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II Clinical Disorders A Endocrine Disorders Murray M. Pollack Paul Kaplowitz Endocrine Disorders of Water Regulation 11 Susan B. Nunez CLINICAL SYNDROMES OF ABNORMAL WATER REGULATION syndrome, there is clinical evidence of a contracted ECF volume. Manifestations of derangements in osmotic homeostasis are due to alterations in cell volume in the central nervous system (CNS), changes in effective circulating volume and local disturbances produced, that is, by an intracranial neoplasm. In the steady state, the net water balance should be zero. Hypertonicity occurs when the renal plus extrarenal water losses exceed water intake, causing the ratio of solutes to water in the body fluids to increase. In hypotonic syndromes, water intake exceeds the sum of renal plus extrarenal water losses; but in chronic hyponatremia, water intake and water output may be equal. SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE HYPONATREMIA Hyponatremia, defined as a serum sodium level <135 mEq per L, is a common electrolyte imbalance in the setting of pediatric critical care. It can occur in children who are volume contracted and have lost sodium in excess of water, as in severe diarrhea, or renal sodium losses due to adrenal insufficiency with inadequate aldosterone production. This is particularly challenging in patients with acute CNS disease, especially if the sodium is low (<125 mEq per L), which can cause seizures and worsen neurologic status. The differential diagnosis is often between the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the cerebral salt wasting (CSW) syndrome. Distinguishing between the two causes is important because the treatment of each condition is very different. In both, there is hyponatremia and inappropriately concentrated urine. SIADH is associated with increased extracellular fluid volume (ECF). In CSW This syndrome, although common in the pediatric critical care setting, is rarely the reason for admission to the pediatric intensive care unit (PICU). The expansion of the ECF volume in SIADH is due to a nonphysiologic or inappropriate secretion of the antidiuretic hormone (ADH), or due to the increased sensitivity of the kidneys to the effect of ADH. ADH acts on the distal collecting ducts and tubules resulting in increased permeability to water, increased fluid reabsorption and increased intravascular volume. In response to the latter, the glomerular filtration rate and renal plasma flow increase, and proximal sodium reabsorption decreases, thereby increasing the urine sodium levels and decreasing the serum sodium level. The increased ECF volume is accompanied by weight gain but is not associated with distended neck veins or edema because only one third of retained water is distributed in the ECF space. With progressively decreasing levels of sodium, the patients gradually develop malaise, hypotonia, nausea, vomiting, anorexia, mental alterations, followed by convulsive crises, stupor, and coma. Other signs and symptoms include pseudobulbar paralysis, Babinski sign, and extrapyramidal symptoms. Patients with existing neurologic disorder will have neurologic symptoms at higher levels of sodium than those without such disorders. SIADH is uncommon in children.1 A summary of the different conditions associated with SIADH is given in 476 Part II: Clinical Disorders TABLE 11.1 CAUSES OF SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE Malignancies Medications Bronchogenic carcinoma Thymoma ALL Lymphoma Neuroblastoma Duodenal or pancreatic adenocarcinoma Vincristine Carbamazepine Cyclophosphamide (IV) SSRI antidepressants Opiates Clofibrate Chlorpropamide Lamotrigine Central Nervous System Disorders Infection: meningitis, encephalitis Neoplasms near the pituitary or hypothalamus Vascular anomalies, stroke Trauma Hydrocephalus Pituitary surgery Hypoxia-ischemia Psychosis Pulmonary Disorders Infection: pneumonia, tuberculosis Asthma Pneumothorax Positive pressure ventilation ALL, acute lymphoblastic leukemia; SSRI, selective serotonin reuptake inhibitors; IV, intravenous. Table 11.1. The release of ADH can be stimulated by pain, stress, increased intracranial pressure, and hypovolemic states.2 SIADH can also develop 1 week after transsphenoidal pituitary surgery in 35% of patients or as phase 2 in a triphasic phase following intrasellar surgery.3 The retrograde neuronal degeneration with cell death and vasopressin release has been thought to be the mechanism behind this phenomenon.4 To confirm the diagnosis of SIADH, the following approximate measurements are used: hyponatremia (Na+ ≤ 135 mEq per L), serum hypo-osmolality (≥280 mOsm per L), decreased urine output to <1 mL/kg/hour with high urine osmolality (>600 mOsm per L), or an inappropriately high urine osmolality (with sodium excretion >20 to 25 mEq per L) in the presence of a low serum osmolality, and in the absence of clinically evident dehydration. Measurement of plasma hormones including ADH, natriuretic peptide, renin activity, and aldosterone are impractical because the results are not immediately available for use in making rapid clinical changes. In addition, the results may cause confusion because of the short half-life and mutual influence of the hormones on each other. Treatment Pediatric intensivists should anticipate the development of SIADH for prompt and effective therapy to be given. Mortality may be as high as 50% in acute hyponatremia if untreated.5 Treatment is based on the duration of the hyponatremia and the intensity of the neurologic disturbance such as seizure or altered mental status. There are two basic principles to be remembered when correcting hyponatremia: (i) the serum sodium level should be increased at a safe rate and (ii) the underlying disease should be treated. In general, the serum sodium should be corrected slowly at a rate not exceeding 1.3 mEq/L/hour with a total correction of no more than 10 mEq per L in the first 24 hours and <20 mEq per L over the first 48 hours.6 If too rapid correction of serum sodium occurs, the patient may develop central pontine myelinolysis.7 This is a disorder characterized by confusion, dysarthria, pseudobulbar palsy, and quadriplegia as a result of demyelination in the base of the pons. In severe ‘‘acute’’ hyponatremia with neurologic symptoms, occurring within <48 hours, 3% saline solution, 3.0 to 5.0 mL per kg can be administered rapidly to increase the serum sodium faster at 1.5 to 2.0 mEq per L for 3 to 4 hours or until the neurologic symptoms resolve. The infusion rate may be calculated by multiplying the body weight in kilograms by the desired rate of increase in Na+ level in mEq/L/hour. A loop diuretic such as furosemide 1.0 to 2.0 mL per kg may be added to increase water excretion. SIADH, which is asymptomatic and therefore has likely developed over a longer period of time, is best treated with fluid restriction. This is usually sufficient to normalize the sodium level. In a young child, fluid intake may be restricted to the range of 30% to 75% of maintenance requirement or to 1,000 mL/m2/day.8,9 If this fails to correct the hyponatremia, the addition of demeclocycline, may be indicated to allow for higher volume intake. Lithium may also be used for this purpose, but demeclocycline is superior in causing a nephrogenic diabetes insipidus (DI)like state, thereby decreasing the renal concentrating ability and decreasing water reabsorption in the collecting ducts and tubules.10 It may take several days before an optimal response is appreciated. CEREBRAL SALT WASTING SYNDROME CSW syndrome is not uncommon in a critically ill pediatric patient. CSW syndrome and SIADH have many similar clinical findings, that is, hyponatremia, high urine osmolality, and elevated urinary sodium concentration higher than 150 mEq per L. They can both be caused by the same intracerebral diseases. Vasopressin level is also elevated in CSW syndrome; however, it is an appropriate response to volume depletion. Unlike SIADH, in CSW syndrome, the urinary output is not low and the ECF volume is decreased due to primary natriuresis.11 Clinical signs of dehydration are evident. Therefore, volume restriction is not effective in restoring normal serum sodium levels in CSW syndrome, and fluid restriction in a patient with CSW syndrome may Chapter 11: Endocrine Disorders of Water Regulation cause further volume depletion, a decrease in brain perfusion and cerebral lesion, and an increase in mortality rate. On the other hand, large amounts of salt infusion required to restore normal sodium concentrations in CSW syndrome may prove detrimental in a patient with SIADH who is already volume expanded. The leading hypothesis in the pathophysiology of CSW syndrome is that brain natriuretic peptide (BNP), produced predominantly in the ventricles of the brain, is secreted in abnormal amounts. These natriuretic peptides, including atrial natriuretic peptide, C-type natriuretic peptide, and the recently discovered dendroaspis natriuretic peptide (DNP), exert their effect by antagonizing the renal effects of ADH, suppressing the renin–angiotensin–aldosterone axis, and centrally inhibiting salt appetite and thirst, causing diuresis and natriuresis.12 Treatment of CSW syndrome consists of restoring normal intravascular volume with water and sodium chloride, as with the treatment of systemic dehydration. The underlying CNS disorder should be also treated, if possible. DIABETES INSIPIDUS DI is not uncommon and its occurrence should be anticipated in the pediatric intensive care setting. Central DI is likely if serum osmolality is >300 mOsm per kg with very dilute and high volume urine, exceeding 200 mL/m2 /hour. Children with an underlying neurologic disturbance are at highest risk. The most common situation is following suprasellar surgery. Here, the onset of DI is anticipated and intervention can be promptly initiated. DI should also be anticipated to occur in patients following accidental head trauma, infection, or massive brain ischemia. Because infants and children have a smaller body size and higher total body water content than adults, a small disturbance in volume homeostasis may cause significant acute fluid and electrolyte disturbance contributing to the course of the critical illness. Therefore, it is important to recognize, evaluate, and promptly treat DI when it occurs. An intact thirst mechanism is an important regulator of volume homeostasis and serum osmolality, particularly in DI. Thirst is stimulated when the osmotic threshold for thirst is exceeded, commonly when the serum osmolality is 2% to 3% above the basal level. The initial perception of thirst is in direct proportion to the sodium level and osmolality. Patients with DI and an intact thirst mechanism will increase their fluid intake to maintain normal serum osmolality if antidiuretic therapy is inadequate, but they are allowed free access to water. The subset of DI patients with absent thirst mechanism (adipsia) are much more likely to present with severe dehydration and hypernatremia if their antidiuretic treatment is stopped or wears off too quickly, and are much more likely to require an admission to the PICU to correct the problem. Acquired DI is more commonly seen than the congenital forms, although the latter should not be overlooked. 477 DI is a heterogeneous group of disorders, which can be divided into: (a) vasopressin-sensitive or (b) vasopressin resistant. The causes of vasopressin-sensitive DI (also called hypothalamic, neurogenic, or central DI) include trauma to the hypothalamic-neurohypophyseal system (either accidental or surgical), infiltrative disease including tumors or infection, destruction by the autoimmune process, genetic defects in vasopressin production, and congenital anomalies or defects of the hypothalamic or pituitary gland. The cause of central DI is unknown in 10% of pediatric cases.13 Vasopressin-resistant DI (also called nephrogenic DI) results from genetic or acquired causes. Genetic causes are more common in children than in adults and are more severe than the acquired form. Familial vasopressinresistant DI is due to a defect in the vasopressin (V2 ) receptor, inherited in an X-linked pattern. An autosomal dominant or recessive form of inheritance linked to a mutation in the aquaporin-2 water channel, with an intact V2 receptor, has also been reported.14 The acquired form of vasopressin-resistant DI is more common and less severe. It may be due to: disorders in the kidney and ureter, sickle cell disease; Sjögren syndrome, intake of drugs such as lithium, demeclocycline, and foscarnet (used to treat cytomegalovirus infection in immunosuppressed patients); electrolyte imbalance such as hypokalemia, osmotic diuresis due to glycosuria in diabetes mellitus; primary polydipsia; hypercalcemia; decreased protein or sodium intake; and washout from massive diuretic use. THE TRIPHASIC RESPONSE Injury to the supraopticohypophyseal tract causes bilateral neuron degeneration in the supraoptic neuron (SON) and the paraventricular neuron (PVN); when approximately 90% of the magnocellular neurons in the SON and PVN are lost, permanent diabetes insipidus ensues. Diabetes insipidus after surgery or trauma to the pituitary or hypothalamus may exhibit one of the three patterns: transient, permanent, or triphasic.15 In the first phase of the triphasic pattern, total or partial DI begins on the first postoperative day and persists for 0.5 to 5 days. This phase is due to edema in the area interfering with normal ADH secretion. This is the most common pattern (50% to 60%) of postsurgical diabetes insipidus. The second phase is the SIADH phase. This is due to the unregulated release of arginine vasopressin (AVP) because of retrograde degeneration of the AVP secreting neurons. This may last for 5 to 10 days, during which the urine output falls abruptly. During the third phase, around the tenth postoperative day, a permanent form of DI appears. The last phase occurs if insufficient neurons survive to release an adequate amount of AVP. Usually, a marked degree of SIADH in the second phase is a preface to permanent DI. In patients with combined vasopressin and adrenocorticotropic hormone 478 Part II: Clinical Disorders (ACTH) deficiency, symptoms of DI may be masked because glucocorticoid deficiency impairs renal free water excretion. Treatment with glucocorticoid may unmask DI with sudden onset of polyuria leading to the diagnosis. In anticipation of this phenomenon, daily monitoring of urinary specific gravity, serum sodium, and review of fluid balance will provide adequate warning of the transition from one phase to another. Recording daily weight is also helpful in this regard. The risk for developing SIADH is greatest in the first and second postoperative weeks. Diagnosis Central DI is characterized by increased urinary flow (≥3 mL/kg/hour), low urine osmolality (<300 mOsm per L; in severe cases, <200 mOsm per L), urine specific gravity <1.010, and serum sodium >145 mEq per L or serum osmolality ≥300 mOsm per L, and polydipsia with craving for cold fluids, especially water. Loss of approximately 75% of the ADH-secreting neurons is required for polyuria to occur. Differential diagnosis of polyuria includes: osmotic diuresis following infusion of mannitol, glycerol, or x-ray contrast agents; normal diuresis of fluids given during surgery; or nonoliguric renal failure. Diuresis following surgery is usually associated with normal serum osmolality, uncharacteristic of true DI. Review of the intraoperative report will help in distinguishing this from acute postsurgical central DI. Management involves limiting or equalizing intake and output. Serum sodium, urine osmolality, and urine specific gravity almost always determine the diagnosis of central DI. In rare situations, it may be difficult to distinguish between central and nephrogenic DI, but the response to administration of desmopressin 1-deamino-8-D-arginine vasopressin (DDAVP) generally confirms the diagnosis. Treatment Newborns and young infants receive their nutrition primarily in the liquid form and have a high oral fluid requirement of approximately 3 L/m2 /day. DI occurring in these children is better managed with fluid therapy alone given by oral, G-tube (if in place), or intravenous routes. If combined with vasopressin treatment, this may cause dangerous hyponatremia and water intoxication. Postoperative DI in young children can be managed with fluids alone; however, addition of antidiuretic therapy is preferred but must be used cautiously to minimize the occurrence of hyponatremia. Table 11.2 provides a summary of the different formulations of antidiuretic therapy. Also, antidiuretic therapy can mask the emergence of SIADH following a neurosurgical procedure or injury. If fluid alone is used, intravenous fluid given as 5% dextrose with 37 mEq of sodium per L (D5 1/4 normal saline) is administered. The amount is calculated between 1 and 3 L/m2 /day (40 to 120 mL/m2 /hour); the initial amount is 40 mL/m2 /hour followed by matching hourly urine output volumes (only if >40 mL per m2 ) up to 120 mL/m2 /hour. This limit is necessary to allow a mildly volume-contracted state to stimulate fluid reabsorption in the renal tubules eventually causing water/solute and osmolality to equilibrate. Otherwise, the kidneys will promptly excrete whatever fluid is given to the patient. This regimen will result in a serum sodium concentration in the 150 mEq/L range and allow one to determine whether the thirst mechanism is intact or whether SIADH is developing. Serum sodium levels measured every 4 hours are a sensitive indicator of the adequacy of replacement therapy. Serum and urine osmolalities (or urine specific gravity) are also determined at frequent intervals for monitoring. The infusion of dextrose may cause some patients to become hyperglycemic, especially if they are receiving glucocorticoid therapy. If there is concomitant hyperglycemia, only half-normal saline should be used until normal blood sugar level is restored. Correction of DI should occur within 48 to 72 hours. If vasopressin therapy is added, it can be given in the form of synthetic aqueous vasopressin (Pitressin). Its effect is maximal within 2 hours of starting the infusion and the duration of action is 4 to 8 hours. The half-life is 10 to 20 minutes allowing convenient dosing as needed. The recommended initial dose is 2.5 to 10 units given IV every 6 to 12 hours. To prevent rapid decrease in sodium level, the smallest dose is started and gradually increased to achieve the desired effect. The therapeutic goals should include: urine output 2 to 3 mL/kg/hour, urine specific gravity of 1.010 to 1.020, and serum sodium of 140 to 145 mEq per L. Urine specific gravity and volume of urine output are the most sensitive parameters in assessing adequacy of treatment. Serum sodium level and serum osmolality do not correlate with the pitressin dose. Intravenous DDAVP should not be used in combination with fluid therapy in the management of acute central DI due to its long halflife (8 to 12 hours), which therefore increases the risk for dangerous hyponatremia. In addition, patients who are receiving fluid infusion and are not fully alert may not be able to regulate their own thirst, possibly leading to significant hyponatremia. Continuous vasopressin infusion is another option for managing central DI. This is most helpful in two situations, (i) during the initial postoperative days in children in whom DI develops following CNS surgery and the child is not eating or drinking, and (ii) in patients with established central DI who require high fluid volume infusion and have high urine output during induction with cancer chemotherapy. Another useful application of continuous vasopressin infusion is intraoperative management of fluid in patients with known DI. Owing to its short halflife, continuous vasopressin infusion can be easily turned off with rapid return of diuresis. Continuous vasopressin infusion may also obviate the need for large volumes of Chapter 11: Endocrine Disorders of Water Regulation 479 TABLE 11.2 SUMMARY OF THE DIFFERENT FORMULATIONS OF ANTIDIURETIC THERAPY Product Administration Formulation Half-life Dosing Duration Indications Vasopressin injection Desmopressin solution IV Synthetic aqueous solution 4 µg/mL 5–10 min 0.5–10 mU/kg/h Max effect in 2 h Acute central DI 8–12 h 0.2 to 1 µg b.i.d IV/SQ Desmopressin intranasal Intranasal spray or rhinal tube (for delivery of <0.1 mL) 10 µg per spray (0.1 mL) 75 min 0.1–0.4 mL (10 to 40 µg) per day divided b.i.d or t.i.d 8–15 h Desmopressin tablets Oral, can be dissolved in water 0.1 mg, 0.2 mg 1.5 to 2.5 h 8–12 h Lysine vasopressin Intranasal spray 50 U/mL 2.5 to 14.5 min Start with 0.05 mg; increase to 0.1–0.4 mg b.i.d or t.i.d Titrate to desired effect 2–8 h Temporary central DI due to trauma or surgery; best if unable to use oral or nasal forms Central DI due to trauma or surgery. May be difficult to give to infants or if nasal congestion exists Maintenance therapy for central DI If duration shorter than desmopressin is desired DI, diabetes insipidus; SQ, subcutaneous; IV, intravenous. fluid infusion and may avoid inducing osmotic diuresis from the dextrose. The recommended dose is 0.25 to 0.5 mU/kg/hour. It is started with the smallest dose and the amount is gradually increased by titrating with the urine output and serum sodium level. It will take 2 hours to establish an antidiuretic effect. Patients on this treatment regimen require careful monitoring of their intake and output. Placement of a urinary catheter is sometimes necessary for the accurate measurement of urine output. Sodium levels should be checked every 2 hours until it becomes stable, and then every 3 to 4 hours. Intake and output are reviewed every 3 hours and adjustments are made accordingly to achieve euvolemia, serum sodium of 135 to 145 mEq per L, and urine output of at least 2 to 3 mL/kg/hour. Patients with established central DI on oral DDAVP, requiring high fluid infusion during cancer chemotherapy are best managed with continuous vasopressin infusion at 0.05 to 0.1 mU/kg/hour titrated according to urine output checked hourly and serum sodium level checked every 2 hours during the induction and infusion of the chemotherapeutic agent. Oral DDAVP should be discontinued 12 hours before the initiation of intravenous fluid and vasopressin infusion to maintain fluid homeostasis. Intravenous, subcutaneous, or oral DDAVP should not be used initially in combination with fluid therapy in the management of acute central DI owing to its long half-life with associated higher risk for dangerous hyponatremia. DDAVP given intranasally or by the subcutaneous route is not as safe. When oral intake is re-established, the patient can be transitioned to oral DDAVP for maintenance therapy. The initial dose should be 0.05 mg for infants and small children, 0.1 mg for older children, and 0.2 mg for adolescents repeated every 8 to 12 hours. Before the next dose of DDAVP, one should wait until the effect of the previous dose has worn off (when diuresis with dilute urine reappears) and the serum sodium is >135 mEq per L. This will prevent severe hyponatremia. After 1 to 3 days, it is usually possible to find a dose of oral DDAVP that controls urine output for close to 12 hours without causing hyponatremia, and the DDAVP can then be given on a fixed schedule. REFERENCES 1. Sklar C, Fertig A, David R. Chronic syndrome of inappropriate secretion of antidiuretic hormone in childhood. Am J Dis Child. 1985;139(7):733–735. 2. Diringer MN. Sodium disturbances frequently encountered in a neurologic intensive care unit. Neurol India. 2001;49(Suppl 1):S19–S30. 3. Sane T, Rantakari K, Poranen A, et al. Hyponatremia after transsphenoidal surgery for pituitary tumors. J Clin Endocrinol Metab. 1994;79(5):1395–1398. 4. Hung SC, Wen YK, Ng YY, et al. Inappropriate antidiuresis associated with pituitary adenoma–mechanisms not involving inappropriate secretion of vasopressin. Clin Nephrol. 2000;54(2):157–160. 5. Baran D, Hutchinson TA. The outcome of hyponatremia in a general hospital population. Clin Nephrol. 1984;22(2):72–76. 6. Sterns RH. The treatment of hyponatremia: First, do no harm. Am J Med. 1990;88(6):557–560. 7. Schwartz WB, Bennett W, Curelop S, et al. A syndrome of renal sodium loss and hyponatremia probably resulting from 480 8. 9. 10. 11. Part II: Clinical Disorders inappropriate secretion of antidiuretic hormone 1957. J Am Soc Nephrol. 2001;12(12):2860–2870. King LS, Kozono D, Agre P. From structure to disease: The evolving tale of aquaporin biology. Nat Rev Mol Cell Biol. 2004; 5(9):687–698. Casulari LA, Costa KN, Albuquerque RC, et al. Differential diagnosis and treatment of hyponatremia following pituitary surgery. J Neurosurg Sci. 2004;48(1):11–18. Judd BA, Haycock GB, Dalton N, et al. Hyponatraemia in premature babies and following surgery in older children. Acta Paediatr Scand. 1987;76(3):385–393. Olson BR, Rubino D, Gumowski J, et al. Isolated hyponatremia after transsphenoidal pituitary surgery. J Clin Endocrinol Metab. 1995;80(1):85–91. 12. Rabinstein AA, Wijdicks EF. Hyponatremia in critically ill neurological patients. Neurologist. 2003;9(6):290–300. 13. Wang LC, Cohen ME, Duffner PK. Etiologies of central diabetes insipidus in children. Pediatr Neurol. 1994;11(4):273–277. 14. Mulders SM, Bichet DG, Rijss JP, et al. An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex. J Clin Invest. 1998;102(1):57–66. 15. Seckl JR, Dunger DB, Lightman SL. Neurohypophyseal peptide function during early postoperative diabetes insipidus. Brain. 1987;110(Pt 3):737–746. Diabetic Ketoacidosis Rajani Prabhakaran 12 Lynne L. Levitsky Diabetic ketoacidosis (DKA) is caused by insufficiently circulating insulin or diminished insulin action. Insulin deficiency induces a profoundly catabolic state. Hyperglycemia is the result of the failure to store or utilize ingested carbohydrate, and the loss of suppression of glycogenolysis and gluconeogenesis. Without insulin, ingested glucose cannot be metabolized or stored in liver, muscle, or other tissues. The muscle and fat glucose transporter, GLUT-4 requires insulin for glucose transport into cells for metabolism and storage. Glycogen synthetase is activated by insulin in the liver to permit glucose storage as glycogen. Insulin deficiency and concomitant elevations in catecholamines and glucagon, deplete the glycogen in the liver and muscle. Insufficient insulin leads to increased substrate for gluconeogenesis from the gluconeogenic amino acids released during proteolysis and glycerol released during lipolysis. Deficiency of insulin is associated with concomitant increases in counter-regulatory hormones including glucagon, cortisol, growth hormone (GH), and catecholamines. Glucagon is particularly important in the maintenance of ketoacidosis because of its role in ketogenesis. Individuals with glucagon deficiency (diabetes secondary to pancreatitis, or cystic fibrosis) rarely develop ketoacidosis. Excess of glucagon stimulates hepatic ketogenesis, and low levels of insulin prevent ketone body utilization by muscle and other tissues. The kidneys can compensate to some extent for the catabolic state induced by insulin deficiency and counterregulatory hormone excess. However, hyperglycemia induces a forced diuresis with renal losses of electrolyte. Insulin deficiency and glucagon excess enhances natriuresis. Dehydration and loss of electrolyte inhibit renal excretion of excess hydrogen ion and promote worsening acidosis. Death eventually results from severe dehydration, myocardial and central nervous system (CNS) energy depletion and electrolyte imbalance. DIAGNOSIS Presentation Patients classically present with lethargy, hyperventilation with deep sighing breaths (Kussmaul breathing), and a fruity breath odor of ketones. Depression of the respiratory center, if the arterial pH is <7.0, may inhibit Kussmaul respirations in very severe DKA. General debility or cachexia may be noted if the illness is of a long duration. Abdominal or back pain, on occasion, can be severe enough to mimic a surgical emergency. Children may show signs of dehydration including dry mucous membranes, tachycardia, and poor capillary perfusion. A flushed face is common. Fever may be a symptom of an underlying precipitating infection, but hypothermia can be seen, and patients with underlying infection may not become febrile until treated for DKA. Patients with severe DKA can be stuporous with profound dehydration. Clinical Evaluation A prodrome of weight loss, polyuria, and polydipsia can usually be elicited. Although questioning about a family history of diabetes is important, more than half of the children with newly diagnosed diabetes mellitus do not have a relevant family history. Confusion of DKA with common viral vomiting illnesses and dehydration often leads to delayed diagnosis in very young children. Urination continues because of osmotic diuresis and cannot be used as a gauge of dehydration. A rapid respiratory rate secondary to metabolic acidosis might lead to initial confusion with pneumonia or asthma, particularly if the clinician does not detect an acetone odor. Other causes of metabolic acidosis including lactic acidosis, uremic acidosis, alcoholic acidosis, and metabolic acidosis secondary to drug ingestion (salicylates) must be 482 Part II: Clinical Disorders considered in the differential diagnosis. In the first 1 to 2 years of life, some inborn errors of metabolism may present with ketoacidosis and variable elevations in blood glucose (BG) levels. Treatment with insulin and glucose is effective in reversing the catabolic state and improving the condition of these children, and so therapy for DKA, followed by a delayed diagnosis of an amino acid or metabolic acid disorder is not an inappropriate approach to diagnosis and therapy. Physical Examination Initial evaluation should include assessment of the level of consciousness, state of hydration, nutritional status, presence of acetone odor, stability of vital signs, presence of signs of infection, hepatomegaly, abdominal or back pain or tenderness, and examination of fundi for papilledema. Laboratory Evaluation The laboratory criteria for diagnosis of DKA are hyperglycemia with a BG level of at least 200 mg per dL, venous pH <7.3, and/or serum bicarbonate of <15 mmol per L. Occasionally, young or partially treated children or pregnant adolescents, may develop ketoacidosis with near normal glucose values. This has been termed euglycemic ketoacidosis. On the basis of the severity of the acidosis, DKA has been classified as mild (pH ≤7.3, serum bicarbonate ≤15), moderate (pH ≤7.2, HCO3 ≤10), or severe (pH ≤7.1, HCO3 ≤5).1 The initial recommended laboratory studies are described under the section on ‘‘Treatment’’. TREATMENT Prognosis DKA is the leading cause of death in children with insulin-dependent diabetes mellitus. Mortality rates are relatively constant in national population-based studies and in North America vary between 0.15% and 0.25%. One in 100 to one in 300 children with DKA develop cerebral edema. This accounts for more than 60% of all DKA deaths. Other causes of morbidity and mortality during treatment include electrolyte disturbances such as hypokalemia and hyperkalemia, hypoglycemia if BG is not carefully monitored, hypercoagulable state and CNS complications, hematomas, deep vein thrombosis, sepsis, infections including rhinocerebral mucormycosis, aspiration pneumonia, pulmonary edema, adult respiratory distress syndrome, subcutaneous emphysema, pneumomediastinum, malignant hyperthermia, and rhabdomyolysis. Although predictors for cerebral edema are recognized, no therapeutic regimen absolutely prevents the occurrence of cerebral edema. The other complications of DKA can be avoided entirely, reduced in frequency, or treated successfully if management is careful and attentive.1,2 Symptomatic cerebral edema is the most serious complication in the treatment of DKA in children. It is unclear why this complication almost never develops after adolescence. Brain swelling occurs in most children with DKA, even before treatment, but in a small number, it is significant enough to cause cerebral herniation and irreversible neurologic damage or death. Risk factors for the development of cerebral edema during therapy include younger age at onset and presentation with a new onset type 1 diabetes mellitus. In one study, children with low partial pressures of arterial carbon dioxide and high serum urea nitrogen at presentation, treated with bicarbonate were at increased risk (see Table 12.1).3 Most studies show no correlation between the degree of hyperglycemia and the risk of cerebral edema. Although case–control studies have not convincingly demonstrated that the rapidity, volume, or osmolality of fluid rehydration correlates with the development of cerebral edema, it is generally conceded that overload with relatively hypotonic fluid could be a risk factor for this serious complication. Children who develop symptomatic cerebral edema generally do so during recovery and are not very acidotic when they develop signs of acute intracranial pressure elevation. Symptoms usually develop between 6 and 24 hours after onset of therapy, but rarely can occur after 24 hours of therapy and have been reported at diagnosis. Initial symptoms and signs include reappearance of vomiting, worsening headache, and depressed sensorium. More ominous signs are slowing pulse rate, decreasing oxygen saturation, widening pulse pressure, and changes in the state of consciousness progressing to stupor, with incontinence and appearance of new neurologic deficits such as change in pupillary response and cranial nerve palsies. An evidence-based protocol has been developed for use in the early diagnosis of cerebral edema in patients with DKA. Clinical diagnostic criteria include abnormal motor/verbal response to pain, decorticate or decerebrate posture, cranial nerve palsy (especially third, fourth, and sixth nerves), and abnormal neurogenic respiratory pattern (e.g., grunting, tachypnea, Cheyne-Stokes respiration, apneusis). The major criteria for impending cerebral edema TABLE 12.1 RISK FACTORS FOR DEVELOPMENT OF CEREBRAL EDEMA ■ ■ ■ ■ ■ ■ Younger age at onset (younger than 5 y) Vigorous rehydration Administration of bicarbonate Presentation with a new onset T1DM Hypocapnia High serum urea nitrogen concentrations at presentation T1DM, type 1 diabetes mellitus.