What is the first action taken by a nurse caring for a newborn with suspected hypoglycemia?

Editor's Note: Hypoglycemia is one of the most common conditions encountered in the care of newborn infants. When it comes to defining neonatal hypoglycemia or establishing treatment thresholds for low blood glucose in this population, consensus is fleeting. And our understanding of transitional glucose regulation in the newborn has been limited as well. To address these knowledge gaps, a committee of the Pediatric Endocrine Society convened an expert panel to develop "Recommendations From the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children."[1] These new recommendations for screening, diagnosing, and managing low blood glucose in the newborn are based on an updated understanding of the mechanisms underpinning transitional neonatal hypoglycemia. Furthermore, the guidelines aim to help clinicians recognize persistent hypoglycemia disorders so that effective treatment can be initiated and the newborn brain protected from a lack of energy substrate.

Medscape spoke with Pediatric Endocrine Society guideline author, Diva D. De León, MD, MSCE, of the Congenital Hyperinsulinism Center at The Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania. Dr De León explained the purpose of the guidelines and highlighted the key points for the neonatal clinicians who care for newborn babies.

Medscape: What is the purpose of the Pediatric Endocrine Society recommendations on hypoglycemia? Do these recommendations pertain to all newborn infants, including preterm and small-for-gestational age (SGA) infants?

Dr De León: The intent of the guidelines is to identify newborns who have persistent hypoglycemia. That may include some babies who are SGA or preterm. Low blood glucose is quite common in the first 2 days of life. A recent study[2] looked at the frequency of low blood glucose in at-risk children and normal neonates during the first 24 hours of life and found that up to 50% of babies considered at risk had low blood glucose levels. (The authors used 45 mg/dL as a cut-off.) In the entire group, independent of risk, 19% had a low blood glucose level in the first 48 hours of life. Thus, the frequency of low blood glucose concentrations in the first 48 hours of life is quite high.

Our purpose was to look at all babies and determine which babies have a persistent problem, beyond 48 hours of life, that needs to be addressed. Most available guidelines for screening at-risk newborns and managing low glucose concentrations in neonates focus on the immediate neonatal period but do not address the diagnosis and management of disorders causing recurrent and prolonged hypoglycemia. We want to distinguish between the infants who may just have neonatal hypoglycemia during that transitional period and those with a persistent problem or hypoglycemia that occurs for the first time after 3 days of life. Furthermore, we wanted to offer guidance on how to manage the hypoglycemia during the first 48 hours and then how to follow-up with those infants who are likely to have a persistent problem and how to arrive at the underlying cause of the persistent hypoglycemia.

Transitional Hypoglycemia in the Newborn

Medscape: In the neonatology world, it has been commonly believed that the postnatal fall in blood glucose is primarily related to withdrawal of the maternal glucose supply and that full-term newborns are protected from hypoglycemic brain damage because their brains can use alternative sources of fuel (eg, ketones) produced by glycogen stores during that time. However, the commentary, "Re-evaluating 'Transitional Neonatal Hypoglycemia': Mechanism and Implications for Management"[3] describes a new, revised understanding of what happens in the immediate postnatal period. Can you summarize this for us?

Dr De León: The abrupt interruption of a continuous glucose supply from the mother definitely contributes to that rapid decline in the neonatal plasma glucose, which usually reaches a nadir in the first 2 hours of life. However, newborns have lower glucose concentrations than older children for a period of time that can go beyond the immediate postnatal period. Studies have shown that the way newborns within the first 48 hours of life respond to these lower blood glucose levels is different from the response of an older infant or child. As you state, it has been a common belief that babies with low blood glucose levels still have ketones, and their brains will be protected. But multiple studies show that the ketones remain suppressed. If you give these babies glucagon and epinephrine, there is a glycemic response at the time of low blood glucose suggesting that there is suppression of ketogenesis and glycogenolysis. So these babies are keeping some of their glycogen stores and not releasing them, as might be expected when their blood glucose concentrations drop.

This direct and indirect evidence suggests incomplete insulin suppression during the first 2 days of life, indicating that there is a different plasma glucose threshold for insulin secretion in neonates during this time—essentially a transient hyperinsulinism. This, in part, explains why plasma glucose in the first 48 hours of a newborn's life is lower than it is in older infants, children, and adults. This transitional period shows a pattern of "hypoketotic hypoglycemia" and resembles the hormonal and fuel milieu of known genetic forms of congenital hyperinsulinism.

Medscape: What is the clinical, practical significance of what we have learned about transitional glucose regulation in the newborn?

Dr De León: The most important thing is the awareness that during periods of transitional hypoglycemia, the brain is still vulnerable to injury because ketone levels are suppressed, and lactate levels may not rise sufficiently to compensate for the lack of glucose. Similarly, we can't assume that the brains of breastfed babies will be protected from the adverse effects of hypoglycemia during an extended postnatal fast. Contrary to previous beliefs, there is no evidence that neonates' brains can tolerate a low glucose concentration better than older infants, children, or adults.

Although we often emphasize "high-risk" infants when speaking of neonatal hypoglycemia, even normal, healthy, full-term infants can experience transitional low plasma glucose concentrations. Usually, this resolves by 72 hours of life. Hypoglycemia that persists beyond 72 hours might have a different etiology and requires investigation.

Normal Blood Glucose Levels

Medscape: Precise, universally accepted definitions of "normal plasma glucose" and "hypoglycemia" in the newborn have eluded us for decades. The Pediatric Endocrine Society statement says that hypoglycemia cannot be defined by a specific plasma glucose level. For practical reasons, however, neonatal caregivers typically set a specific low threshold (eg, 45 mg/dL or 50 mg/dL) and apply it across the board. What plasma glucose concentration does the Pediatric Endocrine Society recommend as a threshold for the treatment of hypoglycemia in neonates?

Dr De León: Unfortunately, no single cut-off for hypoglycemia can address all possible scenarios. We define clinical hypoglycemia generally as a plasma glucose concentration low enough to cause symptoms and/or signs of impaired brain function. We actually provide three different levels of plasma glucose in the guidelines because the "normal" value changes with age, and the treatment threshold is influenced by other variables, such as whether a congenital hypoglycemia disorder is likely. For at-risk neonates without a suspected congenital hypoglycemia disorder, the goal of treatment is to maintain a plasma glucose concentration >50 mg/dL in the first 48 hours of life and >60 mg/dL after 48 hours. For neonates with a suspected congenital hypoglycemia disorder, the goal of treatment is to maintain the plasma glucose concentration >70 mg/dL.

Medscape: The Pediatric Endocrine Society statement mentions that the diagnosis of clinical hypoglycemia includes the presence of symptoms. Aren't clinical symptoms of hypoglycemia fairly rare in neonates; and by the time an infant develops signs and symptoms, wouldn't it be too late to prevent brain damage?

Dr De León: In newborn babies, even if they are symptomatic, the signs and symptoms of hypoglycemia are not very specific. Symptoms and signs of hypoglycemia can be classified as neurogenic (which result from the perception of physiologic changes caused by central nervous system-mediated sympathetic nervous discharge triggered by hypoglycemia) or neuroglycopenic (which arise from the failure of brain function caused by deficient glucose). In neonates, neurogenic signs include jitteriness, tachycardia, pallor, and hypothermia. Neuroglycopenic signs in neonates include lethargy, irritability, poor feeding, cyanosis, tachypnea, apneic episodes, weak or high-pitched cry, floppiness, eye-rolling, lip smacking, and seizures. These overlap with the signs and symptoms of sepsis and many other problems, so in a newborn, one cannot rely on identifying clinical symptoms and signs of hypoglycemia. That's why we recommend screening infants at risk for hypoglycemia. In a newborn at risk for hypoglycemia, the first blood glucose test should be done within the first 2 hours of life. The purpose is to decide which baby needs intervention.

Glucose Screening in the Newborn

Medscape: What is your recommendation for method of screening for low blood glucose in neonates?

Dr De León: Most newborn nurseries use point-of-care glucose meters to screen for low blood glucose, but these are not accurate enough. Many variables can interfere with the measurement of glucose using those meters. They use whole blood, and whole blood glucose values are approximately 15% lower than plasma glucose concentrations. So we recommend that when a baby is found to have a low blood glucose level with a bedside meter, you send blood for a confirmatory plasma glucose level to the lab. Even those samples sent for plasma glucose analysis can be inaccurate if there are any delays in processing. Red cell glycolysis can reduce the glucose concentration by up to 6 mg/dL (0.3 mmol/L) per hour. Those samples must be processed promptly to be accurate.

Medscape: What do you recommend for the timing of the first blood glucose screening test after birth in newborns at risk for hypoglycemia?

Dr De León: The postnatal nadir in blood glucose concentration of most newborns occurs between 1 and 2 hours of age. Therefore, in the guidelines, we recommend checking the blood glucose of newborns at risk for hypoglycemia within the first 2 hours of life. In addition to those with clinical signs and symptoms of hypoglycemia, neonates with elevated risk for hypoglycemia include large-for-gestational age (LGA; with or without gestational diabetes) infants, infants who have experienced perinatal distress, infants who are premature or postmature, infants of diabetic mothers, and infants with either a family history of a genetic hypoglycemia disorder or the presence of physical features characteristic of syndromes associated with hypoglycemia. Screening aids in making decisions about intervention.

Persistent Hypoglycemia in the Newborn

Medscape: An important focus of the recommendations is how to identify and evaluate the neonate whose hypoglycemia persists beyond 2-3 days of age. What problems can cause persistent or recurrent hypoglycemia?

Dr De León: It may not be immediately possible to differentiate between an infant with a persistent hypoglycemia disorder and a transient problem, but it should become feasible after day 2 or 3 of life, when the period of transitional neonatal hypoglycemia has resolved. For this reason, the Pediatric Endocrine Society guidance for hypoglycemia in neonates recommends that the focus for the first 24-48 hours of life should be on stabilization of glucose levels; whereas after 48 hours, neonates whose glucose values remain low or who have other risk factors should be evaluated to determine the etiology of hypoglycemia and ensure their safety before discharge.

Medscape: Let's say that you have a full-term, LGA infant whose mother had gestational diabetes. He was initially treated with intravenous (IV) dextrose and formula feeding on days 1 and 2 of life. He is now 72 hours old and has been exclusively breastfeeding for the past 12 hours, but his prefeeding blood glucose levels are still in the 40- to 45-mg/dL range (confirmed with a plasma glucose). What do you recommend? Is it time for a pediatric endocrinology consult, or should any testing be done first?

Dr De León: The persistence of plasma glucose concentration in the 40s beyond the first 48 hours of life (even with history of gestational diabetes) suggests the possibility of an underlying hypoglycemia disorder. At this point, pediatric endocrinology should be consulted for guidance with the diagnostic evaluation. The first step would be to obtain a critical sample during a spontaneous episode of hypoglycemia when the blood glucose is <50 mg/dL. The tests included in this critical sample can be tailored according to the suspected disorder but should include: plasma glucose, bicarbonate, plasma insulin, plasma lactate, and plasma beta-hydroxybutyrate.

The Safety Fast

Medscape: What is a safety fast, and how is it conducted? Would you share your protocol?

Dr De León: A safety fast is a provocative test to identify persistent or recurrent hypoglycemia and the need for more extensive evaluation. We recommend that neonates identified as at risk for persistent hypoglycemia undergo this safety fast after 48 hours of life and before discharge. Basically, a safety fast involves having a baby skip a feeding and closely monitoring vital signs and blood glucose levels. The blood glucose (using a point-of-care meter) is checked at preset time points—at 3 hours, 4 hours, and 5 hours into the fast. A confirmatory plasma glucose sample is sent to the lab at the end of the fast (6 hours) or at any time during the fast when the bedside glucose meter gives a result <50 mg/dL. The challenge is terminated sooner than 6 hours if the plasma glucose falls below 50 mg/dL or the neonate shows signs or symptoms of hypoglycemia.

If the baby's blood glucose level remains >60 mg/dL, we don't recommend any further evaluation. But if, during the fast, the baby's plasma glucose level falls below 60 mg/dL, or if the baby has a family history of a genetic hypoglycemia disorder, further evaluation, including an endocrinology consult, is warranted. A longer fast and other tests (beta hydroxybutyrate, free fatty acids, lactate, insulin) from samples taken during hypoglycemia (critical samples) can be informative.

Medscape: For which babies do you recommend a safety fast before discharge? Is it sufficient to do just a prefeeding (eg, about a 3-hour fast) point-of-care glucose test?

Dr De León: We think that if a baby required treatment with IV dextrose for hypoglycemia at any point, then a single point-of-care glucose measurement before discharge is not adequate. Those babies should be challenged by skipping at least one feeding and making sure that they can maintain their blood glucose concentrations in the normal range for 6-8 hours without feeding.

Not every baby who experienced transitional hypoglycemia needs a safety fast before discharge. But a baby with significant hypoglycemia during the first 48 hours of life, who required IV dextrose, for example, should have a safety fast to prove that the hypoglycemia was indeed transient and not persistent. Typically, in many hospitals, when babies who required IV dextrose to correct hypoglycemia begin feeding, their blood glucose levels are watched while the infusion is weaned and perhaps for several hours after the infusion is stopped. If the baby's plasma glucose level remains within normal limits, no further evaluation is done. We think that this is insufficient. Those babies should undergo the challenge that we call a "safety fast" before they are discharged.

Furthermore, neonates at known risk for a genetic or other persistent form of hypoglycemia (eg, congenital hyperinsulinism, glucose-6-phosphatase deficiency, fatty acid oxidation disorder) should undergo a safety fast, and a consultation with a specialist should be considered before discharge to determine what other testing should be done to exclude this condition.

Medscape: Clearly, to conduct a safety fast, some otherwise healthy-appearing babies might need to be kept in the hospital longer. Do you find that clinicians, families, and insurance companies accept this approach?

Dr De León: A challenge that we all encounter is that babies are often being discharged even before 48 hours of life. It's very difficult, at that early stage, to make the distinction between babies with a transient problem who are going to be fine and babies with a serious and a persistent hypoglycemia disorder. You need to wait at least 48 hours to make that distinction.

We are implementing this approach within our network. Our goal is that this approach will be implemented nationwide so that babies with persistent or recurrent hypoglycemia don't go unrecognized. It's a little early to assess how successful or widespread the implementation of this guidance is. We are still trying to spread the word.

Medscape: What else would you like clinicians who care for neonates to know about the Pediatric Endocrine Society's guidance statement?

Dr De León: One thing is that often by the time that an endocrinologist is consulted to evaluate a baby, it is too late. We want the community of pediatricians and others to be aware that not all of the hypoglycemia seen in this population in the first 48 hours of life is transient. Some children have an unrecognized hypoglycemia disorder. These infants must be identified and diagnosed before they leave the nursery. To not do so places them at very high risk for brain damage or even death.

We also want to make sure that children who have high genetic risk (ie, a sibling who also had hypoglycemia) are actively screened in the newborn period and proved to be unaffected before they are discharged from the nursery. If you know that a baby has a 25% or 50% chance of having a particular disorder, and you take a wait-and-see approach to symptoms, then you will miss some children because their symptoms are not reliable at this age.

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