Limitation of life support treatments in Spanish Intensive Care Units: Analysis of the ETHICUS II study.

OBJECTIVE: The aim of this study is to describe the results of Spanish ICUs in ETHICUS II study. DESIGN: Planned substudy of patients from ETHICUS II study. SETTING: 12 Spanish ICU. PATIENTS OR PARTICIPANTS: Patients admitted to Spanish ICU who died or in whom a limitation of life-sustaining treatment (LLST) was decided during a recruitment period of 6 months. INTERVENTIONS: Follow-up of patients was performed until discharge from the ICU and 2 months after the decision of LLST or death. MAIN VARIABLES OF INTEREST: Demographic characteristics, clinical profile, type of decision of LLST, time and form in which it was adopted. Patients were classified into 4 categories according to the ETHICUS II study protocol: withholding or withdrawing life-sustaining therapy, active shortening of the dying process, failed cardiopulmonary resuscitation and patients with brain death. RESULTS: A total of 795 patients were analyzed; 129 patients died after CPR, 129 developed brain death. LLST was decided in 537 patients, 485 died in the ICU, 90.3%. The mean age was 66.19 years ± 14.36, 63.8% of male patients. In 221 (41%) it was decided to withdraw life-sustaining treatments and in 316 (59%) withholding life-sustaining treatments. Nineteen patients (2.38%) had advance living directives. CONCLUSIONS: The predominant clinical profile when LTSV was established was male patients over 65 years with mostly cardiovascular comorbidity. We observed that survival was higher in LLST decisions involving withholding of treatments compared to those in which withdrawal was decided. Spain has played a leading role in both patient and ICU recruitment participating in this worldwide multicenter study.

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster. METHODS: Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3. RESULTS: Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3. CONCLUSIONS: During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.

Association of obesity on the outcome of critically ill patients affected by COVID-19 / Asociación de la obesidad en la evolución de los pacientes críticos afectados por COVID-19

Objective To evaluate the impact of obesity on ICU mortality. Design Observational, retrospective, multicentre study. Setting Intensive Care Unit (ICU). Patients Adults patients admitted with COVID-19 and respiratory failure. Interventions None. Primary variables of interest Collected data included demographic and clinical characteristics, comorbidities, laboratory tests and ICU outcomes. Body mass index (BMI) impact on ICU mortality was studied as (1) a continuous variable, (2) a categorical variable obesity/non-obesity, and (3) as categories defined a priori: underweight, normal, overweight, obesity and Class III obesity. The impact of obesity on mortality was assessed by multiple logistic regression and Smooth Restricted cubic (SRC) splines for Cox hazard regression. Results 5,206 patients were included, 20 patients (0.4%) as underweight, 887(17.0%) as normal, 2390(46%) as overweight, 1672(32.1) as obese and 237(4.5%) as class III obesity. The obesity group patients (n = 1909) were younger (61 vs. 65 years, p < 0.001) and with lower severity scores APACHE II (13 [9–17] vs. 13[10−17, p < 0.01) than non-obese. Overall ICU mortality was 28.5% and not different for obese (28.9%) or non-obese (28.3%, p = 0.65). Only Class III obesity (OR = 2.19, 95%CI 1.44–3.34) was associated with ICU mortality in the multivariate and SRC analysis. Conclusions COVID-19 patients with a BMI > 40 are at high risk of poor outcomes in the ICU. An effective vaccination schedule and prolonged social distancing should be recommended. (AU)

Objetivo Evaluar el impacto de la obesidad en la mortalidad de la UCI. Diseño Estudio observacional, retrospectivo y multicéntrico. Ámbito Unidad de Cuidados Intensivos (UCI). Pacientes Pacientes adultos con COVID-19 e insuficiencia respiratoria. Intervenciones Ninguna. Variables de interés principales Características demográficas y clínicas, comorbilidades, pruebas de laboratorio y evolución en la UCI. El impacto del índice de masa corporal (IMC) sobre la mortalidad se estudió como (1) una variable continua, (2) una variable categórica obesidad/no obesidad, y (3) como categorías definidas a priori: bajo peso, normal, sobrepeso, obesidad y obesidad clase III. El impacto de la obesidad se evaluó mediante regresión logística múltiple y splines cúbicos suaves restringidos (SRC) para la regresión de riesgos de Cox. Resultados Se incluyeron 5.206 pacientes, 20 (0,4%) con bajo peso, 887 (17,0%) con peso normal, 2.390 (46%) con sobrepeso, 1.672 (32,1%) con obesidad y 237 (4,5%) con obesidad clase III. Los pacientes obesos (n = 1909) eran más jóvenes (61 vs. 65 años, p < 0,001) y con un nivel más bajo de APACHE II (13 [9–17] frente a 13[10−17, p < 0,01) que los no obesos. La mortalidad global en la UCI fue del 28,5% y no fue diferente entre obesos (28,9%) y no obesos (28,3%,p = 0,65). Sólo la obesidad clase III (OR = 2,19; IC del 95%: 1,44−3,34) se asoció con la mortalidad en la UCI en el análisis multivariante y SRC. Conclusiones Los pacientes con COVID-19 con un IMC > 40 tienen un alto riesgo de mala evolución en la UCI. Debe recomendarse un calendario de vacunación eficaz y un distanciamiento social prolongado. (AU)

Applicability of an unsupervised cluster model developed on first wave COVID-19 patients in second/third wave critically ill patients.

OBJECTIVE: To validate the unsupervised cluster model (USCM) developed during the first pandemic wave in a cohort of critically ill patients from the second and third pandemic waves. DESIGN: Observational, retrospective, multicentre study. SETTING: Intensive Care Unit (ICU). PATIENTS: Adult patients admitted with COVID-19 and respiratory failure during the second and third pandemic waves. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Collected data included demographic and clinical characteristics, comorbidities, laboratory tests and ICU outcomes. To validate our original USCM, we assigned a phenotype to each patient of the validation cohort. The performance of the classification was determined by Silhouette coefficient (SC) and general linear modelling. In a post-hoc analysis we developed and validated a USCM specific to the validation set. The model's performance was measured using accuracy test and area under curve (AUC) ROC. RESULTS: A total of 2330 patients (mean age 63 [53-82] years, 1643 (70.5%) male, median APACHE II score (12 [9-16]) and SOFA score (4 [3-6]) were included. The ICU mortality was 27.2%. The USCM classified patients into 3 clinical phenotypes: A (n = 1206 patients, 51.8%); B (n = 618 patients, 26.5%), and C (n = 506 patients, 21.7%). The characteristics of patients within each phenotype were significantly different from the original population. The SC was -0.007 and the inclusion of phenotype classification in a regression model did not improve the model performance (0.79 and 0.78 ROC for original and validation model). The post-hoc model performed better than the validation model (SC -0.08). CONCLUSION: Models developed using machine learning techniques during the first pandemic wave cannot be applied with adequate performance to patients admitted in subsequent waves without prior validation.

Association of obesity on the outcome of critically ill patients affected by COVID-19.

OBJECTIVE: To evaluate the impact of obesity on ICU mortality. DESIGN: Observational, retrospective, multicentre study. SETTING: Intensive Care Unit (ICU). PATIENTS: Adults patients admitted with COVID-19 and respiratory failure. INTERVENTIONS: None. PRIMARY VARIABLES OF INTEREST: Collected data included demographic and clinical characteristics, comorbidities, laboratory tests and ICU outcomes. Body mass index (BMI) impact on ICU mortality was studied as (1) a continuous variable, (2) a categorical variable obesity/non-obesity, and (3) as categories defined a priori: underweight, normal, overweight, obesity and Class III obesity. The impact of obesity on mortality was assessed by multiple logistic regression and Smooth Restricted cubic (SRC) splines for Cox hazard regression. RESULTS: 5,206 patients were included, 20 patients (0.4%) as underweight, 887(17.0%) as normal, 2390(46%) as overweight, 1672(32.1) as obese and 237(4.5%) as class III obesity. The obesity group patients (n = 1909) were younger (61 vs. 65 years, p < 0.001) and with lower severity scores APACHE II (13 [9-17] vs. 13[10-17, p < 0.01) than non-obese. Overall ICU mortality was 28.5% and not different for obese (28.9%) or non-obese (28.3%, p = 0.65). Only Class III obesity (OR = 2.19, 95%CI 1.44-3.34) was associated with ICU mortality in the multivariate and SRC analysis. CONCLUSIONS: COVID-19 patients with a BMI > 40 are at high risk of poor outcomes in the ICU. An effective vaccination schedule and prolonged social distancing should be recommended.

Ten Issues for Updating in Community-Acquired Pneumonia: An Expert Review.

Community-acquired pneumonia represents the third-highest cause of mortality in industrialized countries and the first due to infection. Although guidelines for the approach to this infection model are widely implemented in international health schemes, information continually emerges that generates controversy or requires updating its management. This paper reviews the most important issues in the approach to this process, such as an aetiologic update using new molecular platforms or imaging techniques, including the diagnostic stewardship in different clinical settings. It also reviews both the Intensive Care Unit admission criteria and those of clinical stability to discharge. An update in antibiotic, in oxygen, or steroidal therapy is presented. It also analyzes the management out-of-hospital in CAP requiring hospitalization, the main factors for readmission, and an approach to therapeutic failure or rescue. Finally, the main strategies for prevention and vaccination in both immunocompetent and immunocompromised hosts are reviewed.

Ten Issues to Update in Nosocomial or Hospital-Acquired Pneumonia: An Expert Review.

Nosocomial pneumonia, or hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) are important health problems worldwide, with both being associated with substantial morbidity and mortality. HAP is currently the main cause of death from nosocomial infection in critically ill patients. Although guidelines for the approach to this infection model are widely implemented in international health systems and clinical teams, information continually emerges that generates debate or requires updating in its management. This scientific manuscript, written by a multidisciplinary team of specialists, reviews the most important issues in the approach to this important infectious respiratory syndrome, and it updates various topics, such as a renewed etiological perspective for updating the use of new molecular platforms or imaging techniques, including the microbiological diagnostic stewardship in different clinical settings and using appropriate rapid techniques on invasive respiratory specimens. It also reviews both Intensive Care Unit admission criteria and those of clinical stability to discharge, as well as those of therapeutic failure and rescue treatment options. An update on antibiotic therapy in the context of bacterial multiresistance, in aerosol inhaled treatment options, oxygen therapy, or ventilatory support, is presented. It also analyzes the out-of-hospital management of nosocomial pneumonia requiring complete antibiotic therapy externally on an outpatient basis, as well as the main factors for readmission and an approach to management in the emergency department. Finally, the main strategies for prevention and prophylactic measures, many of them still controversial, on fragile and vulnerable hosts are reviewed.

Microbiological diagnosis of pulmonary invasive aspergillosis in critically ill patients with severe SARS-CoV-2 pneumonia: a bronchoalveolar study.

BACKGROUND: Diagnosing COVID-19-associated pulmonary aspergillosis (CAPA) can be challenging since radiological and clinical criteria in the critically ill patient are nonspecific. Microbiological diagnostic support is therefore crucial. The aim of this study was to document the incidence of aspergillosis using bronchoalveolar lavage (BAL) as the diagnostic method and to determine the performance of the current mycological diagnostic tests most widely used for the diagnosis of CAPA, together with evaluation of the Asp lateral flow device (LFD). METHODS: Prospective cohort study conducted between March 2020 and June 2022. Inclusion criteria were critically ill patients admitted to the ICU with SARS-CoV-2 pneumonia requiring invasive mechanical ventilation. Diagnostic bronchoscopy and BAL were performed at the beginning of invasive mechanical ventilation. The sensitivity, specificity, positive and negative predictive value (PPV and NPV), positive and negative likelihood ratio (LR + and LR-) of BAL culture, direct examination with calcofluor white stain, ELISA (Platelia) and LFD (AspLFD) for detection of galactomannan (GM) were evaluated. Aspergillus-qPCR was applied when discrepancies between diagnostic tests arose. RESULTS: Of the 244 critically ill patients with SARS-CoV-2 pneumonia admitted to the ICU, the majority (n = 200, 82%) required invasive mechanical ventilation. Diagnostic bronchoscopic procedures were performed in 160 patients (80%), who were enrolled in this study. The incidence of CAPA was 18.7% (n = 30). LFD-GM demonstrated a sensitivity of 84%, specificity of 99%, PPV 94%, NPV 97%, LR(+) of 84, and LR(-) of 0.16. At GM-ELISA indices of ≥ 0.5 and ≥ 1.0, sensitivity was 92% and 79%, specificity was 95% and 99%, PPV 76% and 91%, NPV 99% and 96%, LR(+) 18 and 79, and LR(-) 0.08 and 0.21, respectively. The optimal cut-off index from the ROC curve was 0.48, with sensitivity of 95% and specificity of 95%. CONCLUSIONS: Using a diagnostic strategy based on bronchoscopy and BAL, we documented a high incidence of pulmonary aspergillosis in patients with severe SARS-CoV-2 pneumonia. Asp-LFD showed moderate sensitivity and excellent specificity, with a high PPV, and could be used for rapid diagnosis of patients with suspected CAPA.

Procalcitonin and C-reactive protein to rule out early bacterial coinfection in COVID-19 critically ill patients.

PURPOSE: Although the prevalence of community-acquired respiratory bacterial coinfection upon hospital admission in patients with coronavirus disease 2019 (COVID-19) has been reported to be < 5%, almost three-quarters of patients received antibiotics. We aim to investigate whether procalcitonin (PCT) or C-reactive protein (CRP) upon admission could be helpful biomarkers to identify bacterial coinfection among patients with COVID-19 pneumonia. METHODS: We carried out a multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish intensive care units (ICUs). The primary outcome was to explore whether PCT or CRP serum levels upon hospital admission could predict bacterial coinfection among patients with COVID-19 pneumonia. The secondary outcome was the evaluation of their association with mortality. We also conducted subgroups analyses in higher risk profile populations. RESULTS: Between 5 February 2020 and 21 December 2021, 4076 patients were included, 133 (3%) of whom presented bacterial coinfection. PCT and CRP had low area under curve (AUC) scores at the receiver operating characteristic (ROC) curve analysis [0.57 (95% confidence interval (CI) 0.51-0.61) and 0.6 (95% CI, 0.55-0.64), respectively], but high negative predictive values (NPV) [97.5% (95% CI 96.5-98.5) and 98.2% (95% CI 97.5-98.9) for PCT and CRP, respectively]. CRP alone was associated with bacterial coinfection (OR 2, 95% CI 1.25-3.19; p = 0.004). The overall 15, 30 and 90 days mortality had a higher trend in the bacterial coinfection group, but without significant difference. PCT ≥ 0.12 ng/mL was associated with higher 90 days mortality. CONCLUSION: Our study suggests that measurements of PCT and CRP, alone and at a single time point, are not useful for ruling in or out bacterial coinfection in viral pneumonia by COVID-19.

A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study.

BACKGROUND: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. METHODS: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. RESULTS: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. CONCLUSIONS: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.

Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study.

BACKGROUND: The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19. METHODS: We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero (<1 N1 copies per mL), VIR-N1-Low (1-2747 N1 copies per mL), and VIR-N1-Storm (>2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis. FINDINGS: 1068 patients met the inclusion criteria, of whom 117 had insufficient plasma samples and 115 had key information missing. 836 patients were included in the analysis, of whom 403 (48%) were in the VIR-N1-Low group, 283 (34%) were in the VIR-N1-Storm group, and 150 (18%) were in the VIR-N1-Zero group. Overall, patients in the VIR-N1-Storm group had the most severe disease: 266 (94%) of 283 patients received invasive mechanical ventilation (IMV), 116 (41%) developed acute kidney injury, 180 (65%) had secondary infections, and 148 (52%) died within 90 days. Patients in the VIR-N1-Zero group had the least severe disease: 81 (54%) of 150 received IMV, 34 (23%) developed acute kidney injury, 47 (32%) had secondary infections, and 26 (17%) died within 90 days (OR for death 0·30, 95% CI 0·16-0·55; p<0·0001, compared with the VIR-N1-Storm group). 106 (26%) of 403 patients in the VIR-N1-Low group died within 90 days (OR for death 0·39, 95% CI 0·26-0·57; p<0·0001, compared with the VIR-N1-Storm group). INTERPRETATION: The presence of a so-called viral storm is associated with increased all-cause death in patients admitted to the intensive care unit with severe COVID-19. Preventing this viral storm could help to reduce poor outcomes. Viral storm could be an enrichment marker for treatment with antivirals or purification devices to remove viral components from the blood. FUNDING: Instituto de Salud Carlos III, Canadian Institutes of Health Research, Li Ka-Shing Foundation, Research Nova Scotia, and European Society of Clinical Microbiology and Infectious Diseases. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Risk factors for developing ventilator-associated lower respiratory tract infection in patients with severe COVID-19: a multinational, multicentre study, prospective, observational study.

Around one-third of patients diagnosed with COVID-19 develop a severe illness that requires admission to the Intensive Care Unit (ICU). In clinical practice, clinicians have learned that patients admitted to the ICU due to severe COVID-19 frequently develop ventilator-associated lower respiratory tract infections (VA-LRTI). This study aims to describe the clinical characteristics, the factors associated with VA-LRTI, and its impact on clinical outcomes in patients with severe COVID-19. This was a multicentre, observational cohort study conducted in ten countries in Latin America and Europe. We included patients with confirmed rtPCR for SARS-CoV-2 requiring ICU admission and endotracheal intubation. Only patients with a microbiological and clinical diagnosis of VA-LRTI were included. Multivariate Logistic regression analyses and Random Forest were conducted to determine the risk factors for VA-LRTI and its clinical impact in patients with severe COVID-19. In our study cohort of 3287 patients, VA-LRTI was diagnosed in 28.8% [948/3287]. The cumulative incidence of ventilator-associated pneumonia (VAP) was 18.6% [610/3287], followed by ventilator-associated tracheobronchitis (VAT) 10.3% [338/3287]. A total of 1252 bacteria species were isolated. The most frequently isolated pathogens were Pseudomonas aeruginosa (21.2% [266/1252]), followed by Klebsiella pneumoniae (19.1% [239/1252]) and Staphylococcus aureus (15.5% [194/1,252]). The factors independently associated with the development of VA-LRTI were prolonged stay under invasive mechanical ventilation, AKI during ICU stay, and the number of comorbidities. Regarding the clinical impact of VA-LRTI, patients with VAP had an increased risk of hospital mortality (OR [95% CI] of 1.81 [1.40-2.34]), while VAT was not associated with increased hospital mortality (OR [95% CI] of 1.34 [0.98-1.83]). VA-LRTI, often with difficult-to-treat bacteria, is frequent in patients admitted to the ICU due to severe COVID-19 and is associated with worse clinical outcomes, including higher mortality. Identifying risk factors for VA-LRTI might allow the early patient diagnosis to improve clinical outcomes.Trial registration: This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable.

Anticipatory Antifungal Treatment in Critically Ill Patients with SARS-CoV-2 Pneumonia.

BACKGROUND: The aim of this study was to investigate the incidence of COVID-19-associated pulmonary aspergillosis (CAPA) in critically ill patients and the impact of anticipatory antifungal treatment on the incidence of CAPA in critically ill patients. METHODS: Before/after observational study in a mixed intensive care unit (ICU) of a university teaching hospital. The study took place between March 2020 and June 2022. Inclusion criteria were critically ill patients with severe SARS-CoV-2 pneumonia requiring invasive mechanical ventilation. Two analysis periods were compared according to whether or not antifungal therapy was given early. RESULTS: A total of 160 patients with severe SARS-CoV-2 pneumonia and invasive mechanical ventilation were included. The incidence of CAPA in the first study period was 19 out of 58 patients (32.75%); during the second period, after implementation of the intervention (anticipatory antifungal therapy), the incidence of CAPA decreased to 10.78% (11 out of 102 patients). In patients with CAPA under invasive mechanical ventilation, the mortality rate decreased from 100% to 64%. CONCLUSIONS: Anticipating antifungal treatment in patients with SARS-CoV-2 pneumonia under invasive mechanical ventilation was associated with a decrease in the incidence and mortality of pulmonary aspergillosis.

Managing the Next Wave of Influenza and/or SARS-CoV-2 in the ICU-Practical Recommendations from an Expert Group for CAPA/IAPA Patients.

The aim of this study was to establish practical recommendations for the diagnosis and treatment of influenza-associated invasive aspergillosis (IAPA) based on the available evidence and experience acquired in the management of patients with COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA/IAPA expert group defined 14 areas in which recommendations would be made. To search for evidence, the PICO strategy was used for both CAPA and IAPA in PubMed, using MeSH terms in combination with free text. Based on the results, each expert developed recommendations for two to three areas that they presented to the rest of the group in various meetings in order to reach consensus. As results, the practical recommendations for the management of CAPA/IAPA patients have been grouped into 12 sections. These recommendations are presented for both entities in the following situations: when to suspect fungal infection; what diagnostic methods are useful to diagnose these two entities; what treatment is recommended; what to do in case of resistance; drug interactions or determination of antifungal levels; how to monitor treatment effectiveness; what action to take in the event of treatment failure; the implications of concomitant corticosteroid administration; indications for the combined use of antifungals; when to withdraw treatment; what to do in case of positive cultures for Aspergillus spp. in a patient with severe viral pneumonia or Aspergillus colonization; and how to position antifungal prophylaxis in these patients. Available evidence to support the practical management of CAPA/IAPA patients is very scarce. Accumulated experience acquired in the management of CAPA patients can be very useful for the management of IAPA patients. The expert group presents eminently practical recommendations for the management of CAPA/IAPA patients.

Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic: a matched analysis.

BACKGROUND: The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with coronavirus disease 2019 (COVID-19)-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior noninvasive respiratory support on outcomes. METHODS: This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICUs) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of ICU admission. Propensity score matching was used to achieve a balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different time-point (48 h from ICU admission) for early and delayed intubation. RESULTS: Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After propensity score matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%; p=0.01), ICU mortality (25.7% versus 36.1%; p=0.007) and 90-day mortality (30.9% versus 40.2%; p=0.02) compared with the early intubation group. Very similar findings were observed when we used a 48-h time-point for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth waves, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (HFNC) (n=294) who were intubated earlier. The subgroup of patients undergoing noninvasive ventilation (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. CONCLUSIONS: In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received HFNC.

Clindamycin but not Intravenous Immunoglobulins reduces mortality in a retrospective cohort of critically ill patients with bacteremic Group A Streptococcal infections / Tratamiento con clindamicina, y no con inmunoglobulinas intravenosas, disminuye la mortalidad en una cohorte retrospectiva de pacientes críticos con bacteriemia por Streptococcus del Grupo A

Objectives. Mortality of patients requiring Intensive Care Unit (ICU) admission for an invasive group A streptococcal (GAS) infection continues being high. In critically ill patients with bacteremic GAS infection we aimed at determining risk factors for mortality. Patients and methods. Retrospective multicentre study carried out in nine ICU in Southern Spain. All adult patients admitted to the participant ICUs from January 2014 to June 2019 with one positive blood culture for S. pyogenes were included in this study. Patient characteristics, infection-related variables, therapeutic interventions, failure of organs, and outcomes were registered. Risk factors independently associated with ICU and in-hospital mortalities were determined by multivariate regression analyses. Results. Fifty-seven patients were included: median age was 63 (45-73) years, median SOFA score at admission was 11 (7-13). The most frequent source was skin and soft tissue infection (n=32) followed by unknown origin of bacteremia (n=12). In the multivariate analysis, age (OR 1.079; 95% CI 1.016-1.145), SOFA score (OR 2.129; 95% CI 1.339-3.383) were the risk factors for ICU mortality and the use of clindamycin was identified as a protective factor (OR 0.049; 95% CI 0.003-0.737). Age and SOFA were the independent factors associated with hospital mortality however the use of clindamycin showed a strong trend but without reaching statistical significance (OR 0.085; 95% CI 0.007-1.095). (AU)

Objetivo. La mortalidad de los pacientes que requieren ingreso en la Unidad de Cuidados Intensivos (UCI) por una infección invasiva por estreptococos del grupo A (GAS) continúa siendo inaceptablemente alta. El objetivo del estudio fue determinar los factores de riesgo de mortalidad en pacientes críticos con infección estreptocócica bacterémica del grupo A. Pacientes y métodos. Estudio retrospectivo multicéntrico realizado en nueve UCI del sur de España. Se incluyeron pacientes consecutivos ingresados en las UCI participantes desde enero de 2014 hasta junio de 2019 con un hemocultivo positivo para S. pyogenes. Se registraron las características de los pacientes, las variables relacionadas con la infección, las intervenciones terapéuticas, el fracaso de los órganos y el pronóstico. Se determinaron mediante análisis de regresión multivariante los factores de riesgo asociados de forma independiente con la mortalidad en UCI y hospitalaria. Resultados. Se incluyeron cincuenta y siete pacientes: la mediana de edad fue de 63 (45-73) años, la mediana de la puntuación SOFA al ingreso fue de 11 (7-13). El foco más frecuente fue la infección de la piel y los tejidos blandos (n=32) seguida de la bacteriemia de origen desconocido (n=12). En el análisis multivariante, la edad (OR 1,079; IC del 95%: 1,016-1,145), y la puntuación SOFA (OR 2,129; IC del 95%: 1,339-3,383) se identificaron como factores de riesgo para la mortalidad en UCI. El uso de clindamicina se identificó como un factor protector (OR 0,049; IC del 95%: 0,003-0,737). La edad y la SOFA se asociaron de forma independiente con la mortalidad hospitalaria, mientras que el tratamiento con clindamicina mostró una tendencia fuerte pero sin alcanzar significación estadística (OR 0,085; IC del 95%: 0,007-1,095). (AU)

Effectiveness and Safety of Tecneplase vs. Alteplase in the Acute Treatment of Ischemic Stroke.

Not all hospitals have interventional radiology services. This fact implies that in centers where this resource is not available, the treatment of stroke in the acute phase must be adapted and individualized. The aim of the study is to determine and compare the combined effect of thrombolysis and thrombectomy effectiveness and safety of tenecteplase versus alteplase in the acute treatment of ischemic stroke in patients who are candidates for endovascular therapy according to clinical practice guidelines. This paper details a retrospective multicenter cohort study of patients with ischemic stroke admitted in three hospitals between 2018 and 2020. The main outcome variables were the degree of recanalization and the functional outcome at 3 months; safety variables were mortality and the occurrence of intracranial hemorrhage (ICH). In total, 100 patients were included, 20 of which were treated with tenecteplase (TNK) and 80 with alteplase (rtPA). Of those treated with TNK, 75% obtained a successful recanalization compared to 83.8% in those treated with rtPA (OR 0.58; 95% CI 0.18-1.88; p = 0.56). No differences were found in obtaining an excellent functional result at 3 months (35% TNK vs. 58.8% rtPA; p = 0.38). Tenecteplase showed worse neurological results after 24 h (unfavorable result of 70% with TNK vs. 45% with rtPA; OR = 5.4; 95% CI 1.57-18.6). No significant differences were identified in mortality; 17.5% with rtPA and 20% with TNK (p = 0.79), nor in the appearance of intracranial hemorrhage ICH (15.2% with rtPA vs. 30% with TNK (p = 0.12). In our series, there were not significant differences shown regarding effectiveness and safety between tenecteplase and alteplase.

Host response dysregulations amongst adults hospitalized by influenza A H1N1 virus pneumonia: A prospective multicenter cohort study.

BACKGROUND: Limited knowledge exists on how early host response impacts outcomes in influenza pneumonia. METHODS: This study assessed what was the contribution of host immune response at the emergency department on hospital mortality amongst adults with influenza A H1N1pdm09 pneumonia and whether early stratification by immune host response anticipates the risk of death. This is a secondary analysis from a prospective, observational, multicenter cohort comparing 75 adults requiring intensive care with 38 hospitalized in medical wards. Different immune response biomarkers within 24 h of hospitalization and their association with hospital mortality were assessed. RESULTS: Fifty-three were discharged alive. Non-survivors were associated (p<0.05) with lower lymphocytes (751 vs. 387), monocytes (450 vs. 220) expression of HLA-DR (1,662 vs. 962) and higher IgM levels (178 vs. 152;p<0.01). Lymphocyte subpopulations amongst non-survivors showed a significantly (p<0.05) lower number of TCD3+ (247.2 vs. 520.8), TCD4+ (150.3 vs. 323.6), TCD8+ (95.3 vs. 151.4) and NKCD56+ (21.9 vs. 91.4). Number of lymphocytes, monocytes and NKCD56+ predicted hospital mortality (AUC 0.854). Hospital mortality was independently associated with low HLA-DR values, low number of NKCD56+ cells, and high IgM levels, in a Cox-proportional hazard analysis. A second model, documented that hospital mortality was independently associated with a phenotype combining immunoparalysis with hyperinflammation (HR 5.53; 95%CI 2.16-14.14), after adjusting by predicted mortality. CONCLUSIONS: We conclude that amongst influenza pneumonia, presence of immunoparalysis was a major mortality driver. Influenza heterogeneity was partly explained by early specific host response dysregulations which should be considered to design personalized approaches of adjunctive therapy.