Endocrinology: Endocrine Emergencies

Endocrinology: Endocrine Emergencies

Adrenal crisis

Adrenal crisis, or acute adrenal insufficiency, is a potentially life-threatening emergency which occurs as a result of cortisol deficiency. Prompt identification of affected patients and early initiation of therapy can be life-saving.

Clinical presentation

A history of pre-existing adrenal insufficiency or recent discontinuation of steroids may be apparent but some patients
present de novo, and a high index of suspicion for the diagnosis is needed. Underlying conditions include primary adrenal insufficiency (Chapter 20), secondary adrenal insufficiency (Chapter 20) and chronic exogenous glucocorticoid treatment (doses ≥5 mg prednisolone equivalent for >4 weeks). This can also include patients treated chronically with nasal, topical or inhaled glucocorticoids.
Symptoms and signs include fatigue, dizziness and hypotension (especially postural hypotension), collapse
(including hypovolaemic shock), abdominal pain, nausea, weight loss, fever, confusion, delirium or even coma (Figure 5.1). Patients with primary adrenal insufficiency may be pigmented (Chapter 20), whereas patients with secondary adrenal insufficiency may be pale with symptoms of other pituitary hormone deficiency.
Biochemical findings include hyponatraemia, hyperkalaemia, anaemia, pre-renal failure and hypoglycaemia (predominantly in children).

Management

The initial assessment should check blood pressure (including postural measurement) and fluid balance status (Figure 35.2). Blood tests should include measurement of electrolytes, renal function, FBC, glucose, thyroid function (thyrotoxicosis can trigger a crisis), and paired serum cortisol and plasma ACTH. Definitive confirmation of adrenal insufficiency usually requires a Synacthen test (Chapter 20) but unless the patient is haemodynamically stable, treatment should not be delayed to accommodate this.
Therapy should commence as soon as the diagnosis is suspected. Patients usually have significant reduction in fluid
volume, hence immediate treatment should focus on rehydration with 1 L 0.9% saline IV in the first 1–2 hours, followed by further fluids as required (often 4–6 L in the first 24 hours). Care is needed in the elderly and in those with cardiac or renal failure. If present, hypoglycaemia should be treated with IV glucose.
Hydrocortisone should be given as an immediate IV (or IM) bolus of 100 mg, followed by either an infusion of 200 mg over 24 hours, or 50 mg IV/IM injection every 6 hours. Tapering of hydrocortisone can occur after clinical improvement. Because hydrocortisone has substantial mineralocorticoid activity in high doses, fludrocortisone is not needed until total doses of hydrocortisone are <50 mg/day, and only then in patients with primary adrenal insufficiency (Chapter 20).
A search for precipitants should include a screen for infection (treated as necessary with antibiotics), a review of the history for any recent abrupt discontinuation of chronic glucocorticoid therapy, and review of sick day rules (Chapter 20).
An endocrinologist should be contacted as soon as the diagnosis is suspected. Subsequent tests should look to establish the cause of the adrenal insufficiency as in the non-acute state (Chapter 20).
Before discharge from hospital, a check should be made to ensure that patients are educated about the need to increase their glucocorticoid doses at times of intercurrent illness, they are provided with a hydrocortisone emergency injection kit, they carry a steroid card and are encouraged to wear medical alert jewellery.

Pituitary apoplexy

Pituitary apoplexy is caused by haemorrhage and/or infarction of a pituitary tumour, which may not have been previously recognised. A high index of suspicion is needed for the diagnosis because prompt management can be life and sight saving.

Clinical presentation

Precipitating factors

The diagnosis can be challenging because the symptoms often mimic more common neurological emergencies. Apoplexy generally occurs spontaneously, although precipitating factors are sometimes identifiable and include hypertension, surgery (especially cardiac), anticoagulant therapy, coagulopathies, dynamic pituitary function testing, dopamine agonist therapy, pregnancy and head trauma.

Signs and symptoms

Headache, which is usually severe and often associated with nausea and vomiting, is almost universal. Ocular palsy, most commonly a third nerve palsy, may be present if there is cavernous sinus involvement, while optic chiasmal compression can lead to reduced visual acuity and visual field loss (typically, a bitemporal hemianopia; Figure 36.1). Fever, photophobia, neck stiffness and reduced consciousness can also be present.

Differential diagnosis

This includes the more common presentations of subarachnoid haemorrhage and meningitis, in addition to brainstem infarction and cavernous sinus thrombosis.

Management

Initial assessment

Supportive measures are paramount to ensure haemodynamic stability (Figure 36.2). Urgent bloods for measurement of U&E, FBC, clotting profile and liver function should be taken. Ideally, bloods should also be taken for measurement of random cortisol, TSH, free T4, prolactin, IGF-1, LH, FSH and either testosterone (men) or oestradiol (women).

Steroid replacement

Empirical steroid therapy, given in the form of 100 mg IM/ IV hydrocortisone followed by 50–100 mg 6-hourly by IM/IV
injection (or 2–4 mg/hour by continuous IV infusion) should be considered and is potentially life-saving. Steroid therapy
is particularly important in patients with haemodynamic instability, altered consciousness, reduced visual acuity or visual field defects.

Visual assessment and pituitary imaging

A bedside assessment of visual acuity and fields should be performed; a more detailed ophthalmological assessment
can be undertaken when the patient is stable. If not already performed, CT brain (and lumbar puncture if necessary) should be requested to exclude subarachnoid haemorrhage. This may show evidence of apoplexy but a dedicated MRI of the pituitary is the investigation of choice and confirms the diagnosis in >90% of cases (Figure 36.3). A pituitary CT may be required if MRI is contraindicated. Once the diagnosis is made, patients should be transferred to the regional endocrine and/or neurosurgical team. Surgery may be required, but usually only in patients with reduced visual acuity, severe and persistent visual field defects and/or falling level of consciousness.

Post-discharge follow-up

Repeat assessment of pituitary and visual function should be undertaken at 4–6 weeks after hospital discharge in the
endocrinology clinic. Timing of further imaging will usually be discussed at the pituitary multidisciplinary team meeting.

Myxoedema coma

Myxoedema coma is a rare, life-threatening extreme manifestation of hypothyroidism. It typically affects elderly
women with long-standing but often unrecognised or untreated hypothyroidism. Despite prompt diagnosis and treatment, mortality is high, hence management in an intensive care environment is important.

Clinical presentation

There may be clues to the diagnosis from the history, which should explore potential precipitants such as cold exposure, infection, drugs (antidepressants, sedatives, opiates, lithium, amiodarone) and cardiac or cerebrovascular disease. A collateral history may reveal typical symptoms of hypothyroidism, including recent psychiatric symptoms (‘myxoedema madness’). There can also be direct clues of thyroid disease, such as previous thyroidectomy, ablative radioiodine therapy or recent discontinuation of thyroxine (T4) replacement.
The cardinal signs are hypothermia, which is often profound, and coma, but physical examination can also reveal bradycardia, macroglossia, dry skin, hyporeflexia, a goitre, hypoventilation and evidence of cardiac failure (Figure 37.1). In profound myxoedema, a pericardial effusion may be present.

Investigation

Biochemical findings include hyponatraemia, hypoglycaemia, raised creatine kinase, anaemia, hypercholesterolaemia, hypoxia and/or hypercapnia. An ECG may demonstrate bradycardia, varying degrees of heart block, low-voltage complexes, T-wave inversion and prolongation of the QT interval (Figure 37.2). Thyroid function tests should be requested urgently and will usually show the typical pattern of primary hypothyroidism (i.e. low free T4 and raised TSH). However, in 10% of cases, the thyroid tests will show secondary hypothyroidism (low free T4, low/normal TSH) resulting from pituitary or hypothalamic disease.

Management

Treatment centres on supportive measures for the multiple metabolic abnormalities, together with replenishment of the depleted thyroid hormone stores (Figure 37.3). The patient should be transferred to an intensive care unit. Monitoring should include frequent measurement of core (rectal) temperature, blood pressure, oxygen saturation, urine output, central venous pressure, arterial blood gas and electrolyte status.

Basic resuscitation

The first priority is to ensure maintenance of an adequate airway. Patients with evidence of respiratory failure, characterised by hypoventilation, carbon dioxide retention and respiratory acidosis, will require intubation and mechanical ventilation. Warm, humidified oxygen should be given to all patients. Hypothermia should be corrected gradually by passive external re-warming. Hypotension should be treated with IV fluids (5% dextrose if there is hypoglycaemia; or 0.9% saline) used carefully because cardiac failure is not uncommon. Inotropic therapy may be needed in patients who do not respond to fluids, balancing the benefits of correcting hypotension with the potential risks of inotrope-induced ischaemia.

Endocrine management

Hyponatraemia is often present because of impaired water excretion. In mild cases, fluid restriction is usually sufficient to correct this but in severe cases, hypertonic saline may be needed. Up to 10% of patients have coexisting adrenal insufficiency, either from primary (autoimmune) adrenal failure or secondary to pituitary disease. For this reason, hydrocortisone should be given to all patients (50 mg IV every 8 hours), especially as thyroxine replacement can precipitate a crisis in unrecognised adrenal failure. Because infection is a common precipitant, broad-spectrum antibiotics should also be administered after blood cultures have been taken.

Thyroid replacement

There is controversy as to the optimal type of thyroid hormone replacement, with little evidence to support one treatment regimen over another. The theoretical benefits of a more rapid onset of action of T3 (triiodothyronine) versus T4 replacement may be offset by an increased risk of myocardial ischaemia and arrhythmias. A practical approach is to give T4 initially, with the addition of T3 in carefully selected patients if there is inadequate improvement. T4 should be given at an initial loading dose of 300–500 μg as an intravenous bolus, followed by 50–100 μg/day as a maintenance dose. Serum T3 will rise progressively, because of peripheral conversion from T4, and the TSH will gradually fall.

Thyroid storm

This is a rare and extreme form of hyperthyroidism that demands prompt recognition and treatment in view of its high mortality.

Clinical presentation

A high index of suspicion is needed for the diagnosis as many of the symptoms and signs are non-specific (Figure 38.1):

  • Pyrexia
  • Agitation and confusion
  • Tachycardia (Figure 38.2)
  • Diarrhoea and vomiting
  • Jaundice.
    In addition, there may be specific signs of thyrotoxicosis such as goitre or Graves’ ophthalmopathy, and evidence of
    multi-organ decompensation (cardiac failure, dehydration, respiratory distress). A careful history should be obtained to look for possible precipitants, such as recent antithyroid drug withdrawal, amiodarone therapy, administration of iodinated contrast agents, radioiodine therapy, sepsis or surgery.

Investigations

Biochemical findings can reveal a leucocytosis, raised alkaline phosphatase, hypercalcaemia, in addition to raised free T3 and free T4, and suppressed TSH. It should be noted that the rise in free thyroid hormone levels is often of the same order of magnitude as in uncomplicated thyrotoxicosis, hence these cannot be used to distinguish reliably between the two conditions.

Management

Treatment, which should not be delayed to await thyroid function test results, centres on supportive measures in addition to specific anti-thyroid therapy. Patients should be moved to a high dependency environment to allow for close monitoring of temperature, fluid balance, cardiac (Figure 38.3), respiratory and neurological status.
Dehydration should be treated aggressively with intravenous fluids, used carefully in the elderly or patients with cardiac
failure. Pyrexia should be treated with regular paracetamol and external cooling. Chlorpromazine is useful to treat agitation and has an additional benefit in reducing fever. Cardiac failure and tachyarrhythmias should be treated as per standard clinical practice, although greater than normal doses of digoxin may be needed and hypokalaemia must be corrected to avoid toxicity. Prophylactic anticoagulation should be commenced in view of a high risk of thrombosis.
Beta-blockers are effective in dealing with many of the peripheral manifestations of thyrotoxicosis, including
tachycardia, agitation, fever, tremor and diarrhoea, if present. These are usually given in the form of propranolol 60–120 mg every 6 hours orally, or 2–5 mg/hour IV. Hypotension may require inotropic support. Corticosteroids (hydrocortisone
50 mg IV every 8 hours) should be prescribed, not only on the basis of possible relative adrenal insufficiency, but also
because they inhibit conversion of T4 to active T3. Because sepsis is a common precipitant, antibiotic therapy should be
considered.

Anti-thyroid treatment

Specific anti-thyroid therapy should be given in the form of high dose thionamides, either by mouth or nasogastric tube. PTU is usually preferred to carbimazole because it has an added benefit of inhibiting peripheral conversion of T4 to T3. The starting dose is 300 mg every 6 hours. In addition to blocking new thyroid hormone synthesis, the continued release of preformed thyroid hormone must be stopped. This is achieved by giving Lugol’s solution (8 drops every 6 hours) or a solution of potassium iodide (60 mg every 6 hours). Iodine must always be given after thionamide therapy, otherwise there is the potential to exacerbate thyrotoxicosis by enrichment of thyroid stores. In combination,
iodine and thionamide therapy will usually restore euthyroidism within 4–5 days (Figure 38.4).

Acute hyponatraemia

Although hyponatraemia is common in hospital inpatients, most cases are mild and chronic. In such cases, the brain develops an adaptive response characterised by efflux of osmolytes into the extracellular space, which serves to minimise oedema and preserve neuronal function (Chapter 8). This needs to be distinguished from acute (developing within 48 hours), profound (serum sodium <125 mmol/L) hyponatraemia, where a rapid fall in sodium concentration
leads to potentially life-threatening neurological features before adaptive responses can occur. This is a medical emergency that requires management in a high dependency environment.

Clinical presentation

The symptoms and signs of acute severe hyponatraemia are caused by brain oedema and raised intracranial pressure
(Figure 39.1). These include headache, nausea/vomiting, confusion, drowsiness, seizures, coma/reduced Glasgow coma
scale score, and encephalopathy.

Management

Patients should be transferred to a high dependency monitored environment and a senior endocrinologist should be consulted as soon as possible. Treatment involves the use of hypertonic saline, with careful monitoring of clinical and biochemical status (Figure 39.2).

Hypertonic saline

Hypertonic saline should initially be given as 150 mL of 3% saline administered intravenously over 20 minutes. Serum sodium concentration should be checked after 20 minutes, while repeating an infusion of 150 mL of 3% saline for the next 20 minutes, aiming for a target increase in serum sodium of 5 mmol/L. In cases of symptomatic improvement, hypertonic saline infusion can be stopped while a specific cause for the hyponatraemia is sought (Chapter 8). Diagnosis-specific treatment can then be started. In the absence of clinical improvement, hypertonic saline can be continued while additional diagnoses to account for the symptoms are explored. Serum sodium levels must be checked in all patients at 6, 12, 24 and 48 hours.

Osmotic demyelination syndrome

Patients are at risk of neurological damage from osmotic demyelination syndrome (central pontine myelinolysis) if the
rate of correction of serum sodium occurs too quickly. For this reason, a limit should be set of a rise of no more than 10 mmol/L in the first 24 hours, and 8 mmol/L in the following 24 hours (18 mmol/L in 48 hours). If there is evidence of over-correction then 5% dextrose with or without desmopressin needs to be considered.
High risk patients for osmotic demyelination syndrome include extremes of age (children under 16 or elderly patients),
malnourishment, alcoholism, postoperative patients and individuals with pre-existing neurological disease. More
stringent safety limits for correction, of 8 mmol/L in 24 hours and 14 mmol/L in 48 hours, should be applied in these
circumstances.

Severe hypercalcaemia

Patients with mild–moderate hypercalcaemia (<3 mmol/L) are often asymptomatic and calcium concentrations at this level do not generally require urgent correction. More significant hypercalcaemia (>3 mmol/L) can be well tolerated if
chronic, but is often symptomatic and requires prompt correction, particularly if >3.5 mmol/L, because of the risk of arrhythmia and coma.

Clinical presentation

Hypercalcaemia is associated with:

  • Thirst and polyuria
  • Anorexia, nausea and constipation
  • Cognitive impairment (including confusion and coma)
  • Renal impairment
  • Nephrolithiasis and nephrocalcinosis
  • Shortened QT interval and a risk of arrhythmia
  • Pancreatitis
  • Peptic ulceration
  • Hypertension and cardiomyopathy (Figure 40.1).

Management

Reversal of underlying cause

The causes of hypercalcaemia are discussed in Chapter 16. Over 90% of cases are attributable to primary hyperparathyroidism or malignancy. The initial review should include a careful history to explore symptoms of hypercalcaemia, potential underlying causes, family and drug history, an assessment of fluid balance, ECG (searching for a shortened QT interval in particular) and blood tests (for adjusted calcium, phosphate, PTH and U&E) (Figure 40.2).

Rehydration

The first priority is to rehydrate the patient by the administration of 0.9% saline IV. Up to 4–6 L may be needed in the first 24 hours. However, this should be undertaken with caution in the elderly or in those with cardiac, renal or hepatic impairment. Loop diuretics are not effective in reducing serum calcium levels but can be helpful if fluid overload develops.

Bisphosphonates

After rehydration, an IV bisphosphonate should be commenced. This is usually given as 4 mg zoledronic acid over 15 minutes. Pamidronate 30–90 mg (dependent on severity) at a rate of 20 mg/hour, or ibandronic acid 2–4 mg are alternatives. Bisphosphonates should be given more slowly and in reduced doses in patients with renal impairment. Calcium levels should be monitored daily; they usually reach a nadir at day 2–4. Hypocalcaemia can develop in patients with vitamin D deficiency or a suppressed PTH.

Other treatments

Second line treatments are considered in selected patients who fail to respond to rehydration and bisphosphonate therapy. Calcitonin, in an initial dose of 200 IU three times a day by subcutaneous or IM injection, is less potent than bisphosphonates but has a more rapid onset of action. Glucocorticoids (prednisolone 40 mg/ day orally) are effective in hypercalcaemia related to excess 1,25 dihydroxyvitamin D production (lymphoma, granulomatous diseases or vitamin D poisoning). Cinacalcet, a calcimimetic agent, is licenced for use in hypercalcaemia related to primary hyperparathyroidism, parathyroid carcinoma or renal failure. Parathyroidectomy is reserved for rare patients who present with severe hypercalcaemia resulting from primary hyperparathyroidism who show a poor response to other measures. Finally, dialysis is occasionally required to treat refractory hypercalcaemia in the presence of severe renal failure.

Acute hypocalcaemia

Acute hypocalcaemia is potentially life-threatening and requires urgent treatment. Intravenous calcium forms the
mainstay of initial therapy, but should be followed by a search for the underlying cause and diagnosis-specific treatment

Clinical presentation

The symptoms and signs of hypocalcaemia vary according to biochemical severity (typically occurring when the adjusted serum calcium falls to <1.9 mmol/L) and the rate of onset (Figure 41.1). They are mainly caused by neuromuscular irritability and include:

  • Peri-oral and digital paraesthesiae
  • Carpopedal spasm and tetany
  • Muscular cramps
  • Laryngospasm/stridor
  • Seizures
  • Prolonged QT interval and a risk of arrhythmia
  • Positive Chvostek’s and Trousseau’s signs.

Management

Reversal of underlying cause

The causes of hypocalcaemia are discussed in Chapter 17; the most common cause of acute symptomatic hypocalcaemia is hypoparathyroidism resulting from thyroidectomy, but severe vitamin D deficiency, magnesium deficiency, cytotoxic therapy, pancreatitis and rhabdomyolysis are other causes. The initial review should include a careful history (to explore symptoms of hypocalcaemia, potential underlying causes, family and drug history), ECG (searching for a prolonged QT interval in particular) and blood tests (for adjusted calcium, phosphate, PTH, vitamin D, magnesium and U&E).

Intravenous calcium

Severe hypocalcaemia (<1.9 mmol/L) and/or patients with symptoms at any level of calcium below the reference range
should be treated urgently (Figure 41.2). The first priority is to administer calcium gluconate. Calcium chloride is an alternative but is more irritant to veins and can only be given by a central line. Calcium gluconate should initially be given as 10–20 mL of 10% calcium gluconate in 50–100 mL of 5% dextrose given over 10 minutes. This can be repeated until the patient is rendered asymptomatic, and should be followed by a calcium gluconate infusion (dilute 100 mL of 10% calcium gluconate in 1 L of 0.9% saline or 5% dextrose; infuse at 50–100 mL/hour and titrate according to adjusted calcium level). Patients with cardiac arrhythmias or those on digoxin therapy require continuous ECG monitoring during IV calcium treatment.

Oral calcium and vitamin D analogues

The underlying cause should be treated. In the case of hypoparathyroidism, this should take the form of 1-alfacalcidol
or calcitriol starting at a dose of 0.25–0.5 μg/day. Adjusted calcium levels should be checked regularly as the dose is titrated upwards, in order to avoid hypercalcaemia from over-replacement.

Hypomagnesaemia

It is important to check magnesium levels in all patients, because hypocalcaemia will not resolve in untreated hypomagnesaemia as a result of impaired PTH secretion and increased PTH resistance. Hypomagnesaemia, if present, can be treated by stopping any offending drugs (e.g. proton pump inhibitors) and by commencing intravenous MgSO4: 6 g of MgSO4 (30 mL of 20%, 800 mmol/L, MgSO4) in 500 mL of 0.9% saline or 5% dextrose.