Introduction: Therapeutic hypothermia (TH) to core temperature of 33-34°C is standard of care to treat hypoxic ischemic encephalopathy (HIE) in neonates. TH efficacy is lost with inadequate control of shivering and agitation. Clonidine is a central α2-adrenergic receptor agonist that provides sedation and regulates body temperature without inducing respiratory depression. The purpose of this study was to evaluate the perceived efficacy and safety of using a clonidine-based versus morphine-based sedation and shivering management strategy during TH. Methods: This was a single-center, retrospective cohort study conducted at a tertiary academic level IV neonatal intensive care unit from January 1, 2017 to October 1, 2021, with a washout period from April 13, 2020 to August 12, 2020. Patients were included if they were diagnosed with HIE and underwent TH. The institutional protocol utilized a morphine-based regimen for shivering and agitation prior to April 2020, and was modified to utilize a clonidine-based regimen afterwards, thus patients were grouped into morphine and clonidine epochs. Protocol adherence and the frequency of additional sedating medication use were compared between the two groups. Results: A total of 99 patients were included for analysis, with 74 patients in the morphine epoch and 25 patients in the clonidine epoch. Observed dosing of the primary shivering relief agent per day of TH was consistent with institutional recommendations. The rate of initiation of any sedative continuous infusion was similar between the morphine and clonidine epoch (21.6% vs 20%, p = 0.44). The rate of initiation of fentanyl infusions and cumulative dosing of fentanyl per day of cooling were similar between epochs, but cumulative fentanyl dosing was higher on day 2 of TH (median 55.6 vs 2.0 mcg/kg/day, p = 0.05). Opioid use, as measured in morphine milligram equivalents (MME) per kilogram, was significantly higher in the morphine epoch (median 2.0 vs 1.2 MME/kg, p < 0.0001) but similar in PRN doses (median 1.0 vs 1.6 MME/kg, p = 0.67). Conclusions: Morphine-based protocols for sedation and shivering control during TH resulted in greater cumulative exposure to opiates with unclear long-term consequences. Clonidine, at the proposed dosages, reduced the use of additional opiates, while maintaining effectiveness.
Introduction: Utilizing beta blockers to lower cardiac output and improve oxygenation is safe and effective during venovenous (VV) extracorporeal membrane oxygenation (ECMO) support; however, ivabradine has never been studied in this setting. The purpose of this study is to determine safety, efficacy, and optimal dosing of ivabradine in patients receiving VV ECMO. Methods: This was a single-center, retrospective cohort study conducted at a tertiary academic hospital from January 1, 2020 to July 1, 2022. Patients were included if they were 18 years or older and initiated ivabradine while on VV ECMO. Patients who received concomitant vasopressors or inotropes during baseline evaluation or ivabradine dose titration were excluded, as well as patients in atrial fibrillation within 24 hours prior to baseline evaluation. Efficacy in HR reduction and improvement of oxygenation compared to baseline at each ivabradine dose titration period were assessed, as were the incidence of bradycardia and pertinent drug interactions. Results: Nineteen patients were included in the analysis with 31 dose titration periods. The majority were initiated on 5 mg twice daily (47%) or 10 mg twice daily (42%). Eleven (60%) patients were titrated to maximum dose of 10 mg twice daily. A significant decrease in HR [(median absolute change (25th, 75th percentiles)] was observed in patients receiving 5 mg twice daily [-8 (-17, -2), p=0.005] and 10 mg twice daily [-20 (-25, -12), p=0.008]. No significant changes were observed in PaO2 at the various dose titrations. A total of 9 (47%) patients experienced bradycardia (HR < 50 bpm) and 1 (5%) patient experienced severe bradycardia (HR < 40 bpm). Four (44%) patients receiving 10 mg twice daily were co-administered CYP3A4 inhibitors. Conclusions: Ivabradine did not significantly improve PaO2 in VV ECMO patients and an adequately powered study is needed to further assess efficacy. Approximately half of patients experienced bradycardia while on ivabradine but severe bradycardia was rare. Careful titration of ivabradine is recommended to minimize the risk of bradycardia. While higher than the standard 5 mg twice daily dosing may be appropriate due to potential sequestration of ivabradine in the circuit, concomitant use with CYP3A4 inhibitors should be avoided.
