Characteristics and management of patients with SARS-CoV2 infection admitted to pediatric intensive care units: Data analysis of the Spanish national multicenter registry.

INTRODUCTION: The purpose of this study is to describe the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) disease characteristics and management in children admitted to the pediatric intensive care units (PICU). METHODS: The present study was based on a national multicentric prospective registry including PICU patients with SARS-CoV2 infection or symptoms of multisystem inflammatory syndrome in children (MIS-C). RESULTS: A total of 298 patients were admitted to 41 different Spanish PICUs. A total of 76% of them were previously healthy. The most frequent manifestation was MIS-C (69.8%). On admission, 59.4% of patients did not have respiratory distress, and only 17.4% needed conventional mechanical ventilation (MV). The need for MV was associated with age (incidence rate ratios [IRR] 1.21, p < .012), pediatric sequential organ failure assessment score (p-SOFA) Score (IRR 1.12, p = .001), and need for transfusion (IRR 4.5, p < .004) in MIS-C patients, and with vasoactive drug use (IRR 2.73, p = .022) and the diagnosis of acute respiratory distress syndrome (IRR 2.83, p = .018) in patients admitted for other reasons. During the first day of admission, 56% of patients met shock criteria and 50.7% needed vasoactive drugs. In MIS-C patients, their use was associated with higher p-SOFA score (IRR 1.06, p < .001) and with the diagnosis of shock (IRR 5.78, p < .001). In patients without MIS-C, it was associated with higher p-SOFA score (IRR 1.05, p = .022). The mortality rate was 3%, being lower in MIS-C patients compared to patients admitted for other reasons (0.5% vs. 9.4%, p < .001). It was also lower in previously healthy patients compared to patients with previous comorbidities (0.9% vs. 9.7%, p < .001). CONCLUSIONS: Severe SARS-CoV2 infection is uncommon in the pediatric population. In our series, respiratory distress was rare, being MIS-C the most frequent cause of PICU admission related to SARS-CoV2. In most cases, the course of the disease was mild except in children with previous diseases.

Defining Pediatric Chronic Critical Illness: A Scoping Review.

OBJECTIVES: Children with chronic critical illness (CCI) are hypothesized to be a high-risk patient population with persistent multiple organ dysfunction and functional morbidities resulting in recurrent or prolonged critical care; however, it is unclear how CCI should be defined. The aim of this scoping review was to evaluate the existing literature for case definitions of pediatric CCI and case definitions of prolonged PICU admission and to explore the methodologies used to derive these definitions. DATA SOURCES: Four electronic databases (Ovid Medline, Embase, CINAHL, and Web of Science) from inception to March 3, 2021. STUDY SELECTION: We included studies that provided a specific case definition for CCI or prolonged PICU admission. Crowdsourcing was used to screen citations independently and in duplicate. A machine-learning algorithm was developed and validated using 6,284 citations assessed in duplicate by trained crowd reviewers. A hybrid of crowdsourcing and machine-learning methods was used to complete the remaining citation screening. DATA EXTRACTION: We extracted details of case definitions, study demographics, participant characteristics, and outcomes assessed. DATA SYNTHESIS: Sixty-seven studies were included. Twelve studies (18%) provided a definition for CCI that included concepts of PICU length of stay (n = 12), medical complexity or chronic conditions (n = 9), recurrent admissions (n = 9), technology dependence (n = 5), and uncertain prognosis (n = 1). Definitions were commonly referenced from another source (n = 6) or opinion-based (n = 5). The remaining 55 studies (82%) provided a definition for prolonged PICU admission, most frequently greater than or equal to 14 (n = 11) or greater than or equal to 28 days (n = 10). Most of these definitions were derived by investigator opinion (n = 24) or statistical method (n = 18). CONCLUSIONS: Pediatric CCI has been variably defined with regard to the concepts of patient complexity and chronicity of critical illness. A consensus definition is needed to advance this emerging and important area of pediatric critical care research.

A review of key strategies to address the shortage of analgesics and sedatives in pediatric intensive care.

Importance: Targeted analgosedation is a challenge in critically ill children, and this challenge becomes even more significant with drug shortages. Observations: Published guidelines inform the provision of analgosedation in critically ill children. This review provides insights into general approaches using these guidelines during drug shortages in Pediatric Intensive Care Units as well as strategies to optimize both pharmacological and non-pharmacological approaches in these situations. Conclusions and relevance: Considering that drug shortages are a recurrent worldwide problem, this review may guide managing these drugs in critically ill children in situations of scarcity, such as in pandemics or disasters.

Cytokine Profile in Children with Severe Multisystem Inflammatory Syndrome Related to the Coronavirus Disease 2019.

The multisystem inflammatory syndrome in children (MIS-C) is a novel and concerning entity related to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Although MIS-C has been the subject of intensive research efforts, its pathophysiology and optimal treatment remain elusive. We studied the clinical features, laboratory findings, and immunoinflammatory profiles of seven children prospectively admitted to a pediatric intensive care unit (PICU) during the first wave of the pandemic. All patients had immunoglobulin (Ig)-G against SARS-CoV-2, four of seven patients had both IgM and IgG, and in one of the 7 SARS-CoV-2 was detected in a respiratory sample. All patients received intravenous fluid boluses (median: 15 mL/kg) and norepinephrine. The most common form of respiratory support was supplemental oxygen via nasal cannula. None of the patients needed mechanical ventilation. The cardiovascular system was frequently involved. All patients had an elevated troponin-I (median: 107.3 ng/L). Four out of seven patients had coronary artery abnormalities, and two of seven had both abnormal electrocardiogram (EKG) findings and evidence of left ventricular dysfunction on echocardiogram. Ig levels and complement function were normal. Peripheral blood phenotyping with flow cytometry showed decreased T-cell numbers at the expense of CD8+ T-cells. Cytokine profiling showed a heterogeneous increase in interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-18, IL-2Ra, IL-10, and IL-1Ra that tended to normalize after treatment. Our study shows that children with MIS-C have elevated plasma levels of pro- and anti-inflammatory cytokines in the acute phase of the disease without other relevant immunologic disturbances. These findings suggest the presence of a mixed antagonist response syndrome (MARS) similar to that present in pediatric sepsis. Combining a meticulous differential diagnosis with cautiously coordinated immunomodulatory therapy and high-quality supportive care can help clinicians avoid causing iatrogenic harm in patients with MIS-C.

Diaphragm Ultrasonography to Predict Noninvasive Respiratory Treatment Failure in Infants With Severe Bronchiolitis.

BACKGROUND: Noninvasive respiratory support is commonly used in treatment of bronchiolitis. Determinants of failure are needed to prevent delayed intubation. METHODS: We conducted a prospective observational pilot study in infants admitted to a pediatric ICU. Diaphragmatic excursion (dExc), diaphragmatic inspiratory/expiratory time, and diaphragmatic thickening fraction (dTF) were recorded at admission, 24 h, and 48 h in both hemidiaphragms. RESULTS: Twenty-six subjects were included (14 on HFNC and 12 on NIV) with a total of 56 ultrasonographic evaluations. Three subjects required invasive ventilation. Sixty-four percent of the subjects on HFNC required NIV as rescue therapy and 2/14 invasive ventilation (14.2%). In the HFNC group there were no differences in dExc between those who required escalation to NIV or invasive ventilation and those who didn't. Left dTF was higher in subjects on HFNC requiring invasive ventilation versus those needing NIV (left dTF 47% vs 22% [13-30]; P = .046, r = 0.7). Diaphragmatic I:E ratios were higher in infants on HFNC requiring invasive ventilation and diaphragmatic expiratory time was shorter (left P = .038; right P = .02). In the NIV group there were no differences in dExc, I:E ratios, or dTF between subjects needing escalation to invasive ventilation and those who didn't. We found no correlation between a clinical work of breathing score and echographic dTF. CONCLUSIONS: In infants with moderate or severe bronchiolitis receiving HFNC, the use of ultrasonographic left dTF could help predict respiratory treatment failure and need for invasive ventilation. The use of ultrasonographic dExc is of little help to predict both.

Molecular diagnosis of bacteremia in a pediatric intensive care unit: a step forward.

Aim: T2Bacteria® Panel detects six ESKAPE pathogens in around 3.5 h directly in whole blood. Our aim was to compare T2Bacteria with simultaneous blood culture in critically ill children with suspected bloodstream infection. Materials & methods: Retrospective study of critically ill children admitted to our tertiary-care center (2018-2020). Results: A total of 60 patients were recruited, including 63 episodes and 75 T2Bacteria/blood cultures were performed. Overall agreement between T2Bacteria and blood culture was 78.7% with a discordance of 21.3% (16/75 samples). Conclusion: T2Bacteria Panel may be useful in critically ill children providing an accurate and fast diagnosis of bacteremia directly from blood sample and detecting pathogens not recovered in blood cultures.

Melatonin in the Prophylaxis of SARS-CoV-2 Infection in Healthcare Workers (MeCOVID): A Randomised Clinical Trial.

We evaluated in this randomised, double-blind clinical trial the efficacy of melatonin as a prophylactic treatment for prevention of SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Healthcare workers fulfilling inclusion criteria were recruited in five hospitals in Spain and were randomised 1:1 to receive melatonin 2 mg administered orally for 12 weeks or placebo. The main outcome was the number of SARS-CoV-2 infections. A total of 344 volunteers were screened, and 314 were randomised: 151 to placebo and 163 to melatonin; 308 received the study treatment (148 placebo; 160 melatonin). We detected 13 SARS-CoV-2 infections, 2.6% in the placebo arm and 5.5% in the melatonin arm (p = 0.200). A total of 294 adverse events were detected in 127 participants (139 in placebo; 155 in melatonin). We found a statistically significant difference in the incidence of adverse events related to treatment: 43 in the placebo arm and 67 in the melatonin arm (p = 0.040), and in the number of participants suffering from somnolence related to treatment: 8.8% (n = 14) in the melatonin versus 1.4% (n = 2) in the placebo arm (p = 0.008). No severe adverse events related to treatment were reported. We cannot confirm our hypothesis that administration of melatonin prevents the development of SARS-CoV-2 infection in healthcare workers.

A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensive care unit (MelCOVID study): a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: • Primary objective: to evaluate the effect of intravenous melatonin (IVM) on mortality in adult patients admitted to the intensive care unit (ICU) with COVID-19. • Secondary objectives: ◦ To evaluate the effect of IVM on ICU length of stay. ◦ To evaluate the effect of IVM on the length of mechanical ventilation (MV). ◦ To evaluate if the use of IVM is associated with an increase in the number of ventilator-free days. ◦ To evaluate if the use of IVM is associated with a reduced number of failing organs as determined by the sequential organ failure assessment (SOFA) scale. ◦ To evaluate if the use of IVM is associated with a reduction of the frequency and severity of COVID-19-associated thromboembolic phenomena. ◦ To evaluate if the use of IVM is associated with a decreased systemic inflammatory response assessed by plasma levels of ferritin, D-dimer, C-reactive protein, procalcitonin and interleukin-6. ◦ To evaluate if the use of IVM is associated with an improvement in hematologic parameters. ◦ To evaluate if the use of IVM is associated with an improvement in biochemical parameters. ◦ To evaluate if the use of IVM is associated with an improvement in blood gas analysis parameters. ◦ To evaluate adverse events during the 28 day study period. TRIAL DESIGN: Phase II, single center, double-blind, placebo-controlled randomized trial with a two-arm parallel group design and 2:1 allocation ratio. PARTICIPANTS: Only critically ill adult patients that fulfill all of the inclusion criteria and none of the exclusion criteria will be included. The study will be conducted in a mixed ICU of a publicly funded tertiary referral center in Madrid, Spain with a 30-bed capacity and 1100 admissions per year. • Inclusion criteria: ◦ Patient, family member or legal guardian has provided written Informed Consent. ◦ Age ε 18 years. ◦ Confirmed SARS-CoV-2 infection with compatible symptoms AND a positive RT-PCR. ◦ Admission to the ICU with acute hypoxemic respiratory failure attributed to SARS-CoV-2 infection. ◦ ICU length of stay of less than 7 days prior to randomization with or without MV and without signs of improvement in respiratory failure (MURRAY score at randomization greater or equal to the MURRAY score at ICU admission). • Exclusion criteria: ◦ Participant in a different COVID-19 study in which the study drug is under clinical development and hasn't been previously authorized for commercialization. ◦ Liver enzymes > 5 times the upper normal range. ◦ Chronic kidney disease with GFR < 30 mL/min/1.73 m2 (stage 4 or greater) or need for hemodialysis. ◦ Pregnancy. A pregnancy test will be performed on every woman younger than 55 years of age prior to inclusion. ◦ Terminal surgical or medical illness. ◦ Autoimmune disease. ◦ Any patient condition that can prevent the study procedures to be carried out at the treating physician's judgement. INTERVENTION AND COMPARATOR: All patients will receive standard-of-care treatment according to the current institutional protocols. In addition, patients will be randomized in a 2:1 ratio to receive: • Experimental group (12 patients): 7 days of 5 mg per Kg of actual body weight per day of intravenous melatonin every 6 hours. Maximum daily dose 500 mg per day. • Control group (6 patients): 7 days of 5 mg per Kg of actual body weight per day of intravenous identically-looking placebo every 6 hours. After 3 days of treatment, 3 intensive care physicians will evaluate the participant and decide whether or not to complete the treatment based on their clinical assessment: • If objective or subjective signs of improvement or no worsening of the general clinical condition, respiratory failure, inflammatory state or multi-organ failure are observed, the participant will continue the treatment until completion. • If an adverse effect or clinical impairment is observed that is objectively or subjectively attributable to the study drug the treatment will be stopped. MAIN OUTCOME: Mortality in each study group represented in frequency and time-to-event at day 28 after randomization RANDOMIZATION: The randomization sequence was created using SAS version 9.4 statistical software (programmed and validated macros) with a 2:1 allocation. No randomization seed was pre-specified. The randomization seed was generated using the time on the computer where the program was executed. BLINDING (MASKING): Participants, caregivers and study groups will be blinded to arm allocation. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 18 patients will be randomized in this trial: 12 to the experimental arm and 6 to the control arm. TRIAL STATUS: Protocol version 2.0, June 5th 2020. Trial status: recruitment not started. The first patient is expected to be recruited in October 2020. The last patient is anticipated to be recruited in August 2021. TRIAL REGISTRATION: EU Clinical Trials Register. Date of trial registration: 10 July 2020. URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001808-42/ES FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary objective: to evaluate the efficacy of melatonin as a prophylactic treatment on prevention of symptomatic SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Secondary objectives: To evaluate the efficacy of melatonin as a prophylactic treatment on prevention of asymptomatic SARS-CoV-2 infection.To evaluate the efficacy of melatonin to prevent the development of severe COVID-19 in the participants enrolled in this study who develop SARS-CoV-2 infection along the trial.To evaluate the duration of COVID-19 symptoms in participants receiving melatonin before the infection.To evaluate seroconversion timing post-symptom onset. Exploratory objectives:To compare severity of COVID-19 between men and women.To evaluate the influence of sleep and diet on prevention from SARS-CoV-2 infection.To evaluate the effect of melatonin on the incidence and characteristics of lymphopenia and increase of inflammatory cytokines related to COVID-19. TRIAL DESIGN: This is a two-arm parallel randomised double-blind controlled trial to evaluate the efficacy of melatonin versus placebo in the prophylaxis of coronavirus disease 2019 among healthcare workers. PARTICIPANTS: Inclusion Criteria: Male or female participants ≥ 18 and ≤ 80 years of age.Healthcare workers from the public and private Spanish hospital network at risk of SARS-CoV 2 infection.Not having a previous COVID19 diagnosis.Understanding the purpose of the trial and not having taken any pre-exposure prophylaxis (PrEP) including HIV PrEP from March 1st 2020 until study enrolment.Having a negative SARS-CoV 2 reverse-transcription PCR (RT-PCR) result or a negative serologic rapid test (IgM/IgG) result before randomization.Premenopausal women must have a negative urinary pregnancy test in the 7 days before starting the trial treatment.Premenopausal women and males with premenopausal couples must commit to using a high efficiency anticonceptive method. EXCLUSION CRITERIA: HIV infection.Active hepatitis B infection.Renal failure (CrCl < 60 mL/min/1.73 m2) or need for hemodialysis.Osteoporosis.Myasthenia gravis.Pre-existent maculopathy.Retinitis pigmentosa.Bradycardia (less than 50 bpm).Weight less than 40 Kg.Participant with any immunosuppressive condition or hematological disease.Treatment with drugs that may prolong QT in the last month before randomization for more than 7 days including: azithromycin, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxacin, thioridazine, amiodarone.Hereditary intolerance to galactose, Lapp lactase deficiency or glucose or galactose malabsorption.Treatment with fluvoxamine.Treatment with benzodiazepines or benzodiazepine analogues such as zolpidem, zopiclone or zaleplon.Pregnancy.Breastfeeding.History of potentially immune derived diseases such as: lupus, Crohn's disease, ulcerative colitis, vasculitis or rheumatoid arthritis.Insulin-dependent diabetes mellitus.Known history of hypersensitivity to the study drug or any of its components.Patients that should not be included in the study at the judgment of the research team. Participants will be recruited from the following eight hospitals in Madrid, Spain: Hospital Universitario La Paz, Hospital Ramón y Cajal, Hospital Infanta Sofía, Hospital 12 de Octubre, Hospital Clínico San Carlos, Hospital Central de la defensa Gómez Ulla,Hospital de La Princesa and Hospital Infanta Leonor. INTERVENTION AND COMPARATOR: Experimental: Melatonin (Circadin®, Exeltis Healthcare, Spain): 2 mg of melatonin orally before bedtime for 12 weeks. Comparator: Identical looking placebo (Laboratorios Liconsa, Spain) orally before bedtime for 12 weeks. MAIN OUTCOMES: Number of SARS-CoV-2 (COVID-19) symptomatic infections confirmed by polymerase chain reaction (PCR) test or serologic test or according to each centre diagnosis protocol. Primary outcome will be measured until the end of treatment for each participant (until the date of the last dose taken by each patient). RANDOMISATION: Patients who meet all inclusion and no exclusion criteria will be randomised, stratified by centres, sex and age (<50 and ≥ 50 years old). The randomisation sequence was created using SAS version 9.4 statistical software (procedure 'PROC PLAN') with a 1:1 allocation. No randomisation seed was specified. The randomisation seed was generated taking the hour of the computer where the program was executed. Randomization will be done centrally through the electronic system RedCAP® in order to conceal the sequence until interventions are assigned BLINDING (MASKING): Participants, caregivers, and those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 450 participants are planned to be enrolled in this clinical trial, 225 in the experimental arm and 225 in the placebo arm. TRIAL STATUS: Protocol version 3.0, 17th of April 2020. Recruitment ongoing. First participant was recruited on the 21st of April 2020. The final participant is anticipated to be recruited on the 31st of May 2020. As of May 18th, 2020, a total of 312 participants have been enrolled (154 at Hospital La Paz, 85 at Hospital Infanta Sofía and 73 at Hospital 12 de Octubre). TRIAL REGISTRATION: EU Clinical Trials Register: 2020-001530-35; Date of trial registration: 13th of April 2020; https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001530-35/ES FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.