Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

BACKGROUND: Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. METHODS: In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. RESULTS: A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. CONCLUSIONS: Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

Occurrences of post-traumatic stress disorder, anxiety, depression, and burnout syndrome in ICU staff workers after two-year of the COVID-19 pandemic: the international PSY-CO in ICU study.

PURPOSE: The present study aimed at assessing the prevalences of post-traumatic stress disorder (PTSD) (main objective), anxiety, depression, and burnout syndrome (BOS) and their associated factors in intensive care unit (ICU) staff workers in the second year of the COVID-19 pandemic. MATERIALS AND METHODS: An international cross-sectional multicenter ICU-based online survey was carried out among the ICU staff workers in 20 ICUs across 3 continents. ICUs staff workers (both caregivers and non-caregivers) were invited to complete PCL-5, HADS, and MBI questionnaires for assessing PTSD, anxiety, depression, and the different components of BOS, respectively. A personal questionnaire was used to isolate independent associated factors with these disorders. RESULTS: PCL-5, HADS, and MBI questionnaires were completed by 585, 570, and 539 responders, respectively (525 completed all questionnaires). PTSD was diagnosed in 98/585 responders (16.8%). Changing familial environment, being a non-caregiver staff worker, having not being involved in a COVID-19 patient admission, having not been provided with COVID-19-related information were associated with PTSD. Anxiety was reported in 130/570 responders (22.8%). Working in a public hospital, being a woman, being financially impacted, being a non-clinical healthcare staff member, having no theoretical or practical training on individual preventive measures, and fear of managing COVID-19 patients were associated with anxiety. Depression was reported in 50/570 responders (8.8%). Comorbidity at risk of severe COVID-19, working in a public hospital, looking after a child, being a non-caregiver staff member, having no information, and a request for moving from the unit were associated with depression. Having received no information and no adequate training for COVID-19 patient management were associated with all 3 dimensions of BOS. CONCLUSION: The present study confirmed that ICU staff workers, whether they treated COVID-19 patients or not, have a substantial prevalence of psychological disorders.

Association between combination antibiotic therapy as opposed as monotherapy and outcomes of ICU patients with Pseudomonas aeruginosa ventilator-associated pneumonia: an ancillary study of the iDIAPASON trial.

BACKGROUND: The optimal treatment duration and the nature of regimen of antibiotics (monotherapy or combination therapy) for Pseudomonas aeruginosa ventilator­associated pneumonia (PA-VAP) remain debated. The aim of this study was to evaluate whether a combination antibiotic therapy is superior to a monotherapy in patients with PA-VAP in terms of reduction in recurrence and death, based on the 186 patients included in the iDIAPASON trial, a multicenter, randomized controlled trial comparing 8 versus 15 days of antibiotic therapy for PA-VAP. METHODS: Patients with PA-VAP randomized in the iDIAPASON trial (short-duration-8 days vs. long-duration-15 days) and who received appropriate antibiotic therapy were eligible in the present study. The main objective is to compare mortality at day 90 according to the antibiotic therapy received by the patient: monotherapy versus combination therapy. The primary outcome was the mortality rate at day 90. The primary outcome was compared between groups using a Chi-square test. Time from appropriate antibiotic therapy to death in ICU or to censure at day 90 was represented using Kaplan-Meier survival curves and compared between groups using a Log-rank test. RESULTS: A total of 169 patients were included in the analysis. The median duration of appropriate antibiotic therapy was 14 days. At day 90, among 37 patients (21.9%) who died, 17 received monotherapy and 20 received a combination therapy (P = 0.180). Monotherapy and combination antibiotic therapy were similar for the recurrence rate of VAP, the number of extra pulmonary infections, or the acquisition of multidrug-resistant (MDR) bacteria during the ICU stay. Patients in combination therapy were exposed to mechanical ventilation for 28 ± 12 days, as compared with 23 ± 11 days for those receiving monotherapy (P = 0.0243). Results remain similar after adjustment for randomization arm of iDIAPASON trial and SOFA score at ICU admission. CONCLUSIONS: Except longer durations of antibiotic therapy and mechanical ventilation, potentially related to increased difficulty in achieving clinical cure, the patients in the combination therapy group had similar outcomes to those in the monotherapy group. TRIAL REGISTRATION: NCT02634411 , Registered 15 December 2015.

Impact of continuous hypertonic (NaCl 20%) saline solution on renal outcomes after traumatic brain injury (TBI): a post hoc analysis of the COBI trial.

BACKGROUND: To evaluate if the increase in chloride intake during a continuous infusion of 20% hypertonic saline solution (HSS) is associated with an increase in the incidence of acute kidney injury (AKI) compared to standard of care in traumatic brain injury patients. METHODS: In this post hoc analysis of the COBI trial, 370 patients admitted for a moderate-to-severe TBI in the 9 participating ICUs were enrolled. The intervention consisted in a continuous infusion of HSS to maintain a blood sodium level between 150 and 155 mmol/L for at least 48 h. Patients enrolled in the control arm were treated as recommended by the latest Brain Trauma foundation guidelines. The primary outcome of this study was the occurrence of AKI within 28 days after enrollment. AKI was defined by stages 2 or 3 according to KDIGO criteria. RESULTS: After exclusion of missing data, 322 patients were included in this post hoc analysis. The patients randomized in the intervention arm received a significantly higher amount of chloride during the first 4 days (intervention group: 97.3 ± 31.6 g vs. control group: 61.3 ± 38.1 g; p < 0.001) and had higher blood chloride levels at day 4 (117.9 ± 10.7 mmol/L vs. 111.6 ± 9 mmol/L, respectively, p < 0.001). The incidence of AKI was not statistically different between the intervention and the control group (24.5% vs. 28.9%, respectively; p = 0.45). CONCLUSIONS: Despite a significant increase in chloride intake, a continuous infusion of HSS was not associated with AKI in moderate-to-severe TBI patients. Our study does not confirm the potentially detrimental effect of chloride load on kidney function in ICU patients. TRIAL REGISTRATION: The COBI trial was registered on clinicaltrial.gov (Trial registration number: NCT03143751, date of registration: 8 May 2017).

Early non-invasive ventilation and high-flow nasal oxygen therapy for preventing endotracheal intubation in hypoxemic blunt chest trauma patients: the OptiTHO randomized trial.

BACKGROUND: The benefit-risk ratio of prophylactic non-invasive ventilation (NIV) and high-flow nasal oxygen therapy (HFNC-O2) during the early stage of blunt chest trauma remains controversial because of limited data. The main objective of this study was to compare the rate of endotracheal intubation between two NIV strategies in high-risk blunt chest trauma patients. METHODS: The OptiTHO trial was a randomized, open-label, multicenter trial over a two-year period. Every adult patients admitted in intensive care unit within 48 h after a high-risk blunt chest trauma (Thoracic Trauma Severity Score ≥ 8), an estimated PaO2/FiO2 ratio < 300 and no evidence of acute respiratory failure were eligible for study enrollment (Clinical Trial Registration: NCT03943914). The primary objective was to compare the rate of endotracheal intubation for delayed respiratory failure between two NIV strategies: i) a prompt association of HFNC-O2 and "early" NIV in every patient for at least 48 h with vs. ii) the standard of care associating COT and "late" NIV, indicated in patients with respiratory deterioration and/or PaO2/FiO2 ratio ≤ 200 mmHg. Secondary outcomes were the occurrence of chest trauma-related complications (pulmonary infection, delayed hemothorax or moderate-to-severe ARDS). RESULTS: Study enrollment was stopped for futility after a 2-year study period and randomization of 141 patients. Overall, 11 patients (7.8%) required endotracheal intubation for delayed respiratory failure. The rate of endotracheal intubation was not significantly lower in patients treated with the experimental strategy (7% [5/71]) when compared to the control group (8.6% [6/70]), with an adjusted OR = 0.72 (95%IC: 0.20-2.43), p = 0.60. The occurrence of pulmonary infection, delayed hemothorax or delayed ARDS was not significantly lower in patients treated by the experimental strategy (adjusted OR = 1.99 [95%IC: 0.73-5.89], p = 0.18, 0.85 [95%IC: 0.33-2.20], p = 0.74 and 2.14 [95%IC: 0.36-20.77], p = 0.41, respectively). CONCLUSION: A prompt association of HFNC-O2 with preventive NIV did not reduce the rate of endotracheal intubation or secondary respiratory complications when compared to COT and late NIV in high-risk blunt chest trauma patients with non-severe hypoxemia and no sign of acute respiratory failure. CLINICAL TRIAL REGISTRATION: NCT03943914, Registered 7 May 2019.

Prevalence and risk factors of significant persistent pain symptoms after critical care illness: a prospective multicentric study.

BACKGROUND: Prevalence, risk factors and medical management of persistent pain symptoms after critical care illness have not been thoroughly investigated. METHODS: We performed a prospective multicentric study in patients with an intensive care unit (ICU) length of stay ≥ 48 h. The primary outcome was the prevalence of significant persistent pain, defined as a numeric rating scale (NRS) ≥ 3, 3 months after admission. Secondary outcomes were the prevalence of symptoms compatible with neuropathic pain (ID-pain score > 3) and the risk factors of persistent pain. RESULTS: Eight hundred fourteen patients were included over a 10-month period in 26 centers. Patients had a mean age of 57 (± 17) years with a SAPS 2 score of 32 (± 16) (mean ± SD). The median ICU length of stay was 6 [4-12] days (median [interquartile]). At 3 months, the median intensity of pain symptoms was 2 [1-5] in the entire population, and 388 (47.7%) patients had significant pain. In this group, 34 (8.7%) patients had symptoms compatible with neuropathic pain. Female (Odds Ratio 1.5 95% CI [1.1-2.1]), prior use of anti-depressive agents (OR 2.2 95% CI [1.3-4]), prone positioning (OR 3 95% CI [1.4-6.4]) and the presence of pain symptoms on ICU discharge (NRS ≥ 3) (OR 2.4 95% CI [1.7-3.4]) were risk factors of persistent pain. Compared with sepsis, patients admitted for trauma (non neuro) (OR 3.5 95% CI [2.1-6]) were particularly at risk of persistent pain. Only 35 (11.3%) patients had specialist pain management by 3 months. CONCLUSIONS: Persistent pain symptoms were frequent in critical illness survivors and specialized management remained infrequent. Innovative approaches must be developed in the ICU to minimize the consequences of pain. TRIAL REGISTRATION: NCT04817696. Registered March 26, 2021.

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.

A One-Day Prospective National Observational Study on Sedation-Analgesia of Patients with Brain Injury in French Intensive Care Units: The SEDA-BIP-ICU (Sedation-Analgesia in Brain Injury Patient in ICU) Study.

BACKGROUND: Sedation/analgesia is a daily challenge faced by intensivists managing patients with brain injury (BI) in intensive care units (ICUs). The optimization of sedation in patients with BI presents particular challenges. A choice must be made between the potential benefit of a rapid clinical evaluation and the potential exacerbation of intracranial hypertension in patients with impaired cerebral compliance. In the ICU, a pragmatic approach to the use of sedation/analgesia, including the optimal titration, management of multiple drugs, and use of any type of brain monitor, is needed. Our research question was as follows: the aim of the study is to identify what is the current daily practice regarding sedation/analgesia in the management of patients with BI in the ICU in France? METHODS: This study was composed of two parts. The first part was a descriptive survey of sedation practices and characteristics in 30 French ICUs and 27 academic hospitals specializing in care for patients with BI. This first step validates ICU participation in data collection regarding sedation-analgesia practices. The second part was a 1-day prospective cross-sectional snapshot of all characteristics and prescriptions of patients with BI. RESULTS: On the study day, among the 246 patients with BI, 106 (43%) had a brain monitoring device and 74 patients (30%) were sedated. Thirty-nine of the sedated patients (53%) suffered from intracranial hypertension, 14 patients (19%) suffered from agitation and delirium, and 7 patients (9%) were sedated because of respiratory failure. Fourteen patients (19%) no longer had a formal indication for sedation. In 60% of the sedated patients, the sedatives were titrated by nurses based on sedation scales. The Richmond Agitation Sedation Scale was used in 80% of the patients, and the Behavioral Pain Scale was used in 92%. The common sedatives and opioids used were midazolam (58.1%), propofol (40.5%), and sufentanil (67.5%). The cerebral monitoring devices available in the participating ICUs were transcranial Doppler ultrasound (100%), intracranial and intraventricular pressure monitoring (93.3%), and brain tissue oxygenation (60%). Cerebral monitoring by one or more monitoring devices was performed in 62% of the sedated patients. This proportion increased to 74% in the subgroup of patients with intracranial hypertension, with multimodal cerebral monitoring in 43.6%. The doses of midazolam and sufentanil were lower in sedated patients managed based on a sedation/analgesia scale. CONCLUSIONS: Midazolam and sufentanil are frequently used, often in combination, in French ICUs instead of alternative drugs. In our study, cerebral monitoring was performed in more than 60% of the sedated patients, although that proportion is still insufficient. Future efforts should stress the use of multiple monitoring modes and adherence to the indications for sedation to improve care of patients with BI. Our study suggests that the use of sedation and analgesia scales by nurses involved in the management of patients with BI could decrease the dosages of midazolam and sufentanil administered. Updated guidelines are needed for the management of sedation/analgesia in patients with BI.

Implementation of French Recommendations for the Prevention and the Treatment of Hospital-acquired Pneumonia: A Cluster-randomized Trial.

BACKGROUND: We determined whether an audit on the adherence to guidelines for hospital-acquired pneumonia (HAP) can improve the outcomes of patients in intensive care units (ICUs). METHODS: This study was conducted at 35 ICUs in 30 hospitals. We included consecutive, adult patients hospitalized in ICUs for 3 days or more. After a 3-month baseline period followed by the dissemination of recommendations, an audit on the compliance to recommendations (audit period) was followed by a 3-month cluster-randomized trial. We randomly assigned ICUs to either receive audit and feedback (intervention group) or participate in a national registry (control group). The primary outcome was the duration of ICU stay. RESULTS: Among 1856 patients enrolled, 602, 669, and 585 were recruited in the baseline, audit, and intervention periods, respectively. The composite measures of compliance were 47% (interquartile range [IQR], 38-56%) in the intervention group and 42% (IQR, 25-53%) in the control group (P = .001). As compared to the baseline period, the ICU lengths of stay were reduced by 3.2 days in the intervention period (P = .07) and by 2.8 days in the control period (P = .02). The durations of ICU stay were 7 days (IQR, 5-14 days) in the control group and 9 days (IQR, 5-20 days) in the intervention group (P = .10). After adjustment for unbalanced baseline characteristics, the hazard ratio for being discharged alive from the ICU in the control group was 1.17 (95% confidence interval, .69-2.01; P = .10). CONCLUSIONS: The publication of French guidelines for HAP was associated with a reduction of the ICU length of stay. However, the realization of an audit to improve their application did not further improve outcomes. CLINICAL TRIALS REGISTRATION: NCT03348579.

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.

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.

Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR).

BACKGROUND: Beta-lactam antibiotics (ßLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients. METHODS: A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only "optional" recommendations. RESULTS: After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding ßLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of ßLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement. CONCLUSIONS: The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering ßLA in critically ill patients.

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.

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.

PURPOSE: Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition. METHODS: A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model. RESULTS: A common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error <37.5%). The model predicted the human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error <90%). CONCLUSIONS: A multi-compartmental brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.

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.

Microdialysis as a way to measure antibiotics concentration in tissues.

As for all other drugs, antibiotics must reach their pharmacodynamic target in order to exert their effect, but because infection may occur in various tissues the distribution of antibiotics has always been of particular concern. In this article, we will first critically review the various methodologies available to study antibiotics tissue distribution, including microdialysis, secondly we will show how basic pharmacokinetic concepts may help to predict or interpret antibiotics tissue distribution and third we will address the question of linking antibiotics tissue distribution with their antimicrobial effect, using modern pharmacokinetic-pharmacodynamic methods.

Metronidazole and hydroxymetronidazole central nervous system distribution: 1. microdialysis assessment of brain extracellular fluid concentrations in patients with acute brain injury.

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0-τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 µg ml(-1). This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.

Metronidazole and hydroxymetronidazole central nervous system distribution: 2. cerebrospinal fluid concentration measurements in patients with external ventricular drain.

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0-τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0-τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.