The classification system and diagnostic criteria for diabetes were re-examined in 1996 by the American Diabetes Association and the World Health Organization.¹ The classification of type I and type II diabetes mellitus was retained, although the recommended criterion for the diagnosis of diabetes has become a fasting plasma glucose of 7 mmol/L or greater, or a random plasma glucose of over 11 mmol/L associated with polyuria, polydipsia and weight loss. The oral glucose tolerance test is no longer routinely recommended.

Aetiology

The exact aetiology of diabetes is unclear. Evidence regarding type I diabetes suggests genetic and environmental factors associated with certain human leukocyte antigen (HLA) types (90% of patients are HLA-DR3 or DR4 or both) and abnormal immune responses. Certain genes are also implicated as possible co-contributors, particularly sites on chromosomes 6, 7, 11, 14 and 18. Genetic factors are implied by familial aggregation of cases with type II diabetes, and environmental factors in the context of genetic susceptibility, as well as obesity and diet. For instance, the introduction of a high fat and high calorie ‘Western’ diet rather than traditional crop foods has seen countries such as India now record amongst the fastest growth rate of new diabetes anywhere.

Although type I diabetes occurs most frequently among Caucasians throughout the world, diabetes in Australia is more common in the Aboriginal community. Other groups with a high prevalence include Native Americans and Pacific Islanders.

Diabetes secondary to other conditions

Diabetes mellitus may be secondary to conditions including chronic pancreatitis, carcinoma of the pancreas and pancreatectomy, haemochromatosis, cystic fibrosis, pregnancy, Cushing’s syndrome, acromegaly, phaeochromocytoma and glucagonoma.

Drug-induced diabetic state

Certain drugs can impair glucose tolerance or cause overt diabetes mellitus. These include glucocorticoids, the oral contraceptive pill, thiazide diuretics used at higher doses, tacrolimus and ciclosporin, and HIV protease inhibitors.

Emergency presentations of a high blood sugar

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic non-ketotic state (HHNS) are both life-threatening acute complications of diabetes mellitus. Although important differences do exist, the pathophysiology and treatment are similar. DKA is usually seen in type I diabetes and HHNS in patients with type II, but both complications can occur in type I and type II diabetes. See Chapter 11.2 for the diagnosis and management of DKA and HHNS.

General management of diabetes mellitus

Aims of long-term blood sugar control

The aim of excellent long-term blood sugar control is an HbA1c (glycated haemoglobin) level of less than 7.5% without frequent disabling hypoglycaemia for the prevention of microvascular disease, and 6.5% in those at increased risk of arterial disease.² This should be represented by a pre-prandial blood glucose level of 4.0–7.0 mmol/L, and a post-prandial blood glucose level of less than 9.0 mmol/L.

Insulins

Insulin was first administered to humans in 1922. Animal insulins (bovine, porcine) have been used for many years, but in the 1980s human insulins became commercially available. Today, with the widespread availability of human insulins, animal insulins are of historical interest only.

Types of insulins

Table 11.1.1 illustrates the different types of insulins and the important parameters of each type. Mixtures of short- and intermediate-acting insulins are also available: 70/30 (70% NPH/30% regular) and 50/50 (50% NPH/50% regular).

Table 11.1.1 Pharmacokinetic characteristics of currently available human insulins

Antidiabetic drugs

Two major groups of oral hypoglycaemic agents important in the management of type II diabetes are the sulphonylureas and the biguanides. The sulphonylurea group of drugs acts by stimulating the pancreatic secretion of insulin, and the biguanide metformin acts by suppressing hepatic glucose production and enhancing the peripheral use of glucose.

Two newer types of oral agents are available for the treatment of diabetes. The alpha-glucosidase inhibitor acarbose acts on the gastrointestinal tract to interfere with carbohydrate digestion. The other group is the thiazolidinediones, such as pioglitazone and rosiglitazone. The thiazolidinediones act primarily by reducing insulin resistance, thereby enhancing the effect of circulating insulin. However, roziglitazone increases the risk of myocardial infarction and cardiovascular deaths, and thus should be avoided in ischaemic heart disease.³ In addition, all thiazolidinediones must be avoided in people with moderate or severe heart failure.

Other non-diabetic drugs

Statins are important in the strict treatment of dyslipidaemia in diabetic patients. Angiotensin converting enzyme inhibitors also delay the onset of diabetic nephropathy even in normotensive patients with diabetes.

DIABETIC HYPOGLYCAEMIA

Hypoglycaemia most commonly occurs in type I diabetes. The critical plasma level at which hypoglycaemia manifests varies between different individuals, but symptoms are likely below a plasma glucose of 3.5 mmol/L. Common precipitants include exercise, a late meal, inadequate carbohydrate intake, ethanol ingestion and errors of insulin dosage. Hypoglycaemia may also occur in the non-diabetic patient, precipitated by a variety of conditions (see Table 11.1.2).⁴

Table 11.1.2 Causes of hypoglycaemia

Diabetic patients

• Medication change or error, particularly with insulin or oral hypoglycaemic sulphonylurea (very rarely metformin)

• Inadequate dietary intake

• Excessive calorie use such as exercise

Any patient

• Deliberate self-harm with insulin, sulphonylurea, salicylates, β-blockers, quinine, chloroquine, valproic acid

• Ethanol

• Liver disease

• Sepsis

• Starvation, including anorexia nervosa

• Post-gastrointestinal surgery ‘dumping syndrome’

• Adrenal insufficiency

• Hypopituitarism

• Islet cell tumour/extrapancreatic tumour

• Artefact ‘Munchausen syndrome’

Clinical features

Hypoglycaemia produces neurological and mental dysfunction. Less commonly, it can present as hypothermia, depression and psychosis. In some instances hypoglycaemia is asymptomatic.

References

1 Alberti KGMM, DeFronzo RA, Keen H, et al. International textbook of diabetes mellitus. Chichester: John Wiley & Sons Ltd, 1992;31-98.

2 NICE Clinical Guideline 15. Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people and adults, July 2004. Available http://www.nice.org.uk/nicemedia/pdf/CG015NICEguideline.pdf (accessed Dec 2007)

3 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine. 2007;356:2457-2471.

4 eMedicine. Hypoglycaemia, Dec 2007. Available http://www.emedicine.com/emerg/topic272.htm (accessed)

11.2 Diabetic ketoacidosis and hyperosmolar, hyperglycaemic non-ketotic state

Richard D. Hardern

ESSENTIALS

1 Diabetic ketoacidosis (DKA) gives rise to hyperglycaemia, ketosis and a high anion gap metabolic acidosis.

2 DKA is often caused by insulin error or omission, intercurrent illness (especially infections) or a combination of these.

3 There are four key components to the management of DKA:

Fluids (usually 0.9% normal saline) at 3 L in the first 8 h. This is preferred to faster rates of infusion, in the absence of shock.

Insulin as an intravenous infusion of soluble insulin at 0.1 unit/kg/h to a maximum of 6 units/h. Avoid an insulin sliding scale, as regular review with recent biochemistry results should determine what adjustment to the insulin infusion rate is necessary. Do not commence the insulin until the serum potassium [K] has been confirmed as >3.4 mmol/L (risk of hypokalaemic cardiac arrest).

Potassium replacement will be needed, providing the serum potassium is less than 6.0 mmol/L and there is no anuria (rare in DKA).

Education. All patients treated with insulin need to know the ‘sick day rules’, plus be familiar with regular home testing for capillary blood sugar.

4 The treatment of DKA is not complicated, but meticulous monitoring and documentation are essential.

5 The mortality and morbidity of the hyperglycaemic, hyperosmolar non-ketotic state (HHNS) are greater than with DKA.

6 Treatment of HHNS is similar to that of DKA except:

a lower infusion rate of insulin is often sufficient

this insulin infusion rate is titrated against the serum osmolarity rather than to ketoacids

half normal (0.45%) saline is often used

low molecular weight heparin (LMWH) thromboprophylaxis indicated

shock may have a cardiogenic component.

Introduction

Diabetic ketoacidosis (DKA) is potentially fatal and overall is a common presentation to the emergency department (ED) for insulin-dependent diabetics. Shortfalls in the quality of care for patients with DKA have been highlighted. Hyperglycaemic, hyperosmolar non-ketotic state (HHNS) is less common than DKA, but has a worse prognosis, with an increased mortality and greater morbidity, often related to underlying chronic medical disorders.

Aetiology, genetics, pathogenesis and pathology

DKA may be the presenting feature of diabetes mellitus, and is usually seen in patients with type I diabetes when there has been an insulin error and/or an intercurrent illness. A variant of type II diabetes is also ketosis prone. This is most often seen in racial groups with a high prevalence of inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency.

DKA arises from a lack of insulin and an excess of counter regulatory hormones such as glucagon. Insulin absence leads to increased gluconeogenesis and therefore to hyperglycaemia. The less complete the lack of insulin, the greater the hyperosmolarity.

Lack of insulin and excess counter regulatory hormones increase lipolysis with subsequent ketone body formation and a reduced capacity to prevent ketoacid formation.

HHNS is at the other end of the spectrum from DKA. It occurs with a relative rather than an absolute deficiency of insulin, leading to greater hyperglycaemia, which may approach 100 mmol/L. The hyperosmolarity is therefore greater than that seen in DKA and the degree of dehydration is greater (typically 10–15% body weight), but significant ketosis does not occur. HHNS is more insidious in onset than DKA, and patients with HHNS are typically older patients with pre-existing type II diabetes.

Epidemiology

An annual incidence of DKA of approximately 1:170 patients with type I diabetes has been reported.¹

Clinical features

Although there are no clinical features specific to DKA, often the diagnosis can be made from the end of the trolley. Malaise and fatigue on a background of polyuria, polydipsia and sometimes weight loss are common, but gastrointestinal symptoms such as nausea and abdominal pain may predominate. The lack of a history of diabetes does not rule out the diagnosis, as it may be the first presentation.

An increased rate and depth of respiration, known as Kussmaul breathing, is most noticeable, in association with dehydration causing a dry mouth and tongue. The breath may smell of pear drops but this is not always noticed. The conscious level may be reduced or the patient may present in coma.

Look carefully for signs of the underlying cause such as chest, urinary or skin infection, as many cases of DKA are secondary to a stressor such as this.

The urine output should be measured regularly, although this does not always require urinary catheterization.

Invasive haemodynamic monitoring should not be instituted as a ‘routine’ for patients for DKA, but should be reserved for those with reduced capacity to handle fluid overload.

DKA differential diagnosis

Other causes of high (greater than 16) anion gap metabolic acidosis:

• alcoholic or starvation ketoacidosis

• lactic acidosis

• renal failure

• ethanol, methanol, ethylene glycol, salicylate ingestion.

Other causes of hyperglycaemia:

• HHNS

• hyperglycaemia without DKA or HHNS.

Clinical investigations in DKA

Venous blood

The capillary blood glucose should be measured hourly and the venous pH measured until both are near to the normal range. Venous urea and electrolytes (U&Es) and glucose should also be measured hourly initially, then 2-hourly once the venous glucose and capillary glucose are in agreement.

A mild leukocytosis is often seen in DKA, but should not be interpreted as signifying infection. Likewise hyperamylasaemia is common and does not imply pancreatitis.

Urinalysis

This diagnosis is highly likely in an unwell patient in the presence of glycosuria and ketonuria.

Electrocardiograph (ECG)

T-wave changes may be the first indication of hyperkalaemia (tall and peaked) or hypokalaemia (flat or inverted), or a clinically silent myocardial infarction (MI) may precipitate DKA.

Point-of-care testing

Point-of-care testing for blood ketones such as beta-hydroxybutyrate can be helpful in triage and when monitoring the response to treatment.

Treatment of DKA

The treatment of DKA is not complicated, but requires careful monitoring of the patient both clinically and biochemically. Ideally all observations and results should be recorded on a purpose-designed record sheet, such as an integrated care pathway that includes guidance and data recording.²

Resuscitation environment

Patients with DKA require an environment that provides nursing staff familiar with monitoring patients with DKA and familiar with infusion equipment, and medical staff used to managing DKA and who have access to senior advice and or a written guideline, and, importantly, access to timely laboratory facilities for frequent biochemistry testing.

Access in the ED to glucose strips and a blood gas analyser with the ability to measure electrolytes, anion gap and lactate is also useful.

Standard resuscitative measures should be provided for sicker patients, including oxygen, especially for patients who are shocked, with airway protection in comatose patients, and at least a nasogastric tube to prevent aspiration of gastric contents in patients who are not intubated, but whose airway reflexes are impaired.

Early aggressive volume resuscitation should be used in shocked patients, then slow i.v. fluids and insulin infusion once the shocked circulatory status has been restored to normal.

Fluids

Intravenous fluids should be started within 30 min of the patient’s arrival in the ED. Shocked patients require rapid fluid resuscitation, although care is needed in patients with comorbidities to avoid fluid overload.

Give patients who are not shocked 0.9% normal saline at a rate of 500 mL/h for 4 h, then 250 mL/h for the next 4 h.³ A suggested fluid regime is shown in Table 11.2.1.

Table 11.2.1 Replacement fluid regime in patients with DKA who are not haemodynamically compromised or in shock

Litre	Timing (hours from starting treatment)
First at 500 mL/h	0–2
Second at 500 mL/h	2–4
Third at 250 mL/h	4–8
Fourth at 100 mL/h	8–18
Fifth at 100 mL/h	18–28
Sixth at 100 mL/h	28–38
Seventh at 100 mL/h	38–48

Most intravenous fluid regimes suggest replacing the volume deficit (often 10% of body weight) over 24 h. However, in patients with significant comorbidites, it is prudent (although unproven) to aim to correct half the fluid deficit in the first 24 h, and the remainder in the next 24 h. There are no data from randomized controlled trials to support the choice of one crystalloid over another in the treatment of DKA.

Once serum [glucose] has fallen to <15 mmol/L, change the intravenous fluid to 5% dextrose rather than 0.9% saline, but continue the insulin infusion until the ketoacidosis has cleared.

Insulin

An intravenous insulin infusion should be started within 60 min of the patient’s arrival in the ED.

Insulin infusion regime

The standard regime is a continuous intravenous infusion of soluble insulin, making up 50 units of insulin to a total of 50 mL with 0.9% saline to produce a solution containing 1 unit/mL. When prescribing insulin always write ‘units’ in full rather than as ‘u’, as the latter is too easily confused with a 0 (zero), and a 10-fold dose increase can be given in error.

Run the infusion at an initial rate of 0.1 units/kg/h (to a maximum of 6 units/h). Adjust the rate to reduce the serum [glucose] by not more than 5 mmol/L/h. Avoid using a sliding scale in this setting, as this may lead to a failure of medical staff to review patients regularly and frequently.

When the serum [glucose] is less than 15 mmol/L, halve the insulin infusion rate and then adjust it to maintain the serum [glucose] between 9 and 14 mmol/L.²

Do not start the insulin infusion until it has been checked that the serum [potassium] is not below the bottom of the reference range, i.e. it should be greater than 3.4 mmol/L. If it is lower than this, start an infusion of potassium with i.v. fluid first prior to commencing the insulin infusion.

Although there are few data on the benefits or harm of giving a bolus of insulin before starting the infusion, the short half-life of insulin makes it unnecessary. Providing the insulin infusion is prepared and started with minimal delay, there is no justification for a bolus (despite a bolus appearing in many published guidelines).

Although switching from an insulin infusion to intermittent insulin is most likely to occur in the inpatient setting, ED staff must be aware that the insulin infusion is still needed even after the hyperglycaemia resolves, as the ketoacidosis may persist for longer. It may therefore be necessary to combine the insulin infusion with isotonic 5% or hypertonic 10% dextrose to prevent hypoglycaemia.

Stopping an insulin infusion

If ED staff do supervise cessation of the insulin infusion, they must ensure the first sub cut dose is given at least 1 h before the infusion is stopped, providing all the following criteria have been met before stopping the insulin infusion:

• serum [glucose] < 11 mmol/L

• serum bicarbonate > 18 mmol/L

• pH > 7.30

• patient eating and drinking normally, with normal conscious level.

Potassium replacement

Hyperkalaemia and then hypokalaemia are the most common life-threatening electrolyte problems seen in DKA. Therefore the serum [K] should be monitored closely, and treatment planned to treat either condition rapidly, particularly the risk of hypokalaemia. The typical total body deficit of potassium in DKA is 3–5 mmol/kg.¹

Hyperkalaemia seen in the early phase of DKA may cause life-threatening dysrhythmias due to potassium movement out of the cells from the lack of insulin, prior to insulin and fluid management. Hyperkalaemia resolves soon after insulin treatment begins.

Add potassium to intravenous fluids once serum [K] is below the upper end of the reference range, i.e. <6.0 mmol/L. However, never add potassium to the first fluids infused rapidly for volume resuscitation.

Usually adding 20 mmol/h is sufficient, but this may need to be altered in the light of serum [K] measurements, with the aim of maintaining serum [K] in the range 4–5 mmol/L. Use an intravenous fluid pump or driver to avoid unregulated or inadvertently rapid potassium infusion.

Education

Arguably all episodes of DKA represent a failure of patient education, except for those patients in whom DKA is the first presentation of diabetes mellitus. All patients treated with insulin must understand ‘sick day rules’ to increase their normal insulin dose by 4 units or more when they have an intercurrent illness, even if they are not eating, as their insulin requirements will rise. Stopping insulin because a patient is ‘not eating properly’ is all too common and an entirely avoidable precipitant of DKA.

Treatment of HHNS

The treatment of HHNS is similar to that of DKA. Use 0.9% normal saline for volume resuscitation if there is hypovolaemic shock. Give insulin by intravenous infusion and potassium supplementation to maintain serum [K] between 4 and 5 mmol/L. A typical deficit of sodium in HHNS is 5–13 mmol/kg and of potassium is 4–6 mmol/kg, both generally greater than in DKA.

Important management differences

• The patient with HHNS may be more sensitive to insulin. Give an initial dose of 0.05 units/kg/h to a maximum of 3 units, titrated to a controlled fall in serum osmolarity. Aim for a rate of decline in serum osmolarity of less than 3 mOsm/kg/h, avoiding more rapid falls.

• Reduce the insulin infusion rate when the serum [glucose] drops to 18 mmol/L or less, to maintain serum [glucose] in the range 14–18 mmol/L until the serum osmolarity is less than 315 mOsm/kg.

• Shock may be partly or entirely cardiogenic rather than due to volume depletion. Thus invasive monitoring, central venous access and the use of vasoactive drugs rather than fluid alone will be required in this circumstance.

• LMWH is given for thromboprophylaxis although there are no trial outcome data to support this.

• Infuse 0.45% half-normal saline at 250 mL/h, unless the corrected serum [Na] is low (see below the correction of serum [Na] for an elevated glucose level). Aim for a rate of decline of serum [Na] not exceeding 1 mmol/L/h. If the corrected serum [Na] is low, use 0.9% normal saline.

• To correct serum [Na] for hyperglycaemia, adjust the serum [Na] up by 1 mmol/L for every 3 mmol/L elevation in serum glucose.

Prognosis

DKA has an overall mortality of less than 5%, which has not changed for many years, but this is higher at extremes of age and with significant comorbidity. The mortality is 25–33% in HHNS.

Miscellaneous issues

There are no data to support the use of phosphate in the treatment of DKA, despite there often being hypophosphataemia.

Heparin thromboprophylaxis is not used routinely in DKA, nor are antibiotics in the absence of a focus of infection or sepsis.

Sodium bicarbonate should never be used in DKA if the pH is greater than 7.0 and even below that level its value is unproven. Significant disadvantages of giving i.v. bicarbonate are a rapid fall in serum [K] and a worsened intracellular acidosis.

Controversies

• Choice and rate of intravenous fluid replacement, and whether this has any impact on the unexpected but devastating development of cerebral oedema (usually seen in children).

• Point-of-care measurement of beta-hydroxybutyrate may become more widespread, although the precise role in the care of patients with DKA has yet to be determined.⁴

• Titrating insulin use against beta-hydroxybutyrate rather than against serum glucose.

• Earlier recognition of ketosis by measuring beta-hydroxybutyrate to reduce incidence and severity of DKA.

• Use of ultrafast-acting insulin analogues subcutaneously in the treatment of DKA in children. Although they would not generally be used in adults with DKA, they may have a role when there is inadequate equipment for continuous intravenous insulin infusion.

References

1 American Diabetes Association. Clinical practice recommendations. Diabetes Care. 2004;27(Suppl 1):S94-102.

2 McGeoch SC, Hutcheon SD, Vaughan SM, et al. Practical Diabetes International. 2007;24(5):257-261.

3 Adrogue HJ, Barrero J, Eknoyan G. Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis. Use in patients without extreme volume deficit. Journal of the American Medical Association. 1989;262(15):2108-2113.

4 Wallace TM, Matthews TR. Recent advances in the monitoring and management of diabetic ketoacidosis. Quarterly Journal of Medicine. 2004;97:773-780.

11.3 Thyroid and adrenal emergencies

Andrew Maclean, Pamela Rosengarten

ESSENTIALS

1 The thyroid and adrenal emergencies posing an acute threat to life are thyroid storm, myxoedema coma and acute adrenal insufficiency. Diagnosis of these conditions requires a high index of suspicion and treatment frequently must be initiated on clinical rather than laboratory diagnosis.

2 Common features of thyroid storm are fever, alteration in mental state, cardiovascular complications such as tachyarrhythmias and cardiac failure, and signs of hyperthyroidism. Treatment is with β-blockers, drugs that block thyroid hormone synthesis and release, and corticosteroids.

3 Common clinical features of myxoedema coma are an alteration in conscious state, hypothermia and features of hypothyroidism. Treatment is with intravenous tri-iodothyronine and corticosteroids.

4 The most important clinical feature of acute adrenal insufficiency is hypotension unresponsive to fluid therapy. Although hyponatraemia and hyperkalaemia are usual in acute adrenal insufficiency, serum electrolytes may be normal. Treatment is with intravenous corticosteroid replacement on suspicion of the diagnosis.

5 General supportive measures and the treatment of the precipitating event must parallel the specific treatment regimes in all of these conditions.

Introduction

Four conditions are covered in this chapter: thyrotoxicosis, hypothyroidism, hypoadrenal states and hyperadrenal states. Patients with the first three present relatively infrequently to emergency departments (EDs), but all four conditions are potentially fatal if they go unrecognized and untreated. The most common cause of Cushing’s syndrome is exogenous steroid administration. An inability to produce endogenous steroids in times of physiological stress and therefore the potential for adrenal insufficiency must be considered in such patients.

THYROTOXICOSIS

Aetiology, genetics, pathogenesis and pathology

Normal secretion of thyroid hormone relies on an intact feedback loop involving the hypothalamus, pituitary gland and thyroid gland. Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates thyroid-stimulating hormone (TSH) production in the anterior pituitary, which stimulates thyroid hormone release from thyroid follicular cells. Thyroid hormones suppress TRH and TSH production. Thyroid hormones act at a cellular level, binding with nuclear receptors to enable gene expression and protein synthesis. Thyroid hormone may also have an effect on modulating cellular metabolism.

There are a number of pathological causes of thyrotoxicosis (see Table 11.3.1). Graves’ disease is an autoimmune condition related to a combination of genetic and environmental factors, including iodine intake, stress and smoking. The thyrotoxicosis of Graves’ disease is caused by autoantibodies, which stimulate the thyroid resulting in excess thyroid hormone production.

Table 11.3.1 Causes of thyrotoxicosis

Primary hyperthyroidism	Graves disease
	Toxic multinodular goitre
	Toxic adenoma
Thyroiditis	de Quervains
	Postpartum
	Radiation
Central hyperthyroidism	Pituitary adenoma
	Ectopic thyroid tissue
	Metastatic thyroid tissue
Drug induced	Lithium
	Iodine (including radiographic contrast)
	Amiodarone
	Excess thyroid hormone ingestion (factitious thyrotoxicosis)

Thyroiditis may be acute (rare), subacute or chronic. Inflammation of the thyroid is associated with damage to follicles with release of thyroid hormone. Subacute thyroiditis (de Quervain’s) is related to a viral infection.

Multinodular goitre occurs in areas of both iodine deficiency and sufficiency, indicating that a multiplicity of genetic and environmental factors are at play. Fibrosis, hypercellularity and colloid cysts are the main pathological findings.

Epidemiology

Graves’ disease accounts for at least 80% of cases of thyrotoxicosis.¹ The prevalence increases in areas with high iodine intake. Graves’ disease has a strong female predominance, affecting up to 2% of all women.^1,² Thyrotoxicosis due to Graves’ disease usually occurs in the second to fourth decades of life, whereas the prevalence of a toxic nodular goitre increases with age.

Clinical features

The signs and symptoms of hyperthyroidism are secondary to the effects of excess thyroid hormone in the circulation. The severity of the signs and symptoms is related to the duration of the illness, the magnitude of the hormone excess and the age of the patient. These symptoms and signs are summarized in Table 11.3.2, which illustrates the wide spectrum of possible clinical features.

Table 11.3.2 Clinical features of thyrotoxicosis

Nervousness, irritability

Heat intolerance and increased sweating

Tremor

Weight loss and alterations in appetite

Palpitations and tachycardia, in particular atrial fibrillation

Widened pulse pressure

Exertional intolerance and dyspnoea

Frequent bowel movements

Fatigue and muscle weakness

Thyroid enlargement (depending on cause)

Pretibial myxoedema (with Graves’ disease)

Menstrual disturbance and impaired fertility

Mental disturbances

Sleep disturbances

Changes in vision, photophobia, eye irritation, diplopia, lid lag or exophthalmos

Dependent lower extremity oedema

Sudden paralysis, with or without hypokalaemia.

A comprehensive history and physical examination should be performed, with particular attention to weight, blood pressure, pulse rate and rhythm, looking specifically for cardiac failure, palpation and auscultation of the thyroid to determine thyroid size, nodularity and vascularity, neuromuscular examination, and an eye examination for evidence of exophthalmos or ophthalmoplegia.

Clinical investigation and criteria for diagnosis ¹^–³

The TSH level is the single best screening test for hyperthyroidism. The recent development of sensitive TSH assays has greatly facilitated the diagnosis of hyperthyroidism. Hyperthyroidism of any cause (except excess TSH production from the anterior pituitary) results in a lower than normal TSH. The reference range is 0.4–5.0 mIU/L depending on the method.

Other laboratory and isotope tests may include:

• Free thyroxine (T4) or free tri-iodothyronine (T3) assay, when there is strong clinical suspicion of hyperthyroidism but the TSH is high or high normal.

• Thyroid autoantibodies, including TSH receptor antibody. These are not routine but may be helpful in selected cases.

• Radioactive iodine uptake and/or thyroid scan. These tests are helpful in establishing the cause of hyperthyroidism, but are not part of the ED assessment.

Treatment

Mild hyperthyroidism does not require any treatment in the ED and may simply be referred to an appropriate outpatient clinic. Any features of thyroid storm (see below) mandate admission, as does any significant intercurrent illness. Atrial arrhythmias should be controlled by the use of β-blockers, aiming to achieve a rate of less than 100 beats per minute.

Ensure that all bloods have been collected first if thyroid-blocking drugs are to be commenced in the ED. High doses of thyroid-blocking drugs are often required to gain an initial response, after which the dose can be tapered.

Give carbimazole 10–45 mg daily bd or tds, or propylthiouracil 200–600 mg daily bd or tds initially, using the larger doses for more severe cases.⁴ It is preferable to discuss initiation of these agents with the physician who will be managing the patient after their discharge from the ED. Ninety per cent of patients will be controlled within weeks with these drugs.⁵ Treatment for 12–18 months will result in a long-term remission in 40–60% of patients with Graves’ disease.²

Thyroid storm

Aetiology

Thyroid storm occurs in about 1% of patients with hyperthyroidism. It usually occurs as an acute deterioration in a patient with poorly controlled or undiagnosed hyperthyroidism, precipitated by factors such as surgery, trauma, infection, radioiodine treatment, use of iodinated contrast, exogenous thyroxine ingestion or any other significant stressor.

The diagnosis is entirely clinical, as there is no test to differentiate a thyroid storm from thyrotoxicosis. The mortality rate if left untreated or if the diagnosis is missed is 90%, which with treatment is reduced to 10–15%. Death is usually due to cardiovascular collapse.

Differential diagnosis

The following differential diagnoses need to be considered:

• sepsis

• heat stroke

• malignant hyperthermia

• neuroleptic syndrome

• sympathomimetic ingestion

• drug withdrawal (including alcohol)

• phaeochromocytoma crisis.

Treatment

The treatment of thyroid storm is directed to blocking thyroid hormone synthesis and release, the peripheral effects of the thyroid hormones, and corticosteroids.

Prognosis

Mortality rates are high, at 10–75% despite treatment.

Apathetic hyperthyroidism

Patients with this condition are generally older, although it has been recorded in all age groups. The clinical picture is of a depressed mental state with cardiac complications, in particular cardiac failure. Weight loss is usually not significant and eye signs are rare. Most of the usual hyperkinetic manifestations of hyperthyroidism are absent. Treatment is as for standard hyperthyroidism.

HYPOTHYROIDISM

Aetiology, genetics, pathogenesis and pathology

Hypothyroidism results from undersecretion of thyroid hormone from the thyroid gland. Causes of primary hypothyroidism include iodine deficiency, chronic autoimmune thyroiditis (Hashimoto’s thyroiditis), congenital, surgical removal of the thyroid gland, post-radioactive iodine, thyroid gland ablation and external irradiation. A significant number of cases are idiopathic. Secondary causes of hypothyroidism include pituitary and hypothalamic disease.

Epidemiology

Iodine deficiency is the most common cause worldwide, whereas in areas of iodine sufficiency, autoimmune disease and hypothyoidism secondary to treatment of hyperthyroid disease are most common. The prevalence of hyperthyroidism in adults is of the order of 1.4% in women and <0.1% in men.⁶ Congenital hypothyroidism is rare, occurring in about 1:4000 births.

Clinical features

The symptoms of hypothyroidism are related to the duration and severity of hypothyroidism, the rapidity with which hypothyroidism occurs and the psychological characteristics of the patient. These are summarized in Table 11.3.3.

Table 11.3.3 Clinical features of hypothyroidism

Dry skin and cold intolerance

Coarse facial features

Enlarged tongue

Coarse brittle hair or loss of hair, loss of outer third of eyebrows

Periorbital oedema

Fatigue

Constipation

Weight gain/obesity

Memory and mental impairment, decreased concentration

Depression, personality changes

Yellow skin

Swelling of ankles

Irregular or heavy menses and infertility

Hoarseness

Myalgias

Goitre

Hyperlipidaemia

Delayed relaxation phase of tendon reflexes, ataxia

Sinus bradycardia (atrioventricular block, rare)

Cardiac failure, pericardial effusion (rare)

Hypothermia (uncommon)

A complete evaluation, including a comprehensive history, physical examination and appropriate laboratory evaluation, should be performed in every patient with a goitre. Patients with chronic thyroiditis have a higher incidence of other associated autoimmune diseases such as vitiligo, rheumatoid arthritis, Addison’s disease, diabetes mellitus and pernicious anaemia.

Clinical investigation and criteria for diagnosis

Laboratory evaluation

Perform a TSH assay as the primary test to establish the diagnosis of hypothyroidism. The reference range is 0.4–5.0 mIU/L depending on the method. Additional tests may include free thyroxine assay and thyroid autoantibodies. A combination of an elevated TSH and low free thyroxine is diagnostic.^3,^4,⁶ A patient may be hypothyroid with a TSH greater than twice the reference interval, but with a free thyroxine within the normal range. Subnormal thyroxine with a normal TSH can occur in secondary hypothyroidism.

Thyroid autoantibodies are positive in 95% of patients with autoimmune thyroiditis (Hashimoto’s thyroiditis). The high titres are of great value in making this specific diagnosis.

Other investigations

A thyroid scan and/or an ultrasound are useful if structural thyroid abnormalities are suspected.

Thyroid nodules are not uncommon with chronic thyroiditis and carry a small risk of thyroid cancer.

Treatment

Start thyroxine at 50–100 μg orally daily in adults under 60 years of age without evidence of ischaemic heart disease. Rapid commencement of full thyroid hormone replacement may cause myocardial ischaemia, from increased myocardial oxygen consumption without a corresponding increase in cardiac output. The initial daily replacement dose is therefore 25 μg thyroxine in the elderly and where there is suspicion of heart disease. This dose should remain unchanged for 3–4 weeks to allow a steady state to be reached. It is appropriate to start this in the ED, when a firm diagnosis has been made and appropriate follow-up arranged.

The dose of thyroxine is then increased in 25–50 μg increments until the optimum dose is reached, determined by clinical response and TSH level. Consider admission for any patient with coexistent unstable angina to monitor cardiac function. Any features of myxoedema coma (see below) also mandate admission.

Myxoedema coma

The clinical syndrome of altered mental state, features of hypothyroidism and hypothermia is referred to as myxoedema coma. There is usually a precipitating event such as infection, stroke, trauma, myocardial infarction or administration of drugs, particularly phenothiazines, phenytoin, amiodarone, propranolol or lithium that initiates this terminal decompensation phase of hypothyroidism.

The mortality for myxoedema coma remains up to 50% despite aggressive treatment.

Treatment

Treatment should commence on clinical suspicion.

Administration of thyroid hormones

Tri-iodothyronine

There is no consensus as to whether T3 or T4 replacement is preferable.^7,⁸ Intravenous T3 may give a faster clinical response in myxoedema coma, as it is the active form of the hormone. Give T3 as an initial i.v. bolus of 25–50 μg followed by 10–20 μg 8-hourly to a maximum of 60 μg per day. Alternatively, commence an infusion with a lower total dose of 20 μg per day, as large initial doses appear unnecessary for recovery and may in fact be harmful. Oral or nasogastric replacement of T3 is not recommended in the initial phase of management because of unreliable gastrointestinal absorption.

Thyroxine

The use of T4 is supported as the gradual delivery of T3 through the peripheral conversion of T4 is better tolerated and as the onset of action is more predictable. Give a 400–500 μg i.v. bolus (300 μg/m ²), followed by 50 μg i.v. daily until oral therapy is tolerated. Combined approaches are now also described.

Corticosteroids

These are given as there is impaired response to stress and the potential for coexistent adrenal insufficiency. Give hydrocortisone 100 mg i.v. 6-hourly.

General supportive measures

This requires correction of ventilatory, circulatory, temperature and metabolic abnormalities, and includes the use of warm humidified oxygen. Look for and treat any precipitating cause. Finally avoid sedative drugs and take care to avoid water overload.

HYPOADRENAL STATES

Aetiology, genetics, pathogenesis and pathology

Glucocorticoids act to produce multiple effects on metabolism, including gluconeogenesis, mobilization of fatty acids and amino acids, inhibiting the effects of insulin and ketogenesis. Glucocorticoids have anti-inflammatory effects related to the inhibition of production, and reduction of the effects of cytokines, and reduction of cell-mediated immunity. They also maintain the normal response of the vascular system to vasoconstrictors. Glucocorticoids also affect the regulation of body water by increasing free water excretion. This occurs by an increase in the glomerular filtration rate as well as inhibition of migration of water into cells. Aldosterone acts primarily to cause the reabsorption of sodium and the excretion of potassium and hydrogen ions.

The adrenals normally respond within minutes by elevating corticosteroid levels in response to any physiological or pathological stress. When glucocorticoid insufficiency is present such stressors may result in hypotension, shock and ultimately death if left untreated.

Primary adrenal insufficiency

Primary adrenal insufficiency is due to inability of the adrenal cortex to produce adequate levels of adrenal hormones. Hyponatraemia, hyperkalaemia, acidosis and elevated serum creatinine mainly occur due to aldosterone deficiency in primary adrenal insufficiency. Hypoglycaemia is related to cortisol deficiency. Hypercalcaemia occurs as a result of reduction in glomerular filtration rate as well as increased proximal tubular reabsorption of calcium. There may also be some increased mobilization of calcium from bone in patients with adrenal insufficiency.

Secondary adrenal insufficiency

Secondary adrenal insufficiency is due to failure of adequate adrenocorticotrophic hormone (ACTH) from the pituitay gland (Table 11.3.4). Hyponatraemia still occurs in secondary adrenal insufficiency, but is due to cortisol deficiency.^9,¹⁰

Table 11.3.4 Causes of adrenal insufficiency

Primary	Addison’s disease
	Surgical removal
	Infectious (TB, viral, fungal)
	Haemorrhage, including Waterhouse–Friedrichsen syndrome
	Congenital
Secondary	Exogenous steroid suppression (single most common cause of hypoadrenalism overall)
	Endogenous steroid (tumour)
	Pituitary failure

The majority of presentations of acute adrenal insufficiency occur as an exacerbation of a chronic disease process, where there is a malfunctioning adrenal system. Acute precipitating factors include sepsis, major trauma, surgery and a myocardial infarct.

Causes of primary or secondary adrenal insufficiency

The cause of 80% of primary adrenal insufficiency is autoimmune (Addison’s disease). Other causes include primary or secondary malignancy, infection such as tuberculosis, adrenal infarction or haemorrhage (Waterhouse-Friedrichsen syndrome) seen in meningococcaemia or severe sepsis, and drugs. Primary adrenal insufficiency also occurs in up to 20% of patients with AIDS. Up to 60% of patients with sepsis have a low baseline cortisol level, although fewer meet criteria of insufficiency on suppression testing.^11,¹²

The most common cause of secondary adrenal insufficiency is suppression of the adrenopituitary axis by long-term steroid therapy, although other causes include pituitary failure.

Clinical features

Suspect adrenocortical failure in any hypotensive patient when no apparent cause is found, particularly anyone who is unresponsive to fluid therapy. Orthostatic hypotension is almost always present. Other common features include abdominal pain, which may be severe, with vomiting.

Less obvious findings are weakness, anorexia, diarrhoea, postural syncope, mucocutaneous pigmentation/vitiligo (only with primary adrenal disease) and a dulled mental state.

Hypercalcaemia and/or hyperkalaemia may be the first sign of adrenal insufficiency in the critically ill patient.¹⁰ The other features of adrenal insufficiency may be masked by coexisting illness, but the possibility of adrenal insufficiency should always be considered in such cases.

Differential diagnosis

The diagnosis of adrenal insufficiency in the early stages is difficult as weakness, lethargy and gastrointestinal symptoms are common and non-specific. Consider adrenal insufficiency in any patients presenting with these symptoms when more common causes have been excluded.

Clinical investigation

Laboratory findings

The classical laboratory findings are hyponatraemia (due to sodium depletion and the intracellular movement of sodium), hypochloraemia and hyperkalaemia (due to acidosis and aldosterone deficiency). Mild hypercalcaemia (in 10–20% of cases) and a non-anion gap metabolic acidosis may be present. Hypoglycaemia if present is usually mild. However, all basic laboratory investigations may be within normal limits, even in the presence of an addisonian crisis.

Anti-adrenal antibodies are positive in 70% of patients with autoimmune adrenalitis.

Criteria for diagnosis 3

Baseline cortisol and ACTH levels should be taken prior to treatment. The normal reference range for cortisol is 200–650 nmol/L. ACTH levels should normally be <50 ng/L, although interpretation needs to take into account the time of day the sample is taken. ACTH should be high in primary adrenal disease and low in pituitary disease.

The Synacthen® stimulation test is the definitive test and may be required if the initial test results are not diagnostic, usually performed as an inpatient. Synacthen® 250 μg is administered intramuscularly and cortisol levels are taken at baseline, 30 min and 60 min. A baseline or post-Synacthen® cortisol level of >550 nmol/L is considered normal.

Treatment

Corticosteroid replacement

Do not delay treatment awaiting confirmatory results if acute adrenal insufficiency is suspected.

Give immediate corticosteroid replacement with either intravenous hydrocortisone or dexamethasone. Dexamethasone is recommended when the diagnosis has not been confirmed by laboratory investigations, as it does not interfere with the cortisol assay. Give 10 mg dexamethasone i.v. stat followed by 4 mg i.v. 8-hourly. Alternatively, give hydrocortisone in a dose of 250 mg stat followed by 100 mg i.v. 6-hourly.

Fluid replacement therapy

Give normal saline 1 L stat, then titrated to response, although the total volume deficit is rarely greater than 10% body weight. Intravenous dextrose should be given at the same time, either separately or as 5% dextrose in normal saline to avoid hypoglycaemia.

General supportive measures

General supportive measures include treatment of hypoglycaemia and other electrolyte replacement abnormalities, although most will be corrected with saline rehydration alone. Mineralocorticoid replacement is usually not necessary in the acute crisis if salt and water replacement is adequate.

Once the crisis has been successfully treated it is important to investigate and manage the cause and develop a maintenance regime.

Prognosis

The patient may die with acute adrenal insufficiency if the diagnosis is not made. When the diagnosis is suspected and treatment is early, the outcome is favourable depending on the nature of any precipitating illness.

Response to severe illness

The normal response to severe illness should see cortisol levels rising to at least 500 nmol/L. States of ‘relative adrenal insufficiency’ are described where glucocorticoid administration diminishes or even eliminates the requirements for vasopressor agents, even though measured cortisol levels are normal or close to normal.¹¹ There is no concensus on what constitutes ‘normal’ cortisol levels in severe illness.

Up to 60% of patients in sepsis may have some degree of adrenal insufficiency depending upon the threshold cortisol level used.¹² Moreover, it appears that it is the delta cortisol rather than the basal cortisol level that is associated with clinical outcome.¹³ Repeat adrenal function testing is indicated in patients with severe illness who remain unstable or who fail to improve with aggressive supportive therapy.¹⁴

The use of hydrocortisone has been recommended in septic shock after a 250 μg Synacthen® stimulation test.¹⁵^–¹⁷ This should continue for a week if adrenal insufficiency is confirmed.