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Miguel R Arguedas

Publications and source records attributed to Miguel R Arguedas.

18 recordsLinked to original sources
PubMed2005

Carboxyhemoglobin levels in cirrhotic patients with and without hepatopulmonary syndrome.

BACKGROUND AND AIMS: Heme oxygenase (HO) catalyzes hemoglobin into bilirubin, iron, and carbon monoxide (CO), a known vasodilator. HO expression and CO production as measured by blood carboxyhemoglobin (COHb) levels increase in experimental hepatopulmonary syndrome (HPS) and contribute to vasodilatation. Whether CO contributes to HPS in humans is unknown. Our aim was to assess if arterial COHb levels are increased in cirrhotic patients with HPS relative to those without HPS. METHODS: We collected data prospectively in stable nonsmoking outpatients with cirrhosis. Demographic and clinical data and room-air arterial blood gases were collected and analyzed. HPS was diagnosed using established criteria. RESULTS: A total of 159 patients were studied. HPS was present in 27 (17%) patients. Mean age was 52 +/- 9 years, 54% were men, and hepatitis C and/or alcohol were the most common causes (53%). Fourteen percent were Child-Pugh class A, 53% were Child-Pugh class B, and 33% were Child-Pugh class C. Demographic and clinical features were similar between HPS and non-HPS patients except for the Child-Pugh score, which was lower in patients with HPS. Arterial Pa o 2 levels were lower and the alveolar-arterial oxygen gradient was higher in patients with HPS ( P < .001). COHb levels were increased in HPS relative to non-HPS ( P < .001) and correlated with Pa o 2 ( P < .001) and Aa po 2 ( P < .001) levels. CONCLUSIONS: COHb levels are increased in cirrhotic patients with HPS and correlate with gas exchange abnormalities. These results are consistent with findings in experimental HPS and suggest that CO may contribute to human HPS.

Bilirubin↗
PubMed2004

Hepatitis A.

Hepatitis A infection is typically transmitted by the fecal-oral route. Symptomatic infection is highly dependent on the age of the patient and usually follows a self-limited course. Once diagnosed, clinical and biochemical follow-up in the outpatient setting is generally appropriate. Treatment aims are to achieve symptomatic relief and to maintain adequate hydration and caloric intake. In patients with more severe disease, hospitalization may be needed to accomplish aggressive symptomatic therapy and close monitoring of liver function tests and mental status. Prompt evaluation for liver transplantation is appropriate in the rare case where fulminant liver failure develops. Given the absence of specific therapy for hepatitis A virus infection, the most important health care intervention is prevention of infection and/or transmission, which can be accomplished with the safe and effective use of immune globulin and commercially available vaccines.

Journal Article↗
PubMed2004

Re-examination of the cost-effectiveness of surgical versus medical therapy in patients with gastroesophageal reflux disease: the value of long-term data collection.

OBJECTIVES: For patients with reflux esophagitis, long-term therapeutic options include proton pump inhibitor (PPI) therapy and/or antireflux surgery. An earlier cost-effectiveness analysis concluded that at 5 yr, medical therapy was less expensive but similarly effective to fundoplication, but the results were sensitive to estimates on quality of life and long-term medication usage, which were derived from "expert opinion." Recently, data from randomized controlled trials addressing these variables have become available. We have incorporated these new data into a revised Markov model to examine the cost-effectiveness of surgical versus medical therapy in patients with severe reflux esophagitis. METHODS: A Markov simulation model was constructed using specialized software (DATA PRO 4.0, Williamstown, MA). Total expected costs and quality-adjusted life-years were calculated for long-term medical therapy and for laparoscopic Nissen fundoplication. Probabilities were obtained from the medical literature using Medline. Procedural and hospitalization costs used were the average Medicare reimbursements at our institution. Medication costs were the average wholesale price. The analysis was extended over a 10-yr time horizon at a discount rate of 3%. RESULTS: The discounted analysis shows that medical therapy is associated with total costs of 8,798 dollars and 4.59 quality-adjusted life-years, whereas the surgical strategy is more expensive (10,475 dollars) and less effective (4.55 quality-adjusted life-years). The results were robust to most one-way sensitivity analyses. CONCLUSIONS: Long-term medical therapy with proton pump inhibitors is the preferred strategy for patients with gastroesophageal reflux disease and severe esophagitis. Our study highlights the importance of using primary, patient-derived data rather than expert opinion.

Analysis of Variance↗
PubMed2004

A cost-minimization analysis of alternative strategies in diagnosing pancreatic cancer.

BACKGROUND: Several modalities currently exist for tissue confirmation of suspected pancreatic cancer prior to therapy. Since there is a paucity of cost-minimization studies comparing these different biopsy modalities, we analyzed costs and examined effectiveness of four alternative strategies for diagnosing pancreatic cancer. METHODS: A decision analysis model of patients with suspected pancreatic cancer was constructed. We analyzed costs, failure rate, testing characteristics, and complication rates of four commonly employed diagnostic modalities: 1) computerized tomography or ultrasound-guided fine-needle aspiration (CT/US-FNA), 2) endoscopic retrograde cholangiopancreatography with brushings (ERCP-B), 3) Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA), and 4) laparoscopic surgical biopsy. If the first attempt with a particular modality failed, a different modality was employed to identify the most preferable secondary biopsy strategy. RESULTS: This analysis identifies EUS-FNA as the preferred initial modality for the diagnosis of pancreatic cancer. Resultant expected costs and strategies in decreasing optimality include: 1) EUS-FNA (1,405 dollars), 2) ERCP-B (1,432 dollars), 3) CT/US-FNA (3,682 dollars), and 4) surgery (17,711 dollars). If a patient presents with obstructive jaundice, decision analysis modeling resulted in a total expected costs of 1,970 dollars if ERCP-B is successful at the time of biliary stent placement. Additional analyses to identify the preferred follow-up modality after a failed alternative method showed that EUS-FNA is the preferred secondary modality if any of the other three modalities failed first, in both the setting of and absence of obstructive jaundice. One- and two-way sensitivity analysis of the variables shows unchanged results over an acceptable range. CONCLUSIONS: This cost-minimization study illustrates that EUS-FNA is the best initial and the preferred secondary alternative method for the diagnosis of suspected pancreatic cancer. In addition to local expertise and availability, costs and diagnostic yield should be considered when choosing an optimal diagnostic strategy.

Biopsy↗
PubMed2003

Screening for hepatocellular carcinoma: why, when, how?

Hepatocellular carcinoma (HCC) is a major public health concern in many areas of the world, and its incidence is increasing in the United States and other countries. Screening for HCC in patients with cirrhosis has been advocated to identify those with small lesions who would benefit from transplantation or surgical resection. Despite these recommendations, several issues regarding screening remain controversial. No randomized, controlled trials have confirmed that surveillance for HCC reduces disease-specific mortality. In addition, the most appropriate screening test and optimal screening interval have not yet been defined. Clearly, these unresolved questions have a major impact on the cost-effectiveness of a screening program either at the population or the clinic level. A few studies, however, have suggested that screening may be cost-effective because a minor survival benefit could result in a cost that is acceptable to decision makers.

Biomarkers↗
PubMed2003

Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis.

Cirrhosis is associated with decrements in health-related quality of life (HRQOL), but the specific effects of encephalopathy, especially subclinical, on quality of life are incompletely understood. Therefore, the aim of our study was to define the effects of encephalopathy on specific domains of HRQOL in a sample of patients with advanced liver disease. The sample consisted of 160 patients with cirrhosis presenting for liver transplantation evaluation. Health-related quality of life was measured with the Short Form-36 questionnaire. Clinical, demographic, and laboratory data were collected. The presence and degree of encephalopathy was ascertained clinically and by the use of the Reitan trail test. HRQOL scores were compared according to liver disease severity and to the presence and degree of encephalopathy. In addition, scores were compared to US population norms. Data were obtained from 148 patients. Compared to the US general population, the physical and mental component summary scores were lower in patients with cirrhosis. Among patients with cirrhosis, there were no significant differences in the physical and mental component summary scores according to age, gender, ethnicity, and etiology (hepatocellular versus/cholestatic and HCV versus non-HCV). Increasing severity of liver disease (based on the Child-Pugh score), a history of hospitalizations, and a history of ascites were associated with decreased physical component summary scores but not mental component summary scores. Patients with encephalopathy (overt and subclinical) had decreased physical and mental component summary scores compared to patients without encephalopathy. Compared to patients without encephalopathy, those with subclinical encephalopathy had a lower mental component summary score. In conclusion, cirrhosis is associated with a decreased HRQOL, especially at advanced stages. Increased severity of liver disease is associated with decreased physical aspects of quality of life. Overt hepatic encephalopathy negatively affects both physical and mental aspects of quality of life, whereas subclinical encephalopathy affects mainly the mental aspects, independently of liver disease severity.

Activities of Daily Living↗
PubMed2003

Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation.

The hepatopulmonary syndrome (HPS) occurs in a subgroup of patients with cirrhosis and results from intrapulmonary vasodilatation, which may cause significant hypoxemia. Liver transplantation has emerged as a therapeutic option for patients with HPS based on retrospective case series and reports. However, morbidity and mortality appear to be increased after transplantation for HPS, and no prospective studies evaluating clinical features that may predict poor surgical outcome are available. Therefore, we prospectively evaluated the utility of the degree of hypoxemia, the arterial oxygen response to 100% oxygen administration, and the macroaggregated albumin (MAA) scan quantification of intrapulmonary shunting as predictors for outcome after liver transplantation. Our cohort consisted of 24 patients with cirrhosis and HPS who underwent liver transplantation over a 5-year period at 2 transplant centers who were followed at least 1 year after transplantation. All patients underwent preoperative evaluation for HPS with standardized methods. Seven patients (29%) died postoperatively, 5 of cardiorespiratory complications. All deaths occurred within 10 weeks after transplantation. A preoperative arterial oxygen tension (PaO(2)) of </= 50 mm Hg alone or in combination with a MAA shunt fraction >/= 20% were the strongest predictors of postoperative mortality. In conclusion, we found that mortality is increased after liver transplantation for HPS, particularly in patients with more severe hypoxemia and significant intrapulmonary shunting. Preoperative testing for the severity of HPS can be used to stratify patients according to the risk for postoperative mortality.

Adult↗
PubMed2003

Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis.

OBJECTIVES: Screening for hepatocellular carcinoma (HCC) is advocated in cirrhotic patients to optimize early detection and treatment. However, the cost-effectiveness is not well defined. Our objective was to perform a cost-utility analysis from a third-party payer's perspective of no screening, alpha-fetoprotein (AFP) concentration measurement alone, abdominal ultrasound (US) and AFP, abdominal three-phase CT and AFP, and abdominal magnetic resonance imaging (MRI) and AFP. METHODS: A Markov model was constructed simulating the natural history of hepatitis C-related cirrhosis in a cohort of patients age 50 yr over a time horizon of their remaining life expectancy. Transition probabilities were obtained from published data and U.S. vital statistics. Costs represented Medicare reimbursement data. Costs and health effects were discounted at a 3% annual rate. RESULTS: Screening with ultrasonography and AFP concentration measurement was associated with an incremental cost-utility ratio of 26,689 US dollars per quality-adjusted life year, whereas screening with abdominal three-phase CT and AFP concentration measurement was associated with an incremental cost-utility ratio of 25,232 US dollars per quality-adjusted life year compared with no screening. Compared with three-phase CT and AFP, magnetic resonance and AFP imaging costs 118,000 US dollars per quality-adjusted life year. Sensitivity analysis demonstrated that the results are most sensitive to the annual incidence of HCC, proportion of tumors amenable to treatment, and to transplant candidacy, whereas the choice of screening strategy is most sensitive to the test characteristics and cost. CONCLUSIONS: Screening for HCC with CT is a cost-effective strategy in transplant-eligible patients with cirrhosis secondary to chronic hepatitis C viral (HCV) infection, comparable with other commonly accepted screening interventions such as mammography and colonoscopy.

Aged↗
PubMed2003

Hepatitis A and considerations regarding the cost-effectiveness of vaccination programs.

Hepatitis A vaccines have demonstrated a high degree of immunogenicity and an excellent safety profile. Immunization of certain populations and patient subgroups is recommended according to specific epidemiological and clinical factors, such as a greater likelihood of acquisition of infection or concerns regarding the risk of development of fulminant hepatitis and death. Therefore, the economic implications of routine and/or targeted vaccination programs in the general population and high-risk individuals have been examined. In this manuscript, the available data from the literature regarding the cost-effectiveness of hepatitis vaccination programs in healthy individuals and in those with chronic liver disease are reviewed.

Cost-Benefit Analysis↗
PubMed2003

The critically ill liver patient: the variceal bleeder.

Esophageal varices develop in patients with cirrhosis once portal pressure, measured by hepatic venous pressure gradient, and exceeds 10 mm Hg. At a portal pressure of 12 mm Hg, variceal bleeding may develop that is associated with a mortality of 30% to 50% per episode. In addition to an elevated portal pressure, other risk factors for the development of variceal hemorrhage include: variceal size, endoscopic features on the variceal wall (i.e., red wales), and Child-Pugh class. In patients with suspected variceal hemorrhage, the treatment of the acute episode includes intravascular volume expansion, hemostasis through the use of pharmacological agents and endoscopy, and the prevention and treatment of potential complications associated with variceal hemorrhage such as aspiration pneumonia, spontaneous bacterial peritonitis and hepatic encephalopathy. Given a high rate of rebleeding, long-term prevention through secondary prophylaxis should be instituted in all patients who have survived an episode of variceal bleeding. Current prophylactic options include: non-selective beta-blockers alone (first line) or in combination with long-acting nitrates (isosorbide mononitrate) and/or endoscopic variceal obliteration achieved through sclerotherapy or preferably, band ligation.

Critical Illness↗
PubMed2002

Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status.

BACKGROUND: The current TNM classification system does not consider tumor length or the number of lymph nodes in the staging and classification scheme for patients with esophageal carcinoma. Using data from the National Cancer Institute SEER Program, the authors explored the effect of tumor length and number of positive lymph nodes on survival in patients with esophageal carcinoma. METHODS: Patients with esophageal adenocarcinoma or squamous cell carcinoma were subgrouped according to historic stage with localized, regional, or distant disease. Demographic factors (age at diagnosis, race, and gender) and tumor characteristics (morphology, histologic grade, tumor length, primary site, depth of invasion, number of positive lymph nodes, proportion of positive lymph nodes dissected, and distant metastatic sites) were examined. RESULTS: Overall factors that were associated with an increased mortality risk included increasing age at diagnosis, black race versus white race, histologic grade, primary tumor site in the lower esophagus and abdomen versus upper regions, and increasing depth of invasion. Among patients with regional disease, the number of positive lymph nodes (>/= 5 vs. < 5) was related to an increasing risk (hazard ratio [HR], 1.29; 95% confidence interval [95%CI], 1.06-1.56). The proportion of positive lymph nodes compared with the number of lymph nodes dissected conferred an increased risk (HR, 1.63; 95%CI, 1.26-2.11). Among patients with distant disease, sites other than distant lymph nodes implied an increased mortality risk (HR, 1.37; 95%CI, 1.37-1.65). Tumor length was an independent predictor of mortality when controlling for depth of invasion in patients with localized disease (HR, 1.15; 95%CI, 1.08-1.21). CONCLUSIONS: Tumor length, the number of involved lymph nodes, and the ratio of positive lymph nodes are important prognostic factors for survival in patients with esophageal carcinoma. A revised TNM classification system for patients with esophageal carcinoma might consider adding tumor length and number of positive lymph nodes as two important prognostic factors.

Adenocarcinoma↗
PubMed2002

Implementation of vaccination in patients with cirrhosis.

Vaccination for hepatitis A, hepatitis B, pneumococcus, and influenza in patients with chronic liver disease is recommended. Our purpose was to determine the degree of adherence to these recommendations in cirrhotics presenting for liver transplantation evaluation. Our sample consisted of 105 patients presenting for evaluation for liver transplantation. Data were obtained by medical record review and patient interview. The age of the patients was 52 +/- 9 years (mean +/- SD) and the Child-Pugh score was 9 +/- 2. Twenty-nine patients had natural immunity for hepatitis A. Of the remaining 76, 20 (26.3%) received vaccine. Of the 89 patients without evidence of prior exposure to hepatitis B, 23 (25.8%) received vaccine. Pneumococcal and influenza vaccination was performed in 36 (34%) and 58 (55%) respectively. In conclusion, vaccination for viral hepatitis, pneumococcus, and influenza not being consistently performed. Public health efforts aimed at raising awareness about implementing vaccination in these patients are strongly encouraged.

Female↗
PubMed2002

The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C viral infection in the United States.

OBJECTIVE: Hepatitis A vaccination is recommended for patients with chronic hepatitis C. Our aim was to analyze the cost-effectiveness of hepatitis A vaccination in these patients. The specific strategies evaluated were: no vaccination, targeted vaccination, and universal vaccination. METHODS: Clinical estimates were based on published data. Costs estimates were based on published data and institutional Medicare reimbursement rates. Health-related quality-of-life weights were derived from published data and expert estimates. The target population consisted of patients 45 yr of age with chronic hepatitis C followed every 6 months until death. We adopted a societal perspective. RESULTS: Compared with no vaccination, targeted vaccination was associated with an incremental cost-effectiveness ratio of $51,000 per quality-adjusted life-year. The incremental cost-effectiveness ratio of universal vaccination compared with targeted vaccination was $3,900,000 per quality-adjusted life-year. The results were particularly sensitive to the incidence of hepatitis A, probability of fulminant hepatic failure, and costs of hepatitis A antibody screening and vaccination. CONCLUSIONS: Targeted vaccination for hepatitis A in patients with chronic hepatitis C may be a cost-effective strategy to decrease the morbidity and mortality associated with hepatitis A superinfection. Universal vaccination is not a cost-effective alternative to targeted vaccination in this target population.

Aged↗
PubMed2002

Biliary stents in malignant obstructive jaundice due to pancreatic carcinoma: a cost-effectiveness analysis.

OBJECTIVES: Obstructive jaundice frequently complicates pancreatic carcinoma and is associated with complications such as malabsorption, coagulopathy, progressive hepatocellular dysfunction, and cholangitis in addition to disabling pruritus, which greatly interferes with terminal patients' quality of life. Endoscopic placement of biliary stents decreases the risk of these complications and is considered the procedure of choice for palliation for patients with unresectable tumors. We used decision analysis with Markov modeling to compare the cost-effectivenesses of plastic stents and metal stents in patients with unresectable pancreatic carcinoma. METHODS: A model of the natural history of unresectable pancreatic carcinoma was constructed using probabilities derived from the literature. Cost estimates were obtained from Medicare reimbursement rates and supplemented by the literature. Two strategies were evaluated: 1) initial endoscopic plastic stent placement and 2) initial endoscopic metal stent placement. We compared total costs and performed cost-effectiveness analysis in these strategies. The outcome measures were quality-adjusted life months. Sensitivity analyses were performed on selected variables. RESULTS: Our baseline analysis showed that initial plastic stent placement was associated with a total cost of $13,879/patient and 1.799 quality-adjusted life months. Initial placement of a metal stent cost $13,466/patient and conferred 1.832 quality-adjusted life months. Among the variables examined, expected patient survival was demonstrated by sensitivity analyses to have the most influence on the results of the model. CONCLUSION: Initial endoscopic placement of a metal stent is a cost-saving strategy compared to initial plastic stent placement, particularly in patients expected to survive longer than 6 months.

Biliary Tract Surgical Procedures↗
PubMed2002

Cost-effectiveness of screening, surveillance, and primary prophylaxis strategies for esophageal varices.

OBJECTIVE: Screening for varices is recommended in patients with cirrhosis to institute primary prophylaxis to prevent variceal bleeding. Our aim was to compare the cost-effectiveness of four strategies, including no screening/no prophylaxis, universal screening and primary prophylaxis with beta-blockers, universal screening and primary prophylaxis with variceal ligation, and universal institution of primary prophylaxis with beta-blockers without screening. METHODS: We constructed a Markov simulation model in two hypothetical cohorts of 50-yr-old patients with cirrhosis (one compensated and one decompensated), who were followed for 5 yr. Transition probabilities were derived from the medical literature, and costs reflected Medicare reimbursement rates at our institution. RESULTS: In patients with compensated cirrhosis, screening and primary prophylaxis with beta-blockers is associated with an incremental cost-effectiveness ratio of $3605 per year of life saved. The results were most sensitive to the prevalence of varices and risk of variceal bleeding. In patients with decompensated liver disease, primary prophylaxis without screening was associated with an incremental cost-effectiveness ratio of $1154 per year of life saved. The results were most sensitive to the cost of beta-blockers and endoscopy. CONCLUSIONS: Screening for varices is an affordable strategy in compensated liver disease, whereas universal primary prophylaxis with beta-blockers is cost-effective in decompensated patients.

Cost-Benefit Analysis↗
PubMed2002

Video-assisted thoracoscopic surgery with talc pleurodesis in the management of symptomatic hepatic hydrothorax.

OBJECTIVES: Video-assisted thoracoscopic surgery with talc pleurodesis is a therapeutic option for patients with hepatic hydrothorax that is refractory to medical therapy. We report the outcomes of 15 patients who underwent this procedure for significantly symptomatic disease. METHODS: Data on 15 consecutive patients presenting to our institution between November, 1996, and June, 2000, with refractory hepatic hydrothorax was retrospectively collected. Baseline demographical and clinical characteristics and outcomes after the procedure were analyzed. RESULTS: The mean age of our cohort was 51.5 yr, and eight (53%) of the 15 patients were male. The etiologies of liver disease were hepatitis C virus and/or alcohol (n = 12) and cryptogenic cirrhosis (n = 3). Nine patients were Child-Pugh class C and six class B. Success defined as control of symptomatic hydrothorax in the first 30 days after the procedure was achieved in 11 of 15 patients (73%). Eight of these patients remained asymptomatic at a median follow-up of 5.5 months after the procedure, but three patients experienced symptomatic fluid reaccumulation 45, 61, and 62 days after the initial procedure. After a second VATS procedure, control was achieved in two of these three patients. Complications included pain around the chest tube site, low grade fever with leukocytosis, pleurocutaneous fistula and empyema, all of which responded to medical therapy. Four patients did not respond to the procedure. There were no procedure-related deaths. Overall mortality and baseline clinical characteristics were similar between responders and nonresponders to VATS with pleurodesis. CONCLUSIONS: Symptomatic hepatic hydrothorax can be controlled with a single VATS with pleurodesis in as many as 53% of patients and with two procedures in 73% with no procedure-related mortality. The procedure may be considered as a palliative alternative in patients needing frequent thoracocentesis. It also provides an alternative to transjugular intrahepatic portosystemic shunts and is a bridge toward liver transplantation.

Adult↗
PubMedDate not supplied

Cost implications of administering intravenous proton pump inhibitors to all patients presenting to the emergency department with peptic ulcer bleeding.

OBJECTIVES: Administering proton pump inhibitors (PPI) intravenously (iv) after endoscopic treatment of bleeding peptic ulcers reduces the incidence of rebleeding, the need for operative procedures, and hospitalizations. We assessed the cost implications of iv PPI initiated in all patients presenting to the emergency department (ED) with signs of upper gastrointestinal (UGI) bleeding. METHODS: From a third-party payer perspective with a time horizon of 60 days, we built a decision analytic model comparing standard endoscopic therapy to a strategy in which all patients presenting to the ED with UGI bleeding would start iv PPI before endoscopy. After endoscopy, only those with peptic ulcers would be kept on iv PPI added to standard therapy. Probabilities of health events were extracted from published literature. Resource utilization profiles and costs (iv PPI, hospital stay for medical and operative procedures, and professional fees) were based on Medicare reimbursement data from a large hospital in Alabama. All costs were expressed in 2000 US dollars. Uncertainty was investigated through one-way sensitivity analyses and probabilistic analyses using Monte Carlo simulations. RESULTS: In a hypothetical group of 1000 individuals, routine use of iv PPI prevented 40 rebleeds, 9 surgical procedures, and 223 hospital days, and led to incremental savings of dollars 920 per subject. Probabilistic sensitivity analyses indicated that the strategy of using iv PPI was likely to be dominant even when accounting for uncertainty. CONCLUSIONS: Based on available evidence, routine administration of iv PPI to all persons presenting with UGI bleeding represents good value for money and merits consideration as standard hospital policy.

Anti-Ulcer Agents↗