DISORDERS OF GLUCOSE METABOLISM
Normal postnatal glucose homeostasis is established by increased glucose production and utilization. Factors that promote glucose production include catecholamines and glucagon, which activate glycogenolysis. A high glucagon-to-insulin ratio, which induces synthesis and activity of the enzymes, is required for there to be gluconeogenesis. Once normal feedings are established, glycerol and amino acids continue to fuel gluconeogenesis while dietary fatty acids activate the enzymes responsible for gluconeogenesis. Additionally, galactose derived from the hydrolysis of milk sugar (lactose) in the gut increases hepatic glycogen production for sustained between-feeding hepatic glucose release from glycogen breakdown. Feeding also induces production of intestinal peptides, or incretins, that promote insulin secretion. Insulin decreases hepatic glucose production and increases glucose utilization for energy production and storage as glycogen. These opposing conditions of glucose production and utilization continue in response to normal feed-fast cycles, regulating normal plasma glucose concentrations.
Glucose is the major source of energy for organ function. All organs use glucose, and glucose deficiency leads to impaired cardiac performance, cerebral energy failure, hepatic glycogen depletion, and muscle weakness. Cerebral glucose metabolism accounts for as much as 90% of total glucose consumption in the newborn. Thus, maintenance of glucose delivery to all organs, particularly the brain, is an essential physiological function. Although alternate fuels can substitute for glucose metabolism, concentrations of these substances often are low in newborn infants, especially preterm infants. Newborns, therefore, are especially susceptible to hypoglycemia when they are exposed to conditions that impair glucose homeostasis during the transition from intrauterine to extrauterine life.
Ideally, hypoglycemia should be defined as a glucose concentration below the lower limit of the normal range of blood or plasma/serum glucose concentrations. This concentration, however, is uncertain, controversial, and is variably defined. Early statistical evaluations in term infants historically defined hypoglycemia as a blood glucose concentration below 35 mg/dL, or a plasma glucose value below 40 mg/dL; and even lower concentrations were applied in preterm infants. Such statistical definitions, however, have limited biological or clinical significance. This is because physiological hypoglycemia is present when the concentration of glucose in the plasma yields glucose delivery rates that are inadequate to meet essential requirements for glucose utilization, which vary considerably. Definitions of normal and hypoglycemic glucose concentrations vary according to postnatal feeding practices and timing of the measurement. Postnatally, the blood glucose concentration normally decreases to its lowest value between 1 and 3 hours after birth, followed by a progressive increase to greater than 50 to 60 mg/dL by 12 to 24 hours (Fig. 53-1).
Plasma glucose concentrations during the first week of life in healthy, appropriate-for-gestational-age term infants.
The absolute glucose concentration below which short- or long-term organ dysfunction occurs remains undefined, although animal studies suggest that concentrations below 20 mg/dL sustained over several hours can result in brain injury. Conditions that should be present before relating long-term neurological impairment to neonatal hypoglycemia are given in Table 53-1. Unfortunately, there are no sufficiently large, randomized controlled trials to establish the efficacy of any diagnostic and/or treatment approach, or any set of guidelines for the management of hypoglycemia (however defined). Thus, the key to preventing complications from glucose deficiency, is to focus less on numerical values of glucose concentration. Management should be directed toward identification of infants at risk, promotion of early and frequent feedings, normalization of glucose homeostasis, measurement of glucose concentrations early and frequently in infants at risk, and prompt treatment when glucose deficiency is marked and symptomatic.
TABLE 53-1NECESSARY CONDITIONS FOR ATTRIBUTING LONG-TERM NEUROLOGICAL IMPAIRMENT TO NEONATAL HYPOGLYCEMIA ||Download (.pdf) TABLE 53-1NECESSARY CONDITIONS FOR ATTRIBUTING LONG-TERM NEUROLOGICAL IMPAIRMENT TO NEONATAL HYPOGLYCEMIA
|Blood or plasma glucose concentrations below 18 mg/dL. Such values definitely are abnormal, although if transient, there is no study in the literature confirming that they lead to permanent neurological injury. |
|Persistence of such severely low glucose concentrations for prolonged periods (hours, probably > 2–3 hr, rather than minutes, although there is no study in human neonates that defines this period). |
|Early mild to moderate clinical signs (primarily those of increased adrenalin [epinephrine] activity), such as alternating central nervous system signs of jitteriness/tremulousness versus stupor/lethargy or even a brief convulsion, that diminish or disappear with effective treatment that promptly restores the glucose concentration to the statistically normal range (> 45 mg/dL). |
|More serious clinical signs that are prolonged (many hours or longer), including coma, seizures, respiratory depression and/or apnea with cyanosis, hypotonia or limpness, high-pitched cry, hypothermia, and poor feeding after initially feeding well. These are more refractory to short-term treatment. |
|Concurrence of associated conditions, particularly persistent excessive insulin secretion and hyperinsulinemia with repeated episodes of acute, severe hypoglycemia with seizures and/or coma (although subclinical, often severe, hypoglycemic episodes occur in these conditions and might be just as injurious). |
Most clinicians today use higher values than previously accepted to define hypoglycemia. Several recent studies support this practice. Repeated blood glucose concentrations below 48 mg/dL in preterm infants were associated with adverse neurodevelopmental outcomes. Among a group of normal term infants, most achieved a serum glucose concentration greater than 50 mg/dL by 12 to 24 hours after birth. Human fetuses have a blood glucose concentration greater than 50 mg/dL during normal development. In clinical practice, blood glucose concentrations of 45 to 50 mg/dL (50–60 mg/dL plasma or serum) commonly represent the acceptable lower limit for neonatal glucose concentrations.
The gold standard for measuring blood or plasma/serum glucose concentration is the hexokinase method used by most diagnostic laboratories. Colorimetric reagent strip methods are commonly used at the bedside to screen for hypoglycemia, but they are often inaccurate and must be confirmed by a standard laboratory method as soon as possible.
The incidence of neonatal hypoglycemia, defined by a blood glucose of less than 45 mg/dL, is estimated at being between 1 and 5 per 1000 live births. The reported incidence varies depending on the definition, the time after birth when the concentration of glucose is measured, and the method used to measure the blood, plasma, or serum glucose concentration. In a group of at-risk newborns whose glucose was measured frequently throughout the first 48 hours of life, approximately half were found to have a blood glucose less than 47 mg/dL.
Hypoglycemia is classified as symptomatic or asymptomatic, to indicate the presence or absence of physical signs that accompany a low glucose concentration. The most common and least specific signs include tremulousness and irritability (often alternating with mild hypotonia), diminished arousal (often noted as stupor or lethargy as manifestations of mild changes in level of consciousness), and failure to eat after first eating well.
These signs occur, however, with other common, similarly transient neonatal disorders, including hypocalcemia, subarachnoid hemorrhage, and in the early stages of sepsis. If due to hypoglycemia, signs usually correct quickly upon restoration of normal glucose concentrations. More severe and prolonged hypoglycemia may be associated with abnormal respiratory patterns, such as respiratory depression or apnea leading to cyanosis; cardiovascular signs, such as tachycardia or bradycardia; and neurological signs, such as temperature instability, loss of consciousness or coma, limpness and hypotonia, and seizures. Hypoglycemia should be excluded in any infant who exhibits any of these serious signs, since, if left untreated, severe, prolonged, or repeated, hypoglycemia can impair the function of many organs, especially the brain. In those infants known to be at risk for hypoglycemia, careful observation and screening is required since intermittent, asymptomatic injury that can lead to neurologic injury may occur.
Risk factors for hypoglycemia, such as maternal diabetes or abnormal glucose tolerance, maternal administration of drugs associated with neonatal hypoglycemia, ultrasound evidence of intrauterine growth restriction, or preterm birth, should be identified (Table 53-2). Growth parameters should be plotted on a growth chart to establish whether the infant is small or large for gestational age. Sepsis should be suspected if the infant has no apparent risk factors for hypoglycemia. If hypoglycemia persists for more than 1 week, hyperinsulinism, other endocrine disorders, and inborn errors of metabolism should be investigated, especially if the hypoglycemia is refractory to standard treatment.
TABLE 53-2RISK FACTORS FOR NEONATAL HYPOGLYCEMIA ||Download (.pdf) TABLE 53-2RISK FACTORS FOR NEONATAL HYPOGLYCEMIA
|Maternal Conditions |
|Presence of diabetes or abnormal result from glucose tolerance test |
|Preeclampsia and pregnancy-induced or essential hypertension |
|Previous macrosomic infants |
|Substance abuse |
|Treatment with β-agonist tocolytics |
|Treatment with oral hypoglycemic agents |
|Late antepartum to intrapartum administration of intravenous glucose |
|Neonatal Conditions |
|Preterm birth |
|Intrauterine growth restriction |
|Perinatal hypoxia-ischemia |
|Erythroblastosis fetalis |
|Iatrogenic administration of insulin |
|Congenital cardiac malformations |
|Persistent hyperinsulinemia |
|Endocrine disorders |
|Inborn errors of metabolism |
|Late antepartum to intrapartum administration of intravenous glucose |
|Poor feeding, especially new onset after previously feeding well |
The most common cause of neonatal hypoglycemia is an imbalance of reduced glucose production and increased glucose utilization (Table 53-3). Decreased substrate availability is common among preterm and small-for-gestational-age infants with intrauterine growth restriction (see Chapter 49). Hepatic glycogen stores are diminished in all preterm infants and many small-for-gestational-age infants. These 2 groups of infants also have a relatively increased brain-to-body weight ratio. This will increase glucose demand relative to the capacity for glucose production. Infants with stressful conditions (including asphyxia, hypothermia, or respiratory distress) can break down their glycogen stores more rapidly in response to increased secretion of catecholamines and glucagon. Even normal body stores of glycogen, however, may be inadequate to meet the increased rates of glucose utilization imposed by such conditions. Gluconeogenic and ketogenic enzymes also can be low in preterm and small-for-gestational-age infants, further preventing normal rates of new glucose production, or producing alternative fuel substrates from fatty acids. Infants of diabetic mothers are predisposed to hypoglycemia, due to persistent hyperinsulinemia following the excessive intrauterine glucose stimulation of their pancreas by maternal hyperglycemia. This leads to a persistently high insulin-to-glucagon ratio after birth, when placental glucose supply is abruptly discontinued. The high insulin-to-glucagon ratio inhibits enzymes regulating glycogenolysis (ie, glycogen phosphorylase), gluconeogenesis (ie, phosphoenolpyruvate carboxykinase), and hepatic glucose release (ie, glucose-6-phosphatase). Insulin also increases peripheral glucose utilization in insulin-sensitive tissues such as skeletal muscle, myocardium, and adipose tissue. Infants with erythroblastosis fetalis have increased levels of insulin and an increase in the number of pancreatic β cells. β-Adrenergic drugs, such as terbutaline, which are used to inhibit preterm uterine contractions and labor, also are associated with hyperinsulinemia and reduced glycogen stores.
TABLE 53-3NEONATAL HYPOGLYCEMIA: ETIOLOGIES AND TIME COURSE ||Download (.pdf) TABLE 53-3NEONATAL HYPOGLYCEMIA: ETIOLOGIES AND TIME COURSE
|Clinical Mechanism ||Setting ||Expected Duration |
|Decreased substrate availability || |
Intrauterine growth restriction
| ||Glycogen storage disease ||Prolonged |
| ||Inborn errors (eg, fructose intolerance) ||Prolonged |
|Increased utilization ||Perinatal asphyxia ||Transient |
| ||Hypothermia ||Transient |
|Endocrine Disturbances |
|Hyperinsulinemia ||Infant of diabetic mother ||Transient |
| ||Beckwith-Wiedemann syndrome ||Prolonged |
| ||Congenital hyperinsulinism ||Prolonged |
| ||Erythroblastosis fetalis ||Transient |
| ||Exchange transfusion ||Transient |
| ||Islet cell dysplasias ||Transient |
| ||Maternal β-agonist tocolytics ||Prolonged |
| ||Improperly placed umbilical artery catheter ||Transient |
|Other endocrine disorders || |
| ||Adrenal insufficiency ||Prolonged |
|Miscellaneous/multiple mechanisms || |
Congenital heart disease
| ||Central nervous system abnormalities ||Prolonged |
Hypoglycemia that persists for more than 5 to 7 days most often results from 1 of several types of congenital hyperinsulinism. Although uncommon, these are serious metabolic disorders and are associated with a markedly increased risk of neurologic complications. Several of these disorders are genetic, including those that cause diffuse β-cell/islet hyperplasia or, less commonly, focal β-cell/islet adenomas. Many of these forms of congenital hyperinsulinism have been linked to defects in the sulfonylurea receptor or K+-ATP channel. These genetic defects can be autosomal dominant or recessive. A syndrome of congenital hyperinsulinemia and asymptomatic hyperammonemia associated with mutations in the glutamate dehydrogenase gene also has been described. Beckwith-Wiedemann syndrome is associated with hyperplasia of multiple organs, including the pancreas, with increased insulin secretion.
Inborn errors of metabolism can limit availability of gluconeogenic precursors or the function of the enzymes required for hepatic glucose production. Metabolic defects that present with hypoglycemia include some forms of glycogen storage disease, galactosemia, fatty acid oxidation defects, carnitine deficiency, several of the amino acidemias, hereditary fructose intolerance (fructose-1,6-diphosphatase deficiency), and defects of other gluconeogenic enzymes. Rare endocrine disorders, such as hypopituitarism and adrenal failure, also lead to hypoglycemia because of inadequate hormonal responses, including inadequate growth hormone and adrenal corticosteroid secretion.
HYPOGLYCEMIA AND THE BRAIN
Severe hypoglycemia in the newborn is associated with selective neuronal necrosis in multiple brain regions, including the superficial cortex, dentate gyrus, hippocampus, and caudate-putamen. Energy failure leads to decreased cerebral electrical activity followed by neuronal cell membrane breakdown. Energy failure also prevents postsynaptic uptake of the principal neurotransmitter glutamate. Excess glutamate concentrations then activate NMDA (N-methyl D-aspartate) receptors in the neuronal membranes, which increases cellular entry and cytoplasmic concentrations of sodium and calcium, causing osmotic swelling and acute neuronal necrosis. The high calcium concentrations also activate cellular phospholipases and proteases and prevent normal mitochondrial metabolism, which leads to increased toxic free radical formation. These processes disrupt synaptic transmission and eventually lead to delayed neuronal necrosis. Hypoglycemia also can exacerbate pre-existing cerebral hypoxic brain injury.
Symptomatic neonatal hypoglycemia must be corrected rapidly, and further episodes of hypoglycemia must be prevented by providing adequate substrate until normal glucose homeostasis is established (Fig. 53-2). Early enteral feeding is usually successful in treating mild hypoglycemia in asymptomatic infants. Human milk or standard infant formulas provide carbohydrate in the form of lactose without excessively stimulating insulin secretion, and also include protein and fat, which provide a sustained supply of substrates for gluconeogenesis and alternative fuels. Fat intake also decreases cellular glucose uptake. Blood glucose concentrations should increase by 20 to 30 mg/dL within the first hour after a feeding of 30 to 60 mL of milk or formula.
Algorithm for management of the neonate with hypoglycemia. D10W, 10% dextrose; IV, intravenous.
Intravenous glucose infusion should be used when infants are symptomatic or are unable to tolerate enteral feedings and when hypoglycemia does not respond to enteral feeding. Intravenous glucose also should be used early after birth in those high-risk infants who are likely to experience severe and prolonged disturbances in glucose homeostasis, such as preterm infants, small-for-gestational-age infants with intrauterine growth restriction, infants of diabetic mothers, and infants who have underlying etiologies for hypoglycemia, such as sepsis, known or suspected inborn errors of metabolism, endocrine defects, or erythroblastosis.
In symptomatic newborns, an initial rapid intravenous infusion of 200 mg/kg (2 mL/kg) of 10% dextrose solution should be followed by continuous infusion of 5 to 8 mg/kg/min of glucose—that is, the glucose utilization rate of a healthy term infant (Fig. 53-3). The blood glucose concentration should be measured approximately 30 minutes after the initial rapid infusion and then every 1 to 2 hours until it is stable within the normal range. If the glucose level subsequently falls into the hypoglycemic range, then the rapid infusion should be repeated, and the infusion rate increased by 10% to 15%. In asymptomatic hypoglycemic newborns it may be appropriate to start a continuous infusion of 5 to 8 mg/kg/min of glucose without an initial rapid infusion, and then to follow the glucose response closely, and adjust the infusion rate to obtain a glucose in the normal range.
Plasma glucose response to glucose “minibolus” followed by continuous glucose infusion of 8 mg/min/kg as therapy for severe neonatal hypoglycemia.
Infants with hyperinsulinemia often require as much as 12 to 15 mg/kg/min of intravenous glucose to maintain normoglycemia. At these rates, it is safest to use a central venous catheter to allow infusion of dextrose concentrations greater than 12.5%. Infants requiring intravenous therapy for hypoglycemia should continue feedings as long as there is no evidence of feeding intolerance. An alternate feeding strategy is to provide some carbohydrate as galactose, 1 of the sugars that compose lactose. This can be useful for infants of diabetic mothers and other infants with hyperinsulinism, because the pancreatic production of insulin in response to galactose is less than its response to an equivalent amount of glucose. When a normal blood glucose concentration has been established, and the requirement for intravenous glucose has been stable for 12 to 24 hours, the infant can be weaned. The safest method is to measure preprandial blood glucose concentrations and decrease the infusion rate by 10% to 20% each time the blood glucose is greater than 50 to 60 mg/dL. Failure to tolerate weaning from intravenous glucose may indicate the presence of a pervasive disorder, such as a metabolic defect or idiopathic hyperinsulinemia and warrants further diagnostic investigation, and may require adjunctive therapies (Table 53-4).
TABLE 53-4ADJUNCT THERAPIES FOR PERSISTENT NEONATAL HYPOGLYCEMIA ||Download (.pdf) TABLE 53-4ADJUNCT THERAPIES FOR PERSISTENT NEONATAL HYPOGLYCEMIA
|Therapy ||Effect ||Dose |
|Corticosteroids ||Decreases peripheral glucose utilization ||Hydrocortisone 5–15 mg/kg/d or prednisone 2 mg/kg/d |
|Glucagon ||Stimulates glycogenolysis ||30 μg/kg with normal insulin |
| || ||300 μg/kg with hyperinsulinemia |
|Diazoxide ||Inhibits insulin secretion ||15 μg/kg/d |
|Somatostatin (long-acting: octreotide acetate) ||Inhibits insulin and growth hormone release ||5–10 μg/kg every 6–8 h |
|Pancreatectomy ||Decreases insulin secretion || |
| ||Causes diabetes and pancreatic insufficiency || |
The long-term effects of severe neonatal hypoglycemia remain controversial. Repeated episodes of symptomatic hypoglycemia, particularly in infants with persistent hyperinsulinism, have been associated with selective neuronal necrosis and impaired cognitive and motor function. There is little evidence of long-term sequelae in late preterm and term infants who have experienced relatively few, brief episodes of hypoglycemia, especially if asymptomatic. In preterm infants, however, the evidence with respect to long-term outcomes following repeated daily glucose concentrations below 46 mg/dL is mixed. Thus, mild to moderate hypoglycemia might affect the outcome in high-risk infants, particularly those who cannot respond adequately to hypoglycemia, although such infants have many other confounding problems that independently or in combination lead to abnormal neurodevelopment.
Hyperglycemia is relatively common in infants who are born extremely preterm (< 26 weeks of gestation). It is most often caused by excessive rates of intravenous glucose infusion in the presence of physiological and biochemical mechanisms that lead to excess glucose production, insulin resistance, and glucose intolerance.
Hyperglycemia refers to a blood glucose concentration greater than 120 to 125 mg/dL (plasma concentration > 145–150 mg/dL), regardless of gestational age, weight, or postnatal age.
Hyperglycemia is most common in neonates that are extremely preterm (< 26 weeks of gestation) and of extremely low birth weight (< 1000 g). The incidence of hyperglycemia is inversely related to birth weight in the preterm infant, ranging from about 2% in infants who weigh more than 2000 g to about 45% in those who weigh less than 1000 g, and up to 80% in infants weighing less than 750 g.
Hyperglycemia affects around half of all preterm infants receiving continuous intravenous dextrose infusions at glucose rates greater than 10 to 11 mg/kg/min, and almost all infants at rates greater than 14 mg/kg/min. Even after dextrose infusion rates are decreased to treat hyperglycemia, infusion rates as low as 3 to 4 mg/kg/min can result in persistent hyperglycemia, especially during prolonged periods of stress. Previously stable glucose values becoming hyperglycemic on a stable glucose input may herald new sepsis. Hyperglycemia is associated with the severity of clinical problems in neonates, as estimated by low Apgar scores, high fractional concentrations of inspired oxygen, and respiratory distress. Intravenous lipid infusion also increases the incidence and degree of hyperglycemia, as increased plasma concentrations of free fatty acids decrease peripheral glucose utilization by competing with glucose for oxidation and by stimulating the activity of enzymes that specifically promote fatty acid oxidation.
Stress, as measured by increased plasma cortisol concentrations, is an important risk factor for hyperglycemia, most frequently among infants receiving catecholamine infusions, or undergoing painful procedures such as surgery, venipuncture, vascular cutdowns, and endotracheal tube insertion without adequate analgesia or anesthesia. Narcotic treatment during and after surgery lowers the incidence of hyperglycemia. Recent observations indicate that postsurgical hyperglycemia is likely caused by increased cortisol secretion during surgery, whereas hyperglycemia immediately after the induction of anesthesia more likely is related to increased catecholamine secretion. Thus, narcotic treatment with fentanyl or morphine during and after surgery has been associated with lower circulating concentrations of catecholamines, glucocorticoids, and glucagon as well as a lower incidence of hyperglycemia. Catecholamines reduce insulin secretion and interfere with peripheral insulin action. Glucagon promotes glycogenolysis and release of hepatic glucose. Glucocorticoids promote gluconeogenesis by increasing protein breakdown and the supply of amino acids. Glucocorticoids also enhance hepatic enzyme activity in the gluconeogenic pathway, particularly phosphoenolpyruvate carboxykinase, the rate-limiting enzyme for gluconeogenesis, and glucose-6-phosphatase, which releases glucose into the circulation. Hyperglycemia also occurs more commonly among preterm and small-for-gestational-age infants, who have increased plasma concentrations of counter-regulatory (anti-insulin) hormones. Other, more common causes of neonatal hyperglycemia include the use of medications such as theophylline and dexamethasone. It has also been associated with prostaglandin E1 infusions.
Insulin-dependent diabetes mellitus, either transient or permanent, is an unusual but important cause of hyperglycemia in newborn infants. Neonatal diabetes mellitus usually presents early in postnatal life with weight loss, polyuria, dehydration, glycosuria, and hyperglycemia. It usually does not resolve for several weeks or even months and sometimes is permanent, and it may be associated with chromosomal abnormalities or pancreatic agenesis.
The principal mechanism responsible for hyperglycemia in preterm infants is intravenous infusion of dextrose at rates that exceed the capacity for glucose utilization. Glucose utilization is limited by relatively inadequate insulin secretion rates as well as by decreased peripheral insulin sensitivity (primarily in skeletal muscle) in infants who experience stress and relatively increased secretion rates of catecholamines, glucocorticoids, and glucagon. Some preterm infants also appear to maintain glucose production during insulin, glucose, and lipid infusions, indicating central (hepatic) insulin resistance. Excessive or inappropriate (according to insulin secretion rates and plasma insulin concentrations) glucose production rates also can promote or prolong hyperglycemia. Even extremely low–birth-weight preterm infants can have high rates of glucose production (4–8 mg/min/kg), primarily from gluconeogenesis, relatively soon after birth.
Hyperglycemia in newborn infants is seldom if ever so severe as to cause osmotic injury to tissues, particularly in the brain, unlike the well-known brain damage caused by salt poisoning. Another potential effect of aggressive glucose administration is steatosis, with associated impaired secretion of hepatic triglycerides. Steatosis rarely causes clinical signs in the neonate, but it can be detected by modest elevations of liver transaminases. Another complication of hyperglycemia is electrolyte imbalance in neonates who have glycosuria and increased sodium excretion. Hyperglycemia in older, more mature infants may jeopardize respiratory function by increasing lipogenesis, producing increased amounts of carbon dioxide. This requires an increase in minute ventilation that, theoretically, might compromise infants who already have significant respiratory distress.
Treatment of hyperglycemia must include the simultaneous treatment of underlying conditions. With modest hyperglycemia (plasma glucose concentration < 300 mg/dL), reducing the exogenous glucose (dextrose) infusion rate to as low as 3 to 4 mg/kg/min usually is sufficient to ameliorate or resolve the hyperglycemia. The rate of infusion should be decreased gradually by 1 to 2 mg/kg/min every 2 to 4 hours, with frequent measurement of glucose concentrations until normoglycemia is achieved. Early intravenous amino acid infusions should be considered to prevent or treat hyperglycemia. The rationale for this approach is that certain amino acids are known insulin secretagogues and are important for normal growth and development of the pancreas and the pancreatic islets and β cells. Limiting intravenous lipid infusions also should be considered, as they promote gluconeogenesis and inhibit glucose utilization. Even a minimal enteral feeding regimen may be beneficial unless the infant is very ill or there are clear signs of feeding intolerance, as enteral feeds promote the secretion of insulin by inducing gut production of enteroinsular hormones, also known as incretins. These hormones increase insulin secretion by direct actions on the pancreatic cells.
Intravenous infusion of short-acting, regular insulin should be reserved for infants who have severe hyperglycemia (> 300 mg/dL) that persists despite reducing the glucose infusion rate to less than 3 to 4 mg/kg/min. These infants also may have a metabolic acidosis, lactic acidosis, hyperkalemia, and osmotic diuresis. Infusion rates should be started at 0.02 to 0.05 U/kg/h. Hypokalemia can be prevented by addition of potassium to intravenous fluids. Blood glucose concentrations should be measured frequently, every 1 to 2 hours, or whenever signs of possible hypoglycemia develop.
DISORDERS OF CALCIUM REGULATION
Neonatal hypocalcemia is generally defined as a serum total calcium concentration of less than 2 mmol/L (< 8 mg/dL) in term infants and less than 1.75 mmol/L (< 7 mg/dL) in preterm infants or an ionized calcium concentration of less than 0.75 to 1.1 mmol/L (< 3.0–4.4 mg/dL). Early-onset neonatal hypocalcemia typically is transient and occurs during the first 24 to 48 hours after birth; later-onset hypocalcemia usually occurs after the first week of life and commonly involves lasting pathology.
Early-onset hypocalcemia is most commonly associated with preterm birth, perinatal depression (from hypoxic-ischemic conditions), maternal insulin-dependent diabetes, gestational exposure to anticonvulsants, and maternal hyperparathyroidism. Previous experience was that transient hypocalcemia often occurred in approximately 30% of all preterm infants (up to 90% in those born extremely preterm), approximately 30% of infants who have an Apgar score below 5 at 1 minute of age, and approximately 10% to 20% of infants of insulin-dependent diabetic mothers. However, much lower rates are currently reported, with earlier postnatal administration of intravenous solutions that contain calcium and earlier onset of enteral feeding. Subcutaneous fat necrosis (SCFN) is a rare form of panniculitis in infants that generally occurs following birth trauma, meconium aspiration, or therapeutic cooling. Severe hypercalcemia occurs in a subset of these patients. In addition to the local signs, fever is common, and there is a high incidence of persistent nephrocalcinosis without evidence of adverse renal outcomes.
Later-onset hypocalcemia is much less frequent and is most commonly associated with relatively high phosphate-containing diets, disturbed maternal vitamin D metabolism, intestinal malabsorption of calcium, hypomagnesemia, and hypoparathyroidism.
A normal physiological neonatal calcium nadir occurs at about 48 hours after birth in normal term infants. Early neonatal hypocalcemia generally represents a transient failure of calciotropic hormone secretion in response to the loss of placental calcium supply at birth. Preterm infants often do not appropriately increase parathyroid hormone secretion. This can be aggravated by restricted intravenous and oral calcium intake, end-organ resistance to 1,25-dihydroxyvitamin D [1,25(OH)2D], and increased serum calcitonin. Other contributing factors in infants exposed to hypoxia-ischemia, include an increased endogenous phosphate load, low neonatal glomerular filtration rate that limits phosphorous excretion, bicarbonate therapy, and an increased serum calcitonin concentration. Hypocalcemia in infants of insulin-dependent diabetic mothers appears related to magnesium insufficiency from renal losses and impaired fetal parathormone secretion. Formulas usually contain more phosphorus than human milk, and formula-fed infants often have lower serum ionized calcium and higher serum phosphorus concentrations in the first week of life compared to breastfed infants.
Congenital hypoparathyroidism is the most significant cause of late-onset hypocalcemia that has to be treated early in life. Congenital hypoparathyroidism also occurs as part of the 22q11.2 deletion syndrome (also called DiGeorge syndrome or DiGeorge sequence). Insufficiency of vitamin D arises from maternal vitamin D deficiency, lack of exposure to sunlight coupled with insufficient dietary vitamin D intake, reduced production of vitamin D or its active metabolites caused by liver or renal disease, congenital deficiency of renal 1α-hydroxylase, and 1,25(OH)2D resistance. Deficiency of vitamin D or its metabolites causes decreased intestinal calcium absorption and renal calcium reabsorption. Most infant vitamin D disturbances are not apparent until several months of age.
Magnesium concentrations should be measured in all infants with hypocalcemia because magnesium is necessary for parathyroid secretion and end-organ action.
Most cases of neonatal hypocalcemia are asymptomatic. When severe, the main clinical signs are jitteriness, irritability, tremors, twitching movements, and generalized or focal convulsions. Other nonspecific features include lethargy, poor feeding, vomiting, and abdominal distension. Arrhythmias may occur, but the characteristic prolongation of the electrocardiogram QT interval is not consistently found. Frank convulsions are seen more commonly with late neonatal hypocalcemia (usually calcium < 6 mg/dL). The classical signs of peripheral hyperexcitability of motor nerves (carpopedal spasm and laryngospasm) are uncommon in newborn infants.
The diagnosis of hypocalcemia is based on the determination of serum total and ionized calcium as well as serum phosphorus, magnesium, and glucose concentrations and blood pH. Prolongation of the corrected QT interval on the electrocardiogram should always raise the suspicion of hypocalcemia, and this can may be useful in monitoring the response to calcium therapy.
Symptomatic hypocalcemia that is refractory to therapy may be secondary to less common causes such as primary hypoparathyroidism, malabsorption, and disorders of vitamin D metabolism. Elevated serum phosphorus concentration (> 8 mg/dL) indicates phosphorus loading (a clue to high dietary phosphorus intake), renal insufficiency, or hypoparathyroidism. Absence of a thymic shadow on chest radiograph suggests DiGeorge syndrome. Hypercalciuria associated with hypocalcemia indicates deficient parathyroid hormone. Low serum 25-hydroxyvitamin D concentration (< 11 ng/mL) indicates vitamin D deficiency.
Asymptomatic hypocalcemia is treated by providing intravenous calcium salts followed by formula or milk feeding that provides 75 mg/kg/d of calcium. After normocalcemia is achieved, a stepwise reduction of intravenous calcium may prevent rebound hypocalcemia: 75 mg/kg/d for the first day, half the dose the next day, half again, and discontinue. Infants of diabetic mothers often require as much as 100 to 200 mg/kg daily, and some require 2 to 3 times that amount. If infants can tolerate oral fluids, calcium gluconate can be given enterally at the same total daily dose (divided into 4 to 6 doses) after initial correction. Use of the intravenous form of calcium for enteral administration may cause less gut stimulation than syrup-based (high osmolar) preparations.
Symptomatic hypocalcemia usually responds rapidly to intravenous calcium therapy, and this also helps to confirm the diagnosis. In mildly symptomatic cases, attempts to correct hypocalcemia with rapid bolus infusions are less successful than slower infusions or repeated low dose bolus injections; this approach also helps prevent cardiac dysrhythmias. If hypocalcemia is associated with seizures, calcium can be replaced rapidly with 1 to 2 mL of 10% calcium gluconate per kg (9–18 mg elemental calcium/kg) given intravenously over 5 to 10 minutes; heart rate should be measured continuously during the infusion because of bradycardia, for which the infusion should be stopped temporarily. Additional calcium should be given intravenously as 100 to 200 mg/kg/dose every 4 to 6 hours if symptoms persist. A central venous catheter is preferable for acute intravenous calcium administration, particularly in severely symptomatic cases (eg, with seizures). If a peripheral catheter is used, its patency and the skin around the catheter’s skin entry site should be checked for signs of extravasation before every dose of calcium, as calcium can cause considerable tissue injury with extravasation from the vein. This is more common with calcium chloride, which should only be used in extreme emergencies using a central venous catheter. Vitamin D metabolites are not recommended for treatment of early hypocalcemia because of their variable responses and potential side effects.
Most cases of neonatal hypocalcemia require only 2 to 3 days of treatment, but such treatment is important to prevent adverse cardiovascular and central nervous system (CNS) complications of low serum calcium concentrations. Calcium supplementation usually is required for long periods in cases of hypocalcemia caused by malabsorption or hypoparathyroidism. If hypocalcemia is associated with hypomagnesemia (serum magnesium concentration below 0.6 mmol/L or 1.5 mg/dL), magnesium sulfate 50% solution (500 mg or 4 mEq/mL), 0.1 to 0.2 mL/kg intravenously or intramuscularly, providing 50 to 100 mg/kg, should be given and repeated after 12 to 24 hours. Serum magnesium should be obtained before each dose.
Late hypocalcemia is usually symptomatic and requires treatment. The goals of therapy are to reduce the phosphorus load and to increase calcium absorption by using feedings with a calcium/phosphorus ratio greater than or equal to 4:1. This can be accomplished by the use of low-phosphorus feedings, such as human milk or low-phosphorus formula, in conjunction with an oral calcium supplement. Phosphate binders generally are not necessary. Hypoparathyroidism requires therapy with vitamin D or preferably one of its metabolites: 1,25(OH)2D (or 1α-hydroxyvitamin D3, a synthetic analog) and life-long calcium supplementation.
Early neonatal hypocalcemia can be prevented by oral or intravenous calcium supplementation (80 mg elemental calcium gluconate/kg/d [100 mg/kg/d of calcium gluconate = 9.3 mg of elemental calcium]). Use of continuous calcium infusion by central catheter to maintain a total calcium higher than 8.0 mg/dL and an ionized calcium level higher than 1.0 mmol/L (4.0 mg/dL), may prevent hypocalcemia in sick newborns with cardiovascular compromise requiring cardiotonic drugs or pressor support. Maintenance of normal maternal vitamin D status with exogenous vitamin D supplements may help to maintain adequate amounts of fetal vitamin D; which, in turn, may prevent late hypocalcemia. In addition, the judicious use of bicarbonate administration and avoidance of respiratory alkalosis reduce the risk of developing symptomatic hypocalcemia in ill infants.
Neonatal hypercalcemia is defined as a serum total calcium concentration greater than 2.75 mmol/L (11 mg/dL) or an ionized calcium concentration greater than 1.4 mmol/L (5.6 mg/dL). Pathological hypercalcemia includes increased ionized and total calcium, although increased total calcium may occur without increased ionized calcium.
Hypercalcemia is uncommon but more frequent in preterm infants. It is usually iatrogenic in the setting of excessive vitamin D and/or calcium supplementation, or following the use of parenteral nutrition with insufficient phosphate administration (with or without excessive calcium). Hypercalcemia of the mother and the neonate may result from chronic maternal exposure to excess vitamin D or its metabolites during treatment of maternal hypocalcemia or by maternal self-medication. Chronic maternal diuretic therapy with thiazides during pregnancy also can cause lead to neonatal hypercalcemia.
Much rarer causes of hypercalcemia in the newborn have a metabolic or familial basis, such as primary hyperparathyroidism, familial hypocalciuric hypercalcemia, hypercalcemia associated with subcutaneous fat necrosis, idiopathic infantile hypercalcemia (part of Williams syndrome), severe infantile hypophosphatasia, and Bartter syndrome variant.
Normally, an increase in serum calcium inhibits parathyroid hormone and 1,25(OH)2D synthesis and thereby prevents or reduces hypercalcemia by decreasing calcium mobilization from bone, absorption from intestine, and reabsorption from kidney. A sustained elevation in serum calcium concentration implies an inappropriately increased calcium efflux from 1 of these pools into the extracellular fluid.
Hypophosphatemia can cause elevated circulating 1,25(OH)2D with increased intestinal absorption of calcium and increased bone resorption; calcium cannot be deposited in bone in the absence of phosphate and thereby contributes to hypercalcemia. Pathological conditions associated with parathyroid hormone or vitamin D overactivity that lead to hypercalcemia include increased bone turnover, intestinal calcium absorption, and renal calcium absorption.
Hypercalcemia may be asymptomatic. Mild clinical signs include lethargy, irritability, feeding difficulties, emesis, constipation, polyuria, dehydration, and poor growth. More serious signs include seizures, hypertension, respiratory distress (from hypotonia, demineralization, and deformation of the rib cage), and nephrocalcinosis. Long-standing hypercalcemia can lead to metastatic calcifications such as nephrocalcinosis.
An increased serum calcium concentration confirms the diagnosis. A maternal dietary and drug history (eg, excessive vitamin A or D, thiazides) or history of possible calcium-phosphorus imbalance or polyhydramnios during pregnancy, or a family history of disturbed calcium metabolism, should prompt further evaluation. Very elevated serum calcium level (> 15 mg/dL) usually indicates primary hyperparathyroidism or, in very low–birth-weight infants, phosphate depletion. Further evaluation should include serum phosphorus concentration, percentage of renal tubular phosphorus reabsorption, serum parathyroid hormone concentration, urinary calcium–urinary creatinine ratio, serum alkaline phosphatase concentration, and serum 25-hydroxyvitamin D concentration. Bone x-ray films will identify demineralization and/or osteolytic lesions or osteosclerotic lesions consistent with the etiology of the hypercalcemia.
The treatment of neonatal hypercalcemia consists of correcting specific underlying causes and removing iatrogenic or external causes. This includes the surgical removal of parathyroid glands, stopping of excessive vitamin D intake, and reducing or temporarily stopping calcium supplementation of human milk (mother’s or donor) given to preterm infants. In mild cases in which patients are asymptomatic, maintenance of hydration may suffice. In the first 2 to 3 days after birth, adjustments in the intravenous calcium–phosphorous ratio usually prevent further hypercalcemia. For a moderately to severely hypercalcemic infant, prompt investigation and therapy must be instituted with the following goals: correction of dehydration, enhancement of renal excretion of calcium, inhibition of intestinal absorption or bone resorption (eg, with hydrocortisone treatment), restriction of dietary calcium intake, oral phosphorous supplementation if hypophosphatemia is present, and treatment of the underlying disorder.
For the short-term treatment of acute symptomatic hypercalcemia (or serum calcium > 14 mg/dL), expansion of the extracellular fluid compartment with 10 to 20 mL/kg of 0.9% sodium chloride intravenously, followed by an intravenous injection of a potent loop diuretic such as 1 mg/kg of furosemide every 6 to 8 hours, may increase urinary calcium excretion. In patients with low serum phosphorus concentrations, oral phosphate supplements of 0.5 to 1.0 mmol (16–31 mg) of elemental phosphorus per kilogram per day in divided doses mixed with feeds may normalize the serum phosphorus concentration and lower serum calcium concentration. Parenteral phosphate, however, should be avoided in severely hypercalcemic patients (serum total calcium > 12 mg/dL) unless hypophosphatemia is severe (< 1.5 mg/dL), because extraskeletal calcification may occur. Calcitonin, glucocorticoids and bisphosphonate also have been used for severe hypercalcemia. For severe and unremitting hypercalcemia, either hemodialysis if the infant is hemodynamically stable or peritoneal dialysis may be helpful. Virtually all cases of primary hyperparathyroidism require subtotal or total parathyroidectomy, because the hypercalcemia may be life threatening and does not respond to medical management. The need for treatment should be reassessed at regular intervals because some instances of neonatal hypercalcemia may resolve spontaneously.
DISORDERS OF SODIUM BALANCE
Hypernatremia is defined as a serum sodium concentration of greater than 150 mEq/L.
Incidence and Epidemiology
Hypernatremia is common in preterm infants, particularly in those born before 28 weeks’ gestation and in those of extremely low birth weight (< 1000 g). The frequency of severe hypernatremia has diminished in recent years with improved fluid and electrolyte management.
Etiology and Pathophysiology
The most common cause of neonatal hypernatremia is dehydration from free water deficiency. In the preterm neonate, multiple factors contribute to free water loss. Excessive evaporative water loss in the first 24 hours especially, across the very underdeveloped skin of extremely premature infants contributes to dehydration and hypernatremia. Evaporation is aggravated by radiant warmers, high environmental temperatures, increased body temperatures, low ambient or inspired humidity, congenital skin defects (eg, omphalocele), and phototherapy. Other contributing factors include the poor concentrating capacity of the underdeveloped renal medulla with high urinary water loss.
Hypernatremia in preterm infants can be exacerbated by injudicious use of sodium-containing solutions, including normal saline boluses and sodium bicarbonate. Sodium-containing medications often are overlooked as contributors to hypernatremia. Rarely, congenital or acquired reduction in antidiuretic hormone (diabetes insipidus) can lead to excessive, relatively sodium-free urinary water loss. In the term neonate, dehydration secondary to breast feeding failure is often complicated by various degrees of hypernatremia.
Sodium is the principal cation of extracellular fluid, including the plasma. Hypernatremia from dehydration will deplete intracellular fluid, in any organ and tissue in the body, but most worryingly in the brain. This must be taken into consideration, as rapid correction of hypernatremia can cause complications from cerebral edema.
Mild to moderate hypernatremia usually is well tolerated in both the preterm and term neonate. More severe hypernatremia (> 175 mEq/L) can manifest with symptoms referred to the CNS. Hypernatremia leads to osmotic shifts in capillaries and cells in the CNS, which can rupture and produce neuronal cell necrosis and intracerebral hemorrhage. Late-occurring seizures can occur with very severe hypernatremia, with or without venous thrombosis or intracranial hemorrhage. Dehydrated term infants can present with lethargy, irritability, hypotonia and with seizures if hypernatremia is severe.
Prevention And Management
For the preterm neonate, interventions to prevent the development of hypernatremia include the use of polyethylene occlusive wrapping or plastic bags to minimize evaporative water loss during resuscitation, and the use of humidified isolettes in the NICU. Fluid administration should be guided by frequent measurements of weight and urinary flow rate to adjust fluid intake to prevent dehydration, and judicious use of sodium-containing infusions.
Treatment is directed toward correcting the cause, either free water deficit or total body sodium overload. Serum sodium should be reduced slowly to prevent osmotic swelling in cells, particularly in the CNS. It is appropriate to aim to correct no more than 10 to 12 mEq/L of serum sodium concentration over 24 to 36 hours. Extremely severe hypernatremia, particularly if the infant has CNS signs such as seizures and intracerebral hemorrhage, can be treated with whole blood exchange transfusion.
Multiple studies have correlated hypernatremia with an increased risk of long-term neurologic complications in both the preterm and term neonate. However, given that the clinical course of the neonate with hypernatremia often complicated, it is difficult to link causality between hypernatremia and neurologic injury.
Hyponatremia is defined as a serum sodium concentration of less than 130 mEq/L.
Incidence and Epidemiology
Hyponatremia is common in extremely small preterm infants. It is not uncommon for these infants to be treated in the first 2 to 3 days of life with high intravenous fluid infusion rates to prevent dehydration. However, during this time, glomerular filtration rates and urinary flow rates are low, especially when associated with pulmonary disorders. The imbalance between fluid administration and fluid loss results in hyponatremia. Late hyponatremia also is common in preterm infants, and usually occurs as a result of diuretic use. Hyponatremia in the term infant is rare. When it does occur, it is often the result of excessive fluid administration in the critically ill neonate.
Etiology And Pathophysiology
Hyponatremia in preterm infants is most commonly iatrogenic. This can occur at birth if the mother has received high intravenous infusion rates during labor or cesarean section; water diffuses across the placenta more rapidly than do solutes. Decreased effective blood volume prevents the suppression of antidiuretic hormone (vasopressin) secretion, common with perinatal depression secondary to hypoxic-ischemic conditions, intracranial hemorrhage, sepsis, respiratory distress, intrathoracic air leak syndromes, and medications such as morphine, barbiturates, or carbamazepine. Low glomerular filtration rates at early gestational ages also limit high urine flow rates in response to fluid boluses, particularly in the first 2 to 3 days of life. Further dilution of serum sodium often is augmented by coincident hyperglycemia, which osmotically pulls water from intracellular and extravascular extracellular fluid spaces. Later hyponatremia occurs frequently as a result of renal loss of sodium from diuretic therapy, particularly the potent loop diuretics such as furosemide. The syndrome of inappropriate antidiuretic hormone secretion also can produce hyponatremia. This should be suspected clinically when decreased serum sodium concentrations and urine output occur simultaneously, usually in response to a sudden, often catastrophic change in CNS and cardiovascular status, such as with acute, severe intracranial hemorrhage. Suboptimal sodium intake at any stage contributes to hyponatremia, as does urinary sodium loss once the very preterm infant enters its natural diuretic phase after the first 2 to 3 days of life. Late hyponatremia has been noted with exclusive breast milk feedings without supplements of milk fortifiers that include salts and protein and with certain low-sodium formulas.
Hyponatremia often is asymptomatic because of chronic rather than acute development of sodium imbalance, but a late clinical sign is the onset of seizures. Infants fed unsupplemented breast milk or low-sodium formulas often develop peripheral edema with hyponatremia that sometimes is aggravated by hypoproteinemia from low protein in the diet.
Severe and persistent hyponatremia can lead to pathologic conditions in the CNS (eg, seizures), lung (eg, patent ductus arteriosus, pulmonary edema), and acid–base balance (eg, hypochloremic alkalosis from diuretic therapy, often worsened by bicarbonate generation from retained carbon dioxide in infants with chronic lung disease), as well as poor growth that often is accompanied by peripheral edema.
Diagnostic criteria include (1) low serum sodium, (2) continued urine sodium loss, (3) urine osmolality greater than plasma, and (4) normal adrenal and renal function. The usual management is with water restriction until diuresis follows and is directed toward the etiology. Diuretics to reduce pulmonary edema, particularly in infants with chronic lung disease, will typically aggravate the hyponatremia and promote hypochloremic alkalosis.
Infants with hyponatremia may grow more slowly, although this probably is related to associated nutritional and acid–base disturbances, and they more commonly develop cerebral palsy, although this has not been demonstrated to be an independent risk factor separate from associated pathologies (eg, intracranial hemorrhage) and preterm birth itself.
DISORDERS OF POTASSIUM REGULATION
Hyperkalemia is defined as a serum potassium concentration greater than 7 mEq/L, but the rate of rise is more important than the exact concentration.
Incidence and Epidemiology
Hyperkalemia occurs frequently in very preterm infants, usually in the first few days of life in association with other serious conditions and aggressive forms of treatment. It is important to note that most neonates do not need supplemental potassium in the first 2 to 4 days of life, when normal glomerular filtration rates and urinary flow are being established.
Etiology and Pathophysiology
Causes of hyperkalemia include (1) acidosis with or without tissue destruction; (2) renal failure, particularly with continued potassium treatment; and (3) adrenal insufficiency, which is relatively uncommon. Hyperkalemia often occurs with hyperglycemia in very preterm infants receiving high dextrose infusion rates, and some even refer to this problem as the hyperglycemia–hyperkalemia syndrome.
Potassium is the main cation of intracellular space and contributes to polarization of the cell membrane. High extracellular fluid potassium concentrations, therefore, tend to depolarize the cell membrane and contribute to reduced action potentials in nerves and conductive cells in skeletal, cardiac, and smooth (eg, gut) myocytes.
Clinical signs of hyperkalemia include muscle weakness (hypotonia), ileus, and a variety of cardiac dysrhythmias. Electrocardiographic changes include prolonged PR interval, peaked T waves, widened QRS duration, and subsequently a sine-wave pattern of the QRS-T waves and ventricular arrhythmias.
When severe, hyperkalemia can produce life-threatening cardiac dysrhythmias, including ventricular fibrillation and asystole. Ileus can contribute to feeding intolerance. Muscle weakness in the diaphragm and thoracic muscles can aggravate other causes of respiratory failure.
Hyperkalemia is determined by serum electrolyte concentrations; its severity, along with clinical and electrocardiographic signs, determines the need for and urgency of treatment. Serum electrolytes should be measured frequently. Management is directed toward the causes and nonspecific treatment, depending on the severity of the hyperkalemia. Non–potassium-containing volume expanders can acutely lower high serum potassium concentrations.
When hyperkalemia is severe, the following actions are urgent:
Stop all potassium administration.
Infuse calcium gluconate (100 to 200 mg/kg intravenously [IV]) to lower the cell membrane threshold. This is transient but may be lifesaving.
Infuse sodium bicarbonate (1 to 2 mEq/kg IV, over at least 30 minutes). This transient therapy enhances intracellular sodium and hydrogen exchange for potassium and is particularly useful when the hyperkalemia is associated with acidosis. If hyperkalemia is associated with acute renal failure, the volume of fluid necessary to deliver the sodium bicarbonate may be excessive.
Administer cation exchange resin (sodium polystyrene-sulfonate [Kayexalate], 1 g/kg) as an oral or rectal solution. Little experience has been reported in neonates, and technical problems of retention can be substantial. Furthermore, this may not be an option if the infant is restricted to nothing by mouth or has an injured gastrointestinal tract. When this resin is used, sodium from the resin is exchanged for serum potassium, which may result in hypernatremia, requiring frequent serial electrolyte measurements and increased fluid administration, often with diuretics. This therapy should be used with caution in newborns, and is contraindicated in premature neonates, as it has been associated with the development of necrotizing enterocolitis.
An insulin infusion (0.1 U/kg/hr IV), given simultaneously with a dextrose infusion, can help shift potassium intracellularly. Complications of insulin infusion can occur with this treatment for severe hyperkalemia, and frequent monitoring of blood glucose levels is required.
Administer inhaled albuterol (0.15 mg/kg every 20 minutes for 3 doses then 0.15–0.3 mg/kg) to shift potassium intracellularly. While this is transient, it can be lifesaving.
Administer furosemide (orally [PO]: 1–4 mg/kg/dose 1–2 times/day; IV: 1–2 mg/kg/dose given every 12–24 hours) to increase the urinary excretion of potassium.
Perform renal replacement therapy. This takes time to set up and may be technically impractical in very preterm infants.
Hypokalemia is defined by a serum potassium concentration less than 3.5 mEq/L.
Incidence and Epidemiology
Hypokalemia is most common in very preterm infants during diuretic therapy.
Etiology and Pathophysiology
The most common causes of hypokalemia are (1) increased gastrointestinal losses from an ostomy or drainage from a nasogastric tube when there is lower intestinal obstruction, and (2) renal losses, common in diuretic therapy. Hypokalemia also can occur when insulin and glucose infusions are used to treat severe hyperglycemia.
About 90% of total potassium is intracellular. Loss of intracellular potassium depolarizes cells, leading to cellular dehydration and diminished action potentials in nerves, cardiomyocytes (particularly those involved in contractile conduction), and gut myocytes (leading to ileus).
Clinical Presentation and Complications
Clinical signs of hypokalemia are related to muscle weakness (eg, generalized hypotonia and reduced respiratory effort), cardiac dysrhythmias (eg, abnormal conductions, but most seriously, asystole and cardiac arrest), and diminished gut peristalsis (producing ileus and feeding intolerance).
Serum electrolyte concentrations should be measured frequently to document the disorder. Early electrocardiographic changes include decreased T-wave amplitude and ST-segment depression.
Management is directed toward the causes, such as correction of metabolic acidosis and ostomy and renal losses. Low serum potassium always implies significant intracellular depletion, but intracellular potassium can be low with normal serum potassium. When intravenous treatment is used, the correction dose should be low (0.5 mEq/kg), and usually should not contain more than 40 mEq/L of potassium, and the treatment should be over hours, not by bolus (except for life-threatening cardiac dysrhythmias) and only in the setting of normal renal function. Diuretic-induced hypokalemia can be minimized by using a potassium-sparing diuretic such as spironolactone and increasing potassium salt supplements of milk or formula.
DISORDERS OF ACID-BASE BALANCE
Metabolic acidosis is a decrease in pH due to increased acid (H+ [hydrogen ion or proton]) production greater than any coincident increase in bicarbonate (HCO3–) or decrease in the partial pressure of carbon dioxide (PCO2) or a loss of bicarbonate greater than any coincident decrease in PCO2 or decrease in acid production. Metabolic acidosis can be further divided into those with an elevated anion gap and those with a normal anion gap. The anion gap reflects the balance between certain unaccounted cations and acidic anions in the extracellular fluid. The unmeasured anions normally include the serum proteins, phosphates, sulfates, organic acids, and lactate, whereas the unaccounted cations are the serum potassium, calcium, and magnesium. Thus, the anion gap is estimated using the formula
The normal serum anion gap in newborns is 8 to 16 mEq/L, and can be slightly higher in very premature newborns. Accumulation of strong acids because of increased intake, increased production, or decreased excretion results in an increased anion gap acidosis, whereas loss of bicarbonate (HCO3−) or accumulation of H+ results in a normal anion gap acidosis.
Incidence and Epidemiology
The most common cause of anion gap metabolic acidosis in preterm infants is hypoxia-ischemia with lactic acidosis. The most common cause of normal anion gap metabolic acidosis in the preterm newborn is a mild, developmentally regulated, proximal renal tubular acidosis with renal HCO3− wasting. Other causes include as well as bicarbonate loss in the urine or plasma dilution by rapid fluid expansion of the blood volume and extracellular fluid.
Etiology and Pathophysiology
Increased anion gap acidosis occurs with additional acid to the blood and extracellular fluid, such as with lactic acidosis, renal failure, and metabolic disorders. The serum chloride concentration is normal in these disorders. Normal anion gap acidosis occurs with bicarbonate loss in the urine (proximal renal tubular acidosis), ostomy drainage, the inability to excrete acid due to defects in distal nephron function (distal renal tubular acidosis), or administration of Cl-containing compounds (eg, arginine HCl, HCl, CaCl2, MgCl2, NH4Cl hyperalimentation, high-protein formula). The serum chloride is increased in these disorders. Mild to moderate chronic metabolic acidosis occurs in infants fed too much protein (> 4–5 g/kg/d) and may contribute to growth failure. Acute and relatively severe metabolic acidosis has been associated with decreased cardiac contractile performance and increased pulmonary vascular tone (pulmonary hypertension), although the degree that such conditions are only due to increased acid in the blood is controversial and probably not as marked as previously assumed.
Acute metabolic acidosis usually is associated with clinical conditions that produce it. Chronic metabolic acidosis often is accompanied by growth failure. Complications of metabolic acidosis usually are those of underlying causes or inappropriate treatments.
Metabolic acidosis is measured by blood gas analysis. It is expected with acute abnormalities that include hypoxia, ischemia, hypovolemia, hypotension, and aggressive intravenous fluid treatment. It should be anticipated and looked for in more chronic conditions with high urinary flow rates, excessive ostomy or gastric drainage, and poor growth.
Acid production should be diminished by correcting the underlying pathophysiology. Acute intravenous sodium bicarbonate bolus infusion has been commonly used to treat severe and persistent metabolic acidosis, but this treatment generally is unproven and risky. Bicarbonate infusions in small infants can produce volume overload, intracranial hemorrhage, hypernatremia, respiratory acidosis, decreased capillary oxygen exchange from increased hemoglobin-oxygen affinity, and a paradoxical intracellular acidosis as carbon dioxide, produced when the bicarbonate reacts with water via carbonic anhydrase, diffuses into cells. This treatment should be reserved for severely unstable and acidotic infants when other measures fail. Infants should be intubated and ventilated or spontaneously breathing well enough to lower their PCO2 easily. Infants with dilutional acidosis should have their fluid balance corrected. Chronic metabolic acidosis from bicarbonate loss responds well to daily addition of bicarbonate to feedings.
Chronic metabolic acidosis produces reversible growth failure. Outcomes from acute, severe metabolic acidosis are usually due to its underlying causes or overly aggressive treatment with sodium bicarbonate bolus infusions.
Metabolic alkalosis is an increase in pH due to loss of acid or gain of bicarbonate without sufficient increase in PCO2.
Incidence and Epidemiology
Metabolic alkalosis occurs frequently in newborns but is common to only a few specific conditions.
Etiology and Pathophysiology
Three basic mechanisms contribute to metabolic alkalosis: loss of acid, such as hydrochloric acid from vomiting, or intestinal obstruction and drainage; excessive treatment with, or ingestion of a base, such as alkali bolus infusions during resuscitations; and contraction of the extracellular fluid from dehydration (contraction alkalosis) or loss of fluids containing more chloride than bicarbonate (as occurs with chronic diuretic treatment). Common causes of metabolic alkalosis in neonates include acid loss from vomiting with pyloric stenosis, duodenal stenosis/atresia, or other high intestinal obstructions, or gastric drainage following intestinal surgery or with persistent ileus. Potassium depletion promotes metabolic alkalosis by stimulating renal ammonia genesis and inhibiting movement of hydrogen ions out of cells. Chloride depletion or chronic respiratory acidosis also maintains a metabolic alkalosis.
Bicarbonate is normally excreted by the kidney, except with dehydration and reduced glomerular filtration rate that diminishes urine flow rate and distal tubule chloride-bicarbonate exchange. This condition also promotes proximal bicarbonate resorption that occurs readily with sodium resorption promoted by aldosterone secreted in response to low glomerulus filtration rate or blood volume, as well as hyponatremia.
Metabolic alkalosis is usually asymptomatic but should be suspected in infants with high urine flow rates, ostomy, and gastric drainage, and those treated with alkali and/or hyperventilation. Complications of metabolic alkalosis usually are those of associated conditions.
Metabolic alkalosis is diagnosed by blood gas measurements. The underlying pathophysiology must be corrected. Chronic and marked contraction alkalosis can occur with intracellular potassium deficiency that often is more severe than indicated by the serum potassium concentration.
Chronic alkalosis has been associated with sensorineural hearing loss that is distinct from commonly associated loop diuretic ototoxicity. Neurodevelopmental outcomes appear to be worse with acute, severe alkalosis produced by hyperventilation (respiratory alkalosis) and alkali treatment, though the pathophysiology causing this adverse outcome is not clearly defined.
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