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.

The present experiments were carried out in the rat to investigate the peripheral vascular function prior to the development of posthypothermic circulatory collapse. In the first study, mean arterial blood pressure, heart rate, cardiac output, regional blood flow, and plasma volume of hypothermic (4 h, 15-13 degrees C) and rewarmed rats were compared with normothermic controls. In response to hypothermia, arterial blood pressure, heart rate, and cardiac output declined markedly. After rewarming, arterial blood pressure and heart rate recovered fully, whereas cardiac output was only 33 +/- 7% of the control value (p < 0.025). Tissue blood flow was markedly depressed during hypothermia (p < 0.025), except for the abdominal skin. After rewarming, blood flow in skeletal muscle returned to within control levels, whereas blood flow in internal organs remained low (p < 0.025 vs. control). Posthypothermic plasma volume was 77 +/- 3% of control (p < 0.05). In the second study, the transcapillary colloid osmotic pressure gradient (COPp-COPi) was calculated following measurement of colloid osmotic pressure in plasma (COPp) and interstitium (COPi) in prehypothermic, hypothermic, and posthypothermic rats. The posthypothermic value of COPp-COPi was 76 +/- 4% of the prehypothermic value (p < 0.05). In conclusion this study demonstrates that the reduced cardiac output in rewarmed rats is associated with an altered regional blood flow distribution compared with that of normal rats. Capillary integrity also seemed perturbed. Thus, changes in both control and function of the peripheral vasculature are important mechanisms in the development of a posthypothermic circulatory collapse.

The release and vascular effects of calcitonin gene-related peptide (CGRP) and endothelin-1 (ET-1) during acute alveolar hypoxia (O2 2%) were examined in isolated blood-perfused rat lungs. In 10 lungs, repeatedly ventilated with hypoxic gas for 5 min, samples from effluent blood were taken during hypoxia and analysed for plasma levels of CGRP-like immunoreactivity (-LI) and ET-1-LI. The plasma levels of ET-1-LI were significantly (p < 0.05) increased in hypoxic lungs (5.5 +/- 0.5 pmol l-1) compared with normoxic controls (3.7 +/- 0.56 pmol l-1). Plasma levels of CGRP-LI were significantly (p < 0.01) lower in hypoxic lungs (43.9 +/- 2.9 pmol l-1) than in normoxic controls (55.5 +/- 4.0 pmol l-1). No significant correlation was seen between perfusate peptide levels and pulmonary artery pressure (Ppa) during ventilation with normoxic or hypoxic gas. Infusion of the CGRP receptor blocker, CGRP, did not influence either the baseline Ppa or the development of the hypoxic pulmonary vasoconstriction response (HPV). In lungs undergoing HPV, 2 nmol l-1 ET-1 added to the perfusate, significantly reduced the hypoxic pressor response by 14 +/- 3% (p < 0.05), while addition of 200 nmol l-1 ET-1 caused no significant changes in HPV. CGRP 2 nmol l-1 caused no significant attenuation of HPV (8.9%), while 200 nmol l-1 CGRP significantly reduced HPV by 16 +/- 5% (p < 0.05). To conclude: acute alveolar hypoxia changes release of CGRP and ET-1 to the perfusate in isolated rat lungs. The results further suggest that CGRP and ET-1 are not involved in the development and regulation of the hypoxic pulmonary vasoconstriction response.

In adult respiratory distress syndrome, a major concern is to reduce increments in pulmonary vascular resistance (PVR) and maintain the patency of lung microvessels. We have investigated the effects of adenosine, a potent systemic vasodilator, on PVR and fluid filtration rate (FFR) in isolated blood-perfused rat lungs. The preparations were undamaged or subjected to fat emulsion-induced injury simulating ARDS. In undamaged lungs adenosine caused a significant dose-dependent reduction of hypoxia-induced increases in PVR. Furthermore, the increase in FFR upon elevation of left atrial pressure by 0.77 kPa was significantly hampered by adenosine, 24 nmol.ml-1.min-1. Employing the same rate of infusion, adenosine, in a group of injured preparations, significantly reduced the rise in PVR towards baseline and completely abolished the further increase upon a superimposed injection of serotonin. In another series of preparations with lung injury randomly assigned to an adenosine group and a control group, adenosine significantly reduced FFR. Thus, adenosine, even when infused at low rates, reduced increments in PVR and fluid filtration, both in undamaged and in fat emulsion-injured isolated lungs.