Effect of nutrition status and inflammatory stimuli on ghrelin and peptide-YY levels among critically ill children: A prospective and observational study.

BACKGROUND: Ghrelin and peptide-YY (PYY) are two gut peptides with apparent opposing actions. In normal conditions, ghrelin and PYY work together in synergy to regulate energy homeostasis. During critical illness, series of metabolic, endocrine, and inflammatory changes take place in response to a severe insult. Emerging studies recorded alterations in gut hormone levels in critically ill adults. This study aims to assess the effect of inflammation, nutrition, and feeding status on ghrelin and PYY levels in critically ill children. METHODS: In this prospective study, we collected blood samples from critically ill children on days 2 or 3 of pediatric intensive care unit (PICU) admission for the analysis of serum ghrelin, PYY, and inflammatory markers. Data related to the intake anthropometry, as well as other clinical data, were collected from patients' records. Multiple linear regression analysis was used to identify factors affecting serum levels of these hormones. RESULTS: Forty-two children admitted to the PICU were included in this study. Ghrelin level was influenced by admission nutrition status of the children and age. PYY was influenced by macronutrient intake and age. Inflammatory markers also showed an association with the measured levels of these hormones, with C-reactive protein being positively associated with ghrelin levels and tumor necrosis factor alpha showing a positive association with PYY levels. CONCLUSION: Although ghrelin and PYY have been linked to feeding status in healthy patients, during critical illness there might be other factors, such as inflammation and nutrition status, that might contribute to the changes observed in ghrelin/PYY profiles.

Accuracy of cerebrospinal fluid ferritin for purulent meningitis.

OBJECTIVE: To evaluate the use of cerebrospinal fluid (CSF) ferritin levels in the diagnosis of purulent meningitis (PM). METHOD: We studied 81 children between 28 days and 12 years of age who presented with clinical suspicion of meningitis to the emergency department. CSF ferritin levels were measured and compared between diagnostic groups (PM, aseptic meningitis (AM) and no meningitis). RESULTS: The median age was 24 (IQR 8-69) months. There were 32 patients with AM (39%), 23 with PM (28%) and 26 with no meningitis (32%). Median CSF ferritin was 4.2 ng/mL (IQR 3.0-6.5), 52.9 ng/mL (IQR 30.7-103 ng/mL) and 2.4 ng/mL (IQR 2-4), respectively. CSF ferritin was higher in children with PM compared with AM (p<0.001) or no meningitis (p<0.001). There was no difference between AM and no meningitis. CONCLUSION: CSF ferritin may be a useful biomarker to discriminate PM in children with clinical symptoms of this disease.

Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing.

BACKGROUND: Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. METHODS: We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. RESULTS: We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. CONCLUSIONS: Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.

Neuroprotective measures in children with traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of death and disability in children. Severe TBI is a leading cause of death and often leads to life changing disabilities in survivors. The modern management of severe TBI in children on intensive care unit focuses on preventing secondary brain injury to improve outcome. Standard neuroprotective measures are based on management of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) to optimize the cerebral blood flow and oxygenation, with the intention to avoid and minimise secondary brain injury. In this article, we review the current trends in management of severe TBI in children, detailing the general and specific measures followed to achieve the desired ICP and CPP goals. We discuss the often limited evidence for these therapeutic interventions in children, extrapolation of data from adults, and current recommendation from paediatric guidelines. We also review the recent advances in understanding the intracranial physiology and neuroprotective therapies, the current research focus on advanced and multi-modal neuromonitoring, and potential new therapeutic and prognostic targets.

Prevalence of burnout in pediatric intensivists: an observational comparison with general pediatricians.

OBJECTIVE: To study the prevalence of burnout in general pediatricians and pediatric intensivists and to evaluate factors that may be associated with this syndrome. DESIGN: Observational cohort study. SETTING: Pediatric departments of two hospitals in south Brazil. PATIENTS: Pediatric intensivists working in two regional PICUs and general pediatricians working in the outpatient departments in the same hospitals. INTERVENTION: Two researchers, blinded to the workplace of the physicians, undertook the assessment of burnout using the Maslach Burnout Inventory scale. Burnout was defined as high score in the domains for "emotional exhaustion" or "depersonalization" or a low score in the "professional accomplishment" domain. MEASUREMENTS AND MAIN RESULTS: The PICU and general pediatrician groups were similar demographically, and each had 35 recruits. Burnout was present in 50% of the study recruits and was more frequent among pediatric intensivists than general pediatricians (71% vs 29%, respectively, p < 0.01). In regard to the individual Maslach Burnout Inventory domains, the average score was higher for emotional exhaustion and depersonalization and lower for professional accomplishment in the PICU group (p < 0.01). A cluster analysis showed that pediatric intensivists were more likely to develop the burnout syndrome involving all Maslach Burnout Inventory domains. The multivariate analysis found that the odds ratio for burnout in pediatric intensivists was 5.7 (95% CI, 1.9-16.7; p < 0.01). CONCLUSIONS: Burnout is frequent among pediatric intensivists and characterized by cumulative involvement of emotional exhaustion, depersonalization, and professional accomplishment. Earlier recognition of emotional exhaustion may be important in preventing the development of a complete burnout syndrome. Improvement in workplace characteristics and measures to improve physician resilience are entirely warranted.

Prospective operationalization and feasibility of a glycemic control protocol in critically ill children.

OBJECTIVE: To evaluate the feasibility and safe operationalization of a pediatric glycemic control protocol in the setting of a general pediatric intensive care unit in a developing country. DESIGN: Prospective, observational cohort study carried out over 12 months. SETTING: Fourteen-bed pediatric intensive care unit in Brazil. PATIENTS: Children requiring mechanical ventilation with at least one organ system dysfunction were included. INTERVENTIONS: Glucose was monitored and insulin used for persistent hyperglycemia (glucose >140 mg/dL [7.8 mmol/L] for at least two observations separated by at least a 1-hr interval), with a target glucose during insulin use of 60-140 mg/dL (3.3-7.8 mmol/L). RESULTS: Out of 410 admissions, 144 children met the criteria for applying the protocol. One hundred fourteen of 144 (79%) children had at least one peak glucose level that was hyperglycemic, but only 44 (31%) children required insulin. Insulin infusion was most frequently started on day 1 (61%), with a glucose level at the time of 229 ± 79 mg/dL (12.7 ± 4.4 mmol/L). The mean glucose level after 6 hrs of insulin was 172 ± 87 mg/dL (9.6 ± 4.8 mmol/L), and the time to achieve the target glucose range was 9.5 (2-20) hrs (median [interquartile range]). The overall duration of insulin was 24.5 (10-48) hrs, and the average dose required was 0.06 ± 0.03 U/kg/hr. In the whole series, the peak glucose level was 202 ± 93 mg/dL (11.2 ± 5.2 mmol/L), with no difference between survivors and nonsurvivors. There was no difference in mortality when different glucose bands were considered and no association between glucose level and mortality. The overall rate of hypoglycemia (glucose <40 mg/dL [2.2 mmol/L]) was 8.3%, and it was more common in those receiving insulin (20% vs. 3%, p < .05). CONCLUSIONS: Hyperglycemia is frequent in critically ill children managed in a pediatric intensive care unit in a developing country. Using a glycemic control protocol, one-third of these children required insulin, but attendants should be aware of a significant risk of hypoglycemia in this setting. Based on these data, a trial to detect a 20% relative reduction in mortality (power 90%, p = .05) associated with insulin in a similar population would need to screen >10,000 patients.

Pilot safety study of low-dose vasopressin in non-septic critically ill children.

OBJECTIVE: To assess the safety of low-dose vasopressin infusion in critically ill children requiring prolonged mechanical ventilation (MV) at risk of developing sedation/analgesia-related hypotension. METHOD: Randomized pilot safety study in children expected to require MV for at least 3 days. Children received either vasopressin (0.0005 U/kg/min) or sodium chloride (0.9%) infusion for a period of 48 h. Haemodynamic variables, urine output and serum electrolytes were closely monitored and analyzed. RESULTS: Twelve children in each group had similar baseline characteristics. Vasopressin infusion was associated with an 8 mmol/L fall in serum sodium concentration (p < 0.01) and with higher incidence of hyponatraemia (8 vs. 66%, p < 0.01). In normotensive children, low-dose vasopressin also induced a reversible decrease in urine output, and acutely increased blood pressure (p < 0.01). After stopping the vasopressin there was rebound hypotension (p < 0.01). CONCLUSION: Low-dose vasopressin infusion in haemodynamically stable, but critically ill, children is associated with reduction in urine output and decreased serum sodium level, yielding a high incidence of hyponatraemia. We conclude that these effects limit further study of prophylactic vasopressin for sedation-related hypotension in a randomized controlled trial.

Ferritin levels in children with severe sepsis and septic shock.

AIM: To evaluate serum ferritin level in children with severe sepsis and septic shock and its association with mortality. METHOD: A cohort study of 36 children aged 1 month-16 years with severe sepsis or septic shock requiring intensive care was conducted. Serum ferritin levels were measured at the time of diagnosis of sepsis and a ferritin index (FI=observed serum ferritin divided by the upper limit of normal ferritin for age and gender) was calculated. RESULTS: The median age (range) of the children was 6 (2-100) months. Ferritin was <200 ng/mL in 13 children, 200-500 ng/mL in 11 children and >500 ng/mL in 12 children. The mortality associated with these groups was 23%, 9% and 58%, respectively. A ferritin>500 ng/mL was associated with a 3.2 (1.3-7.9) relative risk of death (p=0.01). FI of 1.7 was the best cutoff value for identifying those who died. In a logistic regression analysis, ferritin level and PRISM were independently associated with mortality. CONCLUSIONS: Ferritin is raised in children with septic shock and high ferritin level is associated with poorer outcome.

Controle glicêmico e terapia insulínica em sepse e doença crítica / Glycemic control and insulin therapy in sepsis and critical illness

OBJETIVO: Revisar a literatura sobre a fisiopatologia de hiperglicemia e controle glicêmico em crianças e adultos com sepse e doença crítica. FONTES DE DADOS: Pesquisa não sistemática da literatura médica através da base de dados MEDLINE usando os termos hiperglicemia, controle glicêmico, terapia insulínica intensiva, sepse e terapia intensiva. Os artigos foram selecionados de acordo com sua relevância, conforme a opinião dos autores. SÍNTESE DOS DADOS: A hiperglicemia é freqüente em crianças com doenças críticas e está associada a desfecho negativo. Em adultos, não há um consenso sobre a eficácia e segurança do controle glicêmico. Descrevemos os possíveis mecanismos envolvidos em toxicidade da glicose e os efeitos benéficos do controle glicêmico. Estudos iniciais demonstraram que o uso de insulina para atingir controle glicêmico reduziu a morbimortalidade em terapia intensiva em adultos; no entanto, estudos recentes não confirmaram esses achados. É importante destacar que o controle glicêmico está evidentemente associado a aumento da incidência de hipoglicemia. A eficácia do controle glicêmico ainda não foi estudada em crianças criticamente doentes. CONCLUSÃO: O controle glicêmico é uma nova opção terapêutica em terapia intensiva. Evidências conflitantes em adultos significam que, antes de aplicar esta abordagem em pediatria, é necessário avaliá-la em ensaio clínico.

OBJECTIVE:To review the literature about the pathophysiology of hyperglycemia and glycemic control in children and adults with sepsis and critical illness. SOURCES: Non-systematic survey of the medical literature using MEDLINE and terms hyperglycemia, glycemic control, intensive insulin therapy, sepsis and intensive care. Articles were selected according to their relevance based on the authors' opinion. SUMMARY OF THE FINDINGS: Hyperglycemia is frequent in critically ill children and it is associated with worsened outcome. In adults, there is no consensus on the efficacy and safety of glycemic control. We describe the possible mechanisms involved in glucose toxicity and the beneficial effects of glycemic control. Initial studies showed that use of insulin to achieve glycemic control reduced morbidity and mortality in adult intensive care; however, recent studies have failed to confirm these findings. Importantly, it is evident that glycemic control is associated with increased incidence of hypoglycemia. The efficacy of glycemic control has not yet been studied in critically ill children. CONCLUSION: Glycemic control is a novel therapeutic option in critical care. Conflicting evidence in adults means that before we apply this approach to pediatrics it will need to be assessed in clinical trial.

Adrenal response in children with septic shock.

OBJECTIVE: To describe the serum cortisol profile and evaluate the adrenal response in children with septic shock, and determine the influence of these factors on the outcome and mortality in this group. METHODS: Between May and November 2003, 22 children with septic shock admitted to two pediatric intensive care units in southern Brazil were followed. Adrenal function was evaluated based on the levels of cortisol measured on the occasion of the diagnosis of septic shock and on the response of serum cortisol 30 min after the administration of intravenous corticotrophin (0.5 microg/1.73m(2)). Adrenal insufficiency was defined as a baseline serum cortisol below 690 nmol/l and/or a cortisol response to corticotrophin less than 250 nmol/l. RESULTS: Adrenal insufficiency was detected in 17 patients (77.3%). All patients who died had baseline cortisol higher than 690 nmol/l. A cortisol response to corticotrophin less than 250 nmol/l was associated with a 60% mortality (RR = 7.2, 1.03-50.28). Regression analysis showed that the combination of baseline cortisol higher than 690 nmol/l and a cortisol response to corticotrophin less than 250 nmol/l were associated with mortality after correction for gender and PRISM. CONCLUSIONS: Adrenal insufficiency is a frequent finding in children with septic shock. The low-dose corticotrophin stimulation test seems to be an important tool to distinguish between a normal cortisol response to stress and evidence of adrenal failure. Mortality was significantly higher in children that failed to respond to a corticotrophin stimulation test.