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1.  Geographic Access to High Capability Severe Acute Respiratory Failure Centers in the United States 
PLoS ONE  2014;9(4):e94057.
Optimal care of adults with severe acute respiratory failure requires specific resources and expertise. We sought to measure geographic access to these centers in the United States.
Cross-sectional analysis of geographic access to high capability severe acute respiratory failure centers in the United States. We defined high capability centers using two criteria: (1) provision of adult extracorporeal membrane oxygenation (ECMO), based on either 2008–2013 Extracorporeal Life Support Organization reporting or provision of ECMO to 2010 Medicare beneficiaries; or (2) high annual hospital mechanical ventilation volume, based 2010 Medicare claims.
Nonfederal acute care hospitals in the United States.
Measurements and Main Results
We defined geographic access as the percentage of the state, region and national population with either direct or hospital-transferred access within one or two hours by air or ground transport. Of 4,822 acute care hospitals, 148 hospitals met our ECMO criteria and 447 hospitals met our mechanical ventilation criteria. Geographic access varied substantially across states and regions in the United States, depending on center criteria. Without interhospital transfer, an estimated 58.5% of the national adult population had geographic access to hospitals performing ECMO and 79.0% had geographic access to hospitals performing a high annual volume of mechanical ventilation. With interhospital transfer and under ideal circumstances, an estimated 96.4% of the national adult population had geographic access to hospitals performing ECMO and 98.6% had geographic access to hospitals performing a high annual volume of mechanical ventilation. However, this degree of geographic access required substantial interhospital transfer of patients, including up to two hours by air.
Geographic access to high capability severe acute respiratory failure centers varies widely across states and regions in the United States. Adequate referral center access in the case of disasters and pandemics will depend highly on local and regional care coordination across political boundaries.
PMCID: PMC3976413  PMID: 24705417
2.  Using Data-Driven Rules to Predict Mortality in Severe Community Acquired Pneumonia 
PLoS ONE  2014;9(4):e89053.
Prediction of patient-centered outcomes in hospitals is useful for performance benchmarking, resource allocation, and guidance regarding active treatment and withdrawal of care. Yet, their use by clinicians is limited by the complexity of available tools and amount of data required. We propose to use Disjunctive Normal Forms as a novel approach to predict hospital and 90-day mortality from instance-based patient data, comprising demographic, genetic, and physiologic information in a large cohort of patients admitted with severe community acquired pneumonia. We develop two algorithms to efficiently learn Disjunctive Normal Forms, which yield easy-to-interpret rules that explicitly map data to the outcome of interest. Disjunctive Normal Forms achieve higher prediction performance quality compared to a set of state-of-the-art machine learning models, and unveils insights unavailable with standard methods. Disjunctive Normal Forms constitute an intuitive set of prediction rules that could be easily implemented to predict outcomes and guide criteria-based clinical decision making and clinical trial execution, and thus of greater practical usefulness than currently available prediction tools. The Java implementation of the tool JavaDNF will be publicly available.
PMCID: PMC3974677  PMID: 24699007
3.  Timing of Tracheostomy in Critically Ill Patients: A Meta-Analysis 
PLoS ONE  2014;9(3):e92981.
To compare important outcomes between early tracheostomy (ET) and late tracheostomy (LT) or prolonged intubation (PI) for critically ill patients receiving long-term ventilation during their treatment.
We performed computerized searches for relevant articles on PubMed, EMBASE, and the Cochrane register of controlled trials (up to July 2013). We contacted international experts and manufacturers. We included in the study randomized controlled trials (RCTs) that compared ET (performed within 10 days after initiation of laryngeal intubation) and LT (after 10 days of laryngeal intubation) or PI in critically ill adult patients admitted to intensive care units (ICUs). Two investigators evaluated the articles; divergent opinions were resolved by consensus.
A meta-analysis was evaluated from nine randomized clinical trials with 2,072 participants. Compared to LT/PI, ET did not significantly reduce short-term mortality [relative risks (RR) = 0.91; 95% confidence intervals (CIs) = 0.81–1.03; p = 0.14] or long-term mortality (RR = 0.90; 95% CI = 0.76–1.08; p = 0.27). Additionally, ET was not associated with a markedly reduced length of ICU stay [weighted mean difference (WMD) = −4.41 days; 95% CI = −13.44–4.63 days; p = 0.34], ventilator-associated pneumonia (VAP) (RR = 0.88; 95% CI = 0.71–1.10; p = 0.27) or duration of mechanical ventilation (MV) (WMD = − 2.91 days; 95% CI = −7.21–1.40 days; p = 0.19).
Among the patients requiring prolonged MV, ET showed no significant difference in clinical outcomes compared to that of the LT/PI group. But more rigorously designed and adequately powered RCTs are required to confirm it in future.
PMCID: PMC3965497  PMID: 24667875
4.  Inflammation-Induced Acute Phase Response in Skeletal Muscle and Critical Illness Myopathy 
PLoS ONE  2014;9(3):e92048.
Systemic inflammation is a major risk factor for critical-illness myopathy (CIM) but its pathogenic role in muscle is uncertain. We observed that interleukin 6 (IL-6) and serum amyloid A1 (SAA1) expression was upregulated in muscle of critically ill patients. To test the relevance of these responses we assessed inflammation and acute-phase response at early and late time points in muscle of patients at risk for CIM.
Prospective observational clinical study and prospective animal trial.
Two intensive care units (ICU) and research laboratory.
33 patients with Sequential Organ Failure Assessment scores ≥8 on 3 consecutive days within 5 days in ICU were investigated. A subgroup analysis of 12 patients with, and 18 patients without CIM (non-CIM) was performed. Two consecutive biopsies from vastus lateralis were obtained at median days 5 and 15, early and late time points. Controls were 5 healthy subjects undergoing elective orthopedic surgery. A septic mouse model and cultured myoblasts were used for mechanistic analyses.
Measurements and Main Results
Early SAA1 expression was significantly higher in skeletal muscle of CIM compared to non-CIM patients. Immunohistochemistry showed SAA1 accumulations in muscle of CIM patients at the early time point, which resolved later. SAA1 expression was induced by IL-6 and tumor necrosis factor-alpha in human and mouse myocytes in vitro. Inflammation-induced muscular SAA1 accumulation was reproduced in a sepsis mouse model.
Skeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis.
Trial Registration
PMCID: PMC3961297  PMID: 24651840
5.  Autophagy-Related IRGM Polymorphism Is Associated with Mortality of Patients with Severe Sepsis 
PLoS ONE  2014;9(3):e91522.
Autophagy is the regulated catabolic process for recycling damaged or unnecessary organelles, which plays crucial roles in cell survival during nutrient deficiency, and innate immune defense against pathogenic microorganisms. Autophagy has been also reported to be involved in various conditions including inflammatory diseases. IRGM (human immunity-related GTPase) has an important function in eliminating Mycobacterium tuberculosis from host cells via autophagy. We examined the association between genetic polymorphism and clinical course/outcome in severely septic patients.
The study included 125 patients with severe sepsis/septic shock (SS) and 104 non-sepsis patients who were admitted to the intensive care unit (ICU) of Chiba University Hospital between October 2001 and September 2008 (discovery cohort) and 268 SS patients and 454 non-sepsis patients who were admitted to ICUs of five Japanese institutions including Chiba University Hospital between October 2008 and September 2012 (multi-center validation cohort). Three hundred forty seven healthy volunteers who consented to this study were also included. Genotyping was performed for a single-nucleotide polymorphism (SNP) within the coding region of IRGM, IRGM(+313) (rs10065172). Lipopolysaccharide challenge of whole blood from randomly selected healthy volunteers (n = 70) was performed for comparison of IRGM mRNA expression among different genotypes.
No significant difference in genotypic distributions (CC/CT/TT) at the IRGM(+313) locus was observed among the three subject groups (SS, non-sepsis, and healthy volunteers) in either cohort. When mortality were compared, no significant difference was observed in the non-sepsis group, while TT homozygotes exhibited a significantly higher mortality than the CC+CT genotype category in the SS group for both cohorts (P = 0.043, 0.037). Lipopolysaccharide challenge to whole blood showed a significant suppression of IRGM mRNA expression in TT compared with the CC+CT genotype category (P = 0.019).
The data suggest that the IRGM(+313), an autophagy-related polymorphic locus, influences outcome in severely septic patients, with the possible involvement of autophagy in sepsis exacerbation.
PMCID: PMC3953488  PMID: 24626347
6.  Frequency of Vital Signs Monitoring and its Association with Mortality among Adults with Severe Sepsis Admitted to a General Medical Ward in Uganda 
PLoS ONE  2014;9(2):e89879.
Optimal vital signs monitoring of patients with severe sepsis in resource-limited settings may improve outcomes. The objective of this study was to determine the frequency of vital signs monitoring of patients with severe sepsis and its association with mortality in a regional referral hospital in Uganda.
We reviewed medical records of patients admitted to Mbarara Regional Referral Hospital in Southwestern Uganda with severe sepsis defined by the presence of infection plus ≥2 of the systemic inflammatory response syndrome criteria, and ≥1 organ dysfunction (altered mental state, hypotension, jaundice, or thrombocytopenia). We recorded frequency of vital signs monitoring in addition to socio-demographic, clinical, and outcome data. We analyzed the data using logistic regression.
We identified 202 patients with severe sepsis. The median age was 35 years (IQR, 25–47) and 98 (48%) were female. HIV infection and anemia was present in 115 (57%) and 83 (41%) patients respectively. There were 67 (33%) in-hospital deaths. The median monitoring frequency per day was 1.1 (IQR 0.9–1.5) for blood pressure, 1.0 (IQR, 0.8–1.3) for temperature and pulse, and 0.5 (IQR, 0.3–1.0) for respiratory rate. The frequency of vital signs monitoring decreased during the course of hospitalization. Patients who died had a higher frequency of vital signs monitoring (p<0.05). The admission respiratory rate was associated with both frequency of monitoring (coefficient of linear regression 0.6, 95% CI 0.5–0.8, p<0.001) and mortality (AOR 2.5, 95% CI 1.3–5.3, p = 0.01). Other predictors of mortality included severity of illness, HIV infection, and anemia (p<0.05).
More research is needed to determine the optimal frequency of vital signs monitoring for severely septic patients in resource-limited settings such as Uganda.
PMCID: PMC3938537  PMID: 24587094
7.  Plasma D-Dimer Predicts Short-Term Poor Outcome after Acute Ischemic Stroke 
PLoS ONE  2014;9(2):e89756.
Haemostatic biomarkers associated with poor outcome in acute ischemic stroke (AIS). The objective of the study was to evaluate the predictive value of plasma D-dimer (D-D) on functional outcome at 90-day follow-up from stroke onset.
We conducted a prospective, observational cohort study in the emergency department and enrolled 220 patients with AIS. Plasma D-D concentrations, determined by a particle-enhanced, immunoturbidimetric assay, were measured. Each patient’s medical record was reviewed, and demographic, clinical, laboratory and neuroimaging information was abstracted.
There was a positive correlation between levels of D-D and the NIHSS (r = 0.361, p<0.001), and the infarct volume (r = 0.449, p<0.001). In the 69 patients with an unfavorable functional outcome, D-D levels were higher compared with those in patients with a favorable outcome [3.24(IQR, 2.18–4.60)mg/L vs 0.88(IQR, 0.35–1.77) mg/L; p<0.001]. After adjusting for all other significant outcome predictors, D-D level remained an independent predictor for unfavorable functional outcome and mortality with an odds ratio of 2.18 (95% CI, 1.55–2.83), 3.22 (95% CI, 2.05–6.43); respectively.
D-D levels are a useful tool to predict outcome and mortality 90-day after acute ischemic stroke and have a potential to assist clinicians.
PMCID: PMC3933671  PMID: 24587013
8.  The Effects of Intracranial Pressure Monitoring in Patients with Traumatic Brain Injury 
PLoS ONE  2014;9(2):e87432.
Although international guideline recommended routine intracranial pressure (ICP) monitoring for patients with severe traumatic brain injury(TBI), there were conflicting outcomes attributable to ICP monitoring according to the published studies. Hence, we conducted a meta-analysis to evaluate the efficacy and safety of ICP monitoring in patients with TBI.
Based on previous reviews, PubMed and two Chinese databases (Wangfang and VIP) were further searched to identify eligible studies. The primary outcome was mortality. Secondary outcomes included unfavourable outcome, adverse events, length of ICU stay and length of hospital stay. Weighted mean difference (WMD), odds ratio (OR) and 95% confidence intervals (CIs) were calculated and pooled using fixed-effects or random-effects model.
two randomized controlled trials (RCTs) and seven cohort studies involving 11,038 patients met the inclusion criteria. ICP monitoring was not associated with a significant reduction in mortality (OR, 1.16; 95% CI, 0.87–1.54), with substantial heterogeneity (I2 = 80%, P<0.00001), which was verified by the sensitivity analyses. No significant difference was found in the occurrence of unfavourable outcome (OR, 1.40; 95% CI, 0.99–1.98; I2 = 4%, P = 0.35) and advese events (OR, 1.04; 95% CI, 0.64–1.70; I2 = 78%, P = 0.03). However, we should be cautious to the result of adverse events because of the substantial heterogeneity in the comparison. Furthermore, longer ICU and hospital stay were the consistent tendency according to the pooled studies.
No benefit was found in patients with TBI who underwent ICP monitoring. Considering substantial clinical heterogeneity, further large sample size RCTs are needed to confirm the current findings.
PMCID: PMC3931613  PMID: 24586276
9.  Record Review to Explore the Adequacy of Post-Operative Vital Signs Monitoring Using a Local Modified Early Warning Score (Mews) Chart to Evaluate Outcomes 
PLoS ONE  2014;9(1):e87320.
1) To explore the adequacy of: vital signs’ recordings (respiratory and heart rate, oxygen saturation, systolic blood pressure (BP), temperature, level of consciousness and urine output) in the first 8 post-operative hours; responses to clinical deterioration. 2) To identify factors associated with death on the ward between transfer from the theatre recovery suite and the seventh day after operation.
Retrospective review of records of 11 patients who died plus four controls for each case.
We reviewed clinical records of 55 patients who met inclusion criteria (general anaesthetic, age >13, complete records) from six surgical wards in a teaching hospital between 1 May and 31 July 2009.
In the absence of guidelines for routine post-operative vital signs’ monitoring, nurses’ standard practice graphical plots of recordings were recoded into MEWS formats (0 = normal, 1–3 upper or lower limit) and their responses to clinical deterioration were interpreted using MEWS reporting algorithms.
No patients’ records contained recordings for all seven parameters displayed on the MEWS. There was no evidence of response to: 22/36 (61.1%) abnormal vital signs for patients who died that would have triggered an escalated MEWS reporting algorithm; 81/87 (93.1%) for controls. Death was associated with age, ≥61 years (OR 14.2, 3.0–68.0); ≥2 pre-existing co-morbidities (OR 75.3, 3.7–1527.4); high/low systolic BP on admission (OR 7.2, 1.5–34.2); tachycardia (≥111–129 bpm) (OR 6.6, 1.4–30.0) and low systolic BP (≤81–100 mmHg), as defined by the MEWS (OR 8.0, 1.9–33.1).
Guidelines for post-operative vital signs’ monitoring and reporting need to be established. The MEWS provides a useful scoring system for interpreting clinical deterioration and guiding intervention. Exploration of the ability of the Cape Town MEWS chart plus reporting algorithm to expedite recognition of signs of clinical and physiological deterioration and securing more skilled assistance is essential.
PMCID: PMC3909075  PMID: 24498075
10.  Assessment of Regional Ventilation Distribution: Comparison of Vibration Response Imaging (VRI) with Electrical Impedance Tomography (EIT) 
PLoS ONE  2014;9(1):e86638.
Vibration response imaging (VRI) is a bedside technology to monitor ventilation by detecting lung sound vibrations. It is currently unknown whether VRI is able to accurately monitor the local distribution of ventilation within the lungs. We therefore compared VRI to electrical impedance tomography (EIT), an established technique used for the assessment of regional ventilation.
Methodology/Principal Findings
Simultaneous EIT and VRI measurements were performed in the healthy and injured lungs (ALI; induced by saline lavage) at different PEEP levels (0, 5, 10, 15 mbar) in nine piglets. Vibration energy amplitude (VEA) by VRI, and amplitudes of relative impedance changes (rel.ΔZ) by EIT, were evaluated in seven regions of interest (ROIs). To assess the distribution of tidal volume (VT) by VRI and EIT, absolute values were normalized to the VT obtained by simultaneous spirometry measurements. Redistribution of ventilation by ALI and PEEP was detected by VRI and EIT. The linear correlation between pooled VT by VEA and rel.ΔZ was R2 = 0.96. Bland-Altman analysis showed a bias of −1.07±24.71 ml and limits of agreement of −49.05 to +47.36 ml. Within the different ROIs, correlations of VT-distribution by EIT and VRI ranged between R2 values of 0.29 and 0.96. ALI and PEEP did not alter the agreement of VT between VRI and EIT.
Measurements of regional ventilation distribution by VRI are comparable to those obtained by EIT.
PMCID: PMC3903564  PMID: 24475160
11.  Recovery of Diaphragm Function following Mechanical Ventilation in a Rodent Model 
PLoS ONE  2014;9(1):e87460.
Mechanical ventilation (MV) induces diaphragmatic muscle fiber atrophy and contractile dysfunction (ventilator induced diaphragmatic dysfunction, VIDD). It is unknown how rapidly diaphragm muscle recovers from VIDD once spontaneous breathing is restored. We hypothesized that following extubation, the return to voluntary breathing would restore diaphragm muscle fiber size and contractile function using an established rodent model.
Following 12 hours of MV, animals were either euthanized or, after full wake up, extubated and returned to voluntary breathing for 12 hours or 24 hours. Acutely euthanized animals served as controls (each n = 8/group). Diaphragmatic contractility, fiber size, protease activation, and biomarkers of oxidative damage in the diaphragm were assessed.
12 hours of MV induced VIDD. Compared to controls diaphragm contractility remained significantly depressed at 12 h after extubation but rebounded at 24 h to near control levels. Diaphragmatic levels of oxidized proteins were significantly elevated after MV (p = 0.002) and normalized at 24 hours after extubation.
These findings indicate that diaphragm recovery from VIDD, as indexed by fiber size and contractile properties, returns to near control levels within 24 hours after returning to spontaneous breathing. Besides the down-regulation of proteolytic pathways and oxidative stress at 24 hours after extubation further repairing mechanisms have to be determined.
PMCID: PMC3903648  PMID: 24475293
12.  Monitoring Vital Signs: Development of a Modified Early Warning Scoring (Mews) System for General Wards in a Developing Country 
PLoS ONE  2014;9(1):e87073.
The aim of the study was to develop and validate, by consensus, the construct and content of an observations chart for nurses incorporating a modified early warning scoring (MEWS) system for physiological parameters to be used for bedside monitoring on general wards in a public hospital in South Africa.
Delphi and modified face-to-face nominal group consensus methods were used to develop and validate a prototype observations chart that incorporated an existing UK MEWS. This informed the development of the Cape Town ward MEWS chart.
One specialist anaesthesiologist, one emergency medicine specialist, two critical care nurses and eight senior ward nurses with expertise in bedside monitoring (N = 12) were purposively sampled for consensus development of the MEWS. One general surgeon declined and one neurosurgeon replaced the emergency medicine specialist in the final round.
Five consensus rounds achieved ≥70% agreement for cut points in five of seven physiological parameters respiratory and heart rates, systolic BP, temperature and urine output. For conscious level and oxygen saturation a relaxed rule of <70% agreement was applied. A reporting algorithm was established and incorporated in the MEWS chart representing decision rules determining the degree of urgency. Parameters and cut points differed from those in MEWS used in developed countries.
A MEWS for developing countries should record at least seven parameters. Experts from developing countries are best placed to stipulate cut points in physiological parameters. Further research is needed to explore the ability of the MEWS chart to identify physiological and clinical deterioration.
PMCID: PMC3901724  PMID: 24475226
13.  Venous Thromboembolism after Community-Acquired Bacteraemia: A 20-year Danish Cohort Study 
PLoS ONE  2014;9(1):e86094.
Infections may increase the risk for venous thromboembolism (VTE), but little is known about VTE risk associated with community-acquired bacteraemia (CAB). We examined the risk for VTE within one year of CAB in comparison to that in matched controls.
We conducted a population-based cohort study in North Denmark 1992–2011, using data from high-quality health-care databases. We included 4,213 adult CAB patients who had positive blood cultures drawn on the day of hospital admission, 20,084 matched hospitalised controls admitted for other acute medical illness, and 41,121 matched controls from the general population. We computed 0–90 and 91–365 day absolute risks for hospital-diagnosed VTE and used regression analyses with adjustment for confounding factors to compare the risk for VTE in bacteraemia patients and controls.
Among CAB patients, 1.1% experienced VTE within 90 days of admission and 0.5% during 91–365 days after admission. The adjusted 90-day odds ratio (OR) for VTE was 1.9 (95% CI 1.4–2.7) compared with hospitalised controls, and 23.4 (95% CI 12.9–42.6) compared with population controls. During 91–365 days after CAB admission, the VTE risk remained moderately increased (adjusted hazard ratio vs. hospitalised controls, 1.4; 95% CI 0.8–2.5, and vs. population controls, 1.9; 95% CI 1.0–3.3). Compared to hospitalised controls, the 90-day VTE risk increase was greater for Gram-positive infection (adjusted OR 2.5; 95% CI 1.6–4.1) than for Gram-negative infection (adjusted OR, 1.2; 95% CI 0.7–2.1), partly due to a high risk after Staphylococcus aureus infection (3.6%).
The risk for VTE is substantially increased within 90 days after community-acquired bacteraemia when compared to hospitalised controls and population controls. However, the absolute risk of VTE following CAB is low.
PMCID: PMC3900448  PMID: 24465892
14.  The Impact of Acute Brain Dysfunction in the Outcomes of Mechanically Ventilated Cancer Patients 
PLoS ONE  2014;9(1):e85332.
Delirium and coma are a frequent source of morbidity for ICU patients. Several factors are associated with the prognosis of mechanically ventilated (MV) cancer patients, but no studies evaluated delirium and coma (acute brain dysfunction). The present study evaluated the frequency and impact of acute brain dysfunction on mortality.
The study was performed at National Cancer Institute, Rio de Janeiro, Brazil. We prospectively enrolled patients ventilated >48 h with a diagnosis of cancer. Acute brain dysfunction was assessed during the first 14 days of ICU using RASS/CAM-ICU. Patients were followed until hospital discharge. Univariate and multivariable analysis were performed to evaluate factors associated with hospital mortality.
170 patients were included. 73% had solid tumors, age 65 [53–72 (median, IQR 25%–75%)] years. SAPS II score was 54[46–63] points and SOFA score was (7 [6]–[9]) points. Median duration of MV was 13 (6–21) days and ICU stay was 14 (7.5–22) days. ICU mortality was 54% and hospital mortality was 66%. Acute brain dysfunction was diagnosed in 161 patients (95%). Survivors had more delirium/coma-free days [4(1,5–6) vs 1(0–2), p<0.001]. In multivariable analysis the number of days of delirium/coma-free days were associated with better outcomes as they were independent predictors of lower hospital mortality [0.771 (0.681 to 0.873), p<0.001].
Acute brain dysfunction in MV cancer patients is frequent and independently associated with increased hospital mortality. Future studies should investigate means of preventing or mitigating acute brain dysfunction as they may have a significant impact on clinical outcomes.
PMCID: PMC3899009  PMID: 24465538
15.  Probiotics for Preventing Ventilator-Associated Pneumonia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials 
PLoS ONE  2013;8(12):e83934.
Ventilator-associated pneumonia (VAP) is considered to be a worldwide issue along with the development of supportive ventilation. The preventing strategy is of great importance for its poor prognostic and difficulties in treatment. Probiotics have been advocated as one of the possible preventive measures. We conducted a systematic review and meta-analysis to explore the potential benefits of probiotics.
The databases, Web of science, PubMed, Ovid and Cochrane lib were searched for randomized controlled trials (RCTs) publications that compared the effectiveness of probiotics with placebo in the prevention of VAP. The incidence of VAP was considered as the primary endpoint, mortality, length of stay in intensive care units (ICUs), etiology of the infections were considered as secondary endpoints.
A total of 844 patients from 5 trials were subjected to meta-analysis. Probiotics did not significantly decrease the incidence of VAP (RR 0.94, 95%CI 0.85-1.04, p=0.22), however, the administration of probiotics reduced the risk of VAP caused by Pseudomonas aeruginosa (P. aeruginosa) (RR 0.30, 95%CI 0.11-0.91, P=0.03). It failed to affect any other endpoints.
Probiotic prophylaxis of ventilator-associated pneumonia remained inconclusive and it failed to improve the prognosis of general mechanically ventilated patients. It was noteworthy that infections caused by P. aeruginosa was reduced by administration of probiotics. In further, it is recommended that advanced studies should exploit transformation in pathogenic microorganisms owing to administration of probiotics as well as the specific population.
PMCID: PMC3867481  PMID: 24367620
16.  Access to urban acute care services in high- vs. middle-income countries: an analysis of seven cities 
Intensive Care Medicine  2013;40:342-352.
Cities are expanding rapidly in middle-income countries, but their supply of acute care services is unknown. We measured acute care services supply in seven cities of diverse economic background.
In a cross-sectional study, we compared cities from two high-income (Boston, USA and Paris, France), three upper-middle-income (Bogota, Colombia; Recife, Brazil; and Liaocheng, China), and two lower-middle-income (Chennai, India and Kumasi, Ghana) countries. We collected standardized data on hospital beds, intensive care unit beds, and ambulances. Where possible, information was collected from local authorities. We expressed results per population (from United Nations) and per acute illness deaths (from Global Burden of Disease project).
Supply of hospital beds where intravenous fluids could be delivered varied fourfold from 72.4/100,000 population in Kumasi to 241.5/100,000 in Boston. Intensive care unit (ICU) bed supply varied more than 45-fold from 0.4/100,000 population in Kumasi to 18.8/100,000 in Boston. Ambulance supply varied more than 70-fold. The variation widened when supply was estimated relative to disease burden (e.g., ICU beds varied more than 65-fold from 0.06/100 deaths due to acute illnesses in Kumasi to 4.11/100 in Bogota; ambulance services varied more than 100-fold). Hospital bed per disease burden was associated with gross domestic product (GDP) (R2 = 0.88, p = 0.01), but ICU supply was not (R2 = 0.33, p = 0.18). No city provided all requested data, and only two had ICU data.
Urban acute care services vary substantially across economic regions, only partially due to differences in GDP. Cities were poor sources of information, which may hinder their future planning.
PMCID: PMC3938845  PMID: 24337401
Urban population; Acute care services; Global burden of disease; Hospital beds; Intensive care beds; Ambulances
17.  Extended Daily Dialysis in Acute Kidney Injury Patients: Metabolic and Fluid Control and Risk Factors for Death 
PLoS ONE  2013;8(12):e81697.
Intermittent hemodialysis (IHD) and continuous renal replacement therapies (CRRT) are used as Acute Kidney Injury (AKI) therapy and have certain advantages and disadvantages. Extended daily dialysis (EDD) has emerged as an alternative to CRRT in the management of hemodynamically unstable AKI patients, mainly in developed countries.
We hypothesized that EDD is a safe option for AKI treatment and aimed to describe metabolic and fluid control of AKI patients undergoing EDD and identify complications and risk factors associated with death.
Study Selection
This is an observational and retrospective study describing introduction of EDD at our institution. A total of 231 hemodynamically unstable AKI patients (noradrenalin dose between 0.3 and 1.0 ucg/kg/min) were assigned to 1367 EDD session. EDD consisted of 6–8 h of HD 6 days a week, with blood flow of 200 ml/min, dialysate flows of 300 ml/min.
Data Synthesis
Mean age was 60.6±15.8 years, 97.4% of patients were in the intensive care unit, and sepsis was the main etiology of AKI (76.2). BUN and creatinine levels stabilized after four sessions at around 38 and 2.4 mg/dl, respectively. Fluid balance decreased progressively and stabilized around zero after five sessions. Weekly delivered Kt/V was 5.94±0.7. Hypotension and filter clotting occurred in 47.5 and 12.4% of treatment session, respectively. Regarding AKI outcome, 22.5% of patients presented renal function recovery, 5.6% of patients remained on dialysis after 30 days, and 71.9% of patients died. Age and focus abdominal sepsis were identified as risk factors for death. Urine output and negative fluid balance were identified as protective factors.
EDD is effective for AKI patients, allowing adequate metabolic and fluid control. Age, focus abdominal sepsis, and lower urine output as well as positive fluid balance after two EDD sessions were associated significantly with death.
PMCID: PMC3859511  PMID: 24349114
18.  Severity Assessment of Lower Respiratory Tract Infection in Malawi: Derivation of a Novel Index (SWAT-Bp) Which Outperforms CRB-65 
PLoS ONE  2013;8(12):e82178.
To assess the validity of CRB-65 (Confusion, Respiratory rate >30 breaths/min, BP<90/60 mmHg, age >65 years) as a pneumonia severity index in a Malawian hospital population, and determine whether an alternative score has greater accuracy in this setting.
Forty three variables were prospectively recorded during the first 48 hours of admission in all patients admitted to Queen Elizabeth Central Hospital, Malawi, for management of lower respiratory tract infection over a two month period (N = 240). Calculation of sensitivity and specificity for CRB-65 in predicting mortality was followed by multivariate modeling to create a score with superior performance in this population.
Median age 37, HIV prevalence 79.9%, overall mortality 18.3%. CRB-65 predicted mortality poorly, indicated by the area under the ROC curve of 0.649. Independent predictors of death were: Male sex, “S” (AOR 2.6); Wasting, “W” (AOR 6.6); non-ambulatory, “A” (AOR 2.5); Temp >38°C or <35°C, “T” (AOR 3.2); BP<100/60, “Bp” (AOR 3.7). Combining these factors to form a severity index (SWAT-Bp) predicted mortality with high sensitivity and specificity (AUC: 0.867). Mortality for scores 0–5 was 0%, 3.3%, 7.4%, 29.2%, 61.5% and 87.5% respectively. A score ≥3 was 84% sensitive and 77% specific for mortality prediction, with a negative predictive value of 95.8%.
CRB-65 performs poorly in this population. The SWAT-Bp score can accurately stratify patients; ≤2 indicates non-severe infection (mortality 4.4%) and ≥3 severe illness (mortality 45%).
PMCID: PMC3855704  PMID: 24324763
19.  Risk Factors for Fatality among Confirmed Adult Dengue Inpatients in Singapore: A Matched Case-Control Study 
PLoS ONE  2013;8(11):e81060.
To identify demographic, clinical and laboratory risk factors for death due to dengue fever in adult patients in Singapore.
Multi-center retrospective study of hospitalized adult patients with confirmed dengue fever in Singapore between 1 January 2004 and 31 December 2008. Non-fatal controls were selected by matching age and year of infection with fatal cases. World Health Organization 1997, 2009 criteria were applied to define dengue hemorrhagic fever (DHF), warning signs and severe dengue. Statistical significance was assessed by conditional logistic regression modeling.
Significantly more fatal cases than matched controls had pre-existing co-morbid conditions, and presented with abdominal pain/tenderness. Median pulse rates were significantly higher while myalgia was significantly less frequent in cases. . Fatal cases also had higher leucocyte counts, platelet counts, serum sodium, potassium, urea, creatine and bilirubin levels on admission compared to controls. There was no statistical significant difference between the prevalence of DHF and hematocrit level among cases and controls. Multivariate analysis showed myalgia and leucocyte count at presentation were independent predictors of fatality (adjusted odds ratios 0.09 and 2.94 respectively). None of the controls was admitted to intensive care unit (ICU) or given blood transfusion, while 71.4% and 28.6% of fatal cases received ICU admission and blood transfusion.
Absence of myalgia and leucocytosis on admission were independently associated with fatality in our matched case-control study. Fatalities were also commonly associated with co-morbidities and clinicians should be alarmed if dengue patients fulfilled severe dengue case definition on admission.
PMCID: PMC3838336  PMID: 24278377
20.  Vitamin D Status and Community-Acquired Pneumonia: Results from the Third National Health and Nutrition Examination Survey 
PLoS ONE  2013;8(11):e81120.
To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] level and history of community-acquired pneumonia (CAP).
Patients and Methods
We identified 16,975 individuals (≥17 years) from the third National Health and Nutrition Examination Survey (NHANES III) with documented 25(OH)D levels. To investigate the association of 25(OH)D with history of CAP in these participants, we developed a multivariable logistic regression model, adjusting for demographic factors (age, sex, race, poverty-to-income ratio, and geographic location), clinical data (body mass index, smoking status, asthma, chronic obstructive pulmonary disease, congestive heart failure, diabetes mellitus, stroke, chronic kidney disease, neutropenia, and alcohol consumption), and season. Locally weighted scatterplot smoothing (LOWESS) was used to depict the relationship between increasing 25(OH)D levels and the cumulative frequency of CAP in the study cohort.
The median [interquartile range (IQR)] serum 25(OH)D level was 24 (IQR 18–32) ng/mL. 2.1% [95% confidence interval (CI): 1.9–2.3] of participants reported experiencing a CAP within one year of their participation in the national survey. After adjusting for demographic factors, clinical data, and season, 25(OH)D levels <30 ng/mL were associated with 56% higher odds of CAP [odds ratio 1.56; 95% confidence interval: 1.17–2.07] compared to levels ≥30 ng/mL. LOWESS analysis revealed a near linear relationship between vitamin D status and the cumulative frequency of CAP up to 25(OH)D levels around 30 ng/mL.
Among 16,975 participants in NHANES III, 25(OH)D levels were inversely associated with history of CAP. Randomized controlled trials are warranted to determine the effect of optimizing vitamin D status on the risk of CAP.
PMCID: PMC3829945  PMID: 24260547
22.  The Impact of Insurance Status on the Outcomes after Aneurysmal Subarachnoid Hemorrhage 
PLoS ONE  2013;8(10):e78047.
Investigation into the association of insurance status with the outcomes of patients undergoing neurosurgical intervention has been limited: this is the first nationwide study to analyze the impact of primary payer on the outcomes of patients with aneurysmal subarachnoid hemorrhage who underwent endovascular coiling or microsurgical clipping. The Nationwide Inpatient Sample (2001–2010) was utilized to identify patients; those with both an ICD-9 diagnosis codes for subarachnoid hemorrhage and a procedure code for aneurysm repair (either via an endovascular or surgical approach) were included. Hierarchical multivariate regression analyses were utilized to evaluate the impact of primary payer on in-hospital mortality, hospital discharge disposition, and length of hospital stay with hospital as the random effects variable. Models were adjusted for patient age, sex, race, comorbidities, socioeconomic status, hospital region, location (urban versus rural), and teaching status, procedural volume, year of admission, and the proportion of patients who underwent ventriculostomy. Subsequent models were also adjusted for time to aneurysm repair and time to ventriculostomy; subgroup analyses evaluated for those who underwent endovascular and surgical procedures separately. 15,557 hospitalizations were included. In the initial model, the adjusted odds of in-hospital mortality were higher for Medicare (OR 1.23, p<0.001), Medicaid (OR 1.23, p<0.001), and uninsured patients (OR 1.49, p<0.001) compared to those with private insurance. After also adjusting for timing of intervention, Medicaid and uninsured patients had a reduced odds of non-routine discharge (OR 0.75, p<0.001 and OR 0.42, p<0.001) despite longer hospital stays (by 8.35 days, p<0.001 and 2.45 days, p = 0.005). Variations in outcomes by primary payer–including in-hospital post-procedural mortality–were more pronounced for patients of all insurance types who underwent microsurgical clipping. The observed differences by primary payer are likely multifactorial, attributable to varied socioeconomic factors and the complexities of the American healthcare delivery system.
PMCID: PMC3812119  PMID: 24205085
23.  Prognostic Value of ICH Score and ICH-GS Score in Chinese Intracerebral Hemorrhage Patients: Analysis From the China National Stroke Registry (CNSR) 
PLoS ONE  2013;8(10):e77421.
No strongevidenceofefficacycurrently exists for different intracerebral hemorrhage (ICH) scoring system in predicting the prognosis of ICH in the Chinese population. This study aimed to test the accuracyof the ICH score and the ICH grading scale (ICH-GS) score in predicting the favorable prognosis in a large cohort of ICH patients in China.
This study was a multicenter, prospective cohort study. Patients diagnosed with ICH between September 2007 and August 2008 from the nationwide China National Stroke Registry (CNSR) databasewere screened andenrolled in this study. Demographics of the patients, treatments, mortalityas well as the clinic and radiologic findings of ICH were collected.AnICH score and anICH-GS score were evaluated for all the patients atadmission. Follow-ups were conducted by phone at 3, 6 and 12 months after ICH onset. The modified Rankin scale (mRS) score was used to evaluate favorable functional outcome and was obtained at hospital dischargeand duringthe 3-, 6- and 12-month follow-up visits.
There were 410 (12.6%) in-hospitalmortalityout of a total of 3,255 ICH patients. Thevalues of the Area Under Curve (AUC)at discharge, 3-, 6- and 12-month follow-up for ICH score were 0.72, 0.76, 0.76 and 0.75, respectively; whilethe numbers for the ICH-GS score were 0.71, 0.77, 0.78 and 0.78, respectively. At 6-month and 12-month follow-up, the ICH-GS score presented a significant better value in predicting favorable prognosis than did the ICH score (P=0.0003 and <0.0001, respectively).
Both the ICH and ICH-GS scores were effective inaccurately predicting the favorable functional outcome of ICH in the Chinese population. For mid-term and long-term prediction, the ICH-GS score was superiorover the ICH score.
PMCID: PMC3797805  PMID: 24146993
24.  The Impact of Nationwide Education Program on Clinical Practice in Sepsis Care and Mortality of Severe Sepsis: A Population-Based Study in Taiwan 
PLoS ONE  2013;8(10):e77414.
We investigated the effect of a nationwide educational program following surviving sepsis campaign (SSC) guidelines. Physicians’ clinical practice in sepsis care and patient mortality rate for severe sepsis were analyzed using a nationally representative cohort.
Hospitalizations for severe sepsis with organ failure from 1997 to 2008 were extracted from Taiwan’s National Health Insurance Research Database (NHIRD), and trends in sepsis incidence and mortality rates were analyzed. A before-and-after study design was used to evaluate changes in the utilization rates of SSC items and changes in severe sepsis mortality rates occurred after a national education program conducted by the Joint Taiwan Critical Care Medicine Committee since 2004. A total of 39,706 hospitalizations were analyzed, which consisted of a pre-intervention cohort of 14,848 individuals (2000-2003) and a post-intervention cohort of 24,858 individuals (2005-2008).
The incidence rate of severe sepsis increased from 1.88 per 1,000 individuals in 1997 to 5.07 per 1,000 individuals in 2008. The cumulative mortality rate decreased slightly from 48.2% for the pre-intervention cohort to 45.9% for the post-intervention cohort. The utilization rates of almost all SSC items changed significantly between the pre-intervention and post-intervention cohorts. These changes of utilization rates were found to be associated with mild reduction in mortality rate.
The nationwide education program through a national professional society has a significant impact on physicians’ clinical practice and resulted in a slight but significant reduction of severe sepsis mortality rate.
PMCID: PMC3790748  PMID: 24124616
25.  Hypertonic Saline Solution Drives Neutrophil from Bystander Organ to Infectious Site in Polymicrobial Sepsis: A Cecal Ligation and Puncture Model 
PLoS ONE  2013;8(9):e74369.
The effects of hypertonic saline solution (HSS) have been shown in several animal models of ischemia and shock. Literature has shown potential benefits of HSS modulating inflammatory response after sepsis in an animal model. We studied the HSS effects in sepsis through cecal ligation and puncture (CLP) in Balb-C mice. Groups studied: 1- CLP without treatment (CLP-C); 2- CLP treated with normal saline solution NaCl 0.9% – 34 ml/Kg (CLP-S); 3- CLP treated with HSS NaCl 7.5% – 4 ml/Kg (CLP-H); and 4- group (Basal) without no CLP or treatment. Volume infusion was always applied 30 min after CLP. Lung and peritoneal lavage were harvested after 6h and 24h of CLP to analyze cytokines amount, oxide nitric, lipid peroxidation and neutrophil infiltration. Neutrophil infiltration, ICAM-1, CXCR-2, and CXCL-1 in lung were reduced by HSS (CLP-H) compared to CLP-C or CLP-S. Neutrophil in peritoneal lavage was increased in 24h with HSS (CLP-H) compared to CLP and CLP-S. Peritoneal CXCR-2 was increased in CLP-C and CLP-S but presented a lower increase with HSS (CLP-H) after 6 hours. GRK-2 presented difference among the groups at 24 h, showing a profile similar to neutrophil infiltration. Pro-inflammatory cytokines (TNF-α and IL-6) were reduced by HSS treatment; CLP-S increased TNF-α. IL-10 was increased in lung tissue by the HSS treatment. The oxidative stress (TBARS and nitric oxide biochemistry markers) was reduced with HSS. Animal survival was 33.3% in CLP-C group, 46.6% in CLP-S group and 60% in the CLP-H group after the sixth day. The HSS protects the animal against sepsis. Our results suggest that the volume replacement modulate pro and anti-inflammatory mediators of an inflammatory response, but HSS presented a more effective and potent effect.
PMCID: PMC3775765  PMID: 24069301

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