Methemoglobin and nitric oxide therapy in Ugandan children hospitalized for febrile illness: results from a prospective cohort study and randomized double-blind placebo-controlled trial.

BACKGROUND: Exposure of red blood cells to oxidants increases production of methemoglobin (MHb) resulting in impaired oxygen delivery to tissues. There are no reliable estimates of methemoglobinemia in low resource clinical settings. Our objectives were to: i) evaluate risk factors for methemoglobinemia in Ugandan children hospitalized with fever (study 1); and ii) investigate MHb responses in critically ill Ugandan children with severe malaria treated with inhaled nitric oxide (iNO), an oxidant that induces MHb in a dose-dependent manner (study 2). METHODS: Two prospective studies were conducted at Jinja Regional Referral Hospital in Uganda between 2011 and 2013. Study 1, a prospective cohort study of children admitted to hospital with fever (fever cohort, n = 2089 children 2 months to 5 years). Study 2, a randomized double-blind placebo-controlled parallel arm trial of room air placebo vs. 80 ppm iNO as an adjunctive therapy for children with severe malaria (RCT, n = 180 children 1-10 years receiving intravenous artesunate and 72 h of study gas). The primary outcomes were: i) masimo pulse co-oximetry elevated MHb levels at admission (>2 %, fever cohort); ii) four hourly MHb levels in the RCT. RESULTS: In the fever cohort, 34 % of children admitted with fever had elevated MHb at admission. Children with a history of vomiting, delayed capillary refill, elevated lactate, severe anemia, malaria, or hemoglobinopathies had increased odds of methemoglobinemia (p < 0.05 in a multivariate model). MHb levels at admission were higher in children who died (n = 89) compared to those who survived (n = 1964), p = 0.008. Among children enrolled in the iNO RCT, MHb levels typically plateaued within 12-24 h of starting study gas. MHb levels were higher in children receiving iNO compared to placebo, and MHb > 10 % occurred in 5.7 % of children receiving iNO. There were no differences in rates of study gas discontinuation between trial arms. CONCLUSIONS: Hospitalized children with evidence of impaired oxygen delivery, metabolic acidosis, anemia, or malaria were at risk of methemoglobinemia. However, we demonstrated high-dose iNO could be safely administered to critically ill children with severe malaria with appropriate MHb monitoring. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01255215 (Date registered: December 5, 2010).

Nitric oxide-associated pulmonary edema in children with pulmonary venous hypertension.

Nitric oxide (NO)-associated pulmonary edema is rarely reported in children; in adults, it is often associated with left-sided heart failure. We report a case series of children with NO-associated pulmonary edema, which was defined as new multilobar alveolar infiltrates and worsening hypoxemia within 24 h of initiation or escalation of NO and radiologic or clinical improvement after NO discontinuation. We identified six patients (0.4-4 years old) with ten episodes of NO-associated pulmonary edema. Diagnoses included atrioventricular canal defect with mitral valve disease (n = 2), pulmonary atresia and major aorta-pulmonary collateral arteries (n = 2), total anomalous pulmonary venous return (n = 1), and pulmonary veno-occlusive disease (n = 1). All patients had evidence of pulmonary venous hypertension, and two had mitral valve disease resulting in clinical evidence of left-sided heart failure. Pulmonary edema improved or resolved within 24 h of discontinuing NO. At cardiac catheterization, mean left atrial pressure was <15 mmHg in three of three patients (none with mitral valve disease), whereas pulmonary artery occlusion pressure was >15 mmHg in two of five patients. In conclusion, we describe six young children with NO-associated pulmonary edema and pulmonary venous hypertension. Only two of these children had left-sided heart failure: Left atrial pressure as well as pulmonary artery occlusion pressure may not be helpful in identifying children at risk for NO-associated pulmonary edema.

Use of sildenafil to facilitate weaning from inhaled nitric oxide in children with pulmonary hypertension following surgery for congenital heart disease.

Pulmonary hypertension frequently complicates the postoperative management of patients after congenital cardiac surgery. Inhaled nitric oxide is an effective treatment option, but rebound pulmonary hypertension can occur upon its withdrawal. Sildenafil may facilitate its withdrawal by restoring cyclic guanosine monophosphate availability via phosphodiesterase-5 inhibition. The purpose of this study was to evaluate the use of sildenafil in facilitating weaning from inhaled nitric oxide after congenital cardiac surgery in patients who had previously failed weaning, and to compare the effects of sildenafil on pulmonary and systemic hemodynamics. Children who received sildenafil after cardiovascular surgery during a 23-month period at Riley Hospital for Children were identified. Medical records were retrospectively reviewed to determine sildenafil and nitric oxide dosing, pulmonary and systemic blood pressures, and adverse effects. Oral sildenafil was administered to 7 children who had failed attempts at inhaled nitric oxide weaning. Inhaled nitric oxide was weaned from 29.8+/-5.9 ppm prior to sildenafil initiation to 12.2+/-3.4 ppm (mean +/- SE; P= .024) in the 24 hours after sildenafil. Mean pulmonary artery and systemic arterial pressure were unchanged from baseline when measured 1 hour after sildenafil dosing (mean pulmonary artery pressure, 29+/-1 to 27+/-0.7 mm Hg, P= .066; mean systemic arterial pressure, 56+/-1.2 to 54+/-1.2 mm Hg, P= .202). Sildenafil may facilitate withdrawal of inhaled nitric oxide and prevent rebound pulmonary hypertension in patients previously failing inhaled nitric oxide weaning attempts.

Nitric oxide and nursing: a review.

AIMS AND OBJECTIVES: This paper, therefore, aimed to review published literature in this area of pharmacological exploitation, to look at the therapeutic applications and clinical relevance and, by so doing, provide an accessible source for nurses to gain insight into the role of nitric oxide in the clinical setting. BACKGROUND: Nitric oxide is a chemical mediator fundamental in the maintenance of adequate tissue perfusion and effective cardiovascular function; a major endogenous regulator of vascular tone. The use of nitrates are well established as pharmacological agents but it is only recently that it has been recognized that they act as a source of nitric oxide. Although widely addressed within the medical literature, there appears to be a paucity of nursing literature that explores either its physiological action, or its relevance to nursing practice. CONCLUSIONS: This literature review provides an overview of the use of nitric oxide and its implications for nursing practice and patient outcomes. RELEVANCE TO CLINICAL PRACTICE: Knowledge of nitric oxide and its action is pertinent to nurses across diverse specialities. It helps in understanding the principles of many nitrogen-derived medications which nurses administer to their patients on a daily basis. In terms of oral medication, this is demonstrated by greater insights into the action of nitrates, the appreciation of surprising developments in medications such as sildenafil and the development of new drug opportunities such as nitric oxide-non-steroidal anti-inflammatory drugs. Equally, the use of inhaled nitric oxide therapy in adult and neonatal critical care units appears to be an increasingly valuable source of treatment. A particular research challenge is found in the attempt at nitric oxide inhibition in the management of septic shock. The authors argue that understanding such esoteric areas of therapeutic developments is increasingly to be part of the repertoire of knowledge and skills for nurses in the 21st century.

The use of nitric oxide in neonatal care.

Knowledge of NO and its role in the human body currently is limited. Further scientific research involving this unique molecule will expand its clinical usefulness. It is an exciting era in research,involving numerous body processes and systems. The initial work on pulmonary vascular response in newborns who have PPHN has opened the door to seemingly endless possibilities involving many aspects of health.