Safety and efficacy of regional citrate anticoagulation in continuous venovenous hemodialysis in the presence of liver failure: the Liver Citrate Anticoagulation Threshold (L-CAT) observational study.

INTRODUCTION: Regional citrate anticoagulation (RCA) for continuous renal replacement therapy is widely used in intensive care units (ICUs). However, concern exists about the safety of citrate in patients with liver failure (LF). The aim of this study was to evaluate safety and efficacy of RCA in ICU patients with varying degrees of impaired liver function. METHODS: In a multicenter, prospective, observational study, 133 patients who were treated with RCA and continuous venovenous hemodialysis (RCA-CVVHD) were included. Endpoints for safety were severe acidosis or alkalosis (pH ≤7.2 or ≥7.55, respectively) and severe hypo- or hypercalcemia (ionized calcium ≤0.9 or ≥1.5 mmol/L, respectively) of any cause. The endpoint for efficacy was filter lifetime. For analysis, patients were stratified into three predefined liver function or LF groups according to their baseline serum bilirubin level (normal liver function ≤2 mg/dl, mild LF >2 to ≤7 mg/dl, severe LF >7 mg/dl). RESULTS: We included 48 patients with normal liver function, 43 with mild LF, and 42 with severe LF. LF was predominantly due to ischemia (39 %) or multiple organ dysfunction syndrome (27 %). The frequency of safety endpoints in the three patient strata did not differ: severe alkalosis (normal liver function 2 %, mild LF 0 %, severe LF 5 %; p = 0.41), severe acidosis (normal liver function 13 %, mild LF 16 %, severe LF 14 %; p = 0.95), severe hypocalcemia (normal liver function 8 %, mild LF 14 %, severe LF 12 %; p = 0.70), and severe hypercalcemia (0 % in all strata). Only three patients showed signs of impaired citrate metabolism. Overall filter patency was 49 % at 72 h. After censoring for stop of the treatment due to non-clotting causes, estimated 72-h filter survival was 96 %. CONCLUSIONS: RCA-CVVHD can be safely used in patients with LF. The technique yields excellent filter patency and thus can be recommended as first-line anticoagulation for the majority of ICU patients. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN92716512 . Date assigned: 4 December 2008.

Simvastatin-associated rhabdomyolysis after coadministration of macrolide antibiotics in two patients.

Two men, aged 83 and 78 years, who received stable therapy with simvastatin 80 mg/day were hospitalized 1-2 weeks after completion of short-term treatment with erythromycin and clarithromycin, respectively. Both patients were admitted with myalgia, muscle weakness, functional disability (inability to raise arms and legs), and serum creatine kinase levels more than 60 times the upper limit of normal (ULN). Substantial elevations in aspartate aminotransferase (> 30 times the ULN) and alanine aminotransferase (> 7 times the ULN) levels were also observed. Rhabdomyolysis was diagnosed in both patients. Both recovered, but the combined events resulted in almost 40 days of hospitalization, the cost of which is considerable. According to the Naranjo adverse drug reaction probability scale, the likelihood that the rhabdomyolysis was secondary to a simvastatin-macrolide interaction was probable. Four cases of rhabdomyolysis after therapy with combined simvastatin and clarithromycin have been reported previously, but this is apparently the first report of rhabdomyolysis after coadministration of erythromycin. The interacting mechanism likely was inhibited cytochrome P450 (CYP) 3A4 metabolism and possibly P-glycoprotein transport of simvastatin as well. Previous reports of simvastatin-clarithromycin-related events involved additional drugs that inhibited CYP3A4 and P-glycoprotein. However, this was not the situation with our two patients. To prevent future events, it is crucial that clinicians recognize the interaction risk associated with concurrent use of simvastatin and clarithromycin or erythromycin. The risk could be managed by temporary interruption of simvastatin treatment or administration of a noninteracting antimicrobial agent.

Methanol and formate kinetics during treatment with fomepizole.

OBJECTIVE: Methanol is metabolized by alcohol dehydrogenase to formaldehyde, and further to formic acid, which is responsible for the toxicity in methanol poisoning. Fomepizole (4-methylpyrazole) is a potent competitive inhibitor of alcohol dehydrogenase and is used as an antidote to treat methanol poisonings. We report serum methanol kinetics in eight patients treated with bicarbonate and fomepizole only. METHODS: Prospective case series study of eight patients with methanol poisoning, who were selected to fomepizole and bicarbonate treatment only, because of moderate metabolic acidosis. Three of the patients were later dialyzed, because of high serum methanol concentrations and very slow methanol elimination. RESULTS: Upon admission the median pH was 7.27 (range 7.12-7.50), median base deficit was 15 mmol/L (5-22 mmol/L) and median serum methanol was 20.4 mmol/L (65 mg/dL) (range 8.4-140.6 mmol/L). The kinetics of methanol during fomepizole treatment in six patients was best described by a first-order elimination one-compartment model. The mean correlation coefficient (R2) describing the first-order elimination model in all eight patients was 0.95 (range 0.90-0.99). The mean plasma half-life (t(1/2)) of methanol during fomepizole treatment was 52 h (range 22-87); the higher the serum methanol, the longer the T(1/2). Mean half-life of serum formate was 2.6 h, when methanol metabolism was assumed blocked by fomepizole and no folinic acid was given. This rapid formate elimination in nonacidotic patients may be explained by high renal excretion of formate. CONCLUSION: Based on our data, methanol-poisoned patients with moderate metabolic acidosis and methanol levels up to 19 mmol/L (60 mg/L) may safely be treated with bicarbonate and fomepizole only, without dialysis.