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

2. Heliox- helium + oxygen 1 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

3. Physical properties CompositionDensity (p) kg/m 3 Viscosity ( ή ) microPoise Thermal conductivity W/m K Air1.184184.330.025 CO21.81148.710.017 Helium0.166197.610.14 Nitrogen1.167177.820.026 oxygen1.33205.350.026

4. Physiological issue To improve ventilation ↑ compliances Resistances airway or Both Bronchodilator and Steroids used to increase Airway caliber.

5. 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 airway’s dynamic of fluids.

6. Heliox = Helium + Oxygen Reduces resistances by reducing REYNOLDS number, the density of mixture is an important determinent of Reynold’s number TURBULENT FLOW LAMINAR FLOW. Reduces work of breathing and improves Gas exchanges

7. Reynolds Number Reynolds 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) ή d= diameter of tube(m) v=linear velocity(m/s) ή= gas viscosity(kg/m/s)

8. Reynolds Number Re < 2000 - Laminar flow Re 2000-4000 - Transition flow Re > 4000 - Turbulent flow Normal physiology: Upper airway & proximal trachea- TURBULENT FLOW Asthma and COPD : Turbulent flow observed more distally.

9. Laminar and Turbulent flow

10. Different type of flow Laminar flow- flow characterized by smooth, parallel layer of fluid Turbulent flow – flow characterized by mixing of adjacent fluid layer

11. Medical Application Upper airwayLower airway Infection – croup, epiglottitis, laryngitis, tracheitis. Trauma and Mass effect – foreign body aspiration, post extubation stridor, Tumour. Other – Tracheomalacia, Tracheal stenosis Asthma, COPD, Bronchiectasis Bronchiolitis Lung cancer HFOV

12. Medical applications Others Assessment of FRC IABP Operation and Cooling of MRI scanner Treatment for Decompression sickness Pneumatosis cystoides Hyperammonaemia

13. NEBULIZED DRUG DELIVERY Nebulized drug delivery  improve gas exchange. Air /O 2 vs He-O 2 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)

14. HELIOX DELIVERY

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

16. Asthma Metaanalysis USEFULLNESS IN MORE SEVERE PATIENTS Risk of intubation, while awaiting the effects of standard therapy. (database systemic review 2006) Level of evidences is low.

17. COPD Multicenter, 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– didn’t show any statistical superiority

18. Problem in using Difficult to obtain Real benefit - ↓ density, Fio2 < 40% Thermal conductivity – Heated humdifier Different function of the valve within the ventilator that controls flow Expensive

19. Clinically not applicable Turbulent 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. Poisueille’s law: R = ( 8.1.ń/π.r ⁴ )

20. Nitric oxide

21. 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 alveolar epithelial cells

22. Pathophysiology of ARDS Starling 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, - Atelectasis

23. Nitric 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.

24. METABOLISM

25. 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.

26. Goal of Inhaled NO Improve oxygenation Decrease PVR Decrease pulmonary edema Reduction or Prevention of inflammation Cytoprotection Protection against infection

27. 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.

28. Effect of PO 2 in ARDS

29. Benefit of inhaled NO

30. Effect of inhaled NO vs NTP

31. Mechanism of action

32. Inhaled vasodilators In ARDS 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.

33. 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 oxygenation

34. Dosing Inhaled NO is typically administered at a dose between 1.25 and 40 parts per million (ppm).

35. 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

36. DELIVERY OF NO IN MV

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

38. 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.

39. 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.

40. 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.

41. OTHER ORGAN EFFECTS GIT – 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 mechanisms

42. 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.

43. Side effects Methemoglobin and NO2 concentrations may increase when high doses of NO are given(500-2000 ppm of NO). Concentration of both should be monitored frequently.

44. Metabolism Nitric 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.

45. Side effects Inhaled 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.

46. Other uses Licensed – persistent Pul.Hypertension RV failure Post cardiac surgery Orthotopic heart and lung transplant Ventricular assist device Ischemic- reperfusion injury- no role

48. Thank you!