replacement is also an option. Macronodular adrenal hyperplasia \200 A rare cause of ectopic Cushing \200\231s syndrome \200 Most commonly due to synthesis of ectopic GIP receptors in adrenal tissues GIP secretion associated with meals results in activation of adrenal glands and food-related hypercortisolemia. Other ectopic receptors reported include B-adrenergic receptors and LH receptors. Carcinoid tumors and ectopic hormone production b See p. 465 and Table 98.1 (p. 551). 98-Draznin-Chap98.indd 553 4/1/2011 5:57:20 PM CHAPTER 98 Endocrinology of critical illness 554 Liver disease Sex hormones \200\224males See Table 98.2. Hypogonadism occurs in 70 \200\22380% of men with chronic liver disease. There is a combina tion of primary testicular failure and failure of hypoth- alamo \200\223pituitary regulatio n. Alcohol acts independently to produce hypogonadism, leading to a com- bination of primary t esticular failure and failure of hypothalamic \200\223pituitary regulation. The effects of elevated estrogens result in i loss of the male escutch- eon, loss of body h air, redistribution of body fat, palmar erythema, spider nevi, and gynecomastia. The i conversion of testosterone and androstenedione to estrone is attributed at least in p art to portosystemic shunting. In addition, the large increase in SHBG concentration will i ncrease the estrogen/testosterone ratio as testosterone has a higher af \201 nity for SHBG . Spironolactone may result in iatrogenic feminization by inhibiting tes- tosterone action. There is no evidence that exogenous administration of androgens reverses hypogonadism in chronic liver disease. Sex hormones \200\224females See Table 98.2. Alcoholism increases the frequency of menstrua l disturbances and sponta- neous abortion but does not affect fertility. Liver dysfunction of whatever etiology is associated with an early menopause. Alcohol rather than liver disease is the prime cause of hypogonad- ism. Nonalcoholic liver disease is only associated with hypogonadism in advanced liver failure when it is accompani ed by encephalopathy and impaired GnRH secretion. Table 98.2 Sex hormone changes in liver disease Hormone Level di i i i/normal Inappropriately low/normal Testosterone SHBG Estrone Estradiol LH FSH Inappropriately low/normal i/normal d d Prolactin IGF-1 IGFBP-3 98-Draznin-Chap98.indd 554 4/1/2011 5:57:20 PM LIVER DISEASE 555 Table 98.3 Thyroid function changes in liver disease Hormone Acute hepatitis id i l d d i i i CAH/PBC i l i d l i i Cirrhosis d i d d il il l T 4 fT 4 T 3 fT 3 rT 3 TSH TBG CAH, chronic active hepatitis; PBC: primary biliary cirrhosis. Plasma testosterone and estrone concentrations are usually normal, androstenedione concentr ation is increased, and dehydroepiandros-tene- dione and dehydroepiandrostenedione sulfate levels are reduced. Thyroid The liver synthesizes albumin, T 4 -binding prealbumin (TBPA), and T 4 - binding go bulin (TBG), all of which bind thyroid hormones covalently and reversibly. Thyroid function tests (TFTs) must be interpreted with caution in patients with liver disea se. In acute liver disease, e.g., acute viral hepatitis, TBG levels are increased, which in creases the measured total circulating T 4 and T 3 levels. In biliary cirrhosis and chronic active hepatitis, TBG may be increased. In other chronic liver disease and in hepatomas, TBG is also increased. In severe cases of acute liver disease, TBG may be low due to reduced synthesis. The liver deiodinates T 4 to T 3 and this is impaired in liver dis- ease. The T 4 is preferentially c onverted to rT 3 and there is an increase in the rT 3 /T 3 ratio. In liver cirrhosis, TBG, T 4 , and T 3 are low. Table 98.3 summarizes the changes in TFTs with liver disease. Free T 4 and T 3 assays are e ssential for the accurate interpretation of thyroid status in liver disease. Adrenal hormones Patients who abuse alcohol may develop a clinical phenotype of Cushing \200\231s syndrome with moon faces, centripetal obesity, striae, and muscle wasting, and ma y have increased plasma cortisol concentrations. This is termed pseudo-Cushing \200\231s sy ndrome . Reversible (on abstention) adrenocorticorticoid hyperresponsiveness occurs in alcoholics. I n liver disease, cortisol metabolism may be impaired, leading to elevated plasma cortisol l evels, loss of diurnal cortisol variation, and failure to suppress with dexamethasone. Further reading Malik R, Hodgson H (2002). The relationship between the thyroid gland and t he liver. Q J Med 95:559 \200\223569. 98-Draznin-Chap98.indd 555 4/1/2011 5:57:20 PM CHAPTER 98 Endocrinology of critical illness 556 Renal disease Calcitriol There is impaired renal conversion of 25-hydroxyvitamin D 3 to 1,2 5 (OH) 2 D 3 in end-stage renal failure (ESRF) leading to metabolic bone disease. Parathyroid hormone and renal osteodystrophy Serum parathyroid hormone (PTH) secretion is s timulated by low serum calcium in ESRF. This is due to the following: \200 d Renal phosph ate clearance (resulting in i cacium/phosphate mineral ion product, precipitation of vascul ar calci \201 cation with consequent hypocalcemia triggering PTH release). Vascular calci \201 cation is a major contributor to vascular death in ESRF. High phosphate may increase PTH secretion directly, but evidence of the mechanism for this is lacking. Impaired renal calcitriol secretion As renal function declines, an elevated PTH and a d cal citriol can be detected with creatinine clearance of 50 mL/min. This rise in PTH is ini- ti ally suf \201 cient to maintain the serum calcium in the normal range. In ESRF, patients are markedly hyperphosphatemic and hypocalcemic. The degree of hyperparat hyroidism progresses inversely with the fall in renal function. Tertiary hyperparathyroidis m occurs when PTH secretion becomes autonomous, and hypercalcemia will persist even after r enal transplantation. Hyperparathyroid bone disease and osteomalacia are the main mech- ani sms behind the development of high-turnover bone disease in renal osteodystrophy. Hypogonad ism is also common in both men and women with ESRF. Adynamic bone disease also contributes, probably due to direct toxic effects from urea and other nitrogenous compounds on bone cel ls. Renal osteodystrophy causes bone pain and fractures. Treatment of renal osteodystrophy The goals are maintenance of normal phosphate levels with phosphate binders (such as calcium carbonate) and treatment of osteomalacia. The i use of calcium carbonate has been suggested as the cause of the i inci- dence of adynamic renal os teodystrophy, but intensive vitamin D therapy and peritoneal dialysis are probably also con tributory. Calcitriol (which does not require renal 1 A-hydroxylation) is effective in treating osteom alacia. A dose of 1 \200\2232 mcg/day is used for established renal osteodystrophy. Lower d oses of calcitriol (0.25 \200\2230.5 mcg/day) are used in early ESRF to prevent the devel-o pment of renal osteodystrophy. Parathyroidectomy is advocated in bone disease uncon-trolled by vitamin D therapy or the development of tertiary hyperpara-thyroidism. Cinacalcet acts directly at the calcium-sensing receptor to lower PTH secretion. This marke dly improves secondary hyperparathy-roidism, cal- cium and phophate levels, and renal osteo dystrophy. Improvement in mortality due to d vascular calci \201 cation has not yet been d emonstrated. 98-Draznin-Chap98.indd 556 4/1/2011 5:57:20 PM RENAL DISEASE 557 Prolactin Hyperprolactinemia is common in ESRF but is usually mild, i.e., <100 mcg/L. The c ause is both i secretion and d renal clearance. Gonadal function Hypogonadism \200\224clinical and biochemical \200\224is common in ESRF. In men, there is impaired pulsatile release of LH, although basal LH lev- els are usually e levated because of impaired renal clearance. Serum FSH is usually normal or mildly elevated . In women, levels of estradiol, progesterone, and FSH are reported to be within the normal r ange in the early follicular phase but fail to show the usual cyclical changes. Menstrual d isturbance is common. Amenorrhea, polymenorrhea, and menorrhagia can also occur on dialysis . Infertility is the rule, and conception on dialysis is the exception. Sexual dysfunction is common in both sexes but has been better studied in men. 60% of men h ave some degree of impotence and examination yields 80% to have testicular atrophy and 14% to have gynecomastaia. Treatment of hypogonadism in ESRF is suboptimal. Testosterone ther- apy is not associated with any clinical bene \201 t in men. Growth hormone and growth retarda-tion Basal GH levels are normal, but there is impaired se cretion following an adequate hypoglycemic stimulus in 40 \200\22370% of patients with ESRF . There is impaired growth in children, particularly during periods of greatest growth veloci ty, and puberty is delayed. This combination leads to short stature. The improved growth ve locity after renal transplantation is often too little too late in order to attain a normal stature. Recombinant human GH (rhGH) has been shown to be an effective treatment for growth retardat ion in children with stable chronic kidney disease (CKD) and ESRF as well as after renal tr ansplantation. Thyroid The \200\234euthyroid sick \200\235 \201 nding is common in CKD ( b see Sick eut hyroid syndrome, p. 15). Adrenal The adrenal axis is not impaired clinically by CKD. There is evidence of blunted cortisol response to hypoglycemia but this is not relevant clinically. Patients with amyloidosis are at risk of hypoadrenalism due to adrenal amyloid in \201 ltration. 98-Draznin-Chap98.indd 557 4/1/2011 5:57:21 PM CHAPTER 98 Endocrinology of critical illness 558 Endocrinology in the critically ill b See Table 98.4. ACTH and cortisol CRH, ACTH, and cortisol increase rapidly during all forms of acute illnes s. Low albumin and CBG cause free cortisol to be substantially higher. This physiological a daptation results in the following: \200 Provision of substrates for major organ energy e xpenditure (via catabolism) Hemodynamic advantages (enhanced sensitivity to angiotensin II, i vaso-pressor and inotropic response to catecholamines Prevention of an ex-cessive immune response In \202 ammatory cytokines result in i cortiso l metabolism and reduced receptors, i.e., peripheral cortisol resistance. After moderate to severe injuries, plasma cortisol starts to fall af-ter a day or two but only reach normal levels after a week. Table 98.4 Endocrine and other changes seen in critical illness Acute illness iii d ii i d i i i i l d d ACTH/CRH Albumin/CBG Free cortisol Catabolism Immune response In \202 ammatory response Cortisol resistance Glucose Insulin resistance TSH FT 4 and FT 3 IGF-1, IGFBPs, GHBPs Prolonged critical illness ii or i d i d d d ACTH/CRH Free cortisol TSH, total T 4 rT 3 LH/FSH/T/estradiol GH Response to GHRH 98-Draznin-Chap98.indd 558 4/1/2011 5:57:21 PM ENDOCRINOLOGY IN THE CRITICALLY ILL 559 Cortisol is elevated for at least 2 weeks in patients with severe burns. Prolonged critical illness results in low CRH and ACTH with a normal or slightly raised cor tisol, perhaps driven by an alternative pathway involv- ing endothelin. Cortisol de \201 ciency should be suspected in an acutely ill patient with a plasma cortis ol of <20 mcg/dL, or an increment of <9 mcg/dL on a 250 mcg cortrosyn test. Drugs used in intensive care may contribute to adrenal insuf \201 ciency by Reducing cortisol metabolism, e.g., etomidate (frequently used in induction of anesthesia) and ketoconazole. Promoting cortisol metabolism, e.g., phenytoin, carbamazepine, and rifampicin. Metabolism Hyperglycemia is common in critical illness (even in non-diabetic subjects) due to i cortisol, catecholamines, GH, and glucagon. These hormones and in \202 ammatory cytok ines also contribute to insulin resistance. IV insulin titrated to maintain normoglycemia (glucose <6.1mmol/L) reduces mortality by >40%. TSH and thyroid hormones TSH levels usually remain stable in acute injury. Total T 4 and T 3 tend to fall but may remain within the normal range. Thyroid hormone metabolism is enhanced by increased activity of liver deiodinase type 3 (peripheral hormone deactivator). With prolonged illness, the total T 4 tends to fall below the normal range. The FT 4 remains in the normal range. Total and free T 3 levels fall after injury and may remain suppressed for 2 \200\2233 weeks after a severe injury. The rT 3 level rises. In prolonged critical illness, the thyroid function conforms to the \200\234sick euthyroid syndrome \200\235 ( b see Euthyroid sick syndrome, p. 15). Gonadotropins and gonadal steroids In prolonged illness hypogonadotropic hypogonadism occur s. Growth hormone In critical illness, the GH axis is profoundly affected with initially raise d GH secretion, but low IGF-1, IGFBPs, and GHBP related to peripheral GH resistance. Prolon ged critical illness >5 \200\2237 days results in low GH and a blunted response to GHRH. Recombinant GH was proposed as a bene \201 cial agent for critical ill- ness, but the evid ence is lacking, and there are reports of a detrimental effect. Hormone replacement and critical illness There is no evidence that, other than insulin, hor monal supplementation in the critically ill improves outcome. 98-Draznin-Chap98.indd 559 4/1/2011 5:57:21 PM CHAPTER 98 Endocrinology of critical illness 560 Further reading Elleger B, Debaveye Y, Van den Berghe G (2005). Endocrine interventions in the ICU. Eur J Intern Med 16:71 \200\22382. Isidori AM, Kaltsas GA, et al. (2006). The ectopic adrenocorticotropin syndrome: clinical f eatures, diagnosis, management, and long-term follow-up. J Clin Endocrinol Me-tab 91(2):371 \200\223377. 98-Draznin-Chap98.indd 560 4/1/2011 5:57:21 PM TRANSSPHENOIDAL SURGERY/CRANIOTOMY 561 Perioperative management of endocrine patients Transsphenoidal surgery/craniotomy Preoperative assessment Con \201 rm the following: \200 Anterior and posterior pituitary function is normal or on adequate replacement: \200 Cortrosyn stimulation test (CST; note both the 0- and 30-minute values) and/or normal ACTH/cortisol before 9 A.M. Patients with recent loss of LFTH will have a no rmal response to CST, as adrenal atrophy will not have evolved. If there is in any doubt, r eplace with glucocorticoids. FT 4 \200 LH, FSH, estradiol, or testosterone \200 Prolactin \200 Serum and urine osm olality and electrolytes if polyuric Recent (<3 months) MRI pituitary \200 Formal visual \201 eld perimetry and visual acuit y assessment \200 Document extraocular muscle movements \200 Urea and electrolytes (<1 week presurgery) \200 Group and save serum Methicillin-resistant Staphylococcus aureus (M RSA) screen should be done at least 2 weeks prior to admission for surgery if the patient h as been in the hospital within the last year. Record therapeutic options discussed with patient: Risks of surgery (e.g., CSF leakage, meningitis, bleeding, partial or total hypopituitarism including diabetes insipidus and potential effects on fertility and visual deterioration) Risk of recurrence requiring further surgery or radiotherapy Warn patients that a sample of fat may be taken from their thigh or abdo- men for packing of the pituitary fossa. Reitera te the need for lifelong follow-up. Ensure antibiotic prophylaxis is given prior to surgery (the precise regimen may vary depen ding on the center and patient. Some surgeons advocate a prolonged course of antibiotics if CSF leakage occurs, whereas others recommend close surveillance and prompt treatment if co ncern about possible meningitis [lower threshold for patients with Cushing \200\231s diseas e]). MRSA-positive patients require prophylaxis with IV vancomycin. 99-Draznin-Chap99.indd 561 3/31/2011 9:30:52 PM CHAPTER 99 Perioperative management 562 If the patient is steroid-de \201 cient, steroid reserve is unknown, or a patient has Cush ing \200\231s disease (inadequate stress response), give hydrocor- tisone 20 mg orally with morning premedication. Postoperative (Table 99.1) Consider steroid status; if the patient requires steroid coverag e: \200 Start IV hydrocortisone (HC), 50 \200\223100 q6 \200\2238h, postoperatively. \200 Convert to oral glucocorticoids once patient is eating and drinking. \200 After nas al packs are removed (following transsphenoidal surgery), stop glucocorticoids (usually <48 hours). Check 9 A.M. cortisol level the following two mornings, having omitted the evening dose for the preceding day. Continue off steroids if patient is asymptomatic, however if symptomati c only omit the evening dose. In patients with Cushing \200\231s disease, 9 A.M. cortisol ( x2) <1.8 mcg/dL indi- cates c ure; occasionally, cortisol takes a few days to fall to undetectable levels. See Table 99.1 for patients without Cushing \200\231s disease. If the patient is acutely un well with postural BP drop when hydrocorti- sone is stopped, check random cortisol and restart HC without delay. Fluid balance \200\224watch for diabetes insipidus: Review the clinical status of the patient at regular intervals (euvolemic, hypovolemic, hypervolemic). Record \202 uid input and output assiduously ( \202 uid replacement in surgery may be ex cessive, therefore always include perioperative \202 uids in \202 uid balance charts an d note sodium content). Check plasma electrolytes and plasma and urine osmolalities on a regular basis (at least on ce daily and more frequently if there are clinical concerns). Postoperatively, restrict to 2 L total \202 uid input (IV and PO). \200 Record \202 u id input and output assiduously. Table 99. 1 Postoperative glucocorticoid management of patients without Cushing \200\231s d isease* 9 A.M. cortisol level Action >20 mcg/dL Stay off hydrocortisone 15 \200\22320 mcg/dL Advise to start hydrocortisone if unwell (give patient supply of oral and parenteral hydroc ortisone to take home with appropriate written advice) <15 mcg/dL Start regular oral hydrocortisone (10mg/5mg/5mg) In female patients who have stopped estrogen replacement therapy <6 weeks before surgery, i nterpret results with caution (potential confounding effect of raised CBG levels). 99-Draznin-Chap99.indd 562 3/31/2011 9:30:53 PM TRANSSPHENOIDAL SURGERY/CRANIOTOMY 563 If the patient becomes polyuric, i.e., >200 mL/h for (cid:2)3 consecutive hours (in the context of a 2 L/24-hour \202 uid restriction), urgently check plasma elect rolytes, plasma and urine osmolalities, and urinary sodium. While waiting for results allow free \202 uids; the aim is to replace the \202 uid de \201 cit. (Fluid replacement in surgery may be excessive, always include perioperative \202 uids in \202 uid balance s heets.) If diabetes insipidus is con \201 rmed by the results, give a single dose of desamino-D-arginine vasopressin (desmopressin) (1 mcg SC). When the \202 uid de \201 cit has been replaced (usually orally), restart 2 \200\2233 L \202 uid restriction (again include IV and PO routes). If polyuria recurs, treat as before. \200 Regular plasma electrolytes and plasma and urin e osmolalities are required. If polyuria continues to recur up to and after 96 hours postoperatively, consider regular D DAVP orally or intranasally, if possible (not if a transsphenoidal approach is used). Hyponatremia occurring 1 week after a transsphenoidal adenectomy is most commonly due to SI ADH; rarely, cerebral salt wasting may occur. Check urinary sodium and assess \202 uid st atus (cerebral salt wasting causes very high urinary sodium and is associated with dehydrat ion). Check thyroid function (FT 4 ) between days 5 and 7 postoperatively. Check for CSF leakage. Recheck visual acuity and visual \201 eld perimetry and eye movements formally prior to discharge. 99-Draznin-Chap99.indd 563 3/31/2011 9:30:53 PM CHAPTER 99 Perioperative management 564 Thyroidectomy Preoperative Ensure euthyroidism. If surgery is required in the presence of hyperthyroidism, give potassium iodide (60 mg 3 x a day for 10 days); this reduces thyroid hormone release and probably decreases perioperat ive blood loss. The radiographic con- trast agent iopanoic acid, which is rich in iodine, p rovides a useful alterna- tive, and has the additional bene \201 t of potently inhibiting the 5-deiodinase, thus reducing T 4 to T 3 conversion. Oral propranolol (30 \200\223120 mg 3 x a day) reduces clinical manifestations of thyrotoxicosis. Check vocal cord function by indirect laryngoscopy. Warn of postoperative risks: recurrent laryngeal nerve damage <1%, keloid scarring, hemorrhage, permanent hypoparathyroidism <0.5% , and hypothyroidism (10% of partial thyroidectomy patients). Postoperative There is a risk of hemorrhage in \201 rst 24 hours, particularly major hemo r- rhage deep to the strap muscles, leading to airway compression. Watch for stridor, respi ratory dif \201 culties, and wound swelling. Drainage from wound drains is unhelpful. Trea t by evacuating the hematoma, and consider intu- bation or a tracheostomy. Clip removers an d artery forceps should be kept to hand on the ward. Recurrent laryngeal nerve damage is permanent in <1% and transient in 2 \200\2234%. The pat ient \200\231s voice is often husky for about 3 weeks postoperatively and may be treated wi th lozenges and humidi \201 ed air. Symptomatic unilateral damage can be treated by stabilization of the affected cord in adduc tion by submucosal Te \202 on injection under direct laryngoscopy. Bilateral damage leads to unopposed adductor action of the cricothyroid muscle, which cause s glottis closure and airway obstruction. Treatment involves reintubation, paralysis, hydro cortisone (100 mg 4 x a day IM for edema), and extubation at 24 hours. If that fails, a tra cheostomy should be performed. If recurrent laryngeal nerve damage is persistent at 9 months, an attempt can be made to resuture the nerve. Monitor calcium. Transient hypoparathyroidism is usually evident within 7 days. b See Hypoparathyroidism (p. 394) for treatment. Following total thyroidectomy for malignancy, thyroid hormone with- drawal may be necessary prior to postoperative radioiodine ablation ( b see Follow-up of papillary and follicular thyroid carcinoma, p. 76). Alternatively, recombinant TSH can be used. If total thyroidectomy is performed for hyperthyroidism, levothyroxine ( 1.5 mcg/kg) should be started 4 \200\2235 days postoperatively, as during the operation, handling of the thyr oid results in release of stored thyroid hor- mones and levothyroxine has a long t . Check TSH in 6 \200\2238 weeks. Following partial thyroidectomy, transient biochemical hypothyroidism may occur during the \201 rst 2 months and does not warrant treatment unless the patient is symptomatic or it becomes persistent. 99-Draznin-Chap99.indd 564 3/31/2011 9:30:53 PM PARATHYROIDECTOMY 565 Parathyroidectomy Parathyroidectomy of one or two glands undertaken for primary hyper- para thyrodism may result in transient and self-limited hypocalcemia. Total parathyroidectomy (e.g., for MEN1 or as part of surgical man- agement of advanced hea d and neck malignancy) may be complicated by severe and permanent hypocalcemia, which may b e very dif \201 cult to manage. Postoperative care for patients undergoing parathyroidectomy of 1 \200\2232 glands Check ca lcium, phosphate, magnesium, and albumin on the evening of surgery and daily thereafter. Ca lcium begins to fall postoperatively after about 4 \200\22312 hours; the nadir is usually r eached by 24 hours. Calcium may recover spontaneously, however 1/3 of patients will require calcium sup- port perioperatively. With the advent of minimally invasive parathryoidectomy and short hos- pital stays (<24 hou rs) many centers advocate prophylactic calcium and vitamin D replacement in all cases in th e immediate aftermath of surgery. This treatment is continued until the patient is reviewed 1 \200\2232 weeks later in the outpatient clinic. Symptoms of hypocalcemia (mainly due to neuromuscular irritability) include perioral parast hesias, Chovstek \200\231s sign, Trousseau \200\231s sign, tetany, laryngospasm, bronchospa sm, seizures, prolonged QT interval on ECG, extrapyramidal movement disorders, and delirium . Calcium levels are often <7.0 mg/dL before symptoms manifest, although rapid changes in c alcium result in more pronounced symptomatology. Magnesium de \201 ciency is common due to previous hyperparathyroidism (causes renal wasti ng of magnesium). Chronic magnesium de \201 ciency impairs release of PTH and causes funct ional hypoparathyroidism and hypocalcemia. Causes of hypocalcemia after 1 \200\2232 gland removal Functional hypoparathyroidism This i s common. Causes include delayed recovery of the other parathyroid glands due to long-term suppression, parathyroid gland ischemia, parathy- roid gland \200\234stunning \200\235 by intraoperative handling, and hypomagnesemia. The PTH level will be detectable; phosphate should be normal. It usually improves spontaneously over days to weeks. Management of symptomatic hypocalcemia (Ca usually <7.2 mg/dL) is with calcium (up to 2 g/d ay in divided doses). Add in vitamin D and vitamin D metabolites for persistent hypocalcemi a. Replace magnesium as necessary. Gradual withdrawal of therapy is needed to assess recovery. Hungry bone syndrome This is due to extensive skeletal remineralization once the skeleton i s released from PTH excess. There is ongoing i alkaline phosphatase (ALP), d calcium, d PO 4 , and d Mg. PTH levels may be normal or high. Pre- existing vitamin D de \201 ciency wil l exacerbate hypocalcemia. The patient may require large doses of calcium and vitamin D and vitamin D metabolites for weeks to months. 99-Draznin-Chap99.indd 565 3/31/2011 9:30:53 PM CHAPTER 99 Perioperative management 566 Permanent hypoparathyroidism. This is rare (<2% of cases). Check PTH level after day 3; the level will be undetectable (<1 pg/mL). Replace with oral calcium and vitamin D and vitamin D metabolites long term. Other complications \200 Recurrent laryngeal nerve palsy (<1%) \200 Failure to correct hypercalcemia Overall, both minimally invasive and conventional parathyroidectomy are very safe operations with low morbidity and mortality. Calcium management following total parathyroidectomy Hypocalcemia is inevitable unless mana gement is instituted. Preemptive treatment is worth considering (e.g., calcitriol 1 \200\2232 mcg/ day \200\224th is dose may be insuf \201 cient to completely prevent hypocalcemia but may prevent life-th reatening hypocalcemia and is unlikely to cause serious toxicity in the short term). Acute management is required in patients with life-threatening hypocal- cemia (e.g., Trousseau \200\231s sign, laryngospasm, seizures): \200 10 mL of 10% calcium gluconate diluted 1 in 10 in normal saline or dextrose 5% infused into a large vein over 10 minutes. Monitor cardiac rhythm. Repeat as necessary to control acute emergency. \200 Patients will need ongoing calcium r eplacement: 100 mL of 10% calcium gluconate in 1 L of 5% dextrose or 0.9% sodium chloride i nfused over 24 hours (monitor calcium regularly (q4 \200\2236h) and adjust rate as necessar y. Start oral vitamin D analogs and oral calcium. Vitamin D analogs (calcitriol) These are pot ent and effective in acute hypocalcemia because of the rapid correction of calcium. The sho rt half-lives allow rapid and careful titration of a dose in response to calcium levels. Th ere is a narrow therapeutic window (hypercalcemia is much shorter-lived if it develops). Reassess often (at least every 1 \200\2232 days) in the early stages of manage- ment. Longe r-term options include ergocalciferol or colecalciferol, but hypercalcemia will be more pro longed if it develops. Calcium Give 1 \200\2232 g/daily in divided doses. A maximum daily absorbable dose of calci um is probably 3 g/day. Absorption may vary from different types of calcium salts and may be greater when calcium is given away from food. The long-term aim is to manage without calcium just on vitamin D or vitamin D metabolites. The long-term goal of management is to prevent symptoms of hypoc- alcemia without toxicity. Aim for the lower half of normal range (8.0 \200\223 9.2 mg/dL) with normal urinary calciu m excretion (to minimize risk of nephrolithiasis and nephrocalcinosis. 99-Draznin-Chap99.indd 566 3/31/2011 9:30:53 PM PHEOCHROMOCYTOMA 567 Pheochromocytoma Preoperative Check for bilateral disease or metastases: MRI chest and abdo men and an MIBG scan (10% multiple). Ensure adequate A- and B-blockade once the diagnosis is made. Start A-blockade before B-blo ckade (unopposed B-blockade can lead to marked vasoconstriction, ischemic damage, and hyper tension). \200 A -blockade: Start phenoxybenzamine (10 \200\22320 mg, orally, 3 \200\2234 x day), an irreversible A-blocker. Adequacy of dosage can be assessed by monitoring hemato crit and postural drop in BP (re \202 ects BP vasodilation). Start treatment at least 1 week, ideally >3 weeks, before surgery. \200 B -blockade: Star t propranolol (20 \200\22380 mg, orally, 3 x day) at least 48 hours after initiating phenoxybenzamine. To control BP, A- and B-blockers are often suf \201 cient. If not, add a calcium channel b locker or ACE inhibitor; A-methyltyrosine 1 \200\2234 g/day (a false cat- echolamine precur sor that inhibits tyrosine hydroxylase, the rate-limiting step for catecholamine synthesis) is rarely used to control BP. Some centers advocate the use of additional IV phenoxybenzamine (0.5 \200\2231.0 mg/kg in 2 50 mL 5% dextrose given over 2 hours) for the 3 days prior to surgery (titrate the dose acc ording to BP; often 0.5 mg/kg is suf \201 cient). Group and save serum, and cross-match 2 units of blood. Ensure that the patient is well hyd rated (if necessary, use an IV infusion of saline) prior to going to surgery. Postoperative Watch for d BP: sudden withdrawal of catecholamines leads to marked arterial and venous dilatation. This is worsened by inadequate volume loading and should initially b e treated with volume replacement rather than by pressor agents. If hypertension persists 2 weeks postoperatively, residual tumor or metastases must be considered. Long-term monitoring is required as approximately 14% recur. If bilateral adrenalectomy is performed, see the next section. Bilateral adrenalectomy Give hydrocortisone (100 mg, 4 x day, IM) postoperatively. This wil l pro- vide adequate mineralocorticoid and glucocorticoid coverage. Continue this until the patient is eating and drinking (often <48 hours). Monitor electrolytes. From day 3, give hydrocortisone PO (double usual replacement dose, e.g., 20 mg/10 mg/10 mg) and add \202 udrocortisone PO (100 mcg daily). Long-term replacement is with hydrocortisone 10/5/5 and \202 udrocorti- sone 50 \200\223150 mcg daily. 99-Draznin-Chap99.indd 567 3/31/2011 9:30:53 PM CHAPTER 99 Perioperative management 568 Pheochromocytoma in pregnancy (see p. 364) This is a rare condition. It may present as para doxical supine hypertension, with pressure from the gravid uterus causing release of catech olamines, and normal blood pressure in the supine and erect positions. Start A-blockade then B-blockade, phenoxybenzamine can cross the placenta but is generally safe for the fetus (may cause perinatal CNS depression and transient hypotension). Surgery is more controversial, although some authors advocate surgery in the \201 rst and second trimesters up to 24 weeks \200\231 gestation. Caesarian section is advocated with a combined tumor resection. Vaginal delivery carries a signi \201 cant maternal risk. 99-Draznin-Chap99.indd 568 3/31/2011 9:30:53 PM GLUCOCORTICOID RESISTANCE 569 Syndromes of hormone resistance De \201 nition In these syndromes there is reduced responsiveness of target organs to a pa rticular hormone, usually secondary to a disorder of the receptor or distal signaling pathw ays. This leads to alterations in feedback loops and elevated circulating hormone levels. Thyroid hormone resistance b see Resistance to thyroid hormones (p. 37). Androgen resistance b see Androgen insensitivity syndrome (p. 335). Glucocorticoid resistance Autosomal dominant and recessive forms have been described. Diminished sensitivity to glucocorticoid leads to reduced glucocorticoid feedback on CRH an d ACTH, leading to i CRH, ACTH, and cortisol concentrations. The clinical features are not due to excess glucocorticoid, as there is reduced peripheral tissue sensitivity. However, elevated ACTH leads to i secretion of mineralocorticoid (e.g., deoxycorticosterone) and andro- gen (DHEA and DHEAS). This may lead to hypertension and hy pokalemic alkalosis, hirsutism, acne, oligomenorrhea in females, and sexual precocity in ma les. Glucocorticoid resistance may be differentiated from Cushing \200\231s syn- drome because, despite evidence of i urinary cortisol, abnormal sup- pression with dexamethasone, and i re sponsiveness to CRH, the diurnal rhythm of cortisol secretion persists, there are no clinic al features of Cushing \200\231s syndrome, BMD is normal or i, and there is a normal respon se to insulin-induced hypoglycemia. Low-dose dexamethasone treatment (2 mg/day) may ef \201 ciently suppress ACTH and androgen production. 100-Draznin-Chap100.indd 569 3/31/2011 9:31:53 PM CHAPTER 100 Syndromes of hormone resistance 570 ACTH resistance This is a rare autosomal recessive disorder in which the adrenal cortex fai ls to respond to ACTH in the presence of an otherwise normal gland. (mineralocorticoid secr etion is preserved under angiotensin II control). The presenting clinical features include hypoglycemia, which is often neonatal, neonatal ja undice, i skin pigmentation, and frequent infections. Occasionally, ACTH resistance is a co mponent of the triple-A syn- drome of alacrima (absence of tears), achalasia of the cardia, and ACTH resistance. Biochemical features include undetectable or low 9 A.M. cortisol, with grossly elevated ACT H (often >1000 ng/mL), and normal renin, aldoster- one, and electrolytes, and impaired resp onse to the cortrosyn stimulation test. Treatment is with steroid replacement. Mineralocorticoid resistance Also known as type 1 pseudohypoaldosteronism, this is a rare i nherited disorder that usually presents in children with failure to thrive, salt loss, and dehydration. Both autosomal dominant and recessive forms have been described. Biochemical features are as follows: d Serum sodium \200 i Serum potassium (hyperkalemic acidosis) \200 i Urinary sodium (de spite hyponatremia) \200 i Plasma and urinary aldosterone \200 i Plasma renin activity Diagnosis requires proof of unresponsiveness to mineralocorticoids (no effect of \202 udr ocortisone on urinary sodium). Treatment with sodium supplementation has been used successfully. With time, treatment can often be weaned, and salt wasting is unusual following childhood. Further reading Charmandari, E, Kino T, Ichijo T, et al. (2008). Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and Implications of a rare gentic diso rder. J Clin Endocrinol Med 93:1563 \200\2231572. 100-Draznin-Chap100.indd 570 3/31/2011 9:31:54 PM DIFFERENTIAL DIAGNOSIS OF POSSIBLE MANIFESTATIONS 571 Differential diagnosis of possible manifestations of endocrine disorders Sweating \200 Me nopause/gonadal failure \200 Thyrotoxicosis \200 Pheochromocytoma \200 Acromegaly \200 Hypoglycemia \200 Diabetes mellitus \200 Autonomic neuropathy (gustatory sweating ) \200 Renal cell carcinoma \200 Chronic infection (e.g., TB) \200 Hematological mali gnancy (e.g., lymphoma) \200 Anxiety \200 Idiopathic \200 Drugs, e.g., \202 uoxetin e Investigation of sweating \200 History \200 Clinical examination \200 Thyroid funct ion tests \200 Serum gonadotropin levels \200 Blood glucose level \200 Speci \201 c investigations according to clinical suspicion Management of sweating \200 Treat the unde rlying cause, where possible \200 Antiperspirants \200 Topical aluminum chloride eth anol \200 Anticholinergics \200\224glycopyrronium bromide (oral or topical) \200 Clonid ine \200\224taken at night to avoid sedation \200 Iontophoresis \200 Botulinum toxin A injections into affected areas (inhibits the release of acetylcholine at the synaptic junction of local nerves) Local excision of axillary sweat glands \200 Sympathetic denervation Video-assisted endoscopic thoracic sympathectomy \200\223 Excision \200\223 Radioablation Sympathotomy (chain disconnection between T2 ganglion and stellate ganglion) Palpitations (often associated with sweating) \200 Thyrotoxicosis \200 Hypoglycemia (in sulinoma) \200 Pheochromocytoma \200 Anxiety states \200 Cardiac arrhythmia 100-Draznin-Chap100.indd 571 3/31/2011 9:31:54 PM CHAPTER 100 Syndromes of hormone resistance 572 Caffeine excess \200 Alcohol or drug withdrawal General malaise, tiredness \200 Addison \200\231s disease \200 Hypo- or hyperthyroidism \200 Hypogonadism \200 Hypopituitarism or GH de \201 ciency \200 Osteomalacia \200 Diabetes mellitus \200 Cushing \200\231s syndrome \200 Anemia \200 Drugs (prescript ion and recreational drugs) Antihistamines \200 Antidepressants \200 Antihypertensives ( B-blockers, methyl-dopa, c lonidine) \200 Neuroleptics \200 Corticosteroids Malignancy \200 Chronic fatigue syndrome (may be associated with reduced cortisol output both basally and in response to a variety of challenges) Chronic illness (cardiac, respiratory, hepatic) \200 Fibromyalgia \200 Depression \200 Sleep disorders (obstructive sleep apnea) \200 Infection \200 Musculoskeletal or neur ological disease (mysthenia gravis) \200 Toxins \200 Idiopathic Investigation of fatigu e \200 Careful history-taking Duration, onset, recovery, and type of fatigue \200 Person \200\231s usual activity level Clinical examination \200 Serum electrolytes \200 Hemoglobin serum ferritin level \200 In \202 ammatory markers (ESR, CRP) \200 Liver function tests \200 Serum calcium and phosphate levels \200 Thyroid function tests \200 Cosyntropin stimulation test Flushing \200 Gonadal failure (with \202 ushing and sweats) \200 Drugs Chlorpropamide \200 Nicotinic acid \200 Antiestrogens \200 LHRH agonists 100-Draznin-Chap100.indd 572 3/31/2011 9:31:54 PM DIFFERENTIAL DIAGNOSIS OF POSSIBLE MANIFESTATIONS 573 Carcinoid (dry \202 ushing \200\224no sweats) \200 Mastocytosis \200 Medullary thyroi d cancer \200 Anaphylaxis \200 Pancreatic cell carcinoma \200 Pheochromocytoma (more often pallor) \200 Fever \200 Alcohol \200 Autonomic dysfunction \200 Some foods \200 Fish \200 Tyramine containing food (cheese) \200 Nitrites (cured meat) \200 Mon osodium glutamate \200 Spicy food \200 Gustatory \202 ushing \200 Benign cutaneous \202 ushing \200 Idiopathic Initial evaluation of patients with \202 ushing \200 Ca reful history \200 Physical examination (ideally during a \202 ush, although this is no t often possible) \200 Examine skin carefully \200 Pulse rate \200 BP \200 Thyroid examinat ion \200 Respiratory examination (wheeze) \200 Careful abdominal examination Biochemistry