Identification of severe acute pediatric asthma phenotypes using unsupervised machine learning.

RATIONALE: More targeted management of severe acute pediatric asthma could improve clinical outcomes. OBJECTIVES: To identify distinct clinical phenotypes of severe acute pediatric asthma using variables obtained in the first 12 h of hospitalization. METHODS: We conducted a retrospective cohort study in a quaternary care children's hospital from 2014 to 2022. Encounters for children ages 2-18 years admitted to the hospital for asthma were included. We used consensus k means clustering with patient demographics, vital signs, diagnostics, and laboratory data obtained in the first 12 h of hospitalization. MEASUREMENTS AND MAIN RESULTS: The study population included 683 encounters divided into derivation (80%) and validation (20%) sets, and two distinct clusters were identified. Compared to Cluster 1 in the derivation set, Cluster 2 encounters (177 [32%]) were older (11 years [8; 14] vs. 5 years [3; 8]; p < .01) and more commonly males (63% vs. 53%; p = .03) of Black race (51% vs. 40%; p = .03) with non-Hispanic ethnicity (96% vs. 84%; p < .01). Cluster 2 encounters had smaller improvements in vital signs at 12-h including percent change in heart rate (-1.7 [-11.7; 12.7] vs. -7.8 [-18.5; 1.7]; p < .01), and respiratory rate (0.0 [-20.0; 22.2] vs. -11.4 [-27.3; 9.0]; p < .01). Encounters in Cluster 2 had lower percentages of neutrophils (70.0 [55.0; 83.0] vs. 85.0 [77.0; 90.0]; p < .01) and higher percentages of lymphocytes (17.0 [8.0; 32.0] vs. 9.0 [5.3; 14.0]; p < .01). Cluster 2 encounters had higher rates of invasive mechanical ventilation (23% vs. 5%; p < .01), longer hospital length of stay (4.5 [2.6; 8.8] vs. 2.9 [2.0; 4.3]; p < .01), and a higher mortality rate (7.3% vs. 0.0%; p < .01). The predicted cluster assignments in the validation set shared the same ratio (~2:1), and many of the same characteristics. CONCLUSIONS: We identified two clinical phenotypes of severe acute pediatric asthma which exhibited distinct clinical features and outcomes.

Asthma Inception: Epidemiologic Risk Factors and Natural History Across the Life-Course.

Asthma is a descriptive label for an obstructive, inflammatory disease in the lower airways manifesting with symptoms including breathlessness, cough, difficulty in breathing and wheezing. From a clinician's point of view, asthma symptoms can commence at any age although most asthma patients - regardless of their age of onset - seem to have had some form of airway problems during childhood. Asthma inception and related pathophysiologic processes are therefore very likely to occur early in life, further evidenced by recent lung physiologic and mechanistic research. Herein, we present state-of-the-art updates on the role of genetics and epigenetics, early viral and bacterial infections, immune response and pathophysiology as well as lifestyle and environmental exposures in asthma across the life-course. We conclude early environmental insults in genetically vulnerable individuals to induce an abnormal, pre-asthmatic airway response as key events in asthma inception and highlight disease heterogeneity - across ages - and the potential shortness of treating all patients with asthma using the same treatments. Although there are no interventions that, at present, can modify long-term outcomes, a precision-medicine approach should be implemented to optimize treatment and tailor follow-up for all patients with asthma. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

NOVEL ECHOCARDIOGRAM ANALYSIS OF CARDIAC DYSFUNCTION IS ASSOCIATED WITH MORTALITY IN PEDIATRIC SEPSIS.

ABSTRACT: Objectives: The objective of our study was to semiautomatically generate echocardiogram indices in pediatric sepsis using novel algorithms and determine which indices were associated with mortality. We hypothesized that strain and diastolic indices would be most associated with mortality. Design: Retrospective cohort study of children with sepsis from 2017 to 2022. Survivors and nonsurvivors were compared for echocardiogram indices. Multivariate Cox proportional hazard models were constructed for our primary outcome of in-hospital mortality. Linear regression was performed for secondary outcomes, which included multiple composite 28-day outcomes. Results: Of the 54 patients in the study, 9 (17%) died. Multiple echocardiogram indices of both right (RV) and left ventricles (LV) were associated with in-hospital mortality [RV GLS adjusted hazard ratio (aHR): 1.16 (1.03-1.29), P = 0.011; RV global longitudinal early diastolic strain rate (GLSre) aHR: 0.24 (0.07 to 0.75), P = 0.014; LV GLSre aHR: 0.33 (0.11-0.97), P = 0.044]. Impairment in GLS was associated with fewer ventilator-free days [RV GLS ß-coefficient: -0.47 (-0.84 to -0.10), P = 0.013; LV GLS ß-coefficient -0.62 (-1.07 to -0.17), P = 0.008], organ-support free days [RV GLS ß-coefficient: -0.49 (-0.87 to -0.11), P = 0.013; LV GLS ß-coefficient: -0.64 (-1.10 to -0.17), P = 0.008], and days free from ICU [RV GLS ß-coefficient: -0.42 (-0.79 to -0.05), P = 0.026; LV GLS ß-coefficient: -0.58 (-1.03 to -0.13), P = 0.012]. Systolic indices were not associated with mortality in this cohort. Conclusion: Our study demonstrates the feasibility of obtaining echocardiogram indices in a semiautomatic method using our algorithms. We showed that abnormal strain is associated with worse outcomes in a cohort of children with sepsis.

In Vivo Analysis of Tissue S-Nitrosothiols in Pediatric Sepsis.

S-nitrosothiols are endogenous, bioactive molecules. S-nitrosothiols are implicated in many diseases, including sepsis. It is currently cumbersome to measure S-nitrosothiols clinically. We have previously developed an instrument to measure tissue S-nitrosothiols non-invasively using ultraviolet light. We have performed a prospective case control study of controls and children with sepsis admitted to the PICU. We hypothesized that tissue S-nitrosothiols would be higher in septic patients than controls. Controls were patients with no cardiopulmonary instability. Cases were patients with septic shock. We measured S-nitrosothiols, both at diagnosis and after resolution of shock. A total of 44 patients were enrolled: 21 controls and 23 with sepsis. At baseline, the controls were younger [median age 5 years (IQR 0, 9) versus 11 years (IQR: 6, 16), p-value = 0.012], had fewer comorbidities [7 (33.3%) vs. 20 (87.0%), p-value < 0.001], and had lower PELOD scores [0 (IQR: 0, 0) vs. 12 (IQR: 11, 21), p-value < 0.001]. S-nitrosothiol levels were higher in sepsis cohort (1.1 ppb vs. 0.8 ppb, p = 0.004). Five patients with sepsis had longitudinal measures and had a downtrend after resolution of shock (1.3 ppb vs. 0.9 ppb, p = 0.04). We dichotomized patients based on S-nitrosothiol levels and found an association with worse clinical outcomes, but further work will be needed to validate these findings.

Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia.

Nasal nitric oxide (nNO) is low in most patients with primary ciliary dyskinesia (PCD). Decreased ciliary motion could lead to antigen stasis, increasing oxidant production and NO oxidation in the airways. This could both decrease gas phase NO and increase nitrosative stress. We studied primary airway epithelial cells from healthy controls (HCs) and patients with PCD with several different genotypes. We measured antigen clearance in fenestrated membranes exposed apically to the fluorescently labeled antigen Dermatophagoides pteronyssinus (Derp1-f). We immunoblotted for 3-nitrotyrosine (3-NT) and for oxidative response enzymes. We measured headspace NO above primary airway cells without and with a PCD-causing genotype. We measured nNO and exhaled breath condensate (EBC) H2O2 in vivo. Apical Derp1-f was cleared from HC better than from PCD cells. DUOX1 expression was lower in HC than in PCD cells at baseline and after 24-h Derp1-f exposure. HC cells had less 3-NT and NO3- than PCD cells. However, NO consumption by HC cells was less than that by PCD cells; NO loss was prevented by superoxide dismutase (SOD) and by apocynin. nNO was higher in HCs than in patients with PCD. EBC H2O2 was lower in HC than in patients with PCD. The PCD airway epithelium does not optimally clear antigens and is subject to oxidative and nitrosative stress. Oxidation associated with antigen stasis could represent a therapeutic target in PCD, one with convenient monitoring biomarkers.NEW & NOTEWORTHY The PCD airway epithelium does not optimally clear antigens, and antigen exposure can lead to NO oxidation and nitrosative stress. Oxidation caused by antigen stasis could represent a therapeutic target in PCD, and there are convenient monitoring biomarkers.

Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations.

Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation. Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations. Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations. Measures and Main Results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46×10-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (FENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007). Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.

Cirugía de control de daños abdominopélvica. Experiencia en un hospital de 3er Nivel / Abdominopelvic damage control surgery

La cirugía de control de daños (CCD), surge con el afán de mejorar los pobres resultados obtenidos con el abordaje quirúrgico tradicional en traumatismos abdominales graves y exanguinantes en pacientes críticos con escasa reserva fisiológica. Se define con una "cirugía por etapas", con un primer tiempo quirúrgico corto para controlar el sangrado y la contaminación con cierre temporario abdominal, seguido de un período de reanimación en unidad de cuidados intensivos y, finalmente, de reparación definitiva de las lesiones. Se revisaron las histrias clínicas de 41 pacientes sometidos a éste tipo de cirugía en el período comprendido entre marzo de 2011 y octubre de 2017 en el Hospital Municipal de Urgencias de la ciudad de Córdoba, 29 hombres y 12 mujeres, en cuanto al mecanismo lesional 23 casos fueron por trauma cerrado y 18 penetrantes. La edad promedio fue de 30 años, 28 pacientes presentaron lesiones asociadas, siendo las más frecuentes las torácicas en 14 pacientes y la mortalidad global de la serie del 41% (17 pacientes). El grupo etario involucrado, la distribución por sexo, y la mortalidad de nuestra serie no difiere de la bibliografía consultada

Damaage control surgery (CCD) arises with the aim of imporving the poor results obtained with the traditional surgical approach in severe and exanguinating abdominal trauma in critically ill patients with scarce physiological reserve. It is defined as a "step surgery", with a short surgical first time to control bleeding and contamination with temporary abdominal closure, followed by a period of resuscitation in the intensive care unit and, finally, definitive repair of the injuries. We revierwed the medical rcords of 41 patients undergoing this type of surgery in the period between arch 2011 and October 2017 at the Municipal Emergenci Hospital of the city of Córdoba, 29 men and 12 women, regarding the mechanism of injury 23 cases were due to closed trauma and 18 penetrating. The average age was 30 years, 28 patients had associated injuries, the most frequent being thoracic in 14 patients and the overall mortality of the series of 41% (17 patients). The age group involved, the distributin by sex, and the mortality of our series does not differ from the bibliography consulted

Tratamento atual de crianças com asma crítica e quase fatal / Contemporary treatment of children with critical and near-fatal asthma

RESUMO A asma é a mais comum das doenças da infância. Embora a maioria das crianças com exacerbações agudas de asma não demanda cuidados críticos, algumas delas não respondem ao tratamento padrão e necessitam de cuidados mais intensos. Crianças com asma crítica ou quase fatal precisam de monitoramento estrito quanto à deterioração e podem requerer estratégias terapêuticas agressivas. Esta revisão examinou as evidências disponíveis que dão suporte a terapias para asma crítica e quase fatal, e resumiu o cuidado clínico atual para essas crianças. O tratamento típico inclui uso parenteral de corticosteroides e fármacos beta-agonistas, por via inalatória ou intravenosa. Para crianças com resposta inadequada ao tratamento padrão, pode-se lançar mão do uso inalatório de brometo de ipratrópio ou intravenoso de sulfato de magnésio, metilxantinas e misturas gasosas com hélio, além de suporte ventilatório mecânico não invasivo. Pacientes com insuficiência respiratória progressiva se beneficiam de ventilação mecânica com uma estratégia que emprega grandes volumes correntes e baixas frequências do ventilador, para minimizar a hiperinsuflação dinâmica, o barotrauma e a hipotensão. Sedativos, analgésicos e bloqueadores neuromusculares são frequentemente necessários na fase inicial do tratamento para facilitar um estado de hipoventilação controlada e hipercapnia permissiva. Pacientes que não conseguem melhorar com a ventilação mecânica podem ser considerados para abordagens menos comuns, como inalação de anestésicos, broncoscopia e suporte extracorpóreo à vida. Esta abordagem atual resultou em taxas de mortalidade extremamente baixas, mesmo em crianças com necessidade de suporte mecânico.

ABSTRACT Asthma is the most common chronic illness in childhood. Although the vast majority of children with acute asthma exacerbations do not require critical care, some fail to respond to standard treatment and require escalation of support. Children with critical or near-fatal asthma require close monitoring for deterioration and may require aggressive treatment strategies. This review examines the available evidence supporting therapies for critical and near-fatal asthma and summarizes the contemporary clinical care of these children. Typical treatment includes parenteral corticosteroids and inhaled or intravenous beta-agonist drugs. For children with an inadequate response to standard therapy, inhaled ipratropium bromide, intravenous magnesium sulfate, methylxanthines, helium-oxygen mixtures, and non-invasive mechanical support can be used. Patients with progressive respiratory failure benefit from mechanical ventilation with a strategy that employs large tidal volumes and low ventilator rates to minimize dynamic hyperinflation, barotrauma, and hypotension. Sedatives, analgesics and a neuromuscular blocker are often necessary in the early phase of treatment to facilitate a state of controlled hypoventilation and permissive hypercapnia. Patients who fail to improve with mechanical ventilation may be considered for less common approaches, such as inhaled anesthetics, bronchoscopy, and extracorporeal life support. This contemporary approach has resulted in extremely low mortality rates, even in children requiring mechanical support.