HELIOXAND DR.NANDAKUMAR.V., M.D.,I.D.C.C.M.,E.D.I.C KMCH INHALED NITRIC OXIDE- IS IT USEFUL?

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HELIOX ANDDR.NANDAKUMAR.V.,M.D.,I.D.C.C.M.,E.D.I.CKMCHINHALED NITRIC OXIDE-IS IT USEFUL?

Heliox- helium + oxygen1 st clinical use Charles Look 1923 for decompression sickness

1934 Barach grandfather of heliox therapy

Inert/ Non toxic/tasteless/non- flammable gas.

Non carcinogenic, no lasting effect on human organ

Lower in density than in Nitrogen/ O2

Physical propertiesCompositionDensity (p) kg/m 3Viscosity ()microPoiseThermal conductivity W/m KAir1.184184.330.025CO21.81148.710.017Helium0.166197.610.14Nitrogen1.167177.820.026oxygen1.33205.350.026Physiological issueTo improve ventilation compliances Resistances airway or Both

Bronchodilator and Steroids used to increase Airway caliber.

Heliox = Helium+ Oxygen No broncho dilating or anti inflammatory properties.

Airway resistance in turbulent flow is directly related to density of gas

Heliox -low density than N2 or O2 lower airway resistances

Low density exert important potential benefits with regards to airways dynamic of fluids.

Heliox = Helium + Oxygen Reduces resistances by reducing REYNOLDS number, the density of mixture is an important determinent of Reynolds number TURBULENT FLOW LAMINAR FLOW.

Reduces work of breathing and improves Gas exchangesReynolds NumberReynolds number is a dimensionless number that can used to predict conditions of laminar or turbulences flow depending on the situation

Re = pdv p=density of gas (kg/L) d= diameter of tube(m) v=linear velocity(m/s) = gas viscosity(kg/m/s)Reynolds NumberRe < 2000 - Laminar flowRe 2000-4000 - Transition flowRe > 4000 - Turbulent flow

Normal physiology: Upper airway & proximal trachea- TURBULENT FLOWAsthma and COPD : Turbulent flow observed more distally.

Laminar and Turbulent flow

Different type of flow

Laminar flow- flow characterized by smooth, parallel layer of fluid

Turbulent flow flow characterized by mixing of adjacent fluid layerMedical ApplicationUpper airwayLower airwayInfection croup, epiglottitis, laryngitis, tracheitis.

Trauma and Mass effect foreign body aspiration, post extubation stridor, Tumour.

Other Tracheomalacia, Tracheal stenosisAsthma,COPD,BronchiectasisBronchiolitisLung cancerHFOVMedical applicationsOthers Assessment of FRC IABP Operation and Cooling of MRI scanner Treatment for Decompression sickness Pneumatosis cystoides HyperammonaemiaNEBULIZED DRUG DELIVERY Nebulized drug delivery improve gas exchange .

Air /O2 vs He-O2 nebulized albuterol in acute severe asthma NO shorten hospital stay NO clinical improvement. (Respiratory care 2013)

In COPD acute exacerbation- (FEF25-75) and (FEV1) no improvement in FEV1,faster improvementin FEF25-75 (Critical care med 2000)HELIOX DELIVERY

Upper airway obstructionB/L Vocal cord palsy, post extubation stridor-compared Heliox vs Adrenaline neb. (PEDIATRICS2001)AsthmaMetaanalysis

USEFULLNESS IN MORE SEVERE PATIENTS Risk of intubation, while awaiting the effects of standard therapy. (database systemic review 2006)

Level of evidences is low.

COPDMulticenter, randomized trial on NIV with heliox mixture vs standard therapy in COPD exacerbation. (critical care 2010 Jan; maggiore SM,)

Complication of NIV and MV, ET intubation, Icu and hospital discharge, 28 days mortality, Serious adverse effect were recorded didnt show any statistical superiorityProblem in usingDifficult to obtain

Real benefit - density, Fio2 < 40%

Thermal conductivity Heated humdifier

Different function of the valve within the ventilator that controls flow

ExpensiveClinically not applicableTurbulent flow- depends on density of the solution.

Laminar flow- depends on viscosity.

In distal airways laminar flow is maintained in COPD & Asthma due to large cross sectional area.

Poisueilles law:R = ( 8.1./.r)Nitric oxide

Pathophysiology of ARDS Insult

Activation of inflammatory mediators and cellular components

Cytokines ( TNF, IL-1, IL-6, IL-8) Neutrophilic infiltartion

Damage to capillary endothelial and alveolar epithelial cells Pathophysiology of ARDSStarling forces fall out of balance - in capillary hydrostatic pressure pulmonary capillary - oncotic pressure gradient. permeability

Exudative fluid in interstitium and alveoli - Impaired gas exchange --- ventilation- perfusion mismatch - Physiological shunting, decreased compliance - Increased pulmonary arterial pressure - Type 2 pneumocyte damage, - AtelectasisNitric oxide was formerly known as endothelium-derived relaxing factor (EDRF).

It is one of the nitrogen oxides ("NOx")

Synthesized within cells by an enzyme NO synthase (NOS).

This enzyme catalyses the oxidation of L-arginine to L-citrulline, producing NO.

METABOLISM

NOS is present in two forms

The constitutive form (eNOS)

Present in vascular, neuronal, cardiac tissue, skeletal muscle and platelets, producing small quantities of NO continuously. Here NOS is Ca2+/calmodulin dependant-stimulated by cGMP.

The inducible form (iNOS)

Present in endothelium, myocytes, macrophages and neutrophils, which produces relatively large quatities of NO after exposure to endotoxins in sepsis.

Following induction high levels of NO produced may form cytotoxic radicals and cause capillary leakage.

Goal of Inhaled NOImprove oxygenation

Decrease PVR

Decrease pulmonary edema

Reduction or Prevention of inflammation

Cytoprotection

Protection against infection

Respiratory

Basal vasodilatation in pulmonary vessels - reverses hypoxia. Nitric oxide inhibits hypoxic pulmonary vasoconstriction increases blood flow through well ventilated areas of the lung

Improves V/Q relationships.

Effect of PO2 in ARDS

Benefit of inhaled NO

Effect of inhaled NO vs NTP

Mechanism of action

Inhaled vasodilators In ARDSInhaled 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.

Basic Concept in using NO Pulmonary hypertension - one of the hallmark of ARDS

Severe hypoxemia caused by physiologic shunting and V/Q mismatching.

Inhaled vasodilators selectively dilate vessels that has perfuse well ventilated lung zones resulting in improved V/Q matching shunting Improves oxygenationDosing Inhaled NO is typically administered at a dose between 1.25 and 40 parts per million (ppm).

Continuous inhaled NO might become sensitized-Lowerdoses improve oxygenation -Continued higher doses have little or no effect.

When used continuously and weaned, it causes worsened oxygenation increased pulmonary artery pressure

DELIVERY OF NO IN MV

Monitoring Chemiluminescence and electrochemical analysers should be used and are accurate to 1 ppm.

Storage

NO is stored in aluminium or stainless steel cylinders which are typically 40 liters.

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 inspiratory circuit of a ventilator.

The delivery system is designed to minimize the oxidation of nitric oxide to nitrogen dioxide.

Other Organ Effects-Cardiovascular

Nitric oxide is a potent vasodilator.

Shear stresses in vessels increase NO production and may account for flow dependant vasodilatation. Endothelial NO inhibits platelet aggregation.

In septic shock the overproduction of NO results in hypotension and capillary leak.

NOS inhibitors have been investigated experimentally in the treatment of sepsis.

OTHER ORGAN EFFECTSGIT determinant of gastro intestinal motility appears to modulate morphine induced constipation

GENITOURINARY play sodium homeostasis in kidney

IMMUNE macrophage and neutrophils synthesize NO which can be toxic to certain pathogens and may be important in host defence mechanismsPotential 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.Side effectsMethemoglobin and NO2 concentrations may increase when high doses of NO are given(500-2000 ppm of NO).

Concentration of both should be monitored frequently.

MetabolismNitric oxide combines with hemoglobin that is 60% to 100% oxygenated. Nitric oxide 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.Side effectsInhaled NO is associated with renal dysfunction.

Inhaled NO has immunosuppressant properties that, in theory, could increase the risk of nosocomial infection.

NO can cause DNA strand breaks and base alterations, which are potentially mutagenic.

Other usesLicensed persistent Pul.Hypertension

RV failure

Post cardiac surgery

Orthotopic heart and lung transplant

Ventricular assist device

Ischemic- reperfusion injury- no role

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