This study of a multicenter cohort of mechanically ventilated subjects is the first to assess variables potentially associated with VAEs. VAEs were common, being PVAP six times more frequent than IVAC alone, which emphasizes the relevance of efforts to prevent respiratory infections. Interestingly, both SDD implementation and long-acting sedative/analgesic agents use, variables that are amenable to intervention, significantly influenced VAEs, and their influence remained significant when subjects with tracheostomy were excluded. Lastly, our study confirms the association of VAEs with worse outcomes.
Our findings indicate that compliance with SDD can influence the risk of developing VAEs. The high proportion of IVAC-plus in our cohort may explain why SDD implementation independently reduced VAE rates in subjects submitted to long periods of MV. Another explanation for the effect of SDD on VAE is that much of VAE consists of tracheal colonization combined with a non-infectious pulmonary pathology such as pleural effusion, atelectasis, or pulmonary edema. Preventing tracheal colonization is the mechanism by which many VAP-prevention strategies such as subglottic suction, silver impregnated tubes, and oral decontamination work.
Moreover, our results also identify long-acting sedatives/analgesic agents as an independent risk factor for VAEs, rather than delirium, suggesting that intervention in sedative/analgesic prescription might be a possible strategy of prevention. This may be related with a higher probability of impregnation when prescribing drugs prone to being accumulated, and also with an underestimation of delirium if a systematic delirium-screening instrument is not used for its diagnosis in the ICU. If only clinical criteria are applied, it is the hyperactive subtype that will usually be detected [10]. However, recent data show that most delirious ICU patients have hypoactive delirium, which is more frequent in patients with more severe illness and undergoing MV [11]. Thus, the spontaneous breathing trial was not found to protect against VAE in our cohort. These findings are in line with the association between benzodiazepines and increased MV duration and ICU stay compared with other sedatives, as described in two recent meta-analyses [12, 13] and a cohort study [14]. Although midazolam may be considered as a short-acting benzodiazepine, its pharmacokinetic profile, with phase 1 and phase 2 metabolism and an end-active metabolite with renal excretion, frequently results in accumulation, over-sedation, and delayed wakening in the ICU, particularly in older and sicker patients, as it has been pointed out by Wyncoll et al. [15]. When analyzed midazolam in conjunction with morphine and fentanyl, those continuous around-the-clock drugs resulted the most important factor for developing VAE.
In the coming years, it would be interesting to analyze the role of alpha-2 agonists, which were hardly used in Europe during our study recruitment period [16], and the impact of new non-benzodiazepine sedation approach and ICU delirium guidelines on VAE [17,18,19]. In recent years, there has been an increasing concern with delirium in the ICU and its impact on patient safety and outcomes, and indeed delirium has been included in some evidence-based interventions designed to reduce adverse events in hospitals [20]. On the other hand, the difficulty of ventilator-associated pneumonia (VAP) diagnosis and the discrepancies in antibiotic consumption despite reporting/achieving low VAP rates [21] have shifted the focus of quality-improvement on patient outcomes beyond the mere recording of VAP rates in ventilated patients, and the concept of VAE has emerged.
Conservative rather than liberal fluid resuscitation will increase the number of ventilator-free days and several studies [14, 22] have reported a relation between VAEs and excess fluids. However, our data did not find this association, perhaps due to differences in case mix, comorbidities (cardiomyopathy), VAC rates or measurement of fluid overload, or because the other studies limited their assessment to the first 4 days of ICU stay [14]. Other studies of potentially modifiable VAE risk factors [14, 22,23,24,25,26] have identified blood transfusions and mandatory modes of MV with high inspiratory pressure.
This study has several limitations. First, in spite of the multicenter design, the fact that only a few events per site were analyzed limits its power to identify potential risk factors. Second, dexmedetomidine was not properly evaluated due to its low use in the ICUs during the period of study, and further studies are needed to identify its potential effect. Third, this study was conducted in Europe and the interpretations may not be applicable to other settings, due to the large variation in therapeutic strategies, and duration of MV. Fourth, some potentially relevant variables such as average gastric retention were not evaluated. Five, the number of trauma patients is small and variables can be different in other case-mixes. Lastly, we considered the entire period of MV: other variables may be relevant if the time span is limited, for instance to the first 4 days of ventilation.