Thyrotoxic storm is arguably the most serious complication of hyperthyroidism, with reported mortality ranging from 10 to 75% in hospitalised patients.^4,⁵ Crisis most commonly occurs as a result of unrecognised or poorly controlled Graves disease; however, other underlying diseases may be the cause.^6,⁷ Females outnumber males. Laboratory findings are inconsistent due to acute disruption of the normal steady state of the circulating hormones, and there is no definitive value that separates thyrotoxicosis from thyroid storm. The latter is a clinical diagnosis and a scoring system has been proposed to guide the likelihood of the diagnosis (Figure 52.1).⁸ Precipitating factors are not always present, though many have been identified (Table 52.2).

Figure 52.1 Severity assessment in thyroid crisis. CNS, central nervous system; GI, gastrointestinal.

(Adapted from Tewari K, Balderston KD, Carpenter SE et al. Papillary thyroid carcinoma manifesting as thyroid storm of pregnancy: case report. Am J Obstet Gynecol 1998; 179: 818–19.)

Table 52.2 Factors associated with precipitating thyroid storm

CLINICAL PRESENTATION (Table 52.3)

The classic signs of thyroid crisis include fever, tachycardia, tremor, diarrhoea, nausea and vomiting.⁹ However presentation is extremely variable and may range from apathetic hyperthyroidism (apathy, depression, hyporeflexia and myopathy)¹⁰ to multiple-organ dysfunction.^11,¹² Differential diagnosis includes sepsis and other causes of hyperpyrexia such as adrenergic and anticholinergic syndromes.

Table 52.3 Clinical features of hyperthyroidism/thyroid crisis

FEVER

This is the most characteristic feature. Temperature may rise above 41°C. There have been suggestions that pyrexia is present in all cases of thyroid storm,¹³ though normothermia has been reported.¹¹ Pyrexia is rare in uncomplicated thyrotoxicosis and should always raise suspicion of thyroid storm. It is not clear whether this febrile response is due to alteration of central thermoregulation or elevation of basal metabolic thermogenesis beyond the body’s ability to lose heat.

CARDIOVASCULAR FEATURES

Fluid requirements may be substantial in some patients, whereas diuresis may be required in those with severe cardiac congestion. Cardiac decompensation can occur in young patients with no known antecedent cardiac disease. Systolic hypertension with widened pulse pressure is common initially; however hypotension supervenes later. Cardiogenic shock with vascular collapse is a preterminal sign.¹⁴ Arrhythmias are common and include atrial and polymorphic ventricular tachycardias. The latter may result from prolonged QTc interval, the presence of which may complicate and contraindicate the use of amiodarone therapy.

NEUROMUSCULAR FEATURES

Tremor is a common early sign, but as ‘storm’ progresses, central nervous dysfunction evolves with progression to encephalopathy or even coma.¹⁵ Thyroid storm has been reported in association with status epilepticus and cerebrovascular accident.¹⁶ Weakness may be a feature, particularly with apathetic thyrotoxicosis.¹⁰ Thyrotoxic myopathy and rhabdomyolysis may be present,^11,¹⁷ the latter being differentiated from the former by its association with markedly elevated creatine phosphokinase levels. A number of other syndromes of neuromuscular weakness have been described, including hypokalaemic periodic paralysis¹⁸ and myasthenia gravis.¹⁹

GASTROINTESTINAL FEATURES

Diarrhoea, nausea and vomiting are common, though the patient may present with symptoms of an acute abdomen.²⁰ Severe abdominal tenderness should raise the possibility of an abdominal emergency. Liver function tests may be abnormal due to congestion or necrosis and tenderness over the hepatic area may be present. Hepatosplenomegaly may be present. The presence of jaundice is a poor prognostic sign.¹⁴

RESPIRATORY CONSIDERATIONS

Dyspnoea at rest or on exertion may be present for a number of reasons. Oxygen consumption and carbon dioxide production are increased with subsequent increase in the respiratory burden. This may be exacerbated by pulmonary oedema, respiratory muscle weakness and tracheal obstruction from enlarged goitre (rare).

LABORATORY FINDINGS

Numerous abnormalities may be found:

• fT₄ and fT₃ are usually increased, though this does not correlate with clinical severity: TSH is undetectable

• hyperglycaemia in non-diabetics

• leukocytosis with a left shift, even in the absence of infection (leukopenia may be present in patients with Graves disease)

• abnormal liver function tests and hyperbilirubinaemia

• hypercalcaemia due to haemoconcentration and the effect of thyroid hormones on bone resorption

• hypokalaemia and hypomagnesaemia (particularly in apathetic thyrotoxicosis)

• serum cortisol should be elevated. If low values are found, adrenal insufficiency should be considered and treated. Adrenal reserve in thyrotoxic patients is often exceeded in the absence of absolute adrenal insufficiency

MANAGEMENT

Treatment is aimed at:

• control and relief of adrenergic symptoms

• correction of thyroid hormone abnormalities

• the precipitating cause

• investigation and treatment of the underlying thyroid disease

• supportive measures

β-ADRENERGIC BLOCKADE

This is the mainstay of controlling adrenergic symptoms.²¹ Intravenous propranolol titrated in 0.5–1-mg increments, while monitoring cardiovascular response, diminishes the systemic hypersensitivity to catecholamines. In addition it inhibits peripheral conversion of T₄ to T₃.²² Concurrent administration of enteral propranolol is the norm, with doses as high as 60–120 mg 4–6-hourly often being necessary due to enhanced elimination during thyroid crisis.²³ An alternative regimen uses intravenous esmolol with a loading dose of 250–500 μg/kg followed by infusion at 50–100 μg/kg per min. This allows rapid titration of β-blockade while minimising adverse reactions.²⁴ β₁-selective antagonists such as metoprolol may be of use, particularly in the presence of reactive airways and heart failure. These agents do not inhibit conversion of T₄ to T₃ to the extent of non-selective β-antagonists and should be combined with other therapy. Patients who exhibit resistance to β-adrenergic blockade may be successfully treated with reserpine or guanethidine, though their onset of action is slow and side-effects may be significant.

DIGOXIN

Control of heart rate and rhythm may result in significant improvement in cardiac performance. Electrolyte imbalance, particularly hypokalaemia and hyomagnesaemia, should be corrected prior to drug therapy. Relative resistance to digoxin may occur due to increased renal clearance ²⁵ and increased Na/K-ATPase units in cardiac muscle.²⁶ Arterial thromboembolic phenomena are common (10–40%) in thyrotoxicosis-related atrial fibrillation. This may be due to a procoagulant state or an increased incidence of mitral valve prolapse. Anticoagulation is controversial given the increased sensitivity to warfarin and potential for bleeding; however it should be considered in the management of these patients.

AMIODARONE

Amiodarone has theoretical benefits in thyrotoxicosis as it inhibits peripheral conversion of T₄ to T₃ and reduces the concentration of T₃-induced adrenoceptors.²⁷ It does however cause profound (and sometimes physiologically irrelevant) changes to thyroid function tests and should not therefore be used as the first-line agent. The presence of prolonged QTc interval should be excluded before commencing therapy.

SUPPORTIVE THERAPY

Fluid management

Fluid management may be extremely difficult in patients suffering from thyroid storm, particularly the elderly. Fluid losses may be profound due to diarrhoea, vomiting, pyrexia and reduced intake. However, cardiac failure may also develop as a result of the high cardiac demand. Echocardiography and cardiac output monitoring may be invaluable in guiding therapy for such patients.

Nutrition

Thyrotoxic patients have high energy expenditure and may present with a significant energy, vitamin and nitrogen deficit. Nutritional requirements should take account of any deficit and the ongoing hypercatabolic state. Thiamine is usually supplemented.

Drug therapy

Consideration should be given to the enhanced metabolism and elimination of drugs that occur in thyrotoxic patients. Salicylates and furosemide should be avoided as they both displace thyroid hormones from their binding proteins and can rapidly exacerbate systemic symptoms.

Precipitating factors

Both the precipitating factors and the disease process underlying the thyroid crisis should be sought and treated aggressively. Infection is the leading precipitant of crisis; thus early microbiological cultures and antibiotic therapy should be considered.

MYXOEDEMA COMA

Myxoedema coma is the extreme manifestation of hypothyroidism which, although rare, carries a mortality ranging from 30% to 60%. The term is a misnomer in that the majority of patients present with neither the non-pitting oedema, known as myxeodema, nor coma.³⁰ The condition should be considered in any patient presenting with reduced level of consciousness and hypothermia. The crisis occurs most commonly in elderly women with long-standing undiagnosed or undertreated hypothyroidism in whom an additional significant stress is experienced. Numerous precipitating factors have been identified (Table 52.4).

Table 52.4 Factors precipitating myxoedema coma

CLINICAL PRESENTATION (TABLE 52.5)

Myxoedema coma can be defined when decreased mental status, hypothermia and clinical features of hypothyroidism are present (see Table 52.5). When these features are present, diagnosis is straightforward; however, asymptomatic or atypical presentation (e.g. decreased mobility) may occur.³¹

Table 52.5 Clinical features of myxoedema coma

NEUROMUSCULAR

Alteration of conscious or mental state is present in all patients. This can range from personality changes to coma, with about 25% of patients experiencing seizures prior to the onset of coma. Electroencephalogram usually reveals non-specific changes. Weakness is common and skeletal muscle dysfunction may develop secondary to increased membrane permeability. The latter can lead to a rise in creatine phosphokinase. Hyponatraemia is present in up to 50% of patients and may contribute to alterations in conscious level (see below). Lumbar puncture often reveals elevated protein levels and a high opening pressure.

HYPOTHERMIA

Hypothermia represents the decrease in thermogenesis that accompanies reduced metabolism and is exacerbated by low ambient temperatures. Mortality is proportional to the degree of hypothermia. A low-reading thermometer should be used during assessment.

CARDIOVASCULAR FEATURES

Diastolic hypertension is due to increased systemic vascular resistance and blood volume reduction;³² however myxoedema is associated with bradycardia and impaired myocardial contractility, with reduced cardiac output and hypotension a common feature. While pericardial effusions may occur, tamponade is uncommon. Creatine phosphokinase may be elevated, though this more commonly originates from skeletal rather than cardiac muscle. Acute coronary syndrome must nevertheless be excluded as a precipitant of the crisis. Electrocardiographic changes include bradycardia, decreased voltage, non-specific ST and T changes, varying types of block and prolonged QT interval. All of the cardiovascular abnormalities are reversible with thyroid hormone treatment.³³

RESPIRATORY FEATURES

Hypothyroidism causes numerous respiratory alterations (see Table 52.5). There is a propensity to respiratory alkalosis, particularly during artificial ventilation. This is due to low metabolic rate, which may be compounded by iatrogenic hyperventilation.³⁴ Diaphragmatic weakness may occur due to abnormalities of the phrenic nerve; as a result, exercise tolerance may be significantly reduced. These abnormalities improve with thyroid hormone replacement, though full recovery can take several months.

LABORATORY FINDINGS

Thyroid function tests will reveal low T₄ and T₃; TSH is raised in primary and low in secondary and tertiary hypothyroidism. Hyponatraemia is common and usually develops due to free water retention resulting from excess vasopressin secretion or impaired renal function.³⁵ It may be severe and can contribute to diminished mental function. Although total body water is increased, intravascular volume is usually decreased. Hypoglycaemia may result from hypothyroidism alone, or as a result of concurrent adrenal insufficiency (Schmidt’s syndrome). The mechanism is probably reduced gluconeogenesis, but infection and starvation may contribute. Azotaemia and hypophosphataemia are common; renal function may be severely abnormal due to low cardiac output and vasoconstriction. Mild leukopenia and normocytic anaemia are frequently present, though macrocytic and pernicious anaemia due to autoimmune dysfunction may occur. Arterial blood gases often reveal respiratory acidosis, hypoxia and hypercapnia.

MANAGEMENT

The mainstay of therapy consists of thyroid hormone replacement, steroid replacement and supportive measures. Once clinical diagnosis has been made or is suspected, blood should be collected for thyroid function and plasma cortisol tests. This should be followed by thyroid hormone treatment, which should not be delayed to await laboratory results. Consideration should be given to identifying and treating precipitating factors and complications of the crisis.

THYROID HORMONE THERAPY

All patients with suspected myxoedema coma should receive presumptive treatment with thyroid hormone. The optimum speed, type, route and dose of thyroid hormone replacement in myxedema coma are unknown due to the rarity of the condition and paucity of trials. The severity of clinical presentation does not correlate with the doses of replacement hormone required. Rapid replacement can result in life-threatening myocardial ischaemia or arrhythmias; delayed therapy exposes patients to prolonged risk of complications from the crisis. Both scenarios are associated with increased mortality.

Some experts favour administration of T₃ as it is biologically more active; has more rapid onset of action; and bypasses the impaired deiodination of T₄ to T₃ which occurs in hypothyroidism and non-thyroidal illness. High serum T₃ concentration has, however, been associated with increased mortality ³⁶ and T₃ is expensive and may be difficult to obtain. T₃ may be administered orally or intravenously and has been combined with T₄ therapy.³⁷

Most authorities recommend use of T₄ alone ^38,³⁹ as the delayed conversion to T₃ allows more gradual replacement of the deficient hormone. Bioavailability of orally administered T₄ is unpredictable given the high incidence of gastrointestinal dysfunction; therefore intravenous administration is more frequently used. A loading dose of intravenous levothyroxine 100–500 mcµg is recommended³⁸ as this saturates the binding proteins. This should be followed by 50–100 mcµg daily until conversion to the bioequivalent oral formulation is possible. The doses must be adjusted to allow for patient age, weight and cardiovascular risk factors; the lower doses should be administered to patients who are elderly, frail or have comorbidities (particularly cardiovascular disease).

CORTICOSTEROIDS

Corticosteroids are an important part of treatment as relative or absolute hypoadrenalism may occur concurrently with hypothyroid disease. A random serum cortisol level should be collected prior to commencing hydrocortisone therapy at 100 mg 8-hourly. If ACTH stimulation test is warranted, dexamethasone 4 mg 6-hourly should be commenced with conversion to hydrocortisone or cessation of treatment once the results are known. If random serum cortisol levels return at normal levels, steroid treatment can be discontinued.

SUPPORTIVE THERAPY

Hypothermia should be treated by passive rewarming where possible but active measures may be required. Appropriate cardiovascular, temperature gradient, electrolyte and acid–base monitoring should be provided during the rewarming phase in order to prevent haemodynamic and metabolic compromise.

Numerous alterations in respiratory physiology occur, including hypoventilation and altered response to arterial oxygen and carbon dioxide tensions. In addition, anatomical changes to the airway, delayed gastric empyting and increased sensitivity to sedative drugs may be present. These changes should be considered when mechanical ventilation is required, particularly during intubation and the weaning process.³⁴

Patients usually present with intravascular fluid depletion despite peripheral oedema. Cardiac output monitoring may help guide fluid resuscitation and therapy. Echocardiography is useful in identifying cardiac dysfunction and pericardial effusions and assisting in assessment of intravascular volume status. Cardiac monitoring should be used to alert to the presence of arrhythmias. Inotropes and vasopressors should be avoided where possible due to their potential to precipitate cardiac arrhythmias. Where inotropes are required, increased dosage may be necessary as reduction in β-adrenoceptors is common. α-adrenoceptor function is usually preserved.

Hyponatraemia is reversible with thyroid hormone treatment, but severe abnormalities contributing to neurological dysfunction may require more expeditious correction. Free water intake should be restricted and hypertonic saline solutions may be required. Hypotonic fluid therapy should be avoided. If glucose therapy is required, hypertonic solutions (20–50%) should be infused via a central venous catheter.

Precipitating factors must be considered. As with all critically ill patients, microbial cultures should be collected and antibiotic therapy commenced unless cultures are negative. Prophylaxis against venous thromboembolism and peptic ulceration should be considered. Enteral feeding should be attempted but may be unsuccessful if gastrointestinal dysfunction and stasis are present.

NON-THYROIDAL ILLNESS

Non-thyroidal illness describes the phenomenon of starved or systemically unwell patients with abnormal serum thyroid function tests but with no apparent thyroidal illness. Low T₃, T₄ and TSH are commonly found; the degree of abnormality correlates with the severity of illness. Variants of these hormone levels are well described. Low serum T₃ is a frequent finding and occurs due to downregulation of the monodeiodinase enzyme that converts T₄ to T₃, while rT₃ may increase due to increased activity of the T₄-to-rT₃ monodeiodinase.⁴⁰

Serum T₄ is also commonly low in the critically ill. This is due to a decrease in the concentration of thyroid hormone-binding proteins and the presence of inhibitors that reduce T₄ binding to these proteins. There is also the suggestion that T₄ entry into cells may be impaired.⁴¹ Free T₄ levels should be normal in less severe illness; however, in severe illness, the level may be low due to inadequate correction during the fT₄ assay.⁴²

Low serum TSH levels were previously thought to be associated with the euthyroid state; however more recent work suggests that acquired transient central hypothyroidism is present in these patients.⁴³ Cytokines such as tumour necrosis factor-α are known to inhibit TSH secretion. Such phenomena are probably evolutionary adaptations to conserve protein and energy during severe illness. Elevated TSH may also occur in non-thyroidal illness, but few of these patients prove to have hypothyroidism following recovery from their acute illness.

Changes in thyroid function test are well described during starvation, sepsis, bone marrow transplantation, surgery, myocardial infarction, coronary artery bypass surgery and probably any critical illness. However, replacement of thyroid hormone in these patients is of no benefit and may be harmful;⁴⁴ hence thyroid function should not be assessed in critically ill patients unless there is a strong clinical indication to do so. A number of specific non-thyroidal illnesses are associated with abnormal thyroid function tests. These include: some psychiatric illnesses; hepatic disease; nephritic syndrome; acromegaly; acute intermittent porphyria; and Cushing’s syndrome.⁴⁵ Where assays are performed, TSH should not be interpreted in isolation as low values will not discriminate between true thyroid and non-thyroidal disease. If low T₄ is also present, non-thyroidal illness is likely. If T₄ is elevated then hyperthyroidism is the likely diagnosis, though elevated T₄ has been documented in non-thyroidal illness.

Given the alterations in these hormones and difficulties with their assay during critical illness, thyroid hormone replacement should not be undertaken on the strength of thyroid function test results alone: additional laboratory and clinical indications must also be present (Table 52.6).

Table 52.6 Changes in thyroid hormone concentrations