Incidence, risk factors and long-term outcomes for extubation failure in intensive care unit in patients with obesity A retrospective analysis of a multicenter prospective observational study.

BACKGROUND: No large observational study has compared the incidence and risk factors for extubation failure within 48 hours and during intensive care unit (ICU) stay in the same cohort of unselected critically ill patients with and without obesity. RESEARCH QUESTION: Which are the incidence and risk factors of extubation failure in patients with and without obesity? STUDY DESIGN AND METHODS: In this prospective multicenter observational FREE-REA study in 26 intensive care units, the primary objective was to compare the incidence of extubation failure within 48 hours in patients with and without obesity. Secondary objectives were to describe and to identify the independent specific risk factors for extubation failure using first a logistic regression model and second a decision tree analysis. RESULTS: Of 1,370 extubation procedures analyzed, 288 (21%) were performed in patients with obesity and 1082 (79%) in patients without obesity. The incidence of extubation failure within 48 hours among patients with or without presence of obesity was 23/288 (8.0%) versus 118/1082 (11%) respectively; unadjusted odds ratio (OR) 0.71 95% confidence interval (CI, 0.45-1.13), P=0.15); alongside patients with obesity receiving significantly more noninvasive ventilation (87/288, 30% versus 233/1082, 22%, P=0.002) and physiotherapy (165/288, 57% versus 527/1082, 49%, P=0.02) than patients without obesity. Risk factors for extubation failure also differed according to obesity status: female gender [adjusted (a)OR 4.88 95%CI(1.61-13.9), P=0.002] and agitation before extubation [aOR 6.39 95%CI (1.91-19.8), P=0.001] in patients with obesity; absence of strong cough before extubation [aOR 2.38 95%CI (1.53-3.84), P=0.0002] and duration of invasive mechanical ventilation before extubation [aOR 1.03 per day 95%CI (1.01-1.06), P=0.01] in patients without obesity. The decision tree analysis found similar risk factors. INTERPRETATION: Our findings indicate that anticipation and application of preventive measures for patients with obesity before and after extubation led to similar rate of extubation failure among patients with and without obesity. CLINICAL TRIAL REGISTRATION: NCT XXX.

Effects of induced arterial hypertension for vasospasm on unruptured and unsecured cerebral aneurysms (growth and rupture). A retrospective case-control study.

OBJECTIVES: Unruptured cerebral aneurysms (UCAs) often coexist with the ruptured one but are typically left unsecured during the weeks following aneurysmal subarachnoid hemorrhage (aSAH). We compared the rate of UCAs rupture or volume growth (≥5 mm3) between patients exposed to induced arterial hypertension (iHTN) for vasospasm and those not exposed (control group). MATERIALS AND METHODS: From 2013 to 2021, we retrospectively included consecutive adult patients with aSAH who had ≥1 UCA. Custom software for digital subtraction angiography (DSA) image analysis characterized UCAs volume, going beyond merely considering UCAs long axis. RESULTS: We analyzed 118 patients (180 UCAs): 45 in the iHTN group (64 UCAs) and 73 in the control group (116 UCAs). Systolic blood pressure in the iHTN group was significantly higher than in the control group for several days after aSAH. During the 107 day-monitoring period [interquartile range(IQR):92;128], no UCA rupture occurred in either group. UCA volume analysis was performed in 44 patients (60 UCAs): none of the UCAs in the iHTN group and 3 out of 42 (7%) in the control group had a >5 mm3 volume growth (p=0.55). Other morphologic parameters did not exhibit any variations that might indicate an increased risk of rupture in the iHTN group compared to the control group. CONCLUSION: iHTN did not increase the risk of rupture or volume growth of UCAs within several weeks following aSAH. These reassuring results encourage not to refrain, because of the existence of UCAs, from iHTN as an option to prevent cerebral infarction during cerebral vasospasm.

Renal replacement therapy initiation strategies in comatose patients with severe acute kidney injury: a secondary analysis of a multicenter randomized controlled trial.

PURPOSE: The effect of renal replacement therapy (RRT) in comatose patients with acute kidney injury (AKI) remains unclear. We compared two RRT initiation strategies on the probability of awakening in comatose patients with severe AKI. METHODS: We conducted a post hoc analysis of a trial comparing two delayed RRT initiation strategies in patients with severe AKI. Patients were monitored until they had oliguria for more than 72 h and/or blood urea nitrogen higher than 112 mg/dL and then randomized to a delayed strategy (RRT initiated after randomization) or a more-delayed one (RRT initiated if complication occurred or when blood urea nitrogen exceeded 140 mg/dL). We included only comatose patients (Richmond Agitation-Sedation scale [RASS] < - 3), irrespective of sedation, at randomization. A multi-state model was built, defining five mutually exclusive states: death, coma (RASS < - 3), incomplete awakening (RASS [- 3; - 2]), awakening (RASS [- 1; + 1] two consecutive days), and agitation (RASS > + 1). Primary outcome was the transition from coma to awakening during 28 days after randomization. RESULTS: A total of 168 comatose patients (90 delayed and 78 more-delayed) underwent randomization. The transition intensity from coma to awakening was lower in the more-delayed group (hazard ratio [HR] = 0.36 [0.17-0.78]; p = 0.010). Time spent awake was 10.11 days [8.11-12.15] and 7.63 days [5.57-9.64] in the delayed and the more-delayed groups, respectively. Two sensitivity analyses were performed based on sedation status and sedation practices across centers, yielding comparable results. CONCLUSION: In comatose patients with severe AKI, a more-delayed RRT initiation strategy resulted in a lower chance of transitioning from coma to awakening.

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

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

Risk factors for poor performance in finger cuff non-invasive monitoring of arterial pressure: A prospective multicenter study.

BACKGROUND: Compared to the invasive technique, non-invasive monitoring of arterial pressure favors easier and faster implementation while potentially sacrificing some reliability. This may be particularly true for the Clearsight™ system (Edwards Lifesciences), which enables continuous monitoring. We evaluated the risk factors for its poor performance. METHODS: Patients with an arterial catheter and stable mean arterial pressure (MAP) over a 5-min period were included. Six pairs of invasive and Clearsight measurements of MAP were collected and the bias between the two techniques was calculated. Poor performance of the Clearsight™ system was defined as either a failure to measure and display MAP or displaying an erroneous MAP (individual bias > 5 mmHg). Fingertip perfusion was assessed using the plethysmographic perfusion index (PI) and the capillary refill time (CRT). RESULTS: Among 152 ICU patients (MAP of 81 ± 14 mmHg, norepinephrine in 78 [51%]), 78 (51%) experienced a poor performance of the Clearsight™ system: failure to display MAP in 19 (13%) patients, and erroneous value displayed in 59 (44%). In multivariate analysis, PI ≤ 0.85% (adjusted odds ratio [aOR] = 2.94 [95% confidence interval (95%CI):1.34;6.45]), CRT > 4 s (aOR = 5.28 [95%CI 1.39;20.05]), and the presence of hand edema (aOR = 2.06 [95%CI 1.01;4.21]) were associated with a higher likelihood of poor performance. Cardiac arrhythmia (aOR = 1.39 [95%CI 0.64;3.02]) and other tested variables were not associated with poor performance. CONCLUSIONS: Half of the included patients exhibited poor Clearsight™ system performance. Our results caution against using finger cuff arterial pressure monitoring in patients with low PI (≤0.85%), protracted CRT (>4 s), or hand edema. REGISTRATION: ClinicalTrials.gov, NCT04269382, Dr. G. Muller, February 13, 2020. https://classic. CLINICALTRIALS: gov/ct2/show/NCT04269382.

Cerebral Vasospasm After Subarachnoid Hemorrhage: Respective Short-Term Effects of Induced Arterial Hypertension and its Combination With IV Milrinone: A Proof-of-Concept Study Using Transcranial Doppler Ultrasound.

OBJECTIVES: It is unclear whether IV milrinone relaxes spasmed cerebral arteries and therefore reduces cerebral blood mean velocity (Vmean). In patients treated for cerebral vasospasm, we aimed to assess and delineate the respective impacts of induced hypertension and its combination with IV milrinone on cerebral hemodynamics as assessed with transcranial Doppler. DESIGN: Observational proof-of-concept prospective study. SETTING: ICU in a French tertiary care center. PATIENTS: Patients with aneurysmal subarachnoid hemorrhage who received induced hypertension (mean arterial blood pressure [MBP] of 100-120 mm Hg) and IV milrinone (0.5 µg/kg/min) for moderate-to-severe cerebral vasospasm. We excluded patients who underwent invasive angioplasty or milrinone discontinuation within 12 hours after the diagnosis of vasospasm. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Vmean was measured at vasospasm diagnosis (TDIAGNOSIS), after the induction of hypertension (THTN), and 1 (THTN+MILRINONE_H1) and 12 hours after the adjunction of IV milrinone (THTN+MILRINONE_H12). Thirteen patients were included. Median Vmean was significantly lower (p < 0.01) at THTN+MILRINONE_H1 (99 [interquartile range (IQR) 89; 134] cm.s-1) and THTN+MILRINONE_H12 (85 [IQR 73-127] cm/s) than at TDIAGNOSIS (136 [IQR 115-164] cm/s) and THTN (148 [IQR 115-183] cm/s), whereas TDIAGNOSIS and THTN did not significantly differ. In all patients but one, Vmean at THTN+MILRINONE_H1 was lower than its value at TDIAGNOSIS (p = 0.0005). Vmean-to-MBP and Vmean-to-cardiac output (CO) ratios (an assessment of Vmean regardless of the level of MBP [n = 13] or CO [n = 7], respectively) were, respectively, similar at TDIAGNOSIS and THTN but were significantly lower after the adjunction of milrinone (p < 0.01). CONCLUSIONS: The induction of arterial hypertension was not associated with a significant decrease in Vmean, whereas the adjunction of IV milrinone was, regardless of the level of MBP or CO. This suggests that IV milrinone may succeed in relaxing spasmed arteries.

Noninvasive Monitoring of Arterial Pressure: Finger or Lower Leg As Alternatives to the Upper Arm: A Prospective Study in Three ICUs.

OBJECTIVES: When the upper arm is inaccessible for measurements of arterial pressure (AP), the best alternative site is unknown. We performed a between-site comparison of the agreement between invasive and noninvasive readings of AP taken at the lower leg, the finger, and the upper arm. The risk associated with measurement errors and the trending ability were also assessed. DESIGN: Prospective observational study. SETTING: Three ICUs. PATIENTS: Patients having an arterial catheter and an arm circumference less than 42 cm. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three triplicates of AP measurements were collected via an arterial catheter (reference AP), a finger cuff system (ClearSight; Edward Lifesciences, Irvine, CA), and an oscillometric cuff (at the lower leg then the upper arm). Trending ability was assessed through an additional set of measurements after a cardiovascular intervention. The default bed backrest angle was respected. Failure to measure and display AP occurred in 19 patients (13%) at the finger, never at other sites. In 130 patients analyzed, the agreement between noninvasive and invasive readings was worse at the lower leg than that observed at the upper arm or the finger (for mean AP, bias ± sd of 6.0 ± 15.8 vs 3.6 ± 7.1 and 0.1 ± 7.4 mm Hg, respectively; p < 0.05), yielding a higher frequency of error-associated clinical risk (no risk for 64% vs 84% and 86% of measurements, respectively, p < 0.0001). According to the International Organization for Standardization (ISO) 81060-2:2018 standard, mean AP measurements were reliable at the upper arm and the finger, not the lower leg. In 33 patients reassessed after a cardiovascular intervention, both the concordance rate for change in mean AP and the ability to detect a therapy-induced significant change were good and similar at the three sites. CONCLUSIONS: As compared with lower leg measurements of AP, finger measurements were, when possible, a preferable alternative to upper arm ones.

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

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

The accuracy of intensive care nurses' interpretation of chest radiographs to recognise misplacement of endotracheal and nasogastric tubes after a single training session and comparison with residents' interpretation.

BACKGROUND: Misplacements of endotracheal and nasogastric tubes are frequent encounters in critically ill patients. OBJECTIVES: The purpose of this study was to assess the effectiveness of a single standardised training session on the ability of intensive care registered nurses (RNs) to recognise the misplacement of endotracheal and nasogastric tubes on bedside chest radiographs of patients in intensive care units (ICUs). METHODS: In eight French ICUs, RNs received a 110-min standardised teaching on the position of endotracheal and nasogastric tubes on chest radiographs. Their knowledge was evaluated within the subsequent weeks. For 20 chest radiographs, each with an endotracheal and nasogastric tube, RNs had to indicate whether each tube was in the proper or incorrect position. Training success was defined as >90% for the lower bound of the 95% confidence interval (95% CI) of the mean correct response rate (CRR). Residents of the participating ICUs underwent the same evaluation (without prior specific training). RESULTS: In total, 181 RNs were trained and evaluated and 110 residents were evaluated. The global mean CRR for RNs was 84.6% (95% CI: 83.3-85.9), significantly higher than for residents (81.4% [95% CI: 79.7-83.2]) (P < 0.0001). The mean CRR for RNs and residents was 95.9% (93.9-98.0) and 97.0% (94.7-99.3) for misplaced nasogastric tubes (P = 0.54), 86.8% (85.2-88.5) and 82.6% (79.4-85.7) (P = 0.07) for nasogastric tubes in the correct position, 86.6% (83.8-89.3) and 62.7% (57.9-67.5) for misplaced endotracheal tubes (P < 0.0001), and 79.1% (76.6-81.6) and 84.7% (82.1-87.2) for endotracheal tubes in the correct position (P = 0.01), respectively. CONCLUSIONS: The ability of trained RNs to detect tube misplacement did not reach the predetermined arbitrary level, indicating training success. Their mean CRR was higher than that for residents and was considered satisfactory for detecting misplaced nasogastric tubes. This finding is encouraging but insufficient to ensure patient safety. Transferring responsibility for reading radiographs to detect the misplacement of endotracheal tubes to intensive care RNs will need a more advanced or more in-depth teaching method.

Plasma haemolysis index and interleukine-6 for the early prediction of cardiac surgery-associated acute kidney injury. A proof-of-concept study.

INTRODUCTION: Haemolysis and inflammation contribute to cardiac surgery-associated acute kidney injury (CS-AKI). We aimed to assess the performance of plasma haemolysis index (HI) and interleukine-6 (IL-6) for the prediction of all-stage CS-AKI. We also assessed their ability to predict moderate-to-severe CS-AKI and to discriminate persistent from transient CS-AKI. METHODS: Adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) were prospectively included. Haemolysis index and IL-6 were measured immediately after the end of CPB and 6 hours later. Correction for haemodilution relied upon changes in albuminaemia. Persistent CS-AKI was defined as a steady/increasing CS-AKI stage between the 48th and the 60th postoperative hour as compared with the worst stage observed within the 48 first hours. RESULTS: Among 82 patients, CS-AKI occurred in 37 (45%) patients. Postoperative HI and IL-6 were positively correlated to the duration of CPB (r ≤ 0.51, p ≤ 0.0003). Whether we considered isolated measurements of HI or IL-6, their indexation to haemodilution or not, their kinetics and/or their combination, the prediction of all stage CS-AKI was inaccurate (area under the receiver operating characteristic curve [AUCROC]≤ 0.68) whereas moderate-to-severe CS-AKI (6 patients only) was predicted with an honourable performance (AUCROC = 0.77 [95%CI 0.67;0.86] and 0.87 [95%CI 0.77;0.93] for HI and IL-6, respectively). The persistent/transient nature of CS-AKI was inaccurately predicted (AUCROC ≤ 0.68). CONCLUSIONS: In a population in which most CS-AKI cases were mild, although they frequently (41%) persisted >48 hours, CS-AKI was inaccurately predicted by HI and/or IL-6. A better performance for moderate-to-severe CS-AKI prediction is likely. These preliminary findings are yet to be validated.

Empirical Antibiotic Therapy for Gram-Negative Bacilli Ventilator-Associated Pneumonia: Observational Study and Pharmacodynamic Assessment.

Background: Strong evidence suggests a correlation between pharmacodynamics (PD) index and antibiotic efficacy while dose adjustment should be considered in critically ill patients due to modified pharmacokinetic (PK) parameters and/or higher minimum inhibitory concentrations (MICs). This study aimed to assess pharmacodynamic (PD) target attainment considering both antibiotics serum concentrations and measured MICs in these patients. Method: A multicentric prospective open-label trial conducted in 11 French ICUs involved patients with Gram-negative bacilli (GNB) ventilator-associated pneumonia (VAP) confirmed by quantitative cultures. Results: We included 117 patients. Causative GNBs were P. aeruginosa (40%), Enterobacter spp. (23%), E. coli (20%), and Klebsiella spp. (16%). Hence, 117 (100%) patients received ß-lactams, 65 (58%) aminoglycosides, and two (1.5%) fluoroquinolones. For ß-lactams, 83% of the patients achieved a Cmin/MIC > 1 and 70% had a Cmin/MIC > 4. In the case of high creatinine clearance (CrCL > 100 mL/min/1.73 m2), 70.4% of the patients achieved a Cmin/MIC ratio > 1 versus 91% otherwise (p = 0.041), and 52% achieved a Cmin/MIC ratio > 4 versus 81% (p = 0.018). For aminoglycosides, 94% of the patients had a Cmax/MIC ratio > 8. Neither ß-lactams nor aminoglycosides PK/PD parameters were associated clinical outcomes, but our data suggest a correlation between ß-lactams Cmin/MIC and microbiological success. Conclusion: In our ICU patients treated for GNB VAP, using recommended antibiotic dosage led in most cases to PK/PD targets attainment for aminoglycosides and ß-lactams. High creatinine clearance should encourage clinicians to focus on PK/PD issues.

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

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

Early Acute Kidney Injury in Patients with Non-Traumatic Subarachnoid Hemorrhage who Undergo Catheter Angiography: Incidence, Associated Risk Factors and Impact on Outcome.

OBJECTIVES: After subarachnoid hemorrhage (SAH), potential renal insults are numerous but the burden of early acute kidney injury (AKI) is unclear. We determined its incidence, rate of persistence, risk factors, and impact on patients' outcomes. MATERIALS AND METHODS: Patients with non-traumatic SAH were retrospectively included if they underwent catheter angiography within the 48 h after their admission to the intensive care unit. Early AKI was defined according to Kidney Disease Improving Global Outcome (KDIGO) criteria, analyzed from the time of catheter angiography. Early AKI was considered as persistent if the KDIGO stage did not decrease between the 48th and the 60th hour. RESULTS: Among 499 consecutive patients, early AKI (mostly oliguria) occurred in 132 (26%): stage 1, 2 and 3 in 72 (14%), 44 (9%), and 16 (3%) patients, respectively. It persisted in 36% of cases. Early AKI occurred more likely when SAH was severe or renal function was impaired at hospital admission: adjusted odds ratio of 2.76 [95% 1.77-4.30] and 3.32 [1.17-9.46], respectively. ICU and hospital lengths of stay were longer in patients who developed early AKI than in patients who did not: 16 [9-29] versus 12 [4-24] days (p = 0.0003) and 21 [14-43] versus 16 [11-32] days (p = 0.007), respectively. There was an independent link between early AKI and renal outcome (n = 274 in the model) but not with hospital mortality (n = 453). CONCLUSIONS: One quarter of our population developed early AKI, mostly oliguria. It persisted beyond the 48th hour in one third of cases. The associated risk factors we identified were non-modifiable.