Track topics on Twitter Track topics that are important to you
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.
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.
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.
- 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
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.
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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
St. Michael's Hospital
St. Michael's Hospital, Toronto
Published on BioPortfolio: 2014-08-27T03:43:07-0400
Hepatopulmonary Syndrome is a respiratory complication of liver cirrhosis defined as a triad: hypoxemia (PaO2 < 80 mmHg in room air), chronic liver disease and intrapulmonary vasodilatatio...
This proof-of-concept clinical trial will determine the safety and tolerability of midodrine in patients with hepatopulmonary syndrome (HPS). Exploratory endpoints will assess the effect o...
to investigate the prevalence of hepatopulmonary syndrome in cirrhosis patients caused by Hepatitis B in western China
Advanced liver disease and low ascitic fluid protein concentration have been identified as risk factors for spontaneous bacterial peritonitis in cirrhosis. Moreover, renal impairment and h...
Patients with advanced cirrhosis have abnormal translocation of Gram-negative bacteria across the intestinal barrier and subsequent systemic inflammatory response. We hypothesized that thi...
s: Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect - defined by an increased alveolar-arterial oxygen gradient - induced by pulmonay vascular dilatations in the conte...
Hepatopulmonary syndrome (HPS) is defined as a triad characterized by arterial deoxygenation, intrapulmonary vascular dilatations (IPVDs), and liver disorder. The aims of this study were to assess the...
Pulmonary transit time (PTT) is the transit time of blood from the right side of the heart to the left side of the heart. The aim of the present study was to evaluate the role of the PTT derived from ...
A high proportion of patients with irritable bowel syndrome (IBS) respond to placebo in clinical trials (estimated at about 40%). We aimed to identify factors that contribute to the high placebo respo...
A synthetic fluoroquinolone (FLUOROQUINOLONES) with broad-spectrum antibacterial activity against most gram-negative and gram-positive bacteria. Norfloxacin inhibits bacterial DNA GYRASE.
A syndrome characterized by the clinical triad of advanced chronic liver disease, pulmonary vascular dilatations, and reduced arterial oxygenation (HYPOXEMIA) in the absence of intrinsic cardiopulmonary disease. This syndrome is common in the patients with LIVER CIRRHOSIS or portal hypertension (HYPERTENSION, PORTAL).
Misunderstanding among individuals, frequently research subjects, of scientific methods such as randomization and placebo controls.
An effect usually, but not necessarily, beneficial that is attributable to an expectation that the regimen will have an effect, i.e., the effect is due to the power of suggestion.
Condition with a variable constellation of phenotypes due to deletion polymorphisms at chromosome location 22q11. It encompasses several syndromes with overlapping abnormalities including the DIGEORGE SYNDROME, VELOCARDIOFACIAL SYNDROME, and CONOTRUNCAL AMOMALY FACE SYNDROME. In addition, variable developmental problems and schizoid features are also associated with this syndrome. (From BMC Med Genet. 2009 Feb 25;10:16) Not all deletions at 22q11 result in the 22q11deletion syndrome.
Hepatology is the study of liver, gallbladder, biliary tree, and pancreas, and diseases associated with them. This includes viral hepatitis, alcohol damage, cirrhosis and cancer. As modern lifestyles change, with alcoholism and cancer becoming more promi...
Asthma COPD Cystic Fibrosis Pneumonia Pulmonary Medicine Respiratory Respiratory tract infections (RTIs) are any infection of the sinuses, throat, airways or lungs. They're usually caused by viruses, but they can also ...