ACCEPTED ARTICLE PREVIEW
Accepted Article Preview: Published ahead of advance online publication Effects of antenatal magnesium sulphate treatment for neonatal neuroprotection on cerebral oxygen kinetics
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Michael J Stark, Nicolette A Hodyl, Chad C Andersen
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Cite this article as: Michael J Stark, Nicolette A Hodyl, Chad C Andersen, Effects of antenatal magnesium sulphate treatment for neonatal neuro-protection on cerebral oxygen kinetics, Pediatric Research accepted article preview online 18 May 2015; doi:10.1038/pr.2015.96
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m
an
This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG is providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.
Received 08 August 2014; accepted 13 February 2015; Accepted article preview online 18 May 2015
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
Effects of antenatal magnesium sulphate treatment for neonatal neuro-protection on cerebral oxygen kinetics
Running Title: Magnesium sulphate and oxygen kinetics
Michael J Stark1, 2, Nicolette A Hodyl1, Chad C Andersen1, 2 1
Robinson Research Institute & School of Paediatrics and Reproductive Health, University of Adelaide,
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t
South Australia, Australia 2
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Department of Neonatology, Women’s & Children’s Hospital, North Adelaide, South Australia, Australia
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Financial support: Financial support for this study was provided by a Channel 7 Research Foundation
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Project Grant, Australia and a Women’s and Children’s Hospital Research Foundation Project Grant,
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Adelaide, Australia.
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Disclosure: The authors have no potential /perceived conflicts of interest to disclose.
Corresponding Author
Associate Professor Michael Stark
Department of Neonatal Medicine Women’s and Children’s Hospital 72 King William Road Adelaide, South Australia, Australia Telephone: +61 8 81617631
Email: [email protected]
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
Abstract Background: The underlying neuro-protective mechanisms of antenatal magnesium sulphate (MgSO4) in infants born preterm remain poorly understood. Early neonatal brain injury may be preceded by low cerebral blood flow and elevated cerebral fractional oxygen extraction (cFTOE). This study investigated the effect of antenatal MgSO4 on cerebral oxygen delivery, consumption and cFTOE in preterm infants. Methods: Cerebral blood flow and tissue oxygenation index were measured, and oxygen delivery, consumption and cFTOE calculated within 24 hours of birth and at 48 and 72 hours of life in 36 infants ≤
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t
30 weeks gestation exposed to MgSO4 and 29 unexposed infants.
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Results: Total internal carotid blood flow and cerebral oxygen delivery did not differ between the groups at the 3 study time-points. Cerebral oxygen consumption and cFTOE were lower in infants exposed to
an
antenatal MgSO4 (p=0.012) compared to unexposed infants within 24 hours of delivery. This difference
m
was not evident by 48 hours of age. Fewer infants in the MgSO4 group developed P/IVH by 72 hours of
d
age (p=0.03).
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Conclusions: Infants exposed to MgSO4 had similar systemic and cerebral haemodynamics but lower cFTOE compared to non-exposed. These findings suggest reduced cerebral metabolism maybe a
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component of the neuro-protective actions of antenatal MgSO4.
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
Introduction Despite significant improvements in survival for infants born preterm, the rate of major neurodevelopmental impairment in survivors has not diminished 1. As a result, strategies designed to reduce adverse neurological outcomes have been a major perinatal research focus. Antenatal magnesium sulphate (MgSO4) is one such strategy. Following the first report of an association between perinatal administration of MgSO4 and a reduction in the risk of peri/intraventricular haemorrhage (P/IVH) 2, its use as a neuro-protective therapy when given to women at risk of preterm birth has
rip
t
become established practice 3. While MgSO4 has been shown to decrease the risk of P/IVH 4, cerebral
us c
palsy and the rate of substantial gross motor dysfunction 5, the mechanisms underlying these effects
an
remain poorly understood.
m
Proposed mechanisms by which MgSO4 exerts a neuro-protective effect include effects on the
d
cardiovascular system through its role in the regulation of vascular tone 6, cerebral metabolism including
ep te
prevention of excess glutamate release 7, and reductions in systemic pro-inflammatory cytokine production 8. The effect of antenatal MgSO4 administration on the neonatal systemic and cerebral
A cc
vasculature is unclear. While increased cerebral blood flow velocities have been reported in infants whose mothers received MgSO4 for the management of pre-eclampsia or tocolysis 9,10 another study has reported significant lowering of neonatal cerebral perfusion
11
. The sole study reporting neonatal
cardiovascular effects of antenatal MgSO4 for neuro-protection found no difference in echocardiographic measures of systemic blood flow on the first day of life 12.
For extremely preterm infants, the transition to extra-uterine life is characterised by low baseline cerebral blood flow (CBF) and high cerebral oxygen consumption 13, with cerebral oxygen consumption reflecting cerebral metabolic activity 14. Elevated cerebral fractional oxygen extraction (cFTOE), derived
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
by near infrared spectroscopy (NIRS), is a readily measurable variable of the relationship between cerebral oxygen delivery and consumption and precedes early neonatal brain injury following very preterm birth 15,16. While studies in fetal sheep have reported temporary reductions in cerebral oxygen consumption following MgSO4 administration
17
it is only recently that similar effects have been
described in infants born to women given antenatal MgSO4 for pre-eclampsia 18. We hypothesized that reduced neonatal cerebral oxygen consumption contributes to the observed neuro-protective actions of antenatally administered MgSO4. Therefore, the aim of the current study was to investigate the effect of
rip
t
antenatal MgSO4 on cerebral oxygen delivery, consumption and cFTOE in preterm infants less than 30
us c
weeks gestation. Results
an
Clinical characteristics of infants are shown in Table 1. Thirty-six infants were exposed to MgSO4 for
m
neuro-protection, with 3 receiving a 4g loading dose alone prior to preterm delivery. The mean
d
(minimum-maximum) maintenance dose received was 8g (0.5-23g). There was no significant difference
ep te
for any clinical characteristics between those infants exposed to MgSO4 prior to delivery and those not. For the 28 infants not exposed to antenatal MgSO4, 12 (43%) delivered vaginally within 1 hour of
A cc
presentation to hospital and 16 (57%) required urgent emergency caesarean section following presentation (7 as a result of a significant cardiotocographic abnormality (such as persistent fetal tachycardia or prolonged fetal heart rate decelerations), 6 secondary to antepartum haemorrhage, 2 secondary to acute maternal sepsis/chorioamnionitis and 1 following umbilical cord prolapse). The mean (SD) age of the infants at time of the initial NIRS and cranial ultrasound study was 11 (6) hours for the non-exposed group and 12 (7) hours for the MgSO4 group. While four infants had cranial ultrasound evidence of P/IVH at the time of the NIRS study (all unilateral grade 1 IVH), fewer infants in the MgSO4 group (n=4) were diagnosed with P/IVH (all grades) compared to those not exposed to MgSO4 (n=9) by 72 hours of life (p=0.03).
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
A significant main effect for time was observed for mean arterial blood pressure (Figure 1A, p=0.01) and right ventricular output (Figure 1B, p=0.02). On post-hoc analysis mean arterial pressure at 72 hours of age was significantly higher compared to 24 hours (p
Accepted Article Preview: Published ahead of advance online publication Effects of antenatal magnesium sulphate treatment for neonatal neuroprotection on cerebral oxygen kinetics
rip
t
Michael J Stark, Nicolette A Hodyl, Chad C Andersen
us c
Cite this article as: Michael J Stark, Nicolette A Hodyl, Chad C Andersen, Effects of antenatal magnesium sulphate treatment for neonatal neuro-protection on cerebral oxygen kinetics, Pediatric Research accepted article preview online 18 May 2015; doi:10.1038/pr.2015.96
A cc
ep te
d
m
an
This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG is providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.
Received 08 August 2014; accepted 13 February 2015; Accepted article preview online 18 May 2015
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
Effects of antenatal magnesium sulphate treatment for neonatal neuro-protection on cerebral oxygen kinetics
Running Title: Magnesium sulphate and oxygen kinetics
Michael J Stark1, 2, Nicolette A Hodyl1, Chad C Andersen1, 2 1
Robinson Research Institute & School of Paediatrics and Reproductive Health, University of Adelaide,
rip
t
South Australia, Australia 2
us c
Department of Neonatology, Women’s & Children’s Hospital, North Adelaide, South Australia, Australia
an
Financial support: Financial support for this study was provided by a Channel 7 Research Foundation
m
Project Grant, Australia and a Women’s and Children’s Hospital Research Foundation Project Grant,
ep te
d
Adelaide, Australia.
A cc
Disclosure: The authors have no potential /perceived conflicts of interest to disclose.
Corresponding Author
Associate Professor Michael Stark
Department of Neonatal Medicine Women’s and Children’s Hospital 72 King William Road Adelaide, South Australia, Australia Telephone: +61 8 81617631
Email: [email protected]
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
Abstract Background: The underlying neuro-protective mechanisms of antenatal magnesium sulphate (MgSO4) in infants born preterm remain poorly understood. Early neonatal brain injury may be preceded by low cerebral blood flow and elevated cerebral fractional oxygen extraction (cFTOE). This study investigated the effect of antenatal MgSO4 on cerebral oxygen delivery, consumption and cFTOE in preterm infants. Methods: Cerebral blood flow and tissue oxygenation index were measured, and oxygen delivery, consumption and cFTOE calculated within 24 hours of birth and at 48 and 72 hours of life in 36 infants ≤
rip
t
30 weeks gestation exposed to MgSO4 and 29 unexposed infants.
us c
Results: Total internal carotid blood flow and cerebral oxygen delivery did not differ between the groups at the 3 study time-points. Cerebral oxygen consumption and cFTOE were lower in infants exposed to
an
antenatal MgSO4 (p=0.012) compared to unexposed infants within 24 hours of delivery. This difference
m
was not evident by 48 hours of age. Fewer infants in the MgSO4 group developed P/IVH by 72 hours of
d
age (p=0.03).
ep te
Conclusions: Infants exposed to MgSO4 had similar systemic and cerebral haemodynamics but lower cFTOE compared to non-exposed. These findings suggest reduced cerebral metabolism maybe a
A cc
component of the neuro-protective actions of antenatal MgSO4.
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
Introduction Despite significant improvements in survival for infants born preterm, the rate of major neurodevelopmental impairment in survivors has not diminished 1. As a result, strategies designed to reduce adverse neurological outcomes have been a major perinatal research focus. Antenatal magnesium sulphate (MgSO4) is one such strategy. Following the first report of an association between perinatal administration of MgSO4 and a reduction in the risk of peri/intraventricular haemorrhage (P/IVH) 2, its use as a neuro-protective therapy when given to women at risk of preterm birth has
rip
t
become established practice 3. While MgSO4 has been shown to decrease the risk of P/IVH 4, cerebral
us c
palsy and the rate of substantial gross motor dysfunction 5, the mechanisms underlying these effects
an
remain poorly understood.
m
Proposed mechanisms by which MgSO4 exerts a neuro-protective effect include effects on the
d
cardiovascular system through its role in the regulation of vascular tone 6, cerebral metabolism including
ep te
prevention of excess glutamate release 7, and reductions in systemic pro-inflammatory cytokine production 8. The effect of antenatal MgSO4 administration on the neonatal systemic and cerebral
A cc
vasculature is unclear. While increased cerebral blood flow velocities have been reported in infants whose mothers received MgSO4 for the management of pre-eclampsia or tocolysis 9,10 another study has reported significant lowering of neonatal cerebral perfusion
11
. The sole study reporting neonatal
cardiovascular effects of antenatal MgSO4 for neuro-protection found no difference in echocardiographic measures of systemic blood flow on the first day of life 12.
For extremely preterm infants, the transition to extra-uterine life is characterised by low baseline cerebral blood flow (CBF) and high cerebral oxygen consumption 13, with cerebral oxygen consumption reflecting cerebral metabolic activity 14. Elevated cerebral fractional oxygen extraction (cFTOE), derived
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
by near infrared spectroscopy (NIRS), is a readily measurable variable of the relationship between cerebral oxygen delivery and consumption and precedes early neonatal brain injury following very preterm birth 15,16. While studies in fetal sheep have reported temporary reductions in cerebral oxygen consumption following MgSO4 administration
17
it is only recently that similar effects have been
described in infants born to women given antenatal MgSO4 for pre-eclampsia 18. We hypothesized that reduced neonatal cerebral oxygen consumption contributes to the observed neuro-protective actions of antenatally administered MgSO4. Therefore, the aim of the current study was to investigate the effect of
rip
t
antenatal MgSO4 on cerebral oxygen delivery, consumption and cFTOE in preterm infants less than 30
us c
weeks gestation. Results
an
Clinical characteristics of infants are shown in Table 1. Thirty-six infants were exposed to MgSO4 for
m
neuro-protection, with 3 receiving a 4g loading dose alone prior to preterm delivery. The mean
d
(minimum-maximum) maintenance dose received was 8g (0.5-23g). There was no significant difference
ep te
for any clinical characteristics between those infants exposed to MgSO4 prior to delivery and those not. For the 28 infants not exposed to antenatal MgSO4, 12 (43%) delivered vaginally within 1 hour of
A cc
presentation to hospital and 16 (57%) required urgent emergency caesarean section following presentation (7 as a result of a significant cardiotocographic abnormality (such as persistent fetal tachycardia or prolonged fetal heart rate decelerations), 6 secondary to antepartum haemorrhage, 2 secondary to acute maternal sepsis/chorioamnionitis and 1 following umbilical cord prolapse). The mean (SD) age of the infants at time of the initial NIRS and cranial ultrasound study was 11 (6) hours for the non-exposed group and 12 (7) hours for the MgSO4 group. While four infants had cranial ultrasound evidence of P/IVH at the time of the NIRS study (all unilateral grade 1 IVH), fewer infants in the MgSO4 group (n=4) were diagnosed with P/IVH (all grades) compared to those not exposed to MgSO4 (n=9) by 72 hours of life (p=0.03).
© 2015 International Pediatric Research Foundation, Inc. All rights reserved
ACCEPTED ARTICLE PREVIEW
A significant main effect for time was observed for mean arterial blood pressure (Figure 1A, p=0.01) and right ventricular output (Figure 1B, p=0.02). On post-hoc analysis mean arterial pressure at 72 hours of age was significantly higher compared to 24 hours (p
