrhage and bleeding disorders can occur especially in premature infants (5). In those with left ventricular failure, inhaled nitric oxide can lead to pulmonary edema. Sudden withdrawal of nitric oxide therapy can lead to rebound hypoxemia and pulmonary hypertension. Thus, it is recommended that nitric oxide must be withdrawn gradually and high oxygen levels need to be administered at the time of withdrawal (2). Dosing of inhaled nitric oxide According to the American Academy of Pediatrics (1), "it is critical that infants with hypoxic respiratory failure in whom conventional ventilator therapy fails or is predicted to fail be cared for in institutions that have immediate availability of personnel, including physicians, nurses, and respiratory therapists, who are qualified to use multiple modes of ventilation and rescue therapies. Radiologic and laboratory support required to manage the broad range of needs of these infants is also essential." Inhaled nitric oxide is a very expensive drug and must be used only in conditions where other forms of treatment have failed. The treatment must be instituted only in tertiary level intensive care unit with expertise round the clock. Advanced forms of ventilatory support and multispecialist support must be available. American Academy of Pediatrics (1) also recommends that "inhaled nitric oxide should be administered using FDA-approved devices that are capable of administering inhaled nitric oxide in constant concentration ranges in parts per million or less throughout the respiratory cycle. Infants who receive inhaled nitric oxide therapy should be monitored according to institutionally derived protocols designed to avoid the potential toxic effects associated with inhaled nitric oxide administration. " The drug has a very short life of 2- 6 seconds (5). In the newborns, the dosing is 1-80ppm. Doses above 40ppm have risk of toxicity. The recommended dose is to start from 20 ppm and increase or decrease based on response. The response that is expected is rapid and can be seen within 30 minutes and PaO2 can increase by more than 20mmHg. In case there is no response, the dose may be increased to 40ppm. In preterm infants however, the initial dose can be 10ppm and this can be increased to 20ppm in non-responders. It is important to monitor nitrogen di oxide in the inspired mixture and that must be less than 0.5ppm. After an improvement has been noted in oxygenation and the infant is stable for 4-6 hours, during which time the oxygen requirement has decreased by 60-80 percent, nitric oxide therapy may be weaned. Every four hours, the dose must be decreased by 50 percent. As the dose reaches 1ppm and PaO2 is maintained consistently above 50mmHg, gradual cessation must be done and at this time, oxygen must be administered to prevent rebound of pulmonary hypertension. Weaning should be done over 24- 48 hours. The duration of safety with inhaled nitric oxide therapy is unknown. In most situations, the therapy is administered for 48 hours to 96 hours (5). According to American academy of Pediatrics (1) "generally, inhaled nitric oxide should be initiated in centers with ECMO capability. If inhaled nitric oxide is offered by a center without ECMO capability, for geographic or other compelling reasons, mutually acceptable treatment failure criteria and mechanisms for timely transfer of infants to a collaborating ECMO center should be established prospectively. Transfer must be accomplished without interruption of inhaled nitric oxide therapy. " Conclusion Inhaled nitric oxide therapy is a useful mode of treatment in infants with hypoxic respiratory failure. It improves oxygenation and also decreases the need to use extracorporeal membrane oxygenation. Clinical conditions in which it used has been ascertained are term and near term infants with meconium aspiration syndrome, primary persistent pulmonary hypertension and respiratory distress syndrome. It is clear currently, that there is not much role of this treatment in congenital diaphragmatic hernia cases. It role in preterm infants is unclear and guarded because of risk of intraventricular hemorrhage. The drug is safe to use when monitored in a tertiary level intensive care unit. The starting dose in term infants is 20 ppm and gradual weaning is crucial to prevent rebound pulmonary hypertension. When used in recommended doses, toxicity risk is minimal. References 1. American Academy of Pediatrics. Use of Inhaled Nitric Oxide. Pediatrics 2000; 106 (2): 344 -345. 2. Baysal A. Nitric Oxide II: Therapeutic Uses and Clinical Applications. Turk J med Sci. 2000; 32:1-6. 3. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2006; (4):CD000399. 4. Barrington KJ, Finer N. Review Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2010; (12):CD000509. 5. Peliowski A. Inhaled nitric oxide use in newborns. Paediatr Child Health. 2012; 17(2):95-100. 6. Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Preemie Inhaled Nitric Oxide Study Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353:13–22. Read More