Hypothesis

We hypothesize that pentoxifylline in hepatopulmonary syndrome would improve oxygenation by inhibiting TNF alpha and thereby reducing macrophage, endothelium induced NO production compared to placebo

Aim

To study efficacy of pentoxifylline in reducing AaPO2 in hepatopulmonary syndrome when compared to placebo

Methodology:

Study design: Prospective double-blind randomized placebo-controlled trial

DATA and SPECIMEN collection 

Patient data, demographics, etiology of liver disease, PFT, abdominal radiological studies will be collected 

6-minute walk test will be done at the baseline, 3 months, and 6 months 

Sampling for ABG will be performed with the subject seated while breathing room air at baseline and at the end of 3 and 6 months and A-aPO2 values will be calculated using Alveolar gas equation.

TNF alpha levels, vWF, ET-1, VEGFR-3, iNOS, eNOS and IL-1 β levels will be measured at baseline and after 3 and 6 months. 

DLCO and exhaled NO will be measured at the baseline and at the end of 3 and 6 months

Blinding 

The study drug and placebo will be administered in identical packaging and labelling to ensure that investigators and participants are blinded to study treatment. The study drug and placebo will be labelled with a unique label letter that will be used to allocate treatment to the patient, but the allocation will not be indicated to the investigators or participants. Except for the trial pharmacists and biostatistician, no member of the study team or their extended personnel will have access to the randomization method during the study’s execution. The investigator will get the treatment assignment from trial pharmacists in the case of a medical emergency in which breaking the blind is necessary to give medical care to the participant.

DEFINITION -

Hepatopulmonary syndrome will be defined by 

a. Presence of liver disease and / or portal hypertension AND

b. Partial pressure of oxygen <80mm Hg or Alveolar-arterial oxygen gradient [P (A-a)O2 gradient ≥ 15mmHg (0r 20 mmHg for patients >65 years] AND

c. Documented Intrapulmonary Vascular Dilatation by saline contrast echocardiogram 

Sample size:   Assuming that the improvement in oxygenation in the pentoxifylline group is 50% and that in the control group it would be 1%, with an alpha error of 5% and power of 90% we need to enroll 38 cases in the study.

Further assuming a dropout rate of 5% we need to enroll 40 cases randomized into two groups, 20 each, by block randomization method taking a block size of 4.

 

STATISTICAL ANALYSIS: Continuous data- Student’s t test 

- Nonparametric analysis- Mann Whitney test 

- Survival outcome By Kaplan-Meier method curve.

- For all tests, p≤ 0.05 will be considered statistically significant. 

- Analysis will be performed using SPSS.

- The analysis will be done with intention to treat and per protocol analysis if applicable.

Stopping rule:  

Development of serious adverse effects leading to withdrawal of the drug or death from any cause 

Adverse events 

It is defined as the new onset event that is considered as a part of intervention which otherwise may be absent in absence of such intervention or therapy. All adverse events will be recorded.