Hepatopulmonary Vascular Disorders Nawaid Shakir, MD North Shore University Hospital December 13, 2006.

Hepatopulmonary Vascular Hepatopulmonary Vascular DisordersDisorders

Nawaid Shakir, MDNawaid Shakir, MD

North Shore University North Shore University HospitalHospital

December 13, 2006December 13, 2006

Case of Ms. AM: 54 y/o female Case of Ms. AM: 54 y/o female with worsening dyspnea on with worsening dyspnea on

exertion, platypnea, and fatigueexertion, platypnea, and fatigue Past medical history includes Hepatitis C Past medical history includes Hepatitis C

cirrhosis diagnosed 4 years agocirrhosis diagnosed 4 years ago Physical exam was significant for Physical exam was significant for

tachypnea, clubbing, a spider nevi on the tachypnea, clubbing, a spider nevi on the thorax, and splenomegalythorax, and splenomegaly

Arterial blood gas revealed hypoxemia with Arterial blood gas revealed hypoxemia with a PaOa PaO22 of 43 mmHg and patient was placed of 43 mmHg and patient was placed on 100% oxygenon 100% oxygen

CXR was normal and CT Angiogram CXR was normal and CT Angiogram revealed possible dilated peripheral revealed possible dilated peripheral pulmonary vessels but no pulmonary pulmonary vessels but no pulmonary embolusembolus

Liver-Related Causes of Dyspnea in Liver-Related Causes of Dyspnea in a Patient with Chronic Liver Diseasea Patient with Chronic Liver DiseasePulmonary - ParenchymalPulmonary - Parenchymal AlveolarAlveolar

– Aspiration pneumoniaAspiration pneumonia– Basal atelectasisBasal atelectasis

Interstitial lung diseaseInterstitial lung disease– Lymphocytic interstitial Lymphocytic interstitial

pneumoniapneumonia– Fibrosing alveolitisFibrosing alveolitis– BOOPBOOP– Noncardiogenic pulmonary Noncardiogenic pulmonary

edemaedema VascularVascular

– Pulmonary hemorrhagePulmonary hemorrhage– HPSHPS– PPHTNPPHTN

ExtraparenchymalExtraparenchymal– Pleural effusionsPleural effusions– Restriction from tense Restriction from tense

ascitesascites

ExtrapulmonaryExtrapulmonary– Cirrhotic cardiomyopathyCirrhotic cardiomyopathy– Cirrhotic myopathyCirrhotic myopathy– Chronotropic dysfunctionChronotropic dysfunction– Muscle wastingMuscle wasting– Deconditioning from Deconditioning from

impaired mobilityimpaired mobility

Circulatory Changes in Circulatory Changes in Patients with CirrhosisPatients with Cirrhosis

Systemic circulationSystemic circulation Plasma volume Plasma volume Total blood volume Total blood volume Central/arterial volume Central/arterial volume (()) Cardiac output (Cardiac output () ) Blood pressure Blood pressure Heart rate Heart rate SVR SVR Pulmonary circulationPulmonary circulation Pulmonary blood flow Pulmonary blood flow PVR PVR (())Renal circulationRenal circulation Renal blood flow Renal blood flow Renal vascular resistance Renal vascular resistance

HeartHeart LA volume LA volume LV volume (LV volume ()) RA volume RA volume RV volume RV volume RA pressure RA pressure RVEDP RVEDP PA pressure PA pressure PCWP PCWP LVEDP LVEDP Cerebral circulationCerebral circulation Cerebral blood flow Cerebral blood flow

Liver Lung InteractionLiver Lung Interaction

Liver Failure

Acute Liver Failure Chronic Liver Failure

ARDS

Vasodilatation Vasoconstriction

HPS Portopulm HTN

Hepatopulmonary Hepatopulmonary SyndromeSyndrome

Triad of liver disease, hypoxemia, and Triad of liver disease, hypoxemia, and pulmonary vascular dilatationspulmonary vascular dilatations

Hypoxemia caused by hepatopulmonary Hypoxemia caused by hepatopulmonary syndrome ranges from 5 to 20%syndrome ranges from 5 to 20%

Most commonly associated with Most commonly associated with cirrhosis but also reported in cirrhosis but also reported in noncirrhotic portal hypertensionnoncirrhotic portal hypertension

No consistent relationship between No consistent relationship between hepatic dysfunction and Child-Pugh hepatic dysfunction and Child-Pugh classification with severity of classification with severity of hypoxemia or shunthypoxemia or shunt

Clinical Clinical ManifestationsManifestations

DyspneaDyspnea PlatypneaPlatypnea OrthodeoxiaOrthodeoxia ClubbingClubbing Liver dysfunctionLiver dysfunction Spider neviSpider nevi Elevated Cardiac Elevated Cardiac

OutputOutput Decreased SVR and Decreased SVR and

PVRPVR Narrowed A-V ONarrowed A-V O22

differencedifference

PathogenesisPathogenesis

V/Q mismatchV/Q mismatch Intrapulmonary shuntingIntrapulmonary shunting Limitation of oxygen Limitation of oxygen

diffusiondiffusion Failure to clear and Failure to clear and

production of circulating production of circulating vasodilators by damaged vasodilators by damaged liverliver

Inhibition of Inhibition of vasoconstrictive substance vasoconstrictive substance by damaged liverby damaged liver

Pathogenesis of HPSPathogenesis of HPS

Increased exhaled NO levels in HPS Increased exhaled NO levels in HPS as compared to normoxemic as compared to normoxemic cirrhotics and healthy controls and cirrhotics and healthy controls and normalize after OLTnormalize after OLT

Increased NO synthase level Increased NO synthase level following CBD ligation in ratsfollowing CBD ligation in rats

Cremona G et al. Eur Respir J 1995;8:1883-1885

Chang SW et al. Am Rev Respir Dis 1992;148:798-805

Hypothesis of Pulmonary Vessel Dilatation in Hypothesis of Pulmonary Vessel Dilatation in Hepatopulmonary SyndromeHepatopulmonary Syndrome

Pathophysiology of Pathophysiology of Hypoxemia in HPSHypoxemia in HPS

Ramsay MA. Int Anesthesiol Clin. 2006 Summer;44(3):69-82

Pathophysiology of Pathophysiology of Hypoxemia in HPSHypoxemia in HPS

Hoeper MM et al. Lancet 2004 May 1;363(9419):1461-8

Diagnostic Criteria for Diagnostic Criteria for Hepatopulmonary Hepatopulmonary

SyndromeSyndrome Portal hypertension with or without Portal hypertension with or without

cirrhotic liver diseasecirrhotic liver disease Arterial hypoxemiaArterial hypoxemia

PaOPaO22 < 70 mmHg or PA-a, O < 70 mmHg or PA-a, O22 15 mmHg 15 mmHg Pulmonary vascular dilatation Pulmonary vascular dilatation

demonstrated bydemonstrated byDelayed “positive” contrast enhanced Delayed “positive” contrast enhanced transthoracic echocardiography ortransthoracic echocardiography orAbnormal brain uptake (>6%) after Abnormal brain uptake (>6%) after 99mTc99mTcMAA MAA lung perfusion scanninglung perfusion scanning

Contrast-enhanced Contrast-enhanced EchocardiographyEchocardiography

IV administration of hand-agitated IV administration of hand-agitated normal saline (using 3-way stop cock)normal saline (using 3-way stop cock)

Microbubbles average 10 to 20 Microbubbles average 10 to 20 microns (normal capillary is 8 microns (normal capillary is 8 microns)microns)

Diffuse dilatations allows passage of Diffuse dilatations allows passage of microbubbles within 3 to 6 cardiac microbubbles within 3 to 6 cardiac cyclescycles

Right-to-left intracardiac shunt if Right-to-left intracardiac shunt if within 3 cardiac cycleswithin 3 cardiac cycles

Transesophageal echocardiography Transesophageal echocardiography further distinguishes intracardiac and further distinguishes intracardiac and intrapulmonary shuntingintrapulmonary shunting

99mTc99mTcMAA Lung Perfusion MAA Lung Perfusion ScanningScanning

Peripheral injection of Peripheral injection of 99mTc99mTcMAAMAA Aggregates are 20 to 90 micronsAggregates are 20 to 90 microns Demonstration of abnormal uptake Demonstration of abnormal uptake

over the brain (>6%) over the brain (>6%) Does not distinguish between Does not distinguish between

intracardiac and intrapulmonary intracardiac and intrapulmonary shuntsshunts

May offer complementary May offer complementary information for stratification of HPS information for stratification of HPS patients at greater risk of OLT patients at greater risk of OLT mortalitymortality

Grading of Severity of Grading of Severity of Hepatopulmonary Hepatopulmonary

SyndromeSyndromeStageStage PA-a,OPA-a,O22

(mmHg(mmHg))

Pa,OPa,O22 (mmHg) (mmHg)

MildMild 1515 8080

ModerateModerate 1515 < 80 - < 80 - 60 60

SevereSevere 1515 < 60 - < 60 - 50 50

Very Very SevereSevere

1515 < 50 (< 300 on 100% < 50 (< 300 on 100% OO22))

No HPS

Negative CEE

Follow-up

PaO2 >60 - <80 m m Hg(and/or)

PA-aO2 > 15 m m Hg

OLT

PaO2 >50 - <60 m m Hg

OLTHigh risk for post-op m ortality

PaO2 <50 m m HgM AA >20%

Positive CEE + PFTs + HRCT

CEE

PaO2 < 80 m m Hg(and/or)

PA-aO2 > 15 m m Hg

No HPS

PaO2 > 80

Arterial B lood Gases

O LT candidatesHepatic disease patients w ith dyspnea

Pre-OLT PaOPre-OLT PaO22 in HPS in HPS PatientsPatients

Krowka MJ et al. Liver Transpl 2004;10:174-82

All HPS All HPS N=40N=40

Denied OLT Denied OLT N=8N=8

TransplantTransplant

Survivors Survivors NonsurvivorsNonsurvivors

N=27 N=5N=27 N=5

PaOPaO22 (mmHg(mmHg))

51 51 10 10 47 47 10 10 55 55 10 10 37 37 8 8

Range Range (mmHg(mmHg))

(29-70)(29-70) (35-47)(35-47) (34-70)(34-70) (29-47)(29-47)

Management of Management of Hepatopulmonary Hepatopulmonary

SyndromeSyndromePharmacological Pharmacological

TreatmentTreatment Somatostatin analogueSomatostatin analogue B-blockersB-blockers Cyclooxygenase Cyclooxygenase

inhibitorinhibitor GlucocorticoidsGlucocorticoids NO inhibitorsNO inhibitors ImmunosuppressorsImmunosuppressors VasoconstrictorsVasoconstrictors AntimicrobialsAntimicrobials Garlic preparationGarlic preparation

Nonpharmacological Nonpharmacological TreatmentTreatment

Long term oxygen Long term oxygen therapytherapy

Transjugular Transjugular intrahepatic intrahepatic portosystemic shuntsportosystemic shunts

CavoplastyCavoplasty EmbolizationEmbolization Orthotopic Liver Orthotopic Liver

TransplantationTransplantation

Survival in HPS Patients and Survival in HPS Patients and Controls undergoing OLTControls undergoing OLT

Swanson KL et al. Hepatology 2005;41:1122-9

Survival based on Initial PaO2 in Survival based on Initial PaO2 in 61 Patients with HPS61 Patients with HPS

Swanson KL et al. Hepatology 2005;41:1122-9

Sequential Oxygen Assessment Sequential Oxygen Assessment of 14 Patients with HPS awaiting of 14 Patients with HPS awaiting

OLTOLT

Swanson KL et al. Hepatology 2005;41:1122-9

The MELD Score:The MELD Score:Model for End-Stage Liver Model for End-Stage Liver

DiseaseDisease Determines priority for Orthotopic Liver Determines priority for Orthotopic Liver

TransplantTransplant Uses the following formula:Uses the following formula:

3.8 x log (e) (bilirubin mg/dL) + 11.2 x log 3.8 x log (e) (bilirubin mg/dL) + 11.2 x log (e) (INR) + 9.6 log (e) (creatinine mg/dL)(e) (INR) + 9.6 log (e) (creatinine mg/dL)

Scores range from 6 to 40Scores range from 6 to 40 Score can be increased if PaO2 < 60 in Score can be increased if PaO2 < 60 in

patient with Hepatopulmonary Syndromepatient with Hepatopulmonary Syndrome

Case of Mr. PB: 46 y/o male with Case of Mr. PB: 46 y/o male with progressive shortness of breath, progressive shortness of breath,

lower extremity edema, and lower extremity edema, and syncopal episodessyncopal episodes

Past Medical HistoryPast Medical History Cirrhosis – diagnosed 3/2000 after liver Cirrhosis – diagnosed 3/2000 after liver

biopsybiopsy Alcoholic hepatitisAlcoholic hepatitis Atrial fibrillationAtrial fibrillation Congestive heart failureCongestive heart failure

Past Surgical HistoryPast Surgical History NoneNone

MedicationsMedications WarfarinWarfarin ProcritProcrit RanitidineRanitidine FlomaxFlomax Folic acidFolic acid LactuloseLactulose FurosemideFurosemide Potassium chloridePotassium chloride AtenololAtenolol

Social HistorySocial History No use of tobacco or illicit drugsNo use of tobacco or illicit drugs H/o alcohol abuse, quit 4 years agoH/o alcohol abuse, quit 4 years ago Married with 2 daughtersMarried with 2 daughters

Family HistoryFamily History Mother – EmphysemaMother – Emphysema Father – Coronary artery diseaseFather – Coronary artery disease No family history of Pulmonary No family history of Pulmonary

HypertensionHypertension

Physical ExaminationPhysical Examination

General: anxious, no acute distressGeneral: anxious, no acute distress HEENT: NCAT, PERRLA, pharynx clearHEENT: NCAT, PERRLA, pharynx clear Neck: supple, Neck: supple, +JVD+JVD Chest: clear to auscultate bilaterallyChest: clear to auscultate bilaterally CV: S1, S2, CV: S1, S2, irreg. irregularirreg. irregular, , +murmur+murmur right right

sternal bordersternal border Abdomen: soft, nontender, +bowel sounds, Abdomen: soft, nontender, +bowel sounds,

+shifting dullness consistent with +shifting dullness consistent with ascitesascites, , splenomegalysplenomegaly

Extremities: Extremities: +edema+edema lower extremities lower extremities bilaterallybilaterally

Laboratory DataLaboratory Data WBC 4.8WBC 4.8 Hgb Hgb 10.410.4 Hct Hct 37.837.8 Platelets Platelets 9898 Sodium Sodium 134134 Potassium 3.9Potassium 3.9 Chloride Chloride 9494 CO2 23CO2 23 BUN 28BUN 28 Creatinine 1.2Creatinine 1.2 Glucose 98Glucose 98 Calcium 9.3Calcium 9.3

AST 26AST 26 ALT 12ALT 12 Alk Phos 73Alk Phos 73 T. Bili 1.1T. Bili 1.1 Albumin 4.0Albumin 4.0 BNP BNP 349349 TSH 4.2TSH 4.2 Free T4 1.4Free T4 1.4

Chest x-ray showingenlarged pulmonaryarteries

CT of CT of Chest/Abdomen/PelvisChest/Abdomen/Pelvis

enlarged pulmonary artery enlarged pulmonary artery and right chambers of the and right chambers of the heart heart

ascites ascites splenomegaly splenomegaly cirrhosis and signs of portal cirrhosis and signs of portal

hypertensionhypertension

ElectrocardiogramElectrocardiogram Right atrial enlargement Right atrial enlargement Right ventricular hypertrophyRight ventricular hypertrophy

EchocardiogramEchocardiogram Preserved LV function with ejection Preserved LV function with ejection

fraction of 60%fraction of 60% Marked enlargement of right heart with Marked enlargement of right heart with

PA systolic of 60 mmHgPA systolic of 60 mmHg Severe tricuspid regurgitationSevere tricuspid regurgitation Dilated inferior vena cavaDilated inferior vena cava

Right Heart Right Heart CatheterizationCatheterization

BaselineBaseline After 40 PPM After 40 PPM Nitric OxideNitric Oxide

RA meanRA mean 3030

RVRV 102/33102/33

PA meanPA mean 5656 4949

PCWPPCWP 1919

COCO 4.274.27 6.236.23

CICI 2.312.31 3.373.37

PVRPVR 693.2 (8.67)693.2 (8.67) 385.2 (4.82)385.2 (4.82)

Portopulmonary Portopulmonary HypertensionHypertension

Pulmonary arterial hypertension Pulmonary arterial hypertension occuring in the setting of portal occuring in the setting of portal hypertensionhypertension

Prevalence of 5% in hepatic patientsPrevalence of 5% in hepatic patients First described in 1951 in a woman First described in 1951 in a woman

with portal vein stenosis and a with portal vein stenosis and a portocaval shunt thrombusportocaval shunt thrombus

25% sudden death reported due to 25% sudden death reported due to syndromesyndrome

Clinical Clinical ManifestationsManifestations

Dyspnea (exertional Dyspnea (exertional and at rest)and at rest)

Chest painChest pain SyncopeSyncope PalpitationsPalpitations Split second heart Split second heart

soundsound Right ventricular heaveRight ventricular heave Right-sided S3 gallopRight-sided S3 gallop JVDJVD AscitesAscites LE edemaLE edema

PathogenesisPathogenesis

Vasoproliferation and Vasoproliferation and obstructionobstruction

GeneticsGenetics InflammationInflammation Neurohormones (ET-1)Neurohormones (ET-1) Abnormal levels of Abnormal levels of

vasoconstrictors vasoconstrictors (noradrenalin, renin-(noradrenalin, renin-angiotensin-aldosterone angiotensin-aldosterone and vasopressin) and and vasopressin) and vasodilators (NO, vasodilators (NO, glucagon, VAP, and glucagon, VAP, and substance P)substance P)

Possible Pathogenetic Mechanisms Possible Pathogenetic Mechanisms Leading to Portopulmonary Leading to Portopulmonary

HypertensionHypertension

Budhiraja R et al. Chest. 2003 Feb;123(2):562-76

Shear stress from increased pulmonary blood flow

Endothelial cell dysfunction

Endothelial cell proliferation

Vascular luminal obliteration

Smooth muscle hypertrophy,Adventitial hypertrophy

VasoconstrictionVasoactive compoundsescaping hepatic metabolism

? Gene mutation

Humoral imbalanceCytokine / Growth factor imbalance

Down regulatedPotassium channels

Autoimmunity

Histological Sample of Lungs in Histological Sample of Lungs in Severe Portopulmonary Severe Portopulmonary

HypertensionHypertension

Intimal and medial thickening of pulmonary arteryand outspread channel-like structures forming plexiform lesions

Diagnostic Criteria for Diagnostic Criteria for Portopulmonary Portopulmonary

HypertensionHypertension Liver disease (causing clinical Liver disease (causing clinical

portal hypertensionportal hypertension MPAP > 25 mmHgMPAP > 25 mmHg Mean PAOP < 15 mmHgMean PAOP < 15 mmHg PVR > 240 dyn/sec/cmPVR > 240 dyn/sec/cm-5-5

Transpulmonary gradient > 10 Transpulmonary gradient > 10 mmHgmmHg

P ro ce e d to O LT

M ild (ea rly)P p a < 35 m m Hg

G o od ca rd ia c fu n ction

C on s id er pu lm o na ryv a so d i la to r the ra py

p r io r to O LT

M od era teP p a > 3 5 - 4 5 m m H gG o od ca rd ia c fu n ction

C on s id er pu lm o na ryv a so d i la to r the ra py

S ev ereP p a > 45 m m Hg

C a nce l O LT

D e te rm in e r isk p ro fi le fo r O LT(p re - an d in tra -ope ra tiv e ly)

a n d trea tm en t op tio ns

C o n du c t R H C a n d e s tab lishP P H T N d iag no s is

R V sys > 5 0 m m H g o r ab n orm a l RV

C o nd u ct scre en ing tran sth o ra c icd op p le r e ch ocard io gra phy

P P H T N su spe c ted

Transthoracic Doppler Transthoracic Doppler EchocardiographyEchocardiography

Screening procedure of choice for Screening procedure of choice for portopulmonary hypertensionportopulmonary hypertension

Measures tricuspid systolic peak velocityMeasures tricuspid systolic peak velocity RV systolic pressure calculated using RV systolic pressure calculated using

following equation:following equation:

RVsys = RA pressure + 4 x TR peak RVsys = RA pressure + 4 x TR peak velocityvelocity22

PA systolic pressure > 50 mmHg should be PA systolic pressure > 50 mmHg should be referred for right heart catheterizationreferred for right heart catheterization

958 screened; 100 had RVsys > 50 958 screened; 100 had RVsys > 50 mmHg; 86% with PVR > 120 and 64% mmHg; 86% with PVR > 120 and 64% with PVR >240 dyne/sec/cmwith PVR >240 dyne/sec/cm-5-5

PPV of 38% and NPV of 92% in PPV of 38% and NPV of 92% in detecting pulmonary hypertension on detecting pulmonary hypertension on right heart catheterization when PAP right heart catheterization when PAP > 50 mmHg by echocardiography> 50 mmHg by echocardiography

Transthoracic Doppler Transthoracic Doppler EchocardiographyEchocardiography

Kim WR et al. Liver Transpl 2000;6:453-8

Cotton CL et al. Liver Transpl 2002;8:1051-4

Pulmonary Hemodynamic Patterns Pulmonary Hemodynamic Patterns in 101 Patients with Liver Disease in 101 Patients with Liver Disease

and RVSP > 50 mmHg on and RVSP > 50 mmHg on EchocardiographyEchocardiography

MPAPMPAP COCO PVRPVR PAOPPAOP TPGTPG

High flow (High flow (PVR) PVR) (n=35)(n=35)

31+931+9 8.6+2.8.6+2.66

142+58142+58 16+616+6 16+716+7

Normal volume Normal volume (n=20)(n=20)

28+828+8 8.2+2.8.2+2.33

154+60154+60 12+212+2 17+717+7

Increased volume Increased volume (n=15)(n=15)

34+1034+10 9.1+3.9.1+3.00

125+52125+52 21+421+4 141477

PPHTN (PPHTN (PVR) PVR) (n=66)(n=66)

49+1149+11 6.1+2.6.1+2.00

533+24533+2477

12+612+6 37+137+111

Normal volume Normal volume (n=50)(n=50)

48+1148+11 5.9+2.5.9+2.00

571+25571+2577

10+310+3 38+138+111

Increased volume Increased volume (n=16)(n=16)

53+953+9 6.8+2.6.8+2.00

407+17407+1711

21+521+5 34341100

Krowka MJ et al. Hepatology. 2006 Nov 28;44(6):1502-1510

Right Heart Catheterization of Mr. Right Heart Catheterization of Mr. PBPB

BaselineBaseline After 40 PPM After 40 PPM Nitric OxideNitric Oxide

RA meanRA mean 3030

RVRV 102/33102/33

PA meanPA mean 5656 4949

PCWPPCWP 1919

COCO 4.274.27 6.236.23

CICI 2.312.31 3.373.37

PVRPVR 693.2 (8.67)693.2 (8.67) 385.2 (4.82)385.2 (4.82)

TPGTPG 3737

Relationship between Cardiac Relationship between Cardiac Output and Transpulmonary Output and Transpulmonary

GradientGradient

Rodriguez-Roisen R et al. Eur Respir J 2004;24:861-80

Mayo Clinic Classification of Pulmonary Mayo Clinic Classification of Pulmonary Hypertension in the setting of Portal Hypertension in the setting of Portal

HypertensionHypertension

TypeType MPAPMPAP PAOPPAOP COCO PVRPVR

Pulmonary artery high-flow Pulmonary artery high-flow statestate

N or N or

Excess pulmonary venous Excess pulmonary venous volumevolume

Portopulmonary Portopulmonary hypertensionhypertension

with vascular obstructionwith vascular obstruction

a)a) Normal volumeNormal volume

b)b) Excess volumeExcess volume

N or N or

Hemodynamic Progression of Hemodynamic Progression of Pulmonary Arterial Pulmonary Arterial

HypertensionHypertensionL

eve

l

Pre-symptomatic Symptomatic /Stable Progressive/Declining

Pulmonary pressure

Cardiac output

Time

Increasing PVR

PVR = 80 x (MPAP - PCWP ) / CO

Normal PVR is 20-120 (dyne*sec)/cm5

or 0.25 to 1.7 woods unit (mmHg/ L. min.)

Intraoperative ConcernsIntraoperative Concerns

Initial diagnosis of PPHTN made in Initial diagnosis of PPHTN made in operating room at the time of OLT in operating room at the time of OLT in 28 of 43 cases (65%)28 of 43 cases (65%)

14% intraoperative and 36% in-14% intraoperative and 36% in-hospital mortality rate in multicenter hospital mortality rate in multicenter database report of 36 patients with database report of 36 patients with PPHTN who underwent OLTPPHTN who underwent OLT

Krowka MJ et al. Liver Transpl 2004;10:174-82

Krowka MJ et al. Liver Transp 2000;6:443-50

Mayo Clinic Intraoperative Mayo Clinic Intraoperative Guidelines Concerning Guidelines Concerning

Hemodynamics in Patients with Hemodynamics in Patients with Portopulmonary HypertensionPortopulmonary Hypertension

Krowka MJ et al. Liver Transp 2000;6:443-50

Mean Mean Pulmonary Pulmonary

Artery Pressure Artery Pressure

Intraoperative Intraoperative GuidelineGuideline

Reported Reported MortalityMortality

< 35 mmHg< 35 mmHg Proceed with Proceed with OLTOLT

0/14 (0)0/14 (0)

35-50 mmHg35-50 mmHg If PVR < 250 If PVR < 250 proceed with proceed with OLTOLT

If PVR If PVR 250 250 cancel OLTcancel OLT

0/6 (0)0/6 (0)

7/14 (50)7/14 (50)

50 mmHg50 mmHg Cancel OLTCancel OLT 6/6 (100)6/6 (100)

Outcome and Pulmonary Outcome and Pulmonary Hemodynamic Subgroups in PPHTN Hemodynamic Subgroups in PPHTN

PatientsPatients

Denied Denied OLTOLT

(N=30)(N=30)

Following OLT:Following OLT:

Died SurvivedDied Survived

(N=13) (N=23)(N=13) (N=23)

MPAP < 35MPAP < 35 00 11 55

35 35 MPAP MPAP 5050

1515 88 1212

50 < MPAP50 < MPAP 1515 44 66

Krowka MJ et al. Liver Transpl 2004;10:174-82

Reperfusion of Liver Graft in Reperfusion of Liver Graft in Patient with PPHTNPatient with PPHTN

Ramsay M. Adv Pulmon Hypertens 2004;2:9-18

Mean Pre-orthotopic Liver Transplant Mean Pre-orthotopic Liver Transplant Pulmonary Hemodynamics in Patients Pulmonary Hemodynamics in Patients

with Portopulmonary Hypertensionwith Portopulmonary Hypertension

Parameter

All PortoP

H (N=66)

Denied OLT

(N=30)

Transplante

d

Survivors (N=23)

Nonsurvivors (N=13)

MPAP 48 ± 11 53 ± 11 45 ± 14 44 ± 8

PVR 462 ± 202

614 ± 288 341 ± 181 322 ± 139

CO 7.3 + 3.1

6.2 ± 3.3 8.2 ± 2.7 8.6 ± 4.3

RA 10 ± 6 11 ± 7 8 ± 3 7 ± 3

PCWP 11 ± 6 10 ± 6 11 ± 5 14 ± 6Krowka MJ et al. Liver Transpl 2004;10:174-82

Management of Management of Portopulmonary Portopulmonary

HypertensionHypertensionPharmacological Pharmacological TreatmentTreatment

DiureticsDiuretics DigoxinDigoxin B-blockersB-blockers Calcium channel blockersCalcium channel blockers NitratesNitrates Prostacyclin analogues Prostacyclin analogues

(epoprostenol, treprostinil, (epoprostenol, treprostinil, iloprost, and beraprost)iloprost, and beraprost)

Endothelin receptor Endothelin receptor antagonists (bosentan)antagonists (bosentan)

SildenafilSildenafil

Nonpharmacological Nonpharmacological TreatmentTreatment

Long term oxygen Long term oxygen therapytherapy

Transjugular Transjugular intrahepatic intrahepatic portosystemic shuntportosystemic shunt

Orthotopic liver Orthotopic liver transplantationtransplantation

Deleterious Effects of B-Blockers on Deleterious Effects of B-Blockers on Exercise Capacity and Exercise Capacity and

Hemodynamics in Patients with Hemodynamics in Patients with PPHTNPPHTN

Provencher S et al. Gastroenterology. 2006 Jan;130(1):120-6

EpoprostenolEpoprostenol

Prostacyclin or Prostaglandin I2Prostacyclin or Prostaglandin I2 Potent systemic and pulmonary Potent systemic and pulmonary

vasodilatorvasodilator Powerful inhibitor of platelet Powerful inhibitor of platelet

aggregationaggregation Increased permeability of the peritoneal Increased permeability of the peritoneal

membrane possibly leading to membrane possibly leading to worsening ascitesworsening ascites

Significant and favorable changes in Significant and favorable changes in Ppa, PVR, CO, and 6MWDPpa, PVR, CO, and 6MWD

Survival in Portopulmonary Survival in Portopulmonary Hypertension with the use of Hypertension with the use of

Epoprostenol Epoprostenol

Swanson KL et al. Am J Respir Crit Care Med 2003;167:A683

Pulmonary Hemodynamics in a Pulmonary Hemodynamics in a Patient with Cirrhosis and Severe Patient with Cirrhosis and Severe

PPHTNPPHTN

Krowka MJ et al. Clin Chest Med. 2005 Dec;26(4):587-97

Hemodynamic and Hemodynamic and Echocardiographic Profile of a Echocardiographic Profile of a Patient before and after OLTPatient before and after OLT

Pre-OLTPre-OLT Post-OLTPost-OLT

BaselinBaselinee

IloprosIloprostt

IloprostIloprost No No therapytherapyDay 1Day 1 Month Month

11Month Month 44

HR beats/minHR beats/min 6868 6464 8080 8282 6868 7070

BP mmHgBP mmHg 104/54104/54 100/46100/46 120/85120/85 130/90130/90 130/80130/80 120/75120/75

Ppa mmHgPpa mmHg 5454 3838 4545

PAOP mmHgPAOP mmHg 88 1010 99

Cardiac index Cardiac index L/min/mL/min/m22

3.73.7 3.93.9 4.24.2

PVR PVR dyn.s.cmdyn.s.cm-5-5

524524 302302 361361

SVOSVO22 % % 7474 7777 7676

RVSP mmHgRVSP mmHg 7474 6868 2727 2929

6MWD m6MWD m 462462 579579 570570 572572 582582Minder S et al. Eur Respir J 2004 Oct;24(4):703-7

Pulmonary Hemodynamics and Outcomes of Pulmonary Hemodynamics and Outcomes of Patients Treated with Prostaglandins prior to Patients Treated with Prostaglandins prior to

OLTOLTFirst First

AuthorAuthorBaselineBaseline PreoperativPreoperativ

eePostoperatiPostoperati

veveEpoprostenolEpoprostenol StatuStatu

ssSurvivSurviv

al al monthmonth

ssPpPpaa

mmmHmHgg

PVRPVR

dyn.dyn.s.cms.cm

-5-5

PpaPpa

mmmmHgHg

PVRPVR

dyn.sdyn.s.cm.cm-5-5

PpaPpa

mmmmHgHg

PVRPVR

dyn.sdyn.s.cm.cm-5-5

DoseDose

ng.kng.kg.mig.minn-1-1

Therapy Therapy monthsmonths

Pre-Pre-OLTOLT

PostPost-OLT-OLT

PLOTKINPLOTKIN 4747 678678 2626 271271 2828 253253 2323 44 33 AliveAlive 33

KROWKKROWKAA

3939 358358 4040 187187 NANA NANA 1111 33 44 AliveAlive 88

RAMSAYRAMSAY 3838 587587 2929 193193 NANA NANA 77 11 33 AliveAlive 33

TANTAN 4848 472472 3333 248248 3232 355355 5050 3636 1010 AliveAlive 1212

MAIRMAIR 4646 960960 3939 240240 4747 520520 66 DiedDied 11

MINDERMINDER 5454 524524 3838 302302 4545 361361 Ilo-Ilo-prostprost

88 33 AliveAlive 2525

Minder S et al. Eur Respir J 2004 Oct;24(4):703-7

Endothelin Receptor Endothelin Receptor Antagonists (Bosentan)Antagonists (Bosentan)

ETETAA and ET and ETBB receptor antagonist receptor antagonist 14% transient increase in hepatic enzyme 14% transient increase in hepatic enzyme

levels have been reportedlevels have been reported Severe cases of acute hepatitis with one Severe cases of acute hepatitis with one

fatality reported with sitaxsentan, an ETfatality reported with sitaxsentan, an ETAA receptor selective antagonistreceptor selective antagonist

Reduction of PVR and and increased Reduction of PVR and and increased 6MWD in 11 patients with cirrhosis and 6MWD in 11 patients with cirrhosis and severe PPHTN after 1 year therapy with severe PPHTN after 1 year therapy with bosentan without liver injurybosentan without liver injury

Barst RJ et al. Chest 2002;121:1860-1868

Hoeper MM et al. Eur Respir J 2005; 25:502-508

SildenafilSildenafil

Phosphodiesterase type 5 inhibitorPhosphodiesterase type 5 inhibitor Enhances effects of nitric oxide-Enhances effects of nitric oxide-

activated increases in cGMPactivated increases in cGMP Used as monotherapy and as Used as monotherapy and as

combination therapy for reduction of combination therapy for reduction of PpaPpa

Increased 6MWD and reduction in Pro-Increased 6MWD and reduction in Pro-BNP in 14 PPHTN patients (8 as BNP in 14 PPHTN patients (8 as monotherapy, 5 with iloprost, and 1 monotherapy, 5 with iloprost, and 1 with treprostinil)with treprostinil)Reichenberger F et al. Eur Respir J 2006; 28:563-567

Case of Mr. PBCase of Mr. PB

Started on Treprostinil with Started on Treprostinil with improvement in quality of lifeimprovement in quality of life

Two years later develops Two years later develops worsening shortness of breath and worsening shortness of breath and switched to Iloprost with switched to Iloprost with improvementimprovement

Liver Transplant?Liver Transplant?

HPSHPS PPHTNPPHTNSymptomsSymptoms Progressive dyspneaProgressive dyspnea Progressive dyspneaProgressive dyspnea

Clinical ExamClinical Exam Cyanosis, finger Cyanosis, finger clubbing, spider clubbing, spider angiomasangiomas

No cyanosis, RV heave, No cyanosis, RV heave, pronounced P2 pronounced P2 componentcomponent

ECG findingsECG findings NoneNone RBBB, RAD, RV RBBB, RAD, RV hypertrophyhypertrophy

ABGABG Mod/severe hypoxemiaMod/severe hypoxemia No/mild hypoxemiaNo/mild hypoxemia

Chest x-rayChest x-ray NormalNormal CMG, hilar enlargementCMG, hilar enlargement

CEECEE Always +, left atrial Always +, left atrial opac for >3-6 cardiac opac for >3-6 cardiac cyclescycles

Usually -, + <3 cardiac Usually -, + <3 cardiac cycles if ASD or PFOcycles if ASD or PFO

99m99mTcMAA TcMAA indexindex

6%6% <6%<6%

Pulmonary Pulmonary hemodynamihemodynamicscs

Normal/low PVRNormal/low PVR Elevated PVR, normal Elevated PVR, normal mPAOPmPAOP

Pulmonary Pulmonary angiographyangiography

Normal/”spongy” (type Normal/”spongy” (type I)I)

Discrete arteriovenous Discrete arteriovenous communications (type communications (type II)II)

Large main PA, distal Large main PA, distal arterial pruningarterial pruning

OLTOLT Always indicated in Always indicated in severe stagessevere stages

Only indicated in mild to Only indicated in mild to moderate stagesmoderate stages

Summary of Liver Transplant Summary of Liver Transplant ConsiderationsConsiderations

Hepatopulmonary syndrome

Portopulmonary hypertension

High risk for OLT (↑mortality)

PaO 2<50 mm Hg MPAP>35 mm Hg

99mTcMAA brain uptake >20%

UNOS indication for OLT Yes No

Higher priority for OLT Yes, if PaO 2<60 mmHg

No

Syndrome deterioration awaiting OLT

Yes Yes

Sudden death due to syndrome

No 25%

5-Year survival without OLT 23% 30%

Pharmacologic treatment before OLT helpful

Not proven Strongly suggested

Intraoperative death Not reported Yes

Transplant hospitalization mortality

16% 35%

Syndrome resolution after OLT

Common Extremely variable

Recommendations for HPS Recommendations for HPS and PPHTNand PPHTN

Diagnose it early, transplant earlyDiagnose it early, transplant early Pulse oximetry and Arterial blood gas to Pulse oximetry and Arterial blood gas to

screen for HPSscreen for HPS Annual screening echocardiography for Annual screening echocardiography for

patients on the OLT waiting list to patients on the OLT waiting list to evaluate for PPHTNevaluate for PPHTN

Use of anti-pulmonary hypertension meds Use of anti-pulmonary hypertension meds as a bridge to transplantation in PPHTNas a bridge to transplantation in PPHTN

Close monitoring of patients after OLT Close monitoring of patients after OLT because recurrence of HPS and because recurrence of HPS and conversion to PPHTN have been reportedconversion to PPHTN have been reported

I can breath betternow that I got a

new liver!