Nitric Oxide Story

Abstract Inhaled Nitric Oxide in Persistent Pulmonary Hypertension of the Newborn. By Roberts JD, Polaner DM, Lang P, and Zapol WM. Lancet 1992; 130:435–40. Reprinted with permission. NO has vasodilatory effects on the pulmonary vasculature in adults and animals. We examined the effects on systemic oxygenation and blood pressure of inhaling up to 80 parts per million by volume of NO at fraction of inspired oxygen 0.9 for up to 30 min by six infants with persistent pulmonary hypertension of the newborn. In all infants, this treatment rapidly and significantly increased preductal oxygen saturation; in five infants, postductal oxygen saturation and oxygen tensions also increased. Inhalation of NO did not cause systemic hypotension or raise methemoglobin. These data suggest that low levels of inhaled NO have an important role in the reversal of hypoxemia due to persistent pulmonary hypertension of the newborn.

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Efficacy and safety of endotracheal instillation of iloprost for persistent pulmonary hypertension of the newborn

Cardiology in the Young ◽

10.1017/s1047951121005072 ◽

2022 ◽

pp. 1-7

Author(s):

Asli Okbay Gunes ◽

Murat Ciftel ◽

Mehmet Emcet Timur ◽

Ceren Dedebali ◽

Betul Zehra Pirdal

Keyword(s):

Pulmonary Hypertension ◽

Oxygen Saturation ◽

Saturation Index ◽

Persistent Pulmonary Hypertension ◽

Systolic Pulmonary Artery Pressure ◽

Mean Airway Pressure ◽

Pressure Oxygen ◽

Before And After ◽

Fraction Of Inspired Oxygen ◽

Inspired Oxygen

Abstract Objective: To determine the efficacy and safety of endotracheal instillation of iloprost as a rescue therapy for persistent pulmonary hypertension of the newborn. Methods: Neonates diagnosed with persistent pulmonary hypertension who were unresponsive to standard treatment protocol applied for persistent pulmonary hypertension in our unit, and who were being followed up with mechanical ventilation, were included in the study. Iloprost was instilled endotracheally as a rescue treatment. Systolic pulmonary artery pressure, oxygen saturation index, mean airway pressure, fraction of inspired oxygen, preductal and postductal venous oxygen saturation, heart rate, and blood pressure were recorded before and after 30 minutes of endotracheal iloprost instillation. Adverse events after endotracheal iloprost were recorded. Results: Twenty neonates were included. The median gestational age and birth weight were found to be 37 (30.5-38) weeks and 2975 (2125-3437.5) grams, respectively. When compared to the period before endotracheal iloprost instillation, systolic pulmonary artery pressure, oxygen saturation index, mean airway pressure, and fraction of inspired oxygen values significantly decreased (p < 0.001, p < 0.001, p = 0.021, p = 0.001, respectively), whereas preductal and postductal oxygen saturation values significantly increased 30 minutes after the endotracheal iloprost instillation (p = 0.002, p < 0.001, respectively). There were no significant differences in heart rate and blood pressure values before and after the iloprost administration. No adverse events were observed. Conclusion: Endotracheal instillation of iloprost was found to be an effective and safe therapy for persistent pulmonary hypertension unresponsive to conventional treatment.

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Inhaled Nitric Oxide at Birth Reduces Pulmonary Vascular Resistance and Improves Oxygenation in Preterm Lambs

Children ◽

10.3390/children8050378 ◽

2021 ◽

Vol 8 (5) ◽

pp. 378

Author(s):

Satyan Lakshminrusimha ◽

Sylvia F. Gugino ◽

Krishnamurthy Sekar ◽

Stephen Wedgwood ◽

Carmon Koenigsknecht ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Vascular Resistance ◽

Preterm Infants ◽

Vascular Resistance ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension ◽

Inhaled No ◽

Birth Preterm

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147–150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

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Inhaled nitric oxide in the management of persistent pulmonary hypertension of the newborn: a meta-analysis

Revista do Hospital das Clínicas ◽

10.1590/s0041-87812000000400006 ◽

2000 ◽

Vol 55 (4) ◽

pp. 145-154 ◽

Cited By ~ 9

Author(s):

Carlos Augusto Cardim de Oliveira ◽

Eduardo J Troster ◽

Crésio R Pereira

Keyword(s):

Nitric Oxide ◽

Central Nervous System ◽

Pulmonary Hypertension ◽

Nervous System ◽

Pulmonary Disease ◽

Diaphragmatic Hernia ◽

Persistent Pulmonary Hypertension ◽

Chronic Pulmonary Disease ◽

The Central Nervous System ◽

Inhaled No

OBJECTIVES: To evaluate the use of inhaled nitric oxide (NO) in the management of persistent pulmonary hypertension of the newborn. METHODS: Computerized bibliographic search on MEDLINE, CURRENT CONTENTS and LILACS covering the period from January 1990 to March 1998; review of references of all papers found on the subject. Only randomized clinical trials evaluating nitric oxide and conventional treatment were included. OUTCOMES STUDIED: death, requirement for extracorporeal membrane oxygenation (ECMO), systemic oxygenation, complications at the central nervous system and development of chronic pulmonary disease. The methodologic quality of the studies was evaluated by a quality score system, on a scale of 13 points. RESULTS: For infants without congenital diaphragmatic hernia, inhaled NO did not change mortality (typical odds ratio: 1.04; 95% CI: 0.6 to 1.8); the need for ECMO was reduced (relative risk: 0.73; 95% CI: 0.60 to 0.90), and the oxygenation was improved (PaO2 by a mean of 53.3 mm Hg; 95% CI: 44.8 to 61.4; oxygenation index by a mean of -12.2; 95% CI: -14.1 to -9.9). For infants with congenital diaphragmatic hernia, mortality, requirement for ECMO, and oxygenation were not changed. For all infants, central nervous system complications and incidence of chronic pulmonary disease did not change. CONCLUSIONS: Inhaled NO improves oxygenation and reduces requirement for ECMO only in newborns with persistent pulmonary hypertension who do not have diaphragmatic hernia. The risk of complications of the central nervous system and chronic pulmonary disease were not affected by inhaled NO.

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Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00144.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. L27-L35 ◽

Cited By ~ 12

Author(s):

Gregory A. Ross ◽

Peter Oishi ◽

Anthony Azakie ◽

Sohrab Fratz ◽

Robert K. Fitzgerald ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Soluble Guanylate Cyclase ◽

Pulmonary Vasculature ◽

Protein Levels ◽

Endothelial Response ◽

Endogenous Nitric Oxide ◽

Acute Increase ◽

Clinically Significant ◽

Inhaled No

Clinically significant increases in pulmonary vascular resistance (PVR) have been noted upon acute withdrawal of inhaled nitric oxide (iNO). Previous studies in the normal pulmonary circulation demonstrate that iNO increases endothelin-1 (ET-1) levels and decreases endogenous nitric oxide synthase (NOS) activity, implicating an endothelial etiology for the increase in resistance upon iNO withdrawal. However, the effect of iNO on endogenous endothelial function in the clinically relevant pulmonary hypertensive circulation is unknown. The objective of this study was to determine the effects of iNO on endogenous NO-cGMP and ET-1 signaling in lambs with preexisting pulmonary hypertension secondary to increased pulmonary blood flow. Eight fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt lambs). After delivery (4 wk), the shunt lambs were mechanically ventilated with iNO (40 ppm) for 24 h. After 24 h of inhaled NO, plasma ET-1 levels increased by 34.8% independently of changes in protein levels ( P < 0.05). Contrary to findings in normal lambs, total NOS activity did not decrease during iNO. In fact, Western blot analysis demonstrated that tissue endothelial NOS protein levels decreased by 43% such that NOS activity relative to protein levels actually increased during iNO ( P < 0.05). In addition, the β-subunit of soluble guanylate cyclase decreased by 70%, whereas phosphodiesterase 5 levels were unchanged ( P < 0.05). Withdrawal of iNO was associated with an acute increase in PVR, which exceeded baseline PVR by 45%, and a decrease in cGMP concentrations to levels that were below baseline. These data suggest that the endothelial response to iNO and the potential mechanisms of rebound pulmonary hypertension are dependent upon the underlying pulmonary vasculature.

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Nitric oxide in persistent pulmonary hypertension of the newborn

Jornal de Pediatria ◽

10.2223/jped.582 ◽

1996 ◽

Vol 72 (3) ◽

Author(s):

Humberto H. Fiori ◽

Renato M. Fiori

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Persistent Pulmonary Hypertension

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Methemoglobin and the response to inhaled nitric oxide in persistent pulmonary hypertension of the newborn

Journal of Neonatal-Perinatal Medicine ◽

10.3233/npm-180082 ◽

2020 ◽

Vol 13 (2) ◽

pp. 175-182

Author(s):

R. Dadiz ◽

J. Nair ◽

C.T. D’Angio ◽

R.M. Ryan ◽

S. Lakshminrusimha

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension

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Recombinant Human Superoxide Dismutase Enhances the Effect of Inhaled Nitric Oxide in Persistent Pulmonary Hypertension

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/ajrccm.164.5.2010104 ◽

2001 ◽

Vol 164 (5) ◽

pp. 834-839 ◽

Cited By ~ 77

Author(s):

ROBIN H. STEINHORN ◽

GEORGE ALBERT ◽

DANIEL D. SWARTZ ◽

JAMES A. RUSSELL ◽

CAROLYN R. LEVINE ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Superoxide Dismutase ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension

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Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.2.435 ◽

1998 ◽

Vol 84 (2) ◽

pp. 435-441 ◽

Cited By ~ 30

Author(s):

Christophe Adrie ◽

Fumito Ichinose ◽

Alexandra Holzmann ◽

Larry Keefer ◽

William E. Hurford ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Vascular Resistance ◽

Pulmonary Circulation ◽

Half Life ◽

Hemodynamic Effects ◽

Pulmonary Vasodilation ◽

Short Half Life ◽

Acute Pulmonary Hypertension ◽

Inhaled No

Adrie, Christophe, Fumito Ichinose, Alexandra Holzmann, Larry Keefer, William E. Hurford, and Warren M. Zapol. Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension. J. Appl. Physiol. 84(2): 435–441, 1998.—Sodium 1-( N, N-diethylamino)diazen-1-ium-1,2-diolate {DEA/NO; Et2N[N(O)NO]Na} is a compound that spontaneously generates nitric oxide (NO). Because of its short half-life (2.1 min), we hypothesized that inhaling DEA/NO aerosol would selectively dilate the pulmonary circulation without decreasing systemic arterial pressure. We compared the pulmonary selectivity of this new NO donor with two other reference drugs: inhaled NO and inhaled sodium nitroprusside (SNP). In seven awake sheep with pulmonary hypertension induced by the infusion of U-46619, we compared the hemodynamic effects of DEA/NO with those of incremental doses of inhaled NO gas. In seven additional awake sheep, we examined the hemodynamic effects of incremental doses of inhaled nitroprusside (i.e., SNP). Inhaled NO gas selectively dilated the pulmonary vasculature. Inhaled DEA/NO produced nonselective vasodilation; both systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were reduced. Inhaled SNP selectively dilated the pulmonary circulation at low concentrations (≤10−2 M), inducing a decrease of PVR of up to 42% without any significant decrease of SVR (−5%), but nonselectively dilated the systemic circulation at larger doses (>10−2 M). In conclusion, despite its short half-life, DEA/NO is not a selective pulmonary vasodilator compared with inhaled NO. Inhaled SNP appears to be selective to the pulmonary circulation at low doses but not at higher levels.

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Comparison of the hemodynamic effects of nitric oxide and endothelium-dependent vasodilators in intact lungs

Journal of Applied Physiology ◽

10.1152/jappl.1990.68.2.735 ◽

1990 ◽

Vol 68 (2) ◽

pp. 735-747 ◽

Cited By ~ 51

Author(s):

S. L. Archer ◽

K. Rist ◽

D. P. Nelson ◽

E. G. DeMaster ◽

N. Cowan ◽

...

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Pulmonary Hypertension ◽

Feedback Inhibition ◽

Pressor Response ◽

Pulmonary Vasculature ◽

Hemodynamic Effects ◽

Isolated Lung

The effects of endothelium-dependent vasodilation on pulmonary vascular hemodynamics were evaluated in a variety of in vivo and in vitro models to determine 1) the comparability of the hemodynamic effects of acetylcholine (ACh), bradykinin (BK), nitric oxide (NO), and 8-bromo-guanosine 3′,5′-cyclic monophosphate (cGMP), 2) whether methylene blue is a useful inhibitor of endothelium-dependent relaxing factor (EDRF) activity in vivo, and 3) the effect of monocrotaline-induced pulmonary hypertension on the responsiveness of the pulmonary vasculature to ACh. In isolated rat lungs, which were preconstricted with hypoxia, ACh, BK, NO, and 8-bromo-cGMP caused pulmonary vasodilation, which was not inhibited by maximum tolerable doses of methylene blue. Methylene blue did not inhibit EDRF activity in any model, despite causing increased pulmonary vascular tone and responsiveness to various constrictor agents. There were significant differences in the hemodynamic characteristics of ACh, BK, and NO. In the isolated lung, BK and NO caused transient decreases of hypoxic vasoconstriction, whereas ACh caused more prolonged vasodilation. Pretreatment of these lungs with NO did not significantly inhibit ACh-induced vasodilation but caused BK to produce vasoconstriction. Tachyphylaxis, which was agonist specific, developed with repeated administration of ACh or BK but not NO. Tachyphylaxis probably resulted from inhibition of the endothelium-dependent vasodilation pathway proximal to NO synthesis, because it could be overcome by exogenous NO. Pretreatment with 8-bromo-cGMP decreased hypoxic pulmonary vasoconstriction and, even when the hypoxic pressor response had largely recovered, subsequent doses of ACh and NO failed to cause vasodilation, although BK produced vasoconstriction. These findings are compatible with the existence of feedback inhibition of the endothelium-dependent relaxation by elevation of cGMP levels. Responsiveness to ACh was retained in lungs with severe monocrotaline-induced pulmonary hypertension. Many of these findings would not have been predicted based on in vitro studies and illustrate the importance for expanding studies of EDRF to in vivo and ex vivo models.

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