[Retrospective analysis of venlafaxine-induced hypoglycemia in patients with overdose]. / Análisis retrospectivo de las hipoglucemias inducidas por venlafaxina en pacientes con sobredosis.

INTRODUCTION: Recent publications relate the presence of hypoglycemia in venlafaxine (VLX) poisoning depending on the dose. Our aim was to analyze the clinical characteristics of patients who presented hypoglycemia induced by VLF overdose. PATIENTS AND METHODS: Retrospective study carried out in the Balearic Islands (2020-2023). INCLUSION CRITERIA: serum concentrations of VLX + O-desmethyl-venlafaxine (O-VLX)>800 ng/mL. The characteristics of patients with and without hypoglycemia were compared. RESULTS: Twenty-one patients were included, 8 (38.1%) with hypoglycemia. No differences were found in the doses referred to in both groups. Peak concentrations of VLX + O-VLX (ng/mL) were 9,783 [4,459-17,976] in patients with hypoglycemia and 1,413 [930-1,719] in patients without hypoglycemia (p<0.0001). The presence of hypoglycemia was associated with: lower age and level of consciousness; and higher frequency of suicide attempts, seizures, mydriasis, tachycardia and serotonin syndrome, invasive respiratory support, fluid therapy and ICU admission (p<0.05). CONCLUSIONS: The detection of hypoglycemia in a VLX overdose case is a readily available marker to suspect the severity of the patient. In any case, serum concentrations when available allow us to confirm intoxication.

Transcriptomics reveals shared immunosuppressive landscapes in ventilator-associated lower respiratory tract infections (VA-LRTI) patients.

BACKGROUND: Ventilator-associated pneumonia (VAP) represents a transitory status of immunoparalysis, and we hypothesized that ventilator-associated tracheobronchitis (VAT) could share also some degree of immune response to a respiratory infection. RESEARCH DESIGN AND METHODS: A prospective observational study in five medical ICUs to evaluate immunological alterations of patients with VA-LRTI. Immunological gene expression profiles in the blood using whole transcriptome microarrays in the first 24 hours following diagnosis. The area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of mRNA levels to differentiate VA-LRTI and lack of infection. A principal component analysis (PCA) was employed for analyzing the impact of each genetic expression footprint variable in explaining the variance of the cohort. RESULTS: There was overlapping between the three classes of patients encompassing gene expression levels of 8 genes (i.e. HLA, IL2RA, CD40LG, ICOS, CCR7, CD1C, CD3E). HLA-DRA was equally low among VAT and VAP patients characterizing immune depression, and significantly lower than the control group. CONCLUSIONS: Our findings suggest that VAP and VAT are not so different regarding gene expression levels suggesting a degree of immunosuppression. Our results indicate a state of immunoparalysis in respiratory infections in critically ill patients.

Design of a new mortality indicator in acute coronary syndrome on admission to the Intensive Care Unit.

OBJECTIVE: To design a mortality indicator in acute coronary syndrome (ACS) in the intensive care unit (ICU). DESIGN: A multicenter, observational descriptive study was carried out. PARTICIPANTS: Patients with ACS admitted to the ICUs included in the ARIAM-SEMICYUC registry between January 2013 and April 2019. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Demographic parameters, time of access to the healthcare system, and clinical condition. Revascularization therapy, drugs and mortality were analyzed. Cox regression analysis was performed, followed by the design of a neural network. A receiver operating characteristic curve (ROC) was plotted to calculate the power of the new score. Lastly, the clinical utility or relevance of the ARIAM indicator (ARIAM's) was assessed using a Fagan test. RESULTS: A total of 17,258 patients were included in the study, with a mortality rate of 3.5% (n = 605) at discharge from the ICU. The variables showing statistical significance (P < .001) were entered into the supervised predictive model, an artificial neural network. The new ARIAM's yielded a mean of 0.0257 (95%CI: 0.0245-0.0267) in patients discharged from the ICU versus 0.27085 (95%CI: 0.2533-0.2886) in those who died (P < .001). The area under the ROC curve of the model was 0.918 (95%CI: 0.907-0.930). Based on the Fagan test, the ARIAM's showed the mortality risk to be 19% (95%CI: 18%-20%) when positive and 0.9% (95%CI: 0.8%-1.01%) when negative. CONCLUSIONS: A new mortality indicator for ACS in the ICU can be established that is more accurate and reproducible, and periodically updated.

Multiplex protein profiling of bronchial aspirates reveals disease-, mortality- and respiratory sequelae-associated signatures in critically ill patients with ARDS secondary to SARS-CoV-2 infection.

Introduction: Bronchial aspirates (BAS) obtained during invasive mechanical ventilation (IMV) constitutes a useful tool for molecular phenotyping and decision making. Aim: To identify the proteomic determinants associated with disease pathogenesis, all-cause mortality and respiratory sequelae in BAS samples from critically ill patients with SARS-CoV-2-induced ARDS. Methods: Multicenter study including 74 critically ill patients with COVID-19 and non-COVID-19 ARDS. BAS were obtained by bronchoaspiration after IMV initiation. Three hundred sixty-four proteins were quantified using proximity extension assay (PEA) technology. Random forest models were used to assess predictor importance. Results: After adjusting for confounding factors, CST5, NADK, SRPK2 and TGF-α were differentially detected in COVID-19 and non-COVID-19 patients. In random forest models for COVID-19, CST5, DPP7, NADK, KYAT1 and TYMP showed the highest variable importance. In COVID-19 patients, reduced levels of ENTPD2 and PTN were observed in nonsurvivors of ICU stay, even after adjustment. AGR2, NQO2, IL-1α, OSM and TRAIL showed the strongest associations with in-ICU mortality and were used to construct a protein-based prediction model. Kaplan-Meier curves revealed a clear separation in mortality risk between subgroups of PTN, ENTPD2 and the prediction model. Cox regression models supported these findings. In survivors, the levels of FCRL1, NTF4 and THOP1 in BAS samples obtained during the ICU stay correlated with lung function (i.e., DLCO levels) 3 months after hospital discharge. Similarly, Flt3L and THOP1 levels were correlated with radiological features (i.e., TSS). These proteins are expressed in immune and nonimmune lung cells. Poor host response to viral infectivity and an inappropriate reparative mechanism seem to be linked with the pathogenesis of the disease and fatal outcomes, respectively. Conclusion: BAS proteomics identified novel factors associated with the pathology of SARS-CoV-2-induced ARDS and its adverse outcomes. BAS-based protein testing emerges as a novel tool for risk assessment in the ICU.

Corticosteroid treatment and mortality in mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients: a multicentre cohort study.

BACKGROUND: Some unanswered questions persist regarding the effectiveness of corticosteroids for severe coronavirus disease 2019 (COVID-19) patients. We aimed to assess the clinical effect of corticosteroids on intensive care unit (ICU) mortality among mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients. METHODS: This was a retrospective study of prospectively collected data conducted in 70 ICUs (68 Spanish, one Andorran, one Irish), including mechanically ventilated COVID-19-associated ARDS patients admitted between February 6 and September 20, 2020. Individuals who received corticosteroids for refractory shock were excluded. Patients exposed to corticosteroids at admission were matched with patients without corticosteroids through propensity score matching. Primary outcome was all-cause ICU mortality. Secondary outcomes were to compare in-hospital mortality, ventilator-free days at 28 days, respiratory superinfection and length of stay between patients with corticosteroids and those without corticosteroids. We performed survival analysis accounting for competing risks and subgroup sensitivity analysis. RESULTS: We included 1835 mechanically ventilated COVID-19-associated ARDS, of whom 1117 (60.9%) received corticosteroids. After propensity score matching, ICU mortality did not differ between patients treated with corticosteroids and untreated patients (33.8% vs. 30.9%; p = 0.28). In survival analysis, corticosteroid treatment at ICU admission was associated with short-term survival benefit (HR 0.53; 95% CI 0.39-0.72), although beyond the 17th day of admission, this effect switched and there was an increased ICU mortality (long-term HR 1.68; 95% CI 1.16-2.45). The sensitivity analysis reinforced the results. Subgroups of age < 60 years, severe ARDS and corticosteroids plus tocilizumab could have greatest benefit from corticosteroids as short-term decreased ICU mortality without long-term negative effects were observed. Larger length of stay was observed with corticosteroids among non-survivors both in the ICU and in hospital. There were no significant differences for the remaining secondary outcomes. CONCLUSIONS: Our results suggest that corticosteroid treatment for mechanically ventilated COVID-19-associated ARDS had a biphasic time-dependent effect on ICU mortality. Specific subgroups showed clear effect on improving survival with corticosteroid use. Therefore, further research is required to identify treatment-responsive subgroups among the mechanically ventilated COVID-19-associated ARDS patients.

Sudden cardiac death in persons aged 50 years or younger: diagnostic yield of a regional molecular autopsy program using massive sequencing.

INTRODUCTION AND OBJECTIVES: Sudden cardiac death (SCD) in young people often has a genetic cause. Consequently, the results of "molecular autopsy" may have important implications for their relatives. Our objective was to evaluate the diagnostic yield of a molecular autopsy program using next-generation sequencing. METHODS: We performed a prospective study of a cohort of consecutive patients who died from nonviolent SCD, aged ≤ 50 years, and who underwent molecular autopsy using large panels of next-generation sequencing, with subsequent clinical and genetic family screening. We analyzed demographic, clinical, toxicological, and genetic data. RESULTS: We studied 123 consecutive cases of SCD in persons aged ≤ 50 years. The incidence of SCD was 5.8 cases/100 000 individuals/y, mean age was 36.15±12.7 years, and 95 were men (77%). The cause was cardiac in 53%, unexplained SCD in 24%, toxic in 10.6%, and infant SCD in 4%. Among cardiac causes, ischemic heart disease accounted for 38% of deaths, arrhythmogenic cardiomyopathy for 7%, hypertrophic cardiomyopathy for 5%, and idiopathic left ventricular hypertrophy for 11%. Genetic analysis was performed in 62 cases (50.4%). Genetic variants were found in 42 cases (67.7%), with a mean of 3.4±4 genetic variants/patient, and the variant found was considered to be pathogenic or probably pathogenic in 30.6%. In unexplained SCD, 70% showed some genetic variant. Family screening diagnosed 21 carriers or affected individuals, 5 of whom were at risk, indicating an implantable cardiac defibrillator. CONCLUSIONS: Protocol-based and exhaustive study of SCD from cardiac causes in persons aged ≤ 50 years is feasible and necessary. In a high percentage of cases, the cause is genetic, indicating the existence of relatives at risk who could benefit from early diagnosis and treatment to avoid complications.

Amphetamine and methamphetamine poisonings attended in hospital emergency departments: clinical features and the usefulness of laboratory confirmation. / Intoxicaciones por anfetamina y metanfetamina atendidas en los servicios de urgencias: características clínicas y utilidad de la confirmación analítica.

OBJECTIVES: To determine whether clinical and toxicologic findings differed between cases of amphetamine (AMP) and methamphetamine (mAMP) poisoning attended in 2 Balearic Island hospital emergency departments. MATERIAL AND METHODS: Retrospective observational study of AMP and mAMP cases with laboratory confirmation between 2013 and 2018. We compared clinical and toxicologic variables as well as clinical management between groups. RESULTS: 1) A total of 120 cases were found: 86 (71.7%) with AMP poisoning and 34 (28.3%) with mAMP poisoning. 2) Drug poisoning was confirmed by gas chromatography associated with mass spectrometry (GC-MS) in 787 urine samples found to be positive during screening. One hundred fifty-four (19.6%) were confirmed by GC-MS. Thirtyfour of them did not meet the inclusion criteria. 3) Significant differences between AMP and mAMP cases were found for age (32.3 vs 28.4 y, respectively); sex (72.1% vs 94.1% men); and Spanish nationality (64.0% vs 29.4%). Reasons for admission and clinical features also differed: the reasons were aberrant behavior (15.1% in the AMP group vs 0% in the mAMP group) and palpitations (1.2% vs 20.6%); agitation was observed in 27.9% and 8.8%, respectively. Clinical management was similar in the 2 groups. Multiple drug poisoning was detected in 76.6% patients and was more common in patients in the AMP group (82.6% vs 61.8%). The additional drugs in these cases were mainly cocaine (63.0%), cannabis (48.9%), 3,4-methylenedioxy-N-methamphetamine (MDMA) (38.0%), and alcohol (35.9%). Cannabis was detected in a significantly higher proportion in the AMP group (45.3%) than in the mAMP group (17.6%). False positives were found in 78.7% of the samples. The culprit drug was most often MDMA (71.2%). CONCLUSION: AMP poisonings were associated with age over 30 years, Spanish nationality, aberrant behavior, agitation, multiple drug findings, and the use of cannabis. Poisonings caused by mAMP abuse were associated with age under 30 years, non-Spanish nationality, palpitations, and single-drug use.

OBJETIVO: Investigar si existen diferencias clínicas y toxicológicas en pacientes intoxicados por anfetamina (ANF) y metanfetamina (MANF) atendidos en servicios de urgencias. METODO: Estudio observacional retrospectivo de intoxicaciones por ANF y MANF con confirmación analítica en Baleares (2013-2018). Se compararon variables clínicas, toxicológicas y de manejo clínico entre grupos. RESULTADOS: 1) Se incluyeron 120 pacientes, 86 (71,7%) grupo ANF y 34 (28,3%) grupo MANF. 2) La confirmación de derivados anfetamínicos se realizó por cromatografía de gases-espectrometría de masas en 787 muestras de orina previamente positivas mediante un método de cribado cualitativo. Se confirmaron 154 (19,6%) muestras. De ellas, 34 fueron excluidas. 3) Se encontraron diferencias significativas entre ANF y MANF en: edad (32,3 vs 28,4 años); sexo (72,1 vs 94,1% hombres); nacionalidad española (64,0 vs 29,4%); en motivos de admisión: alteración de conducta (15,1 vs 0%) y palpitaciones (1,2 vs 20,6%); y en características clínicas: agitación (27,9 vs 8,8%). No hubo diferencias de manejo clínico. El 76,6% de casos fueron polintoxicaciones, más comunes en ANF (82,6 vs 61,8%). En estos casos se detectó principalmente cocaína (63,0%), cannabis (48,9%), MDMA (38,0%) y alcohol (35,9%). La mayor asociación del cannabis con el grupo de ANF fue estadísticamente significativa (45,3 vs 17,6%). La causa de los falsos positivos se identificó en el 78,7% de muestras, siendo el MDMA (71,2%) la principal. CONCLUSIONES: Se observaron diferencias entre ANF y MANF en cuanto a variables demográficas y motivo de asistencia; no obstante en esta serie hubo un alto porcentaje de polintoxicaciones.

Diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy.

OBJECTIVE: We wished to explore the use, diagnostic capability and outcomes of bronchoscopy added to noninvasive testing in immunocompromised patients. In this setting, an inability to identify the cause of acute hypoxaemic respiratory failure is associated with worse outcome. Every effort should be made to obtain a diagnosis, either with noninvasive testing alone or combined with bronchoscopy. However, our understanding of the risks and benefits of bronchoscopy remains uncertain. PATIENTS AND METHODS: This was a pre-planned secondary analysis of Efraim, a prospective, multinational, observational study of 1611 immunocompromised patients with acute respiratory failure admitted to the intensive care unit (ICU). We compared patients with noninvasive testing only to those who had also received bronchoscopy by bivariate analysis and after propensity score matching. RESULTS: Bronchoscopy was performed in 618 (39%) patients who were more likely to have haematological malignancy and a higher severity of illness score. Bronchoscopy alone achieved a diagnosis in 165 patients (27% adjusted diagnostic yield). Bronchoscopy resulted in a management change in 236 patients (38% therapeutic yield). Bronchoscopy was associated with worsening of respiratory status in 69 (11%) patients. Bronchoscopy was associated with higher ICU (40% versus 28%; p<0.0001) and hospital mortality (49% versus 41%; p=0.003). The overall rate of undiagnosed causes was 13%. After propensity score matching, bronchoscopy remained associated with increased risk of hospital mortality (OR 1.41, 95% CI 1.08-1.81). CONCLUSIONS: Bronchoscopy was associated with improved diagnosis and changes in management, but also increased hospital mortality. Balancing risk and benefit in individualised cases should be investigated further.

Efficacy and safety of caspofungin in critically ill patients. ProCAS Study.

INTRODUCTION: Caspofungin is an echinocandin with proven efficacy in invasive candidiasis (IC) and invasive aspergillosis (IA). ProCAS is a study sponsored by the Working Group of the Infectious Diseases of the Spanish Society of Intensive Care Medicine, which analyzes the effectiveness and safety of caspofungin in routine clinical practice conditions in the critically ill. METHODS: A prospective, multicenter, observational study designed to estimate the clinical effectiveness and safety of caspofungin acetate in the treatment of IC and IA in patients refractory to or intolerant of conventional antifungal therapy. The assessment of effectiveness both clinic and the microbiological was carried out at the end of the treatment with caspofungin. RESULTS: We included 98 patients, 62 IC proven, 25 probable and 11 IA probable, from 24 centers during 2005 and 2006. Treatment with caspofungin monotherapy was performed in 89.8% of cases and as first line therapy in 54.1%. The favorable clinical response obtained for IC, probable IC, and probable IA was 91.9, 84, and 81.8%, respectively. The microbiological response was favorable in 74.6, 68, and 54.6% for proven cases of IC, probable IC, and probable IA, respectively. No serious adverse effects were observed. CONCLUSIONS: In routine clinical practice conditions, caspofungin is effective and safe for the treatment of invasive fungal infections (IC/IA). The efficacy and safety profile was similar to that observed in published clinical trials.