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`Title : Inhaled nitric oxide therapy in neonates and children: reaching a European consensus
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`Intensive Care Med (2004) 30:372–380
`DOI 10.1007/s00134-003-2122-3
`
`C O N S E N S U S C O N F E R E N C E
`
`Inhaled nitric oxide therapy in neonates
`and children: reaching a European consensus
`
`Duncan J. Macrae
`David Field
`Jean-Christophe Mercier
`Jens Møller
`Tom Stiris
`Paolo Biban
`Paul Cornick
`Allan Goldman
`Sylvia Göthberg
`Lars E. Gustafsson
`Jürg Hammer
`Per-Arne Lönnqvist
`Manuel Sanchez-Luna
`Gunnar Sedin
`Nim Subhedar
`
`Abstract Inhaled nitric oxide (iNO)
`was first used in neonatal practice in
`1992 and has subsequently been used
`extensively in the management of
`neonates and children with car-
`diorespiratory failure. This paper as-
`sesses evidence for the use of iNO in
`this population as presented to a
`consensus meeting jointly organised
`by the European Society of Paediatric
`and Neonatal Intensive Care, the
`European Society of Paediatric Re-
`search and the European Society of
`Neonatology. Consensus Guidelines
`on the Use of iNO in Neonates and
`Children were produced following
`discussion of the evidence at the
`consensus meeting.
`
`Keywords Inhaled nitric oxide ·
`Pulmonary hypertension · Persistent
`pulmonary hypertension of the
`newborn · Extracorporeal membrane
`oxygenation · Vasodilator ·
`Pulmonary
`
`Received: 8 May 2003
`Accepted: 1 December 2003
`Published online: 13 January 2004
` Springer-Verlag 2004
`
`A. Goldman
`Great Ormond Street Children’s Hospital,
`Great Ormond Street,
`WC1 N 3JH London, U.K.
`
`Electronic Supplementary Material
`Supplementary material is available in the
`online version of this article at
`http://dx.doi.org/10.1007/s00134-003-
`2122-3
`.
`
`D. J. Macrae ())
`Royal Brompton Hospital,
`Sydney Street,
`SW3 6NP London, U.K.
`e-mail: d.macrae@rbh.nthames.nhs.uk
`Tel.: +44-20-73528121
`Fax: +44-20-73518360
`
`D. Field · P. Cornick
`Department of Child Health,
`Leicester Royal Infirmary,
`LE1 5WW Leicester, U.K.
`
`J.-C. Mercier
`Hôpital Robert DebrØ,
`48 Boulevard SØrurier,
`75935 Paris Cedex 19, France
`
`J. Møller
`Klinikum Saarbrucken,
`Winterberg 1, 66119 Saarbrucken,
`Germany
`
`T. Stiris
`Barn. Afd, Ullevål sykehus,
`0407, Norway
`
`P. Biban
`Neonatal and Paediatric Intensive Care Unit,
`Major City Hospital,
`Piazzale Stefania, 37126 Verona, Italy
`
`S. Göthberg
`Drottning Silvias Barnsjukhus,
`Sahlgrenska University Hospital,
`41685 Gothenburg, Sweden
`
`L. E. Gustafsson
`Department of Physiology
`and Pharmacology,
`Karolinska Institutet,
`17177 Stockholm, Sweden
`
`J. Hammer
`Kinderspital, Roemerstrasse 8, 4005 Basel,
`Switzerland
`
`P.-A. Lönnqvist
`Department of Paediatric Anaesthesia
`and Intensive Care,
`Astrid Lindgren Children’s Hospital,
`Karolinska Institutet,
`17176 Stockholm, Sweden
`
`M. Sanchez-Luna
`Servicio de Neonatologia,
`Hospital General Universitario
`Gregorio Maranon,
`Dr. Esquerdo 46, 28009 Madrid, Spain
`
`G. Sedin
`Akademiska sjukhuset,
`75185 Uppsala, Sweden
`
`N. Subhedar
`Neonatal Unit,
`Liverpool Women’s Hospital,
`Crown Street, L8 7SS Liverpool, U.K.
`
`372
`
`

`

`373
`
`Introduction
`
`Inhaled nitric oxide (iNO) has been used in Europe to
`treat a variety of conditions in neonates and children since
`1992, foremost in persistent pulmonary hypertension of
`the newborn (PPHN), which has remained a major
`therapeutic challenge in the NICU [1, 2]. Introduction
`of iNO into clinical use was virtually unregulated in
`Europe, where supplies of industrially produced gas were
`freely available. Subsequently clinical trials have estab-
`lished roles for iNO therapy in the treatment of term
`neonates with severe respiratory failure and a pharma-
`ceutical quality product has recently become available in
`Europe and the United States. The high cost of the
`licensed product, compared to previous industrial sup-
`plies, and the narrow scope of
`the drug’s licensed
`indications suggested to our group that a consensus
`should be established on the use of iNO therapy in
`neonates and children covering both its approved and
`potential indications.
`
`Methods
`
`An Advisory Board was established under the auspices of the
`European Society of Neonatal and Paediatric Intensive Care to co-
`ordinate the scientific programme of the meeting. The board
`consisted of experts with proven scientific or clinical expertise
`relevant to the clinical use of iNO. The board identified a further
`panel of experts who were invited to act as section leaders whose
`role was to review the literature in their designated subject area.
`Section leaders were asked to produce written summaries of their
`subject area, which were then circulated to delegates prior to the
`meeting and which formed the basis of the evidence presented to
`delegates at the consensus meeting itself.
`A further panel of opinion leaders were invited to attend the
`meeting on the basis of their known interest in the use of iNO or
`their status as opinion leaders in the field of neonatal and paediatric
`intensive care. The European Society of Paediatric Research and
`the European Society of Neonatology were officially represented at
`the meeting. At
`the consensus meeting each subject area was
`presented in summary by the section leader(s), following which
`open discussion led to the composition of draft consensus
`statements. These were then edited and re-presented to delegates
`with further discussion leading to final agreement on the individual
`consensus statements.
`
`Results
`
`Inhaled nitric oxide in term and near-term neonates
`
`Neonatal hypoxaemia may result from intra-pulmonary
`shunting,
`from extra-pulmonary shunting (so-called
`PPHN) or from cyanotic congenital heart disease. The
`presence of interstitial pulmonary infiltrates or a low
`volume lung (<6–7 ribs) on chest X-ray strongly suggests
`parenchymal lung disease. Alveolar recruitment has been
`shown to render babies with severe hypoxaemic respira-
`tory failure responsive to iNO, when they were previously
`
`unresponsive [2]. Exogenous surfactant and ventilatory
`manoeuvres [3] should therefore be deployed to optimise
`lung volume before iNO is introduced. If cyanosis persists
`after any necessary lung recruitment manoeuvres have
`been applied, an echocardiogram should be obtained to
`confirm or exclude the presence of congenital heart
`disease or pulmonary hypertension as causes of cyanosis.
`Inhaled NO is most likely to benefit babies with PPHN
`with recruited lung volume and is unlikely to benefit
`babies with cyanotic heart disease.
`The recent Cochrane Review was used as a framework
`in this discussion [4]. The review,
`last updated in
`December 2000, included 12 relevant trials in its analysis,
`all of which used random allocation [5, 6, 7, 8, 9, 10, 11,
`12, 13, 14, 15]. One further on-going study received
`limited analysis since, at the time of review, it was on-
`going and published only as an abstract [16]. A literature
`search up to October 2003 failed to reveal any new
`randomised, controlled trials not already included in the
`Cochrane review.
`The limitations of the studies presented within the
`Cochrane review were highlighted. Of major importance,
`the entry criteria differed markedly between trials as did
`dosage and ventilatory strategies, there being a suggestion
`that high frequency oscillatory ventilation (HFOV)
`appears beneficial in achieving a response to iNO [10].
`Eight of the 12 clinical trials studied the effect of iNO on
`the overall clinical course of the babies included and, in
`particular, whether the need for extracorporeal membrane
`oxygenation (ECMO) was reduced. Only six trials did not
`allow crossover [6, 7, 8, 11, 12, 13]. Of the six studies
`which did not allow crossover, three [6, 11, 12] found a
`statistically significant reduction in the combined out-
`come of death or requirement for ECMO in the NO group.
`A meta-analysis of all six studies found that
`iNO
`treatment resulted in a reduction in the incidence of
`death or requirement for ECMO (relative risk 0.65) [4].
`Inhaled nitric oxide therefore appears to improve
`outcome in hypoxaemic term and near-term infants. The
`improvement is due mainly to a reduction in the need for
`ECMO, since mortality was not reduced. The two largest
`studies [6, 11] included infants with congenital diaphrag-
`matic hernia as sub-groups. A separate analysis has been
`presented from one of these studies [17]. There was no
`evidence that outcome was improved in these babies
`through the use of iNO, even if short-term improvements
`in oxygenation did occur. It is important to note that
`whilst iNO reduced the need for ECMO, the majority of
`mature babies in these studies went on to ECMO.
`Only one study has considered long-term follow-up as
`a primary or secondary hypothesis. In this study, the
`incidence of disability, the incidence of deafness and
`infant development scores were all similar between tested
`survivors who received NO and those who did not [18].
`The major randomised, controlled trials of iNO in term
`or near-term babies have used echocardiography to
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`374
`
`exclude congenital heart disease as a cause of hypox-
`aemia prior to exposure to iNO. Babies with such lesions
`are at best unlikely to benefit from iNO, as cyanosis is due
`to extra-pulmonary shunting. Inhaled NO exposure may
`even be harmful in some babies with congenital heart
`disease, such as those with obstructed total anomalous
`pulmonary venous drainage or severe left ventricular
`dysfunction with right-to-left ductal shunting [19],
`in
`whom pulmonary arteriolar vasoconstriction may be
`clinically beneficial by reducing left heart filling.
`
`Dosage and response to inhaled nitric oxide treatment
`in term and near-term neonates
`
`Decisions regarding continued use of iNO therapy cannot
`be based on the primary end points used in the pivotal
`studies, such as reduced mortality or ‘avoidance’ of
`ECMO. Instead clinicians must use surrogate physiolog-
`ical end points in order to establish whether an initial test
`exposure to iNO is effective. Improvement in oxygen-
`ation of approximately 20% over baseline values at 30–
`60 min has been used in many studies as an indicator of
`early response to iNO including six of the studies in the
`Cochrane review [5, 6, 7, 9, 11, 12].
`Four published studies have reported dose-response
`data for this group of babies [7, 20, 21, 22]. All four
`studies suggest that a maximal beneficial effect of iNO is
`already seen at concentrations of less than 30 ppm.
`Further increases of iNO (to 80–100 ppm) do not appear
`to result in further improvement of oxygenation above
`that achieved at 20–30 ppm. The large NINOS study [11]
`used initial doses of 20 ppm iNO, but exposed ‘partial
`responders’
`to 80 ppm. Only 6% of
`these partial
`responders were converted to full response by 80 ppm
`iNO.
`In the small study published by Tworetzky et al. a
`maximum reduction of pulmonary artery pressure was
`observed at 20 ppm NO, whereas maximal improvement
`in oxygenation occurred at 5 ppm [23]. Response to the
`introduction of iNO usually occurs rapidly in ‘respon-
`ders’. Some investigators attribute clinical improvements
`seen several hours later to iNO administration [24].
`However it was the expert group’s view that there is a
`serious danger that babies with very severe hypoxaemia
`could be harmed if ECMO referral were to be delayed
`whilst waiting for a ‘late’ response.
`If no substantial effect has been achieved during a trial
`of iNO, treatment with iNO should be rapidly discontin-
`ued or the baby transferred on iNO to a level 3 or tertiary
`neonatal unit. This should occur as soon as the clinician is
`convinced that iNO is not inducing a beneficial effect
`judged by improving oxygenation. The trial to improve
`oxygenation with NO should not last longer than 4 h. The
`reason not to prolong NO therapy unnecessarily is that
`NO synthase is down-regulated, with suppression of
`
`endogenous NO production. Down-regulation of endog-
`enous NO synthase by the use of iNO has been suggested
`[25, 26, 27].
`We were unable to identify studies establishing the
`optimal regime for maintenance of iNO therapy once an
`initial response has been established. It
`is, however,
`logical
`in clinical practice to seek to minimise iNO
`exposure by lowering the iNO dose, provided the
`beneficial effects on oxygenation and general clinical
`stability are maintained. This approach was described by
`Kinsella et al. [28] in the early stages of the clinical
`exploration of iNO therapy and further validated by Clark
`et al. [6].
`
`Discontinuation and weaning
`
`Some information is available on strategies for weaning
`patients from iNO as clinical improvement occurs. In a
`prospective study, Demirakca et al. evaluated the clinical
`response to iNO in neonates and children with acute
`respiratory distress syndrome (ARDS) [21]. Attempts to
`discontinue iNO were made as soon as a stable respiratory
`status (PEEP<6 cmH2O, inspiration/expiration ratio of
`1:2, FiO2 <0.8 and an iNO concentration of 5 ppm) had
`been achieved. Oxygenation index (OI) values of less
`than 5 predicted successful withdrawal with a sensitivity
`of 75%, a specificity of 89%, a positive predicted value of
`69% and a negative predictive value of 91% [21].
`Aly et al. [29] adopted a weaning strategy for babies
`with PPHN which included step-wise 5 ppm decrements
`of iNO doses. Discontinuation of iNO was performed as
`soon as the patient was stable with an FiO2 less than 0.5.
`Weaning was successful at the first attempt in 9 out of 16
`patients. In the remaining seven neonates, major signs of
`deterioration (oxygen saturation drop >10% or below
`85%) prompted a reinstitution of iNO treatment for
`30 min. Subsequently, FiO2 was raised by 0.4 and a
`successful withdrawal of iNO was then obtained. Inter-
`estingly, FiO2 could be returned to the pre-weaning value
`in a few hours. Sokol et al. [30] noted that significant
`deterioration of PaO2 occurred in some babies even when
`weaned from 1 to 0 ppm, suggesting that
`iNO is
`physiologically active even at very low concentrations.
`There may be a role for other vasodilators such as
`epoprostenol, iloprost, endothelin antagonists or selective
`phosphodiesterase inhibitors [31] when weaning babies
`from iNO after treatment courses of sufficient duration to
`down-regulate NO synthase.
`
`Toxicity
`
`Nitric oxide reacts with oxygen to form nitrogen dioxide
`(NO2) where the reaction rate is proportional to the square
`of the NO concentration and directly proportional to the
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`

`oxygen concentration. Whilst NO itself is a relatively
`reactive molecule, NO2 is demonstrably more reactive
`and toxic and is a radical (it has an unpaired electron).
`Due to the fact
`that NO is usually administered in
`combination with high inhaled oxygen concentrations and
`that NO2 in animal experiments is damaging to the lungs
`already at low concentrations when administered with
`other oxidants, the main toxicological concern should be
`focused on NO2 exposure and this should be kept to a
`minimum. In long-term exposure lung damage may occur
`at 0.5 ppm NO2 and acute lethal effects are seen from
`100 ppm. Human subjects inhaling 2–3 ppm NO2 for 5 h
`demonstrated reductions in antioxidant defences and an
`increase in alveolar permeability [32]. Reactive species
`such as peroxynitrite formed from NO2, as well as being
`implicated in short-term toxicity, have the potential to
`cause damage to DNA, raising the possibility of muta-
`genic or carcinogenic effects. However, the concentra-
`tions of iNO and NO2 to which patients are exposed
`clinically are largely within the permitted limits for
`occupational exposure [33]. There is as yet no evidence
`that inhalation of NO has any lasting adverse effects.
`Long-term follow-up of children exposed to iNO therapy
`will be required to establish any late adverse effect.
`When NO reacts with haemoglobin, methaemoglobin
`(metHb) is formed. MetHb is not directly toxic, but is
`unable to carry oxygen. If metHb is allowed to accumu-
`late it can significantly reduce the oxygen-carrying
`capacity of blood. The monitoring and management of
`metHb during clinical iNO therapy is discussed below.
`Inhalation of NO has been shown by some investiga-
`tors [34], but not by others [35],
`to inhibit platelet
`function. The randomised controlled neonatal trials have,
`however, not shown any difference in bleeding compli-
`cations between groups administered iNO or control gas
`[4].
`
`Delivery and monitoring
`
`Nitric oxide administration systems should deliver con-
`stant concentrations of iNO within the respiratory gas
`mixture independent of ventilator mode or settings,
`ensure a rapid mixing and minimise contact time between
`NO and oxygen,
`thereby reducing the possibility of
`generating high NO2 levels [36, 37, 38]. The delivery
`system should display the pressure within the NO cylinder
`to permit
`timely cylinder changes to be undertaken
`without loss of gas supply. The system should ideally
`encompass a backup power supply for use in the event of
`mains failure or during intra-hospital transport. A manual
`backup or ‘hand bagging’ facility must be provided for
`use in the event of ventilator failure or other indications
`for hand ventilation, as sudden discontinuation of iNO
`therapy can be life-threatening [36, 37, 39].
`
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`
`The safest approach to iNO delivery is probably to use
`only pharmaceutical grade NO stored in cylinders and at
`concentrations and conditions approved by drug regula-
`tory bodies and delivered by devices tested and approved
`according to the appropriate medical device legislation.
`In the clinical setting, measurement of iNO and NO2
`concentrations can be undertaken using chemilumines-
`cence or electrochemical devices. There are a number of
`practical disadvantages of chemiluminescence analysers
`in the clinical setting, including their high cost, their need
`for relatively high sample volumes, noise, their need for
`regular calibration and their
`relative inaccuracy in
`measuring NO2 due to the “quenching” effect [37].
`Electrochemical analysers use two separate fuel cell
`sensors for NO and for NO2, placed either in the gas
`mainstream or side stream of the ventilatory circuit.
`Electrochemical devices do not underestimate NO2 levels,
`are inexpensive, silent, easy to calibrate and require very
`low gas sample volumes. Most devices are portable.
`Electrochemical analysers are, however, relatively insen-
`sitive (resolution 0.5 ppm) and their measurements may
`be affected by temperature, pressure, humidity and the
`presence of other gases in the environment [37]. Although
`many early studies of
`iNO delivery systems were
`constructed by investigators for their own studies, a
`number of delivery and monitoring systems have been
`developed for clinical use and are commercially available
`[39, 40].
`to a
`Inhaled NO2 concentrations should be kept
`minimum. Clinical and experimental evidence show that
`it is possible to administer 20 ppm iNO whilst generating
`NO2 concentrations of less than 0.2 ppm [38]. Direct
`comparisons with tolerable environmental NO2 concen-
`trations should take into account that the awake person
`inhaling NO2 is exposed to at least 50% lower NO2
`concentrations in their trachea due to efficient scavenging
`of NO2 in the upper airways.
`Nitric oxide has been supplied for clinical use by a
`number of suppliers as a compressed gas diluted in a
`balance of nitrogen with final NO concentrations of
`between 100 and 1000 ppm. The gas is supplied in
`aluminium cylinders filled to pressures of 150–200 bar.
`Very concentrated preparations may be difficult to deliver
`accurately whilst mixtures with low NO concentrations
`can reduce FiO2 excessively [41]. The final choice of
`cylinder NO concentration will, therefore, depend on the
`characteristics of the delivery system in use and the
`required FiO2 and FiNO. The future availability of iNO as
`a pharmaceutical within Europe may encourage standard-
`isation.
`
`Environmental safety
`
`The US National Institute for Occupational Safety and
`Health (NIOH) suggest a “Permitted Exposure Limit” for
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`376
`
`NO2 of 5 ppm and NO 25 ppm over an 8-h period for
`these potentially toxic substances [33]. Several European
`countries have regulated maximal occupational exposure
`to 2 ppm NO2. Extrapolating this to the ICU in which iNO
`would be administered for a 24-h period, it would be
`prudent to aim for environmental levels of NO2 in the
`ICU below 1.5 ppm. Environmental NO contamination
`can occur from two sources during iNO administration:
`dumped waste ventilator gas and accidental leakage of
`concentrated gas from a delivery system or cylinder. The
`US Food and Drug Administration state, in their speci-
`fication for medical delivery of NO, that such delivery
`“does not individually or cumulatively have a significant
`effect on the human environment. Therefore, neither an
`environmental assessment nor an environmental impact
`statement is required” [42]. A similar ruling is applied by
`the UK National Health Service, which states that
`scavenging of waste NO is unnecessary provided that
`ventilation in the ICU meets required standards [43].
`Several studies confirm that this advice is sound [44, 45].
`There must, however, be a small risk of high environ-
`mental levels occurring from uncontrolled release of a
`large volume of concentrated gas from a cylinder in the
`event of a serious error or accident. For this reason, the
`consensus group suggest that it is reasonable to measure
`environmental levels of NO2 continuously.
`
`Transport
`
`In 30–50% of babies given a trial of iNO the therapy does
`not result in a sustained positive oxygenation response
`[4]. Most babies who fail to respond to iNO are potential
`ECMO candidates. Since acute withdrawal of iNO may
`be associated with severe rebound hypoxaemia, even in
`babies who apparently respond poorly [46, 47], arrange-
`ments must be in place for these babies to be transferred
`to an ECMO centre without interruption of iNO delivery.
`Occasionally non-neonates may require transport within
`or between hospital whilst receiving iNO.
`Apart from the ability to deliver iNO safely to the baby
`during transport, consideration must also be given to
`safety of the staff and crew within the transport vehicle,
`and compliance with any regulations governing such use.
`Kinsella et al. recently reported concentrations of NO and
`in the cabin environment of various transport
`NO2
`vehicles during iNO use and confirmed them to be
`negligible. Furthermore, they calculated the effects of
`uncontrolled release of a full US D-type NO cylinder
`containing 350 l NO gas. In this “ worst case scenario”
`environmental NO levels were unlikely to reach danger-
`ous levels (maximum 40 ppm fixed wing aircraft, 34 ppm
`ground ambulance, 94 ppm small helicopter) [48].
`for
`The expert group recommend that equipment
`delivery and monitoring of iNO during transport should
`comply with standards for medical devices and the safety
`
`and test requirements of the specific aircraft or other
`transport vehicle used. Several delivery systems have
`been used during transport and at
`least
`two portable
`systems are commercially available, one of which is
`specifically designed as a transport system [48].
`
`Staff training
`
`Clinical use of iNO involves potential hazards for both
`staff and patients, mainly from the risk of exposure to
`toxic levels of NO and NO2, but also issues such as safe
`handling of gas cylinders. The safe and appropriate use of
`medical equipment requires adequate preparation and
`training. Regulatory authorities frequently recommend
`standards for training in the use of m