Henry P Foote, Huali Wu, Stephen J Balevic, Elizabeth J Thompson, Kevin D Hill, Eric M Graham, Christoph P Hornik, Karan R Kumar
{"title":"使用药代动力学模型和电子健康记录数据预测新生儿体外循环期间甲基强的松龙暴露后的临床和安全性结果。","authors":"Henry P Foote, Huali Wu, Stephen J Balevic, Elizabeth J Thompson, Kevin D Hill, Eric M Graham, Christoph P Hornik, Karan R Kumar","doi":"10.32604/chd.2023.026262","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) frequently receive intraoperative methylprednisolone (MP) to suppress CPB-related inflammation; however, the optimal dosing strategy and efficacy of MP remain unclear.</p><p><strong>Methods: </strong>We retrospectively analyzed all infants under 90 days-old who received intra-operative MP for cardiac surgery with CPB from 2014-2017 at our institution. We combined real-world dosing data from the electronic health record (EHR) and two previously developed population pharmacokinetic/pharmacodynamic models to simulate peak concentration (Cmax) and area under the concentration-time curve for 24 h (AUC24) for MP and the inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10). We evaluated the relationships between post-operative, safety, and other clinical outcomes obtained from the EHR with each predicted exposure using non-parametric tests.</p><p><strong>Results: </strong>A total of 142 infants with median post-natal age 8 (interquartile range [IQR]: 5, 37) days received a total dose of 30 (19, 49) mg/kg of MP. Twelve (8%) died, 37 (26%) met the composite post-operative outcome, 114 (80%) met the composite safety outcome, and 23 (16%) had a major complication. Predicted median Cmax and AUC24 IL-6 exposure was significantly higher for infants meeting the composite post-operative outcome and those with major complications. Predicted median Cmax and AUC24 MP exposure was significantly higher for infants requiring insulin. No exposure was associated with death or other safety outcomes.</p><p><strong>Conclusions: </strong>Pro-inflammatory IL-6, but not MP exposure, was associated with post-operative organ dysfunction, suggesting current MP dosing may not adequately suppress IL-6 or increase IL-10 to impact clinical outcomes. Prospective study will be required to define the optimal exposure-efficacy and exposure-safety profiles in these infants.</p>","PeriodicalId":10666,"journal":{"name":"Congenital Heart Disease","volume":"18 3","pages":"295-313"},"PeriodicalIF":0.3000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361697/pdf/","citationCount":"0","resultStr":"{\"title\":\"Using Pharmacokinetic Modeling and Electronic Health Record Data to Predict Clinical and Safety Outcomes after Methylprednisolone Exposure during Cardiopulmonary Bypass in Neonates.\",\"authors\":\"Henry P Foote, Huali Wu, Stephen J Balevic, Elizabeth J Thompson, Kevin D Hill, Eric M Graham, Christoph P Hornik, Karan R Kumar\",\"doi\":\"10.32604/chd.2023.026262\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) frequently receive intraoperative methylprednisolone (MP) to suppress CPB-related inflammation; however, the optimal dosing strategy and efficacy of MP remain unclear.</p><p><strong>Methods: </strong>We retrospectively analyzed all infants under 90 days-old who received intra-operative MP for cardiac surgery with CPB from 2014-2017 at our institution. We combined real-world dosing data from the electronic health record (EHR) and two previously developed population pharmacokinetic/pharmacodynamic models to simulate peak concentration (Cmax) and area under the concentration-time curve for 24 h (AUC24) for MP and the inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10). We evaluated the relationships between post-operative, safety, and other clinical outcomes obtained from the EHR with each predicted exposure using non-parametric tests.</p><p><strong>Results: </strong>A total of 142 infants with median post-natal age 8 (interquartile range [IQR]: 5, 37) days received a total dose of 30 (19, 49) mg/kg of MP. Twelve (8%) died, 37 (26%) met the composite post-operative outcome, 114 (80%) met the composite safety outcome, and 23 (16%) had a major complication. Predicted median Cmax and AUC24 IL-6 exposure was significantly higher for infants meeting the composite post-operative outcome and those with major complications. Predicted median Cmax and AUC24 MP exposure was significantly higher for infants requiring insulin. No exposure was associated with death or other safety outcomes.</p><p><strong>Conclusions: </strong>Pro-inflammatory IL-6, but not MP exposure, was associated with post-operative organ dysfunction, suggesting current MP dosing may not adequately suppress IL-6 or increase IL-10 to impact clinical outcomes. Prospective study will be required to define the optimal exposure-efficacy and exposure-safety profiles in these infants.</p>\",\"PeriodicalId\":10666,\"journal\":{\"name\":\"Congenital Heart Disease\",\"volume\":\"18 3\",\"pages\":\"295-313\"},\"PeriodicalIF\":0.3000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361697/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Congenital Heart Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.32604/chd.2023.026262\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Congenital Heart Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.32604/chd.2023.026262","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Using Pharmacokinetic Modeling and Electronic Health Record Data to Predict Clinical and Safety Outcomes after Methylprednisolone Exposure during Cardiopulmonary Bypass in Neonates.
Background: Infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) frequently receive intraoperative methylprednisolone (MP) to suppress CPB-related inflammation; however, the optimal dosing strategy and efficacy of MP remain unclear.
Methods: We retrospectively analyzed all infants under 90 days-old who received intra-operative MP for cardiac surgery with CPB from 2014-2017 at our institution. We combined real-world dosing data from the electronic health record (EHR) and two previously developed population pharmacokinetic/pharmacodynamic models to simulate peak concentration (Cmax) and area under the concentration-time curve for 24 h (AUC24) for MP and the inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10). We evaluated the relationships between post-operative, safety, and other clinical outcomes obtained from the EHR with each predicted exposure using non-parametric tests.
Results: A total of 142 infants with median post-natal age 8 (interquartile range [IQR]: 5, 37) days received a total dose of 30 (19, 49) mg/kg of MP. Twelve (8%) died, 37 (26%) met the composite post-operative outcome, 114 (80%) met the composite safety outcome, and 23 (16%) had a major complication. Predicted median Cmax and AUC24 IL-6 exposure was significantly higher for infants meeting the composite post-operative outcome and those with major complications. Predicted median Cmax and AUC24 MP exposure was significantly higher for infants requiring insulin. No exposure was associated with death or other safety outcomes.
Conclusions: Pro-inflammatory IL-6, but not MP exposure, was associated with post-operative organ dysfunction, suggesting current MP dosing may not adequately suppress IL-6 or increase IL-10 to impact clinical outcomes. Prospective study will be required to define the optimal exposure-efficacy and exposure-safety profiles in these infants.
期刊介绍：
Congenital Heart Disease is an open-access journal focusing on congenital heart disease in children and adults. Though the number of infants born with heart disease each year is relatively small (approximately 1% of the population), advances in treating such malformations have led to increased life spans for this population. Consequently, today most patients treated for congenital heart disease are over the age of 20. What are the special needs of adults with congenital heart disease? What are the latest developments in the care of the fetus, infants, and children? Who should treat these patients? How should they be treated?
Congenital Heart Disease focuses on these questions and more. Conceived as a forum for the most up-to-date information on congenital heart disease, the journal is led by Editor-in-Chief Vladimiro L. Vida, MD, Ph.D., Professor in Cardiac Surgery, University of Padua in Italy, as well as an international editorial board. Congenital Heart Disease publishes articles on heart disease as it relates to the following areas:
• Basic research of congenital heart disease
• Clinical pediatric and adult cardiology
• Cardiac imaging
• Preventive cardiology
• Diagnostic and interventional cardiac catheterization
• Electrophysiology
• Surgery
• Long-term follow-up, particularly as it relates to older children and adult congenital heart disease
• Exercise and exercise physiology in the congenital patient
• Post-op and critical care
• Common disorders such as syncope, chest pain, murmurs, as well as acquired disorders such as Kawasaki syndrome
The journal includes clinical studies, invited editorials, state-of-the-art reviews, case reports, articles focusing on the history and development of congenital heart disease, and CME material. Occasional issues focus on special topics.
Readership: Congenital Heart Disease was created for pediatric cardiologists; adult cardiologists who care for patients with congenital heart disease; pediatric and pediatric cardiology nurses; surgeons; radiologists; anesthesiologists; critical care physicians and nurses; and adult support staff involved in the care of patients with congenital heart disease.
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