4: Acute metabolic complications

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Section 4 Acute metabolic complications

Diabetic ketoacidosis

Diabetic hyperosmolar non-ketotic syndrome – hyperosmolar hyperglycaemic syndrome

Lactic acidosis

Hypoglycaemia

Type 1 diabetes

Hypoglycaemia is the most-feared complication of therapy in insulin-treated patients. Unfortunately, iatrogenic hypoglycaemia is a common and serious hazard of treatment. It has a substantial clinical impact in terms of mortality, morbidity and quality of life. The risk of hypoglycaemia increases as glycaemic control is improved and in intensive insulin therapy it is the principal factor limiting the attainment of lower glycaemic targets.

The risk of severe hypoglycaemia is inversely related to glycaemic control.

Iatrogenic hypoglycaemia usually results from a mismatch between:

• supply of glucose for metabolic requirements (e.g. as a result of a missed meal)

• rate of utilization (e.g. an increase due to physical exercise)

• a relative excess of insulin leading to a fall in the circulating glucose concentration.

In the Diabetes Control and Complication Trial, the overall risk of severe hypoglycaemia was increased approximately 3-fold in the intensively treated group. This was observed despite strenuous efforts to exclude patients who were thought to be at high risk of hypoglycaemia. The relation between rate of severe hypoglycaemia and mean glycated haemoglobin (HbA1c) level was inverse and curvilinear. Factors predisposing to severe hypoglycaemia are presented in Table 4.1. However, in a significant proportion of hypoglycaemic episodes, a clear predisposing factor cannot be identified even with very careful scrutiny of the circumstances.

Table 4.1 Risk factors for severe hypoglycaemia

• History of severe hypoglycaemia

• History of symptomatic unawareness of hypoglycaemia

• Impaired counter-regulatory hormone responses

• Intensive insulin therapy

• Glycated haemoglobin within the non-diabetic range

• Long-duration type 1 diabetes

• Alcohol consumption

Asymptomatic hypoglycaemia is a contraindication to intensive insulin therapy.

In patients with type 1 diabetes, insulin levels reflect the absorption of exogenous insulin and do not fall as the plasma glucose levels fall.

Other causes of hypoglycaemia in insulin-treated patients are presented in Table 4.2. Their effects in individual patients are variable.

Table 4.2 Causes of recurrent hypoglycaemia in insulin-treated patients

Changes in insulin pharmacokinetics

• Change of anatomical injection site

• Development of renal impairment

• Effect of ambient temperature

• Effect of exercise on insulin absorption

• Change of insulin, e.g. human to quick-acting analogue (take analogue with meal rather than 30–40 min before)

Altered insulin sensitivity

• Acute resolution of insulin resistance postpartum

• Hypopituitarism or Addison’s disease

• Hypothyroidism

• Weight loss or calorie/carbohydrate restriction

• Resolution of drug-induced insulin resistance, e.g. withdrawal of steroid therapy

Others

• Recovery of partial endogenous insulin secretion (honeymoon period)

• Malabsorption syndrome, e.g. coeliac disease

• Gastroparesis due to autonomic neuropathy

• Severe liver disease

• Eating disorders (anorexia/bulimia)

The symptoms and signs of acute hypoglycaemia may be divided into two main categories:

• Autonomic (adrenergic) – arising from activation of the sympathoadrenal system (Table 4.3). During hypoglycaemia, the body normally releases adrenaline (epinephrine) and related substances. This serves two purposes:

1. the β-effect of adrenaline is responsible for the typical symptoms of hypoglycaemia (tremor, sweating, palpitations, etc.) warning the patient that hypoglycaemia is present

2. the β-effect of adrenaline also stimulates the liver to release glucose (gluconeogenesis and glycogenolysis).

• 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.

Hypoglycaemia and the brain

Cerebral function is critically dependent on an adequate supply of glucose from the circulation. Glucose is transported into the brain across the blood–brain barrier by a facilitative glucose transporter protein, GLUT-1. Studies in humans indicate that the rate of glucose transport into the brain can be modified by changes in plasma glucose levels. In particular, antecedent hypoglycaemia causes upregulation of glucose transport, so that more glucose is transported across the blood–brain barrier during subsequent episodes of hypoglycaemia. This adaptive response has important clinical implications.

Cognitive impairment progresses ultimately to loss of consciousness as plasma glucose falls. Seizures and transient focal neurological deficits may occur.

Recurrent severe hypoglycaemia may cause intellectual impairment.

The most serious consequence of acute hypoglycaemia is cerebral dysfunction with the risk of:

• injury (to self or others). As a result of neuroglycopenia, the patient may become irrational and aggressive. Prompt assistance from another party may then be required to avert loss of consciousness and more serious sequelae.

• Generalized epileptic seizures.

Clinically, hypoglycaemia may be usefully graded as follows:

Grade 1 Biochemical hypoglycaemia in the absence of symptoms.

Grade 2 Mild symptomatic – treated successfully by the patient.

Grade 3 Severe – assistance required from another person.

Grade 4 Very severe – may cause coma or convulsions.

Hypoglycaemia – counter-regulation

The physiological response to acute hypoglycaemia comprises:

• suppression of endogenous insulin secretion.

• activation of a hierarchy of counter-regulatory responses (Fig. 4.1).

Figure 4.1 Hierarchy of hormonal responses to acute hypoglycaemia. NB: Thresholds are modifiable by factors such as antecedent hypoglycaemia.

Counter-regulatory hormone responses

As plasma glucose concentration progressively falls, hormones that antagonize the actions of insulin are secreted in the following sequence:

• catecholamines – adrenaline and noradrenaline (epinephrine and norepinephrine)

• growth hormone.

Secretion of catecholamines occurs in the setting of generalized sympathetic nervous system activation. Glucagon and catecholamines are the principal hormones that protect against acute hypoglycaemia. These hormones stimulate glycogenolysis and gluconeogenesis, thereby increasing hepatic glucose production; enhanced hormone-stimulated lipolysis also contributes to recovery from hypoglycaemia through stimulatory effects on gluconeogenesis. If the response of either glucagon or catecholamines is inadequate, the other will usually compensate. However, deficiency of both will result in severe hypoglycaemia.

Cortisol and growth hormone play a less important role during acute hypoglycaemia, being more important in the later recovery of glucose levels. However, deficiencies of these hormones, for example cortisol deficiency in autoimmune Addison’s disease (which is more common in patients with type 1 diabetes), can lead directly to or exacerbate hypoglycaemia. Hypopituitarism may have a similar effect.

Failure of counter-regulatory hormone responses predisposes to severe recurrent hypoglycaemia.

Hypoglycaemia unawareness

Hypoglycaemic unawareness is particularly common in patients:

• with long-standing type 1 diabetes

• who attempt to maintain glucose levels close to the normal range.

In addition, certain drugs and alcohol may impair a patient’s perception of these symptoms. β-Blockers are designed to blunt the β-effect of adrenaline and related substances. Hence, if hypoglycaemia occurs in someone who is using this type of drug, he or she may have reduced adrenergic warning symptoms such as tremor and palpitations. β-Blockers may also reduce adrenaline’s effect of stimulating the liver to make glucose, and therefore may lead to the hypoglycaemia being slightly more severe and/or more protracted. β-Blockers are not contraindicated in diabetes, but patients should be aware of these possible problems.

During hypoglycaemia, the body normally releases adrenaline and related substances. The reduction in the β-effect of adrenaline reduces the typical symptoms of hypoglycaemia and blunts liver glycogenolysis and gluconeogenesis. As a result the patient may not be aware that their glucose level is low and the liver produces less glucose.

Attenuation of the adrenaline response is usually due to the glycaemic threshold for the response being shifted to a lower plasma glucose concentration. This can be aggravated by previous episodes of hypoglycaemia.

‘Hypoglycaemia begets hypoglycaemia’ – antecedent hypoglycaemia alters the glycaemic threshold for counter-regulatory hormone secretion – the brain becomes ‘used to’ the low glucose concentration. Clinical studies have shown that intensive insulin therapy leads to symptoms that develop at lower plasma glucose levels. Neuronal glucose transporters increase in number in response to repeated hypoglycaemia. As a result, the hypoglycaemic threshold for the brain to signal adrenaline release falls. Consequently, the patient has less time between the onset of symptoms and the development of severe neuroglycopenia.

Although the loss of warning symptoms has been described as a form of acquired autonomic dysfunction, it is generally accepted that classical diabetic autonomic neuropathy per se is not usually responsible for loss of hypoglycaemia awareness.

Recurrent hypoglycaemia, even if asymptomatic, is therefore a contraindication to intensive insulin therapy in patients with type 1 diabetes. Hypoglycaemic unawareness will sometimes disappear when the frequency of hypoglycaemic episodes has declined, but this is not always the case. With care and expert supervision, this may not necessarily compromise overall glycaemic control as judged by glycated haemoglobin concentrations.

Severe hypoglycaemia carries risks of coma, convulsions, injury and sometimes death.

As adrenaline release is a function of the autonomic nervous system, the presence of autonomic neuropathy causes the adrenaline release in response to hypoglycaemia to be lost or blunted. However, it is accepted that classical autonomic neuropathy is not usually responsible for loss of hypoglycaemic awareness.

Advice about driving

Patients with loss of warning symptoms of hypoglycaemia should not continue driving motor vehicles. Hypoglycaemia while driving can have serious consequences. This should be conveyed to the patient and the advice recorded in the patient’s case notes. Fatalities have occurred occasionally involving innocent bystanders. In the UK, patients should also be reminded that it is their legal responsibility to inform the driving licensing authority – the UK Driver and Vehicle Licensing Authority (DVLA). If the patient has a history of moderate or severe hypoglycaemic episodes, a hospital specialist’s report is usually requested by the DVLA. The patient should be advised to do regular blood glucose tests before driving (which they should record) and to carry simple carbohydrate in the car.

Patients with loss of warning symptoms of hypoglycaemia must not drive motor vehicles.

Nocturnal hypoglycaemia

Hypoglycaemia in type 1 diabetes is particularly common during the night and often goes undetected. Prevention of severe nocturnal hypoglycaemic events remains one of the most challenging goals in the treatment of diabetes. With the prevention of severe hypoglycaemia, it is likely that more people would be able to move toward optimal glycaemic control. Insulin-induced hypoglycaemia is also implicated in occasional sudden death in young patients. Prolonged severe hypoglycaemia, often exacerbated by excessive alcohol consumption, may produce cerebral oedema and permanent brain damage. The risk of hypoglycaemia bars insulin-treated diabetics from certain occupations.

Nocturnal hypoglycaemia is often asymptomatic in insulin-treated patients.

The frequent occurrence of nocturnal hypoglycaemia – which may affect more than 50% of patients and often goes unrecognized – may be an important cause of hypoglycaemia unawareness. In addition, the physiological responses to insulin-induced hypoglycaemia are impaired during stages 3–4 (slow wave) of sleep.

Conventional strategies to minimize nocturnal hypoglycaemia include:

• reducing the dose of evening intermediate insulin

• moving the time of the evening injection of intermediate insulin to 2200 hours

• eating a snack containing 10–20 g carbohydrate before bed

• avoiding excess alcohol consumption.

In patients on an intensified basal-bolus insulin regimen, insulin analogues are recommended in adults with type 1 diabetes who are experiencing severe or nocturnal hypoglycaemia.

Nocturnal hypoglycaemia often due to poor dietary compliance, and excess alcohol intake has been implicated in the sudden death of some young patients (so-called ‘dead in bed’ syndrome). The cause remains unproven, but catecholamine-mediated falls in plasma potassium concentration leading to cardiac arrhythmias have been implicated.

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.

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.

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.

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