CAPHC iNO Collaborative

CAPHC Guidelines for

Inhaled Nitric oxide in
Neonates
Dosing, Administration and Weaning
September 2015

CAPHC iNO Collaborative

Table of Contents
Introduction: ....................................................................................................................... 2
Guideline ............................................................................................................................. 7
Conditions .................................................................................................................................................... 7
Inclusion Criteria ......................................................................................................................................... 7
Policy............................................................................................................................................................. 7
Contraindications/Cautions ........................................................................................................................ 7
Equipment and Procedure........................................................................................................................... 7
Monitoring & Documentation .....................................................................................................................8
Prior to Administration of iNO ...................................................................................................................8
Starting Dose ................................................................................................................................................8
Assessment of Response ..............................................................................................................................8
Weaning ........................................................................................................................................................8
Monitoring for Complications ..................................................................................................................... 9

Appendices and other guideline-related material ............................................................ 10

Appendix 1: Guideline development methods: description and material .................... 10
Generating evidence process: .................................................................................................................... 10
Guideline development process .................................................................................................................11
Guideline management process: ............................................................................................................... 12

Appendix 2: Funding used in the development of the document ................................ 13

Appendix 3: Glossary/definitions and acronyms ......................................................... 14
Appendix 4: Equipment and Procedures ...................................................................... 15
Appendix 5: Stewardship Framework ........................................................................... 16
Appendix 6: Flow Charts ................................................................................................17
..................................................................................................................................................................... 18

Appendix 7: About Us .................................................................................................... 19

References: ........................................................................................................................ 21

CAPHC iNO Collaborative

Introduction:
Preamble
Despite generally good quality evidence to guide the use of inhaled nitric oxide (iNO) in
term and near-term newborns, a recent survey conducted by CAPHC demonstrated
considerable variation in practice across NICUs in Canada. Moreover, the high cost of
iNO and recent trends toward increasing off-label use (1) necessitates a critical reexamination of the role of iNO in neonatal intensive care. The Canadian consensus
guidelines contained herein were therefore developed with the goal of promoting safe,
rational and cost-effective use of iNO therapy in newborns.
Biological effects of nitric oxide
Nitric oxide (NO) is a colourless, odourless, readily diffusible and highly-reactive free
radical gas, first identified as the endothelium-derived relaxing factor in 1987 (2).
Shortly thereafter, iNO gas was introduced into clinical practice as a short-acting
pulmonary-selective vasodilator. NO is now understood to play vital roles in many
physiologic processes other than vasodilation, including regulation of
neurotransmission, cell growth, inflammation and platelet function. Endogenous NO is
derived from L-arginine via the actions of nitric oxide synthases of which three isoforms
exist, all of which are expressed in the lung (3). NO-mediated vasodilation is critical to
the rapid decrease in pulmonary vascular resistance (PVR) following birth and to the
maintenance of a normally-low pulmonary vascular tone (4). Thus, attenuated
endogenous vascular NO production and signaling contributes to the pathogenesis of
acute and chronic pulmonary hypertension in early life (5) (6) (7) (8) (9) (10) (11) (12)
(13). NO signals in vascular smooth muscle by binding to soluble guanylate cyclase
(sGC), thereby increasing production of cyclic guanosine monophosphate (cGMP),
which leads to relaxation by desensitising the smooth muscle contractile apparatus to
calcium.
Several phosphodiesterases (PDEs), particularly PDE 5, catalyse the
breakdown of cGMP, thus counter-regulating NO-mediated effects on smooth muscle
(14). NO also signals indirectly via conversion to nitrite or by nitrosylating amino acids
(cysteine thiols) to produce s-nitrosothiols. These molecules act as stable reservoirs of
NO in the circulation and tissue and are believed to mediate extrapulmonary effects of
iNO, both beneficial and adverse (15) (16) (17) (18). Among adverse effects, the most
significant and well-described is inhibited platelet adherence and aggregation,
potentially causing increased bleeding time (19) (20) (21).
NO metabolism and toxicity
When inhaled, NO gas rapidly reaches the pulmonary capillaries. Once in the
circulation, the vast majority of free NO reacts with oxyhaemoglobin to produce
methaemoglobin (metHb), which is subsequently metabolised by endogenous MetHb
reductase to haemoglobin and nitrate. This reaction largely accounts for the short
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CAPHC iNO Collaborative

duration of iNO effect on the lung vasculature (< 1 min), conferring relative pulmonary
selectivity of action. As metHb cannot carry oxygen, high levels of metHb (> 10%) may
contribute to tissue hypoxia (19). NO is unstable in air, reacting with oxygen to form
nitrogen dioxide (NO2), which is a major component of atmospheric pollution and is
toxic to the lung when levels exceed 2-5 ppm (19). In addition, NO reacts readily with
superoxide to produce a highly damaging molecule, peroxynitrite. Peroxynitrite is both
a nitrating agent (22) (23) and a potent oxidant (24) (25), leading to permanent
alterations in lipid and protein function (22) (26) (27) (28) (29). Nitration is linked to
numerous disease states by triggering cellular responses ranging from pathological
alterations in signaling to abnormal proliferation or cell death (30).
Importantly, at the dose range generally applied clinically (5-20 ppm), iNO rarely leads
to clinically-significant bleeding, or to potentially toxic levels of either metHb or NO2.
Nor has iNO been demonstrated to increase peroxynitrite formation in the lungs or
other tissues of human newborns (31). However, the potential for such effects argues
for administering iNO judiciously, at the lowest effective dose and for the shortest
possible time.
Use of iNO for hypoxaemic respiratory failure (HRF) in term and near-term
neonates
Persistent pulmonary hypertension of the newborn (PPHN) is a major cause of HRF
that affects 1-2 per 1000 term and near-term infants born in North America (32) and
carries an associated mortality of 10-20% (32) (33). Survivors frequently sustain major
lifelong morbidities, including cerebral palsy (~ 10%), cognitive impairment (15-20%),
hearing loss (~ 25%) and chronic lung injury (34) (35). PPHN arises either as a primary
condition or secondary to respiratory distress syndrome, meconium aspiration, sepsis or
asphyxia (36) (37) and is characterised by persistently raised PVR and arterial pressure,
generally associated with extrapulmonary right-to-left shunting across the ductus
arteriosus and/or foramen ovale. Prior to the availability of iNO, therapy was largely
supportive and included induction of hypocapneic and/or metabolic alkalosis,
inotropes, muscle relaxation and extracorporeal membrane oxygenation (ECMO) as a
last resort. Improved oxygenation with iNO in cases of PPHN were first reported in
1992 (38) (39), with subsequent large randomised trials confirming a significant
reduction in the need for ECMO (40) (41) (42)
Large improvements in oxygenation with iNO therapy are generally related to reduction
of extrapulmonary right-to-left shunting secondary to pulmonary vasodilation.
Improved oxygenation may also result from improved matching of ventilation to
perfusion with redistribution of pulmonary blood flow to well-ventilated regions of the
lung that are preferentially exposed to exogenous NO. Indeed, effects of iNO on
oxygenation are frequently suboptimal when lung volume is decreased, especially with
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CAPHC iNO Collaborative

parenchymal lung disease (43) Unfortunately, even when used optimally, iNO has not
led to improvements in mortality, length of hospital stay or the incidence of adverse
neurodevelopmental outcomes (35) (44) (45) (46) (47) (48) following PPHN. In spite of
these disappointing findings, the availability of iNO has greatly simplified the
management of PPHN, with no evidence of adverse effects either in the short- or longterm (35).
Use of iNO for HRF in premature infants.
Premature infants 34 weeks gestation may also develop severe HRF either as a
primary event or secondary to respiratory distress syndrome, congenital
pneumonia/sepsis, asphyxia or prolonged oligohydramnios (49). The pathophysiology
of HRF in the preterm may be identical to the term infant with PPHN, making the use of
iNO a logical and potentially useful extension of therapy, though responsiveness appears
to diminish with decreasing gestational age (49). Similar to term infants with PPHN,
clinical trials examining effects of iNO for HRF in premature infants have confirmed
short-term improvements in oxygenation, but no reduction in mortality (50) (51) (52)
(53). Early, prolonged use of iNO in severely preterm infants at risk of developing
chronic lung disease has also indicated no benefit on risk of death or chronic lung
disease (54) (55) (56) (57). Therefore, while this guideline does not specify a
gestational age cut-off for use of iNO for treatment of HRF secondary to pulmonary
hypertension, the use of iNO for respiratory failure or for the prevention of chronic
lung disease in preterm infants is currently not recommended (57) (58). iNO may be
useful in providing short-term improvements in oxygenation for select patients with
documented pulmonary hypertension not responsive to other measures, but the risks
versus benefits of iNO in the preterm infant remain unknown. Caution should
especially be exercised in patients 28 weeks gestation, at highest risk for
intraventricular haemorrhage.
In such patients, use of echocardiography for
confirmation of diagnosis and evaluation of response is highly recommended, as is a
pre-initiation cranial ultrasound. In the absence of evidence to specifically guide iNO
therapy in this population, recommendations for starting dose, cessation and weaning of
iNO are the same as for term and near-term infants.
Late respiratory failure in infants with chronic lung disease.
Ex-premature infants with chronic lung disease (also known as bronchopulmonary
dysplasia (BPD)) frequently have co-existent chronic pulmonary hypertension (59) (60)
(61). It remains unclear whether pulmonary hypertension is simply a marker for
severity of lung disease or whether it contributes to adverse outcomes in its own right
(62). Nevertheless, the diagnosis of pulmonary hypertension in patients with chronic
lung disease imposes a far greater burden of illness, resulting in lengthening of NICU
stay, prolongation of need for oxygen therapy, and greatly increased mortality (63).
Given experimental data indicating benefits of iNO in prevention of lung injury, it is no
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CAPHC iNO Collaborative

surprise that iNO has been employed in this population, both in an effort to prevent
BPD (as described above) and as rescue therapy for infants with severe BPD-associated
pulmonary hypertension. While iNO may produce short-term improvements in
oxygenation and PVR in infants with BPD (64) (65), there is no data on long-term
effects. In patients where significant right ventricular dysfunction is evident, iNO has
been utilised for prolonged periods with the goal of minimising afterload and of
preventing or reversing pulmonary vascular injury. However, the limited available
evidence suggests that iNO does not reverse or slow the progression of chronic
pulmonary hypertension (44) (65). Use of iNO for chronic pulmonary hypertension in
neonates may occasionally be used as a bridge prior to initiation of other therapies
(66) (67) (68) (69) (70) and is therefore best undertaken in consultation with
practitioners with expertise in the evaluation and management of chronic pulmonary
hypertension in children.
Summary of evidence guiding optimal use of iNO:
Contraindications to iNO: Contraindications include known or suspected
congenital heart disease with left-ventricular outflow obstruction, hypoplasia and/or
dysfunction, in which pulmonary vasodilation may worsen systemic hypoperfusion or
aggravate pulmonary oedema. Whether iNO is useful in the management of pulmonary
hypertension secondary to congenital diaphragmatic hernia is unclear and its routine
use in this condition is currently not recommended (48).
Other aspects of care: The potential for improvement in oxygenation with iNO can
be maximised by optimisation of lung recruitment, especially with parenchymal lung
disease, which may be facilitated by the use of exogenous surfactant and/or highfrequency modes of ventilation (43) (71). All aspects of care, including adequacy of
sedation, correction of acidosis and provision of circulatory support, when necessary,
should be optimised prior to initiation of iNO. Optimisation of these aspects alone may
frequently improve oxygenation to the point that initiation of iNO need no longer be
considered. Hyperoxia (PaO2 > 60-80 mmHg) should be avoided due to the potential
for damaging effects of high concentrations of oxygen on the lung and in light of
evidence from animal studies indicating that hyperoxia does not reduce PVR in excess of
normoxia (72) and may in fact further increase vasoreactivity (73). Insertion of an
indwelling arterial catheter for blood pressure and blood gas monitoring should be
undertaken whenever possible. Performance of echocardiography as early as feasible is
also recommended, in order to confirm the diagnosis of PPHN, to exclude congenital
heart disease and to provide information on adequacy of cardiac output and ventricular
function (74).
Initiation of iNO: The majority of clinical trials initiated iNO for PPHN at between 20
and 80 ppm, when patients reached an oxygenation index (OI) of > 25. Earlier
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initiation at an OI of 15-25 resulted in similar improvements in oxygenation, shorter

duration of therapy and a decreased likelihood of worsening hypoxaemia, but no
significant improvement in mortality (75) (76). The starting and maximal dose of iNO is
generally 20 ppm. Higher doses appear to provide no additional benefit (77) and have
greater potential to lead to toxic levels of metHb and NO2, especially for doses above 40
ppm (78). Initiation at a moderately low dose (5 ppm), while frequently effective, may
not produce a peak effect (77) and initiation at a very low dose (2 ppm) does not
improve oxygenation and may lessen subsequent response to higher doses of iNO (79).
Monitoring for toxicity: A MetHb level should be undertaken within 1 hour of
initiation of iNO, preferably at the same time as a post-initiation blood gas. Provided
the initial metHb level is reassuring (< 2.5%) and that the dose of iNO does not exceed
20 ppm (80), subsequent measurement of metHb level can be performed less
frequently, particularly if the iNO dose is rapidly weaned to 10 ppm or less (80).
Weaning and cessation of iNO: Up to 40% of neonates with PPHN do not
demonstrate acute or sustained improvements in oxygenation when treated with iNO
(41) (42) (44) (78) (81) (82) (83) (84) (85) (86). In the case of no response, it appears
safe to discontinue iNO within 30-60 minutes of initiation (87). An acute response or
duration of therapy > 1 hour in a non-responder should prompt rapid weaning to 5 ppm,
after which step-wise reduction by 1 ppm is the recommended strategy (88) (89). Prior
to weaning from 1 ppm iNO to OFF, an increase in FiO2 by 0.1-0.2 will limit rebound
hypoxaemia (90). Should rebound hypoxaemia occur upon weaning or cessation, an
increase to the previous dose of iNO is generally effective. Failure in improvement with
an increase in dose or recommencement of iNO should stimulate examination for causes
of hypoxaemia other than pulmonary vasoconstriction, such as lung hyperinflation or
pneumothorax, especially with co-existent systemic hypotension. By employing the
above weaning strategy, the vast majority of infants can be safely weaned off iNO within
96 hours of initiation, and most within 24 hours.

CAPHC iNO Collaborative

Guideline
Conditions
1.

Neonates with hypoxemic respiratory failure associated with clinical or echocardiographic

evidence of pulmonary arterial hypertension.

Inclusion Criteria
Persistent hypoxemic respiratory failure secondary to pulmonary hypertension despite measures to
ensure adequacy of lung expansion (including evaluation by CXR and use of exogenous surfactant and/or
high-frequency modes of ventilation, when appropriate) and correction of acidosis (pH < 7.25)
Patients will meet one or more of the following criteria:
1.
2.
3.
4.

Oxygenation Index of 15-25 or higher

Pre- and post-ductal saturation difference of 20%
Post-ductal PaO2 < 60 mm Hg with FiO2 of > 0.6
Post-ductal SaO2 < 92% with FiO2 of 1.0

Policy
1.

An order to initiate iNO should be made by a staff physician, by resident medical staff with staff
physician approval, or by a Registered Respiratory Therapist (RRT) under the auspices of a
medical directive. A clear care plan should be articulated including goal/s of therapy, the
identification of physiological targets and parameters indicating response to therapy.

2. iNO will be administered and titrated by the RRT as per staff physician order and/or a medical
directive.
3. Documentation to explain reasons for deviation from the guideline are recommended for the
purposes of providing new evidence to inform future guidelines.

Contraindications/Cautions
Contraindications:
1. Known or suspected congenital heart disease with increased pulmonary venous pressure or
where systemic perfusion is dependent upon extrapulmonary right-to-left shunting.
Relative contraindications:
1. Known or suspected severe intraventricular hemorrhage (IVH).
2. Active pulmonary or gastrointestinal hemorrhage.
Cautions or considerations:
1. Caution in infants < 28 weeks gestation during the first 3 days of life (due to high risk for
IVH). Cranial ultrasound should ideally be performed prior to initiation.
2. Caution in patients with bleeding tendency (e.g., thrombocytopenia) and/or
coagulopathy/DIC. Consider correction with blood products prior to initiation.
3. Literature does not support prolonged use in chronic pulmonary hypertension or in right
ventricular dysfunction in the absence of associated pulmonary hypertension.

Equipment and Procedure

It is recommended that Health Canada-approved INO delivery systems should be used to assure
consistent and safe gas delivery and monitoring during therapy. (See Appendix 4)
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CAPHC iNO Collaborative

Staff operating such equipment should have evidence of education, training and competencies.

Monitoring & Documentation

Document: (frequency as per local NICU protocol)
1. Vital signs: Blood pressure, heart rate, pre- and post-ductal SaO2, FiO2
2. Respiratory status: pulmonary ausculatation, work of breathing, ventilator parameters and
endotracheal tube placement
3. Post-ductal arterial blood gas and calculation of Oxygenation Index (recommended, but not
mandatory)

Prior to Administration of iNO

1.
2.
3.
4.
5.

Echocardiographic confirmation of PPHN is desirable but not mandatory

Optimize lung inflation (using maneuvers as suggested under inclusion criteria)
Correct acidosis
Optimize sedation
Optimize cardiac output (consider volume loading and/or inotropes)

Starting Dose
1.

20 ppm is the recommended starting dose (doses > 40 ppm have greater potential to cause
toxicity without evidence of incremental or additional benefit)
2. Evaluation of response time should be 30 60 minutes
3. Avoid other changes during the evaluation period as much as possible.

Assessment of Response
Complete, partial or no response based on changes in Fi02, SaO2, and PaO2
Complete Response
Partial Response
No Response

Increase in PaO2 >20 mmHg or SaO2 >10 % or reduction in Fi02 by greater

than 0.2.
Increase in PaO2 by 10-20 mmHg or SaO2 5-10 % or reduction in Fi02 by 0.050.1.
Increase in PaO2 < 10 mmHg or SaO2 < 5 % or change in FiO2 by < 0.05.

In the event of no response, iNO can be safely discontinued abruptly within 1 hour of initiation. In nonresponders treated with iNO for > 1 hour, follow the weaning protocol (below) without reference to FiO2.

Weaning
1.
2.
3.
4.
5.

A review of iNO weaning criteria and patient readiness for weaning should be discussed as part of
the patient care plan (daily as a minimum).
Weaning of iNO should commence as soon as criteria are met and patient readiness is
established.
When iNO is being weaned, every effort should be made to minimize changes to other treatments.
The minimum time between initiation of iNO and initial wean should be 2-6 hours.
Consider weaning when patient is stable and Fi02 is < 0.4-0.6

Process:
1. Wean from 20 to 10 ppm.
2. Within 1- 2 hours, if no deterioration occurs, wean to 5 ppm.
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3. Then, wean iNO in increments of 1 ppm every 1-2 hours until discontinuation.
4. Prior to discontinuing iNO, consider temporarily increasing FiO2 by 0.1-0.2 for 10 min (preoxygenation).

Monitoring for Complications

Methemoglobin
Measurement of methemoglobin level is highly recommended, ideally within 1 - 2 hours of initiation, then
minimum daily or as determined by the medical team.
Methemoglobin level

Action

Greater than 10%:

Wean as quickly as possible to OFF

5-10%:

Wean to 50% of current dose and repeat level

within 1-2 hours, consider early and rapid weaning

2.5 5%:

Consider early weaning

Monitoring of Nitrogen Dioxide (NO2)

Continuous NO2 monitoring should be routine practice.
Consistent Nitrogen Dioxide Level

Action

NO2 < 2 ppm

Safe

NO2 >2 ppm

Wean iNO (and FiO2) as quickly as possible

Rebound Pulmonary Hypertension

Definition: Absolute increase in Fi02 requirement of > 0.2
Management:
Return to previous iNO dose for minimum 4 hours before reinitiating weaning then, wean by 1 ppm every
1-2 hours until OFF.
Consider pre-oxygenation prior to weaning from 1 ppm to OFF, as described above.

CAPHC iNO Collaborative

Appendices and other guideline-related material

Disclaimer:
This guideline represents the views of the CAPHC Community of Practice and was arrived
at after careful consideration of the available evidence as well as a consensus building
process. The guideline does not override the responsibility of individual clinicians and
organizations to make decisions and provide the most appropriate care to infants, children
and youth in consultation with the patient and family/guardian.

Appendix 1: Guideline development methods: description and material

Generating evidence process:
Guideline Review
A review of hospital guidelines for administration of inhaled Nitric Oxide (iNO) was completed. Eighteen
documents from eleven hospitals across Canada and a systematic review of the literature, the American
Association for Respiratory Care: Evidence-Based Clinical Practice Guideline: Inhaled Nitric Oxide for
Neonates With Acute Hypoxic Respiratory Failure, were analyzed. There are two documents from IWK
Health Centre. The first document is a literature review and guideline from 2006 and the second is a
guideline with some content based upon the first document. Two of the documents from London Health
Science Centre consisted of tables used to document monitoring levels.
Two researchers extracted all the content from the documents to a platform for comparison. Due to the
heterogeneous nature of the documents, time was devoted to independently identify categories common
among the documents. After a discussion, categories were agreed upon. Inclusion and exclusion criteria
were then determined. Information was grouped using the criteria. Information within categories was
summarized and standardized for ease of comparison. The researchers compared the results for
similarities and differences. A conclusion was prepared for each category highlighting key results.
The attached document, Administration of Inhaled Nitric Oxide A Review of Canadian Hospital
Guidelines and a Systematic Review of the Literature for the Canadian Association of Paediatric Health
Centres (CAPHC) consists of our key results by category and is followed by summary tables. It is
important to note that direct comparisons were complicated by the nature of the documents which were
heterogynous in their goals and target audience

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The evidence used to support the indication of use being HRF in term/near term newborn infants is Class
1 level A, the remaining neonatal recommendations are rated at Class 2A or 2B, Level C.

Guideline development process

For purposes of safety and operational optimization, paediatric centres have developed, independently,
iNO usage protocols/guidelines. Although these guidelines were developed via evidence based practice, as
identified in the guideline review there is a degree of diversity in practice in our childrens hospitals across
the country.
An approach to guideline development was taken that would:

Provide a focus for quality control and patient safety;

Reduce variations in practice; and
Promote efficient use of iNO.

Recognizing that there are differences in the maturity of evidence for use of iNO in neonates versus the
paediatric population, two separate working groups were established. A national inter-professional
collaborative including physician, registered respiratory therapists and directors for quality improvement
met monthly over a 12 month period using the evidence as well as tacit knowledge to develop
recommendations for implementation in the neonatal setting.
Using the results of the guideline review as the framework for the recommendations, draft guidelines were
developed under each category. These draft guidelines were then reviewed, discussed and modified until
consensus was reached by the full guideline development group.
Neonatal Guideline Development Group:
Cheryl Bailey RRT Clinical Team Leader, Respiratory Therapy, Janeway Child Health Centre, St. Johns NL
Karrie Beck BSc, RRT Practice Lead, Inhaled Nitric Oxide Project Critical Care Strategic Clinical Network, Alberta
Health Services
Michael Finelli RRT NRCP Neonatal Respiratory Care Practitioner, NICU Hospital for Sick Children Toronto ON
Lydia Hatton RRT Clinical Leader, Respiratory Therapy IWK Health Centre Halifax, NS
Dr. Robert Jankov MB BS PhD FRACP Staff Physician, Division of Neonatology, Senior Scientist, Physiology and
Experimental Medicine, Hospital for Sick Children, Associate Professor, Paediatrics and Physiology, University of
Toronto, Toronto ON
Dr. Amish Jain Staff Neonatologist, Assistant Professor in Paediatrics Mount Sinai Hospital Toronto ON
Dr. Faiza Kurshid NICU Kingston General Hospital, Kingston ON
Marisa Leone Respiratory Therapy Assistant Chief, Montreal Children's Hospital, Montreal QC
Linda Levesque RRT Respiratory NICU Educator Consultant, Jewish General Hospital, Montreal QC
Courtney Maguire Director of Respiratory Therapy, Mount Sinai Hospital Toronto ON
Carrie Lynn Meyer RRT BA RRT-Clinical Manager NICU, Level 2 Nursery and Neonatal Transport Team
McMaster Childrens Hospital
Allison Nykolaychuk RRT PCCU McMaster Childrens Hospital Hamilton ON

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Dr. Horacio Osiovich Neonatologist , British Columbia Childrens Hospital, Vancouver BC

Dr. Mosarrat Qureshi MBBS, FAAP, FRCPC Staff Neonatologist, Northern Alberta Neonatal Program, Clinical
Assistant Professor, Department of Pediatrics, Stollery Childrens Hospital, Edmonton AB
Adelle Riehl Saskatoon Health Region Saskatoon SK
Gerald Spence RRT Unit Manager Respiratory Pediatric Intensive Care Unit Alberta Childrens Hospital, Calgary
AB
Dr. Matthew Weiss M.D., FRCPC, FAAP Pediatric Intensivist Dpartement de pdiatrie Centre Mre-Enfant Soleil
du CHU de Qubec, Quebec City, QC

Other Reviewers
Zelia DaSilva Clinical, Director NICU, Neonatal Follow-up Clinic and Respiratory Services, The
Hospital For Sick Children
Leanne Davidson Clinical Educator Respiratory Therapy CCM The Hospital For Sick Children
Chris Devlin Respiratory Therapy PICU Program Specialist, Stollery Childrens Hospital, Edmonton AB
Jeff Dmytrowich RRT, FCSRT Respiratory Therapy Clinical Supervisor Saskatoon Health Region
Amanda Hurdowar, MSc Quality Management, SickKids Length of Stay Task Force Standardize
Care Project Lead The Hospital For Sick Children
Dr. Philippe Jouvet MD PhD Full professor/professeur titulaire de Clinique Director of the Pediatric
Intensive Care Unit/chef de service des soins intensifs pdiatriques, CHU Sainte-Justine
Dr. Peter Laussen MB.BS.,FCICM Chief, Department of Critical Care Medicine, David and Stacey
Cynamon Chair in Critical Care Medicine, Hospital for Sick Children, Professor, Department of
Anaesthesia, University of Toronto, Toronto ON
Suzanne Libbey RRT II Respiratory Therapy Clinical Lead
Jason Macartney Clinical Educator Respiratory Therapy PICU The Hospital For Sick Children
Dr Marie-ve Samson, pdiatre intensiviste - Centre mre-enfant du CHUQDr. Ram Singh
Elizabeth Schurmann Improvement Consultant, Quality & Patient Safety, Strategy & Organizational
Performance, IWK Health Centre
Christina Sperling RRT Clinical Manager, Respiratory Therapy The Hospital For Sick Children

Guideline management process:

This guideline was originally developed in June 2015. A Nitric Oxide Stewardship Network is being
established and will facilitate data collection, benchmarking and a guideline review process to support
quality improvement.
Data will be collected prospectively from participating network members. Reasons for deviation from
guideline will be captured as well as demographic data, indications, responses and outcome data. A new
body of evidence will be amassed to support the guideline and/or support change of the guideline.

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Appendix 2: Funding used in the development of the document

The development of this guideline was supported in part by the Canadian Association of Paediatric Health
Centres through a grant from Medbuy Corporation and the in-kind contributions of time and expertise
from the iNO Collaborative members and their respective health care organizations.

There are no conflicts of interest to declare

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Appendix 3: Glossary/definitions and acronyms

ABG

Arterial Blood Gas

ARDS

Acute Respiratory Distress Syndrome

CCM

Critical Care Medicine

CCU

Critical Care Unit

CDH

Congenital Diaphragmatic Hernia

ECMO

Extracorporeal membrane oxygenation

FiO2

Fraction of Inspired Oxygen

iNO

Inhaled Nitrogen Oxide

MPAW

Mean Airway Pressure

MRSP

Medical Readiness Strategic Plan

NICU

Neonatal intensive Care Unit

NO

Nitric Oxide

OI

Oxygenation index (OI) = Mean airway pressure (MPAW) FiO2 100

OR

Operating Room

PaO2

Partial Pressure of Oxygen in Arterial Blood

PICU

Pediatric Intensive Care Unit

ppm

Parts per million

PPROM

Preterm Premature Rupture of Membranes

PPHN

Persistent pulmonary hypertension of newborn

PVR

Pulmonary Vascular Resistance

RDS

Respiratory Distress Syndrome

RRT

Registered Respiratory Therapist

SaO2

Arterial Oxygen Saturation

SpO2

Saturation of Peripheral Oxygen

SvO2

Venous Oxygen Saturation

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Appendix 4: Equipment and Procedures

Publication of several large randomized trials (40) (41) (42) led to approval of iNO by the US Food and
Drug Administration (FDA) in December 1999 as an orphan drug for use in infants up to 14 days of life,
born at > 34 weeks gestation with HRF and clinical or echocardiographic evidence of pulmonary
hypertension. At the time, no approved devices were available for the monitoring and delivery of iNO. In
2001, a method-of-use patent was obtained by INO Therapeutics (subsequently, Ikaria, Clinton, NJ,
USA, and now Mallinckrodt Pharmaceuticals, St. Louis, MO, USA), which covered both the gas
(INOmax) and the device for monitoring and delivery (INOvent). In September 2005, the
Therapeutic Products Directorate for Health Canada issued a Notice of Compliance for INOmax,
essentially providing Ikaria with exclusive rights to market iNO in Canada.

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Appendix 5: Stewardship Framework

Practice
Analysis

Engagement

Data analysis to determine current practices

Identify opportunities for improvement/standardization
Update existing guidelines or develop a new guideline

Identify physician leads to support this work

Engage inter-professional clinical staff
Engage technical team and administrative support
Share data and plans with senior executive - gain their support

Determine who will collect utilization data and how often

Determine a means of collecting patient data in real time
Determine how data will be shared with key stakeholders and how often
Implementation Determine goals and targets for the team to strive for - (Hours,
appropriateness of use, adherence to the guidelines, etc)
Planning

Sustainability

Ongoing and regular presentation of iNO utilization and practices

Ongoing evaluation of the processes and identifying further opportunities
Ongoing analysis of patient utilization data to identify trends in use and/or
opportunities for more appropriate utilization
Celebrate successes with all stakeholders

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CAPHC iNO Collaborative

Appendix 6: Flow Charts

PRIOR TO INITIATION OF iNO
Optimize lung inflation
Correct acidosis (Aim for pH > 7.25)
Optimize sedation
Optimize cardiac output (consider volume and/or inotropic agents)
Obtain post-ductal ABG if possible

INITIATION OF iNO
An order to initiate iNO should be written by authorized individual

Start iNO at 20ppm

Avoid other changes during the evaluation period (30-60 min)
as much as possible

RESPONSE
Definition:
Increase in PaO2 >20 mmHg or SaO2 >10 % or
reduction in Fi02 by > 0.2.
Action:
Once Optimal FiO2 established leave iNO at 20 ppm
for 2 6 hours

17

PARTIAL RESPONSE
Definition:
Increase in PaO2 by 10-20 mmHg or
SaO2 5-10 % or
Reduction in Fi02 by 0.05-0.1.
Action:
Once Optimal FiO2 established leave
iNO at 20 ppm for 2 6 hours

NO RESPONSE
Definition:
Increase in PaO2 < 10 mmHg
SaO2 < 5 % or
Change in FiO2 by < 0.05
Action:
Discontinue iNO within 60 min of
initiation, otherwise follow weaning
protocol

CAPHC iNO Collaborative

Weaning Flowchart
Infants with a complete or partial
response on iNO for 2 to 6 hours
are suitable for weaning when
FiO2 < 0.4-0.6

Wean iNO from 20ppm to 10

ppm

Wean iNO to 5ppm after 1-2

hours as long as weaning criteria
are met

Wean by 1ppm every 1 to 2

hours as long as weaning criteria
are met

At 1 ppm:
Prior to discontinuation, increase
FiO2 by 0.1-0.2 for 10 min then
DISCONTINUE iNO

Hold weaning if:

Increase in FiO2 by > 0.2 is required

Return to previous iNO dose for minimum of 4 hours

before recommencing wean

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CAPHC iNO Collaborative

Appendix 7: About Us
The Canadian Association of Paediatric Health Centres (CAPHC) was established in 1968 as the Canadian
Association of Paediatric Hospitals, representing all childrens hospitals in Canada. In 2001, the
organization expanded its national reach to include all childrens hospitals in the country, many
community healthcare centres, regional and provincial health authorities, rehabilitation centres and home
care provider agencies.
Today, CAPHC supports multi-disciplinary child and youth healthcare professionals from more than 70
organizations in Canada. Each year, 8.75 million children and youth rely on the services of CAPHCs
member organizations. These organizations provide essential healthcare services to Canadas children and
youth.
As a national organization, CAPHC is uniquely positioned to influence system-wide change, advocating
for the very best child and youth healthcare.
CAPHC WORKS BY

Establishing programs and activities that address current and emerging child and youth
healthcare priorities;
Advocating to transform health service delivery for children and youth;
Connecting service providers and key stakeholders;
Fostering research, brokering knowledge, facilitating educational opportunities and enhancing
information exchange for members and stakeholders.

CAPHC EMPOWERS CHANGE BY

Building a national infrastructure to support information dissemination (knowledge translation)

and the application of new knowledge;
Facilitating the identification and sharing of best practice;
Providing the child and youth healthcare community across Canada with simple tools to share
knowledge;
Maintaining an unprecedented and dynamic repository of knowledge on the CAPHC Knowledge
Exchange Network: www.ken.caphc.org.

CAPHCS VALUES
Collaboration: We work and respond to the needs of the full spectrum of the community that is
committed to advancing child and youth health service delivery. This involves health practitioners,
educators, researchers, administrators, children, youth and families, and policy decision makers alike.
Consultation: We recognize the expertise that exists within our community and engage a broad interprofessional child and youth healthcare community in all our undertakings.
Respect: We are respectful of the cultures, diversities, strengths, knowledge and needs of all member
organizations, stakeholders and partners. We listen to what is important to our constituency and work
with organizational stakeholders to effect change at a system-wide level.
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CAPHC iNO Collaborative

Stewardship: We are responsible and accountable for the resources provided to us by our member
organizations and partners to carry out CAPHCs goals and objectives.
OUR 4 STRATEGIC IMPERATIVES
Make a Difference: Keeping pace with the rapid release of available data and best practice;
synthesizing and disseminating this information to all CAPHC members.
Be the Voice: Being a strong advocate for the healthcare needs of Canadas children and youth.
Take the Stage: Increasing the awareness of child and youth healthcare needs and challenges through
improved messaging, communications and visibility.
Be Here for Tomorrow: Strengthening the value proposition of CAPHC by building capacity to
provide high value products and services to all CAPHC members

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CAPHC iNO Collaborative

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99. Outcome in neonates with congenital heart disease referred for respiratory extracorporeal
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100. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in
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