Endocrine and Metabolic Crises in the Pediatric Intensive Care Unit

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168 Endocrine and Metabolic Crises in the Pediatric Intensive Care Unit

Increasing numbers of endocrine and metabolic conditions are being recognized, and the number of children in treatment programs for them is increasing. Although improved screening programs and therapy may decrease the number of children requiring critical care for these conditions, it is likely they will be recognized in increasing numbers of critically ill children for the foreseeable future. There is also increasing awareness of the significance of metabolic changes such has hypo- and hyperglycemia in the pediatric intensive care unit (PICU).¹ General principles of PICU management apply to patients with endocrine and metabolic crises (Table 168-1).^2,³ Crises may cause damage with long-term sequelae for the child and family; however, they also present unique diagnostic opportunities. The intensivist has a particular responsibility to:

• Be aware of endocrine and metabolic problems.

• Consider them in the differential diagnosis of particular clinical syndromes.

• Perform appropriate clinical and biochemical investigations.

• Seek advice from specialists in the clinical and laboratory diagnosis and management of the conditions.

• Consider the implications of metabolic and endocrine problems for the family of the affected child.⁴

• Support the development of structures for the comprehensive management of metabolic problems from infancy through adulthood.⁵

TABLE 168-1 Principles of Management of Metabolic and Endocrine Crises

Principle	Specifics of Conditions
Airway management	Many patients have depressed level of consciousness, and airway management is essential to prevent complications.
Breathing support	Acidotic patients may make huge respiratory effort; ventilatory support may help decrease the metabolic demands on these patients. Although administration of sodium bicarbonate may help to settle some of the acidosis-related symptoms such as hyperventilation, bicarbonate may aggravate some problems seen in conjunction with urea cycle defects. Give bicarbonate only if the plasma bicarbonate <10 mmol/L, and then only half correct deficits.
Circulatory support	Ensure adequate circulating volume; this may be a particular issue if there has been excessive fluid loss from vomiting or diarrhea.
Disability	Control seizures using anticonvulsant agents. Administer pyridoxine if possibility of pyridoxine dependency.
Dialysis to remove toxins where necessary	Hemodialysis is the most efficient means of removing toxins such as ammonia and leucine. Hemofiltration is less efficient but may be more applicable in critically ill children. Peritoneal dialysis is slower but has the advantage of ease of initiation.¹ In some conditions, it may be possible to remove toxins by stimulating alternative pathways of metabolism.
Ensure that glucose is maintained in the normal range	A normal glucose level should be maintained at all times. Excessive administration of glucose in the mitochondrial energy chain problem may exacerbate lactic acidosis. Also, attempt to provide an adequate energy supply (may use medium-chain fatty acids where appropriate). Minimize energy demands on patient.
Fluids	In general, provide 1.5× normal fluid maintenance requirements to accelerate excretion of water-soluble toxins. In the context of encephalopathy (MSUD or urea cycle defects), be careful to avoid overhydration, which may contribute to development of cerebral edema.
Feeds	If there is accumulation of a product, this needs to be eliminated from the diet (e.g., fructose, galactose). Start with protein-free diet, but do not continue beyond 2 days, because the catabolic state also creates problems. If diagnosis not identified, need gradual reintroduction of feeds and nutrition. If there is deficiency of any nutrient (e.g., carnitine, which may have a primary or a secondary deficiency), supplement that nutrient. Ensure there is an adequate energy source along a metabolic route that is functional. Provide specific vitamin therapy where indicated.
Family support and information	The diagnosis of an inborn error of metabolism has major implications for families, and considerable support is required.²
Treat infection	Infections are an important component of pediatric ICU presentation of inborn errors of metabolism. Some conditions such as galactosemia are related to specific infections such as Escherichia coli. Other conditions are related to pyogenic infections because of neutropenia. Children who are in a poor nutritional or metabolic state are more susceptible to infection. Intercurrent infections may be the precipitating factor for metabolic decompensation.
Investigations	A wide variety of investigations are relevant to inborn errors of metabolism. Biochemical testing on a range of body fluids and on tissues is fundamental to accurate diagnosis of the problem. Biochemical tests may range from simple screening tests to more complex tests on tissue culture. Imaging techniques such as CT, MRI, magnetic resonance spectroscopy, and echocardiography may be relevant. Functional tests such as EEG, ECG, and EMG may be useful in diagnosis. Increasingly, genetic diagnosis is available if children have recognized genetic mutations.
Monitor response to therapy	Clinical monitoring is essential. Biochemical monitoring of the appropriate metabolites is essential to ensure that metabolic control is established.

CT, computed tomography; ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; ICU, intensive care unit; MRI, magnetic resonance imaging.

Abnormalities of glucose control are relatively common in the PICU, but with the possible exception of diabetes mellitus, endocrine and metabolic crises are uncommon, and most intensivists do not see sufficient case numbers to become expert at managing these disorders. It is crucial to manage children with suspected or proven endocrine or metabolic crises in conjunction with specialist teams. The laboratory investigation of inborn errors of metabolism may be complex, and there are relatively few laboratories worldwide that have the capacity to fully elucidate most of the inborn errors of metabolism. Close cooperation with specialist laboratory centers is essential for accurate diagnosis and management.

A particular problem of endocrine and metabolic crises is that laboratory investigation of specific conditions may take time while patients require urgent therapeutic intervention. Because it may not always be possible to follow algorithms of investigation, a reasonable approach is to collect all relevant specimens immediately,⁶ store them appropriately, and liaise with laboratory services to use the specimens in a logical and cost-effective manner to confirm the diagnosis.

Endocrine Crises

Endocrine crises present in a limited number of ways that include abnormalities of glucose control, fluid and electrolyte balance, and blood pressure control. Management of these crises consists of identifying the problem, investigating the cause, and correcting the abnormality directly or managing the underlying problem. This section provides a clinical overview of pediatric endocrine crises; detailed pathophysiology is discussed in other chapters.

Abnormalities of Glucose Control

Abnormalities of glucose control, including diabetic ketoacidosis, are the most common endocrine crises encountered in the PICU. Hypoglycemia and hyperglycemia are associated with increased mortality ^1,⁷ in sick children and may be part of a wide variety of disease processes. Measurement of blood glucose is part of the initial biochemical evaluation of any sick child, particularly if a depressed level of consciousness or shock is present. When an abnormal glucose level has been identified, it must be addressed and levels be remeasured at appropriate intervals until the problem has been resolved. The situation is further complicated by technical issues in the measurement of blood glucose,^8,⁹ with differences between blood and plasma glucose level (glucose concentration in plasma is approximately 11% higher than whole blood because of the higher water content in plasma, but this may be affected by anemia or polycythemia); differences between arterial, venous, and capillary glucose levels (which may also vary depending on clinical context),⁸ and potentially significant differences between measurement techniques.⁹ A particular concern is that in general, inaccuracies increase at lower glucose levels.⁹ Generally, central laboratory devices are taken as the standard, although there is increasing utilization (and convenience) of point-of-care devices.

Hypoglycemia

Hypoglycemia may be associated with devastating damage to the brain and requires immediate attention. In general, a diagnosis of hypoglycemia depends on the presence of symptoms and a low blood glucose level, and resolution of symptoms on correction of the low glucose level. Unfortunately, symptoms of hypoglycemia are relatively nonspecific, ranging from lethargy, poor feeding, hypotonia, and “jitteriness” to convulsions, apneic episodes, cardiovascular collapse, and sudden infant death syndrome (SIDS). Hypoglycemia may be hidden in the complex of critical illness, particularly if patients are deeply sedated and paralyzed. In addition, some diabetic patients have reduced awareness of hypoglycemia.¹⁰ Thus, regular monitoring of blood glucose is an important component of the management of any critically ill child.

Hypoglycemia immediately following birth may be common, but there are considerable controversies in the definition of hypoglycemia in this period.¹¹^–¹³ Table 168-2 lists an approach to hypoglycemia immediately following birth.

TABLE 168-2 At-Risk Infants for Whom Routine Monitoring of Blood Glucose Is Recommended

Associated with Changes in Maternal Metabolism

Intrapartum administration of glucose

Drug treatment:

Terbutaline, ritodrine, propranolol

Oral hypoglycemic agents

Diabetes in pregnancy/infant of diabetic mother

Associated with Neonatal Problems

Idiopathic condition or failure to adapt

Perinatal hypoxia-ischemia

Infection

Hypothermia

Hyperviscosity

Erythroblastosis fetalis, fetal hydrops

Other:

Iatrogenic causes

Congenital cardiac malformations

Intrauterine Growth Restriction Hyperinsulinism Endocrine Disorders Inborn Errors of Metabolism

From Cornblath M, Hawdon JM, Williams AF et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics. 2000;105:1141-5.

Symptomatic hypoglycemia occurs more frequently during the neonatal period than in any other period of childhood. Infants at particular risk include infants with poor hepatic glycogen stores (e.g., preterm or small-for-gestational-age infants); poor glucose intake (e.g., preterm or ill infants); and hyperinsulinism, either primary or secondary to high intrauterine glucose levels (e.g., infants of diabetic mothers).¹⁴ Hypoglycemia also may be a feature of perinatal illness including asphyxia, polycythemia, hypothermia, septicemia, and respiratory distress syndrome. Much less common causes include growth hormone¹⁵ or adrenal insufficiency,¹⁶ inborn errors of metabolism, and glucagon insufficiency. Drugs administered to the mother during pregnancy, including oral hypoglycemic agents, also must be considered.

In childhood, hypoglycemia may result from inadequate glucose intake (prolonged starvation, malabsorption); defects in glycogenolysis (glycogen storage disorders) or gluconeogenesis (fructose-1,6-diphosphatase deficiency, ethanol intoxication, Jamaican vomiting sickness, etc.), fatty acid oxidation disorders and defects in ketogenesis, deficiency of gluconeogenic hormones (e.g., adrenalin, corticosteroids, glucagons, growth hormone, thyroid hormone), excessive insulin secretion (hyperinsulinism), and a variety of specific disorders including abnormalities of amino acid metabolism.¹⁷

The amount of glucose required to achieve normoglycemia and the duration of fast that can be endured without the development of hypoglycemia may assist in identifying a likely cause. Transient hypoglycemia that can be reversed with normal infusion rates of glucose (4-6 mg/kg/min) and does not recur is unlikely to be associated with an endocrine problem. Hyperinsulinemia is associated with rapid development of hypoglycemia and high glucose requirements (>6-8 mg/kg/min to >15-20 mg/kg/min). Hypoglycemia associated with adrenal insufficiency, growth hormone deficiency, and hypothyroidism tends to occur after several hours of fasting, is associated with ketosis, and can be reversed with normal infusion rates of glucose. Fatty acid oxidation defects are associated with hypoglycemia after a fast of some hours.

As soon as hypoglycemia is noted, specimens should be collected immediately for appropriate tests (Table 168-3). Treatment of hypoglycemia with intravenous (IV) glucose should be initiated promptly. An initial bolus dose of 0.5 g/kg of glucose (may need 0.5-2 g/kg in neonates) should be given as a 10% or 25% (in older children) dextrose solution, followed by an ongoing infusion of glucose at a rate of 4 to 8 mg/kg/min. The concentration of the ongoing infusion depends on the fluid requirements of the child and the availability of central venous access (for higher concentrations). Glucagon may be given at a dose of 0.1 to 0.3 mg/kg (IV or intramuscularly [IM]) but is unlikely to be effective in patients with low glycogen stores, glycogen storage disorders, or hepatic dysfunction. Hydrocortisone at a dose of 5 mg/kg every 12 hours may be useful in some patients. Diazoxide and IV octreotide decrease insulin release and may be useful in the management of hyperinsulinemia.

TABLE 168-3 Investigation of Hypoglycemia

Blood glucose	Measurement of glucose using blood from capillary specimens and using test strips may be unreliable (particularly in poorly perfused patients or patients with high hematocrit); where possible, low glucose levels should be confirmed using laboratory assays on venous or arterial blood.
Actual glucose intake	Hypoglycemia in the presence of normal glucose intake or after brief fast suggests hyperinsulinism. Hypoglycemia after hours of fasting is associated with fatty acid oxidation defects and endocrine insufficiency.
Non–glucose-reducing substances in the urine	Particularly in neonates and probably not relevant in older children. If present in the urine, consider galactosemia, hereditary fructose intolerance, or tyrosinemia.
Serum and urinary ketones	Low ketones suggest hyperinsulinism or fatty acid oxidation problem.
Serum free fatty acids	Free fatty acids are low in hyperinsulinism but high in fatty acid oxidation defect.
Serum insulin (and C peptide), cortisol, glucagon, growth hormone, and thyroid levels	Normal serum insulin in the presence of hypoglycemia is evidence of hyperinsulinism. C peptide may be necessary to ascertain whether exogenous insulin was administered. Release of C peptide may not be as pulsatile as that of insulin.
Serum ammonia	To recognize hyperinsulinism/hyperammonemia syndrome
Urinary organic acids and serum amino acids	To diagnose fatty acid oxidation defects (urinary organic acids). Aminoacidopathies such as MSUD, propionic acidemia, isovaleric acidemia, methylmalonic acidemia, and tyrosinemia may also present with hypoglycemia.
Total and free carnitine with acylcarnitine profile	To recognize primary and secondary deficiency of carnitine and fatty acid oxidation defects

If non–glucose-reducing substances are present in the urine, galactosemia, hereditary fructose intolerance, or tyrosinemia should be considered. In the absence of reducing substances, low urinary ketones with hypoglycemia suggest hyperinsulinism or defects of fatty acid oxidation. The latter can be distinguished from hyperinsulinemia by the presence of high serum free fatty acids. Assays of insulin levels can confirm the diagnosis of hyperinsulinism.

Abnormalities of growth hormone, cortisol, or thyroid hormone typically are associated with high urinary ketones, the absence of hepatomegaly, and increased lactate. Hypoglycemia also may occur as a complication of insulin therapy for diabetes mellitus. Patients with diabetes mellitus may have inadequate responses to hypoglycemia.

Neonates

In the neonatal period, glucose is not the only energy source from oxidative metabolism in the brain, and alternative energy sources such as ketones may be used.¹¹ In fact, breast-fed babies routinely have lower glucose levels and higher ketone levels than formula-fed infants. Recent reviews have highlighted that “there is inadequate information in the literature to define any one value of glucose below which irreparable hypoglycemic injury to the central nervous system occurs, at any one time or for any defined period of time, in a population of infants or in any given infant.”¹⁸ However, there is evidence that hypoglycemic injury is more likely to occur at very low levels of glucose (20-25 mg/dL [1.1-1.4 mmol/L]) and if hypoglycemia is prolonged, is the consequence of hyperinsulinemia (when alternative energy sources for the brain may be very limited), and in the presence of other potential injuries.^18,¹⁹

A suggested approach to hypoglycemia in the neonatal period is shown in Figure 168-1. Although the threshold for treatment in the asymptomatic neonate is 25 to 30 mg/dL (1.1-1.4 mmol/L), the recommended levels during treatment are above 45 mg/dL (2.5 mmol/L).

Figure 168-1 A suggested approach to management of the neonate with low glucose.

(From Rozance PJ, Hay WW. Hypoglycemia in newborn infants: features associated with adverse outcomes. Biol Neonate 2006;90:74-86.)

Although the exact definition of hypoglycemia in children is controversial, a minimal level of 2.6 mmol/L or greater should be maintained to ensure normal neural function.^12,^20,²¹ It probably is safer to maintain a level of greater than 3.5 mmol/L. Because there are multiple causes for hypoglycemia, and symptoms may not be due to the hypoglycemia alone, it is essential to identify the cause.

Hypoglycemia is associated with severe illness. A wide range of illnesses including infections,²² cyanotic and acyanotic congenital heart disease, and cardiomyopathy/myocarditis have been associated with hypoglycemia. Hepatic failure from infection, toxin ingestion, or drug reactions may be associated with severe hypoglycemia, and Reye syndrome classically presents with hypoglycemia. Toxins such as salicylates and ethanol also may cause hypoglycemia. Hypoglycemia has been linked with increased mortality from malaria,²³^–²⁶ gastroenteritis,²⁷ and acute bacterial meningitis²⁸ among other conditions. Hypoglycemia also has been described as a complication of therapy for leukemia with mercaptopurine and methotrexate.^29,³⁰ Although severe illness or sepsis may be an adequate explanation for hypoglycemia, a diagnosis of sepsis should not exclude the possibility of an endocrine or metabolic crisis.

Hyperinsulinemic Hypoglycemia

Hyperinsulinism is the most common cause of persistent or recurrent hypoglycemia in infancy.³¹^–³³ Hyperinsulinism may be secondary to risk factors in the perinatal period (associated with high maternal glucose levels,³⁴ rhesus incompatibility, intrauterine growth retardation,³⁵ and perinatal asphyxia³⁶) but may also be congenital^37,³⁸ or associated with Beckwith-Weidemann syndrome and some other developmental syndromes.³³

Although most patients with hyperinsulinemic hypoglycemia present in the neonatal period, first presentation may be during infancy and occasionally during childhood,³⁹ when the condition may be more likely to respond to medical therapy. Neonates with hypoglycemia may have the macrosomia typical of infants of diabetic mothers, but hyperinsulinemic hypoglycemia may occur in apparently normal infants of normal or low birth weight. Hypertrophic cardiomyopathy and hepatomegaly may be seen³¹ in affected infants. The characteristic features of hyperinsulinism include hypoglycemia with glucose requirements of greater than 6 to 8 mg/kg/min to maintain normoglycemia, absence of ketonemia and ketonuria, low plasma free fatty acids and branch chain amino acids, detectable insulin at the time of hypoglycemia, and response to glucagon administration.³¹ The combination of hypoglycemia with low free fatty acids and absence of ketonemia is responsible for the potentially devastating effects of this condition on the brain, as it is deprived of both normal and alternate substrates.³²

Hyperinsulinemic hypoglycemia with hyperammonemia (previously called leucine-sensitive hypoglycemia) is well described ^40,⁴¹ and is attributed to mutations in the gene for glutamate dehydrogenase. Patients generally respond well to therapy with diazoxide, and consumption of extra carbohydrate before protein meals may help ameliorate symptoms. Special low-leucine milks are available.

Congenital hyperinsulinemic hypoglycemia is caused by abnormalities in genes controlling the secretion of insulin by the beta cells of the pancreas, with abnormalities described in seven genes.³²

Initial stabilization therapy consists of glucose infusions to achieve normoglycemia. Because there may be extremely high glucose requirements and any cessation of infusion may be associated with severe hypoglycemia, it is essential to ensure that secure vascular access is always available, and central venous access may be required. Glucagon (0.5-1 mg/kg as an emergency dose IM or by IV bolus; alternatively, subcutaneously or as an IV infusion of 1-20 µg/kg/h) must always be available and can be used as short-term, emergency therapy to maintain normoglycemia if there are problems with vascular access. Administration of glucagon may be associated with rebound hypoglycemia, and frequent glucose monitoring must be continued. Octreotide (5-30 µg/kg/day subcutaneously or as an IV infusion) may also be given together with glucagon, but this drug may be associated with an increased risk of enterocolitis. As soon as normoglycemia has been achieved, the child should be transported to a center with specific expertise in the management of hyperinsulinemia. Great care must be taken to ensure that hypoglycemia does not occur during transport.

The aim of further management is to confirm the diagnosis and ensure normoglycemia (keep glucose levels > 3.5 mmol/L in view of low alternative sources of energy) without the ongoing use of glucose infusions. Glucose polymers can be added to the diet to provide an enteral source of glucose, but care must be taken to limit the osmolar load on the gut, particularly in premature infants.

Clinically, hyperinsulinemic hypoglycemic patients may be categorized by their response to diazoxide (5-20 mg/kg/d in 2-3 divided doses), with most responding. Exceptions include those with congenital hyperinsulinemia related to focal hyperinsulinemia and those with diffuse hyperinsulinemia related to inactivating mutations in ABCC8 and KCNJ11. Unfortunately, diazoxide may predispose to fluid retention, and use must be carefully monitored. Chlorothiazide (7-10 mg/kg/day in 2 divided doses) may be added (particularly in neonates).³² Nifedipine (0.25-2.5 mg/kg/d in 3 divided doses) may also be useful in some patients.⁴²

A suggested approach to ongoing diagnosis and management is outlined in Figure 168-2, showing a marked change from previous practice. In those patients who are responsive to diazoxide, that will remain the basis of therapy. In those with no response to diazoxide, genetic testing (for homozygous or compound heterozygous mutations in ABCC8 and KCNJ11), followed by fluorine-18 (¹⁸F)-dopa positron emission tomography (PET) scanning for those with potentially focal pancreatic lesions will enable identification of those who may benefit from resection of the pancreas. Pancreatic islets cells take up L-3, 4-dihydroxyphenylalanine (L-dopa), where it is converted to dopamine by dopa-decarboxylase. Uptake of the positron-emitting tracer ¹⁸F-dopa PET is increased in beta cells with a high rate of insulin synthesis and secretion provides visualization of the focal lesion.⁴³^–⁴⁶ Patients with focal lesions should respond to partial pancreatectomy, which may be done laparoscopically.^47,⁴⁸ Diffuse disease that is unresponsive to diazoxide therapy will require a near-total pancreatectomy and may be associated with a high incidence of both endocrine and exocrine problems.⁴⁹

Figure 168-2 Flow chart outlining the management cascade of neonates with hyperinsulinemic hypoglycemia (HH). Clinically, HH can be classified into diazoxide-responsive and diazoxide-unresponsive disease. A fluorine-18 L-3, 4-dihydroxyphenylalanine positron emission tomography (¹⁸F-dopa PET) scan is currently only indicated in neonates who are unresponsive to diazoxide and do not have genetically confirmed diffuse disease.

(From Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K. Hyperinsulinaemic hypoglycaemia. Arch Dis Child 2009;94:450–7.)

Close long-term follow up will be required in all these patients, and there may be significant neurologic and psychological problems to be dealt with.⁴⁹

Ketotic Hypoglycemia

Although ketotic hypoglycemia (“accelerated starvation”) is probably the most common cause of hypoglycemia in previously healthy children,⁵⁰ it is unlikely to present in the PICU. This condition usually affects children aged 6 months to 8 years, and the clinical features include ketosis, severe nausea, and hypoglycemia, usually occurring in the morning after a moderate fast. Treatment consists of ensuring that there is an adequate and regular intake of glucose, particularly during intercurrent infections. Urinary ketones may act as a warning signal, because the ketosis usually precedes the onset of hypoglycemia by several hours.

Adrenal Insufficiency

Adrenal insufficiency after high-dose inhaled corticosteroid therapy has presented with hypoglycemia ⁵¹^–⁵⁴ and should be considered if there is a past history of inhaled steroid use (particularly fluticasone).^53,⁵⁵ Adrenal insufficiency also may occur after adrenal bleeds (e.g., after meningococcal septicemia or difficult delivery), as part of adrenal disease (e.g., congenital adrenal hyperplasia or hypoplasia) in which ambiguous genitalia may (or may not) be a pointer in females, or as part of hypopituitarism (e.g., congenital, after craniopharyngioma, or after cranial irradiation⁵⁶). Some patients with primary adrenal insufficiency may present with hypoglycemia, particularly during acute illnesses.^16,⁵⁷ Adrenoleukodystrophy should be considered as part of the etiologic diagnosis in any male patient with Addison’s disease (pigmentation may be a clue) and should be tested for by measurement of very-long-chain fatty acids.^58,⁵⁷

There has been considerable interest in adrenocorticoid deficiency in children with critical illness and particularly acute severe sepsis (see Chapter 131).⁵⁹^–⁶³ Currently, supplementary steroids are recommended for children with acute severe sepsis and catecholamine resistant shock,^64,⁶⁵ but there are not clear definitions for either adrenal insufficiency or catecholamine resistance, nor are there firm recommendations for the dose of adrenal replacement therapy.

Adrenocorticoid deficiency also has been shown in preterm infants.⁶⁶ A randomized controlled study of “stress” dose hydrocortisone therapy in hypotensive very low-birthweight infants showed that steroids were effective in treating refractory hypotension.⁶⁷

Congenital adrenal hyperplasia is associated rarely with hypoglycemia. Female patients are usually diagnosed early in life as a result of virilization, whereas male patients tend to present later. Patients with the salt-losing form of congenital adrenal hyperplasia present with hyponatremic dehydration and shock, usually associated with hyperkalemia. Because patients with salt-wasting 21-hydroxylase deficiency also may have catecholamine deficiency, shock may be a significant feature. Diagnosis is based on the clinical picture, typical electrolyte pattern, hypoaldosteronism, and hyperreninemia.⁶⁸ Long-term treatment consists of hydrocortisone (to suppress excess secretion of corticotropin-releasing hormone and corticotropin), 10 to 20 mg/m² of body surface area per day in three divided doses, although larger doses may be required during adrenal crises, together with mineralocorticoid replacement (0.1-0.2 mg of fludrocortisone daily) and sodium chloride supplementation. Little is known about the dose of hydrocortisone required during critical illness, although Charmandari et al.⁶⁹ showed that when 6-hourly bolus doses of 15 mg/m² of hydrocortisone are given, high immediate serum levels are achieved, followed by rapid decline to undetectable levels by 4 hours after administration. These authors postulated that continuous infusion of hydrocortisone may be more appropriate in critical illness.

Growth Hormone Deficiency

In the neonatal period, growth hormone deficiency presents with hypoglycemia (possibly with seizures), prolonged jaundice, and in boys, micropenis and undescended testes. Growth failure becomes apparent only toward the end of the first year of life. In later childhood, growth failure is a more common presentation, and hypoglycemia rarely occurs ⁵⁶ unless associated with adrenocorticotropic hormone deficiency.

Hyperglycemia Other Than Diabetes Mellitus

Hyperglycemia is relatively common in the PICU.⁷⁰ In a retrospective study of 948 nondiabetic patients admitted to the PICU, there was a high prevalence of hyperglycemia, with 70.4% of patients having a glucose value above 120 mg/dL, 44.5% above 150 mg/dL, and 22.3% above 200 mg/dL within 10 days of admission. A 2.5-fold increased risk of dying was seen if the maximum glucose obtained within 24 hours of admission was over 150 mg/dL and a 5.68-fold increased risk if the maximum glucose obtained within 10 days of admission to the PICU was over 120 mg/dL.⁷¹ However, that study was retrospective and not corrected for severity of illness. In addition, ascertainment bias was present,⁷² so the study could not really provide insight in terms of causality or the potential impact of therapy.⁷³

Hyperglycemia is common in a wide variety of conditions including bronchiolitis,⁷⁴ sepsis, hemolytic uremic syndrome,⁷⁵ tetanus,⁷⁶ and toxin ingestion (e.g., theophylline poisoning⁷⁷). Other studies have confirmed that high glucose levels are not only common in the PICU population but are associated with increased mortality and/or morbidity in a wide variety of conditions.⁷⁸^–⁸¹

Iatrogenic causes of hyperglycemia in the PICU include resuscitation using glucose-containing fluids, parenteral nutrition or high load of administered glucose, and high-dose corticosteroid therapy. Continuing hyperglycemia may also be an indication of ongoing stress or undiagnosed type 1 diabetes and should prompt the clinician to investigate further.

An initial report from an adult surgical unit (predominantly cardiac)⁸² provided evidence that “tight” control of glucose levels was associated with a significant improvement in patient outcomes. The same group studied a cohort of patients in a medical ICU, and there was no difference in mortality between groups.⁸³ There have been numerous studies in a variety of adult critical care populations since that time, with positive effects of tight glucose control noted on cholestasis,⁸⁴ renal function,⁸⁵ neurologic and neuromuscular complications,^86,⁸⁷ and endothelial function.⁸⁸ Unfortunately, there have also been increased reports of iatrogenic hypoglycemia, and a recent meta-analysis of studies in adults⁸⁹ concluded that tight glucose control was not associated with an improvement in hospital mortality and was associated with an increased incidence of hypoglycemia. Subsequently, a large randomized controlled trial (RCT) of adult patients compared “tight” (81-108 mg/dL or 4.5-6.0 mmol/L) with “conventional” glucose control (target of ≤180 mg/dL or ≤10.0 mmol/L). The 90-day mortality was higher in the group on tight glucose control, and subgroup analysis showed that the outcomes favored conventional control in all groups except trauma patients and patients on steroids.

Pediatricians have been more cautious in their approach to control of hyperglycemia, but a number of protocols for PICU management of hyperglycemia have been implemented and reported.^90,⁹¹ An RCT of protocols for tight glucose control in the PICU showed no difference between a paper-based protocol and a computerized decision support tool.⁹²

In a study of glycemic control in 177 postoperative cardiac patients,⁹³ there was no difference in glucose levels on day 1 between survivors and nonsurvivors, but the 5-day mean peak glucose levels were significantly higher in nonsurvivors. Insulin usage was higher in the nonsurvivors, and nonsurvivors had more hypoglycemic events. The authors speculated that targeting a more permissive glucose level of 90-140 mg/dL (5-7.7 mmol/L) might be associated with both improved outcomes and reduced risk of hypoglycemia. In a retrospective review of 100 postoperative cardiac patients, there was high incidence of hyperglycemia (and an association with higher severity of illness), and implementation of a pediatric glycemic control protocol had a low incidence of hypoglycemia.⁷⁹

A prospective RCT of 700 critically ill children (317 infants and 383 children) admitted to PICU ⁹⁴ randomized patients to targeted blood glucose levels (throughout PICU stay) of 2.8 to 4.4 mmol/L in infants and 3.9 to 5.6 mmol/L in children, with insulin infusion throughout PICU stay (intensive group [n=349]) or to insulin infusion only to prevent blood glucose from exceeding 11.9 mmol/L (conventional group [n=351]). Mean blood glucose concentrations were lower in the intensive group than in the conventional group, and hypoglycemia (glucose ≤2.2 mmol/L) occurred in 87 (25%) patients in the intensive group (P < 0.0001) versus 5 (1%) patients in the conventional group. Severe hypoglycemia (blood glucose less than 117 mmol/L) occurred in 17 (5%) of the intensive group versus 3 (1%) of the conventional group (P=0.001). Duration of PICU stay was reduced in the intensively treated group (5.51 days [95% CI, 4.65-6.37] versus 6.15 days [95% CI, 5.25-7.05]; P=0.017). The number of patients with stay in PICU longer than the median was 132 (38%) in the intensive group versus 165 (47%) in the conventional group (P=0.013). Nine (3%) patients died in the intensively treated group versus 20 (6%) in the conventional group (P = 0.038). There is ongoing debate about appropriate targets for glucose, optimization of protocols, balance of nutrient and glucose intake versus insulin therapy, and the like.

In the context of major burns there is also some evidence that insulin therapy to maintain lower blood glucose levels may be associated with improvements in metabolism.⁹⁵

A recent review ⁹⁶ concluded:

Hence, efficacy and safety of intensive insulin therapy may be affected by patient-related and ICU setting-related variables. Therefore, no single optimal blood glucose target range for ICU patients can be advocated. It appears safe not to embark on targeting “age-normal” levels in PICUs that are not equipped to accurately and frequently measure blood glucose, and have not acquired extensive experience with intravenous insulin administration using a customized guideline. A simple fallback position could be to control blood glucose levels as close to normal as possible without evoking unacceptable blood glucose fluctuations, hypoglycemia, and hypokalemia.

Pediatricians have been reluctant to implement tight glucose control in PICU because of concerns about the deleterious effects of hypoglycemia.^97,⁹⁸

A recent review of hyperglycemia in the preterm infant ⁹⁹ suggested the following pragmatic approach to management: confirm hyperglycemia with laboratory test; treat any underlying problem such as sepsis, stress, etc.; calculate glucose infusion rates, and if above 12 mg/kg/min, reduce infusion rate; treat with insulin if glucose is over 10 mmol/L (or other symptoms such as polyuria), but start cautiously with very low doses; finally, if hyperglycemia persists, consider other diagnoses such as diabetes.

Diabetes Mellitus

Children with diabetes mellitus have a higher mortality than healthy children,^100,¹⁰¹ with standardized mortality ratios of 2.15¹⁰² to 4.2,¹⁰³ although some deaths are not directly related to diabetes. The highest mortality is in children aged 1 to 4 years, in whom the standardized mortality ratios may be 9.2¹⁰⁴ to 13.7.¹⁰⁵ Most deaths attributable to diabetes mellitus occur as a consequence of diabetic ketoacidosis (DKA) or hyperglycemia, with the remainder attributable to hypoglycemia.¹⁰⁴ Diabetic ketoacidosis is relatively common at the time of first presentation, particularly in younger children,¹⁰⁶ in whom diagnosis may be delayed. Although the incidence of type 1 diabetes mellitus has been increasing in many parts of the world, the hospitalization rate for DKA in established and new cases of type 1 diabetes mellitus has not increased in Canada and Europe since the 1990s^107,¹⁰⁸ because of earlier diagnosis and safer ambulatory management with the help of a multidisciplinary team.

The mortality rate in the developed world for DKA ranges from 0.15% to 0.31%¹⁰⁹ but may be far higher in other settings.¹¹⁰ The most common cause of death among patients with DKA is cerebral edema. Other causes of death in DKA include electrolyte disturbances, hypoglycemia, pulmonary edema, rhabdomyolysis, infections (including mucormycosis), and thrombosis. The management of DKA in childhood has been extensively reviewed elsewhere,^109,^111,¹¹² with current recommendations.

Cerebral Edema in Diabetic Ketoacidosis

In affluent countries, symptomatic cerebral edema occurs in 0.5% to 1% of pediatric DKA episodes,¹¹³ with risks being higher in young children and previously undiagnosed diabetics. Mortality is high (21%-24%), and 15% to 26% of survivors will have permanent morbidity (including pituitary insufficiency).¹¹³

The exact mechanisms of cerebral edema in DKA are not clear,¹¹⁴ although some imaging studies suggest that cerebral edema may be related to vasogenic factors rather than osmotic factors.¹¹⁵ Cerebral hyperemia has also been demonstrated as part of abnormal autoregulation.^116,¹¹⁷ Factors that have been associated with the development of cerebral edema include the administration of bicarbonate, a higher plasma urea, arterial partial pressure of carbon dioxide (PCO₂),^118,¹¹⁹ and a smaller increase in plasma sodium concentration during therapy.¹²⁰ However, a recent systematic review¹²¹ of the literature concluded that there was no clear evidence that treatment was related to the development of cerebral edema. Cerebral ischemia and reperfusion injury have also been considered.¹²² Cerebral edema may be present before therapy for DKA in 5% of cases, although most cases develop 4 to 12 hours after initiation of therapy.^118,¹²³ The clinical signs of cerebral edema in DKA are variable and include headache, deterioration in level of consciousness, inappropriate slowing of pulse rate, and increased blood pressure. However, children with no clinical signs of cerebral edema have been documented to have brain swelling,¹²⁴ and a significant proportion of children have disrupted memory function following episodes of DKA.¹²⁵

Adverse outcomes have been associated with greater neurologic depression at the time of diagnosis, high initial serum urea nitrogen,^118,¹²⁶ and intubation with hyperventilation to a PCO₂ less than 22 mm Hg.^126,¹²⁷

Although the biochemical derangements of hyperglycemia, metabolic acidosis with ketosis, and electrolyte abnormalities are the most obvious problems in DKA, significant derangements in other systems have been documented, including plasma tryptophan levels,¹²⁸ thiamine levels,¹²⁹ cytokine¹³⁰ and lymphocyte responses,¹³⁰ and coagulation abnormalities.¹³⁰ There is little doubt that DKA is associated with a thrombotic state¹³¹ and an increased incidence of cerebrovascular accidents, and care should be taken about the use of femoral central venous access because this may have a higher than usual complication rate in these patients.¹³² A reported case of myocardial infarction related to DKA¹³³ may be a complication of the thrombotic state. Although myocardial function is generally normal in DKA, myocarditis¹³⁴ has been noted in occasional case reports, whereas pulmonary edema may be more common than previously recognized.¹³⁵ Prolongation of the QTc interval may be common in DKA (it correlates with ketosis), and careful cardiac monitoring is essential.¹³⁶

Principles of Management

Management of DKA should be coordinated by an experienced diabetes team. The biochemical criteria for the diagnosis of DKA include a serum glucose concentration above 11 mmol/L (~200 mg/dL), ketonemia and ketonuria, and acidosis with venous pH below 7.3, or serum bicarbonate level below 15 mEq/L.¹¹² The severity of DKA is defined by the level of acidosis, with mild having venous pH less than 7.3 (or bicarbonate <15 mmol/L); moderate, pH less than 7.2 (or bicarbonate <10 mmol/L); and severe, pH less than 7.1 (or bicarbonate <5 mmol/L).¹¹² Children with severe DKA should be managed in a specialized diabetic unit or in the PICU.

Baseline Assessment

An admission weight should be obtained if at all possible, and future therapy should be based on this weight. Blood samples should be taken for the following investigations: serum or plasma glucose, electrolytes (including bicarbonate or total carbon dioxide), blood urea nitrogen, creatinine, osmolality, venous (or arterial in critically ill patient) pH, PCO₂, calcium, phosphorus, and magnesium concentrations (if possible), HbA_1c, hemoglobin and hematocrit or complete blood count. Measurement of blood β-hydroxybutyrate concentration, if available, is useful to confirm ketoacidosis and may be used to monitor the response to treatment.¹³⁷^–¹⁴⁰ Urine specimens should be analyzed for ketones. Electrocardiograms may be useful if delays are expected in getting potassium results.

Fluid Management

The objectives of fluid and electrolyte replacement therapy are restoration of circulating volume, replacement of sodium and body fluid deficit, improved renal function with enhanced clearance of glucose and ketones from the blood, and minimization of risk of cerebral edema.¹¹² There is a wide range in the amount and rate of fluid and electrolyte loss in patients presenting with DKA (depending on the rate of onset and duration of symptoms, the severity of vomiting or diarrhea or both, and the fluid ingested by the patient).¹¹² There is a wide range of intravascular status ranging from normovolemia to severe hypovolemia (uncommon). Clinical assessment of dehydration is notoriously inaccurate, and there is an unpredictable rate of ongoing fluid loss related to the osmotic diuresis. In the (unusual) presence of hypovolemic shock, it is reasonable to infuse 0.9% saline using aliquots of 5 to 10 mL/kg until an acceptable blood pressure is obtained.¹⁴¹ Typically, 10 to 20 mL/kg needs to be infused over 1 to 2 hours.¹⁰⁹ Ringer’s lactate may be a reasonable alternative, because administration of large volumes of 0.9% saline has been associated with the development of hyperchloremic acidosis. There is no evidence to support the use of colloid solutions.

Thereafter the acceptable principles are that hypovolemia, rapid changes in plasma osmolality, and large volumes of sodium uptake should be avoided. Fluid therapy should be calculated to achieve rehydration over 48 hours.^109,^112,¹¹³ Careful monitoring of fluid balance is essential to ensure that patients are neither losing excessive fluid (via osmotic diuresis) nor gaining excessive fluid. Fluid with a tonicity less than that of 0.45% saline should not be used, and a positive balance of around 6 mmol of sodium chloride per kilogram over 24 hours should be regarded as the upper limit.¹⁴¹ The rate of fluid infusion rarely exceeds 1.5 to 2 times the usual daily requirement.

Despite the fact that almost all patients with DKA are potassium depleted, serum potassium levels frequently are increased at presentation. With initiation of insulin therapy and correction of acidosis, there is rapid intracellular movement of potassium, and careful monitoring of potassium levels is essential. As soon as potassium levels are less than 5.5 mEq/L, 30 to 40 mEq/L of potassium should be added to the fluid infusions, and 0.5 to 1 mEq/kg/h of potassium may be required to correct potassium deficits. Potassium may be given as chloride or phosphate. Although severe hypophosphatemia is relatively common,¹⁴² and symptomatic hypophosphatemia has been reported,¹⁴³ there is no evidence that phosphate administration is routinely necessary in the management of DKA, and the clinical effects of severe hypophosphatemia rarely are seen in DKA. Theoretically, phosphate administration may reduce insulin resistance and depletion of adenosine triphosphate and have positive effects on 2,3-diphosphoglycerate.¹⁴⁴ Administration of potassium phosphate helps decrease the chloride load given to patients with DKA. Potassium phosphate may be used safely,¹⁴⁵ provided that calcium levels are monitored carefully.^146,¹⁴⁷ Glucose must be added to the infusion of fluids when the glucose levels are 14 to 17 mmol/L to avoid hypoglycemia.

Bicarbonate

The use of bicarbonate in DKA is extremely limited. Many studies have shown no clinical benefit from its administration.¹⁴⁸^–¹⁵⁰ More recently, bicarbonate administration has been associated with the development of cerebral edema. It should not be given routinely, not in bolus form, and possibly only in patients who have a pH of less than 6.9 despite appropriate correction of intravascular volume and ongoing adequate insulin therapy.

The osmotic load of glucose also decreases serum sodium levels, with a decrease in sodium concentration of approximately 1.6 to 1.8 mEq/L per 100 mg/dL increase in glucose ¹⁵³ (alternatively, Corrected sodium = measured Na + 2([plasma glucose − 5.6]/5.6) (mmol/L). The expectation is that with decreasing levels of hyperglycemia and hyperlipidemia, sodium levels should increase. This increase may be offset, however, by urinary losses of sodium secondary to osmotic diuresis. Careful and frequent monitoring of potassium and glucose levels is essential. If phosphate is being administered, calcium levels should be monitored. Regular acid-base monitoring is required.

Monitoring of end-tidal PCO₂ ¹⁵⁴ or transcutaneous PCO₂¹⁵⁵ could be used as a noninvasive method for continuous monitoring of response to therapy for DKA. The only proviso (as pointed out by the authors and in an accompanying editorial¹⁵⁶) is that any changes in respiratory drive or efficiency of the respiratory system may mask changes in acid-base that otherwise might be reflected by capnometry.

Investigations for Possible Cerebral Edema in Diabetic Ketoacidosis

Although cerebral edema is the most common cause of depressed level of consciousness in DKA, there are other causes that are amenable to alternative therapy, including cerebral venous thrombosis ¹⁵⁷ and acute hydrocephalus.¹⁵⁸ Other abnormalities such as brain infarction¹⁵⁹ and extrapontine myelinolysis¹⁶⁰ have been shown. Computed tomography (CT) of patients with a depressed level of consciousness may be recommended to exclude other treatable pathology. Because the risks are relatively low, however, excluding other pathology must be balanced against the risks associated with moving ill patients to the radiology suite.

Mannitol has been used for the management of cerebral edema ¹⁶¹ (0.25-1 g/kg over 20 minutes), although there are no controlled studies. Hypertonic saline (5-10 mL/kg of 3% saline) may be an alternative to mannitol.¹⁶² Hyperventilation after intubation for cerebral edema may be associated with worse outcomes.¹²⁶

Despite improvements in the management of DKA, it remains a serious illness with significant morbidity and mortality. In addition to improving management of the condition, strong focus must be brought to ensure that the condition is avoided where possible and diagnosed and treated promptly when it occurs.

Thyroid Insufficiency

Neonates exposed to large amounts of iodine in iodine-containing antiseptics may develop transient hypothyroidism ¹⁶³^–¹⁶⁷ (also called the Wolff-Chaikoff effect) as a result of transcutaneous absorption of iodine. This condition also has been shown in infants undergoing cardiac catheterization and cardiac surgery.¹⁶⁸ Care should be taken to limit the exposure of infants to iodine-containing agents. Triiodothyronine supplementation may be considered in children who have been exposed to significant amounts of iodine before or during a critical illness.

The sick euthyroid syndrome has been well documented in the PICU, particularly in patients undergoing cardiac surgery. The subject has been reviewed elsewhere.¹⁶⁹ Although there may be benefit to some children from triiodothyronine supplementation after cardiac surgery,¹⁷⁰^–¹⁷² there is no established role for triiodothyronine supplementation after cardiac surgery.¹⁷³

Children with Down syndrome have a high incidence of hypothyroidism.^174,¹⁷⁵ Attention should be paid to the possible need for triiodothyronine supplementation in critically ill children with Down syndrome.

Metabolic Crises

Epidemiology

Population data on inborn errors of metabolism suggest that there is a minimal incidence of 35 to 40 per 100,000 live births ^176,¹⁷⁷ in countries such as Canada or Italy, while the incidence may be as high as 150 per 100,000 live births in other countries.¹⁷⁸ In addition, some conditions have a particularly high incidence in particular population groups (e.g., maple syrup urine disease has an incidence of 568 per 100,000 births in the Mennonite community in Pennsylvania). Inborn errors of metabolism have a diverse presentation and are part of the differential diagnosis of many children admitted to the PICU with acute illness. Until more recently, only conditions such as phenylketonuria and galactosemia had been identified at birth using screening programs. With increasing availability of technology such as tandem mass spectrometry, screening of other inborn errors of metabolism (including fatty acid oxidation abnormalities and aminoacidopathies) has been introduced in some parts of the world,¹⁷⁹^–¹⁸² and this potentially may decrease the number of children presenting with acute metabolic decompensation.

There is evidence that SIDS may be related to inborn errors of metabolism in at least 1% of cases,^183,¹⁸⁴ and inborn errors of metabolism must be considered as part of the differential diagnosis of any infant who presents to the PICU or neonatal ICU after a near-SIDS episode. A family history of SIDS also should raise the possibility of inborn errors of metabolism in siblings presenting to the PICU with acute illness.

Although there are a bewildering number of inborn errors of metabolism, many are amenable to therapy, and screening may be performed using relatively simple tests. Patients with incurable conditions may derive considerable relief of suffering from diagnosis and appropriate therapy. Even when a condition is not amenable to therapy, it is important to make a diagnosis to facilitate counseling for the family involved and prevent unnecessary suffering in future children. Long-term management of most inborn errors of metabolism requires a team approach including metabolic experts, dietitians, geneticists, biochemists, and social workers to elucidate the exact nature of the problem, provide appropriate therapy and therapeutic plans, and give genetic and family counseling. Although many screening tests for inborn errors of metabolism can be done in most diagnostic laboratories, the specialized tests required to identify the exact nature of an inborn error of metabolism can be done at relatively few laboratories. Despite the complexity of inborn errors of metabolism, there are principles germane to the management of all children who are admitted to a PICU, and these should apply (see Table 168-1).

When to Consider an Inborn Error of Metabolism in the Pediatric Intensive Care Unit

Inborn errors of metabolism may be classified into diagnostically useful groups ¹⁸⁵: (1) disorders that give rise to intoxication (e.g., organic acidemias and urea cycle defects); (2) disorders involving energy metabolism (e.g., fatty acid oxidation defects and respiratory chain defects); (3) disorders involving complex molecules in which symptoms are permanent, progressive, and independent of intercurrent events (e.g., peroxisomal disorders, lysosomal disorders, and congenital defects of glycosylation); and (4) those disorders that present with seizures (particularly in the neonatal period). The conditions most likely to present acutely in the PICU are conditions involving intoxication and energy metabolism. There is overlap, however, between all of these groups in terms of clinical presentation. There also may be considerable variation in the clinical presentation of conditions that have the same underlying genetic abnormality; this may apply even within families.

Although the clinical features of an inborn error of metabolism may be related primarily to the accumulation of a toxic metabolite, the condition may be complicated by the relative deficiency of another compound or increased stress put on other metabolic pathways by the primary problem.¹⁸⁶ Management may involve limiting the intake of potentially toxic substances, increasing the removal of toxic substances, supplementation of deficient substances, and supplementation of other metabolic pathways that are being stressed.

Inborn errors of metabolism should be considered as part of the differential diagnosis of any child or infant who presents with a severe illness, particularly during the neonatal period.¹⁸⁵ Acute symptoms that are particularly associated with inborn errors of metabolism include encephalopathy (acute or acute on chronic), intractable seizures, hepatic failure, cardiomyopathy, metabolic acidosis, and hypoglycemia (Table 168-4). Family history of SIDS or of previous childhood deaths may suggest an inborn error of metabolism. Particular attention should be paid to the identification of specific risk factors for the differential diagnoses, including drug exposure, prolonged rupture of membranes, and perinatal asphyxial episodes.

TABLE 168-4 Factors That Should Alert the Intensivist to the Possibility of an Inborn Error of Metabolism

History
General	Population group with high incidence of inborn errors of metabolism
Consanguinity of parents
Previous history of apparent SIDS or childhood deaths in the family
Presence of dysmorphic features associated with inborn error of metabolism
During pregnancy	Previous history multiple spontaneous abortions
Hyperemesis may be associated with fat oxidation disorders,²⁴⁰ as may frank hepatic symptoms such as acute fatty liver of pregnancy or the more severe HELLP syndrome (hemolysis, liver enzymes, low platelets).
In neonatal period	Deterioration after apparently being normal at birth, particularly if Apgar scores and early neonatal period were normal
Earliest signs of inborn error of metabolism in the neonatal period may include lethargy and poor feeding, which may progress rapidly to obvious depressed level of consciousness.
Depressed level of consciousness without obvious explanation
Vomiting is an unusual clinical feature of illness in neonates and is strongly associated with inborn errors of metabolism.
Strange odors
In childhood	Previous history of being “sickly” with episodes of intermittent vomiting
Previous hospital admissions (even for apparent respiratory symptoms as this may be acidosis)
Unusual dietary preferences by the child
Onset of virtually any organ dysfunction (liver, heart, renal, etc.) may be related to inborn error.
Examination
General in neonatal period	Dysmorphic features that may be associated with inborn errors of metabolism
Strange odors
Neurologic signs in inborn errors of metabolism tend to include increased tone and abnormal movements, in contrast to the features of sepsis, which usually is associated with decreased tone.
In childhood	Acute or intermittent ataxia is a common feature of inborn errors of metabolism in children.

SIDS, sudden infant death syndrome.

Clinical Presentations of Inborn Errors of Metabolism

Intractable Seizures

Seizures (in isolation) are an uncommon presentation of inborn errors of metabolism and, with the exception of the pyridoxine-dependent seizures, tend to be associated with other clinical and metabolic abnormalities. In neonates or some infants presenting with intractable seizures, (particularly if associated with grimacing and abnormal eye movements), pyridoxine-dependent seizures (PDS),¹⁸⁷ pyridoxine phosphate oxidase deficiency (PNPO) hypophosphatasia, and folinic acid–responsive seizures¹⁸⁸ should be considered. The clinical diagnosis of both PDS and PNPO depends on demonstration that seizure control is dependent on continuous pharmacologic doses of pyridoxine or pyridoxal-5′-phosphate, respectively. However, it has recently been shown that detection of elevated levels of α-amino-adipic semialdehyde in blood, urine, or cerebrospinal fluid (CSF), along with the demonstration of mutations in the ALDH7A1 (antiquitin) gene, confirm a diagnosis of PDE¹⁸⁹; whereas an abnormal pattern of CSF catecholamine and indole amine metabolite levels, together with elevated CSF and plasma glycine and threonine concentrations and urinary vanillactic acid excretion are characteristic but not uniformly present in PNPO.^190,¹⁹¹ It has also been shown that patients with folinic acid–dependent seizures have the same mutation in the antiquitin gene.¹⁸⁸ There is a considerable range in clinical presentation, and pyridoxine-dependent seizures probably should be considered in any infant up to age 18 months presenting with seizures.

Patients with defects in transport of glucose across the blood-brain barrier associated with mutations in the GLUT1 gene may present with seizures. The only clue is the presence of low CSF glucose in the presence of normal blood glucose. Patients may improve on a ketogenic diet.¹⁹²

Inborn errors of metabolism that may present with seizures associated with lactic acidosis include biotinidase deficiency, disorders of mitochondrial energy metabolism (including pyruvate dehydrogenase deficiency and mitochondrial electron transport chain defects), and peroxisomal and storage disorders.

Biotinidase deficiency (an autosomal recessively inherited disorder of biotin recycling—estimated incidence of biotinidase deficiency is about 1 in 60,000 ¹⁹³) can be ameliorated or prevented by administering pharmacologic doses of the vitamin biotin (5-20 mg daily independent of age). A large proportion of cases present with seizures and hypotonia, associated with failure to thrive, and rash or alopecia. Some 50% of cases have ataxia, developmental delay, and eye problems (conjunctivitis and optic atrophy), with more than 75% developing hearing loss. There is a considerable variation in clinical presentation, even within affected families,¹⁹⁴ with features ranging from mild episodes of seizure and ataxia to severe metabolic failure and death. Onset of symptoms may occur at any time from the neonatal period through to adulthood. Untreated individuals may have ketoacidosis, lactic acidosis, and/or hyperammonemia, with a wide range of other metabolic anomalies.¹⁹⁴ Diagnosis can be made from analysis of organic acids in urine, whereas an enzyme assay can be done on blood. Guidelines for testing have recently been published.¹⁹⁴

Intractable tonic/clonic seizures also may be a feature of molybdenum cofactor deficiency.^195,¹⁹⁶ This condition presents in early infancy with seizures, encephalopathy in the absence of metabolic acidosis, hypoglycemia or hyperammonemia, and failure to thrive. Imaging of the brain initially shows cerebral edema, which may progress to cerebral atrophy. There are typical imaging findings.¹⁹⁷ Clinical features, CT findings, and neuropathology may be similar to that seen in severe hypoxic-ischemic brain injury.^198,¹⁹⁹ Lens dislocation may be a clinical feature.²⁰⁰ Uric acid levels are low, whereas urinary amino acid analysis shows increased S-sulfocysteine. Sulfite may be demonstrated on fresh urine specimens. Electrospray tandem mass spectrometry of urine or urine-soaked filter paper may facilitate rapid diagnosis.²⁰¹ Seizures may be part of the clinical presentation of many other disorders, including seizures with lactic acidosis (Leigh disease; mitochondrial encephalopathy lactic acidosis and strokelike episodes [MELAS]; mitochondrial encephalopathy with ragged red fibers [MERRF]), GM₂ gangliosidosis, and peroxisomal disorders. Other clinical features predominate in these conditions and should direct investigation.

Investigation and Management

In infants presenting primarily with intractable seizures, investigations should include measurement of blood glucose, blood acid-base status, blood lactic acid (in association with pyruvate levels), CSF glucose, lactic acid and pyruvic acid levels, urinary organic acids, and sulfite. CT and magnetic resonance imaging (MRI) help diagnose disorders of abnormal accumulation of metabolites and exclude structural brain problems that are responsible for symptoms. Treatment focuses on control of the airway and respiration, together with control of seizures. Pyridoxine or biotin should be administered early in appropriate doses if indicated.

Encephalopathy

The onset of acute encephalopathy always constitutes a medical emergency, and the cause must be elucidated as rapidly as possible. The differential diagnosis includes trauma, infection, intracranial space-occupying lesions, toxin ingestion, acute hepatic failure or Reye syndrome, intracranial vascular problems (including thrombosis, hemorrhage, and embolic phenomena), and seizure disorders. There is often a strong tendency to attribute neurologic symptoms to hypoglycemia or hypocalcemia, but because these may be associated with inborn errors of metabolism, it is vital to consider an inborn error of metabolism as part of the cause of the hypoglycemia.

The inborn errors of metabolism that present with acute encephalopathy vary with age. In the neonatal period, the common inborn errors of metabolism include urea cycle defects (with hyperammonemia), maple syrup urine disease, nonketotic hyperglycinemia, and organic acidopathies.²⁰² All of these conditions, with the exception of nonketotic hyperglycinemia, also may present during childhood. During childhood, the common inborn errors of metabolism presenting with acute encephalopathy include fatty acid oxidation defects and maple syrup urine disease.

Investigation

The specimens that normally would be collected for diagnosis of sepsis should be collected, including blood culture, hemoglobin, white blood cell count (including differential), and platelets. Serum electrolytes should be checked, including sodium, potassium, calcium, phosphate, and magnesium. Liver function tests are essential because acute hepatic failure may cause acute encephalopathy, and the liver may be affected by inborn errors of metabolism. Specimens for testing for inborn errors of metabolism must be collected at the time of presentation, because this may provide the best opportunity for diagnosis (Table 168-5).

TABLE 168-5 Specimen Collection for Inborn Errors of Metabolism

Blood Glucose Levels

The reader is referred to the earlier discussion of the approach to hypoglycemia. Hypoglycemia may be a particular feature of fatty acid oxidation defects and organic acidurias. Immediate correction of hypoglycemia is an essential element of treatment.

Plasma Ammonia Levels

Plasma ammonia levels should be checked in all children, especially neonates with unexplained depressed level of consciousness, particularly if there is hypotonia and apnea (see section on hyperammonemia for management and investigation). Treatment of severe hyperammonemia is an emergency.

Liver Function Tests

Reye syndrome is part of the differential diagnosis of acute encephalopathy, but fatty acid oxidation defects such as medium-chain acyl-CoA dehydrogenase deficiency, carnitine deficiency (usually with associated myopathy), and far less frequently, long-chain acyl-CoA dehydrogenase deficiency and short-chain acyl-CoA dehydrogenase deficiency, may present with encephalopathy (usually in the neonatal period).

Blood Gas Analysis

Arterial blood gas analysis should be performed, with particular attention to the presence of metabolic acidosis and calculation of the anion gap (this should be corrected for the presence of hypoalbuminemia).²⁰³^–²⁰⁵

Blood Lactate Levels

Blood lactate levels may be increased in many situations but typically are very elevated in mitochondrial electron transport chain defects.

Plasma Carnitine

Levels of carnitine may be substantially decreased in organic acidurias and fatty acid oxidation defects. Analysis of acylcarnitine and amino acid profile may help to make the diagnosis of isovaleric aciduria, methylmalonic aciduria, and propionic acidemia.

Quantitative Amino Acid Analysis

Quantitative amino acid analysis is necessary to identify the aminoacidopathies. This test is not always available, and results may take some time. Screening tests on the urine may point in the direction of certain conditions.

Urinary and Blood Ketones

Ketones are unusual in the neonatal period but tend to be a feature of maple syrup urine disease and propionic, isovaleric, and methylmalonic acidemia. Quantitative determination of blood ketones (acetoacetate using urine ketone strips or β-hydroxybutyrate by specific blood strip) may be a useful bedside screen.

Urinary Organic Acids

Urinary organic acids are abnormal in maple syrup urine disease, organic aciduria, and fatty acid oxidation defects.

Management

The principles of therapy are as follows:

1 Maintain airway control and breathing.

2 Maintain circulation.

3 Treat underlying or associated sepsis.

4 Remove toxic compounds.

5 Ensure an appropriate energy source for the body.

6 Provide any specific therapy that is available.

The toxic compounds that potentially can be removed include ammonia and leucine (see details subsequently).

Specific Inborn Errors of Metabolism

Maple Syrup Urine Disease

If there is no acidosis and the ammonia is not increased, maple syrup urine disease (MSUD) should be considered. Patients typically are not dehydrated, are not acidotic, have no hyperammonemia, and have no hematologic abnormalities. Cerebral edema is a feature of maple syrup urine disease within the neonatal period and during later presentations.

The urine may smell like maple syrup, but the smell is also similar to that of burned sugar.²⁰² The urine smell may be difficult to detect in the first few days of life, then may be detected on diapers that have been allowed to dry.²⁰⁶ Urine tests for ketones are usually strongly positive, and dinitrophenylhydrazine is usually positive, although both tests may be negative before 3 days of age.²⁰⁶ Tandem mass spectrometry is the quickest and most efficient screening test in neonates. Leucine levels can be checked rapidly on whole-blood filter paper specimens, or quantitative amino acid analysis should be done on plasma or serum. Principles of management have been to remove leucine using dialysis and to reduce the production of leucine by dietary manipulation. Hemodialysis has been shown to decrease leucine levels rapidly,²⁰⁷ particularly if used in conjunction with dietary therapy. Previously, exchange transfusion, peritoneal dialysis, and hemofiltration were reported to decrease leucine levels. Morton and colleagues²⁰⁶ have used a protocol consisting of total caloric intake of 120 to 140 kcal/kg/d, with lipid forming 40% to 50% of calories; 3 to 4 g/kg/d of protein as essential and nonessential amino acids, with 80 to 120 mg/kg/d each of isoleucine and valine and 250 mg/kg/d each of glutamine and alanine, with tyrosine, histidine, and threonine supplemented to normalize plasma amino acid ratios; careful attention to sodium balance to ensure that serum sodium is kept at greater than 140 mEq/L; and hyperosmolar therapy if cerebral edema develops. This protocol produces decreases in leucine equal to that seen after dialysis. Recent studies suggest that norleucine may have a place in reducing brain injury in patients with MSUD.²⁰⁸

Isovaleric Aciduria, Methylmalonic Aciduria, and Propionic Acidemia

Isovaleric aciduria, methylmalonic aciduria, and propionic acidemia may present in the neonatal period with encephalopathy hyperammonemia, ketoacidosis (occasionally hyperammonemia may induce a respiratory alkalosis), moderate lactic acidosis, and hypocalcemia. The smell associated with isovaleric aciduria may be distinctive (“sweaty feet”). Blood glucose levels may be variable from hypoglycemia to hyperglycemia. Dehydration is a feature of the clinical presentation, partly related to vomiting and poor intake and partly related to poor renal concentrating ability. One-third of patients may present later in life.

Strokelike episodes are a feature of isovaleric aciduria, methylmalonic aciduria, and propionic acidemia in later life, although there may be a wide range of neurologic presentations including hypotonia and developmental delay. Extrapyramidal signs related to infarction of the basal ganglia may be a feature of methylmalonic aciduria and propionic acidemia. Neutropenia, thrombocytopenia, and anemia are common in the neonatal presentation, whereas neutropenia also may be a feature of a later presentation. Sepsis may be a significant component of clinical exacerbations, particularly in propionic acidemia. Pancreatitis has been reported to be associated with these disorders.²⁰⁹ Cardiomyopathy also may develop, particularly during metabolic decompensation.²¹⁰ Isovaleric aciduria, propionic acidemia, and methylmalonic aciduria are diagnosed by the organic acid profiles, and tandem mass spectroscopy may be useful by looking at the acylcarnitine profiles.

Patients presenting in the neonatal period with encephalopathy require treatment with limitation of protein intake (this requires varied adjustment to a diet with appropriate amino acid profile), removal of toxin (exchange transfusion may be useful; methylmalonic aciduria can be cleared renally if adequate fluid volumes are given), ensuring normal glucose levels, promoting anabolism, and management of sepsis. Some patients with methylmalonic aciduria may respond to therapy with hydroxycobalamin, and this should be given for several days to assess response. Supplemental glycine should be given to patients with isovaleric aciduria, and carnitine supplementation is useful for all. Some patients with propionic acidemia may benefit from metronidazole to decrease propionate metabolites from the bowel.

Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia presents in early infancy with severe encephalopathy in the absence of acidosis, ketosis, hypoglycemia, hyperammonemia, or any other clinical abnormalities. Although the outcome is almost invariably poor, there have been more recent descriptions of transient neonatal hyperglycinemia.²¹¹ There also is an association of abnormality of the corpus callosum with nonketotic hyperglycinemia.²¹² Diagnosis is confirmed by the presence of high CSF glycine. The enzyme defect can be confirmed on a liver biopsy specimen.^213,²¹⁴ Sodium benzoate may be helpful in therapy, possibly in combination with imipramine.²¹⁵

Hypoglycemia and Inborn Errors of Metabolism

The reader is referred to the section on endocrine crises for an approach to hypoglycemia. In hyperinsulinemia, the hypoglycemia typically develops soon after the intake of a feed, whereas patients with defects in fatty acid oxidation tend to be able to tolerate fasts of 4 to 8 hours. In hyperinsulinemia, it often is difficult to provide adequate amounts of glucose to correct the hypoglycemia (may require >12 mg/kg/min together with glucagon to control the hypoglycemia). In defects of gluconeogenesis, the hypoglycemia is relatively easy to control but usually does not respond to glucagon administration. In hereditary fructose intolerance, the onset of hypoglycemia is concurrent with the introduction of sucrose (source of fructose) into the diet. Although hypoglycemia may occur in association with sepsis, many inborn errors of metabolism are associated with sepsis (e.g., direct association with Escherichia coli and galactosemia, sepsis as precipitant of crisis, or ill health from inborn error of metabolism causing increased risk of sepsis) and should be considered diagnostically even if sepsis is proven.

Investigation and Management

If the glucose level is low, a venous specimen of blood should be collected immediately for laboratory glucose estimation (because bedside measuring techniques may be inaccurate at low levels of glucose). The clinician should give 0.5 g/kg of 10% to 25% dextrose in water (diluted with water for injection) promptly as a bolus IV followed by administration of 4 to 8 mg/kg/min of glucose. The glucose level should be reviewed within 30 minutes. The rate of glucose infusion may need to be increased, and high requirements suggest hyperinsulinemia.

Urine for Reducing Substances

Glucose should be excluded, but in the setting of hypoglycemia, this is unlikely unless there have been substantial doses of glucose given. If reducing substances are positive, this suggests galactosemia, hereditary fructosemia, or tyrosinemia.

Urinary Ketones

If urinary ketones are positive, the clinician should assess for urinary and plasma organic acids and quantitative amino acids. High urinary ketones in the presence of hepatomegaly suggest glycogen storage disease type 1, fructose-1,6-diphosphatase (FDPase) deficiency, or β-ketothiolase deficiency.²¹⁶ In the last-mentioned condition, lactate levels are normal, whereas they are increased in glycogen storage disease type 1 and FDPase deficiency. In the absence of hepatomegaly, high ketones suggest ketotic hypoglycemia or deficiencies of growth hormone or glucocorticoids.

Glycogen storage disease type 1 may present in the neonatal period with hypoglycemia which may be mild or easily controlled. However, the patients present later with hepatomegaly and lactic acidosis. Characteristically, the hypoglycemia does not respond to therapy with glucagon.

Fatty Acid Oxidation Defects

Fatty acids are metabolized primarily via β-oxidation in the mitochondria and to a lesser extent in the peroxisomes (β-oxidation) and the microsomes (ω-oxidation). Defects in the mitochondrial oxidation of free fatty acid result in the accumulation of fatty acid oxidation products, which may be responsible for encephalopathy, hepatocellular dysfunction, and cardiac arrhythmias, which are a potentially fatal complication of fatty acid oxidation defects. Defects in fatty acid oxidation also may result in failure to meet the energy requirements of tissues such as skeletal muscles or cardiac muscles, resulting in myopathy or cardiomyopathy.

Many studies have suggested that fatty acid oxidation defects may be an important cause of SIDS. Fatty acid oxidation defects are an important cause of cardiomyopathy.²¹⁷

Medium-chain acyl-CoA deficiency is the most common of the fatty acid oxidation defects and most frequently presents with a Reye-like episode, with acute or recurrent Reye-like episodes with vomiting, encephalopathy hypoglycemia, and hyperammonemia. Cardiomyopathy never occurs in medium-chain acyl-CoA deficiency. Cardiomyopathy is a more common presentation of carnitine deficiency and long-chain acyl-CoA dehydrogenase deficiency.

Diagnosis is based on the clinical features described earlier: tolerance of 8 to 24 hours of fasting, high plasma free fatty acid levels, normal to low ketone levels, increased urinary organic acids (C-6 to C-10 dicarboxylic acids), and low plasma carnitine levels. The abnormal findings may not be present between acute exacerbations, and it is crucial to collect specimens during the acute illness. Urine specimens must be collected; blood can be collected on filter paper for tandem mass spectrometry (these assays may be abnormal while the child is well). Specific mutation analysis is available for the most common medium-chain acyl-CoA deficiency. Treatment consists of supplying adequate glucose, supplementing carnitine, and providing symptomatic support.

Hyperammonemia

Transient hyperammonemia may occur in preterm infants in so-called transient hyperammonemia of the newborn, which is not associated with an inborn error of metabolism. Aggressive therapy may be associated with completely normal outcome. Hyperammonemia results in a marked encephalopathy, although patients typically are more hypotonic than in other metabolic encephalopathies and may develop a respiratory alkalosis, which is uncommon in other encephalopathies.

Primary hyperammonemia occurs in the urea cycle defects, but a secondary hyperammonemia may occur in defects of fatty acid oxidation or organic acidemia. Hyperammonemia also may be a consequence of acute hepatic failure (e.g., with acute viral infection; toxin ingestion; and drug reactions, particularly antituberculosis drugs).

Investigation

Ammonia is potentially toxic, and therapy must be instituted urgently to remove ammonia. It is crucial to collect appropriate diagnostic specimens at the time of presentation because it may be difficult to establish a diagnosis when dialysis and other therapy have been instituted. The following tests enable an approach to diagnosis.²¹⁸

2 Administer arginine (L-arginine hydrochloride, 600 mg/kg IV over 1 hour, followed by 2 to 4 mmol/kg/24 h in 4 divided doses).

3 Administer sodium benzoate (250 mg/kg IV followed by 250 mg/kg/d in 4 divided doses) and sodium phenylacetate (250 mg/kg IV immediately followed by 250 mg/kg/24 h in 4 divided doses).

4 Dialyze to remove excessive ammonia. Hemodialysis is the most efficient means to remove ammonia, hemofiltration is the next option (and may be particularly useful in neonates who are too unstable to tolerate hemodialysis), and finally peritoneal dialysis may be used. Exchange transfusion has been performed but is relatively inefficient at removal of ammonia.

Metabolic Acidosis

Metabolic acidosis can occur in many ways. It may be related to inadequate excretion of acid via the kidneys (e.g., proximal and distal renal tubular acidosis) or excessive production of acid in the body. In the case of inadequate excretion of acid from the kidneys, the pH of the urine almost always is inappropriately high. In addition, there is no anion gap. In the context of excessive acid production, there is an excessive anion gap.

The most common acids related to an increased anion gap are lactic acid and ketoacids, such as acetoacetate and 3-butyrobutyrate. All the organic acidopathies and aminoacidopathies may be associated with an increased anion gap, however. A variety of inborn errors of metabolism may be associated with proximal renal tubular acidosis, particularly cystinosis and Lowe syndrome.

Acid also may be produced by bacterial overgrowth in the bowel and absorbed, as occurs in D-lactic acidosis.²¹⁹ D-Lactic acid is not detected by routine blood tests for lactic acid, which employ a lactic dehydrogenase, but is detected by urinary assays for organic acids. These patients present with acidosis with increased anion gap.

Patients with organic acidemias rarely present with metabolic acidosis as a primary feature of the illness, and the rest of the clinical presentation frequently provides clues as to the appropriate line of investigation. Investigation of organic acids remains an important component of the investigation of any patient, however, with unexplained metabolic acidosis.