Rapamycin Augments the NMDA-Mediated TNF Suppression of MRSA-Stimulated RAW264.7 Murine Macrophages

Background. Methicillin-resistant Staphylococcus aureus (MRSA) can stimulate massive cytokine release. Ketamine suppresses tumor necrosis factor (TNF) secretion by MRSA-stimulated RAW264.7 macrophages, and the mechanism likely involves N-methyl-D-aspartic acid (NMDA) receptor antagonism. The downstream effects of NMDA-mediated TNF suppression, specifically the PI3K/Akt and mTOR modulation, have not been described. Methods. RAW264.7 cells were stimulated for 18 hrs with 10(5) to 10(7) CFU/mL inocula of either of two prototypical community-acquired- (CA-) MRSA isolates, USA300 strain LAC and USA400 strain MW2. Then we added the NMDA inhibitors ketamine or 2R-amino-5-phosphonopentanoate (AP5), NMDA substrate, LY294002, and rapamycin in various combinations. Results. NMDA inhibition suppressed TNF secretion by almost a third compared to the no-ketamine control. When NMDA substrate was added, the TNF secretion increased by 10%. Addition of LY294002 suppressed TNF production by macrophages by 20%. Rapamycin exhibited a concentration-dependent TNF induction-suppression response: induction at doses of 0.1 and 1 ng/mL and suppression at 10 and 100 ng/mL. Induction of TNF was abolished when LY294002 was added and the suppression became uniform. Ketamine-induced suppression of TNF secretion was intensified 10–15% when rapamycin was added, but not when LY294002 was added. Conclusion. These findings suggest that NMDA-induced TNF suppression can be augmented by concurrent mTOR inhibition

Rapamycin Augments the NMDA-Mediated TNF Suppression of MRSA-Stimulated RAW264.7 Murine Macrophages

Background. Methicillin-resistant Staphylococcus aureus (MRSA) can stimulate massive cytokine release. Ketamine suppresses tumor necrosis factor (TNF) secretion by MRSA-stimulated RAW264.7 macrophages, and the mechanism likely involves Nmethyl-D-aspartic acid (NMDA) receptor antagonism. The downstream effects of NMDA-mediated TNF suppression, specifically the PI3K/Akt and mTOR modulation, have not been described. Methods. RAW264.7 cells were stimulated for 18 hrs with 10 5 to 10 7 CFU/mL inocula of either of two prototypical community-acquired-(CA-) MRSA isolates, USA300 strain LAC and USA400 strain MW2. Then we added the NMDA inhibitors ketamine or 2R-amino-5-phosphonopentanoate (AP5), NMDA substrate, LY294002, and rapamycin in various combinations. Results. NMDA inhibition suppressed TNF secretion by almost a third compared to the no-ketamine control. When NMDA substrate was added, the TNF secretion increased by 10%. Addition of LY294002 suppressed TNF production by macrophages by 20%. Rapamycin exhibited a concentration-dependent TNF inductionsuppression response: induction at doses of 0.1 and 1 ng/mL and suppression at 10 and 100 ng/mL. Induction of TNF was abolished when LY294002 was added and the suppression became uniform. Ketamine-induced suppression of TNF secretion was intensified 10-15% when rapamycin was added, but not when LY294002 was added. Conclusion. These findings suggest that NMDA-induced TNF suppression can be augmented by concurrent mTOR inhibition

Hemodynamic and oximetric response to sodium bicarbonate boluses in children with single ventricle parallel circulation: A retrospective, single-center study

The aim of the study was to evaluate the hemodynamic and oximetric changes in patients with parallel circulation (Norwood, hybrid, and BT-shunted) after sodium bicarbonate bolus administration. This study was a retrospective analysis of physiologic data. To eliminate confounders, sodium bicarbonate boluses concurrently administered with normal saline, 5% albumin, epinephrine boluses, blood transfusions, change in vasoactive inotropic score or mechanical circulatory support were excluded. Blood pressure, arterial oxygen saturation, heart rate (HR), and cerebral and renal near infrared spectroscopy were continuously recorded from 1-hour pre to 1-hour post each intervention. Out of 429 boluses, 293 boluses met the inclusion criteria. Measurements show an increase in blood pressure (p = 0.01) and HR (p \u3c 0.01), and a decrease in pulmonary-to-systemic flow ratio (p = 0.02) and renal oxygen extraction ratio (rOER) (p = 0.04) at some point during the first hour postbolus. The arterial oxygen saturation increased, and the rOER decreased for those patients with pre-bolus pH \u3c 7.20 and/or pre-bolus serum bicarbonate level \u3c 18 mEq/L, according to linear regression models (p \u3c 0.05). Sodium bicarbonate was associated with improvement of hemodynamic and oximetric parameters in this cohort, particularly for those patients with pH \u3c 7.20 and/or serum bicarbonate level \u3c 18 mEq/L. This finding is consistent with an increase in cardiac output due to the removal of the acidotic negative inotropic effect by the sodium bicarbonate

Hemodynamic response to fluid boluses in patients with single-ventricle parallel circulation

The purpose of this study is to assess the effect of fluid bolus in response to a hypotensive episode by evaluating high-fidelity hemodynamic data obtained from children with single-ventricle anatomy and parallel circulation. Single center, retrospective analysis of hemodynamic and oximetric data after fluid bolus administrations within the first 2 weeks post-surgery. A baseline (- 60 to - 10 min), hypotensive episode (- 10 to 0 min), and response interval (0 to 60 min) were defined to quantify the dynamics of vital signs. The responses assessed include heart rate, blood pressure, oxygen saturation, oxygen extraction ratios, and pulmonary-to-systemic flow ratios. Mixed effects models were used to account for the repeated measures over the response interval. The analysis included 67 fluid boluses. There is a decrease in heart rate and an increase in blood pressure during the response in comparison to the hypotensive time. These vitals rapidly return to the baseline values. The boluses induced a significant decrease in renal and cerebral oxygen extraction ratios, with no significant change in arterial oxygen saturation or pulmonary-to-systemic flow ratio. The type of bolus (normal saline versus albumin) did not affect the response in blood pressure. However, in comparison with albumin, normal saline had a more favorable effect on the renal and cerebral oxygen extraction ratios. This study demonstrates that fluid boluses are an effective rescue medication for hypotensive episodes in children with parallel circulation by improving hemodynamics, as well as markers of oxygen delivery. The type of bolus (normal saline versus albumin) did not affect the blood pressure response. However, normal saline had a more pronounced effect on the renal and cerebral oxygen extraction ratios than albumin

Fluid overload and AKI after the norwood operation: The correlation and characterization of routine clinical markers

The purpose of this study was to determine the correlation of different methods of assessing fluid overload and determine which metrics are associated with development of acute kidney injury (AKI) in the period immediately following Norwood palliation. This was a retrospective single-center study of Norwood patients from January 2011 through January 2021. AKI was defined using the Kidney Disease Improving Global Outcomes (KDIGO). Patients were separated into two groups: those with AKI and those without. A logistic regression analysis was conducted with AKI at any point in the study period as the dependent variable and clinical and laboratory data as independent variables. Analysis was conducted as a stepwise regression. The coefficients from the logistic regression were then used to develop a cumulative AKI risk score. Spearman correlations were conducted to analyze the correlation of fluid markers. 116 patients were included, and 49 (42.4%) developed AKI. The duration of open chest, duration of mechanical ventilation, need for dialysis, need for extracorporeal membrane oxygenation, and inpatient mortality were associated with AKI (p ≤ 0.05). Stepwise logistic regression demonstrated the following significant independent associations AKI: age at Norwood in days (p \u3c 0.01), blood urea nitrogen (p \u3c 0.01), central venous pressure (p = 0.04), and renal oxygen extraction ratio (p \u3c 0.01). The area under the receiver operating characteristic curve for the logistic regression was 0.74. The fluid markers had weak R-value. Urea, central venous pressure, and renal oxygen extraction ratio are associated with AKI after the Norwood operation. Common clinical metrics used to assess fluid overload are poorly correlated with each other for postoperative Norwood patients

The use of neutrophil-lymphocyte ratio for the prediction of refractory disease and coronary artery lesions in patients with Kawasaki disease

Background: Kawasaki disease is a vasculitis that can lead to cardiac complications, including coronary artery disease and cardiogenic shock. Various scoring systems have been developed to determine those that will be refractory to routine intravenous immunoglobulin therapy or develop coronary artery disease. The objective of this study was to determine if the neutrophil-lymphocyte ratio could predict refractory disease and coronary artery lesions in patients with Kawasaki disease. Methods: A systematic review of the literature was performed to identify manuscripts describing comparisons of neutrophil-lymphocyte ratio between those who had refractory disease and those who did not, and between those who developed coronary artery lesions and those who did not. Mean difference was compared between groups. Areas under the curve were utilised to determine the pooled area under the curve. Results: 12 studies with 5593 patients were included in the final analyses of neutrophil-lymphocyte ratio for the prediction of refractory disease. Neutrophil-lymphocyte ratio before therapy was higher in refractory disease with a mean difference of 2.55 (p \u3c 0.01) and pooled area under the curve of 0.724. Neutrophil-lymphocyte ratio after therapy was higher in refractory disease with a mean difference of 1.42 (p \u3c 0.01) and pooled area under the curve for of 0.803. Five studies with 1690 patients were included in the final analyses of neutrophil-lymphocyte ratio for the prediction of coronary artery lesions. Neutrophil-lymphocyte ratio before therapy was higher in coronary artery lesions with a mean difference of 0.65 (p \u3c 0.01). Conclusion: The use of neutrophil-lymphocyte ratio may help physicians in the identification of patients at risk of refractory disease and coronary artery lesions in patients with Kawasaki disease

Xanthine derivatives for kidney protection in the critically ill pediatric population: A systematic review

Different types of diuretics have been used to minimize fluid overload after resuscitation. This meta-analysis determined the effects of xanthine derivatives on creatinine, creatinine clearance, and urine output. Studies included data from pediatric patients, whoused theophylline or aminophylline, and included pre- and postxanthine data for at least one of the outcomes of interest. A total of 13 studies with 198 patients were included in the pooled analyses. The study recorded data prior, and a mean of 36 hours after xanthine administration. This meta-analysis demonstrates that xanthine derivatives in critically ill children, using a dose of approximately5 mg/kg, lead to a statistically significant increase in creatinine clearance and urine output without significantly altering serum creatinine. Xanthine derivatives may be beneficial for fluid management in critically ill children. Further studies are warranted assessing the association with additional clinical outcomes