Upregulated expression of long non-coding RNA MEG3 serves as a prognostic biomarker in severe pneumonia children and its regulatory mechanism.

Severe pneumonia is a high-mortality disorder in children. The expression and underlying effects of lncRNA maternally expressed 3 (MEG3) were detected. The relationships between MEG3 and other parameters were reported by Pearson correlation. The prognostic importance of MEG3 was assessed by Kaplan-Meier (K-M) curve and COX analysis and its diagnostic potential was uncovered by the receiver operating characteristic (ROC) curve. Luciferase activity assay was performed to demonstrate the target gene of MEG3. Elevated expression of MEG3 and reduced microRNA-29 c (miR-29 c) were evaluated in severe pneumonia children, and a negative relationship between MEG3 and miR-29 c was propounded. MEG3 might function as an independent prognostic indicator. The diagnostic efficiency of MEG3 was also indicated for severe pneumonia children. In MRC-5 cell models and MH-S cell models, lipopolysaccharide (LPS) contributed to the increased expression of MEG3. Interference of MEG3 restricted the upregulation of MEG3 triggered by LPS. Silenced MEG3 protected MRC-5 and MH-S cells against damages managed by LPS on cell apoptosis, viability, and inflammation. MiR-29 c was a ceRNA of MEG3 and the absence of MEG3 abrogated the decreased expression of miR-29 c caused by LPS. Overall, the increased expression of MEG3 and the reduced levels of miR-29 c were identified in severe pneumonia. Prognostic and diagnostic significances of MEG3 provided a novel perspective for severe pneumonia. Disruption of MEG3 alleviated cell injury and inflammation as characterized by high LPS by binding miR-29 c.

miR-26a-5p mediates TLR signaling pathway by targeting CTGF in LPS-induced alveolar macrophage.

To explore the regulation mechanism of miR-26a-5p and connective tissue growth factor (CTGF) in lipopolysaccharide (LPS)-induced alveolar macrophages, which is a severe pneumonia cell model. MH-S cells were grouped into Normal group, Model group, negative control (NC) group, miR-26a-5p mimic group, oe-CTGF group, miR-26a-5p mimic + oe-CTGF group. The expression level of miR-26a-5p, CTGF and Toll-like receptor (TLR) signaling related molecules (TLR2, TLR4 and nuclear factor-κB p65) were detected by qRT-PCR and WB, respectively. The cell viability and apoptosis rate were detected by methyl thiazolyl tetrazolium (MTT) and flow cytometry, respectively. Compared with the Normal group, the expression level of miR-26a-5p was significantly decreased, while CTGF protein level was significantly increased in the Model group. Compared with the Model group, MH-S cells with miR-26a-5p overexpression showed enhanced cell viability, decreased apoptosis rate, declined expression level of TLR signaling related molecules and reduced level of tumor necrosis factor-α (TNF-α), interleukin (IL) 6 (IL-6) and IL-1ß, while those with CTGF overexpression had an opposite phenotype. In conclusion, miR-26a-5p can inhibit the expression of CTGF and mediate TLR signaling pathway to inhibit the cell apoptosis and reduce the expression of proinflammatory cytokines in alveolar macrophages which is a cell model of severe pneumonia.

Hospitalised adults with pneumonia are frequently misclassified as another diagnosis.

Using data from a large randomised controlled trial of adults hospitalised with acute respiratory illness, we examined the reliability of pneumonia diagnosis on discharge documentation. 50 (28.2%) of 177 patients with a pneumonia diagnosis had no radiological evidence of pneumonia. 67 (34.9%) of 192 patients with clinico-radiological evidence of pneumonia did not have a diagnosis of pneumonia listed; 'COPD exacerbation' or 'lower respiratory tract infection' was often listed instead. These patients more frequently had a respiratory comorbidity and lower oxygen saturations, CRP and temperature at presentation. Pneumonia diagnoses misclassification on discharge documentation may have clinical, financial, and research data implications.

Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia.

Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.

Lung Defense through IL-8 Carries a Cost of Chronic Lung Remodeling and Impaired Function.

IL-8-dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible, pathological changes associated with elevated levels of IL-8 in the lung. To better understand the duality of IL-8-dependent host immunity to bacterial infection and lung pathology, we expressed human IL-8 transgenically in murine bronchial epithelium, and investigated the impact of overexpression on lung bacterial clearance, host immunity, and lung pathology and function. Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation and activation, and chemotaxis. There was enhanced protection against challenge with Pseudomonas aeruginosa, and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL-2, and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen OprF, indicating a regulatory T-cell phenotype. However, this enhanced bacterial immunity came at a high price of progressive lung remodeling, with increased inflammation, mucus hypersecretion, and fibrosis. There was increased expression of Ccl3 and reduced expression of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all of which resulted in impaired lung function with reduced compliance, increased resistance, and bronchial hyperreactivity as measured by whole-body plethysmography. These results show that IL-8 overexpression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodeling, and damaged tight junctions, leading to impaired lung function.

Prediction Equations Underestimate Resting Energy Expenditure in Patients With End-Stage Cystic Fibrosis.

BACKGROUND: Resting energy expenditure (REE) is increased in patients with cystic fibrosis (CF) with end-stage lung disease due to chronic inflammation and pulmonary infections. After lung transplantation (LTx), energy expenditure is expected to be lower because inflammation will decrease. We assessed the agreement between measured and predicted REE in pre-LTx CF and post-LTx patients with CF and differences in REE in pre-LTx CF and post-LTx patients with CF in a cross-sectional study. METHODS: Included were 12 pre-LTx patients with CF (9 women; median age 31.6 years; interquartile range [IQR], 23.3-40.0) and 12 patients with CF within 2 years after LTx (6 women; median age 33.5 years; IQR, 22.3-40.3). REE was measured in a fasted state using indirect calorimetry. Values were compared with predicted REE calculated by formulas of Harris-Benedict (1919 and 1984), Schofield, and the World Health Organization (1985). A calculated REE between 90% and 110% of REE measured was considered adequate. RESULTS: Prediction equations underestimate REE in at least 75% of pre-LTx and 33% of post-LTx patients with CF. Mean (SD) REE measured by indirect calorimetry was 1735 (251) kcal pre-LTx and 1650 (235) kcal post-LTx ( P = .40). REE expressed per kilogram of fat-free mass (FFM) was 40.5 kcal/kg in pre-LTx patients with CF, which was higher than the 34.3 kcal/kg in post-LTx patients with CF ( P = .01). CONCLUSIONS: Prediction equations underestimate REE in patients with end-stage CF. REE per kg of FFM is lower post-LTx than pre-LTx in patients with CF. Measurement of REE is recommended for patients with CF, especially pre-LTx, to optimize energy requirements for improving nutrition status.

Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia.

Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.

Assessment of oxygenation and comorbidities improves outcome prediction in patients with community-acquired pneumonia with a low CRB-65 score.

BACKGROUND: Addition of assessment of comorbid diseases ('D') and oxygen saturation ('S') to the CRB-65 score has been recommended to improve its accuracy for risk stratification in community-acquired pneumonia (CAP). The aim of this study was to validate the resulting DS-CRB-65 score in a large cohort of patients with CAP. METHODS: A total of 4432 patients prospectively enrolled in the CAPNETZ cohort were included in this study. Predefined end points were 28-day mortality, requirement for mechanical ventilation or vasopressors (MV/VS) and requirement for MV/VS or intensive care unit admission (MV/VS/ICU). Receiver operating characteristic curve analysis was used to determine the accuracy of the CRB-65 score and the addition of D (extra-pulmonary comorbidities) and S (oxygen saturation <90% or partial pressure of oxygen <8 kPa). Binary logistic regression and the method of Hanley and McNeil were used to compare the criteria. RESULTS: The mortality rate was 4.0%, and 4.2% of patients required MV/VS and 6.6% required MV/VS/ICU. After multivariate analysis, D and S independently were added to the CRB-65 criteria for mortality prediction, but only S improved prediction of MV/VS and MV/VS/ICU (P < 0.001 for all). The area under the curve of the CRB-65 score was significantly improved by adding D and S for all end points (P < 0.02). Amongst patients who died or required MV/VS despite a CRB-65 score of 0, 64-80% would have been identified by the DS-CRB-65 score. CONCLUSIONS: The addition of assessment of oxygenation and comorbidities significantly improved the prognostic accuracy of the CRB-65 score. Consequently, the DS-CRB-65 score may have a useful role in risk stratification algorithms for CAP.

Inhibition of airway inflammation by the roots of Angelica decursiva and its constituent, columbianadin.

ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Angelica decursiva Fr. Et Sav (Umbelliferae) have been frequently used in traditional medicine as anti-inflammatory, antitussive, analgesic agents and expectorant, especially for treating cough, asthma, bronchitis and upper respiratory tract infections. To establish the scientific rationale for the clinical use of Angelica decursiva and to identify new agents for treating inflammatory lung disorders, pharmacological evaluation of the roots of Angelica decursiva and the isolated constituents was performed. METHODS: In vitro study was carried out using two lung cells, lung epithelial cells (A549) and alveolar macrophages (MH-S). The inflammatory markers such as IL-6 and nitric oxide (NO) for each cell line were examined. For in vivo study, a mouse model of lipopolysaccharide (LPS)-induced acute lung injury was used and the effects on lung inflammation were established by measuring the cell numbers in bronchoalveolar lavage fluid (BALF) and by histological observation. RESULTS: Water and 70% ethanol extracts of the roots of Angelica decursiva showed considerable inhibitory activity against LPS-induced lung inflammation in mice following oral administration at a dose of 400 mg/kg. Five coumarin derivatives including columbianadin, umbelliferone, umbelliferone 6-carboxylic acid, nodakenin and nodakenetin were isolated. Among the isolated compounds, columbianadin was found to possess strong inhibitory activity against the inflammatory response of IL-1ß-treated A549 cells and LPS-treated MH-S cells. Columbianadin was found to inhibit NO production by down-regulation of inducible NO synthase. Moreover, columbianadin was also proved to possess significant inhibitory activity against LPS-induced lung inflammation following oral administration at a dose of 20-60 mg/kg. CONCLUSIONS: The roots of Angelica decursiva were proved to be effective in the treatment of lung inflammation. Columbianadin can be a potential new agent for treating inflammatory lung disorders.

Non-invasive assessment of upper and lower airway infection and inflammation in CF patients.

BACKGROUND: The upper (UAW) and lower (LAW) airways of patients with cystic fibrosis (CF) have the same ion-channel defects, but little is known about similarities and differences in host immunological responses at the two levels. AIM: Identification and comparison of both levels' pathogen colonization and resulting immunological host responses. METHODS: The UAW and LAW of 40 CF patients were non-invasively assessed by nasal lavage and induced sputum. Pathogen colonization, cytology, and the concentrations of inflammatory mediators (TNF-α, MPO, matrix metalloprotease (MMP)-9, tissue inhibitor of metalloprotease (TIMP)-1, regulated upon activation, normal T-cell expressed and presumably secreted (RANTES), and interleukin (IL)-1ß, -5, -6, -8, and -10) were measured. RESULTS: Inflammatory responses were more pronounced in the LAW than the UAW. Pseudomonas aeruginosa LAW colonization is accompanied by a significantly enhanced neutrophil (PMN)-dominated response (P = 0.041) and IL-8 concentration (P = 0.01) not observed in P. aeruginosa UAW colonization. In contrast, sinonasal P. aeruginosa colonization resulted in elevated RANTES (P = 0.039) and reduced MMP-9 (P = 0.023) and TIMP-1 (P = 0.035) concentrations. Interestingly, LAW P. aeruginosa colonization was associated with reduced sinonasal concentrations of MMP-9 (P = 0.01) and TIMP-1 (P = 0.02), a finding independent of UAW colonization for MMP-9. CONCLUSION: CF UAW and LAW show distinct inflammatory profiles and differentiated responses upon P. aeruginosa colonization. Assessment of UAW colonization and MMP-9 are predictive of chronic pulmonary colonization with P. aeruginosa. Thus, this linkage between CF UAW and LAW can provide new clinical and scientific implications.

Assessment of oxidative stress biomarkers in exhaled breath condensate and blood of Thoroughbred foals.

This study reports preliminary data on systemic and local biomarkers of oxidative stress (OS) in Thoroughbred foals. Blood and exhaled breath condensate (EBC) were sampled from 13 foals on two farms. Values of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), antioxidant barrier (OXY-ads), thiol antioxidant barrier (SHp) and advanced oxidation protein products (AOPPs) were determined in blood, while EBC samples were assayed for hydrogen peroxide (H(2)O(2)) levels. Systemic and local OS biomarkers did not differ between farms and gender. Increased oxidative stress index (OSI) values in a foal recovering from pneumonia and elevated H(2)O(2) in EBC coupled with low SHp and elevated AOPPs in the blood of a foal with overt upper respiratory tract disease suggested that the OS markers measured in this study may relate to the respiratory health status of foals.

Pulmonary biocompatibility assessment of inhaled single-wall and multiwall carbon nanotubes in BALB/c mice.

With the widespread application of carbon nanotubes (CNTs) in diverse commercial processes, scientists are now concerned about the potential health risk of occupational exposures. In this study, CNT-induced pulmonary toxicity was investigated by exposing BALB/c mice to aerosolized single-wall (SW) CNT and multiwall (MW) CNT (5 µg/g of mice) for 7 consecutive days in a nose-only exposure system. Microscopic studies showed that inhaled CNTs were homogeneously distributed in the mouse lung. The total number of bronchoalveolar lavage polymorphonuclear leukocytes recovered from the mice exposed to SWCNT and MWCNT (1.2 × 10(6) ± 0.52 and 9.87 × 10(5) ± 1.45; respectively) was significantly greater than control mice (5.46 × 10(5) ± 0.78). Rapid development of pulmonary fibrosis in mice that inhaled CNT was also confirmed by significant increases in the collagen level. The lactate dehydrogenase levels were increased nearly 2- and 2.4-fold in mice that inhaled SWCNT and MWCNT, respectively, as compared with control mice. In addition, exposure of CNTs to mice showed a significant (p < 0.05) reduction of antioxidants (glutathione, superoxide dismutase, and catalase) and induction of oxidants (myloperoxidase, oxidative stress, and lipid peroxidation) compared with control. Apoptosis-related proteins such as caspase-3 and -8 activities were also significantly increased in mice that inhaled CNT than in control mice. Together, this study shows that inhaled CNTs induce inflammation, fibrosis, alteration of oxidant and antioxidant levels, and induction of apoptosis-related proteins in the lung tissues to trigger cell death.

Image-derived input function for assessment of 18F-FDG uptake by the inflamed lung.

UNLABELLED: Pulmonary uptake of (18)F-FDG assessed with PET has been used to quantify the metabolic activity of inflammatory cells in the lung. This assessment involves modeling of tracer kinetics and knowledge of a time-activity curve in pulmonary artery plasma as an input function, usually acquired by manual blood sampling. This paper presents and validates a method to accurately derive an input function from a blood-pool region of interest (ROI) defined in dynamic PET images. METHODS: The method is based on a 2-parameter model describing the activity of blood and that from spillover into the time-activity curve for the ROI. The model parameters are determined using an iterative algorithm, with 2 blood samples used to calibrate the raw PET-derived activity data. We validated both the 2-parameter model and the method to derive a quantitative input function from ROIs defined for the cavities of the right and left heart and for the descending aorta by comparing them against the time-activity curve obtained by manual blood sampling from the pulmonary artery in lungs with acute inflammation. RESULTS: The model accurately described the time-activity curve from sampled blood. The 2-sample calibration method provided an efficient algorithm to derive input functions that were virtually identical to those sampled manually, including the fast kinetics of the early phase. The (18)F-FDG uptake rates in acutely injured lungs obtained using this method correlated well with those obtained exclusively using manual blood sampling (R(2) > 0.993). Within some bounds, the model was found quite insensitive to the timing of calibration blood samples or the exact definition of the blood-pool ROIs. CONCLUSION: Using 2 mixed venous blood samples, the method accurately assesses the entire time course of the pulmonary (18)F-FDG input function and does not require the precise geometry of a specific blood-pool ROI or a population-based input function. This method may substantially facilitate studies involving modeling of pulmonary (18)F-FDG in patients with viral or bacterial infections, pulmonary fibrosis, and chronic obstructive pulmonary disease.

Energy cost of infection burden: an approach to understanding the dynamics of host-pathogen interactions.

A mathematical model of long-term immune defense against infection was used to estimate the energy involved in the principal processes of immune resistance during periods of health and infection. From these values, an optimal level of energy was determined for immune response depending on infection burden. The present findings suggest that weak but prevalent pathogens lead to latent or chronic infection, whereas more virulent but less prevalent pathogens result in acute infection. This energy-based approach offers insight into the mechanisms of immune system adaptation leading to the development of chronic infectious diseases and immune deficiencies.

Necrotizing pneumonia in children.

AIM: Clinical features and outcome of 36 patients with necrotizing pneumonia (NP) as well as 36 children with parapneumonic effusions (PPE) and 36 with severe control pneumonia (CP) were investigated. The mean age of the patients in the NP, PPE and CP groups were similar (3.8 +/- 3.3 (mean +/- SD), 4.2 +/- 3.0 and 4.2 +/- 3.0 y, respectively (p > 0.05)). The duration of symptoms at presentation were 11.9 +/- 8.5, 9.2 +/- 7.2 and 6 +/- 3.6 d, respectively (p < 0.01). The diagnosis of NP was established by computerized tomography. The mean (mean +/- SD) laboratory results in patients with NP revealed a white blood cell (WBC) count of 19,300 +/- 8700/mm3, erythrocyte sedimentation rate (ESR) of 71 +/- 22 mm/h, C-reactive protein (CRP) of 13.6 +/- 11.7 mg/dl and aspartate aminotransferase (AST) of 66 +/- 132 U/L. The values of WBC, ESR, CRP and AST in the NP group were significantly higher than those of the other groups (p < 0.001). The duration of hospitalization in the NP, PPE and CP groups was 26 +/- 9, 16 +/- 6 and 10 +/- 5 d, respectively (p < 0.001). The number of febrile days was 8 +/- 4, 4 +/- 3 and 3 +/- 3 (p < 0.001), and the duration of normalization of CRP was 14 +/- 4, 11 +/- 4 and 7 +/- 3 d (p < 0.001), respectively. The average cost of treatment was 3476 US dollars, 1646 US dollars and 844 US dollars, respectively (p < 0.001). CONCLUSION: All NP patients except two (94%) were complicated with PPE. The effusion in patients with NP and PPE was complicated with bronchopleural fistula (55% and 0%, respectively, p < 0.001). Surgical treatment was required in 66%, 8% and 0% in patients with NP, PPE and CP, respectively (p < 0.001). The mortality rate was 5.5%, 2.7% and 0% (p > 0.05).

Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice.

Acute lung inflammation and injury were induced by intranasal instillation of lipopolysaccharide (LPS) in normal and type 2 nitric oxide synthase (NOS2)-deficient (NOS2-/-) C57BL/6 mice. LPS-induced increases in extravasated airway neutrophils and in lung lavage fluid of TNF-alpha and macrophage inflammatory protein-2 were markedly lower in NOS2-/- than in wild-type mice, indicating that NOS2-derived nitric oxide (NO.) participates in inflammatory cytokine production and neutrophil recruitment. Instillation of LPS also increased total lung lavage protein and induced matrix metalloproteinase-9 and mucin 5AC, as indexes of lung epithelial injury and/or mucus hyperplasia, and increased tyrosine nitration of lung lavage proteins, a marker of oxidative injury. All these responses were less pronounced in NOS2-/- than in wild-type mice. Inhibition of NOS activity also suppressed production of TNF-alpha and macrophage inflammatory protein-2 by LPS-stimulated mouse alveolar MH-S macrophages, and this was restored by NO. donors, illustrating involvement of NO. in macrophage cytokine signaling. Oligonucleotide microarray (GeneChip) analysis of global lung gene expression revealed that LPS inhalation induced a range of transcripts encoding proinflammatory cytokines and chemokines, stress-inducible factors, and other extracellular factors and suppressed mRNAs encoding certain cytoskeletal proteins and signaling proteins, responses that were generally attenuated in NOS2-/- mice. Comparison of both mouse strains revealed altered expression of several cytoskeletal proteins, cell surface proteins, and signaling proteins in NOS2-/- mice, changes that may partly explain the reduced responsiveness to LPS. Collectively, our results suggest that NOS2 participates in the acute inflammatory response to LPS by multiple mechanisms: involvement in proinflammatory cytokine signaling and alteration of the expression of various genes that affect inflammatory-immune responses to LPS.

Achieving a safe and early discharge for patients with community-acquired pneumonia.

The rationale for achieving an early discharge for patients with CAP is that reduced length of stay can result in lower costs. When hospital discharge is premature, however, use of resources after discharge from the hospital may increase. This situation could increase overall cost and worsen quality of care. The objective should be to achieve a safe and early discharge. Several studies have evaluated methods for achieving this goal. Key findings from these studies are as follows: When a patient achieves clinical stability (e.g., systolic blood pressure, > or = 90 mm Hg; heart rate, < or = 100 beats/min; respiratory rate, < or = 24 breaths/min; temperature, < or = 38.3 degrees C [101 degrees F]; oxygen saturation, > or = 90%; able to eat; and stable mental status) or fulfills appropriate criteria (see Table 2), the patient may be eligible for switch from parenteral to oral antibiotics and early discharge. For many patients, this switch or discharge may occur on day 3 of hospitalization. When a patient is switched from parenteral to oral antibiotics, in many cases there does not appear to be a demonstrable clinical benefit to in-hospital observation. Elimination of in-hospital observation for patients who do not have an obvious reason for continued hospitalization potentially could reduce length of stay by 1 day. Improving efficiency of care reduces length of stay. This reduction may be accomplished by implementing clinical pathways, identifying and correcting causes of medically unnecessary hospital days, initiating early discharge planning, enlisting the services of a discharge coordinator, and organizing outpatient parenteral antibiotic treatment programs. These strategies are effective in many but not all patients, and their application should be tempered with careful clinical judgment.

Resting energy expenditure and nitrogen balance in critically ill pediatric patients on mechanical ventilation.

Nutritional support is important in critically ill patients, with variable energy and nitrogen requirements (e.g., sepsis, trauma, postsurgical state) in this population. This study investigates how age, severity of illness, and mechanical ventilation are related to resting energy expenditure (REE) and nitrogen balance. Nineteen critically ill children (mean age, 8 +/- 6 [SD] y and range 0.4-17.0 y) receiving total parenteral nutrition (TPN) were enrolled. We used indirect calorimetry to measure REE. Expected energy requirements (EER) were obtained from Talbot tables. Pediatric Risk of Mortality (PRISM) and Therapeutic Intervention Scoring System (TISS) score were calculated. Total urinary nitrogen was measured using the Kjeldahl method. PRISM and TISS scores were 9 +/- 5 and 31 +/- 6 points, respectively. REE was 62 +/- 25 kcal.kg-1.d-1, EER was 42 +/- 11 kcal.kg-1. d-1, and caloric intake was 49 +/- 22 kcal.kg-1.d-1. Nitrogen intake was 279 +/- 125 mg.kg-1.d-1, total urinary nitrogen was 324 +/- 133 mg.kg-1.d-1, and nitrogen balance was -120 +/- 153 mg.kg-1.d-1. The protein requirement in this population was approximately 2.8 g.kg-1.d-1. These critically ill children were hypermetabolic, with REE 48% higher (20 kcal.kg-1.d-1) than expected. Nitrogen balance significantly correlated with caloric and protein intake, urinary nitrogen, and age, but not with severity of illness scores or ventilatory parameters.

Pleural fluid chemical analysis in parapneumonic effusions. A meta-analysis.

Controversy exists regarding the clinical utility of pleural fluid pH, lactate dehydrogenase (LDH), and glucose for identifying complicated parapneumonic effusions that require drainage. In this report, we performed a meta-analysis of pertinent studies, using receiver operating characteristic (ROC) techniques, to assess the diagnostic accuracy of these tests, to determine appropriate decision thresholds, and to evaluate the quality of the primary studies. Seven primary studies reporting values for pleural fluid pH (n = 251), LDH (n = 114), or glucose (n = 135) in pneumonia patients were identified. We found that pleural fluid pH had the highest diagnostic accuracy for all patients with parapneumonic effusions as measured by the area under the ROC curve (AUC = 0.92) compared with pleural fluid glucose (AUC = 0.84) or LDH (AUC = 0.82). After excluding patients with purulent effusions, pH (AUC = 0.89) retained the highest diagnostic accuracy. Pleural fluid pH decision thresholds varied between 7.21 and 7.29 depending on cost-prevalence considerations. The quality of the primary studies was the major limitation in determining the value of pleural fluid chemical analysis. We conclude that meta-analysis of the available data refines the application of pleural fluid chemical analysis but a clearer understanding of the usefulness of these tests awaits more rigorous primary investigations.

Energy expenditures of mechanically ventilated nonsurgical patients.

Mechanically ventilated, nonsurgical, critically ill patients represent a group not rigorously studied by energy expenditure measurements for formulating nutritional support guidelines. Most strategies for predicting caloric requirements in this group are based on studies of spontaneously breathing surgical patients. It is unclear whether "severity of disease" or "stress" factors employed in this group are justifiable in medical patients with compromised pulmonary function, who may be particularly prone to the complications of overfeeding. We therefore measured the energy expenditures of 73 consecutive ventilator-supported patients with various primary diagnoses in a medical ICU. These results are compared to estimates of caloric requirements based on the Harris-Benedict equations, without modification for severity of disease or other factors. These comparisons are (kcal/day +/- SE, measured vs predicted): sepsis, 1,982 +/- 97 vs 1,534 +/- 56 (p less than 0.0001); cardiogenic shock, 1,452 +/- 119 vs 1,339 +/- 62; cardiogenic pulmonary edema, 1,427 +/- 87 vs 1,338 +/- 93; ARDS, 1,732 +/- 203 vs 1,550 +/- 125; pneumonia, 1,508 +/- 148 vs 1,259 +/- 55; and "other" 1,585 +/- 104 vs 1,419 +/- 55. These data reveal that in mechanically ventilated nonsurgical patients without sepsis, no modifications of the Harris-Benedict equations are necessary; in those with sepsis an increase of approximately 20 percent over these predictions is appropriate.