3/8/2019 Disclosures: When Critical Illness is Complicated By Pulmonary Hypertension: Back to the Scientific Advisory Boards: Beginning Nima Hound Labs David N. Cornfield, M.D. Tueo Inc. Anne T. and Robert M. Bass Professor of Pulmonary Medicine Molecular Stethoscope Director-Center of Excellence in Pulmonary Biology Divisions of Pulmonary and Critical Care Medicine RxHale Professor of Pediatrics Stanford University Medical School Service Chief-Pulmonary, Asthma, and Sleep Medicine Unrestricted Educational Grants: Lucile Salter Packard Children ’ s Hospital Mallinckrodt An endorsement for the physician- Objectives: scientist Test the hypotheses: …. studying medicine without books Context and narrative motivate durable and reproducible knowledge; and Is like sailing an uncharted sea, but studying Discovery drives care, Care drives discovery medicine without patients is like not going to sea at all… Discuss: (i) Functions of the pulmonary circulation; Sir William Osler (ii) Increased PVR in critically ill patients; (iii) Vasodilator therapy in ARDS; Giving, helping, teaching, learning (iv) Clinical trial design. Bringing comfort to the ill Working to replace fear with hope Tomorrow might be better than today 1
3/8/2019 Gas exchange enables electron transport and energy generation •Gas Exchange Pulmonary circulation: •Blood reservoir for the left ventricle •High flow •Nutrition for the alveoli and alveolar ducts •Low resistance •Filtering particles from the mixed venous blood •Barrier function •Diffusion •Removing excess fluid from lung •Hypoxic pulmonary vasoconstriction (V:Q) In concluding…I predict Metabolic functions important new functions will be uncovered in the future…..I hope you will find them. West, Pulmonary Physiology Comroe, Circulation, 1966 O 2 sensing is intrinsic to the pulmonary V:Q Matching-Hypoxia and hypercarbia circulation-even in unique environments cause vasoconstriction PaO 2 ~25-30 torr. PVR>SVR Fluid filled lungs, rhythmic distention Pulm blood flow < 10% of biventricular output Extrapulmonary shunt- ductus arteriosus, PFO Gas exchange at the level Hypoxia, hypercarbia 100% O 2 , PaCO 2 =40 of the placenta Accurso, Resp Physiol., 1986 Staub, N.C. and Storey, W.F, JAP, 1962 2
3/8/2019 Pulmonary circulation produces vasoactive mediators. Angiogenesis drives alveolarization first At birth, NO mediates ventilation- and O 2 - induced dilation. exponentially, then linearly Pulmonary Blood Flow (ml/min) Dr. Comroe’s list of PC functions now includes production of vasoactive molecules : nitric oxide, Mean prostacyclin, Pulmonary endothelin, Artery bradykinin Pressure (ml/min) Cornfield, AJP, 1992 Herring, MJ, et al. AJP, 2014 Cells of the Alveolar Region, Diffusion Barriers Surface Areas in the Lung for Gas Exchange Type 2 epithelial cell Lamellar Body Type 1 epithelial cell Fibroblast Endothelial Cell Tennis court (one side, including doubles) surface area~130 m 2 Weibel, ER, Cell Tissue Research, 2017 Gehr, P., et al, Resp Physiol, 1978 3
3/8/2019 Diffusion Capacity Increases with Increasing When is pulmonary hypertension complicated by When is critical illness complicated by Pulmonary Blood Flow. pulmonary hypertension ? critical illness ? Adapted from Carlin et al, JAP, 1991 Simmonneau, et al., JACC, 2013 Adult Respiratory Distress Syndrome: Acute Respiratory Distress Syndrome Diagnostic Criteria: • Initial description Adult Respiratory Distress Syndrome (ARDS) • Acute Onset • Diffuse alveolar damage • Identifiable insult • Compromised gas exchange • Decrease in pulmonary compliance • Bilateral infiltrates • Increase in intrapulmonary shunting • Well preserved LV function, PCWP<18 mmHg • Impaired hypoxic pulmonary vasoconstriction • PaO 2 :FiO 2 ratio < 300, >200 = acute lung injury • Abnormal Surfactant protein function • PaO 2 :FiO 2 ratio < 200 = acute respiratory distress Ashbaugh, et al., Lancet, 1967 syndrome Negative pressure ventilation was standard, submission rejected x 4 prior to Lancet acceptance. Concerns over positive pressure effects on venous return ! Bernard et al., AJRCCM, 149, 1994 4
3/8/2019 ARDS-The Berlin Definition Many Insults Can Cause ARDS With mild, moderate, and severe ARDS: Mortality increases with 27%; 32%; and 45%; P < .001 Median duration of MV in survivors increases- 5, 7, 9 days; P < .001 JAMA. 2012;307(23):2526-2533. Matthay MA. And Zimmerman, G., AJRCCM 2005. Date of download: 5/3/2017 Clinical Course: Ori Shadmon, July Ori Shadmon, 17 y.o. with coarctation of his aorta as an infant, prior kidney transplant in 2001, a cold that turned into severe respiratory distress and failure. Multiple chest tubes (7), difficult to oxygenate and ventilate; multi-organ failure; MV included (at various times) HFOV, iNO, high PEEP (max 20 cm H 2 O), LTV, BiPAP. Walked out of hospital after 7 months. Predicted mortality risk approached 1. 5
3/8/2019 Diffuse, Severe Lung Injury: Recovering Lungs, July: Oxygenation was severely compromised during the initial month of hospitalization Acute and chronic lung injury: iNO PaO 2 :FiO 2 PaO 2 :FiO 2 HFOV RVSP = Hospital Day ~46mmHg +CVP April August 6
3/8/2019 Patients with ARDS have elevated PAP First time in a Chair, High School Prom Did pulmonary vasodilator therapy help Ori to survive and thrive? Zapol WM, Snider MT. N Engl J Med 1977;296:476-480. Patients with ARDS have endothelial injury and iNO decreased PAP, intrapulmonary shunting and improved thrombotic disease oxygenation Viral Control Pneumonia, MV x 16d Inhalational Injury, MV x 16d Endothelial Cell “Understanding…basic mechanisms…of ARDS Injury May lead to development of specific pharmacologic agents to protect the vascular endothelium…” Tomashefski, et al. Am J Pathol 1983, Rossaint R et al. N Engl J Med 1993;328:399-405. 7
3/8/2019 Acute PH worsens outcome in sepsis Outcomes in ALI are worse with pulmonary vascular dysfunction. Bull, TM, et al., AJRCCM, 2010 Vallabhajosyula, et al. Journal of Critical Care, 2019 iNO does not reduce mortality in Low tidal volume improves survival ARDS, regardless of severity Transiently improved oxygenation, associated with more renal failure What is the rationale for low tidal volume strategies? Adhikari, et al, BMJ. 2007 Apr 14; 334(7597): 779 . NEJM, 2000, 342 8
3/8/2019 High Volume But Not High Pressure Ventilation Injurious Ventilation Increases End Results in Pulmonary Edema Organ Apoptosis Might high Vt strategies obscure benefit of pulmonary vasodilator therapies? Imai Y , JAMA, 2003 Dreyfuss et al, Am Rev Respir Dis, 1998 Early pediatric trials demonstrated an acute, iNO does not improve outcome in children with ARDS but unsustained response to iNO Michael, J. et al. AJRCCM, 1998 Dobyns, E. et al. J. Peds, 1999 Consistent with subsequent adult ARDS patient trials Dobyns, J. Peds, 1999 9
3/8/2019 In children with ARDS, iNO improved outcome in iNO had a marked effect in immune compromised children with severe ARDS (OI>25) children with severe ARDS (OI>25) Dobyns, J. Peds, 1999 Dobyns, J. Peds, 1999 Combination of HFOV and iNO improves oxygenation more Multicenter RCT of iNO in Pediatric ARDS than either alone in children with ARDS • Study design by E. Dobyns, conducted 2003-2005 • 9 Centers, powered for 338 patients, 53 enrolled • Randomized to iNO or placebo, no crossover • No prescribed ventilator strategy, HFOV included • Immune compromised children excluded • Trial concluded early, industry- driven decision? Dobyns, et al, CCM, 2003 Bronicki, et al. J. Peds,166, 2015 10
3/8/2019 In infants with PPHN and parenchymal disease, In ARDS, prognosis is better in children combination of HFOV and iNO improves than adults oxygenation more than either alone Mortality Rate PaO 2 :FiO 2 <300, >200 PaO 2 :FiO 2 <200 Flori, et al, AJRCCM, 2005 Does the relatively better outcome in children result from preserved organ function or a developmental difference in lung biology ? The Physiology Matters! Open Lung Strategies Kinsella, et al., J. Peds, 1997 Systemic LPS increases lung permeability in Hypothesis: adult, but not neonatal, mouse lung Maturational-related differences intrinsic A B to the vasculature might underlie the PBS PBS 20 ** 4 LPS LPS * better outcomes in childhood ARDS (normalized to control) Lung Wet to Dry Ratio EBD Concentration 15 3 10 2 Pulmonary barrier 5 function inflammatory response is 1 developmentally regulated. 0 0 Neo Adult Neo Adult *p<0.05, **p<0.01 Do well preserved pulmonary barrier function may underlie maturational Ying, et al., AJP Lung 2018 differences in iNO response? 11
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