Single Center Outcomes of Status Epilepticus at a Paediatric Intensive Care Unit.

BACKGROUND: Status epilepticus (SE) is a frequent admission diagnosis to paediatric intensive care units (PICUs) and is associated with variable outcomes. We have audited our experience of patients presenting in SE at a Canadian PICU to determine unfavorable outcome variables. METHODS: Charts of patients <18 years of age presenting in SE to a tertiary care PICU over a 10-year period were audited. Data were analyzed at three care-points: transport, the emergency department (ED) and the PICU. Patient outcome before PICU discharge was categorized as "favorable" for return to pre-status functioning level or "unfavorable" for new deficit/death. Student's t-test and the Kruskal-Wallis test were used for analysis of normal and skewed continuous variables, respectively, and either Chi-square test or Fisher's exact test for categorical variables. RESULTS: 189 patients (54% males) were identified with a median age of 1.9 years. Idiopathic SE had the highest incidence; infectious/vascular etiologies were associated with more unfavorable outcomes. Progression to refractory SE in the ED had a higher incidence of death (p<0.05). Patients with an unfavorable outcome had a higher incidence of apnea during transport (p=0.01), longer hospital stays (p<0.05), need for therapeutic coma (p=0.01), longer duration of therapeutic coma (p<0.05), need for mechanical ventilation (p<0.05), and recurrent or refractory seizures during inpatient stay (p<0.05). Multivariate analysis of unfavorable outcomes of patients in SE presenting to the PICU included renal failure, cerebral edema, apnea during transport, refractory seizures, and recurrent seizures. CONCLUSIONS: Refractory seizures in children presenting with SE are associated with worsened outcomes in the PICU.

Peripheral vascular access as exclusive access mode in pediatric intensive care unit.

Introduction: The type of vascular access (central or peripheral) in pediatric critical care depends on several factors, including the duration of treatment, the properties of the medication (osmolarity or vesicant), and the need for central pressure monitoring. The utilization of peripheral intravascular catheters (PIVCs) has shown a notable increase in the number of patients being treated. Extended dwell or midline catheters are another peripheral access option in addition to PIVCs. However, there are currently no established guidelines on their placement. Objectives: The aim of this study is to estimate the duration of dwell time for PIVCs, analyze the specific parameters affecting it, and develop recommendations for switching to extended dwell and midline catheter placement as an alternative to peripheral access. Methods: The study enrolled patients aged 0-18 years admitted to the pediatric intensive care unit (PICU) for over 24 h and managed with peripheral access only over 2 years (2019-2021). Measurements and main results: A total of 484 patients met the specified criteria. Patients who had peripheral access exhibited a lower PRISM score and a shorter length of stay in the PICU, with mean values of 18 (SD: 8.5) and 9.5 (SD: 6.4) days, respectively, compared with patients who had central access with mean values of 8.9 (SD: 5.9) and 5.7 (SD: 3.6) days, respectively. The PIVC dwell time was found to be 50.1 h (SD: 65.3) and required an average of 1.6 insertion attempts. Patients with three or more insertions exhibited an increased odds ratio of 5.2 (95% CI: 3.1-8.5) for receiving an extended dwell or midline insertion. Increased dwell time was associated with female gender, 59.5 h (P < 0.001), first attempt insertion, 53.5 h (P < 0.001), use of 24 Ga bore, 56.3 h (P = 0.04), left-sided insertions, 54.9 (P = 0.07), less agitation, 54.8 h (P = 0.02), and less edema, 61.6 (P < 0.001). Decreased dwell time was associated with the use of vancomycin infusion at 24.2 h (P < 0.001) and blood transfusions at 29.3 h (P < 0.001). Conclusions: Extended catheters last longer than PIVCs in PICU patients. Extended catheter placement requires consideration of the length of treatment, as well as the overall body edema, the level of the patient's restlessness, and the need for vancomycin infusion or blood transfusions, as these factors reduce PIVC dwell time and expose the patients to painful insertions. For such cases, an extended dwell catheter may be a better option, even if the projected treatment time is less than 6 days.

Regulation and function of the two-pore-domain (K2P) potassium channel Trek-1 in alveolar epithelial cells.

Hyperoxia can lead to a myriad of deleterious effects in the lung including epithelial damage and diffuse inflammation. The specific mechanisms by which hyperoxia promotes these pathological changes are not completely understood. Activation of ion channels has been proposed as one of the mechanisms required for cell activation and mediator secretion. The two-pore-domain K(+) channel (K2P) Trek-1 has recently been described in lung epithelial cells, but its function remains elusive. In this study we hypothesized that hyperoxia affects expression of Trek-1 in alveolar epithelial cells and that Trek-1 is involved in regulation of cell proliferation and cytokine secretion. We found gene expression of several K2P channels in mouse alveolar epithelial cells (MLE-12), and expression of Trek-1 was significantly downregulated in cultured cells and lungs of mice exposed to hyperoxia. Similarly, proliferation cell nuclear antigen (PCNA) and Cyclin D1 expression were downregulated by exposure to hyperoxia. We developed an MLE-12 cell line deficient in Trek-1 expression using shRNA and found that Trek-1 deficiency resulted in increased cell proliferation and upregulation of PCNA but not Cyclin D1. Furthermore, IL-6 and regulated on activation normal T-expressed and presumably secreted (RANTES) secretion was decreased in Trek-1-deficient cells, whereas release of monocyte chemoattractant protein-1 was increased. Release of KC/IL-8 was not affected by Trek-1 deficiency. Overall, deficiency of Trek-1 had a more pronounced effect on mediator secretion than exposure to hyperoxia. This is the first report suggesting that the K(+) channel Trek-1 could be involved in regulation of alveolar epithelial cell proliferation and cytokine secretion, but a direct association with hyperoxia-induced changes in Trek-1 levels remains elusive.

Evidence Limitations in Determining Sexually Dimorphic Outcomes in Pediatric Post-Traumatic Hypopituitarism and the Path Forward.

Neuroendocrine dysfunction can occur as a consequence of traumatic brain injury (TBI), and disruptions to the hypothalamic-pituitary axis can be especially consequential to children. The purpose of our review is to summarize current literature relevant to studying sex differences in pediatric post-traumatic hypopituitarism (PTHP). Our understanding of incidence, time course, and impact is constrained by studies which are primarily small, are disadvantaged by significant methodological challenges, and have investigated limited temporal windows. Because hormonal changes underpin the basis of growth and development, the timing of injury and PTHP testing with respect to pubertal stage gains particular importance. Reciprocal relationships among neuroendocrine function, TBI, adverse childhood events, and physiological, psychological and cognitive sequelae are underconsidered influencers of sexually dimorphic outcomes. In light of the tremendous heterogeneity in this body of literature, we conclude with the common path upon which we must collectively arrive in order to make progress in understanding PTHP.

Gene expression profiling of childhood adrenocortical tumors.

Pediatric adrenocortical tumors (ACT) are rare and often fatal malignancies; little is known regarding their etiology and biology. To provide additional insight into the nature of ACT, we determined the gene expression profiles of 24 pediatric tumors (five adenomas, 18 carcinomas, and one undetermined) and seven normal adrenal glands. Distinct patterns of gene expression, validated by quantitative real-time PCR and Western blot analysis, were identified that distinguish normal adrenal cortex from tumor. Differences in gene expression were also identified between adrenocortical adenomas and carcinomas. In addition, pediatric adrenocortical carcinomas were found to share similar patterns of gene expression when compared with those published for adult ACT. This study represents the first microarray analysis of childhood ACT. Our findings lay the groundwork for establishing gene expression profiles that may aid in the diagnosis and prognosis of pediatric ACT, and in the identification of signaling pathways that contribute to this disease.

Identification of a novel germ line variant hotspot mutant p53-R175L in pediatric adrenal cortical carcinoma.

Hotspot mutations in the p53 tumor suppressor gene result in the disruption of DNA contact points or alter the overall structure of the protein to prevent DNA binding. When inherited, hotspot mutants are associated with Li-Fraumeni syndrome (LFS), a familial cancer predisposition. One of the most common hotspot mutations occurs at codon 175, resulting in an arginine to histidine substitution. We have identified a novel germ line variant of the 175 mutant (Arg to Leu; R175L) in a pediatric patient who developed adrenal cortical carcinoma. Surprisingly, the family is not tumor prone or associated with LFS. In vitro, the R175L mutant displayed an attenuated tumor suppressor activity in the regulation of transcription, colony formation, and apoptosis when compared with wild-type p53 and the R175H mutant. These findings suggest that p53-R175L retains sufficient activity to suppress LFS, but not adrenal cortical carcinoma. Therefore, not all hotspot mutants are functionally equivalent and the biochemical nature of the mutant may significantly influence clinical outcome. The implications of these results for genetic counseling are discussed.

Nephroblastoma overexpressed/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 (NOV/CCN3), a selective adrenocortical cell proapoptotic factor, is down-regulated in childhood adrenocortical tumors.

CONTEXT: Childhood adrenocortical tumors (ACTs) have a fetal adrenal phenotype and overexpress steroidogenic factor-1 (SF-1). Nephroblastoma overexpressed (NOV)/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 mRNA is significantly down-regulated in childhood ACTs. OBJECTIVE: The objective of the study was to measure NOV protein levels in childhood ACTs and characterize NOV expression regulation and biological function in human adrenocortical cells. DESIGN AND SETTING: Protein extracts from ACT and normal adrenal cortex samples, human adrenocortical carcinoma H295R, primary adrenocortical tumors and fetal adrenal cultures, tissue culture supernatants, and cell lysates from H295R cells overexpressing SF-1 in an inducible fashion were used. MAIN OUTCOME MEASURES: NOV protein levels were measured by enzyme-linked immunoassay and immunoblot. Transient transfection assays were used to study the activity of NOV promoter. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, caspase assays, and flow cytometry were used to assess the proapoptotic activity of NOV on cells in culture. RESULTS: NOV mRNA and protein expression is lower in childhood ACTs than in normal adrenal cortex. No significant difference was observed between adenomas and carcinomas. SF-1 overexpression down-regulates NOV at the transcriptional level. NOV has a selective proapoptotic activity toward human adrenocortical cells. The C-terminal domain of NOV is responsible for its proapoptotic effect. NOV protein is expressed in DAX-1-positive human fetal adrenal cells. CONCLUSIONS: NOV is a selective proapoptotic factor for human adrenocortical cells. Reduced expression of NOV in ACTs may play an important role in the process of childhood ACT tumorigenesis, accounting at least in part for the defect of apoptotic regression of the fetal adrenal that has been proposed to be responsible for tumor formation.

Transpyloric Feeding Tube Placement Using Electromagnetic Placement Device in Children.

BACKGROUND: Transpyloric feeding tubes (TPT) are often recommended in critically ill children. Blind tube placement, however, can be difficult, be time-consuming, and incur multiple radiation exposures. An electromagnetic device (EMD) is available for confirmation of successful placement of TPTs. We conducted a retrospective cohort study to evaluate the efficacy of an EMD for TPT placement in children and determine its impact on placement success, radiation exposure, confirmation time, and cost for tube placement compared with traditional blind TPT placement. MATERIALS AND METHODS: Retrospective data were collected in patients receiving a TPT before (pre-EMD group) and after implementation of an EMD (EMD group). RESULTS: Need for radiographic exposure decreased significantly in the EMD group (n = 40) compared with the pre-EMD group (n = 38) (0.6 vs 1.6 x-rays, P < .001). TPTs were placed and confirmed without abdominal x-ray in 21 of 40 patients in the EMD group. There were no serious adverse events such as misplacement into the lung or pneumothorax or perforation injury of the stomach. Successful tube confirmation took a significantly shorter time in the EMD group than in the pre-EMD group (1.45 vs 4.59 hours, P < .0001). There was an estimated cost savings of $245.10 per placement associated with decreased x-ray and fluoroscopy. CONCLUSION: The use of an EMD in children significantly decreased radiation exposure and confirmation time while maintaining TPT placement success. The use of an EMD can potentially offer large cost savings. Elimination of abdominal x-ray with EMD during TPT placement was achieved without any serious complications in approximately half of the children.

Clinical risk factors for central line-associated venous thrombosis in children.

BACKGROUND: Identifying risk factors related to central venous line (CVL) placement could potentially minimize central line-associated venous thrombosis (CLAVT). We sought to identify the clinical factors associated with CLAVT in children. METHODS: Over a 3-year period, 3733 CVLs were placed at a tertiary-care children's hospital. Data were extracted from the electronic medical records of patients with clinical signs and symptoms of venous thromboembolism, diagnosed using Doppler ultrasonography and/or echocardiography. Statistical analyses examined differences in CLAVT occurrence between groups based on patient and CVL characteristics (type, brand, placement site, and hospital unit). RESULTS: Femoral CVL placement was associated with greater risk for developing CLAVT (OR 11.1, 95% CI 3.9-31.6, p < 0.0001). CVLs placed in the NICU were also associated with increased CLAVT occurrence (OR 5.3, 95% CI 2.1-13.2, p = 0.0003). CVL brand was also significantly associated with risk of CLAVT events. CONCLUSION: Retrospective analyses identified femoral CVL placement and catheter type as independent risk factors for CLAVT, suggesting increased risks due to mechanical reasons. Placement of CVLs in the NICU also led to an increased risk of CLAVT, suggesting that small infants are at increased risk of thrombotic events. Alternative strategies for CVL placement, thromboprophylaxis, and earlier diagnosis may be important for reducing CLAVT events.