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.

Recognition and successful treatment of priapism and suspected black widow spider bite with antivenin.

Priapism, although uncommon in preadolescent children, is considered a true emergency. Envenomation by a black widow spider bite has been reported to induce priapism as a manifestation of its toxicity. Early recognition and timely administration of antivenin have been reported to be effective in relieving priapism. Clinicians who care for children need to be aware of this unusual presentation. The diagnosis is traditionally from either direct observation of a spider bite or capture of a spider. We report a case of a previously healthy 2-year-old boy who presented with severe irritability, leg cramps, and stomach ache. The diagnosis of a likely black widow spider envenomation was made on the basis of clinical suspicion and suggestive physical findings in absence of demonstrated exposure. This case highlights the importance of early recognition and successful resolution of symptoms with administration of antivenin and supportive care.

Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock.

INTRODUCTION: Adrenal insufficiency may be common in adults and children with vasopressor-resistant shock. We developed a protocolized approach to low-dose adrenocorticotropin testing and empirical low-dose glucocorticoid/mineralocorticoid supplementation in children with systemic inflammatory response syndrome and persistent hypotension following fluid resuscitation and vasopressor infusion. HYPOTHESIS: We hypothesized that absolute and relative adrenal insufficiency was common in children with systemic inflammatory response syndrome requiring vasopressor support and that steroid administration would be associated with decreased vasopressor need. METHODS: Retrospective review of pediatric patients with systemic inflammatory response syndrome and vasopressor-dependent shock receiving protocol-based adrenocorticotropin testing and low-dose steroid supplementation. The incidence of absolute and relative adrenal insufficiency was determined using several definitions. Vasopressor dose requirements were evaluated before, and following, initiation of corticosteroids. RESULTS: Seventy-eight patients met inclusion criteria for systemic inflammatory response syndrome and shock; 40 had septic shock. Median age was 84 months (range, 0.5-295). By adrenocorticotropin testing, 44 (56%) had absolute adrenal insufficiency, 39 (50%) had relative adrenal insufficiency, and 69 (88%) had either form of adrenal insufficiency. Adrenal insufficiency incidence was significantly higher in children >2 yrs (p = .0209). Therapeutic interventions included median 80-mL/kg fluid resuscitation; 65% of patients required dopamine, 58% norepinephrine, and 49% dopamine plus norepinephrine. With steroid supplementation, median dopamine dose decreased from 10 to 4 µg/kg/min at 4 hrs (p = .0001), and median dose of norepinephrine decreased from 0.175 µg/kg/min to 0.05 µg/kg/min at 4 hrs (p = .039). CONCLUSIONS: Absolute and relative adrenal insufficiency was prevalent in this cohort of children with systemic inflammatory response syndrome and vasopressor-dependent shock and increased with age. Introduction of steroids produced a significant reduction in vasopressor duration and dosage. Use of low-dose adrenocorticotropin testing may help further delineate populations who require steroid supplementation.

The bioflavonoid compound, sinupret, stimulates transepithelial chloride transport in vitro and in vivo.

OBJECTIVES/HYPOTHESIS: Dehydration of airway surface liquid (ASL) disrupts normal mucociliary clearance in sinonasal epithelium leading to chronic rhinosinusitis. Abnormal chloride (Cl(-)) transport is one mechanism that contributes to this disorder, as demonstrated by the disease cystic fibrosis. Identifying safe compounds that stimulate transepithelial Cl(-) transport is critical to improving hydration of the ASL and promoting mucociliary transport. Sinupret (Bionorica, LLC, San Clemente, CA), a combination of naturally occurring bioflavonoids, is a widely used treatment for respiratory ailments in Europe. However, the effects of Sinupret on target respiratory epithelium have yet to be fully investigated. The present study evaluated the mechanisms underlying this bioflavonoid therapeutic on transepithelial Cl(-) transport in respiratory epithelium. STUDY DESIGN: In vitro and in vivo investigation. METHODS: Well characterized murine nasal septal epithelial (MNSE) cultures, and murine nasal potential difference (NPD) techniques were used to evaluate the effects of Sinupret on Cl(-) secretion. RESULTS: The change in Sinupret-stimulated current (Delta I(SC) expressed as microA/cm(2)) in MNSE, representing Cl(-) secretion, was significantly increased when compared to controls (19.04 + or - 1.67 microA/cm(2) vs. 1.8 + or - 0.35 microA/cm(2), respectively; P = .00005). Transepithelial Cl(-) transport measured in the murine NPD in vivo assay (n = 42) was also significantly enhanced when compared to controls (-0.8 mV vs. -0.9 mV; P = .0004). Importantly, Sinupret-stimulated Cl(-) transport was substantially more robust in vivo than forskolin, a compound among the strongest known cystic fibrosis transmembrane conductance regulator activators (-3.8 mV vs. -1.65 mV; P = .01). CONCLUSIONS: Sinupret strongly activates transepithelial Cl(-) secretion through a mechanism known to hydrate the ASL of respiratory epithelium. This is one means by which the medication is likely to exert therapeutic benefit.

Use of antivenin to treat priapism after a black widow spider bite.

Black widow spider envenomation (BWSE) is commonly associated with severe abdominal pain, muscle cramping, and hypertension. Treatment is primarily symptomatic with the use of opiates and benzodiazepines. Priapism is a complication of BWSE that has only rarely been reported. We describe a 17-month-old male who developed priapism after known BWSE. His priapism did not respond to opiates or benzodiazepines, and he was treated with black widow spider antivenin. Complete detumescence followed within several hours. The patient required no additional opiates for pain and was discharged from the hospital the following day. The patient's rapid improvement after antivenin suggests its efficacy in treating BWSE-associated priapism.