Blood transfusions may impair endothelium-dependent vasodilatation during coronary artery bypass surgery.

OBJECTIVE: The hemolytic product free-hemoglobin (fHb) reduces nitric oxide (NO) bioavailability. The present study aims to establish whether administration of different blood transfusions result in increased circulating fHb levels and NO consumption with effects on arterial NO-dependent blood flow in patients undergoing CABG surgery. METHODS: Ninety-five consecutive patients undergoing elective CABG surgery were prospectively divided in four groups based on blood transfusion requirements during surgery: stored blood cells (SBC, n. 21), intraoperative autologous salvaged blood (ASB, n. 25), SBC and ASB (n.22), no transfusion (control, n. 27). Blood samples were collected before and after intervention to analyse plasma levels of fHb and NO consumption. Endothelium-dependent relaxation was assessed in left internal mammary artery (LIMA) rings harvested before chest closure. Peripheral artery tonometry was assessed after intervention. RESULTS: Transfusions with SBC increased plasma fHb (p<0.05). Transfusions of ASB resulted in higher plasma fHb compared to SBC (p<0.01). fHb concentrations directly correlated with NO consumption (r=0.65, p<0.001). Maximal endothelium-dependent relaxation in LIMA was significantly attenuated in SBC and ASB patients compared to control (15.2±3.1% vs 21.1±2.5% vs 43±5.0% respectively; p<0.01). Significant correlations were identified between the aortic pressure wave velocity, plasma fHb concentration and NO consumption (p<0.01). CONCLUSIONS: Intraoperative blood transfusions and particularly autologous salvaged blood impair endothelium-dependent relaxation through NO scavenging by fHb. These findings obtained in vitro and in vivo provide new insights into the adverse relation between blood transfusions and patient outcome.

Soluble urokinase-type plasminogen activator receptor as a prognostic biomarker in critically ill patients.

PURPOSE: The aim of this study was to assess the role of blood soluble urokinase-type plasminogen activator receptor (suPAR) levels in the diagnosis and prognostication of sepsis in critically ill patients. METHODS: Serum suPAR levels were measured prospectively in adult intensive care unit (ICU) patients on admission and then daily until ICU discharge (maximum of 14 days) using an enzyme-linked immunosorbent assay kit. Normal levels were established in 31 healthy controls. RESULTS: We included 258 patients (161 men); median admission Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 17 (9-23) and 6 (3-9), respectively. The mortality rate was 13.6%. Sepsis was diagnosed on admission in 94 patients (36%), of whom 23 had severe sepsis and 49 had septic shock. On admission, septic patients had higher suPAR levels than did nonseptic patients (8.9 [5.9-12.7] vs 3.7 [2.7-5.4] ng/mL), but the predictive value of suPAR for diagnosing sepsis was weaker than that of C-reactive protein. During the week after ICU admission, serum suPAR concentrations correlated with Sequential Organ Failure Assessment scores over time. High suPAR levels on admission were a strong independent predictor for ICU and 28-day mortality. In the global population, a suPAR level higher than 6.15 ng/mL had 66% sensitivity and 64% specificity for prediction of ICU mortality, with a receiver operating characteristic area under the curve of 0.726 (95% confidence interval, 0.645-0.808). CONCLUSIONS: In ICU patients, serum suPAR concentrations have limited use for identifying sepsis, but their time course correlated with the degree of organ dysfunction, and they have prognostic value in septic and nonseptic populations.

Can population pharmacokinetic modelling guide vancomycin dosing during continuous renal replacement therapy in critically ill patients?

Treatment of resistant bacteria such as meticillin-resistant Staphylococcus aureus (MRSA) relies on achieving adequate antibiotic concentrations at the site of infection. Strategies to attain such targets in septic critically ill patients receiving renal replacement therapy (RRT) are uncommon but could be useful for increasing the likelihood of therapeutic dosing. The aim of this study was to conduct a population pharmacokinetic (PK) analysis in septic patients undergoing continuous RRT and to determine which parameters were associated with inadequate vancomycin concentrations. In total, 81 patients with 199 blood samples were included in the study. All patients received vancomycin dosing according to the local protocol, which included a weight-based loading dose followed by continuous infusion. The vancomycin concentration-time points were adequately described with a one-compartment model with zero order input. The median population PK estimate for vancomycin clearance (CL) was 2.9 L/h [interquartile range (IQR) 2.4-3.4 L/h] and for volume of distribution (Vd) was 0.8 L/kg (IQR 0.6-1.1 L/kg). The goodness-of-fit plots for the model were adequate. When covariates were tested, none were found to adequately explain changing vancomycin CL or Vd in the population PK model. In particular, the lack of correlation between CL and RRT settings was likely due to the multiple confounders known to influence antibiotic prescription in this setting. These data provide a cautionary tale of the challenges of describing pharmacokinetics in critically ill patients receiving RRT and highlights the need for a detailed, prospective, multicentre study to better inform dosing practice.

Continuous infusion of vancomycin in septic patients receiving continuous renal replacement therapy.

Vancomycin is frequently administered as a continuous infusion to treat severe infections caused by Gram-positive bacteria. Previous studies have suggested a loading dose of 15 mg/kg followed by continuous infusion of 30 mg/kg in patients with normal renal function; however, there are no dosing recommendations in patients with renal failure undergoing continuous renal replacement therapy (CRRT). Data from all adult septic patients admitted to a Department of Intensive Care over a 3-year period in whom vancomycin was given as a continuous infusion were reviewed. Patients were included if they received vancomycin for ≥48h during CRRT. Vancomycin levels were obtained daily. During the study period, 85 patients (56 male; mean age 65±15 years; weight 85±24kg) met the inclusion criteria. Median (interquartile range) APACHE II and SOFA scores were 24 (20-29) and 11 (7-14), respectively, and the overall mortality rate was 59%. Mean vancomycin doses were 16.4±6.4 (loading dose), 23.5±8.1 (Day 1), 23.2±7.4 (Day 2) and 23.3±11.0 (Day 3) mg/kg, resulting in blood concentrations of 24.7±9.0 (Day 1), 26.0±8.1 (Day 2) and 27.7±9.3 (Day 3) µg/mL. On Day 1, 43 patients (51%) had adequate drug concentrations (20-30 µg/mL), 17 (20%) had levels >30 µg/mL and 25 (29%) had levels <20 µg/mL. Most patients with adequate drug concentrations received a daily dose of 16-35 mg/kg. The intensity of CRRT directly influenced vancomycin concentrations on Day 1 of therapy.

suPAR as a prognostic biomarker in sepsis.

Sepsis is the clinical syndrome derived from the host response to an infection and severe sepsis is the leading cause of death in critically ill patients. Several biomarkers have been tested for use in diagnosis and prognostication in patients with sepsis. Soluble urokinase-type plasminogen activator receptor (suPAR) levels are increased in various infectious diseases, in the blood and also in other tissues. However, the diagnostic value of suPAR in sepsis has not been well defined, especially compared to other more established biomarkers, such as C-reactive protein (CRP) and procalcitonin (PCT). On the other hand, suPAR levels have been shown to predict outcome in various kinds of bacteremia and recent data suggest they may have predictive value, similar to that of severity scores, in critically ill patients. This narrative review provides a descriptive overview of the clinical value of this biomarker in the diagnosis, prognosis and therapeutic guidance of sepsis.