Correlation between antifungal clinical practices and a new clinical decision support system ANTIFON-CLIC® for the treatment of invasive candidiasis: a retrospective multicentre study.

BACKGROUND: Invasive candidiasis is still recognized as a major cause of morbidity and mortality. To support clinicians in the optimal use of antifungals for the treatment of invasive candidiasis, a computerized decision support system (CDSS) was developed based on institutional guidelines. OBJECTIVES: To evaluate the correlation of this newly developed CDSS with clinical practices, we set-up a retrospective multicentre cohort study with the aim of providing the concordance rate between the CDSS recommendation and the medical prescription (NCT05656157). PATIENTS AND METHODS: Adult patients who received caspofungin or fluconazole for the treatment of an invasive candidiasis were included. The analysis of factors associated with concordance was performed using mixed logistic regression models with department as a random effect. RESULTS: From March to November 2022, 190 patients were included from three centres and eight departments: 70 patients from centre A, 84 from centre B and 36 from centre C. Overall, 100 patients received caspofungin and 90 received fluconazole, mostly (59%; 112/190) for empirical/pre-emptive treatment. The overall percentage of concordance between the CDSS and medical prescriptions was 91% (173/190) (confidence interval 95%: 82%-96%). No significant difference in concordance was observed considering the centres (P > 0.99), the department of inclusion (P = 0.968), the antifungal treatment (P = 0.656) or the indication of treatment (P = 0.997). In most cases of discordance (n = 13/17, 76%), the CDSS recommended fluconazole whereas caspofungin was prescribed. The clinical usability evaluated by five clinicians was satisfactory. CONCLUSIONS: Our results demonstrated the high correlation between current antifungal clinical practice and this user-friendly and institutional guidelines-based CDSS.

Acute liver failure after out-of-hospital cardiac arrest: An observational study.

RATIONALE: Apart from hypoxic hepatitis (HH), the hepatic consequences of out-of-hospital cardiac arrest (OHCA) have been little studied. This cohort study aimed to investigate the characteristics of liver dysfunction resulting from OHCA and its association with outcomes. METHODS: Among the conventional static liver function tests used to define acute liver failure (ALF), we determined which one correlated more closely with the reference indocyanine green (ICG) clearance test in a series of OHCA patients from the CYRUS trial (NCT01595958). Subsequently, we assessed whether ALF, in addition to HH (i.e., acute liver injury), was an independent risk factor for death in a large cohort of OHCA patients admitted to two intensive care units between 2007 and 2017. RESULTS: ICG clearance, available for 22 patients, was impaired in 17 (77.3%) cases. Prothrombin time (PT) ratio was the only static liver function test that correlated significantly (r = -0.66, p < 0.01) with ICG clearance and was therefore used to define ALF, with the usual cutoff of < 50%. Of the 418 patients included in the analysis (sex ratio: 1.4; median age: 64 [53-75] years; non-shockable rhythm: 73%), 67 (16.0%) presented with ALF, and 61 (14.6%) had HH at admission. On day 28, 337 (80.6%) patients died. Following multivariate analysis, ALF at admission, OHCA occurring at home, absence of bystander, non-cardiac cause of OHCA, low-flow duration ≥ 20 min, and SOFA score excluding liver subscore at admission were independently associated with day 28 mortality. CONCLUSIONS: ALF occurred frequently after OHCA and, unlike HH, was independently associated with day 28 mortality.

Effects on mechanical power of different devices used for inhaled sedation in a bench model of protective ventilation in ICU.

BACKGROUND: Inhaled sedation during invasive mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) has received increasing attention. However, inhaled sedation devices increase dead-space ventilation and an undesirable effect is the increase in minute ventilation needed to maintain CO2 removal. A consequence of raising minute ventilation is an increase in mechanical power (MP) that can promote lung injury. However, the effect of inhaled sedation devices on MP remains unknown. METHODS: We conducted a bench study to assess and compare the effects of three devices delivering inhaled sevoflurane currently available in ICU (AnaConDa-50 mL (ANA-50), AnaConDa-100 mL (ANA-100), and MIRUS) on MP by using a test lung model set with three compliances (20, 40, and 60 mL/cmH2O). We simulated lung-protective ventilation using a low tidal volume and two levels of positive end-expiratory pressure (5 and 15 cmH2O) under ambient temperature and dry conditions. Following the insertion of the devices, either the respiratory rate or tidal volume was increased in 15%-steps until end-tidal CO2 (EtCO2) returned to the baseline value. MP was calculated at baseline and after EtCO2 correction using a simplified equation. RESULTS: Following device insertion, the EtCO2 increase was significantly greater with MIRUS (+ 78 ± 13%) and ANA-100 (+ 100 ± 11%) than with ANA-50 (+ 49 ± 7%). After normalizing EtCO2 by adjusting minute ventilation, MP significantly increased by more than 50% with all inhaled sedation devices compared to controls. The lowest increase in MP was observed with ANA-50 (p < 0.05 versus ANA-100 and MIRUS). The Costa index, another parameter assessing the mechanical energy delivered to the lungs, calculated as driving pressure × 4 + respiratory rate, significantly increased by more than 20% in all experimental conditions. Additional experiments performed under body temperature, ambient pressure, and gas saturated with water vapor conditions, confirmed the main results with an increase in MP > 50% with all devices after normalizing EtCO2 by adjusting minute ventilation. CONCLUSION: Inhaled sedation devices substantially increased MP in this bench model of protective ventilation, which might limit their benefits in ARDS.

Factors associated with short- and long-term outcomes in lung cancer patients requiring unplanned invasive mechanical ventilation.

OBJECTIVE: Unplanned invasive mechanical ventilation (IMV) is associated with high mortality in lung cancer patients. We aimed to identify factors associated with weaning from IMV, intensive care unit (ICU) survival and 1-year survival in lung cancer patients requiring unplanned IMV. DESIGN: Retrospective observational study (2007-2017). SETTING: University-affiliated ICU. PATIENTS: Lung cancer patients requiring unplanned IMV. INTERVENTION: None. MAIN VARIABLES OF INTEREST: Weaning from IMV, ICU and 1-year survival. RESULTS: Of the 136 patients included in the analysis (age 64 (9) years, male 110 (81%), metastatic disease 97 (62%)), 52 (38%) were weaned from IMV, 51 (38%) were discharged from ICU and 22 (16%) were alive at 1year. The main indication for intubation was acute respiratory failure. In multivariate analysis, PaO2/FiO2 >175mmHg at ICU admission and intubation before ICU admission were associated with successful weaning from IMV while intubation for cardiac arrest was associated with weaning failure. Same factors were associated with ICU survival. Absence of metastasis at ICU admission and lung resection surgery were independently associated with 1-year survival. CONCLUSIONS: A significant proportion of patients with lung cancer treated with unplanned IMV could be weaned from IMV and survived to ICU discharge, especially in the absence of severe hypoxemia at ICU admission. The low one-year survival was mostly driven by metastatic status.

Persistent NLRP3 inflammasome activation is associated with delayed immunosuppression in septic patients.

Sepsis triggers a complex response marked by the simultaneous presence of proinflammatory and immunosuppressive elements, disrupting the mechanisms intended to maintain homeostasis. While the NLRP3 inflammasome has been demonstrated to contribute to the inflammatory side, its connection with delayed sepsis-induced immunosuppression remains unexplored. The present objective was to concomitantly and prospectively assess NLRP3 activation (IL-1ß, IL-18, and soluble receptors) and features of immune failure (IL-10, mHLA-DR, myeloid-derived suppressor cells) in septic patients. To validate our findings, we conducted a transcriptomic analysis of mRNA of NLRP3-related genes (IL-18R1, IL-1R2) on an additional cohort of 107 patients. Two distinct endotypes were identified. One cluster displayed moderate inflammation rapidly returning to normal values, while the other exhibited a higher inflammatory response persisting until day 28, which was associated with persistent marked immunosuppression and higher 28-d mortality. Identifying endotypes with different pro/anti-inflammatory trajectories could hold important clinical implications for the management of sepsis.

Altered Ex Vivo NLRP3 Inflammasome Activation Is Associated with 28-Day Mortality in Septic Patients.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated response to infection. In this context, the aberrant activation of the NLRP3 inflammasome has been documented mostly through the measurement of increased plasmatic concentrations of IL-1ß and IL-18. At the cellular level, contradictory results have been published. However, no study has comprehensively monitored NLRP3 inflammasome activation at the basal level and after ex vivo reactivation of whole blood monocytes and neutrophils focusing on ICU patients with bacterial and viral sepsis, including a longitudinal analysis. Thus, we conducted a prospective longitudinal study, examining NLRP3 inflammasome functionality in COVID-19 ICU patients (n = 15) and bacterial septic shock patients (n = 17) during the first week of ICU hospitalization, compared with healthy donors. Using two whole-blood flow cytometry assays, we detected ASC speck-positive monocytes (i.e., monocytes presenting the polymerization of ASC proteins) and activated caspase-1 in polymorphonuclear cells as read-outs, both at baseline and following nigericin stimulation, a drug that forms pores and activates the NLRP3 inflammasome. Our findings showed that, at baseline and regardless of the type of infection, patients exhibited reduced ASC speck-positive monocytes and decreased activated caspase-1 in PMN compared to healthy volunteers. This decrease was prominent at day 0. Following nigericin stimulation, this reduction was also observed and persisted throughout the first week of hospitalization, irrespective of the cellular population or parameter being considered. Notably, at day 0, this diminished activation and response to stimulation of NLRP3 was associated with a higher 28-day mortality rate. Consequently, our observations highlighted a concurrent decline in both basal expression and ex vivo activation of the NLRP3 inflammasome in circulating myeloid cells from patients with bacterial and viral sepsis in association with increased mortality.

Prospective comparison of prognostic scores for prediction of outcome after out-of-hospital cardiac arrest: results of the AfterROSC1 multicentric study.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a heterogeneous entity with multiple origins and prognoses. An early, reliable assessment of the prognosis is useful to adapt therapeutic strategy, tailor intensity of care, and inform relatives. We aimed primarily to undertake a prospective multicentric study to evaluate predictive performance of the Cardiac Arrest Prognosis (CAHP) Score as compare to historical dataset systematically collected after OHCA (Utstein style criteria). Our secondary aim was to evaluate other dedicated scores for predicting outcome after OHCA and to compare them to Utstein style criteria. METHODS: We prospectively collected data from 24 French and Belgium Intensive Care Units (ICUs) between August 2020 and June 2022. All cases of non-traumatic OHCA (cardiac and non-cardiac causes) patients with stable return of spontaneous circulation (ROSC) and comatose at ICU admission (defined by Glasgow coma score ≤ 8) on ICU admission were included. The primary outcome was the modified Rankin scale (mRS) at day 90 after cardiac arrest, assessed by phone interviews. A wide range of developed scores (CAHP, OHCA, CREST, C-Graph, TTM, CAST, NULL-PLEASE, and MIRACLE2) were included, and their accuracies in predicting poor outcome at 90 days after OHCA (defined as mRS ≥ 4) were determined using the area under the receiving operating characteristic curve (AUROC) and the calibration belt. RESULTS: During the study period, 907 patients were screened, and 658 were included in the study. Patients were predominantly male (72%), with a mean age of 61 ± 15, most having collapsed from a supposed cardiac cause (64%). The mortality rate at day 90 was 63% and unfavorable neurological outcomes were observed in 66%. The performance (AUROC) of Utstein criteria for poor outcome prediction was moderate at 0.79 [0.76-0.83], whereas AUROCs from other scores varied from 0.79 [0.75-0.83] to 0.88 [0.86-0.91]. For each score, the proportion of patients for whom individual values could not be calculated varied from 1.4% to 17.4%. CONCLUSIONS: In patients admitted to ICUs after a successfully resuscitated OHCA, most of the scores available for the evaluation of the subsequent prognosis are more efficient than the usual Utstein criteria but calibration is unacceptable for some of them. Our results show that some scores (CAHP, sCAHP, mCAHP, OHCA, rCAST) have superior performance, and that their ease and speed of determination should encourage their use. Trial registration https://clinicaltrials.gov/ct2/show/NCT04167891.

Outcome and factors associated with mortality in patients receiving urgent chemotherapy in the ICU: A retrospective study.

PURPOSE: This study aimed to assess the outcome and factors associated with mortality in patients who received urgent chemotherapy (CT) in the intensive care unit (ICU) in Lyon, France. MATERIAL AND METHODS: A total of 147 adult patients diagnosed with cancer and requiring urgent CT during ICU stay between October 2014 and December 2019 were included in this retrospective study. RESULTS: Hematological cancer was found in 77% of patients, and acute respiratory failure was the leading cause of ICU admission (46.3%). The 6-month mortality rate was 69.4%; patients with solid cancer had a higher risk of mortality. Patients who died within 6 months had a poor performance score and a higher SOFA score at admission. The multivariate analysis showed that solid tumors, sepsis on the day of CT, and SOFA score on the day of CT were associated with 6-month mortality. Additionally, 95% of patients who survived the ICU resumed conventional CT, with a higher likelihood of resuming CT among those with hematological cancer. CONCLUSION: Urgent CT in the ICU is feasible in a specific subset of patients, mainly those with hematological cancer, with resumption of the curative treatment regimen after ICU discharge.

Fully automated interferon-γ release assay to monitor antigen-independent T cell functionality: A proof of concept study in septic shock.

In sepsis, personalized immunotherapy is being evaluated as a means of restoring immune function in the most severely affected patients. Biomarkers play a crucial role in this process, as there are no clear clinical indicators of immune dysfunction. Functional testing is considered a gold standard for assessing immune function, but this approach faces analytical challenges in terms of clinical implementation. The use of technician-dependent, time-consuming, home-made protocols often leads to poor standardization. This study represents the first beta testing of a fully automated interferon-γ release assay (IGRA) for monitoring the functionality of antigen-independent T lymphocytes. We observed a significant decrease in IFN-γ release capacity, which was associated with typical alterations in immunological cellular parameters (such as low mHLA-DR expression and decreased CD8 T lymphocyte count), in 22 patients with septic shock. Since the test is performed using whole blood and requires no technician intervention, with results available within 4 h, it may offer new possibilities for monitoring patients with immune alterations in routine clinical conditions. Further investigations in larger cohorts of patients are now needed to validate its clinical potential.

Skin biopsy in adult patients with meningococcal purpura fulminans: a multicenter retrospective cohort study.

BACKGROUND: Neisseria meningitidis is the leading responsible bacterium of Purpura Fulminans (PF) accounting for two thirds of PF. Skin biopsy is a simple and minimally invasive exam allowing to perform skin culture and polymerase chain reaction (PCR) to detect Neisseria meningitidis. We aimed to assess the sensitivity of skin biopsy in adult patients with meningococcal PF. METHODS: A 17-year multicenter retrospective cohort study including adult patients admitted to the ICU for a meningococcal PF in whom a skin biopsy with conventional and/or meningococcal PCR was performed. RESULTS: Among 306 patients admitted for PF, 195 had a meningococcal PF (64%) with a skin biopsy being performed in 68 (35%) of them. Skin biopsy was performed in median 1 day after the initiation of antibiotic therapy. Standard culture of skin biopsy was performed in 61/68 (90%) patients and grew Neisseria meningitidis in 28 (46%) of them. Neisseria meningitidis PCR on skin biopsy was performed in 51/68 (75%) patients and was positive in 50 (98%) of them. Among these 50 positive meningococcal PCR, five were performed 3 days or more after initiation of antibiotic therapy. Finally, skin biopsy was considered as contributive in 60/68 (88%) patients. Identification of the meningococcal serogroup was obtained with skin biopsy in 48/68 (71%) patients. CONCLUSIONS: Skin biopsy with conventional culture and meningococcal PCR has a global sensitivity of 88% and should be systematically considered in case of suspected meningococcal PF even after the initiation of antimicrobial treatment.

Respiratory multiplex PCR and procalcitonin to reduce antibiotic exposure in severe SARS-CoV-2 pneumonia: a multicentre randomized controlled trial.

OBJECTIVES: We aimed at assessing the efficacy and safety on antibiotic exposure of a strategy combining a respiratory multiplex PCR (mPCR) with enlarged panel and daily procalcitonin (PCT) measurements, as compared with a conventional strategy, in adult patients who were critically ill with laboratory-confirmed SARS-CoV-2 pneumonia. METHODS: This multicentre, parallel-group, open-label, randomized controlled trial enrolled patients admitted to 13 intensive care units (ICUs) in France. Patients were assigned (1:1) to the control strategy, in which antibiotic streamlining remained at the discretion of the physicians, or interventional strategy, consisting of using mPCR and daily PCT measurements within the first 7 days of randomization to streamline initial antibiotic therapy, with antibiotic continuation encouraged when PCT was >1 ng/mL and discouraged if < 1 ng/mL or decreased by 80% from baseline. All patients underwent conventional microbiological tests and cultures. The primary end point was antibiotic-free days at day 28. RESULTS: Between April 20th and November 23rd 2020, 194 patients were randomized, of whom 191 were retained in the intention-to-treat analysis. Respiratory bacterial co-infection was detected in 48.4% (45/93) and 21.4% (21/98) in the interventional and control group, respectively. The number of antibiotic-free days was 12.0 (0.0; 25.0) and 14.0 (0.0; 24.0) days, respectively (difference, -2.0, (95% CI, -10.6 to 6.6), p=0.89). Superinfection rates were high (51.6% and 48.5%, respectively). Mortality rates and ICU lengths of stay did not differ between groups. DISCUSSION: In severe SARS-CoV-2 pneumonia, the mPCR/PCT algorithm strategy did not affect 28-day antibiotics exposure nor the major clinical outcomes, as compared with routine practice.

A 9-mRNA signature measured from whole blood by a prototype PCR panel predicts 28-day mortality upon admission of critically ill COVID-19 patients.

Immune responses affiliated with COVID-19 severity have been characterized and associated with deleterious outcomes. These approaches were mainly based on research tools not usable in routine clinical practice at the bedside. We observed that a multiplex transcriptomic panel prototype termed Immune Profiling Panel (IPP) could capture the dysregulation of immune responses of ICU COVID-19 patients at admission. Nine transcripts were associated with mortality in univariate analysis and this 9-mRNA signature remained significantly associated with mortality in a multivariate analysis that included age, SOFA and Charlson scores. Using a machine learning model with these 9 mRNA, we could predict the 28-day survival status with an Area Under the Receiver Operating Curve (AUROC) of 0.764. Interestingly, adding patients' age to the model resulted in increased performance to predict the 28-day mortality (AUROC reaching 0.839). This prototype IPP demonstrated that such a tool, upon clinical/analytical validation and clearance by regulatory agencies could be used in clinical routine settings to quickly identify patients with higher risk of death requiring thus early aggressive intensive care.

Automatic Tube Compensation During Spontaneous Breathing Trials.

BACKGROUND: Automatic tube compensation (ATC) is an option available in any ICU ventilator that compensates for the resistive pressure drop due to the endotracheal tube. The goal of the present study was to compare ATC to other patient triggered modes of support in terms of spontaneous breathing trial (SBT) and extubation success. METHODS: Two authors (JB and PCF), independently and blinded to each other, searched through PubMed, Web of Science, and Cochrane from inception-May 26, 2021, with the following search terms entered as MeSH terms in all fields: "Automatic Tube Compensation." INCLUSION CRITERIA: randomized studies that included subjects > 16 y old undergoing an SBT. EXCLUSION CRITERIA: crossover studies, pediatric studies, animal studies, or experimental studies on test lungs or on computer simulation; other languages than French, Spanish, or English; studies not published in a full-text format (eg, abstract or letter); and reviews. A frequentist network meta-analysis was conducted with the aim to investigate the effectiveness of ATC on SBT and extubation outcomes. SBT was defined as successful if patients could tolerate the SBT based on predetermined criteria, whether it was followed by extubation. Successful extubation was defined as the absence of re-intubation, noninvasive ventilation, or signs of respiratory distress within the 48 h after extubation. The pooled analyses used random-effect models, and the effect size was expressed as relative risk or mean difference for categorical and continuous variables, respectively. P-scores were used to rank all treatments and to identify the intervention with the highest probability of being the best. RESULTS: Of the 234 retrieved papers, 7 met the inclusion criteria. In terms of SBT success, ATC100+PEEP < 7.5 and PS10+PEEP < 7.5 were superior to T-piece. Likewise, PS10+PEEP < 7.5 was the intervention with the highest probability of being the best (P-score: 0.90). In terms of extubation success, ATC100+PEEP < 7.5 cm H2O was significantly better than PEEP < 7.5 and T-piece. Likewise, it had the highest probability of being the best (P-score= 0.90). CONCLUSIONS: ATC is the modality with the highest probability of extubation success but not in terms of SBT success.

Remote ischemic conditioning in septic shock: the RECO-Sepsis randomized clinical trial.

PURPOSE: To determine whether remote ischemic conditioning (RECO), compared to standard care, limits the severity and the consequences of multiple organ failure in patients with septic shock. METHODS: The RECO-Sepsis trial, a prospective, multicenter, randomized, open-label, parallel group trial with blinded assessment of the outcome, was conducted at six intensive care units in France in adult patients with septic shock. Within 12 h after the onset of septic shock, patients were randomized (1:1 ratio) to receive either RECO applied by inflating/deflating (200/0 mmHg for 5/5 min) 4 times a cuff around an arm or a sham procedure every 12 h for 24 h. The primary endpoint was the severity of multiple organ failure assessed by the mean daily Sequential Organ Failure Assessment (SOFA) score from inclusion to the fourth day after inclusion (day 4). Patients were followed for 90 days. RESULTS: Among 180 randomized patients, 178 completed the trial (RECO group: 87; control group: 91) and were included in the intention-to-treat analysis (108 men [60.7%], median age 68 [59-75] years). There was no significant difference in the mean daily SOFA score between the intervention group and the control group (7.2 points [5.2-10.7] versus 7.6 points [4.9-10.7], respectively; p = 0.919). Cumulative mortality within 90 days was 27.6% in the RECO group and 39.6% control group (Log-rank test, p = 0.10; adjusted hazard ratio 0.59, 95% CI, 0.35 to 0.99; p = 0.049). CONCLUSIONS: In patients with septic shock, RECO failed to reduce the severity of organ failures assessed by mean daily SOFA score from inclusion to day 4. Adequately powered trials are needed to assess potential delayed benefits of RECO.

A Bench Comparison of the Effect of High-Flow Oxygen Devices on Work of Breathing.

BACKGROUND: Oxygen therapy via high-flow nasal cannula (HFNC) has been extensively used during the COVID-19 pandemic. The number of devices has also increased. We conducted this study to answer the following questions: Do HFNC devices differ from the original device for work of breathing (WOB) and generated PEEP? METHODS: Seven devices were tested on ASL 5000 lung model. Compliance was set to 40 mL/cm H2O and resistance to 10 cm H2O/L/s. The devices were connected to a manikin head via a nasal cannula with FIO2 set at 0.21. The measurements were performed at baseline (manikin head free of nasal cannula) and then with the cannula and the device attached with oxygen flow set at 20, 40, and 60 L/min. WOB and PEEP were assessed at 3 simulated inspiratory efforts (-5, -10, -15 cm H2O muscular pressure) and at 2 breathing frequencies (20 and 30 breaths/min). Data were expressed as median (first-third quartiles) and compared with nonparametric tests to the Optiflow device taken as reference. RESULTS: Baseline WOB and PEEP were comparable between devices. Over all the conditions tested, WOB was 4.2 (1.0-9.4) J/min with the reference device, and the relative variations from it were 0, -3 (2-4), 1 (0-1), -2 (1-2), -1 (1-2), and -1 (1-2)% with Airvo 2, G5, HM80, T60, V500, and V60 Plus devices, respectively, (P < .05 Kruskal-Wallis test). PEEP was 0.9 (0.3-1.5) cm H2O with Optiflow, and the relative differences were -28 (22-33), -41 (38-46), -30 (26-36), -31 (28-34), -37 (32-42), and -24 (21-34)% with Airvo 2, G5, HM80, T60, V500, and V60 Plus devices, respectively, (P < .05 Kruskal-Wallis test). CONCLUSIONS: WOB was marginally higher and PEEP marginally lower with devices as compared to the reference device.

Reassessment of mitochondrial cyclophilin D as a target for improving cardiac arrest outcomes in the era of therapeutic hypothermia.

Uncertainty exists regarding whether cyclophilin D (CypD), a mitochondrial matrix protein that plays a key role in ischemia-reperfusion injury, can be a pharmacological target for improving outcomes after cardiac arrest (CA), especially when therapeutic hypothermia is used. Using CypD knockout mice (CypD-/-), we investigated the effects of loss of CypD on short-term and medium-term outcomes after CA. CypD-/- mice or their wild-type (WT) littermates underwent either 5 minute CA followed by resuscitation with and/or without hypothermia at 33°C-34°C (targeted temperature reached within minutes after resuscitation), or a sham procedure. Brain and cardiac injury were assessed using echocardiography, neurological scores, MRI and biomarkers. Seven day survival was compared using Kaplan-Meier estimates. The rate of restoration of spontaneous circulation was significantly higher in CypD-/- mice (with shorter cardiac massage duration) than in WT mice (P < 0.05). Loss of CypD significantly attenuated CA-induced release of troponin and S100ß protein, and limited myocardial dysfunction at 150 minutes after CA. Loss of CypD combined with hypothermia led to the best neurological and MRI scores at 24 hours and highest survival rates at 7 days compared to other groups (P < 0.05). In animals successfully resuscitated, loss of CypD had no benefits on day 7 survival while hypothermia was highly protective. Pharmacological inhibition of CypD with cyclosporine A combined with hypothermia provided similar day 7 survival than loss of CypD combined with hypothermia. CypD is a viable target to improve success of cardiopulmonary resuscitation but its inhibition is unlikely to improve long-term outcomes, unless therapeutic hypothermia is associated.

Prone Positioning and Neuromuscular Blocking Agents as Adjunctive Therapies in Mechanically Ventilated Patients with Acute Respiratory Distress Syndrome.

Neuromuscular blocking agents (NMBAs) and prone position (PP) are two major adjunctive therapies that can improve outcome in moderate-to-severe acute respiratory distress syndrome. NMBA should be used once lung-protective mechanical ventilation has been set, for 48 hours or less and as a continuous intravenous infusion. PP should be used as early as possible for long sessions; in COVID-19 its use has exploded. In nonintubated patients, PP might reduce the rate of intubation but not mortality. The goal of this article is to perform a narrative review on the pathophysiological rationale, the clinical effects, and the clinical use and recommendations of both NMBA and PP.