Gerardo Aguilar

Diagnostic accuracy and potential clinical value of the LightCycler SeptiFast assay in the management of bloodstream infections occurring in neutropenic and critically ill patients

OBJECTIVES The objectives of this study were to compare the performance of the LightCycler SeptiFast Test MGRADE and conventional blood culture in the etiological diagnosis of febrile episodes occurring in neutropenic and critically ill patients (in the intensive care unit; ICU), and to assess the potential clinical value of the SeptiFast test in patient management. METHODS A total of 86 febrile episodes occurring in 33 neutropenic patients and 53 ICU patients were analyzed. Blood samples for blood culture and SeptiFast testing were obtained at the onset of fever, before the implementation of empirical antimicrobial therapy. RESULTS The overall microorganism-to-isolate agreement between the SeptiFast test and blood culture was 69% (κ=0.37) in neutropenic patients and 75% (κ=0.56) in ICU patients. The sensitivity of the SeptiFast assay for clinically relevant episodes of bacteremia and fungemia was 62% in neutropenic patients and 70% in ICU patients. Based on SeptiFast results, empirical treatments were deemed adequate in all but one of the febrile episodes. Nevertheless, early antibiotic treatment readjustment was judged feasible in most of clinically significant episodes overall. CONCLUSIONS The SeptiFast assay is a valuable ancillary method for the diagnosis of bloodstream infections in neutropenic and ICU patients. In these clinical settings, results of the SeptiFast assay may lead to a more targeted antibiotic therapy early after the onset of fever.

Virological and immunological features of active cytomegalovirus infection in nonimmunosuppressed patients in a surgical and trauma intensive care unit.

Cytomegalovirus (CMV) reactivation occurs frequently in critically ill patients. The natural course of CMV infection and the interaction between CMV and the adaptive immune system in this setting remain poorly defined. Fifty‐three CMV‐seropositive patients in a surgical and trauma intensive care unit were included in this study. The CMV DNA load in tracheal aspirates (TA) and plasma (PL) was monitored by qPCR. CMV‐specific T‐cell immunity was assessed by intracellular cytokine staining. Plasma TNF‐α levels were determined by ELISA. CMV reactivation occurred in 39.7% of patients (23% had CMV DNA detected only in TA). The analysis of TA allowed an earlier diagnosis in 28% of patients. Clearance of CMV DNAemia preceded that of CMV DNA in TA in some episodes. Peak CMV DNA levels were significantly higher in TA than in PL (P = 0.02). CMV reactivation developed in the presence of CMV‐specific T cells. Termination of CMV reactivation was associated with an expansion of functional CMV‐specific T cells. Plasma levels of TNF‐α did not allow for the prediction of the occurrence of CMV reactivation. CMV‐specific T‐cell immunity is preserved in most critically ill patients experiencing CMV reactivation. Analysis of respiratory specimens is imperative for an optimal monitoring of CMV reactivation in this setting. J. Med. Virol. 82:1384–1391, 2010.

The Predictive Performance of a Pharmacokinetic Model for Manually Adjusted Infusion of Liquid Sevofluorane for Use with the Anesthetic-Conserving Device (AnaConDa) : A Clinical Study

BACKGROUND: The Anesthetic-Conserving Device (AnaConDa) can be used to administer inhaled anesthetics using an intensive care unit (ICU) ventilator. We evaluated the predictive performance of a simple manually adjusted pump infusion scheme, for infusion of liquid sevoflurane to the AnaConDa. METHODS: We studied 50 ICU patients who received sevoflurane via the AnaConDa. They were randomly divided into three groups. A 6-h infusion of liquid anesthetic was adjusted according to the infusion scheme to a target end-tidal sevoflurane concentration of 1% (Group 1%, n = 15) and 1.5% (Group 1.5%, n = 15). The initial rate was adjusted to reach the target concentration in 10 min and then the infusion was reduced to the first hour maintenance rate and readjusted once each hour afterwards. The actual concentrations were measured in the breathing circuit and compared with the target values. In the third group (n = 20) we used the model to increase and decrease the target concentration (±0.3%) for 3 h and evaluated the actual change in concentration achieved. The ability of the infusion scheme to provide the target concentration was quantified by calculating the performance error (PE). Infusion scheme performance was evaluated in terms of accuracy (median absolute PE, MDAPE) and bias (median PE, MDPE). RESULTS: Performance parameters (mean ± sd, %) were for 1%, 1.5%, increase of concentration by 0.3% and decrease of concentration by 0.3% groups, respectively: MDAPE 5.3 ± 5.5, 2.6 ± 4.0, 5.0 ± 5.6, 5.5 ± 5.4; MDPE −5.3 ± 5.5, −2.3 ± 4.1, −0.1 ± 7.1, 0.2 ± 5.4. No significant differences were found between means of all performance parameters when the 1% and 1.5% groups were compared. CONCLUSIONS: There is an excellent 6-h predictive performance of a simplified pharmacokinetic model for manually adjusted infusion of liquid sevoflurane when using the AnaConDa to deliver sevoflurane to ICU patients.

Anidulafungin dosing in critically ill patients with continuous venovenous haemodiafiltration

BACKGROUND Anidulafungin is indicated as a first-line treatment for invasive candidiasis in critically ill patients. In the intensive care unit, sepsis is the main cause of acute renal failure, and treatment with continuous renal replacement therapy (CRRT) has increased in recent years. Antimicrobial pharmacokinetics is affected by CRRT, but few studies have addressed the optimal dosage for anidulafungin during CRRT. PATIENTS AND METHODS We included 12 critically ill patients who received continuous venovenous haemodiafiltration to treat acute renal failure. Anidulafungin was infused on 3 consecutive days, starting with a loading dose (200 mg) on Day 1, and doses of 100 mg on Days 2 and 3. Blood and ultradiafiltrate samples were collected on Day 3 (during steady-state) before, and at regular intervals after, the infusion had started. Anidulafungin concentrations were determined with HPLC. RESULTS On Day 3, peak plasma concentrations with the 100 mg dose were 6.2 ± 1.7 mg/L and 7.1 ± 1.9 mg/L in the arterial and venous samples, respectively. The mean, pre-filter trough concentration was 3.0 ± 0.6 mg/L. The mean AUC0-24 values for plasma anidulafungin were 93.9 ± 19.4 and 104.1 ± 20.3mg·h/L in the arterial and venous samples, respectively. There was no adsorption to synthetic surfaces, and the anidulafungin concentration in the ultradiafiltrate was below the limit of detection. CONCLUSION The influence of CRRT on anidulafungin elimination appeared to be negligible. Therefore, we recommend no adjustments to the anidulafungin dose for patients receiving CRRT.

Evaluation of cytomegalovirus (CMV)-specific t-cell immunity for the assessment of the risk of active CMV infection in non-immunosuppressed surgical and trauma intensive care unit patients

The current study was designed to assess the predictive value of the evaluation of cytomegalovirus (CMV)‐specific T‐cell immunity early following admission to the intensive care unit for inferring the risk of active CMV infection in non‐immunosuppressed surgical and trauma patients. A total of 31 CMV‐seropositive patients were included. Patients were screened for the presence of CMV DNA in plasma and in tracheal aspirates by real‐time PCR. Enumeration of CMV pp65 and IE‐1‐specific IFN‐γ CD8+ and CD4+ T cells was performed by flow cytometry for intracellular cytokine staining. Virological and immunological monitoring was conducted once or twice a week. Active CMV infection occurred in 17 out of 31 patients. Undetectable levels of pp65 and IE‐1‐specific IFN‐γ CD8+ and CD4+ T‐cell subsets cells were observed in 10 patients who developed active CMV infection and in one who did not (at a median of 2 days following ICU admission). Peak CMV DNA loads in both tracheal aspirates and plasma were substantially higher (P = 0.018 and P = 0.091, respectively) in patients with undetectable IFN‐γ T‐cell responses than in patients with detectable responses. The expansion of both CMV‐specific T‐cell subsets following detection of active CMV infection was demonstrated in 9 out of 14 patients with active CMV infection. In conclusion, the evaluation of CMV pp65 and IE‐1‐specific IFN‐γ‐producing CD8+ and CD4+ T cells early following ICU admission may allow the identification of patients most at risk of either having or developing an episode of active CMV infection, particularly those associated with high‐level virus replication. J Med. Virol. 85:1802–1810, 2013.

Sevoflurane, but not propofol, reduces the lung inflammatory response and improves oxygenation in an acute respiratory distress syndrome model: a randomised laboratory study.

CONTEXT Acute respiratory distress syndrome is characterised by activation of the inflammatory cascade. The only treatment that reduces the mortality rate associated with this syndrome is lung protective ventilation, which requires sedation of patients. Sedation in critical care units is usually induced intravenously, although there is reason to believe that inhaled anaesthetics are a suitable alternative. Sevoflurane has recently been shown to modulate the lung inflammatory response in a model of lung injury more favourably than propofol. OBJECTIVE The goal of this study was to confirm whether or not sevoflurane is more effective than propofol in ameliorating the inflammatory response in an animal model of acute respiratory distress syndrome. DESIGN A prospective, randomised, controlled study. SETTING Research foundation laboratory at the Hospital Clínico Universitario, Valencia, Spain. EXPERIMENTAL ANIMALS Sixteen Landrace/large white crossbred pigs weighing 30 to 45 kg. INTERVENTIONS Animals were allocated randomly to one of two groups: one sedated with intravenous propofol 5 to 7 mg kg−1 h−1 (group P) and the other with sevoflurane, administered using an AnaConDa device to obtain an end-tidal concentration of 1.5% (group S). Monitoring, lung protective ventilation and anaesthetic management were identical in both groups. MAIN OUTCOME MEASURES The PaO2/FiO2 ratio and cytokine concentrations in bronchoalveolar lavage specimens were determined at 10, 150 and 240 min after confirmation of acute respiratory distress syndrome (PaO2/FiO2 <26.7 kPa). RESULTS At 240 min, median and interquartile range (IQR) concentrations of cytokines in bronchial lavage specimens in group S were lower than those in group P [interleukin-1&bgr; (IL-1&bgr;) 53, IQR 16–140 vs. 311, IQR 183–637 pg ml−1, P = 0.04; tumour necrosis factor-&agr; 347, IQR 161–433 vs. 552, IQR 475–649 pg ml−1, P = 0.04; and IL-6 101, IQR 76–282 vs. 580, IQR 369–701 pg ml−1, P = 0.03]. The polymorphonuclear neutrophil count was also lower in group S (P = 0.007), which also had a higher PaO2/FiO2 ratio. TRIAL REGISTRATION GE-015/09. CONCLUSION In an animal model of acute respiratory distress syndrome, sevoflurane ameliorates the lung inflammatory response and improves oxygenation to a greater extent than propofol.

Immunological insights into the pathogenesis of active CMV infection in non-immunosuppressed critically ill patients.

Dissociation of cytomegalovirus (CMV) DNA loads between the lower respiratory tract and blood, with high levels in the former compartment and low or undetectable levels in the latter, commonly occurs during active CMV infection in critically ill patients despite the presence of high frequencies of CMV‐specific IFN‐γ‐producing CD8+ and CD4+ T cells in blood. Data presented in this case report suggest that inter‐compartmental differences in interleukin‐10 (IL‐10) levels may, in part, explain the pathobiology of this phenomenon. In the absence of ganciclovir treatment, a significant correlation was observed between IL‐10 levels and CMV DNA loads in lower respiratory tract specimens (P = 0.016), but not in plasma samples (P = 0.46). Comparable data were obtained during the course of active CMV infection episodes that developed in six CMV‐seropositive critically ill patients with no canonical immunosuppression. The presence of higher levels of IL‐10 in the lower respiratory tract than in plasma may result in increased impairment of CMV‐specific T‐cell effector responses in the lung compared to the systemic compartment, facilitating local CMV replication. J. Med. Virol. 83:1966–1971, 2011.

The accuracy of the anesthetic conserving device (AnaConDa©) as an alternative to the classical vaporizer in anesthesia.

BACKGROUND: The Anesthetic Conserving Device—AnaConDa® (ACD)—has been compared with a conventional vaporizer. However, the accuracy of the administered concentration of volatile anesthetics was not examined. In the present study we measured the accuracy of the ACD when used as a portable vaporizer. METHODS: This prospective study included 30 ASA I–III patients scheduled for elective surgery under general anesthesia. The patients were randomly organized into 3 groups of 10 patients per group. In each group, the sevoflurane infusion rate was adjusted to deliver 1.0 vol%, 1.5 vol%, and 2.0 vol% alveolar concentration. Hemodynamic data, bispectral index, and end-tidal sevoflurane concentrations were recorded every 2 minutes. RESULTS: We analyzed 801 data points from 30 patients. The mean difference between the end-tidal sevoflurane concentration and the target concentration was −11.0 ± 9.3% of the target when the target was 1.0 vol%, −5.4 ± 6.4% when the target was 1.5 vol%, and −4.0 ± 7.4% when the target was 2.0 vol%. No significant differences were found in the error at the different target concentrations. CONCLUSIONS: We found that the ACD may be a valid alternative to the conventional vaporizer. The ACD is very simple to use, delivery rate needs to be adjusted only once per hour, and the anesthetic savings are independent of the circuit characteristics and fresh gas flow rate.

effects of prone position on alveolar dead space and gas exchange during general anaesthesia in surgery of long duration

Background and objective: We investigated the effects of prone position on respiratory dead space and gas exchange in 14 anaesthetized healthy patients undergoing elective posterior spinal surgery of more than 3 h of duration. Methods: The patients received a total intravenous anaesthetic with propofol/remifentanil/cisatracurium. They were ventilated at a tidal volume of 8–10 mL kg−1, zero positive end‐expiratory pressure and an inspired oxygen fraction of 0.4. Physiological, airway and alveolar dead spaces were calculated by analysis of the volumetric capnography waveform. Measurements were made in supine position (20 min after the beginning of mechanical ventilation) and 30, 120 and 180 min after turning to prone position. Results: We found that the alveolar dead space/tidal volume ratio did not change. PaO2/FiO2 increased, although not statistically significantly. Dynamic compliance was reduced due to a reduction in tidal volume and an increase in plateau pressure. Conclusions: Patients undergoing surgery in prone position for a duration of 3 h under general anaesthesia including muscle relaxation and mechanical ventilation without positive end‐expiratory pressure have stable haemodynamics and no significant changes in the alveolar dead space to tidal volume ratio. Oxygenation tended to improve.

Looking for biological factors to predict the risk of active cytomegalovirus infection in non-immunosuppressed critically ill patients

The identification of non‐immunosuppressed critically ill patients most at risk for developing cytomegalovirus (CMV) reactivation is potentially of great clinical relevance. The current study was aimed at determining (i) whether single nucleotide polymorphisms in the genes coding for chemokine receptor 5 (CCR5), interleukin‐10 IL‐10), and monocyte chemoattractant protein‐1 (MCP‐1) have an impact on the incidence rate of active CMV infection, (ii) whether serum levels of CMV‐specific IgGs are associated with the risk of CMV reactivation, and (iii) whether detection of CMV DNA in saliva precedes that in the lower respiratory tract or the blood compartment. A total of 36 out of 78 patients (46%) developed an episode of active CMV infection. The incidence rate of active CMV infection was not significantly associated with any single nucleotide polymorphisms. A trend towards a lower incidence of active CMV infection (P = 0.06) was noted in patients harboring the IL10 C/C genotype. Patients carrying the CCR5 A/A genotype had high CMV DNA loads in tracheal aspirates. The serum levels of CMV IgGs did not differ significantly between patients with a subsequent episode of active CMV infection (median, 217 IU/mL) or without one (median, 494 IU/mL). Detection of CMV DNA in saliva did not usually precede that in plasma and/or tracheal aspirates. In summary, the analysis of single nucleotide polymorphisms in the IL10 and CCR5 genes might help to determine the risk of active CMV infection or the level of CMV replication within episodes, respectively, in non‐immunosuppressed critically ill patients. J. Med. Virol. 86:827–833, 2014.