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