Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

43.Thyrotoxic Storm

Leonard Wartofsky

Thyrotoxic storm or crisis is a rare, life-threatening syndrome characterized by exaggerated clinical manifestations of thyrotoxicosis. Its incidence is not precisely known because there are no widely accepted criteria for its diagnosis. However, a scoring system to indicate the diagnosis has been proposed (1) based on signs and symptoms and is proving useful (Table 43.1). It appears that the syndrome is much less common today than in the past, due to earlier diagnosis and treatment of thyrotoxicosis, and storm may account for no more than 1% to 2% of hospital admissions for thyrotoxicosis. On the basis of routine thyroid function tests, most patients with thyrotoxic storm are indistinguishable from those with uncomplicated thyrotoxicosis. Therefore, the diagnosis typically is a clinical one, based on the severity of the symptoms and signs of thyrotoxicosis and presence of functional decompensation of one or more organ systems in a thyrotoxic patient. Because of the potential high mortality, it is often necessary to begin treatment without waiting for biochemical confirmation of the diagnosis of thyrotoxicosis.

TABLE 43.1. DIAGNOSTIC CRITERIA FOR THYROTOXIC CRISIS


 Points


Thermoregulatory dysfunction

    Temperature (°F):

99–99.9

5

 100–100.9

10

 101–101.9

15

 102–102.9

20

 103–103.9

25

≥104

30

Central nervous system effects

    Absent

0

   Mild agitation

10

   Delirium, psychosis, lethargy

20

   Seizure or coma

 

30

Gastrointestinal dysfunction

   Absent

0

   Diarrhea, nausea, vomiting, or abdominal pain

10

   Unexplained jaundice

 20

Cardiovascular dysfunction

    Tachycardia (beats/min):

90–109

5

 110–119

10

 120–129

15

 130–139

20

≥140

25

   Congestive heart failure:

Absent

0

 Mild (edema)

5

Moderate (bibasilar rales)

10

Severe (pulmonary edema)

15

   Atrial fibrillation:

Absent

0

 Present

10

History of precipitating event (surgery, infection, etc.)

  Absent

0

 Present

10


Points are assigned as applicable and the score totaled. When it is not possible to distinguish a finding due to an intercurrent illness from that of thyrotoxicosis, the higher point score is given so as to favor empiric therapy. Interpretation: Based on the total score, the likelihood of the diagnosis of thyrotoxic storm is: unlikely, < 25; impending, 25–44; likely, 45–60; highly likely, >60.

Adapted from Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: thyroid storm. Endocrinol Metab Clin North Am 1993;22:263, with permission

The cardinal manifestations of thyrotoxic storm may not all be present or may be present in variable degree, and can include fever (temperature usually >102°F), tachycardia (out of proportion to the fever), gastrointestinal dysfunction (including nausea, vomiting, diarrhea, and, in severe cases, jaundice), and central nervous system (CNS) dysfunction, varying from marked hyperirritability and anxiety to confusion to apathy and even coma. Prompt diagnosis and vigorous therapy are required to avoid a fatal outcome; the mortality rates of hospitalized patients have ranged from 10% to 75% (1,2,3,4).

CLINICAL FEATURES

Most patients with thyrotoxic storm have rather obvious symptoms and signs of thyrotoxicosis, including goiter and, in the presence of Graves' disease, ophthalmopathy, although it can occur in patients with masked or apathetic thyrotoxicosis (5). There is usually a several-month history of untreated or partially treated thyrotoxicosis, but in an occasional patient the onset of thyrotoxicosis seems to be recent. Typically, those cases of more recent onset will be more rapidly progressive in severity of manifestations.

Two types of events have been associated with the precipitation of thyrotoxic crisis (Table 43.2). One is an intercurrent illness or injury that exacerbates the effects of thyrotoxicosis either systemically or on one or more particular organ systems. The other, now rare, is an acute event that suddenly increases thyroid secretion. This latter situation is best exemplified by the occurrence of thyrotoxic storm soon after thyroidectomy, which was relatively common before the need for preoperative antithyroid therapy was recognized. The presumed explanation was increased thyroxine (T4) and triiodothyronine (T3) release caused by manipulation of the thyroid gland, compounded by the systemic effects of surgical stress. The rare occurrence of thyrotoxic storm after radioiodine therapy for thyrotoxicosis is the modern counterpart of this phenomenon.

TABLE 43.2. EVENTS ASSOCIATED WITH THE ONSET OF THYROTOXIC STORM


Infection

Other acute medical illness

Acute emotional stress

Acute psychosis

Nonthyroid surgery

Parturition

Trauma

Thyrotoxicosis factitia

After radioiodine therapy

Postthyroidectomy

After high-dose iodine administration

Iodinated radiographic contrast agent administration

Discontinuation of antithyroid drug therapy

Vigorous palpation of thyroid gland


Many illnesses and trauma, including the trauma of surgery, can precipitate thyrotoxic storm in patients with previously undiagnosed or poorly treated thyrotoxicosis, and storm has been seen following the trauma of an automobile accident (6). The most common precipitating event now is probably an infection, and in a patient with thyrotoxicosis and infection it is difficult if not impossible to determine whether fever and tachycardia herald impending crisis or merely reflect the infection. Excessive diaphoresis with high fever out of proportion to the infection may be a clue to the presence of thyrotoxic storm. Indeed, when it is not recognized and treated, the fever may reach an extremely high and life-threatening level. An exception to this may be the elderly “apathetic” patient or those with concomitant pituitary or adrenal insufficiency (7). Symptoms of CNS dysfunction indicative of a metabolic encephalopathy, with anxiety, emotional lability, restlessness, agitation, confusion, psychosis, and coma (5,8,9,10), are common, and are important further clues to the diagnosis. In one case, thyrotoxic storm was associated with status epilepticus and stroke (11), and in another with bilateral basal ganglia infarction (12). Storm due to excessive ingestion of thyroid hormone (thyrotoxicosis factitia) has been reported (13) but must be extremely rare.

In addition to marked sinus tachycardia, other atrial tachyarrhythmias may be present, as may symptoms and signs of congestive heart failure. Although the latter is more likely to occur in elderly patients with underlying heart disease, it can occur in relatively young or middle-aged patients with no known antecedent (or subsequently demonstrable) heart disease. Systolic hypertension with widened pulse pressure is likely to be noted in most patients, at least initially, although some patients have postural hypotension, particularly those with volume depletion due to vomiting or diarrhea, and vascular collapse may supervene. Other gastrointestinal manifestations include presentation as an acute abdomen (14) or intestinal obstruction (15), or with diffuse abdominal pain, hepatomegaly, splenomegaly, and various abnormalities in liver function. The liver may be tender, as a result of either congestion or hepatic necrosis. The presence of jaundice is a poor prognostic sign.

LABORATORY FINDINGS

Serum total T4 and T3 concentrations and thyroid radioiodine uptake values are high in patients with thyrotoxic storm, but not necessarily more so than in patients with uncomplicated thyrotoxicosis (16). Serum free T4 and T3 concentrations are also high, and may be on average slightly higher than in patients with uncomplicated thyrotoxicosis (17). On the other hand, serum T3 concentrations may be normal in patients who have been sick for more than a few days, due to the decrease in extrathyroidal conversion of T4 to T3 that occurs in many nonthyroidal illnesses (18,19,20,21,22) (see section on nonthyroidal illness in Chapter 11).

In a patient with previously undiagnosed thyrotoxicosis, the most rapid confirmation of the diagnosis may be obtained by measuring thyroid radioiodine uptake 2 hours after administration of the radioiodine or thyroid pertechnetate uptake 20 or 30 minutes after administration of pertechnetate (see Chapter 12). It should be possible to obtain the results of serum T4 and thyrotropin (TSH) determinations in a few hours on an emergency basis in many hospitals.

In any event, given the high mortality of untreated thyrotoxic storm, the presence of severe clinical thyrotoxicosis with high fever and marked tachycardia and some other illness in a patient with a goiter, with or without ophthalmopathy, should be considered as sufficient support for the diagnosis of thyrotoxic crisis to warrant immediate initiation of therapy. In most patients the cause of the thyrotoxicosis is Graves' disease, but thyrotoxic storm has been reported in patients with other causes of thyrotoxicosis (23,24).

Patients with thyrotoxic storm may have mild to moderate hyperglycemia, probably caused by increased glycogenolysis and catecholamine-mediated inhibition of insulin release. A leukocytosis with a mild shift to the left is common, even in the absence of infection, whereas other hematologic values tend to be normal. Serum electrolyte concentrations usually are normal, but mild hypercalcemia is common, as a result of both hemoconcentration and thyroid hormone–stimulated bone resorption. Serum lactate dehydrogenase, aspartate and alanine aminotransferase, and bilirubin concentrations may be high as a result of hepatic dysfunction, and serum alkaline phosphatase concentrations may be high as a result of both increased osteoblastic activity and hepatic dysfunction. Serum cortisol concentrations should be high, and as in any other acute illness, a normal value should be interpreted as being inappropriately low. Even in the absence of adrenal insufficiency, adrenal reserve may be reduced in patients with thyrotoxic storm because of the inability of the adrenal gland to increase cortisol secretion sufficiently to meet the need for more cortisol in the presence of the increase in cortisol clearance caused by thyrotoxicosis (see Chapter 37).

PATHOGENESIS

The mechanism by which acute illness or injury precipitates thyrotoxic storm is poorly understood, and it is likely that several factors are important. The magnitude of the increase in thyroid secretion alone does not appear to be critical; many less ill thyrotoxic patients have equally high serum T4 and T3concentrations, and children who accidentally ingest large doses of T4 and have very high serum T4 and T3 concentrations do not have thyrotoxic storm (25). Therefore, an acute increase in release of T4 or T3 from the thyroid is not thought to be important in the pathogenesis of most cases of thyrotoxic storm, but this mechanism probably does play a role in those cases that have been reported after radioiodine therapy (2), thyroidectomy, discontinuation of an antithyroid drug or lithium (26,27), or administration of iodine or iodinated radiographic contrast agents (18). Whether it is the discontinuation of antithyroid drugs prior to radioiodine therapy or the radioiodine itself that may be the precipitant of thyroid storm remains somewhat controversial (28,29). Furthermore, there may be rapid improvement after abrupt reductions in serum T4 and T3 concentrations, such as may be achieved with peritoneal dialysis or plasmapheresis (30,31,32,33). Therefore, although serum total T4 and T3 concentrations may not be dramatically higher in patients with thyrotoxic storm than those in otherwise uncomplicated thyrotoxicosis, the concentrations in the former patients could have increased acutely before the onset of the storm (34). Furthermore, many acute illnesses cause a decrease in protein binding of T4 and T3 in serum, due to decreases in binding protein production (particularly transthyretin) or inhibitors of T4 and T3 binding to protein (35), resulting in a relative increase in the percentage and absolute serum concentrations of free T4and T3. Transient increases in serum free T4 and T3 concentrations have been reported in patients with thyrotoxic storm (17,36).

Many of the symptoms and signs of severe thyrotoxicosis mimic those of catecholamine excess (37,38) (see Chapter 38), suggesting a role for sympathetic nervous system activation in thyrotoxic storm. Although serum catecholamine concentrations and urinary catecholamine excretion are normal, arguing against the concept of increased sympathetic activity per se, there is little doubt that in patients with thyrotoxic storm, dramatic clinical improvement follows the administration of drugs that either deplete tissue catecholamines, such as reserpine (39), or block β-adrenergic receptors, such as propranolol. Indeed, treatment with propranolol or other β-adrenergic antagonist drugs may be responsible for the improvement in survival in recent years, notwithstanding a report that customarily used doses of propranolol may not prevent the occurrence of thyrotoxic storm (40).

Another phenomenon postulated to play a role in the pathogenesis of thyrotoxic storm is augmentation of peripheral cellular responses to thyroid hormone, which may be especially relevant to those patients with hypoxemia, ketoacidosis, lactic acidosis, or infection. In them, partial uncoupling of the process of oxidative phosphorylation leading to generation of adenosine triphosphate could result in excess substrate utilization, oxygen consumption, and thermogenesis, and therefore hyperthermia. The excess heat is partially dissipated by increased sweating and cutaneous vasodilatation, which are common in severe thyrotoxicosis.

TREATMENT

There are four components of treatment for patients with thyrotoxic storm (Table 43.3), their relative importance varying among different patients (1). First, an antithyroid drug must be given to decrease thyroidal production and secretion of T4 and T3. Second, systemic disturbances such as fever and hypovolemia must be ameliorated by appropriate treatment. Third, the tissue effects of the high serum T4 and T3 concentrations should be ameliorated by administration of a β-adrenergic antagonist drug. Fourth, any underlying precipitating illness or injury must be treated appropriately.

TABLE 43.3. TREATMENT OF THYROTOXIC STORM


Reduction of thyroid hormone production and secretion

   Inhibition of T4 and T3 synthesis

      Propylthiouracil, methimazole

   Inhibition of T4 and T3 secretion

      Inorganic iodide (potassium iodide, Lugol's solution)

      Radiographic contrast agents (sodium ipodate, iopanoic acid)

      Lithium carbonate

      Thyroidectomy

Therapy directed against systemic disturbances

   Treatment of fever

      Acetaminophen

      External cooling

   Correction of volume depletion and poor nutrition

      Intravenous fluid and electrolyes

      Glucose (calories)

      Vitamins

   Supportive therapy

      Oxygen

      Vasopressor drugs

   Treatment for congestive heart failure (diuretics, digoxin)

   Amelioration of the peripheral actions of thyroid hormone

      Inhibition of extrathyroidal conversion of T4 to T3

      Propylthiouracil

      Radiographic contrast agents (sodium ipodate, iopanoic acid)

      Glucocorticoids

   Propranolol or other β-adrenergic antagonist drugs

Removal of T4 and T3 from serum

   Cholestyramine, plasmapheresis, hemodialysis, hemoperfusion

Treatment of any precipitating or underlying illness


T3, triiodothronine; T4, thyroxine.

All patients with thyrotoxic storm should be treated in an intensive care unit because of the need for close monitoring of temperature, cardiac function and fluid and electrolyte balance. Serious consideration should be given to insertion of a Swan-Ganz catheter to monitor central hemodynamics in patients with prominent cardiovascular problems.

Therapy to Reduce Thyroid Hormone Synthesis and Secretion

A thionamide antithyroid drug, either propylthiouracil (PTU) or methimazole (MMI), is given to block T4 and T3 synthesis (see Chapter 45). No parenteral preparations of these drugs are available; therefore, they must be given by mouth or by nasogastric tube. Rectal administration also has been used successfully in a few patients (41,42,43,44). It is customary to give high doses of the drug, for example, 200 to 250 mg PTU every 4 hours or 20 mg MMI every 4 hours. PTU is favored because it not only inhibits T4 and T3 synthesis, but also inhibits extrathyroidal conversion of T4 to T3, thereby reducing serum T3 concentrations and perhaps also the clinical manifestations of thyrotoxicosis more rapidly than MMI.

These drugs do not inhibit release of already synthesized T4 and T3 from the thyroid, but that can be accomplished by administration of inorganic iodide (45) (see Chapter 45). It may be given either orally as Lugol's solution or as a saturated solution of potassium iodide (eight drops every 6 hours). These doses provide several hundred milligrams of iodide daily, much more than is needed for effective inhibition of thyroglobulin proteolysis and T4 and T3 release. Potassium iodide for intravenous administration is no longer available, although it probably could be prepared quickly in a hospital pharmacy.

The antithyroid drug should be given about an hour before the iodide is given, because a sudden influx of iodide into the thyroid can increase T4 and T3synthesis and therefore increase the stores of the two hormones, thereby prolonging the period of thyrotoxicosis. When iodide is administered in conjunction with a high dose of an antithyroid drug, serum T4 and T3 concentrations decrease substantially within a few days and approach the normal range in 5 to 7 days (45).

Another approach is to administer a lipid-soluble radiographic contrast agent such as sodium ipodate and iopanoic acid instead of iodide. These agents, which must be given orally, contain organically bound iodine. The iodide released by deiodination of the agent inhibits T4 and T3 release, and the agents themselves inhibit the extrathyroidal conversion of T4 to T3 and perhaps also binding of T3 to its nuclear receptors (see section on effects of drugs and other substances on thyroid hormone synthesis and metabolism in Chapter 11). Administration of one of these agents can lead to rapid clinical and biochemical improvement (46). These agents may also be useful in the therapy of massive acute thyroid hormone poisoning secondary to ingestion of T4, especially in children, due to the peripheral inhibition of the conversion of T4 to T3. A loading dose of 2 g is usually given, followed by 1 g daily. These agents are no longer available in the U.S.

In patients who may be allergic to iodine, lithium carbonate may be used as an alternative drug to inhibit T4 and T3 synthesis (47,48). Lithium also may be given as an alternative drug in thyrotoxic patients known to have had serious toxic reactions (e.g., hepatitis or agranulocytosis) to PTU or MMI; however, a history of minor allergic reactions to either PTU or MMI, such as rash, should not interdict their use in a critically ill patient with thyrotoxic storm. Lithium should be administered initially in a dose of 300 mg every 6 hours, with subsequent adjustment of dosage as necessary to maintain serum lithium concentrations at about 1 mEq/L. Finally, thyroidectomy may be done on an emergent basis (49,50).

Therapy Directed Against Systemic Disturbances

Fever should be promptly treated with an antipyretic drug, preferably acetaminophen rather than salicylate. The latter competitively inhibits T4 and T3 binding to serum proteins and therefore increases serum free T4 and T3 concentrations, which might theoretically temporarily worsen the thyrotoxicosis. External cooling with alcohol sponging, ice packs, or a hypothermia blanket also may be used.

Fluid losses caused by fever and diaphoresis, as well as by vomiting or diarrhea, when present, should be replaced, primarily with isotonic saline containing 5% or 10% glucose and supplemental vitamins, to avoid vascular collapse and provide nutritional support. Care must be taken to avoid overreplacement in older patients with cardiac disease. Hypotension refractory to fluid resuscitation has been reported (51). In such patients, vasopressor drug therapy may be indicated. Hypercalcemia, if present, usually can be reversed by volume repletion.

Congestive heart failure should be treated by administration of furosemide or hydrochlorothiazide and digoxin, especially in patients with atrial fibrillation. Somewhat higher than usual doses of digoxin may be needed because its clearance is accelerated in patients with thyrotoxicosis (see Chapter 31). In patients with marked tachycardia and congestive heart failure, slowing of the rate with propranolol or a related drug often alleviates the heart failure, notwithstanding the negative inotropic effects of these drugs (see Chapter 31).

High doses of a glucocorticoid have long been given on empirical grounds because of the postulated risk of relative adrenal insufficiency, as discussed above. High doses also inhibit extrathyroidal conversion of T4 to T3, and in patients with Graves' thyrotoxicosis they also directly inhibit thyroid secretion, although these two actions are probably not important in patients receiving aggressive antithyroid therapy as described above. Hydrocortisone is often given in an initial dose of 200 or 300 mg, followed by 100 mg every 8 hours for several days, after which the dose should be tapered quickly, but equivalent doses of dexamethasone or methylprednisolone can be given instead. In one case, thyrotoxic storm returned when glucocorticoid therapy was discontinued after initial clinical improvement (52).

Therapy Directed Against the Peripheral Actions of Thyroid Hormone

Many of the peripheral manifestations of thyrotoxic storm can be ameliorated rapidly by administration of propranolol or another β-adrenergic antagonist drug. The use of these drugs evolved from the earlier demonstration that drugs such as reserpine and guanethidine could blunt the apparently increased sympathetic activity in patients with thyrotoxicosis (29,53,54). Propranolol is the drug most commonly given today, at least in the United States. High doses are usually given to patients with thyrotoxic storm, for example, 60 to 80 mg orally every 6 hours (55,56), to achieve rapid adrenergic blockade and because drug clearance is increased in patients with severe thyrotoxicosis.

Propranolol also may be given intravenously. By that route, the initial dose should be 0.5 to 1 mg given over 10 minutes while the patient's cardiac rhythm is continuously monitored. Subsequently, 1 to 3 mg may be given intravenously over 10 to 15 minutes every several hours, until propranolol given orally at the start of treatment takes effect or oral therapy can be initiated (57). The primary role of propranolol is to attenuate the effects of catecholamines, but it is also a weak inhibitor of extrathyroidal conversion of T4 to T3. However, this inhibition occurs over about a week, and clearly does not account for the beneficial effects of propranolol in patients with thyrotoxic storm.

The most dramatic effects of β-adrenergic blockade are on the cardiovascular system. Effective doses of either orally or intravenously administered propranolol result in rapid reduction in heart rate and an increase in cardiac output, if the latter was low because of the rapid rate (58). Patients who previously seemed refractory to digoxin and diuretic therapy may respond rapidly after initiation of propranolol therapy. If there is an underlying cardiomyopathy, however, propranolol may have the adverse effect of reducing sympathetic drive to the myocardium, and would need to be given cautiously in such patients.

Other beneficial effects of propranolol in thyrotoxic storm include improvement in agitation, psychotic behavior, tremor, diarrhea, fever, and diaphoresis. In some patients, there may be relative risks or contraindications to propranolol therapy, for example, in patients being treated for diabetes mellitus, in whom it may mask some of the symptoms of hypoglycemia, or in patients with asthma, in whom it may exacerbate bronchospasm. Untoward bradycardia caused by propranolol may be reversed by administration of atropine, and isoproterenol should be given to counteract bronchospasm or failing left ventricular function. In patients at risk for adverse effects of propranolol, a more cardioselective β-adrenergic antagonist drug may be given. A very short-acting β-adrenergic antagonist, esmolol, can be given intravenously instead of propranolol. The initial dose is 0.25 to 0.5 mg/kg given in 5 to 10 minutes, followed by a continuous infusion of 0.05 to 0.1 mg/kg/min (59,60).

Reserpine and guanethidine, which were the first sympatholytic drugs used for treatment of patients with thyrotoxic storm, are no longer used. As compared with propranolol and other β-adrenergic antagonist drugs, they are both less effective and more likely to have adverse effects, particularly hypotension and CNS depression.

Several methods to remove T4 and T3 from the serum have been devised. Among them the simplest is to administer cholestyramine orally, to interrupt the enterohepatic circulation of T4 and T3 by binding the hormones in the gastrointestinal tract (61). Serum T4 and T3 concentrations also can be reduced by either peritoneal dialysis or plasmapheresis (31,32,33).

Hemoperfusion through a bed of resin or charcoal, to which T4 and T3 will bind, also has been demonstrated to be effective experimentally (62,63). These are cumbersome procedures and should be considered only in exceptional cases.

L-carnitine is a quaternary amine that acts to inhibit thyroid hormone action by reducing nuclear binding of T3 and has been proposed as a therapy for both thyrotoxicosis and thyroid storm. Carnitine along with low-dose methimazole was effective in one patient who survived three sequential episodes of thyroid storm (64).

Therapy Directed Against a Precipitating Illness

All patients with thyrotoxic storm should be evaluated carefully for the presence of another illness that may have precipitated or at least exacerbated the patient's thyrotoxicosis, and appropriate treatment initiated. In some patients, for example those with an infection or trauma, the problem is obvious, but in others it is less so and can be uncovered only by thorough evaluation. This is especially important in patients who are obtunded or psychotic, and therefore may not be able to provide relevant historical information.

Most patients treated as described above improve considerably within 12 or 24 hours. The pulse rate slows, fever subsides, and mental status improves. With continued improvement, antipyretic and glucocorticoid therapy can be reduced and discontinued, and oral hydration and nutrition can be initiated. Subsequently, attention should be turned to further treatment of thyrotoxicosis. If the patient has Graves' thyrotoxicosis, as is usually the case, the antithyroid drug therapy can be continued in the hope that a remission of Graves' disease will occur, but in general radioiodine therapy or thyroidectomy is preferred for patients who have had thyrotoxic storm. Because virtually all patients are treated with inorganic iodide, an iodine-containing radiographic contrast agent, or both, radioiodine therapy cannot be given for several weeks or months. Given that radioiodine therapy must be delayed, thyroidectomy may be more expedient, but it should not be undertaken until the patient has been euthyroid for several weeks (see Chapter 45).

There has been a revival of interest in surgical approaches to thyroid storm, as noted above (49,50) although thyroidectomy in a severely thyrotoxic patient has been considered risky until the thyrotoxicosis was brought under control. Proponents of thyroidectomy point to the relatively long latent period before improvement and the potential high mortality with medical therapy. Scholz et al. (50), after reviewing their experience with 10 patients and others treated by thyroidectomy in the literature, noted a mortality of only 10%. They concluded that thyroidectomy should be considered for storm, particularly if the usual therapies outlined above do not lead to significant improvement within 12 to 24 hours.

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