Cangrelor Dosing and Monitoring for Prevention of Acute Systemic-to-Pulmonary Artery Shunt Thrombosis in Neonates.

OBJECTIVE: Systemic-to-pulmonary artery shunts are amongst the most common palliative procedures performed in neonates with congenital heart defects. These procedures require immediate postoperative thromboprophylaxis to prevent life-threatening shunt thrombosis. The novel use of intravenous P2Y12 platelet receptor antagonists has led to a need for dosing recommendations and monitoring. This study aims to determine cangrelor dosing in neonates through laboratory assessment of P2Y12 receptor reactivity and adverse events. METHODS: Observational retrospective cohort study on the use of cangrelor for thromboprophylaxis in the immediate postoperative period of neonates undergoing placement of systemic-to-pulmonary artery shunts in a tertiary children's hospital from March 2020 to March 2021. RESULTS: Ten neonates receiving cangrelor post systemic-to-pulmonary artery shunt placement were included in the study. Median age and weight were 4 days (IQR, 2.75-5.25) and 3.49 kg (IQR, 3.1-3.75), respectively. Five (50%) patients received a 3.5-mm shunt, while the remaining patients received a 4-mm shunt. For thrombin inhibition, 5 (50%) patients received heparin and 5 (50%) received bivalirudin. Median cangrelor dose was 0.1 mcg/kg/min (IQR, 0.1-0.1). Median achieved P2Y12 reaction units (PRU) at this cangrelor dose was 127.5 (IQR, 72.5-173.75). No shunt thrombosis occurred in these patients; however, there was 1 minor hemorrhagic event. CONCLUSIONS: Our study suggests that a cangrelor dose of 0.1 mcg/kg/min is associated with therapeutic PRU and prevents shunt thrombosis in neonates post systemic-to-pulmonary artery shunt, with minimal hemorrhagic complications.

Use of Aminophylline to Reverse Acute Kidney Injury in Pediatric Critical Care Patients.

OBJECTIVE: Acute kidney injury (AKI) is a complication encountered in 18% to 51% of pediatric critical care patients admitted for treatment of other primary diagnoses and is an independent risk factor for increased morbidity and mortality. Aminophylline has shown promise as a medication to treat AKI, but published studies have shown conflicting results. Our study seeks to assess the reversal of AKI following the administration of aminophylline in critically ill pediatric patients. METHODS: We performed a single-institution retrospective chart review of pediatric inpatients who were diagnosed with AKI and subsequently treated with non-continuous dose aminophylline between January 2016 and December 2018. Data were collected beginning 2 days prior to the initial dose of aminophylline through completion of the 5-day aminophylline course. RESULTS: Nineteen therapies among 17 patients were included in analysis. Twelve of the therapies resulted in resolution of AKI during the study period. We observed urine output increase of 19% (p = 0.0063) on the day following initiation of aminophylline therapy in the subset of patients whose AKI resolved. Trends toward decreased serum creatinine and lower inotropic support were also noted. CONCLUSIONS: Based on these findings, aminophylline could be considered a potentially effective medication for use as rescue therapy in critically ill children with AKI. Limitations include small study population and retrospective nature. Further research in this area with a larger study population and a randomized control trial would allow for better characterization of the efficacy of aminophylline in reversal of AKI.

Effect of thyroid hormone on cardiac function following orthotopic heart transplantation in piglets.

Studies in adult HT have demonstrated improved cardiac function in the recipient following administration of T3 to the donor. The purpose of this experiment was to assess the effects of T3 on the function of the immature donor heart following HT in a piglet model. A total of 32 piglets were divided into 16 donors and 16 recipients. Following creation of brain death, half of the donor piglets were randomized to receive three doses of T3 (0.2 µg/kg) along with hydrocortisone (1 mg/kg). The donor hearts were then transplanted into the recipient piglets on CPB. Duration of survival off CPB, inotrope score, and EF of heart following CPB were evaluated. There were no differences between the two groups in age, weight, pre-brain death EF, T3 levels, and CPB times. Post-CPB survival times were inversely related to the ischemic times in both groups (Pearson r=-0.80, P<.001), and this relationship was not influenced by T3. There was no difference in inotrope score, EF, or biochemical assessment between the two groups. Administration of T3 in combination with hydrocortisone to the brain-dead donor confers no beneficial effect on myocardial function or survival following HT in a piglet model.

Bumetanide continuous infusions in critically ill pediatric patients.

OBJECTIVE: Limited data exist for the use of bumetanide continuous infusions in children. The purpose of this study was to evaluate the use of bumetanide continuous infusions in critically ill pediatric patients. DESIGN: This study was an institutional review board approved, single-center, retrospective chart review of 95 patients. Dosing practices were described by rate (µg/kg/hr), duration (days), and previous diuretic use. Efficacy, determined by ability to achieve negative fluid balance and time to reach negative fluid balance, was assessed at 12, 24, and 48 hours. Safety was evaluated based on prevalence of adverse drug reactions. Adverse drug reactions were predefined as serum potassium concentration less than 3 mEq/L, serum chloride concentration less than 90 mEq/L, serum carbon dioxide concentration greater than 35 mEq/L, and serum creatinine increased greater than 1.5 times baseline and above patient-specific normal range. SETTING: Le Bonheur Children's Hospital, Memphis, TN. PATIENTS: Critically ill patients who are 18 years old or younger and received bumetanide continuous infusions. A total of 95 patients were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean dose of bumetanide was 5.7 ± 2.2 µg/kg/hr (1-10 µg/kg/hr) with a median duration of 3.3 days (0.3-18.5). The total percentage of patients achieving negative fluid balance by 48 hours was 76% with 54% of patients reaching negative fluid balance within 12 hours. CONCLUSIONS: This study showed that a bumetanide dose of 5.7 µg/kg/hr was effective in achieving negative fluid balance in the majority of critically ill pediatric patients. Additionally, bumetanide appears to be a safe loop diuretic for use as a continuous infusion at the doses described in critically ill pediatric patients.

Double-blind, placebo-controlled pilot randomized trial of methylprednisolone infusion in pediatric acute respiratory distress syndrome.

OBJECTIVE: Low-dose methylprednisolone therapy in adults with early acute respiratory distress syndrome reduces systemic inflammation, duration of mechanical ventilation, and ICU length of stay. We report a pilot randomized trial of glucocorticoid treatment in early pediatric acute respiratory distress syndrome. DESIGN: Double-blind, placebo-controlled randomized clinical trial. SETTING: Le Bonheur Children's Hospital, Memphis, TN. PATIENTS: Children (0-18 yr) with acute respiratory distress syndrome undergoing mechanical ventilation. INTERVENTIONS: Patients were randomly assigned to steroid or placebo groups within 72 hours of intubation. IV methylprednisolone administered as loading dose (2 mg/kg) and continuous infusions (1 mg/kg/d) on days 1-7 and then tapered over days 8-14. Both groups were ventilated according to the Acute Respiratory Distress Syndrome Network protocol modified for children. Daily surveillance was performed for adverse effects. MEASUREMENTS AND MAIN RESULTS: Thirty-five patients were randomized to the steroid (n = 17, no death) and placebo groups (n = 18, two deaths). No differences occurred in length of mechanical ventilation, ICU stay, hospital stay, or mortality between the two groups. At baseline, higher plateau pressures (p = 0.006) and lower Pediatric Logistic Organ Dysfunction scores (p = 0.04) occurred in the steroid group; other characteristics were similar. Despite higher plateau pressures on days 1 (p = 0.006) and 2 (p = 0.025) due to poorer lung compliance in the steroid group, they had lower PaCO2 values on days 2 (p = 0.009) and 3 (p = 0.014), higher pH values on day 2 (p = 0.018), and higher PaO2/FIO2 ratios on days 8 (p = 0.047) and 9 (p = 0.002) compared with the placebo group. Fewer patients in the steroid group required treatment for postextubation stridor (p = 0.04) or supplemental oxygen at ICU transfer (p = 0.012). Steroid therapy was not associated with detectable adverse effects. CONCLUSION: This study demonstrates the feasibility of administering low-dose glucocorticoid therapy and measuring clinically relevant outcomes in pediatric acute respiratory distress syndrome. Changes in oxygenation and/or ventilation are consistent with early acute respiratory distress syndrome pathophysiology and results of similar clinical trials in adults. We propose and design a larger randomized trial to define the role of glucocorticoid therapy in pediatric acute respiratory distress syndrome.

Initial experience with conivaptan use in critically ill infants with cardiac disease.

OBJECTIVE: Arginine vasopressin (AVP) is the primary regulator of free water retention through its interactions with the AVP type 2 receptor (V(2)). As opposed to the natriuresis and diuresis that occur with loop and thiazide diuretics, conivaptan is an AVP V(1A)/V(2) receptor antagonist, which enhances free water excretion while minimizing sodium loss. We report our preliminary experience with conivaptan to promote diuresis in infants with functional or structural cardiac disease. METHODS: A retrospective cohort study was conducted of infants who had received conivaptan from August 2007 to January 2008. A loading dose of conivaptan (0.3-0.6 mg/kg) was followed by a continuous infusion of 0.01-0.02 mg/kg/hr for 24 hours. Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, bicarbonate, and urine output were measured prior to the start of conivaptan and at 24 hours after initiation of the infusion. RESULTS: Conivaptan was administered intravenously on 6 occasions to 5 patients with hypervolemic hyponatremia. Patients ranged in age from 8 to179 days, and body weight ranged from 3 to 4.12 kg. Mean sodium concentration increased from 130.17 ± 1.94 mEq/L to 133.67 ± 3.88 mEq/L (p=0.048), and median urine output increased from 4.15 to 5.05 mL/kg/hr (p=0.286). No significant changes were noted in serum potassium, bicarbonate, creatinine, or BUN. No adverse effects were noted during conivaptan infusion. CONCLUSION: Intravenous conivaptan is effective for increasing serum sodium levels and may be a potential adjuvant to enhance diuresis in children with cardiac disease. Given the potential benefits of conivaptan compared to diuretic therapy, with all their potential complications, prospective trials are warranted.

Ketamine inhibits tumor necrosis factor secretion by RAW264.7 murine macrophages stimulated with antibiotic-exposed strains of community-associated, methicillin-resistant Staphylococcus aureus.

BACKGROUND: Infections caused by community-associated strains of methicillin-resistant Staphylococcus aureus (CA-MRSA) are associated with a marked and prolonged host inflammatory response. In a sepsis simulation model, we tested whether the anesthetic ketamine inhibits the macrophage TNF response to antibiotic-exposed CA-MRSA bacteria via its antagonism of N-methyl-D-aspartate (NMDA) receptors. RAW264.7 cells were stimulated for 18 hrs with 105 to 107 CFU/mL inocula of either of two prototypical CA-MRSA isolates, USA300 strain LAC and USA400 strain MW2, in the presence of either vancomycin or daptomycin. One hour before bacterial stimulation, ketamine was added with or without MK-801 (dizocilpine, a chemically unrelated non-competitive NMDA receptor antagonist), APV (D-2-amino-5-phosphono-valerate, a competitive NMDA receptor antagonist), NMDA, or combinations of these agents. Supernatants were collected and assayed for TNF concentration by ELISA. RESULTS: RAW264.7 cells exposed to either LAC or MW2 in the presence of daptomycin secreted less TNF than in the presence of vancomycin. The addition of ketamine inhibited macrophage TNF secretion after stimulation with either of the CA-MRSA isolates (LAC, MW2) in the presence of either antibiotic. The NMDA inhibitors, MK-801 and APV, also suppressed macrophage TNF secretion after stimulation with either of the antibiotic-exposed CA-MRSA isolates, and the effect was not additive or synergistic with ketamine. The addition of NMDA substrate augmented TNF secretion in response to the CA-MRSA bacteria, and the addition of APV suppressed the effect of NMDA in a dose-dependent fashion. CONCLUSIONS: Ketamine inhibits TNF secretion by MRSA-stimulated RAW264.7 macrophages and the mechanism likely involves NMDA receptor antagonism. These findings may have therapeutic significance in MRSA sepsis.