Dose-dependent exacerbation of ventilation-induced lung injury by erythropoietin in preterm newborn lambs

Abstract

Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury, but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs. Ventilation was initiated in anaesthetized preterm lambs [125 ± 1 (SD) days gestation] using an injurious strategy for the first 15 min. Lambs were subsequently ventilated with a protective strategy for a total of 2 h. Lambs were randomized to receive either intravenous saline (Vent; n = 7) or intravenous 300 ( n = 5), 1,000 (EPO1000; n = 5), or 3,000 (EPO3000; n = 5) IU/kg of human recombinant EPO via an umbilical vein. Lung tissue was collected for molecular and histological assessment of inflammation and injury and compared with unventilated control lambs (UVC; n = 8). All ventilated groups had similar blood gas and ventilation parameters, but EPO1000 lambs had a lower fraction of inspired oxygen requirement and lower alveolar–arterial difference in oxygen. Vent and EPO lambs had increased lung interleukin (IL)-1β, IL-6, and IL-8 mRNA, early lung injury genes connective tissue growth factor, early growth response protein 1, and cysteine-rich 61, and liver serum amyloid A3 mRNA compared with UVCs; no difference was observed between Vent and EPO groups. Histological lung injury was increased in Vent and EPO groups compared with UVCs, but EPO3000 lambs had increased lung injury scores compared with VENT only. Early low-doses of EPO do not exacerbate ventilation-induced lung inflammation and injury and do not provide any short-term respiratory benefit. High doses (≥3,000 IU/kg) likely exacerbate lung inflammation and injury in ventilated preterm lambs. NEW & NOTEWORTHY Trials are ongoing to assess the efficacy of erythropoietin (EPO) to provide neuroprotection for preterm infants. However, high doses of EPO increase ventilation-induced lung injury (VILI) in preterm lambs. We investigated whether early lower doses of EPO may reduce VILI. We found that lower doses did not reduce, but did not increase, VILI, while high doses (≥3,000 IU/kg) increase VILI. Therefore, lower doses of EPO should be used in preterm infants, particularly those receiving respiratory support.

Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research

“…These findings led in turn to clinical trials (see below). Subsequent studies in preterm lambs suggested that a lower single dose of EPO at 1000 IU/kg may be the optimal dose, compared with 3000 IU/kg and 5000 IU/kg, to achieve both lung and brain protection in preterm infants [139][140][141][142]. The latter results are particularly relevant to ventilated preterm infants, which constitute the majority of these neonates.…”

Erythropoietin for preventing bronchopulmonary dysplasia in preterm infants: A systematic review and meta‐analysis

“…54,55 In addition, recent studies shown that administration of bone marrow MSCs in combination with rEPO, which could suppress EMT process by inhibiting the transforming growth factor-β1 signaling pathway, significantly attenuated hyperoxia-induced lung damage and maybe a promising therapeutic strategy. 53,56,57 However, Polglase et al 58,59 investigated whether a single dose of rEPO administration can protect the lung from ventilation induced injury in preterm lambs. Their findings demonstrated that administration of high-dose rEPO (i.v.…”

Respiratory Support of the Preterm Neonate: Lessons About Ventilation-Induced Brain Injury From Large Animal Models

“…When administered to preterm lambs that received 15 min of injurious high V T ventilation, single early low doses of 300 IU/kg and 1,000 IU/kg human recombinant EPO did not reduce or exacerbate lung and brain injury (124,125), suggesting that EPO doses presently used in clinical trials appear to be safe for preterm infants receiving respiratory support. However, they appear to not be efficacious as a therapy for VIBI given the lack of therapeutic potential observed.…”

“…High doses of EPO of 3,000 IU/kg and 5,000 IU/kg increased cerebrospinal fluid EPO levels to “neuroprotective levels” [>100 mU/ml ( 126 )] within 2 h of administration ( 73 , 124 ). These high doses, respectively, had a protective effect on blood-brain barrier integrity ( 124 ) and differential regional effects on white matter ( 73 ) despite both doses amplifying lung inflammation and injury ( 125 , 127 ). Together, these data highlight a complex dose response with distinct effects on the lungs and brain, indicating that further investigation is required to elucidate the efficacy of EPO in the context of a preterm infant requiring respiratory support.…”