Impacto de la edad, las comorbilidades y las complicaciones en pacientes con COVID-19 con síndrome de dificultad respiratoria aguda en la ventilación mecánica invasiva. Estudio multicéntrico observacional / Impact of Age, Comorbidities and Complications in COVID-19 Patients with Acute Respiratory Distress Syndrome on Invasive Mechanical Ventilation. An Observational Multicenter Study

Objetivos: Millones de pacientes con COVID-19 fueron internados en terapia intensiva en el mundo, la mitad desarrollaron síndrome de dificultad respiratoria aguda (SDRA) y recibieron ventilación mecánica invasiva (VMI), con una mortalidad del 50%. Analiza-mos cómo edad, comorbilidades y complicaciones, en pacientes con COVID-19 y SDRA que recibieron VMI, se asociaron con el riesgo de morir durante su hospitalización.Métodos: Estudio de cohorte observacional, retrospectivo y multicéntrico realizado en 5 hospitales (tres privados y dos públicos universitarios) de Argentina y Chile, durante el segundo semestre de 2020.Se incluyeron pacientes >18 años con infección por SARS-CoV-2 confirmada RT-PCR, que desarrollaron SDRA y fueron asistidos con VMI durante >48 horas, durante el se-gundo semestre de 2020. Se analizaron los antecedentes, las comorbilidades más fre-cuentes (obesidad, diabetes e hipertensión), y las complicaciones shock, insuficiencia renal aguda (IRA) y neumonía asociada a la ventilación mecánica (NAV), por un lado, y las alteraciones de parámetros clínicos y de laboratorio registrados.Resultados: El 69% era varón. La incidencia de comorbilidades difirió para los diferentes grupos de edad. La mortalidad aumentó significativamente con la edad (p<0,00001). Las comorbilidades, hipertensión y diabetes, y las complicaciones de IRA y shock se asociaron significativamente con la mortalidad. En el análisis multivariado, sólo la edad mayor de 60 años, la IRA y el shock permanecieron asociados con la mortalidad. Conclusiones: El SDRA en COVID-19 es más común entre los mayores. Solo la edad >60 años, el shock y la IRA se asociaron a la mortalidad en el análisis multivariado.

Objectives: Millions of patients with COVID-19 were admitted to intensive care world-wide, half developed acute respiratory distress syndrome (ARDS) and received invasive mechanical ventilation (IMV), with a mortality of 50%. We analyzed how age, comor-bidities and complications in patients with COVID-19 and ARDS who received IMV were associated with the risk of dying during their hospitalization.Methods: Observational, retrospective and multicenter cohort study carried out in 5 hospitals (three private and two public university hospitals) in Argentina and Chile, during the second half of 2020.Patients >18 years of age with SARS-CoV-2 infection confirmed by RT-PCR, who devel-oped ARDS and were assisted with IMV for >48 hours, during the second half of 2020, were included. History, the most frequent comorbidities (obesity, diabetes and hyper-tension) and the complications of shock, acute renal failure (AKI) and pneumonia as-sociated with mechanical ventilation (VAP), on the one hand, and the alterations of re-corded clinical and laboratory parameters, were analyzed.Results: 69% were men. The incidence of comorbidities differed for different age groups. Mortality increased significantly with age (p<0.00001). Comorbidities, hyper-tension and diabetes, and complications of ARF and shock were significantly associat-ed with mortality. In the multivariate analysis, only age over 60 years, ARF and shock remained associated with mortality.Conclusions: ARDS in COVID-19 is more common among the elderly. Only age >60 years, shock and ARF were associated with mortality in the multivariate analysis

The Predictive Validity of the Berlin Definition of Acute Respiratory Distress Syndrome for Patients With COVID-19-Related Respiratory Failure Treated With High-Flow Nasal Oxygen: A Multicenter, Prospective Cohort Study.

OBJECTIVES: The Berlin definition of acute respiratory distress syndrome (ARDS) was constructed for patients receiving invasive mechanical ventilation (IMV) with consideration given to issues related to reliability, feasibility, and validity. Notwithstanding, patients with acute respiratory failure (ARF) may be treated with high-flow nasal oxygen (HFNO) and may not fall within the scope of the original definition. We aimed to evaluate the predictive validity of the Berlin definition in HFNO-treated patients with COVID-19-related respiratory failure who otherwise met ARDS criteria. DESIGN: Multicenter, prospective cohort study. SETTING: Five ICUs of five centers in Argentina from March 2020 to September 2021. PATIENTS: We consecutively included HFNO-treated patients older than 18 years with confirmed COVID-19-related ARF, a Pa o2 /F io2 of less than 300 mm Hg, bilateral infiltrates on imaging, and worsening respiratory symptoms for less than 1 week. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the predictive validity of mortality at day 28 using the area under the receiver operating characteristics curve (AUC), compared the predictive validity across subgroups, and characterized relevant clinical outcomes. We screened 1,231 patients and included 696 ARDS patients [30 (4%) mild, 380 (55%) moderate, and 286 (41%) severe]. For the study cohort, the AUC for mortality at day 28 was 0.606 (95% CI, 0.561-0.651) with the AUC for subgroups being similar to that of the overall cohort. Two hundred fifty-six patients (37%) received IMV. By day 28, 142 patients (21%) had died, of whom 81 (57%) had severe ARDS. Mortality occurred primarily in patients who were transitioned to IMV. CONCLUSIONS: The predictive validity of the Berlin ARDS definition was similar for HFNO-treated patients as compared with the original population of invasively ventilated patients. Our findings support the extension of the Berlin definition to HFNO-treated patients with ARDS.

Evaluation of the Kinetics of Pancreatic Stone Protein as a Predictor of Ventilator-Associated Pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a severe condition. Early and adequate antibiotic treatment is the most important strategy for improving prognosis. Pancreatic Stone Protein (PSP) has been described as a biomarker that increases values 3-4 days before the clinical diagnosis of nosocomial sepsis in different clinical settings. We hypothesized that serial measures of PSP and its kinetics allow for an early diagnosis of VAP. METHODS: The BioVAP study was a prospective observational study designed to evaluate the role of biomarker dynamics in the diagnosis of VAP. To determine the association between repeatedly measured PSP and the risk of VAP, we used joint models for longitudinal and time-to-event data. RESULTS: Of 209 patients, 43 (20.6%) patients developed VAP, with a median time of 4 days. Multivariate joint models with PSP, CRP, and PCT did not show an association between biomarkers and VAP for the daily absolute value, with a hazard ratio (HR) for PSP of 1.01 (95% credible interval: 0.97 to 1.05), for CRP of 1.00 (0.83 to 1.22), and for PCT of 0.95 (0.82 to 1.08). The daily change of biomarkers provided similar results, with an HR for PSP of 1.15 (0.94 to 1.41), for CRP of 0.76 (0.35 to 1.58), and for PCT of 0.77 (0.40 to 1.45). CONCLUSION: Neither absolute PSP values nor PSP kinetics alone nor in combination with other biomarkers were useful in improving the prediction diagnosis accuracy in patients with VAP. CLINICAL TRIAL REGISTRATION: Registered retrospectively on August 3rd, 2012. NCT02078999.

European Network for ICU-Related Respiratory Infections (ENIRRIs): a multinational, prospective, cohort study of nosocomial LRTI.

PURPOSE: Lower respiratory tract infections (LRTI) are the most frequent infectious complication in patients admitted to the intensive care unit (ICU). We aim to report the clinical characteristics of ICU-admitted patients due to nosocomial LRTI and to describe their microbiology and clinical outcomes. METHODS: A prospective observational study was conducted in 13 countries over two continents from 9th May 2016 until 16th August 2019. Characteristics and outcomes of ventilator-associated pneumonia (VAP), ventilator-associated tracheobronchitis (VAT), ICU hospital-acquired pneumonia (ICU-HAP), HAP that required invasive ventilation (VHAP), and HAP in patients transferred to the ICU without invasive mechanical ventilation were collected. The clinical diagnosis and treatments were per clinical practice and not per protocol. Descriptive statistics were used to compare the study groups. RESULTS: 1060 patients with LRTI (72.5% male sex, median age 64 [50-74] years) were included in the study; 160 (15.1%) developed VAT, 556 (52.5%) VAP, 98 (9.2%) ICU-HAP, 152 (14.3%) HAP, and 94 (8.9%) VHAP. Patients with VHAP had higher serum procalcitonin (PCT) and Sequential Organ Failure Assessment (SOFA) scores. Patients with VAP or VHAP developed acute kidney injury, acute respiratory distress syndrome, multiple organ failure, or septic shock more often. One thousand eight patients had microbiological samples, and 711 (70.5%) had etiological microbiology identified. The most common microorganisms were Pseudomonas aeruginosa (18.4%) and Klebsiella spp (14.4%). In 382 patients (36%), the causative pathogen shows some antimicrobial resistance pattern. ICU, hospital and 28-day mortality were 30.8%, 37.5% and 27.5%, respectively. Patients with VHAP had the highest ICU, in-hospital and 28-day mortality rates. CONCLUSION: VHAP patients presented the highest mortality among those admitted to the ICU. Multidrug-resistant pathogens frequently cause nosocomial LRTI in this multinational cohort study.

Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS: a propensity score analysis.

BACKGROUND: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. METHODS: We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. RESULTS: Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0-25) and 25 (IQR 7-26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0-87) and 87 (IQR 0-88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177). CONCLUSIONS: In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.

Effectiveness of rAd26-rAd5, ChAdOx1 nCoV-19, and BBIBP-CorV vaccines for risk of infection with SARS-CoV-2 and death due to COVID-19 in people older than 60 years in Argentina: a test-negative, case-control, and retrospective longitudinal study.

BACKGROUND: In January, 2021, a vaccination campaign against COVID-19 was initiated with the rAd26-rAd5, ChAdOx1 nCoV-19, and BBIBP-CorV vaccines in Argentina. The objective of this study was to estimate vaccine effectiveness at reducing risk of SARS-CoV-2 infection and COVID-19 deaths in people older than 60 years. METHODS: In this test-negative, case-control, and retrospective longitudinal study done in Argentina, we evaluated the effectiveness of three vaccines (rAd26-rAd5, ChAdOx1 nCoV-19, and BBIBP-CorV) on SARS-CoV-2 infection and risk of death in people with RT-PCR confirmed COVID-19, using data from the National Surveillance System (SNVS 2.0). All individuals aged 60 years or older reported to SNVS 2.0 as being suspected to have COVID-19 who had disease status confirmed with RT-PCR were included in the study. Unvaccinated individuals could participate in any of the analyses. People with suspected COVID-19 who developed symptoms before the start of the implementation of the vaccination programme for their age group or district were excluded from the study. The odds ratio of SARS-CoV-2 infection was evaluated by logistic regression and the risk of death in individuals with RT-PCR confirmed COVID-19 was evaluated by proportional hazard regression models, adjusted for possible confounders: age at the time of the symptom onset date, sex, district of residence, epidemiological week corresponding to the symptom onset date, and history of COVID-19. The estimation of vaccine effectiveness to prevent death due to COVID-19 was done indirectly by combining infection and death estimates. In addition, we evaluated the effect of the first dose of viral vector vaccines across time. FINDINGS: From Jan 31, to Sept 14, 2021, 1 282 928 individuals were included, of whom 687 167 (53·6%) were in the rAd26-rAd5 analysis, 358 431 (27·6%) in the ChAdOx1 nCoV-19 analysis, and 237 330 (18·5%) in the BBIBP-CorV analysis. Vaccine effectiveness after two doses was high for all three vaccines, adjusted odds ratio 0·36 (95% CI 0·35-0·37) for rAd26-rAd5, 0·32 (0·31-0·33) for ChAdOx1 nCoV-19, and 0·56 (0·55-0·58) for BBIBP-CorV. After two doses, the effect on deaths was higher than that on risk of infection: adjusted hazard ratio 0·19 (95% CI 0·18-0·21) for rAd26-rAd5, 0·20 (0·18-0·22) for ChAdOx1 nCoV-19, and 0·27 (0·25-0·29) for BBIBP-CorV. The indirectly estimated effectiveness on deaths was 93·1% (95% CI 92·6-93·5) for rAd26-rAd5, 93·7% (93·2-94·3) for ChAdOx1 nCoV-19, and 85·0% (84·0-86·0) for BBIBP-CorV following two doses. First dose effect of viral vector vaccines remained stable over time. INTERPRETATION: The vaccines used in Argentina showed effectiveness in reducing infection and death by SARS-CoV-2 and COVID-19. FUNDING: None.

Perioperative Continuous Noninvasive Cardiac Output Monitoring in Cardiac Surgery Patients by a Novel Capnodynamic Method.

OBJECTIVES: To test the clinical performance of a novel continuous noninvasive cardiac output (CO) monitoring based on expired carbon dioxide kinetics in cardiac surgery patients. DESIGN: A prospective feasibility pragmatic clinical study. SETTING: A single-center, large community hospital. PARTICIPANTS: Thirty-two patients undergoing cardiac surgery were studied during the intraoperative (before cardiopulmonary bypass) and postoperative (in the intensive care unit before extubation) periods. INTERVENTIONS: CO was measured simultaneously by the continuous capnodynamic method and by transpulmonary thermodilution during changes in the patient's hemodynamic and/or respiratory conditions. MEASUREMENTS AND MAIN RESULTS: The current recommended comparative statistics for CO measurement methods were analyzed, including bias, precision, and percentage error obtained from Bland-Altman analysis, and concordance between methods obtained from the four-quadrant plot analysis to evaluate the trending ability. Bias ± limits of agreement and percentage error were -0.6 (-1.9 to +0.8; 95% CI of 3.73-5.25) L/min and 31% (n = 147 measurements) for the intraoperative period, -0.8 (-2.4 to +0.9; 95% CI of 3.03-5.21) L/min and 41% (n = 66) for the postoperative period, and -0.6 (-2.1 to +0.8; 95% CI of 3.74-5.00) L/min and 34% (n = 213) for the pooled data. The trending analysis obtained a concordance of 82% (n = 65) for the intraoperative and 71% (n = 24) for the early postoperative periods. Aggregation of both data sets gave a concordance of 79% (n = 89). CONCLUSIONS: The continuous capnodynamic method was reliable and in good agreement with the reference method, and had an accuracy and trending ability good enough to make it a possible future alternative for hemodynamic monitoring in the studied population of elective adult cardiac surgery patients.

Impact of exposure time in awake prone positioning on clinical outcomes of patients with COVID-19-related acute respiratory failure treated with high-flow nasal oxygen: a multicenter cohort study.

BACKGROUND: In patients with COVID-19-related acute respiratory failure (ARF), awake prone positioning (AW-PP) reduces the need for intubation in patients treated with high-flow nasal oxygen (HFNO). However, the effects of different exposure times on clinical outcomes remain unclear. We evaluated the effect of AW-PP on the risk of endotracheal intubation and in-hospital mortality in patients with COVID-19-related ARF treated with HFNO and analyzed the effects of different exposure times to AW-PP. METHODS: This multicenter prospective cohort study in six ICUs of 6 centers in Argentine consecutively included patients > 18 years of age with confirmed COVID-19-related ARF requiring HFNO from June 2020 to January 2021. In the primary analysis, the main exposure was awake prone positioning for at least 6 h/day, compared to non-prone positioning (NON-PP). In the sensitivity analysis, exposure was based on the number of hours receiving AW-PP. Inverse probability weighting-propensity score (IPW-PS) was used to adjust the conditional probability of treatment assignment. The primary outcome was endotracheal intubation (ETI); and the secondary outcome was hospital mortality. RESULTS: During the study period, 580 patients were screened and 335 were included; 187 (56%) tolerated AW-PP for [median (p25-75)] 12 (9-16) h/day and 148 (44%) served as controls. The IPW-propensity analysis showed standardized differences < 0.1 in all the variables assessed. After adjusting for other confounders, the OR (95% CI) for ETI in the AW-PP group was 0.36 (0.2-0.7), with a progressive reduction in OR as the exposure to AW-PP increased. The adjusted OR (95% CI) for hospital mortality in the AW-PP group ≥ 6 h/day was 0.47 (0.19-1.31). The exposure to prone positioning ≥ 8 h/d resulted in a further reduction in OR [0.37 (0.17-0.8)]. CONCLUSION: In the study population, AW-PP for ≥ 6 h/day reduced the risk of endotracheal intubation, and exposure ≥ 8 h/d reduced the risk of hospital mortality.

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.

BACKGROUND: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials. METHODS: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. RESULTS: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.).

Association between sepsis at ICU admission and mortality in patients with ICU-acquired pneumonia: An infectious second-hit model.

PURPOSE: We explore the hypothesis that critically ill patients developing ICU-acquired pneumonia (ICU-AP) have worse outcomes and an altered inflammatory response if their ICU admission was sepsis-related. METHODS: Prospective cohort study in two centers. Patients with ICU-AP were evaluated according to their previous exposure to sepsis at ICU-admission. Demographic variables, comorbidities, severity scores at admission and at the time of acquisition of ICU-AP, and serum biomarkers of the inflammatory response were evaluated. PRIMARY OUTCOME: 90-day mortality. SECONDARY OUTCOMES: ICU and hospital length of stay, mortality at days 28 and 180, in-hospital mortality, ventilator-free days (day-28), and inflammatory response. Propensity scoring weighted the risk of previously-acquired sepsis. Multivariate analysis evaluated the risk of mortality by day-90. Sensitivity analyses evaluated the primary outcome in different subgroups. RESULTS: Of 341 patients enrolled, 147 had sepsis on ICU-admission. Adjusted risk of mortality at 90 days did not differ overall [hazard ratio (HR) = 0.94(CI:0.65-1.37)], nor in subpopulations with a confirmed etiology of pneumonia [HR = 0.93(CI:0.57-1.53)] or sepsis [HR = 0.91(0.54-1.55)], ventilator-associated pneumonia (VAP) [HR = 1.01(CI:0.61-1.68)], nor non-VAP ICU-AP [HR = 0.83(CI:0.40-1.71)]. No differences were found in clinical secondary outcomes, the inflammatory response was similar. CONCLUSIONS: Previous sepsis does not appear to predispose to higher mortality nor worse outcomes in patients who develop ICU-acquired pneumonia.

Biomarkers kinetics in the assessment of ventilator-associated pneumonia response to antibiotics - results from the BioVAP study.

PURPOSE: Our aim was to evaluate the role of biomarker kinetics in the assessment of ventilator-associated pneumonia (VAP) response to antibiotics. MATERIALS AND METHODS: We performed a prospective, multicenter, observational study to evaluate in 37 microbiologically documented VAP, the kinetics of C-reactive protein (CRP), procalcitonin (PCT), mid-region fragment of pro-adrenomedullin (MR-proADM). The kinetics of each variable, from day 1 to 6 of therapy, was assessed with a time dependent analysis comparing survivors and non-survivors. RESULTS: During the study period kinetics of CRP as well as its relative changes, CRP-ratio, was significantly different between survivors and non-survivors (p=0.026 and p=0.005, respectively). On day 4 of antibiotic therapy, CRP of survivors was 47% of the initial value while it was 96% in non-survivors. The kinetics of other studied variables did not distinguish between survivors and non-survivors. In survivors the bacterial load also decreased markedly. Adequate initial antibiotic therapy was associated with lower mortality (p=0.025) and faster CRP decrease (p=0.029). CONCLUSIONS: C-reactive protein kinetics can be used to identify VAP patients with poor outcome as soon as four days after the initiation of treatment. (Trial registration - NCT02078999; registered 3 August 2012).

Intensive care unit-acquired pneumonia due to Pseudomonas aeruginosa with and without multidrug resistance.

OBJECTIVE: Pseudomonas aeruginosa often presents multi-drug resistance (MDR) in intensive care unit (ICU)-acquired pneumonia (ICUAP), possibly resulting in inappropriate empiric treatment and worse outcomes. We aimed to identify patients with ICUAP at risk for these pathogens in order to improve treatment selection and outcomes. METHODS: We prospectively assessed 222 consecutive immunocompetent ICUAP patients confirmed microbiologically. We determined the characteristics, risk factors, systemic inflammatory response and outcomes of P. aeruginosa pneumonia (Pa-ICUAP), compared to other aetiologies. We also compared patients with MDR vs. non-MDR Pa-ICUAP. RESULTS: Pseudomonas aeruginosa was the most frequent aetiology (64, 29%); 22 (34%) cases had MDR. Independent predictors for Pa-ICUAP were prior airway colonization by P. aeruginosa, previous antibiotic treatment, solid cancer and shock; alcohol abuse and pleural effusion were independently associated to lower risk for Pa-ICUAP. Chronic liver disease independently predicted MDR among Pa-ICUAP. The inflammatory biomarkers were similar between all groups. Patients with Pa-ICUAP had lower unadjusted 90-day survival (p = 0.049). However, the 90-day survival adjusted for confounding factors using a propensity score did not differ between all groups. CONCLUSION: Pseudomonas aeruginosa remains the most frequent aetiology of ICUAP, with high prevalence of MDR. These risk factors should be taken into account to avoid inappropriate empiric antibiotics for Pa-ICUAP. Pseudomonas aeruginosa, regardless multidrug resistance, was not associated with different propensity-adjusted survival.

Biomarker kinetics in the prediction of VAP diagnosis: results from the BioVAP study.

BACKGROUND: Prediction of diagnosis of ventilator-associated pneumonia (VAP) remains difficult. Our aim was to assess the value of biomarker kinetics in VAP prediction. METHODS: We performed a prospective, multicenter, observational study to evaluate predictive accuracy of biomarker kinetics, namely C-reactive protein (CRP), procalcitonin (PCT), mid-region fragment of pro-adrenomedullin (MR-proADM), for VAP management in 211 patients receiving mechanical ventilation for >72 h. For the present analysis, we assessed all (N = 138) mechanically ventilated patients without an infection at admission. The kinetics of each variable, from day 1 to day 6 of mechanical ventilation, was assessed with each variable's slopes (rate of biomarker change per day), highest level and maximum amplitude of variation (Δ (max)). RESULTS: A total of 35 patients (25.4 %) developed a VAP and were compared with 70 non-infected controls (50.7 %). We excluded 33 patients (23.9 %) who developed a non-VAP nosocomial infection. Among the studied biomarkers, CRP and CRP ratio showed the best performance in VAP prediction. The slope of CRP change over time (adjusted odds ratio [aOR] 1.624, confidence interval [CI]95% [1.206, 2.189], p = 0.001), the highest CRP ratio concentration (aOR 1.202, CI95% [1.061, 1.363], p = 0.004) and Δ (max) CRP (aOR 1.139, CI95% [1.039, 1.248], p = 0.006), during the first 6 days of mechanical ventilation, were all significantly associated with VAP development. Both PCT and MR-proADM showed a poor predictive performance as well as temperature and white cell count. CONCLUSIONS: Our results suggest that in patients under mechanical ventilation, daily CRP monitoring was useful in VAP prediction. Trial registration NCT02078999.

Real-time images of tidal recruitment using lung ultrasound.

BACKGROUND: Ventilator-induced lung injury is a form of mechanical damage leading to a pulmonary inflammatory response related to the use of mechanical ventilation enhanced by the presence of atelectasis. One proposed mechanism of this injury is the repetitive opening and closing of collapsed alveoli and small airways within these atelectatic areas-a phenomenon called tidal recruitment. The presence of tidal recruitment is difficult to detect, even with high-resolution images of the lungs like CT scan. The purpose of this article is to give evidence of tidal recruitment by lung ultrasound. FINDINGS: A standard lung ultrasound inspection detected lung zones of atelectasis in mechanically ventilated patients. With a linear probe placed in the intercostal oblique position. We observed tidal recruitment within atelectasis as an improvement in aeration at the end of inspiration followed by the re-collapse at the end of expiration. This mechanism disappeared after the performance of a lung recruitment maneuver. CONCLUSIONS: Lung ultrasound was helpful in detecting the presence of atelectasis and tidal recruitment and in confirming their resolution after a lung recruitment maneuver.

Endotracheal tube biofilm translocation in the lateral Trendelenburg position.

INTRODUCTION: Laboratory studies demonstrated that the lateral Trendelenburg position (LTP) is superior to the semirecumbent position (SRP) in the prevention of ventilator-associated pulmonary infections. We assessed whether the LTP could also prevent pulmonary colonization and infections caused by an endotracheal tube (ETT) biofilm. METHODS: Eighteen pigs were intubated with ETTs colonized by Pseudomonas aeruginosa biofilm. Pigs were positioned in LTP and randomized to be on mechanical ventilatin (MV) up to 24 hour, 48 hour, 48 hour with acute lung injury (ALI) by oleic acid and 72 hour. Bacteriologic and microscopy studies confirmed presence of biofilm within the ETT. Upon autopsy, samples from the proximal and distal airways were excised for P.aeruginosa quantification. Ventilator-associated tracheobronchitis (VAT) was confirmed by bronchial tissue culture ≥3 log colony forming units per gram (cfu/g). In pulmonary lobes with gross findings of pneumonia, ventilator-associated pneumonia (VAP) was confirmed by lung tissue culture ≥3 log cfu/g. RESULTS: P.aeruginosa colonized the internal lumen of 16 out of 18 ETTs (88.89%), and a mature biofilm was consistently present. P.aeruginosa colonization did not differ among groups, and was found in 23.6% of samples from the proximal airways, and in 7.1% from the distal bronchi (P = 0.001). Animals of the 24 hour group never developed respiratory infections, whereas 20%, 60% and 25% of the animals in group 48 hour, 48 hour-ALI and 72 hour developed P.aeruginosa VAT, respectively (P = 0.327). Nevertheless, VAP never developed. CONCLUSIONS: Our findings imply that during the course of invasive MV up to 72 hour, an ETT P.aeruginosa biofilm hastily colonizes the respiratory tract. Yet, the LTP compartmentalizes colonization and infection within the proximal airways and VAP never develops.

Gravity predominates over ventilatory pattern in the prevention of ventilator-associated pneumonia.

OBJECTIVE: In the semirecumbent position, gravity-dependent dissemination of pathogens has been implicated in the pathogenesis of ventilator-associated pneumonia. We compared the preventive effects of a ventilatory strategy, aimed at decreasing pulmonary aspiration and enhancing mucus clearance versus the Trendelenburg position. DESIGN: Prospective randomized animal study. SETTING: Animal research facility, University of Barcelona, Spain. SUBJECTS: Twenty-four Large White-Landrace pigs. INTERVENTIONS: Pigs were intubated and on mechanical ventilation for 72 hours. Following surgical preparation, pigs were randomized to be positioned: 1) in semirecumbent/prone position, ventilated with a duty cycle (TITTOT) of 0.33 and without positive end-expiratory pressure (control); 2) as in the control group, positive end-expiratory pressure of 5 cm H2O and TITTOT to achieve a mean expiratory-inspiratory flow bias of 10 L/min (treatment); 3) in Trendelenburg/prone position and ventilated as in the control group (Trendelenburg). Following randomization, Pseudomonas aeruginosa was instilled into the oropharynx. MEASUREMENTS AND MAIN RESULTS: Mucus clearance rate was measured through fluoroscopic tracking of tracheal markers. Microspheres were instilled into the subglottic trachea to assess pulmonary aspiration. Ventilator-associated pneumonia was confirmed by histological/microbiological studies. The mean expiratory-inspiratory flow in the treatment, control, and Trendelenburg groups were 10.7 ± 1.7, 1.8 ± 3.7 and 4.3 ± 2.8 L/min, respectively (p < 0.001). Mucus clearance rate was 11.3 ± 9.9 mm/min in the Trendelenburg group versus 0.1 ± 1.0 in the control and 0.2 ± 1.0 in the treatment groups (p = 0.002). In the control group, we recovered 1.35% ± 1.24% of the instilled microspheres per gram of tracheal secretions, whereas 0.22% ± 0.25% and 0.97% ± 1.44% were recovered in the treatment and Trendelenburg groups, respectively (p = 0.031). Ventilator-associated pneumonia developed in 66.67%, 85.71%, and 0% of the animals in the control, treatment, and Trendelenburg groups (p < 0.001). CONCLUSIONS: The Trendelenburg position predominates over expiratory flow bias and positive end-expiratory pressure in the prevention of gravity-dependent translocation of oropharyngeal pathogens and development of ventilator-associated pneumonia. These findings further substantiate the primary role of gravity in the pathogenesis of ventilator-associated pneumonia.

A novel porcine model of ventilator-associated pneumonia caused by oropharyngeal challenge with Pseudomonas aeruginosa.

BACKGROUND: Animal models of ventilator-associated pneumonia (VAP) in primates, sheep, and pigs differ in the underlying pulmonary injury, etiology, bacterial inoculation methods, and time to onset. The most common ovine and porcine models do not reproduce the primary pathogenic mechanism of the disease, through the aspiration of oropharyngeal pathogens, or the most prevalent human etiology. Herein the authors characterize a novel porcine model of VAP due to aspiration of oropharyngeal secretions colonized by Pseudomonas aeruginosa. METHODS: Ten healthy pigs were intubated, positioned in anti-Trendelenburg, and mechanically ventilated for 72 h. Three animals did not receive bacterial challenge, whereas in seven animals, a P. aeruginosa suspension was instilled into the oropharynx. Tracheal aspirates were cultured and respiratory mechanics were recorded. On autopsy, lobar samples were obtained to corroborate VAP through microbiological and histological studies. RESULTS: In animals not challenged, diverse bacterial colonization of the airways was found and monolobar VAP rarely developed. In animals with P. aeruginosa challenge, colonization of tracheal secretion increased up to 6.39 ± 0.34 log colony-forming unit (cfu)/ml (P < 0.001). VAP was confirmed in six of seven pigs, in 78% of the cases developed in the dependent lung segments (right medium and lower lobes, P = 0.032). The static respiratory system elastance worsened to 41.5 ± 5.8 cm H2O/l (P = 0.001). CONCLUSIONS: The authors devised a VAP model caused by aspiration of oropharyngeal P. aeruginosa, a frequent causative pathogen of human VAP. The model also overcomes the practical and legislative limitations associated with the use of primates. The authors' model could be employed to study pathophysiologic mechanisms, as well as novel diagnostic/preventive strategies.

Importance of Aspergillus spp. isolation in Acute exacerbations of severe COPD: prevalence, factors and follow-up: the FUNGI-COPD study.

BACKGROUND: Acute exacerbations of COPD (AECOPD) are often associated with infectious agents, some of which may be non-usual, including Aspergillus spp. However, the importance of Aspergillus spp. in the clinical management of AECOPD still remains unclear. OBJECTIVES: The aims of the study were to analyze the prevalence and risk factors associated with Aspergillus spp. isolation in AECOPD, and to investigate the associated clinical outcomes during a 1-year follow-up period. METHODS: Patients presenting with an AECOPD requiring hospitalization were prospectively included from four hospitals across Spain. Clinical, radiological and microbiological data were collected at admission and during the follow-up period (1, 6 and 12 months after discharge), and re-admissions and mortality data collected during the follow-up. RESULTS: A total of 240 patients with severe AECOPD were included. Valid sputum samples were obtained in 144 (58%) patients, and in this group, the prevalence of Aspergillus spp. isolation was 16.6% on admission and 14.1% at one-year follow-up. Multivariate logistic-regression showed that AECOPD in the previous year (OR 12.35; 95% CI, 1.9-29.1; p < 0.001), concurrent isolation of pathogenic bacteria (OR 3.64; 95% CI 1.65-9.45, p = 0.001) and concomitant isolation of Pseudomonas aeruginosa (OR 2.80; 95% IC, 1.81-11.42; p = 0.001) were the main risk factors for Aspergillus spp. isolation. CONCLUSIONS: The main risk factors for Aspergillus spp. isolation were AECOPD in the previous year and concomitant isolation of Pseudomonas aeruginosa. However, although Aspergillus spp. is often isolated in sputum samples from patients with AECOPD, the pathogenic and clinical significance remains unclear.

Assessment of severity of ICU-acquired pneumonia and association with etiology.

OBJECTIVES: We evaluated the association between severity of illness and microbial etiology of ICU-acquired pneumonia to define if severity should be used to guide empiric antibiotic choices. DESIGN: Prospective observational study. SETTING: ICUs of a university hospital. PATIENTS: Three hundredy forty-three consecutive patients with ICU-acquired pneumonia clustered, according to the presence of multidrug resistant pathogens. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred eight patients had ventilator-associated pneumonia and 135 had nonventilator ICU-acquired pneumonia. We determined etiology in 217 patients (63%). The most frequent pathogens were Pseudomonas aeruginosa, Enterobacteriaceae, and methicillin-sensitive and methicillin-resistant Staphylococcus aureus. Fifty-eight patients (17%) had a multidrug-resistant causative agent. Except for a longer ICU stay and a higher rate of microbial persistence at the end of the treatment in the multidrug-resistant group, no differences were found in clinical and inflammatory characteristics, severity criteria, and mortality or survival between patients with and without multidrug-resistant pathogens, even after adjusting for potential confounders. Patients with higher severity scores (Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment) and septic shock at onset of pneumonia had significantly lower 28- and 90-day survival and higher systemic inflammatory response. The results were similar when only patients with microbial diagnosis were considered, as well as when stratified into ventilator-associated pneumonia and nonventilator ICU-acquired pneumonia. CONCLUSIONS: In patients with ICU-acquired pneumonia, severity of illness seems not to affect etiology. Risk factors for multidrug resistant, but not severity of illness, should be taken into account in selecting empiric antimicrobial treatment.

Impact of chronic liver disease in intensive care unit acquired pneumonia: a prospective study.

PURPOSE: To assess the impact of chronic liver disease (CLD) on ICU-acquired pneumonia. METHODS: This was a prospective, observational study of the characteristics, microbiology, and outcomes of 343 consecutive patients with ICU-acquired pneumonia clustered according to the presence of CLD. RESULTS: Sixty-seven (20%) patients had CLD (67% had liver cirrhosis, LC), MELD score 26 ± 9, 20% Child-Pugh class C). They presented higher severity scores than patients without CLD both on admission to the ICU (APACHE II, LC 19 ± 6 vs. other CLD 18 ± 6 vs. no CLD 16 ± 6; p < 0.001; SOFA, 10 ± 3 vs. 8 ± 4 vs. 7 ± 3; p < 0.001) and at onset of pneumonia (APACHE II, 19 ± 6 vs. 17 ± 6 vs. 16 ± 5; p = 0.001; SOFA, 11 ± 4 vs. 9 ± 4 vs. 7 ± 3; p < 0.001). Levels of CRP were lower in patients with LC than in the other two groups (day 1, 6.5 [2.5-11.5] vs. 13 [6-23] vs. 15.5 [8-24], p < 0.001, day 3, 6 [3-12] vs. 16 [9-21] vs. 11 [5-20], p = 0.001); all the other biomarkers were higher in LC and other CLD patients. LC patients had higher 28- and 90-day mortality (63 vs. 28%, p < 0.001; 72 vs. 38%, p < 0.001, respectively) than non-CLD patients. Presence of LC was independently associated with decreased 28- and 90-day survival (95% confidence interval [CI], 1.982-17.250; p = 0.001; 95% confidence interval [CI], 2.915-20.699, p = 0.001, respectively). CONCLUSIONS: In critically ill patients with ICU-acquired pneumonia, CLD is associated with a more severe clinical presentation and poor clinical outcomes. Moreover, LC is independently associated with 28- and 90-day mortality. The results of this study are important for future trials focused on mortality.