Nagelhout - Nurse Anesthesia (2017) PDF

37 The Endocrine System and Anesthesia MARY C. KARLET General Principles of Endocrine Physiology catecholamine hormones stored in the adrenal medulla; they are Body homeostasis is controlled by two major regulating systems: the released by the appropriat...

37 The Endocrine System and Anesthesia MARY C. KARLET General Principles of Endocrine Physiology catecholamine hormones stored in the adrenal medulla; they are Body homeostasis is controlled by two major regulating systems: the released by the appropriate stimulation.4 nervous system and the endocrine or hormonal system.1,2 Both these Steroid Hormones. All steroid hormones are lipid soluble and systems communicate, integrate, and organize the body’s response to a derived from cholesterol or have a chemical structure similar to that of changing internal or external environment.1,3 cholesterol.4 Common steroid hormones include hormones of the Organs that secrete hormones are called endocrine glands; collec- adrenal cortex (cortisol, aldosterone) and reproductive hormones tively, these glands make up the endocrine system. The purpose of the (estrogen, progesterone, testosterone). Active metabolites of vitamin D endocrine system is regulation of behavior, growth, metabolism, fluid are also steroid hormones.1 In contrast to most other hormones, steroid and electrolyte status, development, and reproduction. To accomplish hormones are not stored in discrete secretory granules but are compart- these complex processes, multiple hormones interact to produce precise mentalized within the endocrine cell and released into the extracellular biochemical and physiologic responses. fluid by simple diffusion through the cell membrane into the blood.1 Endocrine glands secrete their hormone products directly into the surrounding extracellular fluid. This distinguishes them from exocrine Transport of Hormones glands, such as salivary or sweat glands, whose products are discharged Once released into the circulation, steroid and thyroid hormones are through ducts. Important endocrine glands include the pituitary gland, bound to transport proteins. Circulating catecholamine hormones and thyroid gland, parathyroid glands, adrenal glands, pancreas, ovaries and most protein hormones are not bound to carriers. Plasma protein testes, and placenta. binding protects hormones from metabolism and renal clearance.2 The circulating half-life of steroid and thyroid hormones is therefore typi- Hormones cally much longer than that of peptide and catecholamine hormones. Endocrine function is mediated by hormones. Hormones are the sig- For example, the thyroid hormone thyroxine, which is over 99% naling molecules or chemical messengers that transport information protein bound, has a plasma half-life of 6 to 7 days, whereas insulin, from one set of cells (endocrine cells) to another (target cells). Hor- which has essentially no plasma protein binding, has a half-life of mones are released from endocrine glands into body fluids in minute approximately 7 minutes.1 quantities, but they exert powerful control over most metabolic The major sites of hormone degradation and elimination are the functions.1,2,4 liver and the kidneys, respectively. Some hormone degradation also Transmission of a hormonal signal through the bloodstream to a occurs at target-cell sites.1,2,4 distant target cell (e.g., pituitary gland to the adrenal gland) is called an endocrine function. If a hormone signal acts on a neighboring cell of Hormone Receptors a different type (e.g., pancreas α cells to pancreas β cells), the interac- Binding to a specific target-cell receptor is the primary event that initi- tion is termed a paracrine function. If the secreted hormone acts on the ates a hormone response.2 The hormone receptor displays high specific- producer cell itself, the interaction is called an autocrine function.4 ity and affinity for the proper hormone ligand, and the location of the receptor directs the hormone to the specific target organ or target-cell Types of Hormones site.3 Some hormones, such as insulin and GH, act on widespread target Hormones can be classified into three major categories: (1) proteins or sites; others, such as thyroid-stimulating hormone (TSH), act on one peptides, (2) tyrosine amino acid derivatives, and (3) steroids. Table target tissue. After binding, the hormone-receptor complex induces a 37.1 outlines common endocrine glands, hormones, their functions, cascade of intracellular events that produce specific physiologic and their structures. responses in the target cell.2 Peptide or Protein Hormones. Most hormones in the body have a Hormone Receptor Activation. Hormone receptors are located (1) peptide or protein structure. This group of hormones includes insulin, on the surface of the target cell membrane, (2) in the target cell cyto- growth hormone (GH), vasopressin (antidiuretic hormone [ADH]), plasm, or (3) in the target cell nucleus.4 Receptors for protein, peptide, angiotensin, prolactin, erythropoietin, calcitonin, somatostatin, adre- and catecholamine hormones are located in or on the surface of the nocorticotropic hormone (ACTH), oxytocin, glucagon, and parathy- target-cell membrane. Hormone binding to a cell membrane receptor roid hormone. Peptide hormones are synthesized in endocrine cells as triggers a response by activating enzyme systems in or near the plasma prehormones and prohormones. They are processed by the cell and membrane bilayer. The activated enzymes generate intracellular signals, stored in secretory granules within the endocrine gland.1,2,4 The proper called second messengers, which carry the hormone’s message within the stimulus to secretion causes exocytosis of the peptide or protein intracellular space. hormone into the extracellular fluid. Several different second-messenger systems operate in response to Protein hormones, such as insulin, erythropoietin, and GH, can cell membrane receptor-hormone binding. Probably the most widely now be synthesized for therapeutic purposes by recombinant deoxyri- described second-messenger system is the cyclic adenosine monophos- bonucleic acid (DNA) techniques. phate (cAMP) system. This transduction mechanism is initiated when Tyrosine Amino Acid Derivative Hormones. Thyroid hormones hormone-receptor occupation activates the plasma membrane enzyme (thyroxine and triiodothyronine) and catecholamine hormones (dopa- adenyl cyclase. The membrane-bound adenyl cyclase then catalyzes the mine, epinephrine, and norepinephrine) are derived from the amino intracellular conversion of adenosine triphosphate to cAMP; cAMP acid tyrosine. Thyroid hormones are stored in the thyroid gland and in turn becomes the hormone’s intracellular messenger, activating 782  C HAP TE R 37 The Endocrine System and Anesthesia 783 T A B L E 3 7.1 Common Endocrine Glands, Hormones, Their Functions, and Structures Gland/Tissue Hormones Major Functions Chemical Structure Hypothalamus Thyrotropin-releasing hormone Stimulates secretion of thyroid-stimulating hormone and prolactin Peptide Corticotropin-releasing hormone Causes release of adrenocorticotropic hormone Peptide Growth hormone–releasing hormone Causes release of growth hormone Peptide Growth hormone inhibitory hormone Inhibits release of growth hormone Peptide (somatostatin) Gonadotropin-releasing hormone Causes release of luteinizing hormone and follicle-stimulating hormone Dopamine or prolactin-inhibiting factor Inhibits release of prolactin Amine Anterior pituitary Growth hormone Stimulates protein synthesis and overall growth of most cells and tissues Peptide Thyroid-stimulating hormone Stimulates synthesis and secretion of thyroid hormones (thyroxine and Peptide triiodothyronine) Adrenocorticotropic hormone Stimulates synthesis and secretion of adrenocortical hormones (cortisol, Peptide androgens, and aldosterone) Prolactin Promotes development of the female breasts and secretion of milk Peptide Follicle-stimulating hormone Causes growth of follicles in the ovaries and sperm maturation in Sertoli Peptide cells of testes Luteinizing hormone Stimulates testosterone synthesis in Leydig cells of testes; stimulates Peptide ovulation, formation of corpus luteum, and estrogen and progesterone synthesis in ovaries Posterior pituitary Antidiuretic hormone (also called vasopressin) Increases water reabsorption by the kidneys and causes vasoconstriction Peptide and increased blood pressure Oxytocin Stimulates milk ejection from breasts and uterine contractions Peptide Thyroid Thyroxine (T4) and triiodothyronine (T3) Increases the rates of chemical reactions in most cells, thus increasing Amine body metabolic rate Calcitonin Promotes deposition of calcium in the bones and decreases extracellular Peptide fluid calcium ion concentration Adrenal cortex Cortisol Has multiple metabolic functions for controlling metabolism of proteins, Steroid carbohydrates, and fats; also has anti-inflammatory effects Aldosterone Increases renal sodium reabsorption, potassium secretion, and hydrogen Steroid ion secretion Adrenal medulla Norepinephrine, epinephrine Same effects as sympathetic stimulation Amine Pancreas Insulin (β cells) Promotes glucose entry in many cells, and in this way controls Peptide carbohydrate metabolism Glucagon (α cells) Increases synthesis and release of glucose from the liver into the body Peptide fluids Parathyroid Parathyroid hormone Controls serum calcium ion concentration by increasing calcium Peptide absorption by the gut and kidneys and releasing calcium from bones Testes Testosterone Promotes development of male reproductive system and male secondary Steroid sexual characteristics Ovaries Estrogens Promotes growth and development of female reproductive system, Steroid female breasts, and female secondary sexual characteristics Progesterone Stimulates secretion of “uterine milk” by the uterine endometrial glands Steroid and promotes development of secretory apparatus of breasts Placenta Human chorionic gonadotropin Promotes growth of corpus luteum and secretion of estrogens and Peptide progesterone by corpus luteum Human somatomammotropin Probably helps promote development of some fetal tissues, as well as Peptide the mother’s breasts Estrogens See actions of estrogens from ovaries Steroid Progesterone See actions of progesterone from ovaries Steroid Kidney Renin Catalyzes conversion of angiotensinogen to angiotensin I (acts as an Peptide enzyme) 1,25-Dihydroxycholecalciferol Increases intestinal absorption of calcium and bone mineralization Steroid Erythropoietin Increases erythrocyte production Peptide Heart Atrial natriuretic peptide Increases sodium excretion by kidneys, reduces blood pressure Peptide Stomach Gastrin Stimulates hydrogen chloride secretion by parietal cells Peptide Small intestine Secretin Stimulates pancreatic acinar cells to release bicarbonate and water Peptide Cholecystokinin Stimulates gallbladder contraction and release of pancreatic enzymes Peptide Adipocytes Leptin Inhibits appetite, stimulates thermogenesis Peptide From Hall JE. Guyton and Hall Textbook of Medical Physiology. 13th ed. Philadelphia: Elsevier; 2016:927. 784 U NIT V Intraoperative Management insulin, for example, has a normal half-life of only approximately 7 resting state hours.2 Regulation of receptor turnover, and thus hormone receptor number, is a mechanism by which hormone activity can be precisely extracellular G-protein modulated. Hormone receptor destruction may be part of a normal endocrine response or part of an acquired or genetic disease state. cell In many instances, the hormone receptor number is inversely membrane receptor β related to the concentration of the circulating hormone. A sustained α γ elevation of the plasma level of a given hormone may cause the target intracellular site to decrease the number of receptors per cell. This down-regulation GDP of receptor number serves to decrease the responsiveness of a target cell to hormone excess.1 The insulin resistance observed in obesity and type hormone present 2 diabetes mellitus (DM) may be partly explained by down-regulation hormone of the insulin receptors in response to chronically high levels of circulat- ing insulin.2 effector proteins Conversely, a low circulating hormone concentration may cause the cell receptor target gland to increase the number of hormone receptors per cell. This membrane up-regulation of hormone receptor number amplifies the cell’s sensitiv- β ity to hormone stimulation.1,2 α γ Regulation of Hormone Secretion. The synthesis and secretion of hormones by endocrine glands are regulated by three general control (GDP lost, GTP cAMP 2nd mechanisms: neural controls, biorhythms, and feedback mechanisms. GTP gained) messenger Neural controls can evoke or suppress hormone secretion. Pain, emotion, smell, touch, injury, stress, sight, and taste can alter hormone intracellular release through neural mechanisms.5 Glucagon, cortisol, ADH, and actions catecholamines, for example, are all stimulated by the stress response to surgery and trauma. Deep general anesthesia or regional anesthesia FIGURE 37.1 Mechanism of action of a G-protein receptor. cAMP, Cyclic blunts this stress response, but does not eliminate it. adenosine monophosphate; GDP, guanosine diphosphate; GTP, guanosine The secretion of other hormones is governed by genetically encoded triphosphate. (From O’Neill R, Murphy R. Crash Course: Endocrinology: or acquired biorhythms. These intrinsic hormonal oscillations may be Updated. 4th ed. Philadelphia: Elsevier; 2015:7.) circadian (e.g., the daily variability in glucocorticoid secretion), weekly (e.g., the menstrual cycle), or seasonal (e.g., thyroxine production).3,5 The biorhythms also may vary at different stages of development and intracellular enzymes, modifying cell-membrane permeability or trans- life (e.g., GH secretion).6 port, and altering cellular gene expression1 (Fig. 37.1). The enzyme Feedback control is another sophisticated mechanism through phosphodiesterase catalyzes the hydrolysis of cAMP and terminates its which a hormonal response is controlled. Many endocrine disorders intracellular actions. Hormones that use cAMP as their second mes- arise from the breakdown of feedback loops.1,2 Negative feedback acts senger include TSH, vasopressin (V2 receptor), parathyroid hormone, to limit or terminate the production and secretion of a given hormone glucagon, catecholamines (β-receptors), follicle-stimulating hormone once the appropriate response has occurred. Negative feedback of a (FSH), and luteinizing hormone (LH). target-cell product to the hormone producer (the endocrine gland) Other intracellular second messengers include calcium, diacylglyc- limits or prevents hormone excess. When concentrations of the product erol, inositol triphosphate, and cyclic guanosine monophosphate. The are low, feedback inhibition to the endocrine gland is lessened and primary intracellular messenger has not been identified for many hormone secretion enhanced. hormones. Virtually all hormones are controlled by some type of negative In contrast to peptide and catecholamine hormones, thyroid and feedback mechanism.3,6 For example, parathyroid hormone is con- steroid hormones produce the desired target-cell response chiefly by trolled by calcium, insulin and glucagon are controlled by glucose, and interacting with specific intracellular hormone receptors.1 Thyroid and vasopressin is controlled by serum osmolarity.5 The negative feedback steroid hormones are small, lipophilic molecules that enter target cells mechanism is a very important system for the regulation of hormones by simple diffusion or by special transport mechanisms. Once within of the hypothalamus and pituitary gland. Hypothalamic hormones the cell, these hormones occupy specific intracellular receptors.2 In stimulate the release of pituitary hormones from the pituitary gland. combination with their receptors, the hormones interact with DNA in The pituitary hormones in turn may stimulate an output of product the cell nucleus to enhance or suppress gene transcription or transla- from peripheral target cells. Product from peripheral target tissues may tion.2 Thyroid and steroid hormones cause target cells to synthesize then initiate feedback to the pituitary gland or the hypothalamus to proteins that function as enzymes and transport either proteins or inhibit pituitary or hypothalamic hormone synthesis and discharge.2 structural proteins. Fig. 37.2 shows negative feedback control of the hypothalamic- Every hormone has a specific onset and duration of action. Hor- pituitary axis. mones that act by binding to cell membrane receptors (peptide, protein, Positive feedback is a less common hormone-regulating mechanism and catecholamine hormones) usually generate a hormonal effect in in which a given hormone response initiates signals amplifying hormone seconds to minutes. Hormones that bind to intracellular receptors and release. The surge in LH that precedes ovulation is stimulated by LH; activate the transcription processes of specific genes (thyroid and steroid this is an example of positive feedback.2 hormones) may require several hours or even days to generate a hor- monal response.1,4 Pituitary Gland Hormone Receptor Regulation. Each target cell that is stimulated by a hormone has 2000 to 100,000 receptors specific to that hormone. Relationship Between Pituitary Gland and Hypothalamus These receptors are dynamic molecules that are constantly being The pituitary gland, or hypophysis, is known as the master endocrine destroyed and replaced, changing from day to day.4 The receptor for gland.7 It secretes hormones that have far-reaching effects on various  C HAP TE R 37 The Endocrine System and Anesthesia 785 Thyroid gland Growth hormone Thyrotropin Anterior pituitary gland Ovary ACTH Prolactin Follicle-stimulating hormone Adrenal Mammary Luteinizing hormone cortex gland FIGURE 37.4 Major target sites for anterior pituitary hormones. ACH, Adre- nocorticotropic hormone. sensations, electrolyte concentrations) from almost all parts of the body and uses this information to control the secretion of vital pituitary hormones.5,6 Pituitary hormone secretion also is regulated by feed- FIGURE 37.2 Negative feedback control of hypothalamic-pituitary axis. (From Nicholson G, Hall GM. Hypothalamic-pituitary-adrenal function: back control from peripheral target-organ hormones or other target- anaesthetic implications. Anaesth Int Care Med. 2014;15(10):473–476.) organ products. The pituitary gland and hypothalamus have virtually no blood-brain barrier, allowing feedback products to exert potent effects.8,9 Functionally and histologically, the pituitary gland is divided into HYPOTHALAMUS two distinct portions: the anterior lobe (adenohypophysis) and the Median Mammillary eminence posterior lobe (neurohypophysis).5,6 The anterior pituitary lobe is body embryologically derived from an upward invagination of pharyngeal Optic chiasm epithelial cells (Rathke pouch). The posterior pituitary lobe develops Superior from a downward outpouching of ectoderm from the brain. hypophyseal artery Pons Anterior Pituitary Lobe Portal vessel The anterior pituitary lobe, which constitutes approximately 80% of Sphenoid the pituitary gland by weight, secretes six major peptide hormones.6 sinus Inferior Target sites for the anterior pituitary hormones are shown in Fig. 37.4. hypophyseal In addition to secreting the six “classic” hormones, the pituitary also artery secretes other hormones, including melanocyte stimulating hormone, Anterior lobe beta-endorphins, substance P, and others. Intermediate lobe Posterior lobe 1. Growth hormone (GH, somatotropin) promotes skeletal develop- ment and body growth, stimulates insulin-like growth factor-1 FIGURE 37.3 The pituitary gland is located at the base of the brain. It is connected to the overlying hypothalamus by the pituitary or hypophysial (IGF-1), and inhibits action of insulin on carbohydrate and fat stalk. metabolism. 2. Corticotropin or adrenocorticotropic hormone (ACTH) regulates the growth of the adrenal cortex and the release of cortisol and androgenic hormones from the adrenal gland. ACTH possesses homeostatic, developmental, metabolic, and reproductive functions of mild melanocyte-stimulating properties, resulting in skin pigmenta- the body. The pituitary is a small endocrine gland (only 500–1000 mg tion at high levels. in weight and approximately the size of a pea) centrally located at the 3. Thyroid-stimulating hormone (thyrotropin or TSH) controls the base of the brain. It is enclosed within a bony cavity of the sphenoid growth and metabolism of the thyroid gland and the secretion bone called the sella turcica.5,6 The pituitary gland is connected to the of thyroid hormones (thyroxine and triiodothyronine), which overlying hypothalamus by the hypophysial stalk (pituitary stalk). The regulate intracellular metabolic activity in virtually all cells of hypothalamus is located below the thalamus, behind the optic chiasm the body.6 and between the optic tracts. The pituitary, hypothalamus, and some 4. Follicle-stimulating hormone (FSH) stimulates ovarian follicle of the surrounding structures are shown in Fig. 37.3. development in females and spermatogenesis in males. The brain, via the hypothalamus, is an important regulator of pitu- 5. Luteinizing hormone (LH) induces ovulation and corpus luteum itary gland secretion. The hypothalamus collects and integrates infor- development in females and stimulates the testes to produce testos- mation (e.g., pain, emotions, energy needs, water balance, olfactory terone in males. 786 U NIT V Intraoperative Management 6. Prolactin promotes mammary gland development and milk produc- Anterior Pituitary Disorders tion (lactogenesis) by the breasts. Prolactin also exerts an effect on Disorders involving the anterior pituitary system may be due to a defect reproductive function by inhibiting the synthesis and secretion of at the peripheral endocrine gland (primary disorder), the pituitary LH and FSH. Prolactin synthesis is markedly increased during gland (secondary disorder), or the hypothalamus (tertiary disorder).5 pregnancy. Pituitary tumors account for approximately 15% of all intracranial Anterior pituitary hormones are synthesized and secreted by five dis- tinct endocrine cell types within the gland: somatotrophs synthesize 3 1 GH; gonadotrophs synthesize the two gonadotropic hormones, LH (±) and FSH; thyrotrophs synthesize TSH; corticotrophs synthesize (–) 2 (+) ACTH; and lactotrophs (mammotrophs) synthesize prolactin. Approx- imately 30% to 40% of the anterior pituitary cells are somatotrophs Optic tract and approximately 20% are corticotrophs.6 Median eminence Superior Control of Anterior Pituitary Hormone Secretion hypophyseal Long portal vessels artery Synthesis of anterior pituitary hormones is controlled by signals from the hypothalamus. Neurosecretory cells in various hypotha- Middle Posterior hypophyseal lamic nuclei respond to input from the body by synthesizing spe- pituitary artery cific neurohormones that have corresponding anterior pituitary target-cell types.6 Anterior Inferior Internal Hypothalamic neurohormones are released into a capillary bed of hypophyseal pituitary carotid the hypothalamus in an area called the median eminence. The hypotha- artery artery lamic hormones travel from the capillary plexus of the median emi- Short portal vessels nence, down the pituitary stalk, in a specialized vascular system called the hypothalamic-hypophysial portal vessels (Fig. 37.5). At the anterior pituitary lobe, the hypothalamic hormones are released in high con- FIGURE 37.5 Neuroendocrine organization of the hypothalamus and pitu- centrations into capillary sinuses located among the glandular cells.6 itary gland. The posterior pituitary is fed by the inferior hypophyseal artery The hypothalamic hormones then locate and bind to their specific and the hypothalamus by the superior hypophyseal artery, both branches of target-cell type. the internal carotid artery. Most of the blood supply to the anterior pituitary Specific hypothalamic hormones have either an inhibitory or a is venous by way of the long portal vessels, which connect the portal capil- stimulatory effect on their corresponding anterior pituitary target lary beds in the median eminence to the venous sinusoids in the anterior cells. Synthesis and release of most anterior pituitary hormones pituitary. Hypophysiotropic neuron 3 in the parvocellular division of the depend on a positive stimulatory signal from a given hypotha- paraventricular nucleus and neuron 2 in the arcuate nucleus are shown to terminate in the median eminence on portal capillaries. These neurons of lamic hormone. Some anterior pituitary cells are subject to both the tuberoinfundibular system secrete hypothalamic releasing and inhibit- inhibitory and stimulatory control by more than one hypothalamic ing hormones into the portal veins for conveyance to the anterior pituitary neurohormone.5 gland. Neuron 2 is innervated by monoaminergic neurons. Note that the Synthesis of prolactin from anterior pituitary lactotroph cells multiple inputs to such neurons, using neuron 2 as an example, can be is unique in that it is tonically restrained by inhibitory hormonal stimulatory, inhibitory, or neuromodulatory, in which another neuron may signals (dopamine) from the hypothalamus. In essence, these inhibi- affect neurotransmitter release. Neuron 1 represents a peptidergic neuron tory signals serve as a “physiologic brake” for lactotroph growth originating in the magnocellular division of the paraventricular nucleus or and prolactin synthesis. The inhibitory effect of dopamine agonists, supraoptic nucleus and projecting directly to the posterior pituitary by way such as bromocriptine or cabergoline, is exploited therapeutically of the hypothalamic-neurohypophyseal tract. (In Goldman L, Schafer AI. for suppressing pathologic production of prolactin from pituitary Goldman-Cecil Medicine. 25th ed. Philadelphia: Elsevier; 2016:1473. From tumors.5,7 Table 37.2 outlines the major hypothalamic releasing or Gay VL. The hypothalamus: physiology and clinical use of releasing factors. inhibiting hormones and their corresponding anterior pituitary Fertil Steril. 1972;23:50–63, with permission of the American Society for target sites. Reproductive Medicine.) TABLE 37.2 Hypothalamic Hormones and Corresponding Anterior Pituitary Hormones Hypothalamic Releasing/ Anterior Pituitary Anterior Pituitary Hormone Primary Peripheral Hormone Inhibiting Hormones Target-Cell Type Produced Hormone Target Site Involved in Negative Feedback Thyrotropin-releasing hormone Thyrotroph Thyroid-stimulating hormone Thyroid gland Triiodothyronine (T3) (TSH, thyrotropin) Corticotropin-releasing hormone Corticotroph Adrenocorticotropic hormone Zona fasciculata and zona reticularis Cortisol (ACTH, corticotropin) of adrenal cortex Gonadotropin-releasing Gonadotroph Follicle-stimulating hormone Gonads (testes, ovaries) Estrogen, progesterone, testosterone hormone Luteinizing hormone Prolactin-inhibitory factor Lactotroph Inhibits prolactin None (dopamine, PIF) Growth hormone–releasing Somatotroph Growth hormone All tissues Growth hormone, insulin growth hormone factor-1 Growth hormone–inhibitory Somatotroph Inhibits growth hormone Growth hormone, insulin growth factor (somatostatin) factor-1  C HAP TE R 37 The Endocrine System and Anesthesia 787 tumors.10 Most pituitary tumors, both functional, secreting tumors and of GH is the liver, where it stimulates the production of somatomedin nonfunctional, nonsecreting tumors, are benign adenomas. Pituitary C (also called IGF-1). Somatomedin C and other somatomedins carcinoma is exceedingly rare.7,10 mediate many of GH’s effects.6,10 Skeletal muscle, the heart, skin, and Hyposecretion. Anterior pituitary hormone deficiency states may visceral organs undergo hypertrophy and hyperplasia in response to occur when large nonfunctional pituitary tumors (e.g., chromophobe GH and somatomedins.6,10,15 adenoma, craniopharyngioma, Rathke pouch cysts) compress and The most obvious effect of GH is on the skeletal frame. It produces destroy normal anterior pituitary cells. Postpartum hemorrhagic shock linear bone growth by stimulating the epiphyseal cartilage or growth causing pituitary apoplexy (Sheehan syndrome), irradiation, trauma, plate at the ends of long bones. Throughout childhood, under the and infiltrative disorders (e.g., sarcoidosis, amyloidosis) are less common influence of GH, bone forming cells, called osteoblasts are stimulated. causes of pituitary hyposecretion. Generalized pituitary hypofunction Bones elongate at the epiphyseal plate, and the skeletal frame enlarges. (panhypopituitarism) is more common than reduced output of a single After puberty, the growth plates unite with the shaft of the bone, anterior pituitary hormone.7,11 bone lengthening stops, and GH has no further capacity to increase Important effects of panhypopituitarism include a decrease in bone length.6 thyroid function due to reduction in levels of TSH, depression of GH and IGF-1 support growth by increasing amino acid transport glucocorticoid production by the adrenal cortex due to the lowering of into cells and enhancing protein synthesis in the cell. GH also decreases ACTH levels, and suppression of sexual development and reproductive the catabolism of existing proteins by stimulating lipolysis and mobiliz- function due to deficient gonadotropic hormone secretion.6 In addi- ing free fatty acids for energy use, a protein-sparing effect. In addition tion, large pituitary tumors (macroadenomas greater than 1 cm) may to its growth-promoting activities, GH is said to be a “diabetogenic extend into or compress the surrounding brain tissue, producing dip- hormone.” It increases blood glucose levels by decreasing the sensitivity lopia, visual loss, facial numbness, facial pain, or seizures.12 of cells to insulin (promoting insulin resistance) and inhibiting glucose Surgical intervention may be implemented for decompression or uptake into cells.6,15 removal of the pituitary tumor or to control bleeding. Surgical patients As is true of other anterior pituitary hormones, GH secretion is with hypopituitary disorders will require glucocorticoid coverage in the subject to negative feedback control. GH, as well as IGF-1, exert perioperative period.13 Because of the possibility of diabetes insipidus negative feedback control on the pituitary and hypothalamus. GH after removal of the tumor, vasopressin should also be available. release is also inhibited by hyperglycemia and increased plasma free Hypersecretion. Most pituitary tumors are benign hypersecreting fatty acids.5 pituitary adenomas.12 The three most common hypersecreting pituitary Hyposecretion. Deficient GH production in childhood can result tumors are those that produce prolactin, ACTH, or GH. Tumors that in insufficient bone maturation and short stature, a condition known secrete gonadotropin and thyrotropin hormones are rare. Pituitary as dwarfism. Mild obesity, decreased lean body mass, and hypoglycemia tumors may also be inherited as part of multiple endocrine neoplasia are common in GH-deficient dwarfs. Puberty is usually delayed. Symp- (MEN) type 1.10,14 toms of GH deficiency may be the result of hypothalamic dysfunction, Preparation of the patient awaiting pituitary surgery is guided in pituitary disease, failure to generate normal insulin growth factor hor- part by the results of preoperative endocrine tests. Hypersecreting pitu- mones, or GH-receptor defects.6,7 itary tumors may become so large that they compress and destroy The biosynthesis of human GH by recombinant DNA techniques normal anterior pituitary cells, producing a deficiency in some anterior has enhanced the outlook for patients with GH deficiency. Treatment pituitary hormones. of these patients with GH leads to a positive nitrogen balance, accretion Prolactin-secreting tumors commonly produce symptoms of galac- of lean body mass, and an improvement in metabolic homeostasis.7 torrhea, amenorrhea, and infertility in women, and decreased libido Hypersecretion. Hypersecretion of GH, usually caused by a GH– and impotence in men.12 Dopamine agonists (cabergoline, bromo- secreting pituitary adenoma (99% of cases), can produce a highly criptine) are used to control prolactin levels, decrease tumor size, and distinctive syndrome in adults called acromegaly. Acromegaly is pro- restore normal gonadal function. Patients who have a suboptimal duced by the excessive action of GH and IGF-1 after adolescence, response to medical therapy benefit from microsurgical removal of the leading to anatomical changes and metabolic dysfunction.12,15,16 If pituitary tumor.12 hypersecretion of GH occurs before puberty, that is, before closure Specific anesthetic management implications for patients with of the growth plates, all body tissues grow and the individual excess ACTH (Cushing disease) and excess GH (acromegaly) are grows very tall (8 to 9 feet), an extremely rare condition known as described in this chapter. gigantism. Because growth plates close with adolescence, the excessive produc- Growth Hormone tion of GH associated with acromegaly does not induce bone lengthen- GH (somatotropin) is synthesized and secreted by somatotroph cells of ing but rather enhances the growth of periosteal bone by the stimulatory the anterior pituitary lobe and is under dual control by the hypothala- effects of GH on bone osteoblasts. Periosteal growth causes new bone mus.6 GH–releasing hormone stimulates GH release, and GH– to be deposited on the surface of existing bone.6 The unrestrained bone inhibiting hormone (somatostatin) is a powerful inhibitor of GH growth in patients with acromegaly produces bones that are massive in release. size and thickness. Bones of the hands and feet (acral) become particu- Pulsatile fluctuations of the hypothalamic releasing and inhibiting larly large, almost twice normal size. hormones regulate somatotroph activity throughout the day.5 In addi- Soft-tissue changes are also prominent with GH hypersecretion. The tion, GH secretion is stimulated by stress, trauma, hypoglycemia, exer- patient develops coarsened facial features (acromegalic facies) that cise, and deep sleep.5,6 The GH secretion rate is generally increased in include a large, bulbous nose, supraorbital ridge overgrowth, dental childhood, followed by a further increase in adolescence, a plateau in malocclusion, and a prominent prognathic mandible.10 The changes in adulthood, and declining values in old age. The normal physical decline appearance are insidious, and many patients do not seek treatment until associated with aging may be due, in part, to the age-related decline in the diagnosis is obvious and the disease course advanced.10,17 GH production.5,6 Overgrowth of internal organs is less apparent clinically but no less Unlike the other anterior pituitary hormones, GH does not exert serious. The liver, heart, spleen, and kidneys become enlarged. Pulmo- its principal effects through a specific target gland but functions nary function tests are consistent with increased lung volumes, but gas through all or almost all tissues of the body; it promotes the growth exchange is usually not grossly abnormal.10 Exercise tolerance may be and development of most tissues capable of growing.6 A major target limited due to increased body mass and skeletal muscle weakness. 788 U NIT V Intraoperative Management antagonist), and gland irradiation are adjunctive treatments for tumor BOX 37.1 regression or treatment options for patients who are not surgical can- didates.10,16,21 A further discussion of anesthesia for pituitary surgery Common Features of Acromegaly can be found in Chapter 31. Anesthetic Implications of Acromegaly. Preanesthetic assessment Skeletal overgrowth (enlarged hands and feet, prominent prognathic mandible) of patients with acromegaly should include a careful examination of Soft-tissue overgrowth (enlarged lips, tongue, and epiglottis; distortion of facial the airway. Facial deformities and the large nose may hamper adequate features) fitting of an anesthesia mask. Endotracheal intubation may be a chal- Visceromegaly lenge because of the patient’s large and thick tongue (macroglossia), Hypertension prognathism, enlarged thyroid gland, hypertrophy and distortion of Osteoarthritis the epiglottis, and general soft-tissue overgrowth in the upper Glucose intolerance Peripheral neuropathy airway.12,17,24–27 Subglottic narrowing and vocal-cord enlargement may Skeletal muscle weakness dictate the use of a smaller-diameter endotracheal tube. Nasotracheal Extrasellar tumor extension (headache, visual field defects) intubation should be approached cautiously because of possible turbi- nate enlargement.11 The occurrence of Mallampati III and IV grades is higher in patients with acromegaly, and the incidence of difficult intu- bations may be four to five times higher than patients without acro- Cardiomyopathy and hypertension in patients with acromegaly can megaly.24,26 Preoperative dyspnea, stridor, or hoarseness should alert the lead to symptomatic cardiac disease (e.g., diastolic dysfunction, heart anesthetist to airway involvement.11 Indirect laryngoscopy and com- failure).17,18 Hypertension occurs in more than 40% of patients and puted tomography (CT) of the neck may be performed for thorough evidence of left ventricular hypertrophy is common.12,15 Baseline echo- assessment. Airway adjuncts should be readily available during induc- cardiography is indicated.15 tion of anesthesia. If difficulties in maintaining an adequate airway are The insulin-antagonistic effect of GH produces glucose intolerance anticipated, optically-guided intubation or fiberoptic-guided intuba- in most patients and frank diabetes in up to 25% of patients with tion in an awake patient is of proven value.12,13,17 Equipment for tra- acromegaly.7 cheostomy should be available if airway changes are advanced.12 The Clinical manifestations resulting from the local effects of the endotracheal tube should remain in place until the patient is fully expanding tumor may include headaches, papilledema, and visual field awake and has total return of reflexes. defects. Significant increases in intracranial pressure are uncommon. Arthropathy affects approximately 75% of acromegaly patients.15 Compression or destruction of normal pituitary tissue by the tumor Overgrowth of vertebrae may cause kyphosis and osteoarthritis and may eventually lead to panhypopituitarism.7 Common features of acro- may make central neuraxial anesthesia a challenge. megaly are summarized in Box 37.1. Up to 70% of patients with acromegaly have a history of sleep Acromegaly is associated with decreased life expectancy, with cardiac apnea.13,15,17 The predisposition to airway obstruction in these patients and respiratory complications being the most common cause of makes assiduous perioperative monitoring of the patient’s respiratory death.10,15 Hormonal control has a definite impact on survival. Lower- status an absolute precaution.12,15,17 ing serum GH levels results in reduction of the mortality rate to levels The frequent occurrence of cardiomyopathy, coronary artery disease, comparable with the general population.19,20 and hypertension in acromegalic patients warrants a thorough preanes- Treatment for acromegaly is aimed at restoring normal GH levels thetic cardiac evaluation. Hyperglycemia may complicate the periop- through surgical, pharmacological, and radiotherapeutic approaches.16 erative period, mandating careful perioperative monitoring of blood The preferred initial therapy, especially for small, well-circumscribed glucose and electrolyte levels.15,17 adenomas, is microsurgical removal of the pituitary tumor, with pres- Stress-level glucocorticoid therapy is often administered to address ervation of the gland.12 Surgery achieves biochemical cure in approxi- any impairment of the adrenal axis.12 Entrapment neuropathies, such mately 70% to 90% of microadenomas (less than 1 cm). Cure rates for as carpal tunnel syndrome, are common in patients with acromegaly. macroadenomas by surgery are lower (approximately 50%).7,10,21 Hypertrophy of the carpal ligament may cause inadequate ulnar artery The surgical approach to the pituitary tumor is most often via the flow, which should be considered in the decision to place a radial arte- endonasal transsphenoidal route, and this route is generally well toler- rial catheter.7,11 ated by most patients10,13,22 (see Fig. 31.19). A transcranial approach may be used for very large tumors with suprasellar extension.13 Posterior Pituitary Lobe For transsphenoidal pituitary surgery, the head of the bed is typi- The posterior pituitary lobe secretes two important peptide hormones: cally elevated 15 degrees to improve venous drainage. Venous air embo- antidiuretic hormone (vasopressin or ADH) and oxytocin. Oxytocin lism is usually not a concern, unless there is cavernous sinus invasion and ADH are almost identical structurally, but they have quite different by the tumor and the patient is positioned in a steep head-up tilt. actions. ADH controls water excretion and reabsorption in the kidney The approach and exposure of the tumor is not usually associated and is a major regulator of serum osmolarity. Oxytocin stimulates with significant blood loss.10,22 The use of submucosal injection of contraction of myoepithelial cells of the breast for milk ejection during epinephrine-containing solutions or topical vasoconstrictors to assist in lactation. It also powerfully stimulates uterine smooth muscle contrac- hemostasis may result in blood pressure increases.23 An anesthetic tech- tion during delivery of the baby at the end of gestation.5 Oxytocin and nique that incorporates muscle relaxation and allows for smooth extu- its derivatives are used clinically for inducing labor and decreasing bation and rapid neurologic assessment is desirable.10,22 The patient postpartum bleeding. should be prepared preoperatively for awakening with nasal packing. In contrast to the anterior pituitary lobe, which communicates with Surgical complications are not common, but may include epistaxis, the hypothalamus via a vascular system, the posterior pituitary lobe transient diabetes insipidus, cranial nerve damage, hyponatremia, and communicates with the hypothalamus through a neural pathway. cerebral spinal fluid leaks.17 Surgical ablation is usually successful in Unlike anterior pituitary hormones, posterior pituitary hormones are rapidly reducing tumor size, inhibiting GH secretion, and alleviating not synthesized within the pituitary gland itself but rather within two some symptoms.7,17,22 large nuclei of the hypothalamus, the supraoptic nucleus and the para- Administration of octreotide or lanreotide (somatostatin receptor ventricular nucleus. ADH is chiefly synthesized in the supraoptic ligands), cabergoline (a dopamine agonist), pegvisomant (a GH-receptor nucleus and oxytocin in the paraventricular nucleus.5,6,28 As shown in  C HAP TE R 37 The Endocrine System and Anesthesia 789 Paraventricular BOX 37.2 nucleus Stimulators of Antidiuretic Hormone Action or Release Supraoptic nucleus Increased plasma sodium ion concentration Optic Increased serum osmolarity nucleus Decreased blood volume Decreased blood pressure Anterior Smoking (nicotine) lobe Posterior Stress lobe Pain Nausea Vasovagal reaction Intermediate lobe Various medications (chlorpropamide, clofibrate, thiazide diuretics, FIGURE 37.6 Nerve fibers arising from the supraoptic nucleus and the para- carbamazepine, nicotine, cyclophosphamide, vincristine, morphine, high-dose ventricular nucleus transport antidiuretic hormone and oxytocin to the pos- oxytocin) terior pituitary. Angiotensin II Positive-pressure ventilation Fig. 37.6, nerve fibers arising from these hypothalamic nuclei transport ADH and oxytocin down the pituitary stalk by axoplasmic flow to the posterior pituitary lobe. There, the hormones are stored in secretory plasma osmotic threshold for ADH release is only 1% to 4% higher granules at the nerve terminals. With proper excitation, nerve impulses than normal plasma osmolarity.5,28 Therefore, when the plasma tonicity originating in the cell bodies of the supraoptic or paraventricular increases even subtly, healthy individuals release ADH into the blood. nucleus are transmitted down the pituitary stalk and stimulate the The interplay between ADH and water is controlled by a delicate nega- release of ADH or oxytocin from the posterior pituitary lobe. The tive feedback loop. Water deprivation (increased plasma osmolarity) hormones then diffuse into nearby blood vessels and are transported to initiates signals in the hypothalamic osmoreceptors that cause ADH their distant target sites. release from the pituitary gland to increase three- to fivefold. ADH, in Three major types of vasopressin receptors have been identified: V1, turn, enhances renal tubular water reabsorption, dilutes the extracel- V2 (subtype 1a and 1b), and V3. Activation of the V1 receptor medi- lular fluid, and restores normal osmotic composition.6 Conversely, ates vasoconstriction. V2 receptors mediate water reabsorption in the water ingestion (decreased plasma osmolarity) suppresses the osmore- renal collecting ducts. V3 receptors are found within the central ceptor signal for ADH release. Thirst provides a second line of defense nervous system and their stimulation modulates corticotrophin of water balance. The thirst threshold is set approximately 5% higher secretion.9,29 than the osmotic threshold for ADH.6,28 A 15% to 25% decrease in blood volume or blood pressure also Antidiuretic Hormone provokes ADH release.28 Changes in blood volume are sensed in ADH is the body’s principal preserver of water balance. It acts on V2 peripheral baroreceptors (especially the great veins and pulmonary receptors on renal collecting ducts to increase the absorption of solute- vessels) and atrial stretch receptors. When these baroreceptors sense free water through water channels called aquaporins. The integrated role underfilling (volume depletion), they transmit afferent signals through of thirst, vasopressin, and renal response conserves water in the body vagal and glossopharyngeal nerves to the hypothalamus.5,28 The hypo- and supports normal body-fluid osmolarity. Plasma osmolarity is physi- thalamus responds by increasing ADH synthesis and stimulating ADH ologically controlled within a small range (285 to 290 mOsm/L).9 release, sometimes as high as 50-times normal rate.6 Without ADH, the collecting ducts are impermeable to water reabsorp- The perioperative period is characterized by enhanced ADH secre- tion; in this setting, water loss in the urine is excessive, and serious tion.31,32 Pain, emotional stress, nausea, hemorrhage, and various drugs dehydration and hypernatremia is provoked.6 can be potent stimuli to ADH release. Positive-pressure ventilation ADH acts primarily to increase urine osmolarity, decrease serum enhances ADH release by reducing central blood volume.8 The mild osmolarity, and increase blood volume.6 Additionally, high levels of hyponatremia sometimes observed postoperatively may be at least ADH stimulate V1 receptors and cause potent systemic vasoconstric- partly explained on the basis of ADH action.33 Box 37.2 lists factors tion, especially in splanchnic and renal vascular beds. ADH-induced that stimulate ADH release or enhance the action of ADH at the renal vasoconstriction of vascular beds has been exploited therapeutically for tubules.11 control of catecholamine-resistant vasodilatory shock, hemorrhage, and Deficient Antidiuretic Hormone and Anesthetic Implications. sepsis.9,30,31 The recommended infusion rate for vasopressin in the treat- Inadequate ADH secretion from the posterior pituitary lobe or the ment of shock in adults is 0.01–0.04 units/min. Desmopressin inability of renal collecting duct receptors to respond to ADH (impaired (1-deamino-8-D-arginine vasopressin [DDAVP]), a synthetic arginine receptor sensitivity) results in a disorder called diabetes insipidus (DI). analog of ADH, increases circulating levels of von Willebrand factor Decreased ADH release from the posterior pituitary produces neuro- and factor VIII. In addition to treating ADH deficiency, DDAVP is genic or central DI. Renal tubular resistance to vasopressin is termed used to reverse coagulopathy associated with platelet adhesion defects, nephrogenic DI.28,34 including the coagulopathy of renal failure.9 Common causes of neurogenic DI include head trauma, neurosur- Consonant with its role of maintaining normal fluid homeostasis, gical procedures (e.g., pituitary surgery), meningitis/encephalitis, infil- ADH is secreted in response to an increase in plasma osmolarity or trating pituitary lesions, and brain neoplasms.28,34,35 Neurogenic DI plasma sodium ion concentration, a decrease in blood volume, or a that develops after pituitary surgery is usually transient and often decrease in blood pressure.6 resolves in 5 to 7 days.8,13 The osmolarity of body fluids is the main variable controlling ADH Nephrogenic DI may be due to genetic mutations or acquired secretion. Serum osmolarity changes are sensed by hypothalamic osmo- in association with hypercalcemia, hypokalemia, and medication- receptors, which in turn alter ADH synthesis and secretion.5 The induced nephrotoxicity.28,36 Ethanol, demeclocycline, temozolomide, 790 U NIT V Intraoperative Management phenytoin, chlorpromazine, and lithium all inhibit the action of ADH Inappropriate hypersecretion of ADH can result from various or its release.8 pathologic processes, including hypothyroidism, pulmonary infection, The hallmark of DI is the excretion of abnormally large volumes of carcinoma, head trauma, intracranial tumors, and following pituitary dilute urine (polyuria). The inability to produce a concentrated urine surgery.11 Secretion of ADH by neoplasms, especially small-cell car- results in dehydration and hypernatremia.34,35 The syndrome is charac- cinomas of the lung, is a common cause of SIADH.8 The ectopic terized by low urine osmolarity (< 300 mOsm/L), urine specific gravity ADH produced by these tumors is identical to the ADH of hypo- less than 1.010, and urine volumes greater than 2 mL/kg per hr.28 The thalamic origin. Certain drugs are associated with enhanced ADH tremendous urinary water loss produces serum osmolarities greater secretion or response; these include carbamazepine, tricyclic antide- than 290 mOsm/L and serum sodium concentrations greater than pressants, chlorpropamide, cyclophosphamide, oxytocin, nicotine, and 145 mEq/L. Neurologic symptoms of hypernatremia reflect neuronal clofibrate.28 dehydration and include hyperreflexia, weakness, lethargy, seizures, The patient with mild SIADH not associated with symptoms of and coma.28 hyponatremia is often managed effectively with fluid restriction of 800 The thirst mechanism assumes a primary role in maintaining water to 1000 mL/day with 0.9% normal saline.13,35 Patients with severe balance in awake patients with DI, preventing serious hyperosmolarity hyponatremia (plasma Na+ < 115–120 mEq/L) may require more and life-threatening dehydration.8 In the unconscious patient, intravas- aggressive treatment with an IV infusion of hypertonic (3%) saline, cular volume and serum sodium concentrations are restored slowly to with or without furosemide.28,35,37 To prevent acute loss of brain water avoid consequences of overrapid correction such as pulmonary and and possible permanent neurologic damage (central pontine demyelin- cerebral edema.35 ation syndrome), the plasma sodium concentration must be corrected Treatment protocols for DI depend on the degree of ADH defi- slowly. Many investigators recommend that acute hyponatremia be ciency. Most patients have incomplete DI and retain some capacity to corrected at a rate not to exceed 1 to 2 mEq/L per hr or 6 to 12 mEq/L concentrate their urine and conserve water. Treatment in general is in 24 hours.11,35,38 Serum sodium levels should be measured at least enhanced by restricting sodium intake. In patients with central DI, every 2 hours during treatment.28 Definitive treatment for SIADH is DDAVP, a selective V2 agonist, is often a preferred agent. It has less directed at the underlying disorder. vasopressor (V1) activity than vasopressin, a prolonged duration of Clinical assessment of the patient’s volume status is an essential part action, and enhanced antidiuretic properties.9,28,34 DDAVP may be of the preoperative evaluation. Perioperative fluid management of the administered nasally, intravenously, subcutaneously, and orally. surgical patient with SIADH can usually be accomplished with fluid Other treatment options for DI include medications that either restriction that involves the use of isotonic solutions.8 Estimating augment the release of ADH or increase the receptor response to ADH. central volume status on the basis of central venous pressure measure- Drugs may include chlorpropamide (sulfonylurea hypoglycemic agent), ments can help guide fluid replacement. Frequent determinations of carbamazepine (anticonvulsant), and thiazide diuretics. urine output, urine osmolarity, and plasma osmolarity also can help Preoperative assessment of the patient with DI includes careful direct fluid management. Nausea should be prevented, because it is a appraisal of plasma electrolytes (especially serum sodium), hydration potent stimulus of ADH release.28 Table 37.3 compares SIADH status, renal function, and plasma osmolarity. Dehydration will make and DI. these patients especially sensitive to the hypotensive effects of anesthesia agents. Plasma osmolarity, urine output, and serum sodium concentra- Parathyroid Gland tion should be measured hourly during surgery and in the immediate The parathyroid glands are small (approximately 3 × 6 × 2 mm) postoperative period.8 Isotonic fluids can generally be administered oval bodies located on the posterior surface of the thyroid gland. safely during the intraoperative period.8 Most individuals have four parathyroid glands, one on each pole of Perioperative administration of vasopressin is usually not necessary the thyroid, but some individuals have five glands and some have in the patient with partial DI, because the stress of surgery causes only three.39 enhanced ADH release.8,32 The surgical patient with complete DI may be treated with aqueous vasopressin (5–10 units intramuscular [IM]/ Calcium Regulation subcutaneously every 8–12 hr) or desmopressin (1 to 2 mcg IV/ The adult human body contains approximately 1 to 2 kg of the divalent subcutaneously every 12 hr or 5–40 mcg spray intranasally twice a cation calcium. Approximately 99% of the calcium exists in the bony day).34 Caution is advised when administering aqueous vasopressin to skeleton, and only approximately 1% is in the extracellular space and patients with coronary artery disease or hypertension because of the arterial constrictive action.28 Hypersecretion of Antidiuretic Hormone and Anesthetic Implica- TA BL E 3 7.3 tions. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a disorder characterized by high circulating vasopressin Syndrome of Inappropriate Antidiuretic Hormone levels relative to plasma osmolarity and serum sodium concentration. (SIADH) and Diabetes Insipidus (DI) With SIADH, the kidneys, under ADH stimulation, continue to reab- sorb water from the renal tubules despite the presence of hyponatremia SIADH DI and plasma hypotonicity.8 Hormone-induced water reabsorption causes Serum osmolarity Less than 270 mOsm/L Greater than 290 mOsm/L expansion of intracellular and extracellular fluid volumes, hemodilu- Serum sodium Less than 130 mEq/L Greater than 145 mEq/L tion, and weight gain. The urine is hypertonic relative to the plasma, Urine volume Low High (greater than 2 mL/ and urine output is typically low. kg per hr) Clinical features of severe SIADH reflect water intoxication, dilu- Urine osmolarity Hypertonic urine relative to Hypotonic urine relative tional hyponatremia, and brain edema.28 The swelling of brain cells plasma to plasma may cause lethargy, headache, nausea, mental confusion, seizures, Treatment Fluid restriction; if patient DDAVP or vasopressin and coma. Typically, hypertension and peripheral edema are not symptomatic or serum Na+ common. The severity of symptoms is related to the degree of hypo- less than 115–120 mEq/L, natremia and the rate of decrease of serum sodium.33,35,37 Further- consider hypertonic saline more, acute hyponatremia leads to a greater mortality than chronic hyponatremia.35 DDAVP, 1-Deamino-8-D-arginine vasopression.  C HAP TE R 37 The Endocrine System and Anesthesia 791 Calcium complexed to anions 9% (0.2 mmol/L) UV light 7-Dehydrocholesterol Ionized calcium Protein-bound calcium in skin 50% 41% (1.2 mmol/L) (1.0 mmol/L) Cholecalciferol Vitamin D in food Liver Kidney FIGURE 37.7 Serum calcium exists in three different forms: ionized, bound 25-Hydroxycholecalciferol to serum proteins, and bound to diffusible anions. Only the ionized form of calcium exerts physiologic effects. (From Hall JE. Guyton and Hall Textbook 1,25-Dihydroxycholecalciferol of Medical Physiology. 13th ed. Philadelphia: Elsevier; 2016:1001.) (active vitamin D hormone) FIGURE 37.8 Conversion of cholecalciferol or vitamin D to an active form soft tissues.39–41 Bone therefore serves as a large reservoir that can store (1,25-dihydroxycholecalciferol) involves hydroxylation in the liver and or release calcium as needed. kidneys. Active vitamin D is important in transporting calcium across the The concentration of the total serum calcium is tightly regulated gastrointestinal tract. UV, Ultraviolet. within a range of approximately 8.5 to 10.5 mg/dL.42,43 Serum calcium exists in three different forms (Fig. 37.7): 1. Approximately 9% exists complexed to anions such as citrate, Active vitamin D increases plasma calcium, magnesium, and phos- bicarbonate, and phosphate and is diffusible across capillaries phate ion concentrations by promoting their absorption across the membranes. intestinal epithelium to the extracellular fluid. 2. Approximately 41% is combined with plasma proteins (primarily Inadequate vitamin D intake or absorption, or insufficient exposure albumin) and is not diffusible across capillary membranes. to sunlight, can lead to poor intestinal absorption of calcium and 3. Approximately 50% exists in an ionized and diffusible form (normal phosphate. In children, the resulting calcium and phosphate deficiency level 4.7 to 5.2 mg/dL). leads to defective mineralization of bone, a condition known as Only the free, ionized form of calcium exerts physiologic effects, hence rickets.40,41,45 In adults, vitamin D deficiency results in impaired bone measurement of serum ionized calcium levels provides the most clini- mineralization, a condition known as osteomalacia.39,41 cally relevant determination.39,40 Ionized calcium performs a wide range of vital physiologic functions, including hemostasis (platelet aggrega- Parathyroid Hormone tion, blood coagulation), hormone release, muscle contraction (skeletal, PTH is an 84-amino acid polypeptide hormone secreted from chief smooth and cardiac muscle), bone formation, cell division, and many cells of the parathyroid gland in response to low serum ionized calcium other aspects of cell function. Even small changes in calcium levels can concentrations. Hyperphosphatemia (indirect effect) also stimulates cause extreme and immediate physiologic effects.39,44 PTH secretion.41 Total blood calcium levels may not always reflect the ionized PTH is the body’s major hormonal regulator of calcium and phos- calcium status. Alterations in serum protein levels cause parallel changes phate metabolism. In PTH, the body possesses an extremely potent in total blood calcium levels without modifying ionized calcium values. negative feedback agent for controlling serum calcium levels. In general, A decrease in serum albumin causes an associated decrease in total PTH increases the extracellular calcium concentration and decreases serum calcium levels. Because of this, calcium levels may be reported the extracellular phosphate concentration42 (Fig. 37.9). A small decline as albumin-adjusted total calcium.43 in the level of circulating ionized calcium produces a rapid increase in Alterations in the pH of blood affect ionized calcium levels. Plasma PTH secretion from the parathyroid glands. A sustained deficit in proteins are more ionized in an alkaline pH, providing an increase in serum calcium levels (e.g., lactation, pregnancy) may produce hyper- the number of anion-binding sites for the positively charged calcium. trophy of the parathyroid glands, sometimes fivefold or greater, to Alkalosis decreases ionized serum calcium by increasing protein- maintain adequate PTH output.39,41 calcium binding. Acidosis, on the other hand, increases ionized serum An elevation in serum calcium ion concentration produces an calcium by decreasing calcium-protein binding.40,41 abrupt decline in PTH synthesis and output. Conditions associated Two principal hormones, vitamin D and parathyroid hormone with chronic elevations of serum calcium (e.g., immobility, malignancy, (PTH) operate in concert to regulate the plasma concentration of Paget disease) blunt PTH output and provoke a diminution in gland calcium. Both vitamin D and PTH raise serum calcium levels, but of size. Parathyroid gland function and PTH secretion may be inhibited the two, PTH has by far the strongest effect. by chronic hypomagnesemia, but acute hypermagnesemia may also depress gland function.41,42,46 Vitamin D The increase in serum calcium levels and decrease in serum phos- Vitamin D compounds ingested from food or formed by the action of phate levels in response to PTH secretion is the result of the hormone’s ultraviolet light on the skin are inactive prohormones.40,42 Inactive direct effect on bone and the kidney and its indirect effect on the vitamin D, called cholecalciferol, is converted by a series of reactions in intestinal tract (Fig. 37.10). the liver and kidneys to an active metabolite. The final step in the Effect on Bone. Bone is a living tissue that is constantly being conversion of vitamin D to an active form is controlled in the kidneys remodeled.40 In the healthy adult, bone-forming cells called osteoblasts by PTH.42 The in vivo conversion of inactive vitamin D to the final are balanced by bone-destroying cells called osteoclasts.39 Exchangeable active product, 1,25-dihydroxycholecalciferol, is shown in Fig. 37.8. calcium salts in bone serve as a large, rapid buffer that plays a vital role 792 U NIT V Intraoperative Management " to keep calcium in the extracellular fluid stable. In addition to calcium, bone also provides an important reservoir for other ions such as mag- nesium and phosphorus.39,41 The most pronounced immediate control of blood calcium is due PTH to PTH effects on bone.42 When ionized serum calcium levels decline, ! ! PTH is released and acts directly on bone to mobilize skeletal calcium stores.40 PTH promotes the activation and proliferation of osteoclasts, stimulating rapid resorption of calcium (and phosphate) from bone tissue to the extracellular fluid. Over time, abnormally high levels of 1,25 D circulating PTH can produce extensive absorption of calcium from the bone matrix.39,42 The reservoir of calcium in bone is approximately 1000 times greater than the amount of calcium in the extracellular fluid. Only after Ca Ca Ca sustained PTH activation, therefore, does bone erosion and destruction become apparent. With protracted PTH stimulation, however, the bones eventually become severely depleted of calcium.39 ECF Ca An increase in extracellular fluid calcium causes PTH levels to decline via a negative feedback loop. Decreased PTH levels stimulate FIGURE 37.9 Parathyroid hormone (PTH)-calcium feedback loop that con- rapid deposition of calcium and phosphate bone salts, an effect that trols calcium homeostasis. Four organs—the parathyroid glands, intestine, lowers serum calcium levels back to normal. kidney, and bone—together determine the parameters of calcium homeosta- Effect on the Intestinal Tract. Parathyroid hormone indirectly sis. –, Negative effect; +, positive effect; 1,25 D, 1,25-hydroxyvitamin D; enhances both calcium and phosphate absorption from the intestines ECF, extracellular fluid. (From Melmed S, et al., eds. Williams Textbook of by promoting formation of 1,25-dihydroxycholecalciferol, the active Endocrinology. 13th ed. Philadelphia: Elsevier; 2016:1256.) form of vitamin D. When the plasma calcium level is low, PTH stimulates 1α-hydroxylase, an enzyme in the kidney necessary for the formation of 1,25-dihydroxycholecalciferol. Active vitamin D in turn increases intestinal absorption of calcium and phosphate.40 Ca2+ HOMEOSTASIS 1000 mg 1,25-Dihydroxycholecalciferol + Extracellular Absorption Bone deposition fluid 350 mg Secretion Bone resorption [Ca2+] = 10 mg/dL 150 mg + – PTH, Calcitonin 1,25-dihydroxycholecalciferol Filtration Reabsorption 800 mg + PTH Excretion 200 mg FIGURE 37.10 Ca2+ homeostasis in an adult eating 1000 mg/day of elemental Ca2+. Hormonal effects on Ca2+ absorption from the gastrointestinal tract, bone remodeling, and Ca2+ reabsorption in the kidney are shown. PTH, Parathyroid hormone. (From Costanzo LS. Physiology. 5th ed. Philadelphia: Elsevier; 2014;436.)  C HAP TE R 37 The Endocrine System and Anesthesia 793 In the absence of PTH, or in the presence of severe kidney disease, CLINICAL MANIFESTATIONS OF HYPOCALCEMIA 1,25-dihydroxycholecalciferol is not formed, and the effect of vitamin Laryngospasm D on calcium and phosphate regulation is lost. Patients with chronic (as seen through a Trousseau sign renal failure often suffer from hypocalcemia, in part because the dis- laryngeal mirror) eased kidneys lose their ability to form active vitamin D. Consequently, these patients are unable to absorb a sufficient amount of calcium from the gastrointestinal tract.42 Effect on the Kidney. PTH has two major effects on the kidney: it increases calcium reabsorption, and it increases phosphate excretion. PTH elevates serum calcium by augmenting the reabsorption of calcium from nephron tubules to the extracellular fluid. The major site of PTH-mediated calcium reabsorption is the distal convoluted Chvostek sign Hyperreflexia tubule.39,42 Accompanying calcium reabsorption is enhanced phosphate excre- tion. PTH promotes phosphaturia by reducing phosphate ion reab- sorption from the proximal convoluted tubule. The PTH-mediated phosphate loss from the kidney is generally strong enough to overcome the PTH-induced phosphate absorption from bone and intestines.39 Calcitonin Calcitonin is a hormone secreted from the thyroid parafollicular cells, or C cells, in response to elevated serum ionized calcium.40 It has an effect opposite to that of the PTH system, lowering the serum ionized FIGURE 37.11 Hypocalcemia produces hyperexcitability of nerve and muscle cells. Chvostek sign and Trousseau sign are two classic manifestations of calcium concentration. Calcium levels are reduced by a calcitonin- hypocalcemic tetany. Deep tendon reflexes may be hyperactive. Laryngeal mediated inhibition of bone osteoclasts, which shifts the balance muscles are sensitive to tetanic spasm. toward osteoblasts and bone deposition.40,42 The serum calcium–lowering effect of calcitonin is weak, especially in adults. Its effect in lowering serum calcium is rapidly outweighed by the more powerful activity of PTH.39 The rather weak effect of calci- restless or hyperirritable. Life-threatening laryngeal muscle spasm may tonin is demonstrated by the observation that removal of the thyroid occur, producing stridor, labored respirations, and asphyxia.39,42,43 gland causes no significant alterations in bone density or long-term Two classic manifestations of latent hypocalcemic tetany are serum calcium levels.39,40,42 Chvostek sign and Trousseau sign. Chvostek sign is a contracture or twitching of ipsilateral facial muscles produced when the facial nerve Parathyroid Gland Dysfunction is tapped at the angle of the jaw. Trousseau sign is elicited by the infla- Hypoparathyroidism tion of a blood pressure cuff slightly above the systolic level for three Hypoparathyroidism is characterized by low PTH levels or a peripheral minutes. The resultant ischemia enhances muscle irritability in hypo- resistance to PTH effects.42,43,47 It may be an inherited or acquired calcemic states and causes flexion of the wrist and thumb with exten- disorder. Patients with hypoparathyroidism typically have low plasma sion of the fingers (carpopedal spasm).39 Fig. 37.11 illustrates some of calcium levels (ionized calcium < 4.5 mg/dL and total calcium < the clinical manifestations of hypoparathyroidism and hypocalcemia. 8.5 mg/dL).11 The serum phosphate concentration may be elevated because of decreased renal excretion of phosphate. Hyperparathyroidism Inadvertent surgical removal of the parathyroid glands or damage Primary hyperparathyroidism is a common endocrine disorder charac- to gland blood supply during parathyroid surgery, radical neck dissec- terized and diagnosed by the presence of elevated serum PTH levels tion, or thyroid surgery are the most common causes of hypoparathy- despite high serum calcium levels. It may result from a parathyroid roidism.43,47 Hereditary hypoparathyroidism, parathyroid gland injury adenoma, gland hyperplasia, or parathyroid cancer.41,42,44 In approxi- from irradiation or trauma, amyloidosis, chronic severe magnesium mately 80% of cases, primary hyperparathyroidism is caused by hyper- deficiency (e.g., alcohol abuse, poor nutrition, malabsorption) and secretion of a single parathyroid adenoma.41,44,49,50 Multi-gland disease acute hypermagnesemia are other possible causes of hypoparathyroid- accounts for 10% to 15% of cases. Hyperparathyroidism may also ism.43,46,47 Clinical signs of hypoparathyroidism reflect the degree of exist as part of a multiple endocrine neoplastic syndrome (MEN-1, hypocalcemia and the rapidity of calcium decline. A sudden drop in MEN-2A).41,42 Carcinoma of the parathyroid gland is found in less ionized calcium usually produces more severe symptoms than a slow than 1% of patients and is associated with particularly high serum d