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30 Critical Illness-Related Corticosteroid Insuffi ciency in the Intensive Care Patient
357
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34. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301:2362–75.
35. Park HY, Suh GY, Song J, Yoo H, Jo IK, Shin TG, Lim SY, Woo S, Jeon K. Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study. Crit Care. 2012;16:R3.
36. Patel GP, Balk RA. Systemic steroids in severe sepsis and septic shock. Am J Respir Crit Care Med. 2012;185:133–9.
37. Lefering R, Neugebauer EA. Steroid controversy in sepsis and sep­tic shock: a meta-analysis. Crit Care Med. 1995;23:1294–303.
38. Funk D, Doucette S, Pisipati A, Dodek P, Marshall JC, Kumar A, Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Low-dose corticosteroid treatment in septic shock: a propensity-matching study. Crit Care Med. 2014;42(11):2333–41.
39. Kalil AC, Sun J. Low-dose steroids for septic shock and severe sep­sis: the use of Bayesian statistics to resolve clinical trial controver­sies. Intensive Care Med. 2011;37(3):420–9.
40. Kaufman I, Briegel J, Schliephake F, et al. Stress doses of hydrocor­tisone in septic shock: benefi cial effects on opsonization- dependent neutrophil function. Intensive Care Med. 2008;33:344–9.
41. Roquilly A, Mahe PG, Seguin P, et al. Hydrocortisone therapy for corticosteroid insuffi ciency related to trauma. The HYPOLYT study. JAMA. 2011;305:1201–9.
42. Yildiz O, Doganay M, Aygen B, Güven M, Keleştimur F, Tutuu A. Physiological-dose steroid therapy in sepsis. Crit Care. 2002;6(3):251.
43. Moran JL, Graham PL, Rockliff S, Bersten AD. Updating the evi­dence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective. Crit Care. 2010;14(4):R134.
44. Minneci PC M.D., Deans KJ M.D., Banks SM Ph.D., Eichacker PQ M.D., Natanson C M.D. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141(1):47–56.
45. Weber-Carstens S, KEh D. Bolus or continuous hydrocortisone – that is the question. Crit Care. 2007;11(1):113.
46. Keh D, Boehnke T, Weber-Cartens S, et al. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock:
a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med. 2003;167:512.
47. Kaufman Da, Mancebo J. Corticosteroid therapy in septic shock. Available form
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49. Marik PE, Varon J. Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature. Arch Surg. 2008;143(12):1222–6.
50. Yong SL, Marik P, Esposito M, et al. Supplemental perioperative steroids for surgical patients with adrenal insuffi ciency. Cochrane Database Syst Rev. 2009;4:CD005367.
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54. Agarwal R, Nath A, Aggarwal AN, Gupta D. Do glucocorticoids decrease mortality in acute respiratory distress syndrome? A meta­analysis. Respirology. 2007;12:585–90.
55. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M. Effi cacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354:1671–84.
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http://www.uptodate.com/contents/corticosteroid-
. Uptodate Accessed 5.15.2015.

Thyroid Disorders

Scott B. Grant and Stanley Z. Trooskin
3 1

Introduction

There are few thyroid conditions that are acutely life threatening, but the most notable are thyroid storm and myxedema coma, which result from thyroid hormone dysregulation. Thyroid storm is a severe manifestation of thyrotoxicosis (also known as thyrotoxic crisis). Thyroid storm was fi rst described in an article in 1931 by Dr. Frank Lahey where he distinguished between the “activation type” of hyperthyroidism and what he dubbed “apathetic thyroid­ism” [
5 ]. Many physiologic changes result from thyroid
storm including dysfunction of the central nervous system, cardiovascular system, thermoregulatory system, and gastro­intestinal and hepatic systems, with varying degrees of organ failure [ 1 ]. The most common cause of death in thyroid storm is multisystem organ failure, followed by congestive heart failure, respiratory failure, arrhythmia, disseminated intravascular coagulation, gastrointestinal perforation, hypoxic brain syndrome, and sepsis [ 3 , 6 ]. Burch and Wartofsky [ 2 ] developed a scoring system for thyroid storm in 1993 to aid in creating standardized diagnostic criteria. Akamizu et al. [ 3 ] tried to refi ne the diagnostic criteria based on a nationwide survey from the Japan Thyroid Association. Efforts at creating universal diagnostic criteria are important because early recognition can lead to lifesaving treatment. Diagnosis can be challenging because there are no laboratory abnormalities that are specifi c for thyroid storm [ 1 ].
S. B. Grant , MD, MBE General Surgery , Rutgers Robert Wood Johnson Medical School , New Brunswick , NJ 08901 , USA
Scott.B.Grant@gmail.com
e-mail: S. Z. Trooskin , MD (
Rutgers Robert Wood Johnson Medical School , New Brunswick , NJ 08901 , USA
Division of General Surgery , Robert Wood Johnson University Hospital , New Brunswick , NJ 08901 , USA
troosksz@rwjms.rutgers.edu
e-mail:
*)

Epidemiology

According to the American Thyroid Association, more than 12 % of the United States population will develop a thyroid disorder in their life, and an estimated 20 million Americans have some form of thyroid disease [ that up to 60 % of those with thyroid disorders are unaware of their disease [ 7 ].
Thyroid storm accounts for about 1–2 % of hospital admissions for thyrotoxicosis (or at least less than 10 %) [ 8 , 9 ]. The incidence of thyroid storm in hospitalized patients in a nationwide survey in Japan was 0.2 per 100,000 per year or 0.22 % of all patients with thyrotoxi­cosis and 5.4 % of those patients admitted to the hospital with thyrotoxicosis [ 3 , 6 ]. The current incidence is lower than previous estimates, perhaps for two reasons; fi rst, maybe the increased screening for thyroid disorders has led to earlier diagnosis and more prompt treatment of hyperthyroidism which prevents the development of thy­roid storm [ 10 ]; second, perhaps better preoperative man- agement of hyperthyroidism prevents surgery from inducing thyroid storm [ 1 ]. Thyroid storm is more com- mon in females than in males (10 % versus 2 %) [ 11 , 12 ]. Thyroid storm occurs most commonly in those aged 20–49 years [ 12 ]. Thyroid storm is more common among patients with Graves’ disease, and Graves’ disease is the cause of hyperthyroidism 85 % of the time [ 11 , 13 ]. Even with early diagnosis, the overall mortality of thyroid storm is high between 10 and 30 % and has been reported as high as 75 % in hospitalized patients [ 3 , 8 , 14 ].
The incidence of myxedema coma is estimated to be as low as 0.22 per million people per year [ 15 , 16 ]. Myxedema coma occurs most commonly in hospitalized elderly women with long-standing hypothyroidism [ 15 , 17 ]. Eighty percent of women affected by myxedema coma are older than 60 years, but it can occur in younger patients [ myxedema coma cases commonly occur in the winter, some have suggested that cold weather may lower the threshold in people at risk [ 15 , 17 , 18 ]. Mortality rates with myxedema
7 ]. More concerning is
15 ]. Since
© Springer International Publishing Switzerland 2016 N.D. Martin, L.J. Kaplan (eds.), Principles of Adult Surgical Critical Care, DOI 10.1007/978-3-319-33341-0_31
359
360
S.B. Grant and S.Z. Trooskin
coma have decreased from 60 to 70 % historically to 20–25 %, but mortality is highest in patients with severe hypothermia and hypotension [
15 , 19 , 20 ].

Thyroid Storm

Pathophysiology

To understand the pathophysiology behind how uncompli­cated hyperthyroidism can develop into thyroid storm, it is important to fi rst understand normal thyroid hormone physi­ology. Thyroid hormones have widespread effects impacting the function of virtually every organ system [ 19 ]. There is a feedback loop between the hypothalamus, the anterior pitu­itary, and the thyroid gland that regulates thyroid function. The hypothalamus releases thyrotropin-releasing hormone (TRH) which causes the anterior pituitary to release thyroid­stimulating hormone (TSH), which then binds to a receptor on the surface of thyroid cells. Iodide is transported into the thyroid follicular cell with a sodium-iodide symporter and then iodide is oxidized by thyroid peroxidase (TPO). TPO catalyzes tyrosine residues on thyroglobulin to be iodinated, forming triiodothyronine (T3) and thyroxine (T4) [ 21 ]. The synthesis and secretion of T3 and T4 are stimulated by TSH. Thionamides inhibit TPO. Almost 90 % of the thyroid hormones released from the thyroid are T4, whereas only about 10 % is T3 [ 22 ]. About 10–20 % of circulating T3 was directly secreted by the thyroid, whereas the other 80–90 % was peripherally converted from T4 to T3 by the removal of one of the four iodine atoms in T4 [ 1 , 22 ]. The liver and kid- ney 5′-deiodinases convert T4 to T3. Deiodinase D2 is the main active enzyme in the euthyroid state and deiodinase D1 is the main active enzyme in the hyperthyroid state. Deiodinase D1 can be inhibited by thionamides and propyl­thiouracil (PTU). T3 is more physiologically active than T4 and T3 is about four times more potent than T4 [ 22 ]. Peripherally circulating thyroid hormone (T3 and T4) inhib­its the release and synthesis of TSH and TRH in a negative feedback loop. Glucocorticoids and propranolol inhibit the peripheral conversion of T4 to T3.
More than 99 % of T3 and T4 are bound to thyroid­binding globulin (TBG), albumin, and transthyretin [ 23 ]. The unbound (free) hormone is available to be taken up by peripheral tissues (and enter cells and carry out thyroid func­tions), whereas the bound hormone serves as a storage capac­ity in the circulation [ 22 ]. TBG has a higher affi nity for T3 and T4 than albumin and transthyretin, so most of the thyroid hormone delivered to peripheral tissues is delivered by albu­min and transthyretin.
Although the mechanism behind progression from uncomplicated hyperthyroidism to thyroid storm remains controversial, a heightened response to thyroid hormone is
often implicated [ abruptly available free (unbound) thyroid hormone and enhanced binding of thyroid hormone to receptors are other often suggested mechanisms behind the development of thy­roid storm [ nostic laboratory abnormalities for thyroid storm, and thus total T3 and T4 concentrations are not necessarily higher in patients in thyroid storm than in patients with uncomplicated hyperthyroidism. However, the mean dialyzable fraction of T4 and mean free T4 concentrations are higher in patients with storm compared to those with uncomplicated thyrotoxi­cosis who have similar total T4 levels [ 25 ]. It has been sug- gested that the mean free T4 concentrations are higher because the thyroid hormone binding affi nity of TBG, albu­min, and transthyretin is decreased due to various stressors [ 25 , 26 ]. The rate at which free thyroid hormone levels increase is potentially more important than the absolute con­centration of free thyroid hormone in determining whether the presentation is uncomplicated thyrotoxicosis or thyroid storm [ 24 ].
Activation of the adrenergic system has a signifi cant role in the clinical manifestations of thyroid storm. There is no evidence that there is increased plasma concentrations or increased secretion of epinephrine or norepinephrine in patients with hyperthyroidism compared to patients who are euthyroid or hypothyroid [ 27 , 28 ]. Instead, patients who are hyperthyroid are more responsive to catecholamines perhaps because of an increase in the density of beta-adrenergic receptors or downstream signaling from the receptors [ 2 , 29 , 30 ]. This is important because nonselective beta-adrenergic antagonists like propranolol can be used to dampen these adrenergic effects [ 24 , 30 ].
Patients in thyroid storm have several hematologic changes. They have a leukocytosis even without an infection and an increased red blood cell mass from erythropoietin upregulation [ 15 ]. Thyroid storm patients may become hypercoagulable, with 18 % of thyroid deaths attributed to thromboembolic complications [ factor IX, and von Willebrand factor can increase in thyroid storm [
2 , 8 , 24 ]. As mentioned earlier, there are no diag-
15 , 19 ].
2 , 8 , 24 ]. Additionally, increased or
15 ]. Fibrinogen, factor VIII,

Precipitating Causes

The change from uncomplicated thyrotoxicosis to thyroid storm usually requires a precipitating cause or insult. Historically thyroid surgery was the most common precipi­tating cause of thyroid storm, but better preoperative prepa­ration and the increased use of radioactive iodine instead of surgery have rendered thyroid surgery a rare precipitating cause [ 1 ]. Incomplete or inadequate treatment of hyperthy- roidism or interruptions in the drug regimen for hyperthy­roidism are a risk factor for progression to thyroid storm [
1 ].
31 Thyroid Disorders
361
Anything that causes hyperthyroidism can lead to thyroid storm, but Graves’ disease is the most common etiology (60–80 % of cases), with toxic multinodular goiter or a toxic adenoma being other primary hyperthyroidism etiologies [
1 , 19 ]. A pituitary adenoma can be another cause of thyro-
toxicosis and secondary hyperthyroidism [
31 , 32 ]. Infection
is the most common precipitating cause of thyroid storm in hospitalized patients [
2 , 3 , 8 ]. The list of precipitating causes
is extensive and in addition to the causes listed above includes (in alphabetical order) alcohol abuse, antithyroid treatment withdrawal, burns, cardiac failure, cerebrovascular acci­dents, diabetic ketoacidosis, emotional stress, exercise, H1N1 infection, hypoglycemia, interferon treatment, iodine exposure from radiocontrast dyes or amiodarone, medica­tions (amiodarone, anesthetics, fl udrocortisone, insulin, non­steroidal anti-infl ammatory drugs, pseudoephedrine, salicylates, steroids, thiazide diuretics, tricyclic antidepres­sants), molar pregnancy, myocardial infarction, non-thyroid surgery, parturition, pulmonary embolism, radioactive iodine treatment, thyroid cancer, thyroid gland manipulation, thy­roid hormone ingestion (especially when large doses are ingested acutely), thyroiditis, and trauma [ 1 , 8 , 9 , 12 , 31 , 33 – 40 ]. Despite the long list of known precipitating causes, between 25 and 43 % or patients with thyroid storm present without a clearly identifi able precipitating cause [ 41 ].

Clinical Features and Diagnosis

The diagnosis of thyroid storm is a clinical diagnosis, and a low index of suspicion is important so that treatment is not delayed given the high mortality. The patient will have an exaggerated presentation of hyperthyroidism as well as multi-organ dysfunction [ 42 ]. High fever (as high as 104– 106 °F) and heat intolerance are very common and often accompanied by profuse sweating and signifi cant insensible fl uid losses, as well as tachycardia out of proportion to the underlying disease process [ libido, oligomenorrhea and polyuria, weakness, and weight loss despite increased appetite are common constitutional symptoms [
31 , 32 ]. Cardiovascular manifestations of thyroid
storm have been well described and may include atrial fi bril­lation, cardiac ischemia, dyspnea on exertion, exercise intol­erance, heart failure, palpitations, tachycardia (sinus or supraventricular), and/or widened pulse pressure [ 22 , 31 , 32 , 43 – 45 ]. The arrhythmias, tachycardia, and increased cardiac output can lead to heart failure and cardiogenic shock [ 31 , 32 , 45 , 46 ]. Central nervous system and psychiatric manifes- tations are very common including agitation, apathy, coma, confusion, delirium, dysphoria, hyperactivity, irritability, obtundation, restlessness, seizures, stupor, or tremor [ 3 , 22 , 31 , 32 ]. Gastrointestinal symptoms may be present including abdominal pain, diarrhea, nausea, and vomiting which lead
1 , 24 , 31 , 32 ]. Fatigue, loss of
to hypovolemia and electrolyte imbalances [
1 , 22 , 31 , 32 ].
Hepatic manifestations including liver dysfunction with ele­vated aspartate aminotransferase and alkaline phosphatase, hepatomegaly from hepatic congestion, and inadequate per­fusion may be present; jaundice portends a poor prognosis [ 15 , 22 , 47 , 48 ]. Other atypical presentations of thyroid storm have been published in case reports, including acute abdomen, disseminated intravascular coagulation, hypogly­cemia, lactic acidosis, rhabdomyolysis, status epilepticus, and stroke [
49 – 52 ].
Burch and Wartofsky [ 2 ] developed a scoring system for thyroid storm in 1993 to aid in creating standardized diag­nostic criteria, which has been widely accepted, but should not replace clinical judgment. The scoring system assigns points based on temperature (0–30), heart rate (0–25), cen­tral nervous system dysfunction (0–30), heart failure (0–15), gastrointestinal and hepatic dysfunction (0–20), atrial fi bril­lation (0–10), and precipitant history (0–10), with a score of 45 or greater highly suggestive of thyroid storm, a score of 25–44 suggestive of impending storm, and a score below 25 unlikely to suggest thyroid storm [ 2 ].
Akamizu et al. [ 3 ] tried to refi ne the diagnostic criteria put forth by Burch and Wartofsky [ 2 ] based on a nationwide sur- vey from the Japan Thyroid Association for cases of thyroid storm in Japanese hospitals from 2004 to 2008. Akamizu et al.’s [ 3 ] study is the largest single case series of thyroid storm [ 1 , 3 ]. Similar to Burch and Wartofsky [ 2 ], the diag- nostic criteria included temperature/fever, heart rate/tachy­cardia, central nervous system dysfunction, heart failure, and gastrointestinal and hepatic dysfunction, but the Akamizu et al. [ 3 ] criteria are based on combinations of symptoms rather than an absolute score. More than 75 % of patients had a pulse greater than 130 beats per minute, and 84 % of patients had central nervous system manifestations [ 3 ]. Forty percent of patients had heart failure and 69 % had gastroin­testinal symptoms [ 3 ], while 76 % of patients had more than three organ system manifestations (multisystem organ dys­function/failure) [
3 ]. One caveat to this study is that it may
not be generalizable outside of Japan given the specifi c pop­ulation surveyed and the somewhat unique high iodine diet customary in Japan [
6 ].
Although the diagnosis of thyroid storm is clinical, lab­oratory values can still be useful. Although there is no absolute cutoff for serum T3 or T4 that distinguishes uncomplicated thyrotoxicosis from thyroid storm, check­ing TSH, free T3, free T4, blood urea nitrogen, liver func­tion tests, calcium, and glucose levels is important. Patients can have a leukocytosis in the presence or absence of infection, and elevated blood urea nitrogen is correlated with irreversible complications [
3 ]. Patients with thyroid
storm can be hyperglycemic from catecholamines inhibit­ing insulin release and increasing gluconeogenesis or rarely can be hypoglycemic [ 10 , 49 ]. Systemically ill
362
S.B. Grant and S.Z. Trooskin
patients are less able to convert T4 to T3 so a minimally elevated or free T3 that is in the “normal” range may be inappropriately elevated [
8 ].

Medical Treatment

Treatment of thyroid storm should begin as soon as possible with a low index of suspicion given the high mortality, and patients should be transferred to an intensive care unit for close monitoring. There are three main goals in thyroid storm treatment: (1) create a euthyroid state, (2) prevent cardiovas­cular collapse, and (3) control hyperthermia [ 22 ]. A multi- disciplinary approach is important, and treatment should be both supportive as well as targeting the synthesis, release, peripheral effect, and enterohepatic circulation of thyroid hormone.
The fi rst-line therapy for thyroid storm is thioamides/thi­onamides, which inhibit new thyroid hormone production [ 1 ]. The most common agents are propylthiouracil (PTU) and the imidazoles (methimazole and carbimazole) [ 1 ]. As mentioned above, thionamides inhibit thyroid peroxidase (TPO, which helps form T3 and T4) [ 21 ]. Although both PTU and methimazole are used to treat hyperthyroidism, PTU is preferred in the treatment of thyroid storm because it also decreases conversion of T4 to T3 in the periphery [ 1 ]. When treating thyroid storm, the dose of PTU or methima­zole should be much higher than the doses used to treat hyperthyroidism, with 600–1,500 mg per day of PTU divided into doses every 4–6 hours (possible loading dose of 600 mg) and 80–120 mg per day of methimazole divided into doses every 4–6 hours [ 2 , 8 , 53 ]. The American Association of Clinical Endocrinologists/American Thyroid Association guidelines recommend a PTU loading dose of 500–1,000 mg and then 250 mg every 4 hours and for methimazole 60–80 mg per day in divided doses [ 54 ]. Side effects of pro- pylthiouracil and methimazole include arthralgias, benign transient leukopenia, fevers, hepatotoxicity (less hepatotox­icity with methimazole than with PTU), and rashes [ 19 ].
For patients without enteral access, rectal formulations of PTU and methimazole have been developed, but have lower bioavailability [ 55 – 57 ]. Rectal suppositories have a lower bioavailability than retention enemas, but the suppositories are preferred since they are easier for nurses to administer and less uncomfortable for patients [ 55 – 58 ]. PTU is rela- tively insoluble at a physiologic pH, and so compounding for intravenous administration is diffi cult, but intravenous methimazole is commercially available in Europe and can be compounded in the United States by dissolving methimazole powder in normal saline [ via nasogastric tube [
Iodine administration can also decrease new thyroid hor­mone synthesis by inhibiting binding of iodide to thyroglobulin
1 , 59 ]. Treatment can also be given
19 ].
via the Wolff-Chaikoff effect [
1 ]. This mechanism prevents
binding once a critical threshold of iodide is reached in the plasma, but only lasts 26–50 hours, as the thyroid will adapt to the excessive iodide over time [ 60 ]. Iodine can be adminis- tered as potassium iodine 250 mg (0.25 mL or fi ve drops) every 6 hours or as Lugol’s solution with eight drops given orally every 6 hours (iopanoic acid and sodium ipodate are not commercially available in the United States) [
2 , 54 ]. Side
effects of potassium iodide include hypersensitivity reactions, metallic taste, and salivary gland swelling [ 19 ]. Iodine can also be administered rectally or intravenously. Potassium iodide can be compounded for rectal administration by plac­ing 1 g of iodide in 60 mL of water and giving 2 g per day in divided doses [ 61 ]. Lugol’s solution can be administered rec- tally in doses of 4 mL (80 drops) per day [ 62 ]. Iodine should be given at least 30–60 minutes after giving thionamides to prevent it serving as material for further thyroid hormone synthesis, and thionamides must be continued during the time that iodine is used for therapy [ 1 ]. Additionally, giving iodine may delay treatment of hyperthyroidism with radioactive iodine and thus is often utilized when the plan is for thyroid­ectomy [ 1 , 2 , 8 ]. Finally, lithium (carbonate) inhibits T3 and T4 synthesis by inhibiting the coupling of iodotyrosine resi­dues and can be used as an alternative to iodine; 300 mg should be given every 6–8 hours with repeated monitoring of serum drug levels because of the narrow therapeutic window (goal range is 0.6–1 mEq/L) [ 2 , 8 , 15 ].
Once new thyroid hormone synthesis is stopped, another agent of thyroid storm treatment is preventing release of thyroid hormone that has already been formed into systemic circulation [ 1 ]. Iodine also inhibits release of already formed thyroid hormone by inhibiting the proteolytic release of T3 and T4 from thyroglobulin [ 2 , 63 ]. This action gives iodine treatment a faster onset than PTU [ 41 ]. The combination of thionamides and iodine treatment can decrease serum T4 levels to close to the normal range within 4–5 days [ 64 ]. Lithium can also be used to decrease thyroid hormone release [
1 ].
Oral iodinated contrast agents inhibit deiodinases D1 and D2 and profoundly decrease T3 levels, and because of their iodine content, both decrease new thyroid hormone synthesis and preformed thyroid hormone release [
1 ]. These contrast
agents should be given as a 2 g loading dose then 1 g daily to treat thyroid storm, or in lower doses to rapidly prepare for thyroid surgery, or in addition to thionamides when treating Graves’ disease [ 65 – 67 ].
An additional treatment modality is aimed at preventing the recirculation of thyroid hormone metabolites after being processed by the liver [ 1 ]. Thyroid hormone is conjugated to glucuronides and sulfates in the liver, and these metabolites are excreted in bile into the intestine where they are reab­sorbed and then recirculated in a process known as enterohe­patic circulation of thyroid hormone [
1 ]. Cholestyramine
31 Thyroid Disorders
363
when dosed at 1–4 g twice a day will bind the metabolites, promote their excretion, and thus decrease enterohepatic cir­culation of thyroid hormones [
15 , 68 – 70 ].
Thyroid storm treatment should also focus on mitigating the downstream effects of thyroid hormone via adrenergic blockade. Hughes was the fi rst to report using a beta-blocker (pronethalol) along with carbimazole to treat thyrotoxicosis in 1966 [ 71 ]. Propranolol has become the most commonly used beta-blocker in thyroid storm because it is nonselective and decreases conversion of T4 to T3 in the periphery [ 1 ]. Propranolol ameliorates symptoms by decreasing pulse and oxygen demand, reducing convulsive symptoms and tremor, psychotic behavior, agitation, and fever [ 15 , 19 , 22 ]. Propranolol dosing can be as high as 60–120 mg orally every 6 hours (or 40–80 mg orally every 4 hours) since it is metab­olized more rapidly in thyroid storm [ 10 , 19 ]. Beta-blockade can also be accomplished intravenously for a faster effect with IV propranolol or esmolol; IV propranolol dosing is
0.5–1.0 mg slow IV push then 1–2 mg every 15 minutes (or just 2 mg IV every 4 hours) with telemetry monitoring of the pulse, whereas esmolol is 0.25–0.5 mg/kg initial bolus then a continuous infusion at 0.05–0.1 mg/kg per minute [ 19 , 41 , 72 ]. Side effects of propranolol include bradycardia, nausea, and vomiting and should be avoided in patients with decom­pensated heart failure [ 19 ]. Calcium channel blockers can be utilized to treat thyroid storm in patients with pulmonary conditions like asthma or chronic obstructive pulmonary dis­ease (COPD), but may not be as effective as beta-blockers [ 22 ].
Supportive resuscitative treatment is also important, including temperature regulation with cooling and antipyretics, intravenous fl uid resuscitation for dehydra­tion, monitoring hemodynamic status and fl uid status in patients with congestive heart failure, oxygen, treatment of dysrhythmias as they arise, and prevention of adrenal insuffi ciency. In managing fever, acetaminophen is pre­ferred to salicylates because salicylates can increase free thyroid hormone levels by limiting the binding to T4-binding globulin [ 15 , 73 ]. Peripheral cooling can be achieved with cooling blankets and/or ice packs. Shivering should be avoided since it can increase temperature and cardiac demands by increasing the metabolic rate [ 22 ]. Intravenous fl uid resuscitation is important to support insensible losses from fever and fl uid losses for diarrhea and vomiting. A central venous line for central venous pressure monitoring and pulmonary wedge pressure moni­toring with a Swan-Ganz catheter can also be useful adjuncts. Vasopressors may be needed to treat hypotension that does not resolve with intravenous fl uids. The hypothalamic- pituitary-adrenal axis is impaired in thyrotoxicosis, and despite increased cortisol production by the adrenal gland which compensates for the increased glucocorticosteroid metabolism in hyperthyroidism, an
inadequate response to adrenocorticotropic hormone (ACTH) occurs. Stress dose steroids are recommended with a loading dose of 300 mg of hydrocortisone intrave­nously and then 100 mg every 8 hours to prevent adrenal insuffi ciency and decrease the peripheral conversion of T4 to T3 [ hydrocortisone [
74 ]. Hyperglycemia is a notable side effect of
19 ].
Finally, medical treatment of thyroid storm includes cor­recting the precipitating cause if possible. Sometimes the precipitating cause is obvious like trauma or surgery, but sometimes it is more subtle, and fever and/or leukocytosis should prompt a search for an infectious source. Evaluate for exposure to iodine or iodinated contrast or withdrawal of thi­onamides, and treat other precipitating causes like burns, diabetic ketoacidosis, myocardial infarction, stroke, or pul­monary emboli in the standard fashion.

Therapeutic Plasma Exchange

For refractory cases of thyroid storm, therapeutic plasma exchange (TPE) is an additional option which rapidly reduces circulating thyroid hormone levels and can effec­tively yield clinical improvement. During TPE, the patient’s plasma is extracted and a colloid replacement like albumin and/or plasma is infused [ 75 , 76 ]. Ashkar et al. [ 77 ] described the fi rst use of plasmapheresis in thyroid storm in a case series of three patients who failed conventional therapy pub­lished in 1970. In thyroid storm, thyroid-binding globulin (TBG) is removed from the circulation along with the thy­roid hormone bound to TBG, and the colloid replacement, which is most often albumin, provides available binding sites for circulating free thyroid hormone to bind too, thus decreas­ing free thyroid hormone concentrations [ 26 ].
Most case series show a reduction in free T3 and free T4 with TPE, and Ezer et al. [ 76 ] published the largest plasma exchange series in thyrotoxicosis with 11 patients who underwent preoperative TPE before thyroid or non-thyroid surgery. Free T3 decreased among patients 22.2–89.9 % and free T4 decreased 8.3–64.8 %, but these declines were not statistically signifi cant, although all patients improved in signs and symptoms of thyrotoxicosis [ 76 ]. Clinical improve- ment often occurs within a few hours of the fi rst TPE session, especially cardiac signs and symptoms of thyroid storm [ 78 ]. Plasmapheresis and therapeutic plasma exchange provide only temporary reductions in T3 and T4 (for up to 36 hours), and so they must be continued or defi nitive therapy instituted [ 15 ]. Despite this the American Society of Apheresis 2010 guidelines only recommended TPE as a grade IIc (weak rec­ommendation, low-quality evidence based on observational studies or case series) and a category III (optimal role of apheresis therapy is not established; decision- making should be individualized) recommendation, suggesting that further
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more rigorous research needs to be performed to clarify the role of TPE in thyroid storm, especially regarding the timing or triggers for initiation.
Muller et al. [ 78 ], in contrast, recommended initiating TPE early for the following indications: severe symptoms (cardiac or neurologic manifestations, severe myopathy, etc.), rapid clinical deterioration, contraindications to other therapies, and refractory cases. The American Society of Apheresis recom­mends performing TPE daily to once every 2 or 3 days until clinical improvement and monitoring free T3 and T4 before and after each session, but continuing TPE regardless of hor­mone levels if clinical stabilization occurs with TPE therapy [
75 ]. The complication rate of TPE is about 5 %, and compli-
cations include allergic reactions, coagulopathy, hemolysis, hypotension, infection, and vascular injury [ 76 , 78 , 79 ].

Thyroid Surgery

While thyroid surgery is a defi nitive therapy for thyroid storm producing rapid resolution of hyperthyroidism, it is only rarely needed emergently in the modern era given recent advances in medical treatment and critical care to treat thy­roid storm patients [ 1 ]. A multidisciplinary approach to thy- roid storm is critical, and the surgical team should be consulted within the fi rst 12–72 hours [ 1 ]. However, medical management should be attempted fi rst, and there are only three types of patients who qualify for emergent surgery: (1) patients who clinically deteriorate or are refractory to medi­cal treatment within 24–48 hours; (2) patients with side effects from medical management, such as agranulocytosis or hepatitis or severe thrombocytopenia from thionamides; or (3) patients with severe cardiac or pulmonary comorbidi­ties who lack the reserve to tolerate prolonged thyroid storm [ 1 , 80 ]. There are several treatment plans to quickly prepare patients for surgery with most utilizing iopanoic acid (an oral cholecystographic agent) which is unavailable commercially in the United States [ exchange (TPE)/plasmapheresis is an alternative to iopanoic acid to quickly prepare a patient for thyroid surgery by con­trolling thyroid storm [ roidism in general, it is customary to achieve euthyroidism prior to surgery via medical management [ 8 ].
The recommended surgery for thyroid storm is a subtotal or near-total thyroidectomy, just like for Graves’ disease [ 41 ]. For the patient on steroids or beta-blockers preoperatively, they should be continued perioperatively and slowly weaned over the following weeks [ 8 ]. Given that medical and critical care man- agement have rendered emergency surgery for thyroid storm so rare, there is limited surgical outcome data available. Scholz et al. [ 80 ] reported their own series of ten patients and summa- rized the literature of early thyroidectomy for thyroid storm, noting a long-term overall mortality of 10 % (5 of 49 patients).
22 , 65 , 66 , 81 ]. Therapeutic plasma
1 , 75 – 78 ]. However, for hyperthy-

Thyroid Storm in Pregnancy

Hyperthyroidism occurs in 1 in 500 pregnancies [ 13 ]. Women with thyrotoxicosis with limited access to prenatal care or with medical or obstetrical complications have an increased risk of developing thyroid storm [ toms of thyroid storm are the same in pregnant women but are more likely to be mistaken for the normal hypermetabolic state of pregnancy [ zole cross the placenta, with PTU recommended for the fi rst trimester and methimazole recommended for the remainder of the pregnancy [ 13 , 19 ]. Delivery of the fetus during thyroid storm is not recommended, unless the fetal condition demands it [ 19 ]. Radioactive iodine is contraindicated during preg- nancy and breastfeeding since it may also ablate the thyroid gland of the fetus or neonate [ 13 , 22 ]. Thyroidectomy should be avoided during pregnancy because of an increased risk of preterm delivery or of spontaneous abortion [ 13 ]. A full review of thyroid storm during pregnancy is beyond the scope of this chapter, and additional information can be found in the cited article by Waltman et al. [ 13 ].
13 ]. Both propylthiouracil and methima-
13 ]. The signs and symp-

Long-Term Management of Hyperthyroidism

After the acute thyroid storm episode is over, defi nitive treat­ment of hyperthyroidism should be offered. Given the long half-life of T4 (about 1 week), treatment should be slowly weaned to prevent a recurrent episode of thyroid storm [ 1 ]. If nonadherence to thionamides is suspected as the precipitat­ing cause for the thyroid storm, defi nitive treatment with sur­gery or radioactive iodine should be initiated as soon as possible. If the patient received iodine treatment for their thyroid storm episode, radioactive iodine ablation would need to be postponed until the intrathyroidal iodine stores are eliminated [ 1 ]. While waiting for the intrathyroidal iodine stores to clear, thionamide treatment should continue and thyroid function studies should be monitored for stability [ 1 ]. If the patient is compliant, continued thionamide treat- ment is acceptable [ 1 ]. Improvement from thyroid storm can occur rapidly within as little as 24 hours [ 15 ]. Once a patient has stabilized from thyroid storm and the precipitating cause(s) has been addressed, iodide therapy and glucocorti­coids can be withdrawn [ 19 ]. Beta-blockers should be con- tinued until thyroid function tests return to normal [ 19 ].

Outcomes of Thyroid Storm

A high index of suspicion, early diagnosis, and rapid treat­ment result in the best outcomes and can signifi cantly impact the outcomes for thyroid storm. While early case series reported mortality rates as high as 37.5 %, more recent stud-
31 Thyroid Disorders
365
ies report a 10.7 % mortality rate for thyroid storm [ 3 , 82 ]. The most common causes of death in Akamizu et al.’s [ study with the Japan Thyroid Association were multisystem organ failure and congestive heart failure. Even if the patient survives, there was often signifi cant morbidity, including brain injury, cerebrovascular disease, muscular disuse atro­phy, psychosis, and/or renal function impairment [ 1 ].
3 ]

Myxedema Coma

Myxedema coma is the life-threatening end stage of inade­quately treated or untreated hypothyroidism and is often trig­gered by a precipitating cause [ 19 ]. Precipitating causes include cerebrovascular accident, diuretics, excessive hydra­tion, exposure to cold, gastrointestinal bleeding, heart fail­ure, infection, medications (amiodarone, lithium, phenytoin, lack of compliance with thyroid replacement), myocardial infarction, narcotics, sedatives, surgical procedures, or trauma [ 12 , 17 , 19 , 20 , 83 – 85 ]. Although usually it is pri- mary hypothyroidism that leads to myxedema coma, in 5–15 % of cases, a pituitary or hypothalamic source of hypo­thyroidism is identifi ed [ 86 ].

Clinical Features and Diagnosis

Myxedema coma typically begins with lethargy and worsen­ing mental status that progresses to coma, then respiratory decompensation and hypothermia [ 17 ]. Hypothermia may be profound (temperature as low as 74 °F and often 91–95 °F) [ 19 , 22 , 31 ]. Those patients with myxedema without coma can have central nervous system and psychiatric manifestations including adiadochokinesia, ataxia, cerebellar signs (poorly controlled purposeful movements of the hands and feet), delayed deep tendon refl exes, depression, disorientation, hal­lucinations (myxedema madness), mental status changes, paranoia, poor memory and recall, or seizures [ Up to 25 % of patients with myxedema coma may experience seizures, possibly secondary to hypoglycemia, hyponatremia, and hypoxemia [ edema coma can include arrhythmias (especially bradycardia, varying types of heart block, prolonged QT intervals, torsades de pointes), cardiac contractility impairment, cardiac tampon­ade (from an accumulation of mucopolysaccharide fl uid in the pericardial sac), hypotension from low intravascular volumes, and shock from cardiac dysfunction [ 15 , 17 ]. Respiratory manifestations include airway obstruction from edema of the tongue and vocal cords, decompensation requiring mechanical ventilation because of decreased hypoxic respiratory drive and decreased ventilator response to hypercapnia, pleural effu­sions, and prolonged need for mechanical ventilation from slow respiratory recovery [
15 ]. Cardiovascular manifestations of myx-
15 , 17 , 20 , 87 ].
15 , 17 , 20 , 22 ].
Myxedema coma also affects the gastrointestinal, hematologic, and renal systems. Renal and genitourinary manifestations include atonic bladder with urinary retention, decreased glomerular fi ltration rate, hyponatremia (from increased serum antidiuretic hormone and impaired diuresis because less water gets to the distal nephron), increased total body water, and rhabdomyolysis with increased creatine kinase levels and increased risk of kidney failure [ Critically ill patients with symptomatic hyponatremia have a higher mortality rate than patients who do not [ 15 ]. Hematologic manifestations include anemia (microcytic from hemorrhage or macrocytic from vitamin B12 defi ciency), bleeding and coagulopathy (secondary to decreased factors V, VII, VIII, IX, and X and acquired von Willebrand syndrome type 1), disseminated intravascular coagulation (if patients become septic), and granulocytopenia (increasing infection risk and decreasing cell-mediated immune response) [ The von Willebrand syndrome is reversible with T4 treatment [
15 ]. Gastrointestinal manifestations include ascites, decreased
motility (secondary to mucopolysaccharide infi ltration and gut edema and ranging from gastric atony and impaired peri­stalsis to paralytic ileus), and gastrointestinal bleeding (from coagulopathy) [ 15 , 17 ]. Other manifestations can include dry skin and hoarseness [ 15 ].
Laboratory studies, imaging, and other testing are useful in the diagnosis of myxedema coma. Thyroid function tests will reveal a decreased free T4 and increased TSH [ 22 ]. Hyponatremia, respiratory acidosis, hypercapnia, hypox­emia, hypoglycemia, and hyperlipidemia are all common in myxedema coma [ 22 ]. An EKG may show bradycardia, varying types of heart block, low voltage, fl attened or inverted T waves, prolonged QT intervals, or torsades de pointes [ 15 , 22 ]. A chest X-ray may reveal cardiac and/or pleural effusions [ 22 ].
Popoveniuc et al. [ 4 ] described a scoring system for myx- edema coma diagnosis. The scoring system assigns points based on temperature (0–20), heart rate (0–30), central ner­vous system effects (0–30), cardiovascular dysfunction (10 for other EKG changes besides bradycardia, 10 for pericardial/ pleural effusions, 15 for pulmonary edema, 15 for cardiomeg­aly, 20 for hypotension), gastrointestinal fi ndings (0–20), met­abolic disturbances (10 each for hyponatremia, hypoglycemia, hypoxemia, hypercarbia, decrease in glomerular fi ltration rate), and precipitant history (0–10), with a score of 60 or greater highly suggestive/diagnostic of myxedema coma, a score of 25–59 suggestive of risk for myxedema coma, and a score below 25 unlikely to indicate myxedema coma [ 4 ].
15 , 17 , 20 ].
15 , 88 ].

Treatment

The treatment of myxedema coma involves thyroid hormone replacement, supportive care, and addressing the underlying
366
S.B. Grant and S.Z. Trooskin
precipitating cause [ 20 ]. Additional treatment goals include (1) thermoregulation, (2) stabilization of cardiac status, and (3) improved ventilation [
22 ]. Optimal thyroid hormone replace-
ment dosing is lacking because there are few well- controlled trials given the rarity of cases [ 15 , 20 ]. Replacement can be with T3 or T4 or both and some advocate replacing both since T4 to T3 conversion is impaired in myxedema coma [ 15 , 19 ]. If treating with levothyroxine (T4) only, a loading dose of 300– 600 mcg IV then 50–100 mcg IV daily is recommended [ 15 ]. If treating with liothyronine (T3), only a 10–25 mcg IV bolus loading dose followed by 10 mcg every 4 hours for the fi rst 24 hours then 10 mcg every 6 hours for days 2 and 3 is recom­mended [ 15 , 19 ]. In the combined approach, an initial bolus loading dose of 4 mcg/kg lean body weight (or about 200– 300 mcg) of T4 is given IV, followed by 100 mcg 24 hours later and then a daily maintenance dose of 50 mcg by the third day, which can be given orally when the patient is conscious and extubated; simultaneously, a bolus loading dose of 10 mcg of T3 is given IV and then 10 mcg every 8–12 hours is given until the patient is conscious [ 15 ]. Overly aggressive replacement of T4 is undesirable as it can cause myocardial infarction [ 19 ]. Antacids and iron interfere with the absorption of levothyrox­ine so it should be taken on an empty stomach [ 22 ].
Supportive care includes intravenous fl uid resuscitation with 0.9 % sodium chloride and possibly sodium replacement for hyponatremia with hypertonic saline (50–100 mL of 3 % sodium chloride followed by 40–120 mg furosemide) [ 15 , 19 ]. Sodium levels should be corrected slowly to prevent central pontine myelinolysis. Hypothermia will resolve with T3 and T4 treatment, but a warm ambient temperature and warming blankets can be used; however, aggressive rewarming should be avoided to prevent vasodilation [ 15 , 20 ]. Ventilation is improved with oxygen, but may require either continuous posi­tive airway pressure (CPAP) or Bi-PAP or even endotracheal intubation with mechanical ventilation [ 22 ]. Hydrocortisone 100 mg IV every 8 hours is recommended for patients with hypotension for at least 48 hours and up to the fi rst 7 or 10 days or until adrenal suppression is ruled out, as the patient may have relative adrenal insuffi ciency [ 15 , 19 ]. If the patient has a seizure, phenytoin should be avoided in the treatment, since phenytoin decreases thyroid hormone levels via breakdown of thyroid hormone [ 22 ]. Drugs including anesthetics, antidepres- sants, narcotics, sedatives, and tranquilizers may depress the respiratory drive and thus exacerbate the hypothyroid patient into a coma and thus should be minimized or avoided [ 15 , 20 ]. Additionally, all patients should have continuous telemetry monitoring given the risk for arrhythmias and bradycardia.
myxedema coma during pregnancy is beyond the scope of this chapter, and additional information can be found in the cited articles by Blignault and Patel et al. [
Conclusion
89 , 90 ].
Thyroid storm and myxedema coma are endocrine emer­gencies with high morbidity and mortality, where early rec­ognition with a low index of suspicion and prompt treatment can signifi cantly impact outcomes [
1 ]. The diagnosis of
thyroid storm is made clinically and cannot be based on laboratory abnormalities, and diagnostic criteria have been put forth by Burch and Wartofsky and by Akamizu et al. [ 2 , 3 ]. Multidisciplinary care in a critical care setting is recom- mended, and identifi cation of the precipitating cause and reversal or treatment of that cause should be sought if pos­sible [ 1 ]. Medical treatment of thyroid storm involves understanding the pathophysiology underlying its develop­ment and then targeting all steps of thyroid hormone syn­thesis, release, and action in a specifi ed order, along with supportive care [ 1 ]. Treatment should begin with thion- amides (propylthiouracil/PTU preferred over methima­zole), then iodine administration (potassium iodine or Lugol’s solution) or alternatively lithium, then cholestyr­amine to block the enterohepatic circulation of thyroid hor­mone, and beta- blockers (propranolol or esmolol), temperature regulation with cooling and antipyretics (Tylenol preferred over salicylates), intravenous fl uid resuscitation for dehydration, and stress dose steroids (hydrocortisone) with vasopressors as needed. Therapeutic plasma exchange (TPE) or plasmapheresis can also be uti­lized. Finally, defi nitive therapy is surgery (subtotal or near-total thyroidectomy) or radioactive iodine ablation. Myxedema coma is severe hypothyroidism, often with sig­nifi cant hypothermia, bradycardia, and mental status changes as substantial as a coma, often with a precipitating cause. Popoveniuc et al. [ 4 ] have proposed a diagnostic scoring system for myxedema coma. Medical treatment for myxedema coma involves thyroid hormone replacement (with T3 and/or T4), supportive care (warm ambient tem­perature and warming blankets, IV fl uids including poten­tially hypertonic saline for hyponatremia, mechanical ventilation or other ventilation support, and hydrocorti­sone), and treatment of the precipitating cause and any other sequelae of myxedema coma including seizures. The mortality of both thyroid storm and myxedema coma has improved over the years with improvements in critical care.

Myxedema Coma in Pregnancy

There have been at least 36 documented cases of myxedema coma in pregnant women [
15 , 89 , 90 ]. A full review of

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