Glycemic control in neonates with Hypoxic Ischemic Encephalopathy: A Goldilocks moment
Myron Yaster MD, Shawn Jackson MD PhD, and Ethan Sanford MD
We often provide anesthesia to “sick” neonates in the first few hours and days of their lives. Indeed, our ability to do this is the very essence of being a pediatric anesthesiologist. Many of these newborns have, or are at risk of developing, hypoxic-ischemic encephalopathy (HIE). A universal issue in the perioperative management of newborns is glycemic control. As you are all aware, newborns have little to no glucose reserves, often have limited fuels for the brain like lactate and ketone bodies, and because of their immature kidney function and glomerular glucose resorption ability, often spill glucose at blood levels less than the accepted 198 mg/dL seen in older children and adults.1, 2 In the ORs, the stress response of surgery and anesthesia results in the release of a cascade of counterregulatory hormones, like cortisol, glucagon, growth hormone, and thyroid hormone to name just a few that that increase blood glucose and complicates glycemic control. Thus, we are often left with many decisions about whether to provide glucose, how much glucose and in what concentrations, and what target glucose to aim for? As you will see, the very definitions of what is considered hypo-, normo-, or hyperglycemia in the neonate are hardly set in stone2 and what blood levels we should be aiming for in the operating rooms and in transport to and from the ORs is unclear. Finally, as an attending anesthesiologist, how to treat either HYPO or HYPER glycemia in the OR is assumed, but should it be? Indeed, this has been omitted from the PEDI crisis app and I think it should be added.
Today’s PAAD1 and its accompanying editorial2 review glycemic control as a secondary analysis of newborns in the first 12 hours of their lives and who were part of an HIE therapeutic hypothermia study. The results are hardly surprising AND are associations. And as Dr. Jim DiNardo always reminds the PAAD readership “associations are not causations”! Nevertheless, I would urge all of you to discuss today’s papers amongst yourselves or in a journal club to help develop practice guidelines for perioperative glycemic management of neonates in your home institutions. Finally, I’ve asked Drs. Shawn Jackson and Ethan Sanford, SPA members who are Board certified in Pediatrics, Anesthesiology, Pediatric Anesthesiology, and Pediatric Critical Care Medicine to help. Myron Yaster MD
Editorial
Raul Chavez-Valdez, Khyzer Aziz, Vera Joanna Burton, Frances J. Northington; Worse Outcomes From HIE Treatment Associated With Extreme Glycemic States. Pediatrics October 2023; 152 (4): e2023062521. 10.1542/peds.2023-062521
Original article
Ulrike Mietzsch, Thomas R. Wood, Tai-Wei Wu, Niranjana Natarajan, Hannah C. Glass, Fernando F. Gonzalez, Dennis E. Mayock, Bryan A. Comstock, Patrick J. Heagerty, Sunny E. Juul, Yvonne W. Wu, HEAL Study Group; Early Glycemic State and Outcomes of Neonates With Hypoxic-Ischemic Encephalopathy. Pediatrics October 2023; 152 (4): e2022060965. 10.1542/peds.2022-060965
As a pediatric anesthesia fellow, I remember very distinctly being coached through a neonatal intestinal obstruction case by Bob Holzmann. What stood out was his advice to not let the surgeons mess around too long (he may have used different verbiage) and to mind the glucose. The latter advise is supported by Mietzsch et al.1 in their analysis of blood glucose and outcomes in a group of neonates undergoing therapeutic hypothermia due to moderate or severe HIE.
HYPOglycemia was defined as a glucose level <50 mg/dL, NORMOglycemia as a glucose of 50-200 mg/dL, and HYPERglycemia as a glucose >200 mg/dL. Glucose levels in the first 12 hours of life were analyzed among 491 infants. “Hyperglycemia was significantly more common among neonates with severe [HIE] compared with those with moderate HIE (42.3% vs 16.9%; P < .001), whereas the rate of hypoglycemia was similar among both groups (severe, 21.4% vs moderate, 19.5%; P = .69).” The odds of death were increased for both the hypoglycemia (AOR 2.85, 1.09-7.43) and hyperglycemia (AOR 2.52, 1.10-5.77) groups, but only the hypoglycemia group had greater odds of neurodevelopmental impairment (AOR 2.50, 1.09-7.43).
Ok, hypo- and hyper-glycemia were both associated with poor outcomes. This is not surprising. Abnormal glycemic states are caused by severe illness. In this study, the infants with severe HIE were much more likely to have hyperglycemia, while hypoglycemia rates were similar among the study populations. However, the study cannot determine if the glycemic state itself causes the worsened outcomes. In other words, these associations do NOT mean causation. The results do, however, raise several possibly important factors we should consider in the anesthetic care of these infants. 1) does the preop level of glycemic control matter and if so, should glycemic control be optimized prior to anesthesia, 2) does intraoperative correction of either hypo- or hyper-glycemia improve outcomes? 3) how should we go about correcting hyper or hypoglycemia.
The underlying surgical pathology is often driving the poor glycemic control, so delaying an emergent surgical repair is probably unwise. However, for infants undergoing semi-elective procedures, correcting hypoglycemia and possibly giving some time for correction of hyperglycemia may be considered.
Correcting abnormal glycemic state in the OR seems like a good idea. To do so we must first identify abnormalities. We believe protocols regarding intraop glucose checks should be adopted for all neonates. Equally important for us is the actual definition of HYPOglycemia and HYPERglycemia. As Chavez-Valdez et al. in their editorial point out, “the Pediatric Endocrine Society recommends a higher hypoglycemia threshold of 70 mg/dL for neonates receiving glucose-containing intravenous fluids”3 than the 50 mg/dL used in this study and by many of you. Further, these glucose levels assume the neonates are otherwise healthy, which in our practice is usually not the case! “HYPERglycemia is usually based on glucose excretion in urine, which in healthy adults occurs at 198 mg/dL. Because of the immature glomeruli glucose resorption in neonates, glucose excretion occurs at much lower blood concentrations and more so in the setting of acute kidney injury, as can occur with HIE. Thus, neonatal hyperglycemia is often defined as a level exceeding 144 to 150 mg/dL.”2 These levels should be further defined for the perioperative space.
Finally, after determining whether a baby is hyper or hypoglycemic, how should we respond? Hypoglyecmia on first pass seems simple, give dextrose. But how much, and when should we re-check? Is it better to err on the side of overshooting? Hyperglycemia may be even more complicated. Should we lower the glucose infusion rate (GIR)* by decreasing the fluid rate, decreasing the dextrose concentration, or both? Or should we give insulin? Should we attempt to increase depth of anesthesia to prevent adrenocortical stress responses? At what glucose levels should any of these interventions be considered?
Answering these questions with outcomes-based research is a monumental task. But that doesn’t mean we should turn a blind eye to our practice. How much glucose (or insulin) to administer, in what concentrations, and at what rates is something that should be institutionally formalized and monitored. This entire space is ripe for QI interventions to improve our ability to do what we think we should do (hello Lynne Martin, AdaptX, and quality improvement and patient safety networks). Further, we think that it is impossible to know glucose levels without measuring them and despite the difficulties, obtaining an intraoperative glucose measurement in neonates may be as important as measuring blood pressure, ECG, and temperature. So, just like Goldilocks, not too much, not too little, just right.
What do you think? Send your responses to Myron who will post in a Friday Reader Response.
* A quick pearl regarding the Glucose Infusion Rate (GIR). GIR refers to the milligrams of glucose being administered per kilogram body weight per minute (mg/kg/min). A typical (non-stressed) neonatal GIR is often 4-8 ml/kg/min, but how does this relate to our typical administration of IV fluids at the standard 4-2-1 maintenance rates? As it turns out, for patients under 10kg, running a D10 solution at maintenance (4 ml/kg/hr) results in a GIR of 6.67 mg/kg/min! This both provides support for a common practice and can be a good starting point when thinking about changing rates or glucose concentrations as it relates to GIR! And remember when running D10 W always use an infusion pump and never do this with as free drip infusion!
References
1. Mietzsch U, Wood TR, Wu T-W, et al. Early Glycemic State and Outcomes of Neonates With Hypoxic-Ischemic Encephalopathy. Pediatrics. 2023;152(4)doi:10.1542/peds.2022-060965
2. Chavez-Valdez R, Aziz K, Burton VJ, Northington FJ. Worse Outcomes From HIE Treatment Associated With Extreme Glycemic States. Pediatrics. 2023;152(4)doi:10.1542/peds.2023-062521
3. Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. The Journal of pediatrics. Aug 2015;167(2):238-45. doi:10.1016/j.jpeds.2015.03.057