Thyroid Emergencies - Department of Critical Care Medicine

386Klubo-Gwiezdzinska & WartofskyTable 1Factors precipitating thyroid emergencies: myxedema coma and thyrotoxic stormMyxedema ComaDrugsWithdrawal of L-thyroxineAnestheticsSedativesTranquilizersNarcoticsAmiodaroneLithium carbonateInfections, sepsisCerebrovascular accidentsCongestive heart failureLow temperaturesTraumaMetabolic disturbancesAcidosisHypoglycemiaHyponatremiaHypercapniaOtherGastrointestinal bleedingIngestion of raw bok choyPrecipitating FactorsThyrotoxic StormDrugsWithdrawal of antithyroid drug treatmentRadioactive iodine treatmentThyroxine/triiodothyronine overdosageCytotoxic chemotherapyAspirin overdosageIodinated contrast dyesOrganophosphatesSepsis, infectionSeizure disorderPulmonary thromboembolismBurn injurySurgery, trauma, vigorous palpation of thyroidMetabolic disturbancesDiabetic ketoacidosisHypoglycemiaOtherParturitionEmotional stressPatients with myxedema coma generally present in the winter months, suggestingthat external cold may be an aggravating factor. 5 Some abnormalities such as hypoglycemia,hypercalcemia, hyponatremia, hypercapnia, and hypoxemia, may be eitherprecipitating factors or secondary consequences of myxedema coma. Moreover, thecomatose state is associated with the risk of aspiration pneumonia and sepsis. Inhospitalized patients, drugs such as anesthetics, narcotics, sedatives, antidepressants,and tranquilizers may depress respiratory drive and thereby either cause orcompound the deterioration of the hypothyroid patient into coma. 6,7 The effect ofthese drugs should be taken into consideration as a potential causative mechanism.In fact, Church and Callen 8 described a 41-year-old male patient without any historyof thyroid disease who developed myxedema coma after being administered combinedtherapy with aripiprazole and sertraline.There is also a report of myxedema coma induced by chronic ingestion of largeamounts of raw bok choy. This Chinese white cabbage contains glucosinolates, whichbreak down products such as thiocyanates, nitriles, and oxazolidines, and inhibitiodine uptake and production of thyroid hormones by the thyroid gland. When eatenraw, digestion of the vegetable releases the enzyme myrosinase, which acceleratesproduction of the aforementioned thyroid disruptors. 9Clinical Signs and SymptomsHypothermia (often profound to 80 F [26.7 C]) and unconsciousness constitute 2 ofthe cardinal features of myxedema coma. 10 Of importance is that coincident infectionmay be masked by hypothyroidism, with a patient presenting as afebrile despite anunderlying severe infection. In view of the latter and the fact that undiagnosed infection

Thyroid Emergencies 387might lead inexorably to vascular collapse and death, some authorities have advocatedthe routine use of antibiotics in patients with myxedema coma. Underlyinghypoglycemia may further compound the decrement in body temperature.Although coma is the predominant clinical presentation, a history of disorientation,depression, paranoia, or hallucinations (myxedema madness) may often be elicited.The neurologic findings may also include cerebellar signs (poorly coordinatedpurposeful movements of the hands and feet, ataxia, adiadochokinesia), poor memoryand recall, or even frank amnesia, and abnormal findings on electroencephalography(low amplitude and a decreased rate of a-wave activity). Status epilepticus has beenalso described 11 and up to 25% of patients may experience seizures possibly relatedto hyponatremia, hypoglycemia, or hypoxemia.Respiratory SystemThe mechanism for hypoventilation in profound myxedema is a combination ofa depressed hypoxic respiratory drive and a depressed ventilatory response to hypercapnia.12,13 Partial obstruction of the upper airway caused by edema of the tongue orvocal cords may also play a role. Hypothyroid patients may be predisposed toincreased airway hyperresponsiveness and chronic inflammation. 14 Tidal volumemay be additionally reduced by other factors such as pleural effusion or ascites. toachieve appropriately effective pulmonary function in myxedema coma, prolongedmechanically assisted ventilation is usually required.Cardiovascular ManifestationsPatients diagnosed with myxedema coma are at increased risk for shock and potentiallyfatal arrhythmias. Typical electrocardiographic (ECG) findings includebradycardia, varying degrees of block, low voltage, flattened or inverted T waves,and prolonged Q-T interval, which can result in torsades de pointes ventricular tachycardia.15 Myocardial infarction should also be ruled out by the usual diagnostic procedures,because aggressive or injudicious T4 replacement may increase the risk ofmyocardial infarction. Moreover, cardiac contractility is impaired, leading to reducedstroke volume and cardiac output. Reduced stroke volume in severe cases may alsobe due to the cardiac tamponade caused by the accumulation of fluid rich in mucopolysaccharideswithin the pericardial sac.Electrolyte Disturbances and Renal ManifestationsHyponatremia is a common finding observed in patients with myxedema coma. Themechanism accounting for the hyponatremia is associated with increased serum antidiuretichormone 16 and impaired water diuresis caused by reduced delivery of waterto the distal nephron. 17 Depending on its duration and severity, hyponatremia will addto altered mental status, and when severe may be largely responsible for precipitatingthe comatose state. Alterations in renal function observed in myxedema coma includedecreases in glomerular filtration rate and renal plasma flow, and increases in totalbody water. Atony of the urinary bladder with retention of large residual urine volumesis commonly seen. Renal failure may occur as a result of underlying rhabdomyolysiswith extremely high levels of creatine kinase. 18–21Gastrointestinal ManifestationsThe gastrointestinal tract in myxedema may be marked by mucopolysaccharide infiltrationand edema of the muscularis, as well as neuropathic changes leading to gastricatony, impaired peristalsis, and even paralytic ileus. Ascites may occur, and has beendocumented in one report of 51 cases. 22 Another potential complication is

388Klubo-Gwiezdzinska & Wartofskygastrointestinal bleeding secondary to an associated coagulopathy. 23 It is importantto recognize the underlying mechanisms of these acute gastrointestinal complicationsso as to avoid unnecessary surgery for an apparent acute abdomen. 24Hematological ManifestationsIn contrast to the tendency to thrombosis seen in mild hypothyroidism, severe hypothyroidismis associated with a higher risk of bleeding caused by coagulopathy relatedto an acquired von Willebrand syndrome (type 1) and decreases in factors V, VII, VIII,IX, and X. 25 The von Willebrand syndrome is reversible with T4 therapy. 26 Anothercause of bleeding may be disseminated intravascular coagulation associated withsepsis. Patients with myxedema coma have increased preponderance to severe infections,including sepsis, because of granulocytopenia and a decreased cell-mediatedimmunologic response. Such patients may also present with a microcytic anemiasecondary to hemorrhage, or a macrocytic anemia caused by vitamin B 12 deficiency,which may also worsen the neurologic state.DiagnosisTo summarize the aforementioned clinical manifestations, the typical patient presentingwith myxedema coma is a woman in the later decades of life who may havea history of thyroid disease and who is admitted to hospital, typically in winter, withpneumonia. Physical findings could include bradycardia, macroglossia, hoarseness,delayed reflexes, dry skin, general cachexia, hypoventilation, and hypothermia,commonly without shivering. Laboratory evaluation may indicate hypoxemia, hypercapnia,anemia, hyponatremia, hypercholesterolemia, and increased serum lactatedehydrogenase and creatine kinase. On lumbar puncture there is increased pressureand the cerebrospinal fluid has high protein content.Although an elevated serum thyrotropin (TSH) concentration is the most importantlaboratory evidence for the diagnosis, the presence of severe complicating systemicillness or treatment with drugs such as dopamine, dobutamine, or corticosteroids mayserve to reduce the elevation in TSH levels. 27,28 There may also be a pituitary cause forthe hypothyroidism, in which case an increased TSH would not be found.TreatmentMyxedema coma as a true medical emergency requires a multifaceted approach totreatment in a critical care setting.Airways and ventilationThe patient’s comatose state is perpetuated by hypoventilation, with CO 2 retentionand respiratory acidosis. The maintenance of an adequate airway is the single mostimportant supportive measure, because of the high mortality rate associated withthe inexorable respiratory failure. Mechanical ventilation is usually required duringthe first 36 to 48 hours, but in some patients it may be necessary to continue assistedventilation for as long as 2 to 3 weeks. The hypercapnia may be rapidly relieved withmechanical ventilation, but the hypoxia tends to persist, possibly because of shuntingin nonaerated lung areas. 29 It is advisable, therefore, not to extubate the patientsprematurely and to wait until full consciousness is attained.Thyroid hormone therapyOne of the most controversial aspects of the management of myxedema coma is whichthyroid hormone preparation to give and how to give it (dose, frequency, and route ofadministration). The optimum treatment remains uncertain, because of the scarcity ofclinical studies and obvious difficulties with performing controlled trials. There is

Thyroid Emergencies 389a necessity to balance the need for quickly attaining physiologically effective thyroidhormone levels against the risk of precipitating a fatal tachyarrhythmia or myocardialinfarction. All patients should have continuous ECG monitoring, with reduction inthyroid hormone dosage should arrhythmias or ischemic changes be detected.Parenteral preparations of either T4 or T3 are available for intravenous administration.Although oral forms of either T3 or T4 can be given by nasogastric tube in thecomatose patient, this route is fraught with risks of aspiration and uncertain absorption,particularly in the presence of gastric atony or ileus. The single intravenous bolusof T4 was popularized by reports 30 suggesting that replacement of the entire estimatedpool of extrathyroidal T4 (usually 300–600 mg) was desirable to restore nearnormalhormonal status. This initial loading dose is followed by the maintenancedose of 50 to 100 mg given daily (either intravenously or by mouth if the patient isadequately alert). Larger doses of T4 probably have no advantage and may, in fact,be more dangerous. 31 There is also evidence showing improved outcomes with lowerdoses of thyroid hormone. 32 Rodriguez and colleagues 1 performed a prospective trialin which patients were randomized to receive either a 500-mg loading dose of T4 followedby a 100-mg daily maintenance dose, or only the maintenance dose. The overallmortality rate was 36.4%, with a lower mortality rate in the high-dose group (17%) thanin the low-dose group (60%). Although suggestive, the difference was not statisticallysignificant.The rate of conversion of T4 to T3 is reduced in many systemic illnesses (the euthyroidsick or low T3 syndrome), 28 hence T3 generation may be reduced in myxedemacoma as a consequence of any associated illness (hypothyroid sick syndrome). Asa consequence, some clinicians suggest that small supplements of T3 should be givenalong with T4 during the initial few days of treatment, especially if obvious associatedillness is present. When therapy is approached with T3 alone, it may be given as a 10-to 20-mg bolus followed by 10 mg every 4 hours for the first 24 hours, dropping to 10 mgevery 6 hours for days 2 to 3, by which time oral administration should be feasible. 6 T3has a much quicker onset of action than T4, and increases in body temperature andoxygen consumption may occur 2 to 3 hours after intravenous T3, compared with 8to 14 hours after intravenous T4. The other advantage of T3 is that it crosses theblood-brain barrier more rapidly than T4, which may be particularly important inpatients with profound neuropsychological symptoms. 33 One clinical example of thepossible benefit of T3 is a case report of a patient with myxedema coma and cardiogenicshock who responded to T3 therapy but not to T4 therapy. 34 On the other hand,treatment with T3 alone is associated with large and unpredictable fluctuations inserum T3 levels, and high serum T3 levels during treatment have been associatedwith fatal outcomes. 35 A more conservative but seemingly rational approach is toprovide combined therapy with both T4 and T3. 36 Rather than administer 300 to500 mg T4 intravenously initially, a dose of 4 mg/kg lean body weight (or about 200–300 mg) is given, and an additional 100 mg is given 24 hours later. By the third day,the dose is reduced to a daily maintenance dose of 50 mg, which can be given bymouth as soon as the patient is conscious. 36 Simultaneously with the initial dose ofT4, a bolus of 10 mg T3 is given and intravenous T3 is continued at a dosage of 10mg every 8 to 12 hours until the patient is conscious and taking maintenance T4. Clinicalimprovement has been seen with even a single dose of only 2.5 mg of T3. 37HypothermiaTreatment with T4 and/or T3 enables restoration of body temperature to normal.Simultaneously, blankets or increasing the room temperature can be used as additionalinterventions to keep the patient warm until the thyroid hormone effect is

390Klubo-Gwiezdzinska & Wartofskyachieved. Too aggressive warming may cause peripheral vasodilatation, which maythen lead to hypotension or shock.HypotensionHypotension should also be correctable by treatment with T4 and/or T3. However,a hypotensive patient may require additional volume-repletion therapy. Fluids maybe administered cautiously as 5% to 10% glucose in 0.5 N sodium chloride if hypoglycemiais present, or as isotonic normal saline if hyponatremia is present. An agentsuch as dopamine might be used to maintain coronary blood flow, but patients shouldbe weaned off the vasopressor as soon as possible because of the risk of a pressorinducedischemic event.Because of the risk of relative adrenal insufficiency, it is wise to administer hydrocortisoneuntil the hypotension is corrected. The typical dosage of hydrocortisone is 50 to100 mg every 6 to 8 hours during the first 7 to 10 days, with tapering of the dosagethereafter based on clinical response and any plans for further diagnostic evaluation.Decreased adrenal reserve has been found in 5% to 10% of patients, based on eitherhypopituitarism or primary adrenal failure accompanying Hashimoto disease (Schmidtsyndrome). The other rationale for the treatment with corticosteroids is the potentialrisk of precipitating acute adrenal insufficiency caused by the accelerated metabolismof cortisol that follows T4 therapy. The clinicians should be aware of signs and symptomssignaling coexisting adrenal insufficiency such as hypotension, hypothermia,hypoglycemia, hyperkalemia, and hyponatremia.HyponatremiaLow serum sodium may cause a semicomatose state or seizures even in euthyroidpatients, and the severe hyponatremia (105–120 mmol/L) in profound myxedema islikely to contribute substantially to the coma in these patients. Mortality rates in criticallyill patients with symptomatic hyponatremia have been reported to be 60-foldhigher than in patients without hyponatremia. 38 The appropriate management ofsevere hyponatremia often requires administration of a small amount of hypertonicsaline (50–100 mL 3% sodium chloride), enough to increase sodium concentrationby about 2 mmol/L early in the course of treatment, followed by an intravenous bolusdose of 40 to 120 mg furosemide to promote a water diuresis. 39 A small, quickincrease in the serum sodium concentration (2–4 mmol/L) is effective in acute hyponatremiabecause even a slight reduction in brain swelling results in a substantialdecrease in intracerebral pressure. 40 On the other hand, too rapid correction of hyponatremiacan cause a dangerous complication, the osmotic demyelinizationsyndrome. In patients with chronic hyponatremia, this complication is avoided bylimiting the sodium correction to less than 10 to 12 mmol/L in 24 hours and lessthan 18 mmol/L in 48 h. After achieving a sodium level of more than 120 mmol/L,restriction of fluids may be all that is necessary to correct hyponatremia. It must beemphasized that fluid or saline therapy requires careful monitoring of volume statusbased on clinical parameters and measurements of central venous pressure, especiallyin patients with significant cardiovascular decompensation.The other therapeutic option is treatment with an intravenous vasopressin antagonist,conivaptan. Conivaptan has been approved by the US Food and DrugAdministration for the treatment of hospitalized patients with euvolemic and hypervolemichyponatremia in a setting of the syndrome of inappropriate secretion ofantidiuretic hormone, hypothyroidism, adrenal insufficiency, or pulmonary disorders.41 The rationale for application of conivaptan in this clinical setting is basedon the high vasopressin levels observed in myxedema coma. Current dosing

Thyroid Emergencies 391recommendations are for a 20-mg loading dose to be infused over 30 minutes followedby 20 mg/d continuous infusion for up to 4 days. Unfortunately, no data areavailable on the use of conivaptan in severe hyponatremia (

392Klubo-Gwiezdzinska & Wartofskyto be associated with increased free fraction of T4 and T3 include stress, infections,burns, cytotoxic chemotherapy for acute leukemia, aspirin overdose, ketoacidosis,or organophosphate intoxication (see Table 1). 45,51–55 Amiodarone, an antiarrhythmicand antianginal drug that is also rich in iodine, may cause either an iodine-inducedthyrotoxicosis (type 1) or a destructive thyroiditis (type 2); the latter has been reportedas a cause of thyroid storm refractory to the usual treatment. 56 There is also a casereport of thyrotoxic storm precipitated by food poisoning with marine neurotoxin afteringestion of seafood. 57 Notwithstanding the multiplicity of precipitating factors, inhospitalized patients the most common event associated with thyrotoxic storm issome type of infection.Clinical Signs and SymptomsThe clinical diagnosis is based on the identification of signs and symptoms thatsuggest decompensation of several organ systems. Some of these cardinal manifestationsinclude fever out of proportion to an apparent infection and dramatic diaphoresis.Hyperthermia in thyroid crisis can represent defective thermoregulation by thehypothalamus and/or increased basal metabolic rate, increased oxidation of lipidsbeing responsible for more than 60% of the resting energy expenditure. 58 The otherkey components of thyrotoxic storm include tachycardia out of proportion to the fever,and gastrointestinal dysfunction, which can include nausea, vomiting, diarrhea and, insevere cases, jaundice. As the storm progresses, symptoms of central nervoussystem dysfunction simulating an encephalopathic picture will appear, which mayinclude increasing agitation and emotional lability, confusion, paranoia, psychosis,and coma. 59 Patients have been reported who presented with thyroid storm associatedwith status epilepticus and stroke and with bilateral basal ganglia infarction. 60In patients with neurologic symptoms, a high index of suspicion for cerebral sinusthrombosis should be considered, because of the higher prevalence of this conditionin severe hyperthyroidism. 61 Paralysis observed in thyroid crisis might be due to notonly the cerebrovascular accident but also thyrotoxic periodic paralysis with hypokalemia,as frequently may present in Asian men. 62 In older patients, the thyrotoxic stormmay present as so-called masked or apathetic thyrotoxicosis. 63Cardiovascular ManifestationsThe most common cardiovascular manifestations are rhythm disturbances such assinus tachycardia, atrial fibrillation, or other supraventricular tachyarrhythmias, andrarely, ventricular tachyarrhythmias, which can be observed even in patients withoutprevious heart disease. 64 Congestive heart failure or a reversible dilated cardiomyopathy65 also may be present even in young or middle-aged patients without knownantecedent cardiac disease. A high-output state is present, attributable to theincreased preload secondary to activation of the renin-angiotensin-aldosterone axisand to decreased afterload secondary to a direct relaxing effect of thyroid hormoneson vascular muscle cells. Therefore, most patients present with systolic hypertensionwith widened pulse pressure. The hyperthyroid heart is characterized by higher thanusual oxygen demands and hence myocardial infarction can be observed, even inyoung patients. 66,67 A relatively rare complication of severe hyperthyroidism is pulmonaryhypertension, which is presumed to be on an autoimmune basis when associatedwith Graves disease, but which also may be secondary to an augmented bloodvolume, cardiac output, and sympathetic tone, leading to pulmonary vasoconstrictionand increased pulmonary arterial pressure. This condition is usually reversible aftertreatment with antithyroid drugs. The other possible reason for pulmonary

Thyroid Emergencies 393hypertension is pulmonary embolism caused by the thrombotic or hypercoagulablestate that has been observed in severe hyperthyroidism.Respiratory ManifestationsThe main pulmonary symptom is dyspnea and tachypnea related to an increasedoxygen demand. The excessive work of the respiratory muscles may eventuallylead to diaphragmatic dysfunction. 68 Respiratory failure may result from the hyperdynamiccardiomyopathy but also from preexistent underlying pulmonary disease. 69,70Gastrointestinal ManifestationsThe most common symptoms are diarrhea and vomiting, which can aggravate volumedepletion, postural hypotension, and shock with vascular collapse. The diffuseabdominal pain, possibly caused by impaired neurohormonal regulation of gastricmyoelectrical activity with delayed gastric emptying, 71 may even lead to a presentationsuch as acute abdomen 72 or intestinal obstruction. 73 The liver function abnormalitiesand presence of jaundice warrant immediate and vigorous therapy. Although mostpresentations of an acute abdomen in thyrotoxicosis are medical in nature, surgicalconditions may also occur. 74Electrolyte Disturbances and Renal ManifestationsIncreased serum calcium levels, caused by both hemoconcentration and knowneffects of thyroid hormone on bone resorption, may be seen. The sodium, potassium,and chloride levels are usually normal. Because of the augmented lipolysis and ketogenesis,and the basal metabolic demands that exceed oxygen delivery, ketoacidosisand lactic acidosis are observed.Hyperthyroidism is often associated with an accelerated glomerular filtration rate,which may progress to glomerulosclerosis and excessive proteinuria. There arecase reports of renal failure caused by rhabdomyolysis, 75 urinary retention associatedwith dyssynergy of the detrusor muscle and bladder dysfunction, 76 and an autoimmunecomplex–mediated nephritis concomitant with Graves disease. 77Hematological ManifestationsA moderate leukocytosis with a mild shift to the left is a common finding, even in theabsence of infection. Hyperthyroidism may be associated with hypercoagulabilitycaused by increased concentrations of fibrinogen, factors VIII and IX, tissue plasminogenactivator inhibitor 1, von Willebrand factor, increase in red blood cell masssecondary to erythropoietin upregulation, and a tendency to augmented plateletplug formation. 78 Major thromboembolic complications are responsible for 18% ofdeaths caused by thyrotoxicosis. 79–83DiagnosisDiagnosis can be established predominantly on the basis of clinical presentation,because the laboratory findings may not be much different than those observed inuncomplicated hyperthyroidism. Indeed, serum total T3 levels may be even withinnormal limits, as these patients may have some underlying precipitating illness thatreduces T4 to T3 conversion as is seen in the euthyroid sick syndrome. 84 Therefore,a semiquantitative scale (Table 2) assessing the presence and severity of the mostcommon signs and symptoms has been developed to aid in the diagnosis. 85Other laboratory abnormalities may include a modest hyperglycemia in the absenceof diabetes mellitus, probably as a result of augmented glycogenolysis andcatecholamine-mediated inhibition of insulin release, as well as increased insulin

Thyroid Emergencies 395of glucocorticoids. Moreover, there is known coincidence of adrenal insufficiency withGraves disease. This diagnosis should be considered when there is hypotension andsuggestive electrolyte abnormalities.TreatmentTo avoid a disastrous outcome, a complex approach to management is recommended.87 First, specific antithyroid drugs must be used to reduce the increased thyroidproduction and release of T4 and T3. The second approach comprises treatmentintended to block the effects of the remaining but excessive circulating concentrationsof free T4 and T3 in blood. The third arm involves treatment of any systemic decompensation,for example, congestive heart failure, and shock. The final componentaddresses any underlying precipitating illness such as infection or ketoacidosis.Therapy directed to the thyroid glandInhibition of new synthesis of the thyroid hormones is achieved by administration ofthionamide antithyroid drugs, such as carbimazole, methimazole (Tapazole), and propylthiouracil.These drugs in the comatose or uncooperative patient are given by nasogastrictube or per rectum as enemas or suppositories. 88–91 There are no availableintravenous preparations of these compounds in the United States, but they aresuccessfully used in some European countries such as the United Kingdom, Germany,and Poland. 92–94 According to the recently published guidelines by the AmericanThyroid Association and the Association of Clinical Endocrinologists, propylthiouracilcan be started with a loading dose of 500 to 1000 mg followed by 250 mg every 4hours, and methimazole should be administered at daily dose of 60 to 80 mg. 87 It isthought that propylthiouracil will provide more rapid clinical improvement because ithas the additional advantage of inhibiting conversion of T4 to T3, a property not sharedby methimazole. Because thionamides reduce new hormone synthesis but notthyroidal secretion of preformed glandular stores of hormone, separate treatmentmust be administered to inhibit proteolysis of colloid and the continuing release ofT4 and T3 into the blood. Either inorganic iodine or lithium carbonate may be usedfor this purpose. Iodides may be given either orally as Lugol solution or as a saturatedsolution of potassium iodide (3–5 drops every 6 hours). An earlier mainstay of treatment,the use of an intravenous infusion of sodium iodide (0.5–1 g every 12 hours),has not been feasible recently because sterile sodium iodide has not been availablefor intravenous use.It is important that iodine should be administered no sooner than 1 hour after priorthionamide dosage. Otherwise iodine will enhance thyroid hormone synthesis, enrichhormone stores within the gland, and thereby permit further exaggeration of thyrotoxicosis.When iodine is administered in conjunction with full doses of antithyroid drugs,dramatic rapid decreases in serum T4 are seen, with values approaching the normalrange within 4 or 5 days. 95 Other agents that theoretically could be used in this mannerare the radiographic contrast dyes ipodate (Oragrafin) and iopanoic acid (Telepaque),which act not only by decreasing thyroid hormone release but also by slowing theperipheral conversion of T4 to T3, as well as possibly blocking binding of both T3and T4 to their cellular receptors. Unfortunately, these agents are no longer availablein the United States.In patients who may be allergic to iodine, lithium carbonate may be used as an alternativeagent to inhibit hormonal release. 96,97 Lithium should be administered initially as300 mg every 6 hours, with subsequent adjustment of dosage as necessary to maintainserum lithium levels at about 0.8 to 1.2 mEq/L.

Thyroid Emergencies 397is necessary in elderly patients with congestive heart failure or other cardiac compromise.Intravenous fluids containing 10% dextrose in addition to electrolytes will betterrestore depleted hepatic glycogen. Vitamin supplements may be added to the intravenousfluids to replace probable coexistent deficiency. Hypotension not readilyreversed by adequate hydration may temporarily require pressor and/or glucocorticoidtherapy.For fever, acetaminophen rather than salicylates is the preferred antipyretic,because salicylates inhibit thyroid hormone binding and could increase free T4 andT3, thereby transiently worsening the thyrotoxic crisis. Hyperthermia also respondswell to external cooling with alcohol sponging, cooling blankets, and ice packs.Some investigators advocate the use of the skeletal muscle relaxant dantrolene, 115but significant risk associated with its use precludes routine recommendation.When present, congestive heart failure should be treated routinely. Although lesscommonly used today, when digoxin is used, larger than usual doses may be requiredbecause of its increased turnover in the thyrotoxic state.Therapy directed at the precipitating illnessThe therapy is not complete unless a diagnosis of the possible precipitating event ismade and early treatment as indicated for that underlying illness is implemented.This is not a problem in obvious cases, when trauma, surgery, labor, or prematurewithdrawal of antithyroid drugs are known to have been the precipitants of thyrotoxiccrisis, and which may require no additional management. However, when none of thelatter precipitating factors is apparent, a diligent search for some focus of infectionmust be performed. Routine cultures of urine, blood, and sputum should be obtainedin the febrile thyrotoxic patient, and cultures of other sites may be warranted on clinicalgrounds. Broad-spectrum antibiotic coverage on an empiric basis may be requiredinitially while awaiting results of cultures.Conditions such as ketoacidosis, pulmonary thromboembolism, or stroke mayunderlie thyrotoxic crisis, particularly in the obtunded or psychotic patient, and requirethe same vigorous management as routinely indicated.PrognosisEven with early diagnosis, death can occur, and reported mortality rates haveranged from 10% to 75% in hospitalized patients. 85,116,117 In most patients whosurvive thyrotoxic crisis, clinical improvement is dramatic and demonstrable withinthe first 24 hours. During the recovery period of the next few days, supportivetherapy such as corticosteroids, antipyretics, and intravenous fluids may be taperedand gradually withdrawn, based on patient status, oral intake of calories and fluids,vasomotor stability, and continuing improvement. After the crisis has been resolved,attention may be turned to consideration of the definitive treatment of thyrotoxicosis.Should thyroidectomy be considered, thyrotoxicosis will need to have beenadequately treated preoperatively, to obviate any likelihood of another episode ofcrisis during the surgery. Total thyroidectomy is the procedure of choice, in viewof reports of recurrent severe thyrotoxicosis and thyroid crisis after less than totalthyroidectomy. 118Radioactive iodine as definitive treatment is often precluded by the recent use ofinorganic iodine in virtually all cases of storm, but it could be considered at a laterdate, in which case antithyroid thionamide therapy is continued to restore and maintaineuthyroidism until such a time as ablative therapy can be administered.Continuing treatment with antithyroid drugs alone, in the hope of the patient’ssustaining a spontaneous remission, is also possible.

398Klubo-Gwiezdzinska & WartofskySUMMARYThe life-threatening thyroid emergencies of myxedema coma and thyrotoxic crisisrequire a high index of suspicion in the appropriate clinical setting, followed by promptand accurate diagnosis and urgent multifaceted therapy to reduce the risk of fataloutcome.REFERENCES1. Rodriguez I, Fluiters E, Perez-Mendez LF, et al. Factors associated with mortalityof patients with myxedema coma: prospective study in 11 cases treated ina single institution. J Endocrinol 2004;80:347–50.2. Blignault EJ. Advanced pregnancy in severely myxedematous patient. A casereport and review of the literature. S Afr Med J 1980;57:1050–1.3. Patel S, Robinson S, Bidgood RJ, et al. A pre-eclamptic-like syndrome associatedwith hypothyroidism during pregnancy. Q J Med 1991;79:435–41.4. Mathew V, Misgar RA, Ghosh S, et al. Myxedema coma: a new look into an oldcrisis. J Thyroid Res 2011;2011:493462.5. Dutta P, Bhansali A, Masoodi SR, et al. Predictors of outcome in myxedemacoma: a study from a tertiary care centre. Crit Care 2008;12:1–8.6. Klubo-Gwiezdzinska J, Wartofsky L. Myxedema coma. In: Oxford textbook of endocrinologyand Diabetes. 2nd edition. Oxford: Oxford Univ. Press; 2011. p. 537–43.7. Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med 2007;22:224–31.8. Church CO, Callen EC. Myxedema coma associated with combination aripiprazoleand sertraline therapy. Ann Pharmacother 2009;43:2113–6.9. Chu M, Seltzer TF. Myxedema coma induced by ingestion of raw bok choy.N Engl J Med 2010;20(362):1945–6.10. Reinhardt W, Mann K. Incidence, clinical picture and treatment of hypothyroidcoma. Results of a survey. Med Klin 1997;92:521–4.11. Jansen HJ, Doebe SR, Louwerse ES, et al. Status epilepticus caused bya myxedema coma. Neth J Med 2006;64:202–5.12. Zwillich CW, Pierson DJ, Hofeldt FD, et al. Ventilatory control in myxedema andhypothyroidism. N Engl J Med 1975;292:662–5.13. Ladenson PW, Goldenheim PD, Ridgway EC. Prediction of reversal of bluntedrespiratory responsiveness in patients with hypothyroidism. Am J Med 1988;84:877–83.14. Birring SS, Patel RB, Parker D, et al. Airway function and markers of airwayinflammation in patients with treated hypothyroidism. Thorax 2005;60:249–53.15. Schenck JB, Rizvi AA, Lin T. Severe primary hypothyroidism manifesting withtorsades de pointes. Am J Med Sci 2006;331:154–6.16. Skowsky RW, Kikuchi TA. The role of vasopressin in the impaired water excretionof myxedema. Am J Med 1978;64:613–21.17. DeRubertis FR Jr, Michelis MF, Bloom ME, et al. Impaired water excretion inmyxedema. Am J Med 1971;51:41–53.18. Ardalan MR, Ghabili K, Mirnour R, et al. Hypothyroidism-induced rhabdomyolysisand renal failure. Ren Fail 2011;33:553–4.19. Nikolaidou C, Gouridou E, Ilonidis G, et al. Acute renal dysfunction in a patientpresenting with rhabdomyolysis due to hypothyroidism attributed to Hashimoto’sdisease. Hippokratia 2010;4:281–3.20. Kar PM, Hirani A, Allen MJ. Acute renal failure in a hypothyroid patient with rhabdomyolysis.Clin Nephrol 2003;60:428–9.

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