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“After 25 years What Do We Know “After 25 years What Do We Know About Nitric Oxide”About Nitric Oxide”About Nitric OxideAbout Nitric OxideBob Kacmarek PhD, RRTBob Kacmarek PhD, RRT

Massachusetts General Hospital, Massachusetts General Hospital,

Harvard Medical School,Harvard Medical School,

Boston, MassachusettsBoston, Massachusetts55--55--17 FOCUS17 FOCUS

Conflict of Interest DisclosureConflict of Interest DisclosureRobert M KacmarekRobert M Kacmarek

I disclose the following financial relationships with I disclose the following financial relationships with commercial entities that produce healthcarecommercial entities that produce healthcare--related related products or services relevant to the content I am products or services relevant to the content I am presenting:presenting:presenting:presenting:

Company Relationship Content AreaCompany Relationship Content AreaMedtronic Consultant Artificial AirwaysMedtronic Consultant Artificial AirwaysMedtronic Grant Mech VentMedtronic Grant Mech VentOrange Medical Consultant Mech VentOrange Medical Consultant Mech VentTeleflex Consultant HumidificationTeleflex Consultant Humidification

Presentation ObjectivesPresentation ObjectivesUpon completion of this presentation the attendee will Upon completion of this presentation the attendee will

be able to:be able to:

1.1. Discuss the rational for the use of inhaled nitric Discuss the rational for the use of inhaled nitric oxide over the administration of systemic oxide over the administration of systemic vasodilatorsvasodilators

2.2. Discuss the current use of nitric oxide in neonates Discuss the current use of nitric oxide in neonates and adultsand adults

3.3. Discuss the experimental trials of nitric oxide use Discuss the experimental trials of nitric oxide use in various settingsin various settings

4.4. Discuss the future of nitric oxide production and Discuss the future of nitric oxide production and deliverydelivery

Physiologic Effects of NO

Vasorelaxation

Bronchodilitation

Inhibition of Mitochondrial Respiration

Inhibition of Platelet and Leukocyte Activation

Regulation of Smooth Muscle Proliferation

Siobal RC 2007;52:885Siobal RC 2007;52:885

NO

Selective Pulmonary Vascular Dilation by Inhaled NO

NO

NO

NO

NO

NO

QQ(Decreased blood flow)

PaO2

Shunting and V/Q mismatch

NO

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Steudel Anes 1999;91:1090Steudel Anes 1999;91:1090

Frostell, Zapol Circulation 1991;83:2038

Roberts, Zapol Lancet 1992;340:818:19Roberts, Zapol Lancet 1992;340:818:19 Rossaint, Falke, Zapol NEJM Rossaint, Falke, Zapol NEJM 1993;328(6):3991993;328(6):399

9pts with ARDS treated with 18 and 36 ppm NO9pts with ARDS treated with 18 and 36 ppm NO

Rossaint, Zapol NEJM 1993;328(6):399Rossaint, Zapol NEJM 1993;328(6):399NO NO -- Neonates Neonates -- RCT’sRCT’s

NINOS NEJM 1997; 336:567NINOS NEJM 1997; 336:567

Roberts NEJM 1997; 336:605Roberts NEJM 1997; 336:605

Davidson Ped 1998; 101:325Davidson Ped 1998; 101:325

Clark NEJM 2000; 342:469Clark NEJM 2000; 342:469

NINOS J Pediatr 2000; 136:611NINOS J Pediatr 2000; 136:611

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NO NO -- FDA IndicationFDA IndicationDecember 23,1999December 23,1999

“Term or near“Term or near--term (> 34 weeks)term (> 34 weeks)

neonates with hypoxic respiratoryneonates with hypoxic respiratoryyp p yyp p y

failure associated with clinical orfailure associated with clinical or

echocardiographic evidence ofechocardiographic evidence of

pulmonary hypertension.”pulmonary hypertension.”

RCT’s iNO in ARDS:RCT’s iNO in ARDS:No improvement in Outcome with No improvement in Outcome with

iNO!iNO!Dellinger et al CCM 1998;26:15Dellinger et al CCM 1998;26:15--2323

Michael et al AJRCCM Michael et al AJRCCM 1998;157:13721998;157:1372--13801380

Troncy et al AJRCCM Troncy et al AJRCCM 1998;157:14831998;157:1483--14881488

Lundin et al ICM 1999;25;911Lundin et al ICM 1999;25;911--919919

Phase III Trial Unpublished Data 2000Phase III Trial Unpublished Data 2000

Oxygenation MortalityOxygenation MortalitySiobal and Hess RC 2010;55:145Siobal and Hess RC 2010;55:145

The impact of Nitric Oxide in ARDSThe impact of Nitric Oxide in ARDS Dellinger CCM1998;26:15Dellinger CCM1998;26:15

Gerlach Gerlach AJRCCM AJRCCM

2003;167:10152003;167:1015

Gerlach Gerlach AJRCCM AJRCCM 2003;167:2003;167:

10151015

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Kacmarek, Zapol AJRCCM 1996;153(1);12814 patients stable mild Asthma

NO NO -- Acute RV FailureAcute RV Failure

Solina J Invest Surg 2002;15:5Solina J Invest Surg 2002;15:5Maxey Ann Thoracic Surg 2002;73:529Maxey Ann Thoracic Surg 2002;73:529Kadosaki Anes 2002;96:835Kadosaki Anes 2002;96:835Sablotzki Eur J Cardiothorac Surg Sablotzki Eur J Cardiothorac Surg 2002;22:7462002;22:7462002;22:7462002;22:746King Br J Anes 2000;85:628King Br J Anes 2000;85:628Argenziano Ann Thoracic Surg 1998; 65:340Argenziano Ann Thoracic Surg 1998; 65:340Goldman Ann Thoracic Surg 1995; 60:300Goldman Ann Thoracic Surg 1995; 60:300Journois J Thoracic Cardiovasc Surg 1994; Journois J Thoracic Cardiovasc Surg 1994; 107:1129107:1129Rich Anes 1993; 78:1028Rich Anes 1993; 78:1028

NO Heart/Lung TransplantationNO Heart/Lung Transplantation

Rajek Anesth Analg 2000; 90:523Rajek Anesth Analg 2000; 90:523

Adatia Ann Thorac Surg 1994; Adatia Ann Thorac Surg 1994; 57:131157:1311

Kemming ICM 1998; 24:1173Kemming ICM 1998; 24:1173

Bate J Thorac Cardiovasc Surg 1996; Bate J Thorac Cardiovasc Surg 1996; 111:913111:913

2011;1(2):2502011;1(2):250>30% decrease in PVR, 53% reduction or>30% decrease in PVR, 53% reduction or

>12% decrease in mPAP, 55% reduction in >12% decrease in mPAP, 55% reduction in MortalityMortality (80 patients studied)(80 patients studied)

Checchia J Thor Cardiovas Surg 2013;146(9):530

RCT 16 Children undergoing CPB randomized to 20 ppm NO vs. placeboplacebo

NO delivered to membrane oxygenator

NO Less Diuretic use, greater Hb at 48 Hrs in spite of similar blood loss

ChecchiaChecchia J Thor J Thor CardiovasCardiovas SurgSurg2013;146(3):5302013;146(3):530

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MwangaMwanga--Amumpaire, Zapol Amumpaire, Zapol Open Forum Infectious Diseases Open Forum Infectious Diseases

20162016

NO as an Adjunctive Rx NO as an Adjunctive Rx for Cerebral Malaria in for Cerebral Malaria in Children: A Phase II Children: A Phase II

Randomized Open Label Randomized Open Label Clinical Trial.Clinical Trial.

MwangaMwanga--Amumpaire, Zapol Open Amumpaire, Zapol Open Forum Infectious Diseases 2016Forum Infectious Diseases 2016

Lei, Berra. Zapol et al Circulation Lei, Berra. Zapol et al Circulation 2015;(23);2214 Abstract 209912015;(23);2214 Abstract 20991

Hypothesis Hypothesis –– Exposure to Nitric Oxide during Exposure to Nitric Oxide during CPB protects the kidneys:CPB protects the kidneys:

Selective vasodilatation of pulmonary circulation increasing Selective vasodilatation of pulmonary circulation increasing renal blood flowrenal blood flow

Reduction of ischemiaReduction of ischemia--reperfusion renal injury reperfusion renal injury

Oxidation of plasma Hb to MetHb which cannot scavenge Oxidation of plasma Hb to MetHb which cannot scavenge NONO

RCT double blind 80 ppm NO vs. NRCT double blind 80 ppm NO vs. N22 via via oxygenatoroxygenator

217 pts with normal kidney function undergoing 217 pts with normal kidney function undergoing elective multiple valve replacementelective multiple valve replacement

Lei, Berra, Zapol et al Circulation Lei, Berra, Zapol et al Circulation 2015;(23);2214 Abstract A209912015;(23);2214 Abstract A20991

NO an important role in the NO an important role in the pathophysiology of inflammatory pathophysiology of inflammatory disordersdisorders

Sharma Inflammopharmacology Sharma Inflammopharmacology 2007;15:2522007;15:252

NO releasing agents have been studies in NO releasing agents have been studies in the treatment of inflammatory disordersthe treatment of inflammatory disorders

Marshall Br J Pharmacol 2006;149:516Marshall Br J Pharmacol 2006;149:516

NO may have gastrointestinal protective NO may have gastrointestinal protective

Nitric Oxide Administration Today

Gas Cylinders

Distribution System

A Complex Delivery DeviceA Complex Delivery Device

Gas Monitoring

Calibration equipment

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Yu, Zapol Science Translational Medicine Yu, Zapol Science Translational Medicine 2015;294(7):294ra1072015;294(7):294ra107

Yu, Zapol Science Translational Medicine Yu, Zapol Science Translational Medicine 2015;294(7):294ra1072015;294(7):294ra107

Yu, Zapol Science Translational Medicine Yu, Zapol Science Translational Medicine 2015;294(7):294ra1072015;294(7):294ra107 Berra, Zapol AJRCCM 2016 In PressBerra, Zapol AJRCCM 2016 In Press

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Berra, Zapol AJRCCM 2016 In PressBerra, Zapol AJRCCM 2016 In Press The FutureThe FutureNO used in the management of a wide range NO used in the management of a wide range of pathophysiological disordersof pathophysiological disorders

NO manufactured and delivered by small NO manufactured and delivered by small portable devicesportable devices

Patients able to use NO at homePatients able to use NO at homePatients able to use NO at homePatients able to use NO at home

Patients able to be mobile and receive NO Patients able to be mobile and receive NO continuouslycontinuously

Cost of NO therapy markedly reducedCost of NO therapy markedly reduced

NO available in developing and under NO available in developing and under developed countriesdeveloped countries

Thank YouThank You