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.
Patients eligible for enrollment are admitted to the hospital from the emergency
department or transferred from another ICU. A legal representative will be asked for
written informed consent once a patient classifies as acute brain trauma, stroke, or
brain hemorrhage patient. Therefore, eligibility screening can start, and exclusion
criteria will first be assessed. If the patient does not meet any exclusion criteria, he
will also be considered for inclusion criteria. If the patient meets all the inclusion
criteria, he can be successfully enrolled in the study.
The patient will be blindly assigned at a 1:1 ratio to either the interventional
(probiotics) group or the control ( placebo) group.
The research coordinator and the sub-investigators will assess patients daily in the ICU,
where most data will be gathered. The investigators and the clinicians evaluating the
patients will be blind to the allocated treatment for the entire study duration.
This includes:
Baseline data: demographics (age, gender, height, weight, country of origin), total
comorbidities number on admission, cardiovascular axis on admission, pulmonary axis
on admission, metabolic axis on admission, liver axis on admission, rheumatic axis
on admission, renal axis on admission, neurologic axis on admission, history of
smoking, Glasgow Coma Scale (GCS) on admission, sequential organ failure assessment
(SOFA) score on admission, Acute Physiology and Chronic Health Evaluation (APACHE
II) score on admission, Simplified Acute Physiology Score (SAPS) II score on
admission, Charlson Comorbidity Index. Before start of the study drug, one sample of
tracheobronchial secretions will be collected and analyzed quantitatively. This step
is necessary to define the modified intention-to-treat (mITT) population.
Daily data: vital signs, sepsis, septic shock, CRBSI, Catecholamine support, Enteral
feeding, Parenteral feeding, Enteral + Parenteral feeding, prokinetics,
beta-lactamase inhibitor, second-generation cephalosporin, third-generation
cephalosporin, piperacillin/tazobactam, metronidazole, clindamycin, amikacin,
glycopeptide, microbiology and antibiogram (if available), GCS score, SOFA score,
diarrhoea (type 6/7 bristol stool chart), mechanical ventilation, Oxygen saturation
(SpO2), culture results, adverse events.
VAP screening: every day, the patient will be screened explicitly for VAP by the
attending physician. The screening protocol begins with clinical suspicion. The
presence of new or progressive radiographic infiltrates and at least two of three
clinical criteria [19] ( fever/hypothermia, leukocytosis/leukopenia, purulent
secretions) represent the protocol trigger. Leukocytosis is defined as an elevation
in the absolute White Blood Cells (WBC) count (10,000 cells/μL), while leukopenia is
defined as a reduction in the WBC count (<3500 cells/μL) [20]. Hypothermia is
defined as a body core temperature of <35.0 °C (95.0 °F) [21], while fever is
defined as a body core temperature of ≥38.3°C (101° F) [22]. Once the clinical
suspicion is realized, samples of respiratory secretions, i.e. tracheal aspirate and
bronchoalveolar lavage (BAL), are obtained non-invasively. Samples will be
quantitatively cultured at the local hospital laboratory. Part of the samples will
be stored at -20 °C and shipped by air transport to the Laboratory of Immunology of
Infectious Diseases of the 4th Department of Internal Medicine of ATTIKON University
General Hospital (124 62 Athens, Greece) for molecular testing. A VAP diagnosis will
be established if either quantitative cultures yield more than 105 cfu/ml growth of
one pathogen or when more than 104 copies of a pathogen are grown in molecular
testing.
FOLLOW-UP: The data collection will continue for at least 30 days unless the patient is
successfully extubated, interrupting mechanical ventilation. In this case, the data
collection and the probiotic administration will continue for 72 hours after successful
weaning to pass the time window for a late VAP diagnosis. The data collection will
continue for two additional days if a patient is still in the ICU after the thirtieth day
until discharge, although the intervention stops. If VAP is diagnosed, the patient will
continue the probiotic administration for up to 30 days as per the study protocol since
there may still be a beneficial effect on the secondary outcomes.
Biological samples will be collected pre- and post-treatment (after 30 days or 72h after
successful extubation) to study how probiotics administration affects GM's composition.
The samples are going to be faeces, blood and urine.