Randomized, double-blind, placebo-controlled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness.

BACKGROUND: Critical illness is characterized by hypoferremia, iron-deficient erythropoiesis (IDE), and anemia. The relative risks and benefits of iron supplementation in this setting are unknown. METHODS: Anemic, critically ill surgical patients with an expected intensive care unit length of stay (ULOS) >or= 5 days were randomized to either enteral iron supplementation (ferrous sulfate 325 mg three times daily) or placebo until hospital discharge. Outcomes included hematocrit, iron markers (i.e., serum concentrations of iron, ferritin, and erythrocyte zinc protoporphyrin [eZPP]), red blood cell (RBC) transfusion, transfusion rate (mL RBC/study day), nosocomial infection, antibiotic days, study length of stay (LOS), ULOS, and death. Iron-deficient erythropoiesis was defined as an elevated eZPP concentration. RESULTS: Two hundred patients were randomized; 97 received iron, and 103 received placebo. Socio-demographics, baseline acuity, hematocrit, and iron markers were similar in the two groups. No differences were observed between the iron and placebo groups with respect to either hematocrit or iron markers following up to 28 days. However, patients treated with iron were significantly less likely to receive an RBC transfusion (29.9% vs. 44.7%, respectively; p = 0.03) and had a significantly lower transfusion rate (22.0 mL/day vs. 29.9 mL/day; p = 0.03). Subgroup analysis revealed that these differences were observed in patients with baseline IDE only. Iron and placebo groups did not differ with respect to incidence of infection (46.8% vs. 48.9%; p = 0.98), antibiotic days (14 vs. 16; p = 0.45), LOS (14 vs. 16 days; p = 0.24), ULOS (12 vs. 14 days; p = 0.69), or mortality rate (9.4% vs. 9.9%; p = 0.62). CONCLUSIONS: Enteral iron supplementation of anemic, critically ill surgical patients does not increase the risk of infection and may benefit those with baseline IDE by decreasing the risk of RBC transfusion. A trial comparing enteral and parenteral iron supplementation in this setting is warranted (ClinicalTrials.gov number, NCT00450177).

Sublingual tacrolimus: a pharmacokinetic evaluation pilot study.

STUDY OBJECTIVE: To evaluate and compare the pharmacokinetic parameters of sublingual and oral tacrolimus in the presence and absence of a drug that interacts with tacrolimus at the intestinal level. DESIGN: Prospective, randomized, open-label, parallel-group pilot study. SETTING: Large, urban, academic medical center. PATIENTS: Six adults with end-stage renal disease who were awaiting kidney transplantation; five completed the study. INTERVENTION: Patients were randomized in a 1:1 ratio to receive tacrolimus plus a clotrimazole troche (a drug that interacts with tacrolimus at the intestinal level) or tacrolimus plus nystatin suspension. For the tacrolimus route of administration, patients first received sublingual tacrolimus for five doses; after a 2-day washout period, they received oral tacrolimus for five doses. MEASUREMENTS AND MAIN RESULTS: Demographic characteristics, concomitant medications, tacrolimus dosing information, and steady-state venous whole blood specimen values after tacrolimus administration were collected. Noncompartmental pharmacokinetics were calculated from the tacrolimus blood concentrations in samples collected at multiple time points after drug administration. The area under the concentration-time curve from 0-6 hours for sublingual and oral tacrolimus ranged from 27.2-66 and 32.4-76 mg·hour/L, respectively, in the tacrolimus plus clotrimazole group and from 9.3-63 and 4.9-23.2 mg·hour/L, respectively, in the tacrolimus plus nystatin group. The average maximum concentration was higher during sublingual administration than during oral administration: 16.7 versus 12.9 ng/ml in the tacrolimus plus clotrimazole group and 9.5 versus 6 ng/ml in the tacrolimus plus nystatin group. CONCLUSION: An oral-to-sublingual tacrolimus dose conversion should be evaluated on an individual basis. A 1:1 dose conversion may be appropriate in the presence of clotrimazole, whereas a 2:1 oral-to-sublingual conversion may be appropriate when there are no concomitantly interacting drugs. These findings should be investigated further in pharmacokinetic studies conducted in solid organ transplant recipients.

Immunotherapy with canarypox vaccine and interleukin-2 for HIV-1 infection: termination of a randomized trial.

OBJECTIVES: To determine whether immunotherapy of chronic HIV-1 infection can prevent or attenuate viremia upon antiviral discontinuation. DESIGN: This was a Phase II randomized, partially double blinded, 2x2 factorial study of three steps of 12 wk/step. Step I involved four groups: (1) vaccine placebo, (2) vaccine (ALVAC, vCP1452), (3) placebo + interleukin 2 (IL-2), and (4) vaccine + IL-2. Step II involved a 12-wk diagnostic treatment interruption (DTI). Step III involved an extension of the DTI for an additional 12 wk. SETTING: The Weill-Cornell General Clinical Research Center. PARTICIPANTS: Chronically infected HIV-1 positive adults with undetectable HIV-1 levels and > 400 CD4+ T cells/microl. INTERVENTIONS: An HIV canarypox vaccine (vCP1452) and vaccine placebo, administered every 4 wk for four doses, and low-dose IL-2 administered daily for 12-24 wk. OUTCOME MEASURES: Primary endpoints: (1) Proportion of participants with undetectable plasma HIV RNA during trial Step II, (2) mean log10 HIV RNA copies/ml ([HIV]) from weeks 21-25, and (3) proportion of individuals eligible for trial Step III. RESULTS: 44 participants were randomized, but 16 withdrew or were withdrawn before completing Step II. As all participants underwent viral relapse in Step II, the study was terminated after 28 participants completed Step II. Among the four groups, there was no difference in mean [HIV] or the proportion of individuals with < log10 4.48 HIV; no difference between the mean [HIV] of the two groups that received ALVAC (n = 17) versus placebo (n = 11); and no significant difference between the mean [HIV] of the two groups that received IL-2 (n = 11) versus placebo (n = 17). CONCLUSIONS: Neither ALVAC (vCP1452) nor low-dose daily IL-2 nor their combination prevented the relapse of viremia upon discontinuation of antiviral therapy.