Ebook Pediatric critical care medicine: Part 2

(BQ) Part 2 book Pediatric critical care medicine presents the following contents: Endocrine disorders, disorders of host defense, hematologic and oncologic disorders, cardiac diseases, respiratory disorders, neurologic disorders, gastrointestinal disorders, renal disorders.

Clinical Disorders

Endocrine Disorders

Murray M Pollack Paul Kaplowitz

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

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

syndrome, there is clinical evidence of a contracted ECFvolume

SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE

This syndrome, although common in the pediatric criticalcare setting, is rarely the reason for admission to thepediatric intensive care unit (PICU) The expansion ofthe 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 collectingducts and tubules resulting in increased permeability

to water, increased fluid reabsorption and increasedintravascular volume In response to the latter, theglomerular filtration rate and renal plasma flow increase,and proximal sodium reabsorption decreases, therebyincreasing the urine sodium levels and decreasing the serumsodium level The increased ECF volume is accompanied

by weight gain but is not associated with distended neckveins or edema because only one third of retained water isdistributed in the ECF space

With progressively decreasing levels of sodium, the tients gradually develop malaise, hypotonia, nausea, vom-iting, anorexia, mental alterations, followed by convulsivecrises, stupor, and coma Other signs and symptoms includepseudobulbar paralysis, Babinski sign, and extrapyramidalsymptoms Patients with existing neurologic disorder willhave neurologic symptoms at higher levels of sodium thanthose without such disorders

pa-SIADH is uncommon in children.1 A summary of thedifferent conditions associated with SIADH is given in

TABLE 11.1

CAUSES OF SYNDROME OF INAPPROPRIATE

SECRETION OF ANTIDIURETIC HORMONE

Bronchogenic carcinoma Vincristine

Thymoma Carbamazepine

ALL Cyclophosphamide (IV)

Lymphoma SSRI antidepressants

Infection: meningitis, encephalitis

Neoplasms near the pituitary or

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

trans-sphenoidal 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

follow-ing 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

ex-cretion >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

addi-tion, 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 ofthe hyponatremia and the intensity of the neurologicdisturbance such as seizure or altered mental status Thereare two basic principles to be remembered when correctinghyponatremia: (i) the serum sodium level should beincreased at a safe rate and (ii) the underlying diseaseshould be treated In general, the serum sodium should becorrected slowly at a rate not exceeding 1.3 mEq/L/hourwith 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.6If 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 ofdemyelination in the base of the pons

In severe ‘‘acute’’ hyponatremia with neurologic

symp-toms, occurring within <48 hours, 3% saline solution, 3.0

to 5.0 mL per kg can be administered rapidly to increasethe serum sodium faster at 1.5 to 2.0 mEq per L for 3

to 4 hours or until the neurologic symptoms resolve Theinfusion rate may be calculated by multiplying the bodyweight 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 likelydeveloped over a longer period of time, is best treatedwith fluid restriction This is usually sufficient to normalizethe sodium level In a young child, fluid intake may berestricted to the range of 30% to 75% of maintenancerequirement or to 1,000 mL/m2/day.8,9If this fails to correctthe hyponatremia, the addition of demeclocycline, may

be indicated to allow for higher volume intake Lithiummay also be used for this purpose, but demeclocycline issuperior in causing a nephrogenic diabetes insipidus (DI)-like state, thereby decreasing the renal concentrating abilityand decreasing water reabsorption in the collecting ductsand tubules.10It may take several days before an optimalresponse is appreciated

CEREBRAL SALT WASTING SYNDROME

CSW syndrome is not uncommon in a critically ill atric patient CSW syndrome and SIADH have many similarclinical findings, that is, hyponatremia, high urine osmo-lality, and elevated urinary sodium concentration higherthan 150 mEq per L They can both be caused by the sameintracerebral diseases Vasopressin level is also elevated inCSW syndrome; however, it is an appropriate response tovolume depletion Unlike SIADH, in CSW syndrome, theurinary output is not low and the ECF volume is decreaseddue to primary natriuresis.11Clinical signs of dehydrationare evident Therefore, volume restriction is not effective inrestoring normal serum sodium levels in CSW syndrome,and fluid restriction in a patient with CSW syndrome may

pedi-cause further volume depletion, a decrease in brain

per-fusion 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

pep-tide, C-type natriuretic peppep-tide, and the recently discovered

dendroaspis natriuretic peptide (DNP), exert their effect by

antagonizing the renal effects of ADH, suppressing the

ren-in–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

DI is a heterogeneous group of disorders, which can bedivided into: (a) vasopressin-sensitive or (b) vasopressinresistant The causes of vasopressin-sensitive DI (also called

hypothalamic, neurogenic, or central DI) include trauma

to the hypothalamic-neurohypophyseal system (eitheraccidental or surgical), infiltrative disease including tumors

or infection, destruction by the autoimmune process,genetic defects in vasopressin production, and congenitalanomalies or defects of the hypothalamic or pituitary gland.The cause of central DI is unknown in 10% of pediatriccases.13

Vasopressin-resistant DI (also called nephrogenic DI)

results from genetic or acquired causes Genetic causesare more common in children than in adults and aremore severe than the acquired form Familial vasopressin-resistant DI is due to a defect in the vasopressin (V2)receptor, inherited in an X-linked pattern An autosomaldominant or recessive form of inheritance linked to amutation 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 lesssevere It may be due to: disorders in the kidney andureter, sickle cell disease; Sj ¨ogren syndrome, intake ofdrugs such as lithium, demeclocycline, and foscarnet (used

to treat cytomegalovirus infection in immunosuppressedpatients); electrolyte imbalance such as hypokalemia,osmotic diuresis due to glycosuria in diabetes mellitus;primary polydipsia; hypercalcemia; decreased protein orsodium intake; and washout from massive diuretic use

THE TRIPHASIC RESPONSE

Injury to the supraopticohypophyseal tract causes bilateralneuron degeneration in the supraoptic neuron (SON) andthe paraventricular neuron (PVN); when approximately90% of the magnocellular neurons in the SON and PVNare lost, permanent diabetes insipidus ensues Diabetesinsipidus after surgery or trauma to the pituitary orhypothalamus may exhibit one of the three patterns:transient, permanent, or triphasic.15 In the first phase ofthe triphasic pattern, total or partial DI begins on thefirst postoperative day and persists for 0.5 to 5 days Thisphase is due to edema in the area interfering with normalADH secretion This is the most common pattern (50%

to 60%) of postsurgical diabetes insipidus The secondphase is the SIADH phase This is due to the unregulatedrelease of arginine vasopressin (AVP) because of retrogradedegeneration 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 postoperativeday, a permanent form of DI appears The last phaseoccurs if insufficient neurons survive to release an adequateamount of AVP Usually, a marked degree of SIADH in thesecond phase is a preface to permanent DI In patients withcombined vasopressin and adrenocorticotropic hormone

(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 (D51/4 normal

saline) is administered The amount is calculated between

1 and 3 L/m2/day (40 to 120 mL/m2/hour); the initialamount 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 mildlyvolume-contracted state to stimulate fluid reabsorption

in the renal tubules eventually causing water/solute andosmolality to equilibrate Otherwise, the kidneys willpromptly 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 determinewhether the thirst mechanism is intact or whether SIADH isdeveloping Serum sodium levels measured every 4 hoursare a sensitive indicator of the adequacy of replacementtherapy Serum and urine osmolalities (or urine specificgravity) are also determined at frequent intervals formonitoring The infusion of dextrose may cause somepatients to become hyperglycemic, especially if they arereceiving glucocorticoid therapy If there is concomitanthyperglycemia, only half-normal saline should be useduntil normal blood sugar level is restored Correction of DIshould occur within 48 to 72 hours

If vasopressin therapy is added, it can be given in theform of synthetic aqueous vasopressin (Pitressin) Its effect

is maximal within 2 hours of starting the infusion andthe duration of action is 4 to 8 hours The half-life is 10

to 20 minutes allowing convenient dosing as needed Therecommended initial dose is 2.5 to 10 units given IV every 6

to 12 hours To prevent rapid decrease in sodium level, thesmallest dose is started and gradually increased to achievethe desired effect The therapeutic goals should include:urine output 2 to 3 mL/kg/hour, urine specific gravity of1.010 to 1.020, and serum sodium of 140 to 145 mEqper L Urine specific gravity and volume of urine outputare the most sensitive parameters in assessing adequacy oftreatment Serum sodium level and serum osmolality donot correlate with the pitressin dose Intravenous DDAVPshould not be used in combination with fluid therapy inthe management of acute central DI due to its long half-life (8 to 12 hours), which therefore increases the risk fordangerous hyponatremia In addition, patients who arereceiving fluid infusion and are not fully alert may not

be able to regulate their own thirst, possibly leading tosignificant hyponatremia

Continuous vasopressin infusion is another option formanaging central DI This is most helpful in two situations,(i) during the initial postoperative days in children inwhom DI develops following CNS surgery and the child isnot eating or drinking, and (ii) in patients with establishedcentral DI who require high fluid volume infusion andhave high urine output during induction with cancerchemotherapy Another useful application of continuousvasopressin infusion is intraoperative management of fluid

in patients with known DI Owing to its short life, continuous vasopressin infusion can be easily turnedoff with rapid return of diuresis Continuous vasopressininfusion may also obviate the need for large volumes of

half-TABLE 11.2

SUMMARY OF THE DIFFERENT FORMULATIONS OF ANTIDIURETIC THERAPY

or nasal forms Desmopressin

8–15 h Central DI due to

trauma or surgery May be difficult to give to infants or if nasal congestion exists Desmopressin

or t.i.d

8–12 h Maintenance

therapy for central DI

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

discon-tinued 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 patientcan be transitioned to oral DDAVP for maintenance ther-apy The initial dose should be 0.05 mg for infants andsmall children, 0.1 mg for older children, and 0.2 mg foradolescents repeated every 8 to 12 hours Before the nextdose of DDAVP, one should wait until the effect of the previ-ous dose has worn off (when diuresis with dilute urine reap-

pears) and the serum sodium is >135 mEq per L This will

prevent severe hyponatremia After 1 to 3 days, it is usuallypossible to find a dose of oral DDAVP that controls urineoutput 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 ated with pituitary adenoma–mechanisms not involving inappro-

associ-priate 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

inappropriate secretion of antidiuretic hormone 1957 J Am Soc

Nephrol 2001;12(12):2860–2870.

8 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.

9 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.

10 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.

11 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 Lynne L Levitsky

Diabetic ketoacidosis (DKA) is caused by insufficiently

circulating insulin or diminished insulin action Insulin

deficiency induces a profoundly catabolic state

Hyper-glycemia is the result of the failure to store or utilize

ingested carbohydrate, and the loss of suppression of

glycogenolysis and gluconeogenesis Without insulin,

in-gested glucose cannot be metabolized or stored in liver,

muscle, or other tissues The muscle and fat glucose

trans-porter, 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

sub-strate for gluconeogenesis from the gluconeogenic amino

acids released during proteolysis and glycerol released

dur-ing lipolysis

Deficiency of insulin is associated with

concomi-tant increases in counter-regulatory hormones including

glucagon, cortisol, growth hormone (GH), and

cate-cholamines Glucagon is particularly important in the

maintenance of ketoacidosis because of its role in

ke-togenesis Individuals with glucagon deficiency (diabetes

secondary to pancreatitis, or cystic fibrosis) rarely develop

ketoacidosis Excess of glucagon stimulates hepatic

keto-genesis, 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

counter-regulatory hormone excess However, hyperglycemia

in-duces 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,

myocar-dial and central nervous system (CNS) energy depletion

and electrolyte imbalance

DIAGNOSIS

PresentationPatients classically present with lethargy, hyperventilationwith deep sighing breaths (Kussmaul breathing), and afruity 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 orcachexia may be noted if the illness is of a long duration.Abdominal or back pain, on occasion, can be severeenough to mimic a surgical emergency Children may showsigns of dehydration including dry mucous membranes,tachycardia, and poor capillary perfusion A flushed face

is common Fever may be a symptom of an underlyingprecipitating infection, but hypothermia can be seen, andpatients with underlying infection may not become febrileuntil treated for DKA Patients with severe DKA can bestuporous with profound dehydration

Clinical Evaluation

A prodrome of weight loss, polyuria, and polydipsiacan usually be elicited Although questioning about afamily 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 DKAwith common viral vomiting illnesses and dehydrationoften leads to delayed diagnosis in very young children.Urination continues because of osmotic diuresis andcannot be used as a gauge of dehydration A rapidrespiratory rate secondary to metabolic acidosis mightlead to initial confusion with pneumonia or asthma,particularly if the clinician does not detect an acetoneodor Other causes of metabolic acidosis including lacticacidosis, uremic acidosis, alcoholic acidosis, and metabolicacidosis secondary to drug ingestion (salicylates) must be

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

hyper-glycemia with a BG level of at least 200 mg per dL, venous

pH <7.3, and/or serum bicarbonate of <15 mmol per L

Oc-casionally, young or partially treated children or pregnant

adolescents, may develop ketoacidosis with near normal

glucose values This has been termed euglycemic

ketoacido-sis 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

mortal-ity 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,

aspi-ration pneumonia, pulmonary edema, adult respiratory

distress syndrome, subcutaneous emphysema,

pneumome-diastinum, 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

success-fully if management is careful and attentive.1,2

Symptomatic cerebral edema is the most serious plication in the treatment of DKA in children It is unclearwhy this complication almost never develops after adoles-cence Brain swelling occurs in most children with DKA,even before treatment, but in a small number, it is signif-icant enough to cause cerebral herniation and irreversibleneurologic damage or death Risk factors for the develop-ment of cerebral edema during therapy include youngerage at onset and presentation with a new onset type 1diabetes mellitus In one study, children with low partialpressures of arterial carbon dioxide and high serum ureanitrogen at presentation, treated with bicarbonate were atincreased risk (see Table 12.1).3 Most studies show nocorrelation between the degree of hyperglycemia and therisk of cerebral edema Although case–control studies havenot convincingly demonstrated that the rapidity, volume,

com-or osmolality of fluid rehydration ccom-orrelates with the velopment of cerebral edema, it is generally conceded thatoverload with relatively hypotonic fluid could be a riskfactor for this serious complication

de-Children who develop symptomatic cerebral edema erally do so during recovery and are not very acidotic whenthey develop signs of acute intracranial pressure elevation.Symptoms usually develop between 6 and 24 hours afteronset of therapy, but rarely can occur after 24 hours of ther-apy and have been reported at diagnosis Initial symptomsand signs include reappearance of vomiting, worseningheadache, and depressed sensorium More ominous signsare slowing pulse rate, decreasing oxygen saturation, widen-ing pulse pressure, and changes in the state of consciousnessprogressing to stupor, with incontinence and appearance

gen-of new neurologic deficits such as change in pupillaryresponse and cranial nerve palsies

An evidence-based protocol has been developed foruse in the early diagnosis of cerebral edema in patientswith DKA Clinical diagnostic criteria include abnormalmotor/verbal response to pain, decorticate or decerebrateposture, cranial nerve palsy (especially third, fourth, andsixth nerves), and abnormal neurogenic respiratory pattern(e.g., grunting, tachypnea, Cheyne-Stokes respiration, ap-neusis) The major criteria for impending cerebral edema

are altered mentation or fluctuating level of consciousness,

sustained heart rate deceleration (decline of >20 bpm)

not attributable to improved intravascular volume or sleep

state, and age-inappropriate incontinence The minor

crite-ria are vomiting, headache, lethargy or difficulty in arousing

from sleep, diastolic blood pressure (BP) >90 mm Hg, and

age <5 years One study showed that appearance during

treatment of one diagnostic criterion or two major criteria,

or one major and two minor criteria had a sensitivity of

92% with a false-positive specificity of 4% in the diagnosis

of cerebral edema.4Further prospective validation of these

criteria is needed

Treatment should begin as soon as cerebral edema is

suspected (discussed later in this chapter)

Management

The guidelines proposed in this chapter for the

manage-ment of DKA are compatible with a recent international

consensus statement on the treatment of DKA in children.1

If there is frequent evaluation by health care providers

ex-perienced in diabetes management (by telephone or direct

observation), mild cases of ketoacidosis without vomiting

can be managed at home or in an outpatient care facility

Moderate to severe DKA should be treated in an intensive

care or specialized pediatric setting An experienced and

trained nursing staff, availability of frequent on-site

physi-cian monitoring, clear written guidelines, and access to

frequent laboratory evaluation are essential Compromised

circulation, depressed level of consciousness, risk factors

of cerebral edema such as younger age (<5 years) or new

onset mandates treatment in an intensive care unit (ICU)setting where minute-to-minute monitoring is possible andneurosurgical consultation is readily available

In a child appearing sick, documentation of a BG

level >250 mg per dL on bedside testing and ketonuria

documented on a urine ketone strip should be sufficient

to begin treatment while waiting for the remaining labresults Venous blood gas results are sufficient to guidemanagement in most children with mild to moderateDKA, but in severe DKA, arterial blood gases might bemore appropriate

See Table 12.2 for a concise guide to management

■ Hourly monitoring of heart rate, respiratory rate, and BP

■ Strict fluid input and output, measured hourly, withbladder catheterization if necessary on the basis of theseverity of illness and state of consciousness

• At least hourly monitoring of clinical condition forsigns and symptoms of impending cerebral edema

■ An initial electrocardiogram (ECG) may be helpful

in identifying EKG changes associated with hypo- orhyperkalemia EKG can be repeated at 4-hour intervals ifthere is concern about cardiac status or hyperkalemia

TABLE 12.2

CONCISE PLAN FOR MANAGEMENT OF DIABETIC KETOACIDOSIS

1 Administer bolus of 0.9% saline or Ringer lactate Repeat bolus if necessary Begin IV fluids calculated as fluid deficit (to be replaced over 36 h) and maintenance of fluid at a constant rate Fluids should consist of 0.45% saline Once the patient has voided, add 40 mEq/L

of potassium salts (20 mEq of Kphos and 20 mEq of KCl or acetate) to the IVF If the serum sodium begins to decrease or remains

132 mEq/L or less as glucose decreases, increase the saline concentration to 0.9% and re-evaluate the rate of rehydration

2 Once the BG level has decreased to 300 mg/dL, add 5% dextrose to the infusion If acidosis persists, even after the BG level drops to

200 mg/dL or less, increase the dextrose infusion to 10% Simultaneous administration of two bags (one with 5% dextrose and the other with 10% dextrose in salt solution) speeds IVF therapy changes

3 Give regular insulin intravenously at a rate of 0.1 U/kg/h (made up as 1 U/kg in 100 mL of 0.9% saline) The risk of hypoglycemia, if the IVF stops infusing accidentally, is reduced if the insulin is piggybacked into the IVF infusion Do not decrease the insulin infusion rate while acidosis persists Occasionally, higher rates of infusion (0.2 U/kg/h) may be needed to achieve the goal of reducing the level of BG

by 75–100 mg/dL/h (4.2–5.6 mM), indicating resistance to insulin or a problem with dilution The rate of insulin infusion can be reduced

to 0.05 U/kg/h after acidosis has cleared (pH ≥7.3) and BG level is ≤300 mg/dL Transition to subcutaneous insulin regimen should be

considered only after the venous pH is >7.3, the patient is ready to eat, and the glucose is <300 mg/dL

4 Add potassium to the infusate after the patient voids; add 40 mEq/L of K salts, half as potassium phosphate (to replace phosphate

losses) and the other half as KCl If the patient is hyperchloremic, use potassium acetate instead of KCl Persistently low (<3.6 mEq/L) or high (>5 mEq/L) potassium suggests the need for ECG monitoring to detect arrhythmias

5 Avoid bicarbonate administration, except if necessary for resuscitation

6 Monitor constantly the vital signs, fluid balance, neurologic state, hourly glucose levels, blood gases, and ketones with at least q2h electrolyte levels including HCO3levels while the patient is acidotic Also monitor the calcium and phosphorus levels q4–6h Measure urine output q4–6h once the patient has stabilized, more frequently in the first 6 h of treatment Urinary catheterization may be needed depending upon neurologic status

7 Treat the underlying condition/precipitating illness, if possible

DKA, diabetic ketoacidosis; ECG, electrocardiogram; IVF, intravenous fluid; BG, blood glucose.

Hour Heart Headache Eyes Emesis pH

rate

Blood pressure

Mental status

Fluid intake

Fluid output

Fluid balance

Blood glucose

O2sat

Initial laboratory studies should include a venous blood

gas (arterial may be indicated in the most severely ill

children), BG, electrolytes, bicarbonate level, phosphate,

calcium, magnesium, blood urea nitrogen (BUN),

creati-nine, complete blood count and differential white blood

cell count, and a urinalysis to document urine glucose and

ketones A serum osmolality is sometimes of interest and

may be important in a child where there is concern about

a complicated course

■ Other laboratory studies may be indicated on the basis

of clinical findings, such as serum lactate if acidosis is

disproportionate to ketonuria, serum lipase and amylase

if abdominal pain is severe, or blood, urine or sputum

culture if infection is a concern If the laboratory

can provide rapid β-hydroxybutyrate results or bedside

monitoring capacity is available, measurement of serum

β-hydroxybutyrate can be useful

■ BG should be obtained hourly Hourly, bedside

moni-toring values using state-of-the-art calibrated meters are

often adequate, but formal laboratory values should be

obtained every 2 hours for confirmation

■ Blood gases and serum bicarbonate should be obtained

at 2-hour intervals until the serum pH is clearly

improving, and then every 4 hours until pH is normal

■ Potassium, phosphate, and calcium can be repeated

every 4 hours until resolution of ketoacidosis and unless

abnormal values prompt more frequent analysis

Pitfalls in laboratory assessment include:

■ Overinterpretation of a high white blood cell count

with a shift to the left as a sign of infection It usually

represents the stress of DKA

■ Misinterpretation of a low serum sodium concentration

as true hyponatremia It usually represents a response

to hyperglycemia because water is driven from cellsinto the extracellular fluid to balance osmolality, ormay be factitious because of elevated triglycerides Theserum sodium concentration should be corrected forhyperglycemia by adding 1.6 mmol to the reportedsodium level for every 5.6 mmol per L (100 mg per

dL) increase in glucose >5.6 mmol per L.

■ Overinterpretation of an elevated amylase level aspancreatitis If the lipase is not concomitantly elevated,this represents release of salivary amylase

■ Factitiously elevated serum creatinine levels may createconcern for renal failure if the laboratory uses an oldernonenzymatic creatinine assay, which cross-reacts withacetoacetate

■ Rising levels of acetoacetate may be seen in the first

4 to 6 hours of treatment Acetoacetate (measured as

urine or serum ketones) and β-hydroxybutyrate are in

equilibrium related to the redox state of the body Asacidosis and perfusion improves, the ratio of acetoac-

etate to β-hydroxybutyrate, which may be as high as

1:8 in the patient with severe acidosis, drops to 1:2 as

β-hydroxybutyrate is converted to acetoacetate The sulting transient increase in urine ketones should not betaken as a sign of worsening ketoacidosis

re-RehydrationGeneral Guidelines to Fluid ManagementPatients presenting with DKA are generally, moderately

to severely (7% to 10%) volume depleted.5 The highosmolality because of hyperglycemia is compounded bydehydration, and results in the shift of fluid from the in-tracellular compartment to the extracellular compartment

In addition, patients have both intracellular and

extracel-lular electrolyte deficits Studies in adults have shown fluid

deficits of up to 5 L and approximately 20% loss of total

body sodium and potassium The goal of the treatment

is to restore circulatory volume, replace extracellular and

intracellular fluid losses, replace the electrolyte deficits, and

restore the glomerular filtration rate, while avoiding

devel-opment of symptomatic cerebral edema or other serious

complications of treatment The following general

man-agement suggestions are assumed to decrease the risk of

cerebral edema, although one retrospective case–control

study did not confirm their validity:

■ Fluid and electrolyte deficits should be replaced gradually

over at least 36 hours

■ Treatment should cause a gradual decrease in BG levels,

not exceeding 75 to 100 mg/dL/hour (4.2 to 5.6 mmol

per hour)

■ Rapid reductions in osmolality should be avoided by the

use of rehydration solutions that are relatively isosmolar

to serum

Initial Fluid Bolus

Rehydration can begin with a 20 mL per kg bolus

of isotonic fluid (normal saline or Ringer lactate) If

circulation remains compromised, this bolus can be

repeated if necessary The initial fluid rehydration may

lower blood and serum osmolality substantially because

hyperglycemia and hyperosmolality is in part related to

dehydration If self-hydration with sugar-containing fluids

had contributed to a markedly elevated blood sugar level at

presentation (>500 mg per dL or 27.8 mmol), rehydration

can cause a precipitous drop in serum glucose levels

Rehydration Fluids

After the initial bolus, rehydration should be continued

using at least 0.45% saline solution Use of either colloid

or more dilute solutions is likely to lead to rapid decreases

in osmolality and movement of fluid into the intracellular

compartment The use of large amounts of 0.9% saline

so-lution leads to hyperchloremic metabolic acidosis Urinary

loss leads to depletion of potassium, but serum potassium

concentration may initially be normal or elevated because

of shifts of potassium from the intracellular to the

ex-tracellular compartment Because there is a small risk of

prerenal failure early in the course of rehydration,

potas-sium should be replaced only after the patient has voided

and the serum potassium level is 5 mEq per L or less We

recommend beginning with 40 mEq per L of potassium

salts in the form of 20 mEq per L potassium phosphate

and 20 mEq per L potassium chloride This replenishes

phosphate losses to some extent and minimizes

hyper-chloremia while avoiding hypocalcemia as a result of larger

quantities of infused phosphate Alternatively, potassium

acetate may be used to replace potassium losses without

in-creasing hyperchloremia Potassium supplementation can

be increased to 60 mEq per L if required Serum phosphatelevels are usually replaced from endogenous stores, buteffects of phosphate depletion such as muscle weaknessmight be prevented by exogenous supplementation.When the BG level has decreased to 300 mg per dL,5% dextrose can be added to the intravenous infusion Ifacidosis persists after the BG level drops to 200 mg per dL

or less, the dextrose infusion should be increased to 10% topermit continued administration of insulin Elevated bloodglucose almost always improves more rapidly than acidosis.Simultaneous administration of two bags of intravenousfluid (IVF) (each with different dextrose concentrationswhose rates can be titrated) decreases response time inmaking fluid therapy changes (Table 12.2).6

Insulin TherapyInsulin should be given as soon as DKA is confirmed

by documentation of hyperglycemia and urine ketones.Insulin is necessary for reversal of the catabolic state of DKA

It stimulates peripheral glucose uptake, suppresses glucoseproduction, and inhibits lipolysis and ketogenesis Regularhuman insulin should be administered by a continuousintravenous drip at a usual initial rate of 0.1 U/kg/hour.Insulin-resistant individuals may require 0.2 U/kg/hour ormore, and babies who are very insulin sensitive may require

a rate of 0.05 U/kg/hour Lispro (Humalog) and insulinaspart (NovoLog), act faster when given subcutaneouslybecause they do not form tight hexamers, and offer noadvantage when given intravenously There is no evidencethat an initial insulin bolus improves the outcome orrapidity of recovery from DKA The insulin preparation,usually diluted in saline for ease of infusion and flushedthrough the tubing to block insulin binding, should bepiggybacked into the infusate to decrease the risk ofhypoglycemia if there is a failure of the intravenous infusate.Adequacy of the insulin infusion is assessed by glycemicresponse and improvement in serum pH If the BG level

is not decreasing by 75 to 100 mg/dL/hour, the rate can

be increased, and if it is decreasing more rapidly, glucoseconcentration in the infusate can be increased to preventhypoglycemia while facilitating recovery from acidosis Theneed for a higher dose of insulin in the first few hoursaugurs insulin resistance or a problem with the insulin orthe insulin dilution Acidosis is monitored by measuring

pH with the goal being a venous pH >7.3 If the BG level falls <300 mg per dL before acidosis has resolved, as often

happens, the glucose infusion rate should be increased byincreasing the dextrose concentration The rate of insulininfusion can be reduced to 0.05 U/kg/hour only afteracidosis has cleared (pH≥7.3) and BG is ≤300 mg per dL.Treatment of Acidosis

Acidosis in DKA is associated with an increased anion gap.Anion gap= [Na+]− ([Cl−]+ [HCO3 −])

× Normal range is 12 ± 2 mmol per L

The contributing anions are primarily the ketoacids

β-hydroxybutyrate and acetoacetate (see Chapter 2), and to

a lesser extent (approximately 25%) lactic acid associated

with poor tissue perfusion Administration of IVFs to

correct the dehydration helps in the correction of the

lactic acidosis Administration of insulin halts further

generation of ketoacids As renal perfusion improves,

excretion of ketoacid increases Metabolism of acetoacetate

and β-hydroxybutyrate the acidosis.

Bicarbonate therapy in the treatment of DKA is

contro-versial There are several controlled trials in the pediatric

and adult population that have been unable to show any

advantage in using bicarbonate, and there are potential

risks associated with bicarbonate therapy Intracellular

aci-dosis can be aggravated owing to the increased production

of CO2 Bicarbonate therapy may cause paradoxical CNS

acidosis because of the delayed equilibration of

bicarbon-ate ion compared to CO2across the blood–brain barrier

In addition, the rapid correction of the acidosis can cause

intercompartmental movement of potassium leading to

hypokalemia, putting the patient at a risk for cardiac

arrhythmias However, patients with life-threatening

hyper-kalemia, or decreased cardiac contractility and peripheral

vasodilatation because of extreme acidosis (arterial pH <7)

may on rare occasions benefit from rapid administration

of bicarbonate In such patients, bicarbonate should be

administered to replace one third of the calculated deficit,

solely as a resuscitative measure to treat or prevent

im-pending circulatory collapse Close laboratory follow-up is

imperative

Hyperosmolar Hyperglycemic State

Hyperosmolar hyperglycemic state (HHS) is a serious

potentially life-threatening hyperglycemic complication in

diabetes mellitus It is characterized by hyperglycemia,

hyperosmolality, and a mild metabolic acidosis The

diagnostic criteria for HHS are a BG level >33 mmol per

L (>600 mg per dL) and a serum osmolality >320 mmol

per kg (>320 mOsm per kg) in the absence of severe

acidosis (pH >7.3) and ketosis HHS is more common

in patients with type 2 than with type 1 diabetes,7 and

is occasionally seen in pediatric patients who either have

type 2 diabetes or who are developmentally disabled and

not able to communicate their need for oral hydration to

replace urinary losses

The pathogenesis of HHS is not well understood; but

the basic mechanism is a net reduction in the effect

of circulating insulin coupled with the hyperglycemic

action of counter-regulatory hormones Insulin activity

is insufficient to prevent glucose production or promote

glucose utilization Lower circulating levels of free fatty

acids and/or higher portal vein insulin levels decrease

ketogenesis BG levels are often much higher than in DKA,

and therefore associated with more pronounced osmotic

diuresis, leading to more profound dehydration HHS can

take days or weeks to fully develop Water loss is estimated

as 15% to 20% rather than the 5% to 7% in DKA andhypertonic dehydration is pronounced Patients frequentlypresent in coma

Treatment guidelines for HHS in pediatric patientshave been developed by a consensus group under theauspices of the American Diabetes Association.8 Theseguidelines are based on expert opinion but not confirmed

by clinical studies Because HHS can also be associatedwith the development of symptomatic cerebral edema,

we recommend that it be managed in a manner similar

to DKA, but with a recognition of the severity of thedehydration and hyperosmolality Initial fluid replacementwith boluses of 0.9% saline, followed by continuedreplacement with 0.7% to 0.9% saline with appropriatepotassium supplementation provides a relatively hypo-osmolar replacement fluid Sodium levels should bemonitored and the percent of saline in the infusate reduced,

if levels rise Fluid replacement should be similar to that forDKA and based upon changes in glycemia and electrolytes.Insulin replacement should be initiated at 0.1 U/kg/hourbut insulin infusion rates may need to be increased inobese, insulin-resistant young individuals

Monitoring for cerebral edema should be similar to that

in DKA Rhabdomyolysis and multiorgan failure are some

of the important complications of HHS Creatine kinase els, electrolyte levels, glucose levels, and osmolality should

lev-be monitored frequently Despite intensive treatment, themortality rate continues to be as high as 15%

Treatment of Cerebral EdemaCerebral edema in other disorders has been attributed tovasogenic edema (increases in extracellular volume) or cy-totoxic edema (astrocytic brain cell swelling) The develop-ment of cerebral edema by vasogenic mechanisms has beenattributed to cerebral ischemia/hypoxia and the generation

of various inflammatory mediators, reperfusion injury, anddisruption of cell membrane ion transport and aquaporinchannels Cytotoxic edema has been attributed to the gen-eration of intracellular organic osmolytes (myoinositol,taurine, glycerylphosphoryl choline, betaine—previously

known as idiogenic osmoles) and subsequent cellular

os-motic imbalance and swelling It is likely that both generalmechanisms are important at different stages of the evolu-tion of symptomatic cerebral edema.9,10

Therapy must be instituted as soon as cerebral edema issuspected It should not be postponed for confirmation

by radiologic studies This delays treatment, and alsoplaces the patient at potential risk during transport orimaging because intensive monitoring and treatment might

be less available in the event of brain herniation Thepatient should be given intravenous mannitol at 0.25

to 1.0 g per kg over 20 minutes If there is no initialresponse, the mannitol may be repeated in 1 to 2 hours.Hypertonic saline 5 to 10 mL per kg over 30 minutes

can be used as an alternative to mannitol in controlling

apparent intracranial hypertension.11 The rate of fluid

administration should usually be reduced Intubation and

mechanical ventilation may be necessary The value of

hyperventilation is questioned in cerebral edema, and

there is at least one retrospective study that has shown

an association of aggressive hyperventilation with adverse

outcomes in DKA-related cerebral edema Intracranial

pressure monitoring and neurosurgical decompression are

sometimes required

Transition to a Subcutaneous Insulin Regimen

Once the venous pH has improved to >7.3, the BG level

has fallen to <300 mg per dL, and the patient is ready to

eat, plans should be made for transition to a subcutaneous

insulin regimen Intravenous insulin must be continued for

half an hour after the administration of subcutaneous

in-sulin to permit time for absorption In children with known

diabetes, restoration of the previous regimen is usually

ap-propriate There are many insulin management protocols

Two relatively simple approaches to management that are

relatively easily implemented in children whose families

have not yet become sophisticated in diabetes

manage-ment are suggested The initial daily dose for subcutaneous

insulin is between 0.5 and 1.0 U per kg

■ NPH/short-acting insulin: Give two third of the dose in

the morning and one third at dinnertime Two thirds of

the morning dose is given as NPH insulin and one third

of the morning dose is given as short-acting insulin; the

predinner dose is similarly split or can be given half the

evening dose as NPH with the remaining half as short

acting

■ Glargine (Lantus) and short-acting insulin (Humalog,

or NovoLog): With this regimen, half of the total dailydose is given as glargine, and the rapidly acting insulin

is given at mealtimes Ideally, one must match insulin tocarbohydrate with this regimen but at early stages, threeequal short-acting insulin doses will be adequate.REFERENCES

1 Dunger DB, Sperling MA, Acerin CLi, et al ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents.

Arch Dis Child 2004;89:188–194.

2 Worly JM, Fortenberry JD, Hansen I, et al Deep venous thrombosis

in children with diabetic ketoacidosis and femoral central venous

catheters Pediatrics 2004;113:e57–e60.

3 Glaser N, Barnett P, McCaslin I, et al Risk factors for cerebral

edema in children with diabetic ketoacidosis N Engl J Med.

2001;344:264–269.

4 Muir AB, Quisling RG, Yang MCK, et al Cerebral edema in

child-hood diabetic ketoacidosis Diabetes Care 2004;27:1541–1546.

5 Koves I, Neutze J, Donath S, et al The accuracy of clinical ment of dehydration during diabetic ketoacidosis in childhood.

assess-Diabetes Care 2004;27:2485–2487.

6 Poirier MP, Greer D, Satin-Smith M A prospective study of

the ‘‘two-bag system’’ in diabetic ketoacidosis management Clin

Pediatr 2004;43:809–813.

7 Morales AE, Rosenbloom AL Death caused by hyperglycemic

hyperosmolar state at the onset of type 2 diabetes J Pediatr.

2004;144:270–273.

8 Position Paper, American Diabetes Association Hyperglycemic

crises in diabetes Diabetes Care 2004;27:S94–S102.

9 Glaser NS, Wootton-Gorges SL, Marcin JP, et al Mechanism of

cerebral edema in children with diabetic ketoacidosis J Pediatr.

2000;145:164–171.

10 Levitsky LL Symptomatic cerebral edema in diabetic ketoacidosis:

The mechanism is clarified but still far from clear J Pediatr.

Thyroid Disorders

Audrey Austin

Alterations in thyroid functions are the most common

metabolic changes that occur in critically ill patients

There may be overproduction of thyroid hormone causing

hypermetabolic activity, or underproduction promoting a

hypometabolic state Either state might affect the healing

process in a seriously ill child and negatively impact the

outcome of the illness This chapter discusses thyroid storm

and the abnormalities associated with the use of

iodine-containing products, and the sick euthyroid syndrome

Normal thyroid physiology and the regulation of thyroid

function in critical illness have been discussed in Chapter 2

Diagnosis and management of the specific conditions are

discussed in this chapter

THYROID STORM

Hyperthyroidism is a state of increased production and

sustained release of the thyroid hormones thyroxine (T4)

and tri-iodothyronine (T3) into the circulation A

hyper-metabolic state, thyrotoxicosis, develops when peripheral

tissues are exposed to excessive thyroid hormones By far,

the most common cause is autoimmune-mediated Graves

disease due to the production of antibodies, which bind to

and stimulate the thyroid stimulating hormone (TSH)

re-ceptors in the thyroid gland The clinical symptoms include

tachycardia, hyperactivity, anxiety, and tremors Weight loss

is common and may be dramatic A goiter is usually evident

and exophthalmos may be present initially or develop later

Thyroid storm is a life-threatening exacerbation of

hy-perthyroidism The condition may be precipitated by the

stress of surgery in children and adolescents with

hyperthy-roidism in the postoperative period after thyroidectomy,

and by the use of certain drugs or by discontinuing

an-tithyroid drug therapy Early recognition and treatment are

essential in reducing the morbidity and mortality associated

with this condition

Thyroid storm may also occur in the neonatal period, ininfants born to mothers with Graves disease Although thisdisease is rare in neonates, when it occurs it may presentwithin hours of birth, but symptoms may be delayed up to

10 days postnatally if the mother was treated with amide drugs, and up to 6 weeks when the transplacentalpassage of maternal blocking antibodies occurs.1 Thereare no specific laboratory tests that distinguish thyroidstorm from hyperthyroidism; therefore the treating physi-cian must always have a high degree of clinical suspicion

thion-to make the diagnosis

Iodine-containing agents have been implicated in thedevelopment of thyroid storm Specifically, amiodarone,useful in the management of cardiac arrhythmias, iodine-containing contrast medium, and topical iodine-containingantiseptic agents have been documented to trigger this con-dition, which is sometimes refractory to medical treatment.Clinical Manifestations

The signs and symptoms of thyroid storm are an ated replica of those in thyrotoxicosis and are characterized

exagger-by hyperthermia, high output cardiac failure, nal (GI) disturbances, and mental status changes.2 (SeeTable 13.1) The precipitating causes of thyroid storm inchildren and adolescents are frequently different from those

gastrointesti-in adult patients (see Table 13.2), and most cases gastrointesti-in thepediatric population are associated with a prior history ofGraves disease The thyroid is not always enlarged, butwhen a goiter is present it will help direct attention to thepossibility of thyroid storm

Laboratory TestingThe diagnosis of thyroid storm is made on the basis ofclinical factors and this condition must be treated withthe utmost urgency if morbidity is to be prevented Todocument that a hyperthyroid state exists, one needs to

CNS, central nervous system; GI, gastrointestinal.

measure total or free thyroxine (FT4), tri-iodothyronine

(T3), and TSH levels FT4 and T3 levels are increased and

TSH is suppressed to <0.1 µU per mL; however, the severity

of the clinical condition does not correlate well with the

degree of elevation of FT4and T3

TABLE 13.2

PRECIPITATING FACTORS OF THYROID

STORM IN CHILDREN AND ADOLESCENTS

An electrocardiogram will identify the presence of atrialfibrillation, the most common arrhythmia associated withthyroid storm.3

TreatmentThe cardiac status of the patient must receive immediateattention, especially if atrial fibrillation is present Atrialfibrillation rates of 32% to 39% in elderly individuals havebeen reported,4but there is less information on how oftenthis occurs in children and adolescents The most importantaspect of therapy is stability of the cardiac function, and

the use of β-blocking agents is of primary importance.

Esmolol given intravenously has been used successfully

in the emergency treatment of thyroid storm because

of its rapid onset and shorter duration of action thanpropranolol It also has the benefit of blocking peripheralconversion of T4to T3 The recommended dose for children

(2 to 16 years) is 300 to 1,000 µg/kg/minute intravenously (IV) until the desired effect has been achieved The β-

blocking agent most frequently recommended for use inchildren is propranolol at an initial dose of 0.1 mg/kg/dosegiven intravenously, slowly over 5 minutes, followed by anoral dose of 10 to 20 mg at 6- or 8-hour intervals Neonataldoses are 0.05 to 0.15 mg per kg IV given slowly over 5minutes followed by oral doses of 0.2 to 0.5 mg per kgevery 6 hours.5

The same thionamide antithyroid drugs used in thetreatment of uncomplicated hyperthyroidism are effective

in patients with thyroid storm Propylthiouracil (PTU) can

be given at 5 to 10 mg/kg/day in three divided dosesand methimazole (MMI) is used at 0.5 to 1 mg/kg/day intwo divided doses.5Because iodide in large doses will blockthyroid hormone synthesis and release, a saturated solution

of potassium iodide (SSKI) is an additional therapeuticagent used in the treatment of thyroid storm The dose forchildren and adolescents is 0.3 to 0.5 mL orally at 6- to8-hour intervals

Lithium carbonate may be used as an alternative drug

in patients with an allergy to iodine or with serioustoxic reactions to the thionamides However, this drug

is also implicated in rare cases of thyroid storm because itdecreases glomerular filtration and may therefore affect theclearance of thyroxine

Fever should be controlled with an antipyretic agent, butnot with salicylates, which competitively inhibit binding

of thyroid hormones to serum proteins Fluid losses due

to fever and diaphoresis, nausea, and vomiting must be

replaced to prevent dehydration, vascular collapse, and to

provide nutritional support

Glucocorticoid therapy plays an important role in the

management of those patients who seem to develop a

relative adrenal insufficiency This treatment also has the

effect of reducing peripheral conversion of T4 to T3 and

therefore aids in decreasing the hypermetabolic state

Hydrocortisone at a dose of 2 mg per kg IV at 8-hour

intervals, is recommended.5

Additional treatment modalities that may be needed

to correct other systemic dysfunction include oxygen,

vasopressor agents, diuretics, and nutritional support

SICK EUTHYROID SYNDROME

The complex of different patterns of thyroid abnormalities

in critically ill patients have been studied in detail, and

the degree of abnormality appears to correlate with the

severity of the illness Investigators have determined that

the syndrome has been estimated to occur in approximately

50% of all patients in the medical intensive care6 and

is associated with a high mortality rate.7 The syndrome

has no clear etiology, and what is known about the

pathophysiology associated with the syndrome has been

discussed in Chapter 2

Diagnosis

Thyroid function studies show abnormalities of

tri-iodothyronine (T3), thyroxine (T4), and TSH levels (see

Table 13.3).8 Elevations of T4 levels could be explained

by thyroid hormone–binding abnormalities, but the

con-siderable changes that occur in response to the stress of

severe or chronic illnesses may make a correct diagnosis

difficult If there is a concern for hyperthyroidism in a

patient with a low TSH, a serumfree T4must be obtained,

preferably by an equilibrium dialysis method with

mini-mum dilution of the serum, to prevent alteration of the

equilibrium between free and bound T4.9 Elevated FT4

in the presence of suppressed TSH (<0.1 µU per mL) is

consistent with a hyperthyroid state Greater difficulty exists

in interpreting results with minimally decreased TSH (0.1

to 0.5 µU per mL) associated with low T4and T3 In thesecases, a serum reverse T3 (rT3) that is increased will aid

in making a diagnosis of sick euthyroid syndrome Serum

T3 and rT3are affected by fasting and they rapidly return

to baseline within 24 to 36 hours of refeeding.10 Similarabnormalities are observed in patients within a few hoursafter initiation of general anesthesia and surgery, and theyreturn to normal in a few days if the postoperative course

is uncomplicated.10

In most cases, serum TSH concentration is normal inpatients with nonthyroidal illnesses However, moderately

elevated TSH level (>20 µU per mL) in the presence of

low FT4 is consistent with a primary hypothyroid state,and abnormally low TSH in the presence of low FT4

concentration is consistent with a secondary hypothyroidstate (TSH deficiency)

TreatmentAlthough it is important to make the diagnosis of sickeuthyroid syndrome, the question of whether to use thyroidhormone replacement remains controversial Brent and

Hershman gave l-thyroxine at a dose of 1.5 µg/kg/day IV

for 2 weeks to half of a group of 23 critically ill patientswho had a serum T4level of <5, and found that although

total and free T4 increased as early as 3 days, there was

no difference in mortality (approximately 75% in bothgroups) They suggested that the inhibition of TSH secretion

by giving T4may suppress an important mechanism for thenormalization of thyroid function during recovery.11Thisformulation is supported by Stathatos and Wartofsky in arecent review, in which, having discussed the components

of the thyroid axis involved in the syndrome, theyspeculated that the low TSH levels are likely related inpart to suppression by steroids, dopamine, and othermedications used in critically ill patients.12

Patients with clearly determined hypothyroid states,primary or secondary, should be prescribed l-thyroxine in

doses normally used in children (usually 50 to 100 µg

per day according to age and size) and the dose should

be titrated after at least a week to achieve an euthyroid

state

REFERENCES

1 Smith CM, Gavranich J, Cotterill A, et al Congenital neonatal

thyrotoxicosis and previous maternal radioiodine therapy BMJ

2000;320:1260–1261.

2 Wartofsky L Thyrotoxic storm In: Braverman LE, Utiger RD, eds.

Werner and Ingbar’s the thyroid: A fundamental and clinical text 8th

ed Philadelphia, PA: Lippincott Williams & Wilkins; 2000.

3 Klein I, Omajaa K Thyroid hormone and the cardiovascular

system N Engl J Med 2001;344:501–509.

4 Cobler JL, Williams ME, Greenland P Thyrotoxicosis in

institu-tionalized elderly patients with atrial fibrillation Arch Intern Med.

1984;144:1758–1760.

5 Drugdex System Thompson Micromedex Healthcare Series,

Vol 125 Greenwood Village, CO; 2005.

6 Tuazon CU, Labriola AM Infectious diseases and endocrinology.

In: Becker KL, ed Principles and practice of endocrinology and

metabolism Philadelphia, PA: JB Lippincott; 1990.

7 Kaptein E, Weiner JM, Robinson WS, et al Relationship of altered

thyroid hormone indices to survival in nonthyroidal illnesses J

assays Clin Chem 1991;37:2002.

10 Wiersinga WM Nonthyroidal illness In: Braverman LE, Utiger R,

eds Werner and Ingbar’s the thyroid: A fundamental and clinical text.

8th ed Philadelphia, PA: Lippincott Williams & Wilkins; 2000.

11 Brent GA, Hershman JM Thyroxine therapy with severe

nonthy-roidal illnesses and low serum thyroxine concentration J Clin

Endocrinol Metab 1986;63:1–8.

12 Stathatos N, Wartofsky L The euthyroid sick syndrome: Is there a

physiologic rationale for thyroid hormone treatment? J Endocrinol

Invest 2003;26:1174–1179.

Adrenal Disorders

Christiane O Corriveau

The adrenal glands produce four classes of hormones:

catecholamines, glucocorticoid, mineralocorticoid, and

an-drogens (see Chapter 2) Catecholamine synthesis occurs in

the adrenal medulla and requires cortisol and so it may be

decreased in patients with hypothalamic–pituitary disease

The adrenal glands release cortisol under the control of the

hypothalamic–pituitary axis, in response to stresses such

as infection, surgery, and trauma Aldosterone primarily

responds to the renin–angiotensin system and potassium

levels Secretion of adrenal androgen is partly under the

control of pituitary adrenocorticotropic hormone (ACTH),

but other poorly understood factors regulate their

produc-tion.1 This chapter focuses on adrenal responsiveness to

illness affecting production of glucocorticoids and

miner-alocorticoids

SYNDROMES OF ADRENAL

INSUFFICIENCY

Adrenal insufficiency is caused by a large variety of

in-sults It can be acute or chronic and may result from

primary direct destruction of the adrenal glands (primary

adrenal insufficiency) or from the loss of the hypothalamic–

pituitary axis function (secondary adrenal insufficiency)

The central pathophysiologic alteration secondary to

adrenal insufficiency is cardiovascular—reduced cardiac

output and decreased vascular tone with relative

hypov-olemia Cardiac output is related to catecholamines and

they have decreased inotropic and pressor effects in the

absence of cortisol Patients with catecholamine-resistant

shock need to be evaluated for the presence of adrenal

insufficiency Relative hypovolemia is multifactorial The

response to hypovolemia is increased vasopressin secretion,

leading to water retention, decreased plasma osmolality,

and hyponatremia Hyponatremia is exacerbated by

aldos-terone deficiency causing excessive urinary sodium loss,

which is usually accompanied by moderate to severe perkalemia Therefore, hyperkalemia is often an importantlaboratory finding in aldosterone deficiency

hy-Primary Adrenal InsufficiencyPrimary adrenal insufficiency is relatively rare The primarycauses are listed in Table 14.1 The adrenal glands have

a large reserve but adrenal insufficiency develops in

pa-tients who have >90% destruction or replacement of the

adrenal glands with inflammation, tumor, infection, orhemorrhage In primary adrenal insufficiency, congenital oracquired lesions of the adrenal cortex prevent production

of cortisol and often aldosterone Autoimmune adrenalinsufficiency spares the adrenal medulla Depending onthe pathologic lesion, symptoms may be severe or mild,and become manifest abruptly or insidiously The mostcommon pediatric causes are discussed subsequently

Congenital Adrenal HyperplasiaThe most common cause of adrenocortical insufficiency

in infancy is the salt-losing form of congenital adrenalhyperplasia (CAH) The most prevalent form of CAH

(>90% of cases) is caused by the deficiency of the

cytochrome P-450 enzyme, 21-hydroxylase, which in itsseverest form causes deficiency of both cortisol andaldosterone In women, ambiguous genitalia withoutpalpable testes provide a clue to the diagnosis

HemorrhageHemorrhage may occur during difficult labor, especiallyduring breech presentation, or its cause may be unknown

An incidence of 3 per 100,000 live births has been reported.Postnatal adrenal hemorrhage occurs in patients beinganticoagulated or those injured after blunt trauma, mostnotably nonaccidental trauma

Secondary Adrenal Insufficiency

After exogenous glucocorticoids

Hypothalamic and pituitary lesions Uncommon

Adapted with permission from Loriaux DL Adrenocortical insufficiency.

In: Becker KL, ed Principles and practice of endocrinology and

metabolism 3rd ed Philadelphia, PA: Lippincott Williams & Wilkins;

2001:739.

Autoimmune Adrenal Insufficiency (Addison

Disease)

The most common cause of Addison disease is

autoim-mune destruction of the adrenal glands In advanced

disease, all adrenal cortical function is lost, but early in

the clinical course, isolated cortisol deficiency may occur

Usually the adrenal medulla is not affected Addison

dis-ease sometimes occurs as a part of two syndromes, each

consisting of a constellation of autoimmune disorders

Type 1 autoimmune polyendocrinopathy syndrome (APS-1)

is a recessive disorder also known as autoimmune

polyen-docrinopathy/candidiasis/ectodermal dystrophy (APECED)

syn-drome The first disease manifestation is often chronic

mucocutaneous candidiasis, commonly followed by

hy-poparathyroidism and then by Addison disease, which

typically develops by adolescence Adrenal failure may

de-velop rapidly in APS-1 Type 2 autoimmune

polyendocrinopa-thy (APS-2) consists of Addison disease with autoimmune

thyroid disease or type 1 diabetes mellitus Gonadal

fail-ure, vitiligo, alopecia, and chronic atrophic gastritis, with

or without pernicious anemia may occur

InfectionInfection and systemic inflammation are the most commoncauses of primary adrenal insufficiency in the critical caresetting Waterhouse-Friderichsen syndrome is adrenal fail-ure caused by meningococcemia Patients with HIV/AIDSmay have a spectrum of clinical abnormalities associ-ated with the hypothalamic–pituitary–adrenal (HPA) axis.Although adrenal insufficiency may result from direct inva-sion of the glands by the human immunodeficiency virus,more cases result from opportunistic infections (fungus,cytomegalovirus, tuberculosis).1

DrugsKetoconazole can cause adrenal insufficiency by directlyinhibiting adrenal steroidogenic enzymes Anticonvulsivedrugs such as phenobarbitol and phenytoin may reducethe effectiveness and bioavailability of corticosteroidreplacement therapy by inducing liver enzymes thatare involved in steroid metabolism, leading to adrenalinsufficiency

Secondary Adrenal InsufficiencySecondary adrenal insufficiency has three causes: adrenalsuppression after exogenous glucocorticoid or ACTH ad-ministration, adrenal suppression after the correction ofendogenous glucocorticoid hypersecretion, and abnormal-ities of the hypothalamus or pituitary gland leading toACTH deficiency

Adrenal suppression by exogenous glucocorticoids isthe most common cause of secondary adrenal insuffi-ciency.2Supraphysiologic doses of glucocorticoids suppresscorticotropin-releasing hormone (CRH) production andthe ability of the anterior pituitary gland to produce ACTH.The degree of adrenal suppression depends on three vari-ables: dosage, schedule of administration, and duration

of administration Significant adrenal suppression is rarelyseen with doses of hydrocortisone (or its equivalent) of

<15 mg/m2/day Treatment periods of <14 days, rarely

lead to significant suppression of adrenal function.Secondary adrenal insufficiency can manifest shortly af-ter the cessation of corticosteroid therapy or months later in

a stressful situation such as surgery or injury Full recovery ofthe HPA axis may take up to a year.2Patients with secondaryadrenal insufficiency usually have intact mineralocorti-coid function through the renin–angiotensin–aldosteronesystem, but require stress dose glucocorticoid supplementa-tion when an acute disease develops or a stressful procedure

is performed

Functional HypoadrenalismSevere, acute stress leads to a strong activation of theHPA axis Major stress can increase glucocorticoid pro-duction by 5- to 10-fold.2An insufficient response of the

TABLE 14.2

SIGNS AND SYMPTOMS OF ADRENAL

INSUFFICIENCY IN PEDIATRIC PATIENTS

Symptoms

Findings on ClinicalExamination

Generalized weakness and

fatigue

Increased pigmentation

Anorexia, vomiting, nausea Hypotension (postural)

±Weight loss Tachycardia

Abdominal pain Fever

Myalgia or arthralgia Decreased body hair

Postural dizziness Vitiligo

Craving for salt Features of hypopituitarism

Memory impairment Intolerance of cold

Hemodynamic instability Hyponatremia

Hyperdynamic (common) Hyperkalemia

Hypodynamic (rare) Hypoglycemia

Ongoing inflammation with no

obvious source

Eosinophilia

Multiorgan dysfunction Elevated thyrotropin levels

Hypoglycemia

Poor linear growth

HPA axis in critical illness has been termed functional

hy-poadrenalism (also called adrenocortical dysfunction, transient

hypoadrenalism, or adrenal hyporesponsiveness) During severe

illness, many factors can impair the normal corticosteroid

response.3

It is difficult to assess the adequacy of glucocorticoid

secretion in critically ill adults and children; normal

physiologic responses will vary on the basis of stimulus

and insult There is no agreement on the definition

of an ‘‘insufficient’’ cortisol level during critical illness

Elevated plasma cortisol levels can be detrimental as

well, contributing to the hyperglycemia, leukocytosis,

immune suppression, and hypermetabolism seen in critical

illness Recent studies have focused on functional adrenal

insufficiency in critically ill adults and neonates The

reported incidence varies with the criteria used to define

the condition Although there is lack of data of functional

adrenal insufficiency in children, there is a belief that

adrenal dysfunction is as common in children as it is in

critically ill adults Pediatric studies with limited numbers

of subjects report an incidence close to that observed in

adults, 52% in patients with septic shock4 and 31% in

critically ill pediatric patients.5In a recent prospective study

in pediatric patients with septic shock, relative adrenal

insufficiency ranged from 9% to 44% depending on the

criteria used to classify adrenal function.6

Clinically, the signs and symptoms of adrenal

insuffi-ciency are nonspecific; therefore, all patients with sudden

unexplained deterioration should be screened for adrenal

insufficiency Patients with coagulopathy, thromboembolicdisease, chronic or recent glucocorticoid usage, hypona-tremia, hyperkalemia, hypoglycemia, traumatic shock, andsepsis are more likely to have adrenal insufficiency (seeTable 14.2)

DIAGNOSIS

The controversy about ‘‘relative’’ functional adrenal axisfailure in acute stress conditions such as sepsis focuses ondiagnosis There is no consensus definition of corticosteroidinsufficiency in critically ill adults, newborns, or children,and common diagnostic approaches are lacking.7Several

of the more common methods are discussed subsequently.Random Cortisol Levels

The highest levels of cortisol are found in patients withthe severest of illness; however, both low and high cortisollevels are associated with increased mortality in critically illadults.8 Presumably, low cortisol levels indicate adrenalinsufficiency, whereas high levels are associated withincreased severity of illness and adequate stress responses;this is consistent with limited pediatric data.9 Proposed

‘‘normal’’ levels of cortisol in adult critical illness have

ranged from 10 to 34 µg per dL Unfortunately, no

absolute serum cortisol level exists that distinguishes anadequate from an insufficient adrenal response.1 Several

studies have identified <15 µg per dL as the threshold that

best identifies the patient with clinical features of adrenalinsufficiency or who would benefit from steroids.3Baseline

random cortisol levels of <25 µg per dL were shown to

be a better discriminator of adrenal insufficiency whencompared to the standard or low-dose ACTH stimulationtest (see subsequent text) in patients with septic shock.10

On the basis of hemodynamic response to corticosteroids,

adult studies have used a ‘‘random’’ cortisol of 25 µg per dL

for the diagnosis of an adequate adrenal response to criticalillness In patients with vasopressor-dependent conditionstreated with corticosteroids, a baseline serum cortisol of

20 µg per dL has been used to define steroid-responsive patients and 49 µg per dL to define nonresponders.11 Incatecholamine-resistant septic shock, adrenal insufficiency

is assumed at random total cortisol concentrations≤18 µg

per dL An increase in serum cortisol of≤9 µg per dL, 30

or 60 minutes post-ACTH, also supports the diagnosis.12

There are no strict definitions of adrenal ‘‘sufficiency’’ forcritically ill children Children with adrenal insufficiency,defined as low serum cortisol concentrations after an ACTHstimulation test, required higher doses of vasopressors for

a longer period than those with a normal HPA, but therewas no difference in mortality.4 An important problem

in interpreting cortisol levels is that >90% of cortisol

measured in the serum is protein bound (80% to binding protein and 10% to albumin), whereas only 10%

cortisol-is in the free biologically active form During acute illness,

there is a decrease in the corticosteroid-binding globulins

and alterations in the concentrations of cortisol-binding

protein, and this would be expected to affect the utility

of the total plasma cortisol levels Consistent with this

data, baseline and ACTH-stimulated total serum cortisol

concentrations were lower in critically ill patients with

hypoproteinemia compared to those with higher albumin

concentrations, and the response to ACTH correlated better

with free cortisol changes than with the changes of the

total cortisol levels.13 Although the total plasma cortisol

response to an ACTH challenge was low in some patients,

the response of free bioactive cortisol was appropriate,

suggesting that the HPA axis feedback was intact This

study indicates that initiating steroid replacement on the

basis of absolute total cortisol levels may be in error most

of the time Currently, free plasma cortisol measurements

are not widely available for clinical use

Cortrosyn (Adrenocorticotropic Hormone)

Stimulation Test

The best single test for the evaluation and diagnosis of

primary adrenal insufficiency is the response to a challenge

with synthetic ACTH 1 to 24 (250 µg of Cortrosyn)

ad-ministered as a single intravenous bolus Cortisol levels

are measured at baseline, 30 and 60 minutes after

ACTH stimulation Normally, the plasma cortisol response

should be >20 µg per dL This test has clear limitations

with hypoadrenalism This test remains controversial in

detecting functional adrenal insufficiency in critical illness

because the ‘‘appropriate’’ response to ACTH stimulation

has not been defined Circulating ACTH concentrations

during stress are in the range of 20 to 200 pg per mL, but

levels reached after the administration of a 250 µg dose of

Cortrosyn can be as high as 60,000 pg per mL Therefore,

a low-dose 1-µg Cortrosyn test has also been used which

better approximates ACTH levels found in severe stress,

with the suggestion that it might be more sensitive than the

250 µg test to assess adrenal competency.14

Recent pediatric recommendations define adrenal

insuf-ficiency in the face of catecholamine-resistant septic shock

as a random total cortisol concentration <18 µg per dL

or a post-ACTH increase in cortisol ≤9 µg per dL.6,12 It

is possible that the HPA axis (secondary adrenal

insuf-ficiency) may not be as serious a problem as primary

adrenal insufficiency in children In a recent

prospec-tive study in 57 pediatric patients with septic shock,

relative adrenal insufficiency was observed in 26% of

chil-dren; of this, 80% had catecholamine resistance and 20%

had dopamine/dobutamine-responsive shock.6 Although

children with adrenal insufficiency had increased risk of

catecholamine-resistant shock, this was not associated with

higher mortality In a smaller study, pediatric patients with

septic shock likely had secondary adrenal insufficiency

with baseline cortisol level <7 µg per dL and low–normal

ACTH levels Cortisol levels increased after ACTH tion and all patients survived.5Hatherill et al found thatthere was no difference in the mortality rates, or changes

stimula-in the peak cortisol stimula-in response to ACTH stimulation stimula-incritically ill children with adrenal insufficiency and in thosewith normal adrenal function.4In the few pediatric studiespublished, none have demonstrated that responsiveness tocortrosyn or hydrocortisone replacement positively affectedmortality

TreatmentThe overall significance of relative adrenal insufficiency inchildren is still unclear Although glucocorticoid replace-ment will effectively treat patients with known or acquiredabsolute adrenal insufficiency, supplementation in patientswith relative insufficiency or impaired-adrenergic receptorsmay also be beneficial This positive effect is postulated

to be a consequence of enhanced antiinflammatory tivity, inhibition of deleterious proinflammatory activity,and/or diminution of nitric oxide-induced vasodilatationand hypotension Although acute adrenal insufficiency is anemergency and immediate replacement of glucocorticoids,and fluids are essential, treatment of critical illness with glu-cocorticoids can potentially aggravate muscle wasting, andlead to immune suppression and metabolic derangements.The ‘‘Surviving Sepsis Campaign’’ recommends treatmentwith ‘‘low dose’’ hydrocortisone (adult dose: 200 to 300 mgper day for 7 days) in adults with inotrope-dependentshock.12

ac-Recent pediatric recommendations for pediatric sepsisare that hydrocortisone therapy should be reserved forchildren with catecholamine-resistant hypotension and

as well as suspected or proven adrenal insufficiency.12High-risk patients include those with severe septic shockand purpura, those who have previously received steroids,and children with pituitary or adrenal abnormalities Doserecommendations for hydrocortisone vary from 1 to 2 mgper kg for stress coverage (based on a clinical diagnosis ofadrenal insufficiency) to 50 to 100 mg/m2/day for empiricaltherapy for shock followed by the same dose given as a 24-hour infusion Two randomized controlled trials used veryhigh doses of hydrocortisone (25 times higher than thestress dose) in children with dengue fever and shock, andhad conflicting results.12

REFERENCES

1 Zaloga GP, Marik P Endocrine and metabolic dysfunction

syndromes in the critically ill Crit Care Clin 2001;17:1–20.

2 Loriaux DL Adrenocortical insufficiency In: Becker KL, ed.

Principles and practice of endocrinology and metabolism 3rd ed.

Philadelphia, PA: Lippincott Williams &Wilkins; 2001:739–742.

3 Cooper MS, Stewart PM Current concepts: Corticosteroid

insuffi-ciency in acutely ill patients N Engl J Med 2003;348:727–734.

4 Hatherill M, Tibby SM, Hilliard T, et al Adrenal insufficiency in

septic shock Arch Dis Child 199;80:51–55.

5 Menon K, Clarson C Adrenal function in pediatric critical illness.

Pediatr Crit Care Med 2002;3:112–1166; Annane D Time for a

consensus definition of corticosteroid insufficiency in critically ill

patients Crit Care Med 2003;31:1868.

6 Pizarro CF, Troster EJ, Daiani D, et al Absolute and relative

adrenal insufficiency in children with septic shock Crit Care Med.

2005;33:855–859.

7 Annane D Time for a consensus definition of corticosteroid

insufficiency in critically ill patients Crit Care Med 2003;31:1868.

8 Annane D, Sebile V, Troche G, et al A three-level prognostic

classification in septic shock based on cortisol levels and cortisol

response to corticotrophin JAMA 2000;283(2):10448.

9 De Kleijn ED, Joosten KFM, Van Rijn B, et al Low serum cortisol

in combination with high adrenocorticotrophic hormone

concen-trations are associated with poor outcome in children with severe

meningococcal disease Pediatr Infect Dis J 2002;21:330–336.

10 Marik PE, Zaloga GP Adrenal insufficiency during septic shock.

Crit Care Med 2003;31:141–145.

11 Rivers EP, Gaspari M, Abi Saad H, et al Adrenal insufficiency in

high-risk surgical ICU patients Chest 2001;119:889–896.

12 Dellinger RP, Carlet JM, Masur H, et al Surviving Sepsis Campaign

guidelines for management of severe sepsis and septic shock Crit

Care Med 2004;32:858–873.

13 Hamrahian AH, Oseni TS, Arafah BM Measurements of serum

free cortisol in critically ill patients N Engl J Med 2004;350:

1629–1638.

14 Richards ML, Caplan RH, Wickus GC, et al The rapid low-dose (1 microgram) cosyntropin test in the immediate postoperative period: Results in elderly subjects after major abdominal surgery.

Surgery 1999;125:431–440.

Disorders of

Micronutrients

Angela A Hsu Cynthia L Gibson

Electrolyte disturbances are very common in critically ill

children Early recognition and proper therapy for these

disorders are vital This chapter focuses on the etiologies,

clinical manifestations, and therapies for these disorders,

because the pathophysiology of these disorders has been

discussed elsewhere (see Chapter 2 and Chapter 13) The

micronutrients that are discussed in this chapter include

sodium, potassium, calcium, phosphorus, and magnesium

SODIUM

Serum sodium concentration is closely linked to water

homeostasis and a disruption of this balance manifests as

either hyponatremia or hypernatremia

Hyponatremia

Etiologies

Hyponatremia is defined as a serum Na+ of <135 mEq

per L with severe hyponatremia characterized by a serum

Na+<125 mEq per L The etiologies of hyponatremia are

extensive; however, they can be categorized on the basis of

serum osmolality and urine Na+concentration A

diagnos-tic algorithm for hyponatremia is shown in Figure 15.1

Pseudohyponatremia occurs if a plasma substance draws

water into the vascular space owing to the oncotic or

osmolar forces This can be caused by hyperlipidemia,

hyperproteinemia, hyperglycemia, or mannitol use

Hyponatremia may be classified into three categories on

the basis of the total body water balance—hypovolemic,

euvolemic, or hypervolemic Hyponatremic dehydration

can be caused by either extrarenal or renal losses (see

Fig 15.1)

Hypervolemic hyponatremia occurs from acute or

chronic renal failure and edematous states such as those

listed in Figure 15.1 There is an effective circulatory volumedepletion and low urine Na+(<25 mEq per L).

With euvolemic hyponatremia, the serum osmolality is

low, the urine osmolality is usually >100 mOsm per L, and

the urine Na+is usually >25 mEq per L After exclusion of

hypothyroidism and glucocorticoid deficiency, the der fit into the category of secretion of antidiuretic hormone(SIADH) SIADH is one of the most common causes of hy-ponatremia and frequently leads to severe hyponatremia.Table 15.1 lists some common causes of SIADH

remain-Clinical ManifestationsSymptoms of hyponatremia vary greatly from mild(headache, nausea, vomiting, lethargy, weakness, and dizzi-ness), to moderate (behavioral changes with agitation,mild confusion or psychosis, and encephalopathy), to se-vere (seizures, respiratory arrest, decorticate posturing, andcoma) Symptoms may present acutely or be progressive.Laboratory Data

Useful laboratory values in the evaluation of hyponatremiainclude BUN/Cr, serum Na+, K+, osmolality, glucose, urine

Na+, urine osmolality, and occasionally serum triglycerideand total protein levels

ManagementSymptomatic hyponatremia is a medical emergency Treat-ment regimens should be instituted to restore serum Na+

to 120 mEq per L or until symptoms are alleviated Finalcorrection to the normal range can then occur over the next

24 to 48 hours Hypertonic saline solutions (including 3%and 11.5%) have been used to immediately treat severe hy-ponatremia Infusion of these solutions would be adjusted

to raise the Na+level by 1 mEq/L/hour The amount of Na+necessary to achieve a desired Na+level can be calculated

Serum sodium <135 mEq per L

No

Euvolemic states

Urine Na >25 mEq per L:

SIADH Renal insufficiency Adrenal insufficiency Hypothyroidism Reset osmostat Drugs

Urine Na <25 mEq per L:

Repeat algorithm

>280 mOsm per kg:

Hyperglycemia Mannitol Pseudohyponatremia

<100 mOsm per kg:

Psychogenic polydipsia Water intoxication Reset osmostat

Yes Hypovolemic states Extrarenal losses (urine Na <25 mEq per L):

Renal losses (urine Na >25 mEq per L):

Gl—vomiting, diarrhea, draining tubes Skin—burns, cystic fibrosis, sweat, heat stroke Third space—pancreatitis, muscle trauma, effusions, peritonitis, ascites Salt-losing nephritis

Cerebral salt wasting Diuretic use/osmotic diuresis Mineralcorticoid deficiency Bicarbonaturia—RTA, metabolic alkalosis Pseudohypoaldosteronism

Hypervolemic states (urine Na <25 mEq per L) Nephrosis

Cirrhosis Congestive heart failure Renal failure

hormone; GI, gastrointestinal; RTA, renal tubular acidosis (Adapted from Adrogue H Primary care:

Hypernatremia N Engl J Med 2000;342(20):1493–1499; Fouser L Disorders of calcium, phosphorus, and magnesium Pediatr Ann 1995;24(1):38–46; Sperling M Pediatric endocrinology Philadelphia, PA: WB Saunders; 2002.)

by the formula:

mEq Na+required= Desired Na+(mEq/L)− Present Na+

× 0.6 × Weight (kg)

As a guide, approximately 1 mL/kg/hour of 3% saline will

normally raise the serum Na+by 1 mEq/L/hour

Brain damage as a result of cerebral demyelination can

develop if there is an excessive change in Na+levels Central

pontine myelinolysis is a rare complication of the treatment

of hyponatremia Patients may be asymptomatic or develop

symptoms of confusion, quadriplegia, pseudobulbar palsy,

and pseudocoma These symptoms may present one to

several days after the correction of hyponatremia The rate

of correction may have no relationship to the development

of these demyelinating lesions, but rather the magnitude of

the correction and the underlying diagnosis are the major

contributing factors

Mild hyponatremia with few or no symptoms can

be treated in a conservative manner with isotonic saline

to maintain the extracellular volume If SIADH or anedematous state is present, a trial of water restriction isindicated If the Na+is unresponsive to water restriction,treatment with demeclocycline could be used to inhibitantidiuretic hormone (ADH) All medications known tocause SIADH should be discontinued, as well as treatment

of any underlying conditions

HypernatremiaEtiologiesHypernatremia represents a deficit of water in relation tothe body’s Na+stores and can result from a net water loss orhypertonic Na+gain Hypernatremia is usually multifacto-rial and a thorough history evaluating for gastrointestinal(GI) water losses, dermal water losses, medication his-tory, sources of exogenous sodium intake, and decreasedfluid intake may be helpful in the diagnosis Table 15.2lists the causes of hypernatremia As in hyponatremia,children may be hypovolemic, euvolemic, or hypervolemic

TABLE 15.1

CAUSES OF SYNDROME OF INAPPROPRIATE

SECRETION OF ANTIDIURETIC HORMONE

Bronchogenic carcinoma Vincristine

Thymoma Carbamazepine

ALL Cyclophosphamide (IV)

Lymphoma SSRI antidepressants

Neuroblastoma Opiates

Duodenal or pancreatic

adenocarcinoma

NSAIDS

Central Nervous System

Infection: meningitis, encephalitis

ALL, acute lymphoblastic leukemia; SSRI, selective serotonin reuptake

inhibitors; NSAIDS, nonsteroidal anti-inflammatory drugs; IV,

intra-venous.

Hypovolemia (hypernatremic dehydration) and a low

urine Na+(<20 mEq per L) implies extrarenal water losses,

whereas a high urine Na+ (>20 mEq per L) implies renal

water losses Children with euvolemia have variable urine

Na+ levels, whereas those with hypervolemia normally

have increased urine Na+(as well as increased total body

Na+in relation to total body water)

Clinical Manifestations

Children are often agitated and may manifest signs of

hy-perpnea, muscle weakness, lethargy, seizures, and coma

In-fants may exhibit a high-pitched cry, but older children will

normally exhibit increased thirst as a primary symptom

Laboratory Data

As in hyponatremia, blood urea nitrogen (BUN), creatinine

(Cr), serum Na+, glucose, osmolality, urine Na+, and urine

osmolality must be measured

Management

Treating the underlying condition, as well as correcting

the serum Na+and circulatory volume is vital Circulatory

collapse should be treated first with normal saline, with

subsequent correction of the Na+abnormality The serum

Na+ should be reduced by 1 mEq/L/hour to a goal of

145 mEq per L More rapid corrections of hypernatremia

can lead to complications, including cerebral cell swelling,

edema, and herniation in extreme cases However, if

hypernatremia has developed over a period of several

hours, rapid correction improves the prognosis without

TABLE 15.2

CAUSES OF HYPERNATREMIA

Central diabetes insipidus Nephrogenic diabetes insipidus

Diuretics Tubulopathy, renal dysplasia Hyperglycemia

Neurologic impairment Hypothalamic disorder Restricted access to fluids Fluid restriction

Ineffective breastfeeding

Fever Exercise Burns Respiratory illness Excessive sweating

Hypertonic sodium chloride Sodium bicarbonate administration Blood products Sodium ingestion

↑ solute feed from improper formula mixing

Gastrointestinal Water Loss

Gastroenteritis, vomiting Osmotic diarrhea Colostomy/ileostomy Malabsorption

↑, increased.

increasing the risk of cerebral edema Judicious use ofhypotonic fluids will provide adequate free water to correctthe sodium level A simple method of determining theminimum amount of fluid necessary is by calculating thefree water deficit:

Free water deficit= 4 mL × Body weight (kg)

× Desired change in serum Na+The calculated deficit does not account for insensible losses

or those that are ongoing Therefore, fluids required formaintenance should be continued The rate of correctiondepends on the severity of symptoms In severe hyper-

natremia (>170 mEq per L), serum Na+ should not becorrected to below 150 mEq per L in the first 48 hours Incases of excessive Na+ intake, diuretics may be useful tofacilitate Na+ excretion

POTASSIUM

Potassium plays an important role in a variety of cellularfunctions Disturbances, if untreated, can be associatedwith high mortality and morbidity

HypokalemiaEtiologiesHypokalemia is defined as a serum K+<3.5 mEq per L with

severe hypokalemia being <2.5 mEq per L Hypokalemia

can result from increased loss, transcellular shift, or

de-creased intake Potassium is excreted through either the

GI tract (diarrhea) or the kidney Excessive renal losses

of K+ occur with diuretic use, and direct tubule damage

by chronic interstitial nephritis, pyelonephritis, or

nephro-toxic medications The distal tubule may be a site for K+loss

because of excess mineralocorticoid, increased Na+delivery

to the distal tubule because of proximal renal tubular

acido-sis (RTA), Fanconi syndrome, diuretics, or hypercalcemia

Increased sweat loss and magnesium depletion can cause

hypokalemia Transcellular shifts of K+from metabolic

al-kalosis, medications (particularly, β2 sympathomimetics,

insulin, and phosphodiesterase inhibitors), and from

syn-dromes (such as familial hypokalemic periodic paralysis)

can cause decreased serum K+concentrations

Clinical Manifestations

Mild hypokalemia is usually asymptomatic, although

non-specific changes in electrocardiograms (EKGs) can be

observed The manifestations of severe K+ depletion are

skeletal muscle weakness with hyporeflexia (ultimately

cul-minating in rhabdomyolysis), smooth muscle dysfunction,

and disorders of GI motility Lethargy, confusion, and

car-diac dysrhythmias (see Table 15.3 for EKG findings) are

common manifestations of severe hypokalemia, and

chil-dren with an underlying heart disease are at increased risk

for the cardiovascular effects

Laboratory Data

In addition to an EKG, other lab values to be obtained in

the evaluation of hypokalemia include arterial blood gas

Hypokalemia A prominent U wave with a flattened T

wave Hyperkalemia

Hypocalcemia

Hypercalcemia

Prolonged QT interval Shortened QT interval Hypomagnesemia Ventricular arrhythmias (i.e., torsades

de pointes) Moderate Widening QRS complex with peaked T

waves Severe Prolonged PR interval, progressive

widening of the QRS complex, diminution of T wave

(ABG), serum electrolytes with BUN, Cr, glucose, and urineelectrolytes

ManagementAny concurrent conditions or medications that may result

in K+ shift should be treated and disorders of acid/basehomeostasis should be addressed K+ replacement can

be accomplished through oral or intravenous dosing Theacute K+deficit can be calculated by the following formula:

K+deficit= [ICF K+]× 40% of total fluid deficitCare must obviously be taken when infusing K+ intra-venously because rapid infusion can cause dysrhythmias

or asystole, and extravasation of K+ can cause severe localinjury

HyperkalemiaEtiologiesMild to moderate hyperkalemia is defined as a serum K+

level between 6 to 7 mEq per L Levels >7 mmol per L are

considered severe hyperkalemia Artifactual hyperkalemiacan be caused by tight tourniquets or squeezing at thesite of blood collection, hemolysis, thrombocytosis, orleukocytosis of the blood sample True hyperkalemia iscaused by increased K+ intake, abnormal distribution, ordecreased renal output Increased intake can be iatrogenicowing to K+ salts of medications or increased K+ content

of red cell products reaching their time of expiration.Abnormal distribution occurs with metabolic acidosis,tissue catabolism, hyperosmolarity due to hypernatremia

or hyperglycemia, decreased insulin, and drug side effects

(i.e., digitalis, β-blockers, or succinylcholine) Decreased

renal output occurs with renal failure, hypoaldosteronism,

or K+-sparing diuretics

Clinical ManifestationsMild hyperkalemia is often asymptomatic Severe hyper-kalemia may present with generalized weakness, paralysis,paresthesias, and cardiac arrhythmias and represents amedical emergency Typical EKG findings are listed inTable 15.3

Laboratory DataSerum electrolytes with BUN/Cr should be obtained, aswell as an ABG, EKG, and urine electrolytes

ManagementSevere hyperkalemia with EKG changes should be treatedemergently with intravenous (IV) calcium gluconate(100 mg/kg/dose), glucose (2 mL per kg of D25 W), andinsulin (0.1 U per kg) The EKG should be continuouslymonitored Sodium bicarbonate can be beneficial even inthe absence of acidosis Diuretics may be helpful to increasethe K+excretion These therapies may only be transient in

the presence of renal failure, and in such cases,

hemodial-ysis should be instituted In mild hyperkalemia, sodium

polystyrene resin (kayexelate) may be effective to increase

excretion

CALCIUM

Calcium exists in the serum in three forms: bound to

pro-tein (40% to 45%), complexed to inorganic anions (5%

to 10%), and ionized (40% to 50%) The ionized fraction

is the physiologically active form Normal Ca2+levels vary

with age in the pediatric population Normal neonatal

val-ues are between 9 to 10 mg per dL This remains the average

serum Ca2+concentration until approximately 18 months

of life Serum Ca2+ levels between 8.5 to 10.5 mg per dL

are considered to be normal in children and adolescents

Hypocalcemia

Etiologies

Hypocalcemia is defined as a serum Ca2+level <8.5 mg per

dL in older children and <8.0 mg per dL in neonates The

to-tal protein or albumin level is necessary to interpret the toto-tal

Ca2+ level because of the considerable amount of serum

Ca2+ that is protein bound In recent years, accurate and

immediate ionized calcium determination has improved

Therefore, ionized calcium concentrations <1.0 mg per

dL can also be used to define hypocalcemia The causes

of hypocalcemia vary with age Common etiologies in

neonates include birth asphyxia, prematurity, toxemia in

pregnancy, infants of diabetic mothers, intrauterine growth

restriction, maternal hyperparathyroidism, and DiGeorge

syndrome with congenital heart diseases Other

etiolo-gies in childhood include hypoparathyroidism (primary

or secondary), vitamin D deficiency, hyperphosphatemia,

malabsorption states/malnutrition, pancreatitis,

hypomag-nesemia, and medications (i.e., anticonvulsants)

Hypocal-cemia is common after cardiac surgery because of induced

hypocalcemia during preischemic cooling by using a Ca2+

free crystalloid priming solution and citrate in the pump

prime This has been found to provide myocardial

preser-vation and reduce ischemic injury during the cooling phase

of cardiopulmonary bypass

Clinical Manifestations

Symptoms of hypocalcemia include tetany and its

associ-ated symptoms such as neuromuscular irritability,

weak-ness, fatigue, paresthesias, cramping, altered mental status,

seizures, laryngospasm, and cardiac arrhythmias Infants

with hypocalcemia may also demonstrate vomiting due to

pylorospasm, wheezing from bronchospasm, and

inspira-tory stridor from laryngospasm Many infants may also be

asymptomatic Trousseau and Chvostek signs are clinical

signs of hypocalcemia EKG changes are listed in Table 15.3

Laboratory DataInitial evaluation of suspected hypocalcemia in a childshould include a serum total and ionized Ca2+, phosphate,magnesium, alkaline phosphatase, 25-OH vitamin D, totalprotein, pH, BUN, Cr, parathyroid hormone (PTH), and anEKG The albumin level should also be obtained because adecrease in serum albumin of 1.0 g per dL decreases serum

Ca2+ by 0.8 mg per dL Other tests to be obtained in theevaluation of hypocalcemia include urinary Ca2+, phos-phate, Cr, and radiographic tests to evaluate for evidence

of rickets, the presence of a thymic shadow, and bone age.Management

Treatment of hypocalcemia is best accomplished by ing the underlying cause or disease However, in acutesymptomatic patients, Ca2+ supplementation is best ac-complished with IV forms of Ca2+ such as calcium glu-conate, calcium chloride (CaCl2), or calcium gluceptate.CaCl is three times as potent as calcium gluconate, and

treat-it should be infused through a central venous catheter toprevent tissue necrosis owing to extravasation Oral Ca2+supplements may be used in less acute situations Refractoryhypocalcemia may also be due to hypomagnesemia and

so magnesium supplementation may be required beforehypocalcemia can be corrected

HypercalcemiaEtiologiesHypercalcemia is defined as a serum Ca2+level >10.5 mg

per dL or an elevated ionized Ca2+ Hypercalcemia occursrarely in children owing to the relatively low incidence ofhyperparathyroidism and various malignancies common

to adults (i.e., lung, breast, kidney, myeloma, etc.) calcemia in children with malignancies is usually a result

Hyper-of direct bony invasion, tumor metastasis, and tumor lysis.Other etiologies of hypercalcemia vary widely on the basis

of the child’s age and the differential diagnosis is listed inTable 15.4 Hypophosphatemia is associated with hypercal-cemia as elevated levels of the PTH leads to decreased phos-phate absorption Hypercalcemia is also seen in Williamsyndrome as a result of increased sensitivity to vitamin D.Clinical Manifestations

Common symptoms of hypercalcemia include weakness,respiratory distress/apnea, headache, irritability, seizures,lethargy, abdominal pain, anorexia, nausea, vomiting, con-stipation, and bone pain Other findings associated withhypercalcemia include polydipsia, polyuria, renal calculi,pancreatitis, abnormal deep tendon reflexes, and hyperten-sion A shortened QT interval is seen on EKG (Table 15.3).Dysmorphisms and hypercalcemia, such as elflike faciesand hypertelorism, can be suggestive of William syndrome.Laboratory Data

Initial laboratory evaluation of hypercalcemia shouldinclude serum total and ionized Ca2+, phosphate, albumin,

FHH, familial hypocalciuric hypercalcemia; MEN, multiple endocrine

neoplasia; TPN, triphosphopyridine nucleotide.

total protein, PTH, BUN, Cr, alkaline phosphatase, vitamin

D levels, and an EKG Additional laboratory tests may

include thyroid function tests, complete blood count (CBC)

with differential, urinary Ca2+, phosphate and Cr levels,

and radiography to evaluate for metastatic bone lesions

and possible renal calculi as clinically indicated Maternal

Ca2+ and PTH levels may prove helpful in neonates with

hypercalcemia

Management

The treatment of hypercalcemia is based on an

under-standing of the etiology and its mechanism of action In

malignancy-associated hypercalcemia, which results from

enhanced intestinal absorption, oral phosphorous therapy

can be effective Vitamin D intoxication or sarcoidosis can

be treated with glucocorticoids, which suppress calcitriol

effects and inhibit lymphokine secretions Steroids may

also be useful in the setting of malignancy to decrease

vita-min D and Ca2+absorption However, irrespective of the

underlying cause, (i) discontinuing or restricting further

Ca2+ intake, (ii) correcting dehydration with saline

infu-sion followed by furosemide, (iii) avoiding medications

or supplements that will increase the serum Ca2+

con-centration such as vitamin D, Ca2+ containing antacids,

and thiazide diuretics, and (iv) administering phosphate

can lead to decreases in serum Ca2+ Severe or persistent

hypercalcemia can be treated with calcitonin or

bisphos-phonate It is important to note that correcting dehydration

in the setting of hypercalcemia is crucial The use of

diuret-ics before rehydration can cause volume contraction and

subsequently increase serum Ca2+ Normal saline is the

replacement fluid of choice because Na+ blocks tubular

Ca2+reabsorption and enhances its excretion

Accelerated bone resorption is an important factor in thepathogenesis of hypercalcemia in most patients with acutehypercalcemia Bisphosphonates such as pamidronate isthe treatment of choice for the inhibition of boneresorption Other treatment modalities for hypercalcemia

in extreme cases include dialysis and parathyroidectomy

HypophosphatemiaEtiologies

Causes of hypophosphatemia include starvation, trition, malabsorption syndromes, increased renal losses,vitamin D deficiency and vitamin D-resistant rickets, in-tracellular shifts associated with respiratory or metabolicalkalosis, treatment of diabetic ketoacidosis (DKA), andthe administration of corticosteroids Hypophosphatemiaalso occurs commonly in the very low birth weight (VLBW)neonates because their demands are usually greater thantheir intake

malnu-Clinical ManifestationsSigns and symptoms of hypophosphatemia are only

evident at very low levels (<1.0 mg per dL) At these

levels, irritability, paresthesias, confusion, seizures, apnea

in VLBW infants, and coma may be seen Rare cases ofcardiomyopathy have been reported However, it is unclear

if these symptoms are caused by the electrolyte disturbance

or by the illness associated with hypophosphatemia.Laboratory Data

The evaluation of hypophosphatemia should includeserum phosphate, total and ionized Ca2+, Na+, K+, magne-sium, BUN, Cr, vitamin D, and PTH levels Urinary studiessuch as urine Ca2+, phosphate, Cr, and pH may provehelpful

ManagementAcute symptomatic hypophosphatemia should be treatedwith potassium phosphate or sodium phosphate as a slowinfusion over 6 hours Caution must be exercised in theadministration of these solutions because an increase inserum K+or Na+can be anticipated

HyperphosphatemiaEtiologies

Hyperphosphatemia is relatively rare Common etiologiesinclude hypoparathyroidism, renal insufficiency with a

reduction of glomerular filtration rate (GFR) of <25%,

excessive intake/iatrogenic administration, and use of

cytotoxic drugs to treat malignancies resulting in tumor

lysis syndrome

Clinical Manifestations

Signs and symptoms of hyperphosphatemia are generally

the result of hypocalcemia caused by the effects of the

PTH As such, clinical symptoms include tetany and

neuro-muscular sequelae, altered mental status and seizures, and

cardiac manifestations such as dysrhythmias and prolonged

QT interval can be observed (Table 15.3)

Laboratory Data

Similar to children with hypocalcemia, laboratory analysis

should begin with BUN, Cr, and serum phosphate, total and

ionized Ca2+levels Vitamin D, PTH levels, and ABG may

also be helpful In cases of tumor lysis syndrome, a CBC

should also be obtained along with urinary studies such as

urinalysis and urine phosphate, calcium, and Cr levels

Management

Treatment of hyperphosphatemia includes: (i) restricting

further dietary phosphate intake, (ii) giving phosphate

binders such as calcium carbonate and aluminum

hydrox-ide (must be used with caution in patients with renal

failure), (iii) hydrating with normal saline and IV mannitol

in tumor lysis syndrome, and (iv) instituting dialysis if

patient has poor renal function and hyperphosphatemia is

refractory to above measures

MAGNESIUM

Magnesium plays a critical role in metabolic processes and

its deficiency is often associated with multiple biochemical

abnormalities Hypermagnesemia is much less common

Ionized magnesium is the physiologically active form;

however, measurement of the ion is not yet available in

most laboratories and so total magnesium is the monitored

electrolyte

Hypomagnesemia

Etiologies

Magnesium deficiency can occur from decreased intake or

from increased losses (from the GI tract or kidney) GI losses

may occur from intestinal malabsorption including cystic

fibrosis, regional enteritis, ulcerative colitis, small bowel

resection, and familial primary hypomagnesemia Renal

losses are generally a result of diuretic use, RTA, diffuse

tubular disorders, hypercalciuria, and nephrotoxic

medica-tions Other etiologies are DKA, hyperaldosteronism, and

PTH disorders Hypomagnesemia may also develop

dur-ing cardiopulmonary bypass possibly owdur-ing to chelation

by free fatty acids or citrate and enhanced cellular uptake

induced by circulating catecholamines

Clinical ManifestationsLow serum magnesium is manifested by anorexia, nausea,weakness, malaise, depression, and nonspecific psychiatricsymptoms Neurologic signs include clonus, tetany, hyper-reflexia, and positive Chvostek and Trousseau signs It canalso be associated with hypokalemia, hypocalcemia, andmetabolic acidosis, and arrhythmias may present as atrial

or ventricular ectopy or torsades de pointes (Table 15.3).Laboratory Data

Serum electrolytes including total and ionized magnesium(if available), Ca2+, BUN/Cr, glucose, and urine electrolytesshould be obtained

ManagementReplacement of magnesium with intravenous magnesiumsulfate is the therapy for hypomagnesemia Because a widevariety of clinical conditions can cause this electrolyte dis-turbance, an underlying condition should be determinedand corrected promptly

HypermagnesemiaEtiologies

The most common cause of hypermagnesemia is acute

or chronic renal failure As with other electrolyte turbances, excessive administration of magnesium (fromenemas, cathartics, triphosphopyridine nucleotide (TPN),

dis-or in the treatment of preeclampsia/eclampsia) can alsocause this disorder

Clinical ManifestationsIncreased magnesium can cause lethargy, hyporeflexia,confusion, hypotension, respiratory failure, and cardiacdysfunction

Laboratory DataInitial laboratory evaluation should include total magne-sium, ionized magnesium (if available), Ca2+, BUN and Cr.Management

Stopping any supplemental magnesium is vital Diuresisand calcium administration are beneficial in the treatment

of hypermagnesemia Hemodialysis may be necessary inrenal failure or life-threatening cases

CARDIAC EFFECTS OF ELECTROLYTE ABNORMALITIES

Abnormal serum electrolytes can have profound effects

on cardiac conduction These effects can be demonstrated

as mild or dramatic changes on the EKG Fluctuations

in extracellular K+, Ca2+, and Mg2+ levels can changemyocyte membrane potential gradients and alter the cardiac

action potential Characteristic EKG changes may provide

diagnostic clues to these abnormalities Table 15.3 is a

summary of these changes and their associated electrolyte

abnormality

Increases in serum K+can have dramatic effects on the

EKG and cardiac disorders should be suspected when the

amplitude of the T wave is greater than or equal to the R

wave in more than one lead

Calcium affects the duration of the ST segment

Hy-percalcemia shortens the ST segment thereby shortening

the QT interval, and hypocalcemia has the reverse effects

At high Ca2+ concentrations, the duration of the T wave

increases and the QT interval may become normal These

ef-fects may be more pronounced in patients receiving digoxin

therapy

Magnesium regulates several cardiac ion channels,

in-cluding Ca2+channels and outward K+currents Low Mg2+

increases these outward currents, shortening the action

potential and increasing the susceptibility to arrhythmias

RECOMMENDED READINGS

1 Adrogue H Primary care: Hypernatremia N Engl J Med 2000;

342(20):1493–1499.

2 Agus Z Hypomagnesemia J Am Soc Nephrol 1999;10:1616–1622.

3 Avner E Clinical disorders of water metabolism: Hyponatremia

and hypernatremia Pediatr Ann 1995;24(1):23–30.

4 Becker KL Principles and practice of endocrinology and metabolism.

Philadelphia, PA: Lippincott Williams & Wilkins; 2001.

5 Chang A Pediatric cardiac intensive care Philadelphia, PA:

Lippincott Williams & Wilkins; 1998.

6 Fouser L Disorders of calcium, phosphorus, and magnesium.

Pediatr Ann 1995;24(1):38–46.

7 Moritz M Disorders of water metabolism in children:

Hypona-tremia and hypernaHypona-tremia Pediatr Rev 2002;23(11):371–379.

8 Pescovitz OH, Eugster EA Pediatric endocrinology: Mechanisms,

manifestations, and management Philadelphia, PA: Lippincott

Williams & Wilkins; 2004.

9 Rastergar A Hypokalemia and Hyperkalemia Postgrad Med 2001;

Inborn Errors

of Metabolism

Dina J Zand Cynthia J Tifft

Scientific and medical advances have challenged our

ini-tial approach to and understanding of inborn errors of

metabolism (IEM) In 1908, when Sir Archibald Garrod

first suggested the term, he believed that these diagnoses

affected an individual throughout life and were

essen-tially untreatable Although most IEM are still life-long

afflictions, advances in biochemistry, genetics, and

patho-physiology have significantly altered our understanding of

them In general, IEM are disorders affecting the

interme-diary metabolism of protein, glucose, fat, and complex

substrates Some IEM, such as phenylketonuria (PKU), are

treatable with consistent dietary intervention Many, but

not all IEM present during infancy or childhood Our

im-proved diagnostic abilities demonstrate that IEM are more

common than initially believed And, although

consan-guinity often increases the risk for diagnosis of IEM, most

affected families are without known consanguinity

The presenting symptomatology for IEM is often

nonspecific Within the first few weeks of birth, clinical

findings may include lethargy, poor feeding, emesis,

irritability, hypotonia, and seizures However, loss of

developmental skills, encephalopathy, and organ-specific

abnormalities such as cardiomyopathy, hepatomegaly, and

cataracts may present additional clues IEM should be

included in the differential diagnosis with any of these

presentations

A few general concepts are essential in understanding

IEM First, the pathophysiology most commonly results

from a specific defect in metabolism This may be a

dysfunctional enzyme, a cofactor, or a transport protein

Second, this defect results in the accumulation of substrate

and/or the deficiency of metabolic product Either of

these metabolic perturbations may give rise to clinical

symptoms Abnormally elevated levels of substrate may

act as a toxin, affecting normal cellular mechanism

or organ pathophysiology Similarly, decreased levels ofproduct may force the cell to ‘‘overuse’’ other systems tocompensate Secondary affects from toxin buildup can also

be observed For example, elevations of plasma ammoniacan be seen during illness with propionic aciduria (PA) andmethylmalonic aciduria (MMA), although they are organicacidurias and not primary hyperammonemia disorders

In general, the pathophysiology of IEM is caused by aperturbation in normal cellular function, and clues topinpointing the precise abnormality include a thoroughhistory, repetitive clinical examinations, particularly duringacute metabolic crisis, and prompt laboratory evaluation.Above all, clinical suspicion is paramount

early identification of a greater number of presymptomatic

newborns with disorders that would typically present

with metabolic coma and neurologic decompensation A

negative screen, however, does not exclude a diagnosis

of IEM because some disorders, such as nonketotic

hyperglycinemia (NKH) or tyrosinemia remain difficult to

diagnose using this technology Clinical suspicion should

always prevail

ACUTE NEUROLOGIC

DECOMPENSATION

OR METABOLIC COMA

When a child presents with acute decompensation and

encephalopathy, particularly in the newborn period, sepsis

is the most common etiology However, IEM should also

be strongly considered Because metabolic pathways often

converge at common points, the clinical presentations of

different IEM may, in fact, be quite similar Fortunately,

acute management is also similar to the goal of

provid-ing enough calories to reverse catabolism The laboratory

studies listed in Table 16.1 should be considered for any

child with an unexplained acute encephalopathy

Special-ized testing should be anticipated, and may require special

tubes or sample handling (see Table 16.2) Intravenous

flu-ids containing dextrose and electrolytes should be started

immediately while laboratory results are pending

Test-ing performed at the bedside (dextrostick, I-STAT, and/or

urine dipstick) may give quick clues toward changes in

management For example, hypoglycemia should be

ad-dressed immediately, with enough glucose to normalize

levels promptly and provide the calories needed to reverse

catabolism For IEM, this may mean a continuous infusion

of 8 to 10 mg/kg/minute or 10% dextrose at

one-and-a-half-times the maintenance level (see Fig 16.1) During these

interventions, a complete and thorough history may help

elucidate the etiology of the clinical symptoms Specific

in-formation about changes in oral intake, illnesses, decrease

in urine production, unusual odors (see Table 16.3), and

family history inclusive of neonatal deaths and stillbirths

should be elicited A thorough and accurate clinical

exami-nation is essential Any indication of increased intracranial

pressure (pupillary reflexes, papilledema, increased reflexes,

exaggerated startle, or clonus) should be evaluated quickly

If increased dextrose is required in the context of cerebral

edema, a central line should be placed and the dextrose

should be concentrated to limit further cerebral injury from

excess intravenous fluid An insulin drip may be needed to

force dextrose into the cells, to further promote anabolism

Cataracts, cardiac arrhythmia, hepatosplenomegaly, poor

growth, and dysmorphia are all important clues and should

be documented while the patient is being stabilized The

results of initial laboratory studies for urine ketones,

hypo-glycemia, metabolic acidosis or alkalosis, and lactate may

preliminarily place a child into the IEM diagnostic category(see Table 16.4)

With the advent of MS/MS NBS, some patients may

be referred for evaluation on the basis of the report of

an abnormal newborn screen Evaluation of these infantsshould be the same as for a child with an unknownpresentation, with targeting of specialized testing on thebasis of the screening result NBS may also identify childrenwho, although not acutely ill, may have biochemicalevidence of a partial deficiency that under conditions ofmetabolic stress could/would produce clinical symptomsand neurologic compromise Disorders of branched-chainamino acid (BCAA) metabolism, such as maple syrup urinedisease (MSUD), PA, and MMA are some of the mostcommon IEM in the pediatric population (see Fig 16.2) PAand MMA are considered as organic acidurias because theseenzyme deficiencies result in an abundance of organic acidmetabolites found in plasma and urine MSUD is located inthe same pathway, and results in an elevation of the initialsubstrates—leucine, valine, and isoleucine The initialpresentation of all three conditions, as well as isovalericacidemia (IVA) is similar with acidosis, ketone bodyformation, hypoglycemia, and possible encephalopathy.Maple Syrup Urine Disease

The most common cause of this disorder is a decrease

in the branched-chain α-keto dehydrogenase EI activity.

Thiamin (vitamin B1) is an important cofactor, and itsadministration may reduce the symptomatology in somecases The characteristic sweet odor of maple syrup may be

TABLE 16.1

LABORATORY TESTS FOR INBORN ERRORS

OF METABOLISM

Stat Initial Tests

Bilirubin (total and direct) Blood gas

Blood glucose (D-stick and serum) CBC with differential

Creatinine and BUN Liver function tests (ALT and AST) Plasma ammonia

Plasma lactate Serum electrolytes to include calcium, magnesium, and phosphorus

Urine analysis: pH, ketones, glucose, protein, reducing substances

Additional Specialized Testing

Acylcarnitine profile Carnitine level (total and free) Plasma amino acids

Urine organic acids

CBC, complete blood count; BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

TABLE 16.2

SPECIALIZED TESTING FOR INBORN ERRORS OF METABOLISM

PAA 1–3 mL Green (Na heparin) If cannot be processed

immediately, spin down to separate and freeze plasma (not the entire sample) Branched-chain amino

acids

1–3 mL Green (Na heparin) Same as with PAA

Acylcarnitine profile 1–3 mL Green (Na heparin) Same as with PAA Carnitine, total and

free

1–3 mL, on ice Green (Na heparin) Same as with PAA

Biotinidase 1–3 mL Green (Na heparin) Same as with PAA Homocysteine, total

and free

3 mL, on ice Green (Na heparin) Same as with PAA

Lactate/pyruvate 1–2 mL, on ice Grey (K oxalate and

NaCl) or 8%

perchloric acid

Collection container is institution

dependent Very long-chain fatty

acids

3 mL Lavender (EDTA)

Karyotype 1–3 mL Green (Na heparin) DO NOT freeze or

separate Transferrin isoelectric

focusing

5 mL Yellow (acid citrate

dextran) UOA 5–10 mL Urine container If it cannot be

processed immediately, it may

be frozen Urine amino acids 5–10 mL Urine container Same as with UOA

PAA, plasma amino acids; EDTA, ethylenediaminetetraacetic acid; UOA, urine organic acids.

emer-gency treatment algorithm for

indi-viduals with known inborn errors of

metabolism (IEM) with a tendency

toward catabolism and

encephalopa-thy during illness ABG, arterial blood

gas; CBG, capillary blood gas; IVF,

intravenous fluid.

Prompt clinical evaluation

Alert metabolic physician

Immediate IV placement and laboratory studies

Immediately start

Normalize glucose

Re-evaluate

Re-evaluate

Re-evaluate clinical examination and laboratory tests

Consider central line placemnt

ABG or CBG Electrolytes CBC with differential Blood glucose Liver function tests Amylase Lipase Ammonia Urinalysis

Dextrose-containing electrolyte solution Begin at 8–10 mg/kg/min glucose infusion rate

TABLE 16.3

UNUSUAL ODORS IN INBORN ERRORS OF

METABOLISM

Maple syrup urine disease Maple syrup, burned sugar

Isovaleric acidemia Cheesy or sweaty feet

Multiple carboxylase deficiency Cat’s urine

Phenylketonuria Musty

Hypermethioninemia Rancid butter, rotten cabbage

Trimethylaminuria Fishy

appreciated in either urine or cerumen, particularly during

periods of acute illness, and allo-isoleucine detected by

plasma amino acid analysis is diagnostic Elevations of

leucine-induced cerebral edema, and acute treatment with

high dextrose-containing fluids are imperative The leucine

level returns to normal only by its incorporation into

synthesized proteins; therefore, either formula or total

parenteral nutrition (TPN) lacking BCAAs are also essential

for therapy Because valine and isoleucine levels fall more

quickly, supplementation with these amino acids is usually

needed to reduce plasma leucine to keep up with new

protein synthesis Repeat acute metabolic episodes of

encephalopathy, as a result of routine childhood illness

may result in cognitive impairment and dysmyelination

Propionic Aciduria

Deficiency of propionyl-CoA carboxylase, a

biotin-depen-dent enzyme, results in PA The α subunit of the heteromeric

enzyme binds biotin However, as mutations are more

commonly identified in the β subunit, most of the affected

individuals do not respond to biotin supplementation.Elevations of free propionic acid in blood or urine may not

be easily detectable, but organic acid by-products can beidentified in urine (3-hydroxypropionate, methylcitrate,tiglylglycine, and unusual ketone bodies) by plasmaacylcarnitine (propionylcarnitine) analysis Elevations oforganic acids may also be seen in multiple carboxylasedeficiency owing to similar dependence on biotin as acofactor

Treatment begins during the acute metabolic crisis

by arresting catabolism with intravenous dextrose (8 to

10 mg/kg/minute) and lipid (2 g/kg/day) Hypoglycemia,acidosis, vomiting, lethargy, and ketonuria are common ini-tial features A secondary effect of hyperammonemia owing

to the toxin-mediated effects upon the urea cycle may be nificant enough to warrant consideration of hemodialysis.Parenteral administration of a formula that is deficient

sig-in the offendsig-ing BCAAs is preferable once vomitsig-ing has solved and the encephalopathy has improved A secondarycarnitine deficiency is common, and supplementation withl-carnitine (50 to 100 mg/kg/day) may aid in the removal

re-of excess propionic acid and prevent the cardiomyopathycaused by carnitine depletion Once the acidosis and urineketones have resolved, the child should be maintained on

a diet that is low in natural protein (0.5 to 1.5 g/kg/day)and a formula that is deficient in BCCAs to provide theremaining recommended daily protein allowance for thatage Because gut flora may contribute significantly to propi-onic acid production, some children have derived clinicalbenefit from metronidazole (10 mg/kg/day for 1 week twiceper month) to decrease fecal propionate production.Methylmalonic Aciduria

MMA is most often caused by mutations in the ylmalonyl-CoA mutase gene Vitamin B12, or cobalamin,

Urea Cycle

Production)

Fatty AcidOxidation

EnergyMetabolism

CarbohydrateUtilization

Example

diagnosis

MSUD PA OTC deficiency MCAD deficiency PDH deficiency GSD type I

Test

Blood pH Acidotic Acidotic Alkalotic Normal/ ++ Acidotic Acidotic

Ammonia Normal/++ Normal/++ + + ++ Normal/++ Normal/++ Normal Glucose Normal/−− Normal/−− Normal/−− − − −− Normal/−− −−

Lactate Normal Normal/++ Normal Normal/−− + + ++ ++

Urine

ketones

Normal/+ + ++ Normal/+ + ++ Normal Inappropriately/−− Variable Normal MSUD, maple syrup urine disease; PA, propionic aciduria; OTC, ornithine transcarbamylase; MCAD, medium-chain acyl-CoA dehydrogenase; PDH, pyruvate dehydrogenase; GSD, glycogen storage disease.

Figure 16.2 Inborn errors of

meta-bolism within the branched-chain

amino acid (BCAA) pathway Both

aminoacidopathies and organic

acidu-rias can result from aberrations within

the BCAA pathway MSUD, maple

syrup urine disease; IVA, isovaleric

aci-demia; MCC, 3-methylcrotonyl-CoA

carboxylase; PA, propionic aciduria;

MMA, methylmalonic aciduria.

is an essential cofactor, and less severe symptomatology

may also arise with severe malabsorption or a strict

ve-gan diet Other derangements in cobalamin metabolism

may also cause MMA (subtypes labeled cobalamin A

through F) Cobalamin C has symptomatology of both

MMA and homocystinuria, with a high risk of

throm-boembolism As in PA, patients with severe MMA present

with hypotonia, lethargy, hypoglycemia, ketonuria, and

acidosis Marked elevation of methylmalonate in urine is

observed, as well as the presence of 3-hydroxypropionate

and methylcitrate The brain magnetic resonance

imag-ing (MRI) may reflect basal ganglia, thalamic edema,

and necrosis, and magnetic resonance (MR) spectroscopy

can be helpful for identifying metabolites such as

lac-tate Additionally, vascular concerns may be present in

MMA (cobalamin C and D), and ocular disease is

com-mon Long-term renal disease caused by thrombotic

microangiopathy and pancreatitis (also present in PA)

are concerns Formal diagnosis of the MMA subtype

re-quires enzyme complementation analysis on cultured skin

fibroblasts

Acute management for MMA, similar to PA, involves

aggressive therapy with intravenous dextrose and lipids to

promote anabolism Immediate dialysis may be needed if

hyperammonemia and obtundation are present Interim

administration of high doses of vitamin B12 with both

clinical and laboratory re-evaluation is important to rule

out a rare but more easily treated form of MMA The

long-term management of MMA requires a protein-restricted

diet, vitamin, andL-carnitine supplementation

Urea Cycle DisordersHyperammonemia with hyperventilation and worseningencephalopathy in the newborn are hallmarks of ureacycle disorders (see Fig 16.3); however, symptoms andage of onset vary considerably In the most severe forms,newborns also develop lethargy, poor feeding habits,seizures, temperature instability, loss of reflexes, andintracranial hemorrhage due to coagulopathy Infants andchildren with less severe disease may present with failure tothrive, feeding difficulty, vomiting, and chronic neurologicsymptoms, or episodic ataxia, lethargy, and seizures

In addition to lethargy and recurrent encephalopathy,adolescents may show psychiatric or behavioral problems,

or episodes of disorientation particularly during times ofstress or in association with high protein intake Patientswith less severe or episodic symptoms may have partialenzyme deficiencies

The diagnosis of urea cycle defect should be considered

in any sick neonate Plasma ammonia level should

be drawn, placed on ice and run within 30 minutes.Improper sample handling can result in an ammonialevel two to three times the normal level The nonspecificsigns of feeding intolerance and somnolence can rapidlyprogress to lethargy and coma if hyperammonemia goesunrecognized and therapy is delayed Any infant withsymptomatic hyperammonemia should be transported to

a tertiary care center where hemodialysis and scavenging drugs are available Initial management shouldinclude stopping all protein feeds and infusing glucoseand lipid to prevent catabolism Patients may also be

Sepsis Fatty acid oxidation disorders (SCAD, MCAD, LCAD, etc.) Multiple carboxylase deficiency

No acidosis With or without alklosis

Very elevated Citrullinemia

argininosuccinate

Carbamyl phosphate synthetase deficiency

Ornithine transcarbamylase deficiency

Argininosucccinase deficiency

pyruvate carboxylase; SCAD, short-chain acyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; LCAD, long-chain acyl-CoA dehydrogenase.

dehydrated During hyperammonemic crisis, particularly in

the newborn, plasma ammonia is usually >300 µm per L

and may be much higher Samples should be sent for

PAA, plasma acylcarnitine profile, urine amino acids, urine

organic acids, and urine orotic acid determinations in order

to determine the etiology of the hyperammonemia (see

Figs 16.3 and 16.4)

Intravenous therapy with ammonia-scavenging drugs

should be started in the child with suspected or

docu-mented urea cycle defect when ammonia elevation

corre-sponds with central nervous system (CNS)

symptomatol-ogy It may be prudent to contact a metabolic specialist

who has experience with these drugs because they are not

without potentially toxic side effects For acute

neona-tal hyperammonemic coma where the specific defect has

not been documented, a 600 mg per kg loading dose of

10%L-arginine–HCl in 10% dextrose and 250 mg per kg

loading dose each of sodium benzoate and sodium

pheny-lacetate in 10% dextrose over a 2-hour period followed by

a sustaining infusion of 250 mg per kg each of sodium

benzoate and sodium phenylacetate over 24 hours are

given The arginine-sustaining dose varies according to the

particular suspected or known enzyme deficiency Arginine

should ideally be given through a central catheter because

extravasation into the peripheral tissues causes sclerosis

Hemodialysis is the most rapid way to remove ammoniafrom the circulation If hemodialysis is unavailable,then hemofiltration should be used Peritoneal dialysismay be helpful but may not remove ammonia quicklyenough to be clinically effective Nitrogen-scavenging drugsshould be continued during hemodialysis because they actsynergistically and ammonia levels should be monitoredfrequently (every 2 to 4 hours initially, if the patient isobtunded)

After 48 hours, and following the acute phase ofmanagement, small amounts of protein (0.5 g/kg/day)should be added to the intravenous dextrose and lipids

to prevent further catabolism An experienced metabolicnutritionist should be involved in the care of the patient

as oral feeding begins Despite aggressive management,neonates with severe hyperammonemic coma may havesignificant residual neurologic deficits

Other Inborn Errors with Acute Neurologic Presentation

There are many rare IEM that can produce acute neurologicdecompensation in an infant or young child Carefulphysical examination and laboratory testing may be

Figure 16.4 Urea cycle enzymes and

cellular localization Ornithine

transbamylase (OTC) binds ornithine to

car-bamoylphosphate, to form citrulline.

After citrulline is transported into the

cy-tosol, aspartate is bound by

argininosuc-cinate synthetase (ASS) to form

argini-nosuccinate, which is then converted by

argininosuccinate lyase (ASL) to arginine

and fumarate Arginase then converts

arginine to urea and ornithine Ornithine

is then transported into the

mitochon-dria by an ornithine transporter to

com-plete the urea cycle.

NH4+

HCO3−

Mitochondrion Cytosol

Carbamyl phosphate

OTC

ASL ASS

Citrulline

Ornithine Urea

Urea cycle Arginase Arginine

Fumarate Argininsuccinate Aspartate

Orotic acid Orotidine Uracil

suggestive of one of these disorders and a few of them

are listed here

Glutaric acidemia type 1 presents with macrocephaly

and acute encephalopathic crisis with a dystonic–dyskinetic

movement disorder typically between 6 and 18 months

The presence of glutaric acid and 3-hydroxyglutaric acid on

urine organic acid analysis is diagnostic Patients should

be treated with carnitine 100 mg/kg/day and a

lysine-and tryptophan-restricted diet Glutaric acidemia type 2 or

multiple acyl-CoA dehydrogenase deficiency presents with

facial and cerebral malformations, metabolic acidosis,

hy-poglycemia, Reye syndrome, progressive encephalopathy,

and epilepsy Diagnostic testing shows elevated

acylcar-nitines (C4 to C18 species), and elevated organic acids

(lactic, glutaric, ethylmalonic, and dicarboxylic acids)

Treatment consist in the inclusion of a low-fat diet and

avoidance of fasting

Nonketotic hyperglycinemia presents acutely in the

neonate or more transiently in early childhood with

se-vere epileptic encephalopathy, hypotonia, and progressive

neurologic symptoms Diagnosis is based on elevations of

glycine in the plasma and cerebrospinal fluid (CSF) with a

CSF/plasma ratio >0.06 (normal <0.04) Valproate

treat-ment may complicate interpretation of the CSF/plasma

ratio Treatment is experimental and suspected patients

should be referred to a tertiary care center with experience

in NKH Sulfite oxidase and molybdenum cofactor

defi-ciencies present in early infancy with intractable seizures,

psychomotor retardation, microcephaly, and lens

dislo-cation Diagnosis is based on the presence of sulfites in

fresh urine, measured at the bedside with diagnostic urine

dipsticks (e.g., Merckoquant 10013, Merck Darmstadt,

Ger-many), and a very low serum uric acid The presence of

S-sulfocysteine in plasma is diagnostic Again, therapy is

supportive and experimental

Menkes disease presents in male infants with neonatal

hypothermia, severe jaundice, epilepsy, a typical facial

profile, ‘‘kinky’’ hair, and connective tissue and bone

abnormalities Decreased levels of serum copper andceruloplasmin are diagnostic Microscopic examination ofthe hair reveals characteristic ‘‘pili torti.’’ Daily copperinjections may be helpful if started early in the diseasecourse

Biotinidase deficiency is tested in some, but not inall neonatal screening programs, and is characterized

by metabolic acidosis, hypotonia, seizures, psychomotorretardation, hair loss, a skin rash, and immune defects.Metabolic abnormalities such as elevations in serum lactateand ammonia and plasma alanine may be present, butdeficient biotinidase activity is diagnostic The condition istreatable with 5 to 10 mg per day of oral biotin Infantsidentified by NBS often are asymptomatic and have only apartial deficiency

INBORN ERRORS OF ENERGY METABOLISM

The generation of energy by oxidative phosphorylationtakes place in most organ systems and involves mito-chondrial and nuclear genes Consequently, deficiencies inrespiratory chain enzymes can give rise to any symptom, inany tissue, at any age, and by any inheritance pattern

A respiratory chain deficiency should be considered inany infant or child who presents with progressive neuro-muscular symptoms in association with symptoms in aseemingly unrelated organ system Typically, an increasingnumber of organ systems are involved with advancing age,and worsening of symptoms often accompanies an intercur-rent illness These patients often experience a ‘‘stair steplike’’downhill course that may be rapid or may progress overyears Clinical presentation can include progressive skeletaland cardiomyopathies, failure to thrive or poor growth ac-companied by anorexia and poor feeding, proximal renaltubulopathy, hepatic failure, sensorineural hearing loss,diabetes, anemia, neutropenia, dermatologic changes, and

facial dysmorphism Leukodystrophy may be apparent on

MRI Progressive cardiomyopathy with recurrent apnea,

dyspnea, cyanosis, or bronchitis in the newborn period

may be the only finding in a severe presentation Screening

for respiratory chain deficiencies includes a plasma lactate

and pyruvate An elevated lactate to pyruvate ratio >20 is

suggestive of a respiratory chain disorder These samples are

very sensitive to improper handling For example, pyruvate

degrades if the sample is not handled in a timely

man-ner, and a difficult blood draw may artificially raise lactate

levels—which may affect the ratio An increase in plasma

alanine and proline by quantitative amino acid analysis is

also suggestive of the disorder, as is an elevation in CSF

lactate or a lactate peak on MR spectroscopy

Mitochondrial DNA mutation analysis on peripheral

blood, if positive, is diagnostic; however, most genes

encod-ing respiratory chain proteins are nuclear genes Ragged-red

fibers on muscle biopsy indicate mitochondrial disease and

the diagnosis can be established by demonstrating reduced

enzyme activity of one or more of the respiratory chain

com-plexes or mitochondrial DNA mutations on snap frozen

muscle Treatment is symptomatic and includes

avoid-ance of drugs that inhibit the respiratory chain (sodium

valproate and barbiturates) or mitochondrial protein

syn-thesis (tetracyclines and chloramphenicol), administration

of additional respiratory chain cofactors (coenzyme Q10

5 to 10 mg/kg/day, biotin 20 mg per day), and the use

ofL-carnitine (50 to 100 mg/kg/day) if a secondary

carni-tine deficiency is present Acidosis can be corrected with

sodium bicarbonate Adequate caloric consumption should

be ensured with a high-lipid, low-carbohydrate diet, and

ag-gressive treating conditions with high-energy consumption

(i.e., fevers and seizures) will minimize sequelae

Pyruvate Dehydrogenase and Pyruvate

Carboxylase Deficiency

The pyruvate dehydrogenase (PDH) complex is crucial

for the oxidative metabolism of pyruvate catalyzing the

production of acetyl-CoA, an important substrate for

the Krebs cycle—the final common pathway for the

oxidation of fatty acids, amino acids, and carbohydrates

Deficiency of PDH complex is the most common disorder

producing lactic acidemia The complex is composed

of several subunits and deficiency of the E1 subunit,

located on the X chromosome, is the most common

The spectrum of clinical manifestations reflects mutation

severity, from overwhelming lactic acidemia and death

in the newborn period, to moderate lactic acidemia and

profound progressive psychomotor retardation and death

in infancy, to carbohydrate-induced episodic ataxia and

mild developmental delay seen only in women Elevation

of plasma and CSF lactate and pyruvate is suggestive of

the diagnosis, but enzyme assay on cultured fibroblasts is

confirmatory Children with PDH deficiency benefit from

a high-fat diet, and indeed the ketogenic diet has been

beneficial for seizure control for some patients A highcarbohydrate diet appears to worsen the lactic acidosis inthese patients

By contrast, pyruvate carboxylase (PC) is anotherenzyme important for the conversion of pyruvate tooxaloacetate, a substrate required at the end of the Krebscycle for synthesis of citrate These patients can also presentwith severe lactic acidosis at birth Later presentationscan involve failure to thrive, microcephaly, hepatomegalydevelopmental delay, and proximal renal tubular acidosis,and multiple carboxylase Initial testing for PC is similar

to that of testing for PDH deficiency Skin biopsy withenzymatic analysis of PC activity is diagnostic In contrast

to PDH, treatment of PC with carbohydrates appears to bebetter tolerated

PRIMARY INBORN ERRORS OF METABOLISM OF THE LIVER

The pathophysiology of many IEM are because of abnormalliver metabolism as a result of genetic mutations with pre-dominant hepatic expression The enzymes responsible forthe IEM previously mentioned, such as aminoacidopathies(tyrosinemia type I, with concern for hepatocellular car-cinoma), organic acidurias (MMA and PA), and the ureacycle are vital for routine hepatic processes The IEM related

to energy metabolism—glycogen synthesis, glycogenolysis,glycolysis, and gluconeogenesis—are also essential hepaticprocesses Clinical presentation of these diagnoses can besomewhat varied and a thorough examination elicitingsubtle clinical differences may be essential for diagnosis.Aminoacidopathies

Aminoacidopathies with acute neurologic involvement,such as MSUD, PA, and MMA have been previously dis-cussed Of the aminoacidopathies which present acutelyowing to primary hepatic symptoms, tyrosinemia type

I hepatorenal tyrosinemia is the most common Theenzyme deficiency of fumarylacetoacetase results in the ac-cumulation of fumarylacetoacetate and maleylacetoacetatebelieved to be responsible for hepatic damage TandemMS/MS newborn screening does not consistently identifyinfants at birth, and so clinical suspicion must be high ifNBS is negative The presence of succinylacetone in urine ispathognomonic for diagnosis However, analysis in bloodshould be considered if levels in urine are only mildly ele-vated The presentation of tyrosinemia type I during infancycan be severe, and may be accompanied by any combi-nation of sepsis, vomiting, hypoglycemia, renal tubularacidosis, and signs of liver synthetic dysfunction (bleed-ing, edema, ascites, and jaundice) Dietary restriction oftyrosine and phenylalanine combined with treatment withnitisinone(NTBC) (1 to 2 mg/kg/day) helps limit the level

of toxic metabolites However, the risk for hepatocellular