Glucose management in Neonatal Resuscitation: NLS 5602 /tf ScR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: Chris McKinlay – investigator on grants related to neonatal hypoglycemia, author of 19 publications related to neonatal hypoglycemia, recipient of research funding related to a device for assessing neonatal hypoglycemia. These conflicts were assessed and managed as follows: Author CJD McKinlay has published studies relating to the topics addressed in the review and was excluded from study selection for any studies on which he is an author. The review contains no discussion of specific devices for glucose monitoring, so the industry patent is not a significant conflict. For other authors, there are no conflicts of interest.

Task Force Synthesis Citation

Insert citation for ILCOR.org posting of a Task Force Synthesis of a Scoping Review

Example – Note: this should reflect the TF members who contributed to the Synthesis not an author list of the Scoping review

McKinlay CJD, Quek BH, Yeo CL, Ozawa Y, Hirakawa E. Schmölzer G, Weiner G, Liley HG for the Neonatal Life Support Task Force. Glucose Management in Neonatal Resuscitation; Task Force Synthesis of a Scoping Review [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, November 2024. Available from: http://ilcor.org

Methodological Preamble and Link to Published Scoping Review

Glucose management for neonatal resuscitation was addressed for the 2010 CoSTR {Perlman 2010 S516} which concluded that; “Newborns with lower blood glucose levels are at increased risk for brain injury and adverse outcomes after a hypoxic-ischemic insult, although no specific glucose level associated with worse outcome has been identified. Increased glucose levels after hypoxia or ischemia were not associated with adverse effects in a recent pediatric series or in animal studies, and they may be protective. However, there are no randomized controlled trials that examine this question. Due to the paucity of data, no specific target glucose concentration range can be identified at present.

Recommendation: Intravenous glucose infusion should be considered as soon as practical after resuscitation, with the goal of avoiding hypoglycemia (Class IIb, LOE C).

The PICOST was reassessed in an Evidence Update in 2020 using an updated literature search strategy and sufficient new literature was identified to justify updating the review. In 2022, the NLS Task Force prioritized a new review, and because of uncertainty as to how best to frame a revised PICOST question, decided to use Scoping Review methods.

The protocol for this review was developed using the Participants, Concepts and Context (PCC) framework. {Pollock 2021 2102}. Relevant sections of PCC framework for each question have been transferred to the PICOST/PECOST template. The PCC framework is outlined in section 4 (definitions).

Scoping Review

Webmaster to insert the Scoping Review citation and link to Pubmed using this format when/if it is available.

PICOST

1. When and how should blood glucose be monitored in newborn infants receiving resuscitation?

Population Newborn infants (preterm and term) who receive resuscitation at birth in all healthcare settings that provide birthing services.

Intervention Strategy of monitoring glucose or metabolites (lactate, ketones, insulin) or post-resuscitation care bundles that include such monitoring.

Comparison No monitoring or no defined strategy or alternative monitoring strategy.

Outcomes

• Dysglycemia
• Metabolites
• Feasibility
• Success of resuscitation
• Neonatal morbidity
• Neonatal brain injury
• Long-term neurological function

Study Design The following study designs were considered for inclusion: animal trials, human trials (randomized, non-randomized, historically controlled) and human observational studies (cohort, before-and-after, case-control, case series if ≥6 participants). Studies were eligible for inclusion if they directly or indirectly addressed the review questions. Studies were excluded if they had not been peer-reviewed or published in full text.

Timeframe All years and all languages will be included if there is an English abstract.

2. When and how should glucose therapies be used during and after neonatal resuscitation?

Population Newborn infants (preterm and term) receiving resuscitation at birth in all healthcare settings that provide birthing services.

Intervention Exogenous dextrose (intravenous, intraosseous, buccal) or glucagon or post-resuscitation care bundles that include glucose therapies.

Comparison No glucose therapies or alternative glucose therapy.

Outcomes

• Dysglycemia
• Metabolites
• Feasibility
• Success of resuscitation
• Neonatal morbidity
• Neonatal brain injury
• Long-term neurological function

Study Design The following study designs were considered for inclusion: animal trials, human trials (randomized, non-randomized, historically controlled) and human observational studies (cohort, before-and-after, case-control, case series if ≥6 participants). Studies were eligible for inclusion if they directly or indirectly addressed the review questions. Studies were excluded if they had not been peer-reviewed or published in full text.

Timeframe All years and all languages will be included if there is an English abstract.

3. What is the optimal blood glucose concentration range for newborn infants during and after resuscitation?

Population Newborn infants (preterm and term) receiving resuscitation at birth in all healthcare settings that provide birthing services.

Exposure Dysglycemia or defined blood glucose target range.

Comparison Normoglycemia or alternative target range.

Outcomes

• Success of resuscitation
• Neonatal morbidity
• Neonatal brain injury
• Long-term neurological function

Study Design The following study designs were considered for inclusion: animal trials, human trials (randomized, non-randomized, historically controlled) and human observational studies (cohort, before-and-after, case-control, case series if ≥6 participants). Studies were eligible for inclusion if they directly or indirectly addressed the review questions. Studies were excluded if they had not been peer-reviewed or published in full text.

Timeframe All years and all languages will be included if there is an English abstract.

Literature search updated to 6 October, 2024.

Search Strategies

Articles for review were obtained by searching Ovid Medline, EMBASE, the World Health Organisation and United States Clinical Trial registries and the Cochrane Database of Systematic Reviews for all entries from database inception to 6 October 2024. The search strategy was designed in consultation with an information specialist (University of Auckland, New Zealand).

For detailed search strategy - see appendix.NLS 5602 Appendix 1 Search Strategy

Definitions:

Scoping review exposures and outcomes were defined as follows:

• Neonatal resuscitation is the restoration/preservation of life by the establishment and/or maintenance of airway, breathing and circulation, and related emergency care, including such measures when used to promote transition from intrauterine to extrauterine life.

• Post-resuscitation care refers to the first 1 to 2 hours after birth, or up to 6 hours for infants with hypoxic-ischaemic encephalopathy.

• Glucose monitoring can be performed with intermittent blood glucose measurements or continuous sensors. The type, frequency, duration and feasibility of glucose monitoring in included studies is described.

• Metabolites. In addition to glucose, other metabolic markers may be useful in characterizing metabolic transition and cerebral energy supply, including blood lactate, ketone and insulin concentrations.

• Glucose therapies relevant to resuscitation include exogenous dextrose (intravenous, intraosseous, buccal) and glucagon (intramuscular, intravenous). These could be given during resuscitation in infants with poor response or in post-resuscitation care, with or without prior glucose monitoring. In post-resuscitation care, glucose therapies could be provided as part of a bundles of care.

• Dysglycemia includes hypoglycemia (low blood glucose concentration [BGC]) and hyperglycemia (high BGC), which are usually characterized as episodes (periods of consecutive low or high BGC). Clinical thresholds vary and are widely debated. For this review, hypoglycemia was defined as an episode of BGC ≤2.5 mmol/L (≤45 mg/dL) {McKinlay 2015 1507} and hyperglycemia as an episode of BGC ≥7 mmol/L (≥126 mg/dL), {Hay 2018 6}, or as per author definitions.

• Success of resuscitation includes survival in the delivery room; chest compressions; time to heart rate >100; time to first breath; intubation; duration of positive pressure ventilation and final oxygen concentration in the delivery room. {Strand 2020 328}.

• Neonatal morbidity. The Neonatal Life Support Task Force has prioritized the following short-term clinical outcomes for resuscitation studies: admission to neonatal intensive care, survival to discharge, moderate-severe bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage, pneumothorax, duration of oxygen supplementation, blood transfusion and length of hospital stay. {Strand 2020 328}

• Neonatal brain injury due to hypoglycemia is demonstrated by seizures, abnormal brain imaging and though rarely available, histopathological changes. Restricted diffusion on magnetic resonance imaging is common in acute neonatal hypoglycemia, especially in the posterior brain,{Kim 2006 144} although wider patterns of injury have been reported. {Burns 2008 65, Cakmakci 2001 2585} In contrast to ischemia, the restricted diffusion associated with hypoglycemia does not necessarily imply cell death and may represent intramyelinic oedema, which can resolve. {Moritani 2005 216} Variable chronic abnormalities have been reported, including atrophy of occipital cortical and white matter and deep grey matter.{Murakami 1999 23, Nivins 2022 102943} Apart from seizures, neonatal hypoglycemia does not have any distinct features on electroencephalography. {Harris 2009 271, Harris 2011 755} Hyperglycemia has been associated with measurable EEG changes in preterm infants but the long-term significance of these changes is unclear. {Wikström 2011 e1028}

• Outcomes relating to long-term neurological function include standardized tests from 1.5 years’ corrected age of cognitive, language, motor, visual, executive and emotional-behavioral function; the presence of epilepsy and cerebral palsy; and educational achievement.

• Feasibility. It is important that any interventions undertaken during resuscitation can be performed in a timely manner and do not adversely impact on staff performance. We sought quantitative and qualitative information relating to the feasibility of providing glucose monitoring and therapies in resuscitation and during post-resuscitation care.

Inclusion and Exclusion criteria

The following study designs were included if they addressed one or more review questions: animal randomized trials, human trials (randomized, non-randomized, historically controlled) and human observational studies (cohort, before-and-after, case-control, case series if ≥6 participants). Studies were excluded if they were not peer-reviewed, not available in full text or an English translation could not be obtained. For studies of interventions/exposures in infants with moderate-to-severe perinatal acidosis or hypoxic-ischemic encephalopathy (HIE), the resuscitation criterion was assumed to have been met, even if not explicitly reported, provided there was evidence of compromise from birth. Relevant studies that reported dysglycemia after the first 6 hours (as exposure or outcome) were included, but the evidence was considered indirect. Narrative reviews, commentaries and guidelines without primary data were excluded, but were reviewed for relevant citations. Systematic reviews were considered eligible if they provided meta-analysis of one or more scoping review outcomes.

Data tables

Table 1: Frequency of dysglycemia among newborn infants receiving resuscitation at birth: NLS 5602 Data tables

See appendix for characteristics of included human and animal studies: NLS 5602 Appendix 2 Characteristics of included human and animal studies

Task Force Insights

1. Why this topic was reviewed.

Successful newborn life support is underpinned by physiological transition in several key organ systems, especially the lungs and circulation. Activation and adaptation of metabolic tissues, namely the liver and pancreas, also becomes essential the moment the cord is cut. The liver must replace the placenta as the main source of fuels for cellular energy, primarily glucose and ketones, and the pancreas must adapt to a new pattern of insulin secretion, with suppression of insulin as glucose concentrations fall. This metabolic transition may be disturbed in infants who undergo resuscitation and/or have perinatal hypoxia-ischemia leading to hypoglycemia, either because of underlying risk factors, impaired postnatal adaptation or more rapid utilization of glucose during anaerobic metabolism. Hypoglycemia may affect the success of resuscitation through adverse effects on cardiac contraction or respiratory drive, and/or may exacerbate brain injury, particularly as hypoxic-ischemic and metabolic encephalopathy share many pathophysiological features in the newborn. Conversely, sympathetic-mediated stress responses and/or epinephrine exposure may cause hyperglycemia after resuscitation, which can also contribute to brain injury. Thus, there is increasing concern that metabolic perturbations soon after birth, especially of glucose, may impact on short and long-term outcomes of newborn infants undergoing resuscitation. A comprehensive review of glucose management in newborn resuscitation, including post-resuscitation care, is needed, addressing questions of monitoring, treatment and influence on clinical outcomes.

2. Narrative summary of evidence identified

• When and how should blood glucose be monitored in newborn infants receiving resuscitation?

There is a high incidence of dysglycemia in infants receiving resuscitation at birth, especially among those with hypoxic ischemic encephalopathy (HIE), with approximately 1 in 7 and 1 in 4 experiencing hypoglycemia and hyperglycemia, respectively, over the first 6 h (6 studies{Basu 2016 F149, Frazier 2007 82, Galderisi 2023 837, Montaldo 2020 218, Nadeem 2011 10, Parmentier 2022 30}). This increases to approximately 1 in 5 for hypoglycemia and 1 in 2 for hyperglycemia at 24 h or more (11 studies{Ali 2024 262, Alsaleem 2021 490, Basu 2018 137, Davis 1999 76, Guellec 2023 113350, Nadeem 2011 10, Parmentier 2022 30, Pinchefsky 2019 23, Tam 2012 88, Tan 2017 e000175, Wang 2023 105878}). Almost all the included infants were born at ≥34 weeks’ gestation, and most either had or were at risk of hypoxic-ischemic encephalopathy.

No data were available to determine the optimal methods or protocol for blood glucose concentration (BGC) screening. For example, the accuracy and feasibility of heel prick vs. venous sampling during or immediately after resuscitation is unknown, although 1 study reported that BCG could be measured in the delivery room.{Basu 2009 833}

Subgroups: In a study of 895 infants, the risks of both hypoglycemia and hyperglycemia in the first 12 h after birth were two to three times higher in infants with severe acidosis compared with mild acidosis (4% vs 8%, and 8% vs. 23%, respectively).{Liu 2023 562} Another study also reported that infants with dysglycemia at <12 h of age had more severe perinatal acidosis.{Mietzsch 2023 e2022060965} In a study of 122 infants, those receiving epinephrine compared with no epinephrine had a lower risk of hypoglycemia in the first 6 h after birth (24% vs. 34%).{Tan 2017 e000175} Similarly, in a study of 47 infants, all of whom received epinephrine, the risk of hypoglycemia on NICU admission was halved in those receiving epinephrine via the intravenous compared with the endotracheal route, although the risk of hypoglycemia remained high overall (total 23%; intravenous epinephrine 22% vs. endotracheal epinephrine 43%).{Barber 2006 1028} In another study, among 62 late preterm and term infants, those receiving epinephrine (65% via the IV route), compared with no epinephrine, had increased BGC over the first 12 h by ~2.2 mmol/L (40 mg/dL), with mean BGC >7 mmol/L (>125 mg/dL) from 1 h of age.{Alsaleem 2021 490} This association was not seen in moderate and very preterm infants, among whom the overall risk of hypoglycemia in the first 24 hours was 34%.{Alsaleem 2021 490}

• When and how should glucose therapies be used during and after neonatal resuscitation?

There were no human studies addressing this question. While there was some animal evidence that supra-physiological glucose concentrations in blood and brain at the time of a perinatal HI insult may protect against infarction, the findings were not universal, and exposure to hyperglycemia from exogenous glucose treatment during recovery from HI, while increasing cerebral glucose utilization, consistently had adverse effects on brain function and increased mortality. Thus, while infants undergoing resuscitation at birth remain at risk of hypoglycemia, a cautious approach to the use of glucose therapies in the context of HI appears prudent, due to the risk of iatrogenic hyperglycemia. For infants with severe depression at birth, it remains unknown if empiric use of glucose therapies improves the success of resuscitation. During post-resuscitation care, routine commencement of maintenance IV dextrose was a common practice in infants admitted to NICU, typically at 4 mg/kg/min, but there was no analysis of the impact of this on the high incidence of hyperglycemia, especially during therapeutic hypothermia (TH). Although several studies noted that hypoglycemia was corrected with increases in IV dextrose and/or glucagon, there were no data to indicate the best strategy to achieve euglycemia and avoid subsequent iatrogenic hyperglycemia during the treatment of hypoglycemia.

• What is the optimal blood glucose concentration range for newborn infants during and after resuscitation?

While adverse associations between early dysglycemia and neonatal brain injury, death and NDI were widely reported in animal and human studies, especially in HIE, with and without TH, no studies directly investigated the optimal BGC target range for infants immediately after perinatal HI or during subsequent recovery. Nevertheless, the relatively large absolute increases in the risk of death and NDI seen in infants with HIE exposed to early (<6 h of age) hypoglycemia or early hyperglycemia, compared with those not so exposed (from 15% to 37%), although not adjusted for potential confounding, suggest that there may be clinical benefit from targeting a BGC range and/or adopting strategies to increase time in range during neonatal post-resuscitation care. However, whether a lower or higher target is better, remains unknown.

3. Narrative Reporting of the task force discussions

This scoping review did not identify sufficient evidence to support progression to systematic review and meta-analysis of specific interventions in glucose management in neonatal resuscitation; thus, there is currently insufficient evidence to make treatment recommendations.

However, the Task Forced judged that the following Good Practice Statements (GPS) could be made based on the findings of this scoping review:

1. Among newborn infants receiving resuscitation, blood glucose concentration should be measured early in the post-resuscitation period and monitored with serial measurements until maintained within a normal range. Infants at greatest risk of hypo- and hyperglycemia during the post-resuscitation period include preterm infants, infants receiving chest compressions or epinephrine, and those with hypoxic ischemic encephalopathy.

1. Treatment with intravenous dextrose infusions should be guided by the infant’s blood glucose concentration with the goal of avoiding both hypoglycemia and hyperglycemia.

Importantly, it remains unclear if or when exogenous glucose should be used during neonatal cardiopulmonary resuscitation, and for infants at risk of hypoxic-ischemic encephalopathy, whether a lower or higher BGC target is superior during post-resuscitation care.

Knowledge Gaps

In newborns who are receiving or have received resuscitation, further evidence is needed for:

• Dysglycemia in moderate or very preterm infants and its short and long-term effects
• Optimal strategies and devices for monitoring of blood glucose
• Role of other metabolites (e.g., ketones, lactate) and hormone responses (glucagon, cortisol, catecholamines) in mitigating or exacerbating dysglycemia and in glycemic management
• Optimal targets for blood glucose levels
• Optimal strategies for intravenous glucose administration

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Park WS, Chang YS, Lee M. Effect of hypothermia on brain cell membrane function and energy metabolism after transient global hypoxia-ischemia in the newborn piglet. Journal of Korean medical science. 2001;16(3)335-41.

Park WS, Chang YS, Lee M. Effects of hyperglycemia or hypoglycemia on brain cell membrane function and energy metabolism during the immediate reoxygenation-reperfusion period after acute transient global hypoxia-ischemia in the newborn piglet. Brain research. 2001;901(1-2)102-8.

Parmentier CEJ, de Vries LS, van der Aa NE, Eijsermans MJC, Harteman JC, Lequin MH, et al. Hypoglycemia in Infants with hypoxic-ischemic encephalopathy is associated with additional brain injury and worse neurodevelopmental outcome. The Journal of pediatrics. 2022;24530-38 e1.

Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010;122(16 Suppl 2)S516-38.

Pinchefsky EF, Hahn CD, Kamino D, Chau V, Brant R, Moore AM, et al. Hyperglycemia and glucose aariability are associated with worse brain function and seizures in neonatal encephalopathy: a prospective cohort study. The Journal of pediatrics. 2019;20923-32.

Pollock D, Davies EL, Peters MDJ, Tricco AC, Alexander L, McInerney P, et al. Undertaking a scoping review: A practical guide for nursing and midwifery students, clinicians, researchers, and academics. Journal of advanced nursing. 2021;77(4)2102-2113.

Raveendran AT, Skaria PC. Learning and cognitive deficits in hypoxic neonatal rats intensified by BAX mediated apoptosis: protective role of glucose, oxygen, and epinephrine. The International journal of neuroscience. 2013;123(2)80-8.

Rosenberg AA, Murdaugh E. The effect of blood glucose concentration on postasphyxia cerebral hemodynamics in newborn lambs. Pediatric research. 1990;27(5)454-9.

Salhab WA, Wyckoff MH, Laptook AR, Perlman JM. Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia. Pediatrics. 2004;114(2)361-6.

Sheldon RA, Partridge JC, Ferriero DM. Postischemic hyperglycemia is not protective to the neonatal rat brain. Pediatric research. 1992;32(4)489-93.

Spies EE, Lababidi SL, McBride MC. Early hyperglycemia is associated with poor gross motor outcome in asphyxiated term newborns. Pediatric neurology. 2014;50(6)586-90.

Stonestreet BS, Laptook AR, Siegel SR, Oh W. The renal response to acute asphyxia in spontaneously breathing newborn lambs. Early human development. 1984;9(4)347-61.

Strand ML, Simon WM, Wyllie J, Wyckoff MH, Weiner G. Consensus outcome rating for international neonatal resuscitation guidelines. Archives of disease in childhood Fetal and neonatal edition. 2020;105(3)328-330.

Tam EW, Haeusslein LA, Bonifacio SL, Glass HC, Rogers EE, Jeremy RJ, et al. Hypoglycemia is associated with increased risk for brain injury and adverse neurodevelopmental outcome in neonates at risk for encephalopathy. The Journal of pediatrics. 2012;161(1)88-93.

Tan JKG, Minutillo C, McMichael J, Rao S. Impact of hypoglycaemia on neurodevelopmental outcomes in hypoxic ischaemic encephalopathy: a retrospective cohort study. BMJ paediatrics open. 2017;1(1)e000175.

Thorngren-Jerneck K, Ley D, Hellström-Westas L, Hernandez-Andrade E, Lingman G, Ohlsson T, et al. Reduced postnatal cerebral glucose metabolism measured by PET after asphyxia in near term fetal lambs. Journal of neuroscience research. 2001;66(5)844-50.

Wang J, Liu N, Zheng S, Wang X, Zhang P, Lu C, et al. Association between continuous glucose profile during therapeutic hypothermia and unfavorable outcome in neonates with hypoxic-ischemic encephalopathy. Early human development. 2023;187105878.

Wikström S, Lundin F, Ley D, Pupp IH, Fellman V, Rosén I, et al. Carbon dioxide and glucose affect electrocortical background in extremely preterm infants. Pediatrics. 2011;127(4)e1028-34.

Yager JY, Heitjan DF, Towfighi J, Vannucci RC. Effect of insulin-induced and fasting hypoglycemia on perinatal hypoxic-ischemic brain damage. Pediatric research. 1992;31(2)138-42.

Young RS, Petroff OA, Aquila WJ, Cheung A, Gore JC. Hyperglycemia and the rate of lactic acid accumulation during cerebral ischemia in developing animals: in vivo proton MRS study. Biology of the neonate. 1992;61(4)235-42.

Yuan SZ, Blennow M, Runold M, Lagercrantz H. Effects of hyperglycemia on gasping and autoresuscitation in newborn rats. Biology of the neonate. 1997;72(4)255-64.]Paste any tables of included studies here, if there are any that are short and illustrative as a summary. Would keep much longer, more detailed tables as appendices to the paper. See CoSTR website (by searching Scoping reviews) for examples