Department of Neonatology, Astrid Lindgren Children’s Hospital

Simon Carlquist

Study Programme in Medicine, KI

Degree project 30 credits

Spring 2012

Neonatal Use of Inhaled Nitric Oxide

a registry study of treatment indications, extent and outcomes

at Astrid Lindgren Children’s Hospital

Final version

Author: Simon Carlquist

Supervisor: Baldvin Jónsson

Coordinator: Isis Amer-Wåhlin

Inhalerad kväveoxid till nyfödda – en registerstudie av behandlingens indikationer,

omfattning och utfall vid Astrid Lindgrens Barnsjukhus.

Bakgrund: Inhalerad kväveoxid är en lungselektiv kärlvidgande behandling vid andningssvikt

orsakad av pulmonell hypertension hos nyfödda. Den har även studerats som profylax mot

bronkopulmonell dysplasi, en kronisk lungfunktionsnedsättning vanlig bland för tidigt födda

barn. Evidensen till stöd för denna kostsamma behandling är bristfällig för spädbarn födda

före 34 veckor. Trots detta används behandlingen frekvent på nyfödda i alla gestationsåldrar.

Syfte: Att undersöka om kväveoxidbehandling av nyfödda på Astrid Lindgrens Barnsjukhus,

Solna, Sverige, skett i enlighet med tillgänglig evidens, och att presentera deskriptiv statistik

rörande vissa behandlings- och patientrelaterade variabler. Ett sekundärt syfte var att

identifiera signifikanta skillnader i dessa variabler mellan barn födda före och efter 34 veckor. Material och Metoder: Alla nyfödda som behandlades med inhalerad kväveoxid på

neonatalintensivvårdsavdelningen vid nämnda sjukhus mellan 2006 och 2010 inkluderades.

Data rörande demografi, diagnostik, behandlingen i sig samt dess utfall samlades in från

patientjournaler och fördes in i ett web-baserat register. Resultat: 96 nyfödda behandlades

med inhalerad kväveoxid. 50% var födda före vecka 34. Denna åldersgrupp behandlades

under signifikant längre tid, samt stod för nära 75% av alla behandlingstimmar. Majoriteten

behandlades för hypoxemisk andningssvikt, och 2% fick behandling i profylaktiskt syfte.

Allvarliga biverkningar var sällsynta. Slutsats: Inhalerad kväveoxid användes inte i enlighet

med tillgänglig evidens. Behandlingsrutinerna bör möjligen ses över.

Neonatal use of inhaled nitric oxide – a registry study of treatment indications, extent

and outcomes at Astrid Lindgren Children’s Hospital.

Introduction: Inhaled nitric oxide is a selective pulmonary vasodilator, used to resolve

respiratory failure complicated by persistent pulmonary hypertension in newborns. It has also

been suggested as a prophylaxis to prevent bronchopulmonary dysplasia, a long-term

respiratory disability associated with preterm birth. Evidence supporting this expensive

therapy is limited in infants born before 34 weeks, but the therapy remains frequently used in

newborns of all gestational ages. Aims: To determine whether neonatal use of inhaled nitric

oxide at Astrid Lindgren Children’s Hospital, Solna, Sweden, has been consistent with

available evidence, and to present descriptive statistics on selected treatment- and patient-

related variables. A secondary aim was to detect significant differences in these parameters

between infants born before and after 34 weeks of gestation. Material and Methods: All

newborns who received inhaled nitric oxide therapy at the neonatal intensive care unit at said

hospital between 2006 and 2010 were included. Information on demographics, diagnostics,

treatment variables and outcomes was gathered from patient data records and submitted to a

web-based registry. Results: 96 infants received inhaled nitric oxide therapy. 50% were born

before 34 weeks. This group also had a significantly longer duration of therapy, and

accounted for nearly 75% percent of therapy hours. The majority had hypoxemic respiratory

failure, and 2% were treated prophylactically. Adverse effects were rare. Conclusions:

Inhaled nitric oxide was not used in an evidence-based manner. Therapy practices should

perhaps be revised.

Keywords: “Nitric oxide”, “Infant, newborn”, “Administration, inhalation”, “Evidence-based

medicine”. “Persistent pulmonary hypertension of the newborn”, “Bronchopulmonary

dysplasia”

Abbreviations

ALCH Astrid Lindgren Children’s Hospital

BPD Bronchopulmonary dysplasia

CDH Congenital diaphragmatic hernia

CMV Conventional mechanical ventilation

CPAP Continuous positive airway pressure

FiO2 Fraction inspired O2

GA<34w Gestational age < 34 weeks (born before 34 completed weeks)

GA≥34w Gestational age ≥ 34 weeks (born after 34 completed weeks)

HFOV High-frequency oscillatory ventilation

iNO Inhaled nitric oxide

NICU Neonatal intensive care unit

OI Oxygenation index

PICU Pediatric intensive care unit

PMA Post-menstrual age (gestational age at birth + post-natal age)

PPHN Persistent pulmonary hypertension of the newborn

PVR Pulmonary vascular resistance

RCT Randomised controlled trial

RDS Respiratory distress syndrome

SVR Systemic vascular resistance

Table of contents

1. Introduction .............................................................................................................. 1

1.1 Brief overview ................................................................................................................ 1

1.2 Persistent pulmonary hypertension of the newborn .................................................. 1

1.2.1 Overview and demographics ................................................................................... 1

1.2.2 Circulatory and pulmonary physiology before and after birth ................................. 1

1.2.3 Causal factors ........................................................................................................... 2

1.2.4 Diagnosis and treatment strategies .......................................................................... 3

1.3 Bronchopulmonary dysplasia ...................................................................................... 4

1.3.1 Overview and demographics ................................................................................... 4

1.3.2 Causal factors ........................................................................................................... 4

1.3.3 Diagnosis and treatment strategies .......................................................................... 6

1.4 Inhaled nitric oxide ....................................................................................................... 6

1.4.1 Overview.................................................................................................................. 6

1.4.2 Mechanism of pulmonary vasodilation .................................................................... 7

1.4.3 Pulmonary selectivity of inhaled NO ....................................................................... 7

1.4.4 Toxic and adverse effects of iNO ............................................................................ 8

1.4.5 iNO administration, economy and indications......................................................... 9

1.5 Evidence base for neonatal iNO therapy .................................................................... 9

1.5.1 Terminology ............................................................................................................ 9

1.5.2 Evidence for iNO therapy in term/near term newborns ........................................... 9

1.5.3 Evidence for iNO therapy in preterm newborns .................................................... 10

1.7 Motive for this study ................................................................................................... 11

2. Aims ......................................................................................................................... 12

2.1 Primary aim ................................................................................................................. 12

2.2 Secondary aims ............................................................................................................ 12

3. Material and methods ............................................................................................ 13

3.1 Study design and setting ............................................................................................. 13

3.1.1 Neonatal care at Astrid Lindgren Children’s Hospital .......................................... 13

3.1.2 The iNOcare registry ............................................................................................. 13

3.2 Study population ......................................................................................................... 14

3.2.1 Inclusion and exclusion criteria ............................................................................. 14

3.2.2 Identifying eligible infants ..................................................................................... 14

3.3 Data collection ............................................................................................................. 14

3.4 Statistical analysis ....................................................................................................... 15

3.5 Databases and search strategy ................................................................................... 15

3.6 Ethical considerations ................................................................................................. 16

4. Results ..................................................................................................................... 18

4.1 Patient demographics ................................................................................................. 18

4.2 Pre-treatment variables .............................................................................................. 18

4.2.1 Diagnostics and indication for iNO therapy .......................................................... 18

4.2.2 Treatments prior to iNO therapy ............................................................................ 20

4.2.3 Baseline clinical data ............................................................................................. 20

4.3 iNO therapy ................................................................................................................. 20

4.3.1 Initiation, duration and dosing ............................................................................... 20

4.3.2 Concomitant therapies ........................................................................................... 21

4.4 Outcomes...................................................................................................................... 22

4.4.1 Initial response gas exchange ................................................................................ 22

4.4.2 Survival .................................................................................................................. 22

4.4.3 Bronchopulmonary dysplasia ................................................................................ 22

4.4.4 Final cranial ultrasound ......................................................................................... 23

4.4.5 Other adverse events .............................................................................................. 23

5. Discussion................................................................................................................ 24

5.1 Major findings ............................................................................................................. 24

5.2 Comments on therapy in preterm infants ................................................................. 24

5.3 Comments on therapy in term/near term infants .................................................... 25

5.4 Other comments .......................................................................................................... 26

5.5 Outcomes...................................................................................................................... 26

5.6 Limitations ................................................................................................................... 27

6. Conclusions ............................................................................................................. 28

7. Acknowledgements ................................................................................................ 30

8. References ............................................................................................................... 31

Appendix 1 .................................................................................................................. 35

Overview of data parameters submitted to the iNOcare registry. ................................... 35

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1. Introduction

1.1 Brief overview

Inhaled nitric oxide (iNO) is an advanced and expensive vasodilating therapy for

newborn infants in whom the pulmonary circulation fails to adapt to the extra-uterine

environment after birth; a condition known as persistent pulmonary hypertension of

the newborn (PPHN). In addition, iNO has been studied as a prophylactic drug to

prevent development of bronchopulmonary dysplasia (BPD), a long-term respiratory

disability strongly associated with preterm birth. Evidence supports iNO therapy in

infants born at or near term but not in the preterm population. Yet iNO is frequently

used in both term and preterm infants at neonatal intensive care units across Europe

and in the U.S. This study aims to investigate to what extent iNO use at Astrid

Lindgren Children’s Hospital in Solna, Sweden, has been consistent with available

evidence.

1.2 Persistent pulmonary hypertension of the newborn

1.2.1 Overview and demographics

Respiratory failure, defined as an inability of the respiratory system to maintain

adequate gas exchange, accounts for one third of all neonatal mortality. 10% of cases

are either caused – or complicated – by a syndrome known as persistent pulmonary

hypertension of the newborn (PPHN) [1], a potentially life-threatening condition in

which pulmonary vascular resistance (PVR) remains higher than systemic vascular

resistance (SVR) in the newborn period. This results in hypoxia that often is

unresponsive to maximum oxygen administration and ventilation, i.e. hypoxemic

respiratory failure [1–3]. PPHN occurs in approximately one to two of 1000 live

births and is most common in full term or post term infants [4]. It is associated with

significant neurodevelopmental and respiratory morbidity later in childhood, and

carries a 5-10% short-term mortality even with modern treatment [1].

1.2.2 Circulatory and pulmonary physiology before and after birth

A now obsolete synonym for PPHN is persistent fetal circulation. The fetal circulation

is characterised by a high PVR since the lungs are collapsed and not ventilated, and a

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low SVR since the placenta acts as a volume reservoir. This resistance gradient,

where PVR>SVR, causes a functional right-to-left shunting of blood from the

pulmonary artery to the aorta through the open ductus arteriosus [5]. Thereby, the

high-resistance pulmonary circulation is bypassed and blood from the right ventricle

enters the low resistance systemic circulation to be oxygenated by the placenta [5].

Immediately following birth and the infant’s first breath of air, PVR normally

decreases rapidly, so that PVR<SVR. This is mediated by mechanical distension of

pulmonary vessels as the lungs fill with air, and by endogenous chemical mediators of

vasodilation such as increased oxygen tension, prostaglandins and nitric oxide [1,6].

At the same time, SVR increases as the placental circulation is discontinued [3]. This

set of events causes a tenfold increase in pulmonary blood flow [1], and the

subsequent rise in oxygen tension is believed to contribute to the spontaneous closing

of the ductus arteriosus and foramen ovale, which normally occurs within two days

after birth [5]. If for some reason the reduction of PVR after birth is inadequate, or if a

reduced PVR should return to suprasystemic levels, a resistance gradient analogous to

that seen in the fetal circulation would cause a similar right-to-left shunt of blood

across the open ductus arteriosus. Thereby, deoxygenated blood would continue to

bypass the pulmonary circulation to some degree, but without being oxygenated by

the now disconnected placenta. This is essentially the case in PPHN [1–3].

1.2.3 Causal factors

PPHN is usually classified as either primary or secondary based on its etiology. In

general, primary PPHN is considered a result of long-term dysregulation of fetal

pulmonary development resulting in abnormal muscularisation of alveolar arteries

and/or pulmonary hypoplasia (i.e. underdeveloped lung parenchyme, not to be

confused with bronchopulmonary dysplasia which is covered in section 1.3) [4].

Congenital diaphragmatic hernia (CDH; abdominal organs protruding into the thorax,

mechanically obstructing pulmonary growth), oligohydramnios (lack of amniotic

fluid), long-standing fetal hypoxia and pharmacological factors are some suggested

causal factors [1,2]. For example, maternal intake of selective serotonin reuptake

inhibitors (SSRIs) [7], or non-steroid anti-inflammatory drugs (NSAIDs) in late

pregnancy is associated with PPHN, as is also maternal diabetes and obesity [4].

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By contrast, secondary PPHN, being the more common form, is the result of hypoxic

pulmonary vasoconstriction due to acidemia and hypoxia caused by acute perinatal

events [4]. Hypoxic pulmonary vasoconstriction is a normal physiological mechanism

by which vessels in poorly ventilated parts of the healthy lung constricts in response

to low oxygen pressure, thereby rerouting blood flow to better-ventilated parts,

optimising oxygenation [8]. In secondary PPHN, however, this mechanism becomes

the culprit as it results in a downward spiral of hypoxia and further vasoconstriction.

The acute perinatal events causing secondary PPHN include meconium aspiration

syndrome (pre-natal aspiration of amniotic fluid stained with fetal excrement),

respiratory distress syndrome (RDS; inadequate pulmonary compliance due to lack or

dysfunction of surfactant proteins), perinatal asphyxia, and congenital infections [1,2].

The onset of PPHN usually occurs within 12 hours from birth [3].

A note on terminology: the iNOcare registry, the data of which this study relies on,

defines PPHN caused by congenital diaphragmatic hernia and pulmonary hypoplasia

as secondary PPHN (even though they both belong to the long-term type of causality,

rather than the acute vasoconstriction type) since both are distinct conditions. The

registry further considers any PPHN case of unknown etiology to be primary, or

idiopathic, even though the cause might be any of the secondary ones listed above.

This report will use the same definition as the registry does in the following text.

1.2.4 Diagnosis and treatment strategies

PPHN is a key differential diagnosis in any newborn with persisting cyanosis despite

optimal ventilation and oxygen administration [3]. The latter is usually measured as

fraction of inspired air (FiO2), where FiO2 0.21 is equivalent to room air (21% O2),

and FiO2 1.0 represents 100% O2. A measure of respiratory failure severity that takes

FiO2 and the amount of respiratory support given into account is the oxygenation

index (OI), explained in Figure 1.

Figure 1. Calculation of the oxygenation index as a measure of respiratory failure severity.

FiO2=fraction inspired oxygen (0.21-1.0), MAP=mean airway pressure (cm H2O), PaO2=arterial partial

pressure of oxygen (mmHg). Illustration: the author, modified from [9].

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Echocardiography with colour doppler is the preferred diagnostic modality when

PPHN is suspected, since it can detect elevated or suprasystemic pulmonary artery

pressures, tricuspid valve insufficiencies, and right-to-left shunting of blood across

the ductus arteriosus and/or foramen ovale [3], all of which are considered to be

evidence of pulmonary hypertension. Echocardiography can also rule other causes of

cyanosis such as structural heart disease or ventricular dysfunction [1,3].

Selective pulmonary vasodilation using inhaled nitric oxide, high levels of inspired

oxygen, surfactant instillation, hemodynamic support and lung volume recruitment

through high frequency oscillatory ventilation (HFOV) or continuous positive airway

pressure (CPAP) are key components of the modern therapeutic approach to PPHN

[1]. A last resort in cases of refractory respiratory failure in term/near term newborns

is extracorporeal membrane oxygenation (ECMO). Although this technically

advanced therapy buys time to await spontaneous PVR decline or further lung

maturation, and has an overall survival rate of 85% in cases of neonatal respiratory

support, it is a highly invasive, risk-associated and resource-consuming procedure

available only at highly specialised centres [9].

1.3 Bronchopulmonary dysplasia

1.3.1 Overview and demographics

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of

prematurity (CLD), can be described as a chronic disruption of growth and maturation

of alveoli and alveolar capillaries, causing a prolonged oxygen and/or ventilator

dependency in the newborn period, sometimes for several months or years [10]. It

occurs mainly in preterm infants. Around one third of all newborns with birth weight

<1000g develop BPD to some degree, and conversely, 97% of all BPD cases occur in

infants with birth weight <1250g [11]. Similarly to PPHN, BPD also contributes to

considerable neurodevelopmental morbidity in later childhood [11].

1.3.2 Causal factors

BPD was first described in 1967, as the result of oxygen toxicity and mechanically

induced lung injury (volutrauma) following aggressive mechanical ventilation in

5

mildly preterm infants suffering from RDS [12]. Pathological findings included

scattered severe airway fibrosis, epithelial metaplasia and smooth muscle hypertrophy

as well as hyperinflation and “white-outs” on chest radiographs [13]. Since the advent

of antenatal corticosteroids and exogenous surfactant therapy in the 1980’s and 90’s,

which allowed for much more gentle ventilation strategies and greater survival rates

in RDS therapy, and thereby contributed to the marked reduction of the lowest viable

gestational age, BPD has evolved from its classical form. From previously affecting

mildly preterm infants, it is now a “post-surfactant”, “new BPD” [10] featuring a

different pathology, and affecting primarily infants of lower gestational age and birth

weight than before.

Alveolar development occurs mainly during gestational weeks 32-36 [14].

Histological markers of “new BPD” include fewer-than-normal, large and immature

alveoli, dysmorphic capillaries and general mild fibrosis of alveolar septa [10,15].

Current pathophysiological models suggest that the “new BPD” is a product of an

arrested development of the distal airways at the stage of gestation in which the infant

is born [13]. The abrupt environmental change from intra- to extra-uterine life and a

subsequent complex interplay of oxidative stress, disrupted growth factor signalling,

inflammatory mechanisms, and genetic predisposition are suggested contributory

causal factors [14]. Contrary to “old BPD”, “new BPD” does not exclusively occur in

infants that have undergone aggressive mechanical ventilation. Instead, its main

predictors are low gestational age and low birth weight [16]. Figure 2 compares the

pathology of PPHN and BPD, although they are two completely separate conditions,

to give the reader a clearer understanding of their differences and similarities.

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Figure 2. A schematic comparison of the pathogenesis behind secondary and primary PPHN and “old”

and “new” BPD. Note that PPHN is more common in term infants, and that BPD primarily occurs in

preterm infants, although exceptions occur. PPHN=Persistent pulmonary hypertension of the newborn,

PVR=pulmonary vascular resistance, BPD=bronchopulmonary dysplasia, RDS=respiratory distress

syndrome. *: For example abnormal muscularisation or pulmonary hypoplasia (not to be confused with

bronchopulmonary dysplasia). Illustration: the author.

1.3.3 Diagnosis and treatment strategies

Present diagnostic criteria for BPD are based on the infants need for supplemental

oxygen at specific cut-off ages; 36 weeks post-menstrual age (PMA=gestational age +

postnatal age) or 56 days post-natal age, for infants of gestational age <32 and >32

weeks, respectively [10]. Prophylactic and therapeutic approaches to BPD include

minimising the use of invasive ventilation modes, achieving optimal nutritional status

and preventing postnatal infections [13].

1.4 Inhaled nitric oxide

1.4.1 Overview

Nitric oxide (NO) is an endogenous paracrine signal substance, acting as a potent

vasodilator and regulator of basal vascular tone [17,18]. Apart from its vasodilatory

effects, NO plays multiple roles in many organ systems of the body, including platelet

inhibition, neural transmission, and the immune system [19,20]. NO is synthesised

from the precursor L-arginine [21] by several isoforms of the enzyme NO-synthase,

7

an enzyme expressed both in airway epithelium and vascular endothelium, as well as

various other cell types throughout the body [20].

1.4.2 Mechanism of pulmonary vasodilation

Endogenous NO mediates pulmonary vasodilation through vascular smooth muscle

cell (SMC) relaxation. Due to its lipophilic characteristics, NO easily reaches SMCs

by diffusion, either from adjacent vascular endothelial cells or from the luminal side

of adjacent alveoli, into which NO travels by auto-inhalation from sites of synthesis in

the mucosa of the upper airways [20]. The target molecule of NO is the heme

component of soluble guanylyl cyclase, an enzyme present in SMCs [20]. By binding

with, and activating this enzyme, NO causes intracellular levels of cyclic guanosine

monophosphate (cGMP) to rise. cGMP in turn activates protein kinase G which

mediates SMC relaxation through changes in intracellular calcium levels and by

altering the sensitivity of the contractile system for calcium [20]. See Figure 3 for an

overview of NO routes and its mechanism of action.

1.4.3 Pulmonary selectivity of inhaled NO

Being a gas, NO is suitable for inhalation therapy. Its half-life in vivo is short (about 7

s) [20], partly due to its high affinity for heme; about 1500 times greater than that

between heme and carbon monoxide [22]. Endothelial-derived or inhaled NO does

not have to reach the circulation to exert its vasodilatory effect, and any NO that does

reach the bloodstream is metabolised or bound, either by heme (forming

methemoglobin) or as other rapidly forming metabolites [17,20], see Figure 3.

Thereby, inhaled NO (iNO) is a selective pulmonary vasodilator that reduces PVR

without affecting systemic blood pressure, as studies of pulmonary hypertension in

both animals and humans have confirmed [23,24].

Either administered as an exogenous inhalation or auto-inhaled from the upper

airways, most of the NO will by default end up in well-ventilated parts of the lung.

This causes local vasodilation and increased arterial blood flow where oxygen is most

abundant, at the expense of lung regions with less ventilation. This rerouting of

arterial blood flow optimises the overall ventilation/perfusion ratio and contributes to

the improved oxygenation seen with iNO therapy in cases of PPHN and/or respiratory

failure [20].

8

Figure 3. A. An overview of the routes of endogenous NO (1) from vascular endothelium (2), and

endogenous or exogenous NO from alveolar airspace (3) to its destination inside vascular smooth

muscle cells (4). (5) represent NO that reaches the bloodstream and is inactivated. B. Schematic

representation of the vasodilating mechanism of action of NO inside a vascular smooth muscle cell.

NO=nitric oxide, GTP=guanosine-triphosphate, cGMP=cyclic guanosine monophosphate.

Illustration: the author.

1.4.4 Toxic and adverse effects of iNO

One common adverse effect of iNO therapy is a rebound hypoxemia if therapy is

suspended too rapidly. A carefully monitored weaning process is recommended, until

the infant sustains adequate oxygenation with only 1 part per million (ppm) of iNO

and an FiO2 of <0.5 [4]. The platelet-inhibiting effect of NO rises concerns about its

potential to cause or worsen intracranial (intraventricular) hemorrhage, a common

complication of pre-term birth. A cranial ultrasound should therefore precede the

initiation of iNO therapy in infants at risk, to provide a baseline reference and to rule

out any on-going hemorrhagic event that could be worsened by the therapy.

Methemoglobin, the product of NO and hemoglobin, is unable to carry oxygen.

Methemoglobinemia is therefore a toxic condition that might severely hinder the O2

carrying capacity of the blood. A methemoglobinemia of <7% (of total hemoglobin)

is considered safe [4], and with standard dosing regimens, iNO therapy in newborns

rarely cause levels above this [25]. Being a free radical with an unpaired electron, NO

also rapidly reacts with oxygen to form toxic nitrous oxide (NO2) [20]. Clinical trials

9

have not demonstrated a serious risk to cause toxic damages by accumulation of NO2

using standard iNO dosing strategies [26,27].

1.4.5 iNO administration, economy and indications

iNO can be administered via conventional mechanical ventilation (CMV), HFOV,

CPAP, or inhaled separately by mask or nasal cannulae. Normal starting

concentration is 20 ppm [25]. A specialised iNO delivery and monitoring system

feeds the gas from large cylinders of 400 ppm concentration to the ventilation

equipment. This system allows for dose regulation in steps of 0.5 ppm and also

monitors the levels of NO2 present in inspired air. The cost of iNO administration is

calculated per hour regardless of dosing, at present 15000 SEK/h. However, the

manufacturer (INO Therapeutics) allows for expense limitation if therapy exceeds

96h for one patient (Dr Baldvin Jonsson, April 2012, personal communication). The

registered indication for neonatal iNO therapy in Sweden is hypoxemic respiratory

failure with clinical or echocardiographic signs of pulmonary hypertension in

newborn infants of GA≥34w [28]. Since a portion of infants with PPHN do not

achieve improved oxygenation with iNO therapy, it should be used exclusively at

centres with ECMO capabilities, since this is the final therapeutic option [4].

1.5 Evidence base for neonatal iNO therapy

1.5.1 Terminology

This report uses a cutoff gestational age (GA) of 34 completed weeks (34w) to define

infants as either preterm (GA<34w) or term/near term (GA≥34w). This terminology

differs from the ICD-10 definitions of preterm birth, which is set at <37 completed

weeks. Nonetheless, the 34 weeks cutoff has been used in most clinical trials of iNO

therapy, and is a pivotal part of its registered indication [28].

1.5.2 Evidence for iNO therapy in term/near term newborns

In early animal models of PPHN, iNO treatment lowered and sustained a reduced

PVR in the newborn period [29,30]. Subsequent human studies of iNO for PPHN in

infants born at GA≥34w demonstrated a significantly improved oxygenation without

lowering systemic vascular resistance or causing methemoglobinemia [31,32]. Since

10

then, several randomised placebo-controlled trials (RCTs) in this age group have

shown significant improvements in short-term oxygenation with iNO therapy, as well

as a significantly reduced need for ECMO, albeit not a reduced mortality [27,33,34].

Furthermore, no increased occurrence of severe adverse neurologic/hemorrhagic

events or methemoglobinemia were seen [27,33,35].

A recently updated Cochrane review of iNO therapy for respiratory failure in infants

born at GA≥34w confirmed the significantly reduced need for ECMO therapy, with a

number-needed-to-treat (NNT) of 5.3 [25]. Mortality rates remained unaffected by

iNO therapy vs. placebo in this analysis, potentially explained by the fact that no

critically ill infant in a control group would be allowed to die without an attempt to

reverse the course by initiating ECMO therapy [25]. However, long term follow-up of

neurodevelopmental disabilities revealed no difference between iNO and placebo

groups, and the Cochrane review thus concluded that in newborn infants born at

GA≥34w, suffering from hypoxemic respiratory failure unresponsive to other

treatment iNO therapy in starting doses of 20 ppm is consistent with current evidence

[25]. Today, iNO is the gold standard therapy for this indication. A notable exception

is the treatment of infants with congenital diaphragmatic hernia (CDH), a condition

often accompanied by pulmonary hypoplasia and a component of PPHN. iNO therapy

did not reduce the combined outcome of death or ECMO in an RCT performed in this

population, but instead significantly increased the need for ECMO alone [36].

1.5.3 Evidence for iNO therapy in preterm newborns

The rationale for iNO therapy in preterm newborns (GA<34w) differs slightly from

that in term/near term ones. Respiratory failure in the preterm group has a different

pathophysiology and higher mortality due to incomplete lung maturation. Although

components of PPHN occur in this age group as well, it is only part of a more

complicated causality [37]. However, laboratory studies have suggested that iNO

attenuates pulmonary oxidative injuries [38] and promotes alveolar and capillary

development in animal models of BPD [39]. iNO as a prophylaxis for this disease has

therefore been the focus of several RCTs, in addition to evaluating its efficacy to

resolve hypoxemic respiratory failure. Since preterm infants are not eligible for

ECMO therapy for primarily technical reasons, these trials have often used a

combined endpoint of “death or BPD at 36 weeks PMA”, or sometimes “survival

11

without BPD” (the inverse outcome) instead of the endpoint “death or ECMO” used

in term/near term infant trials [37]. The majority of these RCTs have been unable to

prove a reduced risk of death or BPD with iNO therapy [40–43]. This lack of effect

was confirmed in a large meta-analysis that also failed to prove any iNO therapy

effect on mortality alone, or on the incidence of adverse neurological events in any

direction [44]. One RCT that did find a significant effect on “death or BPD” initiated

iNO therapy at later postnatal age (>7 days) and in higher starting doses (20 ppm)

compared with other trials [45], and subgroup results from the meta-analysis by Askie

et al. [44] lend some support to this approach. Many authors therefore promote further

adequately powered trials to determine the efficacy of different dosing and timing

strategies of iNO therapy in preterm infants [44,46].

1.7 Motive for this study

Evidence supporting iNO therapy for PPHN in term/near term newborns (GA≥34w) is

considered solid [25]. However, a recent large meta-analysis and a Cochrane Library

review both concluded that iNO therapy in the preterm population (GA<34w),

whether used in rescue regimens for respiratory failure, or as a prophylactic strategy

to prevent BPD, cannot be supported by current evidence [37,44]. Despite this, iNO

therapy is frequently used “off-label”, i.e. in preterm infants of GA<34w, inconsistent

with its registered indication [28].

An American retrospective multi-centre study showed that of infants treated with iNO

between 2000 and 2008, the proportion born at GA<34w increased from 20% to 43%

in the nine-year period. The authors estimated that in 2008, the preterm population

accounted for 53.5% of all iNO used, measured in days. They also pointed out that

iNO use seemed to have shifted towards the “less recoverable preterm neonates” [47].

Similarly, preliminary results from the European iNOcare registry showed that 40%

of newborn infants treated with iNO between 2006 and 2007 were born at GA<34w

[48]. In light of these results, considering the lack of evidence for iNO therapy in the

preterm population [37,44] and the high cost of iNO administration, our opinion is

that an analysis and discussion of iNO therapy practices and outcomes locally at

Astrid Lindgren Children’s Hospital (ALCH) would be of great interest.

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2. Aims

2.1 Primary aim

The primary aim of this study was to examine to what extent iNO use in the treatment

of respiratory conditions, at the neonatal intensive-care unit (NICU) at ALCH, during

2006-2010, was consistent with available evidence, i.e. “on-label”. Our intention was

to present descriptive statistics of selected clinical parameters such as patient

demographics, iNO therapy indications, therapy duration, dosing and clinical

outcomes. A hypothesis was that a large number of patients were treated outside

evidence based treatment recommendations.

2.2 Secondary aims

The secondary aim was to identify any significant differences regarding indication for

iNO treatment, the extent of treatment (dosing, duration etc.) or its outcomes (death,

need for ECMO, development of BPD etc.) for newborn infants of GA <34 weeks

compared to newborn infants of GA ≥34 weeks.

13

3. Material and methods

3.1 Study design and setting

This study was conducted as a retrospective, cross-sectional registry study at the

department of neonatology at Astrid Lindgren Children’s Hospital (ALCH) in Solna,

Sweden. Analyses were performed on clinical data related to neonatal iNO therapy

retrieved from the European Inhaled Nitric Oxide Registry, iNOcare.

3.1.1 Neonatal care at Astrid Lindgren Children’s Hospital

Three neonatal care units form the department of neonatology at ALCH. The units are

geographically situated at hospitals in Solna, Huddinge and Danderyd. The Solna and

Huddinge units have international Level-3 classification, i.e. they both provide full

neonatal intensive care, but with slight differences in profile. For example, extremely

preterm infants (GA<26 weeks) are cared for at the Solna unit exclusively. ECMO

therapy is available only at Solna, and therefore this is the only unit with prolonged

iNO therapy capabilities. Altogether, the department of neonatology at ALCH is the

largest neonatal care centre in the Nordic countries, accounting for about one fourth

of all neonatal care in Sweden with approximately 2600 infants admitted annually

[49]. ALCH is one of seven Swedish centres with experience in neonatal iNO therapy,

and both the neonatal intensive care unit (NICU) and pediatric intensive care unit

(PICU) provide it. This study focuses on iNO therapy in the NICU alone.

3.1.2 The iNOcare registry

This registry, operational since 2006, is a joint collaboration between seven neonatal

and pediatric centres in six European countries, one of which is the NICU at ALCH.

The main purposes of the registry is to monitor trends and routines in the clinical use

of iNO as well as its outcomes and potential adverse effects. It may also serve as a

hypothesis-generating knowledge base for future research on efficacy and safety of

iNO therapy [48]. Clinicians at the participating centres submit de-identified, patient-

and treatment-specific clinical information related to iNO therapy using a web-based

interface. The information is stored in a central repository (MedSciNet, Stockholm,

Sweden). Preliminary results from the registry, covering the years 2006-2007, have

been published on the European data set as a whole [48].

14

3.2 Study population

3.2.1 Inclusion and exclusion criteria

All newborn infants who were admitted to the NICU at ALCH in Solna, and

subsequently commenced on iNO therapy on any indication between January 1st 2006

and December 31st 2010 were included in this study. Second and third courses of iNO

therapy were recorded and treated as separate cases if therapy was initiated more than

24 hours after the previous course, since therapy indication, duration, dosing and

several other parameters might differ between courses in the same infant. Both infants

who survived until discharge or transfer, and infants who died while in the NICU (but

after initiation and/or termination of iNO therapy) were included. No exclusion

criteria were used, as the purpose of this study was to present descriptive statistics

regarding the iNO treated population in the NICU as a whole.

3.2.2 Identifying eligible infants

Upon commencing this degree project, data on iNO-treated infants born between

January 1st 2006 and December 31

st 2007 (n=24) had previously been submitted to the

iNOcare registry. The remaining infants (born between January 1st 2008 and

December 31st 2010) were identified in a hard-copy ledger of iNO therapy cases kept

by the NICU.

3.3 Data collection

Data on patient demographics such as gestational age and birth weight, initial

diagnosis, baseline clinical data such as gas exchange and ultrasound results, therapy

duration and dosing, other treatments before and during iNO therapy, initial gas

exchange response, adverse events and final outcomes were collected. Each included

infant’s patient record was scanned manually (in the hospitals patient record system

software TakeCare), from the time of admission to the NICU up until

discharge/transfer or death, to identify all relevant information before completing the

iNOcare form and submitting it electronically. Two important approximations were

used in the data collection procedure. First, the time of birth was in most cases

approximated as equal to the time of NICU admission, since the actual birth time

rarely was noted in the infants patient record. This information is usually found in the

15

mothers delivery record, which the ethical permission for this study did not include.

This approximation was considered justifiable, since the infants in the majority of

cases were admitted to the NICU immediately or shortly after birth. Second, for

infants born before 36 weeks of gestation, a 36 weeks PMA time was approximated to

exactly X weeks after birth, where X = 36 – (GA in weeks at birth). This

approximation was used since the iNOcare registry only notes completed gestational

weeks at birth, and not additional days. The calculated 36 weeks PMA point in time

could therefore in reality be as much as 36 weeks + 6 days PMA. An overview of all

parameters prompted by the iNOcare web-based form is presented in Appendix 1.

When information was missing or incomplete in a patient’s record, the corresponding

input field in the iNOcare form was either left empty (=missing data) or marked as

“unknown” where applicable. After completing data collection on all included infants,

tabular data was extracted as a Microsoft Excel file from the iNOcare web interface.

3.4 Statistical analysis

The analytical approach of this study was mainly descriptive. The intention was to

present numbers, medians and ranges of the recorded parameters as well as to test for

any significant differences in specific parameters between two gestational age groups;

infants born at <34 and ≥34 weeks. A null hypothesis was postulated, stating no

difference between the groups. The Mann-Whitney U test was used for continuous

variables, and the asymptotical 2-sided Chi-square test for categorical variables. A p-

value of <0.05 was considered significant. All analyses were performed by the author,

using IBM SPSS Statistics v.20 and Microsoft Excel 2011 v 14.1.3, both for

Macintosh.

3.5 Databases and search strategy

References for this report were found mainly through the databases PubMed, The

Cochrane Library and Web of Science. The following MeSH terms were used to

identify relevant citations: “Nitric oxide”, “Infant, newborn”, “Persistent fetal

circulation syndrome”, “Respiratory insufficiency” and “Bronchopulmonary

dysplasia”. Several non-MeSH terms were used in addition to these. Useful

publications were also identified in reference lists of review articles. An overview of

the search terms, limits used and results is found in Table 1.

16

Table 1. Example of search strategies using different databases.

Search Database Type Terms Citations

#1 PubMed M, F “Nitric oxide (MeSH)” AND (“Infant, newborn

(MeSH)” OR “neonat*”)

1840

#2 PubMed M, F ”Persistent fetal circulation syndrome (MeSH)” OR

”Respiratory insufficiency (MeSH)” OR ”Persistent

pulmonary hypertension” OR ”Respiratory failure”

59740

#3 PubMed C, L #1 AND #2. Limits: RCTs, meta-analyses, humans,

reviews, editorials, Swedish, English, published in last

10 years, link to full text provided.

106

#4 PubMed C, L #1 AND (“Bronchopulmonary dysplasia (MeSH)” OR

“Chronic lung disease”). Limits: RCTs, meta-analyses,

reviews, editorials, humans, Swedish, English, published

in last 10 years, link to full text provided

58

#5 WoS F “Nitric oxide” AND (“Infant” OR “Newborn”) 3725

#6 WoS F, L #5 AND (”Persistent pulmonary hypertension” OR

”respiratory failure” OR ”Bronchopulmonary dysplasia”

OR ”chronic lung disease”). Limits: Subject=pediatrics

or respiratory system, document types=article or review,

English, published in last 10 years.

408

#7 Coch F “Nitric oxide” AND “Infant” 8

M=MeSH, F=Free text, C=combined MeSH and free text searches, L=limits activated. PubMed

searches performed in “title/abstract” search fields. WoS=Web of Science, searches performed in the

“topic” search field. Coch=Cochrane Library, search performed in “title/abstract/keyword” search

field.

3.6 Ethical considerations

Due to its retrospective design, using pre-existing patient data, this study did not

involve any experimental therapeutic or diagnostic procedure of potential harm to the

included infants. No patient identifiers other than date and time of birth and/or NICU

admission were submitted to the iNOcare registry. All analyses were performed on

group level. There was thus no traceability of specific data to individual patients. In

the data collection procedure, we accessed individual patient data records without

prior written consent from parents and/or treating physicians. All included infants

were at the time of treatment in very poor condition, and in several cases they did not

survive until discharge. Our accessing these records could be regarded as a breach of

integrity not only of the patients, but in some way also of their parents and treating

physicians, which we at all times strived to keep in mind. Permission to access patient

data records was obtained from the head of the neonatology section in Solna, and the

student signed a confidentiality agreement before commencing data collection.

17

There was no personal benefit for the infants included in this study. However, being

part of a truly vulnerable patient group subjected to a debated therapy, our hope was

that they might one day appreciate our efforts to promote an evidence-based approach

to neonatal iNO therapy. In order to conduct this study as a degree project by a

medical student, a formal advice was requested from the Regional Ethical Review

Board of Stockholm, registration number 2012/149-31. The board declared no ethical

objections or reservations.

18

4. Results

4.1 Patient demographics

92 newborn infants received iNO therapy in the NICU at ALCH between January 1st

2006 and Dec 31st 2010. Three infants received two to three courses of therapy and

the actual number of therapy cases was therefore n=96. Table 2 shows an overview of

patient demographics and Figure 4 shows the number of infants treated per year and

gestational age.

Table 2. Patient demographics grouped by gestational age. Data shown as n (%), or median (range).

Gestational age group All ages

n=96

GA<34w

n=48

GA≥34w

n=48

p

Birth weight (kg) 1.83 (0.46-4.63) 0.99 (0.46-2.5) 3.14 (1.68-4.63) <0.01

Female/male 31/65 (32.3/67.7) 12/36 (25/75) 19/29 (39.6/60.4) 0.167

Gestational age at birth 33 (23-42) 26 (23-33) 38 (34-42) -

Figure 4. Number of infants treated with iNO during 2006-2010, grouped by gestational age.

4.2 Pre-treatment variables

4.2.1 Diagnostics and indication for iNO therapy

In 94/96 infants (97.9%), the indication for iNO therapy was hypoxemic respiratory

failure due to primary or secondary PPHN. Two infants (2.1%, all GA<34w) received

iNO exclusively as a prophylactic therapy to prevent BPD. Respiratory distress

syndrome (RDS) and meconium aspiration syndrome (MAS) were the most common

secondary PPHN etiologies in the preterm and term population, respectively. No

6 5 8

17 12

8 5

17

10

8

0

5

10

15

20

25

30

2006 2007 2008 2009 2010

Pati

en

ts, n

Year

48

48

0

20

40

60

80

100

2006-2010

GA≥34w

GA<34w

19

infant had congenital diaphragmatic hernia. Table 3 shows overall indications for iNO

therapy and Figure 5 shows the distribution of secondary PPHN etiologies.

Table 3. Overall indication for iNO therapy, grouped by gestational age. Data shown as n (%).

Gestational age group All ages

n=96

GA<34w

n=48

GA≥34w

n=48

p

Primary (idiopathic) PPHN 8 (8.3) 2 (4.2) 6 (12.5) 0.206

Secondary PPHN 86 (89.6) 44 (91.7) 42 (87.5) 0.504

BPD prophylaxis 2 (2.1) 2 (4.2) 0 0.018

Figure 5. Etiology behind secondary PPHN grouped by gestational age. “Other” includes various

conditions that is beyond the scope of this report to explain further, such as trisomy 21, trisomy 18,

Jeunes syndrome, alveocapillary dysplasia, chronic fetal anemia, hydrops fetalis, congenital cystic

adenomatoid malformation (CCAM), status post laparotomy, cardiomyopathy, vena galena

malformation and necrotising enterocolitis.

Baseline echocardiography was performed prior to initiating iNO therapy in 90/96

infants (93.8%), and baseline cranial ultrasound in 65/96 (67.7%). Table 4 shows

results of echocardiography and cranial ultrasound by gestational age.

20

Table 4. Baseline echocardiography and cranial ultrasound results grouped by gestational age. Data

shown as n (%).

Gestational age group Total

n=96

GA<34w

n=48

GA≥34w

n=48

p

Baseline echocardiography performed 90 (93.8) 46 (95.8) 44 (91.7) 0.399

Evidence of pulmonary hypertension * 80 (88.9) 38 (82.6) 42 (95.5) 0.053

Evidence of right-to-left shunt * 56 (62.2) 23 (50) 33 (75) 0.014

Baseline cranial ultrasound performed 65 (67.7) 40 (83.3) 25 (52.1) <0.01

Ultrasound status abnormal * 18 (27.7) 14 (35) 4 (16) 0.096

Abnormal cranial ultrasound cases represented intracranial hemorrhages grade 1-5 and findings of

echodensity or echolucency. *: percentages are relative to number of infants in whom examination was

performed.

4.2.2 Treatments prior to iNO therapy

Data on pre-iNO treatments was fully available only for the years 2008-2010 (n=72)

due to changes in registry design. During these years, pre-iNO use of surfactant and

HFOV was employed in 66.7% and 75% of infants in the total population,

respectively. Their uses also differed significantly between the gestational age groups,

with preterm infants receiving these therapies more often (in 89.2% vs. 42.9% and

94.6% vs. 54.3% of infants for surfactant and HFOV respectively, p<0.01 for both).

CPAP use was more common in the term/near term population (62.9% vs. 29.7%,

p<0.01). Overall use of inotropes/vasopressors (59.7% of cases) and conventional

mechanical ventilation (CMV; 40.3% of cases) did not differ between the gestational

age groups.

4.2.3 Baseline clinical data

Baseline OI could be calculated in only 56/96 infants (58.3%), 32/48 preterm (66.7%)

and 24/48 term/near term ones (50%; p=0.285), due to incomplete information in

patient records. Median OI was 32 (range 0-190) in the total population (n=56), and

differed significantly between gestational age groups; 49.3 (0-128.6) vs. 22.4 (0-190)

in the preterm and term/near term groups respectively (p<0.01).

4.3 iNO therapy

4.3.1 Initiation, duration and dosage

iNO therapy was started at a median age of 19 hours in the overall population, and the

overall median duration of therapy was 71 hours. Both parameters differed

21

significantly between gestational age groups, see Table 5. Preterm infants accounted

for 73.6% of all accumulated iNO therapy hours over the five years studied. iNO

therapy hours per year and gestational age are shown in Figure 6.

Figure 6. Distribution of iNO therapy hours in percent per year, grouped by gestational age. Numbers

inside bars are actual therapy hours.

iNO dosage did not differ significantly between the gestational age groups in any

aspect. The most common starting dose was 20 ppm. One infant received a starting

dose of 21 ppm and four received starting doses of 5-10 ppm. 20 ppm was also the

most common maximum dose, although five infants received maximum doses of 22-

40 ppm. Further dosing variables are shown in Table 5.

Table 5. iNO therapy parameters grouped by gestational age. Data shown as median (range).

“n” indicates number of infants with available data for each row.

Gestational age group All ages GA<34w GA≥34w p

Age at iNO start, hours (n=96) 19 (0-1894) 37 (0-1894) 11 (0-1651) 0.022

Starting dose, ppm (n=92) 20 (5-21) 20 (5-20) 20 (10-21) 0.691

Maximum dose, ppm (n=88) 20 (10-40) 20 (10-25) 20 (20-40) 0.229

Maintenance dose, ppm (n=87) 13 (1-20) 15 (1-20) 10 (1-20) 0.334

Final dose, ppm (n=60) 2 (0.1-20) 2 (0.5-20) 2.5 (0.1-20) 0.712

iNO duration, hours (n=96) 71 (0-1010) 113 (0-1010) 60 (2-655) <0.01

Ppm=parts per million. Final dose=last dose used before iNO cessation.

4.3.2 Concomitant therapies

Concomitant use of HFOV was more common in the preterm group than in the

term/near term group (97.9 vs. 79.2%, p<0.01). It was also more common than use of

CPAP or CMV in both groups (88.5% vs. 19.8% and 19.8% respectively, for the total

population). The use of CPAP and CMV did not differ significantly between the

1498 952

1566

3588 3945 11549

818 370

1986

451 516 4141

0%

20%

40%

60%

80%

100%

2006 2007 2008 2009 2010 Total

Perc

en

t o

f iN

O h

ou

rs

Year

GA≥34w

GA<34w

22

groups. Other concomitant cardiorespiratory support therapies used were inotropes,

systemic vasodilators and surfactant and in neither of these could significant

differences between gestational age groups be detected.

4.4 Outcomes

4.4.1 Initial response gas exchange

Initial response OI (OI within 1 hour of commencing iNO therapy) could be

calculated only in 41/96 infants (42.7%) due to incomplete data in patient records.

Median initial response OI was 20.6 (range 3-76) and did not differ significantly

between gestational age groups. Median OI reduction in percent of baseline value

could be calculated in 30/96 infants (31.3%), and an unsignificant trend was seen

towards a greater reduction in the preterm group; median reduction 60% vs. 39.3%,

(p=0.061).

4.4.2 Survival

66/96 infants (69%) survived until discharge from the NICU. 8/96 infants (8.3%, all

GA≥34w) were transferred to ECMO. In the term/near term group, 35/48 infants

(72.9%) survived without ECMO therapy. Table 6 shows survival grouped by

gestational age.

4.4.3 Bronchopulmonary dysplasia

Data on development of BPD defined as the need for supplemental oxygen at 28 days

post-natal age and at 36 weeks PMA could only be analysed for the years 2008-2010

(n=72) due to changes in registry design. The above outcomes were known in 47/72

(65.3%) and 41/72 (56.9%) infant records respectively. Of the cases with known

outcome, 24/47 patients (51.1%) had developed BPD at 28 days, and 16/41 (39%) at

36 weeks PMA. The composite outcome of “survival without BPD at 36 weeks

PMA” could be calculated in 41/72 patients (56.9%), of which 25/41 patients (61%)

met the outcome criteria. Table 6 shows survival and BPD outcomes grouped by

gestational age.

23

Table 6. Survival and development of BPD. Data related to BPD is from 2008-2010 only due to

differences in registry design. BPD outcome was known in a portion of these patients as indicated in

left column. Data shown as n (%).

Gestational age group All ages GA<34w GA≥34w p

Survival to discharge or ECMO (n=96) 66 (68.6) 28 (58.3) 38 (79.2) 0.042

Survival without ECMO (n=96) 63 (65.6) * 35 (72.9) 0.133

BPD at 28 days (n=47) 24 (51.1) 22 (88.0) 2 (9.1) <0.01

BPD at 36 weeks PMA (n=41) 16 (39) 15 (71.4) 1 (5.0) <0.01

Survival without BPD at 36wPMA, (n=41) 25 (61) 6 (28.6) 19 (95) <0.01

*=preterm infants are not eligible for ECMO.

4.4.4 Final cranial ultrasound

A comparison of baseline and final ultrasound status could be performed in 54/96

infants (56.3%) due to missing data; 36/48 preterm (75%) and 18/48 term/near term

ones (37.5%), p<0.01. Overall, 10 (26.3%) of 38 patients with a normal baseline

status deteriorated to an abnormal final status after iNO therapy. There was no

significant difference in the number of preterm or term/near term infants who

deteriorated. Six of eight preterm infants who deteriorated to an abnormal final status

had birth weights <1000g.

4.4.5 Other adverse events

Adverse effects of iNO therapy were rare in the study population. Rebound

hypoxemia after iNO cessation was reported in five infants (four preterm and one

term/near term). Two infants (one preterm and one term/near term) developed

pulmonary hemorrhage. One term infant receiving a maximum dose of 20 ppm

developed a slight tendency towards methemoglobinemia, however methemoglobin

levels did not exceed 5%.

24

5. Discussion

5.1 Major findings

Our data shows that 50% of all infants receiving iNO therapy at the NICU at ALCH

between 2006 and 2010 were born at GA<34w, and that infants in this age group had

a significantly longer duration of therapy. They also accounted for nearly 75% of all

iNO therapy hours. The corresponding proportion seen in an american study by Clark

et al. [47] was 53.5% for the years 2000-2008. This is notable, since the regulatory

approvals for neonatal iNO therapy [28] as well as a recently updated Cochrane

review [25] agree that the gas should be tried in infants born at GA≥34w with severe

hypoxemic respiratory failure and echocardiographic evidence of PPHN.

5.2 Comments on therapy in preterm infants

Clark et al. further point out that in their material, preterm infants receiving iNO

therapy were more critically ill than term/near term infants, since a larger proportion

were on HFOV before iNO initiation [47]. This circumstance is also seen in our data.

Furthermore, preterm infants in our study had a lower survival rate, and a

significantly higher baseline oxygenation index than term/near term infants (although

this parameter could only be calculated for approximately half of our patients). The

longer duration of iNO therapy in preterm infants seen in our material could thus

possibly be explained by their greater illness severity, and also by the general fragility

and the abundance of potential complications that accompanies preterm birth.

In one RCT that supported iNO as a BPD-prophylaxis, published by Ballard et al.

[45], a significantly reduced risk for death or BPD was seen in preterm infants who

received prolonged iNO therapy started after 7 days of age. In our study, only 2

infants (4.2% of the preterm group) explicitly received iNO therapy as a BPD-

prophylaxis according to patient records, and median therapy duration in the preterm

group (113h) was well below the duration used by Ballard et al. (>24 days) as was the

median age at therapy start (37 hours vs. 7-21 days). It therefore seems that iNO use

in preterm infants at ALCH has not been focused on BPD-prophylaxis, which is

consistent with the conclusions of large meta-analyses and systematic reviews

[37,44].

25

Conversely, the implications for its use in this group appear to have been attempts to

curb hypoxemic respiratory failure with or without echocardiographic evidence of

PPHN. 82.6% of preterm cases that had an echocardiography performed showed such

evidence, near-significantly less than the 95.5% portion of term/near term infants.

Furthermore, the number of infants showing evidence of right-to-left shunt was

significantly lower in the preterm group. Short-term oxygenation improvement may

well occur as a result of iNO therapy, despite lack of such evidence, and it is

suggested that the effect is not solely attributable to reducing overall PVR, but also to

intrapulmonary ventilation/perfusion matching [37]. Our material shows an

unsignificant trend towards a better OI improvement after 1h of therapy in preterm

infants than in term/near term ones, which might explain the persisting role of the gas

as a straw to clutch for in severe situations where therapeutic options are scarce.

Having said this, “rescue” iNO therapy in preterm infants has still not been shown to

improve long-term outcomes [37], and can thus not be considered evidence-based.

However, a National Institute of Health (NIH) Consensus Development Conference

[46] stated that iNO therapy in situations including pulmonary hypertension and

hypoplasia in infants of GA<34w is inadequately studied and that this subset of

infants might benefit from iNO therapy, provided that clinicians communicate the

uncertainties and potential risks and benefits to the family beforehand. 27% of our

preterm infants had a suspected pulmonary hypoplasia as the cause of PPHN, and our

population might partly fall within the bounds of the NIH reservation [46]. Of note,

nearly half of the preterm infants treated at ALCH had a birth weight <1000g, which

according to a post hoc analysis in an RCT by Van Meurs et al. [43] could be

associated with an increased risk of intracranial hemorrhage. A majority of the

preterm infants who showed deterioration on cranial ultrasound after iNO therapy in

our study were also of birth weight <1000g.

5.3 Comments on therapy in term/near term infants

iNO therapy for term/near term infants appear to have been used in accordance with

current evidence. Overall diagnosis in this group was exclusively primary and

secondary PPHN. In 92% of all term/near term cases was a baseline echocardiography

performed, in turn showing evidence of PPHN in 95.5% of cases. A Cochrane review

26

[25] states that iNO therapy should be reserved for severely ill infants, i.e. with an OI

of >25, until further studies has established whether an earlier start of iNO therapy (at

a lesser OI) leads to less clinical deterioration. Median OI in our term/near term group

was 22.5, albeit only calculated for a small portion of the total population due to

missing data, and was close to the cut-off level specified by the Cochrane review.

5.4 Other comments

No infants in this study were treated with iNO on the indication of CDH. This is

consistent with therapeutic recommendations [25,36]. However, at ALCH, most

infants with CDH are cared for at another unit (PICU), at which iNO is occasionally

used on this indication [Dr Baldvin Jonsson, April 2012, personal communication].

iNO patients at the PICU are not reported to the iNOcare registry and were thus not

included in this study. Baseline cranial ultrasonography was performed significantly

more often in preterm infants than in term/near term ones. It is however not a pre-

requisite for therapy initiation in the term/near term group since the risk for severe

intracranial hemorrhage is markedly lower than for the preterm group. A cause for

concern is the lack of cranial ultrasound follow-up, with only 75% of preterm infants

having both baseline and final cranial ultrasound status noted in their record.

5.5 Outcomes

The overall survival rates were 58% vs. 79% (preterms vs. term/near terms),

comparable with the 48% vs. 73% survival rates seen across several European centres

in an interim analysis of the iNOcare registry [48]. The rate of survival without

ECMO in our term/near term group was 73%, higher than results of large RCTs by

Clark et al. (60%) [33] and the NINOS group (54.4%) [27]. Our preterm group

demonstrated a 28.6% rate of survival without BPD at 36 weeks, which should be

related to the 41% rate found in the meta-analysis by Askie et al. [44]. However, the

iNOcare registry does not note gestational days, and a BPD diagnosis at 36 weeks

PMA was therefore based on whether the infant continuously received supplemental

O2 (as noted in patient records) at a date that in reality could be 36 weeks + 6 days

PMA. It can be questioned whether this sole bit of information, gathered in retrospect,

provides a confident base for a BPD diagnosis, and our outcome data in this matter

should be cautiously interpreted.

27

Methemoglobinemia or elevated NO2 levels did not occur, and the number of cases

where iNO suspension led to a rebound hypoxemia were few. Dosing regimens

followed recommendations by a Cochrane analysis [25] as the overall starting dose

most often was 20 ppm. Moreover, median final dose was 2 ppm, and no dosing

parameter differed significantly between our groups. The clinical management and

monitoring of on-going iNO therapy at ALCH thus appears adequate.

5.6 Limitations

There are several limitations to this study. It was not our intention to perform any in-

depth analysis of iNO efficacy in relation to other therapies or placebo. We can

therefore only relate our results concerning survival, BPD and gas exchange to that of

other authors who have established this efficacy [25,37]. Furthermore, gathering

clinical information in retrospect presupposes a reliable and comprehensive

information source. In this study, this was only the case for parts of the data collected,

and sometimes the information found in the patient records was scanty. In one record,

the only note concerning iNO therapy was: “NO therapy suspended today”; clearly

not a solid base for scientific analysis. The type of data most often missing was

baseline and initial response gas exchange, with both categories completely available

in only a quarter of our patients. This missing data might however possibly serve as a

reminder to researchers and clinicians at ALCH on the importance of keeping

accurate patient data records, and of gathering patient data in real-time, even in a non-

prospective research project such as the iNOcare registry. Another important

limitation regarding the generalizability of our results as a quality marker of iNO

therapy in the whole of ALCH, is that only infants receiving iNO therapy at the

NICU, and not the PICU, were included. A potential confounder to our conclusions is

the fact that only infants born in 2006-2010 were included for analysis, whereas

several important publications clarifying the lack of iNO efficacy in preterm infants

were published or revised in 2010 and 2011 [37,41,44,46]. Furthermore, one RCT that

suggested such an efficacy exists was published in 2006 [45]. It could therefore be

argued that iNO practices at ALCH might well be on their way towards greater

concordance with evidence. However, our results show that the preterm portion was

greater in 2009 and 2010 than in the previous years, both in patients and in therapy

hours. Further studies similar to this one, including patients treated in 2011 and 2012,

could clarify this issue.

28

5.7 Overall reflexions

The lack of iNO efficacy on long-term outcomes in the preterm population should in a

rational mind ideally prevail above its short-term positive effects when making

therapeutic decisions. Our results show that this is not always the case, possibly

explained by the short-term improvement often seen. The inherently slow pace at

which new scientific conclusions are transformed into clinical routine appears to be a

global problem affecting every branch of medicine, resulting in persistence of

obsolete, evidence-lacking methods. The reasons for this could include inadequate

ways of implementing new clinical guidelines, irrational decision-making in clinically

desperate situations and various other phenomena. Studies such as this one are

important parts of paving the way towards a greater consistency between actual

clinical practices and scientific evidence. A final rhetorical question to provide a

starting point for local discussions of iNO therapy is therefore whether this very

expensive therapy should be used so extensively in a population where its evidence

for efficacy is slim despite several large studies, and where its potential risks are

incompletely understood.

29

6. Conclusions

The use of iNO therapy at the NICU at ALCH between 2006 and 2010 was not

completely consistent with current evidence, since half of the treated infants were

born before 34 weeks of gestation. Infants born after 34 weeks of gestation were

treated according to evidence-based recommendations. In some aspects the clinical

information available in patient records was meagre. A suggestion is that clinicians at

ALCH revise their approach to iNO therapy in preterm infants.

30

7. Acknowledgements

This study could not have been designed, carried out or finished without the

inspiration and support from my supervisor, dr. Baldvin Jonsson, who always had an

optimistic attitude towards having a student taking up part of his time. Thanks also for

the book [4]! Denise Jansson cheerfully helped me out with keys, system passwords,

printing issues and the coffee machine, and understood a student’s need for a semla

on the fat-Tuesday. Nancy Lindqvist did some date-and-time magic in Excel for

which I am grateful. I would also like to thank dr. Per Häggström and all other staff

members at the NICU ward for letting me hang around to see what life might be like

for a newborn in an incubator, and for letting me participate hands-on in some of the

daily routines. Merci to dr. Farid Boubred for many impromptu French lessons in our

common office at ALCH. Last but not least, lots of love to my family, Sara and

Torsten, who put up with my behaviour and supported me during this semester.

31

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35

Appendix 1

Overview of data parameters submitted to the iNOcare registry.

Data category Parameter Options/unit Comments

Patient admission Patient type 1 - Neonatal without cardiac

diagnosis

2 – Neonatal or pediatric with

cardiac diagnosis

3 – Pediatric without cardiac

diagnosis

Single choice

Date/time of birth Date/time

Date/time of ICU admission Date/time

Gender Male, female

Birth weight g

Gestational age at birth Completed weeks

Weight at admission kg

Age at admission Years/months/days Calculated

automatically

Pre-treatment

diagnosis

Overall diagnosis -Hypoxemic respiratory

failure

-Prophylactic to prevent

chronic lung disease

Single choice

If hypoxemic respiratory

failure:

-Primary PPHN

-Secondary PPHN

Single choice

If secondary PPHN: -Respiratory distress

syndrome

-Meconium aspiration

syndrome

-Sepsis

-Congenital pneumonia

-Congenital diaphragmatic

hernia

-Pulmonary hypoplasia

-Chronic lung disease

-Perinatal hypoxia-ischemia

-Other (specify with text)

Single choice

Other diagnosis -Hemodynamically significant

PDA

-Pneumothorax

Multiple choice

Treatment prior to

iNO therapy

Treatment prior to iNO

therapy performed?

-Yes, No, Unknown Single choice

If yes, specify: -Surfactant

-Inotrope/vasopressor

-IV vasodilator

-Continuous positive airway

pressure

-Non-invasive ventilation

-Conventional mechanical

ventilation

-High-frequency ventilation

-Other (specify with text)

Multiple choice

Baseline

echocardiography

Baseline echocardiography

performed?

Yes, No Single choice.

Evidence of pulmonary

hypertension?

Yes, No, Unknown Single choice

36

Evidence of right-to-left

shunt?

Yes, No, Unknown Single choice

Evidence of left ventricular

dysfunction?

Yes, No, Unknown Single choice

Evidence of right ventricular

dysfunction?

Yes, No, Unknown Single choice

Baseline gas

exchange

FiO2 No unit (0.21-1.0)

PaO2 kPa and/or mmHg

Mean airway pressure cm H2O

Oxygenation index and P/F

ratio

No unit Calculated

automatically

SpO2, pre and post ductal %

Baseline

cardiovascular

status

Mean systemic arterial

pressure

mmHg

Systolic systemic arterial

pressure

mmHg

Heart rate b/min

Baselie cranial

ultrasonography

Status Normal, Abnormal Single choice

Periventricular hemorrhage None or grade 1-5 Single choice

Parenchymal echolucency Yes, no Single choice

Parenchymal echodensity Yes, no Single choice

iNO therapy iNO started during transport Yes, no Single choice

iNO started after admission Yes, no Single choice

iNO started date/time Date/time

Duration from admission Days, hours Calculated

automatically

iNO discontinued date/time Date/time

Duration of iNO treatment Days, hours Calculated

automatically

Starting dose ppm

Maximum dose ppm

Maintenance dose ppm

Final dose ppm

Delivery device INOvent, other

iNO source INOmax, other

Concentration in cylinder ppm 400 ppm default if

source is INOmax

Concomitant

therapies

Treatment while receiving

iNO

Nasal cannula/prongs

CPAP

Non-invasive ventilation

CMV

HFOV

Prostacyclin analog

PDE5 inhibitor

PDE3 inhibitor

Inotropes

Surfactant

Other (specify with text)

IV or inhaled

IV or oral

Gas exchange

within 60 minutes

of starting iNO

FiO2

No unit (0.21-1.0)

PaO2 kPa and/or mmHg

Mean airway pressure cm H2O

Oxygenation index and P/F

ratio

No unit Calculated

automatically

37

SpO2 %

Cardiovascular

status within 60

minutes of starting

iNO

Mean systemic arterial

pressure

mmHg

Systolic systemic arterial

pressure

mmHg

Heart rate b/min

Adverse effects of

iNO therapy

Adverse events occurred? Yes, no Single choice

If yes -Methemoglobinemia (>5%)

-Elevated NO2 (>1ppm)

-Pulmonary hemorrhage

-Rebound hypoxemia after

cessation of iNO

-Other (specify with text)

Multiple choice

Post treatment

diagnosis

Final cranial ultrasound status Normal, abnormal Single choice

Periventricular hemorrhage None or grade 1-5 Single choice

Parenchymal echolucency Yes, no Single choice

Parenchymal echodensity Yes, no Single choice

Chronic lung disease (oxygen

dependency at 28d)

Yes, no, unknown Single choice

Chronic lung disease (oxygen

dependency at 36w)

Yes, no, unknown Single choice

Final outcome ECMO Yes, no Single choice

Survival Yes, no, unknown Single choice

If survival: Yes, date of

discharge from unit

date

If survival: Yes, date of

discharge home

date

If survival: No, date of death date

If survival: No, cause of death Free text

Duration from ICU admission

to discharge/transfer or death

Days Calculated

automatically