Effects of Low Doses of Inhaled Nitric Oxide Combined with Oxygen for the Evaluation of Pulmonary Vascular Reactivity in Patients with Pulmonary Hypertension (original) (raw)
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Inhaled NO in the experimental setting
Early Human Development, 2008
Nitric oxide, a gas molecule, is a unique pharmaceutical agent that can be inhaled and thus delivered directly to the lung. More than a decade of intensive laboratory and clinical investigation has culminated in the current role for inhaled NO as the only selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn (PPHN). Not surprisingly, this potent and successful therapy continues to be studied intensively to better define its mechanism of action and role in PPHN treatment. In addition, there remains intense interest in possible new applications for newborns, as well as strategies that may enhance its efficacy. This review describes several areas of current research on amplification of NO signaling in the neonatal pulmonary vasculature, and reviews our current knowledge about the role of iNO in other conditions such as congenital diaphragmatic hernia and congenital heart disease. In addition, laboratory and clinical studies addressing a potential role for iNO as a therapeutic modality for the preterm infant are reviewed.
Thorax, 1997
sistent pulmonary hypertension of the newborn. 5 In many patients with acute respiratory Background-Inhaled nitric oxide (NO) is a selective pulmonary vasodilator which distress syndrome (ARDS) inhaled NO reduces the pulmonary artery pressure and increases can improve gas exchange in acute lung injury. However, it is uncertain that this arterial oxygenation by lessening intrapulmonary shunt. 6 Experimentally, inhaled NO effect on arterial oxygenation can be generalised to all lung diseases. reverses hypoxic pulmonary vasoconstriction. 7 Inhaled NO, however, can worsen gas exchange Methods-The effects of inhaled NO on gas exchange were studied in nine patients by overcoming the usual physiological mechanisms of matching ventilation (V) and per-with chronic obstructive pulmonary disease (COPD), 11 patients with severe pul-fusion (Q). Whilst inhaled NO acts as a selective pulmonary vasodilator in some monary hypertension, and 14 healthy volunteers. A randomised sequence of patients with chronic obstructive pulmonary disease (COPD), it fails to improve 40 ppm of NO or air was inhaled for 20 minutes through an orofacial mask. oxygenation. 8 9 It is important to establish in which diseases inhaled NO fails to improve Results-Inhaled NO reduced mean (SE) transcutaneous arterial oxygen tension gas exchange. We have studied the change in arterial oxygenation during NO inhalation in (TcPO 2) from 9.6 (0.3) to 8.9 (0.4) kPa in healthy volunteers and from 7.4 (0.6) to patients with COPD and compared it with normal volunteers and patients with severe pul-7.0 (0.5) kPa in patients with COPD. There was no change in TcPO 2 in patients with monary hypertension. severe pulmonary hypertension. During inhalation of NO and air no change occurred in transcutaneous arterial carbon Methods dioxide tension (TcPCO 2), arterial oxygen Nine patients with COPD, 11 with severe pulsaturation (SaO 2) measured by pulse oximonary hypertension, and 14 healthy vometer, or cardiac output determined by lunteers were studied. All gave their informed the transthoracic impedance method. consent and the study was approved by the Conclusions-Inhaled NO does not imlocal hospital ethics committee. The diagnosis prove TcPO 2 nor increase cardiac output in of COPD was established from a history of normal subjects and patients with COPD, clinical and physiological evidence of irsuggesting that inhaled NO worsens gas reversible airway obstruction. All patients with exchange. This could represent inhaled Section of Respiratory COPD ceased bronchodilators 12 hours before NO overriding hypoxic pulmonary vaso-Medicine, the study. The diagnosis of severe pulmonary Floor F, The Medical constriction in COPD. The finding that hypertension was established by previous right School, TcPO 2 also fell when normal subjects in-University of Sheffield, heart catheterisation. All patients with severe haled NO suggests that a similar mech-Sheffield S10 2RX, UK pulmonary hypertension were receiving vaso-Y Katayama anism normally contributes to optimal gas dilator therapy. T W Higenbottam exchange. Whilst inhaled NO can improve Measurements were made after breathing M J Diaz de Atauri oxygenation, this effect should not be con-G Cremona normal air or after breathing air with 40 ppm S Akamine sidered to be a general response but is NO, both for 20 minutes. The order of giving dependent on the type of lung disease. the treatments was randomised and delivered Servei de (Thorax 1997;52:120-124) Pneumologia, in a single blind fashion.
Inhaled NO as a therapeutic agent
Cardiovascular Research, 2007
In 1991, Frostell and colleagues reported that breathing low concentrations of nitric oxide (NO) decreased pulmonary artery pressure (PAP) in awake lambs with experimental pulmonary arterial hypertension (PAH) . Subsequently, efforts of multiple research groups studying animals and patients led to approval of inhaled NO by the US Food and Drug Administration in 1999 and the European Medicine Evaluation Agency and European Commission in 2001. Inhaled NO is currently indicated for the treatment of term and near-term neonates with hypoxemia and PAH. Since regulatory approval, several studies have suggested that NO inhalation can prevent chronic lung disease in premature infants. In addition, unanticipated systemic effects of inhaled NO may lead to treatments for a variety of disorders including ischemia-reperfusion injury.
Inhaled nitric oxide and pulmonary vasoreactivity
Journal of clinical monitoring and computing, 2000
Inhaled nitric oxide is a ubiquitous molecule which is produced endogenously and is also found in air pollution and in cigarette smoke. After describing the chemistry of NO, we review its history from the first description in 1980 to the current clinical indications. The biosynthesis of NO, its effects on pulmonary vasoreactivity, and the administration of inhaled NO will be described. The indications, uses, and side effects of inhaled NO are discussed with an emphasis on withdrawal of NO therapy, specifically the "rebound" phenomenon. Possible drug interactions are listed. Inhaled nitric oxide is here to stay, and future studies will provide more information on its therapeutic dose, duration and potential toxicity.
Inhaled Nitric Oxide: The authors reply
Critical Care Medicine, 1999
Inhaled nitric oxide (NO) plays an important role in treating persistent pulmonary hypertension of the newborn (PPHN), which is marked by a pathologic elevation of pulmonary vascular resistance. There is good evidence that the use of inhaled NO reduces the need for extracorporeal membrane oxygenation for term babies with severe PPHN of any cause, except in those infants with congenital diaphragmatic hernia, for which a benefit has not been shown. Although reducing the need for extracorporeal membrane oxygenation is beneficial in terms of cost and morbidity, inhaled NO has not been shown to decrease mortality in any neonatal population. Inhaled NO has also been shown to improve oxygenation in premature infants, although longer-term benefits have not been consistently demonstrated. This article will review the physiology of NO, its mechanisms of action in PPHN, and examine the evidence that supports its use in term and preterm infants with pulmonary hypertension.
Inhaled nitric oxide: clinical applications
Current Paediatrics, 1995
Up to a decade ago, nitric oxide (NO) was viewed primarily as a toxic gas responsible for a portion of the morbidity related to air pollution. In contrast, NO currently is recognised as a major endogenous mediator of an extraordinary range of functions including vascular regulation, neurotransmission, host defence and cytotoxicity. An increasing volume of literature has shown the importance of NO in the regulation of various cardiopulmonary functions and suggested its involvement in several disease processes. There is now compelling experimental evidence suggesting that inhaled NO may be beneficial in disease states characterised by pulmonary vasoconstriction and ventilationperfusion mismatch. 1 Several diseases of newborns and older children are characterised by potentially life threatening hypoxaemia due to ventilation-perfusion mismatch in the lungs associated with pulmonary vasoconstriction and pulmonary hypertension. Inhaled NO therapy may prove beneficial in a number of these conditions. NO pharmacology Endogenous NO is synthesised in vascular endothelial cells from arginine by the enzyme nitric oxide synthase. The generated NO diffuses into the neighbouring smooth muscle cells where it activates soluble guanylate cyclase to convert guanosine triphosphate into cyclic guanosine monophosphate (cGMP). The intracellular accumulation of cGMP leads to smooth muscle relaxation (Figure). The NO generated by NO synthase is short lived as
Anesthesiology, 1991
S ince the recognition of nitric oxide (NO) as a key endothelial-derived vasodilator molecule in 1987, the field of NO research has expanded to encompass many areas of biomedical research. It is now well established that NO is an important signaling molecule throughout the body. The therapeutic potential of inhaled NO as a selective pulmonary vasodilator was suggested in a lamb model of pulmonary hypertension and in patients with pulmonary hypertension in 1991. 1,2 Because NO is scavenged by hemoglobin (Hb) on diffusing into the blood and is thereby rapidly inactivated, the vasodilatory effect of inhaled NO is limited largely to the lung. This is in contrast to intravenously infused vasodilators that can cause systemic vasodilation and severe systemic arterial hypotension. Recent data indicate that inhaled NO can be applied in various diseases. For example, studies suggest that inhaled NO is a safe and effective agent to determine the vasodilatory capacity of the pulmonary vascular bed. This article summarizes the pharmacology and physiology of inhaled NO and reviews the current uses of inhaled NO for the treatment, evaluation, and prevention of cardiovascular and respiratory diseases. Pharmacology and Physiology of Inhaled NO Chemistry of NO Gas NO is a colorless, odorless gas that is only slightly soluble in water. 3 NO and its oxidative byproducts (eg, NO 2 and N 2 O 4) are produced by the partial oxidation of atmospheric nitrogen in internal combustion engines, in the burning cinder cones of cigarettes, and in lightning storms. Medical-grade NO gas is produced under carefully controlled conditions, diluted with pure nitrogen, and stored in the absence of oxygen. The recent article by Williams 4 provides a review of the chemistry of NO. Therapeutic Versus Endogenous NO Concentrations in the Airway Although early studies of inhaled NO in the treatment of pulmonary hypertension used concentrations of 5 to 80 ppm, it has since been realized that concentrations Ͼ20 ppm provide little additional hemodynamic benefit in most patients. In some adults with acute respiratory failure, the effective concentrations of inhaled NO required to improve oxygenation can be as low as 10 ppb. 5,6 Of note, NO has been detected in exhaled human breath. The majority of exhaled NO in normal humans appears to be derived from nasal bacterial flora (25 to 64 ppb), with lower concentrations measured in the mouth, trachea, and distal airway (1 to 6 ppb). 5,7 From the Departments of Anesthesia and Critical Care (F.I.