Caspofungin PK in critically ill patients after the first and fourth doses: suggestions for therapeutic drug monitoring?

We describe caspofungin pharmacokinetics (PK) after the first and fourth doses in 20 critically ill septic patients. Monte Carlo simulation was used to analyze the probability of target attainment (PTA) (AUC/MIC > 865) for Candida spp. Caspofungin concentrations were analyzed by HPLC in plasma and urine. A great variability in PK parameters was observed after both doses. Patients were divided in two groups according to their AUC values (AUC ≤ 75 mg h/L cut-off). In the low-AUC group Cmax, Cmin and AUC were lower, while Vd and Cl were higher than in the high-AUC group (p < 0.05, both at day 1 and 4). The mean 24-h urinary recovery of the drug was 8 ± 6.3% (day1) and 9.8 ± 6.3 (day4). Monte Carlo simulation analysis (0.03-1 mg/L MIC-range) showed that PTA was guaranteed only for MICs ≤ 0.03 mg/L in the low-AUC group, and for MICs ≤ 0.06 mg/L in the high-AUC group. No group had a PTA ≥ 90% for 0.125 mg/L MIC (the epidemiological cut-off). Mortality was higher in low-AUC group (p < 0.01). In our 'real-world' population, no clinical data can predict which patient will have lower, suboptimal caspofungin exposure, therefore we suggest TDM to optimize caspofungin therapy and reduce the risk of selecting resistances (CEAVC, 32366/2015; OSS.15.114, NCT03798600).

Use of the parenteral antibiotic Ertapenem as short term prophylaxis in bariatric surgery: a pharmaco-kinetic-pharmacodynamic study in class III obese female patients.

BACKGROUND: The objective of this study was to determine the pharmacokinetics-pharmacodynamics (PK/PD) of Ertapenem in extremely obese female patients (Body Mass Index [BMI] ≥ 40 kg/m²) undergoing bariatric surgery. METHODS: Ten patients received 1 g intravenous Ertapenem 0.5 h prior to surgery as short term prophylaxis. Serum Ertapenem concentrations were determined at baseline, at the end of infusion (30 minutes), then at 1, 2, 4, 8, 12 and 24 hours postinfusion. In patients in whom a liver biopsy was necessitated by clinical need, Ertapenem liver concentrations were determined through intraoperative biopsies at 1 and 2 h postadministration. Peritoneal Ertapenem concentrations were determined in drainage fluid samples collected during the 4-8, 8-12, and 12-24 h intervals after Ertapenem administration. A Monte Carlo simulation was performed to estimate the probability of achieving free drug levels above the minimum inhibitory concentration (fT>MIC) for at least 20% and 40% of the dosing interval as PK/PD targets. RESULTS: Peak drug concentration and 24-h area under the concentration-time curve (AUC) were found to be 191.9 ± 37.4 mg/L and 574.3 ± 110.5 mg·h/L, respectively. Ertapenem liver/serum concentration ratios were 6% at 1 h and 5% at 2 h. Drug concentrations in peritoneal fluid were 28.2 ± 6.4 mg/L at 4-8h, declined to 15.2 ± 5.9 at 8-12h and fell further to 4.79 ± 0.2 mg/L at 12-24 h post-administration. The probability to reach the desired PK/PD targets were never reached at any MICs >0.25 µg/mL with a 90% probability. CONCLUSION: Our data suggest that in extremely obese female patients, the standard dose of 1 g i.v. Ertapenem as short term prophylaxis may not provide optimal clinical levels of free drug for prevention of surgical site infections.

Cefazolin bolus and continuous administration for elective cardiac surgery: improved pharmacokinetic and pharmacodynamic parameters.

OBJECTIVE: Cefazolin (1-2 g bolus at induction possibly repeated after cardiopulmonary bypass) remains the standard for antibiotic prophylaxis in cardiac surgery. Data indicate, however, that it is underdosed with this dosing schedule. A prospective, randomized study comparing intermittent versus loading dose plus continuous infusion for the same total dose of cefazolin was performed to assess which modality is pharmacokinetically and pharmacodynamically advantageous. METHODS: Patients received 2 g cefazolin as a starting dose and then were divided into an intermittent group (receiving another 1 g at 3, 9, and 15 hours after the first dose) and a continuous group (continuous infusion started after the first dose, providing 1 g every 6 hours for 18 hours). Cefazolin levels were measured in blood and atria. RESULTS: Mean total and calculated free trough concentrations in blood varied greatly among patients in the intermittent group and were lower than those in the continuous group (P < .05 at 15, 18 and 24 hours). For 9 of 10 (90%) patients in the continuous infusion group, the targeted pharmacokinetic and pharmacodynamic goal (time above minimal inhibitory concentration >90%) was achieved, whereas the goal was met for only 3 of 10 (30%) in the intermittent group (P < .05). The mean atrial tissue concentration was also higher with continuous infusion (P < .05). CONCLUSIONS: Administration of cefazolin as bolus plus continuous infusion has pharmacokinetic and pharmacodynamic advantages relative to intermittent administration. It provides more stable serum levels, lower interpatient variability, and higher myocardial tissue penetration.

Evolution of endotoxin-induced lung injury in the rat beyond the acute phase.

OBJECTIVES: Intratracheal endotoxin in rats causes acute lung injury. Here we have addressed the cellular physiopathology of lung recovery from that injury. METHODS: The lungs of 5 untreated rats and rats treated with intratracheal endotoxin from 2, 3, 5, 8 (5 rats each) and 15 days (2 rats) were studied by light and electron microscopy and immunohistochemistry. RESULTS: In the acute phase there was a reduction in the aerated spaces (p < 0.01); diffuse infiltration of granulocytes and macrophages; hyperplasia of type-II pneumocytes, and hypertrophy of interstitial cells. Aerated spaces improved during recovery. In the early recovery phase (3-8 days) the compartmentalization of infiltrating cells varied significantly (p < 0.01): macrophages remained widespread while neutrophils were inside blood vessels. Many pneumocytes were intermediate between type-I and type-II cells. In the late recovery phase (15 days) the infiltrate disappeared; myofibroblasts were significantly more than previously (p < 0.01) and extracellular matrix was abundant; type-II pneumocytes contained non-lamellated lipid inclusions. CONCLUSIONS: Macrophages play a pivotal role in the damage-repair processes of the lung following endotoxin injury, leading to an increase in extracellular matrix, differentiation of myofibroblasts and altered secretion of surfactant by newly differentiated type-II pneumocytes.

EEG signal processing in anaesthesia. Use of a neural network technique for monitoring depth of anaesthesia.

BACKGROUND: The Bispectral Index (BIS) is a proprietary index of anaesthesia depth, which is correlated with the level of consciousness and probability of intraoperative recall. The present study investigates the use of a neural network technique to obtain a non-proprietary index of the depth of anaesthesia from the processed EEG data. METHODS: Two hundred patients, who underwent general abdominal surgery, were recruited for our trial. For anaesthesia we used a total i.v. technique, tracheal intubation, and artificial ventilation. Fourteen EEG variables, including the BIS, were extracted from the EEG, monitored with an EEG computerized monitor, and then stored on a computer. Data from 150 patients were used to train the neural network. All the variables, excluding the BIS, were used as input data in the neural network. The output targets of the network were provided by anaesthesia scores ranging from 10 to 100 assigned by the anaesthesiologist according to the observer's assessment of alertness and sedation (OAA/S) and other clinical means of assessing depth of anaesthesia. Data from the other 50 patients were used to test the model and for statistical analysis. RESULTS: The artificial neural network was successfully trained to predict an anaesthesia depth index, the NED (neural network evaluated depth), ranging from 0 to 100. The correlation coefficient between the NED and the BIS over the test set was 0.94 (P<0.0001). CONCLUSION: We have developed a neural network model, which evaluates 13 processed EEG parameters to produce an index of anaesthesia depth, which correlates very well with the BIS during total i.v. anaesthesia with propofol.

Microalbuminuria as an early index of impairment of glomerular permeability in postoperative septic patients.

OBJECTIVE: To evaluate whether microalbuminuria increases in post-operative patients developing sepsis, and whether it is correlated to the sepsis severity score (SOFA) and the PaO2/FIO2 ratio. DESIGN: Prospective study. SETTING: University intensive care unit. PATIENT POPULATION: Fifty-five postoperative ASA II-III patients admitted to the ICU after major abdominal or vascular surgery. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Urine collection and measurement of microalbuminuria and urinary creatinine on admission and again as soon as sepsis developed or at the end of the study (72 h after admission). Results are expressed as the microalbuminuria/creatinine ratio (MACR). The MACR significantly increased as soon as sepsis (defined according to the ACPP/SCCM Consensus Conference) appeared. The MACR positively correlated to the SOFA score, but had no relation to the PaO2/FIO2 ratio. Patients not developing sepsis did not show any increase in the MACR during the study period. CONCLUSIONS: Post-operative patients developing sepsis, unlike those with an uncomplicated postoperative evolution, showed an increase in glomerular permeability which was revealed by MACR. The increase in the MACR was positively correlated to the increase in SOFA score, while it had no relation to the PaO2/FIO2 ratio.

[Correlations between molecular biology of sepsis and of other primordial stressors]. / Correlazioni tra la biologia molecolare della sepsi e quella di altri stressors primordiali.

The molecular response to endotoxins includes the molecular responses to light, oxygen and heat which may be regarded as parts of a single ancestral stress. Laboratory data suggest that a) light stress provokes molecular responses that are also caused by oxidative stress and endotoxins; b) heat stress activates heat shock proteins, as do oxidative stress and endotoxins; the former protect against oxidative stress, heat stress and endotoxins; c) oxidative stress activates antioxidant enzymes like endotoxin; these protect against endotoxins; d) endotoxin-related stress activates the molecular responses to all the aforesaid primordial stresses. Many laboratory findings prompt us to conclude that the molecular response to endotoxemia and sepsis is an archetypal response common to all forms of primordial stress.

[Morphologic and biochemical kinetics of the pathogenesis of acute lung injury by endotoxin in rats]. / Cinetica morfologica e biochimica della patogenesi del danno polmonare acuto da endotossina nel ratto.

BACKGROUND AND AIM: To highlight the intervention sequence of cells and their products (RO degree and NO) involved in the pathogenesis of lung injury caused by the instillation of endotoxin in rats. EXPERIMENTAL DESIGN: An experimental comparative study in rats. MATERIALS AND METHODS: The experiments were performed using intratracheal instillation of endotoxin in rats (5 mg/kg in 0.125 ml of saline solution). Untreated rats or those instilled with saline solution alone formed the control group. All animals were sacrificed 12, 24 and 48 hours after instillation and the following studies were performed on both lungs: 1) morphological study (optical and electronic); 2) assay of lung MDA; 3) NADPH-diaphorase evaluation using a histochemical method. RESULTS: Lung damage evolves gradually over 48 hours. After the first 12 hours, neutrophil granulocytes were present in the lung capillaries together with monocytes; monocytes were also present in the interstitium. During the following hours, monocytes differentiated into macrophages and, once activated, the granulocytes passed into the interstitium. The parenchyma appears to be extensively altered. Tissular MDA gradually increases until it reaches a maximum level (p < 0.01 vs basal) at 48 hours. Positivity for NADPH-d in macrophage and/or fibroblastic cells was evident after 24 hours and increased after 48 hours. CONCLUSIONS: Acute lung injury caused by endotoxin involves both NO and RO degree. Their production is related to different cell types and follows slightly different kinetic.

Vitamin E prevents neutrophil accumulation and attenuates tissue damage in ischemic-reperfused human skeletal muscle.

Neutrophil accumulation and the consequent production of oxygen-derived free radicals are involved in the pathogenesis of Ischemia-Reperfusion syndrome. In this study we investigated whether a treatment with Vitamin E, which has antioxidant properties, could attenuate the tissue damage by interfering with the influx of neutrophils within the ischemic and reperfused human skeletal muscle. To this purpose, patients undergoing aortic cross-clamping during the surgical repair of aortic abdominal aneurysm were studied as a model of ischemia-reperfusion of the lower limb muscles. Muscle biopsies from the right femoral quadriceps of patients not receiving and receiving Vitamin E pretreatment before surgery were taken: a) after the induction of anaesthesia, as control samples, and b) after a period of ischemia followed by 30 min of reperfusion. The tissue samples were either routinely processed for morphological study and immunohistochemical analysis to detect an altered expression of specific endothelial adhesion proteins, such as E-selectin and ICAM-1. The results obtained showed that Vitamin E administration was able to prevent the accumulation of neutrophils within the ischemic and reperfused muscle. This beneficial effect of Vitamin E was due to its ability to hinder the expression of E-selectin and ICAM-1, molecules known to increase the adhesiveness of endothelium to circulating neutrophils. After treatment with Vitamin E a marked attenuation of the reperfusion injury was also evident. In conclusion, Vitamin E treatment may be considered a valuable tool for protection against the ischemia-reperfusion damage of human skeletal muscle.

Vitamin E protects human skeletal muscle from damage during surgical ischemia-reperfusion.

PURPOSE: The biochemical and morphological alterations induced in lower limb skeletal muscle by ischemia-reperfusion (I-R) during aortic surgery and the effect of vitamin E pretreatment were investigated. METHODS: Two groups of patients undergoing aortic aneurysm resection, one untreated and one treated with vitamin E, were examined. Quadricep muscle biopsies were taken after induction of anesthesia, at the end of ischemia, and after reperfusion. The malondialdehyde (MDA) content and morphology of biopsies were examined to assess peroxidative processes. RESULTS: Ischemia did not induce an increase in MDA content but did increase neutrophil infiltration in muscle fibers of untreated patients. Reperfusion led to a significant increase in MDA content and to intermyofibrillar edema and mitochondrial swelling. The MDA content was not increased during ischemia and neutrophil infiltration was minimal in vitamin E treated patients. At reperfusion, the MDA content, the ultrastructural injuries and neutrophil infiltration were significantly reduced by the treatment. CONCLUSIONS: Vitamin E is effective in reducing the oxidative muscle damage occurring after a period of I-R.

Evolution of endotoxin induced acute lung injury in the rat.

To clarify the evolution of acute lung injury induced by endotoxin, the progression of lung damage in 26 rats submitted to intratracheal instillation of 5 mg/kg body weight endotoxin was examined by blood gas analysis, computerized tomography, light and electron microscopy. Hypoxaemia, hypercapnia, acidosis and inhomogeneous bilateral infiltrates developed gradually within 48 hours. Monocytes appeared within blood capillaries and the instertitium by 12 hours after treatment, then migrated into alveoli and underwent progressive differentiation into macrophages by 24 hours after treatment. Granulocytes were found within blood capillaries at an early stage, but outside capillaries only at 48 hours. Hyperplasia of type II pneumocytes and hypertrophy of interstitial fibroblasts also occurred at 48 hours. These data suggest that the pathogenesis of endotoxin induced pulmonary injury proceeds through an early phase of granulocyte migration inside capillaries and monocyte extravasation, an intermediate phase of monocyte differentiation into macrophages inside alveoli and a late phase of diffuse infiltration of alveoli by newly differentiated macrophages and late-extravasated neutrophils.

Expression of E-selectin in ischemic and reperfused human skeletal muscle.

This work was undertaken to assess the role of endothelial E-selectin in the development of neutrophil accumulation into the ischemic and reperfused human skeletal muscle and eventually in the genesis of ischemia-reperfusion syndrome. Twelve patients affected by abdominal aortic aneurysm who were undergoing reconstructive vascular surgery were studied. Muscle biopsies from the right femoral quadriceps were taken (1) immediately after anesthesia, as control samples, (2) before declamping the aorta, as ischemic samples, and (3) 30 minutes after reperfusion and then processed for immunohistochemical and ultrastructural analysis. Immunohistochemistry revealed a strong positive reaction for E-selectin on the venular endothelium during ischemia and reperfusion. Ultrastructural investigation showed that reactivity for E-selectin matched neutrophil accumulation of the skeletal muscle tissue. This phenomenon was dependent upon a complex series of events that included neutrophil adhesion to the inner surface of the postcapillary venules, passage through endothelial intercellular junctions, and migration distally into the interstitial spaces of the skeletal muscle tissue. Neutrophil tissue infiltration was also associated with ultrastructural signs of tissue damage at reperfusion. This is in agreement with accumulating evidence indicating a role for tissue infiltrating neutrophils in the genesis of toxic O2 free radicals. Our data suggest that E-selectin expression on the vascular endothelium of human skeletal muscle may represent a key regulatory point in the process of neutrophil tissue accumulation and indicate an active role for the venular endothelium in the development of human ischemia-reperfusion syndrome.

Involvement of interstitial cells in endotoxin-induced acute lung injury. A histochemical and electron microscopical study.

Instillation of endotoxin into the rat trachea causes a disease representative of the lung response to several types of inflammatory injury and--in part--of human acute respiratory distress syndrome. Oxidizing radicals, including nitric oxide (NO), may be suspected to play some role in these conditions. The participation of leukocytes to tissue damage in these conditions has been reported, but the behaviour of lung interstitial cells in unknown. In this study, we have investigated on possible sources of NO and the response of lung interstitial cells during endotoxin-induced experimental lung injury. Rats were subjected to intratracheal instillation of endotoxin (5 mg/kg body weight) and sacrificed after 12, 24 and 48 h; animals treated with saline or sham-operated were used as controls. Analyses included conventional light microscopy, histochemical detection of NADPH-diaphorase (which co-localizes with NO synthase) and electron microscopy. Lung infiltrates appeared after 12 h and became progressively more severe up to 48 h. NADPH-diaphorase positive cells appeared in the septa after 24 h and became more numerous after 48 h; their nuclei were smooth-surfaced and the cytoplasm often extended into projections. By electron microscopy, only interstitial fibroblasts had a morphology similar to that of NO synthase positive cells and increased in number in the septa at the same time. These cells formed incomplete cuffs around blood capillaries and became large and rich in endoplasmic reticulum, as compared to those of the controls. These data suggest that hypertrophic fibroblastic interstitial cells can concur to maintain capillaries dilated (by NO secretion) and impair respiratory gas diffusion (by intervening between capillaries and pneumocytes), during experimental acute respiratory distress in the rat.

Ischemia-reperfusion of human skeletal muscle during aortoiliac surgery: effects of acetylcarnitine.

Our previous study on human skeletal muscle undergoing ischemia and reperfusion has revealed that granulocytes, which infiltrate the muscle tissue in large numbers, play an important role in mediating fibre injuries by producing superoxide anion (O2-) which is responsible for membrane lipid peroxidation. In the current study, five patients undergoing aortic reconstructive surgery were given acetyl-carnitine (2 mg/kg i.v. plus 1 mg/kg/min for 30 min) prior to the induction of ischemia. Muscle biopsies and blood samples were examined: a) after anaesthesia; b) at the end of ischemia; and c) 30 min after reperfusion, with the aim of elucidating whether acetylcarnitine could prevent the infiltration and/or the activation of granulocytes and eventually skeletal muscle injuries. During ischemia and reperfusion complement activation recruited numerous granulocytes into the muscle tissue, but, contrary to the untreated samples, the ability for O2(-)-generation of these cells remained at low levels and was comparable to that of ischemia even when molecular O2 was reintroduced to the tissue. Accordingly, the morphological changes of the postischemic muscle fibers were substantially reduced when compared to the untreated samples; in fact, the mitochondrial swelling was only moderate and the intramitochondrial dense bodies were small and scarce. The current findings support a positive role of acetyl-carnitine in ameliorating the ischemia-reperfusion (I-R)-induced damage of human skeletal muscle.

Neutrophils as mediators of human skeletal muscle ischemia-reperfusion syndrome.

Nine patients with aortic aneurysm undergoing arterial reconstruction with temporary aortic occlusion were studied. Since a typical condition of ischemia-reperfusion of the muscles of the lower limbs was created during this surgery, muscle biopsies from the right femoral quadriceps as well as blood samples from the homolateral saphenous vein were taken: (1) before clamping of the aorta, (2) just before declamping, and (3) 30 minutes after reperfusion. Light microscopy revealed a consistent granulocyte infiltration in the ischemic and reperfused skeletal muscle. Ultrastructural damage to the muscle fibers was seen during ischemia and became more severe upon reperfusion. The recruitment of granulocytes into the muscle tissue paralleled the activation of the blood complement system and an increase in circulating neutrophils. Although a spontaneous superoxide anion (O2-) generation from such granulocytes cannot be proved, upon stimulation with formyl-methionyl-leucyl-phenylalanine neutrophils showed a reduced ability in O2 free radical production at the end of ischemia and enhanced O2- generation at reperfusion as compared with the controls. All these findings indicate an active role of granulocytes in the genesis of reperfusion-induced tissue injuries.

[Comparison of crystalloids and hydroxyethyl starch during normovolemic hemodilution. A study of hemodynamics and saturation measurement]. / Confronto tra cristalloidi ed amido idrossietilico in corso di emodiluizione normovolemica. Uno studio emodinamico e saturimetrico.

Normovolemic hemodilution at two different hematocrit values was performed in ten patients undergoing major surgery to evaluate changes of DO2, VO2 and CI. A Hct of 38% (low hemodilution) was reached by plasma replacement with ringer lactate infusion. A further hemodilution, a Hct of 30% (high hemodilution), was obtained by hydroxyethyl starch plus ringer lactate (1:2 ratio) infusion. A significant VO2 increase (p less than 0.01) occurred when hydroxyethyl starch plus ringer lactate infusions were employed as compared to ringer lactate alone. No changes in DO2 and CI were observed, the increase in VO2 measured during colloid infusion could suggest a better tissue perfusion and metabolic activity.