Life-threatening effects of discontinuing inhaled nitric oxide in severe respiratory failure.

Lavoie, Annick; Hall, Jesse B.; Olson, David M.; Wylam, Mark E.

doi:10.1164/ajrccm.153.6.8665066

Cited by 127 publications

(58 citation statements)

References 11 publications

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“…A clinical rebound phenomenon is reported after discontinuation of long-term NO inhalation (1,10,17). Whether the mechanisms of the clinical rebound are similar to those of the rebound reaction after a short period (30 min) of NO inhalation, as demonstrated here, were not tested in the present study but remains a possibility.…”

Section: Rebound Phenomenon After Ino Withdrawalmentioning

confidence: 77%

“…nitric oxide inhalation; prostanoids INHALED NITRIC OXIDE (INO) is a selective pulmonary vasodilator in the treatment of pulmonary hypertension. However, life-threatening hemodynamic instability, reduced oxygenation, and even death have been observed during attempts to withdraw INO (1,10,17). These phenomena are referred to as the rebound response to INO withdrawal.…”

mentioning

confidence: 99%

“…However, life-threatening hemodynamic instability, reduced oxygenation, and even death have been observed during attempts to withdraw INO (1,10,17). These phenomena are referred to as the rebound response to INO withdrawal.…”

mentioning

confidence: 99%

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Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model

Chen

Mondéjar

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Chen, Luni, Hao He, Enrique Fernandez Mondejar, and Gö ran Hedenstierna. Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model. Am J Physiol Heart Circ Physiol 284: H290-H298, 2003; 10.1152/ajpheart.00535.2002.-This study addressed the possible role of cyclooxygenase (COX) and its products in the rebound response to inhaled nitric oxide (INO). Anesthetized, mechanically ventilated piglets were exposed to endotoxin alone, endotoxin combined with INO, or endotoxin with INO plus the COX inhibitor diclofenac (3 mg/kg iv) (n ϭ 8 piglets/ group). A control group of healthy pigs (n ϭ 6) was also studied. Measurements were made of blood gases, hemodynamic parameters, lung tissue COX expression, and plasma concentrations of thromboxane B2 (TxB2), PGF2␣, and 6-keto-PGF1␣. Endotoxin increased lung inducible COX (COX-2) expression and circulating prostanoids concentrations. Inhalation of NO during endotoxemia increased the constitutive COX (COX-1) expression, and the circulating TxB2 and PGF2␣ increased further after INO withdrawal. The combination of COX inhibitor with INO blocked all these changes and eliminated the rebound reaction to INO withdrawal, which otherwise was seen in endotoxemic piglets given INO only. We conclude that the rebound response to INO discontinuation is related to COX products. nitric oxide inhalation; prostanoids INHALED NITRIC OXIDE (INO) is a selective pulmonary vasodilator in the treatment of pulmonary hypertension. However, life-threatening hemodynamic instability, reduced oxygenation, and even death have been observed during attempts to withdraw INO (1,10,17). These phenomena are referred to as the rebound response to INO withdrawal. Stepwise reduction of the NO dose implies prolongation of the NO therapy and may still not eliminate the rebound response (10).The mechanisms responsible for the rebound response are not fully understood. NO stimulates the release of soluble guanylate cyclase from the tissues, with a consequent increase in cGMP. INO reduces the endogenous NO production as a negative feedback mechanism, and this mechanism is assumed to be related to the rebound reaction to INO withdrawal (1, 2, 9). We have previously found that the production and/or release of the vasoconstrictor peptide endothelin-1 (ET-1) and possibly of other vasoconstrictors is also related to the rebound, and this may be even more important than the downregulation of endogenous NO production by INO (5).ET-1 and some prostanoids, in particular thromboxane A 2 (TxA 2 ) and PGF 2␣ , are important vasoconstriction mediators in primary and secondary pulmonary hypertension (6,22,23). In addition, ET-1-stimulated secondary release of TxA 2 is one of the main modes of signal transduction in ET-1-induced vasoconstriction (21). PGI 2 and TxA 2 , and PGF 2␣ , are important mutually antagonistic vasodilator and vasoconstrictor products, respectively, of arachidonic acid. They are synthesized via a cyclooxygenase (COX)-dependent pathway. A PGI 2 analog has been reported to mitigate th...

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Section: Rebound Phenomenon After Ino Withdrawalmentioning

confidence: 77%

mentioning

confidence: 99%

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Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model

Chen

Mondéjar

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…However, the clinical use of iNO is limited by its need for continuous delivery and by the high cost of the delivery and monitoring system. In addition, sudden discontinuation of iNO therapy can be associated with life-threatening deterioration of oxygenation and rebound pulmonary hypertension (13).…”

Section: Discussionmentioning

confidence: 99%

“…In animal models of pulmonary hypertension induced by GBS sepsis, iNO was effective in reducing pulmonary hypertension in both early and late phase (10 -12). However, the short half-life of iNO is a major shortcoming, which requires its continuous delivery (13).…”

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confidence: 99%

Effects of a Nebulized NONOate, DPTA/NO, on Group B Streptococcus–Induced Pulmonary Hypertension in Newborn Piglets

et al. 2005

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NONOates are chemical compounds that are stable as solids but generate nitric oxide (NO) in aqueous solutions. When nebulized or instilled intratracheally, NONOates can attenuate pulmonary hypertension in adult animals with lung injury. To assess the effect of a nebulized NONOate, DPTA/NO, on group B Streptococcus (GBS)-induced pulmonary hypertension in newborn piglets, we studied 20 anesthetized and mechanically ventilated piglets (4 -10 d). They were randomly assigned to receive nebulized placebo solution or DPTA/NO (100 mg) 15 min after sustained pulmonary hypertension. Pulmonary artery and wedge, systemic, and right atrial pressures; cardiac output; and arterial blood gases were obtained at baseline and every 15 min during 120 min of continuous GBS infusion (6 ϫ 10 8 CFU/min). Methemoglobin levels were measured at baseline and 60 min. A significant decrease in pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic arterial pressure, and systemic vascular resistance (SVR) was observed after DPTA/NO nebulization (p Ͻ 0.001). Whereas the increase in PVR/SVR observed after GBS infusion was sustained for 120 min in the placebo group, this ratio decreased after DPTA/NO nebulization and remained significantly lower throughout the study period (p Ͻ 0.01). Cardiac output, arterial blood gases, and methemoglobin values did not differ between groups. These data demonstrate that the pulmonary hypertension induced by GBS infusion is markedly attenuated by DPTA/NO nebulization. The lower PVR/SVR observed in the treated group indicates that the vasodilatory effect of NONOate is more pronounced in the pulmonary than systemic vasculature. Therefore, NONOates may have clinical application in the management of pulmonary hypertension secondary to sepsis in neonates. Group B Streptococcus (GBS) sepsis is characterized by pulmonary hypertension, arterial hypoxemia, metabolic acidosis, decreased cardiac output (CO), and systemic hypotension progressing sometimes to irreversible shock (1). Despite modern intensive care, this condition continues to carry high morbidity and mortality. Many modalities have been proposed for the management of pulmonary hypertension, including cytokine inhibitors and vasodilators (2-7). However, clinical application of these modalities is limited because of significant side effects and lack of selectivity to the pulmonary vasculature.Inhaled nitric oxide (iNO) has emerged in recent years as an effective and selective treatment modality for pulmonary hypertension. Its effectiveness in treating persistent pulmonary hypertension of the newborn was documented in a number of animal models and also clinical trials (8,9). In animal models of pulmonary hypertension induced by GBS sepsis, iNO was

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Reactive Oxygen Species in Pulmonary Vascular Remodeling

Aggarwal

Groß

Sharma

et al. 2013

Comprehensive Physiology

126

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The pathogenesis of pulmonary hypertension is a complex multifactorial process that involves the remodeling of pulmonary arteries. This remodeling process encompasses concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by vascular smooth muscle cell (SMC) hyperplasia and hypertrophy. In addition, in uncontrolled pulmonary hypertension, the clonal expansion of apoptosis-resistant endothelial cells leads to the formation of plexiform lesions. Based upon a large number of studies in animal models, the three major stimuli that drive the vascular remodeling process are inflammation, shear stress and hypoxia. Although, the precise mechanisms by which these stimuli impair pulmonary vascular function and structure are unknown, reactive oxygen species (ROS)-mediated oxidative damage appears to play an important role. ROS are highly reactive due to their unpaired valence shell electron. Oxidative damage occurs when the production of ROS exceeds the quenching capacity of the anti-oxidant mechanisms of the cell. ROS can be produced from complexes in the cell membrane (nicotinamide adenine dinucleotide phosphate-oxidase), cellular organelles (peroxisomes and mitochondria), and in the cytoplasm (xanthine oxidase). Furthermore, low levels of tetrahydrobiopterin (BH4) and L-arginine the rate limiting co-factor and substrate for endothelial nitric oxide synthase (eNOS), can cause the uncoupling of eNOS, resulting in decreased NO production and increased ROS production. This review will focus on the ROS generation systems, scavenger antioxidants, and oxidative stress associated alterations in vascular remodeling in pulmonary hypertension.

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Life-threatening effects of discontinuing inhaled nitric oxide in severe respiratory failure.

Cited by 127 publications

References 11 publications

Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model

Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model

Effects of a Nebulized NONOate, DPTA/NO, on Group B Streptococcus–Induced Pulmonary Hypertension in Newborn Piglets

Reactive Oxygen Species in Pulmonary Vascular Remodeling

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