We are sorry, but NCBI web applications do not support your browser, and may not function properly. More information here...
`Resources
`How To
`
`US National Library of Medicine
`National Institutes of Health
`
`PMC
`
`
`Limits Advanced
`
`Journal list
`
`Journal List > Images Paediatr Cardiol > v.4(1); Jan-Mar 2002 > PMC3232511
`
`Images Paediatr Cardiol. 2002 Jan-Mar; 4(1): 4–29.
`
`PMCID: PMC3232511
`
`Inhaled nitric oxide applications in paediatric practice
`*
`*
`A Bernasconi and M Beghetti
`
`Author information ► Copyright and License information ►
`
`Abstract
`
`Go to:
`
`The nitric oxide pathway plays a pivotal, yet diverse, role in human physiology, including modulation of
`vascular tone, neural transmission and inflammation. Inhaled nitric oxide is a selective pulmonary
`vasodilator that has emerged rapidly as an important therapeutic agent. It finds its best applications in
`paediatrics; the use of iNO in term neonates with hypoxaemic respiratory failure, in the assessment of
`pulmonary vascular reactivity and in the treatment of postoperative pulmonary hypertension in
`congenital heart disease is well recognised and accepted. This review details the delivery and monitoring
`aspects of inhaled nitric oxide, its potential toxic and side effects and its applications in several
`cardiopulmonary disorders in paediatrics.
`
`MeSH: Heart defects, congenital, Hypertension, pulmonary, Infant, premature, Newborn, Nitric oxide,
`Paediatrics
`
`Introduction
`
`Go to:
`
`Inhaled nitric oxide (iNO) therapy is nowadays recognised as an important tool for the treatment and
`diagnosis of pulmonary vascular and airspace disease. Nitric oxide (NO) is a naturally occurring gas with
`1,2
`multiple biological actions. Endogenous NO plays a role in the modulation of vascular tone,
` the
`3
`regulation of platelet function, neuronal transmission and the inflammatory response. NO is formed, in
`the endothelial cell, from L-arginine and molecular oxygen in a reaction catalysed by the enzyme nitric
`4
`oxide synthase (NOS). Three different isoforms of NOS exist: NOS 1, a constitutive form first identified
`in neurons named nNOS; NOS2, an inducible form, first found in activated leukocytes called iNOS; and
`open in browser PRO version Are you a developer? Try out the HTML to PDF API
`
` Search
`
`Sign in to NCBI
`
`Help
`
`Formats:
`Abstract | Article | PubReader | ePub (beta) | Printer
`Friendly
`
`Related citations in PubMed
`Clinical applications of inhaled nitric oxide in children with
`[Adv Pharmacol. 1995]
`pulmonary hypertension.
`Nitric oxide for respiratory failure in infants born at or near term.
`[Cochrane Database Syst Rev. 2006]
`Inhaled nitric oxide in premature neonates with severe
`[Lancet. 1999]
`hypoxaemic respiratory failure: a randomised controlled trial.
`Residual pulmonary hypertension in children after treatment with
`[Acta Paediatr. 2000]
`inhaled nitric oxide: a follow-up study regarding cardiopulmonary
`and neurological symptoms.
`Disease-related response to inhaled nitric oxide in newborns with
`[Eur J Pediatr. 1998]
`severe hypoxaemic respiratory failure. French Paediatric Study
`Group of Inhaled NO.
`
`See reviews...
`See all...
`
`Links
`PubMed
`Taxonomy
`Taxonomy Tree
`
`Recent activity
`
`Turn Of f
`Inhaled nitric oxide applications in paediatric practice
`
`Clear
`
`PMC
`
`See more...
`
`pdfcrowd.com
`
`001
`
`

`

`NOS 3, identified in endothelial cell also called eNOS. Even if very similar in structure, they show some
`differences. NOS 1 and 3 are constitutively expressed and are calcium calmodulin dependent. NOS 2, in
`contrast, is seen after induction by inflammatory stimuli, and is calcium independent. Nitric oxide
`synthase 2 can produce large amount of NO measured in nanomoles, instead of the picomoles produced
`by the nitric oxide synthase 1 and 3. NO thus formed is a small reactive molecule which diffuses readily to
`adjacent vascular smooth muscle. In the vascular smooth muscle NO activates guanylate cyclase, which
`5
`transforms GTP into cyclic guanylate monophophate (cGMP), which in turn induces vasodilatation. As
`NO exists as a gas, it can be delivered by inhalation, hence NO can vasodilate constricted blood vessels in
`close proximity to the ventilated lung. The rapid inactivation of NO by haemoglobin, when NO reaches
`6
`the intravascular space, limits its effects on the pulmonary circulation.
`
`In this review, we will first describe the delivery and monitoring of inhaled NO (iNO) as well as its
`potential adverse effects and toxicity. These aspects are essential to the safe use of iNO. We shall then
`discuss its different applications in paediatric practice.
`
`Rationale for the use of inhaled nitric oxide
`
`For many years, physicians involved with the care of patients with pulmonary hypertension were in
`search of the ideal pulmonary vasodilator, which should be easy to administer, have a short duration of
`action and above all, be selective for the pulmonary circulation. Approaches to manipulate the pulmonary
`7 ,8
`9,10
`vascular tone were limited to oxygen supplementation
` and respiratory or metabolic alkalosis.
`11,12
`13
` and
`Drug therapy included several intravenous vasodilators such as prostaglandins,
` tolazoline
`14,15
`magnesium sulphate.
` All were characterised by their lack of selectivity, leading to a fall in systemic
`arterial pressure and an increase in intrapulmonary shunt. The introduction of inhaled NO and other
`recent advances in vascular biology have drastically changed the therapeutic approach of pulmonary
`hypertension.
`
`As nitric oxide exists as a gas, it can be easily administered by inhalation. The anatomical proximity of the
`airspaces to the muscular arterioles allows NO to diffuse. Nitric oxide is lipophilic and thus crosses the
`membranes easily. By inducing vasodilation of aerated airspaces, NO can redirect blood flow from poorly
`ventilated areas, atelectatic or diseased lung regions, to better aerated air spaces and improves
`oxygenation and ventilation perfusion mismatch. This effect is the so-called microselective effect of iNO.
`As for endogenous NO, this vasodilator effect is induced through the cyclic cGMP pathway, as
`16,17
`demonstrated by an increase in plasma cGMP during iNO therapy.
` When it reaches the vascular
`18
`lumen, NO avidly binds to haemoglobin and is thereby inactivated with a half-life of 2-6 seconds.
` This
`6,19
`rapid inactivation limits its effects on the pulmonary circulation and accounts for its selective action.
`This is the macroselective effect of iNO. Indeed, red blood cells act as scavengers of iNO as demonstrated
`20
`by Deem et al.
` Between 75 and 90% of iNO is absorbed during inhalation. The metabolic fate of iNO is
`21
`indeed similar to endogenous NO with the formation of nitrites and nitrates eliminated in the urine,
`and more than 70% of the inhaled gas will appear in the urine as nitrates within 48 hours of
`22,23
`inhalation.
`
`open in browser PRO version Are you a developer? Try out the HTML to PDF API
`
`Effect of breathing oxygen on pulmonary artery pressure and
`[Circulation. 1961]
`pulmonary vascular resistance in patients with ventricular
`septal defect.
`Effect of oxygen on pulmonary vascular resistance in patients
`[Circulation. 1959]
`with pulmonary hypertension associated with atrial septal
`defect.
`Effect of pH and PCO2 on pulmonary and systemic
`[J Pediatr. 1988]
`hemodynamics after surgery in children with congenital heart
`disease and pulmonary hypertension.
`Pulmonary vascular resistance in infants after cardiac surgery:
`[Crit Care Med. 1995]
`role of carbon dioxide and hydrogen ion.
`
`See more ...
`
`Use of inhaled nitric oxide and acetylcholine in the evaluation
`[Circulation. 1993]
`of pulmonary hypertension and endothelial function after
`cardiopulmonary bypass.
`The kinetics and equilibria of the reactions of nitric oxide with
`[J Physiol. 1957]
`sheep haemoglobin.
`Selective pulmonary vasodilation by inhaled nitric oxide is due
`[Circulation. 1993]
`to hemoglobin inactivation.
`Nitric oxide inhibition varies with hemoglobin saturation.
`[J Appl Physiol. 1993]
`Red-blood-cell augmentation of hypoxic pulmonary
`[Am J Respir Crit Care Med. 1998]
`vasoconstriction: hematocrit dependence and the importance
`of nitric oxide.
`Metabolism and excretion of nitric oxide in humans. An
`[Circ Res. 1993]
`experimental and clinical study.
`Kinetics of methaemoglobin and serum nitrogen oxide
`[Br J Anaesth. 1996]
`production during inhalation of nitric oxide in volunteers.
`
`See more ...
`
`pdfcrowd.com
`
`002
`
`

`

`In summary, iNO fulfils most of the properties required to be the ideal pulmonary vasodilator; thus its
`use has become of major clinical interest.
`
`Delivery and monitoring
`
`The potential toxicity of iNO calls for reliable modes of delivery and availability of monitoring systems.
`24–32
`Large and extensive reviews of the diverse modes of iNO delivery have been published.
` The exact
`method of delivery and monitoring of NO may vary with the clinical indication and duration of
`treatment as well as the type of ventilator used. NO source tanks should be medical grade quality gas
`manufactured by a process accepted by the medical administration and is available in different
`concentrations of NO in N , from 100 to 10000 ppm. By using continuous flow ventilators, stable NO
`2
`concentrations can be easily delivered by titrating NO directly from the tank into the inspiratory limb of
`the ventilator. The theoretical concentration can be calculated using the following formula: NO
`=
`conc
`32
`NO
`x(Flow
`/Flow
`). However, as demonstrated by Betit et al.
` NO concentrations
`tank
`NOtank
`v entilator
`can be underestimated and direct measurement of NO is mandatory during therapy.
`
`NO can also be administered with demand valve systems using a similar technique but a stable
`concentration of NO may be difficult to obtain. It has been proposed to deliver NO with a synchronised
`33
`inspiratory injection technique to avoid the inconvenience of delivery during expiration.
` Ventilators
`equipped with in-built NO delivery and monitoring systems are currently available. They simplify delivery
`and improve safety. The recent development of new ventilatory techniques such as high frequency
`oscillation ventilation (HFO) in newborns or infants with respiratory failure open new challenges for iNO
`deliveries, but because HFO is also delivered at constant flow, it seems possible to obtain stable NO
`34,35
`concentrations.
` Fujino et al reported that mixing NO during HFO was acceptable at all injection
`sites with a preference for the prehumidifier injection, which offers less fluctuation of NO
`36
`concentration.
` However, with this latter ventilatory technique, measurements may not be accurate, as
`a prolonged residency time of NO in the airways is possible; also the concentrations measured at the
`inspiratory limb of the ventilator do not accurately reflect the effective NO concentrations in the alveoli.
`
`In spontaneously breathing patients NO can be administered by mask or hand ventilation with a
`37 –39
`bag.
` Administration through nasal prong is also possible, opening the possibility of long-term
`40
`treatment with iNO.
`
`The appropriate dose of iNO to assess pulmonary vascular resistance or treat pulmonary hypertension is
`not completely defined. Dose response studies have been performed in persistent pulmonary hypertension
`41–46
`47 ,48
`of the newborn (PPHN) and ARDS
` and in congenital heart disease.
` Inhaled NO doses
`required to treat pulmonary hypertension are higher than those required for improvement of ventilation
`41
`perfusion mismatch and oxygenation.
` The recommended dose by the FDA for the treatment of
`neonatal hypoxic respiratory failure is 20 ppm. Recently, Tworetzky et al suggest an initial dose of 20
`ppm for the treatment of PPHN, as it produced an improvement in the pulmonary to systemic arterial
`49
`pressure ratio, even though 5 ppm iNO was enough to produce peak improvement in oxygenation.
` The
`exact dose required may indeed vary not only with the pathology but also with duration of therapy. Nelin
`
`open in browser PRO version Are you a developer? Try out the HTML to PDF API
`
`Delivery and monitoring of inhaled nitric oxide in patients with
`[Crit Care Med. 1994]
`pulmonary hypertension.
`
`Minimizing the inhaled dose of NO with breath-by-breath
`[Circulation. 1998]
`delivery of spikes of concentrated gas.
`Occupational exposure during nitric oxide inhalational therapy
`in a pediatric intensive care setting. [Intensive Care Med. 1996]
`Inhaled nitric oxide in premature neonates with severe
`[Lancet. 1999]
`hypoxaemic respiratory failure: a randomised controlled trial.
`Nitric oxide delivery during high-frequency oscillatory
`[Respir Care. 2000]
`ventilation.
`
`Inhaled nitric oxide to test the vasodilator capacity of the
`[Am J Cardiol. 1996]
`pulmonary vascular bed in children with long-standing
`pulmonary hypertension and congenital heart disease.
`See more ...
`
`Time-course and dose-response of nitric oxide inhalation for
`[Eur J Clin Invest. 1993]
`systemic oxygenation and pulmonary hypertension in patients
`with adult respiratory distress syndrome.
`Inhaled nitric oxide in full-term and nearly full-term infants with
`[N Engl J Med. 1997]
`hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide
`Study Group.
`Very-low-dose inhaled nitric oxide: a selective pulmonary
`[J Thorac Cardiovasc Surg. 1994]
`vasodilator after operations for congenital heart disease.
`Inhaled nitric oxide in neonates with persistent pulmonary
`[Lancet. 2001]
`hypertension.
`The effect of inhaled nitric oxide on the pulmonary circulation of
`[Pediatr Res. 1994]
`the neonatal pig.
`pdfcrowd.com
`
`003
`
`

`

`et al. showed that the effective dose (the smallest dose effective to obtain a beneficial response) decreases
`50
`as therapy continues.
`
`It has been shown that there is little haemodynamic benefit obtained above 20 ppm. The dose used to
`assess pulmonary vascular reactivity varies between 10 and 40 ppm, rarely 80 ppm, but higher doses had
`no further effect. The same may be applied for postoperative cardiac patients with a starting dose between
`10 and 20 ppm. If there is no response, a trial at 40 and 80 ppm may be attempted but questions about
`the diagnosis must be raised. Higher doses give little or no benefit but may be associated with an
`increased risk of toxicity, in particular NO and methaemoglobin formation. When a response is
`2
`obtained, the dose must be decreased progressively to the lowest effective dose to avoid potential toxic
`effects. Slightly higher doses may be required for PPHN but Finer et al. showed that maximal response
`44
`was obtained with 5 ppm.
` Adequate ventilation and lung recruitment is necessary in these patients to
`deliver NO in the alveoli and obtain a result. ARDS patients sometimes respond to very low doses of some
`hundreds ppb.
`
` An
`Guidelines on the use of NO with an emphasis on safety have emerged from a NHLBI workshop.
`ideal delivery system uses medical grade NO, limits to the maximum the residency time of NO in the
`ventilatory circuit, allows for precise concentrations of NO with a uniform mixing, has alarms notifying
`when excessive concentrations of NO are administered or if inadvertent discontinuation of NO occurs.
`Most important of all, it allows on line monitoring of NO and NO .
`2
`
`51
`
`The formation of NO is in part correlated to the amount of NO administered and a correct
`2
`measurement of NO concentrations is of utmost importance. Two systems are currently available for
`monitoring NO and NO concentrations. Chemiluminescence technique remains the gold standard with
`2
`52
`an accuracy of some ppb.
` Manufacturers have adapted industry materials to the requirement of
`medicine with rapid response analysers requiring small amount of air sampling and therefore not
`interfering with ventilation. However, these devices are expensive and one may prefer the electrochemical
`devices that are somewhat inaccurate to measure very low amount of NO (such as for measurement of
`53
`exhaled NO) but accurate enough by far for treatment monitoring.
`
`the neonatal pig.
`
`[Pediatr Res. 1994]
`
`Nitric oxide and the lung.
`
`[Am J Respir Crit Care Med. 1994]
`
`Chemiluminescence analysis and nitrogen dioxide
`[Lancet. 1994]
`measurement.
`A simple method for monitoring the concentration of inhaled
`[Anaesthesia. 1994]
`nitric oxide.
`
`Toxicity
`
`There has been proper concern about the potential toxicity of NO therapy. NO is a common pollutant.
`The US Occupational Safety and Health Administration has set a limit of NO exposure time to 25 ppm
`54
`when breathed for 8h/day in the workplace.
`
`No severe side effects of iNO have been described, using concentrations up to 40 to 80 ppm (the maximal
`doses used in clinical practice). Studies in rats have shown that inhalation of NO up to 1500 ppm for 15
`55
`min caused no demonstrable injury.
` Moreover cigarette smoke contains NO concentrations up to 1000
`56
`ppm and no acute toxic effects have been reported. However, NO may be one of the substances
`involved in long-term lung toxicity of cigarette smoke. If extreme doses are used it seems to lead rapidly
`to methaemoglobinemia and a toxic pulmonary oedema, which may be more related to the
`57
`transformation of NO to NO than to a direct effect of NO.
` Therefore, particular attention has been
`open in browser PRO version Are you a developer? Try out the HTML to PDF API
`
`Review The biology of nitrogen oxides in the airways.
`[Am J Respir Crit Care Med. 1994]
`
`pdfcrowd.com
`
`004
`
`

`

` Therefore, particular attention has been
`transformation of NO to NO than to a direct effect of NO.
`2
`focused on the possible acute toxic effects such as the production of NO (a pulmonary toxin),
`2
`methaemoglobinemia (which should remain < 5%), and cellular toxicity.
`
`57
`
`NO
`
`2
`
`One of the main concerns of iNO therapy is the chemical reaction of NO to NO in the presence of
`2
`oxygen within the ventilatory system or the airways. NO is thought to be responsible for the pulmonary
`2
`55
`injury caused by exposure to NO. NO is clearly cytotoxic
` and in aqueous solutions is transformed to
`2
`55
`nitric and nitrous acids. It causes pulmonary epithelial cell damage, interstitial atrophy and fibrosis.
` It
`54,58
`is generally accepted that concentrations of NO over 5 ppm are toxic.
` Production of NO is
`2
`2
`function of the NO concentration squared, the fraction of inspired oxygen and the time of residency in the
`ventilatory system.
`
`Based on these findings guidelines should be followed to minimise the risk of toxicity related to the
`formation of NO :
`2
`
`1. Administer the lowest effective dose of iNO with a maximal dose of 40 to 80 ppm
`2. Administer the lowest possible concentration of O
`3. Monitor O , NO and NO concentrations
`2
`2
`4. Minimise the transit time in the ventilator by using high gas flow rates to flush out alveolar gases
`5. Minimise the exposure time of NO to oxygen before it reaches the patient
`
`2
`
`Methaemoglobin
`
`Review The biology of nitrogen oxides in the airways.
`[Am J Respir Crit Care Med. 1994]
`Safety guidelines for use of nitric oxide.
`
`[Lancet. 1992]
`
`Inhaled NO is quickly absorbed into the blood stream, avidly bound to haemoglobin and thereby,
`inactivated with the formation of methaemoglobin. This oxidised form of haemoglobin has impaired
`oxygen transport function. Methaemoglobin is restored to its oxygen carrying capacity by
`methaemoglobin reductase. Increased levels of methaemoglobin in patients receiving iNO therapy are
`unusual, and remain for the great majority in a safe range (<5%). High levels of methaemoglobin have
`59,60
`rarely been reported.
` Neonates have an immature methaemoglobin reductase system and may be
`61
`more susceptible to increased levels.
` Of note, methaemoglobin reductase deficiency is common in
`62
`Native Americans.
`
`Methaemoglobin will indeed remain in a safe range with doses of iNO of 40 ppm and less. If necessary,
`excess methaemoglobin may be treated by reducing the iNO concentrations, or administrating vitamin C
`24,63–65
`or methylene blue.
` Particular caution must be taken when intravenous nitrovasodilators are
`associated with iNO, i.e. in the postoperative cardiac patient, where in our experience higher levels of
`methaemoglobinemia might be encountered.
`
`Inhaled nitric oxide and persistent pulmonary hypertension of
`the newborn. The Inhaled Nitric Oxide Study Group.
`[N Engl J Med. 1997]
`Methaemoglobinaemia after inhalation of nitric oxide in infant
`with pulmonary hypertension.
`[Lancet. 1997]
`Deficient activity of DPNH-dependent methemoglobin
`diaphorase in cord blood erythrocytes.
`[Blood. 1963]
`Hereditary methemoglobinemia in Alaskan Eskimos and
`Indians.
`[Blood. 1958]
`
`Delivery and monitoring of inhaled nitric oxide in patients with
`pulmonary hypertension.
`[Crit Care Med. 1994]
`Inhaled nitric oxide in the treatment of postoperative graft
`dysfunction after lung transplantation. [Ann Thorac Surg. 1994]
`
`See more ...
`
`Cellular effects
`
`NO reacts with O and superoxide anion (O -) to form peroxinitrite. Peroxinitrite is a potent oxidant that
`2
`2
`66
`may damage a wide range of biological molecules.
` In particular, it can induce lipid peroxidation of the
`open in browser PRO version Are you a developer? Try out the HTML to PDF API
`
`Review The chemistry of peroxynitrite: a product from the
`reaction of nitric oxide with superoxide.
`[Am J Physiol. 1995]
`pdfcrowd.com
`
`005
`
`

`

`cell membrane. Peroxinitrite also cause cell apoptosis by DNA strand breakage and by inhibition of
`67
`mitochondrial respiratory enzymes.
` However, NO is also considered as a free radical scavenger which
`can counteract and stabilise peroxinitrite. The significance of peroxinitrite-induced toxicity during inhaled
`NO therapy remains unknown. The antioxidant versus oxidant balance of these reactions may depend of
`the relative concentrations of these molecules and potential toxicity may only appear with high doses of
`NO not routinely used in clinical practice.
`
` These forms may act as NO carriers and
`NO can react with thiol groups and form S-nitrosothiols.
`transport NO far from its delivery site in the lung. Indeed S-nitrosothiols have similar platelet and
`69
`vasorelaxant activities as NO and may prolong its effects or displace its site of action.
`
`68
`
`One of the other major potential toxic effects at the cellular level is the effect on DNA. NO can inhibit
`7 0
`DNA synthesis
` and it has been shown that NO can alter DNA by the direct modification and strand
`7 1,7 2
`breakage of DNA and also by inhibition of enzymes that are necessary to repair DNA lesions.
`
`Long term follow-up
`
`Long-term studies of iNO in paediatrics are still scarce. In 12 newborns who received iNO for up to 4
`days, no signs of lipid peroxidation product, impaired surfactant activity or changed cytokine profile were
`7 3,7 4
`observed.
` On the other hand, nitrotyrosine was detected after 10 days of life in two infants requiring
`7 3
`prolonged ventilation, suggesting potential toxicity of NO.
` Follow-up studies of adult patients treated
`with iNO for ARDS showed no difference in pulmonary function compared to ARDS patients not treated
`7 5
`with iNO.
` Dobyns et al. came to the same conclusions in infants treated with iNO for PPHN and
`7 6
`studied 4 to 12 months after discharge from the hospital.
` In hypoxaemic term neonates, iNO is not
`associated with an increase in neurodevelopmental, behavioral or medical abnormalities at 2 years of
`7 7
`age.
` A recent follow up review of patients with PPHN randomised to a treatment with iNO
`demonstrated no adverse health or neurodevelopmental outcomes have been observed among infants
`7 8
`treated with NO vs controls.
`
`In summary, so far no long-term toxic effects have been reported but caution must be the rule with this
`molecule with its wide variety of biological activities and potential toxicity.
`
`Adverse effects
`
`Some of the unwanted effect of nitric oxide may not be categorised as toxic effects but as adverse effects.
`
`[Am J Physiol. 1995]
`reaction of nitric oxide with superoxide.
`Review DNA strand breakage and activation of poly-ADP
`[Free Radic Biol Med. 1996]
`ribosyltransferase: a cytotoxic pathway triggered by
`peroxynitrite.
`
`Nitric oxide circulates in mammalian plasma primarily as an S-
`[Proc Natl Acad Sci U S A. 1992]
`nitroso adduct of serum albumin.
`
`See more ...
`
`Inactivation of ribonucleotide reductase by nitric oxide.
`[Biochem Biophys Res Commun. 1991]
`
`See more ...
`
`Pulmonary toxicity associated with nitric oxide in term infants
`[J Pediatr. 1998]
`with severe respiratory failure.
`Effects of maternal protein malnutrition on fetal growth, plasma
`[Pediatr Res. 1995]
`insulin-like growth factors, insulin-like growth factor binding
`proteins, and liver insulin-like growth factor gene expression in
`Pulmonary function in adult survivors of severe acute lung
`[Acta Anaesthesiol Scand. 1998]
`injury treated with inhaled nitric oxide.
`Infant lung function after inhaled nitric oxide therapy for
`[Pediatr Pulmonol. 1999]
`persistent pulmonary hypertension of the newborn.
`Inhaled nitric oxide in term and near-term infants:
`[J Pediatr. 2000]
`neurodevelopmental follow-up of the neonatal inhaled nitric
`oxide study group (NINOS).
`Child health status, neurodevelopmental outcome, and parental
`[Pediatrics. 2001]
`satisfaction in a randomized, controlled trial of nitric oxide for
`persistent pulmonary hypertension of the newborn.
`
`Rebound pulmonary hypertension
`
`When iNO is administered over a prolonged period, such early as after cardiac surgery or in newborns
`with hypoxaemic respiratory failure, a considerable rise in pulmonary artery pressure may appear at time
`7 9–83
`of abrupt withdrawal of iNO.
` This may be a self resolving problem in a few minutes but can also
`progress to right ventricular failure and low cardiac output which may be life threatening. Different
`mechanisms can explain this reaction, ie: a possible down regulation of the endogenous production of NO
`by the administration of exogenous iNO, a slow recovery from cell dysfunction taking several days or a
`open in browser PRO version Are you a developer? Try out the HTML to PDF API
`
`Rebound pulmonary hypertension after inhalation of nitric
`[Ann Thorac Surg. 1996]
`oxide.
`Inhaled nitric oxide-induced rebound pulmonary hypertension:
`[Am J Physiol Heart Circ Physiol. 2001]
`role for endothelin-1.
`
`pdfcrowd.com
`
`006
`
`

`

`combination of both. Recently, an increase in endogenous endothelin has also been suggested as a
`84
`potential mechanism.
`
`A negative feedback mechanism is supported by several studies both in vitro and in vivo
`probably the main effect responsible of this phenomenon.
`
`85–89
`
` and is
`
`See links ...
`
`Exhaled NO is reduced after cardiopulmonary bypass due to either a decreased production or increased
`90
`breakdown.
` Endothelial cell dysfunction after cardiopulmonary bypass, as demonstrated by Wessel et
`16
`al., may therefore take some days to recover and resume production of endogenous NO.
` Withdrawal of
`iNO during this period leads to rebound pulmonary hypertension. This was also supported by Combes et
`al. showing that NO inhalation for 48 hours increases the reactivity of the pulmonary vascular bed to
`89
`vasoconstricting agents.
`
`Decreased exhaled nitric oxide may be a marker of
`cardiopulmonary bypass-induced injury.[Ann Thorac Surg. 1998]
`Use of inhaled nitric oxide and acetylcholine in the evaluation
`[Circulation. 1993]
`of pulmonary hypertension and endothelial function after
`cardiopulmonary bypass.
`Effect of 48 hours of nitric oxide inhalation on pulmonary
`[Am J Respir Crit Care Med. 1997]
`vasoreactivity in rats.
`
`In order to avoid this rebound phenomenon, a stepwise slow reduction of iNO is mandatory and this even
`at very low levels of iNO such as 1 ppm. Regular attempts to wean should be performed to avoid self-
`91
`maintaining treatment with iNO leading to a prolonged postoperative course.
` Several other methods
`92
`have been proposed: a transient increase in the fraction of inspired oxygen by Aly et al.,
` the use of
`dipyridamole, a phosphodiesterase inhibitor allowing to maintain high levels of cGMP in the smooth
`93,94
`muscle cell, thus prolonging the effect of iNO.
` The use of sildenafil has also been reported
`95
`recently.
`
`Dipyridamole attenuates rebound pulmonary hypertension after
`[J Thorac Cardiovasc Surg. 1998]
`inhaled nitric oxide withdrawal in postoperative congenital heart
`disease.
`The use of phosphodiesterase inhibitor (dipyridamole) to wean
`[Intensive Care Med. 1996]
`from inhaled nitric oxide.
`Sildenafil ameliorates effects of inhaled nitric oxide withdrawal.
`[Anesthesiology. 1999]
`
`Platelet function
`
`Endogenous NO has multiple biological functions among which the regulation of platelet function.
`Hoggman et al. first reported that iNO inhibits platelet function and prolongs bleeding time in rabbits.
`98
`In patients with ARDS, NO decreased platelet aggregation but had no effect on bleeding time.
`Intracranial haemorrhage is one of the most serious concerns in neonates, particularly in preterm
`neonates. Therefore the application of iNO in this group of patients raises some concerns. Studies in
`99
`neonates are conflicting: George et al.
` showed that the bleeding time was increased after 30 min of 40
`ppm iNO, whereas several other clinical studies demonstrated no change in the frequency of bleeding
`35,59,100
`events in NO treated compared to placebo treated neonates.
` Furthermore, recent studies in near
`terms and premature neonates did not demonstrate an increased risk of intracranial
`100,101
`haemorrhage.
`
`97
`
`96
`
`Review Nitric oxide: physiology, pathophysiology, and
`[Pharmacol Rev. 1991]
`pharmacology.
`Prolonged bleeding time during nitric oxide inhalation in the
`[Acta Physiol Scand. 1994]
`rabbit.
`Inhibition of platelet aggregation by inhaled nitric oxide in
`[Anesthesiology. 1995]
`patients with acute respiratory distress syndrome.
`The effect of inhaled nitric oxide therapy on bleeding time and
`[J Pediatr. 1998]
`platelet aggregation in neonates.
`
`See more ...
`
`We have shown that, in healthy volunteers, 10 min iNO at 30 ppm induced an inhibition of platelet
`102
`aggregation accompanied by an increase in plasma and platelet cGMP.
` This effect is of short duration
`and platelet aggregation studies should be performed as soon as the blood sampling is performed.
`
`Even though, they are conflicting these studies open news questions; if iNO is selective for the pulmonary
`circulation in regard to its vasodilatory activity, this may not be true for others actions such as changes in
`platelet function; here the effect may be mediated by stable compounds such as nitrosothiols formed in
`the pulmonary circulation during inhalation and act systemically.
`
`open in browser PRO version Are you a developer? Try out the HTML to PDF API
`
`pdfcrowd.com
`
`007
`
`

`

`Left ventricular dysfunction
`
`There are several reports of the negative effects of inhaled NO in patients with left ventricular dysfunction
`103–108
`and elevated pulmonary vascular resistance.
` Inhaled NO produces selective pulmonary
`vasodilatation. However, in patients with elevated left atrial pressure due to left ventricular dysfunction, a
`decrease in pulmonary vascular resistance (induced by iNO) will lead to an increase in pulmonary venous
`return and hence to an increase in left atrial and left ventricular filling pressures; this may not be
`108
`tolerated by a failing left ventricle working on the flat portion of the Frank-Starling curve.
` This effect
`may lead to rapid left heart failure and pulmonary oedema, most marked if the right ventricular pressure
`103
`is suprasystemic and the left cavity small.
` Such a phenomenon has been confirmed by Rosales et al. in
`a patient with a small non compliant left atrium and ventricle after repair of total anomalous pulmonary
`109
`venous return.
` Indeed several years ago, Wood already suggested that an elevation in pulmonary
`110
`vascular resistance may protect the lungs from pulmonary oedema in severe mitral stenosis.
` A similar
`postulate may be applicable in patients with severe left ventricular dysfunction or poor left atrial and
`ventricular compliance. This pathophysiologic explanation has been confirmed, and a direct negative
`111,112
`inotropic effect excluded by recent studies
` in pigs and in patients with normal left ventricular
`113
`114
`function.
` Loh et al.,
` in a canine model of cardiomyopathy, showed that iNO decreased pulmonary
`vascular resistance and increased left ventricular filling pressures, which was related to an increase in
`pulmonary venous return, without any effect on the contractile or relaxation properties of the left
`ventricular. This effect was further confirmed by Hayward et al. in patients with dilated
`115
`cardiomyopathy,
`
`Even though iNO does not seem to have direct negative inotropic effects, these factors highlight the need
`for careful observation and intensive monitoring during NO inhalation in patients with left ventricular
`failure, if left ventricular afterload is not lowered concomitantly.
`
`