Browsing by Author "McKinstry, Robert C."

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    Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation
    (BMJ, 2021-04-22) Wisnowski, Jessica L.; Bluml, Stefan; Panigrahy, Ashok; Mathur, Amit M.; Berman, Jeffrey; Chen, Ping-Sun Keven; Dix, James; Flynn, Trevor; Fricke, Stanley; Friedman, Seth D.; Head, Hayden W.; Ho, Chang Y.; Kline-Fath, Beth; Oveson, Michael; Patterson, Richard; Pruthi, Sumit; Rollins, Nancy; Ramos, Yanerys M.; Rampton, John; Rusin, Jerome; Shaw, Dennis W.; Smith, Mark; Tkach, Jean; Vasanawala, Shreyas; Vossough, Arastoo; Whitehead, Matthew T.; Xu, Duan; Yeom, Kristen; Comstock, Bryan; Heagerty, Patrick J.; Juul, Sandra E.; Wu, Yvonne W.; McKinstry, Robert C.; Radiology and Imaging Sciences, School of Medicine
    Introduction: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms. Methods and analysis: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans. Ethics and dissemination: IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor.
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    Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns
    (Massachusetts Medical Society, 2022) Wu, Yvonne W.; Comstock, Bryan A.; Gonzalez, Fernando F.; Mayock, Dennis E.; Goodman, Amy M.; Maitre, Nathalie L.; Chang, Taeun; Van Meurs, Krisa P.; Lampland, Andrea L.; Bendel-Stenzel, Ellen; Mathur, Amit M.; Wu, Tai-Wei; Riley, David; Mietzsch, Ulrike; Chalak, Lina; Flibotte, John; Weitkamp, Joern-Hendrik; Ahmad, Kaashif A.; Yanowitz, Toby D.; Baserga, Mariana; Poindexter, Brenda B.; Rogers, Elizabeth E.; Lowe, Jean R.; Kuban, Karl C. K.; O'Shea, T. Michael; Wisnowski, Jessica L.; McKinstry, Robert C.; Bluml, Stefan; Bonifacio, Sonia; Benninger, Kristen L.; Rao, Rakesh; Smyser, Christopher D.; Sokol, Gregory M.; Merhar, Stephanie; Schreiber, Michael D.; Glass, Hannah C.; Heagerty, Patrick J.; Juul, Sandra E.; HEAL Consortium; Pediatrics, School of Medicine
    Background: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. Methods: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. Results: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). Conclusions: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events.