Probiotics in ICU to Reduce Ventilator-Associated Pneumonia: A Double-blind Multicentre Randomized Clinical Trial

Ventilator-associated pneumonia represents a burden in ICU with a mortality rate approaching 50%. Ventilator-associated pneumonia (VAP) reduction care bundle is a grouping of evidence-based, high-impact interventions.

Among these recommendations:

• raised head of bed (minimizes microaspiration)
• daily sedation hold and assessment of readiness to extubate (decreases length of stay)
• use of subglottic secretion drainage
• avoidance of scheduled ventilator circuit changes
• peptic ulcer prophylaxis (minimizes complications and length of stay)
• venous thrombo-embolism prophylaxis (minimizes complications and length of stay) Probiotics administration does not figure yet in these recommendations despite the literature showing interesting results in VAP reduction, particularly in specific subsets of patients such as trauma. Tsilika et al. demonstrated a VAP reduction in trauma patients with a head injury. The incidence was lowered to 11.9% in the interventional group with a four-probiotic preparation administration from 28.3 % in the placebo group. The same probiotic preparation has been used in multiple trauma patients to reduce surgical site infections, supporting a possibly prophylactic administration of probiotics. A different two-probiotic preparation was given in stroke patients and showed a VAP incidence reduction in the probiotic group. Stroke patients and trauma patients with a head injury share a common pathophysiology, as traumatic brain injury is considered a risk factor for stroke.

Recent reviews and meta-analyses suggest that probiotics administration may reduce VAP incidence, but more studies with a higher level of evidence and low bias are warranted. The rationale for this finding is yet to be understood. Still, it might depend on the communications between the Gut microbiota (GM) and the oral microbiota (OM) on one side and the lung and its microbiota on the other, along the gut-lung and the gut-bone marrow-lung axes. Notably, short-chain fatty acids (SCFAs) such as butyrate, acetate and propionate produced by the GM by fibre fermentation may have anti-inflammatory effects that strengthen the respiratory tract's epithelial barrier. Tailored and early probiotic administration in the critically ill patient when he enters the ICU, may positively modulate the GM and protect the patient from the harmful downside of the GM disruption. The GM imbalance, called dysbiosis, occurs within six hours of ICU admission, leading to lower bacterial diversity and variability while opportunistic pathogens take over symbiotics. Disrupting this vicious cycle which transforms the local GM into a pathobiota, may play a key role in preserving the good functioning of the gut-lung axis. The diversity of the results of published Randomized Controlled Trials (RCT) guiding the necessity for meta-analysis is probably coming from the heterogeneity of the studied patient population and one inclusion bias: it seems that for probiotics to act prophylactically, the enrolled patient population should be as much as possible devoid of any infection. Indeed a recent large-scale RCT from Canada failed to show any benefit of probiotic treatment to reduce the incidence of VAP. However, most participants were already on antibiotics for unspecific infections, and the methods lacked microbiology diagnosis to support VAP detection.

PROACT is a double-blind randomized placebo-controlled clinical trial where the effect of a four probiotic preparation (Lactolevure, Unipharma, Greece) is studied on multi-trauma patients with a head injury OR stroke or brain haemorrhage patients without any sign of aspiration and lung infection to assess whether this supplementation can reduce VAP and mortality.