Inhaled nitric oxide ppt dr jason

DRUG REVIEW : INO
(INHALED NITRIC OXIDE)
Moderator: Dr Parveen Zohara
Presentor: Dr Jason Dsouza

◦ Introduction
◦ Timeline
◦ Role of NO
◦ Mechanism of action
◦ Pharmacokinetics
◦ Indications
◦ Mode of administration
◦ Special indications
◦ Adverse drug reactions
◦ Warning and precautions
Outline

Introduction
◦ NO is a colorless, odorless gas , Lipid soluble, partially water soluble and non
flammable.
◦ It is a diatomic free radical consisting of one atom of nitrogen and one atom of oxygen
◦ Short half life, usually degraded or reacted within a few seconds
◦ Density: 1.245kg/m3 and specific gravity of 1.04 at Room temperature

Introduction(cont.)
◦ Highly unstable in atmosphere ,exist in 3 biologically active forms in tissues
Nitrosonium(NO+), Nitroxyl anions(NO-) and as a free radical (NO)
◦ In presence of moisture, forms nitrous and nitric acids which cause corrosion
◦ NO and NO2 together are potent irritant causing chemical pneumonitis and pulmonary edema
◦ Nitric oxide is supplied with nitrogen as compressed gas in alluminium alloy cylinders

◦ NO is produced in the body by a family of three NOS
◦ They use oxygen and L-arginine to produce NO and L-citrulline

Activation of NO Synthetase
Glutamate neurotransmitter binds to NMDA receptors

Timeline
◦ Recognised as Vasodilator molecule produced by endothelial cells in body in 1987
◦ The therapeutic potential ( Pulmonary vasodilator ) was in 1991, in a lamb model of
pulmonary hypertension
◦ First approved for clinical use by FDA in 1999

nervous system
◦ Signals for inhibition of smooth muscle contraction, adaptive relaxation and localized
vasodilation
◦ Believed to play a role in long term memory

circulatory system
As a vasodilator: Released in response to high blood flow and signaling molecules
(Acetylcholine and bradykinin)
In gaseous exchange(Hb and cells): During O2 delivery, it locally dilates blood vessels to aid
in gas exchange; Excess of it is picked up by Hemoglobin with CO2

muscular system
◦ It signals inhibition of smooth muscle contraction

immune system
NOS II catalyzes synthesis of NO used in host defense reactions
◦ Activation of NOS II in most nucleated cells, especially macrophages is independent of Ca+2 in the
cell. It is a potent inhibitor of viral replication
NO is a bactericidal agent
◦ It is created
from the nitrates extracted from food near the gums, which kills bacteria in the mouth that may be
harmful to the body

digestive system
Adaptive relaxation: It promotes the stretching of the stomach in response to filling
Genitourinary : It plays a role in sodium homeostasis in the kidney.
Hematological: Platelet aggregation is inhibited by NO.

Respiratory system
◦ Pulmonary vasodilatation is provided by endogenous Nitric Oxide
◦ It inhibits hypoxic pulmonary vasoconstriction
◦ Preferentially increases blood flow through well-ventilated areas of the lung thus
Improves Ventilation : Perfusion ratio.

Transition at birth
Clamping of umbilical cord:
Removes low resistance placental circulation
Increases systemic arterial pressure
Other factors:
Initiation of respiration;fluid filled lung distended with air  improved oxygenation.
Increase in pulmonary blood flow increase left artrial pressure PFO closed.
PVR decreases and SVR increases  reversal of flow at ductus arteriosus(DA)  closure of DA.

Mechanism of action
◦ Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic
guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic
guanosine 3',5'-monophosphate, which leads to vasodilation.
◦ When inhaled, pulmonary vasodilation occurs causing an increase in the partial pressure of
arterial oxygen.
◦ Dilatation of pulmonary vessels in well ventilated lung areas redistributes blood flow away from
lung areas where ventilation/perfusion ratios are poor.

Endothelium-derived mediators: the vasodilators prostacyclin (PGI2) and nitric oxide (NO) and the vasoconstrictor endothelin (ET-1).
Satyan Lakshminrusimha, and Martin Keszler Neoreviews 2015;16:e680-e692

Oxygenation index(OI)
◦ Severity of hypoxic respiratory failure
◦ MAP x FiO2 x 100 / PaO2
◦ OI 15-25  indication to start iNO
◦ OI >40  indication to start ECMO

Indications
◦ Persistent Pulmonary Hyperetnsion in newborn
◦ Primary pulmonary hypertension
◦ Pulmonary hypertension after cardiac surgery
◦ Cardiac transplantation(Myocardial Ischemia/Reperfusion injury)
◦ Acute pulmonary embolism

Indications(cont)
Other Indications:
◦ Acute Respiratory Distress Syndrome
◦ Haemolysis, Sickle cell disease
◦ SARS-CoVid infection

Guidelines for Use of Inhaled Nitric Oxide Therapy:
Patient profile: > / = 34 weeks gestational age.
When:
– In the first week of life
– Echocardiographic evidence of extrapulmonary right to-left shunting
– OI greater than 25
– After effective lung recruitment.
Starting dose: 20 ppm

Guidelines for Use of Inhaled Nitric Oxide Therapy:
Duration of treatment: Typically less than 5 days.
Discontinuation:
◦ FiO2 < 60% and PaO2 > 60 ,
◦ Without evidence of:
– Rebound pulmonary hypertension
– Increase in FiO2 >15% after iNO withdrawal.
ECMO availability: If used in a non-ECMO center, arrangements should be in place to
continue iNO during transport

Potential Beneficial Effects of Low-Dose iNO in Hypoxemic Respiratory
Failure:
1. Pulmonary vasodilation → decreased extrapulmonary right-to-left shunting
2. Enhanced matching of alveolar ventilation with perfusion decreased intrapulmonary shunting
3. ↓ Inflammation (↓ lung neutrophil accumulation)
4. ↓ Vascular leak and lung edema
5. Preservation of surfactant function

Potential Beneficial Effects of Low-Dose iNO in Hypoxemic Respiratory
Failure:
6. ↓ Oxidant injury (inhibition of lipid oxidation)
7. Diagnostic value: Failure to respond to iNO rules out anatomic cardiovascular or pulmonary
disease.
8. Preserves of vascular endothelial growth factor expression

PHARMACODYNAMICS / KINETICS
◦ Absorption: Systemic after inhalation
◦ Metabolism : Nitric oxide combines with hemoglobin that is 60% to 100%
oxygenated to produce methemoglobin and nitrate.
◦ Excretion: Urine (as nitrate)
◦ Clearance: Nitrate: At a rate approaching the glomerular filtration rate.

PHARMACODYNAMICS / KINETICS cont.
Storage
◦ NO is stored in aluminium or stainless steel cylinders which are typically 40
litres.
◦ These contain 100/1000/2000 p.p.m. nitric oxide in nitrogen.
◦ Pure NO is corrosive and toxic.

Mode of administration
Administration
Via the patient limb of the inspiratory circuit of a ventilator.
The delivery system is designed to minimize the oxidation of nitric oxide to
nitrogen dioxide.
Monitoring
◦ Monitor percentage methemoglobin within 4 hours of starting and at 24-hour
intervals of starting INo

4 Patterns of response to iNO:
• Pattern 1 : Non-responders
• Pattern 2: Responders: Initial response, but no sustained response.
• Pattern 3: Responders: Initial response + sustained response + successfully weaned within 5 days.
◦ Pattern 4: Responders: Initial response, but sustained dependence on iNO for weeks together.

Contraindications of iNO
◦ CHD that is dependent on right to left shunting across the ductus arteriosus (Eg: Critical
AS, Interrupted aortic arch and HLHS)
◦ iNO may worsen pulmonary edema in TAPVD

ADVERSE REACTIONS
SIGNIFICANT >10%
◦ Cardiovascular: Hypotension (13%)
◦ Miscellaneous: Withdrawal syndrome
(12%)
1% to 10%:
Dermatologic: Cellulitis (5%)
Endocrine & metabolic: Hyperglycemia (8%)
Genitourinary: Hematuria (8%)
Respiratory: Atelectasis (9%), stridor (5%)

ADVERSE REACTIONS(cont)
◦ Miscellaneous: Sepsis (7%), infection (6%)
◦ Post-marketing and/or case reports: Headache (environmental exposure,hospital staff);
hypoxemia; pulmonary edema (in CREST syndrome patients)

WARNINGS / PRECAUTIONS
Disease-related concerns:
◦ Pulmonary artery hypertension (PAH) : Acute vasodilator testing
◦ Patients with concomitant heart failure (LV systolic dysfunction with significantly
elevated left heart filling pressures)
◦ Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis
.

Other warnings/precautions:
◦ Abrupt discontinuation: May lead to worsening hypotension, oxygenation, and
increasing pulmonary artery pressure (PAP).
◦ Appropriate use: Doses above 20 ppm should be carefully be used
(methemoglobinemia and elevated nitrogen dioxide (NO2) levels).
◦ Lack of response: Worsening oxygenation and increasing PAP (Non Responders)

1. ROLE OF INHALED NITRIC OXIDE IN NEWBORNS WITH
CONGENITAL DIAPHRAGMATIC HERNIA
◦ No difference in the combined endpoint of death and/or ECMO use between iNO-treated and control
infants.
◦ Use of iNO therapy in patients with CDH; should be limited to patients with:
– Suprasystemic Pulmonary Vascular Resistance
– After establishing optimal lung inflation and
– After demonstrating adequate Left Ventricular performance
However, there is clearly a role for iNO therapy in the treatment of late pulmonary hypertension (PH) in patients
with CDH.

Special Situations (cont):
2.THE PREMATURE NEWBORN
In preterm infants, iNO can be used for:
– Acute treatment of severe PPHN (as in term infants),
– Management of chronic PH in evolving or established BPD, and
– For prevention of BPD

2. Special Situations THE PREMATURE NEWBORN (cont):
Effects of iNO in preterms may depend on:
– Timing
– Dose of therapy
– Duration
– Nature of underlying disease.
• Low-dose iNO may be safe and effective in reducing risk of death/BPD for infants
with birth weights >1000 g.
• Treatment between 7 and 14 days after birth appears to be safe and effective in
reducing BPD

Key POINTS
◦ Inhaled NO – drug of choice for PAH in Term and near-term infants with Hypoxic Respiratory Failure
◦ Initiate treatment soon for maximum effect
◦ Starting dose – 20 ppm; higher doses not beneficial
◦ In non-responders –Early weaning downgrade iNO faster
◦ Monitor MetHB & NO2 at start and daily/12 hourly
◦ Avoid hyperoxic ventilation
◦ More superoxide anions  more NO consumption
◦ Hyperoxic ventilation – Sildenafil better
◦ Sildenafil can be added while weaning from iNO

References
◦ Inhaled Nitric Oxide:A Selective Pulmonary Vasodilator Current Uses and Therapeutic Potential Fumito
Ichinose, MD; Jesse D. Roberts, Jr, MD; Warren M. Zapol, MD
◦ American academy of pediatrics,Committee on Fetus and Newborn,Use of Inhaled Nitric Oxide
◦ Inhaled nitric oxide use in newborn;ks Abraham Peliowski; Canadian Paediatric Society, Fetus and
Newborn Committee
◦ Clohertys and starks Neonatal Manual
◦ Principles and Practice of Mechanical ventilation- Martin J Tobi 3rd edition
◦ Assisted ventilation of neonate- Goldssmith (6th edition)
◦ Mosbys respiratory care Equipment-J M cairo (8th edition)
◦ Egan’s Fundamentals of respiratory care- 11th edition

Inhaled nitric oxide ppt dr jason

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