Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia

Introduction

In seriously infected patients with acute renal failure and who require continuous renal replacement therapy, data on continuous infusion of ceftazidime are lacking. Here we analyzed the pharmacokinetics of ceftazidime administered by continuous infusion in critically ill patients during continuous venovenous haemodiafiltration (CVVHDF) in order to identify the optimal dosage in this setting.

Method

Seven critically ill patients were prospectively enrolled in the study. CVVHDF was performed using a 0.6 m² AN69 high-flux membrane and with blood, dialysate and ultrafiltration flow rates of 150 ml/min, 1 l/hour and 1.5 l/hour, respectively. Based on a predicted haemodiafiltration clearance of 32.5 ml/min, all patients received a 2 g loading dose of ceftazidime, followed by a 3 g/day continuous infusion for 72 hours. Serum samples were collected at 0, 3, 15 and 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 36, 48 and 72 hours; dialysate/ultrafiltrate samples were taken at 2, 8, 12, 24, 36 and 48 hours. Ceftazidime concentrations in serum and dialysate/ultrafiltrate were measured using high-performance liquid chromatography.

Results

The mean (± standard deviation) elimination half-life, volume of distribution, area under the concentration-time curve from time 0 to 72 hours, and total clearance of ceftazidime were 4 ± 1 hours, 19 ± 6 l, 2514 ± 212 mg/h per l, and 62 ± 5 ml/min, respectively. The mean serum ceftazidime steady-state concentration was 33.5 mg/l (range 28.8–36.3 mg/l). CVVHDF effectively removed continuously infused ceftazidime, with a sieving coefficient and haemodiafiltration clearance of 0.81 ± 0.11 and 33.6 ± 4 mg/l, respectively.

Conclusion

We conclude that a dosing regimen of 3 g/day ceftazidime, by continuous infusion, following a 2 g loading dose, results in serum concentrations more than four times the minimum inhibitory concentration for all susceptible pathogens, and we recommend this regimen in critically ill patients undergoing CVVHDF.     

Lung water assessment by lung ultrasonography in intensive care: a pilot study

Objective

To investigate the accuracy of lung ultrasonography (LUS) in the quantification of lung water in critically ill patients by using quantitative computed tomography (CT) as the gold standard for the determination of lung weight.

Methods

Twenty consecutive patients admitted to an intensive care unit who underwent chest CT as a step in their clinical management were evaluated within 4?h by LUS. Lung weight, lung volume, and physical lung density were calculated from the CT scans using ad hoc software. Semiquantitative ultrasound assessment of lung water was performed by determining the ultrasound B-line score, defined as the total number of B-lines detectable in an anterolateral LUS examination.

Results

Good correlations were found between the B-line score and lung weight (r?=?0.75, p?<?0.05) and density (r?=?0.82, p?<?0.01), that only marginally increased when the lung density of the first 10?mm of subpleural lung tissue was evaluated (r?=?0.83, p?<?0.01). Moreover, values of subpleural lung density were not significantly different from values of the whole lung density (0.34?±?0.11 vs. 0.37?±?0.16?g/ml, p?=?ns). Very good correlations were found between the B-line score and both the weight (r?=?0.85, p?<?0.01) and the density (r?=?0.88, p?<?0.01) of the upper lobes. The weight of the lower lobes was not correlated with the B-line score (r?=?0.14, p?=?ns).

Conclusions

Lung ultrasound B-lines are correlated with lung weight and density determined by CT. LUS may provide a reliable, simple and radiation-free lung densitometry in the intensive care setting.     

Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa

Purpose

Emergence of multidrug-resistant strains in intensive care units has renewed interest in colistin, which often remains the only available antimicrobial agent active against resistant Pseudomonas aeruginosa. The aim of this study is to compare lung tissue deposition and antibacterial efficiency between nebulized and intravenous administration of colistin in piglets with pneumonia caused by P. aeruginosa.

Methods

In ventilated piglets, colistimethate was administered 24 h following bronchial inoculation of Pseudomonas aeruginosa (minimum inhibitory concentration of colistin = 2 μg ml^?1) either by nebulization (8 mg kg^?1 every 12 h, n = 6) or by intravenous infusion (3.2 mg kg^?1 every 8 h, n = 6). All piglets were killed 49 h after inoculation. Colistin peak lung tissue concentrations and lung bacterial burden were assessed on multiple post mortem subpleural lung specimens.

Results

Median colistin peak lung concentration following nebulization was 2.8 μg g^?1 (25–75% interquartile range = 0.8–13.7 μg g^?1). Colistin was undetected in lung tissue following intravenous infusion. In the aerosol group, peak lung tissue concentrations were significantly greater in lung segments with mild pneumonia (median = 10.0 μg g^?1, 25–75% interquartile range = 1.8–16.1 μg g^?1) than in lung segments with severe pneumonia (median = 1.2 μg g^?1, 25–75% interquartile range = 0.5–3.3 μg g^?1) (p < 0.01). After 24 h of treatment, 67% of pulmonary segments had bacterial counts <10² cfu g^?1 following nebulization and 28% following intravenous administration (p < 0.001). In control animals, 12% of lung segments had bacterial counts <10² cfu g^?1 49 h following bronchial inoculation.

Conclusion

Nebulized colistin provides rapid and efficient bacterial killing in ventilated piglets with inoculation pneumonia caused by Pseudomonas aeruginosa.     

A metabolomic approach for diagnosis of experimental sepsis

Background

The search for reliable diagnostic biomarkers of sepsis remains necessary. Assessment of global metabolic profiling using quantitative nuclear magnetic resonance (NMR)-based metabolomics offers an attractive modern methodology for fast and comprehensive determination of multiple circulating metabolites and for defining the metabolic phenotype of sepsis.

Objective

To develop a novel NMR-based metabolomic approach for diagnostic evaluation of sepsis.

Methods

Male Sprague?CDawley rats (weight 325?C375?g) underwent cecal ligation and puncture (n?=?14, septic group) or sham procedure (n?=?14, control group) and 24?h later were euthanized. Lung tissue, bronchoalveolar lavage (BAL) fluid, and serum samples were obtained for ¹H NMR and high-resolution magic-angle spinning analysis. Unsupervised principal components analysis was performed on the processed spectra, and a predictive model for diagnosis of sepsis was constructed using partial least-squares discriminant analysis.

Results

NMR-based metabolic profiling discriminated characteristics between control and septic rats. Characteristic metabolites changed markedly in septic rats as compared with control rats: alanine, creatine, phosphoethanolamine, and myoinositol concentrations increased in lung tissue; creatine increased and myoinositol decreased in BAL fluid; and alanine, creatine, phosphoethanolamine, and acetoacetate increased whereas formate decreased in serum. A predictive model for diagnosis of sepsis using these metabolites classified cases with sensitivity and specificity of 100%.

Conclusions

NMR metabolomic analysis is a potentially useful technique for diagnosis of sepsis. The concentrations of metabolites involved in energy metabolism and in the inflammatory response change in this model of sepsis.     

Prophylactic treatment of local reactions to i.v. vinorelbine: a randomized study

Background

Local reactions on the site of infusion are common with i.v. vinorelbine treatment.

Purpose

The study aims were to evaluate whether an i.v. saline infusion or steroid injection, or the combination of these measures, could decrease vinorelbine-related local reactions and to study to what extent such reactions actually occur.

Methods

Patients with lung cancer and planned chemotherapy containing i.v. vinorelbine were randomized in a 2?×?2 factorial design to receive either 4?mg betamethasone or placebo i.v. prior to and either 20 or 250?ml saline infusion following the vinorelbine infusion. Local infusion site signs and symptoms were recorded during and 1?h after the vinorelbine infusion and collected by a study-specific diary 24–48?h following each treatment course.

Results

A total of 79 patients were randomized and evaluable. Local infusion site signs, symptoms and reactions occurred in 63% of all patients (49% during vinorelbine monotherapy courses), with local pain being most frequently reported. Pre-treatment with i.v. betamethasone was associated with a reduced risk of local pain (5/38 vs. 20/39; p?p?=?0.01) compared with placebo during the 48?h following the vinorelbine infusion. The reduced pain effect was seen both during vinorelbine monotherapy courses and during combination chemotherapy with carboplatin. In contrast, there was no difference between post-treatment infusion with 20 or 250?ml saline with regard to local signs or symptoms.

Conclusion

Local infusion site side effects are common with i.v. vinorelbine. Pre-treatment with 4?mg betamethasone i.v. is associated with a reduced risk of local symptoms or reactions, local pain in particular.     

Levosimendan infusion in newborns after corrective surgery for congenital heart disease: randomized controlled trial

Purpose

To evaluate the safety and efficacy of levosimendan in neonates with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass (CPB).

Methods

Neonates undergoing risk-adjusted classification for congenital heart surgery (RACHS) 3 and 4 procedures were randomized to receive either a 72?h continuous infusion of 0.1?μg/kg/min levosimendan or standard post-CPB inotrope infusion.

Results

Sixty-three patients (32 cases and 31 controls) were recruited. There were no differences between groups regarding demographic and baseline clinical data. No side effects were observed. There were no significant differences in mortality (1 vs. 3 patients, p?=?0.35), length of mechanical ventilation (5.9?±?5 vs. 6.9?±?8?days, p?=?0.54), and pediatric cardiac intensive care unit (PCICU) stay (11?±?8 vs. 14?±?14?days, p?=?0.26). Low cardiac output syndrome occurred in 37?% of levosimendan patients and in 61?% of controls (p?=?0.059, OR 0.38, 95?% CI 0.14–1.0). Postoperative heart rate, with a significant difference at 6 (p?=?0.008), 12 (p?=?0.037), and 24?h (p?=?0.046), and lactate levels, with a significant difference at PCICU admission (p?=?0.015) and after 6?h (p?=?0.048), were lower in the levosimendan group. Inotropic score was significantly lower in the levosimendan group at PCICU admission, after 6?h and after 12?h, (p?Conclusions Levosimendan infused in neonates undergoing cardiac surgery was well tolerated with a potential benefit of levosimendan on postoperative hemodynamic and metabolic parameters of RACHS 3–4 neonates.     

Effects of different mechanical ventilation strategies on the mucociliary system

Objective

To evaluate the effects of different mechanical ventilation (MV) strategies on the mucociliary system.

Design and setting

Experimental study.

Subjects

Twenty-seven male New Zealand rabbits.

Interventions

After anesthesia, animals were tracheotomized and ventilated with standard ventilation [tidal volume (Vt) 8?ml/kg, positive end expiratory pressure (PEEP) 5?cmH₂O, flow 3?L/min, FiO₂ 0.4] for 30?min. Next, animals were randomized into three groups and ventilated for 3?h with low volume (LV): Vt 8?ml/kg, PEEP 5?cmH₂O, flow 3?L/min (n?=?6); high volume (HV): Vt 16?ml/kg, PEEP 5?cmH₂O, flow 5?L/min (n?=?7); or high pressure (HP): Ppeak 30?cmH₂O, PEEP 12?cmH₂O (n?=?8). Six animals (controls) were ventilated for 10?min with standard ventilation. Vital signals, blood lactate, and respiratory system mechanics were verified. Tracheal tissue was collected before and after MV.

Measurements

Lung and tracheal tissue sections were stained to analyze inflammation and mucosubstances by the point-counting method. Electron microscopy verified tracheal cell ultrastructure. In situ tracheal ciliary beating frequency (CBF), determined using a videoscopic technique, and tracheal mucociliary transport (TMCT), assessed by stereoscopic microscope, were evaluated before and after MV.

Results

Respiratory compliance decreased in the HP group. The HV and HP groups showed higher lactate levels after MV. Macroscopy showed areas of atelectasis and congestion on HV and HP lungs. Lung inflammatory infiltrate increased in all ventilated groups. Compared to the control, ventilated animals also showed a reduction of total and acid mucus on tracheal epithelium. Under electron microscopy, injury was observed in the ciliated cells of the HP group. CBF decreased significantly after MV only in the HP group. TMCT did not change significantly in the ventilated groups.

Conclusions

Different MV strategies induce not only distal lung alterations but also morphological and physiological tracheal alterations leading to mucociliary system dysfunction.     

Effects of piroximone on the right ventricular function in severe heart failure patients

Objectives

To assess the effects of piroximone, a phosphodiesterase inhibitor, on right ventricular function in patients with heart failure.

Design

Randomized study: patients were randomly assigned to the piroximone infusion rate of 5 or 10 μg/kg/min.

Setting

Cardiologic intensive care unit.

Patients

12 consecutive patients with severe heart failure.

Interventions

Right heart catheterization was performed using a Swan-Ganz ejection fraction thermodilution catheter.

Measurements and results

Measurements of right ventricular ejection fraction (RVEF), end-diastolic and end-systolic right ventricular volumes were obtained using the thermodilution principle. To determine contractility indexes, the relationships between end-systolic pulmonary arterial pressure (ESPAP) over right ventricular end-systolic volume (RVESV) and ESPAP over RVEF were calculated during the infusion of prostacyclin at incremental infusion rates of 2, 4, 6 and 8 ng/kg/min. The slope of the relation between ESPAP over RVESV shifted during piroximone therapy from 7.635±1.632 to 1.975±0.432 (p<0.01) and from 6.092±1.99 to 1.028±0.853 (p<0.05) at 5 and 10 μg/kg/min piroximone infusion, respectively. The slope of the relation between ESPAP over RVEF decreased from ?0.414±0.296 to ?0.821±0.257 (p<0.01) and from ?0.127±0.048 to ?0.533±0.135 (p<0.05) at 5 and 10 μg/kg/min piroximone infusion, respectively.

Conclusions

This study suggests a positive action of piroximone on right ventricular contractility at these 2 dosages. This approach using this type of catheter allowed us to determine right ventricular inotropic indexes.     

Evaluation of pathogen detection from clinical samples by real-time polymerase chain reaction using a sepsis pathogen DNA detection kit

Introduction

Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Previous studies on β-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock.

Methods

Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration.

Results

80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 μg/mL), 45% for ceftazidime (MIC = 32 μg/mL), 34% for cefepime (MIC = 32 μg/mL), and 33% for piperacillin-tazobactam (MIC = 64 μg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam.

Conclusions

Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.     

Outcome of critically ill lung transplant candidates on invasive respiratory support

Purpose

Lung transplantation (LTx) of patients on mechanical ventilation (MV) or extracorporeal support (ECS) is controversial because of impaired survival. Prognostic factors to predict survival should be identified.

Methods

A retrospective analysis was performed in a single centre of all ventilated LTx-candidates awarded an Eurotransplant (ET) high-urgency (HU) status between November 2004 and July 2009. Clinical data were collected on the first day of HU-status from intubated patients with an approved HU status. Single parameters as well as the lung allocation score (LAS), the Sequential Organ Failure Assessment score (SOFA) and the Simplified Acute Physiology Score (SAPS 2) were calculated. The association of these variables with survival was evaluated.

Results

A total of 100 intubated patients (median age 38?years, 56?% female) fulfilled the inclusion criteria, of whom 60 also required ECS. The main indications were cystic fibrosis (25?%) and idiopathic pulmonary fibrosis (24?%). Median time with HU status was 12?days [interquartile range (IQR) 6–21 days]. Sixty patients were transplanted, five were weaned from mechanical ventilation and 38 died while on the wait list. One-year-survival rates were 57, 36 and 5?% for transplanted patients, all candidates and non-transplanted candidates, respectively (p?24 (median 30, IQR 27–35), a procalcitonin level of >0.5?μg/l (median 0.4, IQR 0.1–1.4?μg/l) and any escalation of bridging strategy were independently associated with mortality (p = 0.021, = 0.003, and?p = 0.92).

Conclusions

High-urgency LTx improves survival in critically ill intubated candidates. Higher SAPS scores, escalating therapy and an abnormal procalcitonin level were associated with a poor outcome.     

Effects of different tidal volumes in pulmonary and extrapulmonary lung injury with or without intraabdominal hypertension

Purpose

We hypothesized that: (1) intraabdominal hypertension increases pulmonary inflammatory and fibrogenic responses in acute lung injury (ALI); (2) in the presence of intraabdominal hypertension, higher tidal volume reduces lung damage in extrapulmonary ALI, but not in pulmonary ALI.

Methods

Wistar rats were randomly allocated to receive Escherichia coli lipopolysaccharide intratracheally (pulmonary ALI) or intraperitoneally (extrapulmonary ALI). After 24?h, animals were randomized into subgroups without or with intraabdominal hypertension (15?mmHg) and ventilated with positive end expiratory pressure?=?5?cmH₂O and tidal volume of 6 or 10?ml/kg during 1?h. Lung and chest wall mechanics, arterial blood gases, lung and distal organ histology, and interleukin (IL)-1??, IL-6, caspase-3 and type III procollagen (PCIII) mRNA expressions in lung tissue were analyzed.

Results

With intraabdominal hypertension, (1) chest-wall static elastance increased, and PCIII, IL-1??, IL-6, and caspase-3 expressions were more pronounced than in animals with normal intraabdominal pressure in both ALI groups; (2) in extrapulmonary ALI, higher tidal volume was associated with decreased atelectasis, and lower IL-6 and caspase-3 expressions; (3) in pulmonary ALI, higher tidal volume led to higher IL-6 expression; and (4) in pulmonary ALI, liver, kidney, and villi cell apoptosis was increased, but not affected by tidal volume.

Conclusions

Intraabdominal hypertension increased inflammation and fibrogenesis in the lung independent of ALI etiology. In extrapulmonary ALI associated with intraabdominal hypertension, higher tidal volume improved lung morphometry with lower inflammation in lung tissue. Conversely, in pulmonary ALI associated with intraabdominal hypertension, higher tidal volume increased IL-6 expression.     

Impact of milrinone on mitral annular velocity in patients with congestive heart failure

Purpose

The purpose of this study is to assess the impact of milrinone on mitral annular velocity in patients with congestive heart failure.

Method

We studied 27 patients with congestive heart failure. All patients underwent transthoracic echocardiography both before and after administration of milrinone. We measured the early transmitral velocity (E) and the mitral annular early diastolic velocity (Ea). The ratio of E to Ea (E/Ea) was calculated. After the baseline echocardiography, milrinone was administered as a continuous infusion at a rate of 0.25 μg/kg/min. Echocardiographic measurements were repeated 4 h after milrinone was begun.

Results

After administration of milrinone, Ea was significantly increased, while E/Ea was significantly decreased. The population of 27 patients was divided into 20 (74 %) with left ventricular ejection fraction (LVEF) <50 % and seven (26 %) with LVEF ≥50 %. Ea was significantly increased in both groups, while E/Ea was significantly decreased.

Conclusion

Even low-dose milrinone produced an improvement in left ventricular (LV) diastolic function, as evidenced by an increase in Ea, and falls in LV filling pressures, as determined by a decrease in E/Ea, in patients with congestive heart failure throughout a wide range of LV systolic function.     

Is there a pharmacodynamic need for the use of continuous versus intermittent infusion with ceftazidime against Pseudomonas aeruginosa? An in vitro pharmacodynamic model

OBJECTIVES: In order to explore the pharmacodynamic need for continuous versus intermittent (three times a day) administration of ceftazidime in critically ill patients, a pharmacokinetic computerized device was used to simulate concentrations of ceftazidime in human serum after 6 g/day. METHODS: Efficacy was measured as the capability of simulated concentrations over time to reduce initial inoculum against four strains of Pseudomonas aeruginosa. MICs of the strains matched NCCLS breakpoints: one susceptible strain (MIC = 8 mg/L), two intermediate strains (MIC = 16 mg/L) and one resistant strain (MIC = 32 mg/L). C(max) was 119.97+/-2.53 mg/L for intermittent bolus and C(ss) (steady-state concentration) was 40.38+/-0.16 mg/L for continuous infusion. AUC(0-24) was similar for both regimens (approximately 950 mg x h/L). Inhibitory quotients were three times higher for the intermittent administration whereas t > MIC was higher for continuous infusion (100%) versus intermittent administration (99.8%, 69% and 47.6% for the susceptible, intermediate and resistant strains, respectively). RESULTS: Against the susceptible and intermediate strains, no differences were found between both regimens with > or = 3 log10 reduction from 8 to 24 h. Against the resistant strain, only the continuous infusion achieved this bactericidal activity in the same time period, minimizing the differences between resistant and susceptible strains. Significantly higher initial inoculum reduction at 32 h was obtained for the continuous versus the intermittent administration (83.35% versus 38.40%, respectively). CONCLUSIONS: These results stress the importance of optimizing t >MIC, even at peri-MIC concentrations, of ceftazidime against resistant strains. Local prevalence of resistance justifies, on a pharmacodynamic basis, electing for continuous infusion versus intermittent administration.     

Pharmacokinetics of inhaled colistimethate sodium (CMS) in mechanically ventilated critically ill patients

Purpose

The purpose of this study was to describe inhaled colistin pharmacokinetics in patients with ventilator-associated tracheobronchitis (VAT) due to polymyxin-only susceptible Gram-negative bacteria (GNB).

Methods

Inhaled colistimethate sodium (CMS) was administered at a dose of 80?mg every 8 h for 7 days. Mini bronchoalveolar lavage (BAL) was performed before and at 1, 4 and 8 h, while blood samples were collected before and at 0.16, 0.5, 1, 2, 4 and 8 h after the first dose. Colistin concentrations in BAL and serum were determined by high-performance liquid chromatography.

Results

Our study population included 20 patients. At the end of treatment, cure was achieved in 16 patients and favorable microbiological response in 12 patients. Median (25–75 % interquartile range) colistin concentrations in epithelial lining fluid (ELF) were 6.7 (4.8–10.1), 3.9 (2.5–6.0) and 2.0 (1.0–3.8)?μg/ml at 1, 4 and 8 h, respectively, and fivefold higher than those achieved in serum. Median ELF concentrations at 1 and 4 h were above the minimum inhibitory concentrations of all isolated pathogens; however, the 4-h median was below the European Committee on Antimicrobial Susceptibility Guidelines (EUCAST) breakpoints for Pseudomonas aeruginosa and the 8-h median was low relative to EUCAST breakpoints for all GNB. Colistin pharmacokinetic/pharmacodynamic parameters in ELF were associated with favorable microbiological response at the end of treatment.

Conclusion

Inhaled colistin may achieve high drug concentrations in the lung. However, a dose of 80?mg of inhaled CMS every 8 h may not be adequate for the treatment of lower respiratory tract infections due to multi-drug resistant GNB.     

Continuous enteral administration can overcome the limited capacity to absorb glucose in rats with methotrexate-induced gastrointestinal mucositis

Background

Patients with chemotherapy-induced gastrointestinal mucositis often suffer from weight loss. It is not well known how to enterally feed mucositis patients, potentially experiencing malabsorption. Recently, we showed in a rat model of methotrexate (MTX)-induced mucositis that intestinal absorption of glucose in trace amounts is still intact. We now determined the quantitative capacity to absorb glucose in rats with mucositis, relative to controls.

Methods

We administered a physiologically relevant amount of [1-¹³C]glucose-enriched glucose (meal size) as a bolus by oral gavage (2 g/kg once) or continuously by intraduodenal infusion (±1.9 g/(kg·h) for 5 h) to rats with MTX-induced mucositis and controls. Blood [1-¹³C]glucose concentrations were determined during the experimental period. To calculate the quantitative absorptive capacity, Steele’s one-compartment model, including simultaneous intravenous infusion of [6,6-²H₂]glucose, was used. After the experiment, jejunal histology and plasma citrulline concentrations were assessed.

Results

MTX-induced mucositis was confirmed by a reduction in villus length and plasma citrulline (both ?57 %, relative to controls, P?<?0.01). When glucose was administered as a bolus, MTX-treated rats only absorbed 15 % of administered glucose, compared with 85 % in controls (medians, P?<?0.01). Upon continuous intraduodenal glucose infusion, the median absorptive capacity for glucose in MTX-treated rats did not differ from controls (80 versus 93 % of administered glucose respectively, P?=?0.06). However, glucose absorption differed substantially between individual MTX-treated rats (range, 21–95 %), which correlated poorly with villus length (rho?=?0.54, P?=?0.030) and plasma citrulline (rho?=?0.56, P?=?0.024).

Conclusion

Continuous enteral administration can almost completely overcome the reduced absorptive capacity for glucose in rats with mucositis.     

Impairment of bacterial clearance induced by norepinephrine infusion in rabbits

Objective

Purpose of the study was to investigate the potential influence of norepinephrine (NE) on immune functions in terms of systemic and organ-specific bacterial clearance in rabbits.

Design

To enable quantification of the clearance process, defined numbers of exogenousEscherichia coli (1.3×10⁸ CFU) were injected intravenously 60 min after starting the NE infusion at a low dose (1 μg/kg per min,n=6), causing an increase (30 mmHg) in mean arterial pressure without affecting the oxygen uptake, and at a higher dose (7.5 μg/kg per min,n=6), resulting in a marked decrease (20%) in oxygen uptake, after infusion of NaCl solution (control,n=6). In additional experiments (n=6) NE (1 μg/kg per min) was tested in endotoxemia induced by simultaneous infusion of endotoxin (40 μg/kg per h). Parameters monitored were arterial pressure, oxygen uptake, and rates of bacterial elimination from the blood. At 180 min afterE. coli injection, the animals were sacrificed, and tissue samples of liver, kidney, spleen, and lung were collected for bacterial counts.

Results

NE infusion resulted in a dose-dependent prolonged elimination of the injectedE. coli from the blood and in significantly higher (p<0.05) numbers of CFU in liver and lung compared to the controls. Significant impairment of bacterial clearance was found after shockproducing endotoxemia, whereas simultaneous infusion of NE and endotoxin caused only a slightly delayed blood clearance of the injected bacteria.

Conclusion

NE dose dependently affected bacterial clearance, which might be due to ischemia-derived hypoxic impairment of the phagocytosis and lysis function of the reticuloendothelial system, whereas NE improved elimination of bacteria in a state of endotoxic shock.     

Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study

Introduction

Sepsis is associated with the generation of oxygen free radicals and (lacking) decreased selenium plasma concentrations. High doses of sodium selenite might reduce inflammation by a direct pro-oxidative effect and may increase antioxidant cell capacities by selenium incorporation into selenoenzymes. We investigated the effects of a continuous administration of high doses of selenium in septic shock patients.

Methods

A prospective, multicentre, placebo-controlled, randomized, double-blind study was performed with an intention-to-treat analysis in severe septic shock patients with documented infection. Patients received, for 10 days, selenium as sodium selenite (4,000 μg on the first day, 1,000 μg/day on the nine following days) or matching placebo using continuous intravenous infusion. The primary endpoint was the time to vasopressor therapy withdrawal. The duration of mechanical ventilation, the mortality rates in the intensive care unit, at hospital discharge, and at 7, 14, 28 and 180 days and 1 year after randomization, and adverse events were recorded.

Results

Sixty patients were included (placebo, n = 29; selenium, n = 31). The median time to vasopressor therapy withdrawal was 7 days in both groups (95% confidence interval = 5–8 and 6–9 in the placebo and selenium groups, respectively; log-rank, P = 0.713). The median duration of mechanical ventilation was 14 days and 19 days in the placebo and selenium groups, respectively (P = 0.762). Mortality rates did not significantly differ between groups at any time point. Rates of adverse events were similar in the two groups.

Conclusion

Continuous infusion of selenium as sodium selenite (4,000 μg on the first day, 1,000 μg/day on the nine following days) had no obvious toxicity but did not improve the clinical outcome in septic shock patients. Trial Registration = NCT00207844.     

In vivo efficacy of continuous infusion versus intermittent dosing of ceftazidime alone or in combination with amikacin relative to human kinetic profiles in a Pseudomonas aeruginosa rabbit endocarditis model

Ceftazidime and amikacin were administered in a Pseudomonas aeruginosa rabbit endocarditis model using computer-controlled intravenous (iv) infusion pumps to simulate human serum concentrations for the following regimens: continuous (constant rate) infusion of 4, 6 or 8 g of ceftazidime over 24 h or intermittent dosing of 2 g every 8 h either alone or in combination with amikacin (15 mg/kg once daily). The in vivo activities of these regimens were tested on four Pseudomonas aeruginosa strains. Animals were killed 24 h after the beginning of treatment. Efficacy was assessed by comparing the effects of the different groups on bacterial counts in vegetations for each strain tested. For a susceptible reference strain (ATCC 27853; MICs of ceftazidime and amikacin 1 and 2 mg/L, respectively), continuous infusion of 4 g alone or with amikacin was as effective as intermittent dosing with amikacin. For a clinical isolate producing an oxacillinase (MICs of ceftazidime and amikacin 8 and 32 mg/L, respectively), continuous infusion of 6 g was equivalent to intermittent dosing. For a clinical isolate producing a TEM-2 penicillinase (MIC of ceftazidime and amikacin 4 mg/L), continuous infusion of 6 g, but not intermittent dosing, had a significant in vivo effect. For a clinical isolate producing an inducible, chromosomally encoded cephalosporinase (MIC of ceftazidime and amikacin 8 and 4 mg/L, respectively), neither continuous infusion nor intermittent dosing proved effective. Determination of ceftazidime concentrations in vegetations showed that continuous infusion produced tissue concentrations at the infection site far greater than the MIC throughout the treatment. It is concluded that continuous infusion of the same total daily dose provides significant activity as compared with fractionated infusion. This study confirms that a concentration of 4-5 x MIC is a reasonable therapeutic target in most clinical settings of severe P. aeruginosa infection.     

Haemodynamic and neuroendocrine effects of tezosentan in chronic experimental pulmonary hypertension

Purpose

Chronic pulmonary hypertension (PH) therapy is poorly investigated in intensive care. Our aim was to evaluate haemodynamic and neuroendocrine effects of the dual endothelin-1 (ET-1) blocker tezosentan in monocrotaline (MCT)-induced PH.

Methods

Male Wistar rats (180–200?g, n?=?194) randomly received 60?mg?kg^?1 MCT or vehicle, subcutaneously, and 2?days later, a subgroup of MCT-injected rats was gavaged with 300?mg?kg^?1?day^?1 bosentan (MCT BOS, n?=?46), while another (MCT, n?=?125) and control rats (Ctrl, n?=?23) received vehicle. At 25–30?days, 48?h after interrupting bosentan, rats randomly underwent either a dose–response evaluation (0.5–20?mg?kg^?1, n?=?7 each group) or a 4?h perfusion of tezosentan (20?mg?kg^?1 in 10?min?+?10?mg?g^?1?h^?1) or vehicle (n?=?8 per group, each). Haemodynamics, including blood gas analysis, were evaluated after thoracotomy under anaesthesia. After plasma, right ventricle (RV) and lung collection, plasma ET-1, cytokines, nitrate and 6-keto-PGF1α, and lung and right ventricular gene expression and cyclooxygenase (COX) and nitric oxide synthase (NOS) activities were quantified.

Results

Monocrotaline resulted in PH, RV dilation and decreased cardiac output (CO) that were attenuated in MCT BOS. Pulmonary hypertension was attenuated by tezosentan without systemic hypotension. Tezosentan increased CO without changing ventilation-perfusion matching. Both bosentan and tezosentan reduced ET-1 and cytokine plasma levels and tissue expression, and inducible NOS and COX-2 RV activities. Bosentan increased nitrate plasma levels and non inducible NOS activities whereas tezosentan decreased circulating 6-keto-PGF1α but increased lung COX-1 activity.

Conclusions

Tezosentan may be useful for haemodynamic handling and bosentan replacement in critically ill PH patients exerting important beneficial neuroendocrine and anti-inflammatory actions.     

Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate,Mechanical Ventilation,and Reason for Admission

The aim of this study was to develop a population-pharmacokinetic model of ceftazidime in intensive care unit patients to include the influence of patients'' characteristics on the pharmacokinetics. Forty-nine patients for model building and 23 patients for validation were included in a randomized study. They received ceftazidime at 2 g three times a day or as 6 g per day continuously. A NONMEM pharmacokinetic model was constructed, and the influences of covariates were studied. The model was validated by a comparison of the predicted and observed concentrations. A final model was elaborated from the whole population. Total clearance (CL) was significantly correlated with the glomerular filtration rate (GFR) calculated by modification of the diet in renal disease (MDRD), the central volume of distribution (V1) with intubation, and the peripheral volume of distribution (V2) with the reason for admission. The mean pharmacokinetic parameters were as follows: CL, 5.48 liters/h, 40%; V1, 10.48 liters, 34%; V2, 32.12 liters, 59%; total volume, 42.60 liters, 45%; and intercompartmental clearance, 16.19 liters/h, 42%. In the polytrauma population (mechanically ventilated), the time above the MIC at steady state never corresponds to 100% for discontinuous administration, and the target concentration of five times the MIC was reached with a 6-g/day dose only for patients with an MDRD of <150 ml/min. We showed that the GFR-MDRD, mechanical ventilation, and the reason for admission may influence the achieved concentrations of ceftazidime. Our model allows the a priori dosing to be adjusted to the individual patient.Ceftazidime is a broad-spectrum cephalosporin generally used in the treatment of severe Pseudomonas aeruginosa infections. Since ceftazidime exhibits time-dependent killing of gram-negative bacteria in vitro or in critically ill patients, studies involving continuous administration of cephalosporin confirm that the steady-state concentration in blood should be four to five times higher than the bacterial MIC (6, 27). When the MIC is not available, the European breakpoint is used to calculate the target concentration (8). In patients with sepsis syndrome, ceftazidime plasma concentrations after a 2-g dose of ceftazidime every 8 h or 4 g by continuous infusion may be inadequate (42).Intensive care unit (ICU) patients represent a highly heterogeneous population ranging from young trauma patients to elderly medical patients and postsurgical patients. This heterogeneity is well known to produce high variability in pharmacokinetic parameters, as was previously demonstrated for the clearance and the total volume of distribution (15, 26, 36). Ceftazidime pharmacokinetics in critically ill patients is altered by an increased volume of drug distribution and a longer elimination half-life (16).In order to determine interindividual pharmacokinetic variability and the influence of some patient characteristics on the pharmacokinetics of ceftazidime, we conducted a population pharmacokinetic study to develop and validate a model to enable an adequate individual dosing strategy to be put in place (3). We used rich data collected in a prospective study comparing continuous infusion versus intermittent administration of ceftazidime, along with the demographic, clinical, and biological characteristics of these ICU patients. This study used the nonlinear mixed-effect model as implemented in the NONMEM program for pharmacostatistical analysis (4).