Thyroid storm, or thyrotoxic crisis, is a life-threatening though rare complication of severe thyrotoxicosis. The diagnosis is clinical, bearing no direct relation to the absolute levels of thyroid hormones in serum. The cardinal features of thyroid storm are marked tachycardia, hypertension, and widened pulse pressure; hyperpyrexia (usually greater than 38.5° C [101° F]); and altered mental status. In extreme cases, cardiovascular collapse and shock may be seen. Some investigators contend that abnormal mentation is the most important diagnostic component of thyroid storm.26 Of course, these clinical features can occur with a multitude of illnesses in the absence of thyrotoxicosis. Some authors propose a “point system” for determining whether a patient's condition represents true storm or severe thyrotoxicosis, but the distinction between these two entities is not useful clinically.47 A blood sample for measurement of the levels of T4 or free T4, or the free T4 index (FT4I), and TSH, by a sensitive method, should be obtained immediately in all individuals suspected of having this disorder. Empirical treatment then should begin. It is prudent to obtain a blood sample for cortisol determination before “stress doses” of steroids are administered for use later in deciding later whether long-term therapy is necessary. Laboratory findings in thyroid storm are listed in Table 80-6.
Patients who develop thyroid storm usually have poorly controlled thyrotoxicosis; often there is an identifiable precipitating factor26,48 (Table 80-7). In many cases it is difficult to determine whether the intercurrent illness is the cause or the consequence of the thyroid storm.
Table 80–7. Factors Precipitating Thyroid Storm ||Download (.pdf)
Table 80–7. Factors Precipitating Thyroid Storm
|Acute psychiatric illness|
|Congestive heart failure|
|Vigorous palpation of thyroid gland|
|Withdrawal of antithyroid medication|
| Sympathomimetic drugs such as pseudoephedrine|
|Radioactive iodide therapy|
|Iodine-containing contrast agents|
|“Health food” preparations containing seaweed or kelp|
To prevent irreversible cardiovascular collapse, the treatment of thyroid storm should take a four-pronged approach: (1) therapy to reduce the serum thyroid hormone levels, (2) therapy to reduce the action of the thyroid hormones on peripheral tissues, (3) therapy to prevent cardiovascular decompensation and to maintain normal homeostasis, and (4) treatment of the precipitating event(s).
Therapy to Reduce Thyroid Hormone Levels
An antithyroid drug, either PTU or methimazole (MMI), is given to prevent further synthesis of thyroid hormone. These drugs are not available in parenteral form; they can only be given orally or by nasogastric tube. Instances may arise in which these drugs cannot be given even by nasogastric tube—such as, for example, in patients with infarcted bowel. PTU offers a slight advantage over MMI in that, in addition to its inhibitory effect on hormone synthesis, it decreases the conversion of T4 to T3 in peripheral tissue. PTU should be given in a dose of 200 to 250 mg every 6 hours, and MMI should be given in a dose of 25 mg every 6 hours. Some authors recommend giving an initial PTU loading dose of 600 to 1000 mg, but this strategy has not been proved to be advantageous. Another regimen that has been reported consists of one 600-mg loading dose of PTU (12 tablets suspended in 90 mL of water) given as a retention enema, followed by 250 mg of PTU every 4 hours plus potassium iodide, 1 g diluted in 60 mL of water, given after the second PTU dose.49 PTU has an immediate onset of action for blocking the synthesis of thyroid hormone, but serum levels of thyroid hormone may take several weeks to normalize because of continuing secretion of stored hormone. In severe thyrotoxicosis with a decreased glandular content of hormone, a significant decline in serum levels may be observed in a matter of a few days. We usually repeat thyroid function tests every other day while the patient is acutely ill to help guide management.
Blockade of hormonal secretion usually is best accomplished by the addition of stable iodine to the antithyroid drug regimen. Iodine can be administered as Lugol's solution or as a saturated solution of potassium iodide (ssKI) (2 drops every 12 hours) or given by intravenous drip as sodium iodide (0.5 mg every 12 hours). It is important not to give iodide prior to antithyroid drug blockade because new hormone synthesis may occur and result in delayed release of hormone. There have been several cases where the use of iodine alone triggered thyroid storm. Administration of antithyroid drugs 1 hour before iodine is given is sufficient to establish blockade of hormone synthesis. A combination of antithyroid drugs and ssKI should decrease the serum T3 level to the normal range in 1 to 5 days; however, the metabolic response may lag behind by 2 to 3 days.50 Corticosteroids and propranolol, which also decrease the peripheral conversion of T4 to T3, can be used to further reduce the serum T3 concentration (Tables 80-8 and 80-9).
Table 80–8. Mechanisms of Action of Antithyroid Drugs ||Download (.pdf)
Table 80–8. Mechanisms of Action of Antithyroid Drugs
|REDUCTION OF SERUM HORMONE LEVELS|
|Blocking of thyroidal I− uptake||−||−||++||+++||−||−||−||−||−||−|
|Blocking of T4 synthesis||+++||+++||−||−||−||+||−||−||−||−|
|Blocking of T4 release||−||−||++||+||+++||+||−||−||−||−|
|Blocking of T4-to-T3 conversion||++||−||−||−||−||+++||+||+||−||−|
|Decrease of intestinal absorption of hormone||−||−||−||−||−||−||−||−||+||−|
|REDUCTION OF ACTION ON PERIPHERAL TISSUES|
|Increase of T4 binding to serum protein||−||−||−||−||−||−||−||−||−||+++|
|Blocking of thyroid hormone receptor||−||−||−||−||−||+||−||−||−||−|
|Blocking of sympathomimetic activity||−||−||−||−||−||−||+++||+||−||−|
Table 80–9. Drugs Used in the Treatment of Thyrotoxicosis ||Download (.pdf)
Table 80–9. Drugs Used in the Treatment of Thyrotoxicosis
|Drug||Dose||How Supplied||Adverse Effects|
|Propylthiouracil||200–250 mg q6h PO||50-mg tablet||Rash, agranulocytosis, hepatic toxicity|
|Methimazole||25 mg q6h PO||5- and 50-mg tablet||Rash, agranulocytosis, hepatic toxicity|
|Lithium carbonate||300 mg q6h PO||150-, 300-, and 600-mg tablets||Nausea, vomiting, arrhythmias, pseudotumor cerebri|
|Lugol's solution||2 drops q12h PO||8-mg iodine drop||Hypersensitivity|
|ssKI||1 drop q12h PO||50-mg iodide drop||Hypersensitivity|
|Iopanoic acid||0.5 g tid PO||0.5-g tablet||Abdominal cramps, diarrhea, hypersensitivity, nephrotoxicity|
|Perchlorate||1.0 g qd||0.5-g tablet (66.7% organically bound)||Aplastic anemia|
|Propranolol||40 mg q6h PO1 mg slow IVP||10-, 20-, 40-, 60-, and 80-mg tablets; 1-mg/mL vials||Asthma, heart block|
|Hydrocortisone||100 mg IV piggyback q8h||100-mg vials||Immunosuppression|
In the event that antithyroid drugs cannot be used because of a previous history of reactions, such as agranulocytosis or hepatotoxicity, iodine and oral cholecystographic agents may have to be used alone—the latter in the form of ipodate or iopanoate (iopanoic acid). These agents are strong inhibitors of the 5′ deiodination of thyroid hormones; thus they decrease serum levels of T3 and increase those of rT3.51 They also bind to the thyroid hormone receptor, but it is unclear whether this results in competitive inhibition of T3 action.52 These agents have a high iodine content (approximately 60% by weight) and thus also act by releasing iodine in the course of their degradation. As in the case of iodine treatment, their administration in the absence of antithyroid drugs requires careful monitoring of the clinical status. Iopanoic acid telepaque) may be given in amounts of 1 to 3 g daily. We have found that 3 g/d often causes diarrhea; this effect can be prevented with no reduction of the drug's therapeutic efficacy by giving 0.5 g three times a day. Alternatively, sodium ipodate oragrafin) may be used at a dose of 0.5 mg/d, which can reduce serum T3 by 62% in 1 day.53,54
For the rare patient with allergic reactions to both antithyroid drugs and to iodine-containing contrast media, lithium carbonate and perchlorate are alternative drugs. Lithium carbonate can be given in doses of 300 mg every 6 hours, with subsequent adjustments to maintain a serum lithium level of 0.7 to 1.4 mEq/L. Caution should be exercised in patients over 60 years of age. This drug acts by blocking iodide uptake and hormone release by the thyroid gland. Sodium or potassium perchlorate (ClO4) competes with iodide for uptake by the thyroid gland, ultimately reducing the production of T4. These compounds are not readily available in the United States. Serious side effects, including aplastic anemia and nephrotic syndrome, occur rarely.
Successful reduction of the serum concentration of thyroid hormones by means of plasma exchange has been reported in three patients (two of whom were pregnant).55,56 Filtration through a resin bed that removes T3 and T4 has been used occasionally.57 Intravenous administration of thyroxine-binding globulin has been shown experimentally to decrease the transfer of thyroid hormone from blood to tissues.58
Prevention of Systemic Decompensation
Reduction of the body temperature decreases the demands on the cardiovascular system. Body temperature can be reduced by cooling and by pharmacologic blockade of the thermoregulatory centers. Use of a cooling blanket and ice packs alone will induce shivering; treatment with chlorpromazine, 25 to 50 mg, and meperidine, 25 to 50 mg, intravenously every 4 to 6 hours will decrease the severe shivering and limit further heat generation.21
Patients in thyroid storm lose excessive amounts of fluid because of (1) increased insensible water loss associated with hyperthermia and tachypnea, (2) decreased levels of antidiuretic hormone, and (3) vomiting and diarrhea associated with increased intestinal motility. Thus patients may present with either high- or low-output failure, and fluid management may necessitate central venous catheterization to determine filling pressures and guide management. Solutions containing crystalloid (for volume replacement) and dextrose (to replenish hepatic glycogen stores and minimize the breakdown of body protein) are used. Treatment with high doses of propranolol, as discussed below, can make it necessary to use 5% to 10% dextrose solutions. Multivitamins often are administered to replenish the B-complex vitamins.
Treatment of congestive heart failure usually is supportive. While reduction of the high body temperature should be attempted before specific treatment is instituted, the judicious use of inotropic agents and diuretics also should be considered. Since patients are often volume depleted, diuretics should be used carefully and always with meticulous monitoring of intravascular volume. Impending shock should be treated with rapid correction of volume and with inotropic agents, as indicated. Atrial fibrillation is a known complication of thyrotoxicosis. Control of ventricular response can be achieved with β blockers, but conversion to sinus rhythm can be achieved only after the patient is made euthyroid.
Since relative hypoadrenalism is thought to occur in thyroid storm because of accelerated metabolism of glucocorticoids, it is prudent to give 300 mg hydrocortisone intravenously, followed by 100 mg every 8 hours to provide adequate stress levels. In addition, glucocorticoids can be beneficial for their effect in reducing the conversion of T4 to T3 in peripheral tissue. Use of parenteral H2 blockers is indicated to reduce the likelihood of ulcer formation. In thyrotoxicosis, there is rapid clearance of drugs. Therefore, doses of digitalis, insulin, and antibiotics need to be increased to be effective. Two exceptions are adrenergic drugs and anticoagulants.59 It is necessary to remember to reduce drug doses as the thyrotoxicosis resolves.
Reduction of Thyroid Hormone Action on Body Tissues
The effects of thyroid hormone can be reduced by (1) decreasing its conversion to the active form, T3, (2) counteracting its sympathomimetic effects, (3) displacing it from its receptor, and (4) reducing its transport to tissues.
The oral cholecystographic agents, as discussed earlier, may act in part by displacing T3 from its site of action at the receptor in cell nuclei. Other analogs of thyroid hormone with reduced thyromimetic activity, which nevertheless compete with thyroid hormone at its site of action, deserve theoretical consideration.60 The activity of 5′-deiodinase is regulated by the concentration of T4, as well as by catecholamines and other factors. PTU, glucocorticoids, propranolol, oral cholecystographic agents, and amiodarone also reduce the activity of this enzyme and thus decrease the generation of T3, resulting in reduction of serum T3 concentration. Severe acute or chronic nonthyroidal illness also suppresses T3 generation in peripheral tissues.
β Blockers, which are useful in the preparation of thyrotoxic patients for surgery, should be used with caution in thyroid storm. Whereas surgical stress clearly is related to increased catecholamine levels, and thyroid storm can be prevented by the use of propranolol, it is unclear whether thyroid storm induced by other mechanisms is equally responsive to β blockers. However, when there is evidence of increased adrenergic activity short of thyroid storm (i.e., no evidence of hyperpyrexia or mental status changes), 1 mg propranolol can be administered by slow intravenous push every 5 minutes until an effect on pulse rate is seen. Usually a total daily dose of 300 to 400 mg oral propranolol is required to achieve effective β blockade in the severely thyrotoxic patient. It appears that younger patients are more susceptible to hyperadrenergic states with more labile courses and do better with β blockers.21 By contrast, elderly patients may present with “apathetic” thyrotoxicosis without elevation in body temperature and without severe tachycardia. These elderly patients more often experience cardiotoxic effects in response to β blockers. Therefore, β blockers should be used with caution in thyroid storm and in severe thyrotoxicosis, except in the elderly, in asthmatics, and in patients with evidence of dilated cardiomyopathy. When surgery is indicated in such patients, careful titration of the adverse adrenergic cardiovascular effects (tachycardia, large pulse pressure) can be implemented with shorter-duration β blockers (esmolol) preceded by maximal bronchodilator therapy in asthmatic patients or right-sided heart catheterization in elderly patients and those with prior heart failure.
Treatment of Precipitating Events
Without an antecedent history of surgery, any patient with thyroid storm should be suspected of being septic until proven otherwise. Blood, urine, and other body secretions (i.e., ascites or pleural fluid and sputum) should be Gram stained and cultured. Empirical use of broad-spectrum antibiotics is recommended.
In a seriously ill patient in whom an infection or other precipitating cause, such as diabetic ketoacidosis, cannot be identified, pulmonary thromboembolism61,62 or bowel infarction should be considered.
Thyroid Storm in Pregnancy
The approach to treatment of thyroid storm in pregnant patients is similar to that outlined earlier. Thyroid storm is clearly a life-threatening condition for the mother. The basic approach to prevent decompensation is aggressive fluid replacement along with treatment of the precipitating event and antithyroid therapy. Because β blockers may have deleterious effects on the fetus at all stages of fetal development, their use must be weighed against maternal safety. While administration of iodide often results in the development of massive fetal goiter, PTU can be given to the toxic pregnant patient with only a small likelihood of adverse effects on the fetus.