• Neuroglycopenic – resulting from inadequate cerebral glucose delivery (Table 4.3). Specific symptoms vary by age, duration of diabetes, severity of the hypoglycaemia and the speed of the decline. The symptoms in a particular individual may be similar from episode to episode, but are not necessarily so and may be influenced by the speed at which glucose levels are dropping, as well as the previous incidence of hypoglycaemia.

Table 4.3 Autonomic, neuroglycopenic and non-specific symptoms and signs in acute hypoglycaemia

Under experimental conditions, adrenergic activation occurs at a higher plasma glucose concentration than the level at which cerebral function becomes impaired (2.7 mmol/L). Thus, the patient is often alerted to the falling plasma glucose concentration by adrenergic activation and is usually able to take corrective action.

Treatment of insulin-induced hypoglycaemia

Grade 1–2 hypoglycaemia

The blood glucose level can usually be raised to normal within minutes with 15–20 g carbohydrate – overtreatment should be avoided if at all possible. Insulin-treated patients are advised to carry dextrose tablets or Lucozade at all times. At the onset of symptoms, patients should take:

• 2–4 dextrose tablets

• 2 teaspoonfuls of sugar (10 g), honey or jam (ideally in water), or

• a small glass of carbonated sugar-containing soft drink.

If there is no improvement within 5–10 min, the treatment should be repeated. If the next meal is not imminent, a snack (e.g. biscuit, sandwich, piece of fruit) should be eaten to maintain blood glucose. Over-treatment should be avoided if possible.

Grade 3–4 hypoglycaemia

Friends, colleagues or relatives may recognize the development of hypoglycaemia before patients themselves. A subtle change in appearance or behaviour may prompt a third party to encourage oral carbohydrate consumption. Unfortunately, cognitive dysfunction may lead to a negative or even hostile response. If the level of consciousness falls, it often becomes hazardous to try forcibly to administer carbohydrate by mouth. Alternatives include:

• Buccal glucose gel. Proprietary thick glucose gels (e.g. Glucogel, formerly known as Hypostop) or honey (with variable efficacy) can be smeared on the buccal mucosa.

• Glucagon. Parenteral glucagon (1 mg = 1 unit) can be given by intravenous, subcutaneous or, most reliably and conveniently, intramuscular injection. Glucagon is a hormone that rapidly counters the metabolic effects of insulin in the liver, causing glycogenolysis and release of glucose into the blood. Glucagon can raise the glucose by 3–6 mmol/L within minutes of administration.

Tip box

Glucagon is unsuitable and ineffective in starved patients, particularly in patients with a history of alcohol abuse.

Glucagon comes in a glucagon emergency rescue kit, which includes tiny vials containing 1 mg, the standard adult dose. The glucagon in the vial is a lyophilized pellet: it must be reconstituted with 1 ml sterile water, which is included in the ‘kit’. Relatives or friends can learn how to reconstitute and administer glucagon, and this should bolster confidence when dealing with a patient prone to recurrent, severe hypoglycaemia. If glucagon is ineffective within 10–15 min, intravenous dextrose should be administered.

Tip box

Intramuscular glucagon may be administered by relatives or friends to hypoglycaemic patients.

• Intravenous glucose. Administer 25 mL 50% dextrose (or 100 mL 20% dextrose) into a large vein. If a person is unconscious, has had seizures, or has an altered mental status and cannot receive oral glucose gel or tablets, emergency personnel should establish a peripheral or central intravenous line and administer a solution containing dextrose and saline. Dextrose 25% and 50% are heavily necrotic owing to their hyperosmolarity, and should be given only through a patent intravenous line – any infiltration can cause tissue necrosis. Thrombophlebitis is also a well-recognized complication of intravenous delivery.

Hypertonic (50%) dextrose must be administered into a large vein in order to avoid extravasation.

Recovery from hypoglycaemia may be delayed if:

• the episode of hypoglycaemia has been prolonged or severe

• an alternative/additional cause for impairment of consciousness (e.g. stroke, drug overdose) coexists

• the patient is postictal (seizure caused by hypoglycaemia).

If the development of cerebral oedema is suspected, computed tomography of the brain should be undertaken and the adjunctive treatment considered: intravenous dexamethasone (4–6 mg 6-hourly) or mannitol. However, evidence for the efficacy of these drugs, or for other measures such as controlled hyperventilation, is poor.

Insulin overdose

Occasionally, patients present having deliberately administered an excessive dose of insulin with the intent of self-harm. It is usually possible to treat the resulting hypoglycaemia with a continuous infusion of 5% or 10% dextrose. Psychiatric assessment is required after recovery. Occasionally, severe, prolonged hypoglycaemia may result in permanent cognitive damage, personality change or chronic behavioural difficulties. The potential for neuronal damage resulting from severe recurrent hypoglycaemia is a particular concern in young children.

Insulin species/type and risk of hypoglycaemia

In the UK, there was intense debate about the effect of insulin species in relation to warning symptoms of hypoglycaemia. The issue arose from complaints from a small number of patients that, on changing from animal to human sequence insulin, symptoms were reduced in intensity predisposing to recurrent hypoglycaemia. This loss of hypoglycaemic awareness cannot be explained on the basis of differences in pharmacokinetics or the presence of high titres of anti-insulin antibodies.

Alternative causes of hypoglycaemia must always be excluded. However, it has been accepted that the patient’s views should be respected; a request to change insulin type should be treated sympathetically.

Behavioural problems specific to type 1 diabetes

Idiopathic ‘brittle diabetes’

This term is well known to most professionals involved with the care of diabetes. Disruptive episodes of hypoglycaemia may alternate with recurrent ketoacidosis leading to repeated hospitalization. This leads to an enormous amount of attention on the individual concerned. The patients are typically females in their teens with psychosocial difficulties. The symptoms are often associated with menstrual irregularities.

No convincing evidence has emerged in favour of an intrinsic difference in the metabolism of these individuals. There is anecdotal evidence of astonishing degrees of deliberate manipulation that has been known to mislead many well-meaning and experienced professionals. The long-term outlook is poor for these patients; some die from acute metabolic emergencies or suicide. Attempts can be made to alter this self-destructive behaviour pattern, but the problem often remains resistant to reasoned support.

Considerable difficulties in glycaemic control can occur as a result of a number of problems including delayed gastric emptying (gastroparesis) (see p. 18), drug interactions (e.g. β-blockers, steroids) and problems with insulin absorption.

Factitious remission of type 1 diabetes

There are rare reports of factitious ‘remission’ of type 1 diabetes. In this situation, patients claim that insulin requirements have fallen dramatically and spontaneously. Uncommon organic causes of increased insulin sensitivity (e.g. hypothyroidism, adrenal insufficiency) must be excluded.

Hypoglycaemia by proxy

This is a particularly disturbing but rare situation in which a patient (usually a child) is subjected to deliberate hypoglycaemia by parents or carers; fatalities have been recorded.

Type 2 diabetes

Most of the research into hypoglycaemia has looked at hypoglycaemia in the insulin-deficient type 1 diabetic population. The occurrence of hypoglycaemia in the treatment of type 2 diabetes is well recognized, but is more protean in nature, having different risk factors and clinical features according to the nature of the antihyperglycaemic therapy, the extent of the insulin secretory deficit and the duration of diabetes.

The most common cause of hypoglycaemia in type 2 diabetes, resulting in significant physical and psychological morbidity, is iatrogenic, occurring with the use of insulin secretagogues (particularly sulphonylureas) and insulin therapy. These may overwhelm the normal defences that should protect against a significant fall in plasma glucose concentration, primarily by preventing a fall in circulating insulin. Risk of severe hypoglycaemia is further increased by any defects in the other systems for maintaining glucose concentrations. For example, defects in glucagon responses to hypoglycaemia develop in type 2 diabetes along with defects in the other stress responses. Specific therapies may worsen these defects; for example, sulphonylurea therapy sustains intrapancreatic insulin levels during hypoglycaemia, which may further impair glucagon responses.

Risk factors for individual episodes of hypoglycaemia in patients with type 2 diabetes include behavioural, physiological and therapeutic factors. The most common behavioural factor that precipitates individual episodes of severe hypoglycaemia is missed or irregular meals. Other lifestyle factors include alcohol, exercise and incorrect use of glucose-lowering medication (dose/timing).

Therapeutic/physiological factors associated with increased risk include older age, duration of diabetes, presence of co-morbidities, renal impairment, loss of residual insulin secretion, defective counter-regulation and loss of awareness of hypoglycaemia. The use of other medications may also increase risk.

Patient age also affects subjective awareness of hypoglycaemia. In the elderly, neuroglycopenic symptoms specifically related to articulation and coordination, which include unsteadiness, blurred or double vision, lack of coordination and slurred speech, are more common. There are experimental data to show that the adrenergic symptoms of hypoglycaemia decline with increasing age, whereas the tendency for cognitive dysfunction in hypoglycaemia increases.

Time of day is also important – even in the absence of pharmacological therapy, the lowest plasma glucose level of the day is just before the evening meal and unsuspected hypoglycaemia can occur at this time once drug therapy is started. Intensification of treatment targets will increase the risk of severe hypoglycaemia, although this effect will depend on the nature of the treatment used and the degree of insulin deficiency in the patient.

In addition, in type 2 diabetes hypoglycaemia has also been suggested as a private experience that is often not discussed with health-care providers. Hypoglycaemia may be a much greater burden for patients than health professionals are aware. Type 2 patients reported in a recent UK survey that they often received very little information and guidance from health professionals regarding adverse effects of their glucose-lowering regimens.

In patients on lifestyle adjustment and/or insulin-sensitizing treatments, the risk of hypoglycaemia is negligible. Based on patient reporting, the UK Prospective Diabetes Study (UKPDS) 73 showed rates of 0.1% and 0.3% for lifestyle and metformin, respectively, in patients receiving diet alone or monotherapy for 6 years from diagnosis. The recent Diabetes Outcome Progression Trial (ADOPT) reported rates of around 10% in patients on insulin sensitizers (metformin or a thiazolidinedione) over the 5 years of treatment (again all self-reported). Severe episodes were reported in very few patients (0.1%) on either treatment. Patients are more at risk of hypoglycaemia when an insulin sensitizer is combined with insulin or insulin secretagogues.

With the increasing drive for more strict glucose control in type 2 diabetes and new therapies that may carry different risks for hypoglycaemia from established therapies, a review of the risks of hypoglycaemia in type 2 diabetes is appropriate.

Tip box

Severe sulphonylurea-induced hypoglycaemia is a medical emergency, requires admission to hospital and has a high case-fatality rate.

Risk factors for severe sulphonylurea-induced hypoglycaemia

Hypoglycaemia rates with the third-generation sulphonylureas (e.g. glimepiride), second-generation sulphonylureas (glipizide and gliclazide) and the metiglinides (e.g. repaglinide and nateglinide) appear to be lower than those with glibenclamide and chlorpropamide. This is thought to be related partly to duration of action, but there may be other contributory factors. For example, agents predominantly excreted via the kidney (e.g. glibenclamide) should be avoided in renal impairment and in the elderly. There is also some evidence for differential effects on insulin sensitivity.

The risk of hypoglycaemia in patients taking an α-glucosidase inhibitor or thiazolidinedione appears to be low, but this risk is increased significantly if these drugs are taken along with a sulphonylurea.

Mild symptomatic hypoglycaemia is not reported to have any serious clinical effects, apart from the potential for inducing defects in counter-regulatory responses and impaired awareness to subsequent hypoglycaemia. Nevertheless, people with diabetes are fearful of hypoglycaemia and even clinically trivial events may be sufficient to inhibit concordance with therapy.

Tip box

Although, all sulphonylureas have the potential to cause severe hypoglycaemia, long-acting sulphonylureas, such as chlorpropamide and glibenclamide, are particularly liable to cause severe hypoglycaemia.

Rates of hypoglycaemia with insulin vary according to the regimen and the stage of evolution of the person’s diabetes. In the UKPDS, patients who were newly diagnosed at the start of the study and randomized to insulin therapy reported ‘any’ hypoglycaemia rates of around 33% at year 1 and around 43% at year 10. Corresponding rates for severe episodes (defined as episodes requiring third-party help or medical intervention) were approximately 1.2% and 2.2%, respectively. In contrast, there is also some evidence to suggest that the frequency and severity of hypoglycaemia reduces with time as β-cell function deteriorates.

Newly emerging therapies based around enhancement of incretin action result in improved glycaemic control through a variety of mechanisms. The incretin, glucagon-like peptide (GLP)-1, released from the small intestine after eating, enhances insulin responses to glucose, as well as suppressing glucagon postprandially. The glucose-lowering effect of GLP-1 analogues and gliptins are glucose-dependent and therefore the hypoglycaemic risk of these agents appears much less.

Management

Recurrent symptoms suggestive of hypoglycaemia should prompt a reduction in dose or withdrawal of the medication responsible. Patients with severe sulphonylurea-induced hypoglycaemia should be admitted promptly to hospital; relapse following initial resuscitation with oral or intravenous glucose may necessitate prolonged infusions of dextrose. Delivery of an intravenous bolus of dextrose – a potent insulin secretagogue – will stimulate further insulin release, especially in patients with relatively well-preserved β-cell function. This predictable consequence of treatment, combined with the long duration of action of drugs such as chlorpropamide and glibenclamide, explains the tendency for hypoglycaemia to recur.

Tip box

Relapse after resuscitation is common in severe sulphonylurea-induced hypoglycaemia.

Treatment of hypoglycaemia in type 2 diabetes

• Intravenous dextrose. This remains the mainstay of therapy; it is well recognized that continuous infusions of 5% or 10% dextrose may be required for several days.

• Glucagon. This is less likely to work in type 2 diabetes as hepatic glycogen stores are usually very low when the patient presents with hypoglycaemia. In addition, glucagon also stimulates endogenous insulin release.

The antihypertensive agent, diazoxide, and the somatostatin analogue, octreotide, offer a more direct approach by inhibiting stimulated endogenous insulin secretion; these drugs have been used successfully as adjuncts to intravenous dextrose. However, neither is licensed for this indication in the UK.

• Diazoxide. This drug antagonizes the actions of sulphonylureas by opening adenosine triphosphate (ATP)-sensitive potassium channels in the membranes of islet β-cells. However, the drug is associated with adverse cardiovascular effects, including tachycardia and orthostatic hypotension, which may be hazardous particularly in elderly patients with a compromised vasculature or impaired baroreceptor reflexes.

• Octreotide. This has been shown to be an effective and well-tolerated agent for the prevention of sulphonylurea-induced hypoglycaemia under controlled experimental conditions. However, clinical experience for this indication remains very limited.

• Mannitol and dexamethasone have been recommended for cerebral oedema; however, the evidence base remains poor.

As high plasma insulin levels increase the transport of potassium into cells, serum potassium levels should always be monitored and intravenous supplements administered if hypokalaemia develops.

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication in type 1 diabetic patients. DKA results from an absolute shortage of insulin; in response, the body switches to burning fatty acids and producing acidic ketone bodies, which cause most of the symptoms and complications.

DKA may be the first symptom of previously undiagnosed diabetes, but it may also occur in known diabetics for a variety of reasons, such as poor compliance with insulin therapy or intercurrent illness. Vomiting, dehydration, deep gasping breathing, confusion and occasionally coma are typical symptoms. DKA is diagnosed with blood and urine tests; it is distinguished from other, rarer forms of ketoacidosis by the presence of high blood sugar levels.

DKA can affect patients in any age group. In some published series, female patients predominate. A small subgroup, predominantly females under the age of 20 years, may present with multiple episodes. Many episodes of DKA are avoidable with appropriate early action.

Definition

The cardinal biochemical features of DKA are:

• hyperketonaemia – glucose and ketones in urine; fingerprick blood ketones > 3.0 mmol/L

• metabolic acidosis – pH < 7.3; bicarbonate < 15 mmol/L

• hyperglycaemia – plasma glucose > 11 mmol/L.

Mortality

DKA was first described in 1886 and, until the introduction of insulin therapy in the 1920s, it was almost universally fatal. Despite adequate and timely treatment, DKA still carries a mortality rate of approximately 3–4%, but varies between centres. Although a number of DKA-related deaths are the inevitable consequence of associated conditions such as overwhelming infection or myocardial infarction, others are still potentially preventable; delays in presentation or diagnosis and errors in management remain important factors.

Mechanism

DKA arises because of absolute lack of insulin in the body. The lack of insulin and corresponding excess of glucagon leads to increased release of glucose by the liver from glycogen through gluconeogenesis. High glucose levels spill over into the urine, taking water and solutes (such as sodium and potassium) along with it in a process known as osmotic diuresis. Renal gluconeogenesis is also enhanced in the presence of acidosis. Glucose disposal by peripheral tissues such as muscle and adipose tissue is reduced by deficiency of insulin while raised plasma levels of catabolic hormones and fatty acids induce tissue insulin resistance. This whole process can lead to significant dehydration.

The absence of insulin leads to the release of free fatty acids from adipose tissue. Fatty acids are the principal substrate for hepatic ketogenesis and are converted to coenzyme A (CoA) derivatives prior to transportation into the mitochondria by an active transport system (the carnitine shuttle). In DKA, the hormonal imbalance strongly favours entry of fatty acids into the mitochondria and the preferential formation of ketone bodies:

• acetoacetate

• 3-hydroxybutyrate.

Within the mitochondria, fatty acyl-CoA undergoes β-oxidation resulting in the formation of acetyl-CoA, which is then oxidized completely in the tricarboxylic acid cycle, utilized in lipid synthesis, or partially oxidized to ketone bodies. Acetone is formed by the spontaneous decarboxylation of acetoacetate. Although acetone concentration is increased in ketoacidosis, it does not contribute to the metabolic acidosis. Acetone is highly fat-soluble and is excreted slowly via the lungs.

In the absence of insulin-mediated glucose delivery, β-hydroxybutyrate can serve as an energy source for the brain, and is possibly a protective mechanism in case of starvation. The ketone bodies have a low pH and therefore cause a metabolic acidosis. The body initially buffers this with the bicarbonate buffering system, but this is quickly overwhelmed and other mechanisms such as hyperventilation compensate for the acidosis, to lower the blood carbon dioxide levels. This hyperventilation, in its extreme form, may be observed as ‘Kussmaul respiration’. In addition, ketones participate in osmotic diuresis and lead to further electrolyte losses.

Ketone body disposal

With the exception of the liver, most tissues have the capacity to utilize ketone bodies. Oxidation of ketone anions during treatment neutralizes the acidosis by the generation of equimolar amounts of bicarbonate ions. Excretion of ketone bodies via the kidney and lung is also important. However, urinary ketone excretion exacerbates the loss of cations such as sodium and potassium.

In various situations, such as infection, insulin demands rise but are often not matched because the patient fails to increase their insulin dose. Blood sugars rise, dehydration ensues, and resistance to the normal effects of insulin increases further by way of a vicious circle.

As a result of the above mechanisms, the average adult patient with DKA has a total body water shortage of about 6 L (or 100 mL/kg). In addition, there are substantial losses of sodium, potassium, chloride, phosphate, magnesium and calcium.

Cause

DKA occurs most frequently in those who already have diabetes, although it may be the first presentation in someone who was not previously known to be diabetic. There is often a particular underlying problem that has led to the DKA episode. This may be intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction, stroke or the use of recreational drugs. Young patients with recurrent episodes of DKA may have an underlying eating disorder, or may be using insufficient insulin for fear that it will cause weight gain. In 30–40% of cases, no cause for the DKA episode is found.

Prevention

Attacks of DKA can be prevented in known diabetic patients by adherence to ‘sick day rules’; these are clear-cut instructions to patients how to treat themselves when unwell. Instructions include advice on:

• how much extra insulin to take when glucose levels appear uncontrolled

• an easily digestible diet rich in carbohydrates and salt

• means to suppress fever and treat infection

• recommendations when to call for medical/nursing help.

Signs and symptoms

The symptoms of an episode of diabetic ketoacidosis usually evolve over the period of about 24 hours. Predominant symptoms are nausea and vomiting, pronounced thirst, excessive urine production and, particularly in the young, abdominal pain that may be severe. Those who measure their glucose levels themselves may notice hyperglycaemia. In severe DKA, breathing becomes laboured and of a deep, gasping character – Kussmaul respiration. Coffee ground vomiting (vomiting of altered blood) occurs in a minority of patients; this tends to originate from erosion of the oesophagus. In severe DKA, there may be confusion, lethargy, stupor or even coma.

On physical examination there is usually clinical evidence of dehydration, such as a dry mouth and decreased skin turgor. If the dehydration is profound enough to cause a decrease in the circulating blood volume, tachycardia and low blood pressure may be observed. Often, a ‘ketotic’ odour is present, which can be described as ‘fruity’ and is often compared to the smell of pear drops. If Kussmaul respiration is present, this is reflected in an increased respiratory rate. The abdomen may be tender to the point that an acute abdomen may be suspected, such as acute pancreatitis, appendicitis or gastrointestinal perforation.

Eruptive xanthomata and lipaemia retinalis are recognized complications that respond to treatment of the ketoacidosis. Serum transaminases and creatine phosphokinase may be non-specifically raised in DKA.

Diagnosis

Investigations

Diabetic ketoacidosis may be diagnosed when the combination of hyperglycaemia, acidosis and ketones on urinalysis is demonstrated (Table 4.4). Arterial blood gas measurement is usually performed to confirm the acidosis. Subsequent measurements taken to monitor progress may be taken from a vein, as there is little difference between the arterial and the venous pH.

Table 4.4 Initial management of a patient with suspected diabetic ketoacidosis

History

Initially, brief and relevant, including:

• Previous episodes of DKA

• Potential precipitating causes

• Co-morbid conditions

Physical examination Rapid but thorough assessment for:

• Signs of dehydration

• Level of consciousness

• Metabolic acidosis (Kussmaul respiration)

• Systemic hypotension

• Hypothermia

• Gastric stasis

• Precipitating conditions (e.g. pneumonia, pyelonephritis)

Biochemical assessment Confirm diagnosis by bedside measurement of:

• Blood glucose (by glucose–oxidase reagent test strip)

• Urinary ketones (Ketostix)

Venous blood is withdrawn for laboratory measurement of:

• Glucose

• Urea (BUN)

• Electrolytes (sodium, potassium ± chloride)

• Complete blood count

• Blood cultures

An arterial blood sample (corrected for hypothermia) is taken for:

Repeat laboratory measurement of blood glucose, electrolytes, urea, gases at 2 and 6 h

Other investigations As indicated by the circumstances:

• Chest X-ray

• Microbial culture of urine, sputum

• ECG

• Sickle cell test

BUN, blood urea nitrogen; DKA, diabetic ketoacidosis; ECG, electrocardiography; PCO₂, partial pressure of carbon dioxide; PO₂, partial pressure of oxygen.

In addition to the above, blood samples are usually taken to measure urea and creatinine (markers of renal function, which may be impaired in DKA as a result of dehydration) plus electrolytes. Furthermore, markers of infection (complete blood count, C-reactive protein (CRP)) and acute pancreatitis (amylase and lipase) may be measured. Given the need to exclude infection, chest radiography and urinalysis are usually performed. However, DKA is associated with the release of various cytokines that lead to increased markers of inflammation (increased white cell count and CRP) even in the absence of infection.

If, as a result of confusion, recurrent vomiting or other symptoms, cerebral oedema is suspected, computed tomography of brain should be performed to assess its severity and to exclude other problems such as stroke.

• Thromboembolism – if the patient is elderly or very dehydrated, subcutaneous low molecular weight heparin should be considered.

Criteria

DKA is distinguished from other hyperglycaemic diabetic emergencies by the presence of large amounts of ketones in blood and urine, and marked metabolic acidosis. Hyperosmolar non-ketotic state (HONK) or hyperglycaemic hyperosmolar syndrome (HHS) is much more common in type 2 diabetes and features increased plasma osmolarity (above 350 mosmol/kg) due to profound dehydration and concentration of the blood. Mild acidosis and ketonaemia may occur in HONK, but not to the extent observed in DKA. There is a degree of overlap between DKA and HONK, as in DKA the osmolarity may also be increased. In most situations it is relatively easy to classify a case as either DKA or HONK.

Ketoacidosis is not always the result of diabetes. It may also result from alcohol excess and from starvation; in both states the glucose level is normal or low. Metabolic acidosis may occur in diabetic patients for other reasons, such as poisoning with ethylene glycol or paraldehyde.

A 2006 American Diabetes Association statement (for adults) categorized DKA into one of three stages of severity:

• Mild: blood pH mildly decreased to between 7.25 and 7.30 (normal 7.35–7.45); serum bicarbonate decreased to 15–18 mmol/L (normal above 20 mmol/L); the patient is alert

• Moderate: pH 7.00–7.25, bicarbonate 10–15 mmol/L; mild drowsiness may be present

• Severe: pH below 7.00, bicarbonate below 10 mmol/L; stupor or coma may occur.

Metabolic acidosis has a number of potential serious pathological effects:

• exert a negative inotropic effect on cardiac muscle

• exacerbate systemic hypotension via peripheral vasodilatation

• increase the risk of ventricular arrhythmias

• induce respiratory depression with pH < 7.0

• exacerbate insulin resistance.

DKA usually presents with an anion gap acidosis (anion gap typically 25–35 mmol/L). A wide variety of acid–base disturbances have been reported. Some causes are listed shown in Table 4.5. The anion gap is increased when plasma:

Table 4.5 Causes of anion gap acidosis

Potassium is not included because the plasma level of this ion may be altered significantly by acid–base disturbances. Proteins, phosphate, sulphate and lactate ions account for the normal anion gap of about 10–15 mmol/L. When the anion gap is increased, measurement of the plasma concentration of specific anions (e.g. ketone bodies, lactate) may confirm the aetiology of the acidosis.

Management

Hyperglycaemia

Delays in initiating therapy may be disastrous and the diagnosis should be considered in any unconscious or hyperventilating patient.

The main aims in the treatment of diabetic ketoacidosis are replacing the lost fluids and electrolytes while suppressing the high blood sugars and ketone production with insulin (Table 4.6). Admission to an intensive care unit or similar high-dependency area for close observation may be necessary.

• A urinary catheter should be inserted if the patient is oliguric.

• Patients with hyperkalaemia should have a cardiac monitor in order to monitor for peaked T waves.

• Patients who are drowsy or have a reduced conscious level should have a nasogastric tube inserted to avoid aspiration.

Table 4.6 Guidelines for the management of severe diabetic ketoacidosis in adults

Fluids and electrolytes

Volumes:

• 1 L/h × 3, thereafter adjusted according to requirements

Fluids:

• Isotonic (‘normal’) saline (150 mmol/L) is routine

• Hypotonic (‘half-normal’) saline (75 mmol/L) if serum sodium exceeds 150 mmol/L (no more than 1–2 L – consider 5% dextrose with increased insulin if marked hypernatraemia)

• 5% dextrose 1 L 4–6-hourly when blood glucose has fallen to 15 mmol/L (severely dehydrated patients may require simultaneous saline infusion)

• Sodium bicarbonate (100 mL) as 1.26% solution * (or 8.4% solution if large vein cannulated) if pH < 7.0 (with extra potassium – see text)

Potassium:

• No potassium in first 1 L unless initial plasma potassium level < 3.5 mmol/L

• Thereafter, add following dosages to each 1 L of fluid, If plasma K⁺:

• < 4.0 mmol/L, add 40 mmol KCl (severe hypokalaemia may require more aggressive KCl replacement)

• 3.5–5.5 mmol/L, add 20 mmol KCl

• > 5.5 mmol/L, add no KCl

Insulin By continuous intravenous infusion:

• A bolus of 20 units intravenously may be given while an insulin infusion is being prepared

• Give 6 units/h initially until blood glucose level has fallen to 15 mmol/L. Thereafter, adjust rate (1–4 units/h usually) during dextrose infusion to maintain blood glucose concentration at 5–10 mmol/L until patient is eating again

Other points

• Search for and treat precipitating cause (e.g. infection, myocardial infarction)

• Hypotension usually responds to adequate fluid replacement

• CVP monitoring in elderly patients or if cardiac disease present

• Pass nasogastric tube if conscious level impaired to avoid aspiration of gastric contents

• Urinary catheter if conscious level impaired or no urine passed within 4 h of start of therapy

• Continuous ECG monitoring may warn of hyperkalaemia or hypokalaemia (plasma potassium should be measured at 0, 2 and 6 h – or more often as indicated)

• Adult respiratory distress syndrome (ARDS) – mechanical ventilation (100% oxygen, IPPV); avoid fluid overload

• Mannitol (up to 1 g/kg intravenously) if cerebral oedema suspected. Dexamethasone as alternative (induces insulin resistance). Consider cranial CT to exclude other pathology (e.g. cerebral haemorrhage, venous sinus thrombosis)

• Treat specific thromboembolic complications if they occur

• Meticulously updated clinical and biochemical record using a purpose-designed flow chart

CT, computed tomography; CVP, central venous pressure; DKA, diabetic ketoacidosis; ECG, electrocardiography; IPPV, intermittent positive-pressure ventilation.

^* 1.26% sodium bicarbonate (NaHCO₃) = 12.6 g NaHCO₃, 150 mmol each of Na⁺ and HCO₃⁻/L.

Fluid replacement

Despite a proportionally greater loss of body water, plasma sodium concentrations are usually normal or low (Table 4.7). However, in DKA, plasma electrolyte concentrations may be falsely depressed by grossly raised plasma lipid concentrations. Plasma should therefore be inspected for turbidity.

Table 4.7 Average electrolyte deficits in adults with diabetic ketoacidosis

Electrolyte	Deficit (mmol)
Sodium	500
Chloride	350
Potassium	300–1000
Calcium	50–100
Phosphate	50–100
Magnesium	25–50

The amount of fluid depends on the estimated degree of dehydration (Table 4.8). If dehydration is so severe as to cause hypovolaemic shock or a depressed level of consciousness, rapid infusion of saline is recommended to restore circulating volume. When the circulating volume has been restored, this should be followed by gradual correction of interstitial and intracellular fluid deficits. Overenthusiastic fluid replacement may lead to respiratory distress syndrome and/or cerebral oedema.

• Use sodium chloride 0.9% (see example, Table 4.9) – infusion rates will vary between patients; remember the risk of possible cardiac failure in elderly patients.

• If hypotension (systolic blood pressure < 100 mmHg) or signs of poor organ perfusion are present, consider use of colloid if increased rate of sodium chloride 0.9% does not restore circulating volume.

• Measure U&Es, venous bicarbonate and laboratory glucose at the end of hour 2 and hour 4.

Table 4.8 Assessment of hydration (over-estimation of dehydration is dangerous)

Degree of dehydration	Clinical signs
Mild, 3%	Only just clinically detectable
Moderate, 5%	Dry mucous membranes, reduced skin turgor
Severe, 8%	As above, plus sunken eyes, poor capillary return
+ Shock	May be severely ill with poor perfusion, thready rapid pulse (reduced blood pressure is not likely and is a very late sign)

Table 4.9 Initial fluid replacement

Fluid	Rate (mL/h)	Time (h)
0.9% sodium chloride 1 L	1000	1
0.9% sodium chloride 1 L with potassium chloride	500	2
0.9% sodium chloride 1 L with potassium chloride	500	2
0.9% sodium chloride 1 L with potassium chloride	250	4
0.9% sodium chloride 1 L with potassium chloride	250	4
0.9% sodium chloride 1 L with potassium chloride	250	4
0.9% sodium chloride 1 L with potassium chloride	125	8
Total	7 L	25

Tip box

Considerable care is required in elderly patients or those with cardiac disease; monitoring of CVP or pulmonary wedge pressure is strongly recommended in these circumstances.

Insulin

The aims of insulin treatment in DKA are:

• inhibition of lipolysis (and hence ketogenesis)

• inhibition of hepatic glucose production

• enhanced disposal of glucose and ketone bodies by peripheral tissues.

Some guidelines recommend a bolus of insulin of 0.1 unit insulin per kilogram of body weight. This may be administered immediately after the potassium level is known. Insulin administration can lead to dangerously low potassium levels (see below). In order to reduce the theoretical risk of cerebral oedema, some guidelines recommend delaying the initiation of insulin until 1 h after fluids have been started.

In adults, insulin can be given at rate of around 6 units per hour to reduce the blood sugar level and suppress ketone production. Guidelines differ as to what dose to use when blood sugar levels start falling; some recommend reducing the dose of insulin (to 3 units/h) once the glucose concentration falls below 14.0 mmol/L. Below this blood glucose level it is often useful to start a glucose/K/insulin infusion.

Blood glucose concentrations tend to fall more slowly during treatment in patients with higher levels of catabolic hormones caused by infection or other serious illnesses.

• Transfer to subcutaneous insulin. The first subcutaneous injection should comprise or include an appropriate dose of short-acting insulin. Precise recommendations are difficult to make. The subcutaneous insulin should continue to be administered for 30–60 min before the intravenous infusion is terminated to allow time for absorption of insulin from the subcutaneous depot, thereby avoiding transient insulinopenia.

• Intramuscular insulin. If intravenous insulin administration is impracticable for any reason, an intramuscular regimen can be used as a safe alternative. This begins with a bolus of 20 units short-acting insulin, followed by 6 units/h into the deltoid until blood glucose level has reached 15 mmol/L. Insufficient rehydration may cause erratic absorption of intramuscular injections, resulting in apparent insulin resistance.

Potassium

Potassium levels can fluctuate severely during the treatment of DKA, because insulin decreases potassium levels in the blood by redistributing it into cells. DKA leads to considerable total body potassium deficit (300–1000 mmol/L). As a result of acidosis, insulin deficiency and renal impairment plasma potassium levels are usually normal or high at presentation. However, potassium concentration will fall during treatment. Target potassium concentration is 4.0–5.0 mmol/L.

Tip box

Plasma potassium concentration is an unreliable indicator of whole-body potassium status.

There should be no potassium in the first litre unless known to be <3.5 mmol/L. Thereafter, add dosages below to each 1 L of fluid, as shown in Table 4.10.

Plasma potassium (mmol/L)	Potassium added (mmol)/L fluid)
< 3.5	40*
3.5–5.5	20
> 5.5	0

^* Severe hypokalaemia may require more aggressive replacement. Must be given in 1 L fluid; avoid infusion rates of potassium > 20 mmol/h.

Tip box

Check plasma potassium on admission, after 2 hours and then 4-hourly until the rate of fluid infusion is 8-hourly or slower.

Hypokalaemia increases the risk of dangerous irregularities in the heart rate.

Severe hypokalaemia complicating treatment of DKA is potentially fatal and is usually avoidable.

Bicarbonate

The administration of sodium bicarbonate solution rapidly to improve the blood pH remains controversial. There is little evidence to indicate that it improves outcome beyond standard therapy.

Administration of bicarbonate into the extracellular space is associated with a number of potentially serious adverse effects, particularly hypokalaemia, and may actually exacerbate intracellular acidosis. Bicarbonate ions (which cannot diffuse across cell membranes) combine with H⁺ ions extracellularly, producing carbonic acid which dissociates into water and carbon dioxide. The latter readily enters cells where the reverse reaction occurs, generating H⁺ (and bicarbonate ions) intracellularly.

Paradoxical acidosis of cerebrospinal fluid (the clinical significance of which is disputed), adverse effects on the oxyhaemoglobin dissociation curve and overshoot alkalosis are other unwanted effects. Concern has also been expressed about the potential for accelerating ketogenesis (and lactate generation) by increasing pH with bicarbonate. The fall in blood ketone body and lactate concentrations is delayed by sodium bicarbonate infusion.

The use of bicarbonate is therefore discouraged, although some guidelines recommend it for extreme acidosis (pH < 6.9), and smaller amounts for severe acidosis (pH 6.9–7.0).

Phosphate

There is always some depletion of phosphate, a predominantly intracellular ion. Plasma levels may be very low. There is no evidence that replacement has any clinical benefit and phosphate administration may lead to hypocalcaemia.

Care must be taken to avoid iatrogenic hypocalcaemia if phosphate replacements are administered.

Cerebral oedema

Cerebral oedema, which is the most dangerous complication of DKA, is probably the result of a number of factors (Table 4.11). Some authorities maintain that it is the result of over-vigorous fluid replacement, but the complication may develop before treatment has been commenced. It is more likely to occur in those with more severe DKA, in children, and in the first episode of DKA. Likely factors in the development of cerebral oedema are dehydration, acidosis, increased level of inflammation and coagulation. Together these factors lead to decreased blood flow to parts of the brain, which may then swell once fluid replacement is commenced. The swelling of brain tissue leads to raised intracranial pressure, which is reflected in a rising blood pressure and a falling heart rate, and ultimately herniation, where the swollen brain compresses vital structures in the brain stem, leading to death.

Table 4.11 Complications of diabetic ketoacidosis

Complication	Clinical findings
Cerebral oedema	This is unpredictable, occurs more frequently in younger children and newly diagnosed diabetics, and has a mortality rate of around 25%. Producing a slow correction of the metabolic abnormalities reduces the risk
Hypokalaemia	This is preventable with careful monitoring and management
Aspiration pneumonia	Use a nasogastric tube in semiconscious or unconscious patients
Gastric stasis	A succussion splash may be evident on abdominal examination
Adult respiratory distress syndrome	ARDS has been reported in patients with DKA, usually in patients under 50 years of age. Clinical features include dyspnoea, tachypnoea, central cyanosis and non-specific chest signs. Arterial hypoxia is characteristic and chest X-ray reveals bilateral pulmonary infiltrates. Management involves respiratory support with IPPV and avoidance of fluid overload
Thromboembolism	Thromboembolic complications can cause mortality in DKA as a consequence of: • dehydration • increased blood viscosity • increased coagulability DIC has also been reported as a rare complication. The role of routine anticoagulation has not been clearly established in DKA and in the absence of other risk factors is not generally recommended

Rhinocerebral mucormycosis Rarely, an aggressive opportunistic fungal infection develops in patients with DKA or other metabolic acidoses. The lesion arises in the paranasal sinuses and rapidly invades adjacent tissues (nose, sinuses, orbit and brain). Treatment comprises correction of acidosis, surgical excision of affected tissue and parenteral antifungal agents. The course is often fulminant and the condition carries a high mortality rate Rhabdomyolysis Increased plasma myoglobin and creatine kinase concentrations may occur in DKA. However, clinically important renal complications of rhabdomyolysis are uncommon. Acute renal failure caused by rhabdomyolysis may be somewhat more common in the diabetic hyperosmolar non-ketotic syndrome but is nonetheless a rare complication

DIC, disseminated intravascular coagulation; DKA, diabetic ketoacidosis; IPPV, intermittent positive pressure ventilation.

Cerebral oedema, if associated with coma, necessitates admission to intensive care, artificial ventilation and close observation. The administration of fluids should be slowed. The ideal treatment of cerebral oedema in DKA is not established, but intravenous mannitol and hypertonic saline (3%) are often used (as in some other forms of cerebral oedema) in an attempt to reduce the swelling.

Resolution

Resolution of DKA is defined as general improvement in the symptoms, such as the ability to tolerate oral nutrition and fluids, normalization of blood acidity (pH > 7.3) and absence of ketones in blood (< 1 mmol/L). Once this has been achieved, insulin may be switched to the usual subcutaneously administered regimen, 1 h after which the intravenous administration can be discontinued.

Tip box

An episode of DKA should prompt a thorough review of the precipitating events; re-education may be indicated.

In patients with suspected ketosis-prone type 2 diabetes, determination of antibodies against glutamic acid decarboxylase (GAD) and islet cells may aid in the decision whether to continue insulin administration long-term (if antibodies are detected), or whether to attempt treatment with oral medication as in type 2 diabetes.

The commonest causes of failure to respond to treatment for DKA are mechanical problems. These include the pump being inadvertently switched off, set at the wrong rate, or blockage of the delivery line. It is sound practice to cross-check (and record on the flow chart) the prescribed rate of insulin delivery against the volume infused each hour during treatment.

During treatment of DKA, there is increased conversion of 3-hydroxybutyrate to acetoacetate. Nitroprusside-based urine tests may therefore raise concerns that ketosis is either not resolving or is even worsening. A rising plasma bicarbonate concentration will allay such fears.

Counselling and follow-up

DKA is a life-threatening condition. It therefore demands a thorough exploration of the circumstances leading to the admission. There is often a need for re-education of the patient (and sometimes of health-care professionals). Re-emphasis of the ‘sick day rules’ may be required – in particular the importance of continuing insulin therapy. The problem of recurrent DKA in adolescents is often more problematic. The elderly patient with type 1 diabetes, particularly if intellectually impaired, or otherwise infirm or socially isolated, is also at risk of recurrent episodes.

All patients with DKA should be referred to the diabetes team on the day after admission.

The patient should not be discharged until biochemically normal, eating normally and established on subcutaneous insulin.

Diabetic hyperosmolar non-ketotic syndrome – hyperosmolar hyperglycaemic syndrome

Diabetic HONK syndrome is a characterized by:

• marked hyperglycaemia (plasma glucose often in excess of 50 mmol/L)

• profound dehydration with pre-renal uraemia

• depression of the level of consciousness; coma is well recognized.

It occurs in type 2 diabetes, is much less common than DKA, and is associated with a much higher mortality rate. The high mortality rate in part reflects the high incidence of serious associated disorders and complications. The preferred term used by the American Diabetes Association is hyperosmolar hyperglycaemic state (HHS).

Pathophysiology

HONK is usually precipitated by an infection or another acute illness. A relative insulin deficiency leads to a serum glucose level that is usually higher than 33 mmol/L and a resulting serum osmolarity that is greater than 350 mosmol/L. Due to an osmotic diuresis patients develop polyuria, which, in turn, leads to volume depletion, haemoconcentration and a further increase in blood glucose level. Unlike DKA, ketosis is absent. It is suggested that the hyperosmolar state and the presence of some plasma insulin suppresses lipolysis.

Clinical presentation

Patients with HONK are usually middle-aged or elderly. Black patients are more frequently represented in big series of hyperosmolar non-ketotic decompensation relative to their contribution to episodes of DKA. Up to two-thirds of cases occur in patients with previously undiagnosed type 2 diabetes.

Characteristic symptoms are:

• polyuria

• intense thirst

• gradual clouding of consciousness.

In the absence of vomiting, which is a prominent symptom of DKA, many patients drink large volumes of carbonated, glucose-containing drinks that only exacerbate thirst and hyperglycaemia. The symptoms may develop over several weeks. Coma and severe dehydration with arterial hypotension are common, and reversible focal neurological signs or motor seizures may occur. Many patients are in a moribund state when admitted to hospital.

The increasing haemoconcentration and volume depletion may result in:

• hyperviscosity and increased risk of thrombosis

• disordered mental functioning

• neurological signs, including focal signs such as sensory or motor impairments or focal seizures or motor abnormalities, such as flaccidity, depressed reflexes, tremors or fasciculations.

Diagnosis

The insidious nature of the condition often leads to delays in diagnosis. The hyperosmolar non-ketotic syndrome must be considered in the differential diagnosis of any patient presenting with otherwise unexplained impairment of consciousness or focal neurological signs, dehydration or shock.

• Urinalysis. This will reveal heavy glycosuria and a negative or perhaps ‘trace’ reaction with Ketostix.

• Blood chemistry. The diagnosis is confirmed by a markedly raised plasma glucose concentration. Pre-renal uraemia, a raised haematocrit and a mild leukocytosis are common. Depression of consciousness generally occurs when plasma osmolality exceeds around 340 mosmol/L. Although there is considerable interindividual variation, alternative causes of an impaired level of consciousness should be considered in patients whose osmolality is less marked (Table 4.12).

Table 4.12 Plasma osmolality

Plasma osmolality (the osmotic pressure exerted by a fluid across a membrane) can be measured in the laboratory (e.g. by freezing point depression) and estimated using the formula:
Plasma osmolality (mosmol/L) = 2 × (plasma Na⁺ + plasma K⁺) + plasma glucose + plasma urea
(where Na⁺, K⁺, glucose and urea are in mmol/L)
The values for Na⁺ and K⁺ are doubled to allow for their associated Cl⁻ anions.

Although total body sodium is reduced, plasma sodium concentration at presentation may be low, normal or high, depending on the degree of concomitant water deficit. The degree of dehydration is generally greater than in DKA. As in DKA, hypertriglyceridaemia and hyperglycaemia may falsely depress the sodium concentration.

Tip box

Plasma sodium concentrations may be depressed by hyperglycaemia or hypertriglyceridaemia.

Although renal impairment may lead to some retention of H⁺ ions, and hypotension may produce a degree of lactic acidaemia, plasma bicarbonate is usually above 15 mmol/L. Non-traumatic rhabdomyolysis may occasionally be severe enough to precipitate acute renal failure.