Validation of the clinical utility of microRNA as noninvasive biomarkers of cardiac allograft rejection: A prospective longitudinal multicenter study.

While studies have shown an association between microRNAs and cardiac rejection, the clinical relevance of a preidentified miRNA signature as a noninvasive biomarker has never been assessed in prospective multicentric unselected cohorts. To address this unmet need, we designed a prospective study (NCT02672683) including recipients from 11 centers between August 2016 to March 2018. The objective was to validate the association between 3 previously identified circulating microRNA (10a, 92a, 155) and the histopathological diagnosis of rejection. Both relative and absolute (sensitivity analysis) quantifications of microRNAs were performed. Overall, 461 patients were included (831 biopsies, 79 rejections). A per-protocol interim analysis (258 biopsies, 49 rejections) did not find any association between microRNA and rejection (microRNA 10a: odds ratio (OR) = 1.05, 95% confidence intervals (CI) = 0.87-1.27, p = 0.61; 92a: OR = 0.98, 95%CI = 0.87-1.10, p = 0.68; 155: OR = 0.91, 95%CI = 0.76-1.10, p = 0.33). These results were confirmed in the sensitivity analysis. The analysis of the remaining sera was stopped for futility. This study shows no clinical utility of circulating microRNAs 10a, 92a, and 155 monitoring in heart allograft recipients.

Assessing physicians' and nurses' experience of dying and death in the ICU: development of the CAESAR-P and the CAESAR-N instruments.

BACKGROUND: As an increasing number of deaths occur in the intensive care unit (ICU), studies have sought to describe, understand, and improve end-of-life care in this setting. Most of these studies are centered on the patient's and/or the relatives' experience. Our study aimed to develop an instrument designed to assess the experience of physicians and nurses of patients who died in the ICU, using a mixed methodology and validated in a prospective multicenter study. METHODS: Physicians and nurses of patients who died in 41 ICUs completed the job strain and the CAESAR questionnaire within 24 h after the death. The psychometric validation was conducted using two datasets: a learning and a reliability cohort. RESULTS: Among the 475 patients included in the main cohort, 398 nurse and 417 physician scores were analyzed. The global score was high for both nurses [62/75 (59; 66)] and physicians [64/75 (61; 68)]. Factors associated with higher CAESAR-Nurse scores were absence of conflict with physicians, pain control handled with physicians, death disclosed to the family at the bedside, and invasive care not performed. As assessed by the job strain instrument, low decision control was associated with lower CAESAR score (61 (58; 65) versus 63 (60; 67), p = 0.002). Factors associated with higher CAESAR-Physician scores were room dedicated to family information, information delivered together by nurse and physician, families systematically informed of the EOL decision, involvement of the nurse during implementation of the EOL decision, and open visitation. They were also higher when a decision to withdraw or withhold treatment was made, no cardiopulmonary resuscitation was performed, and the death was disclosed to the family at the bedside. CONCLUSION: We described and validated a new instrument for assessing the experience of physicians and nurses involved in EOL in the ICU. This study shows important areas for improving practices.

Belatacept-based immunosuppression: A calcineurin inhibitor-sparing regimen in heart transplant recipients.

Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (three centers) included all heart transplant recipients receiving BTC between January 2014 and October 2018. Forty EBV+ patients mean GFR 35 ± 20 mL/min/m2 were identified, among whom belatacept was initiated during the first 3 months after transplantation in 12 patients, and later in 28 patients. Several patients were multiorgan transplant recipients. Study outcomes were GFR, safety, and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study closeout, 24/40 patients were still on BTC therapy. GFR was improved (+59%, P = .0002*) within 1 month, particularly in the early group. More episodes of rejection were observed among "late" patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n = 4), DSA no longer detectable (n = 1), compliance issues (n = 3), poor venous access (n = 2), multiple infections (n = 1), 1 death (fungal lung infection), and treatment failure (n = 4). Median follow-up was 24 months. Four patients developed de novo DSA (MFI<1500). BTC is an effective alternative immunosuppressive for postoperative transient kidney failure, stabilizing delayed renal function, with acceptable safety profile under careful monitoring.

Chronic hepatitis E in a heart transplant patient: sofosbuvir and ribavirin regimen not fully effective.

Hepatitis E virus (HEV) can induce chronic infections in the case of immunosuppression, which are sometimes not cured with ribavirin. Furthermore, sofosbuvir is a highly potent inhibitor of HCV polymerase and was shown to inhibit HEV genotype-3 replication in vitro. We report here the outcome of sofosbuvir/ribavirin therapy on a chronic HEV infection in a heart transplant recipient non-responder to ribavirin. After 24 weeks, the regimen failed to cure the persistent HEV infection, highlighting the need of therapeutic options for HEV-infected immunosuppressed patients.

Posaconazole Tablets in Real-Life Lung Transplantation: Impact on Exposure, Drug-Drug Interactions, and Drug Management in Lung Transplant Patients, Including Those with Cystic Fibrosis.

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations (C0) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure. The tacrolimus (TRL) and everolimus (ERL) C0 measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively (P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C0 exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively (P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C0/dose ratio (C0/D) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution (P = 0.034*). The ERL C0/D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.

Severe varicella-zoster virus pneumonia: a multicenter cohort study.

BACKGROUND: Pneumonia is a dreaded complication of varicella-zoster virus (VZV) infection in adults; however, the data are limited. Our objective was to investigate the clinical features, management, and outcomes of critically ill patients with VZV-related community-acquired pneumonia (VZV-CAP). METHODS: This was an observational study of patients with VZV-CAP admitted to 29 intensive care units (ICUs) from January 1996 to January 2015. RESULTS: One hundred and two patients with VZV-CAP were included. Patients were young (age 39 years (interquartile range 32-51)) and 53 (52%) were immunocompromised. Time since respiratory symptom onset was 2 (1-3) days. There was a seasonal distribution of the disease, with more cases during spring and winter time. All but four patients presented with typical skin rash on ICU admission. Half the patients received mechanical ventilation within 1 (1-2) day following ICU admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) = 150 (80-284), 80% with acute respiratory distress syndrome (ARDS)). Sequential Organ Failure Assessment (SOFA) score on day 1 (odds ratio (OR) 1.90 (1.33-2.70); p < 0.001), oxygen flow at ICU admission (OR 1.25 (1.08-1.45); p = 0.004), and early bacterial co-infection (OR 14.94 (2.00-111.8); p = 0.009) were independently associated with the need for mechanical ventilation. Duration of mechanical ventilation was 14 (7-21) days. ICU and hospital mortality rates were 17% and 24%, respectively. All patients were treated with aciclovir and 10 received adjunctive therapy with steroids. Compared to 60 matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, ICU length of stay, and a similar hospital mortality, but experienced more ICU-acquired infections. CONCLUSIONS: Severe VZV-CAP is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. Steroid therapy did not influence mortality, but increased the risk of superinfection.

CAESAR: a new tool to assess relatives' experience of dying and death in the ICU.

PURPOSE: To develop an instrument designed specifically to assess the experience of relatives of patients who die in the intensive care unit (ICU). METHODS: The instrument was developed using a mixed methodology and validated in a prospective multicentre study. Relatives of patients who died in 41 ICUs completed the questionnaire by telephone 21 days after the death, then completed the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised and Inventory of Complicated Grief after 3, 6, and 12 months. RESULTS: A total of 600 relatives were included, 475 in the main cohort and 125 in the reliability cohort. The 15-item questionnaire, named CAESAR, covered the patient's preferences and values, interactions with/around the patient and family satisfaction. We defined three groups based on CAESAR score tertiles: lowest (≤59, n = 107, 25.9 %), middle (n = 185, 44.8 %) and highest (≥69, n = 121, 29.3 %). Factorial analysis showed a single dimension. Cronbach's alpha in the main and reliability cohorts was 0.88 (0.85-0.90) and 0.85 (0.79-0.89), respectively. Compared to a high CAESAR score, a low CAESAR score was associated with greater risks of anxiety and depression at 3 months [1.29 (1.13-1.46), p = 0.001], post-traumatic stress-related symptoms at 3 [1.34 (1.17-1.53), p < 0.001], 6 [OR = 1.24 (1.06-1.44), p = 0.008] and 12 [OR = 1.26 (1.06-1.50), p = 0.01] months and complicated grief at 6 [OR = 1.40 (1.20-1.63), p < 0.001] and 12 months [OR = 1.27 (1.06-1.52), p = 0.01]. CONCLUSIONS: The CAESAR score 21 days after death in the ICU is strongly associated with post-ICU burden in the bereaved relatives. The CAESAR score should prove a useful primary endpoint in trials of interventions to improve relatives' well-being.

Complicated grief after death of a relative in the intensive care unit.

An increased proportion of deaths occur in the intensive care unit (ICU). We performed this prospective study in 41 ICUs to determine the prevalence and determinants of complicated grief after death of a loved one in the ICU. Relatives of 475 adult patients were followed up. Complicated grief was assessed at 6 and 12 months using the Inventory of Complicated Grief (cut-off score >25). Relatives also completed the Hospital Anxiety and Depression Scale at 3 months, and the Revised Impact of Event Scale for post-traumatic stress disorder symptoms at 3, 6 and 12 months. We used a mixed multivariate logistic regression model to identify determinants of complicated grief after 6 months. Among the 475 patients, 282 (59.4%) had a relative evaluated at 6 months. Complicated grief symptoms were identified in 147 (52%) relatives. Independent determinants of complicated grief symptoms were either not amenable to changes (relative of female sex, relative living alone and intensivist board certification before 2009) or potential targets for improvements (refusal of treatment by the patient, patient died while intubated, relatives present at the time of death, relatives did not say goodbye to the patient, and poor communication between physicians and relatives). End-of-life practices, communication and loneliness in bereaved relatives may be amenable to improvements.

Post-intubation laryngeal injuries and extubation failure: a fiberoptic endoscopic study.

PURPOSE: To describe laryngeal injuries after intubation in an intensive care unit and assess their risk factors and their association with post-extubation stridor (PES) and extubation failure. METHODS: Prospective study including 136 patients extubated after more than 24 h of mechanical ventilation. Fiberoptic endoscopic examination of the larynx was systemically performed within 6 h after extubation in order to record four types of laryngeal anomalies: edema, ulceration, granulation, and abnormal vocal cord (VC) mobility. RESULTS: Median duration of intubation was 3 days (min 24 h, max 56 days). Laryngeal injuries were frequent (73% of patients) and were associated with duration of intubation [odds ratios (OR) 1.11, 95% confidence interval (CI) 1.02-1.21, P = 0.02] and absence of use of myorelaxant drugs at intubation (OR 0.13, 95% CI 0.01-0.99, P = 0.05). Eighteen patients presented a PES. Lesions associated with PES were edema (67%, P < 0.01) and abnormal VC mobility (67%, P < 0.01). These injuries were associated with duration of intubation (OR 1.05, 95% CI 1.01-1.09, P = 0.04), emergency intubation (OR 2.7, 95% CI 1.2-6.4, P = 0.02), and height/endotracheal tube size ratio (OR 0.97, 95% CI 0.95-0.99, P = 0.01). Seventeen patients were reintubated within 48 h following extubation. Laryngeal examination of these patients more frequently showed granulation (29.4%, P = 0.02) and abnormal VC mobility (58.8%, P < 0.01). CONCLUSION: This study found a high frequency of laryngeal injuries after extubation in ICU, which were associated with intubation duration and patient's height/ETT size ratio. Edema was not the only injury responsible for PES, and although edema is frequent it is not the only injury associated with reintubation.

Increased radial force improves stent deployment in tricuspid but not in bicuspid stenotic native aortic valves.

BACKGROUND: Stent deployment within stenotic native aortic valves has been shown to depend on valve anatomy (presence of bicuspid valve or not). This study investigated the influence of stent stiffness on stent expansion. METHODS: The study included 88 patients with severe aortic stenosis, and 36 (41%) had bicuspid aortic valves. Two self-expandable stents with different radial force were deployed intraoperatively inside stenotic aortic valves before surgical aortic valve replacement. Patients in group B received a stent stiffer than that in group A. Effect of stent radial force on stent shape and incidence of paraprosthetic gaps was determined. RESULTS: Noncircular stent deployment was more frequent in bicuspid (81%) than in tricuspid aortic valves (33%; p < 0.0001). Increasing stent radial force significantly improved stent shape in tricuspid valves (circular shape: 60% in group A vs 93% in group B; p = 0.005) but had no significant effect in bicuspid valves (12.5% in group A vs 27% in group B;p = 0.394). Likewise, incidence of paraprosthetic gaps was significantly reduced with the stiff stent in tricuspid valves (64% in group A vs 30% in group B, p = 0.025) but not in bicuspid valves (50% in group A vs 60% in group B; p= 0.722). CONCLUSIONS: Increased stent radial force had a favorable effect on stent deployment in tricuspid but not in bicuspid valves. In bicuspid valves, stent maldeployment was constant. Leaflet distortion of implanted valved stent might be a concern in this setting.

The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation.

OBJECTIVE: Cancer patients requiring mechanical ventilation are widely viewed as poor candidates for intensive care unit (ICU) admission. We designed a prospective study evaluating a new admission policy titled The ICU Trial. DESIGN: Prospective study. SETTING: Intensive care unit. PATIENTS: One hundred eighty-eight patients requiring mechanical ventilation and having at least one other organ failure. INTERVENTIONS: Over a 3-yr period, all patients with hematologic malignancies or solid tumors proposed for ICU admission underwent a triage procedure. Bedridden patients and patients in whom palliative care was the only cancer treatment option were not admitted to the ICU. Patients at earliest phase of the malignancy (diagnosis < 30 days) were admitted without any restriction. All other patients were prospectively included in The ICU Trial, consisting of a full-code ICU admission followed by reappraisal of the level of care on day 5. MEASUREMENTS AND MAIN RESULTS: Among the 188 patients, 103 survived the first 4 ICU days and 85 died from the acute illness. Hospital survival was 21.8% overall. Among the 103 survivors on day 5, none of the characteristics of the malignancy were significantly different between the 62 patients who died and the 41 who survived. Time course of organ dysfunction over the first 6 ICU days differed significantly between survivors and nonsurvivors. Organ failure scores were more accurate on day 6 than at admission or on day 3 for predicting survival. All patients who required initiation of mechanical ventilation, vasopressors, or dialysis after 3 days in the ICU died. CONCLUSIONS: Survival was 40% in mechanically ventilated cancer patients who survived to day 5 and 21.8% overall. If these results are confirmed in future interventional studies, we recommend ICU admission with full-code management followed by reappraisal on day 6 in all nonbedridden cancer patients for whom lifespan-extending cancer treatment is available.

Reliability of HemoCue in patients with gastrointestinal bleeding.

OBJECTIVE: HemoCue is routinely used to manage bleeding patients, but few studies have evaluated its accuracy in this population. We compared HemoCue with laboratory determination of blood hemoglobin in patients with gastrointestinal bleeding. DESIGN AND SETTING: A prospective observational study in a 14-bed medicosurgical ICU and an emergency department in an urban general hospital. PATIENTS: 94 patients admitted to the emergency department or to the ICU for gastrointestinal bleeding. INTERVENTIONS: Blood was drawn at admission to measure laboratory hemoglobin and capillary hemoglobin was measured simultaneously by HemoCue. The unit of hospitalization and the presence or absence of impaired vital signs (tachycardia and/or hypotension and/or shock) were recorded. MEASUREMENTS AND RESULTS: The mean difference between HemoCue and hemoglobin (bias) was -0.06 g/dl and standard deviation (precision) 0.87 g/dl. (95% CI -1.8 to 1.68). Discrepancies between HemoCue and hemoglobin were greater than 1 g/dl in 21% of cases. Bias was comparable between patients admitted to the ICU and those in the emergency department. The accuracy of HemoCue was not affected by the presence of impaired vital signs or by a hemoglobin level below 9 g/dl or 7 g/dl. CONCLUSIONS: Although we demonstrated a low bias between HemoCue and blood hemoglobin determination, large HemoCue vs. hemoglobin differences may still occur, and therefore therapeutic decisions based upon capillary HemoCue alone should be very cautious.

Biomarker-based strategy for screening right ventricular dysfunction in patients with non-massive pulmonary embolism.

OBJECTIVE: To evaluate the usefulness of B-type natriuretic peptide and troponin I measurements in predicting right ventricular dysfunction (RVD) in non-massive pulmonary embolism. DESIGN: Prospective observational study. SETTING: University-affiliated emergency unit, cardiology and pneumology departments. PATIENTS: Sixty-seven patients admitted because of acute pulmonary embolism, without shock on admission, completed the study. INTERVENTIONS: Blood samples and echocardiography were obtained on admission for subsequent and independent assessment of B-type natriuretic peptide (BNP) and troponin I levels as well as RVD. MEASUREMENTS AND RESULTS: Echocardiographic RVD was diagnosed in 36 patients and was severe in 13 on admission. BNP and troponin I levels were higher in patients with RVD than in those with no RVD [62 (27-105) vs. 431 (289-556) pg/ml for BNP, p<0.001; 0.01 (0-0.09) vs. 0.16 (0.03-0.32) microg/l for troponin I, p=0.005]. The area under the receiving operating characteristic curve (AUC) for diagnosing RVD was 0.93 for BNP and 0.72 for troponin I. The troponin I level increased further when RVD was severe, compared with moderate, and the AUC was 0.91 for identifying severe RVD. Diagnoses of RVD and severe RVD were ruled out by BNP100 pg/ml and troponin I >0.10 microg/l. CONCLUSION: In hemodynamically stable pulmonary embolism, BNP/troponin I measurement is helpful on admission, especially for ruling out RVD, i.e. patients with in-hospital high-risk.