Hepatopulmory syndrome in chronic liver disease patient.

1. Hepatopulmonary Syndrome
Under guidance of Dr Pranjal Modi ( Prof. And head
Abdominal organ Transplant surgery and Urology)
Presented by Dr Rahul Amin ( Fellow Abdominal organ
transplant surgery)

2. • 58 year old male,79 kg weight, B positive ,K/c/o diabetes
mellitus and hypertension since 12 years
• Index presentation in 2017 Jaundice followed by ascites and
diagnosed liver parenchymal disease.
• Was on medical management.
• on 10/4/2022 Patient came to liver transplant OPD with
Breathlessness on exertion since 1- 1.5 month. Mild chest pain
sometime.
Case

3. • No addiction
• No history of drug allergy
• No history of surgery
• Patient was on diuretics since 5 years and on antidiabetic and
antihypertensive since 12 years

4. Vital :
P- 60/Min
BP – 120/58 mmhg
Spo2 – 93 % in sitting position ,
98 % in supine position
CVS : S1, S2 normal,
RS : Airway examination- normal
Auscultation : Bilateral air entry equal
Platypnoea
General examination – concious,
oriented
HB 10.5
TC 6620
PC 36000
CREATININE 1.62
SODIUM 133
POTASSIUM 4.32
BILIRUBIN 2.0/0.6/1.4
SGPT/SGOT/ALP 55/31/76
ALBUMIN 2.4
INR 2.16
MELD 22/25

5. As denoting patient having progressive dyspnea

6. •

7. CXR WNL
CT chest No evidence of consolidation, effusion,
oedema, interstitial lung disease
2-D Echo Normal EF:55% ,RVSP:34mmHg,Mild
Pulmonary hypertension, RA RV normal,
Stress 2-D Echo Negative (THR – 132/min)
Contrast Echo Significant contrast noted in LV after 3
beats
s/o extra cardiac Rt-Lt shunt
possibly HPS
Coronary angiography
(I/V/O long standing
DM)
Normal

8. ABGA ON ROOM AIR ON 4 L OXYGEN
ph 7.45 7.48
Po2 52.4 110.3
pco2 26.5 24.6
hco3 18 18.2
BE -4 -3.5
Lactate 1.0 0.9
Na 136 136
k 4.0 4.06
Patient having severe HPS
On the day of liver transplant

9. Introperative
•In patient of HPS require PEEP -0
•And require high FIO2 then other CLD
patient

10. Day Mode/Fio2 Pao2 PF ratio
POD 0 PRVC/100 110.2 % 110.2
POD 1 SIMV/70 127 % 211
POD 2 CPAP/60 122 % 203
POD 3 NRBM 10 L 141 % 276
POD 7 NRBM 8L 90 % 200
POD 10 6L O2 mask Spo2 100
On room air 93 %
POD 13 3L o2Mask Spo2 100
On room air 95 %
POD 14 On room air Spo2 99 %
Post operative course

11. • Insidious onset dyspnoea
• Platypnoea ( Worsening of dyspnoea
moving from supine to upright position)
• Orthodeoxia (decrease of PaO2 of more
than 5% or more than 4 mmHg moving
from supine to upright position)
• Attributed the predominance of the
Intrapulmonary vascular dilatation (IPVD) in
the lung bases, and the increase in the
blood flow through these regions when
upright
• Sleep time oxygen
desaturation
• Digital clubbing
• Cyanosis
• Diffuse telangiectasia
• Spider naevi.

12. Triad
• 1. Patients with liver disease
• 2. Alveolar-arterial oxygen gradient
(AaPO2) >15 mmHg
• 3. Intrapulmonary vasodilatation

13. • Formula for alveolar-arterial gradient P(A-a) O2
• PAO2-PaO2 = (FiO2 [Patm - PH2O] - [PaCO2/0.8]) - PaO2,
• PAO2 partial pressure of alveolar oxygen.
• PaO2 partial pressure of arterial oxygen.
• FiO2 fraction inspired oxygen.
• Patm atmospheric pressure.
• H2O partial pressure of water vapor at body temperature.
• PaCO2 partial pressure of arterial carbon dioxide.
What is P (A-a ) O2 ( alveolar-arterial gradient )

14. Severity of HPS
HPS stage PaO2 mmHg P(A-a)O2,mmHg
Mild ≥ 80 mmhg ≥ 15
Moderate 60 to 80 mmhg ≥ 15
Severe 50 to 60 mmhg ≥ 15
Very Severe <50 mmhg ≥ 15

15. Pathophysiology
• In chronic liver disease patient
Increase release of vasodilators.
• Dilatation of Pulmonary
vasculature.
• Increase perfusion with no change
in Ventilation.
• Mixed blood passed in pulmonary
capillaries.

16. • Imbalance between vasodilators
and vasoconstrictors
• Increased hepatic production of
endothelin 1 (ET1) and
pulmonary endothelin B (ETB)
due to stress
↓
• It stimulate Pulmonary
endothelial nitric oxide
synthetase (eNOS) Enzyme in
the lungs.
↓
• It leads increased nitric oxide
(NO) production, which is a
potent vasodilator.

17. • Translocation of intestinal bacteria and endotoxemia in
liver disease patients
↓
• accumulation of macrophages and monocytes in the
lungs.
↓
• Release tumor necrosis factor-alpha (TNF-alpha) in
pulmonary vessels leading to activation of inducible
nitric oxide synthetase (iNOS)
↓
• iNOS causes increased nitric oxide (NO) production.
• Also, macrophages and monocytes, and TNF alpha
activate vascular endothelial growth factor (VEGF),
leading to increased angiogenesis in the pulmonary
vasculature.

18. • The pulmonary capillaries are dilated to 15-
500micomm in HPS as compared to a normal
diameter between 8-15micromm.
• Vasodilation and angiogenesis lead to
arteriovenous (AV) shunt formation
• Dilatation of vasculature leads large amount of
blood passing without undergoing gas exchange.
↓
• Some blood may pass through AV shunts
without encountering alveoli , so gas exchange
does not happen.

21. Epidemiology and natural history
• 50-60% patient being evaluated for LT have intrapulmonary vascular
abnormalities (Detected by contrast echo)
• But normal gas exchange Hepatopulmonary syndrome
• Prevalence 5-30%
• HPS occur most commonly with portal hypertension and cirrhosis
• May be associated with acute and chronic hepatitis, acute liver failure ,Cavo
pulmonary shunts and Abernathy malformation

22. Diagnosis
• Pulse oximetry
• ABG
• Chest radiographs
• Pulmonary function test
• Contrast enhanced trans thoracic echocardiography (CTTE)
• Radionuclide lung perfusion scan using macroaggregated albumin (MAA)

23. Pulse oximetry
pulse oximetry had a sensitivity and
specificity of 100% and 88%
respectively for detecting patients
with a partial pressure of
oxygen<60 mmHg

24. Arterial blood gas analysis
• Calculation of Pao2
• Calculation of P[A-a]O2
• Severity of HPS
• The P(A-a) gradient is calculated as: [(Patm – PH2O] × 0.21 – PaCO2/0.8) –
PaO2.

25. Chest radiography
• Chest radiography may show
• Bibasilar nodular or
• Reticulonodular opacities
• Majority of HPS patients
have normal findings
Pulmonary function test
Decreased diffusing capacity for
carbon monoxide.

26. Contrast-enhanced transthoracic
echocardiography (CTTE)
• Most sensitive test
• Procedure:
• Performed by injecting agitated saline intravenously during routine transthoracic
echocardiography, producing sonographically visible microbubbles
• Principle:
• Normal diameter of the lung vascular capillary vessels is less than 8 to 15 μm
• Agitated saline creates microbubbles greater than 10 μm in diameter
• These bubbles do not pass through pulmonary capillary bed in normal individual
• But I will pass through Shunt

27. Contrast-enhanced transthoracic
echocardiography (CTTE)
• Microbubbles are visualized in the right ventricle within seconds of administration
• In the absence of right to left shunt, the microbubbles are absorbed at the alveoli
• Early appearance of bubbles (within 3 cardiac cycle) suggest- Intra cardiac shunt
• Delayed appearance of the microbubbles in the left cardiac chambers 3-6 cardiac
cycles after injection- Intrapulmonary vascular disease

28. Radionuclide lung perfusion
scan
• Macro-aggregated albumin (MAA) particles
are used
• Particles of 20-50 μm in size of MAA are
injected intravenously.
• In HPS patients, MAA particles escape
through the abnormal pulmonary capillaries
and stay in downstream capillary beds
supplied by systemic arteries, such as the
brain, kidney, and spleen.

29. Management
• Supplemental oxygen to maintain saturation ≥ 88%
• Medical management
• Supportive

30. Oxygen therapy
• In response to 100% oxygen, if PaO2 rise to levels ≥600mmHg,
shunting of blood is unlikely.
• If it failed to exceed 500 mmHg, shunt can't be ruled out.
• If it didn't rise to levels above 150-200mmHg, shunt is most probably
the main mechanism of hypoxemia.

31. • Pentoxifylline, a tumor necrosis factor-alpha inhibitor,
showed variable results in oxygenation improvement in
HPS[1-3].
• Early-stage HPS having a favorable outcome, while with
advanced-stage HPS had unimproved oxygenation
• also difficulty tolerating pentoxifylline due to gastrointestinal
adverse effects.
Dose : 400 mg TDS
• 1. Zhang J, Ling Y, Tang L, Luo B, Chacko BK, Patel RP, Fallon MB. Pentoxifylline attenuation of experimental hepatopulmonary syndrome. J Appl Physiol
(1985). 2007;102:949-955.
• 2. Gupta LB, Kumar A, Jaiswal AK, Yusuf J, Mehta V, Tyagi S, Tempe DK, Sharma BC, Sarin SK. Pentoxifylline therapy for hepatopulmonary syndrome: a pilot
study. Arch Intern Med. 2008;168:1820-1823.
• 3. Tanikella R, Philips GM, Faulk DK, Kawut SM, Fallon MB. Pilot study of pentoxifylline in hepatopulmonary syndrome. Liver Transpl. 2008;14:1199-1203.

32. • Methylene blue causes vasoconstriction by inhibiting NO
and may also decrease angiogenesis. It has shown some
benefits in improving oxygenation; however, no randomized
clinical trial is available to support its use.
• 3mg/kg bolus is helpful.
Schenk P, Madl C, Rezaie-Majd S, Lehr S, Müller C. Methylene blue
improves the hepatopulmonary syndrome. Ann Intern
Med. 2000;133:701-706.

33. •A study shows the decrease in this bacterial
translocation by Norfloxacin and thus, decreasing
the severity of HPS[1]
Dose 400 mg BD
1. Rabiller A, Nunes H, Lebrec D, Tazi KA, Wartski M, Dulmet E, Libert JM, Mougeot C, Moreau R, Mazmanian
M, Humbert M, Hervé P. Prevention of gram-negative translocation reduces the severity of hepatopulmonary
syndrome.

34. • Sorafenib is a tyrosine kinase inhibitor that can reduce
angiogenesis.
• It significantly decreased alveolar-arterial oxygen gradient in
rat model but failed to show benefit in patients with HPS in a
randomized-controlled trial.
• Kawut SM, Ellenberg SS, Krowka MJ, Goldberg D, Vargas H, Koch D, Sharkoski T, Al-Naamani N, Fox A, Brown
R, Levitsky J, Oh JK, Lin G, Song N, Mottram C, Doyle MF, Kaplan DE, Gupta S, Fallon MB. Sorafenib in
Hepatopulmonary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Liver
Transpl. 2019;25:1155-1164.

35. • 21 Patients to garlic ( 250 mg garlic perls,Ranbaxy india) 1g/m2/day to
2g/m2/day
• 9 month follow up
• 24.66% increase in baseline arterial oxygen levels (83.05 mmHg versus
66.62 mmHg; P <0.001) in garlic vs only 7.37% increase (68.75 mmHg
versus 64.05 mmHg; P=0.02) in placebo arm
• Reversal of HPS was observed in 14 of 21 patients (66.67%) on garlic
supplementation vs in one of 20 patients (5%) on placebo
De et al Can J Gastroenterol 2010

36. Physiotherapy management
• Trendelenburg position : it improves ventilation Perfusion ratio
• Incentive spirometry : increase total lung capacity
• Walking : it also improves ventilation Perfusion ratio.
• Nutrition

37. • The trans jugular intrahepatic portosystemic shunt ( TIPSS )
has been proposed to decrease portal hypertension in HPS. A
small prospective study showed improvement in gas
exchanged, but limited data are available.
Tsauo J, Zhao H, Zhang X, Ma H, Jiang M, Weng N, Li X. Effect of Transjugular Intrahepatic Portosystemic
Shunt Creation on Pulmonary Gas Exchange in Patients with Hepatopulmonary Syndrome: A Prospective Study.
J Vasc Interv Radiol. 2019;30:170-177

38. Other therapies
• Ligation of
congenital
portosystemic
shunt
• Coil embolization
may be selectively
useful in some
patients.

39. Liver transplantation
• The only definitive management for HPS is LT.
• All the patients with the partial pressure of oxygen less than 60 mmHg
should be evaluated for LT.
• A study showed 76% mortality in HPS patients who did not undergo LT
compared to 23% mortality in patients who underwent LT.
• LT has been shown to improve oxygenation and shunt within the first year
of transplant.
• A retrospective study with 74 patients showed improvement in PaO2 from
89% to 94% and a decrease in A-a gradient from 16 to 8 mmHg after
transplantation.

40. MELD
exception
• In 2007, UNOS
recommended
assigning a MELD
score of 22 for the
initial application of
patients with severe
HPS (PaO2 <60
mmHg)
Fallon et al, Liver Transplantation 2006

41. Fallon et al, Gastroenterology 2008

42. • Matched case control study – HPS with LT, HPS without LT.
• Patients with HPS had a mean partial pressure of arterial oxygen (PaO2) decline
of 5.2 ± 2.3 mm Hg per year awaiting for DDLT
• 5-yearsurvival associated with OLT was 76% versus 5-yearsurvival 23% who did
not undergo transplantation
• Baseline PaO2 < 50 mm Hg was associated with worse survival irrespective of
the decision to perform OLT.
Hypoxemia of HPS is frequently progressive, additional MELD points should advance the
priority for LT in patient of HPS
SWANSON, WIESNER, AND KROWKA , Hepatology 2006

43. Post transplant intensive care issue
• Arterial oxygenation may worsen in the immediate post transplant period
• Abrupt reversal of the process may induce transient pulmonary
vasoconstriction and worsen ventilation perfusion ratio
• Early extubation is the goal
• Trendelenburg positioning, continuous lateral rotation, noninvasive
ventilation may help to improve persistent severe hypoxemia

44. High risk for LT
Arguedas et al Hepatology 2003
• 24 patients with HPS and LT followed up for at least 1 year post transplant
• A preoperative arterial oxygen tension (PaO2) of <50 mmHg alone or in
combination with a MAA shunt fraction >20 % were the strongest predictors
of postoperative mortality

45. Intraoperative issue during LT
• During LT, major issue is maintaining satisfactorily arterial
oxygenation
• Monitoring mixed venous oxygen saturation (SvO2) is also important.
• HPS patients are orally intubated and mechanically ventilated with
lung protective ventilation (tidal volume 6-8mL/kg)

46. Take home message
• Hepatopulmonary syndrome- Important entity which can easily be screened using pulse
oximetry
• Contrast-enhanced transthoracic echocardiography (CTTE) is highly sensitive test
• HPS can significantly alter natural history of cirrhosis
• Medical therapies are limited
• Severe Hepatopulmonary syndrome merits MELD exception and liver transplantation
• Post Liver transplant survival is comparable in experienced centre