The influence of cardiopulmonary bypass on pediatric pharmacokinetics.

INTRODUCTION: Every year thousands of children undergo surgery for congenital heart disease. Cardiac surgery requires the use of cardiopulmonary bypass, which can have unexpected consequences for pharmacokinetic parameters. AREAS COVERED: We describe the pathophysiological properties of cardiopulmonary bypass that may influence pharmacokinetic parameters, with a focus on literature published in the last 10 years. We performed a PubMed database search with the keywords 'Cardiopulmonary bypass' AND 'Pediatric' AND 'Pharmacokinetics'. We searched related articles on PubMed and checked the references of articles for relevant studies. EXPERT OPINION: Interest in the influence of cardiopulmonary bypass on pharmacokinetics has increased over the last 10 years, especially due to the use of population pharmacokinetic modeling. Unfortunately, study design usually limits the amount of information that can be obtained with sufficient power and the best way to model cardiopulmonary bypass is yet unknown. More information is needed on the pathophysiology of pediatric heart disease and cardiopulmonary bypass. Once adequately validated, PK models should be integrated in the patient electronic database integrating covariates and biomarkers influencing PK, making it possible to predict real-time drug concentrations and guide further clinical management for the individual patient at the bedside.

A review of European guidelines for patient blood management with a particular emphasis on antifibrinolytic drug administration for cardiac surgery.

The concept of patient blood management (PBM) was introduced by the World Health Organization in 2011 and is defined as a "patient-focused, evidence-based and systematic approach for optimizing the management of patients and transfusion of blood products to ensure high quality and effective patient care". Patient blood management is a multimodal approach based on three pillars: optimization of blood mass, minimization of blood loss and optimization of patient tolerance to anaemia. Antifibrinolytics play a major role in cardiac surgery, where the risk of perioperative bleeding is high and affects a majority of patients, by effectively reducing bleeding, transfusions, re-operations, as well as their associated morbidity and mortality. They represent an essential part of the pharmacological arsenal of patient blood management. However, despite the trend towards high-level PBM practices, currently very few European countries have national PBM guidelines and these guidelines, taken as a whole, are heterogeneous in form and content. In particular, the use of antifibrinolytics in cardiac surgery is often not discussed in detail beyond general prophylactic use and any recommendations lack detail including choice of drug, dosing, and mode of administration. Thus, the implementation of PBM programs in Europe is still challenging. In 2021, the WHO published a new document highlighting the urgent need to close the gap in PBM awareness and implementation and announced their upcoming initiative to develop specific PBM implementation guidelines. This review aims first, to summarize the role played by fibrinolysis in haemostatic disorders; second, to give an overview of the current available guidelines in Europe detailing PBM implementation in cardiac surgery; and third, to analyse the place and use of antifibrinolytics in these guidelines.

Methylprednisolone in Pediatric Cardiac Surgery: Is There Enough Evidence?

Corticosteroids have been used to decrease the inflammatory response to cardiac surgery and cardiopulmonary bypass in children for decades. Sparse information is present concerning the pharmacokinetics and pharmacodynamics of corticosteroids in the context of pediatric cardiac surgery. There is large interindividual variability in plasma concentrations, with indications for a larger volume of distribution in neonates compared to other age groups. There is ample evidence that perioperative use of MP leads to a decrease in pro-inflammatory mediators and an increase in anti-inflammatory mediators, with no difference in effect between doses of 2 and 30 mg/kg. No differences in inflammatory mediators have been shown between different times of administration relative to the start of surgery in various studies. MP has been shown to have a beneficial effect in certain subgroups of patients but is also associated with side effects. In lower risk categories, the balance between risk and benefit may be shifted toward risk. There is limited information on short- to medium-term outcome (mortality, low cardiac output syndrome, duration of mechanical ventilation, length of stay in the intensive care unit or the hospital), mostly from underpowered studies. No information on long-term outcome, such as neurodevelopmental outcome, is available. MP may provide a small benefit that is easily abolished by patient characteristics, surgical techniques, and perfusion management. The lack of evidence leads to large differences in practice between and within countries, and even within hospitals, so there is a need for adequately powered randomized studies.

Methylprednisolone Plasma Concentrations During Cardiac Surgery With Cardiopulmonary Bypass in Pediatric Patients.

Introduction: To our knowledge, methylprednisolone pharmacokinetics and plasma concentrations have not been comprehensively investigated in children with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass. It is unknown whether there is a significant influence of cardiopulmonary bypass on the plasma concentrations of methylprednisolone and whether this may be an explanation for the limited reported efficacy of steroid administration in cardiac surgery with cardiopulmonary bypass. Methods: The study was registered in the Dutch Trial Register (NTR3579; https://www.trialregister.nl/trial/3428). Methylprednisolone 30 mg/kg was administered as an intravenous bolus after induction of anesthesia. Methylprednisolone concentration was measured with liquid chromatography tandem mass spectrometry and analyzed using linear mixed-effects modeling. Results: Thirty-nine patients were included in the study, of which three were excluded. There was an acute decrease in observed methylprednisolone plasma concentration on initiation of cardiopulmonary bypass (median = 26.8%, range = 13.9-48.14%, p < 0.001). We found a lower intercept (p = 0.02), as well as a less steep slope of the model predicted methylprednisolone concentration vs. time curve for neonates (p = 0.048). A lower intercept (p = 0.01) and a less steep slope (p = 0.0024) if the volume of cell saver blood processed was larger than 91 ml/kg were also found. Discussion: We report similar methylprednisolone plasma concentrations as earlier studies performed in children undergoing cardiopulmonary bypass, and we confirmed the large interindividual variability in achieved methylprednisolone plasma concentrations with weight-based methylprednisolone administration. A larger volume of distribution and a lower clearance of methylprednisolone for neonates were suggested. The half-life of methylprednisolone in our study was calculated to be longer than 6 h for neonates, 4.7 h for infants, 3.6 h for preschool children and 4.7 h for school children. The possible influence of treatment of pulmonary hypertension with sildenafil and temperature needs to be investigated further.

A survey of patient blood management for patients undergoing cardiac surgery in nine European countries.

STUDY OBJECTIVE: To describe and compare patient blood management (PBM) practices in cardiac surgery in nine European countries and identify the main risk factors for bleeding or transfusion according to the surveyed centres. DESIGN: We set up an online survey to evaluate PBM practices in two clinical scenarios, risk factors for bleeding or transfusion, and previous experience with antifibrinolytics. SETTING: This survey was completed by European anesthesiologists in 2019. PATIENTS: No patients were included in the survey. INTERVENTION: None. MEASUREMENTS: We evaluated the degree of implementation of PBM practices in patients undergoing cardiac surgery. MAIN RESULTS: Ninety-eight of 177 responses (38%) were complete with variable response rates by country. In a non-emergent situation, no respondents would transfuse red cells preoperatively in an anaemic patient, while cell salvage (89%) and antifibrinolytics (82%) would almost always be used. Optimization of Hemoglobin level (36%) and use of off-pump techniques (34%), minimally invasive surgery (25%) and relatively recently-developed CPB technologies such as mini-bypass (32%) and autologous priming (38%), varied greatly across countries. In an emergent clinical situation, topical haemostatic agents would frequently be used (61%). Tranexamic acid (72%) and aprotinin (20%) were the main antifibrinolytics used, with method of administration and dose varying markedly across countries. Five factors were considered to increase risk of bleeding or transfusion by at least 90% of respondents: pre-operative anaemia, prior cardiac surgery, clopidogrel 5 days or less before surgery, use of other P2Y12 inhibitors at any point, and thrombocytopenia <100.109 platelets/mm3. CONCLUSION: PBM guidelines are not universally implemented in European cardiac surgery centres or countries, resulting in discrepancies in techniques and products used for a given clinical situation.

In Vitro Recovery of Sufentanil, Midazolam, Propofol, and Methylprednisolone in Pediatric Cardiopulmonary Bypass Systems.

OBJECTIVES: To evaluate in vitro drug recovery in cardiopulmonary bypass (CPB) systems used for pediatric cardiac surgery. DESIGN: Observational in vitro study. SETTING: Single-center university hospital. PARTICIPANTS: In vitro CPB systems used for pediatric cardiac surgery. INTERVENTIONS: Three full neonatal, infant, and pediatric CPB systems were primed according to hospital protocol and kept running for 6 hours. Midazolam, propofol, sufentanil, and methylprednisolone were added to the venous side of the systems in doses commonly used for induction of general anesthesia. Blood samples were taken from the postoxygenator side of the circuit immediately after injection of the drugs and after 2, 5, 7, 10, 30, 60, 180, and 300 minutes. MEASUREMENTS AND MAIN RESULTS: Linear mixed model analyses were performed to assess the relationship between log-transformed drug concentration (dependent variable) and type of CPB system and sample time point (independent variables). The mean percentage of drug recovery after 60 and 180 minutes compared with T1 was 41.7% (95% confidence interval [CI] 35.9-47.4) and 23.0% (95% CI 9.2-36.8) for sufentanil, 87.3% (95% CI 64.9-109.7) and 82.0% (95% CI 64.6-99.4) for midazolam, 41.3% (95% CI 15.5-67.2) and 25.0% (95% CI 4.7-45.3) for propofol, and 119.3% (95% CI 101.89-136.78) and 162.0% (95% CI 114.09-209.91) for methylprednisolone, respectively. CONCLUSIONS: The present in vitro experiment with neonatal, infant, and pediatric CPB systems shows a variable recovery of routinely used drugs with significant differences between drugs, but not between system categories (with the exception of propofol). The decreased recovery of mainly sufentanil and propofol could lead to suboptimal dosing of patients during cardiac surgery with CPB.

Recovery of cefazolin and clindamycin in in vitro pediatric CPB systems.

Cardiopulmonary bypass (CPB) is often necessary for congenital cardiac surgery, but CPB can alter drug pharmacokinetic parameters resulting in underdosing. Inadequate plasma levels of antibiotics could lead to postoperative infections with increased morbidity. The influence of pediatric CPB systems on cefazolin and clindamycin plasma levels is not known. We have measured plasma levels of cefazolin and clindamycin in in vitro pediatric CPB systems. We have tested three types of CPB systems. All systems were primed and spiked with clindamycin and cefazolin. Samples were taken at different time points to measure the recovery of cefazolin and clindamycin. Linear mixed model analyses were performed to assess if drug recovery was different between the type of CPB system and sampling time point. The experiments were conducted at a tertiary university hospital. 81 samples were analyzed. There was a significant difference in the recovery over time between CPB systems for cefazolin and clindamycin (P < .001). Cefazolin recovery after 180 minutes was 106% (95% CI: 91-123) for neonatal, 99% (95% CI: 85-115) for infant, and 77% (95% CI: 67-89) for pediatric systems. Clindamycin recovery after 180 minutes was 143% (95% CI: 116-177) for neonatal, 111% (95% CI: 89-137) for infant, and 120% (95% CI: 97-149) for pediatric systems. Clindamycin recovery after 180 minutes compared to the theoretical concentration was 0.4% for neonatal, 1.2% for infants, and 0.6% for pediatric systems. The recovery of cefazolin was high in the neonatal and infant CPB systems and moderate in the pediatric system. We found a large discrepancy between the theoretical and measured concentrations of clindamycin in all tested CPB systems.

Potentially clinically relevant concentrations of Cefazolin, Midazolam, Propofol, and Sufentanil in auto-transfused blood in congenital cardiac surgery.

BACKGROUND: Use of donor blood in congenital cardiac surgery increases the risk for post-operative morbidity and mortality. To reduce the need for allogenic blood transfusion a technique for peri-operative mechanical red cell salvage is applied. Blood from the operation site is collected in a reservoir, processed, passed through a lipophilic filter and returned to the patient. Influence of this cellsaver system on coagulation, fibrinolysis and inflammatory markers is known. To our knowledge no studies have been performed on the effects of autotransfusion on drug concentrations. A clinically relevant drug dose could potentially be returned to the patient through the auto-transfused blood, leading to unwanted drug reactions post-operatively. We aimed to measure drug concentrations in blood salvaged from the operation site and in the auto-transfused blood to determine if a clinically relevant drug dose is returned to the patient. METHODS: The study was performed at the Department of Cardiothoracic Surgery of a tertiary university hospital. Blood samples were taken from the reservoir, after processing before the lipophilic filter, the auto-transfused blood, and the waste fluid. Samples were stored at - 80 C and drug concentration for sufentanil, propofol, midazolam and cefazolin were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Drug concentrations measured in the reservoir and the auto-transfused blood were compared and the relative reduction was calculated for each patient. RESULTS: Blood samples were taken from 18 cellsaver runs in 18 patients, age 0-13 years. Drug concentrations in the reservoir were comparable to concomitant concentrations in the patient. For sufentanil 34% (median, IQR 27-50) of drug concentration was retained from the reservoir in the auto-transfused blood, for midazolam 6% (median, IQR 4-10), for cefazolin 5% (median, IQR 2-6) and for propofol 0% (median, IQR 0-0) respectively. CONCLUSION: Depending on the drug, up to 34% of the drug concentration salvaged from the operation site is returned to the patient through autotransfusion, potentially causing unwanted drug reactions post-operatively. Additionally, influence of a cellsaver system should be considered in pharmacological research during and after congenital cardiac surgery and could result in dose adjustments in the postoperative phase. TRIAL REGISTRATION: Registration at the Dutch Trial Registry ( NTR3579 ) at August 14 2012.

Does pharmacotherapy influence the inflammatory responses during cardiopulmonary bypass in children?

Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) by factors such as contact of the blood with the foreign surface of the extracorporeal circuit, hypothermia, reduction of pulmonary blood flow during CPB and endotoxemia. SIRS is maintained in the postoperative phase, co-occurring with a counter anti-inflammatory response syndrome. Research on the effects of drugs administered before the surgery, especially in the induction phase of anesthesia, as well as drugs used during extracorporeal circulation, has revealed that they greatly influence these postoperative inflammatory responses. A better understanding of these processes may not only improve postoperative recovery but also enable tailor-made pharmacotherapy, with both health and economic benefits. In this review, we describe the pathophysiology of SIRS and counter anti-inflammatory response syndrome in the light of CPB in children and the influence of drugs used on these syndromes.

The effect of adult and pediatric cardiopulmonary bypass on pharmacokinetic and pharmacodynamic parameters.

Cardiopulmonary bypass (CPB) is known to have important effects on the disposition of drugs, which in turn may have important implications for the efficacy and toxicity of drug therapy. These effects constantly change throughout CPB and some continue to exert influence after the patient has been successfully weaned. In children, developmental and disease specific changes in drug disposition and effect also need to be taken into account when studying the effects of CPB. This review will provide an extensive overview of the current literature concerning the mechanisms behind the effects CPB has on pharmacokinetic and pharmacodynamic parameters. Also the effects of CPB on individual anesthetic drugs and sedatives, opioids, neuromuscular blocking agents, antibiotics and miscellaneous medications will be reviewed. Special attention will be paid to the pediatric population.

The impact of extracorporeal life support and hypothermia on drug disposition in critically ill infants and children.

Extracorporeal membrane oxygenation (ECMO) support is an established lifesaving therapy for potentially reversible respiratory or cardiac failure. In 10% of all pediatric patients receiving ECMO, ECMO therapy is initiated during or after cardiopulmonary resuscitation. Therapeutic hypothermia is frequently used in children after cardiac arrest, despite the lack of randomized controlled trials that show its efficacy. Hypothermia is frequently used in children and neonates during cardiopulmonary bypass (CPB). By combining data from pharmacokinetic studies in children on ECMO and CPB and during hypothermia, this review elucidates the possible effects of hypothermia during ECMO on drug disposition.