Disclosures: When Critical Illness is Complicated By Pulmonary - - PowerPoint PPT Presentation

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David N. Cornfield, M.D. Anne T. and Robert M. Bass Professor of Pulmonary Medicine Director-Center of Excellence in Pulmonary Biology Divisions of Pulmonary and Critical Care Medicine Professor of Pediatrics Stanford University Medical School Service Chief-Pulmonary, Asthma, and Sleep Medicine Lucile Salter Packard Children’s Hospital

When Critical Illness is Complicated By Pulmonary Hypertension: Back to the Beginning

Disclosures:

Scientific Advisory Boards:

Nima Hound Labs Tueo Inc. Molecular Stethoscope RxHale

Unrestricted Educational Grants:

Mallinckrodt

Objectives:

Test the hypotheses: Context and narrative motivate durable and reproducible knowledge; and Discovery drives care, Care drives discovery Discuss: (i) Functions of the pulmonary circulation; (ii) Increased PVR in critically ill patients; (iii) Vasodilator therapy in ARDS; (iv) Clinical trial design.

An endorsement for the physician- scientist

…. studying medicine without books Is like sailing an uncharted sea, but studying medicine without patients is like not going to sea at all… Sir William Osler

Giving, helping, teaching, learning Bringing comfort to the ill Working to replace fear with hope Tomorrow might be better than today

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Gas exchange enables electron transport and energy generation

West, Pulmonary Physiology

Pulmonary circulation:

• High flow
• Low resistance
• Barrier function
• Diffusion
• Hypoxic pulmonary

vasoconstriction (V:Q) Metabolic functions

• Gas Exchange
• Blood reservoir for the left ventricle
• Nutrition for the alveoli and alveolar ducts
• Filtering particles from the mixed venous blood
• Removing excess fluid from lung

Comroe, Circulation, 1966

In concluding…I predict important new functions will be uncovered in the future…..I hope you will find them.

V:Q Matching-Hypoxia and hypercarbia cause vasoconstriction

Hypoxia, hypercarbia 100% O2, PaCO2=40

Staub, N.C. and Storey, W.F, JAP, 1962

O2 sensing is intrinsic to the pulmonary circulation-even in unique environments

Accurso, Resp Physiol., 1986

PaO2~25-30 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

• f the placenta

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Pulmonary circulation produces vasoactive mediators. At birth, NO mediates ventilation- and O2- induced dilation.

Cornfield, AJP, 1992

Pulmonary Blood Flow (ml/min) Mean Pulmonary Artery Pressure (ml/min)

• Dr. Comroe’s list
• f PC functions

now includes production of vasoactive molecules : nitric oxide, prostacyclin, endothelin, bradykinin

Angiogenesis drives alveolarization first exponentially, then linearly

Herring, MJ, et al. AJP, 2014

Cells of the Alveolar Region, Diffusion Barriers

Weibel, ER, Cell Tissue Research, 2017

Type 2 epithelial cell Fibroblast Lamellar Body Endothelial Cell Type 1 epithelial cell

Surface Areas in the Lung for Gas Exchange

Gehr, P., et al, Resp Physiol, 1978

Tennis court (one side, including doubles) surface area~130 m2

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Adapted from Carlin et al, JAP, 1991

Diffusion Capacity Increases with Increasing Pulmonary Blood Flow.

When is pulmonary hypertension complicated by critical illness ? When is critical illness complicated by pulmonary hypertension ?

Simmonneau, et al., JACC, 2013

Adult Respiratory Distress Syndrome:

• Initial description

Adult Respiratory Distress Syndrome (ARDS)

• Diffuse alveolar damage
• Compromised gas exchange
• Decrease in pulmonary compliance
• Increase in intrapulmonary shunting
• Impaired hypoxic pulmonary vasoconstriction
• Abnormal Surfactant protein function

Ashbaugh, et al., Lancet, 1967 Negative pressure ventilation was standard, submission rejected x 4 prior to Lancet

• acceptance. Concerns over positive pressure effects on venous return !

Acute Respiratory Distress Syndrome Diagnostic Criteria:

• Acute Onset
• Identifiable insult
• Bilateral infiltrates
• Well preserved LV function, PCWP<18 mmHg
• PaO2:FiO2 ratio < 300, >200 = acute lung injury
• PaO2:FiO2 ratio < 200 = acute respiratory distress

syndrome

Bernard et al., AJRCCM, 149, 1994

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Date of download: 5/3/2017

ARDS-The Berlin Definition

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.

Many Insults Can Cause ARDS

Matthay MA. And Zimmerman, G., AJRCCM 2005.

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 H2O), LTV, BiPAP. Walked out

• f hospital after 7 months.

Predicted mortality risk approached 1.

Clinical Course:

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Diffuse, Severe Lung Injury:

Recovering Lungs, July:

Oxygenation was severely compromised during the initial month of hospitalization

iNO HFOV RVSP = ~46mmHg +CVP Hospital Day PaO2:FiO2

PaO2:FiO2

Acute and chronic lung injury:

April August

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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 elevated PAP Patients with ARDS have endothelial injury and thrombotic disease

Control Viral Pneumonia, MV x 16d Inhalational Injury, MV x 16d

Tomashefski, et al. Am J Pathol 1983,

Endothelial Cell Injury

“Understanding…basic mechanisms…of ARDS May lead to development of specific pharmacologic agents to protect the vascular endothelium…” Rossaint R et al. N Engl J Med 1993;328:399-405.

iNO decreased PAP, intrapulmonary shunting and improved

• xygenation

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Acute PH worsens outcome in sepsis

Vallabhajosyula, et al. Journal of Critical Care, 2019

Outcomes in ALI are worse with pulmonary vascular dysfunction.

Bull, TM, et al., AJRCCM, 2010

iNO does not reduce mortality in ARDS, regardless of severity

Adhikari, et al, BMJ. 2007 Apr 14; 334(7597): 779.

Transiently improved oxygenation, associated with more renal failure

Low tidal volume improves survival

What is the rationale for low tidal volume strategies?

NEJM, 2000, 342

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Dreyfuss et al, Am Rev Respir Dis, 1998

High Volume But Not High Pressure Ventilation Results in Pulmonary Edema

Injurious Ventilation Increases End Organ Apoptosis

Imai Y , JAMA, 2003

Might high Vt strategies obscure benefit of pulmonary vasodilator therapies?

Early pediatric trials demonstrated an acute, but unsustained response to iNO

Dobyns, E. et al. J. Peds, 1999 Michael, J. et al. AJRCCM, 1998

Consistent with subsequent adult ARDS patient trials iNO does not improve outcome in children with ARDS

Dobyns, J. Peds, 1999

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Dobyns, J. Peds, 1999

In children with ARDS, iNO improved outcome in children with severe ARDS (OI>25) iNO had a marked effect in immune compromised children with severe ARDS (OI>25)

Dobyns, J. Peds, 1999

Multicenter RCT of iNO in Pediatric 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?

Bronicki, et al. J. Peds,166, 2015

Combination of HFOV and iNO improves oxygenation more than either alone in children with ARDS

Dobyns, et al, CCM, 2003

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In infants with PPHN and parenchymal disease, combination of HFOV and iNO improves

• xygenation more than either alone

Kinsella, et al., J. Peds, 1997

The Physiology Matters! Open Lung Strategies

In ARDS, prognosis is better in children than adults

Flori, et al, AJRCCM, 2005

Does the relatively better outcome in children result from preserved organ function or a developmental difference in lung biology ?

Mortality Rate

PaO2:FiO2 <300, >200 PaO2:FiO2 <200

Pulmonary barrier function inflammatory response is developmentally regulated.

Hypothesis:

Maturational-related differences intrinsic to the vasculature might underlie the better outcomes in childhood ARDS Do well preserved pulmonary barrier function may underlie maturational differences in iNO response?

EBD Concentration (normalized to control)

A

1 2 3

*

15 10 5 Lung Wet to Dry Ratio

B

Neo Adult

**

20 4

Neo Adult

PBS LPS PBS LPS

Ying, et al., AJP Lung 2018

Systemic LPS increases lung permeability in adult, but not neonatal, mouse lung

*p<0.05, **p<0.01

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Normalized Resistance

Adult Neonate

2 4 6 8 10 12 14 16 18 20 22 24 1.5 1.0 0.5 Time (hours) 2 4 6 8 10 12 14 16 18 20 22 24

A B

****

PBS LPS

2 4 6 8 10 12 14 16 18 20 22 24 1.5 1.0 0.5 Time (hours) 2 4 6 8 10 12 14 16 18 20 22 24

PBS LPS Normalized Resistance

** * * *

LPS induces a greater disruption of barrier function in adult as compared to neonatal PEC.

*p<0.05, **p<0.01, ****p<0.001 Ying, et al., AJP Lung 2018 Schmidt, et al, AJP Lung, 2013

Conditional endothelial FAK deletion disrupts lung vascular barrier function by Destabilizing RhoA and Rac1 activities LPS increases focal adhesion kinase-1 (FAK1) expression in neonatal PEC, but decreases FAK-1 expression in adult PEC.

Neonate PBS LPS 1h LPS 2h LPS 4h LPS 6h LPS 24h Adult b-actin > FAK >

Neo Adult 3 2 1 5 100µm 4

C A B

Relative FAK RNA Expression (normalize to Neo PBS) 6 2

**** **

4

Neo Adult **** ** Neo Adult

PBS LPS PBS LPS

**** ** Relative FAK Expression (normalized to b-actin)

#### ####

****p<0.0001 neo LPS vs neo PBS, and **p<0.01 adult LPS vs adult PBS, and ++++ p<0.001 adult LPS vs. neo LPS

Conclusion- In critical illness:

Physiology Matters- parenchyma & vascular interactions Low Vt, Open lung, Avoid Atelectasis; Context and narrative motivate knowledge creation- Clinical trials are limited by design and execution; and Discovery drives care, Care drives discovery- Developmental differences in PAEC response to inflammation Children with ARDS may benefit from selective pulmonary vasodilator therapy- a definitive trial is long overdue

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Acknowledgements Lihua Ying, Ph.D. Saidie Rodriguez, M.D. Elizabeth A Barnes, Ph.D Judith Ingles, PhD. Reiji Ito, MD, PhD Xibing Che, PhD Cristina M Alvira, MD Steve Quake, PhD

3 ml / kg PEEP = 10 12 ml / kg PEEP = 5 12 ml / kg PEEP = 10 6 ml / kg PEEP = 10

Frank JA et al, Am J Respir Crit Care Med, 2002

Injured Lungs are More Sensitive to the High Tidal Volume Ventilation Injured Lungs are More Sensitive to the Development of VILI

Frank JA et al, Am J Respir Crit Care Med, 2002

PBS LPS 2h LPS 4h LPS 6h LPS 24h Adult Neonate

A B

100µm % of cell gap /cell 6 4 2 8

*** % of cell gap /cell 6 4 2 8 ** % of cell gap /cell 6 4 2 8 ** % of cell gap /cell 6 4 2 8

C D E F G H I

Neo LPS Adult LPS Neo LPS Adult LPS Neo LPS Adult LPS Neo LPS Adult LPS

LPS induces a greater disruption of intercellular junction assembly in adult as compared to neonatal PEC.

**p=0.002 via Mann-Whitney; (H) ***p=0.001 via unpaired t-test; and (I) **p=0.0037.

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With LPS treatment, FAK1 Inhibition disrupts barrier function in neonatal PEC, and overexpression of FAK1 enhances barrier function in adult PEC. FAK response to inflammation in Neonatal PEC may possess important implication for ALI in adults.

Narrative of disease: ARDS

Osler-uncontrolled septicemia leads to frothy pulmonary edema, not CHF Consensus definition

Past Future ?

Laennec- idiopathic lung anasarca; pulmonary edema without heart failure "A Treatise on Diseases of the Chest"

1821 1925

Ashbaugh, et al., Modern description, Lancet

1967 1994 1946

Brewer- The wet lung in war casualties. Ann Surg

Disease definition evolves over time-narrative is important

Berlin Criteria, JAMA

2012

Ware LB, Matthay MA. N Engl J Med 2000;342:1334-1349.

Acute Phase and Late Phase Findings in ARDS

Acute Late

Day 2 Day 14 Day 4 Day 14

PMN PAEC Type 2 Cell Type 1 Cell PMN, RBC Collagen control 5 min 20 min

Ventilation with High Tidal Volumes is Sufficient to Produce Pulmonary Edema

Dreyfuss and Saumon, AJRCCM, 1998

• Rat lungs after

MV at a PIP of 45 cm H20

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Ventilation with High Pressure, Volume is Sufficient to Produce Pulmonary Edema

Ventilation with PIP of 45 cm H20

Dreyfuss and Saumon, AJRCCM, 1998

5 min 20 min

Alveolar Epithelial Cells Secrete IL-8 in Response to Stretch

30% stretch 20% stretch Vlahakis et al, Am J Physiol 1999

Mechanical Ventilation Induces Expression of Neutrophil Chemokines in the Lung

Belperio et al, JCI, 2002 Matthay, M., et al., JCI 122, 2012.

ARDS: PAEC V-E cadherin disruption