Acute Pulmonary Hypertension

and the Right Ventricle

24th Postgraduate Refresher Course

Brussels, December 5, 2018

Acute right heart failure

▪ Clinical presentation: systemic hypoperfusion (pale and clammy skin, confusion, chest pain, arrythmia, ileus, oliguria, lactic acidosis) and systemic congestion (turgescent jugular veins, hepatomegaly, edema, ascites)

▪ Right atrial pressure > left atrial pressure

▪ Echocardiography: dilated right heart chambers and septal shift, increased velocity of tricuspid regurgitation, shortened acceleration time of PA flow waves, with eventually pericardial effusion

CVP 15 mmHg, clinical right heart failure

Causes of the ARHF

- Cardiac surgery: transplantation, congenital, mitral valve, left ventricular assist, cardiopulmonary bypass, protamine, postoperative pulmonary hypertension crisis

- ARDS

- Acute-on-chronic respiratory insufficiency

- High volume/pressure mechanical ventilation

- Pulmonary embolism

- End-stage pulmonary arterial hypertension (idiopathic, cardiac shunts, scleroderma, HIV, liver disease)

- ARHF is associated with a poor prognosis

ARHF

The cause of ARHF is (almost) always an

increase in pulmonary artery pressure

ARHF is a right ventricular failure on an

abnormal increase in afterload

Male, 25 yrs

mPAP = 56 mmHg

Female, 24 yrs

mPAP = 53 mmHg

SV = 90 ml SV = 30 ml

Right ventricular responses to load :

2 different patterns

V Noordegraaf, VUMC

The laws of the heart

• Starling’s law: the heart adapts to increased

afterload (maintained SV) or preload

(increased SV) through increased

dimensions (heterometric adaptation)

• Anrep’s law: the heart adapts to increased

loading through an increased contractility

(homeometric adaptation)

Starling: for beat-to-beat changes or homeometric

failure in case of too rapid increase in PAP – or

endstage PH

Preseved RV-arterial

coupling by increased

homeometric

adaptation (Anrep)

Failing RV-arterial

coupling with

heterometric adaptation

(Starling)

RV failure in PH

V Noordegraaf, VUMC

The Right Ventricle and its Load in Pulmonary

Hypertension Vonk Noordegraaf, Westerhof BE,

Westerhof N. JACC 2017; 69: 236-241

From increased contractility and preserved RV-PA coupling to increased

dimensions and negative ventricular interaction

Coupling RV function to the pulmonary circulation

Volume

Pre

ssu

re

Isometric

Contraction

Ejection

Isometric

Relaxation

Diastolic filling End-diastole

End-systole Pulmonary Valve

Opening

Tricuspid

Valve

Opening

Ees = ESP/ESV

Ea = ESP/SV

After M Pinsky, without

permission

The PV loop allows for the definition of

systolic function and afterload, and thus

of RV-arterial coupling

Systolic function: end-systolic elastance Ees = ESP/ESV

Afterload: arterial elastance Ea = ESP/SV

Optimal RV-arterial coupling: Ees/Ea ratio of 1.5-2

Sagawa et al. Cardiac contraction and the PV relationship,

Oxford University Press, 1988.

The importance of systolic function adaptation to afterload

From M Overbeek

Optimal RV-

arterial

coupling:

Ees/Ea = 1.5-2

RV-arterial coupling in PAH: increased Ees,

decreased Ees/Ea – EDV may be maintained

Ea

Ea

180

150

120

90

60

30

20 40 60 80 100

Volume (ml)

Pre

ssu

re (

mm

Hg

)

Pmax

PmaxEes

Ees

Control:

Ees/Ea = 2

PAH

Ees/Ea = 1

Cardiac phase

60

40

20

100

50

0

1 5 10 15 20 25RV

pre

ssu

re (

mm

Hg

)R

V v

olu

me (

ml)

Kuehne et al. Circulation 2004; 110:2010-6

PV loops in PH: clinical studies

Diagnosis n Ees Ea Ees/Ea

IPAH 42 ↑ ↑ - or ↓, ex ↓

CCTGA 1 ↑ ↑ ↓

SSc-PAH 22 - ↑ - or ↓, ex ↓

CTEPH 13 ↑ ↑ - , ex ↓

1. Kuehne Circulation 2004;110:2010, 2. Wauthy Cardiol Young 2005;15:647,

3. Tedford Circ Heart Fail 2013, 4. McCabe J Appl Physiol 2014; 116: 355-63,

5. Spruijt AJRCCM 2015; 191: 1050-7 , 6. Hsu et al Circulation 2016; 133:

2413-22; Naeije et al Heart Fail Clin 2018; 14: 237-245

Pattern: Increased Ea (PVR), increased Ees, Ees/Ea maintained or

decreased, Ees/Ea decreased during exercise (5,6), EDV increases when

Ees/Ea decreases during exercise (6) - Ees and Ea measured by single

beat or family of PV loops ar decreasing venous return

RV-arterial coupling in experimental PHNaeije et al, Pulm Circ 2014; 4:395-406

Model Animal Ees Ea Ees/Ea EDV

Hypoxia Dog,goat,pig ↑ ↑ - -

Monocrotaline Rat ↑ ↑ ↓ ↑

Sepsis, early Pig ↑ ↑ - -

Sepsis, late Pig - ↑ ↓ ↑

Embolism Dog,goat,pig ↑ ↑ - -

PA banding Dog,goat,pig ↑ ↑ - -

AP shunting 3 mo Pig ↑ ↑ - -

AP shunting 6 mo Pig ↓ ↑ ↓ ↑

RVF on PH crisis Dog,pig ↓ ↑ ↓

↑

Chronic heart failure Dog - ↑ ↓ ↑Brimioulle AJP 2003;284:H1625, Wauthy 2004;286:H1441, Fesler AJP 2006;101:1085,

Rex ICM 2008;34:179, de Man Circ HeartFail 2012;5:97, Lambermont Cardiovasc Res

2003;59:412, de Vroomen AJP2000;278:H100, Leeuwenburgh AJP 2001;281:H2697,

Faber AJP 2006;291:H1580, Kerbaul CCM 2004;32:2814, Rondelet Circulation

2003;107:1329, Rondelet Eur Heart J 2012;33:1017, Pagnamenta JAP 2010;109:1080

RV-arterial coupling in experimental PH

• Contractility is almost always increased to

preserve RV-arterial coupling

• Insufficient increase in Ees in septic or

inflammatory models of PH (monocrotaline),

PH crisis, prolonged aorta-pulmonary

shunting or left heart failure

- Results in increased RV volumes

Pharmacological interventions Naeije et al, Pulm Circ 2014; 4:395-406

Model Drug Ees Ea Ees/Ea

Hypoxia Dobutamine ↑ - ↑

Norepinephrine ↑ - ↑

Sildenafil - ↓ ↑

Isoflurane ↓ ↑ ↓ ↓

Desflurane ↓ ↑ ↓ ↓

Propranolol ↓ ↑ ↓ ↓

RVF on PAB Levosimendan ↑ ↓ ↑ ↑

Dobutamine ↑ - ↑

CHF Milrinone ↑ - ↑

Nitroprusside - - -

Brimioulle AJP 2003;284:H1625, Fesler AJP 2006;101:1085, Rex ICM 2008;34:179,, Kerbaul

CCM 2004;32:2814, Pagnamenta JAP 2010;109:1080, Kerbaul Anesthesiology 2004;101:1357-

1361

Effects of inhaled iloprost on RV contractility,RV-

vascular coupling and ventricular interdependence in

an experimental model of acute pulmonary

hypertension Rex et al, Crit Care 2008, 12:R113

26 pigs, hypoxic pulmonary hypertension, 5 µg inhaled iloprost

Emax/Ea ratio stable at 1

Pharmacological interventions

• Low-dose dobutamine and norepinephrine are

inotropes with no effect on the pulmonary circulation

• Inhaled anesthetics deteriorate RV-arterial coupling

by a combination of negative inotropy and increased

PVR

• Levosimendan improves RV-arterial coupling by a

combination of positive inotropy and pulmonary

vasodilation

Pathophysiology of RV failure in PH

Pulmonary hypertension Increased afterload

Increased contractlity Homeometric adaptation (Anrep) to preserve

RV-arterial coupling

Increased EDV Heterometric adaptation (Starling) to preserve flow output, causes altered ventricular interaction

Pathophysiology of RV failure in PH

Pulmonary hypertension Increased afterload: targeted therapies: iNO, epoprostenol, ERA’s, PDE5i’s, blood gases, lung volumes

Increased contractlity Homeometric adaptation (Anrep) to preserve RV-

arterial coupling: dobutamine,

norepinephrine, levosimendan (?)

Increased EDV Heterometric adaptation (Starling) to preserve flow output diuretics

PAP 62 mmHg

RAP 18 mmHg

PAWP 24 mmHg

CI 1.6 L/min/m2

Case report

Patient admitted for

decompensated

IPAH

Echo: RHF, LVEF

normal

Before diuretics, PAWP 24 mmHg After diuretics, PAWP 13 mmHg

Treatment with iv dobutamine and furosemide

What happened?

• Diastolic left ventricular failure caused by leftward

bowing of the septum during diastole, decreased LV

chamber size, compliance and contractility

• This is called a « reverse Bernheim effect » after the

report by Bernheim et al in 1910 of RV failure in a

patient with aortic stenosis

Bernheim P De l’asystolie veineuse dans l’hypertrophie

du cœur gauche par sténose concomitante du

ventricule droit Rev Med 1910;39:785-801

Diastolic interaction: increased EDV decreases the

other ventricle’s compliance

Naeije & Badagliacca Cardiovasc Res 2017; 113: 1474-1485

LV0

0

RV0

Normal

LHF

RHF

Ventricular interdependence

Right and left ventricles have the

septum and free wall

myocardial fibers in common,

and are constrained within a

non-distensible pericardial

envelope

There is thus ventricular

interdependence, defined as

the forces that are transmitted

from one ventricle to the

other ventricle through the

myocardium and pericardiumSantamore and Dell’Italia, Progr Cardiovasc Dis 1998;40:289

Naeije and Badagliacca, Cardiovasc Res 2017; ; 113: 1474-1485 ,

Friedberg and Redington Circulation 2014;129:1033-1044

Systolic interaction; RV pressure–segment length and pressure-diameter loops during severe pulmonary artery

(PAC) and aortic constriction (AOC)

Belenkie I et al. Circulation 1995;92:546-554

Copyright © American Heart Association

Comparative significance in systolic

ventricular interaction Yamaguchi et al

Cardiovasc Res 1991 ; 25 : 774-783

Systolic ventricular interdependence was quantified by

measurements of instantaneous cross-talk gains during

ventricular pressure changes caused by sudden release of

aortic or pulmonary arterial constriction

20-40 % of RV systolic pressure results from LV

contraction 4-10 % of LV systolic pressure results from

RV contraction

Naeije R, Badagliacca R. The overloaded RV and

ventricular interdependence. Cardiovasc Res 2017; 113:

1474-1485

Pathophysiologic rationale of treatment of

of (after)load-induced RV failure

Pulmonary hypertension

Increased contractlity

Increased EDV diastolic interaction stroke volume

systolic interaction hypotension

ischemia

Treatment of afterload-induced RV failure

Pulmonary hypertension

Increased contractlity

Increased EDV diastolic interaction stroke volume

systolic interaction hypotension

ischemia

Thrombolytic therapy, iNO, iILO,

- PDE5i, ERA, PGI2, FRC, pH,

hypoxemia

Dobutamine, norepinephrine,

levosimendan

Treatment of afterload-induced RV failure

Pulmonary hypertension

Increased contractlity

Increased EDV diastolic interaction stroke volume

systolic interaction hypotension

ischemia

Thrombolytic therapy, iNO, iILO,

- PDE5i, ERA, PGI2, FRC, pH,

hypoxemia

Dobutamine, norepinephrine,

levosimendan

Diuretics

Treatment of afterload-induced RV failure

Pulmonary hypertension

Increased contractlity

Increased EDV diastolic interaction stroke volume

systolic interaction hypotension

ischemia

Thrombolytic therapy, iNO, iILO,

- PDE5i, ERA, PGI2, FRC, pH,

hypoxemia

Dobutamine, norepinephrine,

levosimendan

Norepinephrine

Diuretics

Conclusions

• As there is currently no evidence from randomized

controlled trials, treatment of RV failure in the ICU has

to rely on sound pathophysiological principles

• Interventions include targeted therapies, and

normalisation of blood gases and FRC to decrease

afterload, inotropic drugs to improve systolic function,

correction of hypotension (systolic interaction) and

optimization of RV filling (diastolic interaction)

« La maladie n’est

qu’une altération

de la faculté

physiologique »

C Bernard 1813-1878