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.

Diuretics decrease fluid balance in patients on invasive mechanical ventilation: the randomized-controlled single blind, IRIHS study.

BACKGROUND: Fluid overload has been associated with increased morbidity and mortality in critically ill patients. The goal of this study was to assess the efficacy and safety of a diuretic strategy to overcome positive fluid balance in patients on invasive mechanical ventilation. METHODS: Design: Multicenter, single-blind, randomized-controlled study. Patients were randomized into a diuretic (furosemide) or a control group. Patients were eligible in case of fluid overload defined as in-ICU weight increase ≥ 3%, invasive mechanical ventilation (FiO2 ≤ 60% and PEEP ≤ 10 cm H2O on inclusion) and hemodynamic stabilization. The primary outcome was fluid balance, defined as weight variation from reference weight to successful extubation. The main secondary outcome was the safety of diuretic. RESULTS: 171 patients were randomized. After 5 exclusions, 166 patients were included in the analysis: 77 in the diuretic and 89 in the control group. Fluid balance was 1.4 [- 2.5 to 4.5] kg in the diuretic and 6.4 [0.5-11.2] kg in the control group (p < 0.001). In the multiple imputation analysis, fluid balance was significantly decreased in the diuretic group (mean difference = - 4.8 95% CI [- 7.3 to - 2.5], p < 0.001). Eleven (14%) patients died in the diuretic group and 16 (18%) patients in the control group (p = 0.5). There was a worsening of Acute Kidney Injury in 67 (75.3%) patients of the control group versus 46 (59.7%) patients in the diuretic group (p = 0.03). CONCLUSIONS: In this multicenter randomized-controlled study, protocolized diuretic therapy reduced fluid accumulation in patients receiving mechanical ventilation and was well tolerated with a favorable safety profile. Trial registration NCT02345681, Registered January 26 2015, Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT02345681?term=02345681&draw=2&rank=1 .

Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU). Objective: To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation. Design, Settings, and Participants: This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019. Interventions: Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days. Main Outcomes and Measures: The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Results: Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group. Conclusions and Relevance: Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT02723383.

Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury: The COBI Randomized Clinical Trial.

Importance: Fluid therapy is an important component of care for patients with traumatic brain injury, but whether it modulates clinical outcomes remains unclear. Objective: To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury. Design, Setting, and Participants: Multicenter randomized clinical trial conducted in 9 intensive care units in France, including 370 patients with moderate to severe traumatic brain injury who were recruited from October 2017 to August 2019. Follow-up was completed in February 2020. Interventions: Adult patients with moderate to severe traumatic brain injury were randomly assigned to receive continuous infusion of 20% hypertonic saline solution plus standard care (n = 185) or standard care alone (controls; n = 185). The 20% hypertonic saline solution was administered for 48 hours or longer if patients remained at risk of intracranial hypertension. Main Outcomes and Measures: The primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at 6 months, obtained centrally by blinded assessors and analyzed with ordinal logistic regression adjusted for prespecified prognostic factors (with a common odds ratio [OR] >1.0 favoring intervention). There were 12 secondary outcomes measured at multiple time points, including development of intracranial hypertension and 6-month mortality. Results: Among 370 patients who were randomized (median age, 44 [interquartile range, 27-59] years; 77 [20.2%] women), 359 (97%) completed the trial. The adjusted common OR for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47; P = .92). Of the 12 secondary outcomes, 10 were not significantly different. Intracranial hypertension developed in 62 (33.7%) patients in the intervention group and 66 (36.3%) patients in the control group (absolute difference, -2.6% [95% CI, -12.3% to 7.2%]; OR, 0.80 [95% CI, 0.51-1.26]). There was no significant difference in 6-month mortality (29 [15.9%] in the intervention group vs 37 [20.8%] in the control group; absolute difference, -4.9% [95% CI, -12.8% to 3.1%]; hazard ratio, 0.79 [95% CI, 0.48-1.28]). Conclusions and Relevance: Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months. However, confidence intervals for the findings were wide, and the study may have had limited power to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03143751.

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.

Extubation Success Prediction in a Multicentric Cohort of Patients with Severe Brain Injury.

BACKGROUND: Patients with brain injury are at high risk of extubation failure. METHODS: We conducted a prospective observational cohort study in four intensive care units of three university hospitals. The aim of the study was to create a score that could predict extubation success in patients with brain injury. RESULTS: A total of 437 consecutive patients with brain injury were included, and 338 patients (77.3%) displayed successful extubation. In the multivariate analysis, four features were associated with success the day of extubation: age less than 40 yr, visual pursuit, swallowing attempts, and a Glasgow coma score greater than 10. In the score, each item counted as one. A score of 3 or greater was associated with 90% extubation success. The area under the receiver-operator curve was 0.75 (95% CI, 0.69 to 0.81). After internal validation by bootstrap, the area under the receiver-operator curve was 0.73 (95% CI, 0.68 to 0.79). Extubation success was significantly associated with shorter duration of mechanical ventilation (11 [95% CI, 5 to 17 days] vs. 22 days [95% CI, 13 to 29 days]; P < 0.0001), shorter intensive care unit length of stay (15 [95% CI, 9 to 23 days] vs. 27 days [95% CI, 21 to 36 days]; P < 0.0001), and lower in-intensive care unit mortality (4 [1.2%] vs. 11 [11.1%]; P < 0.0001). CONCLUSIONS: Our score exploring both airway functions and neurologic status may increase the probability of successful extubation in patients with severe brain injury.

Association between continuous hyperosmolar therapy and survival in patients with traumatic brain injury - a multicentre prospective cohort study and systematic review.

BACKGROUND: Intracranial hypertension (ICH) is a major cause of death after traumatic brain injury (TBI). Continuous hyperosmolar therapy (CHT) has been proposed for the treatment of ICH, but its effectiveness is controversial. We compared the mortality and outcomes in patients with TBI with ICH treated or not with CHT. METHODS: We included patients with TBI (Glasgow Coma Scale ≤ 12 and trauma-associated lesion on brain computed tomography (CT) scan) from the databases of the prospective multicentre trials Corti-TC, BI-VILI and ATLANREA. CHT consisted of an intravenous infusion of NaCl 20% for 24 hours or more. The primary outcome was the risk of survival at day 90, adjusted for predefined covariates and baseline differences, allowing us to reduce the bias resulting from confounding factors in observational studies. A systematic review was conducted including studies published from 1966 to December 2016. RESULTS: Among the 1086 included patients, 545 (51.7%) developed ICH (143 treated and 402 not treated with CHT). In patients with ICH, the relative risk of survival at day 90 with CHT was 1.43 (95% CI, 0.99-2.06, p = 0.05). The adjusted hazard ratio for survival was 1.74 (95% CI, 1.36-2.23, p < 0.001) in propensity-score-adjusted analysis. At day 90, favourable outcomes (Glasgow Outcome Scale 4-5) occurred in 45.2% of treated patients with ICH and in 35.8% of patients with ICH not treated with CHT (p = 0.06). A review of the literature including 1304 patients from eight studies suggests that CHT is associated with a reduction of in-ICU mortality (intervention, 112/474 deaths (23.6%) vs. control, 244/781 deaths (31.2%); OR 1.42 (95% CI, 1.04-1.95), p = 0.03, I 2 = 15%). CONCLUSIONS: CHT for the treatment of posttraumatic ICH was associated with improved adjusted 90-day survival. This result was strengthened by a review of the literature.

Empiric antimicrobial therapy for ventilator-associated pneumonia after brain injury.

Issues regarding recommendations on empiric antimicrobial therapy for ventilator-associated pneumonia (VAP) have emerged in specific populations.To develop and validate a score to guide empiric therapy in brain-injured patients with VAP, we prospectively followed a cohort of 379 brain-injured patients in five intensive care units. The score was externally validated in an independent cohort of 252 brain-injured patients and its extrapolation was tested in 221 burn patients.The multivariate analysis for predicting resistance (incidence 16.4%) showed two independent factors: preceding antimicrobial therapy ≥48 h (p<0.001) and VAP onset ≥10 days (p<0.001); the area under the receiver operating characteristic curve (AUC) was 0.822 (95% CI 0.770-0.883) in the learning cohort and 0.805 (95% CI 0.732-0.877) in the validation cohort. The score built from the factors selected in multivariate analysis predicted resistance with a sensitivity of 83%, a specificity of 71%, a positive predictive value of 37% and a negative predictive value of 96% in the validation cohort. The AUC of the multivariate analysis was poor in burn patients (0.671, 95% CI 0.596-0.751).Limited-spectrum empirical antimicrobial therapy has low risk of failure in brain-injured patients presenting with VAP before day 10 and when prior antimicrobial therapy lasts <48 h.

Implementation of an evidence-based extubation readiness bundle in 499 brain-injured patients. a before-after evaluation of a quality improvement project.

RATIONALE: Mechanical ventilation is associated with morbidity in patients with brain injury. OBJECTIVES: This study aims to assess the effectiveness of an extubation readiness bundle to decrease ventilator time in patients with brain injury. METHODS: Before-after design in two intensive care units (ICUs) in one university hospital. Brain-injured patients ventilated more than 24 hours were evaluated during two phases (a 3-yr control phase followed by a 22-mo intervention phase). Bundle components were protective ventilation, early enteral nutrition, standardization of antibiotherapy for hospital-acquired pneumonia, and systematic approach to extubation. The primary endpoint was the duration of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: A total of 299 and 200 patients, respectively, were analyzed in the control and the intervention phases of this before-after study. The intervention phase was associated with lower tidal volume (P < 0.01), higher positive end-expiratory pressure (P < 0.01), and higher enteral intake in the first 7 days (P = 0.01). The duration of mechanical ventilation was 14.9 ± 11.7 days in the control phase and 12.6 ± 10.3 days in the intervention phase (P = 0.02). The hazard ratio for extubation was 1.28 (95% confidence interval [CI], 1.04-1.57; P = 0.02) in the intervention phase. Adjusted hazard ratio was 1.40 (95% CI, 1.12-1.76; P < 0.01) in multivariate analysis and 1.34 (95% CI, 1.03-1.74; P = 0.02) in propensity score-adjusted analysis. ICU-free days at Day 90 increased from 50 ± 33 in the control phase to 57 ± 29 in the intervention phase (P < 0.01). Mortality at Day 90 was 28.4% in the control phase and 23.5% in the intervention phase (P = 0.22). CONCLUSIONS: The implementation of an evidence-based extubation readiness bundle was associated with a reduction in the duration of ventilation in patients with brain injury.

Balanced versus chloride-rich solutions for fluid resuscitation in brain-injured patients: a randomised double-blind pilot study.

INTRODUCTION: We sought to investigate whether the use of balanced solutions reduces the incidence of hyperchloraemic acidosis without increasing the risk for intracranial hypertension in patients with severe brain injury. METHODS: We conducted a single-centre, two-arm, randomised, double-blind, pilot controlled trial in Nantes, France. Patients with severe traumatic brain injury (Glasgow Coma Scale score ≤8) or subarachnoid haemorrhage (World Federation of Neurosurgical Society grade III or higher) who were mechanically ventilated were randomised within the first 12 hours after brain injury to receive either isotonic balanced solutions (crystalloid and hydroxyethyl starch; balanced group) or isotonic sodium chloride solutions (crystalloid and hydroxyethyl starch; saline group) for 48 hours. The primary endpoint was the occurrence of hyperchloraemic metabolic acidosis within 48 hours. RESULTS: Forty-two patients were included, of whom one patient in each group was excluded (one consent withdrawn and one use of forbidden therapy). Nineteen patients (95%) in the saline group and thirteen (65%) in the balanced group presented with hyperchloraemic acidosis within the first 48 hours (hazard ratio = 0.28, 95% confidence interval [CI] = 0.11 to 0.70; P = 0.006). In the saline group, pH (P = .004) and strong ion deficit (P = 0.047) were lower and chloraemia was higher (P = 0.002) than in the balanced group. Intracranial pressure was not different between the study groups (mean difference 4 mmHg [-1;8]; P = 0.088). Seven patients (35%) in the saline group and eight (40%) in the balanced group developed intracranial hypertension (P = 0.744). Three patients (14%) in the saline group and five (25%) in the balanced group died (P = 0.387). CONCLUSIONS: This study provides evidence that balanced solutions reduce the incidence of hyperchloraemic acidosis in brain-injured patients compared to saline solutions. Even if the study was not powered sufficiently for this endpoint, intracranial pressure did not appear different between groups. TRIAL REGISTRATION: EudraCT 2008-004153-15 and NCT00847977.

High-flow oxygen therapy versus facemask preoxygenation in anticipated difficult airway management (PREOPTI-DAM): an open-label, single-centre, randomised controlled phase 3 trial.

Background: Difficult airway management remains a critical procedure with life-threatening adverse events. Current guidelines suggest high-flow therapy by nasal cannulae (HFNC) as a preoxygenation device in this setting. However, there is an evidence gap to support this recommendation. Methods: The PREOPTI-DAM study is an open-label, single-centre, randomised controlled phase 3 trial done at Nantes University Hospital, France. Patients were aged 18-90 years with one major or two minor criteria of anticipated difficult airway management, and requiring intubation for scheduled surgery, were eligible. Patients with body mass index >35 kg/m2 were excluded. Patients were randomly allocated (1:1) to receive 4-min preoxygenation by HFNC or facemask. Randomisation was stratified according to the intubation strategy (laryngoscopic versus fiberoptic intubation). The primary outcome was the incidence of oxygen desaturation ≤94% or of bag-mask ventilation during intubation. The primary and safety analyses included the intention to treat population. This trial is registered with ClinicalTrials.gov (NCT03604120) and EudraCT (2018-A00434-51). Findings: From September 4 2018 to March 31 2021, 186 patients were enrolled and randomly assigned. One participant withdrew consent and 185 (99.5%) were included in the primary analysis (HFNC, N = 95; Facemask, N = 90). The incidence of the primary outcome was not significantly different between the HFNC and the facemask groups, respectively 2 (2%) versus 7 (8%); adjusted difference, -5.6 [95% confidence interval (CI), -11.8 to 0.6], P = 0.10. In the HFNC group, 76 patients (80%) versus 53 (59%) in the facemask group, reported good or excellent intubation experiences; adjusted difference 20.5 [95% CI, 8.3-32.8], P = 0.016. Comparing HFNC with facemask, severe complication occurred in 22 (23%) versus 27 (30%) patients (P = 0.29), and moderate complication in 14 (15%) versus 18 (20%) patients (P = 0.35). No death or cardiac arrest occurred during the study. Interpretation: Compared with facemask, HFNC did not significantly reduce the incidence of desaturation ≤94% or bag-mask ventilation during anticipated difficult intubation but the trial was underpowered to rule out a clinically significant benefit. Patient satisfaction was improved with HFNC. Funding: Nantes University Hospital and Fisher & Paykel Healthcare.

Continuous controlled-infusion of hypertonic saline solution in traumatic brain-injured patients: a 9-year retrospective study.

INTRODUCTION: Description of a continuous hypertonic saline solution (HSS) infusion using a dose-adaptation of natremia in traumatic brain injured (TBI) patients with refractory intracranial hypertension (ICH). METHODS: We performed a single-center retrospective study in a surgical intensive care unit of a tertiary hospital. Fifty consecutive TBI patients with refractory ICH treated with continuous HSS infusion adapted to a target of natremia. In brief, a physician set a target of natremia adapted to the evolution of intracranial pressure (ICP). Flow of NaCl 20% was a priori calculated according to natriuresis, and the current and target natremia that were assessed every 4 hours. RESULTS: The HSS infusion was initiated for a duration of 7 (5 to 10) (8 ± 4) days. ICP decreased from 29 (26 to 34) (31 ± 9) mm Hg at H0 to 20 (15 to 26) (21 ± 8) mm Hg at H1 (P < 0.05). Cerebral perfusion pressure increased from 61 (50 to 70) (61 ± 13) mm Hg at H0 up to 67 (60 to 79) (69 ± 12) mm Hg at H1 (P < 0.05). No rebound of ICH was reported after stopping continuous HSS infusion. Natremia increased from 140 (138 to 143) (140 ± 4) at H0 up to 144 (141 to 148) (144 ± 4) mmol/L at H4 (P < 0.05). Plasma osmolarity increased from 275 (268 to 281) (279 ± 17) mmol/L at H0 up to 290 (284 to 307) (297 ± 17) mmol/L at H24 (P < 0.05). The main side effect observed was an increase in chloremia from 111 (107 to 119) (113 ± 8) mmol/L at H0 up to 121 (117 to 124) (121 ± 6) mmol/L at H24 (P < 0.05). Neither acute kidney injury nor pontine myelinolysis was recorded. CONCLUSIONS: Continuous HSS infusion adapted to close biologic monitoring enables long-lasting control of natremia in TBI patients along with a decreased ICP without any rebound on infusion discontinuation.

Hydrocortisone therapy for patients with multiple trauma: the randomized controlled HYPOLYTE study.

CONTEXT: The role of stress-dose hydrocortisone in the management of trauma patients is currently unknown. OBJECTIVE: To test the efficacy of hydrocortisone therapy in trauma patients. DESIGN, SETTING, AND PATIENTS: Multicenter, randomized, double-blind, placebo-controlled HYPOLYTE (Hydrocortisone Polytraumatise) study. From November 2006 to August 2009, 150 patients with severe trauma were included in 7 intensive care units in France. INTERVENTION: Patients were randomly assigned to a continuous intravenous infusion of either hydrocortisone (200 mg/d for 5 days, followed by 100 mg on day 6 and 50 mg on day 7) or placebo. The treatment was stopped if patients had an appropriate adrenal response. MAIN OUTCOME MEASURE: Hospital-acquired pneumonia within 28 days. Secondary outcomes included the duration of mechanical ventilation, hyponatremia, and death. RESULTS: One patient withdrew consent. An intention-to-treat (ITT) analysis included the 149 patients, a modified ITT analysis included 113 patients with corticosteroid insufficiency. In the ITT analysis, 26 of 73 patients (35.6%) treated with hydrocortisone and 39 of 76 patients (51.3%) receiving placebo developed hospital-acquired pneumonia by day 28 (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.30-0.83; P = .007). In the modified ITT analysis, 20 of 56 patients (35.7%) in the hydrocortisone group and 31 of 57 patients (54.4%) in the placebo group developed hospital-acquired pneumonia by day 28 (HR, 0.47; 95% CI, 0.25-0.86; P = .01). Mechanical ventilation-free days increased with hydrocortisone by 4 days (95% CI, 2-7; P = .001) in the ITT analysis and 6 days (95% CI, 2-11; P < .001) in the modified ITT analysis. Hyponatremia was observed in 7 of 76 (9.2%) in the placebo group vs none in the hydrocortisone group (absolute difference, -9%; 95% CI, -16% to -3%; P = .01). Four of 76 patients (5.3%) in the placebo group and 6 of 73 (8.2%) in the hydrocortisone group died (absolute difference, 3%; 95% CI, -5% to 11%; P = .44). CONCLUSION: In intubated trauma patients, the use of an intravenous stress-dose of hydrocortisone, compared with placebo, resulted in a decreased risk of hospital-acquired pneumonia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00563303.

Feasibility and impact of the implementation of a clinical scale-based sedation-analgesia protocol in severe burn patients undergoing mechanical ventilation. A before-after bi-center study.

BACKGROUND: Severe burn patients undergo prolonged administration of sedatives and analgesics for burn care. There are currently no guidelines for the dose adaptation of sedation-analgesia in severe burn patients. METHODS: We performed a before-after 2-center study to demonstrate the feasibility and efficacy of a sedation-analgesia scale-based protocol in severely burned patients receiving ≥24h of invasive mechanical ventilation. Before the intervention, continuous infusion of hypnotic and morphine derivatives was continued. During the Intervention phase, general anesthesia was relayed from day 1 by RASS/BPS-titrated continuous infusion of hypnotic and morphine derivatives and with short half-life drugs adminstered for daily burn dressings. The primary outcome was the duration of invasive mechanical ventilation in the ICU. RESULTS: Eighty-seven (46.2%) patients were included in the Control phase and 101 (53.7%) in the Intervention phase. The median burned cutaneous surface was 20% [11%-38%] and median ABSI was 7 [5-9]. The durations of hypnotic and opioid infusions were not statistically different between the 2 phases (8 days [2-24] vs. 6 days [2-17] (P=0.3) and 17 days [4-32] vs. 8 days [3-23] (P=0.06), respectively). The duration of mechanical ventilation was 14 days [3-29] in the Control phase and 7 days [2-24] in the Intervention phase (P=0.7). When taking into account the competition between mortality and weaning from mechanical ventilation, we found no significant difference between the 2 phases (Gray test, P=0.4). The time-series analysis showed no difference for the duration of mechanical ventilation in the Intervention phase (P=0.6). Eighteen (20.7%) patients died in the Control phase, and 18 (18%) in the Intervention phase (P=0.6). CONCLUSION: Scale-based lightening of continuous sedation-analgesia with repeated short general anesthesia for dressing is feasible in severe burn patients but failed to demonstrate a decrease in the duration of invasive mechanical ventilation.

Pharmacokinetic data on high dose baclofen administration in unhealthy alcohol user in the ICU.

In the intensive care unit, alcohol intake above the NIAAA recommendations regardless of the existence of an Alcohol Use Disorder (AUD), was associated with an increased risk of death and longer time on ventilator. This rises the hypothesis that unhealthy alcohol use may lead to specific issues when weaning the mechanical ventilation (i.e. agitation or its related complications) regardless of AUD or withdrawal syndrome. Thus, we proposed to use baclofen off-label to avoid agitation. The data presented in this article is related to the research article entitled: "Pharmacokinetics and toxicity of high-dose baclofen in ICU patients" Vourc'h et al., 2019 Data provided in this submission includes 1) the detailed methods for baclofen assay by mass spectrometric detection, 2) the supplementary population pharmacokinetic analysis presenting observed concentration vs. population or individual predicted concentration (raw data of the latter is also available), and 3) the algorithm for the adaptation of baclofen daily doses according of the renal clearance to assess the risk of toxicity in critically ill patients.

Pharmacokinetics and toxicity of high-dose baclofen in ICU patients.

BACKGROUND: High-dose baclofen could prove beneficial in patients with unhealthy alcohol use in intensive care units (ICU). However, the pharmacokinetic properties of baclofen are unknown in this population. Our objectives were to investigate the pharmacokinetics of baclofen and the relationship between baclofen exposure and its toxicity in the ICU. MATERIALS AND METHODS: As part of a healthcare quality improvement project, we conducted a prospective, single-center study in a surgical intensive care unit at Nantes University Hospital in order to assess our local protocol of sedation in patients with consumption of alcohol above the recommended limits by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Baclofen pharmacokinetics were investigated by a non-compartment analysis and a population approach in 20 patients under mechanical ventilation. After a baclofen loading dose on day 1, daily doses were divided into 3 intakes adapted to glomerular filtration rate (GFR) and blood samples were withdrawn on day 3 for pharmacokinetic analysis. Baclofen was administered until extubation or tracheostomy and agitation-related events as well as the potential side effects of baclofen were noted. RESULTS: In this population, pharmacokinetic parameters [absorption latency time = 0.37 h, absorption constant rate = 2.2 h-1, apparent volume of distribution = 105 L, apparent clearance (l/h) = 13.5 × (GFR/103)0.839] were characterized by modified absorption and the influence of renal function: renal failure significantly increased baclofen exposure (p = .007) and significantly decreased baclofen clearance (p = .007) compared with patients without renal failure. When comparing patients with or without possible signs of baclofen toxicity, no difference was found regarding baclofen exposure (p = .34) and plasma peak concentration (p = .26). CONCLUSIONS: The a priori planned algorithm for dose adaptation according to renal clearance appeared to be suitable in our population. Daily administration of 150 mg of baclofen in ICU patients with preserved renal function did not lead to toxic concentrations in the plasma. A dose reduction of approximately 40%, 60% and 70% in patients with mild, moderate and severe renal failure could be suggested.

Nasal high-flow preoxygenation for endotracheal intubation in the critically ill patient: a randomized clinical trial.

PURPOSE: Preoxygenation with high-flow therapy by nasal cannulae (HFNC) is now widespread in the intensive care unit (ICU). However, no large randomized study has assessed its relevance in non-severely hypoxemic patients. In a randomized controlled trial (PROTRACH study), we aimed to evaluate preoxygenation with HFNC vs. standard bag-valve mask oxygenation (SMO) in non-severely hypoxemic patients during rapid sequence intubation (RSI) in the ICU. METHODS: Randomized controlled trial including non-severely hypoxemic patients requiring intubation in the ICU. Patients received preoxygenation by HFNC or SMO during RSI. HFNC was maintained throughout the intubation procedure whereas SMO was removed to perform laryngoscopy. The primary outcome was the lowest pulse oximetry (SpO2) throughout the intubation procedure. Secondary outcomes included drop in SpO2, adverse events related to intubation, and outcome in the ICU. RESULTS: A total of 192 patients were randomized. In the intent-to-treat analysis, 184 patients (HFNC n = 95; SMO n = 89), the median [IQR] lowest SpO2 was 100% [97; 100] for HFNC and 99% [95; 100] for the SMO group (P = 0.30). Mild desaturation below 95% was more frequent with SMO (23%) than with HFNC (12%) (RR 0.51, 95% CI 0.26-0.99, P = 0.045). There were fewer adverse events in the HFNC group (6%) than in the SMO group (19%) (RR 0.31, 95% CI 0.13-0.76, P = 0.007), including fewer severe adverse events, respectively 6 (6%) and 14 (16%) with HFNC and SMO (RR 0.38, 95% CI 0.15-0.95, P = 0.03). CONCLUSIONS: Compared with SMO, preoxygenation with HFNC in the ICU did not improve the lowest SpO2 during intubation in the non-severely hypoxemic patients but led to a reduction in intubation-related adverse events. TRIAL REGISTRATION: Clinical trial Submission: 7 March 2016. Registry name: Benefits of high-flow nasal cannulae oxygen for preoxygenation during intubation in non-severely hypoxemic patients: the PROTRACH study. Clinicaltrials.gov identifier: NCT02700321. Eudra CT: 2015-A00145-44. CPP: 15/13-975 (Comité de protection des personnes de Rennes). URL registry: https://clinicaltrials.gov/ct2/show/record/NCT02700321 .

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.

Fatal coinfection with Legionella pneumophila serogroup 8 and Aspergillus fumigatus.

Legionella pneumophila is an important cause of community-acquired and nosocomial pneumonia. We report on a patient who simultaneously developed L. pneumophila serogroup 8 pneumonia and Aspergillus fumigatus lung abscesses. Despite appropriate treatments, Aspergillus disease progressed with metastasis. Coinfections caused by L. pneumophila and A. fumigatus remain exceptional. In apparently immunocompetent patients, corticosteroid therapy is a key risk factor for aspergillosis.

Baclofen to prevent agitation in alcohol-addicted patients in the ICU: study protocol for a randomised controlled trial.

BACKGROUND: Alcohol is the leading psychoactive substance consumed in France, with about 15 million regular consumers. The National institute on Alcohol Abuse and Alcoholism (NIAAA) considers alcohol abuse to be more than 14 units of alcohol a week for men and 7 units for women. The specific complication of alcoholism is the alcohol withdrawal syndrome. Its incidence reaches up to 30 % and its main complications are delirium tremens, restlessness, extended hospital stay, higher morbidity, and psychiatric and cognitive impairment. Without appropriate treatment, delirium tremens can lead to death in up to 50 % of patients. METHODS/DESIGN: This prospective, double-blind, randomised controlled study versus placebo will be conducted in twelve French intensive care units (ICU). Patients with an alcohol intake level higher than the NIAAA threshold, who are under mechanical ventilation, will be included. The primary objective is to determine whether baclofen is more efficient than placebo in preventing restlessness-related side effects in the ICU. Secondary outcomes include mechanical ventilation duration, length of ICU stay, and cumulative doses of sedatives and painkillers received within 28 days of ICU admission. Restlessness-related side effects in the ICU are defined as unplanned extubation, medical disposal removal (such as urinary catheter, venous or arterial line or surgical drain), falling out of bed, ICU runaway (leaving ICU without physician's approval), immobilisation device removal, self-aggression or aggression towards medical staff. Daily doses of baclofen/placebo will be guided by daily creatinine clearance assessment. DISCUSSION: Restlessness in alcoholic patients is a life-threatening issue in ICUs. BACLOREA is a randomised study assessing the capacity of baclofen to prevent agitation in mechanically ventilated patients. Enrolment of 314 patients will begin in June 2016 and is expected to end in October 2018. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02723383 , registered on 3 March 2016.