Nejvíce citovaný článek - PubMed ID 10445729
Extracorporeal life support (ECLS) is a treatment modality that provides prolonged blood circulation, gas exchange and can partially support or fully substitute functions of heart and lungs in patients with severe but potentially reversible cardiopulmonary failure refractory to conventional therapy. Due to high-volume bypass, the extracorporeal flow is interacting with native cardiac output. The pathophysiology of circulation and ECLS support reveals significant effects on arterial pressure waveforms, cardiac hemodynamics, and myocardial perfusion. Moreover, it is still subject of research, whether increasing stroke work caused by the extracorporeal flow is accompanied by adequate myocardial oxygen supply. The left ventricular (LV) pressure-volume mechanics are reflecting perfusion and loading conditions and these changes are dependent on the degree of the extracorporeal blood flow. By increasing the afterload, artificial circulation puts higher demands on heart work with increasing myocardial oxygen consumption. Further, this can lead to LV distention, pulmonary edema, and progression of heart failure. Multiple methods of LV decompression (atrial septostomy, active venting, intra-aortic balloon pump, pulsatility of flow) have been suggested to relieve LV overload but the main risk factors still remain unclear. In this context, it has been recommended to keep the rate of circulatory support as low as possible. Also, utilization of detailed hemodynamic monitoring has been suggested in order to avoid possible harm from excessive extracorporeal flow.
Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. As the survival and the overall outcome of patients rely on the treatment and reversal of the underlying disease, effective and preferentially evidence-based pharmacotherapy is crucial to target recovery. Currently limited data exist to support the clinicians in their every-day intensive care prescribing practice with the contemporary ECMO technology. Indeed, drug dosing to optimize pharmacotherapy during neonatal ECMO is a major challenge. The impact of the maturational changes of the organ function on both pharmacokinetics (PK) and pharmacodynamics (PD) has been widely established over the last decades. Next to the developmental pharmacology, additional non-maturational factors have been recognized as key-determinants of PK/PD variability. The dynamically changing state of critical illness during the ECMO course impairs the achievement of optimal drug exposure, as a result of single or multi-organ failure, capillary leak, altered protein binding, and sometimes a hyperdynamic state, with a variable effect on both the volume of distribution (Vd) and the clearance (Cl) of drugs. Extracorporeal membrane oxygenation introduces further PK/PD perturbation due to drug sequestration and hemodilution, thus increasing the Vd and clearance (sequestration). Drug disposition depends on the characteristics of the compounds (hydrophilic vs. lipophilic, protein binding), patients (age, comorbidities, surgery, co-medications, genetic variations), and circuits (roller vs. centrifugal-based systems; silicone vs. hollow-fiber oxygenators; renal replacement therapy). Based on the potential combination of the above-mentioned drug PK/PD determinants, an integrated approach in clinical drug prescription is pivotal to limit the risks of over- and under-dosing. The understanding of the dose-exposure-response relationship in critically-ill neonates on ECMO will enable the optimization of dosing strategies to ensure safety and efficacy for the individual patient. Next to in vitro and clinical PK data collection, physiologically-based pharmacokinetic modeling (PBPK) are emerging as alternative approaches to provide bedside dosing guidance. This article provides an overview of the available evidence in the field of neonatal pharmacology during ECMO. We will identify the main determinants of altered PK and PD, elaborate on evidence-based recommendations on pharmacotherapy and highlight areas for further research.
- Klíčová slova
- ECMO, critical illness, developmental pharmacology, neonate, pharmacodynamics, pharmacokinetics,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
