Nitric Oxide Ventilation in

Acute Respiratory Distress Syndrome

Muhammad Asim Rana MBBS, MRCP, FCCP, SF-CCM, EDIC

The structure and nature of Nitric Oxide

Nitric oxide is a diatomic free radical consisting of one atom of nitrogen and one atom of oxygen

Lipid soluble and very small for easy passage between cell membranes

Short lived, usually degraded or reacted within a few seconds

The natural form is a gas

N O

Synthesis of Nitric OxideNitric oxide is synthesized from L-arginine This reaction is catalyzed by nitric oxide

synthase, a 1,294 aa enzyme

COO-

C

(CH2)3

NH

C

H2N

H

NH2+

+H3N

Arginine

NOS

NADPH

+ O2

NAD+

COO-

C

(CH2)3

NH

C

H+H3N

N+

H2NH

OH

N-w-Hydroxyarginine

COO-

C

(CH2)3

NH

H+H3N + NO

NOS

C

O NH2

Citrulline

Activation of NO Synthetase

Glutamate neurotransmitter binds to NMDA receptors

Ca++ channels open causing Ca influx into cell

Activation of calmodulin, which activates NOS

NO synthesis takes place in endothelial cells, lung cells, and neuronal cells

Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.htm

Types of NO Synthetase NOS I

Central and peripheral neuronal cells Ca+2 dependent, used for neuronal communication

NOS II Most nucleated cells, particularly macrophages Independent of intracellular Ca+2 Inducible in presence of inflammatory cytokines

NOS III Vascular endothelial cells Ca+2 dependent Vascular regulation

The Role of NO in human bodyNitric Oxide in the human body has many

uses which are best summarized under five categories.NO in the nervous systemNO in the circulatory systemNO in the muscular systemNO in the immune systemNO in the digestive system

NO in the Nervous System Nitric oxide as a signaling molecule

NO is a signaling molecule, but not necessarily a neurotransmitter

NO signals inhibition of smooth muscle contraction, adaptive relaxation, and localized vasodilation

Nitric oxide believed to play a role in long term memoryMemory mechanism proposed is a retrograde

messenger that facilitates long term potentiation of neurons (memory)

Synthesis mechanism involving Ca/Calmodulin activates NOS-I

NO in the Circulatory System NO serves as a vasodilator

Released in response to high blood flow rate and signaling molecules (Acetylcholine and bradykinin)

Highly localized and effects are brief If NO synthesis is inhibited, blood pressure skyrockets

NO aids in gas exchange between hemoglobin and cellsHemoglobin is a vasoconstrictor, Fe scavenges NONO is protected by cysteine group when O2 binds to

hemoglobinDuring O2 delivery, NO locally dilates blood vessels to

aid in gas exchangeExcess NO is picked up by HGB with CO2

NO in the Muscular System NO was originally called EDRF (endothelium derived relaxation

factor)

NO signals inhibition of smooth muscle contraction Ca+2 is released from the vascular lumen activating NOS NO is synthesized from NOS III in vascular endothelial cells This causes guanylyl cyclase to produce cGMP A rise in cGMP causes Ca+2 pumps to be activated, thus reducing Ca+2

concentration in the cell

This causes muscle relaxation

Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-11.htm

NO in the Immune System NOS II catalyzes synthesis of NO used in host

defense reactionsActivation of NOS II is independent of Ca+2 in the cellSynthesis of NO happens in most nucleated cells,

particularly macrophagesNO is a potent inhibitor of viral replication

NO is a bactericidal agent NO is created from the nitrates extracted from food

near the gumsThis kills bacteria in the mouth that may be harmful to

the body

NO in the Digestive System

NO is used in adaptive relaxation NO promotes the stretching of the stomach in

response to filling. When the stomach gets full, stretch receptors trigger

smooth muscle relaxation through NO releasing neurons

Genitourinary Nitric oxide may play a role in sodium

homeostasis in the kidney.  HematologicalPlatelet aggregation is inhibited by NO.

Respiratory Important basal vasodilatation in

pulmonary vessels is provided by endogenous NO and this may be reversed in hypoxia.  Nitric oxide inhibits hypoxic pulmonary

vasoconstrictionpreferentially increases blood flow through

well-ventilated areas of the lung improving ventilation: perfusion relationships.

ARDS Definition 1994 American - European Consensus Conference

Committee (AECC)  came up with definition that became widely accepted

Also changed the name to acute respiratory distress syndrome from adult respiratory distress syndrome

Defined it as a spectrum of Acute Lung Injury        - Acute onset        - bilateral infiltrates on CXR        - PCWP =< 18 mmHg        - P/F ratio =< 200( ALI if P/F ratio =< 300 )

Causes

DIRECT LUNG INJURYCOMMON Pneumonia Aspiration

LESS COMMON Pulmonary contusions Fat emboli Near-drowning Inhalation injury Reperfusion injury

INDIRECT LUNG INJURYCOMMON Sepsis Severe trauma with shock

and multiple transfusions

LESS COMMON Cardiopulmonary bypass Acute pancreatitis Drug overdose

Pathophysiology

Diffuse alveolar damage

Lung capillary damage

Inflammation/pulmonary edema

Resulting severe hypoxemia and decreased lung compliance

Pathophysiology

Occurs in stages1. Exudative ( Acute Phase)2. Proliferative3. Fibrotic4. Recovery

Diagnosis of ARDSARDS is a clinical diagnosis No specific lab abnormality beyond

disturbance in gas exchange is evidentRadiologic findings may be consistent but

not diagnosticWorkup therefore is useful in identifying

inciting event or excluding other causes of lung injury

CXR findingsDiffuse, fluffy alveolar infiltrates with prominent air

bronchograms

CT findings

Consequences Impaired gas exchange leading to severe

hypoxemia – ventilation-perfusion mismatch, increase in

physiologic deadspace Decreased lung compliance –

due to the stiffness of poorly or nonaerated lung Pulmonary HTN – 25% of pts,

due to hypoxic vasoconstriction, Vascular compression by positive airway compression, airway collapse and lung parenchymal destruction

Novel therapies for the ARDS VENTILATION STRATEGIES

High-frequency ventilation APRV Liquid ventilation

EXTRACORPOREAL TECHNIQUES Oxygenation (ECMO)

ANTIINFLAMMATORY THERAPIES Corticosteroids Prostaglandin E1 Neutrophil elastase inhibitor Arachidonic acid inhibitors Ketoconazole Ibuprofen 

Prone position ventilation

ANTIOXIDANTSGlutathione LisophyllineDietary oil supplementation

INHALED VASODILATORSNitric oxideProstacyclin  

Basic ConceptOne hallmark of ARDS is severe

hypoxemia caused by physiologic shunting and ventilation/perfusion (V/Q) mismatching. Inhaled vasodilators, particularly nitric oxide

can selectively dilate vessels that perfuse well ventilated lung zones, resulting in improved V/Q matching, better oxygenation, and amelioration of pulmonary hypertension.

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 An increase in the partial pressure of arterial oxygen

results. Dilatation of pulmonary vessels in well ventilated lung

areas redistributes blood flow away from lung areas where ventilation/perfusion ratios are poor.

Inhaled vasodilators Inhaled vasodilators

(green circles) preferentially dilate the pulmonary vessels that perfuse functioning alveoli (white circles), recruiting blood flow away from poorly ventilated units (black circles).

The net effect is improved ventilation/perfusion matching.

Inhaled Nitric oxide (NO) has been well-studied in patients with acute lung injury and ARDS.

Inhaled NO has beneficial physiological effects, but there is little evidence that patient outcome improves.

Clinical Trials A well-designed multicenter randomised controlled

assigned 385 patients (PaO2/FiO2 ratio ≤ 250 mmHg) to either placebo or inhaled NO at 5 ppm. (The acute lung injury was not caused by sepsis, and

significant non pulmonary organ dysfunction was absent)

Inhaled NO induced short-term improvement of oxygenation; however,

there was no improvement in the duration of mechanical ventilation,

28-day mortality, or one-year survival.

Another multicenter double-blind trial randomly assigned 177 with ARDS to receive increasing concentrations of

inhaled NO or placebo. Inhaled NO improved oxygenation modestly,

but was not sustained. There was no difference in 28-day mortality,

although this was not a primary end point.

It has also been hypothesized that NO may have benefits unrelated to improved V/Q matching, including

1.antiinflammatory properties, 2.antiplatelet activity, and 3.effects which diminish vascular permeability

Dosing Inhaled NO is typically administered at a dose

between 1.25 and 40 parts per million (ppm). It has been used continuously for days to weeks,

with interruptions or attempts to discontinue therapy resulting in worsened oxygenation and increased pulmonary artery pressure.

However, there is evidence that patients treated with continuous inhaled NO might become sensitized, such that lower doses improve oxygenation and continued higher doses have little or no effect.

Metabolism Nitric oxide combines with hemoglobin that is

60% to 100% oxygenated. NO combines with oxyhemoglobin to produce

methemoglobin and nitrate. Within the pulmonary system, nitric oxide can

combine with oxygen and water to produce nitrogen dioxide and nitrite respectively, which interact with oxyhemoglobin to then produce methemoglobin and nitrate.

At 80 ppm the methemoglobin percent is ~5% after 8 hours of administration. Methemoglobin levels >7% were attained only in patients receiving 80 ppm.

PHARMACODYNAMICS / KINETICS

Absorption: Systemic after inhalation

Excretion: Urine (as nitrate)

Clearance: Nitrate: At a rate approaching the glomerular

filtration rate.

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.

Administration The drug is injected via the patient limb of

the inspiratory circuit of a ventilator.  The delivery system is designed to minimise

the oxidation of nitric oxide to nitrogen dioxide.

Monitoring Chemiluminescence and electrochemical

analysers should be used and are accurate to 1 ppm.

Potential Harms Inhaled NO may produce toxic radicals.

However, it is unknown whether the toxic radicals are more harmful than ongoing exposure to high fractions of inspired oxygen.

Methemoglobin NO2 concentrations

may increase when high doses of NO are given(500-2000 ppm of NO),

the concentration of both should be monitored frequently.

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% - same as placebo), stridor (5%)   Miscellaneous: Sepsis (7%), infection (6%)

Postmarketing and/or case reports: Headache (environmental exposure, eg, 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 not be used because

of the increased risk of methemoglobinemia and elevated nitrogen dioxide (NO2) levels. Methemoglobin levels and NO2 should be monitored.

Lack of response: Worsening oxygenation and increasing PAP may occur in patients who do not respond.

Summary Management of acute respiratory distress

syndrome (ARDS) is supportive, aimed at improving gas exchange preventing complications while the underlying disease that precipitated ARDS is

treated. Potential ARDS-specific therapies like inhaled

NO have been studied & have shown to improve oxygenation & clinical outcome.

Predictors when to use Inhaled NO

Inhaled NO does not improve oxygenation in all patients and the factors that determine responsiveness are uncertain.

One retrospective study found that patients with septic shock responded to inhaled NO less frequently than patients without sepsis or septic shock.

A different study reported that a high baseline pulmonary vascular resistance and responsiveness to positive end-expiratory pressure (PEEP) predicted a positive response.

So the decision lies with treating Intensivist about starting a patient on inhaled NO keeping in view the potential benefits and harms of such therapy.

Thank You