Search

Streptococcus pneumoniae is the most common microbial cause of community-acquired pneumonia. Currently, there are no available models of severe pneumococcal pneumonia in mechanically ventilated animals to mimic clinical conditions of critically ill patients. We studied endogenous pulmonary flora in 4 healthy pigs and in an additional 10 pigs in which we intra-bronchially instilled S. pneumoniae serotype 19 A, characterized by its resistance to penicillin, macrolides and tetracyclines. The pigs underwent ventilation for 72 h. All pigs that were not challenged with S. pneumoniae completed the 72-h study, whereas 30% of infected pigs did not. At 24 h, we clinically confirmed pneumonia in the infected pigs; upon necropsy, we sampled lung tissue for microbiological/histological confirmation of pneumococcal pneumonia. In control pigs, Streptococcus suis and Staphylococcus aureus were the most commonly encountered pathogens, and their lung tissue mean ± s.e.m. concentration was 7.94 ± 20 c.f.u./g. In infected pigs, S. pneumoniae was found in the lungs of all pigs (mean ± s.e.m. pulmonary concentration of 1.26 × 10 5 ± 2 × 10 2 c.f.u./g). Bacteremia was found in 50% of infected pigs. Pneumococcal pneumonia was confirmed in all infected pigs at 24 h. Pneumonia was associated with thrombocytopenia, an increase in prothrombin time, cardiac output and vasopressor dependency index and a decrease in systemic vascular resistance. Upon necropsy, microbiological/histological pneumococcal pneumonia was confirmed in 8 of 10 pigs. We have therefore developed a novel model of penicillin- and macrolide-resistant pneumococcal pneumonia in mechanically ventilated pigs with bacteremia and severe hemodynamic compromise. The model could prove valuable for appraising the pathogenesis of pneumococcal pneumonia, the effects associated with macrolide resistance and the outcomes related to the use of new diagnostic strategies and antibiotic or complementary therapies., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: High-volume low-pressure (HVLP) endotracheal tube (ETT) cuffs for critically ill patients often deflate during the course of mechanical ventilation. We performed an in-vitro study to comprehensively assess HVLP cuff deflation dynamics and potential preventive measures., Methods: We evaluated 24-hour deflation of seven HVLP cuffs of cylindrical or tapered shape, and made of polyvinylchloride or polyurethane. Experiments were performed within a thermostated chamber set at 37 °C. In the first stage of experiments, the cuff pilot balloon valve was not manipulated. The cuff internal pressure was assessed hourly for 24 hours, via a linear position sensor which monitored cuff deflation displacements. Then, we re-evaluated cuff deflation of the worst-performing ETT cuffs with the cuff pilot balloon valve sealed. Finally, we inflated ETT cuffs within an artificial trachea to evaluate deflation dynamics during mechanical ventilation., Results: Initial tests showed an exponential decrease in cuff internal pressure in five out of seven cuffs. Cuffs of cylindrical shape and made of polyurethane demonstrated the fastest deflation rates (P<0.050 vs. cuffs of conical shape and made of polyvinylchloride). When the cuff pilot balloon valve was not sealed, the internal cuff pressure deflation rate differed significantly among ETTs (P=0.005). Yet, upon sealing the cuff pilot balloon valve and during mechanical ventilation, cuff deflation rates decreased (P<0.050)., Conclusions: In controlled in-vitro settings, ETT cuffs consistently deflate over time, and the cuff pilot balloon valve plays a central role in this occurrence. Deflation rate decreases when cuffs are inflated within a plastic artificial tracheal model and mechanical ventilation is activated.

Objectives: Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem., Design: Prospective randomized animal study., Setting: Animal Research, University of Barcelona, Spain., Subjects: Thirty female pigs., Interventions: The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance., Measurements and Main Results: We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004)., Conclusions: Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

Background: We previously evaluated the efficacy of a ventilatory strategy to achieve expiratory flow bias and positive end-expiratory pressure (EFB + PEEP) or the Trendelenburg position (TP) for the prevention of ventilator-associated pneumonia (VAP). These preventive measures were aimed at improving mucus clearance and reducing pulmonary aspiration of bacteria-laden oropharyngeal secretions. This secondary analysis is aimed at evaluating the effects of aforementioned interventions on systemic inflammation and to substantiate the value of clinical parameters and cytokines in the diagnosis of VAP., Methods: Twenty female pigs were randomized to be positioned in the semirecumbent/prone position, and ventilated with duty cycle 0.33 and without PEEP (control); positioned as in the control group, PEEP 5 cmH 2 O, and duty cycle to achieve expiratory flow bias (EFB+PEEP); ventilated as in the control group, but in the Trendelenburg position (Trendelenburg). Following randomization, P. aeruginosa was instilled into the oropharynx. Systemic cytokines and tracheal secretions P. aeruginosa concentration were quantified every 24h. Lung biopsies were collected for microbiological confirmation of VAP., Results: In the control, EFB + PEEP, and Trendelenburg groups, lung tissue Pseudomonas aeruginosa concentration was 2.4 ± 1.5, 1.9 ± 2.1, and 0.3 ± 0.6 log cfu/mL, respectively (p = 0.020). Whereas, it was 2.4 ± 1.9 and 0.6 ± 0.9 log cfu/mL in animals with or without VAP (p < 0.001). Lower levels of interleukin (IL)-1β (p = 0.021), IL-1RA (p < 0.001), IL-4 (p = 0.005), IL-8 (p = 0.008), and IL-18 (p = 0.050) were found in Trendelenburg animals. VAP increased IL-10 (p = 0.035), tumor necrosis factor-α (p = 0.041), and endotracheal aspirate (ETA) P. aeruginosa concentration (p = 0.024). A model comprising ETA bacterial burden, IL-10, and TNF-α yielded moderate discrimination for the diagnosis of VAP (area of the receiver operating curve 0.82, 95% CI 0.61-1.00)., Conclusions: Our findings demonstrate anti-inflammatory effects associated with the Trendelenburg position. In this reliable model of VAP, ETA culture showed good diagnostic accuracy, whereas systemic IL-10 and TNF-α marginally improved accuracy. Further clinical studies will be necessary to confirm clinical value of the Trendelenburg position as a measure to hinder inflammation during mechanical ventilation and significance of systemic IL-10 and TNF-α in the diagnosis of VAP.

Purpose: The lateral Trendelenburg position (LTP) may hinder the primary pathophysiologic mechanism of ventilator-associated pneumonia (VAP). We investigated whether placing patients in the LTP would reduce the incidence of VAP in comparison with the semirecumbent position (SRP)., Methods: This was a randomized, multicenter, controlled study in invasively ventilated critically ill patients. Two preplanned interim analyses were performed. Patients were randomized to be placed in the LTP or the SRP. The primary outcome, assessed by intention-to-treat analysis, was incidence of microbiologically confirmed VAP. Major secondary outcomes included mortality, duration of mechanical ventilation, and intensive care unit length of stay., Results: At the second interim analysis, the trial was stopped because of low incidence of VAP, lack of benefit in secondary outcomes, and occurrence of adverse events. A total of 194 patients in the LTP group and 201 in the SRP group were included in the final intention-to-treat analysis. The incidence of microbiologically confirmed VAP was 0.5% (1/194) and 4.0% (8/201) in LTP and SRP patients, respectively (relative risk 0.13, 95% CI 0.02-1.03, p = 0.04). The 28-day mortality was 30.9% (60/194) and 26.4% (53/201) in LTP and SRP patients, respectively (relative risk 1.17, 95% CI 0.86-1.60, p = 0.32). Likewise, no differences were found in other secondary outcomes. Six serious adverse events were described in LTP patients (p = 0.01 vs. SRP)., Conclusions: The LTP slightly decreased the incidence of microbiologically confirmed VAP. Nevertheless, given the early termination of the trial, the low incidence of VAP, and the adverse events associated with the LTP, the study failed to prove any significant benefit. Further clinical investigation is strongly warranted; however, at this time, the LTP cannot be recommended as a VAP preventive measure. CLINICALTRIALS., Gov Identifier: NCT01138540.

Background: Hemoperfusion through a column containing polymyxin B-immobilized fiber (PMX-HP) is beneficial in abdominal sepsis. We assessed the effects of PMX-HP in a model of severe Pseudomonas aeruginosa pneumonia., Methods: Eighteen pigs with severe P. aeruginosa pneumonia were mechanically ventilated for 76 h. Pigs were randomized to receive standard treatment with fluids and vasoactive drugs, or standard treatment with two 3-h PMX-HP sessions. Antibiotics against P. aeruginosa were never administered. We assessed endotoxemia through the endotoxin activity assay (EA). We measured the static lung elastance, ratio of arterial partial pressure per inspiratory fraction of oxygen (PaO2/FIO2), mean arterial pressure, cardiac output, systemic vascular resistance and inotropic score. Finally, every 24 h, we assessed complete blood count., Results: In comparison with the control group, PMX-HP decreased percentage of circulating neutrophils from 47.4 ± 13.8 to 40.8 ± 11.5 % (p = 0.009). In a subgroup of animals with the worst hemodynamic impairment, EA in the control and PMX-HP groups was 0.50 ± 0.29 and 0.29 ± 0.14, respectively (p = 0.018). Additionally, in the control and PMX-HP groups, static lung elastance was 26.9 ± 8.7 and 25.3 ± 7.5 cm H2O/L (p = 0.558), PaO2/FIO2 was 347.3 ± 61.9 and 356.4 ± 84.0 mmHg (p = 0.118), mean arterial pressure was 81.2 ± 10.3 and 81.6 ± 13.1 mmHg (p = 0.960), cardiac output was 3.30 ± 1.11 and 3.28 ± 1.19 L/min (p = 0.535), systemic vascular resistance was 1982.6 ± 608.4 and 2011.8 ± 750.0 dyne/s/cm(-5) (p = 0.939), and inotropic score was 0.25 ± 0.10 and 0.26 ± 0.18 (p = 0.864)., Conclusions: In mechanically ventilated pigs with severe P. aeruginosa pneumonia, PMX-HP does not have any valuable clinical benefit, and studies are warranted to fully evaluate a potential role of PMX-HP in septic shock associated with severe pulmonary infections.

Background: Tracheal tube biofilm develops during mechanical ventilation. We compared a novel closed-suctioning system vs standard closed-suctioning system in the prevention of tracheal tube biofilm., Methods: Eighteen pigs, on mechanical ventilation for 76 h, with P. aeruginosa pneumonia were randomized to be tracheally suctioned via the KIMVENT* closed-suctioning system (control group) or a novel closed-suctioning system (treatment group), designed to remove tracheal tube biofilm through saline jets and an inflatable balloon. Upon autopsy, two tracheal tube hemi-sections were dissected for confocal and scanning electron microscopy. Biofilm area, maximal and minimal thickness were computed. Biofilm stage was assessed., Results: Sixteen animals were included in the final analysis. In the treatment and control group, the mean (sd) pulmonary burden was 3.34 (1.28) and 4.17 (1.09) log cfu gr(-1), respectively (P=0.18). Tracheal tube P. aeruginosa colonization was 5.6 (4.9-6.3) and 6.2 (5.6-6.9) cfu ml(-1) (median and interquartile range) in the treatment and control group, respectively (P=0.23). In the treatment group, median biofilm area was 3.65 (3.22-4.21) log10 μm2 compared with 4.49 (4.27-4.52) log10 μm2 in the control group (P=0.031). In the treatment and control groups, the maximal biofilm thickness was 48.3 (26.7-71.2) µm (median and interquartile range) and 88.8 (43.8-125.7) µm, respectively. The minimal thickness in the treatment and control group was 0.6 (0-4.0) µm and 23.7 (5.3-27.8) µm (P=0.040) (P=0.017). Earlier stages of biofilm development were found in the treatment group (P<0.001)., Conclusions: The novel CSS reduces biofilm accumulation within the tracheal tube. A clinical trial is required to confirm these findings and the impact on major outcomes., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.

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.

Ventilator-associated pneumonia (VAP) is an iatrogenic pulmonary infection that develops in tracheally intubated patients on mechanical ventilation for at least 48 hours. VAP is the nosocomial infection with the greatest impact on patient outcomes and health care costs. Endogenous colonization by aerobic gram-negative pathogens, that is, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus play a pivotal role in the pathogenesis of VAP. Several preventive strategies have shown efficacy in decreasing VAP incidence and are often implemented altogether as a prevention bundle. In patients with clinical suspicion of VAP, respiratory samples should be promptly collected. The empiric treatment should be based on the local prevalence of pathogens, duration of hospital stay, and prior antimicrobial therapy. The antibiotics can be stopped or adjusted to more narrow-spectrum once cultures and susceptibilities are available., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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.

Objective: To assess the structural characteristics involved in the design of high-volume low-pressure endotracheal tube cuffs that are associated with fluid sealing effectiveness and to determine the extent of transmitted tracheal pressures upon cuff inflation., Design: In vitro study., Settings: Pneumology laboratories., Interventions: Eight high-volume low-pressure cuffs of cylindrical or tapered shape, made of polyvinylchloride or polyurethane, were studied. Cuffs were tested within a tracheal model, oriented 30° above horizontal to assess 1 hr leakage of oropharyngeal secretions simulant at cuff internal pressures of 15-30 cm H2O. The four best performing cuffs were evaluated for 24 hrs using an internal pressure of 30 cm H2O. The extent of transmitted tracheal wall pressure throughout the cuff-trachea contact area was determined using an internal pressure sensor within a tracheal model upon cuff inflation up to 30 cm H2O., Measurements and Main Results: Outer diameter, length, and compliance of each cuff were assessed. Multivariate regression analysis was performed to identify the main determinants of simulant leakage rate. The cuff-trachea contact area and the percentage of tracheal wall pressure measurements greater than 50 cm H2O were computed. Cuff design characteristics significantly differ among tubes. The cuffs made of polyurethane showed the best short- and long-term sealing efficacy. Nevertheless, in the multivariate analysis, the cuff outer diameter (n: 288, p = 0.003) and length (n: 288, p < 0.001), along with the internal pressure (n: 288, p < 0.001), were the only predictors of simulant leakage rate. The tapered cuffs showed the lowest tracheal wall contact area (n: 96, p < 0.001). The tracheal wall pressure distribution pattern was heterogeneous, and the percentage of high tracheal wall pressure significantly differs among the cuffs (n: 96, p < 0.001)., Conclusions: The high-volume low-pressure cuffs' outer diameter, length, material, and internal pressure are the main determinants of sealing efficacy. Despite internal pressure within the safe range, transmitted tracheal pressure is extremely heterogeneous and differs among cuffs, occasionally reaching localized, very high, unsafe levels.