Choice of maintenance intravenous fluids among paediatric residents in Canada.

BACKGROUND: Recent literature and guidelines support routine use of isotonic intravenous (IV) fluids for maintenance therapy in hospitalized infants and children. Current prescribing practices are unknown. OBJECTIVE: To elicit paediatric residents' choice of maintenance IV fluids, particularly with regard to tonicity, in a variety of clinical scenarios and patient ages. We hypothesized that residents would choose isotonic fluids in most cases, but there would be substantially more variability in fluid choice in the neonatal age group. METHODS: An Internet-based survey was e-mailed to trainees in the 17 paediatric residency programs across Canada, via the Canadian Paediatric Program Directors. The survey instrument included questions related to training, followed by a series of questions eliciting choice of IV fluid in a variety of clinical situations. RESULTS: A total of 147 survey responses were submitted (22% response rate). Isotonic solutions were selected by >75% across all clinical scenarios involving infants and children. Very hypotonic fluids were seldom chosen. There was more variability in fluid choice in neonates, with evidence of significant differences in fluid tonicity based on senior versus junior resident status and geographical location. CONCLUSIONS: Results imply a predominance of isotonic fluid use in infants and children, suggesting that clinical practice has changed in response to risk of hyponatremia with hypotonic IV fluids. As hypothesized, there was more variability with respect to choice of maintenance fluids in neonates. This likely reflects a paucity of guidance in an age group with unique physiologic factors affecting fluid and electrolyte status.

CD36 and TLR interactions in inflammation and phagocytosis: implications for malaria.

CD36 participates in macrophage internalization of a variety of particles, and has been implicated in inflammatory responses to many of these ligands. To what extent CD36 cooperates with other receptors in mediating these processes remains unclear. Because CD36 has been shown to cooperate with TLR2, we investigated the roles and interactions of CD36 and TLRs in inflammation and phagocytosis. Using Ab-induced endocytosis of CD36 and phagocytosis of erythrocytes displaying Abs to CD36, we show that selective engagement and internalization of this receptor did not lead to proinflammatory cytokine production by primary human and murine macrophages. In addition, CD36-mediated phagocytosis of Plasmodium falciparum malaria-parasitized erythrocytes (PEs), which contain parasite components that activate TLRs, also failed to induce cytokine secretion from primary macrophages. Furthermore, we demonstrate that CD36-mediated internalization did not require TLR2 or the TLR-signaling molecule IRAK4. However, macrophage pretreatment with TLR agonists markedly stimulated particle uptake via CD36. Similarly, PE uptake was unaffected by TLR deficiency, but in wild-type cells was increased by pretreatment with purified P. falciparum glycosylphosphatidylinositols, which activate TLR2. Our findings indicate that CD36 must cooperate with other receptors such as TLRs to participate in cytokine responses. Although purified P. falciparum components activate TLRs, CD36-mediated internalization of intact PEs is not inflammatory. Further, CD36 mediates internalization of particles, including PEs, independently of TLR signaling, but can functionally cooperate with TLRs to enhance internalization.

Statins fail to improve outcome in experimental cerebral malaria and potentiate Toll-like receptor-mediated cytokine production by murine macrophages.

Cerebral malaria is responsible for a large proportion of the estimated one million deaths caused by Plasmodium falciparum malaria annually. This disease is associated with excessive pro-inflammatory cytokine production resulting from dysregulated host responses to infection. On the basis of reports indicating potent activity against host-mediated inflammatory disorders such as sepsis, we examined the activity of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) on malaria-associated inflammation in vivo and in vitro. Simvastatin failed to improve survival or alter parasitemia in C57BL/6 mice infected with Plasmodium berghei ANKA, an experimental model of cerebral malaria. In vitro statin treatment potentiated production of tumor necrosis factor and interleukin-6 by murine peritoneal macrophages in response to P. falciparum glycosylphosphatidyl inositol, a Toll-like receptor 2 (TLR2) ligand. Statin treatment also potentiated pro-inflammatory cytokine production stimulated by a panel of TLR2 and TLR4 ligands. Our results indicate that statins fail to confer protection in experimental cerebral malaria and potentiate TLR-mediated pro-inflammatory cytokine production by primary murine macrophages.

Failure of two distinct anti-apoptotic approaches to reduce mortality in experimental cerebral malaria.

Cerebral malaria is responsible for a high proportion of mortality in human Plasmodium falciparum infection. Previous studies have reported the presence of apoptosis in endothelial cells, astrocytes, neurons, and glial cells in experimental murine cerebral malaria caused by infection with Plasmodium berghei ANKA. Using this model, we tested two strategies, which have been shown to improve survival in murine models of sepsis: 1) treatment with z-VAD, a pancaspase inhibitor; and 2) overexpression of Bcl-2 using transgenic mice expressing human Bcl-2 (which prevents the release of apoptotic mediators from the mitochondria) from a myeloid cell promoter. Neither of these anti-apoptotic strategies, previously shown to provide therapeutic benefit in sepsis, improved survival in experimental cerebral malaria.