Manuela Lugano

Hyperlactacidemia Potentially Due to Linezolid Overexposure in a Liver Transplant Recipient

Sir—A 59-year-old white liver transplant recipient developed bilateral pneumonia on day 4 after the operation. After performing bronchoscopy with bronchoalveolar lavage, empirical therapy with piperacillin-tazobactam (4.5 g every 6 h) and levofloxacin (500 mg every 12 h) was commenced. During the subsequent 24 h, the patient’s clinical condition worsened until he developed severe sepsis. Drotrecogin-a was administered, but because of the persistence of the patient’s critical condition, and because no bacteria were isolated, antibiotic therapy was shifted 48 h later to meropenem (500 mg every 6 h) plus linezolid (600 mg every 12 h). Over the subsequent days, the patient’s clinical condition slowly improved. However, despite there being no evidence of graft dysfunction or renal failure, a progressive asymptomatic increase in the plasma lactate level was noted (peak level, 8.4 mmol/L) (figure 1). On day 10 of the second-line antibiotic regimen, therapy was de-escalated by withdrawing meropenem. In accordance with our institution’s antibiotic policy, which is oriented at optimizing therapy for critically ill patients [1], multiple blood samples were obtained to assess linezolid exposure during a dosing interval and were subsequentlyanalyzed by high-performance liquid chromatography [2]. Pharmacokinetic analysis revealed significant plasma overexposure to linezolid (12-h area under the curve, 412.55 /L; maximum concentration, 43.32 mg h mg/L; minimum concentration, 26.99 mg/ L) because of impaired clearance (1.51 L/ h) with a prolonged elimination half-life (16.57 h) [3]. We hypothesized that the patient potentially had drug-induced hyperlactacidemia. On day 12 of hospitalization, linezolid was withdrawn, and blood samples were obtained to determine whether plasma drug levels were decreasing. During the subsequent 2 days, concomitantly with a decrease in the plasma linezolid level, a progressive decrease of the plasma lactate level (until complete normalization occurred) was documented (figure 1). Hyperlacticidemia during linezolid therapy has been previously reported to be an adverse event that mainly develops after long treatment periods and that slowly resolves after withdrawal of the drug [4–6]. Conversely, in the case we report, lactate levels started increasing just after the first week of treatment, rapidly achieved the maximum level, and returned to a normal level within 48 h after drug withdrawal. It has been suggested that, on the basis of its mechanism of action, linezolid may cause hyperlacticidemia by inhibiting mitochondrial protein synthesis [6]. Therefore, hyperlacticidemia should be expected to occur earlier in the course of treatment and to be more severe in patients who

Arterial Pulse Cardiac Output Agreement With Thermodilution in Patients in Hyperdynamic Conditions

OBJECTIVE This study aimed to compare continuous cardiac output (CCO) obtained using the arterial pulse wave (APCO) measurement with a simultaneous measurement of the intermittent cardiac output (ICO) and CCO obtained with a pulmonary artery catheter (PAC) in liver transplant patients. DESIGN A prospective, single-center evaluation. SETTING A university hospital intensive care unit. PATIENTS Eighteen patients after liver transplantation. INTERVENTIONS Pulmonary artery catheters were placed in all patients, and ICO and CCO were determined using thermodilution. APCO measurements were made with the Vigileo System (Edwards Lifesciences, Irvine, CA). MEASUREMENTS AND MAIN RESULTS The authors obtained 126 data pairs of ICO and APCO and 864 pairs of CCO and APCO. ICO data were collected after intensive care unit admission and every 8 hours until the 48th postoperative hour. CCO and APCO data were collected every hour from admission until the 48th postoperative hour. Bias and precision were 0.95 +/- 1.41 L/min for ICO versus APCO and 1.29 +/- 1.28 L/min for CCO and APCO. Bias and precision for cardiac output (CO) data pairs less than 8 L/min were 0.32 +/- 1.14 L/min between ICO and APCO and 0.71 +/- 0.98 L/min between CCO and APCO. For CO data pairs higher than 8 L/min, bias and precision were 1.79 +/- 1.54 L/min between ICO and APCO and 2.25 +/- 1.14 L/min between CCO and APCO. CONCLUSIONS APCO enables the assessment of CO with clinically acceptable bias and precision. At higher CO levels, APCO underestimates PAC measurements and it is not as reliable as thermodilution in hyperdynamic liver transplant patients.

Randomized Trial of Micafungin for the Prevention of Invasive Fungal Infection in High-Risk Liver Transplant Recipients

In this randomized clinical trial comparing micafungin 100 mg with standard-care antifungal prophylaxis (fluconazole, liposomal amphotericin B, or caspofungin) in high-risk liver transplant patients, micafungin 100 mg was noninferior and had a better kidney safety profile.

Biliary penetration and pharmacodynamic exposure of linezolid in liver transplant patients.

OBJECTIVES The aim of the study was to assess the biliary penetration of linezolid and the probabilities of attaining optimal pharmacodynamic exposure against vancomycin-resistant enterococci (VRE) in the bile of liver transplant (LTx) patients who received linezolid for the treatment of multidrug-resistant Gram-positive hospital infections. METHODS After at least 2 days of standard 600 mg twice-daily therapy, simultaneous bile and blood samples for linezolid assay were collected from six LTx patients just prior to drug administration to determine trough concentrations (Cmin) at steady-state in both sites. Linezolid concentrations in plasma and in bile were analysed by means of HPLC. Biliary penetration of linezolid was calculated as the ratio between Cmin in bile and in plasma. Optimal theoretical pharmacodynamic exposure of linezolid against VRE in bile was defined as biliary Cmin>MIC90. RESULTS C(min) of linezolid in bile achieved very high values at steady-state, which were significantly higher than in plasma (median of 21.77 versus 8.08 mg/L, P=0.021). The very high biliary penetration of linezolid (median value of 1.93; range 1.31-4.83) enabled achievement of optimal theoretical pharmacodynamic exposure against VRE in bile (Cmin>2 mg/L) on all of the occasions. CONCLUSIONS These preliminary data suggest a potential role for linezolid in the treatment of cholangitis due to VRE in LTx patients. Obviously, further confirmatory data assessing also the AUC/MIC ratio of linezolid in bile are needed.

Perioperative Intra- and Extravascular Volume in Liver Transplant Recipients

UNLABELLED Assessing adequate volemia to avoid fluid overload and pulmonary edema perioperatively in liver transplantation (LT) is a challenge both for the anesthetist and the intensivist. Volumetric preload indices, such as intrathoracic blood volume index (ITBVI), measured by transpulmonary thermodilution, and continuous end-diastolic volume index (EDVI), measured by pulmonary artery thermodilution, were shown to better reflect preload than central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP). An ITBVI increase soon after the graft reperfusion influenced pulmonary perfusion without an alteration of extravascular lung water index (EVLWI) and without impaired oxygenation. This study was designed to evaluate relationships between CVP, PAOP, ITBVI, EDVI, and stroke volume index (SVI) within 48 hours after LT. We also investigated the relationship between EVLWI and arterial partial pressure of oxygen and inspired oxygen fraction ratio (PaO(2)/FiO(2)). METHODS We enrolled 125 patients (103 men and 22 women) undergoing LT. All patients were monitored with the PiCCO system (Pulsion Medical System) and with advanced pulmonary artery catheter connected to the Vigilance System. Hemodynamic-volumetric data were collected upon intensive care unit admission and every 8 hours up to 48 hours. Univariate and multivariate regression models were fitted to assess associations between SVI and EDVI, ITBVI, and filling pressures after adjusting for the right ventricular ejection fraction (RVEF, categorized as ≤30, 31-40, or >40) and the phase of the observation period. We also assessed associations between PaO(2)/FiO(2) and EVLWI. RESULTS SVI was associated with EDVI, ITBVI, and RVEF. The models showing the best fit to the data were those including EDVI and ITBVI. Neither CVP nor PAOP showed correlation with SVI. EVLWI inversely correlated with PaO(2)/FiO(2). CONCLUSIONS In the first 48 hours after LT, ITBVI and EDVI were associated with SVI assessment, whereas CVP and PAOP were not related. EVLWI significantly inversely correlated with PaO(2)/FiO(2).

Does critical illness change levofloxacin pharmacokinetics

ABSTRACT Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function.

Biliary pharmacodynamic exposure to linezolid in two liver transplant patients

Institute of Clinical Pharmacology, Azienda OspedalieroUniversitaria Santa Maria della Misericordia, Udine, Italy; Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy; Department of Anaesthesia and Intensive Care Medicine of the Medical School of the University of Udine, Udine, Italy; Department of Medical and Biological Sciences, University of Udine, Udine, Italy; Clinic of Infectious Diseases, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

Perioperative Considerations in HIV-Infected Liver Transplanted Patients

UNLABELLED The introduction of highly active antiretroviral therapy (HAART) has improved survival in HIV patients, allowing them to undergo liver transplantation (OLT) in cases of end-stage liver disease. HIV patients show a higher incidence of pulmonary hypertension. The aim of this study was to evaluate pulmonary and systemic hemodynamic changes in HIV-infected patients compared with a non-HIV-infected group of patients undergoing OLT. METHODS We analyzed 20 HIV-infected patients and 20 non-HIV-infected patients who underwent OLT. We analyzed preoperative cardiovascular status, as well as intra- and postoperative hemodynamic data. Hemodynamic data were recorded at 4 predefined phases during OLT and at 24, 48, and 72 hours after intensive care unit (ICU) admission. We also evaluated the following perioperative aspects: transfusion requirements, postoperative mechanical ventilation time, ventilation time, and length of ICU and of hospital stay. RESULTS HIV-positive patients were younger than controls with a greater incidence of coinfection with hepatotropic viruses. One HIV-infected patient died in the ICU. Hemodynamic data showed a higher cardiac index and higher pulmonary vascular resistance index among HIV-infected patients, but without any clinical impact. No significant difference in blood unit transfusions, postoperative time on mechanical ventilation, or length of ICU or hospital stay was observed between the groups. CONCLUSIONS Although the number of patients studied is limited, we concluded that HIV-infected patients undergoing OLT showed similar perioperative courses as non-HIV-infected patients.

Renal function and icu

Introduction: The mortality of acute renal failure (ARF) is 50-80% in critically ill patients and has not fallen significantly despite numerous advances in critical care strategies and renal replacement technologies over several decades. (1) A major problem with conducting research into acute renal failure (ARF) is the lack of a consensus definition (2). More than 30 different definitions of ARF have been used in the literature. This lack of a common reference point created confusion and made comparisons difficult. The Acute Dialysis Initiative (ADQI) group of experts developed and published a consensus definition of ARF. This definition goes under the acronym of RIFLE. This definition classified the patients with renal dysfunction according to the degree of impairment into patient at risk (R), with injury (I), with failure (F), with sustained loss (L) and with end stage (E) status in relation to their renal function. (2) Rifle criteria were based on changes in the patients’ glomerular filtration rate (GFR) and/or their urine output. (2) Discussion: The prophylactic and therapeutic use of dopamine, the more studied vasoactive drug, actually has not been supported. For all other vasoactive drugs, at this moment, data available are contradictory and few conclusions can be made. To protect renal function, despite wide use of vasoactive drugs, only the maintenance of adequate volume replacement and perfusion pressure may be certainly recommended. Conclusion: The use of vasoactive drugs is a pervasive practice in intensive care units, and hence, this area needs suitably powered, multi-center, randomized, placebo-controlled, double-blind studies to provide more rational indications for clinical practice.