Efficacy of carbapenem vs non carbapenem ß-lactam therapy as empiric antimicrobial therapy in patients with extended-spectrum ß-lactamase-producing Enterobacterales urinary septic shock: a propensity-weighted multicenter cohort study.

BACKGROUND: The rise in antimicrobial resistance is a global threat responsible for about 33,000 deaths in 2015 with a particular concern for extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) and has led to a major increase in the use of carbapenems, last-resort antibiotics. METHODS: In this retrospective propensity-weighted multicenter observational study conducted in 11 ICUs, the purpose was to assess the efficacy of non carbapenem regimen (piperacillin-tazobactam (PTZ) + aminoglycosides or 3rd-generation cephalosporin (3GC) + aminoglycosides) as empiric therapy in comparison with carbapenem in extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) urinary septic shock. The primary outcome was Day-30 mortality. RESULTS: Among 156 patients included in this study, 69 received a carbapenem and 87 received non carbapenem antibiotics as empiric treatment. Baseline clinical characteristics were similar between the two groups. Patients who received carbapenem had similar Day-30 mortality (10/69 (15%) vs 6/87 (7%), OR = 1.99 [0.55; 5.34] p = 0.16), illness severity, resolution of septic shock, and ESBL-E infection recurrence rates than patients who received an empiric non carbapenem therapy. The rates of secondary infection with C. difficile were comparable. CONCLUSIONS: In ESBL-E urinary septic shock, empiric treatment with a non carbapenem regimen, including systematically aminoglycosides, was not associated with higher mortality, compared to a carbapenem regimen.

Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

BACKGROUND: The optimal calorie and protein intakes at the acute phase of severe critical illness remain unknown. We hypothesised that early calorie and protein restriction improved outcomes in these patients, compared with standard calorie and protein targets. METHODS: The pragmatic, randomised, controlled, multicentre, open-label, parallel-group NUTRIREA-3 trial was performed in 61 French intensive care units (ICUs). Adults (≥18 years) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned to early nutrition (started within 24 h after intubation) with either low or standard calorie and protein targets (6 kcal/kg per day and 0·2-0·4 g/kg per day protein vs 25 kcal/kg per day and 1·0-1·3 g/kg per day protein) during the first 7 ICU days. The two primary endpoints were time to readiness for ICU discharge and day 90 all-cause mortality. Key secondary outcomes included secondary infections, gastrointestinal events, and liver dysfunction. The trial is registered on ClinicalTrials.gov, NCT03573739, and is completed. FINDINGS: Of 3044 patients randomly assigned between July 5, 2018, and 8 Dec 8, 2020, eight withdrew consent to participation. By day 90, 628 (41·3%) of 1521 patients in the low group and 648 (42·8%) of 1515 patients in the standard group had died (absolute difference -1·5%, 95% CI -5·0 to 2·0; p=0·41). Median time to readiness for ICU discharge was 8·0 days (IQR 5·0-14·0) in the low group and 9·0 days (5·0-17·0) in the standard group (hazard ratio [HR] 1·12, 95% CI 1·02 to 1·22; p=0·015). Proportions of patients with secondary infections did not differ between the groups (HR 0·85, 0·71 to 1·01; p=0·06). The low group had lower proportions of patients with vomiting (HR 0·77, 0·67 to 0·89; p<0·001), diarrhoea (0·83, 0·73 to 0·94; p=0·004), bowel ischaemia (0·50, 0·26 to 0·95; p=0·030), and liver dysfunction (0·92, 0·86-0·99; p=0·032). INTERPRETATION: Compared with standard calorie and protein targets, early calorie and protein restriction did not decrease mortality but was associated with faster recovery and fewer complications. FUNDING: French Ministry of Health.

Urine Protein/Creatinine Ratio in Thrombotic Microangiopathies: A Simple Test to Facilitate Thrombotic Thrombocytopenic Purpura and Hemolytic and Uremic Syndrome Diagnosis.

BACKGROUND: Early diagnosis of thrombotic thrombocytopenic purpura (TTP) versus hemolytic and uremic syndrome (HUS) is critical for the prompt initiation of specific therapies. OBJECTIVE: To evaluate the diagnostic performance of the proteinuria/creatininuria ratio (PU/CU) for TTP versus HUS. PATIENTS/METHODS: In a retrospective study, in association with the "French Score" (FS) (platelets < 30 G/L and serum creatinine level < 200 µmol/L), we assessed PU/CU for the diagnosis of TTP in patients above the age of 15 with thrombotic microangiopathy (TMA). Patients with a history of kidney disease or with on-going cancer, allograft or pregnancy were excluded from the analysis. RESULTS: Between February 2011 and April 2019, we identified 124 TMA. Fifty-six TMA patients for whom PU/CU were available, including 35 TTP and 21 HUS cases, were considered. Using receiver-operating characteristic curves (ROC), those with a threshold of 1.5 g/g for the PU/CU had a 77% sensitivity (95% CI (63, 94)) and a 90% specificity (95% CI (71, 100)) for TTP diagnosis compared with those having an 80% sensitivity (95% CI (66, 92)) and a 90% specificity (95% CI (76, 100) with a FS of 2. In comparison, a composite score, defined as a FS of 2 or a PU/CU ≤ 1.5 g/g, improved sensitivity to 99.6% (95% CI (93, 100)) for TTP diagnosis and enabled us to reclassify seven false-negative TTP patients. CONCLUSIONS: The addition of urinary PU/CU upon admission of patients with TMA is a fast and readily available test that can aid in the differential diagnosis of TTP versus HUS alongside traditional scoring.

Impact of early low-calorie low-protein versus standard-calorie standard-protein feeding on outcomes of ventilated adults with shock: design and conduct of a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

INTRODUCTION: International guidelines include early nutritional support (≤48 hour after admission), 20-25 kcal/kg/day, and 1.2-2 g/kg/day protein at the acute phase of critical illness. Recent data challenge the appropriateness of providing standard amounts of calories and protein during acute critical illness. Restricting calorie and protein intakes seemed beneficial, suggesting a role for metabolic pathways such as autophagy, a potential key mechanism in safeguarding cellular integrity, notably in the muscle, during critical illness. However, the optimal calorie and protein supply at the acute phase of severe critical illness remains unknown. NUTRIREA-3 will be the first trial to compare standard calorie and protein feeding complying with guidelines to low-calorie low-protein feeding. We hypothesised that nutritional support with calorie and protein restriction during acute critical illness decreased day 90 mortality and/or dependency on intensive care unit (ICU) management in mechanically ventilated patients receiving vasoactive amine therapy for shock, compared with standard calorie and protein targets. METHODS AND ANALYSIS: NUTRIREA-3 is a randomised, controlled, multicentre, open-label trial comparing two parallel groups of patients receiving invasive mechanical ventilation and vasoactive amine therapy for shock and given early nutritional support according to one of two strategies: early calorie-protein restriction (6 kcal/kg/day-0.2-0.4 g/kg/day) or standard calorie-protein targets (25 kcal/kg/day, 1.0-1.3 g/kg/day) at the acute phase defined as the first 7 days in the ICU. We will include 3044 patients in 61 French ICUs. Two primary end-points will be evaluated: day 90 mortality and time to ICU discharge readiness. The trial will be considered positive if significant between-group differences are found for one or both alternative primary endpoints. Secondary outcomes include hospital-acquired infections and nutritional, clinical and functional outcomes. ETHICS AND DISSEMINATION: The NUTRIREA-3 study has been approved by the appropriate ethics committee. Patients are included after informed consent. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03573739.

Amino acids and vitamins status during continuous renal replacement therapy: An ancillary prospective observational study of a randomised control trial.

BACKGROUND: Continuous renal replacement therapy (CRRT) is associated with micronutrients loss. Current recommendations are to administer 1-1.5g/kg/day of proteins during CRRT. We aim to evaluate the net effect of CRRT on amino acids (AA), vitamins A and C (Vit A, Vit C) levels. METHODS: This is a prospective observational study embedded within a randomised controlled trial comparing two CRRT doses in patients with septic shock. CRRT was provided in continuous veno-venous haemofiltration mode at a dose of either 35ml/kg/h or 70ml/kg/h. All patients received parenteral nutrition with standard trace elements and vitamins (protein intake 1g/kg/d). We measured serum levels of glutamine, valine and alanine as well as Vit A and Vit C upon randomisation, study day four and eight. In addition, we measured a larger panel of AA in a subset of 11 patients. RESULTS: We included 30 patients (17 allocated to 70ml/kg/h and 13 to 35ml/kg/h CRRT). Before CRRT initiation, mean plasma levels of glutamine and valine, Vit A and Vit C were low. CRRT was not associated with any significant change in AA levels except for a decrease in cystein. It was associated with an increase in Vit A and a decrease in Vit C levels. CRRT dose had no impact on those nutrients blood levels. CONCLUSIONS: Irrespective of dose, CRRT was associated with a decrease in cysteine and Vit C and an increase in Vit A with no significant change in other AA. Further studies should focus on lean mass wasting during CRRT.

High-flow nasal cannula oxygen therapy alone or with non-invasive ventilation during the weaning period after extubation in ICU: the prospective randomised controlled HIGH-WEAN protocol.

INTRODUCTION: Recent practice guidelines suggest applying non-invasive ventilation (NIV) to prevent postextubation respiratory failure in patients at high risk of extubation failure in intensive care unit (ICU). However, such prophylactic NIV has been only a conditional recommendation given the low certainty of evidence. Likewise, high-flow nasal cannula (HFNC) oxygen therapy has been shown to reduce reintubation rates as compared with standard oxygen and to be as efficient as NIV in patients at high risk. Whereas HFNC may be considered as an optimal therapy during the postextubation period, HFNC associated with NIV could be an additional means of preventing postextubation respiratory failure. We are hypothesising that treatment associating NIV with HFNC between NIV sessions may be more effective than HFNC alone and may reduce the reintubation rate in patients at high risk. METHODS AND ANALYSIS: This study is an investigator-initiated, multicentre randomised controlled trial comparing HFNC alone or with NIV sessions during the postextubation period in patients at high risk of extubation failure in the ICU. Six hundred patients will be randomised with a 1:1 ratio in two groups according to the strategy of oxygenation after extubation. The primary outcome is the reintubation rate within the 7 days following planned extubation. Secondary outcomes include the number of patients who meet the criteria for moderate/severe respiratory failure, ICU length of stay and mortality up to day 90. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03121482.

Effects of nefopam on early postoperative hyperalgesia after cardiac surgery.

OBJECTIVE: The purpose of this randomized, double-blind placebo-controlled study was to evaluate the effect of nefopam, a centrally acting antinociceptive compound, on the development of hyperalgesia after sternotomy. Preventive strategy giving nefopam from the early stage of anesthesia was compared with a postoperative strategy only and placebo. DESIGN: This study was double-blinded and randomized. SETTING: It was conducted in a single university hospital. PARTICIPANTS: Ninety American Society of Anesthesiologists II to III patients scheduled for elective cardiac surgery. INTERVENTIONS: Patients were assigned randomly to receive a 0.3-mg/kg bolus of nefopam at the induction of anesthesia followed by a continuous infusion of 0.065 mg/kg/h for 48 hours (G1), a 0.3-mg/kg bolus of nefopam at the end of surgery followed by a continuous infusion of 0.065 mg/kg/h for 48 hours (G2), or a placebo (G3). Postoperative analgesia was based on morphine patient-controlled analgesia and rescue analgesia when necessary. Postoperative hyperalgesia, pain scores, morphine consumption, and postoperative cognitive dysfunction were assessed for the first 48 hours and thereafter on postoperative days 4 and 7. MEASUREMENTS AND MAIN RESULTS: The postoperative extent of dynamic hyperalgesia and the decrease of the nociceptive threshold evaluated by von Frey filaments at the sternal midline were smaller in group 1 and group 2 compared with the placebo group at the 24th hour. The primary objective was the extent of hyperalgesia at the midline given as the mean (standard deviation [SD]) (4.4 [2.5] cm for G1, 4.1 [2.7] for G2, and 6.1 [2.7] cm for G3. The punctuate is given as mean (SD) (64 [43] g for G1, 68 [40.8] g for G2, and 32 [27] g for G3; with p < 0.05 for the comparisons of extent and punctuate hyperalgesia between G1 and G3 and G2 and G3). The extent of hyperalgesia was not significantly different among the 3 groups on days 2, 4, and 7 after surgery. There were no significant differences in pain scores, morphine consumption, or postoperative cognitive dysfunctions. CONCLUSIONS: Nefopam administered during the perioperative period slightly reduced acute hyperalgesia after cardiac surgery, but this was not associated with improved analgesic efficacy.

Direct testing of bronchoalveolar lavages from ventilator-associated pneumonia patients.

In line with a rapid de-escalation of empirical antimicrobial therapy, this study assessed the validity of an E-test-based direct specimen testing method on bronchoalveolar lavage (BAL) samples from ventilator-associated pneumonia (VAP) patients. E-test strips were directly applied onto Mueller-Hinton agar plates seeded with BAL samples and read after 24 h of incubation. In parallel, the BAL samples were analyzed by the routine diagnostic laboratory. The microbroth dilution approach was used as a control method. In a cohort of 20 patients, 135 microorganism-antibiotic combinations were studied. Total agreement between the 2 methods was achieved for 88.9% combinations, with 1.5% very major errors (isolates susceptible by E-test and reported resistant by the diagnostic laboratory) and 9.6% major errors (isolates resistant by E-test and reported susceptible by the diagnostic laboratory). These results indicate that applying E-test directly on BAL samples is a promising method for obtaining susceptibility data after 24 h in critical patients with VAP.

Target-controlled dosing of remifentanil during cardiac surgery reduces postoperative hyperalgesia.

OBJECTIVE: One of the strategies to attenuate opioid-induced hyperalgesia (OIH) may be to decrease intraoperative doses of opioids by using target-controlled infusion (TCI). DESIGN: Double-blind and randomized study. SETTING: A single university hospital. PARTICIPANTS: Forty American Society of Anesthesiologists II to III patients scheduled for elective cardiac surgery. INTERVENTIONS: patients were randomized to 1 of the 2 groups: 1 group received an infusion of intraoperative remifentanil using TCI (target: 7 ng/mL), and the 2nd one was given an intraoperative continuous infusion (CI) (0.3 µg/kg/min). The anesthestic protocol and postoperative pain management were the same in both groups. The extent of mechanical dynamic hyperalgesia on the middle line perpendicular to the wound was considered the primary endpoint. The secondary endpoints were other results of dynamic and punctuate hyperalgesia until postoperative day 7, visual analog scale (VAS) and verbal rating scale (VRS) scores, and total morphine consumption until postoperative day 2. MEASUREMENTS AND MAIN RESULTS: Morphometric and demographic characteristics and duration of surgery were comparable in both groups. Intraoperative remifentanil consumption was greater in CI than in TCI group (5,329 [1,833] v 3,662 [1,160] µg, p = 0.003). During the first 44 hours, there were no differences in morphine consumption, VAS, and VRS. The extent of hyperalgesia was significantly lower on postoperative days 1, 2, and 4 in the TCI group than in the CI group on the 3 evaluated lines (p < 0.05). Punctuate hyperalgesia evaluating 3 different points was lower in the TCI than in the CI group from postoperative day 1 until postoperative day 7 (p < 0.05). CONCLUSIONS: The intraoperative decrease of opioid consumption when comparing the CI versus TCI mode of administration of remifentanil led to less OIH after cardiac surgery.