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
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).
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).
DEVELOPMENTAL ANATOMY AND PHYSIOLOGY
A. Hypothalamic–Pituitary Complex (Neuroendocrine System)
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).
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.
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.
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).
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.
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.
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.
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.
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.
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).
Clinical Features of Hyperthyroidism
Clinical Features of Hypothyroidism
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.
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).
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).
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).
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.
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.
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).
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).
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
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).
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.
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).
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.
CLINICAL ASSESSMENT OF ENDOCRINE FUNCTION
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.
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