Methylprednisolone for Heart Surgery in Infants — A Randomized, Controlled Trial

Hill, Kevin D.; Kannankeril, Prince J.; Jacobs, Jeffrey P.; Baldwin, H. Scott; Jacobs, Marshall L.; O’Brien, Sean M.; Bichel, David P.; Graham, Eric M.; Blasiole, Brian; Resheidat, Ashraf; Husain, Adil; Kumar, S. Ram; Kirchner, Jerry; Gallup, Dianne; Turek, Joseph W.; Bleiweis, Mark S.; Mettler, Bret A.; Benscoter, Alexis; Wald, Eric; Karamlou, Tara; Bergen, Andrew H. Van; Overman, David M.; Eghtesady, Pirooz; Butts, Ryan J.; Kim, John S.; Scott, John; Anderson, Brett R.; Swartz, Michael F.; McConnell, Patrick I.; Vener, David F.; Li, Jennifer S.

doi:10.1056/nejmoa2212667

Cited by 37 publications

(15 citation statements)

References 38 publications

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“…Currently, pediatric CPB patients are routinely administered preoperative steroids to limit inflammation. However, a recent large randomized clinical trial demonstrated that prophylactic use of steroids did not improve outcomes 29 . Our data presents several therapeutic targets that have not been previously studied in the context of CPB.…”

Section: Discussionmentioning

confidence: 99%

Cardiopulmonary bypass activates classical monocytes via shear-mediated activation of Store-Operated Calcium Entry

Hsieh

Smith

et al. 2022

Preprint

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Circulating blood cells, such as leukocytes, experience significant hemodynamic stresses. These stresses are significantly higher when a patient requires mechanical support of the circulation, such as cardiopulmonary bypass. To identify molecular mechanisms by which cells sense these stresses, we utilized genome wide CRISPRi and phosphoproteomics data. These screens identified non-erythroid spectrin 1 (SPTAN1) and RAF1 as effectors of hemodynamic stress in monocytes. We show that fluid stress induces SPTAN1/RAF1 signaling to promote STIM1 and ORAI1 interaction resulting in Store-Operated Calcium Entry (SOCE) thereby driving inflammation and cell death.

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Section: Discussionmentioning

confidence: 99%

Cardiopulmonary bypass activates classical monocytes via shear-mediated activation of Store-Operated Calcium Entry

Hsieh

Smith

et al. 2022

Preprint

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“…We performed a single-institution ancillary prospective cohort study of infants less than 1 year old enrolled in the Steroids to Reduce Systemic Inflammation after Infant Heart Surgery trial (NCT03229538), which was a multisite, randomized, double-blind, placebo-controlled trial to evaluate perioperative steroids in infants undergoing heart surgery on cardiopulmonary bypass ( 21 , 22 ). All infants enrolled at Duke between June 2019 and May 2020 could opt-in to additional urine biomarker sampling.…”

Section: Methodsmentioning

confidence: 99%

Association of Urine Biomarkers With Acute Kidney Injury and Fluid Overload in Infants After Cardiac Surgery: A Single Center Ancillary Cohort of the Steroids to Reduce Systemic Inflammation After Infant Heart Surgery Trial

Thompson

Chamberlain

Hill

et al. 2023

Critical Care Explorations

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To examine the association between three perioperative urine biomarker concentrations (urine cystatin C [uCysC], urine neutrophil gelatinaseassociated lipocalin [uNGAL], and urine kidney injury molecule 1 [uKIM-1]), and cardiac surgery-associated acute kidney injury (CS-AKI) and fluid overload (FO) in infants with congenital heart disease undergoing surgery on cardiopulmonary bypass. To explore how urine biomarkers are associated with distinct CS-AKI phenotypes based on FO status.

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“…To identify neonates for inclusion in the PopPK analysis, we leveraged 2 prospective trials: the Steroids to Reduce Inflammation after Infant Heart Surgery (STRESS) trial (NCT03119538) 25,26 and the Opportunistic PK/Pharmacodynamic (PD) Trial in Critically Ill Children with Heart Disease (OPTIC; NCT05055830). 27 In brief, the STRESS trial is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of methylprednisolone on outcomes after CPB.…”

Section: Patient Populationsmentioning

confidence: 99%

Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury

Thompson,

Zimmerman,

Gonzalez

et al. 2023

The Journal of Clinical Pharma

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Cardiac surgery‐associated acute kidney injury (CS‐AKI) occurs in approximately 65% of neonates undergoing cardiac surgery on cardiopulmonary bypass and contributes to morbidity and mortality. Caffeine may reduce CS‐AKI by counteracting adenosine receptor upregulation after bypass, but pharmacokinetics (PK) in this population are unknown. The goal of our analysis is to address knowledge gaps in age‐, disease‐, and bypass‐related effects on caffeine disposition and explore preliminary associations between caffeine exposure and CS‐AKI using population PK modeling techniques and an opportunistic, electronic health record‐integrated trial design.We prospectively enrolled neonates receiving preoperative caffeine per standard of care and collected PK samples. We retrospectively identified neonates without caffeine exposure undergoing surgery on bypass as a control cohort. We followed US Food and Drug Administration guidance for population PK model development using NONMEM. Effects of clinical covariates on PK parameters were evaluated. We simulated perioperative exposures and used multivariable logistic regression to evaluate the association between caffeine exposure and CS‐AKI.Twenty‐seven neonates were included in model development. A 1‐compartment model with bypass time as a covariate on clearance and volume of distribution best fit the data. Twenty‐three neonates with caffeine exposure and 109 controls were included in the exposure‐response analysis. Over half of neonates developed CS‐AKI. On multivariable analysis, there were no significant differences between CS‐AKI with and without caffeine exposure. Neonates with single‐ventricle heart disease without CS‐AKI had consistently higher simulated caffeine exposures. Our results highlight areas for further study to better understand disease‐ and bypass‐specific effects on drug disposition and identify populations where caffeine may be beneficial.

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Methylprednisolone for Heart Surgery in Infants — A Randomized, Controlled Trial

Cited by 37 publications

References 38 publications

Cardiopulmonary bypass activates classical monocytes via shear-mediated activation of Store-Operated Calcium Entry

Cardiopulmonary bypass activates classical monocytes via shear-mediated activation of Store-Operated Calcium Entry

Association of Urine Biomarkers With Acute Kidney Injury and Fluid Overload in Infants After Cardiac Surgery: A Single Center Ancillary Cohort of the Steroids to Reduce Systemic Inflammation After Infant Heart Surgery Trial

Population Pharmacokinetics of Caffeine in Neonates with Congenital Heart Disease and Associations with Acute Kidney Injury

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