Lisboa, T.

Paiva, J.-A.

Póvoa, P.

Intensive Care Medicine

English

Funding: This work was supported by the Calouste Gulbenkian Foundation, Gulbenkian Professorship 121986/2012; the Foundation for Science and Technology through the grant ANR/BEX-BID/0153/2012, contract IF/00951/2012 (to SSL), fellowship PD/BD/52420/2013 (to RJ) and travel ship SFRH/BSAB/114291/2016 (to JM); iNOVA4Health Research Unit, LISBOA-01-0145-FEDER-007344.publishersversionpublishe

Repositório da Universidade Nova de Lisboa

Intensive Care Med (2017) 43:1872–1874DOI 10.1007/s00134-017-4863-4EDITORIALVentilator-associated pneumonia prevention: one good turn does not always deserve anotherPedro Póvoa1,2* , Thiago Lisboa3,4 and José‑Artur Paiva5,6,7© 2017 Springer‑Verlag GmbH Germany and ESICMVentilator-associated pneumonia (VAP) is a frequent complication of patients undergoing invasive mechanical ventilation and its occurrence is associated with consid-erable morbidity and mortality [1–3]. The key factor in the pathogenesis of VAP is the endotracheal tube (ETT) [4]. Its presence compromises the natural anatomical barriers (larynx) and functional mechanisms (mucus clearance and cough), and it expedites the formation of biofilm as well as macro- and microaspiration of oro-pharyngeal secretions. As a result, several strategies have been successfully implemented, namely subglottic secre-tion drainage or cuff pressure control [3, 4].One of the current recommendations for VAP preven-tion is elevation of the head of bed to 30–45° to prevent the reflux of colonized gastric contents that has a poten-tial role in VAP pathogenesis. This strategy has been evaluated in three randomized controlled trials (RCT) enrolling 337 patients, one positive and two negatives [5–7], and in a meta-analysis pooling these three studies that found a significant impact on prevention [8]. However, the quality of evidence is low, being considered a basic practice because of its simplicity, ubiquity, low cost, and potential benefit [3].Simultaneously, we can conceive that in a patient with an ETT, any position above horizontal increases the grav-itational forces exerted by subglottic secretions above the cuff and, consequently, the risk of aspiration [9]. The results of several experimental studies challenged the recommendation of the semirecumbent position in VAP prevention. In animal models, the Trendelenburg posi-tion showed an increase in mucus clearance, decreas-ing aspiration and consequently VAP rates [9, 10]. With this rationale an RCT was designed to evaluate this hypothesis.In the GRAVITY-VAP trial, recently published in Inten-sive Care Medicine, Li Bassi, Panigada, and co-workers performed a multicenter, multinational RCT to assess the impact of the lateral Trendelenburg position (LTP) vs. semi-recumbent position (SRP) in VAP incidence [11]. A total of 395 patients (N = 194 LTP; N = 201 SRP) were included. The trial was prematurely ended because of low incidence of VAP, lack of benefit in secondary out-comes, and serious adverse events (SAE). The incidence of microbiologically confirmed VAP was 0.5% in LTP and 4.0% in the SRP patients (P = 0.04); however, the rate of SAE was significantly higher in the LTP group, namely transient oxygen desaturation and hemodynamic instabil-ity. In addition, mortality (ICU, hospital, and day 28) was non-significantly higher in the LTP group, ranging from an absolute difference of 6.5% in ICU mortality to 4.5% in day 28 mortality. Moreover, in spite of the risk difference of −7.6% (P = 0.02) in microbiologically confirmed VAP in the LTP group, antibiotic consumption was similar in both groups. This may be due to the higher incidence of clinically suspected VAP in LTP patients with pulmonary infiltrates at the time of enrollment, encouraging BAL assessments, and empirical antibiotic prescription or to the fact that LTP patients had more ventilator-associated tracheobronchitis (VAT), promoting antibiotic treatment directed at this entity. As prevention of aspiration—a paramount mechanism for both VAP and VAT—is the rationale behind LTP, this strategy would be expected to reduce the incidence of both infections. In our opin-ion, consumption of antibiotics should be an important *Correspondence:  pedrorpovoa@gmail.com 1 Polyvalent Intensive Care Unit, Unidade de Cuidados Intensivos Polivalente, Hospital de São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Estrada do Forte do Alto do Duque, 1449‑005 Lisbon, PortugalFull author information is available at the end of the article1873outcome variable for studies assessing new preventive strategies for healthcare-associated infections.This is an example of a well-designed RCT, in which safety was carefully monitored. The apparent discrep-ancy between the lower incidence of VAP and higher incidence of SAE could explain the absence of clini-cal impact of this intervention. These results raise two methodological considerations that deserve to be discussed. First, the potential random nature of the reduced rate of microbiologically confirmed VAP in the intervention group as the study was stopped early. Although study interruption was not due to benefit, it is well known that trials stopped early, on average, overestimate the effect of an intervention and that the apparent overestimation is larger in smaller trials [12]. The high rate of SAE seems incompatible with a positive result, suggesting that the study is  clearly underpow-ered. Also, the fragility of positive results regarding the main outcome—microbiologically documented VAP—appears to be high. Walsh et al. [13] published an inter-esting exercise creating a fragility index for clinical trials to identify the number of events required to change sta-tistically significant results to non-significant results. In Li Bassi and Panigada’s study, the fragility index is 1: only one event-change (microbiologically documented VAP) is required to change the significant result.However, this trial brings new data that deserves to be further discussed. The lower incidence of VAP with LTP (eight times lower) reinforces the concept that macro- and microaspiration of oropharyngeal secretions have a key role in the pathogenesis of VAP [4].There is also new data from the interpretation of the SAE, namely in two areas. The central nervous system seems to have been involved in some causes of death and was one of the reasons behind the decision to ter-minate the RCT early. This occurred in spite of the fact that patients with raised intracranial pressure (ICP) were excluded by the study protocol. However, LTP is always associated with a persistent non-quantifiable increase in ICP, with unpredictable consequences.Secondly, the change in chest compliance and intratho-racic pressure as a consequence of LTP may be a prob-lem, especially in the presence of raised intra-abdominal pressure (IAP). In the supine position, on average, 40% of the IAP is transmitted to the intrathoracic pressure and also changing chest wall compliance [14]. This effect can increase the risk of basal atelectasis, worsening of gas exchange, and arterial blood gases.Finally, the incidence of delirium as a marker of acute brain dysfunction [15] was not evaluated. We all know that increased duration and degree of sedation, namely in LTP patients, in particular with benzodiazepines, is associated with increased risk of acute brain dysfunction, namely delirium, and this could potentially be associated with the observed poor outcomes.In conclusion, we should pursue efforts and research to improve our knowledge of the pathophysiology of VAP as well as to design RCT to assess the safety and efficacy of new preventive strategies. But it seems that turning the head down is not a safe turn!Author details1 Polyvalent Intensive Care Unit, Unidade de Cuidados Intensivos Polivalente, Hospital de São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Estrada do Forte do Alto do Duque, 1449‑005 Lisbon, Portugal. 2 NOVA Medi‑cal School, CEDOC, New University of Lisbon, Lisbon, Portugal. 3 Critical Care Department and Infection Control Committee, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 4 Rede Institucional de Pesquisa e Inovação em Medicina Intensiva (RIPIMI), Complexo Hospitalar Santa Casa de Misericórdia, Porto Alegre, Brazil. 5 Emergency and Intensive Care Department, Centro Hospitalar São João, Porto, Portugal. 6 Faculty of Medicine, University of Porto, Porto, Portugal. 7 Grupo de Infecção e Sepsis, Porto, Portugal. Compliance with ethical standardsConflicts of interestThe authors declare no conflict of interest related to this topic.Received: 4 June 2017   Accepted: 7 June 2017Published online: 22 September 2017References 1. Martin‑Loeches I, Povoa P, Rodriguez A, Curcio D, Suarez D, Mira JP, Cor‑dero ML, Lepecq R, Girault C, Candeias C, Seguin P, Paulino C, Messika J, Castro AG, Valles J, Coelho L, Rabello L, Lisboa T, Collins D, Torres A, Salluh J, Nseir S, TAVeM study (2015) Incidence and prognosis of ventilator‑asso‑ciated tracheobronchitis (TAVeM): a multicentre, prospective, observa‑tional study. Lancet Respir Med 3:859–868 2. 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