INTRODUCTION
Neonatal hyperglycemia is a common metabolic disorder, especially seen in low birth weight preterm and critically ill newborns.[1] The estimated incidence of this condition reported in the literatures is around 45%–80%.[23] It is inversely proportional to birth weight in the preterm infant.[4] The incidence is noted to be very high around 80% in extreme premature babies <750 g, 45% in babies <1000 g and around 2% in babies who are more than 2000 g.[4] Hyperglycemia is a recognized cause of mortality and morbidity in the neonatal period.[1] Hyperglycemia usually presents without any definite clinical manifestations in neonates, but it is important to recognize and manage this condition early in neonates to avoid serious complications. Multiple etiologies with different management strategies are mentioned in the literature for this condition.
Here, we discuss a complete understanding on practical management and presents simplified practical approach for the diagnosis and management of neonatal hyperglycemia.
Definition of hyperglycemia
The normal levels of blood glucose (BG) in neonates are not clearly defined in the literature, but for practical management, a BG value of 70–150 mg/dl (3.88–8.33 mmol/L) is taken as a safe range.[5] Hyperglycemia is defined as BG >125 mg/dL (6.9 mmol/L) or plasma glucose >150 mg/dL (8.3 mmol/L).[6] In preterm babies, BG value up to 10 mmol/L is commonly observed with parenteral glucose administration. This may not require any treatment and would only need close glucose monitoring.[67] However, BG values more than 180–200 mg/dl (10–11.1) mmol are of concern in neonates as this can lead to complications due to hyperosmolality and osmotic diuresis with glycosuria.[8] Hyperglycemia is labeled as early onset if it presents within 48 h of life and as late onset if presents after 48 h of life. The severity of neonatal hyperglycemia can be graded as mild if BG >8.3 mmol/L (150 mg/dl), moderate if BG >10 mmol/L (180 mg/dl), and severe if BG >15 mmol/L (270 mg/dl).[9]
Glucose hemostasis in the fetal and neonatal period
Glucose is the main source of energy during fetal development and in the neonatal period. After birth, glucose is the main source of energy substrate to the central nervous system.[1011] During fetal life, glucose hemostasis depends completely on placental glucose transfer and no significant glucose production happens in fetal life.[10]
Maternal glucose source is interrupted suddenly when the cord clamped at birth. The newborn babies maintain BG in the early hours of life by activation of glycogenolysis and gluconeogenesis through a complex hormonal interaction. After birth, the levels of glucagon, adrenaline, growth hormone, and cortisol increase, resulting in the rise of serum glucose levels through glycogenolysis, and the associated suppression in insulin levels helps to maintain a stable plasma glucose concentration in the newborn.[12]
Disturbances in glucose homeostasis are common during this transitional phase to extrauterine life. This becomes more evident in preterm, growth-restricted, and sick infants, especially with reduced metabolic stores and inadequate hormonal reactions.[13] For preterm infants, their glucose reserves are restricted as the glycogen storage occurs mostly in the last trimester,[11] and this deficiency is worsened by a higher calorie intake and fluid requirements in the early neonatal period leading to hyperglycemia.
Glycosuria
The urinary content of glucose in full-term infants is slightly higher than in older children and adults. It is even higher in preterm infants below 32 weeks of gestational age.[14] Increased rate of glycosuria in premature and low birth weight babies is due to renal immaturity as nephrogenesis is completed approximately by 34 weeks of gestation.[14] The approximate glucose reabsorption capacity in babies below 34 weeks gestation is 92.5%, between 34 and 37-week gestation is 99.2%, and in full terms, it is around 99.4%.[14] Isolated glycosuria cannot be taken as a true indicator for diagnosing hyperglycemia in preterm babies because it can present even with normal BG levels[67] due to renal immaturity. Hyperglycemia can manifest in full term babies with minimal or absent glycosuria due to mature kidneys.[15]
The urinary glucose is measured by using reagent strips. Glycosuria is measured in grades ranging from 0, ±, 1+, 2+, 3+ to 4+ which is determined by six different colors. After 30 s of contact of the reagent strip with urine, the test strip is compared with the standardized color scale. The matching glycosuria are graded as follows: Grade 0 for glucose <100 mg/dl, grade ± for glucose 100–250 mg/dl, Grade 1+ for glucose 250–500 mg/dL, Grade 2+ for glucose 500–1000 mg/dL, Grade 3+ for glucose 1000–2000 mg/dL, and Grade 4+ for glucose >2000 mg/dL.[16]
Effect of hyperglycemia on osmolarity
Hyperglycemia increases serum osmolarity. For each increment of 1 mmol/L (18 mg/dL) in BG concentration, serum osmolarity increases by 1 mOsm/L. When serum glucose reaches approximately 22.2 mmol/L (400 mg/dl), the serum osmolarity exceeds 300 mOsm/L which can cause fast shifting of intracellular water in brain, which makes it vulnerable to cerebral hemorrhage.[4] Increase in osmolarity can lead to osmotic diuresis resulting in polyuria and dehydration. The presence of glycosuria >1+ indicates the possibility of causing significant changes in serum osmolarity, so these babies should have close glucose monitoring.[45]
Pathogeneses of hyperglycemia
Hyperglycemia is more commonly observed in preterm babies compared with term neonates. Although the mechanisms of hyperglycemia in preterm infants are not well understood, it may be due to various reasons such as poor insulin response to glucose,[17] failure to suppress gluconeogenesis or glucose production in response to intravenous glucose,[1819] and decreased levels of glucose transporters.[4] Insufficient protein intake in preterm babies results in decreased release of insulin-like growth factor-1 (IGF-1). IGF-1 decreases BG by increasing the utilization of peripheral glucose, increasing glycogen synthesis, and suppressing hepatic glucose production. Amino acids are essential for the normal growth and development of the pancreas which promotes insulin secretion.[420] Sick neonates have decreased insulin production and reduced insulin sensitivity due to immaturity or less sensitive peripheral receptors.[2122] Increased secretion of counter-regulatory hormones, epinephrine, and cortisol due to stress can also contribute to hyperglycemia in these babies.[23]
Etiology of hyperglycemia
Neonatal hyperglycemia may be due to a high glucose production, low glucose uptake, or high exogenous glucose infusion.[20] The following are the main causes of hyperglycemia in neonates.
(1) Parenteral nutrition is commonly used for preterm and sick newborns in the neonatal units. VLBW babies require higher fluid intake because of increased calorie requirement, high insensible fluid loss, and diuresis due to renal immaturity. This potentially leads to iatrogenic hyperglycemia.[1719] (2) Impaired glucose homeostasis in preterm babies can affect glucose metabolism leading to hyperglycemia. Decreased insulin secretion and failure to suppress glucose production in the liver in the presence of high BG level is the main cause for hyperglycemia. They also exhibit insulin resistance and delayed insulin response to glucose infusion. Small for date (small-for-gestational-age) babies can have decreased insulin sensitivity and inhibition of gluconeogenesis[45] which can cause transient hyperglycemia. (3) Sepsis in newborns may manifest with hyperglycemia as a nonspecific clinical sign. Hyperglycemia is caused due to decreased insulin release and decreased peripheral utilization of glucose and stress response[24] (due to counter-regulatory hormones). Preterm babies may present more commonly with hyperglycemia due to fungal sepsis.[25] (4) Drugs causing hyperglycemia are glucocorticoid[26] therapy by causing increased insulin resistance, increased gluconeogenesis, and decreased insulin production, methylxanthines[26] due to increased secretion of catecholamines. Phenytoin[26] causes suppression of insulin release or insulin insensitivity and beta-adrenergic agents[26] (dopamine, epinephrine, and norepinephrine) and affects hepatic and muscle glycogenolysis and gluconeogenesis. Maternal use of diazoxide[27] may cause self-limiting hyperglycemia in the neonates (diazoxide crosses placenta and suppress insulin secretion in neonates). (5) Stress due to hypoxia, seizures, prematurity, sick infants, and pain leads to hyperglycemia due to increased secretion of counter-regulatory hormones (epinephrine and cortisol).[6] (6) Chromosomal anomalies and genetic syndromes. Hyperglycemia is observed in 46, XXDq deletion of chromosome13 and Chromosome 6q24 (paternal uniparental isodisomy), Wolcott-Rallison syndrome, DEND syndrome [Developmental delay, Epilepsy and Neonatal Diabetis], Rogers syndrome and IPEX syndrome [Immune dysregulation, polyendocrinopathy, enteropathy, X-linked]syndrome.[428] (7) Increased lipid infusion in neonates can lead to hyperglycemia by decreasing peripheral utilization of glucose and by affecting the insulin function to inhibit hepatic glucose production[417] [an approach to etiopathogenesis is given in Table 1].
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Table 1: Etiopathogenesis of hyperglycemia in neonates
Diabetes mellitus in newborns
Neonatal diabetes mellitus (DM) is a rare cause of hyperglycemia with incidence approximately 1 in 90,000–160,000 live births.[29] DM is suspected when hyperglycemia persists for more than 2 weeks requiring insulin infusion. It can present as a transient or permanent disease. Neonatal DM can be a monogenic disorder caused by a mutation in genes that encode proteins that can cause abnormal pancreatic beta cell function, beta cell destruction, or abnormal pancreatic development (pancreatic aplasia or hypoplasia). Neonatal diabetes usually presents in the neonatal period but in some cases, it can manifest within the first 12 months of life. Most of these cases present as isolated neonatal diabetes, but some are associated with multiple extrapancreatic clinical abnormalities.[29]
Complications of hyperglycemia
Neonatal hyperglycemia has been associated with a wide range of clinical complications, ranging from the clinically treatable dehydration to lethal complications including death.[4] Hyperglycemia can cause potential osmotic diuresis leading to polyuria and dehydration. Increased glucose infusion rates (GIRs) >15 mg/kg per minute may promote excessive lipogenesis. It rarely causes clinical signs but can be detected by abnormal liver enzymes.[41117]
Hyperglycemia occurring early hours of life in VLBW infants can cause increased osmolality predisposing to severe intraventricular hemorrhage[3031] and increased mortality.[3233] It is also associated with late-onset sepsis (LOS),[34] necrotizing enterocolitis,[3435] retinopathy of prematurity,[36] poor neurodevelopmental outcome,[37] and prolonged hospitalization.[32] Hyperglycemia can lead to electrolyte imbalance by increased sodium loss in neonates with glycosuria. Creatinine clearance can be affected significantly due to acute kidney injury during hyperglycemia.[434]
Blood glucose monitoring
Accurate glucose measurements are very essential in the management of hyperglycemia. Glucose measurement with dextrostix has a high possibility of inaccurate results. It is recommended to measure serum glucose level before initiating treatment for hyperglycemia. Serum glucose is approximately 15% higher than the capillary blood. The American Society for Parenteral and Enteral Nutrition clinical Guidelines recommend to measure venous BG for accurate values. Due to practical difficulties to do frequent venous sampling to measure glucose, it is advised to do capillary glucose measurements.[36]
Continuous glucose monitoring (CGM) by subcutaneous sensors has been found successful in monitoring with better glycemic control in pediatric and adult diabetics. In recent studies in 2019, CGM has proved to be accurate in glucose monitoring and can be tried in preterm infants in the neonatal unit. CGM benefits these babies by avoiding multiple pricks for capillary glucose and shows to be more beneficial in understanding the glucose trends rather than glucose values. It may help to avoid complications related to hyperglycemia and hypoglycemia.[37]
Management of hyperglycemia
Key points in management of hyperglycemia
- Dextrose concentration <5% and GIR below 4 mg/kg/min are not recommended in the management in hyperglycemia. Parenteral nutrition and lipid emulsion can maintain normoglycemia by gluconeogenesis using glycerol as principal substrates. Hence, reducing glucose infusion to an extremely low rate to manage hyperglycemia significantly reduces caloric intake and compromises growth in these babies[38]
- Avoid GIRs >15 mg/kg/min as this may promote excessive lipogenesis causing abnormalities in liver enzymes[11]
- Insulin infusion tubings should be filled and kept for 20 min for the insulin to get adsorbed to the plastic walls of the intravenous tubing to avoid initial medication failure
- Prophylaxis insulin infusion for the prevention of neonatal hyperglycemia is not recommended as it causes hypoglycemic complications
- Routine insulin infusion for the prevention of catabolism is not recommended as it can cause hypoglycemic complications
- Catecholamine infusions and glucocorticoid treatments could be limited or stopped as soon as the infant's circulation has improved
- Overall adequate supportive care that reduces hypoxia, ischemia, and acidosis will reduce stress responses that contribute to hyperglycemia
- Early protein intake by parenteral infusion has shown to decrease the incidence and severity of hyperglycemia. Amino acids are essential for the normal growth and development of the pancreas which promotes insulin secretion[420]
- Increased lipid infusion in neonates can decrease peripheral utilization of glucose and decrease insulin function to inhibit glucose production leading to hyperglycemia[417]
- Nutrition with greater proportion of protein and less fat and carbohydrates has been recommended to have a better BG stabilization with less frequent episodes of hyperglycemia[39]
- Early oral feeding should be encouraged to promote gastric release of incretin hormones (glucose-dependent insulinotropic peptide and glucagon-like peptide-1) that promote insulin secretion from pancreas.[40]
Treatment
Management of neonatal hyperglycemia includes conservative and medical therapy. Conservative management is primarily focused on reducing GIRs to target levels, minimizing triggering factors, adequate supportive care to minimize stress and to provide adequate calorie intake. Medical therapy is provided with insulin boluses and infusion treatment.
Babies are initially given 5–8 mg/kg/min intravenous glucose to maintain normal BG levels. BG is generally measured every 4–6 h in these neonates. If blood sugar is more than 8 mmol/L, then urine should be tested for sugar. When glycosuria is ≥1+, there is a risk for increasing osmolality causing osmotic diuresis and weight loss. Babies should be managed with adequate hydration and frequent glucose monitoring.[1741]
Conservative treatment should be initiated if RBS reading is more than 10 mmol/L (180 mg/dl). Avoid excessive intravenous fluids, drugs and rule out sepsis that causes hyperglycemia. Blood sugar should be frequently monitored in 1–2 hourly. If blood sugar is still more than 10 mmol/L (180 mg/dl), then GIR should be reduced gradually to a minimum of 4 mg/kg/min and dextrose concentration to a minimum of 5%.
Insulin therapy is initiated when the blood sugar is more than 11.1 mmol/L (200 mg/dl). Insulin bolus doses of 0.05–0.1 units/kg IV can be given over 15 min and to check blood sugar after 30–60 min. Maximum of three bolus doses is suggested every 4–6 h If the blood glucose level remains high above 11.1 mmol/L (200 mg/dl). Insulin infusion is initiated if the glucose levels remain still high above 11.1 mmol/L (200 mg/dl) after the boluses doses. The initial starting dosage of insulin dosage is between 0.01 and 0.05 units/kg per hour and gradually increased up to a maximum rate of 0.1 units/kg per hour. Frequent blood glucose monitoring is essential during insulin infusion to maintain glucose levels of 8.3–11.1 mmol/L (150–200 mg/dl). BG concentration should be monitored within 30 min to 1 h of starting of infusion and after any change in the rate of glucose or insulin infusion. BG values should be monitored hourly until stable and then less frequently. Tighter glycemic control aiming for glucose values far below 150 mg/dL (8.3 mmol/L) increases the risk of hypoglycemia.[2141]
The insulin infusion should be tapered gradually and discontinued to avoid hypoglycemia when glucose levels stabilize. Insulin infusion can be discontinued when the glucose level remains stable at or below 8.33 mmol/L (150 mg/dl). The glucose level should be monitored closely for the next 12–24 h [an approach to the management of hyperglycemia is given in Table 2].
Table 2: Flow chart for management of hyperglycemia in neonates
Complications during insulin infusion
Hypoglycemia and hypokalemia remain as potential risk during treatment for neonatal hyperglycemia.[4] Hypoglycemia is a common serious complication observed with insulin infusion. This can be prevented by periodic BG monitoring. During hypoglycemia, insulin infusion must be discontinued and treated with dextrose 10% boluses (2 ml/kg).[45] Hypokalemia is also observed with insulin treatment and can be prevented by periodic laboratory monitoring for electrolytes. Hypokalemia should be managed by adequate potassium supplementation.[4]
CONCLUSION
Hyperglycemia is a recognized cause for mortality and morbidity in the neonatal period. It can lead to high mortality, intraventricular hemorrhage, LOS, and poor neurodevelopmental outcome in neonates. The estimated incidence of neonatal hyperglycemia is between 45% and 80%. Hyperglycemia is more observed in preterm babies compared with term neonates. Glucose values more than 8.3 mmol are defined as neonatal hyperglycemia, but a value more than 10 mmol/L is of concern as it may lead to complications in neonates. Prevention of hyperglycemia should be the mainstay of management. Parenteral amino acids and enteral nutrition should be initiated early as it promotes insulin secretion which helps to stabilize glucose levels. Insulin should be used in hyperglycemia which is persistent, despite decreased GIRs and dextrose concentrations. Frequent BG monitoring is essential for avoid hypoglycemic complications during insulin infusion.
Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.
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