Transjugular intrahepatic portosystemic shunt for refractory ascites: an analysis of the literature on efficacy, morbidity, and mortality

OBJECTIVES: Transjugular intrahepatic portosystemic shunt (TIPS) is frequently used to treat patients with refractory ascites, but its role is controversial. We sought to determine from the literature the efficacy, morbidity, and mortality associated with TIPS for refractory ascites. METHODS: We searched MEDLINE and identified studies published in English from January, 1985, to March, 2003, that evaluated the effect of TIPS in patients with refractory ascites. Outcomes that were analyzed included complete resolution of ascites, reduction in ascites, mortality, encephalopathy, stenosis, and renal function. Data were analyzed on an intention to treat basis. RESULTS: Of 25 studies identified, 16 were included in the analysis. The pooled estimate for complete response at 6 months was 45% and for any response (complete and partial) was 63%. Pooled 6-month mortality after TIPS was 36%. Risk factors for mortality included renal insufficiency (serum creatinine >1.5 mg/dl), hyperbilirubinemia (total bilirubin >3 mg/dl), advanced age (>60 yr), and poor response to TIPS. The pooled rate of new or worsening encephalopathy after TIPS was 32%. In most cases, encephalopathy was managed medically or by reduction in shunt size; however, refractory cases were associated with 100% mortality in most studies. Studies reporting the effect of TIPS on kidney function showed improvement in creatinine clearance and urinary sodium excretion. CONCLUSIONS: TIPS is effective in eliminating ascites or substantially reducing ascites in cases refractory to medical therapy. Renal insufficiency, refractory encephalopathy, and hyperbilirubinemia were consistently associated with mortality after TIPS. In individuals with risk factors for mortality, alternative strategies should be recommended.     

Intravenous epinephrine in life-threatening asthma

STUDY OBJECTIVE: Intravenous epinephrine is a potentially vital therapy for patients with life-threatening asthma but is often avoided because of concerns about its safety. We evaluated the safety of intravenous epinephrine in a series of adults with life-threatening asthma. METHODS: We performed an explicit retrospective chart review on a case series of 27 emergency department patients aged 19 to 58 years (mean 25 years) who were treated with intravenous epinephrine for a life-threatening exacerbation of asthma between 1989 and 1997. Explicit criteria for adverse effects, including cardiac arrhythmia or ischemia, hypotension or hypertension, neurologic injury, and death, were defined before chart review. RESULTS: No patient had an arrhythmia other than sinus tachycardia, and there were no cases of cardiac ischemia, hypotension, neurologic deficit, or death. CONCLUSION: Intravenous epinephrine was safe in this small series of younger adults with acute life-threatening asthma. A prospective trial of its use to better define an efficacy and risk-benefit relationship is justified.     

Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated

Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.     

Disparities in HIV treatment and physician attitudes about delaying protease inhibitors for nonadherent patients

BACKGROUND: Current HIV treatment guidelines recommend delaying antiretroviral therapy for nonadherent patients, which some fear may disproportionately affect certain populations and contribute to disparities in care. OBJECTIVES: To examine the relationship of physician's attitude toward prescribing protease inhibitors (PIs) to nonadherent patients with disparities in PI use and with health outcomes. DESIGN: Prospective cohort study. PATIENTS AND SETTING: A national probability sample of HIV-infected adults in the United States and their health care providers was surveyed between January 1996 and January 1998. We analyzed data on 1717 patients eligible for PI treatment and the 367 providers who cared for them. MEASUREMENTS: Providers' attitude toward prescribing PIs to nonadherent patients, time until patients' first receipt of PIs, mortality, and physical health status. MAIN RESULTS: Eighty-nine percent of providers agreed that patient adherence is important in their decision to prescribe PIs (Selective) while 11% disagreed (Nonselective). Patients who had a Selective provider received PIs later than those with a Nonselective provider (P =.05). Adjusting for patient demographics and health characteristics and provider demographics, HIV knowledge, and experience, Latinos, women, and poor patients received PIs later if their provider had a Selective attitude but as soon as others if their provider had a Nonselective attitude. African-American patients received PIs later than whites, irrespective of their providers' prescribing attitude. Patients with Selective providers had similar odds of mortality than those with Nonselective providers (odds ratio, 1.1; 95% confidence interval, 0.6 to 2.0), but had slightly worse adjusted physical health status at follow-up (49.1 vs 50.4, respectively; P =.04), after controlling for baseline physical health status and other patient and provider covariates. CONCLUSIONS: Most providers consider patient adherence an important factor in their decision to prescribe PIs. This attitude appears to account for the relatively later use of PI treatment among Latinos, women, and the poor. Given the rising HIV infection rates among minorities, women, and the poor, further investigation of this treatment strategy and its impact on HIV resistance and outcomes is warranted.     

Accuracy of transrectal ultrasound in predicting pathologic stage of rectal cancer before and after preoperative radiation therapy

Transrectal ultrasound (TRUS) and CT scan staging of rectal cancers before, and TRUS staging after, 45 Gy of irradiation were compared with the pathologic stage of the resected specimen in 19 patients. Accuracy of TRUS before and after irradiation, and of CT scan before irradiation, was 32 percent, 63 percent, and 53 percent, respectively. CT scan before and TRUS after irradiation predicted lymph node involvement in 79 percent and 68 percent of cases, respectively. Positive predictive value for lymph node involvement before irradiation was 60 percent for CT scan and 37.5 percent for TRUS; after irradiation, it was 50 percent for TRUS. Negative predictive value was 100 percent for CT scan and TRUS before radiation and 88 percent for TRUS after irradiation. Preoperative radiation therapy makes TRUS and CT scan less effective as staging techniques. The absence of lymph nodes on TRUS and CT scan before and after irradiation is reliable.Read in part at the Tripartitate Meeting, Birmingham, England, June 19 to 22, 1989.     

Epidermal growth factor stimulation of DNA synthesis is potentiated by compounds that inhibit its clustering in coated pits

We have used inhibitors of receptor-mediated endocytosis to investigate the mechanism and function of epidermal growth factor uptake by cultured cells. When rhodamine-labeled epidermal growth factor is bound to cell surface receptors on confluent monolayers of BALB/c 3T3 cells, it rapidly collects in cell surface clusters and is internalized. The clustering of occupied receptors requires Ca(2+) and is inhibited by primary alkylamines; both of these properties are shared by the enzyme transglutaminase (R-glutaminyl-peptide:amine gamma-glutamyl-yltransferase, EC 2.3.2.13). In Chinese hamster ovary cell extracts, methylamine inhibits 25-50% of the transglutaminase activity with a K(i) of 0.2 mM, and it inhibits the remaining transglutaminase activity with a K(i) of 20 mM. Clustering is almost completely inhibited by 10 mM methylamine. The polypeptide antibiotic bacitracin inhibits clustering of rhodamine-labeled epidermal growth factor or alpha(2)-macroglobulin at 0.7 mM, and it inhibits approximately 40% of the transglutaminase activity in Chinese hamster ovary cells with a K(i) of 0.03 mM. Fluorescent ligands bound to cell surface receptors in the presence of bacitracin form clusters within 30 min after bacitracin is removed from the culture medium. These results indicate that a transglutaminase-like enzyme may be required for the clustering and subsequent internalization of occupied receptors. The effects of 10 mM methylamine and 0.7 mM bacitracin on epidermal growth factor stimulation of DNA synthesis were examined. The stimulation of DNA synthesis by epidermal growth factor was increased 2- to 7-fold in the presence of methylamine or bacitracin. Alone, methylamine or bacitracin increased DNA synthesis 1.1- to 3-fold. The stimulation of DNA synthesis resulting from the simultaneous presence of the hormone and the clustering inhibitor was always greater than the sum of the stimulations produced by the hormone and the clustering inhibitors alone. The potentiation of epidermal growth factor activity by clustering inhibitors suggests that the hormone acts at the cell surface. We propose that rapid internalization of occupied receptors via coated pits may be a mechanism to limit the response to hormones.     

Treatment of liver failure in rats with end-stage cirrhosis by transplantation of immortalized hepatocytes

The shortage of organ donors has impeded the development of human hepatocyte transplantation. Immortalized hepatocytes could provide an unlimited supply of transplantable cells. To determine whether immortalized hepatocytes could provide global metabolic support in end-stage liver disease, 35 immortalized rat hepatocyte clones were developed by transduction with the gene encoding the simian virus 40 T antigen (SV40Tag). The SV40Tag sequence and a suicide gene, herpes simplex virus thymidine kinase (HSV-tk), were flanked by loxP sequences so that they could be excised by Cre/lox recombination. When transplanted into the spleens of portacaval-shunted rats, 3 of the 35 immortalized hepatocyte clones prevented the development of hyperammonemia-induced hepatic encephalopathy. The protection was reversed by treatment with ganciclovir, which kills HSV-tk-expressing cells. Transplantation of alginate-encapsulated, immortalized hepatocytes into the spleens of cirrhotic rats resulted in significant improvement in prothrombin time, serum albumin and bilirubin levels, hepatic encephalopathy score, and duration of survival. The metabolic support provided by the immortalized cells equaled that observed after transplantation of primary rat hepatocytes. In conclusion, immortalized hepatocytes can function as well as primary hepatocytes following transplantation and can be engineered to contain safeguards that could make them clinically useful. Further investigation is warranted regarding the mechanisms of loss of mass or function of the transplanted hepatocytes over time and how the relatively few engrafted hepatocytes can ameliorate liver decompensation in cirrhosis.     

Use of fractional flow reserve versus stress perfusion scintigraphy in stent restenosis

BackgroundFractional flow reserve (FFR) is a valid surrogate for hemodynamic significance in stenotic native coronary arteries. The aim of this study was to examine the value of FFR compared to stress perfusion myocardial scintigraphy (SPMS) in patients with coronary stent restenosis.MethodsWe studied 42 patients, aged 62 ± 10 years, with stent restenosis 5.3 ± 1.6 months after coronary stent implantation. All patients had a single coronary lesion of intermediate severity (diameter stenosis 40–70%). FFR measurement, SPMS, and quantitative angiography of the stent stenosis were performed in all patients.ResultsThe mean percentage in stent diameter stenosis was 53 ± 9%. FFR was 0.77 ± 0.15. In 20 patients FFR was below 0.75. Nineteen patients had reversible perfusion defects in SPMS. FFR showed good diagnostic accuracy for the detection of reversible perfusion defects in SPMS (AUROC 0.86, 95% CI 0.74–0.98). The percentage of agreement of SPMS and FFR was 88%, with the best cutoff value of 0.75 for FFR.ConclusionsA FFR value of 0.75 is not only valid for diagnosing significant native coronary stenosis, but also for stent restenosis. Thus, FFR measurement should be taken into account when making decisions regarding patients with stent restenosis.