Predictive values of serum amyloid A, toll-like receptor 4, and sTREM-1 for ventilator-associated pneumonia in elderly patients undergoing abdominal surgery with tracheal intubation and general anesthesia.

OBJECTIVES: This study aimed to conduct a retrospective study to identify inflammatory biomarkers for predicting ventilator-associated pneumonia in elderly patients. METHODS: Our retrospective study included 265 elderly patients (age ≥60 years) undergoing abdominal surgery with tracheal intubation and general anesthesia, with 93 experiencing varying degrees of ventilator-associated pneumonia during hospitalization, and 172 without. Serum concentrations of serum amyloid A (SAA), toll-like receptor 4 (TLR4), and soluble myeloid triggering receptor 1 (sTREM-1) were measured at 24 h post-operation using enzyme-linked immunosorbent assay. Comparisons of SAA, TLR4, and sTREM-1 and other risk factors at 24 h post-operation between elderly patients with and without ventilator-associated pneumonia were performed. RESULTS: The study revealed a 35.1% incidence of postoperative ventilator-associated pneumonia among elderly patients. Upregulations of SAA, TLR4, and sTREM-1 were observed in patients with ventilator-associated pneumonia. Chronic obstructive pulmonary disease, smoking, and tracheal intubation were identified as independent risk factors. The joint prediction model was demonstrated with superior predictive accuracy (area under the curve = 0.89) compared to individual biomarkers. Correlations with procalcitonin further supported the predictive potential of SAA, TLR4, and sTREM-1 in an inflammatory response. CONCLUSIONS: SAA, TLR4, and sTREM-1, particularly when combined, serve as valuable prognostic indicators for postoperative ventilator-associated pneumonia in elderly patients undergoing abdominal surgery with tracheal intubation and general anesthesia. The joint prediction model offered a promising tool for early risk assessment.

Association between lactate dehydrogenase and ventilator-associated pneumonia risk: an analysis of the MIMIC database 2001-2019.

BACKGROUND: Serum lactate dehydrogenase (LDH) is a nonspecific inflammatory biomarker and has been reported to be associated with pneumonia prognosis. This study aimed to evaluate the relationship between LDH levels and ventilator-associated pneumonia (VAP) risk in intensive care unit (ICU) patients. METHODS: This retrospective cohort study used data from the Multiparameter Intelligent Monitoring in Intensive Care database from 2001 to 2019. ICU patients aged ≥ 18 years and receiving mechanical ventilation were included. LDH levels were analyzed as continuous and categorical variables (< 210, 210-279, 279-390, > 390 IU/L), respectively. Restricted cubic spline (RCS) curves and quartiles were used to categorize LDH levels. Logistic regression and linear regression were utilized to assess the relationship of LDH levels with VAP risk and duration of mechanical ventilation, respectively. RESULTS: A total of 9,164 patients were enrolled, of which 646 (7.05%) patients developed VAP. High levels of LDH increased the risk of VAP [odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.06-1.24] and LDH levels were positively correlated with the duration of mechanical ventilation [ß = 4.49, 95%CI: (3.42, 5.56)]. Moreover, patients with LDH levels of 279-390 IU/L (OR = 1.38, 95%CI: 1.08-1.76) and > 390 IU/L (OR = 1.50, 95%CI: 1.18-1.90) had a higher risk of VAP than patients with LDH levels < 210 IU/L. Patients with LDH levels of 279-390 IU/L [ß = 3.84, 95%CI: (0.86, 6.82)] and > 390 IU/L [ß = 11.22, 95%CI: (8.21, 14.22)] (vs. <210 IU/L) had a longer duration of mechanical ventilation. CONCLUSION: Elevated serum LDH levels were related to a higher risk of VAP and longer duration of mechanical ventilation and may be useful for monitoring VAP risk.

Significance of sTREM-1 in early prediction of ventilator-associated pneumonia in neonates: a single-center, prospective, observational study.

BACKGROUND: To evaluate whether soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) can be used as an early predictor of ventilator-associated pneumonia (VAP). METHODS: Ventilated neonatal patients admitted into the neonatology department between January 2017 and January 2018 were divided into VAP (n = 30) and non-VAP (n = 30) groups. Serum sTREM, procalcitonin (PCT), C-reactive protein and interleukin-6 levels were measured at 0, 24, 72, and 120 h after initiation of mechanical ventilation (MV). Correlations between blood biomarker concentrations and VAP occurrence were analyzed. Predictive factors for VAP were identified by logistic regression analysis and Hosmer-Lemeshow test, and the predictive value of sTREM-1 and biomarker combinations for VAP was determined by receiver operating characteristic curve analysis. RESULTS: The serum sTREM-1 concentration was significantly higher in the VAP group than in the non-VAP group after 72 and 120 h of MV (72 h: 289.5 (179.6-427.0) vs 202.9 (154.8-279.6) pg/ml, P < 0.001; 120 h: 183.9 (119.8-232.1) vs 141.3 (99.8-179.1) pg/ml, P = 0.042). The area under the curve (AUC) for sTREM-1 at 72 h was 0.902 with a sensitivity of 90% and specificity of 77% for the optimal cut-off value of 165.05 pg/ml. Addition of PCT to sTERM-1 at 72 h further improved the predictive value, with this combination having an AUC of 0.971 (95% confidence interval: 0.938-1.000), sensitivity of 0.96, specificity of 0.88, and Youden index of 0.84. CONCLUSION: sTREM-1 is a reliable predictor of VAP in neonates, and combined measurement of serum levels of sTREM-1 and PCT after 72 h of MV provided the most accurate prediction of VAP in neonatal patients.

The predictive value of procalcitonin in ventilator-associated pneumonia after cardiac valve replacement.

This study aimed to evaluate the predictive value of procalcitonin (PCT) in ventilator-associated pneumonia (VAP) after cardiac valve replacement. A total of 80 patients who underwent cardiac valve replacement in our department were enrolled in this study. Of these patients,40 were diagnosed with VAP and assigned to the observation group, while the other 40 patients not diagnosed with VAP were assigned to the control group. The changes in serum PCT, white blood cell count and C-reactive protein (CRP) were observed before each operation (T0), on the first day after the operation (T1), the second day after the operation (T2) and the third day after the operation (T3). After the operation, the serum PCT in the observation group was significantly higher than those at different time points after the operation, and also significantly higher than those in the control group (p < .05). In the control group, PCT was significantly higher after the operation than before the operation (p < .05), but the differences among the different postoperative time points were not statistically significant (p > .05). In the two groups, the white blood cell count and CRP were significantly higher after the operation than before the operation (p < .05), but the differences between the two groups were not statistically significant (p > .05). Serum PCT is an early, sensitive and highly specific high-risk monitoring index and has an early prediction value for VAP after cardiac valve replacement.

Diagnostic Efficacy of Serum Amyloid A Protein and Soluble Intercellular Adhesion Molecule 1 in Pediatric Ventilator-Associated Pneumonia.

OBJECTIVES: Study of inflammatory biomarkers which may aid in early detection of ventilator-associated pneumonia (VAP) in children and predicting their outcome. PATIENTS: Thirty-five children, aged 2 months to 13 years, needed mechanical ventilation (MV) for more than 48 hours due to causes other than pneumonia. METHODS: Measurement of serum amyloid A (SAA) protein, soluble intercellular adhesion molecule 1 (sICAM-1), and C-reactive protein (CRP), modified clinical pulmonary infection score (CPIS) and performing culture of endotracheal aspirate at the start and on the third day of MV. RESULTS: Ventilator-associated pneumonia was diagnosed by CPIS in 6 (17.1%) of 35 patients. On the third day of MV, there was a significant increase in serum mean levels of SAA, sICAM-1, and CRP in comparison to the start of MV ( P = .005, .004, and .01, respectively). Three (50%) of 6 patients with VAP died, while 4 (14.28%) of 28 patients without VAP died. The sensitivity of serum SAA, sICAM-1, and CPIS were 100% for predicting VAP, while specificity was highest for CPIS (96.55%) followed by SAA (93.1%). Combination of CPIS and SAA increased the specificity to 100%. For predicting nonsurvival, serum SAA and sICAM-1 had a sensitivity of 100% and a specificity of 92.86% and 89.29%, respectively. CONCLUSION: Serum amyloid A and sICAM-1 may be considered as reliable markers for detection of VAP. Combination of serum SAA with CPIS increased the specificity to 100%. Measurement of SAA in patients with VAP also had a good predictive value for nonsurvival in such patients.

Monocyte Chemoattractant Protein-1, a Possible Biomarker of Multiorgan Failure and Mortality in Ventilator-Associated Pneumonia.

Ventilator-associated pneumonia (VAP) leads to increased patients' mortality and medical expenditure. Monocyte chemoattractant protein-1 (MCP-1) plays a role in the pathogenesis of lung inflammation and infection. Therefore, the plasma concentration of MCP-1 was assessed and correlated with the clinical course in VAP patients. This retrospective observational study recruited 45 healthy volunteers, 12 non-VAP subjects, and 30 VAP patients. The diagnostic criteria for VAP were based on the American Thoracic Society guidelines, and the level of plasma MCP-1 was determined by ELISA. Plasma MCP-1 concentration was significantly elevated in the acute stage in VAP patients when compared with the control (p < 0.0001) and non-VAP patient groups (p = 0.0006). Subsequently, it was remarkably decreased following antibiotic treatment. Moreover, plasma MCP-1 concentration was positively correlated with indices of pulmonary dysfunction, including the lung injury score (p = 0.02) and the oxygenation index (p = 0.02). When patients with VAP developed adult respiratory distress syndrome (ARDS), their plasma MCP-1 concentrations were significantly higher than those of patients who did not develop ARDS (p = 0.04). Moreover, plasma MCP-1 concentration was highly correlated with organ failure scores, including simplified acute physiology score II (SAPS II, p < 0.0001), sequential organ failure assessment score (SOFA, p < 0.0001), organ dysfunctions and/or infection (ODIN, p < 0.0001), predisposition, insult response and organ dysfunction (PIRO, p = 0.005), and immunodeficiency, blood pressure, multilobular infiltrates on chest radiograph, platelets and hospitalization 10 days before onset of VAP (IBMP-10, p = 0.004). Our results demonstrate that plasma MCP-1 is an excellent marker for recognizing VAP when the cut-off level is set to 347.18 ng/mL (area under the curve (AUC) = 0.936, 95% CI = 0.863-0.977). In conclusion, MCP-1 not only could be a biological marker related to pulmonary dysfunction, organ failure, and mortality in patients with VAP, but also could be used for early recognition of VAP.

Do we need biomarkers for the follow-up and shortening of antibiotic treatment duration?

PURPOSE OF REVIEW: Clinical and laboratory parameters are useful tools for the diagnosis, follow-up and evaluation of resolution, and to predict outcomes when measured at different time-points onset and serially during follow-up in patients with hospital-acquired pneumonia and/or ventilator-associated pneumonia (HAP/VAP). RECENT FINDINGS: Both, the 2017 ERS/ESICM/ESCMID/Asociación Latino Americana de Tórax (EEEAG) and the 2016 IDSA/ATS guidelines (IAG) for the management of HAP/VAP recommend using clinical criteria alone, rather than biomarkers for diagnosis. Several studies were conducted to assess the value of serum biomarker concentration and kinetics for predicting the outcome in HAP/VAP, including C-reactive protein and procalcitonin (PCT). Although the EEEAG do not recommend routinely performing biomarker determinations in addition to bedside clinical assessment in patients receiving antibiotic treatment for VAP or HAP to predict adverse outcomes and clinical response, the IAG recommend that routine bedside clinical assessment should be accompanied by measurements of PCT to guide antimicrobial therapy. Additionally, the 2016 Surviving Sepsis Campaign also suggests that PCT levels can be used to support the shortening of antibiotic therapy. SUMMARY: Current evidence indicate that there is no recommendation to use biomarkers systematically to guide every decision. However, in some circumstances they might add some relevant information to our everyday practice.

Early increase of VEGF-A is associated with resolution of ventilator-associated pneumonia: Clinical and experimental evidence.

BACKGROUND AND OBJECTIVE: The role of vascular endothelial growth factor (VEGF)-A in the resolution of ventilator-associated pneumonia (VAP) was investigated in clinical and mouse pneumonia models. METHODS: VEGF-A was measured for seven consecutive days by an immunosorbent assay in sera of 82 patients with VAP and changes from baseline were correlated with the resolution of VAP. Experimental animals were challenged intratracheally with Pseudomonas aeruginosa. Mouse bronchoalveolar lavage (BAL) samples and segments of lung tissue were obtained at 24, 48 and 124 h after bacterial challenge. Levels of VEGF-A, tumour Necrosis Factor alpha (TNF-α), interleukin (IL)-1ß, interferon-gamma (IFNγ) and myeloperoxidase (MPO) activity were measured in these samples. RESULTS: VAP resolved in 36.1% of patients with a less than 45% increase of VEGF-A on day 5 compared to 65.2% of patients with a more than 45% increase (P = 0.014). This was also accompanied by an earlier resolution of VAP (log-rank: 7.99; P = 0.005) and it was not pathogen-specific. The increase of VEGF-A was an independent variable associated with VAP resolution in forward logistic regression analysis where Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were included as independent variables. VEGF-A in mouse BAL and lung tissue increased significantly at 124 h but not with the other mediators. In mice pre-treated with bevacizumab, VEGF-A concentrations decreased while TNF-α and MPO significantly increased. CONCLUSION: In patients, an association between increased levels of circulating VEGF-A and VAP resolution was observed. The mouse study suggests that elevated VEGF-A levels may be associated with lung inflammation resolution. CLINICAL TRIAL REGISTRATION: NCT00297674 at www.clinicaltrials.gov.

Duration of pneumonia therapy and the role of biomarkers.

PURPOSE OF REVIEW: Increasing antimicrobial resistance is a worldwide phenomenon that is threatening public health. Lower respiratory infections are one of the leading causes of morbidity that contribute to antibiotic consumption and thus the emergence of multidrug-resistant microbial strains. The goal of shortening antibiotic regimens' duration in common bacterial infections has been prioritized by antimicrobial stewardship programs as an action against this problem. RECENT FINDINGS: Data coming from randomized controlled trials, meta-analyses, and systematic reviews support the shortening of antimicrobial regimens in community-acquired, hospital-acquired, and ventilator-associated pneumonia. Short schedules have been proven at least as effective as long ones in terms of antimicrobial-free days and clinical cure. Procalcitonin-based algorithms have been validated as well tolerated and cost-effective tools for the duration of pneumonia therapy reduction. SUMMARY: Shortening the duration of antibiotic regimens in pneumonia seems a reasonable strategy for reducing selective pressure driving antimicrobial resistance and costs provided that clinical cure is guaranteed. Procalcitonin-based protocols have been proven essentially helpful in this direction. VIDEO ABSTRACT.

The current status of biomarkers for the diagnosis of nosocomial pneumonias.

PURPOSE OF REVIEW: Nosocomial pneumonia is a frequent and severe nosocomial infection divided in two distinct groups: hospital-acquired pneumonia and ventilator-associated pneumonia (VAP). In this context, the VAP is notoriously difficult to diagnose clinically, resulting from the lack of a 'gold standard' method of diagnosis. RECENT FINDINGS: The use of biomarkers may potentially improve the early diagnosis of infections allowing earlier and better identification and treatment. An exhausting list of biomarkers has been studied and although far from perfect, procalcitonin (PCT) and C-reactive protein (CRP) are the most studied biomarkers used in clinical practice. Data coming from literature suggests the use of PCT for VAP prognosis and as a based algorithm tool for the reduction of duration of pneumonia therapy, as well as, the use of the CRP dynamics to the early prediction of VAP and the response to the antibiotics. SUMMARY: The evidence for the use of biomarkers to diagnose nosocomial pneumonia as a stand-alone tool is low to moderate. Improved performance for both PCT and CRP can be obtained by using them in association with clinical features or scoring systems but prospective studies are still needed to validate this hypothesis.

Pathogenic Link Between Postextubation Pneumonia and Ventilator-Associated Pneumonia: An Experimental Study.

BACKGROUND: The presence of an endotracheal tube is the main cause for developing ventilator-associated pneumonia (VAP), but pneumonia can still develop in hospitalized patients after endotracheal tube removal (postextubation pneumonia [PEP]). We hypothesized that short-term intubation (24 hours) can play a role in the pathogenesis of PEP. To test such hypothesis, we initially evaluated the occurrence of lung colonization and VAP in sheep that were intubated and mechanically ventilated for 24 hours. Subsequently, we assessed the incidence of lung colonization and PEP at 48 hours after extubation in sheep previously ventilated for 24 hours. METHODS: To simulate intubated intensive care unit patients placed in semirecumbent position, 14 sheep were intubated and mechanically ventilated with the head elevated 30° above horizontal. Seven of them were euthanized after 24 hours (Control Group), whereas the remaining were euthanized after being awaken, extubated, and left spontaneously breathing for 48 hours after extubation (Awake Group). Criteria of clinical diagnosis of pneumonia were tested. Microbiological evaluation was performed on autopsy in all sheep. RESULTS: Only 1 sheep in the Control Group met the criteria of VAP after 24 hours of mechanical ventilation. However, heavy pathogenic bacteria colonization of trachea, bronchi, and lungs (range, 10-10 colony-forming unit [CFU]/g) was reported in 4 of 7 sheep (57%). In the Awake Group, 1 sheep was diagnosed with VAP and 3 developed PEP within 48 hours after extubation (42%), with 1 euthanized at 30 hours because of respiratory failure. On autopsy, 5 sheep (71%) confirmed pathogenic bacterial growth in the lower respiratory tract (range, 10-10 CFU/g). CONCLUSIONS: Twenty-four hours of intubation and mechanical ventilation in semirecumbent position leads to significant pathogenic colonization of the lower airways, which can promote the development of PEP. Strategies directed to prevent pathogenic microbiological colonization before and after mechanical ventilation should be considered to avert the onset of PEP.

Diagnostic values of CD64, C-reactive protein and procalcitonin in ventilator-associated pneumonia in adult trauma patients: a pilot study.

BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common nosocomial infections; however, its diagnosis remains difficult to establish in the critical care setting. We investigated the potential role of neutrophil CD64 (nCD64) expression as an early marker for the diagnosis of VAP. METHODS: Forty-nine consecutive patients with clinically suspected VAP were prospectively included in a single-center study. The levels of nCD64, C-reactive protein (CRP), and serum procalcitonin (PCT) were analyzed for diagnostic evaluation at the time of intubation (baseline), at day 0 (time of diagnosis), and at day 3. The receiver operating characteristic curves were analyzed to identify the ideal cutoff values. RESULTS: VAP was confirmed in 36 of 49 cases. In patients with and without VAP, the median levels (interquartile range, IQR) of nCD64 did not differ either at baseline [2.4 (IQR, 1.8-3.1) and 2.6 (IQR, 2.3-3.2), respectively; p=0.3] or at day 0 [2 (IQR, 2.5-3.0) and 2.6 (IQR, 2.4-2.9), respectively; p=0.8]. CRP showed the largest area under the curve (AUC) at day 3. The optimum cutoff value for CRP according to the maximum Youden index was 133 mg/dL. This cutoff value had 69% sensitivity and 76% specificity for predicting VAP; the AUC was 0.73 (95% CI, 0.59-0.85). The nCD64 and PCT values could not discriminate between the VAP and non-VAP groups either at day 0 or day 3. CONCLUSIONS: The results of this pilot study suggest that neutrophil CD64 measurement has a poor role in facilitating the diagnosis of VAP and thus may not be practically recommended to guide the administration of antibiotics when VAP is suspected.

Elevated Plasma Matrix Metalloproteinase-9 and Its Correlations with Severity of Disease in Patients with Ventilator-Associated Pneumonia.

Ventilator-associated pneumonia (VAP) increases patient mortality and medical expenditure, and a real-time and reliable method for the rapid diagnosis of VAP may help reduce fatal complications. Matrix metalloproteinases-9 (MMP-9) is considered significant in the pathogenesis of lung inflammation and infection. Therefore, we examined its relationship with the clinical course of VAP. This retrospective observational study recruited 30 healthy volunteers, 12 patients who used mechanical ventilation without the development of VAP (hereafter, patients without VAP), and 30 patients with a clinical diagnosis of VAP (hereafter, patients with VAP). The activity and level of plasma MMP-9 were determined through a gelatin zymography assay and ELISA. Our results report that both plasma MMP-9 activity and concentration were significantly elevated in the acute stage of patients with VAP when compared with control group and patients without VAP (p < 0.001). Subsequently, the plasma MMP-9 of patients with VAP decreased significantly after antibiotic treatment. Furthermore, plasma MMP-9 concentration was positively correlated with the clinical pulmonary infection score (r = 0.409, p = 0.007), WBCs (r = 0.620, p < 0.001), and neutrophils counts (r = 0.335, p = 0.035). In addition, plasma MMP-9 is an excellent tool for recognizing VAP when the cutoff level is set to 92.62 ng/mL (AUC = 0.863, 95% CI = 0.761 to 0.932). In conclusions, we concluded that MMP-9 levels play a role in the development of VAP and might have the potential to be applied in the development of VAP therapies.

Prognostic value of procalcitonin in pneumonia: A systematic review and meta-analysis.

This meta-analysis was performed to determine the accuracy of procalcitonin (PCT) in predicting mortality in pneumonia patients with different pathogenic features and disease severities. A systematic search of English-language articles was performed using PubMed, Embase, Web of Knowledge and the Cochrane Library to identify studies. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. The Q-test and I(2) index were used to test heterogeneity. A total of 21 studies comprising 6007 patients were included. An elevated PCT level was a risk factor for death from community-acquired pneumonia (CAP) (risk ratio (RR) 4.38, 95% confidence interval (CI) 2.98-6.43), particularly in patients with a low CURB-65 score. The commonly used cut-off, 0.5 ng/mL, had low sensitivity (SEN) and was not able to identify patients at high risk of dying. Furthermore, the PCT assay with functional SEN <0.1 ng/mL was necessary to predict mortality in CAP in the clinic. For critically ill patients, an elevated PCT level was associated with an increased risk of mortality (RR 4.18, 95% CI: 3.19-5.48). The prognostic performance was nearly equal between patients with ventilator-associated pneumonia (VAP) and patients with CAP.

Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients.

Colistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS); however, differences between the intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients have not been precisely documented. In this study, CMS and colistin concentrations were measured on two separate occasions within the plasma and epithelial lining fluid (ELF) of critically ill patients (n = 12) who had received 2 million international units (MIU) of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations. The ELF colistin concentrations varied considerably (9.53 to 1,137 mg/liter), but they were much higher than those in plasma (0.15 to 0.73 mg/liter) after aerosol delivery but not after intravenous administration of CMS. Following CMS aerosol delivery, typically, 9% of the CMS dose reached the ELF, and only 1.4% was presystemically converted into colistin. PK-PD analysis concluded that there was much higher antimicrobial efficacy after CMS aerosol delivery than after intravenous administration. These new data seem to support the use of aerosol delivery of CMS for the treatment of pulmonary infections in critical care patients.

Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens.

AIMS: Significant alterations in the pharmacokinetics (PK) of antimicrobials have been reported in critically ill patients. We describe PK parameters of imipenem in intensive care unit (ICU) patients with suspected ventilator-associated pneumonia and evaluate several dosage regimens. METHODS: This French multicentre, prospective, open-label study was conducted in ICU patients with a presumptive diagnosis of ventilator-associated pneumonia caused by Gram-negative bacilli, who empirically received imipenem intravenously every 8 h. Plasma imipenem concentrations were measured during the fourth imipenem infusion using six samples (trough, 0.5, 1, 2, 5 and 8 h). Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm in Monolix 4.2. A Monte Carlo simulation was performed to evaluate the following six dosage regimens: 500, 750 or 1000 mg with administration every 6 or 8 h. The pharmacodynamic target was defined as the probability of achieving a fractional time above the minimal inhibitory concentration (MIC) of >40%. RESULTS: Fifty-one patients were included in the PK analysis. Imipenem concentration data were best described by a two-compartment model with three covariates (creatinine clearance, total bodyweight and serum albumin). Estimated clearance (between-subject variability) was 13.2 l h(-1) (38%) and estimated central volume 20.4 l (31%). At an MIC of 4 µg ml(-1) , the probability of achieving 40% fractional time > MIC was 91.8% for 0.5 h infusions of 750 mg every 6 h, 86.0% for 1000 mg every 8 h and 96.9% for 1000 mg every 6 h. CONCLUSIONS: This population PK model accurately estimated imipenem concentrations in ICU patients. The simulation showed that for these patients, the best dosage regimen of imipenem is 750 mg every 6 h and not 1000 mg every 8 h.

Use of rapid diagnostic techniques in ICU patients with infections.

BACKGROUND: Infection is a common complication seen in ICU patients. Given the correlation between infection and mortality in these patients, a rapid etiological diagnosis and the determination of antimicrobial resistance markers are of paramount importance, especially in view of today's globally spread of multi drug resistance microorganisms. This paper reviews some of the rapid diagnostic techniques available for ICU patients with infections. METHODS: A narrative review of recent peer-reviewed literature (published between 1995 and 2014) was performed using as the search terms: Intensive care medicine, Microbiological techniques, Clinical laboratory techniques, Diagnosis, and Rapid diagnosis, with no language restrictions. RESULTS: The most developed microbiology fields for a rapid diagnosis of infection in critically ill patients are those related to the diagnosis of bloodstream infection, pneumonia -both ventilator associated and non-ventilator associated-, urinary tract infection, skin and soft tissue infections, viral infections and tuberculosis. CONCLUSIONS: New developments in the field of microbiology have served to shorten turnaround times and optimize the treatment of many types of infection. Although there are still some unresolved limitations of the use of molecular techniques for a rapid diagnosis of infection in the ICU patient, this approach holds much promise for the future.

Year in review 2013: Critical Care--respiratory infections.

Infectious complications, particularly in the respiratory tract of critically ill patients, are related to increased mortality. Severe infection is part of a multiple system illness and female patients with severe sepsis have a worse prognosis compared to males. Kallistatin is a protective hormokine released during monocyte activation and low levels in the setting of septic shock can predict adverse outcomes. Presepsin is another biomarker that was recently evaluated and is elevated in patients with severe sepsis patients at risk of dying. The Centers for Disease Control and Prevention has introduced new definitions for identifying patients at risk of ventilator-associated complications (VACs), but several other conditions, such as pulmonary edema and acute respiratory distress syndrome, may cause VACs, and not all patients with VACs may have ventilator-associated pneumonia. New studies have suggested strategies to identify patients at risk for resistant pathogen infection and therapies that optimize efficacy, without the overuse of broad-spectrum therapy in patients with healthcare-associated pneumonia. Innovative strategies using optimized dosing of antimicrobials, maximizing the pharmacokinetic and pharmacodynamic properties of drugs in critically ill patients, and newer routes of drug delivery are being explored to combat drug-resistant pathogens. We summarize the major clinical studies on respiratory infections in critically ill patients published in 2013.

[Role of plasma procalcitonin in the diagnosis of ventilator-associated pneumonia: systematic review and metaanalysis]. / Papel de la procalcitonina plasmática en el diagnóstico de la neumonía asociada a ventilación mecánica: revisión sistemática y metaanálisis.

OBJECTIVE: To determine the role of plasma procalcitonin (PCT) levels in diagnosing ventilator-associated pneumonia. DESIGN: A systematic review of publications prospectively assessing the diagnostic role of PCT in ventilator-associated pneumonia was carried out. The search was performed using Medline, Embase, the Cochrane Collaboration and MEDION, with reviewing of the references of retrieved articles. We extracted data that allowed the calculation of sensitivity, specificity, likelihood ratios and diagnostic odds ratio. Intervention Metaregression was performed to determine whether exposure to previous antibiotic treatment, the time to occurrence of ventilator-associated pneumonia and the type of patients had an impact upon the diagnostic performance of procalcitonin. RESULTS: Seven studies were considered (373 patients, 434 episodes). We found no publication bias or threshold effect. High plasma PCT levels were associated to an increased risk of suffering ventilator-associated pneumonia (OR: 8.39; 95% CI: 5.4-12.6). The pooled data on sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio found were 76% (69-82), 79% (74-84), 4.35 (2.48-7.62), 0.26 (0.15-0.46) and 17.9 (10.1-31.7), respectively. Diagnostic yield was modified by prior exposure to antibiotics (rDOR 0.11, 0.02-0.069), but not by the type of critically ill patient or the time to occurrence of ventilator-associated pneumonia. CONCLUSIONS: Our results suggest that PCT provides additional information on the risk of VAP. Inclusion of PCT in diagnostic algorithms could improve their effectiveness.

Can Biomarkers Correctly Predict Ventilator-associated Pneumonia in Patients Treated With Targeted Temperature Management After Cardiac Arrest? An Exploratory Study of the Multicenter Randomized Antibiotic (ANTHARTIC) Study.

IMPORTANCE: Ventilator-associated pneumonia (VAP) frequently occurs in patients with cardiac arrest. Diagnosis of VAP after cardiac arrest remains challenging, while the use of current biomarkers such as C-reactive protein (CRP) or procalcitonin (PCT) is debated. OBJECTIVES: To evaluate biomarkers' impact in helping VAP diagnosis after cardiac arrest. DESIGN SETTING AND PARTICIPANTS: This is a prospective ancillary study of the randomized, multicenter, double-blind placebo-controlled ANtibiotherapy during Therapeutic HypothermiA to pRevenT Infectious Complications (ANTHARTIC) trial evaluating the impact of antibiotic prophylaxis to prevent VAP in out-of-hospital patients with cardiac arrest secondary to shockable rhythm and treated with therapeutic hypothermia. An adjudication committee blindly evaluated VAP according to predefined clinical, radiologic, and microbiological criteria. All patients with available biomarker(s), sample(s), and consent approval were included. MAIN OUTCOMES AND MEASURES: The main endpoint was to evaluate the ability of biomarkers to correctly diagnose and predict VAP within 48 hours after sampling. The secondary endpoint was to study the combination of two biomarkers in discriminating VAP. Blood samples were collected at baseline on day 3. Routine and exploratory panel of inflammatory biomarkers measurements were blindly performed. Analyses were adjusted on the randomization group. RESULTS: Among 161 patients of the ANTHARTIC trial with available biological sample(s), patients with VAP (n = 33) had higher body mass index and Acute Physiology and Chronic Health Evaluation II score, more unwitnessed cardiac arrest, more catecholamines, and experienced more prolonged therapeutic hypothermia duration than patients without VAP (n = 121). In univariate analyses, biomarkers significantly associated with VAP and showing an area under the curve (AUC) greater than 0.70 were CRP (AUC = 0.76), interleukin (IL) 17A and 17C (IL17C) (0.74), macrophage colony-stimulating factor 1 (0.73), PCT (0.72), and vascular endothelial growth factor A (VEGF-A) (0.71). Multivariate analysis combining novel biomarkers revealed several pairs with p value of less than 0.001 and odds ratio greater than 1: VEGF-A + IL12 subunit beta (IL12B), Fms-related tyrosine kinase 3 ligands (Flt3L) + C-C chemokine 20 (CCL20), Flt3L + IL17A, Flt3L + IL6, STAM-binding protein (STAMBP) + CCL20, STAMBP + IL6, CCL20 + 4EBP1, CCL20 + caspase-8 (CASP8), IL6 + 4EBP1, and IL6 + CASP8. Best AUCs were observed for CRP + IL6 (0.79), CRP + CCL20 (0.78), CRP + IL17A, and CRP + IL17C. CONCLUSIONS AND RELEVANCE: Our exploratory study shows that specific biomarkers, especially CRP combined with IL6, could help to better diagnose or predict early VAP occurrence in cardiac arrest patients.