A Pilot Study of Norfloxacin for Hepatopulmonary Syndrome
A Pilot Study of Norfloxacin for Hepatopulmonary Syndrome
The hepatopulmonary syndrome (HPS)and pre-HPS is a disease seen in patients with chronic
 liver disease, whereby patients develop dilations in the blood vessels of the lungs,
 resulting in low oxygen levels and shortness of breath.

 In this study, each HPS and pre-HPS subject will be treated with a commonly used antibiotic
 called "norfloxacin" (approved for use in the treatment of gonorrhea, prostatitis and urinary
 tract infections) for a 4-week period. In order to ensure that any observed improvement was
 indeed due to norfloxacin, each subject will also be treated with a separate 4-week course of
 an identical placebo. There will also be a 4 week wash-out period (no study
 medication/placebo) between the 2 courses of treatment.

 The primary aim of the study will be to measure improvements in oxygen levels while on
 norfloxacin, although a number of secondary parameters will also be followed.
Research Question:

 This is a pilot study; the fundamental research question is:

 Does norfloxacin administration reduce Alveolar-arterial oxygen gradient (AaDO2) in patients
 with HPS and pre-HPS?

 However, for this particular pilot study, the research question is:

 What is the magnitude and standard deviation of the change in A-a gradient with norfloxacin
 treatment in subjects with HPS and pre-HPS ?

 This is in order to enable accurate sample size estimations for a future large
 randomized-controlled trial of norfloxacin administration in the treatment of HPS and
 pre-HPS.

 Significance:

 HPS and pre-HPS is a disease that carries a high morbidity and an alarmingly high mortality.
 Orthotopic liver transplantation (OLT) is the only effective treatment, and in itself
 threatens a significant operative mortality in these patients.

 A growing body of literature has built an elegant and compelling case for the role of gut
 bacterial translocation and secondary pulmonary nitric oxide (NO) overproduction in the
 pathophysiology of HPS.

 A sophisticated rat model and a case report in a human subject have supported the potential
 for norfloxacin, a widely available, cheap and non-toxic antibiotic, to mitigate these
 effects and improve oxygenation, which is the most important contributor to both morbidity
 and mortality in HPS.

 Given the dismal prognosis of this disease, the biological plausibility of the hypothesis,
 and the minimal foreseeable deleterious consequences of the intervention, it behooves the
 scientific community to formally test this theory.

 A. Objectives

 -  to evaluate the magnitude and standard deviation of the change in AaDO2 with norfloxacin
 treatment in subjects with HPS and pre-HPS, to enable accurate sample size estimations
 for a future large randomized-controlled trial of norfloxacin administration in the
 treatment of HPS

 -  to evaluate subject recruitment and retention, in order to determine the feasibility of
 a future large randomized-controlled trial of norfloxacin administration in the
 treatment of HPS and pre-HPS

 -  to qualitatively evaluate the usefulness of a number of new measures that have never
 been utilized in this subject population (baseline dyspnea index (BDI), transitional
 dyspnea index (TDI), Chronic Respiratory Disease Questionnaire (CRQ)

 -  to evaluate the hypothesized role of alveolar NO (measured by exhaled NO) as an
 intermediary in the relationship between norfloxacin administration and AaDO2

 Methods

 i. Overview of Study Design - intervention and maneuver

 This is a single-university center (University of Toronto), randomized, controlled pilot
 study with a crossover design. The intervention is exposure to norfloxacin (400 mg po bid)
 for a 4-week period, compared to an identical placebo treatment. In the crossover design, all
 subjects will receive both norfloxacin and the placebo medication, but the order of treatment
 will be randomized, as detailed in the study maneuver, below.

 Study maneuver:

 Eligible subjects will be identified by Drs. Faughnan and Gupta. They will subsequently be
 recruited by the respirology research coordinator (see details below). Next, the hospital
 pharmacist will provide each subject with a 4-week supply of either norfloxacin 400 mg po
 bid, or an identical placebo, according to the pre-determined computerized randomization
 scheme. The pharmacist will be the only person aware of the treatment allocation throughout
 the study (subjects, research coordinator, treating physicians and outcome assessors will be
 blinded). After the initial 4-week treatment, there will be a 4-week washout period, after
 which the pharmacist will provide each subject with a 4-week supply of the alternative agent
 (crossover) (see figure 2).

 ii. Measurements - outcomes Outcomes

 The primary endpoint in this study is the difference in the change in AaDO2 over the
 treatment course, between treatment and placebo groups. The secondary endpoints include
 partial pressure of arterial oxygen (paO2), exhaled NO, diffusion lung capacity for carbon
 monoxide (DLCO), cardiac output (CO), total peripheral resistance (TPR), pulmonary artery
 systolic pressure (PAP) (on echocardiogram), endotoxin levels, endothelin-1 (ET-1) levels,
 MELD score (model for end-stage liver disease) (based on creatinine, bilirubin and INR),
 baseline dyspnea index (BDI), transitional dyspnea index (TDI), and Chronic Respiratory
 Disease Questionnaire (CRQ).

 Assessment of Outcomes Please see attached "procedure table," and "data collection sheet."

 Once randomized, subjects will undergo initial assessment at time 0 (week 0), with:

 1. ABG (pO2, AaDO2)

 2. pulmonary function tests: exhaled NO, DLCO

 3. BP, echocardiogram: CO, TPR, PAP

 4. blood tests: INR, bilirubin, creatinine (MELD score), liver enzymes (ALT, AST, ALP,
 bilirubin), albumin, endotoxin level, ET-1 levels

 5. questionnaires: BDI/TDI, CRQ

 6. history and physical exam by study physician

 All of these measures will be repeated after 4 weeks (end of first treatment course), 8 weeks
 (before start of next treatment course), and 12 weeks (end of second treatment course). In
 addition, ABG and exhaled NO alone will be repeated at 2 weeks and 10 weeks (midway through
 each treatment period). Finally, blood (40 ml) will be drawn at time 0, 4, 8, 12 weeks and
 stored for measurement of future variables.
Inclusion Criteria:

 Diagnosis of HPS, based on all of the following:

 evidence of portal hypertension (esophagogastric varices or portal hypertensive gastropathy
 identified on esophagogastroduodenoscopy, and/or varices seen on computerized tomography
 (CT) scan or ultrasound, and/or splenomegaly with no other explanation, and/or ascites with
 no other explanation, and/or hepatic vein wedge pressure greater than 12 mm Hg)
 Intrapulmonary shunt on contrast echocardiography (CE) AaDO2 greater than 20 mm Hg on
 standing, room air arterial blood gas (ABG) OR

 Pre-HPS with elevated exhaled Nitric Oxide:

 evidence of portal hypertension (esophagogastric varices or portal hypertensive gastropathy
 identified on esophagogastroduodenoscopy, and/or varices seen on computerized tomography
 (CT) scan or ultrasound, and or splenomegaly with no other explanation, and/or ascites with
 no other explanation, and/or hepatic vein wedge pressure greater than 12 mm Hg) IPVDs
 diagnosed on contrast echocardiography (CE) exhaled nitric oxide level greater than 12.6
 ppb

 Exclusion Criteria:

 Significant pre-existing respiratory disease (in these cases, the diagnosis of HPS or
 pre-HPS is uncertain, given that observed elevations in AaDO2 may be from underlying lung
 disease):

 forced expiratory volume in 1 second (FEV1) less than 70 percent of predicted forced vital
 capacity (FVC) less than 70 percent of predicted FEV1/FVC less than 0.7 inability to
 perform pulmonary function tests (for the same reasons, it is important to document normal
 underlying lung function) echocardiographic estimated right ventricular systolic pressure
 50 mm Hg or right heart catheterization mean pulmonary artery pressure greater than 25 mm
 Hg (pulmonary hypertension may result in progressive hypoxemia due to intracardiac shunt or
 right ventricular failure) inadequate echocardiographic window to allow for accurate
 transthoracic contrast (bubble) echocardiogram (CE) (this is the test used to identify
 IPVDs) antibiotic use within the last 1 month (this is the intervention being tested) (note
 that all subjects will be under the concurrent care of a gastroenterologist or
 hepatologist, and some patients may accordingly be on prophylactic antibiotic therapy for
 prior SBP or variceal hemorrhage; these patients will be excluded) (20 percent expected
 rate of exclusion due to this criterion) current use of exogenous nitrates (may increase
 exhaled NO levels) norfloxacin intolerance (norfloxacin administration is the study
 intervention): allergy or intolerance to norfloxacin or other fluoroquinolones history of
 tendon rupture associated with norfloxacin or other fluoroquinolones glucose 6-phosphate
 dehydrogenase deficiency (possibility of hemolytic reactions with norfloxacin) known
 prolongation of the QTc interval to a duration that is > 50% of the R-R interval, subjects
 taking QTc-interval prolonging drugs, subjects with uncorrected hypokalemia, clinically
 significant bradyarrhythmias or acute myocardial ischemia (norfloxacin may worsen this)
 pregnancy (norfloxacin contraindicated) age less than 18 or greater than 70 expected
 death/transplantation within 3 mo (treating physician's discretion) lactose intolerance
 (placebo contains lactose) Smoking within the last 1 month