**8. Treatment**

As mentioned previously, there are still no clearly set values to define hypoglycemia in the first 2 h of life. It is known that, in the healthy, full-term neonate, blood glucose levels are lowest between 30 and 60 min of life and rise thereafter to normal baseline values of 60–90 mg/dL between 90 and 180 min of life. This threshold should be considered the physiological goal or therapeutic target at which blood glucose levels should be maintained.

Although one may consider a diagnosis of hypoglycemia when plasma glucose levels are below 45 mg/dL, this is not an absolute cutoff. Depending on the etiology of hypoglycemia and, consequently, on the availability of alternative pathways for gluconeogenesis, patients may be symptomatic in the 45–60 mg/dL range, as in cases of fatty acid oxidation defects.

SGA and late-preterm infants should be fed every 2–3 h and screened before each feeding in the first 24 h. After 24 h, screening needs only be continued in those whose glucose levels remain below 50 mg/dL.

#### **8.1. Newborns asymptomatic in the first 2 h of life**

The need for treatment in these children has been called into question, as hypoglycemia may be transient and may resolve spontaneously through stimulant counter-regulatory mechanisms. In general, if the infant is asymptomatic, to start early breastfeeding without the need to draw blood for glucose measurement, formula feeding, or other special care.

However, in some newborns, this physiological process may fail, which may facilitate the development of hypoglycemia; therefore, the American Academy of Pediatrics suggests that in the first hour of life, asymptomatic at-risk infants should have a glucose check 30 min after feeding; if the blood glucose level remains below 25 mg/dL and the infant is asymptomatic, it should be fed again and blood glucose reassessed 1 h after the first check [67].

#### **8.2. Asymptomatic high-risk newborns**

**6. Laboratory diagnosis**

72 Selected Topics in Neonatal Care

**7. Diagnostic imaging**

**8. Treatment**

remain below 50 mg/dL.

**8.1. Newborns asymptomatic in the first 2 h of life**

high PO2

Glucometry is the method of choice for initial screening of glucose levels, due to its use and minimal blood sample required; however, levels should be confirmed through laboratory measurement in plasma, especially when the glucometer reading is very low, as this method is rather imprecise at the lower limit of detection. Several factors can affect the values obtained by glucometry, such as the expiration date of the test strip, ambient temperature and humidity in the storage environment, the presence of sugars other than glucose, metabolic acidosis,

devices have been tested with the aim of demonstrating that their results may be unreliable

A particular vulnerability of the occipital lobe to hypoglycemia has been observed on MRI [16], with no plausible explanation. Other authors have raised the possibility that variant anatomy of the circle of Willis and occipital lobe infarct may be implicated in these cases [2].

As mentioned previously, there are still no clearly set values to define hypoglycemia in the first 2 h of life. It is known that, in the healthy, full-term neonate, blood glucose levels are lowest between 30 and 60 min of life and rise thereafter to normal baseline values of 60–90 mg/dL between 90 and 180 min of life. This threshold should be considered the physiological goal or

Although one may consider a diagnosis of hypoglycemia when plasma glucose levels are below 45 mg/dL, this is not an absolute cutoff. Depending on the etiology of hypoglycemia and, consequently, on the availability of alternative pathways for gluconeogenesis, patients may be symptomatic in the 45–60 mg/dL range, as in cases of fatty acid oxidation defects.

SGA and late-preterm infants should be fed every 2–3 h and screened before each feeding in the first 24 h. After 24 h, screening needs only be continued in those whose glucose levels

The need for treatment in these children has been called into question, as hypoglycemia may be transient and may resolve spontaneously through stimulant counter-regulatory mechanisms. In general, if the infant is asymptomatic, to start early breastfeeding without the need

However, in some newborns, this physiological process may fail, which may facilitate the development of hypoglycemia; therefore, the American Academy of Pediatrics suggests that

to draw blood for glucose measurement, formula feeding, or other special care.

therapeutic target at which blood glucose levels should be maintained.

and influence the management indicated by a reading [14].

, hyperbilirubinemia, high hematocrit, and edema, among others [25, 66]. Several

Late-preterm, LGA, SGA, and intrauterine growth restriction (IUGR) infants, as well as those born to diabetic mothers, are at particular risk of hypoglycemia. However, they are often asymptomatic. Breastfeeding followed by repeated glucose measurement has been the standard of care. However, if hypoglycemia persists despite frequent feedings, continuous intravenous infusion of glucose may be indicated.

A dextrose infusion rate of 3–5 mg/kg/min may be used in infants born to diabetic mothers, both to prevent overstimulation of glucose secretion and because of the greater fat mass of these infants. A dextrose infusion rate of 4–7 mg/kg/min may be used in most full-term and late-preterm neonates. In IUGR neonates, a glucose infusion rate of 6–8 mg/kg/min is often necessary. A study in an animal model of IUGR revealed increased peripheral insulin sensitivity, which may be associated with increased glucose infusion requirements. However, some children with IUGR should be followed closely, especially preterm infants, who may develop hyperglycemia due to reduced insulin secretion and less muscle mass for glucose utilization. Continuous intravenous glucose infusion, usually preceded by an IV bolus of dextrose (200 mg/kg over 5 min), is also indicated if these newborns develop symptomatic hypoglycemia. However, the need for such massive glucose administration is hotly contested due to the risk of undesirable effects, particularly in very-low-birth-weight preterm infants. Complete or partial resolution of symptoms once glucose concentration is corrected is considered definitive proof that symptoms were caused by hypoglycemia. Nevertheless, IV dextrose infusions are not an entirely appropriate treatment; they cause discomfort to the infant, which is made worse by the need for placement of a deep IV catheter, the need for NICU admission, and physical separation of the newborn from the mother, which hinders timely initiation of breastfeeding. However, when administered safely so as to prevent these complications, IV infusion of dextrose at low concentrations can be beneficial even in asymptomatic high-risk neonates.

#### *8.2.1. Dextrose gel*

Oral administration of glucose in gel form has been considered appropriate and should be part of any protocol to prevent episodes of hypoglycemia in asymptomatic newborns [41]. Current studies have shown that oral administration of 40% dextrose gel may reduce the occurrence of neonatal hypoglycemia by up to 70% [5] and should thus be considered as the first-line treatment in these patients [65].

#### **8.3. Symptomatic newborns**

#### *8.3.1. Glucose*

Symptomatic neonates should be treated with glucose intravenously, not orally. A 200 mg/kg bolus of glucose should be administered over 1 min (10% dextrose at 2 mL/kg). This should be followed by IV infusion at 6–8 mg/kg/min. Glucose levels should be monitored after 30–60 min, with a therapeutic target of >45 mg/dL. Control measurements should be obtained every 1–2 h. Once levels are stable, they can be reassessed every 4–6 h. If values do not reach a normal range, the rate of glucose infusion is increased by 1–2 mg/kg/min every 3–4 h. In cases of hyperinsulinism, a rate of 15–30 mg/kg/min may be necessary. Oral feedings should only resume once blood glucose levels have been stable for 6 h.

genetic defects that affect SUR1 and Kir 6.2, the constituent proteins that form the ATPsensitive potassium channel, may not benefit from administration of this drug. The recommended dose ranges from 10 to 15 mg/kg/day, divided in two or three oral doses, up to a maximum dose of 30 mg/kg/day. It promotes an increase in hepatic glucose production and decreases peripheral glucose utilization. Most of the drug is eliminated by glomerular filtration, and 90% of diazoxide is bound to albumin. Sodium and water retention, plasma volume expansion, edema, thrombocytopenia, anorexia, vomiting, ketoacidosis, and hyperuricemia

When the drug is effective, blood glucose levels will return to normal range within 2–4 days. Any trial of diazoxide therapy should last at least 1 week before the possibility of treatment failure is considered. Onset of action occurs within 1 h of administration, and the duration of

Failure of diazoxide therapy suggests an abnormality in ATP-sensitive potassium channels. In these cases, a course of octreotide therapy, which acts further downstream on the insulin

Octreotide was the first somatostatin analogue approved for clinical use, due to its more prolonged effect. This substance inhibits the secretion of glucagon, insulin, growth hormone, and thyrotropin, as well as the exocrine secretions of the bowel. Due to its ability to inhibit hormones, this drug can be used in infants with congenital hyperinsulinemic hypoglycemia

The management of diffuse hyperinsulinemic hypoglycemia, which does not respond to diazoxide, is a major therapeutic challenge. The successful use of sirolimus, both alone and as adjunctive therapy with octreotide, appears to be a potential alternative to subtotal pancreatectomy. Sirolimus is an immunosuppressant that inhibits the activation and proliferation of T lymphocytes, with effects *downstream* of the IL-2 receptor and other T-cell growth factor

In a study involving four patients with diffuse hyperinsulinemic hypoglycemia [46], therapy with sirolimus allowed discontinuation of intravenous infusions of dextrose and glucagon in all for patients and maintenance treatment with octreotide alone. At the end of the first year of life, the four patients continued to receive sirolimus and were normoglycemic, without any apparent major adverse events. Sevim Ünal et al. [63] reported the use of sirolimus in a neonate with CHH due to a KCNJ11 gene mutation who had already failed treatment with continuous infusions of glucose (14 mg/kg/min) and prednisone (2 mg/kg/day). Addition of intensive therapy with multiple medications (diazoxide, chlorothiazide, octreotide, glucagon, and nifedipine) also failed to produce an adequate response. However, before partial pancreatectomy was attempted, at age 30 days, sirolimus therapy was instituted at a dose of 0.5 mg/m<sup>2</sup>

/day.

Neonatal Hypoglycemia

75

http://dx.doi.org/10.5772/intechopen.69676

[19]. A dose of 5–35 mcg/kg/day via subcutaneous injection has been recommended.

are possible complications of the use of this drug [17].

secretion pathway, is advised.

*8.3.6. Sirolimus (rapamycin)*

*8.3.5. Octreotide*

receptors.

action is approximately 8 h, as long as renal function is normal.

High glucose concentrations (20–25%) may be necessary to maintain a rate of infusion of 15–30 mg/kg/min; concentrations above 12.5% will require a central venous catheter [56].

#### *8.3.2. Glucocorticoids*

Physiologically, glucocorticoids promote increased resistance to insulin action, reduce the secretion of insulin, and activate enzymes involved in gluconeogenesis, mobilizing amino acids for this purpose. Thus, although such effects should theoretically induce an increase in blood glucose, there is no evidence to support glucocorticoid therapy in the treatment of hypoglycemia other than that caused by primary or secondary adrenal insufficiency.

Except in cases of hypoglycemia of self-limiting etiology (e.g., infants born to diabetic mothers), blood and urine samples should be drawn at the time of hypoglycemia for investigation of possible changes in energy and hormone metabolism (lactate, free fatty acids, ketones, insulin, cortisol, growth hormone, urinary organic acids) before any specific medications are administered.

#### *8.3.3. Glucagon*

Endogenous glucagon is the counter-regulatory hormone of insulin, secreted by pancreatic beta cells. Physiologically, hypoglycemia induces glucagon secretion to raise glucose levels [43]. The administration of glucagon has proven to be quite effective in full-term and preterm neonates without hyperinsulinism. Serum sodium levels should be monitored during glucagon infusion. Hyponatremia, thrombocytopenia, and a rare paraneoplastic phenomenon, called necrolytic migratory erythema, have been associated with continuous infusion of glucagon. Hypertonic saline solution (3% sodium chloride) may be indicated to treat glucagonassociated hyponatremia.

A dose of 0.02 mg/kg/dose has been recommended [43]. A 24-h continuous infusion has been used at doses of 20–40 μg/kg/h up to a maximum of 1 mg/day. A 50% rise in blood glucose is expected in normal infants. The effect is transient. Long-acting preparations are employed in patients with glucagon deficiency and, in combination with somatostatin, in the treatment of congenital hyperinsulinism. When the expected rise in blood glucose does not occur, the diagnosis of hepatic glycogen storage disease should be suspected.

#### *8.3.4. Diazoxide*

This agent is indicated in cases of hypoglycemia associated with hyperinsulinism.

Diazoxide is a benzothiazine derivative that acts by opening ATP-sensitive potassium channels, causing inhibition of insulin secretion by pancreatic beta cells. Therefore, patients with genetic defects that affect SUR1 and Kir 6.2, the constituent proteins that form the ATPsensitive potassium channel, may not benefit from administration of this drug. The recommended dose ranges from 10 to 15 mg/kg/day, divided in two or three oral doses, up to a maximum dose of 30 mg/kg/day. It promotes an increase in hepatic glucose production and decreases peripheral glucose utilization. Most of the drug is eliminated by glomerular filtration, and 90% of diazoxide is bound to albumin. Sodium and water retention, plasma volume expansion, edema, thrombocytopenia, anorexia, vomiting, ketoacidosis, and hyperuricemia are possible complications of the use of this drug [17].

When the drug is effective, blood glucose levels will return to normal range within 2–4 days. Any trial of diazoxide therapy should last at least 1 week before the possibility of treatment failure is considered. Onset of action occurs within 1 h of administration, and the duration of action is approximately 8 h, as long as renal function is normal.

Failure of diazoxide therapy suggests an abnormality in ATP-sensitive potassium channels. In these cases, a course of octreotide therapy, which acts further downstream on the insulin secretion pathway, is advised.

#### *8.3.5. Octreotide*

with a therapeutic target of >45 mg/dL. Control measurements should be obtained every 1–2 h. Once levels are stable, they can be reassessed every 4–6 h. If values do not reach a normal range, the rate of glucose infusion is increased by 1–2 mg/kg/min every 3–4 h. In cases of hyperinsulinism, a rate of 15–30 mg/kg/min may be necessary. Oral feedings should only resume once

High glucose concentrations (20–25%) may be necessary to maintain a rate of infusion of 15–30 mg/kg/min; concentrations above 12.5% will require a central venous catheter [56].

Physiologically, glucocorticoids promote increased resistance to insulin action, reduce the secretion of insulin, and activate enzymes involved in gluconeogenesis, mobilizing amino acids for this purpose. Thus, although such effects should theoretically induce an increase in blood glucose, there is no evidence to support glucocorticoid therapy in the treatment of

Except in cases of hypoglycemia of self-limiting etiology (e.g., infants born to diabetic mothers), blood and urine samples should be drawn at the time of hypoglycemia for investigation of possible changes in energy and hormone metabolism (lactate, free fatty acids, ketones, insulin, cortisol, growth hormone, urinary organic acids) before any specific medications are administered.

Endogenous glucagon is the counter-regulatory hormone of insulin, secreted by pancreatic beta cells. Physiologically, hypoglycemia induces glucagon secretion to raise glucose levels [43]. The administration of glucagon has proven to be quite effective in full-term and preterm neonates without hyperinsulinism. Serum sodium levels should be monitored during glucagon infusion. Hyponatremia, thrombocytopenia, and a rare paraneoplastic phenomenon, called necrolytic migratory erythema, have been associated with continuous infusion of glucagon. Hypertonic saline solution (3% sodium chloride) may be indicated to treat glucagon-

A dose of 0.02 mg/kg/dose has been recommended [43]. A 24-h continuous infusion has been used at doses of 20–40 μg/kg/h up to a maximum of 1 mg/day. A 50% rise in blood glucose is expected in normal infants. The effect is transient. Long-acting preparations are employed in patients with glucagon deficiency and, in combination with somatostatin, in the treatment of congenital hyperinsulinism. When the expected rise in blood glucose does not occur, the

diagnosis of hepatic glycogen storage disease should be suspected.

This agent is indicated in cases of hypoglycemia associated with hyperinsulinism.

Diazoxide is a benzothiazine derivative that acts by opening ATP-sensitive potassium channels, causing inhibition of insulin secretion by pancreatic beta cells. Therefore, patients with

hypoglycemia other than that caused by primary or secondary adrenal insufficiency.

blood glucose levels have been stable for 6 h.

*8.3.2. Glucocorticoids*

74 Selected Topics in Neonatal Care

*8.3.3. Glucagon*

associated hyponatremia.

*8.3.4. Diazoxide*

Octreotide was the first somatostatin analogue approved for clinical use, due to its more prolonged effect. This substance inhibits the secretion of glucagon, insulin, growth hormone, and thyrotropin, as well as the exocrine secretions of the bowel. Due to its ability to inhibit hormones, this drug can be used in infants with congenital hyperinsulinemic hypoglycemia [19]. A dose of 5–35 mcg/kg/day via subcutaneous injection has been recommended.

#### *8.3.6. Sirolimus (rapamycin)*

The management of diffuse hyperinsulinemic hypoglycemia, which does not respond to diazoxide, is a major therapeutic challenge. The successful use of sirolimus, both alone and as adjunctive therapy with octreotide, appears to be a potential alternative to subtotal pancreatectomy. Sirolimus is an immunosuppressant that inhibits the activation and proliferation of T lymphocytes, with effects *downstream* of the IL-2 receptor and other T-cell growth factor receptors.

In a study involving four patients with diffuse hyperinsulinemic hypoglycemia [46], therapy with sirolimus allowed discontinuation of intravenous infusions of dextrose and glucagon in all for patients and maintenance treatment with octreotide alone. At the end of the first year of life, the four patients continued to receive sirolimus and were normoglycemic, without any apparent major adverse events. Sevim Ünal et al. [63] reported the use of sirolimus in a neonate with CHH due to a KCNJ11 gene mutation who had already failed treatment with continuous infusions of glucose (14 mg/kg/min) and prednisone (2 mg/kg/day). Addition of intensive therapy with multiple medications (diazoxide, chlorothiazide, octreotide, glucagon, and nifedipine) also failed to produce an adequate response. However, before partial pancreatectomy was attempted, at age 30 days, sirolimus therapy was instituted at a dose of 0.5 mg/m<sup>2</sup> /day. Improvements in glycemic control were achieved, enabling progressive dosage reduction of the other drugs. At the time of publication, at age 5 months, the infant was on minimal doses of hyperglycemic agents and continued to receive twice-daily sirolimus at a dose of 0.3 mg/m2 / day, without any complications.

**Author details**

**References**

2011;**127**(3):575-579

2016;**20**(1):64-74

Adauto Dutra Moraes Barbosa\*, Israel Figueiredo Júnior and Gláucia Macedo de Lima

[1] Adamkin DH. Postnatal glucose homeostasis in late pre-term and term infants. Pediatrics.

[2] Alfonso I, Rerecich A. Neonatal hypoglycemia and occipital cerebral injury (letter). The

[3] Bateman B, Patorno E, Desai RJ, et al. Late pregnancy beta-blocker exposure and risks of

[4] Baujat G, Cormier-Daire V. Sotos syndrome. Orphanet Journal of Rare Diseases. 2007;**2**:36 [5] Bennett C, Fagan E, Chaharbakhshi E, Zamfirova I, Flicker J. Implementing a protocol using glucose gel to treat neonatal hypoglycemia. Nursing for Women's Health.

[6] Brand PL. What is the normal range of blood glucose concentration in healthy term newborns? Archives of Disease in Childhood: Fetal and Neonatal Edition. 2004;**89**(4):F375 [7] Bulut C, Gürsoy T, Ovalı F. Short-term outcomes and mortality of late preterm infants.

[8] Calabria AC, Li C, Gallagher PR, Stanley CA, De Leon DD. GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing

[9] Clark W, O'Donovan D. Transient hyperinsulinism in an asphyxiated newborn infant

[10] Çoban D, Kurtoğlu S, Akın MA, Akçakuş M, Güneş T. Neonatal episodic hypoglycemia: a finding of valproic acid withdrawal. Journal of Clinical Research in Pediatric

[11] Cowett RM, Farrag HM. Selected principles of perinatal-neonatal glucose metabolism.

[12] De Leon DD, Stanley CA. Mechanisms of disease: Advances in diagnosis and treatment of hyperinsulinism in neonates. Nature Clinical Practice. Endocrinology & Metabolism.

with hypoglycemia. American Journal of Perinatology. 2001;**18**(4):175-8

channel. Diabetes. 2012;**61**:2585-2591

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neonatal hypoglycemia and bradycardia. Pediatrics. 2016;**138**(3):e20160731

\*Address all correspondence to: adutra@globo.com

Journal of Pediatrics. 2007;**151**(1):e1-2

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to inactivating mutations in the ATP-sensitive K<sup>+</sup>

Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

#### *8.3.7. Exendin*

Recently, exendin-(9-39), a GLP-1 receptor antagonist that raises blood glucose levels in adults, has been introduced as a possible novel therapy for management of hypoglycemia in patients with CHH. However, further studies on its effectiveness and safety are needed [8].

#### *8.3.8. Other drugs*

Growth hormone is used in cases of hypoglycemia associated with deficiency of this hormone or with hypopituitarism.

In cases of hypoglycemia due to persistent hyperinsulinemic hypoglycemia that does not respond to treatment with diazoxide, glucose, and sirolimus, partial pancreatectomy may be indicated.

#### **9. Consequences**

Recurrent or sustained hypoglycemia can cause neurological damage, mental retardation, epilepsy, and personality disorders [54]. Transient episodes of hypoglycemia are also associated with deficits in math learning around age 10 years [26].

Severe hypoglycemia can lead to impairment of cardiovascular function and is associated with high rates of neonatal mortality in very low-birth-weight infants [15].

Permanent brain damage is found in 25–50% of patients with recurrent severe symptomatic hypoglycemia under age 6 months. Furthermore, hypoxemia and ischemia may potentiate the permanent damage caused by hypoglycemia. The pathological changes described include gyral atrophy, reduced white-matter myelination, and cerebral cortical atrophy. It bears noting that the cerebral infarctions characteristic of hypoxic-ischemic processes are absent in hypoglycemia-associated brain injury [51].
