Transcript Clinical Classification of Pulmonary Hypertension

Portopulmonary Hypertension
(PAH in the setting of liver disease)
George T. Kondos, MD
Associate Professor of Medicine
Department of Medicine
Section of Cardiology
Classification of Pulmonary Hypertension
• 1975 WHO Classification
– Primary pulmonary hypertension (PPH)
• Diagnosis of exclusion
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Secondary pulmonary hypertension
• Presence of identifiable risk factors
• 1998 Evian Classification
– Clinical classification system
– Different categories sharing similarities in pathophysiological
mechanisms, clinical presentations, therapeutic options
• 2003 Revised Clinical Classification of Pulmonary Hypertension
• Other classification systems
– Pathological
– Functional based on the severity of symptoms
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Clinical Classification of Pulmonary Hypertension
Evian 1998
Venice 2003
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Evolution of PAH Classification from
1998-2003
• The need for a genetic classification system
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BMPR2 (50% of cases of FPAH)
<70 mutations
Discontinuing the term PPH
Reclassification of PVOD and PCH
Update on new RFs for PAH
Reassessment of the classification of congenital
systemic-to-pulmonary shunts
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Risk Factors Associated with PAH
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Associate Liver and Lung Disease
Advanced Liver Disease/Dysfunction
Hepatopulmonary syndrome
Portopulmonary Hypertension
Pulmonary vascular dilatation
Pulmonary vasoconstrictive and proliferative
Severe arterial hypoxemia
Leading to pulmonary hypertension
May totally resolve after Tx
Right heart failure
Frequently not reversible by liver Tx
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Hepatopulmonary Syndrome
8 µm
100 µm
Liver disease
Hypoxemia (A-a >20mmHg or PAO2< 70mmHG
Intrapulmonary vascular dilatations (dilated capillaries)
Diffusion-perfusion impairment
Anatomic R->L shunt
Admin of 02 - partial improvement
Admin 02 in pure R->L - no improvement
Admin 02 in pure diffusion - may normalize PO2 at rest
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Differential Diagnosis of Hypoxemia
• Normal A-a 02 gradient
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Hypoventilation
Inhalation of gas with
decreased FIO2
• Elevated A-a 02 gradient
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Ventilation-perfusion
mismatch
Anatomic R->L shunt
Diffusion impairment
Diffusion perfusion
impairment
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Hepatopulmonary Syndrome
• Worsened by
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Inc. C.O. in chronic liver disease
Inc. pulmonary capillary dilatations
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Orthodeoxia (dec in P02 4mmHg, or dec in P02 5%)
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Contrast-enhanced echocardiography
Tc 99m pyrophosphate lung scan with detection over brain or
abdominal organs
ABG after breathing 100% 02 (shunt study)
• Associated clinically with
• Diagnostic studies
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• Treatment
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Liver Tx if PaO2 50-60 mmHg
Individualize Rx if PaO2 <50mmHg
Garlic, Nitric Oxide, portosystemic shuynts, intrapulmonary
embolization
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Portopulmonary Hypertension
(The Challenge)
• Difficult to make precise comparative
evaluations between Tx candidates
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Limited amount accurate data available
Conclusions often conflicting
Failure of development of evidenced based
strategies
• Different pathological presentations
• Various comorbidities
• Lack of complete hemodynamic and
echocardiographic data
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Portopulmonary Hypertension
• Definition
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Presence of portal hyhpertension (ascites, varices,
splenomegaly)
Resting mPAP >25mmHg
Exercise mPAP>30mmHg
PCWP <15mmHG
>240 dynes.s.cm-5
• Incidence
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2-20% of cirrhotic patients
Prevalence may be greater (pts asymptomatic early
in the disease)
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Survival in PAH
(Krowka, Clin Chest Med 2005)
Multicenter study: 10 OLT transplant centers
Despite strong slection criteria 36% in-hospital mortality
- 13 deaths due to right heart failure
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Survival in IPAH
(McGlaughlin, Chest 2004)
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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Portopulmonary Hypertension
Pathology
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Portopulmonary Hypertension
(Clinical Presentation)
• Subtle
• Exertional dyspnia (most common,
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nonspecific)
Fatigue
Leg edema
Chest pain or pressure
syncope
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Portopulmonary Hypertension
(Physical Examination)
• Carotid - decreased volume
• JVP - elevated, a >> v, possible a<v if TR
is present +/- HJR if JVP normal
• Chest - unremarkable
• CVS - +RVI, S1 nl, S2 increased murmur
of TR common, PI uncommon
• Extremities - edema
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Risks of Liver Tx in Portopulmonary HTN
• High risk surgery
• 43 pts with portopulmonary HTN 35%
perioperative mortality (Krowka, Liver Transpl 2004)
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Right heart failure
Cardiopulmonary collapse
Intrapoperative death 5 pts
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Portopulmonary HTN
(Screening)
• CxR and EKG insufficient
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Enlarged pulmonary arteries, cardiomegaly
pulmonary hemodynamics are markdely abnormal
RAD, RBBB, Twv inversions in the precordial leads late findings
• Transthoracic doppler does not differentiate
causes of elevated PAP
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Hyperdynamic circulatory state
Increased central volume
Pulmonary vasculopathy of portopulmonary HTN
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Inc. Rvsys (30-50mmHg) no elevated PVR via RHC
• RHC mandatory for definitive diagnosis
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Reliability of TTD in Detecting and
Quantifying PAH
• TR jets analyzable in 39-86% of pts
• 10 studies have reported correlation coefficients
between RVSP estimated from TR jets and RHC
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1 study - 51 pts poor correlation (r=0.31)
9 studies - >500 pts, significant correlations (0.83,
0.57, 0.95, 0.78, 0.85, 0.76, 0.93, 0.90, 0.89)
• Sensitivity and specificity estimating sPAP
ranges: 0.79-1 and 0.6-0.98
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Differential Diagnosis of RHC Findings
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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PVR in Portopulmonary HTN
• Debate regarding PVR >120, or > 240
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dynes.s.cm-5
Subgroup of Liver Dx pts with
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PVR between 120-240 dynes.s.cm-5 and inc. PCWP
Pts have increased TPG (mPAP-PCWP) >15mmHg
Consider as having mild portopulmonary HTN
Follow very carefully - natural history unclear
Report CO and PVR as indices
Administration of 1L NS over 10 minutes to identify
individuals susceptible of liver ventricular failure
during liver allograft reperfusion
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Screening Algorithm for Portopulmonary HTN
Transthoracic Doppler
Echo
Rvsys >50mmHG and/or
Abn RV size/function
Observe; repeat echo
12 months if Liver Tx
candidate
Right Heart Cath
for hemodynamic data
Measure
RA
mPAP
PCWP
CO
PVR
Characterize Pulmonary
Hemodynamics
mPAP >25 mmHg
and PVR >240 dynes.s.cm5
Portopulmonary
HTN diagnosis established
mPAP >25 mmHg
And PVR<240 dynes.s.cm5
Probable high
flow state
mPAP <25mmHg
Other Patterns
Portopulmonary HTN
Does not exist
Institute Treatment
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QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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Acute Vasodilator Testing
• IV epoprostenol
• Inhaled NO
• IV adenosine
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Acute Vasodilator Testing
• Continue until one of the following criteria is met
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Drop in SBP by 30% or >, or < 85mmHg
Increased in HR by 40% or >100 bpm
Intolerable side effects: HA, nausea, lightheadedness
Target response achieved
Maximum dose of vasodilator
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Decrease of mPAP at least 10mmHG AND mPAP decreasing to
40mmHG or less AND normal or high CO
ALL THREE CRITERIA NEED TO BE SATISFIED
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Validation of abn PCWP
Evaluation of LV diastolic dysfunction
Syspected left-sided valvular dz (aortic, mitral)
Suspected CAD
• Responsiveness
• When should left heart catheterization be done?
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Medical Treatment for Portopulmonary HTN
• Prostacycline - (Epoprostenol) - IV, inhaled
• Prostacycline Analogs
– Treprostinil (SQ)
– Iloprost (inhaled)
– Beraprost
• Inhaled Nitric Oxide
• Phosphodiesterase inhibitors
– Sildenafil
• Endothelian Receptor Antagonists (ET1 potent vasoconstrictor)
– Bosentan (ET-A&B)
– Sitaxsentan (ET-A)
– Ambrisentan (ET-A)
• L-arginine
• Combination therapy
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Prostacycline
• Potent vasodilator produced in endothelial and
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smooth-muscle cells
Antiproliferative and antiplatelet effects
Improvement in survival well documented
compared to historical controls
Efficacy in Rx of portopulmonary HTN
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Therapeutic bridge to liver Tx
• Central venous catheter administration
• Side-effects: flushing, HA, jaw pain, leg pain,
diarrhea, nausea
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Inhaled NO
• Endogenous endothelium derived
vasodilator
• Directly relaxes vascular smooth muscle
by inc. cGMP
• Variable response in pts with liver dz
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Inc. levels of endogenous NO in liver dz
• Utility in predicting acute hemodynamic
responsiveness
• Continuous inhalation device
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Phosphodiesterasse Inhibitors
• Improve pulmonary hemodynamics by
enhancing endogenous NO effects by
inhibiting the breakdown of cGMP
• Sildenafil: PDE type-5 inhibitor
• Dosage adjustments necessary in
cirrhotics because of extensive hepatic
metabolism
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Entothelin Receptor Antagonists
• Increased conc of ET-1 found in the
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plasma and lung tissue of pts with PAH
Bosentan competitive inhibitor of ET A and
B receptors
Sitaxsentan selective ET-A
Ambrisentan selective ET-A
Limited use: hepatotoxicity
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L-arginine
• Endothelial derived
vasodilation predominates
over direct smooth muscle cell
constriction
• EDRF produced by intact
endothelium
• EDRF mediates Ach
vasodilation
• EDRF is the NO radical
derived from L-arginine
Vasodilator Agonists:
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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PAH out of proportion of Left Heart
Disease
• Definition:
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Severely elevated PAP >35-40mmHG
PCWP or LVEDP <22 mmHG and
TPG >18-20
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Main concern in treating with pts with elevated
LVEDP/CPWP with pulmonary vasodilators is an inc.
in CO and venous return to the LV -> pulmonary
edema
Few studies looking and pulmonary vasodilators in
DD
Optimize diuretics, nitrates, HR control
DO NOT use pulmonary vasodilators if PCWP or
LVEDP >16mmHG
• Treatment
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Postoperative Acute Right Heart Failure
• Inc CO seen in 5-18% after reperfusion of the
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new graft
If there is resistance of PBF then pressure must
increase
This leads to systemic increases in PAPs
Leading to acute right ventricular failure
Increase in CO is unpredicatable therefore
reduce mPAP to a MILD level
Mechanism:
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Removal of the obstruction to portal flow, systemic
vasodilation via washout of acid metabolites and
other vasodilator substances from the new graft
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Portopulmonary Hypertension
(Summary)
• Classification
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mPAP 25-30 MILD
mPAP >35-40 MODERATE
MPAP >45 SEVERE
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Determine cause
• PVR >240 dynes.sec.cm-5 (>120)
• Management mPAP >35
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• Volume overload -> Rx (effective with normal LV function) -> Tx
• Poor cardiac function and elevated filling pressures -> ionotropic
agents if no improvement -> no Tx
• PVR low, LV function hyperdynamic -> Tx
If mPAP and PVR remain elevated - survial depends on RV
function and the stressors applied during the perioperative
period
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Pretransplantation issues with
Portopulmonary Hypertension
• Does the degree of PAH warrant therapy before OLT is
attempted?
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mPAP <35 mmHG
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No studies address which agent is efficacious and safe
IV epoprostenol (concerns with thrombycytopenia and
splenomegaly), other prostacyclin analogues, silfandil
MD experience, drug availability and safety concerns
• What therapy should be selected?
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• What pulmonary hemodynamic goals will facilitate a safe
OLT
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mPAP 35-50 with PVR 240-400, 50% perioperative mortality
mPAP >50 exclude OLT at most centers
Repeat doppler echos annually
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High Risk Pulmonary Hemodynamic
Profile
Krowka, Liver Tranplantation2000
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Mayo Clinic Intra-op Guidelines
(Guidelines for Canceling Surgery)
Krowka, Liver Tranplantation2000
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