Population pharmacokinetic/pharmacodynamic study suggests continuous infusion of ceftaroline daily dose in ventilated critical care patients with early-onset pneumonia and augmented renal clearance.

OBJECTIVES: Ceftaroline could be suitable to treat early-onset ventilator-associated pneumonia (VAP) because of its antibacterial spectrum. However, augmented renal clearance (ARC) is frequent in ICU patients and may affect ceftaroline pharmacokinetics and efficacy. The objective of the study was to explore the impact of ARC on ceftaroline pharmacokinetics and evaluate whether the currently recommended dosing regimen (600 mg every 12 h) is appropriate to treat VAP in ICU patients. METHODS: A population pharmacokinetic model was developed using pharmacokinetic data from 18 patients with measured creatinine clearance (CLCR) ranging between 83 and 309 mL/min. Monte Carlo simulations were conducted to determine the PTA and the cumulative fraction of response (CFR) against Streptococcus pneumoniae and MRSA for five dosing regimens. Study registered at ClinicalTrials.gov (NCT03025841). RESULTS: Ceftaroline clearance increased non-linearly with CLCR, with lower concentrations and lower probability of reaching pharmacokinetic/pharmacodynamic targets when CLCR increases. For the currently recommended dosing regimen, the probability of having unbound ceftaroline concentrations above the MIC over the entire dose range is greater than 90% for MICs below 0.125 mg/L. Considering the distribution of MICs, this regimen would not be effective against MRSA infections (CFR between 21% and 67% depending on CLCR), but would be effective against S. pneumoniae infections (CFR >86%). CONCLUSIONS: The recommended dosing regimen of ceftaroline seems sufficient for covering S. pneumoniae in ICU patients with ARC, but not for MRSA. Among the dosing regimens tested it appears that a constant infusion (50 mg/h) after a loading dose of 600 mg could be more appropriate for MRSA infections.

Development and validation of a multivariable prediction model of central venous catheter-tip colonization in a cohort of five randomized trials.

BACKGROUND: The majority of central venous catheters (CVC) removed in the ICU are not colonized, including when a catheter-related infection (CRI) is suspected. We developed and validated a predictive score to reduce unnecessary CVC removal. METHODS: We conducted a retrospective cohort study from five multicenter randomized controlled trials with systematic catheter-tip culture of consecutive CVCs. Colonization was defined as growth of ≥103 colony-forming units per mL. Risk factors for colonization were identified in the training cohort (CATHEDIA and 3SITES trials; 3899 CVCs of which 575 (15%) were colonized) through multivariable analyses. After internal validation in 500 bootstrapped samples, the CVC-OUT score was computed by attaching points to the robust (> 50% of the bootstraps) risk factors. External validation was performed in the testing cohort (CLEAN, DRESSING2 and ELVIS trials; 6848 CVCs, of which 588 (9%) were colonized). RESULTS: In the training cohort, obesity (1 point), diabetes (1 point), type of CVC (dialysis catheter, 1 point), anatomical insertion site (jugular, 4 points; femoral 5 points), rank of the catheter (second or subsequent, 1 point) and catheterization duration (≥ 5 days, 2 points) were significantly and independently associated with colonization . Area under the ROC curve (AUC) for the CVC-OUT score was 0.69, 95% confidence interval (CI) [0.67-0.72]. In the testing cohort, AUC for the CVC-OUT score was 0.60, 95% CI [0.58-0.62]. Among 1,469 CVCs removed for suspected CRI in the overall population, 1200 (82%) were not colonized. The negative predictive value (NPV) of a CVC-OUT score < 6 points was 94%, 95% CI [93%-95%]. CONCLUSION: The CVC-OUT score had a moderate ability to discriminate catheter-tip colonization, but the high NPV may contribute to reduce unnecessary CVCs removal. Preference of the subclavian site is the strongest and only modifiable risk factor that reduces the likelihood of catheter-tip colonization and consequently the risk of CRI. CLINICAL TRIALS REGISTRATION: NCT00277888, NCT01479153, NCT01629550, NCT01189682, NCT00875069.

Nebulized Antibiotics for Healthcare- and Ventilator-Associated Pneumonia.

Global emergence of multidrug-resistant and extensive drug-resistant gram-negative bacteria has increased the risk of treatment failure, especially for healthcare- or ventilator-associated pneumonia (HAP/VAP). Nebulization of antibiotics, by providing high intrapulmonary antibiotic concentrations, represents a promising approach to optimize the treatment of HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria, while limiting systemic antibiotic exposure. Aminoglycosides and colistin methanesulfonate are the most common nebulized antibiotics. Although optimal nebulized drug dosing regimen is not clearly established, high antibiotic doses should be administered using vibrating-mesh nebulizer with optimized ventilator settings to ensure safe and effective intrapulmonary concentrations. When used preventively, nebulized antibiotics reduced the incidence of VAP without any effect on mortality. This approach is not yet recommended and large randomized controlled trials should be conducted to confirm its benefit and explore the impact on antibiotic selection pressure. Compared with high-dose intravenous administration, high-dose nebulized colistin methanesulfonate seems to be more effective and safer in the treatment of ventilator-associated tracheobronchitis and VAP caused by multidrug resistant and extensive-drug resistant gram-negative bacteria. Adjunctive nebulized aminoglycosides could increase the clinical cure rate and bacteriological eradication in patients suffering from HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria. As nebulized aminoglycosides broadly diffuse in the systemic circulation of patients with extensive bronchopneumonia, monitoring of plasma trough concentrations is recommended during the period of nebulization. Large randomized controlled trials comparing high dose of nebulized colistin methanesulfonate to high dose of intravenous colistin methanesulfonate or to intravenous new ß-lactams in HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria are urgently needed.

Ultrasound Guidance and Risk for Central Venous Catheter-Related Infections in the Intensive Care Unit: A Post Hoc Analysis of Individual Data of 3 Multicenter Randomized Trials.

BACKGROUND: Ultrasound (US) guidance is frequently used in critically ill patients for central venous catheter (CVC) insertion. The effect of US on infectious risk remains controversial, and randomized controlled trials (RCTs) have assessed mainly noninfectious complications. This study assessed infectious risk associated with catheters inserted with US guidance vs use of anatomical landmarks. METHODS: We used individual data from 3 large RCTs for which a prospective, high-quality data collection was performed. Adult patients were recruited in various intensive care units (ICUs) in France as soon as they required short-term CVC insertion. We applied marginal Cox models with inverse probability weighting to estimate the effect of US-guided insertion on catheter-related bloodstream infections (CRBSIs, primary outcome) and major catheter-related infections (MCRIs, secondary outcome).We also evaluated insertion site colonization at catheter removal. RESULTS: Our post hoc analysis included 4636 patients and 5502 catheters inserted in 2088 jugular, 1733 femoral, and 1681 subclavian veins, in 19 ICUs. US guidance was used for 2147 catheter insertions. Among jugular and femoral CVCs and after weighting, we found an association between US and CRBSI (hazard ratio [HR], 2.21 [95% confidence interval {CI}, 1.17-4.16]; P = .014) and between US and MCRI (HR, 1.55 [95% CI, 1.01-2.38]; P = .045). Catheter insertion site colonization at removal was more common in the US-guided group (P = .0045) among jugular and femoral CVCs in situ for ≤7 days (n = 606). CONCLUSIONS: In prospectively collected data in which catheters were not randomized to insertion by US or anatomical landmarks, US guidance was associated with increased risk of infection.

The Insertion Site Should Be Considered for the Empirical Therapy of Short-Term Central Venous and Arterial Catheter-Related Infections.

OBJECTIVES: Little is known on causative pathogens of intravascular catheters infection according to the catheter insertion site. The present study aimed to describe the epidemiology of causative microorganisms of catheter-related infection and colonization according to the insertion site. DESIGN: Multicenter observational study using data from four large randomized controlled trials investigating different prevention strategies in which extensive prospective high-quality data collection at catheter insertion and catheter removal was performed. SETTING: Twenty-five ICUs in France. PATIENTS: Patients were recruited from 2006 to 2014 as soon as they required a catheterization with a short-term central venous catheter or peripheral arterial catheter with an expected duration of use of more than 48 hours. We described the distribution of microorganisms in central venous catheter and arterial catheter-related bloodstream infections and colonization according to the insertion type (femoral vs nonfemoral) included in the four studies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 7,235 patients and 15,259 catheters were included. Among central venous catheter, the distribution of microorganisms associated with catheter-related bloodstream infection and colonization was significantly different between femoral and nonfemoral sites. Among central venous catheter catheter-related bloodstream infection, nonfermenting Gram-negative bacilli were more frequently detected at the femoral site (31% vs 4% for nonfemoral site; p < 0.01). After adjustment for confounding factors, the femoral site was still associated with an increased risk for catheter-related bloodstream infection due to nonfermenting Gram-negative bacilli (odds ratio, 6.33; 95% CI, 1.59-25.28; p < 0.01). Among colonized arterial catheters, the distribution of microorganisms was significantly different between femoral and radial site (p < 0.01). Colonized arterial catheters due to nonfermenting Gram-negative bacilli were more frequently observed at the femoral site (20% vs nonfemoral site 12%; p = 0.01). CONCLUSIONS: The proportion of intravascular catheter infections due to nonfermenting Gram-negative bacilli was high for the femoral insertion site. Empirical antipseudomonal therapy should be considered if a femoral catheter-related bloodstream infection is suspected.

Chlorhexidine-impregnated sponge versus chlorhexidine gel dressing for short-term intravascular catheters: which one is better?

BACKGROUND: Chlorhexidine-gluconate (CHG) impregnated dressings may prevent catheter-related bloodstream infections (CRBSI). Chlorhexidine-impregnated sponge dressings (sponge-dress) and gel dressings (gel-dress) have never been directly compared. We used the data collected for two randomized-controlled trials to perform a comparison between sponge-dress and gel-dress. METHODS: Adult critically ill patients who required short-term central venous or arterial catheter insertion were recruited. Our main analysis included only patients with CHG-impregnated dressings. The effect of gel-dress (versus sponge-dress) on major catheter-related infections (MCRI) and CRBSI was estimated using multivariate marginal Cox models. The comparative risks of dressing disruption and contact dermatitis were evaluated using logistic mix models for clustered data. An explanatory analysis compared gel-dress with standard dressings using either CHG skin disinfection or povidone iodine skin disinfection. RESULTS: A total of 3483 patients and 7941 catheters were observed in 16 intensive care units. Sponge-dress and gel-dress were utilized for 1953 and 2108 catheters, respectively. After adjustment for confounders, gel-dress showed similar risk for MCRI compared to sponge-dress (HR 0.80, 95% CI 0.28-2.31, p = 0.68) and CRBSI (HR 1.13, 95% CI 0.34-3.70, p = 0.85), less dressing disruptions (OR 0.72, 95% CI 0.60-0.86, p < 0.001), and more contact dermatitis (OR 3.60, 95% CI 2.51-5.15, p < 0.01). However, gel-dress increased the risk of contact dermatitis only if CHG was used for skin antisepsis (OR 1.94, 95% CI 1.38-2.71, p < 0.01). CONCLUSIONS: We described a similar infection risk for gel-dress and sponge-dress. Gel-dress showed fewer dressing disruptions. Concomitant use of CHG for skin disinfection and CHG-impregnated dressing may significantly increase contact dermatitis. TRIALS REGISTRATION: These studies were registered within ClinicalTrials.gov (numbers NCT01189682 and NCT00417235 ).

Local signs at insertion site and catheter-related bloodstream infections: an observational post hoc analysis using individual data of four RCTs.

BACKGROUND: Little is known on the association between local signs and intravascular catheter infections. This study aimed to evaluate the association between local signs at removal and catheter-related bloodstream infections (CRBSI), and which clinical conditions may predict CRBSIs if inflammation at insertion site is present. METHODS: We used individual data from four multicenter randomized controlled trials in intensive care units (ICUs) that evaluated various prevention strategies for arterial and central venous catheters. We used multivariate logistic regressions in order to evaluate the association between ≥ 1 local sign, redness, pain, non-purulent discharge and purulent discharge, and CRBSI. Moreover, we assessed the probability for each local sign to observe CRBSI in subgroups of clinically relevant conditions. RESULTS: A total of 6976 patients and 14,590 catheters (101,182 catheter-days) and 114 CRBSI from 25 ICUs with described local signs were included. More than one local sign, redness, pain, non-purulent discharge, and purulent discharge at removal were observed in 1938 (13.3%), 1633 (11.2%), 59 (0.4%), 251 (1.7%), and 102 (0.7%) episodes, respectively. After adjusting on confounders, ≥ 1 local sign, redness, non-purulent discharge, and purulent discharge were associated with CRBSI. The presence of ≥ 1 local sign increased the probability to observe CRBSI in the first 7 days of catheter maintenance (OR 6.30 vs. 2.61 [> 7 catheter-days], pheterogeneity = 0.02). CONCLUSIONS: Local signs were significantly associated with CRBSI in the ICU. In the first 7 days of catheter maintenance, local signs increased the probability to observe CRBSI.

Risk factors and events in the adult intensive care unit associated with pain as self-reported at the end of the intensive care unit stay.

BACKGROUND: The short-term and long-term consequences of the most frequent painful procedures performed in the ICU are unclear. This study aimed to identify the risk factors associated with pain-related discomfort perceived by critically ill patients during the whole ICU stay as self-reported by patients at the end of their ICU stay. METHODS: The study involved 34 ICUs. Adult patients who survived an ICU stay of 3 calendar days or more were eligible for inclusion. Discomforts, including the pain-related discomfort, were assessed using the French 18-item questionnaire on discomfort in ICU patients, the "Inconforts des Patients de REAnimation" (IPREA). Patients scored each item from 0 (minimal discomfort) to 10 (maximal discomfort). Associations between patient characteristics at ICU admission, life support therapies and main potentially painful procedures performed during the ICU stay and pain-related discomfort scores assessed at the end of the ICU stay were analyzed. RESULTS: Patients with complete IPREA questionnaires (n = 2130) were included. The median pain-related discomfort score was 3 (IQR 0-5). From the univariate analysis, pain-related discomfort scores were negatively correlated with age and positively correlated with ICU stay duration; surgical patients reported significant higher pain-related discomfort scores than medical patients; chest drain insertion, chest drain removal, use of bladder catheter, central venous catheter (CVC) insertion, complex dressing change, and intra-hospital transport were associated with pain-related discomfort scores. From the multivariate analyses using generalized estimating equations models, only age, chest drain removal, use of a bladder catheter, CVC insertion, and intra-hospital transport were the main risk factors associated with pain-related discomfort scores. CONCLUSION: Patients who underwent chest drain removal, bladder catheter, CVC insertion, and intra-hospital transport during their ICU stay reported higher pain-related discomfort scores (with respect to the whole ICU stay and assessed at the end of their ICU stay) than patients who did not experience these events. This study may pave the way for further targeted studies aiming at investigating a causal link between these common procedures in the ICU and adult critically ill patients' perceptions of their ICU stay regarding recalled pain. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT02442934, retrospectively registered on May 13, 2015.

High-flow nasal cannula oxygen therapy in acute respiratory failure at Emergency Departments: A systematic review.

OBJECTIVES: The use of high-flow oxygen therapy (HFOT) through nasal cannula for the management of acute respiratory failure at the emergency department (ED) has been only sparsely studied. We conducted a systematic review of randomized-controlled and quasi-experimental studies comparing the early use of HFOT versus conventional oxygen therapy (COT) in patients with acute respiratory failure admitted to EDs. METHODS: A systematic research of literature was carried out for all published control trials comparing HFOT with COT in adult patients admitted in EDs. Eligible data were extracted from Medline, Embase, Pascal, Web of Science and the Cochrane database. The primary outcome was the need for mechanical ventilation, i.e. intubation or non-invasive ventilation as rescue therapy. Secondary outcomes included respiratory rate, dyspnea level, ED length of stay, intubation and mortality. RESULTS: Out of 1829 studies screened, five studies including 673 patients were retained in the analysis (350 patients treated with HFOT and 323 treated with COT). The need for mechanical ventilation was similar in both treatments (RR = 0.75; 95% CI 0.41 to 1.35; P = 0.31; I2 = 16%). Respiratory rate was lower with HFOT (Mean difference (MD) = -3.14 breaths/min; 95% CI = -4.9 to -1.4; P < 0.001; I2 = 39%), whereas sensation of dyspnea did not differ. (MD = -1.04; 95% CI = -2.29 to -0.22; P = 0.08; I2 = 67%). ED length of stay and mortality were similar between groups. CONCLUSION: The early use of HFOT in patients admitted to an ED for acute respiratory failure did not reduce the need for mechanical ventilation as compared to COT. However, HFOT decreased respiratory rate. REGISTRATION: PROSPERO ID CRD42019125696.

Reassessing the dosing of cefoxitin prophylaxis during major abdominal surgery: insights from microdialysis and population pharmacokinetic modelling.

OBJECTIVES: Cefoxitin is frequently used for surgical antibiotic prophylaxis (SAP). Using microdialysis, we evaluated whether the currently recommended dosing regimen is appropriate to maintain cefoxitin subcutaneous tissue concentrations above the MIC for pathogens involved in abdominal surgical site infection. METHODS: Data from eight patients undergoing major abdominal surgery were analysed using population pharmacokinetic modelling, and Monte Carlo simulations were conducted to determine the PTA for aerobic and anaerobic pathogens. ClinicalTrials.gov: NCT02703857. RESULTS: Only 2.3% and 47.4% of the simulated patients maintained cefoxitin subcutaneous concentrations above the MIC breakpoint for anaerobic (MIC = 16 mg/L) and aerobic (MIC = 8 mg/L) pathogens, respectively. New simulations with administration of a loading dose followed by a constant infusion of cefoxitin were conducted and demonstrate that, notwithstanding using the same total dose per unit of time, continuous infusion of cefoxitin can cover aerobes in 96.6% of the simulated patients, but remains insufficient for anaerobic bacteria. CONCLUSIONS: The recommended dosing regimen of cefoxitin is insufficient for covering the usual bacteria during abdominal surgery. Administration of a loading dose followed by a constant infusion should be considered for aerobic bacteria and cefoxitin should be avoided as SAP for anaerobic bacteria.

Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment.

Objectives: The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed. Methods: Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC >40 or >80) or toxicity (Cmin >24.3 mg/L) targets. Results: Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin. Conclusions: Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.

Assessment of patients' self-perceived intensive care unit discomforts: Validation of the 18-item version of the IPREA.

BACKGROUND AND AIMS: We reported the validation of the 18-item version of the 'Inconforts des Patients de REAnimation (IPREA)' questionnaire that includes 2 new items exploring feeling depressed and shortness of breath during an intensive care unit (ICU) stay. METHODS: The validation process was integrated in a multicenter, cluster-randomized, controlled, two-parallel group study built to assess the effectiveness of a tailored multicomponent program for reducing self-perceived discomfort in the ICU. All patients aged 18 years or older who survived an ICU stay of 3 calendar days or more were eligible for inclusion. Data collection included demographics (sex, age), type of admission (medical and surgical), health status scores at admission (Knaus score and McCabe index, Simplified Acute Physiology Score (SAPS) II), specific ICU therapeutics such as mechanical ventilation (MV), noninvasive ventilation (NIV), use of vasopressors, or renal replacement therapy (RRT), and ICU stay duration. RESULTS: A total of 994 patients were included. The initial structure of IPREA was confirmed using confirmatory factor analysis showing satisfactory fit (RMSEA at 0.042, CFI at 0.912). No multidimensional structure was identified, allowing the calculation of an overall discomfort score. The three highest discomforts were sleep deprivation, thirst, and perfusion lines and other devices, and the 3 lowest discomforts were limited visiting hours, hunger, and isolation. The overall discomfort score of the 18-item version of IPREA did not differ between men and women. Higher age was significantly correlated with a lower overall discomfort score. While MV was not linked to self-reported discomfort, patients treated by NIV reported higher overall discomfort scores than patients not treated by NIV. CONCLUSION: The 18-item version of IPREA is easy to use and possesses satisfactory psychometric properties. The availability of a reliable and valid French questionnaire asking about patients' self-perceived ICU discomforts enables feedback from the health care team to be incorporated in a continuous quality health care improvement strategy. TRIAL REGISTRATION: clinicaltrial.gov NCT02442934 (registration date: May 18, 2015, retrospectively registered).

Impact of Low-Dose Hydrocortisone on the Incidence of Atrial Fibrillation in Patients With Septic Shock: A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study.

PURPOSE: Atrial fibrillation (AF) is common in the intensive care unit (ICU), notably in patients with septic shock for whom inflammation is an already identified risk factor. The aim of this study was to evaluate the effect of low-dose hydrocortisone on AF occurrence in patients with septic shock. METHODS: We performed a prospective nonrandomized observational study in 5 academic ICUs in France. From November 2012 to June 2014, all patients ≥16 years having septic shock were included, except those who had a history of AF, had a pacemaker, and/or experienced AF during hospitalization before the onset of shock or in whom the onset of shock occurred prior to admission to the ICU. Hydrocortisone was administered at the discretion of the attending physician. The incidence of AF was compared among patients who received hydrocortisone, and the effect of low-dose hydrocortisone on AF was estimated using the inverse probability treatment weighting method based on propensity scores. RESULTS: A total of 261 patients were included (no-hydrocortisone group, n = 138; hydrocortisone group, n = 123). Atrial fibrillation occurred in 57 (22%) patients. Atrial fibrillation rates were 33 (24%) and 24 (19%) in no-hydrocortisone patients and hydrocortisone patients, respectively. In the weighted sample, the proportion of patients who developed AF was 28.8% in the no-hydrocortisone group and 16.8% in the hydrocortisone group (difference: -11.9%; 95% confidence interval: -23.4% to -0.5%; P = .040). CONCLUSION: In patients with septic shock, low-dose hydrocortisone was associated with a lower risk of developing AF during the acute phase.

Early high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure in the ED: A before-after study.

OBJECTIVES: To compare clinical impact after early initiation of high-flow nasal cannula oxygen therapy (HFNC) versus standard oxygen in patients admitted to an emergency department (ED) for acute hypoxemic respiratory failure. METHODS: We performed a prospective before-after study at EDs in two centers including patients with acute hypoxemic respiratory failure defined by a respiratory rate above 25 breaths/min or signs of increased breathing effort under additional oxygen for a pulse oximetry above 92%. Patients with cardiogenic pulmonary edema or exacerbation of chronic lung disease were excluded. All patients were treated with standard oxygen during the first period and with HFNC during the second. The primary outcome was the proportion of patients with improved respiratory failure 1 h after treatment initiation (respiratory rate ≤ 25 breaths/min without signs of increased breathing effort). Dyspnea and blood gases were also assessed. RESULTS: Among the 102 patients included, 48 were treated with standard oxygen and 54 with HFNC. One hour after treatment initiation, patients with HFNC were much more likely to recover from respiratory failure than those treated with standard oxygen: 61% (33 of 54 patients) versus 15% (7 of 48 patients), P < 0.001. They also showed greater improvement in oxygenation (increase in PaO2 was 31 mm Hg [0-67] vs. 9 [-9-36], P = 0.02), and in feeling of breathlessness. CONCLUSIONS: As compared to standard oxygen, patients with acute hypoxemic respiratory failure treated with HFNC at the ED had better oxygenation, less breathlessness and were more likely to show improved respiratory failure 1 h after initiation.

Rapid or Slow Time to Brain Death? Impact on Kidney Graft Injuries in an Allotransplantation Porcine Model.

The use of donors deceased after brain death (DBD) with extended criteria in response to the shortage of grafts leads to the removal of more fragile kidneys. These grafts are at greater risk of not being grafted or delayed function. A better knowledge of the pathophysiology of DBDs would improve this situation. There is a difference between the results from animal models of DBD and the clinical data potentially explained by the kinetics of brain death induction. We compared the effect of the induction rate of brain death on the recovery of post-transplant renal function in a pig model of DBD followed by allografts in nephrectomized pigs. Resumption of early function post-transplant was better in the rapidly generated brain death group (RgBD) and graft fibrosis at three months less important. Two groups had identical oxidative stress intensity but a greater response to this oxidative stress by SIRT1, PGC1-α and NRF2 in the RgBD group. Modulation of mechanistic target of rapamycin (mTOR) stimulation by NRF2 would also regulate the survival/apoptosis balance of renal cells. For the first time we have shown that an allostatic response to oxidative stress can explain the impact of the rapidity of brain death induction on the quality of kidney transplants.

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 6. Aminoglycosides.

Amikacin and gentamicin pharmacokinetic behaviors after nebulization were determined by comparing plasma and pulmonary epithelial lining fluid (ELF) concentrations in rats after intratracheal and intravenous administrations. ELF areas under concentration-time curve were 874 and 162 times higher after nebulization than after intravenous administration for amikacin and gentamicin, respectively. Even if both molecules appear to be good candidates for nebulization, these results demonstrate a much higher targeting advantage of nebulization for amikacin than for gentamicin.

Pharmacokinetics of intravenous and nebulized gentamicin in critically ill patients.

Objectives: Optimal dosing for nebulized gentamicin is unknown. We compared the pulmonary and systemic pharmacokinetics (PK) of gentamicin following intravenous and nebulized administration in mechanically ventilated patients. Methods: Twelve critically ill male patients with ventilator-associated pneumonia received a 30 min intravenous infusion of 8 mg/kg gentamicin , followed 48 h afterwards by the same dose nebulized. Blood samples were collected immediately before and until 24 h after intravenous and nebulized administration; mini-bronchoalveolar lavages (mini-BALs) were performed at 3 and 7 h or 5 and 10 h (six patients each) after each intravenous and nebulized administration. The PK analysis was conducted using a population approach. Results: After intravenous administration, concentrations of gentamicin measured in epithelial lining fluid (ELF) were very variable, and overall in the same range of magnitude (from 0.3 to 28 mg/L) as in plasma. After nebulization, gentamicin concentrations were much higher (∼3800-fold) in ELF than in plasma. The average systemic bioavailability of nebulized gentamicin was estimated to be 5%, with considerable inter-individual variability. Compared with intravenous administration, after nebulization the exposure (expressed as AUC) to gentamicin was 276-fold greater in ELF and 18-fold lower in plasma. Conclusions: Compared with intravenous administration, nebulization of gentamicin in patients with ventilator-associated pneumonia provides higher pulmonary concentrations and lower systemic concentrations but the inter-individual variability is large.

Intra-operative cutaneous temperature monitoring with zero-heat-flux technique (3M SpotOn) in comparison with oesophageal and arterial temperature: A prospective observational study.

BACKGROUND: Continuous monitoring of core temperature is essential during major surgery as a way of improving patient safety. Oesophageal probes or specific arterial catheters are invasive methods used in this setting. A new noninvasive device based on zero-heat-flux (ZHF) technique (SpotOn) seems promising but has been poorly investigated during rapid core temperature changes (RCTC). OBJECTIVE: To assess the accuracy of a SpotOn sensor vs. an oesophageal probe or specific arterial catheter during a slow change in core temperature of less than 1 °C within 30 min and RCTC ≥ 1 °C within 30 min. DESIGN: Prospective observational study. SETTING: Operating rooms at the University Hospital of Poitiers, France. PATIENTS: Fifty patients scheduled for major abdominal surgery under general anaesthesia were enrolled from June 2015 to March 2016. Data from 49 patients were finally analysed. Among these, 15 patients were treated with hyperthermic intraperitoneal chemotherapy. INTERVENTION: Each patient had a ZHF sensor placed on the skin surface of the forehead (TempZHF) and an oesophageal probe (TempEso) used as a reference method. Twenty-two patients also had a thermodilution arterial catheter (TempArt) placed in the axillary artery. MAIN OUTCOME MEASURES: Core temperature was continuously recorded from the three devices after induction of anaesthesia. Comparison of temperature measurements between methods was made using the Bland and Altman method during two separate periods according to the speed of core temperature changes. RESULTS: Compared with TempEso, bias and limits of agreement for TempZHF were 0.1 ±â€Š0.5 °C during slow core temperature changes periods and 0.6 ±â€Š1.8 °C during RCTC periods (P = 0.0002). Compared with TempArt, these values were -0.1 ±â€Š0.4 and 0.5 ±â€Š1.7 °C, respectively (P = 0.0039). The ZHF sensor was well tolerated. CONCLUSION: A SpotOn sensor using the ZHF method seems reliable for core temperature monitoring during abdominal surgery when variations in core temperature are slow rather than rapid. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02869828.

Patient factors and outcomes associated with the withdrawal or withholding of life-sustaining therapies in mechanically ventilated brain-injured patients: An observational multicentre study.

BACKGROUND: Knowledge of the factors associated with the decision to withdraw or withhold life support (WWLS) in brain-injured patients is limited. However, most deaths in these patients may involve such a decision. OBJECTIVES: To identify factors associated with the decision to WWLS in brain-injured patients requiring mechanical ventilation who survive the first 24 h in the ICU, and to analyse the outcomes and time to death. DESIGN: A retrospective observational multicentre study. SETTINGS: Twenty French ICUs in 18 university hospitals. PATIENTS: A total of 793 mechanically ventilated brain-injured adult patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Decision to WWLS within 3 months of ICU admission, and death or Glasgow Outcome Scale (GOS) score at day 90. RESULTS: A decision to WWLS was made in 171 patients (22%), of whom 89% were dead at day 90. Out of the 247 deaths recorded at day 90, 153 (62%) were observed after a decision to WWLS. The median time between admission and death when a decision to WWLS was made was 10 (5 to 20) days vs. 10 (5 to 26) days when no end-of-life decision was made (P < 0.924). Among the 18 patients with a decision to WWLS who were still alive at day 90, three patients (2%) had a GOS score of 2, nine patients (5%) had a GOS score of 3 and five patients (3%) a GOS score of 4. Older age, presence of one nonreactive and dilated pupil, Glasgow Coma Scale less than 7, barbiturate use, acute respiratory distress syndrome and worsening lesions on computed tomography scans were each independently associated with decisions to WWLS. CONCLUSION: Using a nationwide cohort of brain-injured patients, we observed a high proportion of deaths associated with an end-of-life decision. Older age and several disease severity factors were associated with the decision to WWLS.

Accuracy of Zero-Heat-Flux Cutaneous Temperature in Intensive Care Adults.

OBJECTIVES: To compare accuracy of a continuous noninvasive cutaneous temperature using zero-heat-flux method to esophageal temperature and arterial temperature. DESIGN: Prospective study. SETTING: ICU and NeuroICU, University Hospital. PATIENTS: Fifty-two ICU patients over a 4-month period who required continuous temperature monitoring were included in the study, after informed consent. INTERVENTIONS: All patients had esophageal temperature probe and a noninvasive cutaneous device to monitor their core temperature continuously. In seven patients who required cardiac output monitoring, continuous iliac arterial temperature was collected. Simultaneous core temperatures were recorded from 1 to 5 days. Comparison to the esophageal temperature, considered as the reference in this study, used the Bland and Altman method with adjustment for multiple measurements per patient. MEASUREMENTS AND MAIN RESULTS: The esophageal temperature ranged from 33°C to 39.7°C, 61,298 pairs of temperature using zero-heat-flux and esophageal temperature were collected and 1,850 triple of temperature using zero-heat-flux, esophageal temperature, and arterial temperature. Bias and limits of agreement for temperature using zero-heat-flux were 0.19°C ± 0.53°C compared with esophageal temperature with an absolute difference of temperature pairs equal to or lower than 0.5°C of 92.6% (95% CI, 91.9-93.4%) of cases and equal to or lower than 1°C for 99.9% (95% CI, 99.7-100.0%) of cases. Compared with arterial temperature, bias and limits of agreement were -0.00°C ± 0.36°C with an absolute difference of temperature pairs equal to or lower than 0.5°C of 99.8% (95% CI, 95.3-100%) of cases. All absolute difference of temperature pairs between temperature using zero-heat-flux and arterial temperature and between arterial temperature and esophageal temperature were equal to or lower than 1°C. No local or systemic serious complication was observed. CONCLUSIONS: These results suggest a comparable reliability of the cutaneous sensor using the zero-heat-flux method compared with esophageal or iliac arterial temperatures measurements.