IntroductionRegional 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.MethodsIn 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).ResultsWe 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 %.ConclusionsRCA-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 registrationISRCTN Registry identifier: ISRCTN92716512. Date assigned: 4 December 2008.

BackgroundAppropriate utilization of vancomycin is important to attain therapeutic targets while avoiding clinical failure and the development of antimicrobial resistance. Our aim was to observe the use of vancomycin in an intensive care population, with the main focus on achievement of therapeutic serum concentrations (15–20 mg/l) and to evaluate how this was influenced by dose regimens, use of guidelines and therapeutic drug monitoring.MethodsA prospective observational study was carried out in the intensive care units at two tertiary hospitals in Norway. Data were collected from 83 patients who received vancomycin therapy, half of these received continuous renal replacement therapy. Patients were followed for 72 h after initiation of therapy. Blood samples were drawn for analysis of trough serum concentrations. Urine was collected for calculations of creatinine clearance. Information was gathered from medical records and electronic health records.ResultsLess than 40% of the patients attained therapeutic trough serum concentrations during the first 3 days of therapy. Patients with augmented renal clearance had lower serum trough concentrations despite receiving higher maintenance doses and more loading doses. When trough serum concentrations were outside of therapeutic range, dose adjustments in accordance to therapeutic drug monitoring were made to less than half.ConclusionThe present study reveals significant challenges in the utilization of vancomycin in critically ill patients. There is a need for clearer guidelines regarding dosing and therapeutic drug monitoring of vancomycin for patient subgroups.

Increased plasma- and tissue levels of endothelin-1 (ET-1) during inflammatory diseases, have suggested a role of ET-1 in the pathophysiology of inflammatory reactions. The authors have studied the effect of ET-1 on cytokine release from monocytes and monocyte-derived macrophages. ET-1 increased secretion of TNF-α, IL-1β and IL-6 in a dose- and time-dependent manner. Optimal ET-1 concentration ranged from 0.01 to 1 nM. The maximal response was a 200 to 400% increase in cytokine release. A time-course study revealed that the pattern of cytokines induced by ET-1 was different in monocytes and macrophages, although an early increase in TNF-α was observed in both monocyte and macrophage supernatants. In conclusion, ET-1 stimulates monocytes and macrophages to release cytokines thereby demonstrating a potential role for ET-1 in regulation of inflammatory responses.

We previously showed that endothelin-1 (ET-1) causes accumulation of leukocytes in the pulmonary microvasculature and increases vascular permeability in isolated rat lungs provided the presence of leukocytes in the perfusate. In the present study, we examined the time sequence for morphological changes induced by ET-1 in rat alveolar tissue. For this purpose we used morphometric analysis based on lung transmission electron micrographs. Morphometry was performed by point counting, and data were expressed as relative volume density. ET-1 (0.06, 0.6, and 6 nmol/kg) was infused into the internal jugular vein, and the animals were killed at certain points of time. The lungs were fixed by endotracheal instillation of McDowell's fixative. Infusion of ET-1 (0.06 or 0.6 nmol/kg) caused no significant morphological changes in the rat alveolar tissue as assessed by morphometric examination. A sevenfold increase in volume density of platelets was seen 5 min after infusion of ET-1 6 nmol/kg. The platelets were loosely aggregated, adhered partly to the endothelium, and some of them had a spherical shape with vacuoles, indicating activation. The volume density of erythrocytes increased threefold, lasting 30 min. At 120 min, the volume density of polymorphonuclear leukocytes (PMN) increased 10-fold. The PMN adhered closely to the endothelium and partly occluded the capillary lumen. Simultaneously, the endothelial cell surface showed morphological signs of injury. No significant changes were observed in the volume density of alveolar macrophages or monocytes. No significant changes were seen in lung volumes or the volume of the alveolar tissue compartment. The results showed that ET-1 causes a time- and dose-dependent sequential entrapment of platelets and neutrophils in the pulmonary circulation.

In the present study we examined whether endothelin-1 stimulation of human monocytes causes release of chemotactic factors. It was found that monocytes released neutrophil- and monocyte-chemotactic activity in a dose- and time-dependent manner in response to ET-1. ET-1 did not show any chemotactic activity by itself. NCA was detected in monocyte supernatants in response to ET-1 (0.01–100 nM) after 1, 4, 8 and 24 h stimulation. MCA was detected only after 24 h stimulation with ET-1 (0.1–100 nM). Preincubation of the monocyte cultures with the lipoxygenase inhibitors nordihydroguaiaretic acid (10−4 M) or diethylcarbamazine (10−9 M) completely abolished the appearance of NCA and MCA. NCA was neutralized by > 75% using a polyclonal antibody against human interleuktn-8. The ET-1 induced release of IL-8 was confirmed by IL-8 ELISA. A monoclonal antibody against human monocyte chemotactic protein-1 neutralized MCA by > 80%. It is concluded that ET-1 stimulation of monocytes in vitro causes release of neutrophil- and monocyte-chemotactic activity identified as IL-8 and MCP-I respectively. An intact lipoxygenase pathway is crucial for this effect of ET-1 to occur.