Association Between Hyponatremia and Maintenance Intravenous Solutions in Critically Ill Children: A Retrospective Observational Study.

Objetive: We sought to determine the association between maintenance intravenous solutions and the presence of hyponatremia in children in pediatric intensive care (PICU). Materials and Methods: An analytical observational study in children hospitalized in the PICU between January 2015 and December 2018. Patients who received maintenance fluids within the first 48 h after admission and who had at least two serum sodium levels drawn during this time were included. Measurements and Main Results: A total of 1,668 patients were admitted to the PICU during the study period, 503 of whom met the inclusion criteria. The median age was 24 months (IQR 8-96) and 50.9% were female. Altogether, 24.1% of the children developed hyponatremia; it was more frequent in those who received hypotonic solutions (63 vs. 37%; OR 1.41 95% CI 0.92, 2.15 p = 0.106), who also had a longer hospital stay (20 vs. 14 days, difference in means 8 days, 95% CI 2.67, 13.3, p = 0.001). Children who received loop diuretics and those who were post-operative had a greater risk of developing hyponatremia if they received hypotonic solutions (aOR 2.1 95% CI 1.41, 3.0, p = 0.000). Those with balanced isotonic solutions had a lower risk of developing hyponatremia (aOR 0.59 95% CI 0.35, 0.99, p = 0.004) and hyperchloremia (aOR 0.51 95% CI 0.34, 0.77, p = 0.000), adjusted for disease severity. A greater risk of death was found in the group with severe hyponatremia <130 mEq/L (aOR 9.75 95% CI 1.64-58.15; p = 0.01). Conclusions: Hyponatremia associated with the use of hypotonic maintenance solutions occurs in one out of four children in intensive care. The use of these solutions is associated with a longer hospital stay, and the main risk groups are post-operative patients and those who receive loop diuretics. Clinical studies are needed to determine which maintenance solutions have the greatest efficacy and safety in critically ill children.

Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity.

Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.

Group A streptococcal vaccines: paving a path for accelerated development.

Group A streptococci (GAS) are important causes of morbidity and mortality worldwide. These organisms cause a wide spectrum of disease, ranging from uncomplicated sore throat to invasive, life-threatening infections, as well as immune complications such as acute rheumatic fever (ARF), rheumatic heart disease (RHD) and acute post-streptococcal glomerulonephritis (APSGN). Vaccine prevention of GAS infections and their immunological complications has been a goal of researchers for decades. Several vaccine candidates against GAS infection are in various stages of pre-clinical and clinical development, including M protein-based vaccines (N-terminal vaccine candidates and M protein conserved region vaccines), and non-M protein vaccine candidates representing conserved GAS antigens. Some of the obstacles to GAS vaccine development are related to the complexity of the global epidemiology of GAS infections, the limitation in the criteria for selection of antigens to include in combination vaccines as well as the issues around autoimmunity and vaccine safety, among others. Overcoming these obstacles will require collaborative efforts to develop innovative strategies that address key steps in the pre-clinical and clinical development process, as well as clearly defining the global burden of GAS diseases and the molecular epidemiology of infections. Specific recommendations are presented for an accelerated plan leading to the introduction of a broadly protective vaccine designed for deployment in low-, middle-, and high-income countries.

Fetal-placental inflammation, but not adrenal activation, is associated with extreme preterm delivery.

OBJECTIVE: Spontaneous labor at term involves the activation of placental corticotropin-releasing hormone and the fetal adrenal axis, but the basis for extreme preterm labor is unknown. Our objective was to determine whether placental corticotropin-releasing hormone is activated in extreme preterm labor. STUDY DESIGN: One thousand five hundred six mothers delivering at less than 28 weeks' gestation were enrolled. Each mother/infant pair was assigned to the category that described the primary reason for hospitalization. Observers who had no knowledge of patient categorization assessed placenta microbiology, histology, and corticotropin-releasing hormone expression. These were correlated with the primary reason for hospitalization. RESULTS: Among infants delivered at less than 28 weeks' gestation, spontaneous (vs induced) delivery was associated with less placental corticotropin-releasing hormone expression and more frequent signs of placental inflammation and infection. CONCLUSION: Inflammation and infection, rather than premature activation of the fetal adrenal axis, should be the major focus of research to prevent extremely preterm human birth.

Effect of epinephrine deficiency on cold tolerance and on brown adipose tissue.

Catecholamines are involved in thermogenesis. We investigated the specific role of epinephrine in regulation of temperature homeostasis in mice. We subjected adult wildtype (WT) and phenylethanolamine N-methyl transferase knock out mice (Pnmt(-/-)) lacking epinephrine to cold for 24h. Body temperature and thyroid hormone levels were not different between WT and Pnmt(-/-) mice. Although temperature was normal in Pnmt(-/-) mice, the brown fat response to cold was abnormal with no increase in Ucp-1 or Pgc-1alpha mRNA levels (but with an exaggerated cold-induced lipid loss from the tissue). Our results show that epinephrine may have a role in brown fat mitochondrial uncoupling through regulation of Ucp-1 and Pgc-1alpha, although this is not required to maintain a normal temperature during acute cold exposure. We conclude that epinephrine may have an important role in induction of Ucp-1 and Pgc-1alpha gene expression during cold stress.

Glucocorticoid treatment--effect on adrenal medullary catecholamine production.

Glucocorticoid and epinephrine are important stress hormones secreted from the adrenal gland during critical illness. Adrenal glucocorticoid stimulates phenylethanolamine N-methyltransferase (PNMT) to convert norepinephrine to epinephrine in the adrenal medulla. Glucocorticoid is sometimes used in catecholamine-resistant septic shock in critically ill patients. By suppressing adrenal glucocorticoid production, glucocorticoid therapy might also reduce the secretion of epinephrine during stress. To investigate this, we used a mouse model subjected to glucocorticoid therapy under basal conditions (experiment 1) and during stress (experiment 2). In experiment 1, pellets containing 0% to 8% dexamethasone were implanted subcutaneously in mice for 4 weeks. In experiment 2, animals received 14 days of intraperitoneal injections of normal saline, low- or high-dose dexamethasone, followed by 2 h of restraint. We found that in experiment 1, adrenal corticosterone did not differ with dexamethasone treatment. Phenylethanolamine N-methyltransferase messenger RNA levels and adrenal catecholamines were highest in the 8% dexamethasone group. Compared with experiment 1, restrained control mice in experiment 2 had high adrenal corticosterone, which decreased with dexamethasone. Phenylethanolamine N-methyltransferase messenger RNA content doubled with restraint but decreased with dexamethasone treatment. As in experiment 1, adrenal catecholamine content increased significantly with dexamethasone treatment. We conclude that without stress, when adrenocorticotropic hormone is low, high doses of exogenous dexamethasone stimulate PNMT and catecholamine synthesis, likely independently of adrenal corticosterone concentration. After stress, adrenocorticotropic hormone levels are elevated, and exogenous dexamethasone suppresses endogenous corticosterone and PNMT production. Nonetheless, catecholamines increase, possibly due to direct neural stimulation, which may override the hormonal regulation of epinephrine synthesis during stress.