Implications of sedation during the use of noninvasive ventilation in children with acute respiratory failure (SEDANIV Study).

BACKGROUND: The objective of this study was to analyze the effects of sedation administration on clinical parameters, comfort status, intubation requirements, and the pediatric intensive care unit (PICU) length of stay (LOS) in children with acute respiratory failure (ARF) receiving noninvasive ventilation (NIV). METHODS: Thirteen PICUs in Spain participated in a prospective, multicenter, observational trial from January to December 2021. Children with ARF under the age of five who were receiving NIV were included. Clinical information and comfort levels were documented at the time of NIV initiation, as well as at 3, 6, 12, 24, and 48 h. The COMFORT-behavior (COMFORT-B) scale was used to assess the patients' level of comfort. NIV failure was considered to be a requirement for endotracheal intubation. RESULTS: A total of 457 patients were included, with a median age of 3.3 months (IQR 1.3-16.1). Two hundred and thirteen children (46.6%) received sedation (sedation group); these patients had a higher heart rate, higher COMFORT-B score, and lower SpO2/FiO2 ratio than did those who did not receive sedation (non-sedation group). A significantly greater improvement in the COMFORT-B score at 3, 6, 12, and 24 h, heart rate at 6 and 12 h, and SpO2/FiO2 ratio at 6 h was observed in the sedation group. Overall, the NIV success rate was 95.6%-intubation was required in 6.1% of the sedation group and in 2.9% of the other group (p = 0.092). Multivariate analysis revealed that the PRISM III score at NIV initiation (OR 1.408; 95% CI 1.230-1.611) and respiratory rate at 3 h (OR 1.043; 95% CI 1.009-1.079) were found to be independent predictors of NIV failure. The PICU LOS was correlated with weight, PRISM III score, respiratory rate at 12 h, SpO2 at 3 h, FiO2 at 12 h, NIV failure and NIV duration. Sedation use was not found to be independently related to NIV failure or to the PICU LOS. CONCLUSIONS: Sedation use may be useful in children with ARF treated with NIV, as it seems to improve clinical parameters and comfort status but may not increase the NIV failure rate or PICU LOS, even though sedated children were more severe at technique initiation in the present sample.

Impact of different nebulisation systems on patient comfort in bronchiolitis: a randomised controlled cross-over trial.

OBJECTIVE: To test the hypothesis that greater comfort is achieved using a nebuliser integrated into a high-flow nasal cannula (nebulisation system integrated in high-flow nasal cannula (NHF)) than using a jet nebuliser (JN), and to explore differences in analgesia requirement and the possibility of feeding during nebulisation. DESIGN: Randomised cross-over trial. SETTING: Paediatric intensive care unit. PATIENTS: Children aged <24 months diagnosed with bronchiolitis between November 2016 and May 2017. INTERVENTIONS: Nebulisations using NHF and JN. MAIN OUTCOME MEASURES: COMFORT-Behaviour Scale (CBS) and Numerical Rating Comfort Scale (NRSc) were used to measure comfort, and Numerical Rating Satisfaction Scale (NRSs) was used to assess satisfaction before, during and after nebulisation. Other variables included feeding, analgesia, need for being held and respiratory and heart rates. RESULTS: Thirty-three children with 233 nebulisations were included in the study. The median age was 3.0 (IQR 2-9) months. Comfort and satisfaction were greater with NHF than with JN. The median staff-recorded CBS, NRSc and NRSs scores for NHF versus JN were 13 (IQR 9-15) vs 17 (IQR 13-23), 8 (IQR 7-0) vs 7 (IQR 4-8), and 4 (IQR 3-4) vs 2 (IQR 2-3), respectively; and caregiver-recorded scores were 12 (IQR 10-15) vs 19 (IQR 13-24), 9 (IQR 7-10) vs 4 (IQR 1-6), and 4 (IQR 3-4) vs 2 (IQR 1-3), respectively (p<0.001). Children who received NHF had lower cardiac and respiratory rates, needed to be held less often during therapy and required less analgesia (p<0.001). CONCLUSION: Nebulisation through NHF appears to be a better alternative to JN in terms of comfort and satisfaction as well as making feeding possible during nebulisation.

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study.

Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder. Funding: Unstoppable campaign of Josep Carreras Leukaemia Foundation, Fundació La Marató de TV3, Cellex Foundation and CERCA Programme/Generalitat de Catalunya.

Epigenome-wide association study of COVID-19 severity with respiratory failure.

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

Surveillance for Enteroviruses Associated with Hand, Foot, and Mouth Disease, and Other Mucocutaneous Symptoms in Spain, 2006-2020.

Hand, foot, and mouth disease (HFMD) is a mild illness caused by enteroviruses (EV), although in some Asian countries, large outbreaks have been reported in the last 25 years, with a considerable incidence of neurological complications. This study describes epidemiological and clinical characteristics of EV infections involved in HFMD and other mucocutaneous symptoms from 2006 to 2020 in Spain. EV-positive samples from 368 patients were included. EV species A were identified in 85.1% of those typed EV. Coxsackievirus (CV) A6 was the prevalent serotype (60.9%), followed by EV-A71 (9.9%) and CVA16 (7.7%). Infections affected children (1-6 years old) mainly, and show seasonality with peaks in spring-summer and autumn. Clinical data indicated few cases of atypical HFMD as well as those with neurological complications (associated with the 2016 EV-A71 outbreak). Phylogenetic analysis of CVA6 VP1 sequences showed different sub-clusters circulating from 2010 to present. In conclusion, HFMD or exanthemas case reporting has increased in Spain in recent years, probably associated with an increase in circulation of CVA6, although they did not seem to show greater severity. However, EV surveillance in mucocutaneous manifestations should be improved to identify the emergence of new types or variants causing outbreaks and more severe pathologies.

Síndrome de hipertermia maligna: una patología infrecuente / Malignant hyperthermia syndrome: A rare entity

Resumen Introducción: El síndrome de hipertermia maligna es un trastorno farmacogenético del músculo esquelético de carácter hereditario, que se caracteriza por un estado hipermetabólico relacionado con la exposición a anestésicos inhalatorios o relajantes musculares despolarizantes. Se trata de una afección infrecuente en individuos genéticamente predispuestos, con una incidencia muy baja en pediatría (1 de cada 10,000-15,000 procedimientos anestésicos). Caso clínico: Se presenta un caso de hipertermia maligna relacionado con la exposición a sevoflurano durante una cirugía de adenoidectomía en un paciente de sexo femenino de 6 años de edad. La paciente presentó taquicardia, hipercapnia e hipertermia, que precisaron la administración de dos dosis sucesivas de dantroleno sódico. La evolución posterior fue buena. Conclusiones: El síndrome de hipertermia maligna es un cuadro poco frecuente en la edad pediátrica. Se debe sospechar de forma precoz, ya que es fundamental su detección temprana para iniciar el tratamiento.

Abstract Background: Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile anesthetic gases or depolarizing muscle relaxants. It is an infrequent entity that occurs in genetically predisposed individuals, with a very low incidence in pediatrics (1 in 10,000-15,000 anesthetic procedures). Case report: We report a case of malignant hyperthermia related to exposure to sevoflurane during adenoidectomy surgery in a 6-year-old female. The patient presented with tachycardia, hypercapnia, and hyperthermia, requiring two successive doses of dantrolene sodium administration, with an adequate response to the treatment. Conclusions: Malignant hyperthermia syndrome is a rare condition in pediatric patients that should be detected in early stages since it is essential to initiate the treatment as soon as possible.

Malignant hyperthermia syndrome: A rare entity.

Background: Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile anesthetic gases or depolarizing muscle relaxants. It is an infrequent entity that occurs in genetically predisposed individuals, with a very low incidence in pediatrics (1 in 10,000-15,000 anesthetic procedures). Case report: We report a case of malignant hyperthermia related to exposure to sevoflurane during adenoidectomy surgery in a 6-year-old female. The patient presented with tachycardia, hypercapnia, and hyperthermia, requiring two successive doses of dantrolene sodium administration, with an adequate response to the treatment. Conclusions: Malignant hyperthermia syndrome is a rare condition in pediatric patients that should be detected in early stages since it is essential to initiate the treatment as soon as possible.

Background: Introducción">El síndrome de hipertermia maligna es un trastorno farmacogenético del músculo esquelético de carácter hereditario, que se caracteriza por un estado hipermetabólico relacionado con la exposición a anestésicos inhalatorios o relajantes musculares despolarizantes. Se trata de una afección infrecuente en individuos genéticamente predispuestos, con una incidencia muy baja en pediatría (1 de cada 10,000-15,000 procedimientos anestésicos). Caso clínico: Se presenta un caso de hipertermia maligna relacionado con la exposición a sevoflurano durante una cirugía de adenoidectomía en un paciente de sexo femenino de 6 años de edad. La paciente presentó taquicardia, hipercapnia e hipertermia, que precisaron la administración de dos dosis sucesivas de dantroleno sódico. La evolución posterior fue buena. Conclusiones: El síndrome de hipertermia maligna es un cuadro poco frecuente en la edad pediátrica. Se debe sospechar de forma precoz, ya que es fundamental su detección temprana para iniciar el tratamiento.

A comparative in vitro study of standard facemask jet nebulization and high-flow nebulization in bronchiolitis.

Aim of Study: The use of a nebulizer paired with high-flow nasal cannulas (HFNC) has been proposed for drug delivery in bronchiolitis. Particle size nebulized is a relevant factor determining the efficacy of the nebulization. We replicated in vitro the theoretical parameters most widely used in bronchiolitis and we compared the size of the droplet nebulized with a standard nebulizer and a nebulizer integrated into HFNC. Materials and Methods: We used laser diffraction to analyze the particle size nebulized (volume median diameter Dv50). The standard system was a jet nebulizer connected to a facemask with a flow rate of 8 L/min (JN). Three designs were used as nebulizers integrated into HFNC: a vibrating mesh nebulizer set 1) before (HFNC-BH) and 2) after (HFNC-AH) the humidifier, and 3) a jet nebulizer connected before the nasal cannula (HFNC-BNC). HFNC was used with neonatal (3-8 L/min) and infant cannulas (8-15 L/min). Results: Droplet size was similar among the three drugs studied. A lower particle size was obtained when using the nebulization system integrated into HFNC compared to the standard nebulizer, regardless of the flow rate and the nasal cannula used when the position of the nebulizer was before the nasal cannula (p < 0.05): 6.89 µm (JN), 2.49 µm (HFNC-BNC 3 L/min), 2.59 µm (HFNC-BNC 5 L/min), 2.44 µm (HFNC-BNC 8 L/min), 3.22 µm (HFNC-BNC 10 L/min), 3.23 µm (HFNC-BNC 13 L/min), 3.16 µm (HFNC-BNC 15 L/min). The particle size was lower in HFNC-BF compared to the HFNC-AH using neonatal nasal cannula (3-8 L/min) (p < 0.05). Conclusion: The use of a nebulizer integrated with HFNC has shown promising results in an experimental scenario of bronchiolitis. The particle size achieved with the nebulizer placed before the humidifier is equivalent to the one obtained via conventional nebulization, and it is even smaller when the integrated nebulizer is placed before the nasal cannulas.

Observational study of newborn infant parasympathetic evaluation as a comfort system in awake patients admitted to a pediatric intensive care unit.

To compare the newborn infant parasympathetic evaluation system (NIPE) scores with a validated clinical scale using two different nebulizers in children with bronchiolitis admitted to a PICU. Comfort was evaluated using the COMFORT-behavior scale (CBS) before (T1), during (T2) and after (T3) each nebulization. In order to compare NIPE and CBS values during the whole T1 to T3 period, the variable Dif-CBS was defined as the difference between maximal and minimal CBS scores, and Dif-NIPE as the difference between 75th and 25th percentile NIPE values. Analyses were carried out, firstly for the total of nebulizations and secondly comparing two different nebulization systems: a jet nebulizer (JN) and a nebulizer integrated in high flow nasal cannulas (NHF). 84 nebulizations were recorded on 14 patients with a median [25th-75th percentile] age of 6 months (3.1-9.5). A Dif-CBS of 4 points (2-7), as well as changes in CBS scores between T1 and T2, defined the nebulization as a discomfort stimulus. The NIPE system, represented as the Dif-NIPE, showed a median variation of 9 points (7-10), and was poorly correlated to Dif-CBS [rs 0.162 (P = 0.142)]. Discomfort during nebulization, assessed by CBS was greater with the JN system compared to NHF: 17 (13-22) vs 13 (9-15) (P = 0.001). NIPE monitoring detected no significant differences between both nebulization systems (P = 0.706). NIPE monitoring showed a variation in comfort during nebulization in the patient with bronchiolitis, though correlation with CBS was poor. Further research is required before NIPE can be suggested as a comfort monitoring system for the awake infant.

Incorporating a Nebulizer System Into High-Flow Nasal Cannula Improves Comfort in Infants With Bronchiolitis.

BACKGROUND: High-flow nasal cannula (HFNC) is increasingly used to provide respiratory support in infants with bronchiolitis. The delivery of aerosol therapy through a jet nebulizer is widely indicated despite its controversial efficacy and poor tolerability. METHODS: This randomized cross-over study aimed to evaluate the comfort and satisfaction of the delivery of aerosol therapy using a nebulization system integrated into HFNC compared with the standard practice of using a jet nebulizer with a face mask. The COMFORT-Behavior (COMFORT-B) scale, a visual analog scale, and a numeric rating scale were used by health professionals and caregivers to assess subjects' levels of comfort and satisfaction. RESULTS: A total of 113 nebulizations (64 via nebulizer with HFNC; 49 via jet nebulizer) were delivered to the 6 subjects included in the study. Use of the nebulizer with HFNC showed increased comfort and satisfaction during nebulization compared to use of the jet nebulizer, as measured by the COMFORT-B scale, the visual analog scale, and the numeric rating scale, with the following median (interquartile range) scores: 10.7 (7-16) versus 14.5 (10-20) (P = .006), 8.5 (6-10) versus 7 (4-9) (P = .02), and 3.84 (3.61-4.07) versus 1.83 (1.58-2.08) (P < .001), respectively. Correlation between the COMFORT-B scale and the visual analog scale using Spearman's rho was -0.757 (P < .001). The intraclass correlation coefficient for the COMFORT-B scale, visual analog scale, and numeric rating scale, as measured by 2 different nurses, was between 0.75 and 0.87. CONCLUSIONS: The use of a nebulizer incorporated into HFNC therapy results in an increased level of comfort and satisfaction compared to the use of a conventional jet nebulizer in subjects with bronchiolitis who required HFNC therapy. Further studies are needed to determine whether aerosol therapy delivered through HFNC improves the clinical course of this pathology.