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Nitric Oxide Ventilation in
Acute Respiratory Distress Syndrome
Muhammad Asim Rana MBBS, MRCP, FCCP, SF-CCM, EDIC
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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
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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
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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
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Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.htm
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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
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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
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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
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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
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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
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Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-11.htm
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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
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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
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Genitourinary Nitric oxide may play a role in sodium
homeostasis in the kidney. HematologicalPlatelet aggregation is inhibited by NO.
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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.
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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 )
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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
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Pathophysiology
Diffuse alveolar damage
Lung capillary damage
Inflammation/pulmonary edema
Resulting severe hypoxemia and decreased lung compliance
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Pathophysiology
Occurs in stages1. Exudative ( Acute Phase)2. Proliferative3. Fibrotic4. Recovery
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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
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CXR findingsDiffuse, fluffy alveolar infiltrates with prominent air
bronchograms
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CT findings
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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
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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
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Prone position ventilation
ANTIOXIDANTSGlutathione LisophyllineDietary oil supplementation
INHALED VASODILATORSNitric oxideProstacyclin
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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.
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PHARMACODYNAMICS / KINETICS
Absorption: Systemic after inhalation
Excretion: Urine (as nitrate)
Clearance: Nitrate: At a rate approaching the glomerular
filtration rate.
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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.
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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.
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Monitoring Chemiluminescence and electrochemical
analysers should be used and are accurate to 1 ppm.
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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.
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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.
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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)
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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.
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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.
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Predictors when to use Inhaled NO
Inhaled NO does not improve oxygenation in all patients and the factors that determine responsiveness are uncertain.
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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.
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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.
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Thank You