Hypoxic Respiratory Failure in Term andNear-Term … Respiratory Failure in Term andNear-Term Neonates ... • Pulmonary edema, volume loss ... This slide illustrates the complex relationship

Hypoxic Respiratory Failure inTerm and Near-Term NeonatesArun K. Pramanik, M.D.Professor of PediatricsLSU Health SciencesCenter Shreveport, LA

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Disclosure Information

This program is sponsored by Ikaria,manufacturer of INOMAX

®

(nitric oxide) for inhalation

®

SPEAKER: THIS SLIDE MUST BE SHOWN.

Outline

• Acute Hypoxic Respiratory Failure (HRF)in Newborns: The Clinical Problem

• Physiologic Approach to HRF

• Inhaled Nitric Oxide (iNO) in the Treatment of HRF

This program will discuss 3 topics: the clinical problem of acute hypoxicrespiratory failure (HRF) in newborns, a physiologic approach tounderstanding and treating HRF, and the role of inhaled nitric oxide in thetreatment of HRF.

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HRF in the Newborn: A Persistent Challenge

• Definition: A relative deficiency of oxygen, often associated withinsufficient ventilation. This deficiency can be reflected byprogressive respiratory and metabolic acidosis and remains apersistent challenge in the management of some newborns

• Epidemiology1:

– 18 per 1000 for all live births*

– Higher rates in males and blacks

• Mortality1: 9.9% to 14.5%

• Morbidities include neurodevelopmental abnormalities, cognitive delay,and a high rate of chronic childhood diseases, learning disabilities, andsensorineural hearing loss2,3

1. Angus DC, et al. Am J Respir Crit Care Med. 2001;164:1154-1160.2. Eriksen V, et al. Acta Paediatr. 2009;98:304-309.3. Lipkin PH, et al. J Pediatr. 2002;140:306-310.

*As measured by overall rate of mechanical ventilation.

HRF can be defined as a relative deficiency of oxygen, often associated withinsufficient ventilation. This deficiency can be reflected by progressive respiratoryand metabolic acidosis and remains a persistent challenge in the management ofsome newborns.

The overall scope of the problem was described in a large cohort study by Angus etal, who found that the overall incidence of HRF in very low, low, and normal birthweight infants, as measured by the overall rate of mechanical ventilation, was 18 per1000 live births. This rate was 100-fold greater in very low birth weight infants (700 to800 g at birth) and was also greater in males and blacks (20 and 29 per 1000,respectively).1

Overall mortality rates ranged from approximately 10% to 15% at lower and higherlevel hospitals, respectively. The higher rates observed at higher level hospitalsreflect a patient population that typically has more severe illness, as reflected byhigher rates of infection, major congenital abnormalities, and hospital mortality.1

In a separate study, HRF patients were found at follow-up at 5 to 11 years of age tohave a higher frequency of learning disabilities, require more remedial help, andhave higher rates of sensorineural hearing loss than a matched control group.2

References1. Angus DC, Linde-Zwirble WT, Clermont G, Griffin MF, Clark RH. Epidemiology of

neonatal respiratory failure in the United States: projections from California and NewYork. Am J Respir Crit Care Med. 2001;164:1154-1160.

2. Eriksen V, Nielsen LH, Klokker M, Greisen G. Follow-up of 5- to 11-year-old childrentreated for persistent pulmonary hypertension of the newborn. Acta Paediatr.2009;98:304-309.

3. Lipkin PH, Davidson D, Spivak L, Straube R, Rhines J, Chang CT; I-NO/PPHNStudy Group. Neurodevelopmental and medical outcomes of persistent pulmonaryhypertension in term newborns treated with nitric oxide. J Pediatr. 2002;140:306-

Differential Diagnosis of PPHNPulmonary Cardiac Other conditions

MAS AnomalousPulmonary venousreturn:Complete or Partial

Surfactant Protein-BDeficiency

RDS TGV Alveolar capillarydysplasia

Pneumonia/Sepsis Tricuspid atresia Polycythemia

CDH Pulmonary atresia withintact ventricular septum

Maternal drugs

Pulmonary HypoplasiaPulmonary

Sequestration

RV Dysfunction Chronic Asphyxia

CCAM LV outlet obstruction

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Workup of NB with Hypoxic Respiratory failure

• History and Physical exam:

• Hyperoxia test (pre and post-ductal PaO2 &/or SaO2)

• ? Hyperoxia - Hyperventilation test

• Echocardiogram: R/O cyanotic CHD, asses cardiacfunction

• CBC with differential & platelet counts, CRP, Blood culture

• Blood sugar, serum calcium, electrolytes

• X-ray chest

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HRF in Newborns: Some CommonlyOccurring Diseases

MeconiumAspiration Syndrome

RespiratoryDistress Syndrome

IdiopathicPPHN

CongenitalDiaphragmatic Hernia

• Airway obstructionwith gas trapping

• Surfactantinactivation

• Pneumonitis

• Acute lung injury

• Surfactantdeficiency orinactivation

• Pulmonary edema,volume loss

• Lung hypoplasia

• Decreased vascularsurface area

• Increased pulmonaryartery muscularity

• No underlyinglung disease

PPHN = persistent pulmonary hypertension of the newborn.

Images courtesy of John P. Kinsella, MD, and Steven H. Abman, MD.

HRF is a clinical syndrome that occurs in diverse settings that caninclude a wide spectrum of diseases, including but not limited to these 4examples.

HRF can occur in infants with meconium aspiration syndrome (MAS),respiratory distress syndrome (RDS), idiopathic persistent pulmonaryhypertension of the newborn (PPHN), and congenital diaphragmatichernia.1-4

References1. Clark RH; The Near-Term Respiratory Failure Research Group. The

epidemiology of respiratory failure in neonates born at an estimated gestationalage of 34 weeks or more. J Perinatol. 2005;25:251-257.

2. Wirbelauer J, Speer CP. The role of surfactant treatment in preterm infants andterm newborns with acute respiratory distress syndrome. J Perinatol.2009;29(suppl 2):S18-S22.

3. Solarin KO, Zubrow A, Delivoria-Papadopoulos M. Differential diagnosis ofneonatal respiratory disorders. In: Spitzer AR, ed. Intensive Care of the Fetus &Neonate, 2nd ed. Philadelphia, PA: Elsevier Mosby; 2005:570-573.

4. Kinsella JP. Inhaled nitric oxide in the term newborn. Early Hum Dev.2008:84:709-716.

Pathophysiology of HRF:The Cardiopulmonary Triad

• Lung disease

– Low lung volumes

– Regional gas trapping, hyperinflation

• Cardiac disease

– Left ventricular dysfunction

– High right ventricular pressure

• Pulmonary vascular disease

– Increased vascular tone and reactivity

– Decreased vascular growth (lung hypoplasia)

– Hypertensive vascular remodeling

Kinsella JP. Early Hum Dev. 2008:84:709-716.Kinsella JP, Abman SH. J Pediatr. 1995;126:853-864.

Whatever the specific disease, HRF can involve the following 3 distinct butoverlapping areas of pathophysiology:

• Airway and pulmonary parenchymal abnormalities

• Cardiac dysfunction

• Pulmonary vascular disorders

While some cases of HRF are attributable to just one area of dysfunction—cardiac, lung, or pulmonary vascular disease—most cases of hypoxemiawill involve an interplay of these mechanisms at any given time. Moreover,the contribution of each of these mechanisms may change over time.Therefore, clinicians should continually reassess the underlyingpathophysiology and adjust treatment accordingly.

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References1. Kinsella JP. Inhaled nitric oxide in the term newborn. Early Hum Dev.

2008:84:709-716.2. Kinsella JP, Abman SH. Recent developments in the pathophysiology and

treatment of persistent pulmonary hypertension of the newborn. J Pediatr.1995;126:853-864.

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HRF in Newborns: Pathophysiology

• Intrapulmonary shunt: pulmonary arterial blood reaches thepulmonary venous side without passing through ventilated areasof the lung

• Ventilation–perfusion (V/Q) mismatch: imbalance betweenventilation and perfusion; alveolar hypoxia, increased dead-space ventilation

• Extrapulmonary shunt (PPHN): right-to-left shunting of bloodbypasses the lung through fetal channels (ductus arteriosusand/or foramen ovale)

Kinsella JP. Early Hum Dev. 2008:84:709-716.

Features of HRF may include:

• Intrapulmonary shunting, in which arterial blood reaches the pulmonaryvenous side without passing through ventilated areas of the lung

• Extrapulmonary shunting, typically seen in PPHN, in which bloodbypasses the lung through so-called fetal channels of the ductusarteriosus and/or the foramen ovale

• Ventilation–perfusion (V/Q) mismatch, which can occur in bothsituations and involves an imbalance between ventilation andperfusion, such as when there is alveolar hypoxia and increased dead-space ventilation

As noted earlier, patients may have more than 1 contributing cause to theirHRF.

ReferenceKinsella JP. Inhaled nitric oxide in the term newborn. Early Hum Dev. 2008:84:709-716.

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Cardiopulmonary Interactionsin Neonatal HRF

High vascular toneAltered reactivityStructural disease

Lung volume Compliance Intrapulmonary

shunt

HypovolemiaRV pressure overloadLV dysfunction

Adapted with permission from Kinsella JP, Abman SH. J Pediatr. 1995;126:853-864.

FO = foramen ovale; LV = left ventricular; PDA = patent ductus arteriosus; PVR = pulmonary vascular resistance;RV = right ventricular; SVR = systemic vascular resistance.

This slide illustrates the complex relationship between the lung, the heart,and the pulmonary vasculature in hypoxic respiratory failure, and how theyare interrelated.1

Disturbances in hypovolemia, cardiac performance, and increased vascularresistance may compromise the balance between pulmonary and systemiccirculation.1

For example, in an infant with lung disease, hypoxia and resultant acidosismay have negative effects on the pulmonary vasculature as well as on theheart. In combination, this can worsen the relationship of pulmonary vascularresistance (PVR) to systemic vascular resistance (SVR), leading toextrapulmonary right-to-left shunting at the patent ductus arteriosus (PDA) orthe foramen ovale (FO). Similarly, a poorly functioning heart can lead toacidosis, vasoconstriction, and altered shunting.2

Reference1. Kinsella JP, Abman SH. Recent developments in the pathophysiology and treatment

of persistent pulmonary hypertension of the newborn. J Pediatr. 1995;126:853-864.2. Abman SH. Personal communication. August 21, 2009.

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Treatment of Neonatal HRF

• Lung: optimize lung recruitment, ventilation

• Heart: enhance cardiac function and systemicblood pressure

• Pulmonary vascular disease

– Lower PVR

– Improve ventilation–perfusion mismatch by redirecting bloodfrom poorly aerated or diseased lung regions to better aerateddistal air spaces

1. Froese AB. Crit Care Med. 1997;25:906-908.2. Kinsella JP. Early Hum Dev. 2008:84:709-716.

There are 3 pathophysiologic components that can play a role in thedevelopment of HRF—lung, cardiac, and pulmonary vasculaturedisorders—so treatment should be targeted at correcting the underlyingdisorder.

References1. Froese AB. High-frequency oscillatory ventilation for adult respiratory distress

syndrome: let’s get it right this time! Crit Care Med. 1997;25:906-908.2. Kinsella JP. Inhaled nitric oxide in the term newborn. Early Hum Dev.

2008:84:709-716.

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• Extremes of lung volume contribute to high PVR

Low lung volume ventilationtears adhesive surfaces

Adequately Recruiting the Lung:Optimizing Lung Volume Is the First Step

High lung volume ventilationoverdistends, resulting

in volutrauma

Figure reprinted from Froese AB. Crit Care Med. 1997;25:906-908.Copyright 2009, with permission from Society of Critical Care Medicine.

While optimizing lung volume is the first step in recruiting the lung, care must betaken to achieve atelectasis reversal without causing overdistention. Indeed,extremes of overinflation and underinflation must be avoided, as they alterautonomic tone and increase PVR.

Increases in PVR and pulmonary artery pressure associated with hyperinflationimpede right ventricular ejection. Moreover, in what has been called the zone ofoverdistention, lung injury can occur as a result of edema from fluidaccumulation, surfactant degradation, high oxygen exposure, and mechanicaldisruption.

Reduction in lung volume precipitates hypoxia and stimulates increasedvasomotor tone by hypoxic pulmonary vasoconstriction. Additionally, lung injurycan result from direct trauma of repeated closure and reexpansion of airwaysand alveoli, stimulation of the lung’s inflammatory response, inhibition ofsurfactant, and the effects of local hypoxemia and compensatory overexpansionof the rest of the lung as the lung “shrinks.”

References1. Froese AB. High frequency oscillatory ventilation for adult respiratory

distress syndrome: let’s get it right this time! Crit Care Med. 1997;25:906-908.

2. Pinsky MR. Cardiovascular issues in respiratory care. Chest.2005;128(5 suppl 2):592S-597S.

PVR

Lung Volume

PVR Can Increase at Low and HighLung Volumes

Images courtesy of John P Kinsella, MD, and Steven H. Abman, MD.

The bottom line is that PVR can increase at both low and high lung volumes andthus ventilator strategies should seek to avoid these extremes. Both conditionscan lead to progressive lung injury that arises not from the disease itself butfrom well-intentioned interventions.

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References1. Froese AB. High frequency oscillatory ventilation for adult respiratory

distress syndrome: let’s get it right this time! Crit Care Med. 1997;25:906-908.

2. Pinsky MR. Cardiovascular issues in respiratory care. Chest. 2005;128(5 suppl 2) :592S-597S.

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Role of INOMAX®

(nitric oxide) forInhalation in the Treatment of Neonatal HRF

INDICATION

• INOMAX is a vasodilator, which, in conjunction withventilatory support and other appropriate agents, isindicated for the treatment of term and near-term (>34weeks gestation) neonates with hypoxic respiratory failureassociated with clinical or echocardiographic evidence ofpulmonary hypertension, where it improves oxygenationand reduces the need for extracorporeal membraneoxygenation

CONTRAINDICATION

• INOMAX should not be used in the treatment of neonatesknown to be dependent on right-to-left shunting of blood

INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.

SPEAKER: THIS SLIDE MUST BE SHOWN.

In neonates with persistent hypoxemia, INOMAX® can play a therapeutic role.INOMAX for inhalation, in conjunction with ventilatory support and otherappropriate agents, is indicated for the treatment of term and near-term (>34weeks gestation) neonates with hypoxic respiratory failure (HRF) associated withclinical or echocardiographic evidence of pulmonary hypertension (PHT). The useof INOMAX in this setting improves oxygenation and reduces the need forextracorporeal membrane oxygenation (ECMO).

INOMAX should not be used in the treatment of neonates known to be dependenton right-to-left shunting of blood.

ReferenceINOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.

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Reprinted from Wessel DL, Adatia I. In: Ignarro L, Murad F, eds. Advances in Pharmacology: Nitric Oxide: Biochemistry, MolecularBiology, and Therapeutic Implications. Vol. 34. New York, NY: Academic Press; 1995:425-498. Copyright 1995, with permissionfrom Elsevier.

Inhaled Nitric Oxide Causes SelectivePulmonary Vasodilation

This slide illustrates how inhaled nitric oxide causes pulmonaryvasodilation. Inhaled nitric oxide enters the alveolus with inspired air. Nitricoxide molecules diffuse into the vascular smooth muscle adjacent topulmonary arterioles where they activate soluble guanylate cyclase (sGC).Because the vasodilatory effects of inhaled nitric oxide are limited to thearterioles adjacent to the alveoli where it has penetrated, it is a selectivepulmonary vasodilator without the risk of systemic hypotension.

Note to speaker: Point to the air space between the alveolus and thearteriole when describing the process by which nitric oxide is released fromthe alveolus and penetrates the smooth muscle cells of the arteriole.

References1. Wessel DL, Adatia I. Clinical applications of inhaled nitric oxide in children

with pulmonary hypertension. In: Ignarro L, Murad F, eds. Advances inPharmacology: Nitric Oxide: Biochemistry, Molecular Biology, andTherapeutic Implications. Vol. 34. New York, NY: Academic Press; 1995:425-498.

2. Abman SH, Griebel JL, Parker DK, Schmidt JM, Swanton D, Kinsella JP.Acute effects of inhaled nitric oxide in children with severe hyoxemicrespiratory failure. J Pediatr. 1994;124:881-888.

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INOMAX® Phase III Studies for Neonatal HRF

• Clinical Inhaled Nitric Oxide Research Group (CINRGI)

– Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy forpersistent pulmonary hypertension of the newborn. Clinical Inhaled NitricOxide Research Group. N Engl J Med. 2000;342(7):469-474.

• Neonatal Inhaled Nitric Oxide Study Group (NINOS)

– The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl JMed. 1997;336(9):597-604.

• I-NO/PPHN Study Group (INOT 01/02)

– Davidson D, Barefield ES, Kattwinkel J, et al. Inhaled nitric oxide for theearly treatment of persistent pulmonary hypertension of the term newborn:a randomized, double-masked, placebo-controlled, dose-response,multicenter study. Pediatrics. 1998;101(3 pt 1):325-334.

Speaker: Slides 20-26 must be shown together or not at all.

INOMAX® was studied in 3 Phase III studies in infants with HRF. The following slides discuss thedesign and results of these studies.

References1. Clark RH, Kueser TJ, Walker MW, et al; the Clinical Inhaled Nitric Oxide Research Group.

Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N EnglJ Med. 2000;342(7):469-474.

2. INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.3. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly

full-term infantswith hypoxic respiratory failure. N Engl J Med. 1997;336(9):597-604.

4. Davidson D, Barefield ES, Kattwinkel J, et al; and the I-NO/PPHN Study Group. Inhaled nitricoxide for the early treatment of persistent pulmonary hypertension of the term newborn: arandomized, double-masked, placebo-controlled, dose-response, multicenter study.

CINRGI: Study Design

• Randomized, double-blind, placebo-controlled, multicentertrial1,2

• Patients: 186 term/near-term infants (>34 weeks gestation)with HRF and PPHN1,2

• Dosing: 20 ppm, weaned to 5 ppm1,2

• Objective: to reduce the need for ECMO1,2

1. Clark RH et al. N Engl J Med. 2000;342(7):469-474.2. INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.


The CINRGI trial was a double-blind, randomized, placebo-controlled, multicentertrial in term and near-term neonates with persistent pulmonary hypertension andhypoxic respiratory failure. INOMAX® was dosed initially at 20 ppm, and weanedto 5 ppm. The primary objective was to determine whether INOMAX wouldreduce the need for extracorporeal membrane oxygenation support in thesepatients. Note: The population of 186 represents the efficacy population that wasthe basis for approval.

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References1. Clark RH, Kueser TJ, Walker MW, et al; the Clinical Inhaled Nitric Oxide Research

Group. Low-dose nitric oxide therapy for persistent pulmonary hypertension of thenewborn. N Engl J Med. 2000;342(7):469-474.

2. INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.

1818

0

10

20

30

40

50

60

Death and/orECMO

Death ECMO

58

6

57

33

3

31

N=186

P<0.001

*Primary outcome.

1. INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.2. Data on file. Clinton, NJ: Ikaria; 2009.

30-M

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-60

-50

-40

-30

-20

-10

0

P<0.001

PA-aO2 (A:a gradient)

-23

-59.5

N=168

CINRGI: Efficacy Outcomes

*

Placebo INOMAX®

Primary Outcome Secondary Outcome

Ev

en

ts,

%

There was a significant reduction in ECMO in infants treated with INOMAX®,compared with control infants (31% vs 57%, P<0.001). The incidence of deathalone was similar in both groups (3% INOMAX vs 6% placebo).

After the administration of INOMAX, there was a significantly greater decrease inthe alveolar/arterial oxygenation gradient compared with infants in the controlgroup (P<0.001).

References1. INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.2. Data on File. Clinton, NJ: Ikaria; 2009

NINOS: Study Design

• Randomized, double-blind, placebo-controlled, multicentertrial1,2

• Patients: 235 term/near-term infants (>34 weeks gestation)with HRF1,2

• Dosing: 20 ppm, with possible increase to 80 ppm1,2

• Objective: to reduce mortality and/or the need for ECMO1,2

1. INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.2. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336:597-604.


The NINOS trial was a double-blind, placebo-controlled, multicenter study in 235neonates with HRF who were unresponsive to conventional therapy. INOMAXwas dosed at 20 ppm, with a possible increase to 80 ppm. The objective was todetermine if inhaled NO therapy would reduce the occurrence of death and/or theinitiation of ECMO in term and near-term infants who had HRF that wasunresponsive to conventional therapy.

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References1. INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.2. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term

infants with hypoxic respiratory failure. N Engl J Med. 1997:336:597-604.

2020

0

10

20

30

40

50

60

70

Death and/or ECMO Death ECMO

64

17

55

46

14

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1. INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.2. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336:597-604.

Primary Outcome

P=0.60

P=0.014

Ev

en

ts,%

*Primary outcome.

N=235

Placebo INOMAX®

P=0.006

NINOS: Efficacy Outcomes

*

30-M

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-6.7

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-60

Secondary Outcome

There was a significant reduction in death and/or ECMO in infants treated withINOMAX®, compared with control infants (46% vs 64%, P=0.006). Thissignificance was driven by the reduction of ECMO. The incidence of deathalone was lower in the INOMAX patients, but did not achieve statisticalsignificance.1

After the administration of INOMAX, there was a significantly greater decreasein the alveolar/arterial oxygenation gradient, compared with infants in thecontrol group (P<0.001).2


infants with hypoxic respiratory failure. N Engl J Med. 1997:336:597-604.

INOT 01/02: Study Design

• Randomized, double-blind, placebo-controlled, multicenter,dose-ranging trial

• Patients: 155 term infants (≥37 weeks gestation) with HRFand PPHN

• Dosing: 5 ppm, 20 ppm, and 80 ppm

• Objective: to reduce the PPHN Major Sequelae Index(incidence of death, ECMO, neurologic injury or BPD)

• Study was terminated prematurely due to slow enrollment

– No efficacy conclusions can be drawn

Davidson D, Barefield ES, Kattwinkel J, et al. Pediatrics. 1998;101:325-334.

The INOT 01/02 studies were conducted as a randomized, double-blind, placebo-controlled, dose-ranging clinical trial from April 1994 to June 1996. Patientsreceived INOMAX® at doses of 0 (placebo), 5, 20, or 80 ppm. The study wasended prematurely after only 155 patients were enrolled (320 were sought) dueto slow enrollment. Because of the early termination, no efficacy conclusions canbe drawn. Only the control and 20-ppm treatment groups (n=75) are included forcomparison with the 20-ppm groups from the other trials.

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Reference1. Davidson D, Barefield ES, Kattwinkel J, et al; and the I-NO/PPHN Study Group. Inhaled nitric

oxide for the early treatment of persistent pulmonary hypertension of the term newborn: arandomized, double-masked, placebo-controlled, dose-response, multicenter study.Pediatrics. 1998;101:325-334.

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Safety Outcomes From Phase III Studies

• Results from NINOS and CINRGI studies:

– Combined mortality: placebo (11%); INOMAX (9%)

– Treatment groups were similar with respect to incidence andseverity of intracranial hemorrhage, periventricular leukomalacia,cerebral infarction, seizures requiring anticonvulsant therapy, andpulmonary or gastrointestinal hemorrhage

– 6-month follow-up: INOMAX (n=278); control (n=212)

• No differences in pulmonary disease or neurological sequelae,or in the need for rehospitalization or special medical services

INOMAX [package insert]. Clinton, NJ: Ikaria, Inc.; 2009.


There were no significant differences between the groups after randomization in the overallincidence or severity of intracranial hemorrhage (total number, 19 in the control group and18 in the nitric oxide group; grade IV, 8 and 5, respectively).

Neither were there any significant differences between the control group and the nitricoxide group in the occurrence of periventricular leukomalacia (6 vs 3), brain infarction (7 vs7), seizures requiring anticonvulsive therapy (16 vs 24), and either pulmonary (4 vs 6) orgastrointestinal (1 vs 1) hemorrhage.

When the results from both controlled studies (325 patients on INOMAX® doses of 5 to 80ppm and 251 patients on placebo) were pooled, combined mortality was 11% for placeboand 9% for INOMAX.

At least 6 months of follow-up are available for 278 patients who received INOMAX and212 patients who received placebo in the pooled trials. Among these patients, there wereno differences in pulmonary disease or neurological sequelae, or in the need forrehospitalization or special medical services.


and nearly full-term infants with hypoxic respiratory failure. N Engl J Med.1997;336(9):597-604.

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Very SevereSevereModerate

When Is the “Right Time” to Initiate INOMAX®?

Use of oxygenation index (OI) in term and near-term neonatal HRF

• Compares the level of ventilator support (FiO2 and mean airwaypressure [MAP]) with the resultant systemic arterial oxygen levels

15 25 400

Mild

FiO2 mean airway pressure 100

postductal PaO2

[Example: FiO2, 0.60; MAP, 15; PaO2, 50 torr = (0.60 15 100)/50 = 18 OI]

OI =

The oxygenation index was developed as a prognostic tool to estimate theseverity of neonatal pulmonary disease.

References1. Trachsel D, McCrindle BW, Nakagawa S. Bohn D. Oxygenation index predicts

outcome in children with acute hypoxemic respiratory failure. Am J Respir Crit CareMed. 2005;172:206-211.

2. Weis CA, Oxygen therapy: In: Spitzer AR, ed. Intensive Care of the Fetus andNeonate, 1st ed. Philadelphia, PA: Elsevier Mosby; 2005:605-614.

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Additional Studies to Address EarlierINOMAX® Use In Infants With HRF

• Konduri GG, Solimano A, Sokol GM, et al. A randomized trial ofearly versus standard inhaled nitric oxide therapy in term andnear-term newborn infants with hypoxic respiratory failure.Pediatrics. 2004;113(3 pt 1):559-564.

• Golombek SG, Young JN. Efficacy of inhaled nitric oxide forhypoxic respiratory failure in term and late preterm infants bybaseline severity of illness: a pooled analysis of three clinicaltrials. Clin Ther. 2010;32(5):939-948.

• González A, Fabres J, D'Apremont I, et al. Randomizedcontrolled trial of early compared with delayed use of inhalednitric oxide in newborns with a moderate respiratory failure andpulmonary hypertension. J Perinatol. 2010;30(6):420-424.

Three additional studies have recently been published that can shed some lighton when to initiate INOMAX®. Golombek et al used pooled data from theINOMAX Phase III trials to compare results across disease severities (measuredby OI). González et al and Konduri et al performed randomized controlled trialsusing INOMAX in infants with mild-to-moderate HRF.

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Konduri et al: Study Design

• Prospective, randomized, controlled, double-masked,multicenter trial

• Patients: 299 infants (≥34 weeks gestation) with respiratoryfailure that needed assisted ventilation

– OI ≥15 and <25 (moderate severity) on FiO2 ≥0.80

• Dosing: iNO initiated at 5 ppm or simulated (sham) dose

– Dose increased to 20 ppm if the increase in PaO2 was ≤20 mm Hg

– Infants in either group were transitioned to standard iNOif OI increased to ≥25

• Objective: To determine whether early iNO administration resultsin additional reduction of the incidence of ECMOor death

Konduri GG, et al. Pediatrics. 2004;113(3 pt 1):559-564.

A study published in 2004 also looked at early iNO use and tried to determinewhether early iNO administration results in additional reduction of the incidenceof ECMO or death. Konduri et al was a prospective, randomized, double-masked,multicenter trial that planned to enroll 400 infants with respiratory failure thatneeded assisted ventilation. Infants were required to have an OI between 15 and25 and be on at least 80% oxygen.

After randomization, infants were initiated with 5 ppm of iNO or a simulation. Thedose could be increased to 20 ppm if the increase in PaO2 was less than 20 mmHg. Nitrogen was used to pressurize the INOvent

®in control infants, but was not

injected into the breathing circuit. Mock adjustments were made to the INOvent inthese infants.

Infants in both groups were transitioned to standard iNO if HRF progressed frommoderate to severe (OI reached 25), which means they eventually could receivethe benefits of iNO if needed.

iNO as standard therapy is defined as being consistent with practice based onprevious randomized trials (prior to July 1998), including initiation of iNO at an OIof 25 or more and dose of 20 ppm.

Due to slow enrollment, the study was stopped prematurely after 302 infantswere enrolled (3 were excluded due to cardiac malformations).

Reference

Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versusstandard inhaled nitric oxide therapy in term and near-term newborn infants withhypoxic respiratory failure. Pediatrics. 2004;113(3 pt 1):559-564.

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Konduri et al: Primary Outcome

• “The primary outcome incidence observed in the control group (19.5%) isapproximately half of the projected incidence on the basis of our 1997 pilotdata.”

• “iNO improves oxygenation but does not reduce the incidence ofECMO/mortality when initiated at an OI of 15 to 25 compared with initiationat >25 in term and near-term neonates with respiratory failure.”

0

5

10

15

20

25

Perc

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fP

ati

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ts

P=0.53

Primary outcome: death by day 120 or ECMO

16.7% (25/150)

19.5% (29/149)

n=149 n=150

Control Early iNO®


The primary outcome, death by day 120 or need for ECMO was similar betweengroups, 19.5% of the control group and 16.7% of the iNO group (P=0.53).

There are a few factors that may have contributed to this similarity.

1. Infants were monitored very closely and transitioned to standard iNO therapyrapidly after reaching an OI of 25. This could have happened before theprimary endpoint of death or ECMO was reached.

2. The 19.5% incidence in the control group is about half as high as theprojected incidence based on the authors’ pilot study in 1997. Also, the overallincidence of the primary outcome was 18.1%, which is lower than all previousrandomized trials.

3. The average baseline OI in this study was 19.5.

Reference

Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versusstandard inhaled nitric oxide therapy in term and near-term newborn infants withhypoxic respiratory failure. Pediatrics. 2004;113(3 pt 1):559-564. 26

Konduri et al: Additional Outcomes

• More infants in the early iNO group had >20 mm Hg increase inPaO2 in response to study gas initiation compared with thecontrol group (P<0.001)

– 73% of early iNO infants

– 37% of control infants

Variable Early iNO group(n=150)

Control group(n=149)

Pvalue

Duration of study gasadministration*

57 ± 48 hours 39 ± 38 hours <0.003

Initiation of standard iNOtherapy

61 (41%) 81 (54%) <0.02

Duration of standard iNOtherapy†

121 (41-175)hours

100 (56-158)hours

0.52

Progression of OI >40 11 (7%) 21 (14%) 0.056

* Mean ± standard deviation. † Median with first to third quartile ranges in parentheses.


Secondary Outcomes


When we look at oxygenation parameters, we see clear separation between thetwo groups. 73% of infants receiving iNO had at least a 20 mm Hg increase inPaO2 compared to 37% of control infants (P<0.001).

Also, more than half of control infants (54%) reached an OI of 25 and weretransitioned to standard iNO therapy versus 41% of early iNO infants (P<0.02).Infants in the control group progressed to standard iNO therapy and to OI >40more than early iNO infants (14% vs 7%), although this was not statisticallysignificant, (P=0.056.)

The authors conclude: “Although we were unable to demonstrate a significantdecrease in the incidence of ECMO/death with our study design, providing low-dose (5-20 ppm) iNO to neonates earlier in their disease process was apparentlysafe and effective in improving oxygenation.”

iNO as standard therapy is defined as being consistent with practice based onprevious randomized trials (prior to July 1998), including initiation of iNO at an OIof 25 or more and dose of 20 ppm.

Reference


27

Konduri et al: Safety

• None of the study infants had study gas weaned ordiscontinued because of elevated methemoglobinor NO2 levels

• 1 iNO infant and 2 control infants developed severe(grade 3-4) intraventricular hemorrhage and periventricularleukomalacia

• Seizures occurred in 14 iNO infants (9.4%) and 11 controlinfants (7.4%) (P=0.68)



28

Reference


Golombek et al: Study Design

• Methods

– A retrospective pooled analysis of all subjects receiving 20 ppminhaled nitric oxide in the CINRGI, NINOS, and I-NO/PPHNPhase III trials

– No censoring based on underlying diagnosis or baselinecharacteristics

• Objectives

– To analyze the effects of INOMAX on measures of oxygenation

– To analyze the effects of INOMAX across a range of illness severitystrata

– To analyze the effects of INOMAX on the duration of mechanicalventilation

Golombek SG, Young JN. Clin Ther. 2010;32(5):939-948.

Since the published literature does not provide conclusive evidence of a relationshipbetween severity of illness and response to INOMAX® therapy, a retrospective pooledanalysis of the 3 largest INOMAX clinical trials was undertaken.

The objectives of this analysis were:

• To analyze the effects of INOMAX on measures of oxygenation

• To analyze the effects of INOMAX across a range of illness severity strata

• To analyze the effects of INOMAX on the duration of mechanical ventilation

For the purposes of this analysis, only those subjects who received 20 ppm INOMAX,regardless of the underlying diagnosis, were compared with similar placebo-treatedpatients.

29

Reference

Golombek SG, Young JN. Efficacy of inhaled nitric oxide for hypoxic respiratory failure interm and late preterm infants by baseline severity of illness: a pooled analysis of threeclinical trials. Clin Ther. 2010;32(5):939-948.

3030

Golombek et al: Oxygenation Results

• INOMAX® causes rapid improvement (at 30 min) in oxygenation

8.85

60.28

17.95

38.63

19.08

54.64

14.15

54.91

0

20

40

60

80

NINOS I-NO/PPHN CINRGI All Studies

Ventilation Ventilation + INOMAX

Ch

an

ge

inP

aO

2at

30

Min

ute

s(m

mH

g[k

Pa])

Baseline

P<0.001

(N=186)(N=75)(N=227) (N=493)

P<0.001P<0.001 P=0.046


By improving perfusion, INOMAX® delivers a rapid increase in oxygenation. Theblue bars represent ventilation alone, while the red bars represent ventilationplus INOMAX. In each of these 3 NDA-submitted studies, INOMAX significantlyimproved PaO2 within 30 minutes versus ventilation alone.

Reference


31

Golombek et al: Oxygenation Results

• INOMAX® improves oxygenation even in mild and moderate HRF

-23.03

62.39

18.28

52.93

13.95

62.07

18.66

45.17

-40

-20

0

20

40

60

80

≤15 >15 to ≤25 >25 to ≤40 >40

Ventilation Ventilation + INOMAX

Ch

an

ge

inP

aO

2a

t3

0M

inu

tes

by

Ba

se

lin

eO

I(m

mH

g[k

Pa

])

P<0.001P<0.001P=0.004P=0.003

VerySevereSevereModerateMild

(n=40) (n=91) (n=170) (n=186)Baseline OI =


However, it was interesting to see that there was a similar benefit when theanalysis also included infants with mild to moderate HRF (OI ≤25). Thesedata indicate that INOMAX® improves oxygenation across all levels ofseverity (including mild and moderate) versus ventilation alone.

It has been known for a long time that INOMAX improves oxygenation inneonates with severe HRF, but this retrospective analysis indicates that italso improves oxygenation in neonates with mild and moderate HRF.

Reference


0.50

0.25

0.00

1.00

0.75

0 10 20 30 40 50

Days on Mechanical Ventilation

— Placebo— INOMAX 20 ppm

P=0.003

This is a Kaplan-Meier analysis of pooled data from 3 independent controlled studies, NINOS, CINRGI, and INOT01/02 (N=243). Outliers are removed for visual purposes.


Golombek et al: Time on Vent ResultsP

rop

ort

ion

of

Pati

en

tso

nM

ech

an

icalV

en

tila

tio

n• INOMAX® reduces median days on mechanical ventilation (11 vs 14 days)

This is a Kaplan-Meier analysis (ie, the probability of being ventilated over time) ofpooled data from NINOS, CINRGI, and INOT 01/02. Adding INOMAX® shortened themedian time on ventilation. Within this pooled data, at the point that 50% of patients wereoff therapy, the INOMAX patients had a savings of 3 ventilator days (11 vs 14 days)(P=0.003).

NOTE: Patients who died or went to extracorporeal membrane oxygenation wereexcluded from the analysis as their inclusion would have falsely skewed the data in favorof placebo.

32

Reference


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Hypoxic Respiratory Failure in Term andNear-Term … Respiratory Failure in Term andNear-Term Neonates ... • Pulmonary edema, volume loss ... This slide illustrates the complex relationship