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Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children.

ABSTRACT: INTRODUCTION: The response to exogenous epinephrine (Ep) is difficult to predict given the multitude of factors involved such as broad pharmacokinetic and pharmacodynamic between-subject variabilities, which may be more pronounced in children. We investigated the pharmacokinetics and pharmacodynamics of Ep, co-administered with milrinone, in children who underwent open heart surgical repair for congenital defects following cardiopulmonary bypass, including associated variability factors. METHODS: Thirty-nine children with a high risk of low cardiac output syndrome were prospectively enrolled. Ep pharmacokinetics, hemodynamic and metabolic effects were analyzed using the non-linear mixed effects modeling software MONOLIX. According to the final model, an Ep dosing simulation was suggested. RESULTS: Ep dosing infusions ranged from 0.01 to 0.23 ?g.kg-1.min-1 in children whose weight ranged from 2.5 to 58 kg. A one-compartment open model with linear elimination adequately described the Ep concentration-time courses. Bodyweight (BW) was the main covariate influencing clearance (CL) and endogenous Ep production rate (q0) via an allometric relationship: CL(BWi)?=??CL x (BWi)3/4 and q0(BWi)?=??q0 x (BWi )3/4. The increase in heart rate (HR) and mean arterial pressure (MAP) as a function of Ep concentration were well described using an Emax model. The effect of age was significant on HR and MAP basal level parameters. Assuming that Ep stimulated the production rate of plasma glucose, the increases in plasma glucose and lactate levels were well described by turnover models without any significant effect of age, BW or exogenous glucose supply. CONCLUSIONS: According to this population analysis, the developmental effects of BW and age explained a part of the pharmacokinetic and pharmacodynamics between-subject variabilities of Ep administration in critically ill children. This approach ultimately leads to a valuable Ep dosing simulation which should help clinicians to determine an appropriate a priori dosing regimen.

SUBMITTER: Oualha M

PROVIDER: S-EPMC4056810 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children.

Oualha Mehdi M Urien Saïk S Spreux-Varoquaux Odile O Bordessoule Alice A D'Agostino Irène I Pouard Philippe P Tréluyer Jean-Marc JM

Critical care (London, England) 20140124 1

<h4>Introduction</h4>The response to exogenous epinephrine (Ep) is difficult to predict given the multitude of factors involved such as broad pharmacokinetic and pharmacodynamic between-subject variabilities, which may be more pronounced in children. We investigated the pharmacokinetics and pharmacodynamics of Ep, co-administered with milrinone, in children who underwent open heart surgical repair for congenital defects following cardiopulmonary bypass, including associated variability factors.< ...[more]

PMID: 24456639

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Project description:BackgroundBreast cancer is the most common cancer type among women worldwide with over a million new cases each year. More than 40% of these women will struggle with chronic pain and fatigue after surgery, regardless of surgical procedure. These consequences are detrimental and result in distress and disability, including work disability. Few attempts have been made to prevent chronic pain and fatigue after surgery by applying a psychological approach, despite psychological risk factors being crucial in the development of both chronic pain and fatigue. In this study, we aim to develop and test an easily implementable strategy of preventing chronic pain and fatigue after breast cancer surgery. The intervention strategy involves a pre-operative hypnosis session and a web-based post-operative Acceptance and Commitment Therapy (ACT). The hypnosis has previously been found effective in alleviating acute post-operative pain and fatigue in breast cancer patients, while ACT is well suited to cancer populations as it offers a model of healthy adaptation to difficult circumstances. Together they form an intervention strategy with both a preventive and a rehabilitative focus.Methods/designThis randomized controlled trial aims to estimate the effects of the pre- and post- operative interventions compared to attentional control and treatment as usual (TAU) and will also include a qualitative process evaluation. Participants will be randomized to receive either a pre-operative brief hypnosis session and a post-operative web-based psychological intervention (iACT) or a pre-operative one-session mindfulness through an audio file and post-operative TAU. Self-reported questionnaire data and biomarker data will be assessed pre-surgery, post-surgery and 3 and 12 months after surgery. In addition, we will assess registry data on sick leave and prescriptions until 2-year follow-up. In the qualitative process evaluation, data will be collected from participants from both study arms (through interviews and a diary) and two different analyses performed (socio-narrative and Grounded Theory) with the objective to describe the development of chronic post-surgical pain and fatigue and the potential influence of the interventions on these processes. The study is set-up to demonstrate a minimum difference in pain of 1 point on NRS (0-10) and 3 points on FACIT-F (0-52) between the groups at 3-months follow-up by including 200 breast cancer patients in total.DiscussionThis trial will be the first study to estimate the effect of a combined pre-operative hypnosis with a post-operative iACT to prevent pain and fatigue after breast cancer surgery. The results from our study might i) help the large group of women affected by chronic pain and fatigue after breast cancer surgery, ii) shed light on the mechanisms involved in chronic pain and fatigue development, and iii) serve as a model for other surgical procedures.Trial registrationClinicaltrials.gov, registration number NCT04518085. Registered on January 29th, 2020. https://clinicaltrials.gov/ct2/show/NCT04518085.

Dataset Information

Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children.

Publications

Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children.

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