Week 10: Endocrinology pt 1, sweet, salty, and stormy

Hyperthyroidism refers to disorders that result from overproduction of hormone from the thyroid gland. Thyrotoxicosis refers to any cause of excessive thyroid hormone concentration. Thyroid storm represents the extreme manifestation of thyrotoxicosis. This patient has thyroid storm, a condition predominantly seen in patients with Grave’s disease. There are many precipitants of thyroid storm, but infection and sepsis are the most common. Clinically, patients often present with fever, diaphoresis, tachycardia, altered mental status, restlessness, agitation, abdominal pain, and vomiting. The presentation mimics many other hyperadrenergic states such as cocaine intoxication or ethanol withdrawal. It can also be confused with heatstroke and neuroleptic malignant syndrome. The prompt recognition and treatment of thyroid storm is crucial for patient survival. If untreated, the condition is uniformly fatal. Propranolol is the first-line treatment for patients with symptomatic thyrotoxicosis or thyroid storm because it blocks peripheral hyperadrenergic activity in addition to the conversion of T4 to T3. This should be immediately followed by administraiton of propylthiouracil or methimazole to futher block the conversion of T4 to T3. Iodine (after PTU administration), corticosteroids, fluid resuscitation, rapid cooling, and treatment of precipitating illness follows.

After administration of propranolol, management of thyroid storm should proceed with the initiation of propylthiouracil to inhibit the production of thyroid hormone. Once the primary measures are taken, and there is concern that the inciting event may be due to sepsis, then vanc/cefepime should be administered. Inorganic iodine (potassium iodide) blocks the release of thyroid hormone that is still stored in the thyroid gland, but its administration should be delayed at least 60 min after propylthiouracil is administered. It is important to first inhibit the synthesis of thyroid hormone; otherwise, the administered iodine will be incorporated into new hormone. While Methimazole or PTU should be administered expediently, controlling the sympathetic hyperactivity with propanolol is the first priority.

The appropriate dose of intravenous dextrose for a 2-year old child with hypoglycemia is 24 mL of 25% dextrose. To find the correct dose, you must perform a two-step calculation.

1. determine concentration of dextrose. In general think in terms of infants, pediatric pt, adult-ish patient. Formally though, <1 o: D10, 1-8 yo: D25, >8 yo: D50
2. Determine the dose

An easy way to remember the dosing is by the “50 rule” in which you divide 50 by the concentration you intend to use (50, 25, or 10) and you are given the dose you should administer:

Adult (D50): 50/50 = 1 mL/kg

1-8 yrs (D25): 50/25 = 2 mL/kg

< 1 yr (D10): 50/10 = 5 mL/kg

A dose of 12 mL of 50% dextrose (B) is incorrect because a 2-year old child should not be given 50% dextrose as it is a highly concentrated, hypertonic solution. A dose of 12 mL of 25% dextrose (A) is too low of a dose. Although you can give a 2-year old a 10% dextrose solution, 24 mL (C) it is too low of a dose.

Note that in the ED we often don’t have rapid access to D25 or D10. We can rapidly make these solutions though. Take a D50 push (50 cc), and dilute it by 50% with NS (i.e. waste half the syringe and replace it with 25 CC NS), this will give you D25. Then take that syringe and dilute it by 50% again with NS, this will give you D12.5 which is reasonably close to D10.

The patient has hypocalcemia. Calcium is critical to normal cell functioning, neural transmission, membrane stability, bone structure, blood coagulation, and intracellular signaling. Calcium levels are tightly regulated by parathyroid hormone, which induces the bones and kidneys to increase serum calcium levels. Hypocalcemia occurs in 1 to 2% of patients after total thyroidectomy and is due to injury or destruction of the parathyroid glands during surgery. Other causes of hypocalcemia include hypoparathyroidism, vitamin D deficiency, chronic renal failure, hyperphosphatemia, hypomagnesemia, and severe pancreatitis. Because calcium is bound to albumin in the blood, hypoalbuminemia will cause a fall in measured serum calcium. However the active form of calcium, ionized calcium, is not affected by changes in albumin. Hypocalcemia causes primarily neuromuscular and cardiovascular manifestations. Symptoms of mild hypocalcemia include muscle cramping and perioral or finger paresthesias. Severe hypocalcemia can lead to congestive heart failure, dysrhythmias, hypotension, and cardiovascular collapse. Chvostek’s sign is seen in hypocalcemia. Chvostek’s sign refers to twitching of the facial or eye muscles elicited by tapping on the facial nerve. Trousseau’s sign may also be present. In Trousseau’s sign, a blood pressure cuff is inflated to 20 mm Hg above systolic blood pressure for 3 minutes, and a positive sign is carpal spasms due to local ulnar and median nerve ischemia.

This patient presents with signs and symptoms consistent with hyperglycemic hyperosmolar state (HHS) and intravenous fluids should be given aggressively early in management. HHS is a syndrome characterized by dehydration, hyperglycemia, hyperosmolarity and altered mental status. Patients may present with confusion, lethargy, seizures, focal neurologic deficits or frank coma. Pathophysiologically, decreased insulin (or insulin action) leads to gluconeogenesis and increased circulating glucose levels. This in turn draws fluid from the intracellular space into the intravascular space. The resultant osmotic diuresis leads to profound intravascular dehydration, electrolyte abnormalities and hyperosmolarity. Typically, patients will have a blood glucose >600 mg/dl and an osmolarity >320 mOsm/L. Blood urea nitrogen and creatinine are usually elevated. Initial management focuses on supportive care and aggressive fluid resuscitation. Patients with HHS are estimated to be about 8 liters hypovolemic. In addition to fluid administration, electrolyte repletion is paramount.

HCT is used in the diagnosis of ischemic stroke. Although HHS can mimic a stroke, this is not the most important intervention at this time. Unlike in diabetic ketoacidosis, patients with HHS have preserved insulin secretion. While a continuous intravenous insulin infusion and even bolus therapy may be used to help lower the blood glucose level in a controlled manner, intravenous fluids are of greater importance in the initial management of the patient. For the board exam, fluid management for HHS ALWAYS precedes insulin administration.

This patient has evidence of diabetic ketoacidosis (DKA) on his laboratory evaluation. In DKA, patients become hyperglycemic, dehydrated and acidemic with multiple electrolyte abnormalities. The syndrome results from a deficiency of insulin as well as excess of glucagon. Excess serum glucose overwhelms the renal tubules leading to glucosuria and an osmotic diuresis. With glucose in the renal tubules, electrolytes (sodium, potassium, magnesium, calcium and phosphorus) and water are pulled into the tubules and excreted. With the absence of glucose available for metabolism (either due to insulin deficiency or resistance), the body begins to metabolize adipose tissue using fatty acid oxidation. This leads to the production of free fatty acids which are converted to ketones (acetoacetate and beta-hydroxybutyrate) by the liver. Ketosis leads to acidosis and may cause abdominal pain, vomiting and a characteristic fruity odor on the breath. Treatment includes aggressive IV hydration to correct severe dehydration. Patients with DKA need continuous insulin in order to reverse fatty acid metabolism. Insulin is administered as a continuous infusion of 0.1-0.14 units/kg/hour IV up until max of 10 u/hr until the anion gap and ketosis resolve. The ADA recommends 0.14 u/kg/hr while the Joint British Diabetes Societies Inpatient Care Group recommends 0.1 u/kg/hr. while controversial, some may give an initial bolus of 0.1 u/kg IV Insulin followed by infusion of 0.1 u/kg/hr. While this can lead to increased incidence of hypoglycemia/hypokalemia, it is currently controversial whether this actually causes harm. For all purposes and benefits for the test, generally starting with an infusion without a bolus is recommended.

An insulin IV bolus (B) is no longer recommended as first line with concerns for rapid shifts of glucose/potassium, though this is controversial. Regardless, 1.0 u/kg will be far too high of a starting dose. Potassium chloride 20 mEq IV prior to initiation of insulin infusion (C) would be indicated in patients with an initial potassium less than 3.3 mEq/L. Patients with an initial potassium of 3.3 – 5.2 mEq/L can be started on insulin and should also be given potassium with each liter of fluid. Patients with DKA are total body potassium depleted although their serum values are often normal on initial measurement. This results from shifting of potassium ions due to acidemia. As the pH normalizes, potassium values will drop and require repletion. A bolus of sodium bicarbonate 50 mEq IV (D) is not recommended in the treatment of DKA, even in severely acidotic patients as overly aggressive correction of acidemia may worsen outcomes.

The neurologic deficits associated with most toxic and metabolic causes of significant altered levels of consciousness (including hypoglycemia) are typically symmetrical (nonfocal). However, a small but not insignificant number of patients with hypoglycemia presents with focal neurologic deficits, including hemiplegia. The rapid identification and correction of hypoglycemia in all patients, including those with focal neurologic deficits, is critical to avoid severe complications of a rapidly reversible condition and to avoid unnecessary imaging (brain imaging) and potential interventions (thrombolytic therapy).

Although adrenergic symptoms such as diaphoresis and tachycardia are common manifestations of hypoglycemia, bradycardia is less common, and none of these symptoms should be relied on to determine if a patient is hypoglycemic.

Release of the counterregulatory hormone epinephrine in the setting of hypoglycemia can result in a variety of adrenergic symptoms (anxiety, diaphoresis, palpitations, tachycardia, tremors). Hypotension is not expected and is not common.

Syncope is a transient loss of consciousness associated with a loss of postural tone that spontaneously reverses without medical intervention. When a patient becomes comatose from hypoglycemia, the body has exhausted its ability to counteract the hypoglycemia. Spontaneous reversal is very unlikely to occur. Syncope is not a common manifestation of hypoglycemia.

Destruction of the adrenal cortex in primary adrenal insufficiency (Addison disease) manifests with signs and symptoms of steroid deficiency (mineralocorticoids, glucocorticoids, gonadocorticoids) and increased adrenocorticotropic hormone (ACTH). The mineralocorticoid aldosterone stimulates the kidneys to reabsorb sodium and to excrete potassium. Aldosterone deficiency contributes to the presence of hyponatremia (seen 90% of the time), and hyperkalemia (seen 60% of the time). Deficiency in the glucocorticoid cortisol can lead to hypoglycemia, a common finding in children and infants. Signs and symptoms of gonadocorticoid deficiency are more common in women and include decreased axillary and pubic hair and decreased libido. Increased ACTH leads to skin hyperpigmentation. Causes of primary adrenal insufficiency include autoimmune disease (most common cause in Western countries), congenital conditions, drugs, hemorrhage, infections (tuberculosis is traditionally a common cause but is uncommon now in Western countries), infiltrative diseases (such as amyloidosis and sarcoidosis), and metastatic cancer.

Cortisol is involved with maintaining euglycemia. Cortisol deficiency in primary adrenal insufficiency leads to hypoglycemia, not hyperglycemia.

Hypercalcemia, not hypocalcemia, is seen in primary adrenal insufficiency. The hypercalcemia is thought to be a result of increased mobilization from bone and diminished renal excretion. It generally corrects quickly with hydration.

Aldosterone causes sodium resorption and potassium excretion. Aldosterone deficiency in primary adrenal insufficiency causes hyperkalemia, not hypokalemia.

Metanephrine is an intermediate metabolite between epinephrine and vanillylmandelic acid. It is considered the most sensitive and specific test for identifying the presence of pheochromocytoma. Pheochromocytomas are catecholamine-producing adrenal tumors that can lead to hypertensive crises that may be lethal. The average age at diagnosis is approximately 40 years. The classic “rule of 10s” for pheochromocytomas is that approximately 10% are bilateral, 10% are extra-adrenal, and 10% are malignant. These tumors may arise sporadically or as a feature of an inherited condition such as multiple endocrine neoplasia, neurofibromatosis type 1 or von Hippel-Lindau disease. Typical clinical presentations include paroxysms of headaches, palpitations and profuse sweating: the classic triad of pheochromocytomas. Paroxysms usually last less than one hour and are brought about by exercise, position changes, surgery, urination or certain medications (e.g., metoclopramide, tricyclic antidepressants). Patients may present in a hypertensive crisis with acute pulmonary edema, intracranial hemorrhages, heart failure or dysrhythmias. Other clinical features may include anxiety or panic attacks, nausea, flushing, abdominal or back pain, pallor or generalized weakness. The first step in diagnosis is measuring biochemical metabolites called metanephrines, the methylated products of catecholamine catabolism. Diagnostic imaging for tumor localization is a secondary diagnostic method. Treatment includes total or partial adrenalectomy. Preoperative blood pressure management with oral alpha-adrenergic antagonists (e.g., phenoxybenzamine or prazosin) or beta-blockers (e.g., propranolol) can be used to keep blood pressure consistently less than 160/90 mm Hg.

5-HIAA (A), or 5-hydroxyindoleacetic acid, is a serotonin metabolite used in the diagnosis of carcinoid tumors. Serotonin (C) levels are not utilized for diagnosing neuroendocrine tumors, whereas serotonin metabolites (e.g., 5-HIAA) are. Vanillylmandelic acid (D) is the least specific catecholamine metabolite in testing for pheochromocytoma. It has greater utility in the initial diagnosis and surveillance testing for neuroblastomas.

Confusion, confabulation, ataxia, ophthalmoplegia, and nystagmus suggest Wernicke-Korsakoff encephalopathy. Although Wernicke syndrome and Korsakoff syndrome are clinically distinct, they are both caused by thiamine deficiency. Wernicke encephalopathy is often underdiagnosed and carries a mortality rate of 10% to 20%. It is diagnosed clinically with two of the following findings: oculomotor abnormalities (most commonly nystagmus), dietary deficiencies, cerebellar dysfunction, and altered mental status (e.g., lethargy, inattentiveness) or memory impairment. Korsakoff psychosis, also referred to as alcohol-induced persisting amnestic disorder, is an untreatable form of dementia that involves recent retrograde amnesia, anterograde amnesia (inability to learn new information), apathy, and confabulation. Confabulation is not essential to the diagnosis. Treatment is with thiamine followed by dextrose administration, along with an adequate diet and abstinence of alcohol. Ocular manifestations usually respond well to thiamine within days, but ataxia and mental changes usually do not improve as rapidly and portend a worse prognosis.

Dextrose (A) should be given after thiamine for the theoretical prevention of Wernicke-Korsakoff syndrome. Older literature suggests that prolonged treatment with hypertonic IV glucose “precipitated” Wernicke encephalopathy, but this did not occur with single or repeated bolus of IV glucose. Haldol is useful in agitated patients or those with psychosis, but is not required at this time as patient is neither agitated and there are no definitive signs of psychosis. Pyridoxine (C), or vitamin B6, is not the cause of Wernicke-Korsakoff syndrome and has no role in its prevention or treatment.

The patient is likely suffering from myxedema coma based upon her clinical features. Myxedema coma is a rare life-threatening expression of hypothyroidism. It may be precipitated by infection, cold exposure, medications, trauma, or myocardial infarction. Classically it occurs in the winter months in elderly women who are undiagnosed or undertreated. Patients present with hypothermia, bradycardia, hypotension, and altered mental status. Respiratory failure is common, and a difficult airway may be encountered secondary due macroglossia and oropharyngeal edema that can occur. Myxedema coma is a clinical diagnosis, and although thyroid studies and other lab testing should be sent, treatment should not be delayed for test results. Treatment consists initially of medical stabilization, starting with the patient’s ABCs. Initial treatment of hypotension should be with fluids, as vasopressors may be ineffective until thyroid replacement is initiated. Passive rewarming should be the primary method of rewarming, as active rewarming may worsen the patient’s condition. Administration of levothyroxine is key and should be co-administered with stress dose steroids (100 mg hydrocortisone) as there is usually a degree of adrenal crisis which also occurs.

Graves disease is a type of hyperthyroidism. Hyperthyroidism is defined by having excess thyroid hormone circulating due to hyperactivity of the thyroid gland. Thyroid storm is the known life-threatening state of thyrotoxicosis that is most commonly seen in patients with Graves’ disease. Although altered mental status and coma are both associated with thyroid storm other clinical features include fever, tachycardia, dysrhythmias, and heart failure. Sepsis  is defined as an infection that results in a systemic inflammatory response (SIRS). SIRS criteria are HR greater than 90, temperature greater than 38°C or less than 36°C, respiratory rate greater than 20 or PaCO2 less than 32 mm Hg, and white blood cell count greater than 12 x 109/L or less than 4 x 109/L. At least two of the four criteria must be met in combination with an infection or suspected infection. Treatment of sepsis is focused on fluid resuscitation, especially in cases of severe sepsis or septic shock. Broad-spectrum antibiotics as early as possible are also part of early treatment. However, this patient’s clinical picture is consistent with myxedema coma. DKA is a result of improper glucose uptake causing an increase in ketogenesis. Patient’s will often have deep and rapid breathing, tachycardia, and at times a “fruity odor” to their breath.