Gianluigi Li Bassi

Ventilator-associated pneumonia: role of positioning

Purpose of reviewVentilator-associated pneumonia (VAP) is a lung infection commonly acquired following tracheal intubation. This review assesses the role of the supine semirecumbent and the prone position as VAP preventive strategies and calls attention for further investigation on novel body positions that could potentially reduce risks of VAP. Recent findingsThe most recent studies on the semirecumbent position failed to achieve an orientation of the head of the bed higher than 30° and did not corroborate any benefit of the semirecumbent position on VAP, as reported in earlier studies. To date, there is clear evidence that the supine horizontal body position increases risks of pulmonary aspiration and VAP, particularly when patients are enterally fed. Laboratory reports are emphasizing the importance of an endotracheal tube–oropharynx–trachea axis below horizontal to avoid VAP. The prone position potentially increases drainage of oropharyngeal and airways secretions and recent evidence is supporting its beneficial effects. However, several associated adverse effects preclude its regular use as a VAP preventive strategy for patients other than those with acute respiratory distress syndrome. SummaryBody position greatly affects several pathogenetic mechanisms of VAP. The current evidence recommends avoidance of supine horizontal position in order to prevent aspiration of colonized gastric contents. The semirecumbent position has proven benefits and should be routinely used but there is still limited evidence to recommend the lowest orientation of the bed at which the patient can be safely maintained. Results from pioneering laboratory investigation call attention to new possible positions, that is lateral Trendelenburg position, aimed to avoid pulmonary aspiration and to enhance mucus clearance in intubated patients.

An in vitro study to assess determinant features associated with fluid sealing in the design of endotracheal tube cuffs and exerted tracheal pressures.

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.

International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT)

The most recent European guidelines and task force reports on hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) were published almost 10 years ago. Since then, further randomised clinical trials of HAP and VAP have been conducted and new information has become available. Studies of epidemiology, diagnosis, empiric treatment, response to treatment, new antibiotics or new forms of antibiotic administration and disease prevention have changed old paradigms. In addition, important differences between approaches in Europe and the USA have become apparent. The European Respiratory Society launched a project to develop new international guidelines for HAP and VAP. Other European societies, including the European Society of Intensive Care Medicine and the European Society of Clinical Microbiology and Infectious Diseases, were invited to participate and appointed their representatives. The Latin American Thoracic Association was also invited. A total of 15 experts and two methodologists made up the panel. Three experts from the USA were also invited (Michael S. Niederman, Marin Kollef and Richard Wunderink). Applying the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology, the panel selected seven PICO (population–intervention–comparison–outcome) questions that generated a series of recommendations for HAP/VAP diagnosis, treatment and prevention. ERS/ESICM/ESCMID/ALAT evidence-based recommendations for HAP/VAP diagnosis, treatment and prevention http://ow.ly/dGhv30dAVoa

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.

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.

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.

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.

Impact of COPD in the Outcome of ICU-Acquired Pneumonia With and Without Previous Intubation

BACKGROUND COPD seems related to poor outcome in patients with ventilator-associated pneumonia (VAP). However, many patients in the ICU with COPD do not require intubation but can also develop pneumonia in the ICU. We, therefore, compared the characteristics and outcomes of patients with ICU-acquired pneumonia (ICUAP) with and without underlying COPD. METHODS We prospectively assessed the characteristics, microbiology, systemic inflammatory response, and survival of 279 consecutive patients with ICUAP clustered according to underlying COPD or not. The primary end point was 90-day survival. RESULTS Seventy-one patients (25%) had COPD. The proportion of VAP was less frequent in patients with COPD: 30 (42%) compared with 126 (61%) in patients without COPD (P = .011). Patients with COPD were older; were more frequently men, smokers, and alcohol abusers; and more frequently had previous use of noninvasive ventilation. The rate of microbiologic diagnosis was similar between groups, with a higher rate of Aspergillus species and a lower rate of Enterobacteriaceae in patients with COPD. We found lower levels of IL-6 and IL-8 in patients with COPD without previous intubation. The 90-day mortality was higher in patients with COPD (40 [57%] vs 74 [37%] in patients without COPD, P = .003). Among others, COPD was independently associated with decreased 90-day survival in the overall population (adjusted hazard ratio, 1.94; 95% CI, 1.11-3.40; P = .020); this association was observed only in patients with VAP but not in those without previous intubation. CONCLUSIONS COPD was independently associated with decreased 90-day survival in patients with VAP but not in those without previous intubation.

Summary of the international clinical guidelines for the management of hospital-acquired and ventilator-acquired pneumonia

The most recent European guidelines and task force reports on hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) were published almost 10 years ago. Since then, further randomised clinical trials of HAP and VAP have been conducted and new information has become available. Studies of epidemiology, diagnosis, empirical treatment, response to treatment, new antibiotics or new forms of antibiotic administration, and disease prevention have changed old paradigms. In addition, important differences between approaches in Europe and the USA have become apparent. The European Respiratory Society (ERS) launched a project to develop new international guidelines for HAP and VAP. Other European societies, including the European Society of Intensive Care Medicine (ESICM) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), were invited to participate and appointed their representatives. The Latin American Society of Thoracic Diseases (ALAT) was also invited to participate. This manuscript summarises the evidence and recommendations of these international guidelines on HAP and VAP. A summary of the evidence and recommendations made in the ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia http://ow.ly/S3zA30iZfLa

Prone position and VAP incidence in the PROSEVA trial: attention to the causal question when interpreting competing risk analysis

Dear Editor, We read with great interest the study by Ayzac et al. [1] assessing the impact of prone positioning on the incidence of ventilator-associated pneumonia (VAP), as a secondary analysis of the PROSEVA trial. Importantly, given that patients who die early are precluded from developing VAP, the authors appropriately applied competing risk analysis [2]. Indeed, it is important to emphasize that the most severe patient also presents the highest risk of developing VAP (e.g., severity is a risk factor for mortality and VAP). The authors hypothesized a lower risk of VAP in the prone position group, but surprisingly they observed higher 90-day cumulative incidence (CIF) [46.5 % (27–66)], compared with supine patients [33.5 % (23–44)]. Although the authors did not report the subdistribution hazard ratio (subdistribution HR) of the Fine and Gray model, prone position increased the risk of VAP, with a point-estimate difference (risk difference) of 13 %. Ultimately, this result did not reach statistical significance by the Gray’s test (p = 0.11). Fine and Gray models estimate associations in the presence of competing events. Therefore, the CIF in Fig. 1 of the main paper depicts what we would expect [1], because patients in the prone position survived longer and were exposed to the risk of VAP for a longer period [2–4]. In their analysis, the CIF was the final composition of two cause-specific hazard ratios (cause-specific HR), one for survival and the other accounting for VAP. Therefore, when presenting the results of a competing risk analysis aiming to answer causal questions, it is imperative to report also cause-specific HR, because cause-specific HR represents the “actual” direct effect of the exposure on the outcome [2–4]. In order to emphasize the importance of these measures of effect (subdistribution HR and cause-specific HR), we simulated three different scenarios keeping the protective effect on survival constant (Table 1). We performed our analyses through STATA 13.1, using the survsim command to generate the simulated data (codes are available in the electronic supplementary material). We observed that when the “real” direct effect of prone position on VAP incidence was defined as “small” or “null”, interpretation of the study results only reporting subdistribution HR would have been challenging. Indeed, when prone position had a null “real” direct effect on VAP incidence, the cause-specific HR was 0.959 (95 % CI, 0.879– 1.046, p = 0.344); whereas, the subdistribution HR was 1.113 (95 % CI, 1.020–1.214, p = 0.016), contrasting the cause-specific HR. Conversely, when prone position had a small protective “real” direct effect on VAP incidence, the cause-specific HR was 0.905 (95 % CI, 0.829–0.989, p = 0.027); whereas, the subdistribution HR was 1.052 (95 % CI, 0.964–1.149, p = 0.257). These were expected results due to the large effect of prone position on survival. Similar issues have been noted in other contexts [5]. Comprehensive graphical reports of these scenarios can be found elsewhere [2–4]. In conclusion, Fine and Gray models are not well suited to address etiological/causal questions; thus, it would *Correspondence: otavioranzani@yahoo.com.br 2 Respiratory Intensive Care Unit, Pulmonary Division, Heart Institute, Hospital das Clínicas, University of São Paulo, Av. Dr. Arnaldo, 455, Laboratório de Pneumologia, 2o andar, sala 2144, São Paulo, São Paulo 01246903, Brazil Full author information is available at the end of the article