Endocrine System



Jennifer LaMie Joiner

Two types of endocrine problems are seen in pediatric critical care: (a) specific endocrine abnormalities (diabetes mellitus [DM], panhypopituitarism) and (b) endocrine dysfunction secondary to critical illness (sick euthyroid or syndrome of inappropriate antidiuretic hormone [SIADH]).


A.    Role of the Endocrine System

1.    The endocrine system maintains homeostasis, including fluid and electrolyte balance, blood pressure, intravascular volume and maintenance of fat, muscle, and bone.

2.    Functions of the endocrine system involve control and regulation of metabolism, maintenance of energy stores, growth and development, reproduction and sex differentiation, growth and coordination of the body’s response to stress (e.g., trauma, critical illness, infection, major surgery) via the secretion of counter-regulatory hormones (Buzby, 2012; Molina, 2013).

3.    Integrated functions include central nervous system (CNS) input to the endocrine system via the hypothalamic–pituitary complex. The immune system contributes to endocrine regulation via activation of proinflammatory mediators (interleukin-1, tumor necrosis factor; von Saint Andre-von Arnim et al., 2013).

4.    Most diseases from the endocrine system occur as a result of hypersecretion, hyposecretion, altered response at the tissue level, or tumors in an endocrine gland (Buzby, 2012).

5.    Many of the most powerful therapies used in the pediatric intensive care unit (PICU) are mediators of the neuroendocrine system and include epinephrine, norepinephrine, vasopressin, insulin, and steroids.

B.    Endocrine Glands

These glands or organs consist of specialized cells that synthesize and secrete biochemical messengers (hormones) in response to specific signals (e.g., hyperglycemia, hyperosmolality, hypocalcemia).

1.    Endocrine glands secrete hormones directly into the bloodstream (e.g., adrenal glands, endocrine pancreas, thyroid gland).

2.    Exocrine glands secrete biochemical substances that are released into ducts to be delivered to target organs (e.g., salivary glands, sebaceous glands, exocrine pancreas, sweat glands).

3.    Major Glands

a.    Hypothalamus–pituitary complex (anterior and posterior pituitary gland)

b.    Thyroid gland

c.    Parathyroid glands

d.    Adrenal glands

e.    Islets of Langerhans in the pancreas

f.    Gonads

g.    Other sources. Cells that are normally considered outside the endocrine system can manufacture and secrete hormones in response to certain circumstances (e.g., pneumocytes may secrete adrenocorticotropic hormone [ACTH]). Cardiac myocytes secrete atrial natriuretic peptide (ANP), dendroaspis natriuretic peptide (DNP), and brain or B-type natriuretic peptide (BNP) in response to myocardial stretch and overload (Yee, Burns, & Wijdicks, 2010). ANP and BNP cause natriuresis (salt loss) and diuresis. An elevated BNP level serves as a biomarker when left ventricle dysfunction and heart failure exist (Rossano & Shaddy, 2014).

C.    Hormones

1.    Hormones (Table 6.1) are chemical messengers that are released directly into the bloodstream from endocrine glands in response to specific stimuli or signals that cause:

a.    Hormones bind with the specific receptor, target cell, or organ, which initiates specific cell response. Cells that do not possess this specific receptor do not respond (Hall, 2016). Receptors are located on the cell membrane, in cell cytoplasm, or in the nucleus of the cell and activity varies based on cell signaling (Hall, 2016).





b.    Facilitation of communication between cells, both locally and distally.

2.    Chemical Structures of Hormones (Hall, 2016)

a.    Proteins and polypeptides (water-soluble) are synthesized from amino acids. They bind to cell surface membranes. Examples are anterior and posterior pituitary hormones.

b.    Steroids (lipid soluble) are synthesized from cholesterol. They diffuse through the plasma membrane and enter the cytoplasm. Examples are cortisol, aldosterone, estrogen, progesterone, and testosterone.

c.    Derivatives of the amino acid tyrosine are synthesized and stored until needed then released based on mechanism of action. Thyroxine (T4) and triiodothyronine (T3) from the thyroid gland are synthesized by adding iodine to tyrosine and can take months for full effect. Epinephrine and norepinephrine from the adrenal medulla are modified from tyrosine and can be ready for action within seconds to minutes.

3.    Information about hormones, interactions with each other, and their interactions with the nervous system and immune system continue to be investigated. Several second messenger systems exist that are important in the activation of hormones that maintain intracellular functions on cell membranes and include the cyclic adenosine monophosphate, phospholipase, and calcium–calmodulin systems.

4.    Hormones can be exogenously administered to critically ill patients.

D.    Feedback Mechanism

1.    Feedback loops are used to regulate secretion of hormones in the hypothalmic-pituitary loop (Figure 6.1).

2.    Negative feedback (Figure 6.2) is the primary mechanism in controlling hormonal regulation and prevents overproduction of hormones to their target tissues (Hall, 2016; McCance & Huether, 2015). Negative feedback occurs when the specific cell response has been achieved or exceeded and the information is relayed to the secreting gland to inhibit secretion. The feedback can be short or long looped.

3.    Negative feedback in hormonal release is responsible for maintaining homeostasis and inhibition of this system could result in a pathologic condition (Brashers, Jones, & Huether, 2014).


FIGURE 6.1    Feedback loops.

TRH, thyrotropin-releasing; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine.


A.    Hypothalamic–Pituitary Complex (Neuroendocrine System)

1.    Embryology

a.    The hypothalamus arises from the diencephalon after a proliferation of neuroblasts. The fibers of the supraoptic tract are present by 12 weeks gestation with maturation of the neurons by 30 weeks (Schoenwolf, Bleyl, Brauer, & Francis-West, 2015).

i.    Antidiuretic hormone (ADH) and oxytocin production begin at about 12 weeks gestation.

b.    The pituitary gland has a double embryonic origin, which contributes to the differentiation of the anterior and posterior lobes. Pituitary development begins around 4 weeks of gestation (Schoenwolf et al., 2015). Pituitary hormone secretion begins by 8 to 10 weeks gestation (Dattani & Gevers, 2016).

c.    Anterior pituitary is recognizable by 3 to 4 weeks gestation and appears fully functional by 17 weeks. It originates from Rathke’s pouch, which is ectodermal tissue from the oropharynx that migrates to join the posterior pituitary. By week 5 of gestation, a connection between Rathke’s pouch and the infundibulum is present (Dattani & Gevers, 2016).

i.    Secretory granules are found by 10 to 12 weeks gestation and production of ACTH occurs by 8 weeks gestation, somatotropin by 10 or 11 weeks gestation, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by 11 weeks gestation, prolactin by 12 weeks gestation, and TSH by 15 weeks’gestation (Dattani & Gevers, 2016).


FIGURE 6.2    Negative feedback loops and their target cells.

d.    Posterior pituitary originates from the neuroectoderm of the diencephalon (hypothalamus). It develops during week 5 or 6 of gestation (Schoenwolf et al., 2015).

i.    The fetal posterior pituitary is capable of maintaining fetal osmolality and blood volume. In the fetus and newborn, increased levels of ADH are found secondary to hypoxia and stress. Serum levels of ADH in the newborn correlate with the length of labor. Data indicate that ADH secretion is fully mature in the newborn; however, renal responsiveness may be decreased.

2.    Role of the Hypothalamus. The hypothalamus functions as a center to integrate incoming stimuli from the CNS and the peripheral nervous system (PNS). It translates neurotransmitter hormonal signals into appropriate endocrine responses (Hall, 2016). Secretion of pituitary hormones is controlled through either hormonal or nervous system signals from the hypothalamus that terminate in the posterior pituitary (Hall, 2016). The stimulating and inhibiting hormones from the hypothalamus are carried to the anterior lobe of the pituitary gland via the hypothalamic–hypophyseal portal vessels (Figure 6.3). The posterior pituitary is controlled by the hypothalamus via nerve fibers that terminate in the posterior pituitary. The hypothalamus synthesizes ADH and transports it to the posterior pituitary.


FIGURE 6.3    Hypothalamic hypophyseal portal system.

Source: From Hall, J. E. (2016). Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia, PA: Elsevier.

3.    Anatomic Location (Figure 6.4). The hypothalamus is anterior and below the thalamus. It forms the floor and the walls of the third ventricle. The pituitary gland (also called the hypophysis) is located in the sella turcica below the optic chiasm, on the superior surface of the sphenoid bone, and covered by dura. The pituitary gland is connected to the hypothalamus by the pituitary stalk or infundibulum. The pituitary gland can be accessed surgically through the back of the nose. The pituitary gland has two distinct lobes that produce different hormones (Figure 6.4).

a.    Anterior pituitary (adenohypophysis) constitutes 75% of the weight of the pituitary gland (Brashers et al., 2014). Hypothalamic-releasing hormones control hormone secretion. The anterior pituitary secretes growth hormone, ACTH, TSH, prolactin, FSH, and LH.

b.    Posterior pituitary (neurohypophysis) hormones are controlled by nerve fibers in the hypothalamus called the hypothalamohypophysia tract (which contains approximately 100,000 nerve fibers). The posterior pituitary secretes ADH and oxytocin. These hormones are synthesized in the hypothalamus, transported via nerve tracts in the pituitary stalk, and stored in the posterior pituitary (Robinson & Verbalis, 2016).

c.    Pituitary stalk serves as a communication and connection between the brain and the pituitary gland. The stalk contains axons and neuronal cells that originate in the hypothalamus (Brashers et al., 2014).

4.    Cell Types of the Hypothalamus, Neurohypophysis, and Adenohypophysis

a.    The supraoptic and paraventricular nuclei originate in the hypothalamus. Thirst receptors and osmoreceptors are located in the hypothalamus close to the supraoptic nucleus. ADH is formed primarily in the supraoptic nucleus, but small amounts of ADH are produced in the paraventricular nucleus. Oxytocin is formed primarily in the paraventricular nucleus (Hall, 2016).

b.    The posterior pituitary is composed of pituicytes. Pituicytes do not secrete hormones but rather provide support structures for the nerve fibers that come from the hypothalamus (Hall, 2016). These nerve-like endings contain secretory granules that lie on the surface of the capillaries where they release ADH and oxytocin.

c.    The anterior pituitary consists of six different types of secretory cells (Brashers et al., 2014).

i.    Somatotrophs secrete growth hormone (GH) and play a key role in metabolic processes for growth.

ii.    Lactotrophs secrete prolactin and proliferate during pregnancy secondary to elevated estrogen levels to aid in milk production.

iii.    Corticotrophs secrete ACTH, which stimulates steroid production in the adrenals, beta-lipotropin and beta-endorphins in adipose cells for release of fatty acids, regulation of body temperature, and analgesia in brain receptors.

iv.    Gonadotrophs secrete LH and FSH, which are necessary for ovulation, follicle maturation, and spermatogenesis.


FIGURE 6.4    Location and structure of pituitary gland and hypothalamic–pituitary–adrenal complex.

v.    Thyrotrophs secrete TSH, which stimulates thyroid hormone production, iodide uptake, and hyperplasia of thymocytes.

vi.    Melanotrophs secrete melanocyte-stimulating hormone (MSH), which promotes secretion of melanin.

5.    Hypothalamic Hormones

a.    Growth hormone-releasing hormone (GHRH) stimulates release of GH.

b.    Thyrotropin-releasing hormone (TRH) stimulates release of TSH.

c.    Corticotropin-releasing hormone (CRH) stimulates release of ACTH and beta-endorphin.

d.    Gonadotropin-releasing hormone (GnRH) stimulates release of LH and FSH.

e.    Somatostatin inhibits release of GH, renin, and parathyroid hormone (PTH) and decreases secretion of TSH, glucagon, and insulin.

f.    Dopamine (prolactin inhibitory hormone) inhibits synthesis and secretion of prolactin.

g.    Prolactin-releasing factor (PRF) stimulates the secretion of prolactin.

h.    Substance P inhibits synthesis and secretion of ACTH and stimulates secretion of GH, FSH, LH, and prolactin.

i.    These hormones are transported to the anterior pituitary by the hypophyseal portal vessels. The releasing/inhibitory hormones regulate the stimulation and secretion of the anterior pituitary hormones (Brashers et al., 2014; Hall, 2016).

4886.    Anterior Pituitary Hormones (Figures 6.5 and 6.6)

a.    Growth hormone

i.    Biosynthesis. GH is a polypeptide hormone secreted by the somatotroph cells.

ii.    Regulation. The strongest stimulus for release is GHRH, but it can also be stimulated by apomorphine, levodopa, and norepinephrine (Kaiser & Ho, 2016). Endorphins will also cause a release during times of severe stress or exercise (Kaiser & Ho, 2016). GHRH is transported to the anterior pituitary via the hypothalamic–hypophyseal portal vessels. Starvation, hypoglycemia, stress, exercise, and low fatty acid levels can stimulate GH release.


FIGURE 6.5    Pituitary hormones and their target organs.

iii.    The inhibition of GH release occurs secondary to somatostatin, hyperglycemia, exogenous GH, obesity, and corticosteroids. Somatostatin is secreted by cells in the periventricular region (located above the optic chiasm) in the hypothalamus and 489in the delta cells of the pancreas (Hall, 2016). The peptide Gherlin, which is synthesized in gastric mucosa and in the hypothalamus, evokes the release of GH secretion, which induces food intake and is being widely studied in gastric bypass patients (Kaiser & Ho, 2016).

iv.    Secretion. GH is released in a pulsatile fashion with increased levels occurring during slow wave deep sleep (70% of daily secretion) and during adolescence (Kaiser & Ho, 2016).

v.    Effects. GH is an anabolic hormone that facilitates linear growth in all tissues of the body with mediation from insulin-like growth factor 1 (IGF-1). GH increases the mobilization of fatty acids from adipose tissue and enhances their conversion to acetyl coenzyme A to be utilized for energy, which spares protein usage. GH offers protection against hypoglycemia as it decreases carbohydrate utilization and increases blood glucose levels (Kaiser & Ho, 2016). GH stimulates bone, cartilage, and tissue growth with the stimulation of osteoclast and osteoblasts which increase bone mass (Brashers et al., 2014).

vi.    Abnormalities of GH secretion. In growth hormone deficiency (GHD), the anterior pituitary fails to produce enough GH; consequently, stature is less than genetic determination would indicate. Most GHD is idiopathic, however, it is important to rule out intracranial tumor. An excessive level of GH produces gigantism, usually caused by pituitary adenoma. Acromegaly is due to excessive GH secretion after the epiphyses of the long bones have closed, which results in excessive growth of the jaw, hands, and feet.

vii.    Role in critical illness. Catabolic states induced by acute illness, including surgery, burns, multiple organ dysfunction, and trauma, produce a state of GH resistance as well as decreased production and action of IGF-1 (Kaiser & Ho, 2016). Surgeries or disease states that affect the hypothalamic–pituitary system will also cause a state of low GH production. There is widespread interest in the use of GH in elevating sport performance and treating osteoporosis and malnutrition states.

b.    Adrenocorticotropic hormone

i.    Biosynthesis. ACTH is a polypeptide hormone secreted by corticotroph cells.

ii.    Regulation. The stimulation for the release of ACTH is CRH, which is secreted by the hypothalamus. Pain, stress (cytokines and catecholamines), trauma, hypoxia, low cortisol levels, and vasopressin administration also stimulate release of ACTH (Kaiser & Ho, 2016).

iii.    Inhibition to release of ACTH occurs primarily through negative feedback loops in response to an integrated neuroendocrine process to control the stress response. The response will in turn decrease the formation of CRF, vasopressin, and dopamine. Exogenous steroids decrease ACTH secretion and can lead to adrenal insufficiency (AI; Kaiser & Ho, 2016).

iv.    Secretion. ACTH has a 24-hour circadian pattern with ultradian pulsality that is controlled peripherally by corticosteroids (Kaiser & Ho, 2016). However, this circadian rhythm is not established in newborns. Highest levels occur in the early morning and decrease throughout the day and reach the lowest point between 11 p.m. and 3 a.m. The rhythm is affected by the light/dark cycle and is lost during times of stress. ACTH has melanocyte-stimulating abilities, which determine the concentration of melanin in the skin (Hall, 2016).

v.    Effects. ACTH stimulates the secretion of the adrenocortical hormones (glucocorticoids, mineralocorticoids, and androgens to produce and secrete cortisol and aldosterone [refer to text on cortisol and aldosterone in “Adrenal Glands”]).

vi.    Abnormalities of ACTH secretion. Long-term ACTH oversecretion stimulates hypertrophy, proliferation, and hyperfunction of the adrenal cortex (Hall, 2016). Undersecretion of ACTH leads to AI.

vii.    Role in critical illness. Relative AI is seen in critical illness, especially in sepsis. Hydrocortisone therapy is used for treatment. Treatment is reserved for children with catecholamine resistance (more than two vasoactive agents), sepsis, and those refractory to fluid resuscitation (Carcillo & Fields, 2002). Children on chronic 490steroids require stress doses of steroids when undergoing surgery or they are critically ill (see “Critical Illness-Related Corticosteroid Insufficiency”).

c.    Thyroid-stimulating hormone

i.    Biosynthesis. TSH, also known as thyrotropin, is a glycoprotein hormone secreted by the thyrotroph cells.

ii.    Regulation. Stimulations for the release of TSH include TRH, exposure to severe cold, and decreased level of thyroid hormone. Somatostatin and negative feedback from increased blood levels of thyroid hormones inhibit TSH. Dopamine inhibits TSH secretion and other catecholamines raise levels (Brashers et al., 2014).

iii.    Effects. TSH stimulates the thyroid gland to release T3 and T4, increase glucose uptake and oxidation, stimulate iodide metabolism, and increase thyroid cell size and vascularity (Brashers et al., 2014).

iv.    Abnormalities of TSH secretion. Hypersecretion of TSH induces hyperthyroidism. Hyposecretion of TSH induces hypothyroidism.

v.    Role in critical illness. Nonthyroidal illness syndrome, or sick euthyroid syndrome, is the most common thyroid abnormality in acute care. This abnormality occurs in patients with critical illness, postsurgery, or when fasting (not caused by pituitary dysfunction) and can be acute or chronic (von Saint Andre-von Arnim et al., 2013). The situation can be compounded when the child is receiving steroids, amiodarone, iodine dyes, propylthiouracil (PTU), or high-dose propranolol. T3 levels are low, T4 levels are normal or low, and TSH may be normal or reduced secondary to a decreased response to TRH. It is unclear whether these changes reflect a protective response or a maladaptive process, but studies have shown an association between sick euthyroid and severity of illness and clinical outcomes (von Saint Andre-von Arnim et al., 2013). There is debate regarding thyroid supplementation and most authors agree that supplementation is not necessary as a normal TSH reflects a euthyroid state. Thyroid testing should be repeated once the illness has resolved as hypothyroidism and sick euthyroid can be difficult to distinguish; however, true hypothyroid patients will have low T4 and increased TSH, whereas an elevation in reverse T3 level is indicative of sick euthyroid state (von Saint Andre-von Arnim et al., 2013). In premature infants, hypothyroxinemia of prematurity can also result in abnormal thyroid function studies, but this is typically transient.

d.    Follicle-stimulating hormone

i.    Biosynthesis. FSH is a glycoprotein hormone that is secreted by the gonadotroph cells.

ii.    Regulation. The stimulus for FSH release is GnRH secreted by the hypothalamus. FSH secretion is inhibited through negative feedback secondary to increased levels of estrogen secreted by the ovaries and increased levels of inhibin secreted by the testes.

iii.    Effects. In males, FSH stimulates testicular growth; following puberty, FSH promotes spermatogenesis. In females, FSH stimulates the growth of the ovarian follicles and the secretion of estrogen.

iv.    Role in critical illness is unknown.

e.    Luteinizing hormone

i.    Biosynthesis. LH is a glycoprotein hormone that is secreted by the gonadotroph cells.

ii.    Regulation. The stimulus for release of LH is GnRH secreted by the hypothalamus. Inhibition for the release of LH is negative feedback secondary to increased levels of estrogen, progesterone, and testosterone.

iii.    Effects. In males, LH stimulates the production of testosterone from the Leydig cells and maturation of spermatozoa. In females, LH stimulates estrogen and progesterone production. LH is responsible for ovulation and maintenance of the corpus luteum.

iv.    Role in critical illness is unknown.

f.    Prolactin

i.    Biosynthesis. Prolactin is a polypeptide hormone that is secreted by the lactotroph cells.

ii.    Regulation. The stimulus for the release of prolactin is oxytocin, which is secreted by the posterior pituitary, TRH, and prolactin-releasing hormone (PRH) from the hypothalamus (Brashers et al., 2014). Immune-derived cytokines and stress also stimulate prolactin release. Inhibition of the release of prolactin is dopamine, which is secreted by the hypothalamus.

491iii.    Effects. Prolactin stimulates lactation and during pregnancy increases the growth of the ductal system in the breast and the production of breast milk. It maintains the corpus luteum and progesterone production during pregnancy. Prolactin stimulates immune function by supporting the growth and survival of lymphocytes (Brashers et al., 2014).

iv.    Role in critical illness. Exogenous dopamine blocks prolactin production and may be associated with clinically significant effects on the immune system. Prolactin acts as a second messenger in the IL-2 and B-cell activation and differentiation and on several types of lymphocytes that can directly affect the immune system (Clayton & McCance, 2014). These relationships are under investigation for possible immune therapy.

7.    Posterior Pituitary Hormones (Figure 6.5)

a.    ADH, or arginine vasopressin (AVP)

i.    Biosynthesis. ADH is a polypeptide. The prohormone is carried in vesicles through the axons to the posterior pituitary. Final synthesis of the prohormone to ADH occurs in the vesicles during axonal transport.


FIGURE 6.6    Metabolic functions of anterior pituitary hormones.

ACTH, adrenocorticotropic hormone.

ii.    Regulation. Osmoreceptors in the anterior hypothalamus are in close proximity to the supraoptic nucleus. When serum osmolality increases, the cells in this area begin to shrink, stimulating the release of ADH. Nonosmotic regulation occurs with pain, nausea, medications, cardiac failure, and any volume loss (von Saint Andre-von Arnim et al., 2013).

iii.    The most potent stimulus for ADH release is arise in serum osmolality. Osmotic changes as small as 1% stimulate the release of ADH with normal set point of 280 mOsm/kg (Brashers et al., 2014; Robinson & Verbalis, 2016). These small changes in osmolality also stimulate the thirst mechanism, a protective mechanism to maintain water balance and prevent dehydration. A decrease in circulating blood volume perceived by the baroreceptors in the carotid sinus of the aortic arch also stimulates ADH release 492(Robinson & Verbalis, 2016). Infants, small children, patients who are comatose or disoriented, or individuals who have abnormal thirst response are not able to meet these physiologic demands; therefore, they are dependent on others to ensure an adequate intake of water. Hemorrhage (10%–20% circulating blood loss), hypotension, nausea, hypercapnia, morphine, nicotine, and hypoxemia can activate the release of ADH (Hall, 2016; Robinson & Verbalis, 2016). Catecholamines and angiotensin II can modulate the release of ADH, which is a powerful stimulus to ACTH and prolactin release.

iv.    ADH release is inhibited by a serum osmolality below 275 mOsm/kg (Robinson & Verbalis, 2016). The baroreceptors in the carotid sinus and the volume receptors in the left atrium send signals to the brainstem via the vagus and glossopharyngeal nerves. The stimulus is then carried to the hypothalamus. This pathway is primarily inhibitory; however, a fall in pressure or volume decreases the amount of inhibition, facilitating the release of ADH. Vincristine, cyclophosphamide, alcohol, and glucocorticoids inhibit ADH release (Brashers et al., 2014). Atrial natriuretic factor (ANF) inhibits ADH release and its effects on the kidney.

v.    Effects. Three receptors mediated by binding to G proteins are responsive to ADH: V1, V2, and V3. V1 receptors are located in the liver, adrenals, brain, and smooth muscle. When stimulated, they produce smooth-muscle contraction, which leads to powerful vasoconstriction. V2 receptors are located in renal tubular cells, primarily in the collecting tubule and the ascending loop of Henle causing increased permeability leading to increased water reabsorption, increased circulating blood volume leading to an antidiuresis. V3 receptors have a concentrated location in the anterior pituitary as cortotroph cells but are also found in kidney, thymus, heart, lung, spleen, uterus, and breast tissue. These receptors stimulate the activity of phospholipase C, which raises intracellular calcium levels and aids in the release of ACTH (Brashers et al., 2014; Molina, 2013). ADH enhances sodium chloride (NaCl) transport out of the ascending limb of the loop of Henle. This serves to maximize the interstitial osmotic gradient in the renal medulla, facilitating water reabsorption and urine concentration (Figure 6.7).

vi.    Abnormalities of ADH. Deficiency results in diabetes insipidus (DI). Excess ADH results in SIADH (Yee et al., 2010).

vii.    Role in critical illness. Vasopressin is administered to patients who have refractory hypotension with vasodilatory shock states or after cardiac bypass to increase systemic vascular resistance (Brashers et al., 2014). Vasopressin is also administered to patients with acute or chronic ADH deficiency secondary to surgery. The following disorders are associated with ADH: SIADH, cerebral salt wasting (CSW), and DI and are discussed later in this chapter.

b.    Oxytocin

i.    Biosynthesis. Oxytocin is a polypeptide that is almost identical to ADH except for the placement of two of the amino acids in the peptide chain. Like ADH, the prohormone for oxytocin is carried in vesicles through axons from the hypothalamus to the posterior pituitary, where the final 493synthesis of oxytocin occurs during neuronal transport.


FIGURE 6.7    Regulation of vasopressin, secretion, and serum osmolality.

VP, vasopressin.

Source: From Majzoub, J. A., Muglia, L. J., & Srivatsa, A. (2014). Disorders of the posterior pituitary. In M. Sperling (Ed.), Pediatric endocrinology (4th ed., pp. 405–443). Philadelphia, PA: Elsevier.

ii.    Regulation. The stimulus for oxytocin release is an increase in estrogen, the onset of labor from stretch receptors, and stimulation of the cervix and vagina (labor can occur in women with oxytocin deficiency, although the duration is prolonged), suckling stimuli on the nipple, hemorrhage, or psychologic stress. Oxytocin is inhibited by pain, heat, or loud noises (Brashers et al., 2014; Molina, 2013).

iii.    Effects. Rhythmic contraction of the smooth muscle of the uterus occurs to induce labor and help with the involution of the uterus to prevent bleeding postpartum. Additional effects: causes release of ACTH with AVP to produce vasoconstriction with prolactin release that is associated with maternal amnesia (Molina, 2013). Also, causes the myoepithelial cells in the alveoli of the mammary gland to stimulate the release of breast milk and may have a role in sperm motility.

B.    Thyroid Gland

1.    Embryology. The thyroid gland is the first fetal endocrine gland to develop. It is recognizable by embryonic day 16 to 17. The gland can form thyroglobulin by the 28th day of gestation and can concentrate iodide and synthesize T4 by the 11th week of gestation. The development of the thyroid gland begins from the endodermal floor of the primitive pharynx. As the embryo grows, the thyroid gland descends into the neck, passing the laryngeal cartilages. Fetal brain development is dependent on thyroid hormones and lack of it will cause severe disabilities. TSH concentration increases between 18 to 26 weeks gestation. Thyroxine-binding globulin (TBG) levels can be detected by 10 weeks, and progressively increase until term. This causes an elevation of T4 for the second and third trimesters. Thyroid hormone levels peak at 24 hours of postnatal life and slowly decrease over the next few weeks (Brashers et al., 2014; Molina, 2013; Salvatore, Davies, Schlumberger, Hay, & Larsen, 2016).

2.    Location. The thyroid gland consists of two lobes located on each side of the trachea below the larynx. A band of tissue called the isthmus, which lies over the second to fourth tracheal cartilages, connects the lobes.

3.    Cell Types. The thyroid gland consists of a large number of follicles filled with colloid. The main constituent of colloid is thyroglobulin, a glycoprotein containing the thyroid hormones. Follicular cells and a basal membrane constitute the outer boundary of the follicle. Cuboidal epithelioid cells secrete colloid. Between the follicular cells are parafollicular cells that secrete calcitonin. The thyroid gland is highly vascular; follicles are in close contact with blood and lymphatic vessels (Brashers et al., 2014; Hall, 2016).

4.    Regulation of Thyroid Hormone. The thyroid gland secretes T3, T4, and calcitonin. The negative feedback mechanism involves the hypothalamus, anterior pituitary gland, and the thyroid gland. TRH initiates the process with release from the hypothalamus, where it circulates and stimulates the release of TSH by the pituitary. Catecholamines and acetylcholine directly affect the secretory action of the follicular cells and regulate its blood flow (Brashers et al., 2014).

5.    Synthesis of Thyroid Hormone. Synthesis of the thyroid hormones is complex and dependent on iodine and tyrosine. Tyrosine is an amino acid present in the body and iodine must be ingested and absorbed by the GI tract into the blood. The thyroid iodide pump actively transports iodide across the follicular cell membrane to be oxidized into iodine then bind with tyrosine in the thyroglobulin molecule. TSH stimulates the iodide pump. The coupling of iodinated tyrosine forms T3 (triiodothyronine) or tetraiodothyronine (thyroxine, T4). The thyroid gland is unique in its ability to store hormones in the follicular colloid for several months until released into the bloodstream; therefore, when synthesis stops, the physiological effects of hyposecretion are not seen for several months. Thyroglobulin is not released into circulating blood; the thyroid hormones must split from the thyroglobulin molecule before its release (Brashers et al., 2014; Molina, 2013; von Saint Andre-von Arnim et al., 2013).

6.    Thyroxine (T4)

a.    Biosynthesis. In total, 90% of the thyroid hormone production is T4, and 10% is T3. They are circulated bound by one of the three carrier proteins (Brashers et al., 2014).

b.    Regulation. TSH, low iodide levels, and extreme cold stimulate the release of T4. Release of T4 is inhibited by excess iodide and negative feedback resulting from increased levels of thyroid hormones that decrease the anterior pituitary secretion of TSH. Stimulation of the 494sympathetic nervous system causes a decrease in the secretion of TSH with a subsequent decrease in thyroid hormone secretion.

c.    Effects. T4 is a prohormone necessary for the production of T3. The effects of T4 are similar to the effects of T3, although these effects are less potent and have a longer duration of action (half-life 7 days for T4 and 1 day for T3; Molina, 2013).

d.    Factors that impair peripheral conversion of T4 to T3 are propranolol, amiodarone, glucocorticoids (at anti-inflammatory doses), salicylates, liver failure or fatty liver disease, renal insufficiency, malnutrition, pregnancy, and major illness (sick euthyroid; Molina, 2013; Plumpton, Anderson, & Beca, 2010).

e. Role in critical illness. Dopamine administration decreases the response of TSH to TRH and suppresses TSH secretion (Plumpton et al., 2010). Sick euthyroid syndrome is discussed in the Thyroid-stimulating hormone section, Role in critical illness.

7.    Triiodothyronine (T3)

a.    Biosynthesis. T3 constitutes 10% of the hormones released by the thyroid gland, and the remaining are produced by extrathyroidal deiodination of T4 (Molina, 2013).

b.    Regulation of T3 is the same as for T4.

c.    Effects. On release into the bloodstream, the thyroid hormones bind with plasma proteins. Because of their high affinity for the plasma-binding proteins, the thyroid hormones are released into the peripheral cells very slowly. Once they enter the cell, these hormones bind with intracellular proteins and are stored. Intracellular activity may last days or weeks. T3 maintains basal metabolic rate and promotes tissue growth through the stimulation of almost all aspects of carbohydrate and fat metabolism. T3 promotes protein synthesis, regulates body temperature, and stimulates oxygen consumption through an increase in metabolic rate. In addition, T3 maintains cardiac output, heart rate, and strength of myocardial contraction through increased metabolism and direct effect on the heart. T3 increases the rate and depth of respiration secondary to increased metabolism and increased carbon dioxide production. An increase in gastrointestinal (GI) tract motility and secretion of digestive enzymes occurs with T3 (Molina, 2013; Salvatore et al., 2016).

d.    Role in critical illness. Controversy exists on the treatment of abnormalities in thyroid hormone levels in infants who undergo cardiopulmonary bypass (CPB). It has been documented in the literature that this dysfunction is significant enough to affect myocardial function, even in the absence of primary thyroid disease (Talwar, Kumar, Choudhary, & Airan, 2016). This state of hypothyroidism has been associated with prolonged vent support, low cardiac output state, and left ventricular dysfunction. Thyroid supplementation in the early postoperative period has been given as an adjunct to improve cardiac function in neonates after cardiac surgery and enables a smoother recovery, but duration of therapy remains unclear (Talwar et al., 2016). Sick euthyroid syndrome is discussed in the Thyroid-stimulating hormone section, Role in critical illness.

8.    Abnormalities of T3 and T4 Secretion (Table 6.2)

a.    Primary hypothyroidism can be congenital or acquired and is caused by low levels of thyroid hormones (T3 or T4) and an elevated TSH level (von Saint Andre-von Arnim et al., 2013). Worldwide, the leading cause of hypothyroidism is iodine deficiency, but in the United States in children older than 6 years, it is most commonly caused by autoimmune dysfunction (Hashimoto thyroiditis). Symptoms may include lowered metabolic rate with lethargy, hypothermia, bradycardia, growth failure, hypotension, weight gain, fatigue, and constipation. Infants left untreated beyond 6 weeks for congenital hypothyroidism develop profound cognitive defects (Ganeson, Kazmi, & Levy, 2012). Newborn screens in all 50 states now include TSH and T4 (Babler et al., 2013). Severe cases can progress to myxedema coma with symptoms of congestive heart failure, hypotension, hypoglycemia, and hypothermia (Jones, Brashers, & Huether, 2010; von Saint Andre-von Arnim et al., 2013). Treatment is provided with age-based supplementation of levothyroxine sodium in doses to normalize TSH and maintain free T4. Levels must be monitored closely during times of growth and with dose changes (Babler et al., 2013).

b.    Hyperthyroidism is caused by high levels of thyroid hormones and results in a hypermetabolic state with weight loss, tachycardia, hypertension, wide pulse pressure, irritability with restlessness, diarrhea, and tremor (Babler et al., 2013). The most common type in childhood is Graves’ disease, which occurs most frequently in early-adolescent females following an infection (Ganeson et al., 2012). Critical hyperthyroidism or thyroid storm, is rarely seen in the pediatric population, but when present can be life threatening with mortality rates of 20% to 30% (S. Srinivasan & Misra, 2015). Symptoms can escalate to the point of cardiovascular collapse with coma and severe hyperthermia. Immediate treatment with volume resuscitation and beta-blocker infusion (halts T3 activity) is critical. Care must be taken with the use of beta-blockers in this hypermetabolic state if pulmonary artery hypertension or a low cardiac output state are present as these can worsen with their use (Chantra, Limsuwan, & Mahachoklertwattana, 2016). Other treatments are directed at limiting T4 production by blocking thyroid hormone synthesis with methimiazole or propylthiuracil (PTU). Many providers have stopped using PTU due to dangerous effects on the liver and may also limit the use of methimazole due to its teratogenic affects (Clark, Preissig, Rigby, & Bowyer, 2008; Ganeson et al., 2012; von Saint Andre-von Arnim et al., 2013). Glucocorticoids are used in some instances to block the conversion of T4 to T3. Surgery or radioactive iodine treatment is used in many recalcitrant cases and will stop production of thyroid hormone but requires children to be on supplementation for the remainder of their lives (Ganeson et al., 2012).

495TABLE 6.2    Clinical Features of Thyroid Dysfunction

Clinical Features of Hyperthyroidism

Clinical Features of Hypothyroidism











Heat intolerance

Cold intolerance

Weight loss and increased appetite

Weight gain and decreased appetite

Source: Adapted from Babler, E., Betts, K., Courtney, J., Flores, B., Flynn, C., Laerson, M., . . . Wroley, D. (2013). Clinical handbook of pediatric endocrinology (2nd ed.). St Louis, MO: Quality Medical Publishing.

9.    Calcitonin

a.    Biosynthesis. Calcitonin or thyrocalcitonin is a polypeptide produced by the parafollicular or C cells of the thyroid gland. Serum calcitonin is high at birth and slowly decreases over the first week of life, possibly contributing to neonatal hypocalcemia (Molina, 2013).

b.    Regulation. The stimulus for release of calcitonin is an increase in serum calcium and gastrin. A low serum calcium level inhibits release of calcitonin.

c.    Effects. Calcitonin plays a minor role in calcium and phosphorus regulation. It opposes the action of PTH and stimulates osteoblasts to deposit calcium for new bone formation. It also enhances renal excretion of calcium, decreases active vitamin D formation to lower serum calcium, and enhances renal excretion of calcium (Brashers et al., 2014).

C.    Parathyroid Glands

1.    Embryology. The third and fourth pharyngeal pouches differentiate into the thymus and parathyroid glands during the fourth to sixth week of gestation occurring synchronously with thyroid development (Dattani & Gevers, 2016). The fourth pouch eventually takes position at the upper poles of the thyroid as the superior parathyroid glands and increases in size to 1 to 2 mm by birth. During gestation, the placenta is impermeable to PTH and calcitonin, but 25-hydroxyvitamin D and calcitriol are transported across the placenta, and the mother remains the sole source of those minerals for the fetus. During the third trimester, active calcium transport occurs across the placenta maintaining fetal calcium concentrations. This system is dependent upon the activity of parathyroid hormone-related protein (PTHrP). Following birth, the newborn must rapidly adapt to this loss of support. Ionized calcium and PTH levels remain low for 48 hours after birth but appropriate 496PTH response to hypocalcemia slowly develops in infants during the first weeks of life (Brashers et al., 2014; Dattani & Gevers, 2016).

2.    Location. Two pairs are usually present (can number from two to six) behind the upper pole of the thyroid gland on each side of the trachea (Brashers et al., 2014).

3.    Cell Types. The parathyroid gland contains mostly chief cells, which secrete most of the PTH. A small to moderate amount of the poorly understood oxyphil cells are present as well. It is speculated that they might be chief cells that are modified but no longer secrete PTH. The oxyphil cells are absent in infants and children (Hall, 2016).

4.    Parathyroid Hormone (Figure 6.8)

a.    Biosynthesis. PTH is a polypeptide composed of many amino acids synthesized on the ribosomes and cleaved to form PTH. It is stored in the secretory granules in the cytoplasm of the chief cells (Brashers et al., 2014).

b.    Regulation. The stimulus for release of PTH is hypocalcemia, low levels of vitamin D, and mild hypomagnesemia. Release of PTH is inhibited by increased ionized calcium and hypermagnesemia (Molina, 2013).


FIGURE 6.8    PTH effects on bone, kidneys, and intestines.

PTH, parathyroid hormone.

c.    Effects (Figure 6.8). PTH is the major hormone in the regulation of serum calcium. In the kidney, PTH increases calcium reabsorption and phosphorus excretion (there is an inverse relationship between calcium and phosphorus). PTH stimulates the conversion of vitamin D to its active form, increases GI tract calcium and phosphate absorption, and promotes bone resorption of calcium (movement out of the bone into the extracellular fluid).

5.    Abnormalities of Parathyroid Function

a.    Primary hyperparathyroidism occurs when negative feedback loops fail to inhibit the release of PTH and hypercalcemia results. The hypercalcemia is caused primarily by hyperplasia or adenomas of the gland or, secondarily, as part of a chronic disease state with either malabsorption or deficiency of essential vitamins, such as vitamin D, or hyperphosphatemia from renal disease. Other secondary causes include such drugs as phenytoin, phenobarbital, or laxatives (Brashers et al., 2014).

497b.    Hypoparathyroidism is the absence of PTH, resulting in hypocalcemia and hyperphosphatemia. This can occur as a result of surgery near the glands, hypomagnesemia, genetic syndromes (DiGeorge), or from an autoimmune/idiopathic diagnosis.

c.    Role in critical illness. Impaired calcium metabolism resulting from abnormalities of parathyroid function may be seen in infants and lead to profound hypocalcemia with seizures, tetany, and shock (Babler et al., 2013; Molina, 2013). Treatment is with calcium and the active form of vitamin D (Brashers et al., 2014).

D.    Pancreas

1.    Embryology

a.    Dorsal and ventral pancreatic buds arise from the primitive endoderm and the gland is identifiable by week 4 of gestation (Dattani & Gevers, 2016). Acini (secretory cells) develop from cells around the primitive ducts in the pancreatic buds. The islets of Langerhans develop from cell groups that separate from the primitive buds and form next to the acini. The islets of Langerhans appear at 12 to 16 weeks gestation and are clearly differentiated by 31 weeks (Dattani & Gevers, 2016).

b.    Insulin and glucagon secretion are identifiable by 8 to 10 weeks gestation. The main determinant of fetal glucose uptake is maternal blood glucose level. Glucose is the main substrate utilized by the fetus and it passes through the placenta through facilitated diffusion. Glucose supply is usually constant, but if autoregulation is necessary it occurs in the liver. The placenta is relatively impermeable to insulin and there are higher numbers of insulin receptors present in fetal cells when compared to adults but downregulation does not occur. Insulin is the major hormone that drives fetal growth. Glucagon levels are high in fetal plasma but receptors are decreased in number. In the last trimester of gestation, hyperglycemia does not get blunted by glucagon levels, thereby promoting the period of rapid growth that occurs. Glucagon levels rise sharply after birth, remain stable during the first 48 hours of life, and then rise progressively throughout the next days of life (Dattani & Gevers, 2016).

c.    Alpha and beta cells can be recognized by 8 to 10 weeks with alpha cells being the most numerous in number early in gestation, but this becomes equal to beta cells by term (Dattani & Gevers, 2016).

d.    Glucose homeostasis in the term newborn is essential but supply must be constant and becomes rapidly depleted due to large glucose requirements for brain development. Premature or small-for-gestational-age (SGA) infants have less body fat, low glycogen stores, and therefore less reserves than term infants. The neonate and young child also exhibit hypoglycemia when fasting for shorter periods than the older child or adult. Counterregulatory hormonal responses to hypoglycemia are blunted in this population as well (De León, Thornton, Stanley, & Sperling, 2014).

e.    External sources of glucose are more important in the neonate because of limited glycogen stores. Hepatic glycogenolysis must be initiated once fasting occurs. Gluconeogenesis will also begin and muscle proteins will be used as an alternate source of glucose. Glycogenolysis will decline within 8 to 12 hours and the transition to inefficient use of fat as a source of energy will begin. Once glucose levels fall to <50 mg/dL, all of these alternate energy resource systems have been initiated and critical hypoglycemic labs should be obtained (De León et al., 2014).

2.    Location. The pancreas is shaped like a tadpole, with a head, body, and tail, and it lies across the posterior abdominal wall between the spleen and duodenum.

3.    Cell Types

a.    Exocrine function includes the acini cells who secrete enzymes important in the digestive process into the duodenum via a network of ducts (Doig & Huether, 2014).

b.    Endocrine function uses a ductless system that directly secretes insulin, glucagon, and somatostatin into the portal circulation. It constitutes less than 2% of the total pancreatic volume. The islets of Langerhans have four cell types:

i.    Alpha cells, which secrete glucagon, constitute 25% of islet cells.

ii.    Beta cells, which secrete both insulin and amylin, constitute 60% of islet cells.

iii.    Delta cells, which secrete somatostatin, constitute 10% of islet cells.

iv.    Polypeptide cells, which secrete pancreatic polypeptide and gastrin, constitute 5% of islet cells (Brashers et al., 2014).

4.    Insulin

a.    Biosynthesis. Insulin is an anabolic hormone stored in secretory granules in the beta cells of 498the pancreas as proinsulin with a connecting C peptide that has a circulating half-life of 6 minutes (Hall, 2016). It is synthesized on the ribosomes of the beta cells and converted to insulin when the signal comes for its secretion (Brashers et al., 2014; De León et al., 2014).

b.    Secretion. Beta cells are secreted parasympathetically in response to hormonal, neural, and chemical input when the blood glucose rises (Brashers et al., 2014).

c.    Regulation. Release of insulin is predominantly stimulated by an increase in blood glucose and amino acid levels (arginine and lysine). Other factors promoting the release of insulin are GI tract hormones (gastrin, cholecystokinin, and secretin), cortisol, GH, proinflammatory cytokines, and glucagon (Hall, 2016; V. Srinivasan & Agus, 2014). The following will inhibit the release of insulin: hypoglycemia, catecholamines, somatostatin, and prostaglandins (Brashers et al., 2014; Hall, 2016). Once blood glucose levels fall to fasting levels, insulin secretion halts.

d.    Effects

i.    Carbohydrate metabolism. Insulin increases glucose uptake by the liver, muscle, and adipose tissue and stimulates glycogen storage in the liver and muscle (glycogenesis). Insulin inhibits gluconeogenesis (formation of glucose from noncarbohydrate sources) and glycogenolysis (breakdown of glycogen to glucose). Insulin is not necessary for glucose uptake by the brain and most of the cells are impermeable to glucose (Hall, 2016).

ii.    Fat metabolism. Insulin stimulates triglyceride synthesis, transport of fatty acids across the cell membrane, and storage in adipose tissue. Insulin inhibits lipolysis (fat breakdown) and ketogenesis (formation of ketones from fat; Hall, 2016).

iii.    Protein metabolism. Insulin facilitates transport of amino acids into the cells, works synergistically with GH to promote growth, and stimulates protein synthesis. Insulin inhibits proteolysis (protein breakdown; Hall, 2016).

iv.    Secondary effects of insulin. Insulin assists with the transport of potassium, magnesium, and phosphate into the cell, helping to maintain cellular homeostasis.

e.    Hypoinsulinemia. Hypoinsulinemia occurs when an abnormally low level of insulin is present in the body. This lack of insulin markedly reduces the rate of transport of glucose across the cell membrane. Reduced insulin secretion also increases the amount of stored triglycerides in the liver, causing increased serum triglycerides, fatty acids, and cholesterol (Brashers et al., 2014). Falling insulin levels also increase serum levels of acetoacetic acid, acetone, and ketone bodies because of increased oxidation of fat (lipolysis). Liver and muscle glycogen is converted to glucose and released into the blood (glycogenolysis). Gluconeogenesis includes the breakdown of proteins (proteolysis) to form glucose (Brashers et al., 2014; Hall, 2016).

f.    Role in critical illness. Tight control of serum glucose (80–110) utilizing insulin infusions has shown improved outcomes in adult trauma patients but remains debatable in children. The Heart and Lung Failure–Pediatric Insulin Titration (HALF-PINT) study hopes to ascertain whether tight glucose control with intensive insulin therapy can improve outcomes in critically ill children without the deleterious effect of hypoglycemia, as seen in previous studies with tight glucose control (V. Srinivasan & Agus, 2014). Insulin is also used to treat hyperkalemia with concurrent glucose administration.

5.    Glucagon

a.    Biosynthesis. Glucagon is a large peptide that is synthesized and secreted by the alpha cells of the islet cells and by cells that line the GI tract.

b.    Regulation. Hypoglycemia, amino acids (alanine, asparagine, and glycine), ingestion of proteins, sympathetic stimulation, and vigorous exercise are stimulants for the release of glucagon. Hyperglycemia, high levels of circulating fatty acids, and somatostatin suppress release of glucagon (Brashers et al., 2014).

c.    Effects. Glucagon is a catabolic hormone; a hormone of fuel mobilization. It is an insulin antagonistic hormone that directs the breakdown of liver glycogen (glycogenolysis), increases gluconeogenesis in the liver, and increases the availability of fatty acid to make energy available to the tissues (Brashers et al., 2014).

d.    Role in critical illness. Glucagon is used as treatment in calcium channel blocker toxicity and for severe hypoglycemia. A relatively high glucagon level is seen in every type of diabetes and is thought to propagate the metabolic problems seen in the disease and may be an important component in its pathogenesis (Brashers et al., 2014).

4996.    Somatostatin

a.    Biosynthesis. Somatostatin is a polypeptide synthesized from the islet cells and secreted by the delta cells of the pancreas (Brashers et al., 2014). It is present in the hypothalamus, pancreas, and GI tract.

b.    Regulation. Glucose, amino acids, fatty acids, and GI tract hormones stimulate the release of somatostatin, which is essential for their metabolism.

c.    Effects. Somatostatin inhibits the secretion of insulin, glucagon, GH, and TSH. It decreases the production of gastric acid and gastrin and prevents excess insulin from being released. It decreases GI tract motility and absorption and helps with regulation of alpha and beta cell function (Brashers et al., 2014).

d.    Role in critical illness. Octreotide, which is a somatostatin analog, is used to decrease variceal bleeding seen with portal hypertension and hepatorenal syndrome. Octreotide is being used in the management of chylothorax and hypoglycemia seen in sulfa drug overdose (Chan, Chan, Mengshol, Fish, & Chan, 2013).

7.    Amylin

a.    Biosynthesis. Amylin is an islet amyloid cosecreted with insulin in response to intake of food (Brashers et al., 2014).

b.    Regulation. Stimulated in response to high glucose.

c.    Effects. Serves as an antihyperglycemic by regulating uptake of nutrients, providing the sensation of saity, and delaying the release of glucagon (Brashers et al., 2014).

d.    Role in critical illness. Aggregated amylin is cytotoxic and is suspected of contributing to the loss of beta cells in type 2 diabetes. Amylin is also being used in the treatment of diabetes as an agent for glycemic control and it may play a factor in gastric emptying. Ongoing research is looking at the role amylin may have in development of obesity (Brashers et al., 2014).

E.    Adrenal Glands

1.    Embryology

a.    The adrenal glands develop from two different origins: the cortex, arising from the mesoderm, and the medulla, arising from the neuroectoderm and is found above the much smaller kidney by 8 weeks of gestation. Differentiation of the adrenal medulla occurs late in development. The zona reticularis is not developed until the end of the third year of life and is not fully developed until around 15 years of age. The mesoderm is involved in the development of the gonads (Miller & Flück, 2014).

b.    Fetal cortisol is necessary as a fetus prepares for extrauterine transition. An increase in fetal cortisol occurs in the last 10 weeks of gestation and prepares several systems that are critical for survival. As delivery approaches, cortisone, the active form that would be detrimental in early fetal development, is converted by the liver and lung tissues to cortisol (Dattani & Gevers, 2016). Cortisol progressively decreases during the first 2 months of life.

c.    Early in the fetus’s development, there is no epinephrine. Norepinephrine is the dominant catecholamine at birth (Miller & Flück, 2014).

2.    Location. The adrenal glands are small glands that lie atop the kidneys. Each gland has two distinct parts, the cortex, constituting 80% of the gland, and the medulla, constituting 20% of the gland (Babler et al., 2013).

3.    Anatomic Structure. The adrenal gland is surrounded by a fibrous capsule. The adrenal cortex has three histologically different zones: zona glomerulosa, the outermost layer, which constitutes 15% of the cortex; zona fasciculate, the middle layer, which constitutes 75% of the cortex; and the zona reticularis, the innermost layer, constituting 10% of the cortex. The adrenal medulla has sympathetic and parasympathetic innervation but the adrenal cortex does not. The adrenal circulation unlike other organs does not run in parallel. Arterial blood supplied by smaller arteries and flows toward the medulla, so medullary chromaffin cells see high steroid concentration in their circulation. The more conventional veins drain into the left renal vein and the vena cava (Miller & Flück, 2014).

4.    Cell Types (Miller & Flück, 2014)

a.    The adrenal cortex is responsible for the secretion of corticosteroids, which are synthesized from cholesterol. These hormones are released from three separate zones in the adrenal cortex. The three zones each secrete unique hormones and from the outside to inside they are often remembered by saying salt, sugar, and sex.

i.    The zona glomerulosa is responsible for the secretion of mineralocorticoid and aldosterone.

500ii.    The zona fasciculata is responsible for secreting glucocorticoids, mainly cortisol and a small amount of androgen secretion.

iii.    The zona reticularis is responsible for secreting androgen, estrogen, and small amounts of glucocorticoid.

b.    The chromaffin cells are the major cells of the adrenal medulla and they store the catecholamines epinephrine and norepinephrine as secretory granules. They are synthesized from phenylalanine with innervation from the parasympathetic and sympathetic nervous systems. In times of stress, exocytosis occurs after depolarization from acetylcholine, and enhanced amounts of hormones are released (Brashers et al., 2014).


FIGURE 6.9    Cortisol and aldosterone effects during stress.

ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CRH, corticotropin-releasing hormone.

5.    Aldosterone (Figure 6.9)

a.    Biosynthesis. Aldosterone is the most potent mineralcorticoid and it is imperative for life functions due to its sodium-retaining properties. It is a steroid compound synthesized from cholesterol absorbed from the blood. Synthesis begins in the zona fasciculata and reticularis with final conversion to active form in the zona glomerulosa (Brashers et al., 2014).

b.    Regulation. It occurs primarily by angiotensin II via the renin–angiotensin system, but it is 501also activated for release by volume depletion, decreased renal perfusion, ACTH and sodium levels, and hyperkalemia. A small increase in serum potassium will triple aldosterone release. This response is imperative for the prevention of the serious cardiotoxic effects brought about by hyperkalemia. Inhibition of aldosterone release occurs secondary to volume expansion, hypokalemia, and low angiotensin levels (Brashers et al., 2014; Hall, 2016).

c.    Effects. Aldosterone is responsible for 90% of mineralocorticoid activity (Hall, 2016). It acts on the distal tubule, collecting tubule, and collecting duct of the kidney to promote sodium reabsorption and potassium excretion. Along with renal reabsorption of sodium, there is a concurrent movement of water into the vascular bed. The net effect is an increase in extracellular sodium, an increase in extracellular volume, and a decrease in extracellular potassium. Aldosterone promotes reabsorption of sodium and excretion of potassium by the sweat and salivary glands, which promotes hydrogen ion excretion by the kidney and sodium absorption by the intestines. If aldosterone is low or absent, bowel absorption of sodium and water will not occur and diarrhea will result (Brashers et al., 2014; Hall, 2016).

d.    Role in critical illness. Aldosterone is key to maintenance of extracellular volume. Excess release can have lasting effects of more than 1 to 2 days with notable increase in arterial blood pressure. A subsequent natriuresis occurs, which increases the excretion of both water and sodium, and once it normalizes the pressure will return to the previous level (volume rise of 5%–15% causes blood pressure rise of 15–25 mmHg; Hall, 2016).

6.    Cortisol (Figure 6.9)

a.    Biosynthesis. Cortisol is a steroid compound derived mostly from cholesterol and is the main product excreted by the adrenal cortex (Miller & Flück, 2014). It is the most potent of the glucocorticoids and has a half-life of 90 minutes (Brashers et al., 2014).

b.    Regulation. The primary stimulus for secretion of cortisol is ACTH, but stress is another strong stimulus. Release of cortisol is inhibited by negative feedback to either the hypothalamus or the anterior pituitary secondary to increased cortisol levels, which produces a decrease in CRH release in the hypothalamus or decrease in ACTH release in the anterior pituitary (Brashers et al., 2014).

c.    Secretion. Secretion is regulated by the hypothalamus and anterior pituitary. It is released immediately after stimulation from ACTH. It has a diurnal rhythm release with ACTH and peaks in the hours just before awakening. It circulates bound to albumin, the glycoprotein cortisol-binding globulin (CBG; also known as transcortin) or in the unbound active form (Brashers et al., 2014). Transcortin serves an important role in the negative feedback loop for cortisol and is elevated when estrogen levels are high (Clayton & McCance, 2014).

d.    Effects. Cortisol is responsible for 95% of glucocorticoid activity and is necessary in life for stress protection (Hall, 2016). Cortisol increases gluconeogenesis and glycogenolysis to provide a substrate for this stressful time, often leading to hyperglycemia. Protein synthesis decreases, and catabolism of protein increases. Cortisol promotes mobilization of fatty acids from the tissues. An anti-inflammatory cascade occurs with its release that counteracts and modulates the body’s immune response and endothelial integrity. Cortisol is potentiated by nitric oxide and it also provides vascular tone to increase blood pressure and prevent capillary leak (Brashers et al., 2014; Levy-Shraga & Pinhas-Hamiel, 2013).

e.    Role in critical illness. Absolute AI is rare. Relative AI, in which cortisol production is inadequate to the level of stressful stimuli, can be seen in sepsis, trauma, or surgery (Levy-Shraga & Pinhas-Hamiel, 2013). Critical illness-related corticosteroid insufficiency (CIRCI) will be discussed later in the chapter.

7.    Abnormalities of Adrenal Cortical Function

a.    AI results in insufficient glucocorticoid and mineralocorticoid release or production and will require the child to have lifelong administration of exogenous hormones. It presents in childhood primarily as congenital adrenal hyperplasia (CAH) or Addison’s disease. CAH is an autosomal recessive congenital disorder and is the leading cause of AI in childhood (Webb & Krone, 2015). It usually presents in the newborn period with symptoms of shock, ambiguous genitalia, and the very diagnostic electrolyte abnormalities of hyponatremia and hyperkalemia. It has many variants that explain the specific presenting symptoms and is now part of the newborn screen with a 17-hydroxy progesterone level (White, 2016). Addison’s disease is a rare autoimmune or infectious process in children. It results from an absent or damaged adrenal gland. The deficiency produces initial weakness with 502weight loss, hyperpigmentation, dehydration, electrolyte imbalances, and altered metabolism (Brashers et al., 2014). The presentation may progress and lead to adrenal crisis with hypotension and cardiovascular collapse. Children present in shock due to the acute depletion of adrenal cortical hormones. It is precipitated by vomiting, diarrhea, convulsions, coma, hypotension, hyperpyrexia, tachycardia, and cyanosis. AI can also result from exogenous suppression of hormones with oral or intravenous (IV) steroids, as well as an abrupt withdrawal of steroids after chronic use (White, 2016). Children who suffer from severe sepsis, are premature or less than 6 months of age, and those who have had etomidate administration are at higher risk for adrenal sufficiency.

b.    Hyperfunction of the adrenal cortex, or Cushing syndrome, is a rare disorder in children resulting in excess cortisol. Excess cortisol can be rarely caused by a pituitary adenoma but more common causes include administration of high dose of exogenous steroids or chronic use of steroids (Brashers et al., 2014). The very typical “Cushingoid” effects include weight gain, moon facies, truncal striae, atropy of skin or bruising, emotional lability, hyperglycemia, and high blood pressure (Brashers et al., 2014). With long-term steroid excess, children will have problems with bone demineralization and stunted growth.

8.    Epinephrine

a.    Biosynthesis. Epinephrine is a catecholamine derived from the amino acid tyrosine, which is then converted to dopamine in the sympathetic nerve endings. Dopamine is converted to norepinephrine, which is converted to epinephrine in the adrenal medulla. Epinephrine secretion is 80% of the total catecholamine secreted by the adrenal medulla and at rest it is released at 0.2 mcg/kg/min (Hall, 2016).

b.    Regulation. Neuroendocrine (stress, fear, illness) stimulation causes epinephrine and norepinephrine to be directly released into the blood. Any stimulus that produces a sympathetic response stimulates secretion of epinephrine. The effects are rapid but only seen for seconds to minutes (Brashers et al., 2014). ACTH and glucocorticoids also stimulate release of epinephrine. Inhibition of epinephrine is through negative feedback loops; high levels of circulating catecholamines will produce downregulation of sympathetic receptors.

c.    Effects. Epinephrine stimulates the beta-adrenergic receptors in the end organs. The greatest effect is due to stimulation of the sympathetic beta-1-adrenergic receptors in the heart, resulting in increased cardiac contractility, conduction velocity, and heart rate. The net result is an increase in cardiac output and blood pressure. In isolation, stimulation of the beta-2-adrenergic receptors of the vascular bed promotes relaxation; however, during stress the vasoconstricting effects of norepinephrine counteract significant vasodilation. Other effects of stimulation of the beta-2-adrenergic receptors are intestinal, bladder and uterine relaxation, and bronchial dilation. Epinephrine increases metabolic activity to a much greater degree than norepinephrine. It increases glycogenolysis and glucose release, resulting in elevations of blood glucose to supply fuel substrates. Circulating epinephrine accounts for 10% of the sympathetic activity during the stress response (Hall, 2016).

d.    Role in critical illness. Epinephrine is used for hypotension, cold shock, bradycardia, and asystole (Chameides, Samson, Schexnayder, & Hazinski, 2011). Cold shock states are characterized by the presence of cold extremities, delayed capillary refill, and low cardiac output. The actions of epinephrine are dose dependent. At lower doses, epinephrine will have greater beta-2 adrenergic effect and SVR may fall whereas at higher doses alpha-adrenergic effects will be seen and SVR will rise (Davis et al., 2017).

9.    Norepinephrine

a.    Biosynthesis. Norepinephrine is synthesized from its precursor dopamine in the nerve endings of the sympathetic nervous system with only minor sources from the medulla.

b.    Regulation is the same as for epinephrine.

c.    Effects are secondary to stimulation of the alpha-adrenergic receptors in the end organs. The most significant effect during stress is peripheral vasoconstriction supporting blood pressure. Stimulation of the alpha-adrenergic receptors also produces dilation of the iris, contraction of the bladder and intestinal sphincters, and pilomotor contraction.

d.    Role in critical illness. Norepinephrine is used in hypotensive, vasodilated, warm shock states (Chameides et al., 2011). Children with warm shock will have flash capillary refill; warm, pink extremities; and bounding pulses. Norepinephrine is used to reverse this low SVR 503state, which is characterized by a wide pulse pressure (when the diastolic pressure is half of the systolic; Davis et al., 2017).

10.  Hyperfunction of adrenal medulla is rare, and is most often caused by a catecholamine-secreting tumor called pheochromocytoma. This tumor arises when the chromaffin cells of the adrenal gland fail to involute and the excess production can cause life-threatening hypertension, tachycardia, diaphoresis, tremors, and headaches (Kline-Tilford, 2016). Diagnosis is made through measurements of metanephrine and catecholamine levels and urine vanillylmandelic acid (VMA). Hypertension control is imperative and is often initially done with alpha-and beta-blocker infusions with subsequent tumor resection. Care must be taken, however, to avoid using beta-blockers alone as unopposed alpha activity could occur.


Many endocrine disorders develop slowly over time and often go unrecognized by those (parents and caregivers) with daily contact with the child. Assessment through careful history, documentation of past medical conditions, growth patterns, developmental milestones, physical exam findings, and family history are critical to the accurate diagnosis of specific endocrine disorders.

A.    History

1.    Prenatal history includes prenatal care; complications of pregnancy (i.e., hypertension or preeclampsia); exposure to infections; use of drugs, tobacco, and alcohol; maternal gestational diabetes; or other endocrine disorders such as thyroid disease.

2.    Neonatal history includes gestational age, birth weight, complications of labor and delivery, method of delivery, Apgar scores, hospitalization as a newborn, oxygen use, jaundice, neonatal hypoglycemia, newborn screen results, congenital anomalies, and postnatal complications or maladaptions to extrauterine life such as poor weight gain or feeding difficulties (Babler et al., 2013).

3.    Growth and development factors used for evaluation include longitudinal height and weight, recent changes in weight, achievement in developmental milestones, and growth patterns.

a.    Diet is assessed, including food preferences, allergies and aversions, content and time of typical meals, snacking behaviors, changes in appetite, and anorexia. Problems with digestion, such as nausea, bloating, food intolerances, abnormal stool patterns, diarrhea, or constipation, are noted.

b.    School performance and problems or recent changes in performance are discussed. Assessment of personality and behavioral traits includes recent changes in behavior, irritability, sluggishness, disinterest, lethargy, emotional lability, attention deficits, increased aggressiveness, altered self-esteem, perceptions of body image, family roles, and socialization issues.

c.    Sleep and rest patterns are noted, including normal bedtimes, incidence of insomnia, ease of falling asleep, restlessness, snoring, nocturnal enuresis, and night terrors. Also, note activity and exercise patterns, including the types of exercise normally engaged in, stamina, strength, outside interests, and hobbies.

d.    Sexual maturation, including the age of development, abnormalities, timing and character of menarche, and sexual activity are recorded.

4.    Past medical history includes known endocrine disorders, neurosurgery, trauma or stress, and previous hospitalizations or frequent illnesses.

a.    Medication history. Many medications can alter normal endocrine function. Examples of this include:

i.    High-dose steroids can induce hyperglycemia, inhibit normal physiologic release of steroids from the adrenal cortex from, suppressed ACTH release (causing AI during the withdrawal phase causing profound shock), and alter serum electrolytes.

ii.    Antipsychotics can change levels of prolactin and can result in obesity and metabolic abnormalities.

iii.    Propranolol, amiodarone, and glucocorticoids (at anti-inflammatory doses) impair conversion of T4 to T3.

iv.    Lithium may induce hypothyroidism, diminish renal concentrating ability (nephrogenic DI), or cause elevations in PTH levels resulting in hypercalcemia.

v.    Antiepileptics like phenytoin and phenobarbital can cause rickets through effects on vitamin D metabolism.

vi.    Attention deficit hyperactivity disorder (ADHD) medications can affect appetite and growth.

504vii.    Nonsteroidal anti-inflammatory drugs (NSAIDs) enhance renal responsiveness to ADH.

viii.    Sedatives, narcotics, and anesthetics can stimulate the thirst mechanism and alter ADH release.

ix.    Chemotherapy alters ADH release.

x.    Ethanol stimulates the thirst mechanism, alters serum osmolality and ADH release, and alters glucose metabolism.

xi.    Tricyclic antidepressants stimulate the thirst mechanism and alter ADH release.

b.    Other diseases can have a relationship with endocrine disorders. Cystic fibrosis can be an underlying cause of DM. Renal disease can be an underlying cause of DI and part of the differential diagnosis for ADH abnormalities. Lung disease, including pneumonia, can be an underlying cause of SIADH. Pheochromocytoma is a catecholamine-secreting tumor that can produce life-threatening hypertension, hyperthermia, and cardiovascular collapse.

5.    Family history includes parents’ ages; height, weight, and body proportions of family members; the parents’ age at puberty; familial and genetic diseases; health of parents and siblings; presence of known endocrine and other chronic disorders in other family members to include grandparents, aunts, uncles, and cousins (Babler et al., 2013).

B.    Physical Assessment

1.    Height and weight, body mass index, and body surface area are measured. Growth velocity and target height are estimated.

2.    Body size and proportion, fat distribution, upper and lower body ratios, chest circumference, and arm span are compared with previous measurements, if available.

3.    Temperature, blood pressure, and heart rate are recorded.

4.    Head circumference and percentiles on age- and sex-related growth charts are plotted.

5.    Intake and output are monitored.

6.    The head, eyes, ears, nose, and throat (HEENT) survey includes anterior and posterior fontanel, head shape and suture lines, forehead and hair patterns. Observe for sunken or protruding eyes, periorbital edema, gaze, sclera color, pupil symmetry and response, fundus exam, and visual acuity. Examine nose for discharge and patency. Examine ears for pinna placement (low high, posterior), gross hearing, and examination of the tympanic membranes. Palpate the thyroid gland and neck for masses or thrills, lymphadenopathy, and auscultate for the presence of bruits. Assess mucous membranes for moisture and color, and inspect the oral cavity for abnormalities of the lips and palate, presence of caries, and abnormalities in dentition or gum disease.

7.    Skin Assessment. Evaluate skin turgor and moisture, skin color (including hyperpigmentation, hypopigmentation, nevi, and café au lait spots), texture (including the presence of excess oil, rough or dry skin, acne, and temperature), and hair and nail texture.

8.    Neurologic assessment includes the level of consciousness with general demeanor, irritability, lethargy, hyperactivity, or lack of interaction. Function of cranial nerves, pupil responses, fine and gross motor movement, abnormal gait or stance, abnormal movement disorders or rhythmic tics, the presence of tremors, reflexes, abnormal deep tendon reflexes, and the presence of seizure activity or clonus should be noted.

9.    Cardiovascular evaluation includes rate, rhythm, and character of heart tones; peripheral pulses; perfusion, capillary fill time, warmth, and mottling of skin; palpation for thrills, heaves, and point of maximal impulse (PMI); edema; and any blood pressure abnormalities, including hypertension, hypotension or orthostatic hypotension, or syncopal events.

10.  Respiratory assessment includes the rate and depth of respiration, any alterations of breath odor, chest excursion, chest symmetry and deformities, and characteristics of adventitious breath sounds with differentiation of upper or lower airway abnormal sounds.

11.  Abdominal assessment notes the presence of bowel sounds, tenderness or pain, with notice of adiposity. Includes palpation for organomegaly or presence of masses.

12.  Genitourinary assessment includes palpation of the kidneys; examination of external genitalia and assessment of secondary sexual characteristics and Tanner staging of breast, pubic hair, testicular volume, and phallus size.

50513.  Musculoskeletal assessment includes evaluation for disproportionate growth or body habitus with notice of discrepancies of limb length. The presence of genu valgum or genu varum, short or unusually long metacarpals, and palpation of muscles for strength and range-of-motion deficits or scoliosis should be noted.

14.  Check general appearance for cleanliness, alertness level, responsiveness to directions, and ability to follow commands. Determine basic short- and long-term memory per developmental level (Babler et al., 2013; Brashers et al., 2014).

C.    Diagnostic Studies

1.    Laboratory (Babler et al., 2013; Brashers et al., 2014)

a.    Blood chemistries for basic electrolyte screening to include magnesium, phosphorus, calcium and glucose, blood urea nitrogen (BUN), and creatinine (Babler et al., 2013; Brashers et al., 2014). Further important studies include pH, osmolality, and cortisol levels to assess the pituitary–adrenal axis (plasma levels vary with age and time of day). Screening is done for inborn errors of metabolism as age appropriate as inborn errors of metabolism alter fat and glucose metabolism and normal growth. Screening is done for enzyme deficiencies, especially in steroid metabolism through measures of pathway intermediates. Hormone levels are sent to evaluate glands responsiveness to hormones and the target cell or organ. Glycosylated hemoglobin is measured to assess blood glucose control. Vasopressin levels can determine the type of DI.

b.    Urine is tested for electrolytes, fractional excretion of sodium (FENa), specific gravity, osmolality, glucose, ketones, and pH.

c.    Dynamic tests of endocrine function

i.    The water-deprivation test is used to differentiate causes of polyuria and is described in detail later within the section “Diabetes Insipidus.”

ii.    An oral glucose tolerance test is used to assess for abnormalities in glucose tolerance, to assist in diagnosis of impaired glucose tolerance or diabetes. Following an overnight fast, oral glucose load is administered, and serial blood glucose and determinations are made. A glucose level of 140 mg/dL or less at 2 hours postadministration of glucose is considered normal.

iii.    An insulin tolerance test is used to assess the hypothalamic–pituitary–adrenal axis and GH response. Following an overnight fast, regular insulin is administered via IV to produce hypoglycemia. Serial blood sampling is performed to determine cortisol, blood glucose, and GH levels. This test requires continuous patient monitoring.

iv.    TRH stimulation is used to assess TSH reserve and prolactin reserve and secretion. TRH is administered via IV, and serial blood determinations of T3, T4, and TSH are obtained to diagnose thyroid dysfunction. This test is not commonly used at the present time.

v.    An ACTH stimulation test is used to assess the hypothalamic–pituitary–adrenal axis. After obtaining a baseline cortisol level, an IV dose of cortrosyn (synthetic ACTH) is administered and samples are collected for serial timed cortisol levels to diagnose AI. A rise of 9 mcg/dL above baseline level or a cortisol level greater than 18 mcg/dL at 60 minutes demonstrates normal function.

vi.    GH stimulation is used to diagnose GHD. Various physiologic and pharmacologic stimuli are administered to stimulate the release of GH. A level of 10 ng/mL or more is considered evidence of sufficient GH production.

2.    Pitfalls in the Interpretation of Endocrine Function Tests. Many hormones are secreted according to specific triggers, diurnal rhythm, oscillating pulses, or following an inciting event. Plasma hormone levels are dependent on the time and circumstances of measurement. A single measurement may not accurately reflect the actual levels of many hormones. In addition, the hormone levels that are labeled “normal” may be appropriate for the healthy person or for an adult but not necessarily for a child in a certain state of critical illness, age, or pubertal level. Other factors that may interfere with endocrine tests include drug therapy, nutritional status, stress, and pathology.

3.    Radiologic Tests

a.    Chest radiographs are used to evaluate for pleural effusions, chest masses, or cardiomegaly.

b.    CT scan of the head and neck determines the presence of cerebral edema (CE), tumors, or midline defects. CT scan of the abdomen is used to determine the presence of pancreatic, adrenal, or renal tumors.

506c.    MRI of the head is used to determine the presence of tumors.

d.    Ultrasound of the neck and abdomen is used to determine renal and pancreatic function, to evaluate for thyroid, adrenal, and pancreatic tumors and to determine function.

e.    Bone age evaluates growth patterns.

4.    An ECG is used to evaluate myocardial function and the presence of dysrhythmias.


CIRCI is a relatively new diagnosis in adult critical care and its presence is quickly gaining ground in pediatric critical care literature. At this time, pediatric research is ongoing, but guidelines for adult management for CIRCI (made by the International Task Force of Acute Care) were released in 2008 (Marik et al., 2008). Pediatric research is directed at obtaining rapid and accurate diagnosis and the best treatment algorithm. This section presents the latest literature available and possible pathways for diagnosis and treatment.

A.    Pathophysiology

CIRCI occurs when inadequate corticosteroid activity is seen relative to the severity of a patient’s illness (Levy-Shraga & Pinhas-Hamiel, 2013). This weak response occurs when there is a decrease in adrenal steroid production due to dysfunction in the HPA axis or when tissue resistance to glucocorticoids exists. The most supported theory for this development is that critical illness causes peptide signals in the body to release proinflammatory cytokines (IL-1, IL-2, IL-6, TNF-alpha, interferon gamma; Kwon et al., 2010; von Saint Andre-von Arnim et al., 2013). The cytokines elicit the release of CRH from the hypothalamus stimulating the anterior pituitary to release ACTH, which causes the adrenal gland to produce cortisol (von Saint Andre-von Arnim et al., 2013). Concurrently, the body has a sympathetic response initiated in the brainstem (locus cerulus), which stimulates the release of norepinephrine and epinephrine (Clark et al., 2008). Cortisol levels become depleted due to overwhelming stress and 4 to 7 days into the illness insufficient levels are present (Kwon et al., 2010). Other factors that trigger the development of CIRCI include diminished receptors or receptor sensitivity, low free (unbound) cortisol, low CBG, and hypoalbuminemia as cortisol is bound to albumin (Clark et al., 2008).

B.    Etiology and Risk Factors

1.    Although a state of homeostasis exists, cortisol production has diurnal variation with a highest level in the early morning, with total cortisol level of 5 to 10 mcg/dL. During times of stress that level rises to 25 to 60 mcg/dL (over 6 months in age) and the body loses its ability for diurnal variation (von Saint Andre-von Arnim et al., 2013). Controversy exists in the literature as some research supports the idea that exogenous steroid administration blunts the protective, natural inflammatory response of the immune system in critical illness, and worse outcomes may be seen with its use (von Saint Andre-von Arnim et al., 2013).

2.    Conditions Associated With CIRCI

a.    Sepsis. Overwhelms the immune system, hypoalbuminemia results

b.    Burns. Massive fluid shifts, hypoalbunemia, and hypotension occur

c.    Surgery. Stress response

d.    Trauma. Traumatic brain injury, multiple organ injury, and hemorrhage

e.    Hypoglycemia. High substrate needs exist during times of stress

f.    Adrenal insufficiency at baseline. Panhypopituitary, steroid dependence, HPA axis disruption

g.    Etomidate. Inhibits steroidogenesis

C.    Signs and Symptoms

Signs of CIRCI are vague and can be difficult to diagnose. Some presenting symptoms include abdominal pain, mental status changes, hyponatremia, hypoglycemia, hyperkalemia, neutropenia, fever, and eosinophilia (Levy-Shraga & Pinhas-Hamiel, 2013). Symptoms can be found when sepsis is present or following a traumatic event or surgery. Critically ill children will have hypotension that is unresponsive to fluid and may need multiple vasopressor support (Chameides et al., 2011). There could be hypoglycemia or hyperglycemia. Children will have altered mental status due to an overwhelming illness state and may require intubation for airway protection. Tachycardia or bradycardia may be present with some evidence of cardiac insufficiency (diminished left ventricular function). Children with chronic illness often have inadequate adrenal reserves and during times of stress and sepsis have organ dysfunction sooner (von Saint Andre-von Arnim et al., 2013). Some evidence supports that a baseline level of free cortisol less than 2 mcg/dL and total cortisol of less than 10 mcg/dL may reflect CIRCI (Levy-Shraga & Pinhas-Hamiel, 2013; von Saint Andre-von Arnim et al., 2013).

507D.    Lab Data

1.    Low Free Cortisol Levels. Cortisol is depleted under state of persistent stress.

2.    Cytokine Levels (IL-1, 2, and 6, TNF-alpha). May be elevated.

3.    Random Cortisol Levels. May be altered in critical illness.

4.    ACTH Levels Increase. Correlates with high severity of illness scores.

5.    Hyperglycemia or Hypoglycemia. Low at presentation, elevates with steroid dosing.

6.    Hyponatremia or Hyperkalemia. May be present due to mineralcorticoid deficiency.

7.    Hypoalbuminemia. Exists in the face of critical illness.

E.    Interpretation of Diagnostic Studies

A great deal of debate exists in the literature on which diagnostic and laboratory studies are the most useful in diagnosing the presence of cortisol deficiency and resistance in critical illness. Random cortisol levels or early-morning levels have been used with great frequency as well as corticotrophin stimulation tests (von Saint Andre-von Arnim et al., 2013). More recent evidence has shown that routine testing may not be necessary and when clinical triggers are reached, hydrocortisone should be initiated. It has also been shown that routine testing has proven to be uninformative and may not identify the more critically ill patients (von Saint Andre-von Arnim et al., 2013).

1.    Random cortisol levels lack prospective data and support on use in defining adrenal insufficiency but Pediatric Advanced Life Support (PALS) recommends giving hydrocortisone if the random level is less than 18 mcg/dL (Chameides et al., 2011). Many observational studies looking at total cortisol and critically ill children found that as illness worsens IL-6, TNF-alpha, and ACTH levels increase and total cortisol levels drop (von Saint Andre-von Arnim et al., 2013).

2.    Corticotrophin-stimulation tests begin with a random cortisol level followed by obtaining two more levels, 30 and 60 minutes after administering a dose of corticotrophin 250 mcg IV. An adequate response would be a rise of serum cortisol greater than 18 to 20 mcg/dL (Levy-Shraga & Pinhas-Hamiel, 2013). In the adult literature, baseline cortisol levels greater than 34 mcg/dL and a response of less than 9 mcg/dL from a stimulation test were associated with higher mortality.

3.    Salivary cortisol can be obtained from the oral cavity and tested by liquid chromatography/tandem mass spectrometry. This level has been shown in the literature to correlate well with serum free cortisol (Gunnala et al., 2015). Rapid bedside testing in real time remains a challenge and unavailable at many institutions.

F.    Diagnoses

1.    Differential diagnoses may include Addison’s disease, CAH, Waterhouse–Friderichsen syndrome, adrenal hemorrhage or thrombosis, chronic steroid usage, systemic inflammatory response associated with sepsis, and medication use (etomidate and ketoconazole; von Saint Andre-von Arnim et al., 2013). Less common causes of adrenal insufficiency can include cellular level depression of receptor sites or alteration in function of signaling peptides.

2.    Collaborative Diagnoses and Comorbidities

a.    Potential for immunologic compromise related to steroid use

b.    Potential for impaired wound healing and hyperglycemia with steroid use

c.    Potential for cardiovascular collapse secondary to hypotension

d.    Potential for long-term sequelae from overwhelming stress and shock state

G.    Treatment Goals

1.    Replenish intravascular volume

2.    Normalize cardiovascular parameters

3.    Prevent periods of hypotension that can lead to end-organ damage

4.    Normalize blood glucose levels

5.    Initiate antibiotics timely in sepsis

6.    Treat the underlying disease state

H.    Management

When CIRCI has been established in a patient, corticosteroid supplementation should be implemented with hydrocortisone 2 mg/kg bolus dose with maximum dosing of 100 mg (Chameides et al., 2011). No clear evidence has been identified for duration and dosing of continued therapy, but many authors have used 50 to 100 mg/m2/d divided every 4 to 6 hours. More trials are needed in pediatrics to elucidate information on this subject. With steroids, most providers consider 508the lowest dose for the shortest duration possible to be the most prudent and weaning should be initiated when vasopressor support is no longer warranted (Davis et al., 2017; von Saint Andre-von Arnim et al., 2013). Caution should be made to taper steroids used for longer than 5 days or from large doses. Studies completed on children with CIRCI showed a reduction of vasopressor use within 4 hours of steroid dosing (Levy-Shraga & Pinhas-Hamiel, 2013). Studies have also shown that concomitant administration of fludrocortisone (Florinef), a mineralcorticoid agent, was associated with shorter duration of norepinephrine support (Levy-Shraga & Pinhas-Hamiel, 2013).

I.    Complications

There are many adverse effects that should be considered when administering corticosteroids. Steroids place the body into a catabolic state with resultant hyperglycemia. Research indicates that prolonged hyperglycemia results in poor survival in critically ill children (Hazinski, Mondozzi, & Uridales Baker, 2014). This catabolism results in immunodeficiency, which may lead to poor wound healing and can raise the risks of hospital-acquired infections (von Saint Andre-von Arnim et al., 2013). When steroids are administered with neuromuscular blockade, children have an increased risk of myopathy. Infants who receive steroids can have lasting effects on neurodevelopment outcomes and somatic growth (von Saint Andre-von Arnim et al., 2013).


A.    Definitions

DM is a constellation of diseases characterized by an absolute or relative insulin deficiency that causes fasting and postprandial hyperglycemia along with disturbances in the metabolism of protein and fat. Lack of insulin or insulin responsiveness leads to clinical consequences due to alterations in carbohydrate, fat, and protein metabolism (Brashers et al., 2014; Sperling, Tamborlane, Battelino, Weinzimer, & Phillip, 2014).

1.    Type 1a. Autoimmune-mediated disease is the attributable cause of more than 90% of cases of childhood diabetes. This type results in the T-cell-mediated destruction of the beta cells triggered by either environmental or genetic factors (Brashers et al., 2014). The process may be slow, as some children maintain a limited ability to secrete insulin for a few years after diagnosis. Clinical symptoms manifest when beta cells secretion is 20% or less, causing hyperglycemia to develop (Sperling et al., 2014). This process occurs in genetically susceptible children in response to an environmental agent (likely viral) that triggers an autoimmune response. This type of diabetes in infants and children requires insulin replacement therapy and is associated with the development of ketoacidosis (Brashers et al., 2014; Sperling et al., 2014).

2.    Type 1b. Idiopathic disease is less common and is often more fulminant than autoimmune disease. It usually develops in people of Asian or African descent and can be a result of other diseases such as pancreatitis (Brashers et al., 2014). Insulin replacement therapy is needed with the inconsistent insulin deficiency seen with this disease. In 17% to 30% of type 1b patients, autoimmune thyroid disease is also present and in an additional 25% of those children thyroid antibodies are present (American Diabetes Association, 2016).

3.    Type 2. Typical or atypical type 2 DM (T2DM) constitutes approximately 10% of the DM population in children. Previously referred to as adult-onset diabetes or noninsulin-dependent diabetes, this disease is associated with obesity, a strong family history of DM, and older age. In the pediatric population, the numbers are rising due to the epidemic of obesity in children and in those with Native American descent (Brashers et al., 2014). This disease occurs as a result of insulin resistance and has an insidious onset. It could be treated with oral agents, diet modification, and exercise.

4.    Maturity-Onset Diabetes of Youth (MODY). MODY accounts, for only 1% to 2% of diagnosed cases of diabetes, but should be considered in children with strong family history (two generations) of diabetes, and in children who do not have the phenotype of classic T2DM such as obesity or acanthosis nigricans. Six specific types of autosomal dominant mutations can occur and evaluation should be made at the onset of diabetes symptoms (Brashers et al., 2014). MODY 2 and 3 are the most prevalent, and MODY 1 and 3 are likely to require insulin therapy. In each of the six types (except for MODY 2), there are secondary mutations in the factors required for beta-cell differentiation and the expression of insulin genes (Babler et al., 2013).

B.    Diabetic Ketoacidosis

1.    Definition. Diabetic ketoacidosis (DKA) is an emergency condition that, if left untreated, can have life-threatening consequences. DKA occurs as a 509result of relative or absolute insulin deficiency and is diagnosed when blood glucose is greater than 200 mg/dL, venous pH is less than 7.3, or bicarbonate is less than 15 mmol/L, and ketonemia/ketonuria are present (von Saint Andre-von Armin et al., 2013). DKA remains the leading cause of morbidity and mortality in children with type 1 diabetes and is the leading cause of hospital admissions. DKA events most often occur when there is nonadherence to insulin regimen or intercurrent illness, stress, or surgery (Brashers et al., 2014).

2.    Pathophysiology

a.    When the balance of insulin and counterregulatory hormones are disrupted in the body, DKA occurs. In the absence of insulin, hyperglycemia occurs as tissue uptake of glucose is inhibited and glucose production by the liver is increased. Glycogenolysis (breakdown of glycogen), gluconeogenesis (synthesis of glucose from noncarbohydrate sources), proteolysis, and lipolysis contribute to the metabolic changes in DKA (Brashers et al., 2014; Sperling et al., 2014). Insulin deficiency leads to lipolysis and overproduction of ketone bodies such as beta-hydroxybutyrate and acetoacetates. Bicarbonate buffering does not happen and there is a resultant metabolic acidosis. Counterregulatory hormones (glucagon, cortisol, catecholamines, and GH) are released in times of stress, and they also contribute to hyperglycemia. Glycosuria occurs with osmotic diuresis once the renal threshold for glucose is exceeded (usually around 180 mg/dL; von Saint Andre-von Arnim et al., 2013). Passive electrolyte losses (magnesium, phosphorus, sodium) occur secondary to diuresis, but most concerning is the total body loss of potassium, which can reach up to 3 to 5 mEq/kg (Brashers et al., 2014). Hyperosmolality results secondary to hyperglycemia and free water loss with diuresis. Dehydration occurs secondary to osmotic diuresis and vomiting (Brashers et al., 2014; Sperling et al., 2014). There is a total body fluid shift from the intracellular space to the extracellular space to help compensate for the dehydration. Nausea and vomiting occur secondary to ketoacidosis and this worsens the electrolyte imbalances. Serum osmolarity can become very high, putting patients at risk for the development of CE and stroke.

3.    Etiology is related to inadequate endogenous insulin secretion or inadvertent omission of insulin. Initial presentation is often precipitated by nonadherence to insulin, stress, emotional or psychological problems, infection, surgery, or trauma (Sperling et al., 2014). Often, adolescents do not comply with their treatment plan and are repeatedly admitted in DKA due to familial or personal stress and inability to cope with their chronic illness.

4.    Risk factors include a previous history of diabetes with poor control or compliance, young or adolescent age, ethnic minority, lack of health coverage, delayed treatment, lower body mass index, and infection (Brashers et al., 2014).

5.    Signs and symptoms (Table 6.3) include polyuria, polydipsia, polyphagia, and hyperglycemia, generally with a serum glucose level greater than 200 mg/dL, and presence of ketones in urine. Other symptoms include weight loss, weakness and lethargy, nausea and vomiting, abdominal pain, dehydration, tachycardia, hypovolemia, poor perfusion, shock, glycosuria, ketonuria, rapid deep respirations (Kussmaul’s respirations), and stupor that can lead to coma. However, DKA can occur with normoglycemia or hypoglycemia if severe vomiting is present. Also, indicative of DKA is the presence of acidosis demonstrated by a pH less than 7.30, and serum bicarbonate less than 15 mmol/L (Klein, Sathasivam, Novoa, & Rapaport, 2011). Serum sodium levels may be high, low, or normal with total body sodium depletion secondary to urinary losses or dilutional hyponatremia (fluid shifts from intracellular space to extracellular space) secondary to hyperglycemia. Serum potassium may be high, low, or normal with total body potassium depletion. In acidosis with increased osmolality, potassium shifts from intracellular space to extr cellular space creating more available potassium for use by the body. Insulin and acidosis correction shifts potassium back into the intracellular space and levels may fall. Elevated serum triglycerides are present. The white blood cell (WBC) count is elevated with a shift to the left (Sperling et al., 2014).

6.    Classification of the presentation of DKA is based on the degree of acidosis (Klein et al., 2011)

a.    Mild. Venous pH less than 7.30 and bicarbonate less than 15 mmol/L

b.    Moderate. Venous pH less than 7.20 and bicarbonate less than 10 mmol/L

c.    Severe. pH less than 7.10 and bicarbonate less than 5 mmol/L

510TABLE 6.3    Signs and Symptoms of Diabetic Ketoacidosis


Underlying Mechanisms


Relative or absolute insulin deficiency

Metabolic acidosis (gap acidosis)

Build up of B-hydroxybutyrate, acetoacetic acids, and acetone in the serum from incomplete oxidization of fatty acids

Dehydration, shock

Osmotic diuresis secondary to hyperglycemia, vomiting

Kussmaul breathing

Deep, rapid breathing; a compensatory mechanism to blow off carbon dioxide and normalize pH

Cardiac arrhythmia

Hypokalemia, hyperkalemia

Sodium imbalance

Total body sodium depleted secondary to sodium loss from osmotic diuresis

Dilutional hyponatremia secondary to hyperglycemia, fluid drawn into extracellular space, decreases sodium content

Potassium imbalance

Acidosis causes potassium to shift from the intracellular space into extracellular space

Insulin and acidosis correction returns potassium to intracellular space

Total body potassium depletion secondary to losses from osmotic diuresis

Mental status changes

Cerebral edema, level of acidosis, degree of dehydration


Hyperglycemia, osmotic diuresis


Lipolysis causes elevated ketone levels to rise above the renal threshold and spill into the urine


Glucose spills into the urine when blood glucose exceeds renal threshold

7.    Interpretation of Diagnostic Studies

a.    Hyperglycemia is due to insulin deficiency, decreased glucose uptake, gluconeogenesis, and an increase in the counterregulatory hormones.

b.    Glycosuria occurs secondary to hyperglycemia.

c.    pH level less than 7.30 and bicarbonate less than 15 mmol/L are due to acetoacetic acid and beta-hydroxybutyrate dehydrogenase (ketones) production. Acidosis could also be due to poor perfusion and accumulation of lactic acid (lactic acidosis).

d.    Ketonuria is the presence of ketones in the urine. Ketonemia is the presence of high serum ketone levels.

e.    Serum osmolality is greater than 300 mOsm/kg because of hyperglycemia and osmotic diuresis, which leads to dehydration.

f.    Electrolyte disturbances are related to electrolyte loss with osmotic diuresis, shifts between extracellular and intracellular spaces, and metabolic acidosis.

g.    Islet cell antibodies and insulin autoantibodies are not diagnostic for DKA but may offer a screening tool for detecting patients with autoimmunity.

h.    A glucose tolerance test has no role in the diagnosis of DKA but can be used to diagnose glucose intolerance in a child with glucosuria and normal or mildly elevated serum glucose.

i.    Glycosylated hemoglobin (HbA1) reflects blood glucose control over the last 120 days, or the life of red blood cells. Elevated levels are correlated with high serum glucose concentrations and a level of greater than or equal to 6.5% is diagnostic for diabetes (Babler et al., 2013).

511j.    CT scan is used to diagnose CE, an uncommon but ominous manifestation of DKA that clinically occurs in only about 1% of all cases (von Saint Andre-von Arnim et al., 2013).

8.    Diagnoses

a.    Differential diagnoses at presentation include adrenocortical dysfunction, high-dose steroid usage, uremia or lactic acidosis, gastroenteritis with metabolic acidosis, pancreatitis, cystic fibrosis, exogenous catecholamines, stress response (CIRCI), DI, encephalitis, alcoholic ketoacidosis, starvation, hyperosmolar syndrome, and inborn errors of metabolism.

b.    Collaborative diagnoses and comorbidities

i.    Fluid-volume deficit related to osmotic diuresis secondary to hyperglycemia

ii.    Low cardiac output related to fluid-volume deficit

iii.    Potential for CE related to treatment and hyperosmolar state

iv.    Potential for arrhythmias related to electrolyte imbalances

v.    Acid–base imbalance related to ketoacidosis

vi.    Electrolyte imbalances related to both osmotic diuresis and treatment

vii.    Potential for hypoglycemia related to treatment

viii.    Potential for self-care deficits related to lifelong treatment and monitoring with possible noncompliance

ix.    Alteration in body image related to chronic illness and future complications

x.    Alteration in healing related to chronic hyperglycemia

xi.    Potential for infection related to inflammatory response from chronic hyperglycemia

xii.    Knowledge deficit regarding home management

xiii.    Potential for depression related to chronic disease state

9.    Treatment Goals

a.    Correct fluid and electrolyte imbalances slowly

b.    Correct metabolic acidosis

c.    Infuse insulin to treat hyperglycemia and ketosis

d.    Prevent neurologic complications

e.    Maintain good glycemic control (long term)

f.    Treat underlying disorders

g.    Educate and prevent recurrence

10.  Management

a.    Fluid. Cautious rehydration in DKA is imperative to prevent CE. For accurate rehydration, knowledge of preillness weight must be known. To calculate the percentage of dehydration present, subtract illness weight from preillness weight and divide this number by preillness weight then multiply by 100% (Taketomo, Hodding, & Kraus, 2015). In most cases, the preillness weight is unknown, and fluid management is based upon estimation of mild, moderate, or severe dehydration. Hyperosmolality is present and in order to prevent CE, replacement should be done over 48 hours. Moderate DKA has an estimated dehydration of 7% to 10% and severe DKA has more than 10% dehydration. In most cases, dehydration is estimated to be 10% in all patients with DKA (von Saint Andre-von Arnim et al., 2013). When shock is present, it is necessary to administer normal saline (NS) 10 mL/kg for volume expansion. Frequent reassessment is necessary and additional boluses may be required if poor perfusion persists. NS is an isotonic fluid but because children in DKA are hyperosmolar, NS is a hypotonic fluid.

b.    Electrolytes. Potassium and phosphate replacement is imperative in DKA. If hyperkalemia is present initially, an ECG should be performed and it is necessary to wait until urine output is achieved before potassium replacement is initiated. If a normal potassium level is present, initiate replacement with a combination of potassium chloride and potassium phosphate as insulin will drive potassium and phosphate back into the cell, thus decreasing serum levels of potassium and phosphorous (Sperling et al., 2014). Attention should be paid to calcium levels during treatment as rising phosphorus levels will cause hypocalcemia. A hyperchloremic metabolic acidosis can occur during treatment with high chloride-containing fluids, and can be offset with the addition of potassium phosphate (K Phos) to fluid bags. Sodium bicarbonate administration is not routinely recommended and it should never be administered as a bolus as it can precipitate cardiac arrhythmias (Sperling et al., 2014; von Saint Andre-von Arnim et al., 2013).

512c.    Insulin. Rehydration will cause serum glucose to decrease and improve perfusion and acidosis, but an insulin infusion will always be required in DKA. Insulin is needed to normalize serum glucose levels, to suppress ketogenesis and lipolysis, and to resolve ketoacidosis (Sperling et al., 2014). Insulin infusion should begin within an hour of initial fluid replacement at 0.1 units per kilogram of body weight per hour, and should continue until there is a resolution of DKA or a closure in the anion gap. Blood glucose should drop at a rate of 80 to 100 mg/dL per hour, and will occur faster than the resolution of acidosis (Sperling et al., 2014). When the blood glucose falls to near 300 mg/dL with continued acidosis, the addition of 5% or 10% dextrose fluid should be administered via IV and titrated based on hourly glucose parameters to keep blood glucose near 200 mg/dL (von Saint von-Andre Ornim et al., 2013). Insulin dosing may be decreased to 0.05 units/kg/hr if the blood glucose continues to fall despite the addition of 10% dextrose to the IV fluids and acidosis persists. IV insulin should continue until the pH is greater than 7.3, bicarbonate is greater than 15 mmol/L, and the child is tolerating oral intake (von Saint von-Andre Arnim et al., 2013). When transitioning to subcutaneous insulin, give subcutaneous insulin 30 to 60 minutes before discontinuing the continuous infusion.

d.    The goal of insulin replacement therapy is to match the normal pattern of secretion by the body as closely as possible through basal dose therapy and to avoid wide shifts in glucose. It is done with a basal/bolus insulin regimen either through insulin pump or through multiple daily subcutaneous injections. There are more than 10 varieties of insulin formularies, which are most often categorized on the duration of action. There are rapid-acting insulins that have high and sharp peaks of effects with a short duration of therapy. The intermediate-acting insulin, neutral protamine Hagedorn (NPH), which has delayed peaks of action, was previously used in new-onset type 1 diabetes to help cover hyperglycemia (Sperling et al., 2014). Long-acting insulin medications were developed to meet the demands for basal insulin needs, and they help patients and families better manage their diabetes (Sperling et al., 2014). During the initial diagnosis time of type 1 diabetes, there is a honeymoon period that can last several months during which there is residual beta-cell function with minimal insulin requirements to maintain euglycemia and prevent ketoacidosis (Sperling et al., 2014).

e.    Monitoring. Vital signs, blood pressure, intake and output, cardiovascular assessment with continuous ECG monitoring, and neurologic checks are done hourly. Hourly glucometer determination of blood glucose is done at the bedside. Initial laboratory tests should include complete blood count (CBC), chemistry panel, urinalysis, beta-hydroxybutyrate, hemoglobin A1-C, and a blood gas. Electrolytes, beta-hydroxybutyrate, and pH are monitored every 2 to 4 hours until stable, then every 4 to 6 hours until acidosis is resolved. A gradual rise in serum sodium as the glucose levels fall helps prevent rapid changes in serum osmolality and may prevent alteration in mental state. Intake and output, weights, and urine ketones are monitored daily.

11.  Complications

a.    Acute

i.    Hypoglycemia can occur during the treatment of DKA and should be treated with dextrose-containing fluids as described earlier. Persistent acidosis can be related to inadequate fluid replacement, inadequate insulin dosing, insulin resistance, ineffective method of delivery, or a malfunctioning insulin delivery system.

ii.    Hypokalemia can occur because of inadequate potassium replacement and rapid fluid shifts.

iii.    CE occurs in about 1% of episodes of DKA, but continues to have significant mortality and morbidity. It can be apparent on presentation, 4 to 12 hours after treatment has been initiated, or even up to 22 to 48 hours into treatment (von Saint Andre-von Arnim et al., 2013). Mounting evidence supports that many patients in DKA have subclinical CE visible only on CT scans. Symptoms include severe headache, altered mental status, hypertension, bradycardia, and vomiting (Sperling et al., 2014). Risk factors for CE (Table 6.4) include first presentation, high serum BUN and CO2 (reflective of the degree of dehydration and acidosis), administration of insulin bolus doses, bicarbonate treatment, rapid glucose correction, aggressive fluid administration, and younger age at diagnosis. Treatment at recognition of CE should begin with administration of hypertonic saline or mannitol, elevate the head of the bed, and performing an emergent CT scan of the brain to evaluate CE (Klein et al., 2011). Fluid administration should be lowered and support of respiratory and neurologic status may become necessary with intubation for Glasgow Coma Scale less than 9.

iv.    Fluid overload and congestive heart failure can occur as a result of aggressive fluid management during treatment.

513TABLE 6.4    Risk Factors in DKA for Cerebral Edema

First presentation

Younger age at diagnosis

Increased BUN

Decreased CO2

Insulin bolus dosing

Precipitous drops in blood glucose

Aggressive fluid administration

Administration of sodium bicarbonate

BUN, blood urea nitrogen; DKA, diabetic ketoacidosis.

Source: Adapted from Klein, M., Sathasivam, A., Novoa, Y., & Rapaport, R. (2011). Recent consensus statements in pediatric endocrinology: A selective review. Pediatrics Clinic of North America, 58, 1301–1315. doi:10.1016/j.pcl.2011.07.014

v.    Aspiration is possible if the level of consciousness is depressed.

b.    Chronic

i.    Chronic complications of repeated episodes of DKA can have life-altering ramifications for children with diabetes. Hyperglycemia with poor metabolic control can lead to a chronic state of proinflammation, which leads to further insulin resistance. This state leads to harmful release of cytokines and impairment of the coagulation pathways (V. Srinivasan & Agus, 2014). The Diabetes Control and Complications Trial study revealed that intense glycemic control (which led to nearly normal glucose levels) significantly lowered the risk of serious long-term consequences of diabetes and had low risks of hypoglycemia (Sperling et al., 2014). Other significant chronic problems include repeat episodes of hypoglycemia and hyperglycemia, poor growth, hypertrophy and lipoatrophy of injection sites, limited joint mobility, candidiasis (opportunistic infections), retinopathy, nephropathy, neuropathy (rare in childhood), and macrovascular disease (Sperling et al., 2014).


A.    Pathophysiology

The incidence of hyperglycemic hyperosmolar syndrome (HHS) continues to be infrequent in children, but the numbers are increasing. These escalating numbers are associated with a high mortality rate and delayed diagnosis. In HHS, insulin secretion is adequate enough to prevent lipolysis, but not substantial enough to prevent hyperglycemia, thereby producing a state of relative insulin deficiency. The stress response, which includes the release of glucagon, catecholamines, cortisol, and GH, worsen hyperglycemia by increasing gluconeogenesis and glyconeolysis (Zeitler, Haqq, Rosenbloom, & Glaser, 2011). Marked hyperosmolality with significant dehydration and electrolyte losses subsequently occurs. The degree of hyperglycemia, hyperosmolality, and dehydration is much greater in HHS than in DKA and can cause significant sequelae. The absence of ketoacidosis and typical associated physical symptoms seen in DKA may reflect the delay in treatment. This delay can lead to profound shock, kidney dysfunction, altered mental status or coma, rhabdomyolysis, hyperthermia, and ventricular arrhythmias (Price, Losek, & Jackson, 2016; Zeitler et al., 2011).

B.    Precipitating Factors

In adults, the most common coexisting condition associated with HHS is type 2 diabetes. In the pediatric population, rising numbers of children with type 2 diabetes may explain the increasing numbers of HHS being seen. Recent literature reveals that children who are affected are often previously healthy, obese African American males with undiagnosed or uncontrolled type 2 diabetes. In infants, HHS is seen in those affected by transient neonatal DM (Wolfsdorf et al., 2014). It is also seen in children with preexisting cardiovascular or renal disease, infections, trauma, burns, pancreatitis, thyrotoxicosis, pneumonia, heat stroke, dialysis, IV hyperalimentation, or children with poor glucose control. Use of medications, such as phenytoin, corticosteroids, beta-blockers, and thiazide diuretics, have been associated with increased risk of HHS (Price et al., 2016; Wolfsdorf et al., 2014; Zeitler et al., 2011).

C.    Signs and Symptoms (Table 6.5)

Signs and symptoms can be vague initially and can include headache, abdominal pain, and mild signs of dehydration. Polyuria and polydipsia slowly worsen, and caregivers may fail to recognize them, resulting in delay in seeking care. Abnormal labs include serum glucose greater than 600 mg/dL, serum osmolality greater than 330 mOsm/kg, normal pH or mild metabolic acidosis, and serum bicarbonate of 18 to 24 mmol/L. Serum sodium levels may be high, low, or normal with total body sodium depletion secondary to urinary losses or dilutional hyponatremia secondary to hyperglycemia. Serum potassium levels may be high, low, or normal with total body depletion. Tachycardia, hypotension, low central venous pressure, shock, and glycosuria without ketonuria may occur. Lethargy, stupor, or coma also may occur. Neurologic impairment is significantly higher in children with HHS than in those with DKA due to hyperosmolality and its consequences. Mortality rate also increases with high osmolality levels (Price et al., 2016; Wolfsdorf et al., 2014; Zeitler et al., 2011).

514TABLE 6.5    Differentiation Between DKA and HHS

Signs and Symptoms



Nausea and vomiting



Neurologic changes






Respiratory rate

Kussmaul respirations


Blood glucose

Usually >200 mg/dL

>600 mg/dL

Blood ketones



Urine ketones


Absent to mild

Blood HCO3(–)

<18 mmol/L

>18 mmol/L

Arterial blood pH



Serum osmolality

>300 mOsm/kg

>330 mOsm/kg

Sodium deficits

4–11 mEq/kg

2–8 mEq/kg

Potassium deficits

1–10 mEq/kg

0.5–3 mEq/kg

Water deficits

50–100 mL/kg

60–170 mL/kg

DKA, diabetic ketoacidosis; HHS, hyperglycemic hyperosmolar syndrome.

D.    Interpretation of Diagnostic Studies (Table 6.5)

1.    Hyperglycemia is due to relative deficiency of insulin. Insulin levels are adequate to prevent ketosis.

2.    Glycosuria is secondary to hyperglycemia.

3.    Hyperosmolality is secondary to hyperglycemia and loss of free water with osmotic diuresis.

4.    Mild metabolic acidosis is secondary to dehydration, low cardiac output, renal insufficiency, and lactic acidosis.

5.    Electrolyte deficits are due to urinary losses.

E.    Diagnoses

1.    Differential diagnoses include sepsis, pancreatitis, renal insufficiency, and adrenocortical dysfunction.

2.    Collaborative Diagnoses and Comorbidities

a.    Fluid-volume deficit related to osmotic diuresis

b.    Low cardiac output related to fluid-volume deficit

c.    Potential for arrhythmias related to electrolyte disturbances

d.    Acid–base imbalance related to low cardiac output and lactic acidosis

515e.    Electrolyte imbalances related to osmotic diuresis and treatment

f.    Potential for CE and coma related to treatment

g.    Potential for hypoglycemia related to treatment

h.    Potential for renal failure related to rhabdomyolysis

i.    Potential for cardiovascular collapse related to hyperkalemia and hypocalcemia

F.    Treatment Goals

1.    Correct fluid and electrolyte deficits

2.    Correct hyperglycemia and hyperosmolality

3.    Prevent neurologic complications

4.    Educate about symptoms to prevent recurrence

G.    Management

1.    Fluid and electrolyte therapy involves volume resuscitation of poorly perfused, hypovolemic, or hypotensive patients with isotonic fluid via bolus. Choice of fluids would depend on the osmolality, because low osmolality fluids can lead to significant fluid shifts. Fluid-volume deficit can be calculated or assumed to be near 12% to 15% and should be replaced over 48 hours in addition to daily maintenance fluid. Due to the frequency of renal insufficiency with HHS, potassium is not added until renal function is known and urine output is adequate. Potassium levels decrease rapidly when insulin therapy is initiated secondary to potassium and glucose shifts intracellularly. Both of these imbalances will often correct adequately with fluid volume alone. Phosphorus levels are more severely affected in HHS. Potassium and phosphate replacement can be added to the IV fluids as an equal combination of KCl and KPO4 at 40 mEq/L. Once serum glucose reaches 300 mg/dL, dextrose should be added to the IV fluids. If hypomagnesemia is present with hypocalcemia, it should be corrected with dosing of 25 to 50 mg/kg/dose every 4 to 6 hours with a maximum infusion rate of 150 mg/min. Bicarbonate therapy is contraindicated due to increased risk of hypokalemia and poor tissue oxygen uptake (Zeitler et al., 2011).

2.    Insulin Therapy. Often, hyperglycemia is corrected with fluid therapy alone, but insulin may be needed in cases in which more severe ketosis and acidosis is present. Insulin therapy should be used if the drop in glucose is less than 50 mg/dL/hr with fluid therapy. Insulin should be used with caution in HHS and should never be given as a bolus dose. Low-dose insulin therapy at 0.025 to 0.05 units/kg/hr can be used to achieve a gradual decline in hyperglycemia and osmolality, with a goal of a drop of ≤100 mg/dL/hr (Zeitler et al., 2011).

3.    Monitoring. Physical assessment of cardiovascular system, vital signs, blood pressure, and neurologic checks are done at minimum every 30 to 60 minutes, with continuous cardiac monitoring. Hourly determination of blood glucose is performed at the bedside. Initial laboratory studies include CBC, electrolytes, BUN, creatinine, glucose, and pH. Serum electrolytes, BUN, creatinine, osmolality, creatine kinase, and strict input/output (I/O) are monitored every 2 hours until they become stable. Every 3 to 4 hours, serum calcium, phosphorus, and magnesium should be checked. Daily weights are also monitored (Zeitler et al., 2011).

H.    Complications

Complications include thromboembolic phenomenon, malignant hyperthermia, rhabdomyolysis, and infrequently CE or death. If DKA is coexistent, hypoglycemia and CE risks are greater (Zeitler et al., 2011). Neurologic deficits from hyperosmolality generally occur once levels greater than 330 mOsm/kg are reached but are unlikely to cause long-term morbidity. CE or death can occur as a result of rapid correction of the hyperosmolar state. Mortality is caused most frequently by severe dehydration, electrolyte disturbances, and hyperosmolality (Zeitler et al., 2011).


A.    Pathophysiology

Hypoglycemia is defined as a serum glucose level less than 50 mg/dL in all ages. Recent consensus recommendations from the Pediatric Endocrine Society define hypoglycemia using Whipple’s triad (Thornton et al., 2015). This triad includes the presence of signs and symptoms of hypoglycemia, low-plasma glucose, and resolution of the symptoms when the glucose level is raised (De León et al., 2014; Thornton et al., 2015). Glucose control in the body is balanced by dietary intake, tissue glucose uptake, and hepatic glucose production that is tightly regulated by insulin. When hypoglycemia occurs, counterregulatory hormones (glucagon, cortisol, catecholamines, and GH) are released. These hormones inhibit storage of glucose, the formation of 516glycogen, glycolysis, and lipogenesis. In addition, they stimulate glycogenolysis (stored glycogen transforms into glucose), activate lipolysis, increase gluconeogenesis, and ketogenesis to provide alternate energy sources (De León et al., 2014). Hypoglycemia inhibits release of insulin as the body shifts focus to supplying the brain with the limited glucose supply.

B.    Etiology

1.    Neonatal hypoglycemia can be transient (days to weeks) or persistent (beyond neonatal period) and is caused by immature fasting adaptation, lack of or depletion of glycogen stores, hyperinsulinemia (e.g., infants of diabetic mothers), or lack of exogenous supply. Transient cases are the most common, occurring in four per 1,000 infants and six per 1,000 premature infants (Goel & Choudhury, 2012). Transient cases often resolve within 24 to 48 hours after birth. This short-term hypoglycemia can be normal, but if it persists prompt evaluation and management must be completed to avoid long-term neurologic consequences. Infants who demonstrate persistent hypoglycemia may suffer from hypopituitarism, inborn errors of metabolism (fatty acid oxidation defects or glycogen storage diseases), congenital hyperinsulinism, or adrenocortical deficiency (Thornton et al., 2015). Persistent episodes of hypoglycemia pose significant long-term neurodevelopmental sequelae and occur in 25% to 50% of these infants (Thornton et al., 2015). Prompt recognition, intervention, and prevention are vital to avoid repeat hypoglycemic episodes and neurologic problems in these infants.

2.    Childhood hypoglycemia can be caused by inborn errors of metabolism, GHD, cortisol deficiency, hepatic dysfunction, severe malnutrition, infection, or drugs. Congenital sources of hypoglycemia are unlikely after the age of 2.

3.    Hypoglycemia in Diabetes. Hypoglycemia is one of the most acute problems that children with diabetes can encounter (Ly et al., 2014). These population of children are at particular risk due to use of medications such as exogenous insulin and oral glucose control medications (sulfonylureas). In these children, a blood glucose less than 65 mg/dL serves as a definition for hypoglycemia, while in clinical situations a blood glucose of less than 70 mg/dL is used as a guideline to treat as glucose can fall further (Ly et al., 2014). Unfortunately, repeated episodes of hypoglycemia can cause blunting of the body’s response and many children will be asymptomatic until they are severely hypoglycemic. Severe hypoglycemic episodes in the diabetic child pose a significant risk to life.

C.    Risk Factors

1.    Infants of diabetic mothers (large for gestational age with macrosomia)

2.    SGA infants or infants with intrauterine growth retardation

3.    Stress or acute infectious illness

4.    Children with insulin infusion pumps or children on other exogenous insulin support

5.    Infants or children with compromised IV access and nothing-by-mouth (NPO) status

6.    Increased metabolism or catabolic state

7.    Poor nutrition or feeding habits

8.    Medications. Beta-blockers (block the response or release of epinephrine), angiotensin-converting enzyme (ACE) inhibitors, sulfonylureas, salicylates, or alcohol ingestion

9.    Liver disease or inborn errors of metabolism, including fatty acid oxidative disorders

10.  Congenital hyperinsulinism

D.    Signs and Symptoms

1.    Associated With Counterregulatory Hormone Stimulation. Shakiness or trembling, tachycardia, sweating, anxiety, weakness, hunger, nausea, vomiting (Thornton et al., 2015)

2.    Neurologic responses to severe hypoglycemia in infants can be more subtle and difficult to detect and are seen once infants reach a plasma glucose of 50 to 55 mg/dL (Thornton et al., 2015). Symptoms include a high-pitched cry, hypothermia, tremors, poor feeding, pallor, diaphoresis, seizures, abnormal eye movements, or apnea. Every infant with seizures as a presenting complaint should have his or her glucose checked promptly. Many infants will have no symptoms and with repeat episodes of hypoglycemia all children become less responsive to the effects (Babler et al., 2013).

3.    Neurologic responses to severe hypoglycemia in children include lethargy, confusion, headache, weakness, anxiety, irritability with personality and visual changes, diaphoresis, twitches, or tremors that can lead to seizure or coma (Babler et al., 2013). Older children with intact cognitive function can verbalize their symptoms, are able to seek out sources of substrates, and correct hypoglycemia before it progresses to severe levels. Special care is 517needed in children with developmental delays who may be nonverbal or immobile.

E.    Interpretation of Diagnostic Studies

1.    Low blood glucose is a glucose level of less than 50 mg/dL. If glucose is measured by a glucometer, confirm the results with a serum laboratory sample. When low glucose is obtained, in new-onset hypoglycemia, send critical labs before correction is done to help differentiate causes of hypoglycemia (Figure 6.10; Babler et al., 2013). Critical labs include free fatty acids (FFAs), insulin, serum beta-hydroxybutyrate, cortisol, acylcarnitine profile, lactate, pyruvate, ammonia, GH, and urine ketones (Sarafoglou, Hoffmann, & Roth, 2017). Additional labs that are helpful in diagnosis of certain metabolic abnormalities are serum bicarbonate, plasma amino acids, carnitine levels, and C-peptide. Additional urine tests should be sent with the first void after the hypoglycemic event and can be a bagged sample. These urine tests include organic acids, reducing substances and toxicology screen (Sarafoglou et al., 2017).

2.    Low plasma carnitine levels can indicate medium-chain acyl-CoA deficiency (rare).

3.    Low plasma levels of GH indicate GH deficiency could have associated adrenal insufficiency.

4.    Low cortisol levels may indicate adrenal insufficiency, and could be associated with GH deficiency.

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Feb 19, 2020 | Posted by in NURSING | Comments Off on Endocrine System

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