Surender Rajasekaran

Therapeutic role of anakinra, an interleukin-1 receptor antagonist, in the management of secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction/macrophage activating syndrome in critically ill children*.

Objectives: Secondary hemophagocytic lymphohistiocytosis, macrophage activating syndrome, and sepsis share the same inflammatory phenotype leading often to multiple organ dysfunction syndrome needing intensive care. The goal of this article is to describe our experience with anakinra (Kineret), a recombinant interleukin-1 receptor antagonist, in decreasing the systemic inflammation. Design: Retrospective case series. Setting: The PICU at the Helen DeVos Children’s Hospital (Grand Rapids, MI). Patients: The records of eight critically ill children presumed to have secondary hemophagocytic lymphohistiocytosis at our institution between January 1, 2011, and July 31, 2012, were reviewed. Interventions: All of the patients were treated with anakinra (Kineret) and in some cases systemic corticosteroids as first-line therapy for secondary hemophagocytic lymphohistiocytosis. Measurements and Main Results: Patients had a median age of 14 years and a median Pediatric Risk of Mortality score of 11.5. Four were previously healthy and four had underlying diseases that could have made them susceptible to secondary hemophagocytic lymphohistiocytosis. Indications for PICU transfer were respiratory distress 50% (4 of 8), cardiovascular instability 37.5% (3 of 8), and chest pain (1 of 8). Five of the patients (62.5%) were mechanically ventilated and 62.5% (5 of 8) received vasoactive infusions. Inflammatory markers were assessed linearly at the start of therapy and 7 days later. Baseline C-reactive protein was 206 ± 50 mg/L (mean ± SEM) at the start of anakinra and decreased by 67.1% to 68 ± 36 mg/L (p = 0.03). Ferritin decreased by 63.8% to 3,210 ± 1,178 ng/mL (p = 0.30), and fibrinogen decreased by 42% to 158 ± 41 mg/dL (p = 0.03). Absolute neutrophil count (p = 0.38) and absolute lymphocyte count (p = 0.69) did not change significantly. No infections were attributed to anakinra therapy. One patient died long after treatment with anakinra while receiving pre-hematopoietic stem cell transplant chemotherapy. Conclusions: Anakinra could represent a promising therapeutic approach in these life-threatening disorders that are likely underdiagnosed and often difficult to treat.

The safety of propofol sedation for elective nonintubated esophagogastroduodenoscopy in pediatric patients.

Objectives: To evaluate the safety of deep sedation provided by pediatric intensivists for elective nonintubated esophagogastroduodenoscopy. Design: Retrospective observational study. Setting: The sedation program at the Helen DeVos Children’s Hospital. Patients: A 4-year retrospective analysis was done on all outpatient elective pediatric esophagogastroduodenoscopy procedures performed in an intensivist run sedation program. Safety was examined by reviewing the occurrence of minor and major adverse effects during esophagogastroduodenoscopy sedation. Interventions were studied and reported. Interventions: None. Measurements and Main results: During the study period, 12,447 sedations were performed by the pediatric sedation program for various procedures. Two thousand one hundred forty-seven patients received 2,325 sedations (18.6%) for esophagogastroduodenoscopies performed for various indications. During the same time period, 53 (one for every 40 esophagogastroduodenoscopy sedations) were screened, found unsuitable for nonintubated sedation, and referred for general anesthesia. There were 2,254 sedations with propofol, 65 methohexital, five ketamine, and one fentanyl/midazolam sedation. Propofol sedation proved safe with a 2.1% prevalence of minor adverse events and no major events. Methohexital, on the other hand, had higher rate (p < 0.001) of minor events and one patient developed an anaphylactic reaction to its use. Regression analysis showed that other sedative agents were 8.6 times more likely to be associated with complications than propofol (odds ratio, 8.6; 95% CI, 4.1–18.2; p < 0.001). Conclusions: This study demonstrates that deep sedation for elective esophagogastroduodenoscopies can be provided safely in the appropriately screened patient by nonanesthesiologist physicians in a sedation program. These data suggest that propofol is a safe and effective agent for esophagogastroduodenoscopy sedation.

Pediatric Multiple Organ Dysfunction Syndrome: Promising Therapies.

Objective: To describe the state of the science, identify knowledge gaps, and offer potential future research questions regarding promising therapies for children with multiple organ dysfunction syndrome presented during the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop on Pediatric Multiple Organ Dysfunction Syndrome (March 26–27, 2015). Data Sources: Literature review, research data, and expert opinion. Study Selection: Not applicable. Data Extraction: Moderated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities. Data Synthesis: Summary of presentations and discussion supported and supplemented by relevant literature. Conclusions: Among critically ill children, multiple organ dysfunction syndrome is relatively common and associated with significant morbidity and mortality. For outcomes to improve, effective therapies aimed at preventing and treating this condition must be discovered and rigorously evaluated. In this article, a number of potential opportunities to enhance current care are highlighted including the need for a better understanding of the pharmacokinetics and pharmacodynamics of medications, the effect of early and optimized nutrition, and the impact of effective glucose control in the setting of multiple organ dysfunction syndrome. Additionally, a handful of the promising therapies either currently being implemented or developed are described. These include extracorporeal therapies, anticytokine therapies, antitoxin treatments, antioxidant approaches, and multiple forms of exogenous steroids. For the field to advance, promising therapies and other therapies must be assessed in rigorous manner and implemented accordingly.

Circulating Progenitor Cells and Childhood Cardiovascular Disease

Circulating progenitor cells have been extensively studied in the context of heart disease in adults. In these patients, they have been demonstrated to be markers of myocardial injury and recovery as well as potential therapeutic agents. However, studies in children are much more limited. Here we review current knowledge pertaining to circulating progenitor cells in the context of childhood cardiovascular disease. Priorities for further research are also highlighted.

Lethal NARS2-related disorder associated with rapidly progressive intractable epilepsy and global brain atrophy

BACKGROUND Infantile epileptic encephalopathy is a heterogeneous condition that has been associated with variants in more than 200 genes. The variability in findings and prognosis creates challenges to making the correct diagnosis and initiating the appropriate therapy. Biallelic variants in NARS2, a mitochondrial aminoacyl-tRNA synthetase gene, were recently associated with neurodegenerative disorders that include epilepsy. METHODS We describe two infant brothers who presented with focal status epilepticus that progressed to lethal epileptic encephalopathy. We compared the cost of diagnostic laboratory evaluation for each child. Detailed NARS2 protein analysis was performed using a sequence-to-structure-to-function workflow, merging multiple homologous structures, to suggest biologic impact of the NARS2 variants. RESULTS Brain magnetic resonance imaging showed rapid progression to generalized atrophy. Extensive metabolic, infectious, chromosomal and genetic testing of the first infant failed to reach a specific diagnosis. The younger brother presented similarly. Rapid whole exome sequencing was performed revealing novel biallelic variants in NARS2. The variants c.167A>G (p.Gln56Arg) and c.631T>A (p.Phe211Ile) were confirmed in a reserved sample from the older brother. Management was then redirected toward palliative care and the child died at age nine months. CONCLUSIONS NARS2-related disorder should be considered in infants presenting with refractory seizures and rapid brain atrophy. Metabolic screening tests may be normal or yield nonspecific findings. Rapid whole exome sequencing in children with fulminant onset intractable epilepsy may minimize extensive diagnostic evaluation and aid in prognosis and medical management.

Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features

The ornithine decarboxylase 1 (ODC1) gene plays an important role in physiological and cell developmental processes including embryogenesis, organogenesis, and neoplastic cell growth. Here, we report an 32‐month‐old Caucasian female with a heterozygous de novo nonsense mutation in the ODC1 gene that leads to a premature abrogation of 14‐aa residues at the ODC protein c‐terminus. This is the first human case confirming similar symptoms observed in a transgenic ODC1 mouse model first described over 20 years ago. Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss. We here describe for the first time a new pediatric disorder that is directly linked to a de novo pathogenic variant in the ODC1 gene. The ODC1 gene mutation (c.1342 A>T) was identified by whole‐exome sequencing and confirmed by Sanger sequencing. Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls. Our autosomal dominant patient who carries this gain‐of‐function ODC1 mutation may benefit from treatment with α‐difluoromethylornithine, a well‐tolerated, U.S. Food and Drug Administration (FDA). FDA‐approved drug.

Hematology and Oncology in Critical Illness

This chapter will focus on a variety of hematologic issues pertinent to the care of critically ill children. This is an area of intense research with the pathophysiology underlying these clinical conditions becoming progressively better understood. This improved understanding has resulted in new therapeutic strategies that are being assessed in multicenter clinical trials. The chapter will begin by describing the incidence and pathophysiologic significance of anemia in the pediatric intensive care unit (PICU) providing a differential diagnosis of the many conditions that may present with anemia in this setting. The chapter will next consider disseminated intravascular coagulation (DIC) focusing on the pathophysiology of a condition that has been associated with much morbidity and mortality. The underlying conditions predisposing to DIC will be detailed as well as a number of treatment options that have been implemented in clinical trials. In addition to DIC, thrombocytopenia may be caused by a number of other clinical conditions important to the pediatric critical care provider. The clinical and prognostic significance of thrombocytopenia will be addressed and a focused differential diagnosis will be provided. Thrombotic disorders are becoming increasingly recognized in children and are a particular concern for the pediatric intensivist. The epidemiology of thromboembolism in children will be reviewed focusing on the conditions most commonly associated with these thromboses. Finally, a chapter on hematologic issues in the critically ill child would not be complete without a discussion of sickle cell disease. Acute chest syndrome, one of the most frequent complications of sickle cell disease resulting in the need for intensive care services, will be discussed in detail.

Post-operative Cardiac Care

Congenital heart disease (CHD) affects a large, ever-growing population of infants, children, adolescents and adults. The worldwide incidence of CHD is 8 per 1,000 live births and varies little from country to country where surveillance data is adequate. In the United States, the incidence is similar with 9 defects per 1,000 live births or more than 36,000 new patients with CHD per year. Cardiac defects are the most common congenital malformation, occurring in 0.8% of all live births; the incidence is much higher, approximating 5%, if lesions such as bicuspid, non-obstructive aortic valves (1.4%) and small, muscular ventricular septal defects are included (5%). The disease burden for CHD is substantial. Cardiac defects are the most lethal of all birth defects, accounting for 29% of the mortality observed during infancy. Moreover, the care for CHD is costly, estimated at

Red cell transfusions as an independent risk for mortality in critically ill children

2.6 billion per year. Lesions requiring surgical intervention in infancy are particularly costly, often exceeding coverage limits on health insurance policies: hypoplastic left heart syndrome (

CIRCULATING MICRORNA SIGNATURES AS POTENTIAL MARKERS OF TISSUE SPECIFIC STRESS IN CHILDREN UNDERGOING CARDIOPULMONARY BYPASS

199,597); persistent truncus arteriosus (