A multifaceted strategy to optimize pharmacokinetics of antimicrobial therapy in patients with hospital-acquired infections-a monocentre quality improvement project.

OBJECTIVE: We assessed the efficacy of a quality improvement programme to optimize the delivery of antimicrobial therapy in critically ill patients with hospital-acquired infections (HAI). PATIENTS AND METHODS: Before-after trial in a university hospital in France. Consecutive adults receiving systemic antimicrobial therapy for HAI were included. Patients received standard care during the pre-intervention period (June 2017 to November 2017). The quality improvement programme was implemented in December 2017. During the intervention period (January 2018 to June 2019), clinicians were trained to dose adjustment based on therapeutic drug monitoring and continuous infusion of ß-lactam antibiotics. The primary endpoint was the mortality rate at day 90. RESULTS: A total of 198 patients were included (58 pre-intervention, 140 intervention). The compliance with the therapeutic drug monitoring-dose adaptation increased from 20.3% to 59.3% after the intervention (P < 0.0001). The 90-day mortality rate was 27.6% in the pre-intervention period and 17.3% in the intervention group (adjusted relative risk 0.53, 95%CI 0.27-1.07, P = 0.08). Treatment failures were observed in 22 (37.9%) patients before and 36 (25.7%) patients after the intervention (P = 0.07). CONCLUSIONS: Recommendations for therapeutic drug monitoring-dose adaptation and continuous infusion of ß-lactam antibiotics were not associated with a reduction in the 90-day mortality rate in patients with HAI.

Mechanical ventilation in patients with acute brain injury: a systematic review with meta-analysis.

OBJECTIVE: To describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation. DESIGN: Systematic review with an individual data meta-analysis. SETTING: Observational and interventional (before/after) studies published up to August 22nd, 2022, were considered for inclusion. We investigated the effects of low tidal volume Vt < 8 ml/Kg of IBW versus Vt > = 8 ml/Kg of IBW, positive end-expiratory pressure (PEEP) < or > = 5 cmH2O and protective ventilation (association of both) on relevant clinical outcomes. POPULATION: Patients with acute brain injury (trauma or haemorrhagic stroke) with invasive mechanical ventilation for ≥ 24 h. MAIN OUTCOME MEASURES: The primary outcome was mortality at 28 days or in-hospital mortality. Secondary outcomes were the incidence of acute respiratory distress syndrome (ARDS), the duration of mechanical ventilation and the partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio. RESULTS: The meta-analysis included eight studies with a total of 5639 patients. There was no difference in mortality between low and high tidal volume [Odds Ratio, OR 0.88 (95%Confidence Interval, CI 0.74 to 1.05), p = 0.16, I2 = 20%], low and moderate to high PEEP [OR 0.8 (95% CI 0.59 to 1.07), p = 0.13, I2 = 80%] or protective and non-protective ventilation [OR 1.03 (95% CI 0.93 to 1.15), p = 0.6, I2 = 11]. Low tidal volume [OR 0.74 (95% CI 0.45 to 1.21, p = 0.23, I2 = 88%], moderate PEEP [OR 0.98 (95% CI 0.76 to 1.26), p = 0.9, I2 = 21%] or protective ventilation [OR 1.22 (95% CI 0.94 to 1.58), p = 0.13, I2 = 22%] did not affect the incidence of acute respiratory distress syndrome. Protective ventilation improved the PaO2/FiO2 ratio in the first five days of mechanical ventilation (p < 0.01). CONCLUSIONS: Low tidal volume, moderate to high PEEP, or protective ventilation were not associated with mortality and lower incidence of ARDS in patients with acute brain injury undergoing invasive mechanical ventilation. However, protective ventilation improved oxygenation and could be safely considered in this setting. The exact role of ventilatory management on the outcome of patients with a severe brain injury needs to be more accurately delineated.

Cortisol total/CRP ratio for the prediction of hospital-acquired pneumonia and initiation of corticosteroid therapy in traumatic brain-injured patients.

BACKGROUND: To propose a combination of blood biomarkers for the prediction of hospital-acquired pneumonia (HAP) and for the selection of traumatic brain-injured (TBI) patients eligible for corticosteroid therapy for the prevention of HAP. METHODS: This was a sub-study of the CORTI-TC trial, a multicenter, randomized, double-blind, controlled trial evaluating the risk of HAP at day 28 in 336 TBI patients treated or not with corticosteroid therapy. Patients were between 15 and 65 years with severe traumatic brain injury (Glasgow coma scale score ≤ 8 and trauma-associated lesion on brain CT scan) and were enrolled within 24 h of trauma. The blood levels of CRP and cortisoltotal&free, as a surrogate marker of the pro/anti-inflammatory response balance, were measured in samples collected before the treatment initiation. Endpoint was HAP on day 28. RESULTS: Of the 179 patients with available samples, 89 (49.7%) developed an HAP. Cortisoltotal&free and CRP blood levels upon ICU admission were not significantly different between patients with or without HAP. The cortisoltotal/CRP ratio upon admission was 2.30 [1.25-3.91] in patients without HAP and 3.36 [1.74-5.09] in patients with HAP (p = 0.021). In multivariate analysis, a cortisoltotal/CRP ratio > 3, selected upon the best Youden index on the ROC curve, was independently associated with HAP (OR 2.50, CI95% [1.34-4.64] p = 0.004). The HR for HAP with corticosteroid treatment was 0.59 (CI95% [0.34-1.00], p = 0.005) in patients with a cortisoltotal/CRP ratio > 3, and 0.89 (CI95% [0.49-1.64], p = 0.85) in patients with a ratio < 3. CONCLUSION: A cortisoltotal/CRP ratio > 3 upon admission may predict the development of HAP in severe TBI. Among these patients, corticosteroids reduce the occurrence HAP. We suggest that this ratio may select the patients who may benefit from corticosteroid therapy for the prevention of HAP.

A systematic review of reported outcomes in randomized controlled trials targeting early interventions in moderate-to-severe traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Randomized controlled trials (RCTs) are the cornerstone to evaluate the efficacy of an intervention. In order to assess the methodology of clinical research, we performed a systematic review which evaluated the different outcomes used in RCTs targeting the early phase of moderate to severe adult TBI from 1983 to October 31, 2023. We extracted each outcome and organized them according to the COMET and OMERACT framework (core area, broad domains, target domains and finally outcomes). 190 RCTs were included, including 52,010 participants. 557 outcomes were reported and classified between the following core areas: pathophysiological manifestations (169 RCTs (88.9%)), life impact (117 RCTs (61.6%)), death (94 RCTs (49.5%)), resource use (72 RCTs (37.9%)) and adverse events (41 RCTs (21.6%)). We identified 29 broad domains and 89 target domains. Among target domains, physical functioning (111 (58.4%)), mortality (94 (49.5%)), intra-cranial pressure target domain (68 (35.8%)), hemodynamics (53 (27.9%)) were the most frequent. Outcomes were mostly clinician-reported (177 (93.2%)) while patient-reported outcomes were rarely reported (11 (5.8%)). In our review, there was significant heterogeneity in the choice of endpoints in TBI clinical research. There is an urgent need for consensus and homogeneity in order to improve the quality of clinical research in this area.

Clinical evaluation of the BioFire Respiratory Pathogen Panel for the guidance of empirical antimicrobial therapy in critically ill patients with hospital-acquired pneumonia: A multicenter, quality improvement project.

BACKGROUND: We aimed to determine whether implementing antimicrobial stewardship based on multiplex bacterial PCR examination of respiratory fluid can enhance outcomes of critically ill patients with hospital-acquired pneumonia (HAP). METHODS: We conducted a quality improvement study in two hospitals in France. Adult patients requiring invasive mechanical ventilation with a diagnosis of HAP were included. In the pre-intervention period (August 2019 to April 2020), antimicrobial therapy followed European guidelines. In the «intervention¼ phase (June 2020 to October 2021), treatment followed a multiplex PCR-guided protocol. The primary endpoint was a composite endpoint made of mortality on day 28, clinical cure between days 7 and 10, and duration of invasive mechanical ventilation on day 28. The primary outcome was analyzed with a DOOR strategy. RESULTS: A total of 443 patients were included in 3 ICUs from 2 hospitals (220 pre-intervention; 223 intervention). No difference in the ranking of the primary composite outcome was found (DOOR: 50.3%; 95%CI, 49.9%-50.8%). The number of invasive mechanical ventilation-free days at day 28 was 10.0 [0.0; 19.0] in the baseline period and 9.0 [0.0; 20.0] days during the intervention period (p = 0.95). The time-to-efficient antimicrobial treatment was 0.43 ± 1.29 days before versus 0.55 ± 1.13 days after the intervention (p = 0.56). CONCLUSION: Implementation of Rapid Multiplex PCR to guide empirical antimicrobial therapy for critically ill patients with HAP was not associated with better outcomes. However, adherence to stewardship was low, and the study may have had limited power to detect a clinically important difference.

Effect of continuous infusion of hypertonic saline solution on survival of patients with brain injury: a systematic review and meta-analysis.

BACKGROUND: The objective was to determine the effects of continuous infusion of hypertonic saline solutions on outcomes of patients with brain injury. METHODS: Preferred Reported Items for Systemic Reviews and Meta-Analysis guidelines were followed. We searched the MEDLINE and COCHRANE clinical trials register (through December 2021) and reference lists of articles. We included all clinical trials conducted in brain-injured patients hospitalized in intensive care units evaluating continuous infusion of hypertonic saline solution (osmolarity above 308 mOsm/L). Two reviewers extracted data that were checked by two others. The primary outcome was the in-hospital mortality rate. The main secondary outcomes were the rates of intracranial hypertension, an unfavorable neurological outcome at day 90, and adverse events. RESULTS: We identified 23 clinical trials reporting the use of continuous infusion of hypertonic saline solution in brain-injured patients. The primary outcome was available in 10 studies (n = 1883 patients). The odds ratio (OR) for in-hospital death with the intervention was 0.68 (95% confidence interval (CI), 0.54-0.85, I2 = 0%). In the subgroup of studies including only traumatic brain-injured patients (7 studies, n = 1521 patients), the OR for the primary outcome was 0.74 (95%CI 0.57-0.95) with the intervention. The OR for intracranial hypertension and unfavorable neurological outcome at day 90 were 0.66 (95%CI 0.49-0.88, I2 = 42%, n = 787 patients) and 0.61 (95%CI 0.46-0.81, I2 = 15%, n = 956 patients), respectively. Regarding safety, the OR of acute kidney injury and severe hypernatremia were 0.82 (95%CI 0.47-1.44, I2 = 0%) and 3.38 (95%CI 2.16-5.27, I2 = 24%). CONCLUSIONS: Continuous hypertonic saline solution infusion reduced in-hospital mortality without increasing the risk of unfavorable neurological outcome at day 90 in brain-injured patients hospitalized in intensive care units. Given the inclusion of observational and heterogeneous studies, further randomized studies are needed before developing recommendations for implementation at the bedside. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021221367. Registered 13 May 2021.

Cost effectiveness and long-term outcomes of dexamethasone administration in major non-cardiac surgery.

STUDY OBJECTIVES: Postoperative administration of dexamethasone has been proposed to reduce morbidity and mortality in patients undergoing major non-cardiac surgery. In this ancillary study of the PACMAN trial, we aimed to evaluate the cost effectiveness of dexamethasone in patients undergoing major non-cardiac surgery. METHODS: Patients included in the multicentric randomized double-blind, placebo-controlled PACMAN trial were followed up for 12 months after their surgical procedure. Patients were randomized to receive either dexamethasone (0.2 mg/kg immediately after the surgical procedure, and on day 1) or placebo. Cost effectiveness between the dexamethasone and placebo groups was assessed for the 12-month postoperative period from a health payer perspective. RESULTS: Of 1222 randomized patients in PACMAN, 137 patients (11%) were followed up until 12 months after major surgery (71 in the DXM group and 66 in the placebo group). Postoperative dexamethasone administration reduced costs per patient at 1 year by €358.06 (95%CI -€1519.99 to €803.87). The probability of dexamethasone being cost effective was between 12% and 22% for a willingness to pay of €100,000 to €150,000 per life-year, which is the threshold that is usually used in France and was 52% for willingness to pay of €50,000 per life-year (threshold in USA). At 12 months, 9 patients (13.2%) in the DXM group and 10 patients (16.1%) in the placebo group had died. In conclusion, our study does not demonstrate the cost effectiveness of perioperative administration of DXM in major non-cardiac surgery.

Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial.

PURPOSE: We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechanically ventilated patients. METHODS: In a multicenter, placebo-controlled, randomized trial conducted in 11 European hospitals, we randomly assigned critically ill adults, with one or more acute organ failures, under mechanical ventilation to receive interferon gamma-1b (100 µg every 48 h from day 1 to 9) or placebo (following the same regimen). The primary outcome was a composite of hospital-acquired pneumonia or all-cause mortality on day 28. The planned sample size was 200 with interim safety analyses after enrolling 50 and 100 patients. RESULTS: The study was discontinued after the second safety analysis for potential harm with interferon gamma-1b, and the follow-up was completed in June 2022. Among 109 randomized patients (median age, 57 (41-66) years; 37 (33.9%) women; all included in France), 108 (99%) completed the trial. Twenty-eight days after inclusion, 26 of 55 participants (47.3%) in the interferon-gamma group and 16 of 53 (30.2%) in the placebo group had hospital-acquired pneumonia or died (adjusted hazard ratio (HR) 1.76, 95% confidence interval (CI) 0.94-3.29; P = 0.08). Serious adverse events were reported in 24 of 55 participants (43.6%) in the interferon-gamma group and 17 of 54 (31.5%) in the placebo group (P = 0.19). In an exploratory analysis, we found that hospital-acquired pneumonia developed in a subgroup of patients with decreased CCL17 response to interferon-gamma treatment. CONCLUSIONS: Among mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b compared with placebo did not significantly reduce the incidence of hospital-acquired pneumonia or death on day 28. Furthermore, the trial was discontinued early due to safety concerns about interferon gamma-1b treatment.

Immune modulation after traumatic brain injury.

Traumatic brain injury (TBI) induces instant activation of innate immunity in brain tissue, followed by a systematization of the inflammatory response. The subsequent response, evolved to limit an overwhelming systemic inflammatory response and to induce healing, involves the autonomic nervous system, hormonal systems, and the regulation of immune cells. This physiological response induces an immunosuppression and tolerance state that promotes to the occurrence of secondary infections. This review describes the immunological consequences of TBI and highlights potential novel therapeutic approaches using immune modulation to restore homeostasis between the nervous system and innate immunity.

Potential Impact of Rapid Multiplex PCR on Antimicrobial Therapy Guidance for Ventilated Hospital-Acquired Pneumonia in Critically Ill Patients, A Prospective Observational Clinical and Economic Study.

Objectives: To investigate the potential impact of the syndromic multiplex FilmArray® Pneumonia plus Panel (FAPP) on the antimicrobial treatment guidance of patients with ventilated hospital-acquired pneumonia (VHAP). Methods: Respiratory fluids from 100 adult patients with VHAP, receiving invasive mechanical ventilation in three intensive care units from one French university hospital, were tested prospectively using FAPP. Conventional cultures were performed in parallel as routine practice. Clinicians were left blinded to the FAPP results. Antimicrobial therapies based on FAPP results were simulated by independent blinded experts according to a predefined algorithm and compared to 1) those prescribed in practice according to local guidelines (real-life), and 2) those that complied with the international ERS/ESICM/ESCMID/ALAT recommendations. The primary endpoint was the number of days of broad-spectrum antimicrobial therapy. Secondary endpoints were the rates of microbiological treatment failure and cost-effectiveness ratio. Results: The predicted median duration of broad-spectrum antibiotics was 0 [0-1.25] day in the FAPP-based simulation, versus 2 [0-6] days in real-life (p<0.0001) and 2 [2-3.25] days in the recommendations-based simulation (p<0.0001). Treatment failure was predicted in 3% of cases with FAPP results versus observed in 11% in real-life (p=0.08) and 6% with recommendations-based simulation (p=0.37). The incremental cost-effectiveness ratio was 1 121 € [-7021; 6794] to avoid one day of non-optimized antimicrobial therapy. Conclusions: Our results suggest that using FAPP in patients with VHAP has the potential to reduce the use of broad-spectrum antimicrobial therapy without increasing the risk of microbial treatment failure.

Evaluation of the FilmArray® Pneumonia Plus Panel for Rapid Diagnosis of Hospital-Acquired Pneumonia in Intensive Care Unit Patients.

The FilmArray® Pneumonia plus Panel (FAPP) is a new multiplex molecular test for hospital-acquired pneumonia (HAP), which can rapidly detect 18 bacteria, 9 viruses, and 7 resistance genes. We aimed to compare the diagnosis performance of FAPP with conventional testing in 100 intensive care unit (ICU) patients who required mechanical ventilation, with clinically suspected HAP. A total of 237 samples [76 bronchoalveolar lavages (BALDS) and 82 endotracheal aspirates (ETADS) obtained at HAP diagnosis, and 79 ETA obtained during follow-up (ETATT)], were analyzed independently by routine microbiology testing and FAPP. 58 patients had paired BALDS and ETADS. The positivity thresholds of semi-quantified bacteria were 103-104 CFUs/mL or 104 copies/mL for BAL, and 105 CFUs/mL or copies/mL for ETA. Respiratory commensals (H. influenzae, S. aureus, E. coli, S. pneumoniae) were the most common pathogens. Discordant results for bacterial identification were observed in 33/76 (43.4%) BALDS and 36/82 (43.9%) ETADS, and in most cases, FAPP identified one supplemental bacteria (23/33 BALDS and 21/36 ETADS). An absence of growth, or polybacterial cultures, explained almost equally the majority of the non-detections in culture. No linear relationship was observed between bin and CFUs/mL variables. Concordant results between paired BALDS and ETADS were obtained in 46/58 (79.3%) patients with FAPP. One of the 17 resistance genes detected with FAPP (mecA/C and MREJ) was not confirmed by conventional testing. Overall, FAPP enhanced the positivity rate of diagnostic testing, with increased recognition of coinfections. Implementing this strategy may allow clinicians to make more timely and informed decisions.

Impact of a Quality Improvement Program on the Neurological Outcome of Patients with Traumatic Spinal Cord Injury: A Before-After Mono-Centric Study.

Spinal cord injury (SCI) is a major cause of severe disability. This study aims to assess the effectiveness of a quality improvement program on neurological recovery after SCI. Before-after study during two phases was done in one intensive care unit in a university hospital. The quality improvement project comprised protective mechanical ventilation, early tracheostomy in anatomical injury above the sixth cervical vertebra, early enteral nutrition, early mobilization, and active perineal care in adult SCI patients. The primary endpoint was the difference between the American Spinal Injury Association (ASIA) motor score between discharge and intensive care unit (ICU) admission (Delta ASIA). Fifty-seven and 60 patients were included in the control and in the intervention period respectively. The ASIA motor score upon ICU admission was 16 (7-37) before and 11 (2-30) after the implementation (p = 0.30). The implementation phase was associated with lower tidal volumes (p < 0.001), higher positive end-expiratory pressure (p < 0.001), earlier tracheostomy (p = 0.01), earlier enteral nutrition initiation (p < 0.05), earlier mobilization (p < 0.05), and more active perineal care (p < 0.05). The Delta ASIA was +16 [4-32] after versus +6 [0-14] before the intervention (p < 0.05). After adjustment for potential cofounders, the intervention phase was significantly associated with higher Delta ASIA (ß coefficient, 11.4; CI95 [1.9-21]; p = 0.01) in multi-variable analysis. No secular time trend unrelated to the intervention was highlighted. One year after trauma, the Delta ASIA was higher in the intervention period than in the control period (+34 [15-60] vs. +11 [0-33]; p < 0.05). After adjustment on potential confounders, an early in-ICU rehabilitation program in SCI patients was associated with higher neurological score upon ICU discharge.

Contribution of Dendritic Cell Responses to Sepsis-Induced Immunosuppression and to Susceptibility to Secondary Pneumonia.

Dendritic cells (DCs) are bone marrow derived cells which continuously seed in peripheral tissue. During infection, DCs play an essential interface between innate and adaptive immunity. Pneumonia is a lung inflammation triggered by pathogens and is characterized by excessive release of inflammatory cytokines that activate innate and acquired immunity. Pneumonia induces a rapid and protracted state of susceptibility to secondary infection, a state so-called sepsis-induced immunosuppression. In this review, we focus on the role of DCs in the development of this state of immunosuppression. Early during inflammation, activated DCs are characterized by decreased capacity of antigen (cross)- presentation of newly encountered antigens and decreased production of immunogenic cytokines, and sepsis-induced immunosuppression is mainly explained by a depletion of immature DCs which had all become mature. At a later stage, newly formed respiratory immature DCs are locally programmed by an immunological scare left-over by inflammation to induce tolerance. Tolerogenic Blimp1+ DCs produce suppressive cytokines such as tumor growth factor-B and participate to the maintenance of a local tolerogenic environment notably characterized by accumulation of Treg cells. In mice, the restoration of the immunogenic functions of DCs restores the mucosal immune response to pathogens. In humans, the modulation of inflammation by glucocorticoid during sepsis or trauma preserves DC immunogenic functions and is associated with resistance to secondary pneumonia. Finally, we propose that the alterations of DCs during and after inflammation can be used as biomarkers of susceptibility to secondary pneumonia and are promising therapeutic targets to enhance outcomes of patients with secondary pneumonia.

Management and weaning from mechanical ventilation in neurologic patients.

In the early phase following severe brain injury (BI), mechanical ventilation (MV) is often needed to prevent airway from aspiration, control PaCO2 and PaO2 and avoid secondary brain insults. Although patients with BI are frequently hospitalized in the intensive care unit (ICU) without respiratory problems, they display longer durations of MV and a challenging weaning process compared to other ICU populations. Historically, the MV settings of BI patients associated high tidal volume with low or no positive end-expiratory pressure (PEEP), for neurological reasons. The extensive data about the beneficial effects of protective ventilation in patients without acute respiratory distress syndrome, have questioned the consequences of such management in BI patients. Recent studies suggest that protective ventilation is safe and could even bear significant impact on morbidity in these patients. The MV weaning process is also challenging, since these patients display a high rate of extubation failure. Recently, new clinical scales of successful extubation have been highlighted combining airway and neurologic operators. A minimal level of arousal should be achieved before extubation, but the Glasgow Coma Score has been inconsistently associated with successful extubation, probably owing to the challenging quantification in intubated patients. Early tracheostomy seems to bear positive effects on morbidity in BI patients. Nonetheless the level of evidence remains poor and no strong recommendations can be made on this topic. Overall, the respiratory bundle of care in BI patients could be readapted with the new data available in the literature. Even if they bear positive impact on morbidity in ICU, their consequences on neurological recovery have yet to be adequately assessed.