Inhaled Nitric Oxide. A study on the effects of inhaled Nitric Oxide (iNO) in neonatal Pulmonary Hypertension by: Cecilia Cherian Marc Chiappetta.

Inhaled Nitric OxideInhaled Nitric Oxide

A study on the effects of inhaled A study on the effects of inhaled Nitric Oxide (iNO) in neonatal Nitric Oxide (iNO) in neonatal

Pulmonary Hypertension Pulmonary Hypertension

by:by: Cecilia CherianCecilia Cherian Marc ChiappettaMarc Chiappetta Jay SuerteJay Suerte Santos MachokaSantos Machoka

Biological QuestionBiological Question

Is the administration of low dose versus Is the administration of low dose versus high dose nitric oxide effective in the high dose nitric oxide effective in the treatment of persistent pulmonary treatment of persistent pulmonary hypertension of newborn ?hypertension of newborn ?

HypothesisHypothesis

Administering low dose inhaled nitric oxide Administering low dose inhaled nitric oxide improves oxygen delivery and compliance, improves oxygen delivery and compliance, thus is beneficial in treating persistent thus is beneficial in treating persistent pulmonary hypertension of newborns.pulmonary hypertension of newborns.

What is Nitric Oxide ?What is Nitric Oxide ?

Nitric Oxide is a highly diffusible, lipid Nitric Oxide is a highly diffusible, lipid soluble free radical that oxidizes quickly to soluble free radical that oxidizes quickly to nitrogen dioxide (NOnitrogen dioxide (NO22) in the presence of ) in the presence of

oxygenoxygen It is produced internally in every cell and It is produced internally in every cell and

organ in the human body.organ in the human body.

How iNO worksHow iNO works

iNO is a selective pulmonary vasodilator.iNO is a selective pulmonary vasodilator. iNO will dilate only the pulmonary blood iNO will dilate only the pulmonary blood

vessels adjacent to functioning alveoli.vessels adjacent to functioning alveoli. iNO diffuse into the capillaries, free NO iNO diffuse into the capillaries, free NO

immediately binds to hemoglobin forming immediately binds to hemoglobin forming nitrosylhemoglobin, which is rapidly nitrosylhemoglobin, which is rapidly oxidized to methmoglobin and eventually oxidized to methmoglobin and eventually undergoes conversion to reduced the undergoes conversion to reduced the hemoglobinhemoglobin

Indications for iNOIndications for iNO

iNO is used to treat pulmonary hypertension iNO is used to treat pulmonary hypertension such as primary pulmonary hypertenison(PPH) such as primary pulmonary hypertenison(PPH) and persistent pulmonary hypertension of and persistent pulmonary hypertension of newborns (PPHN).newborns (PPHN).

Neonates with hypoxic respiratory failure Neonates with hypoxic respiratory failure associated pulmonary hypertension.associated pulmonary hypertension.

NO therapy is often used with other forms of NO therapy is often used with other forms of therapy including high frequency oscillatory therapy including high frequency oscillatory ventilation and surfactant therapy, both of which ventilation and surfactant therapy, both of which are aimed at improving oxygen delivery and lung are aimed at improving oxygen delivery and lung compliance.compliance.

DosageDosage

Initial dosage was 20 ppm(particles per Initial dosage was 20 ppm(particles per million).million).

Often reduced to 5 ppm at the end of 4 Often reduced to 5 ppm at the end of 4 hours of initial treatment.hours of initial treatment.

Reduce inhaled nitric oxide dose by 50% Reduce inhaled nitric oxide dose by 50% (20, 10,5, 1 ppm).(20, 10,5, 1 ppm).

Methods of administrationMethods of administration

NO is delivered with the O2 at a constant NO is delivered with the O2 at a constant concentration throughout the breathing concentration throughout the breathing cycle.cycle.

Set NO level is stable over a wide range of Set NO level is stable over a wide range of flows and flow patterns, including flows and flow patterns, including spontaneous breathing modes.spontaneous breathing modes.

The flow sensor placed in the outlet of the The flow sensor placed in the outlet of the ventilator upstream from the humidifier ventilator upstream from the humidifier measures minute ventilation (lpm).measures minute ventilation (lpm).

Method of administrationMethod of administration The injector varied the nitric oxide based on the The injector varied the nitric oxide based on the

measured ventilation.measured ventilation. Nitric oxide, nitrogen dioxide and oxygen are Nitric oxide, nitrogen dioxide and oxygen are

measured in the inspiratory limb of the circuit, measured in the inspiratory limb of the circuit, just before the patient wye and a calibration just before the patient wye and a calibration mode verified proper analyzer function. High mode verified proper analyzer function. High and low alarms are provided for all three gases and low alarms are provided for all three gases and an automatic cut-off to prevent nitric oxide and an automatic cut-off to prevent nitric oxide overdose.overdose.

Hazards and contraindicationsHazards and contraindications

Nitric oxide when combined with oxygen Nitric oxide when combined with oxygen produces nitrogen dioxide (NO2), which is a produces nitrogen dioxide (NO2), which is a toxic gas.toxic gas.

Because of it’s very minimal half life (0.1 Because of it’s very minimal half life (0.1 seconds – 5 seconds), it is quickly inactivated seconds – 5 seconds), it is quickly inactivated once it combines with hemoglobin.once it combines with hemoglobin.

Although rare, the patients as well as health care Although rare, the patients as well as health care providers can be adversely affected.providers can be adversely affected.

Factors influencing NO2 production are O2 Factors influencing NO2 production are O2 concentration, NO concentration and time of concentration, NO concentration and time of contact between NO and O2.contact between NO and O2.

Hazards and contraindicationsHazards and contraindications Patients most at risk include those receiving high Patients most at risk include those receiving high

oxygen concentration and low ventilator flow oxygen concentration and low ventilator flow rates.rates.

Production of methemoglobin can be a problem Production of methemoglobin can be a problem due to anemic hypoxia which can be treated with due to anemic hypoxia which can be treated with vitamin C..vitamin C..

A major contraindications of this therapy is A major contraindications of this therapy is children who as a result of congenital cardiac children who as a result of congenital cardiac anomalies need a right-to-left shunt to survive anomalies need a right-to-left shunt to survive and NO therapy corrects the right-to-left shunts.and NO therapy corrects the right-to-left shunts.

methodologymethodology

A patient group of 34 weeks gestation to 8 days A patient group of 34 weeks gestation to 8 days old were selected for the iNO treatment.old were selected for the iNO treatment.

All these patients had persistent pulmonary All these patients had persistent pulmonary hypertension and severe respiratory failure hypertension and severe respiratory failure requiring mechanical ventilation.requiring mechanical ventilation.

Infants that were diagnosed with pneumonia, Infants that were diagnosed with pneumonia, sepsis, and meconium aspiration were included.sepsis, and meconium aspiration were included.

Infants diagnosed with congestive heart defect Infants diagnosed with congestive heart defect (CHD) were excluded because previous studies (CHD) were excluded because previous studies showed that these infants did not respond to iNO showed that these infants did not respond to iNO therapy. therapy.

methodologymethodology

Data collectionData collection After parental consent was obtained, eligible patients After parental consent was obtained, eligible patients

with 2 separate Oxygen Indices (OIs) of >10 were with 2 separate Oxygen Indices (OIs) of >10 were randomized to receive a starting iNO dose of either 1 to randomized to receive a starting iNO dose of either 1 to 2 ppm (low dose group) or 10 to 20 (high dose group).2 ppm (low dose group) or 10 to 20 (high dose group).

In the high dose group the therapy was started at 20 In the high dose group the therapy was started at 20 ppm and could be decreased to 5 ppm in the first 24 ppm and could be decreased to 5 ppm in the first 24 hours.hours.

In the low dose group starting at 1 ppm and not obtaining In the low dose group starting at 1 ppm and not obtaining a positive result, increasing the ppm in small increments a positive result, increasing the ppm in small increments were made until desired results were obtained. were made until desired results were obtained. (increased oxygen index)(increased oxygen index)

methodologymethodology

Data collectionData collection The response of iNO dose was assessed The response of iNO dose was assessed

according to the increase in arterial PaO2 according to the increase in arterial PaO2 and decrease in OI 30 to 60 minutes after and decrease in OI 30 to 60 minutes after exposure to initial starting concentration.exposure to initial starting concentration.

After the first 24 hrs. they had to be After the first 24 hrs. they had to be weaned to 5 ppm for no more than 96 weaned to 5 ppm for no more than 96 hours. hours.

methodologymethodology

Data collectionData collection Failure to improve after 96 hours were Failure to improve after 96 hours were

considered for ECMO therapy.considered for ECMO therapy. All discontinuation of therapy was All discontinuation of therapy was

performed at doses of 0.5 to 1 ppm.performed at doses of 0.5 to 1 ppm. When any response occurred to 40 ppm or When any response occurred to 40 ppm or

greater, attempts were made every 4 greater, attempts were made every 4 hours to halve the dose, until the infant hours to halve the dose, until the infant was receiving 20 ppm.was receiving 20 ppm.

methodologymethodology

Data collectionData collection During the treatment period no changes During the treatment period no changes

were made to ventilator or any other were made to ventilator or any other therapies.therapies.

Methemoglobin analysis was performed Methemoglobin analysis was performed before iNO administration and at 6 hours before iNO administration and at 6 hours and every 8 hours during iNO and every 8 hours during iNO administration.administration.

StatisticsStatistics

An objective discussion of the three An objective discussion of the three research papers clinical findings indicated research papers clinical findings indicated the validity of inhaled nitric oxide on the the validity of inhaled nitric oxide on the neonatal population.neonatal population.

In the neonatal population that In the neonatal population that ended up needing ECMOended up needing ECMO

Of the group that initially had nitric oxide Of the group that initially had nitric oxide therapy 47% of them did survive the hospital therapy 47% of them did survive the hospital stay, while only 36 % of the control group stay, while only 36 % of the control group survived (where N= 248+38=286 patients)survived (where N= 248+38=286 patients)

These patient population was identical in These patient population was identical in gestation (mean 35 wks old), age (mean 2.5 gestation (mean 35 wks old), age (mean 2.5 days old), the control group started with an initial days old), the control group started with an initial treatment of 0ppm iNO, and an oxygenation treatment of 0ppm iNO, and an oxygenation index of >25.index of >25.

ConclusionConclusion

While one paper proves objectively that While one paper proves objectively that starting patients at low doses of nitric starting patients at low doses of nitric oxide can have an inhibiting effect on oxide can have an inhibiting effect on future increments of nitric oxide therapy all future increments of nitric oxide therapy all the papers agree that nitric oxide therapy the papers agree that nitric oxide therapy is more useful than 100 % oxygen in the is more useful than 100 % oxygen in the treatment of PPHN secondary to treatment of PPHN secondary to pulmonary hypoxia.pulmonary hypoxia.

ConclusionConclusion

Gradually weaning of the nitric oxide to an Gradually weaning of the nitric oxide to an acceptable dose is carefully monitored by acceptable dose is carefully monitored by using different criteria including but not using different criteria including but not limited to oxygen indices and ABGs.limited to oxygen indices and ABGs.

Nitric oxide is used in conjunction with Nitric oxide is used in conjunction with oscillator therapy.oscillator therapy.

ConclusionConclusion

Nitric Oxide is used as a precursor to Nitric Oxide is used as a precursor to ECMO therapy which is more expensive ECMO therapy which is more expensive and has more risk factors.and has more risk factors.

GlossaryGlossary

1. 1. Persistent Pulmonary Hypertension ofPersistent Pulmonary Hypertension of Newborn Newborn (PPHN(PPHN)- A syndrome that causes right to left shunt, )- A syndrome that causes right to left shunt, severe hypoxemia, and mixed acidosis. severe hypoxemia, and mixed acidosis.

2. 2. Parts Per Million (ppm)- Parts Per Million (ppm)- Unit of measurement used Unit of measurement used for nitric oxide.for nitric oxide.

3. 3. Nitric Oxide (NO)-Nitric Oxide (NO)- A selective pulmonary vasodilator A selective pulmonary vasodilator that improves blood flow to ventilated alveoli, resulting that improves blood flow to ventilated alveoli, resulting decreased shunt and improve oxygenation.decreased shunt and improve oxygenation.

GlossaryGlossary 4. 4. Nitrogen Dioxide (NO2Nitrogen Dioxide (NO2)- A toxic gas )- A toxic gas

produced when nitric oxide is combined with produced when nitric oxide is combined with oxygen.oxygen.

5. 5. Methemoglobin (metHb)- Methemoglobin (metHb)- The result when The result when Nitric Oxide combines with Hemoglobin, Nitric Oxide combines with Hemoglobin, resulting in oxygen desaturations.resulting in oxygen desaturations.

6. 6. Hemoglobin (HbHemoglobin (Hb)- Oxygen carrying protein )- Oxygen carrying protein found in the blood that carries oxygen from the found in the blood that carries oxygen from the lungs to the cells.lungs to the cells.

ReferenceReference 1. Clark, R.H., Kueser, T.J., & Walker, M.W. 1. Clark, R.H., Kueser, T.J., & Walker, M.W. Low-DoseLow-Dose Nitric Oxide Nitric Oxide

Therapy for Persistent Pulmonary Hypertension of the Newborn.Therapy for Persistent Pulmonary Hypertension of the Newborn. The The New England Journal of Medicine. (Feb. 17, 2000). Retrieved from: New England Journal of Medicine. (Feb. 17, 2000). Retrieved from: http://content.nejm.org/cgi/content/full/342/7/469?ijkey=a3f529d65be4b34d2http://content.nejm.org/cgi/content/full/342/7/469?ijkey=a3f529d65be4b34d2f21ab8cb3bf21ab8cb3b..

2. Finer, N.N., Sun, J.W., Rich, W. 2. Finer, N.N., Sun, J.W., Rich, W. RandomizedRandomized, , Prospective Study of Prospective Study of Low Dose Versus High Dose Inhaled Nitric Oxide in the Neonate with Low Dose Versus High Dose Inhaled Nitric Oxide in the Neonate with HypoxicHypoxic Respiratory FailureRespiratory Failure. Journal of the Academy of Pediatrics. (Oct. . Journal of the Academy of Pediatrics. (Oct. 2001). Retrieved from: 2001). Retrieved from: http://pediatrics.aappublications.org/cgi/content/full/108/4/949http://pediatrics.aappublications.org/cgi/content/full/108/4/949..

3. Cornfield, D.N., Maynard, R.C., & Deregnier, R. 3. Cornfield, D.N., Maynard, R.C., & Deregnier, R. Randomized , Randomized , Controlled Trial of Low Dose Inhaled Nitric Oxide in the Treatment of Controlled Trial of Low Dose Inhaled Nitric Oxide in the Treatment of Term and Near Term Infants with Respiratory Failure and Pulmonary Term and Near Term Infants with Respiratory Failure and Pulmonary Hypertension.Hypertension. Official Journal of the American Academy of Pediatrics. Official Journal of the American Academy of Pediatrics. (Nov. 1999). Retrieved from: (Nov. 1999). Retrieved from: http://pediatrics.aappublications.org/cgi/content/full/105/5/1089http://pediatrics.aappublications.org/cgi/content/full/105/5/1089

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How to set up a nitric oxide systemHow to set up a nitric oxide system

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