Clinical characteristics, systemic complications, and in-hospital outcomes for patients with COVID-19 in Latin America. LIVEN-Covid-19 study: A prospective, multicenter, multinational, cohort study.

PURPOSE: The COVID-19 pandemic has spread worldwide, and almost 396 million people have been infected around the globe. Latin American countries have been deeply affected, and there is a lack of data in this regard. This study aims to identify the clinical characteristics, in-hospital outcomes, and factors associated with ICU admission due to COVID-19. Furthermore, to describe the functional status of patients at hospital discharge after the acute episode of COVID-19. MATERIAL AND METHODS: This was a prospective, multicenter, multinational observational cohort study of subjects admitted to 22 hospitals within Latin America. Data were collected prospectively. Descriptive statistics were used to characterize patients, and multivariate regression was carried out to identify factors associated with severe COVID-19. RESULTS: A total of 3008 patients were included in the study. A total of 64.3% of patients had severe COVID-19 and were admitted to the ICU. Patients admitted to the ICU had a higher mean (SD) 4C score (10 [3] vs. 7 [3)], p<0.001). The risk factors independently associated with progression to ICU admission were age, shortness of breath, and obesity. In-hospital mortality was 24.1%, whereas the ICU mortality rate was 35.1%. Most patients had equal self-care ability at discharge 43.8%; however, ICU patients had worse self-care ability at hospital discharge (25.7% [497/1934] vs. 3.7% [40/1074], p<0.001). CONCLUSIONS: This study confirms that patients with SARS CoV-2 in the Latin American population had a lower mortality rate than previously reported. Systemic complications are frequent in patients admitted to the ICU due to COVID-19, as previously described in high-income countries.

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.

ICU-acquired pneumonia with or without etiologic diagnosis: a comparison of outcomes.

OBJECTIVES: The impact of ICU-acquired pneumonia without etiologic diagnosis on patients' outcomes is largely unknown. We compared the clinical characteristics, inflammatory response, and outcomes between patients with and without microbiologically confirmed ICU-acquired pneumonia. DESIGN: Prospective observational study. SETTING: ICUs of a university teaching hospital. PATIENTS: We prospectively collected 270 consecutive patients with ICU-acquired pneumonia. Patients were clustered according to positive or negative microbiologic results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the characteristics and outcomes between both groups. Negative microbiology was found in 82 patients (30%). Both groups had similar baseline severity scores. Patients with negative microbiology presented more frequently chronic renal failure (15 [18%] vs 11 [6%]; p=0.003), chronic heart disorders (35 [43%] vs 55 [29%]; p=0.044), less frequently previous intubation (44 [54%] vs 135 [72%]; p=0.006), more severe hypoxemia (PaO2/FIO2: 165±73 mm Hg vs 199±79 mm Hg; p=0.001), and shorter ICU stay before the onset of pneumonia (5±5 days vs 7±9 days; p=0.001) compared with patients with positive microbiology. The systemic inflammatory response was similar between both groups. Negative microbiology resulted in less changes of empiric treatment (33 [40%] vs 112 [60%]; p=0.005) and shorter total duration of antimicrobials (13±6 days vs 17±12 days; p=0.006) than positive microbiology. Following adjustment for potential confounders, patients with positive microbiology had higher hospital mortality (adjusted odds ratio 2.96, 95% confidence interval 1.24-7.04, p=0.014) and lower 90-day survival (adjusted hazard ratio 0.50, 95% confidence interval 0.27-0.94, p=0.031), with a nonsignificant lower 28-day survival. CONCLUSIONS: Although the possible influence of previous intubation in mortality of both groups is not completely discarded, negative microbiologic findings in clinically suspected ICU-acquired pneumonia are associated with less frequent previous intubation, shorter duration of antimicrobial treatment, and better survival. Future studies should corroborate the presence of pneumonia in patients with suspected ICU-acquired pneumonia and negative microbiology.

Validation of predictors of adverse outcomes in hospital-acquired pneumonia in the ICU.

OBJECTIVE: To validate a set of predictors of adverse outcomes in patients with ICU-acquired pneumonia in relation to clinically relevant assessment at 28 days. DESIGN: Prospective, observational study. SETTING: Six medical and surgical ICUs of a university hospital. PATIENTS: Three hundred thirty-five patients with ICU-acquired pneumonia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Development of predictors of adverse outcomes was defined when at least one of the following criteria was present at an evaluation made 72-96 hours after starting treatment: no improvement of PaO2/FIO2, need for intubation due to pneumonia, persistence of fever or hypothermia with purulent respiratory secretions, greater than or equal to 50% increase in radiographic infiltrates, or occurrence of septic shock or multiple organ dysfunction syndrome. We also assessed the inflammatory response by different serum biomarkers. The presence of predictors of adverse outcomes was related to mortality and ventilator-free days at day 28. Sequential Organ Failure Assessment score was evaluated and related to mortality at day 28.One hundred eighty-four (55%) patients had at least one predictor of adverse outcomes. The 28-day mortality was higher for those with versus those without predictors of adverse outcomes (45% vs 19%, p<0.001), and ventilator-free days were lower (median [interquartile range], 0 [0-17] vs 22 [0-28]) for patients with versus patients without predictors of adverse outcomes (p<0.001). The lack of improvement of PaO2/FIO2 and lack of improvement in Sequential Organ Failure Assessment score from day 1 to day 5 were independently associated with 28-day mortality and fewer ventilator-free days. The marginal structural analysis showed an odds ratio of death 2.042 (95% CI, 1.01-4.13; p=0.047) in patients with predictors of adverse outcomes. Patients with predictors of adverse outcomes had higher serum inflammatory response accordingly to biomarkers evaluated. CONCLUSIONS: The presence of any predictors of adverse outcomes was associated with mortality and decreased ventilator-free days at day 28. The lack of improvement in the PaO2/FIO2 and Sequential Organ Failure Assessment score was independently associated with mortality in the multivariate analysis.

Effects of manual rib cage compressions on expiratory flow and mucus clearance during mechanical ventilation.

OBJECTIVES: We investigated the effects of two different types of manual rib cage compression on expiratory flow and mucus clearance during prolonged mechanical ventilation in pigs. DESIGN: Prospective randomized animal study. SETTING: Animal research facility, University of Barcelona, Spain. SUBJECTS: Nine healthy pigs. MEASUREMENT AND MAIN RESULTS: Pigs were tracheally intubated, sedated, paralyzed, and mechanically ventilated. The animals were prone on a surgical bed in the anti-Trendelenburg position. The experiments were carried out at approximately 60 and 80 hrs from the beginning of mechanical ventilation. Two types of manual rib cage compressions were tested: Hard and brief rib cage compressions synchronized with early expiratory phase (hard manual rib cage compression) and soft and gradual rib cage compressions applied during the late expiratory phase (soft manual rib cage compression). The interventions were randomly applied for 15min with a 15-min interval between treatments. Respiratory flow and mucus movement were assessed during the interventions. Respiratory mechanics and hemodynamics were assessed prior to and after the interventions. Peak expiratory flow increased to 60.1±7.1L/min in comparison to 51.2±4.6L/min without treatment (p < 0.0015) and 48.7±4.3L/min with soft manual rib cage compression (p = 0.0002). Similarly, mean expiratory flow increased to 28.4±5.2L/min during hard manual rib cage compression vs. 15.9±2.2 and 16.6±2.8L/min without treatment and soft manual rib cage compression, respectively (p = 0.0006). During hard manual rib cage compression, mucus moved toward the glottis (1.01 ± 2.37mm/min); conversely, mucus moved toward the lungs during no treatment and soft manual rib cage compression, -0.28 ± 0.61 and -0.15±0.95mm/min, respectively (p = 0.0283). Soft manual rib cage compression slightly worsened static lung elastance and cardiac output (p = 0.0391). CONCLUSIONS: Hard manual rib cage compression improved mucus clearance in animals positioned in the anti-Trendelenburg position. The technique appeared to be safe. Conversely, soft manual rib cage compression was not effective and potentially unsafe. These findings corroborate the predominant role of peak expiratory flow on mucus clearance.

Linezolid limits burden of methicillin-resistant Staphylococcus aureus in biofilm of tracheal tubes.

OBJECTIVE: To evaluate the effects of systemic treatment with linezolid compared with vancomycin on biofilm formation in mechanically ventilated pigs with severe methicillin-resistant Staphylococcus aureus-induced pneumonia. DESIGN: Prospective randomized animal study. SETTING: Departments of Pneumology, Microbiology, and Pharmacy of the Hospital Clínic, Barcelona, and Scientific and Technological Services of the University of Barcelona. SUBJECTS: We prospectively analyzed 70 endotracheal tube samples. Endotracheal tubes were obtained from pigs either untreated (controls, n=20), or treated with vancomycin (n=32) or linezolid (n=18). INTERVENTIONS: The endotracheal tubes were obtained from a previous randomized study in tracheally intubated pigs with methicillin-resistant Staphylococcus aureus severe pneumonia, and mechanically ventilated for 69±16 hrs. MEASUREMENTS AND MAIN RESULTS: Distal and medial hemisections of the endotracheal tube were assessed to quantify methicillin-resistant Staphylococcus aureus burden, antibiotic biofilm concentration by high-performance liquid chromatography or bioassay, and biofilm thickness through scanning electron microscopy. We found a trend toward a significant variation in biofilm methicillin-resistant Staphylococcus aureus burden (log colony-forming unit/mL) among groups (p=.057), and the lowest bacterial burden was found in endotracheal tubes treated with linezolid (1.98±1.68) in comparison with untreated endotracheal tubes (3.72±2.20, p=.045) or those treated with vancomycin (2.97±2.43, p=.286). Biofilm linezolid concentration was 19-fold above the linezolid minimum inhibitory concentration, whereas biofilm vancomycin concentration (1.60±0.91 µg/mL) was consistently below or close to the vancomycin minimum inhibitory concentration. Biofilm was thicker in the vancomycin group (p=.077). CONCLUSIONS: Systemic treatment with linezolid limits endotracheal tube biofilm development and methicillin-resistant Staphylococcus aureus burden. The potential clinical usefulness of linezolid in decreasing the risk of biofilm-related respiratory infections during prolonged tracheal intubation requires further investigation.

Effects of duty cycle and positive end-expiratory pressure on mucus clearance during mechanical ventilation*.

OBJECTIVES: During mechanical ventilation, air flows may play a role in mucus transport via two-phase gas liquid flow. The aim of this study was to evaluate effects of duty cycles and positive end-expiratory pressure on mucus clearance in pigs using mechanical ventilation, and to assess their safety. DESIGN: Prospective randomized animal study. SETTING: Animal research facility, University of Barcelona, Spain. SUBJECTS: Eight healthy pigs. INTERVENTIONS: Pigs were intubated and on volume-control mechanical ventilation for up to 84 hrs. After 4, 24, 48, and 72 hrs of mechanical ventilation, six levels of duty cycle (0.26, 0.33, 0.41, 0.50, 0.60, and 0.75) with no associated positive end-expiratory pressure or 5 cm H2O of positive end-expiratory pressure were randomly applied. Surgical bed was oriented 30 degrees in the reverse Trendelenburg position, as in the semirecumbent position. MEASUREMENT AND MAIN RESULTS: Inspiratory and expiratory flows and hemodynamics were measured after each 30-min ventilation period. Mucus movement was assessed through fluoroscopy tracking of radio-opaque markers. Mucus velocity was described by a positive vector (toward the glottis) or negative vector (toward the lungs). No effect of positive end-expiratory pressure was found; however, as duty cycle was increasingly prolonged, a trend toward reduced velocity of mucus moving toward the lungs and increased outward mucus velocity was found (p = .064). Two clusters of mucus velocities were identified as duty cycle was prolonged beyond 0.41. Thus, duty cycle >0.41 increased mean expiratory-inspiratory flow bias from -4.1 ± 4.6 to 7.9 ± 5.9 L/min (p < .0001) and promoted outward mucus velocity from -0.22 ± 1.71 mm/min (range, -5.78 to 2.42) to 0.53 ± 1.06 mm/min (-1.91 to 3.88; p = .0048). Duty cycle of 0.75 resulted in intrinsic positive end-expiratory pressure (2.1 ± 1.1 cm H2O [p < .0001] vs. duty cycle 0.26-0.5), with no hemodynamic compromise. CONCLUSIONS: In the semirecumbent position, mucus clearance is improved with prolongation of the duty cycle. However, in clinical practice, positive findings must be balanced against the potentially adverse hemodynamic and respiratory effects.

Nosocomial pneumonia in the intensive care unit acquired by mechanically ventilated versus nonventilated patients.

RATIONALE: Most current information on hospital-acquired pneumonia (HAP) is extrapolated from patients with ventilator-associated pneumonia (VAP). No studies have evaluated HAP in the intensive care unit (ICU) in nonventilated patients. OBJECTIVES: To compare pneumonia acquired in the ICU by mechanically ventilated versus nonventilated patients. METHODS: We prospectively collected 315 episodes of ICU-acquired pneumonia. We compared clinical and microbiologic characteristics of patients with VAP (n = 164; 52%) and nonventilator ICU-acquired pneumonia (NV-ICUAP; n = 151; 48%). Among NV-ICUAP patients, 79 (52%) needed subsequent intubation. MEASUREMENTS AND MAIN RESULTS: Compared with NV-ICUAP, patients with VAP were more severe (APACHE-II 17 ± 6 vs. 15 ± 5; P < 0.001) and pneumonia occurred later in the ICU (8 ± 8 vs. 5 ± 6 d; P < 0.001). Etiologic diagnosis (117, 71% vs. 64, 42%; P < 0.001), nonfermenting (28% vs. 15%; P = 0.009) and enteric gram-negative bacilli (26% vs. 13%; P = 0.006), and methicillin-sensitive Staphylococcus aureus (14% vs. 6%; P = 0.031) were more frequent in VAP, likely caused by more patients with lower respiratory tract samples cultured (100% vs. 84%; P < 0.001). However, in patients with defined etiology only, the proportion of pathogens was similar between groups, except for a higher proportion of Streptococcus pneumoniae in NV-ICUAP (P = 0.045). The hospital mortality also was similar. CONCLUSIONS: Despite a lower proportion of pathogens in NV-ICUAP compared with VAP, the type of isolates and outcomes are similar regardless of whether pneumonia is acquired or not during ventilation, indicating they may depend on patients' underlying severity rather than previous intubation. With the diagnostic techniques currently recommended by guidelines, both types of patients might receive similar empiric antibiotic treatment.

Do guidelines change outcomes in ventilator-associated pneumonia?

PURPOSE OF REVIEW: The purpose of the study is to summarize effects of implementation of current and past guidelines for management and treatment of ventilator-associated pneumonia (VAP) on outcome of intensive care patients, with particular focus on etiology of VAP, pathogens prediction, appropriate empiric antibiotic therapy and mortality. RECENT FINDINGS: Several studies have shown that in patients with clinical suspicion of VAP, appropriate antibiotic therapy administered in a timely manner can improve survival. Guidelines for management and treatment of VAP have been developed to help physicians to achieve those goals. Implementation of guidelines into clinical practice is difficult to achieve and requires extensive education for healthcare personnel and translation of recommendations into local protocols. Studies have shown that guidelines implementation is associated with better outcome. However, extensive research needs to be undertaken in order to validate efficacy of guidelines in predicting etiology of pneumonia, in particular, to promptly identify multidrug-resistant pathogens. Only one recent report has validated the latest guidelines and called attention for further research to improve microbial prediction. SUMMARY: Guidelines implementation can improve outcomes. To achieve this goal, guidelines should be adapted to local microbiology, accurately predict VAP pathogens and help physicians to administer the most appropriate empirical antimicrobial therapy.