Inhaled Nitric Oxide (iNO)

By Joshua Avritt and Rajbeer Singh

What is Nitric Oxide?

This simple molecule is composed of 1 atom of oxygen and 1 atom

of nitrogen.

Nitric oxide (NO) has a short half life and is considered a free
radical which makes it highly volatile and reactive. NO reacts
readily with metals and salts (e.g. iron, copper).

When nitric oxide combines with oxygen, nitrogen dioxide (NO2) is

created.

This reaction depends on the NO and O2 concentration as well as

contact time (dwell time). NO2 is thought to be a toxic gas that can
cause damage to the respiratory system. This damage depends on
the concentration inhaled and the exposure time.

During inhaled NO therapy, it is important to keep NO2 levels as low

as possible. Most clinicians try to keep the NO2 level at less than 2
ppm
 Nitric Oxide and the Lung
(Endogenous)

Our bodies produce nitric oxide endogenously. In the

lung, NO controls the vessels that surround the alveoli.

When nitric oxide is increased, the vessels dilate.

When vasodilation occurs, the inside of a vessel gets
larger and more blood flows through the vessel. The
body is self-regulating; it will try to keep the ventilation
and the blood flow (perfusion) equal in the lung. This is
ventilation / perfusion matching.
 Nitric Oxide (Exogenous)

In low concentrations, nitric oxide is given via inhalation

(exogenously). A positive response may be indicated by an
improvement in clinical markers such as SPO2, PaO2, or
by a reduction in pulmonary vascular resistance (PVR).
When inhaled nitric oxide is delivered to the patient, the nitric
oxide travels down the airways and goes only to the areas of
the lung where ventilation or gas exchange is taking place.
It diffuses rapidly into the smooth muscle of the blood vessel
where it causes vasodilation.
After the NO passes into the capillary blood stream it is bound
by hemoglobin in red blood cells. Once it is bound by
hemoglobin, creating methemoglobin, it can no longer exert
its vasodilator properties.
At clinically therapeutic applied NO levels, the blood that
leaves the lungs cannot exert its vasodilator effects on the
rest of the vessels in the body. Inhaled nitric oxide thus has
minimal systemic effects and is highly selective.
Nitric oxide (NO) and prostacyclin (PG) signaling pathways in regulation of
vascular tone
 Differing pathophysiological effects of inhaled
pulmonary vasodilators and intravenous
vasodilators.

SNP indicates sodium nitroprusside; TNG, nitroglycerine; PGI 2,

prostaglandin I2; Qs/Qt, right-to-left shunt fraction; and SVR,
systemic vascular resistance.
Metabolism of Nitric Oxide in the
Lung
Nitric oxide is rapidly metabolized.
When NO combines with hemoglobin, NO can no
longer exert its vasodilator effects and
methemoglobin is created. O2 carrying capacity
can be decreased with high levels of
methemoglobin. When higher concentrations of
nitric oxide are used, more methemoglobin is
created.
When administering NO to patients the
methemoglobin levels must be measured.
 Indications for iNO

iNO is used to treat pulmonary hypertension

such as primary pulmonary hypertenison(PPH)
and persistent pulmonary hypertension of
newborns (PPHN).
Neonates with hypoxic respiratory failure
associated pulmonary hypertension.
NO therapy is often used with other forms of
therapy including high frequency oscillatory
ventilation and surfactant therapy, both of
which are aimed at improving oxygen delivery
and lung compliance.
 Dosage

Initial dosage was 20 ppm(particles per million).

Often reduced to 5 ppm at the end of 4 hours of

initial treatment.

Reduce inhaled nitric oxide dose by 50% (20, 10,5,

1 ppm).
 Methods of administration

NO is delivered with the O2 at a constant

concentration throughout the breathing cycle.
Set NO level is stable over a wide range of
flows and flow patterns, including spontaneous
breathing modes.
The flow sensor placed in the outlet of the
ventilator upstream from the humidifier
measures minute ventilation (lpm).
 Hazards and
contraindications
Nitric oxide when combined with oxygen
produces nitrogen dioxide (NO2), which is a
toxic gas.
Because of its very minimal half life (0.1
seconds 5 seconds), it is quickly inactivated
once it combines with hemoglobin.
Although rare, the patients as well as health
care providers can be adversely affected.
Factors influencing NO2 production are O2
concentration, NO concentration and time of
contact between NO and O2.
 Hazards and
contraindications
Patients most at risk include those receiving
high oxygen concentration and low ventilator
flow rates.
Production of methemoglobin can be a
problem due to anemic hypoxia which can be
treated with vitamin C..
A major contraindications of this therapy is
children who as a result of congenital cardiac
anomalies need a right-to-left shunt to
survive and NO therapy corrects the right-to-
left shunts.
Dosing and Weaning of Nitric
Oxide
Both the NO and the NO2 levels that are
being delivered to the patient must be
continuously analyzed.
High concentrations of NO may be toxic to the
tissues. NO2 can possibly cause pulmonary
edema, acid pneumonitis, and death.
When the NO is mixed in the patients breathing
circuit, the FiO2 (fraction of inspired oxygen)
delivered to the patient will be lower.
It is important to also monitor inspired
oxygen levels at a point distal to the point
of NO delivery.
Dosing and Weaning of Nitric
Oxide
Clinical monitoring must also be performed to
evaluate the patients progress on nitric oxide therapy.
Nitric oxide must be weaned slowly, and most
hospitals have a set protocol for weaning.
The rate and step-size of weaning that can be
accomplished varies from patient to patient.
Ability to wean nitric oxide is usually evaluated
by reviewing a patients oxygen saturation,
FiO2, pulmonary artery pressures (PAP), and
PEEP levels.
Some patients may exhibit a significant increase in
pulmonary artery pressure following a sudden
discontinuance or a large decrease of nitric
oxide. It is important to monitor the patient closely
while weaning the concentration of NO.
Nitric Oxide Delivery (brief
theory of operation and
features)
http://inomax.com/about-inomax/treating-
hypoxia-respiratory-failure/moa#video
Setup
Pre-use Checkout
iNO Studies
iNO Studies
iNO Studies
 Treatment of PPHN and iNO Alternatives

Initial Therapies
-Treat metabolic derangements: correct acidosis,
hypoglycemia, hypocalcemia
-Optimize lung recruitment: mechanical ventilation,
high-frequency oscillatory ventilation, surfactant
-Optimize cardiac output and left ventricular function:
vasopressors, inotropic agents
Pulmonary Vasodilators
-Inhaled nitric oxide
Future Therapies
-Phosphodiesterase Inhibitors (sildenafil)
-Inhaled prostacyclin analogs (iloprost, prostacyclin)
-Recombinant superoxide dismutase
-Prostacyclin (Flolan)
 References
Roberts JD Jr, Fineman JR, Morin RC 3rd, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension
of the newborn. N Engl J Med 1997;336(9):605-610.

Davidson D, Barefield ED, Kattwinkel J, Dudell G, Damask M, Straube R, et al. Inhaled nitric oxide for the early treatment of persistent
pulmonary hypertension of the term newborn: a randomized, doublemasked, placebo-controlled dose-response, multi-center study. The I-
NO/PPHN Study Group. Pediatrics 1998:101(3 Pt 1): 325-334.

Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock DE, et al. Randomized, multicenter trial of inhaled nitric oxide and
high-frequency ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 1997;131 (1 Pt 1:55-62.

Rossaint R, Gerlach H, Schmidt-Ruhnke H, Pappert D, Lewandowski K, Steudel W, Falke K. Efficacy of inhaled nitric oxide in patients with
severe ARDS. Chest 1995; 107(4):1107-1115.

Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, et al. Effects of inhaled nitric oxide in patients with acute
respiratory distress syndrome: results of a randomized phase II trial. Inhaled nitric oxide in ARDS Study Group. Crit Care Med 1998; 26(1):15-
23.

Micheal JR, Barton RG, Saffle JR, Mone M, Markewitz BA, Hillier K, et al. Inhaled nitric oxide versus conventional therapy: effect on
oxygenation in ARDS. Am J. Respir Crit Care Med 1998;157(5 Pt 1):1372-1380.

Troncy E, Collet JP, Shapiro S. Guimond JG, Blair L, Ducruet T, et al. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot
randomized controlled study. Am J Respir Crit Care Med 1998;157(5 Pt 1):1483-1488.

Lundin S, Mang, H, Smithies M, Stenquist O, Frostell C, for the European Study Group of Inhaled Nitric Oxide. Inhalation of nitric oxide in
acute lung injury : Preliminary results of a European multi-center study (abstract). Int Care Med 1997;23 (Suppl 1):S2. NIOSH
recommendations for occupational safety and health standards 1988. MMWR Morb Mort Wkly Rep 1988;37 (Suppl 7):1-29.

Branson RD, Hess DR, Campbell RS, Johannigman JA. Inhaled nitric oxide: delivery systems and monitoring. Resp Care 1999;44:281-306.

Hess DR. Adverse effects of toxicity of inhaled nitric oxide. Resp Care 1999;44:315-329. Bigatello LM. Strategies to enhance the efficacy of
nitric oxide therapy. Resp Care 1999;44:331-337.

Bigatello LM, Hurford WE, Kacmerek RM, Roberts JD, Zapol WM. Prolonged inhalation of low concentrations of nitric oxide in patients with
severe adult respiratory distress syndrome. Anesthesiology 1994;80(4):761-770.

Miller Ol, Pang SF, Keech A, Celemajer DS. Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide. Lancet
1994:346(8966):51-52.

Buga GM, Griscavage JM, Rogers NE, Ignarro LJ. Negative feedback regulation of endothelial cell function by nitric oxide. Circ Res 1993;73:
808-812.