Functional recovery with peripheral nerve block versus general anesthesia for upper limb surgery: a systematic review.

BACKGROUND: Peripheral nerve block is a common anesthetic technique used during orthopedic upper limb surgery. Injection of local anesthetics around the target nerve inhibits the action of voltage-dependent sodium channels, inhibiting neurotransmission of pain impulses and providing motor immobility. Compared to general anesthesia, it could improve functional recovery by inhibiting nociceptive impulses and inflammation, thus reducing postoperative pain and immobilization and improving postoperative rehabilitation. This systematic review evaluates the impact of peripheral nerve block versus general anesthesia on postoperative functional recovery following orthopedic upper limb surgery. METHODS: We searched CENTRAL, MEDLINE, CINHAL, EMBASE, and Scopus trial databases from inception until September 2021 for studies comparing peripheral nerve block to general anesthesia. We collected data on functional recovery, range of motion, patient satisfaction, quality of life, and return to work. We pooled studies using a random-effects model and summarized the quality of evidence with the GRADE approach. RESULTS: We assessed 373 citations and 19 full-text articles for eligibility, and included six studies. Six studies reported on functional recovery, but failed to detect a significant superiority of peripheral nerve block over general anesthesia (3 RCT studies, N = 160; SMD -0.15; CI at 95% -0.60-0.3; I2 = 45%; p = 0.07; low quality of evidence and 3 observational studies, N = 377; SMD -0.35; CI at 95% -0.71-0.01; I2 = 64%; p = 0.06; very low quality of evidence). CONCLUSIONS: Current literature is limited and fails to identify the benefit of peripheral nerve block on functional recovery. More studies are needed to assess the impact on long-term recovery. Considering the potential impact on clinical practice and training, a prospective study on functional recovery is ongoing (NCT04541745). TRIAL REGISTRATION: PROSPERO ID CRD42018116298. Registered on December 4, 2018.

Functional recovery of wrist surgery with regional versus general anesthesia: a prospective observational study.

PURPOSE: Regional anesthesia may favour postoperative rehabilitation by inhibiting peripheral sensitization and secondary hyperalgesia. The literature on this subject is limited. In the present FUNCTION study, we sought to compare the functional recovery post orthopedic wrist surgery with regional versus general anesthesia. METHODS: We conducted a single-centre prospective observational cohort study in adult patients with a distal radial fracture. Functional recovery was assessed with validated psychometrics questionnaires (Quick Disabilities of Arm, Shoulder and Hand [QuickDASH] and Patient-Rated Wrist Evaluation [PRWE]), range of motion, and grip strength. We used a linear mixed regression model to assess the impact of the anesthesia technique on functional recovery. Postoperative pain and patient satisfaction were evaluated using a visual analog scale. RESULTS: We recruited 76 patients. At 12 weeks post surgery, there was no difference between the type of anesthesia and functional recovery with the QuickDASH (higher scores worse; regional anesthesia [RA], 22.7 vs general anesthesia [GA], 19.3; adjusted mean difference [aMD], -0.3; 95% confidence interval [CI], -9.6 to 9.0; P = 0.9) and PRWE (higher scores worse; RA group, 21.0 vs GA group, 20.5; aMD, -3.3; 95% CI, -12.1 to 5.6; P = 0.93) questionnaires. Range of motion, satisfaction, and postoperative pain were similar between groups. Right-hand grip strength was higher in the GA group. CONCLUSION: Regional anesthesia was not associated with improved functional recovery compared with general anesthesia. The dominance of the operated limb was a confusion factor in all evaluation modalities. Further research taking into account the dominance of the hand is necessary to establish the effects of regional anesthesia on functional recovery. STUDY REGISTRATION: ClinicalTrials.gov (NCT04541745); registered 9 September 2020.

RéSUMé: OBJECTIF: L'anesthésie régionale pourrait favoriser la rééducation postopératoire en inhibant la sensibilisation périphérique et l'hyperalgésie secondaire. La littérature à ce sujet est limitée. Dans la présente étude nommée FUNCTION, nous avons cherché à comparer la récupération fonctionnelle après une chirurgie orthopédique du poignet réalisée sous anesthésie régionale vs sous anesthésie générale. MéTHODE: Nous avons réalisé une étude de cohorte observationnelle prospective monocentrique auprès de patient·es adultes présentant une fracture radiale distale. La récupération fonctionnelle a été évaluée à l'aide de questionnaires psychométriques validés (questionnaires QuickDASH [Quick Disabilities of Arm, Shoulder and Hand] et PRWE [Patient-Rated Wrist Evaluation]), de l'amplitude des mouvements et de la force de préhension. Nous avons utilisé un modèle de régression linéaire mixte pour évaluer l'impact de la technique d'anesthésie sur la récupération fonctionnelle. La douleur postopératoire et la satisfaction des patient·es ont été évaluées à l'aide d'une échelle visuelle analogique. RéSULTATS: Nous avons recruté 76 personnes. Douze semaines après la chirurgie, il n'y avait aucune différence entre le type d'anesthésie et la récupération fonctionnelle selon le questionnaire QuickDASH (scores plus élevés les pires; anesthésie régionale [AR], 22,7 vs anesthésie générale [AG], 19,3; différence moyenne ajustée [DMa], −0,3; intervalle de confiance [IC] à 95 %, −9,6 à 9,0; P = 0,9) et PRWE (scores plus élevés les pires; groupe AR, 21,0 vs groupe AG, 20,5; DMa, −3,3; IC 95 %, −12,1 à 5,6; P = 0,93). L'amplitude des mouvements, la satisfaction et la douleur postopératoire étaient similaires entre les groupes. La force de préhension de la main droite était plus élevée dans le groupe AG. CONCLUSION: L'anesthésie régionale n'a pas été associée à une amélioration de la récupération fonctionnelle par rapport à l'anesthésie générale. La prédominance du membre opéré était un facteur de confusion dans toutes les modalités d'évaluation. D'autres recherches tenant compte du côté dominant au niveau des mains sont nécessaires pour déterminer les effets de l'anesthésie régionale sur la récupération fonctionnelle. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT04541745); enregistrée le 9 septembre 2020.

Opioids for Cesarean delivery under general anesthesia and neonatal outcome: a historical cohort study.

PURPOSE: The lack of evidence-based recommendations for Cesarean delivery under general anesthesia can lead to practice variability and morbidity, particularly concerning the use of opioids. The goal of this study was to describe the practice for Cesarean delivery performed under general anesthesia and identify predictive factors for opioid use at anesthesia induction and the need for neonatal resuscitation. METHODS: We conducted a single-center historical cohort study. We included all adult parturients who underwent Cesarean delivery under general anesthesia between 1 January 2012 and 31 December 2016. We excluded patients who received general anesthesia after delivery or with known intrauterine fetal demise. We collected data on anesthetic medication use, maternal comorbidities, neonatal resuscitation, and anesthetic complications. We used logistic regression models to identify predictors of opioid use at anesthesia induction and predictors of neonatal resuscitation. RESULTS: Two hundred and three patients were included. Propofol was the main induction agent (n = 195), 201 patients received neuromuscular blockers, and 67 received opioids. No maternal factors, including hypertensive disorders of pregnancy (odds ratio [OR], 1.94; 95% confidence interval [CI], 0.96 to 3.95; P = 0.06), were predictors of opioid use at induction of anesthesia. No statistical differences were detected between opioid administration groups, except for Cesarean indication, with preeclampsia being the main contributor. Low gestational age (OR, 0.75; 95% CI, 0.65 to 0.87; P = 0.002) was the only predictor of neonatal resuscitation. CONCLUSION: Hypertensive disorders of pregnancy were not predictors of opioid use and opioid use was not a predictor of neonatal resuscitation. This suggests opioids could be used for maternal indications.

RéSUMé: OBJECTIF: L'absence de recommandations fondées sur des données probantes pour les accouchements par césarienne sous anesthésie générale peut entraîner une variabilité de la pratique et une morbidité, en particulier en ce qui concerne l'utilisation d'opioïdes. L'objectif de cette étude était de décrire la pratique pour les accouchements par césarienne réalisés sous anesthésie générale ainsi que d'identifier les facteurs prédictifs d'une utilisation d'opioïdes lors de l'induction de l'anesthésie et la nécessité d'une réanimation néonatale. MéTHODE: Nous avons mené une étude de cohorte historique monocentrique. Nous avons inclus toutes les parturientes adultes qui ont accouché par césarienne sous anesthésie générale entre le 1er janvier 2012 et le 31 décembre 2016. Nous avons exclu les patientes ayant reçu une anesthésie générale après l'accouchement ou ayant subi une mort fœtale intra-utérine connue. Nous avons recueilli des données sur l'utilisation de médicaments anesthésiques, les comorbidités maternelles, la réanimation néonatale et les complications anesthésiques. Nous avons utilisé des modèles de régression logistique pour identifier les prédicteurs d'une utilisation d'opioïdes lors de l'induction de l'anesthésie et les prédicteurs de réanimation néonatale. RéSULTATS: Deux cent trois patientes ont été incluses. Le propofol était le principal agent d'induction (n = 195), 201 patientes ont reçu des bloqueurs neuromusculaires et 67 ont reçu des opioïdes. Aucun facteur maternel, y compris les troubles hypertensifs de la grossesse (rapport de cotes [RC], 1,94; intervalle de confiance [IC] à 95 %, 0,96 à 3,95; P = 0,06), n'était un prédicteur d'utilisation d'opioïdes au moment de l'induction de l'anesthésie. Aucune différence statistique n'a été détectée entre les groupes d'administration d'opioïdes, à l'exception de l'indication de césarienne, la prééclampsie étant le principal contributeur. Un âge gestationnel bas (RC, 0,75; IC 95 %, 0,65 à 0,87; P = 0,002) était le seul prédicteur de réanimation néonatale. CONCLUSION: Les troubles hypertensifs de la grossesse n'étaient pas des prédicteurs de l'utilisation d'opioïdes et l'utilisation d'opioïdes n'était pas un prédicteur de réanimation néonatale. Cela suggère que les opioïdes pourraient être utilisés pour des indications maternelles.

Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). Design, Setting, and Participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. Main Outcomes and Measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001). Conclusions and Relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02462590.

Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study.

BACKGROUND: Host-associated microbial communities have important roles in tissue homeostasis and overall health. Severe perturbations can occur within these microbial communities during critical illness due to underlying diseases and clinical interventions, potentially influencing patient outcomes. We sought to profile the microbial composition of critically ill mechanically ventilated patients, and to determine whether microbial diversity is associated with illness severity and mortality. METHODS: We conducted a prospective, observational study of mechanically ventilated critically ill patients with a high incidence of pneumonia in 2 intensive care units (ICUs) in Hamilton, Canada, nested within a randomized trial for the prevention of healthcare-associated infections. The microbial profiles of specimens from 3 anatomical sites (respiratory, and upper and lower gastrointestinal tracts) were characterized using 16S ribosomal RNA gene sequencing. RESULTS: We collected 65 specimens from 34 ICU patients enrolled in the trial (29 endotracheal aspirates, 26 gastric aspirates and 10 stool specimens). Specimens were collected at a median time of 3 days (lower respiratory tract and gastric aspirates; interquartile range [IQR] 2-4) and 6 days (stool; IQR 4.25-6.75) following ICU admission. We observed a loss of biogeographical distinction between the lower respiratory tract and gastrointestinal tract microbiota during critical illness. Moreover, microbial diversity in the respiratory tract was inversely correlated with APACHE II score (r = - 0.46, p = 0.013) and was associated with hospital mortality (Median Shannon index: Discharged alive; 1.964 vs. Deceased; 1.348, p = 0.045). CONCLUSIONS: The composition of the host-associated microbial communities is severely perturbed during critical illness. Reduced microbial diversity reflects high illness severity and is associated with mortality. Microbial diversity may be a biomarker of prognostic value in mechanically ventilated patients. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01782755 . Registered February 4 2013.

Coagulase-negative staphylococci species affect biofilm formation of other coagulase-negative and coagulase-positive staphylococci.

Coagulase-negative staphylococci (CNS) are considered to be commensal bacteria in humans and animals, but are now also recognized as etiological agents in several infections, including bovine mastitis. Biofilm formation appears to be an important factor in CNS pathogenicity. Furthermore, some researchers have proposed that CNS colonization of the intramammary environment has a protective effect against other pathogens. The mechanisms behind the protective effect of CNS have yet to be characterized. The aim of this study was to evaluate the effect of CNS isolates with a weak-biofilm phenotype on the biofilm formation of other staphylococcal isolates. We selected 10 CNS with a weak-biofilm phenotype and 30 staphylococcal isolates with a strong-biofilm phenotype for this study. We measured biofilm production by individual isolates using a standard polystyrene microtiter plate assay and compared the findings with biofilm produced in mixed cultures. We confirmed the results using confocal microscopy and a microfluidic system with low shear force. Four of the CNS isolates with a weak-biofilm phenotype (Staphylococcus chromogenes C and E and Staphylococcus simulans F and H) significantly reduced biofilm formation in approximately 80% of the staphylococcal species tested, including coagulase-positive Staphylococcus aureus. The 4 Staph. chromogenes and Staph. simulans isolates were also able to disperse pre-established biofilms, but to a lesser extent. We also performed a deferred antagonism assay and recorded the number of colony-forming units in the mixed-biofilm assays on differential or selective agar plates. Overall, CNS with a weak-biofilm phenotype did not inhibit the growth of isolates with a strong-biofilm phenotype. These results suggest that some CNS isolates can negatively affect the ability of other staphylococcal isolates and species to form biofilms via a mechanism that does not involve growth inhibition.

Characterization of the ability of coagulase-negative staphylococci isolated from the milk of Canadian farms to form biofilms.

Mastitis is the most common and detrimental infection of the mammary gland in dairy cows and has a major economic impact on the production of milk and dairy products. Bacterial mastitis is caused by several pathogens, and the most frequently isolated bacterial species are coagulase-negative staphylocci (CNS). Although CNS are considered minor mastitis pathogens, the importance of CNS has increased over the years. However, the mechanism and factors involved in CNS intramammary infection are poorly studied and defined. Biofilms have been proposed as an important component in the persistence of CNS intramammary infection. Biofilms are defined as a cluster of bacteria enclosed in a self-produced matrix. The objectives of this study were to investigate the ability of CNS to form biofilms. A total of 255 mastitis-associated CNS isolates were investigated using a standard microtiter plate biofilm assay. The biofilms of some isolates were also observed by using confocal microscopy. The presence of biofilm-associated genes icaA, bap, aap, embP, fbe, and atlE was determined by PCR in the 255 isolates. The 5 dominant species assayed were Staphylococcus chromogenes (n=111), Staphylococcus simulans (n=53), Staphylococcus xylosus (n=25), Staphylococcus haemolyticus (n=15), and Staphylococcus epidermidis (n=13), and these represented 85% of the isolates. The data gathered were analyzed to identify significant links with the data deposited in the Canadian Bovine Mastitis Research Network database. Overall, Staph. xylosus is the species with the strongest ability to form biofilm, and Staph. epidermidis is the species with the lowest ability to form biofilm. Regardless of the species, the presence of icaA, bap, or the combination of multiple genes was associated with a greater ability to form biofilm. A strong relationship between the strength of a biofilm and days in milk was also noted, and CNS isolated later in the lactation cycle appeared to have a greater ability to form biofilm than those isolated earlier in the lactation cycle. In conclusion, Staph. xylosus is the species with the strongest biofilm formation ability. Furthermore, days in milk and gene combinations are predicted to be the variables with the strongest effect on biofilm formation by CNS.

Definitions, rates and associated mortality of ICU-acquired pneumonia: A multicenter cohort study.

INTRODUCTION: We aimed to analyze intensive care unit (ICU)-acquired pneumonia according to 7 definitions, estimating associated hospital mortality. METHODS: This cohort study was nested within an international randomized trial, evaluating the effect of probiotics on ICU-acquired pneumonia in 2650 mechanically ventilated adults. Each clinically suspected pneumonia was adjudicated by two physicians blinded to allocation and center. The primary outcome was ventilator-associated pneumonia (VAP) informed by ventilation for ≥2 days, new, progressive or persistent infiltrate plus 2 of: temperature > 38 °C or < 36 °C; leukopenia (<3 × 10(Fernando et al., 20206)/L) or leukocytosis (>10 × 10(Fernando et al., 20206)/L); and purulent sputum. We also used 6 other definitions estimating the risk of hospital mortality. RESULTS: The frequency of ICU-acquired pneumonia varied by definition: the trial primary outcome VAP (21.6%), Clinical Pulmonary Infection Score (CPIS) (24.9%), American College Chest Physicians (ACCP) (25.0%), International Sepsis Forum (ISF) (24.4%), Reducing Oxidative Stress Study (REDOXS) (17.6%), Centers for Disease Control (CDC) (7.8%), and invasively microbiologically confirmed (1.9%). The trial primary outcome VAP (HR 1.31 [1.08, 1.60]), ISF (HR 1.32 [1.09,1.60]), CPIS (HR 1.30 [1.08,1.58]) and ACCP definitions (HR 1.22 [1.00,1.47]) were associated with hospital mortality. CONCLUSIONS: Rates of ICU-acquired pneumonia vary by definition and are associated with differential increased risk of death.

Program of Uncontrolled Donation After Circulatory Death as Potential Solution to the Shortage of Organs: A Canadian Single-Center Retrospective Cohort Study.

Purpose: Worldwide, the number of patients waiting for organ transplantation exceeds the number of organs available. Program for uncontrolled donation after circulatory death (uDCD) implemented in Europe has resulted in a 10-15% expansion of the donor pool. We aimed to describe the number of patients eligible for an uDCD program in a regional tertiary care center. Methods: We conducted a retrospective cohort study in a Canadian tertiary academic center located in a rural area including all adults who received cardiopulmonary resuscitation in 2016 and died in the emergency department (ED) or during their hospitalization. The primary outcome was the number of patients eligible for uDCD defined as aged between 18 and 60 years old whose collapse was witnessed and where the time between cardiac arrest to cardiopulmonary resuscitation and ED arrival was, respectively, less than 30 and 120 minutes. As a secondary outcome, we determined the number of patients eligible for controlled donation after circulatory death. Results: Of the 130 patients included, 84 did not return to spontaneous circulation. We identified 15 potential uDCD candidates, with a mean age of 46.6 (95% Confidence Interval [CI] 41.3 to 52) years. Twelve had an out-of-hospital cardiac arrest with a mean time between collapse and arrival to the ED of 43.2 (29.8 to 56.6) minutes. Among the 46 patients who died after a return of spontaneous circulation, 10 (21.7%) were eligible for organ donation after circulatory death. Conclusion: Implementing an uDCD program in a tertiary hospital covering a rural area could increase the number of donors.

Time-course full profiling of circulating miRNAs in neurologically deceased organ donors: a proof of concept study to understand the onset of the cytokine storm.

Neurologically deceased organ donors (NDDs) generally display an immune response involving an intense production of pro-inflammatory cytokines referred to as the cytokine storm. The sudden surge of inflammatory mediators in circulation promotes tissue and organ damages and ultimately leads to poor transplant outcome. As microRNAs (miRNAs) are frequently proposed as key regulators of inflammation and are relatively stable in circulation, changes in their profiles could play a role in the onset of the cytokine storm in NDDs. In this proof-of-concept study, we sought to investigate differentially abundant circulating miRNAs in a temporal manner between neurological death and organ recovery and to assess the association between specific miRNAs and levels of inflammatory cytokines in blood. Plasma samples from five NDDs were obtained at multiple time points between organ donation consent and organ recovery. Using a time-course analysis and miRNA sequencing, we identified 32 plasma miRNAs fluctuating between consent and organ recovery (false discovery rate; q-value < 0.1). Eleven miRNAs relatively abundant (>100 reads) and detected in all samples were selected for further biological pathway analysis (miR-486-3p, miR-103a-3p, miR-106b-3p, miR-182-5p, miR-101-3p, miR-10a-5p, miR-125a-5p, miR-146b-5p, miR-26a-5p, miR-423-5p, miR-92b-3p). These miRNAs targeted genes such as c-JUN (TNF signalling pathway) and eEF2 (AMPK pathway), suggesting a potential role in regulation of inflammation. Our results contribute to a better understanding of the miRNAs dynamic after neurological death in organ donors and could potentially be used to predict the related early cytokine storm.Trial registration: ClinicalTrials.gov ID NCT03786991. Registered December 2018.

Nasal Tissue Extraction Is Essential for Characterization of the Murine Upper Respiratory Tract Microbiota.

Respiratory infections are a leading cause of morbidity and mortality worldwide. Bacterial pathogens often colonize the upper respiratory tract (nose or mouth) prior to causing lower respiratory infections or invasive disease. Interactions within the upper respiratory tract between colonizing bacteria and the resident microbiota could contribute to colonization success and subsequent transmission. Human carriage studies have identified associations between pathogens such as Streptococcus pneumoniae and members of the resident microbiota, although few mechanisms of competition and cooperation have been identified and would be aided by the use of animal models. Little is known about the composition of the murine nasal microbiota; thus, we set out to improve assessment, including tissue sampling, composition, and comparison between mouse sources. Nasal washes were efficient in sampling the nasopharyngeal space but barely disrupted the nasal turbinates. Nasal tissue extraction increased the yield of cultivable bacterial compared to nasal washes, revealing distinct community compositions. Experimental pneumococcal colonization led to dominance by the colonizing pathogen in the nasopharynx and nasal turbinates, but the composition of the microbiota, and interactions with resident microbes, differed depending on the sampling method. Importantly, vendor source has a large impact on microbial composition. Bacterial interactions, including cooperation and colonization resistance, depend on the biogeography of the nose and should be considered during research design of experimental colonization with pathogens.IMPORTANCE The nasal microbiota is composed of species that play a role in the colonization success of pathogens, including Streptococcus pneumoniae and Staphylococcus aureus Murine models provide the ability to explore disease pathogenesis, but little is known about the natural murine nasal microbiota. This study established techniques to allow the exploration of the bacterial members of the nasal microbiota. The mouse nasal microbiota included traditional respiratory bacteria, including Streptococcus, Staphylococcus, and Moraxella species. Analyses were affected by different sampling methods as well as the commercial source of the mice, which should be included in future research design of infectious disease research.

Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection in critically ill patients. Prior studies suggest that probiotics may reduce VAP and other infections in critically ill patients; however, most previous randomised trials were small, single centre studies. The Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) aims to determine the impact of the probiotic Lactobacillus rhamnosus GG on VAP and other clinically important outcomes in critically ill adults. METHODS: PROSPECT is a multicentre, concealed, randomised, stratified, blinded, controlled trial in patients ≥18 years old, anticipated to be mechanically ventilated ≥72 hours, in intensive care units (ICUs) in Canada, the USA and Saudi Arabia. Patients receive either 1×1010 colony forming units of L. rhamnosus GG twice daily or an identical appearing placebo. Those at increased risk of probiotic infection are excluded. The primary outcome is VAP. Secondary outcomes are other ICU-acquired infections including Clostridioides difficile infection, diarrhoea (including antibiotic-associated diarrhoea), antimicrobial use, ICU and hospital length of stay and mortality. The planned sample size of 2650 patients is based on an estimated 15% VAP rate and will provide 80% power to detect a 25% relative risk reduction. ETHICS AND DISSEMINATION: This protocol and statistical analysis plan outlines the methodology, primary and secondary analyses, sensitivity analyses and subgroup analyses. PROSPECT is approved by Health Canada (#9427-M1133-45C), the research ethics boards of all participating hospitals and Public Health Ontario. Results will be disseminated via academic channels (peer reviewed journal publications, professional healthcare fora including international conferences) and conventional and social media. The results of PROSPECT will inform practice guidelines worldwide. TRIALREGISTRATION NUMBER: NCT02462590; Pre-results.

Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial-PROSPECT: a pilot trial.

BACKGROUND: Probiotics are live microorganisms that may confer health benefits when ingested. Randomized trials suggest that probiotics significantly decrease the incidence of ventilator-associated pneumonia (VAP) and the overall incidence of infection in critically ill patients. However, these studies are small, largely single-center, and at risk of bias. The aim of the PROSPECT pilot trial was to determine the feasibility of conducting a larger trial of probiotics to prevent VAP in mechanically ventilated patients in the intensive care unit (ICU). METHODS: In a randomized blinded trial, patients expected to be mechanically ventilated for ≥72 hours were allocated to receive either 1 × 10(10) colony-forming units of Lactobacillus rhamnosus GG or placebo, twice daily. Patients were excluded if they were at increased risk of L. rhamnosus GG infection or had contraindications to enteral medication. Feasibility objectives were: (1) timely recruitment; (2) maximal protocol adherence; (3) minimal contamination; and (4) estimated VAP rate ≥10 %. We also measured other infections, diarrhea, ICU and hospital length of stay, and mortality. RESULTS: Overall, in 14 centers in Canada and the USA, all feasibility goals were met: (1) 150 patients were randomized in 1 year; (2) protocol adherence was 97 %; (3) no patients received open-label probiotics; and (4) the VAP rate was 19 %. Other infections included: bloodstream infection (19.3 %), urinary tract infections (12.7 %), and skin and soft tissue infections (4.0 %). Diarrhea, defined as Bristol type 6 or 7 stools, occurred in 133 (88.7 %) of patients, the median length of stay in ICU was 12 days (quartile 1 to quartile 3, 7-18 days), and in hospital was 26 days (quartile 1 to quartile 3, 14-44 days); 23 patients (15.3 %) died in the ICU. CONCLUSIONS: The PROSPECT pilot trial supports the feasibility of a larger trial to investigate the effect of L. rhamnosus GG on VAP and other nosocomial infections in critically ill patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01782755 . Registered on 29 January 2013.