Diabetes Mellitus

د. حسين محمد جمعه

اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2011

Hypoglycaemia: diagnosis and management

© 2011 BMJ Publishing Group Ltd

Key points

Hypoglycaemia can occur in people with diabetes treated with insulin or sulphonylureas
When blood glucose falls below 3.2 mmol/l both autonomic and neuroglycopenic symptoms can occur .
You should advise people with diabetes to treat hypoglycaemia when their blood glucose is <4.0 mmol/l.

This is so they can treat it before neuroglycopenic symptoms occur.

Recurrent hypoglycaemia can be associated with the development of hypoglycaemic unawareness when a person can go from feeling normal to unconsciousness without any symptoms.


Clinical tips
If a person is conscious and cooperative you can treat hypoglycaemia with oral glucose.
Admission to hospital should be considered for someone with hypoglycaemia due to treatment with long acting sulphonylureas because the hypoglycaemia may recur following treatment with intravenous glucose.
Remember that hypoglycaemia can be mistaken for drunkenness. If you are unsure remember to check the patient's blood glucose.

If you need to give intravenous glucose to treat someone who has become unconscious from hypoglycaemia, ensure that you use a wide bore needle and have adequate venous access. This is because concentrated glucose solutions can cause tissue damage if they leak out of the vein.

Introduction

Hypoglycaemia is a common side effect in people with diabetes being treated with insulin or oral agents, such as the sulphonylureas. Hypoglycaemia and the fear of hypoglycaemia is thought to be a major reason for people with diabetes not to have optimal glycaemic control. It may deter them from starting or intensifying treatment with insulin.

The brain needs a continuous supply of glucose to function properly. Reduced blood glucose in the cerebral circulation rapidly leads to impaired cognitive function and eventually coma. Hypoglycaemia has been associated with sudden death in people with diabetes treated with insulin.

How common is hypoglycaemia?

About 10% of people with type 1 diabetes on standard insulin therapy have at least one episode of severe hypoglycaemia a year (defined as hypoglycaemia requiring the assistance of another person or medical attention). This can increase up to threefold in people on intensive insulin regimens. It probably occurs with lower frequency in people with type 2 diabetes treated with insulin or sulphonylureas.

The United Kingdom Prospective Diabetes Study in people with type 2 diabetes found that treatment with insulin was associated with an average of 1.8 episodes of severe hypoglycaemia per year. Rates of hypoglycaemia are not normally distributed. In surveys of people with either type 1 or type 2 diabetes, a small proportion have a large number of episodes while most have no episodes.

The risk of hypoglycaemia (both frequency and severity) is increased with:

• Increased duration of diabetes
• Social isolation
• Dementia
• Frailty related to increasing age.


Hormone responses to hypoglycaemia in people without diabetes or people recently diagnosed with diabetes
When blood glucose falls, secretion of insulin is inhibited and secretion of glucagon is stimulated.
The autonomic nervous system is stimulated and catecholamines (mainly adrenaline) are released.
These hormones enhance hepatic release of glucose and oppose hypoglycaemia.

Glucagon stimulates glycogenolysis causing the liver to convert stored glycogen into glucose and release it into the bloodstream.
The beta agonist effects of adrenaline (palpitations and tremor) warn the person with diabetes that hypoglycaemia is present. Adrenaline also stimulates the liver to generate glucose by glycogenolysis and gluconeogenesis.

Symptoms are classified into two groups: autonomic and neuroglycopenic.

Autonomic symptoms occur because of activation of the sympathetic or parasympathetic nervous system. They may include:
• Sweating
• A pounding heart
• Tremor
• Hunger.

Neuroglycopenic symptoms are due to the effects of glucose deprivation on the brain. They include:
• Confusion
• Drowsiness
• Difficulty with speech
• Lack of coordination
• Blurred vision
• Unusual behaviour, for example aggression.


What levels of blood glucose produce symptoms of hypoglycaemia?
In people with diabetes autonomic symptoms typically develop at blood glucose levels of about 3.2 mmol/l and cognitive function starts to deteriorate at about 3.0 mmol/l.
People who have normal awareness of hypoglycaemia get symptoms and can treat themselves before confusion occurs.

Grading hypoglycaemia

A simple scale may be used to grade hypoglycaemia:
Grade 1 - no symptoms but biochemical hypoglycaemia is present, for example a plasma glucose of 3.2 mmol/l
Grade 2 - mildly symptomatic hypoglycaemia successfully treated by the person with diabetes
Grade 3 - severe hypoglycaemia requiring the assistance of another person or medical attention
Grade 4 - very severe hypoglycaemia causing coma or convulsions.

Hypoglycaemic unawareness

Hypoglycaemic unawareness occurs when a person with diabetes no longer has the early symptoms of low blood glucose. As a result the person cannot respond in the early stages and so can go from feeling normal to developing severe hypoglycaemia without a warning.
People who have hypoglycaemic unawareness may have problems with driving and should be told not to drive until the condition is reversed.

Unawareness occurs for the following reasons:

When the brain becomes used to the low glucose and no longer signals for adrenaline to be released. What was once the hypoglycaemic threshold for the brain to signal adrenaline release becomes lower. Adrenaline is not released, if at all, until the blood glucose level has dropped to dangerously low levels.

This occurs:

• With increased duration of diabetes
• In situations of repeated hypoglycaemia.
• This is more common with intensive glycaemic control. In this situation the autonomic nervous system does not respond to further episodes and there is a loss of release of adrenaline and symptoms such as sweating, tremor, and palpitations.


People affected in this way are more likely to experience severe episodes without warning. This is called hypoglycaemia associated autonomic neuropathy. It is distinct from autonomic neuropathy, which is a long term complication of diabetes, especially type 1 diabetes, because it can occur after a short duration of diabetes and can be reversed .

If the person is on drugs that mask the hypoglycaemic symptoms (for example beta blockers).
Unawareness can be reversed, at least in part, by strictly avoiding hypoglycaemia. This will raise the hypoglycaemic threshold for the activation of symptoms. At least three weeks of meticulously avoiding hypoglycemia is usually needed.

Learning bite

Hypoglycaemia can occasionally be confused with diabetic ketoacidosis. Diabetic ketoacidosis typically causes thirst, polyuria, and weight loss and often has a precipitating event such as infection.
To confirm a diagnosis of diabetic ketoacidosis, patients need to have urea and electrolytes and arterial blood gases checked.

Causes of hypoglycaemia

Hypoglycaemia in people with diabetes can occur only when they are being treated with agents that lower blood glucose. These are insulin and oral agents such as sulphonylureas that cause insulin secretion.
Hypoglycaemia does not occur in people with diabetes treated with diet, metformin, or glitazones because these do not cause insulin secretion.
Hypoglycaemia can also occur in people without diabetes.

Possible causes of a raised concentration of insulin are:

Giving too much insulin in error by a person with diabetes or a healthcare professional
A mismatch between insulin dose and the patient's needs or lifestyle .A deliberate overdose
Accelerated absorption of insulin due to exercise, hot weather, or alteration of the injection site.

Possible causes of enhanced insulin effect in people with diabetes are:

Weight loss
Physical activity
Vomiting and absorption problems caused by gastroparesis
Breast feeding.


Possible causes of enhanced insulin effect in people with and without diabetes are:
Drugs, such as pentamidine, quinine, and quinolones
Anorexia nervosa
Hormone deficiency in Addison's disease or hypopituitarism
Liver failure secondary to impaired gluconeogenesis
Chronic renal failure possibly secondary to diminished renal clearance of insulin.

Alcohol inhibits the body's ability to raise blood glucose during hypoglycaemia and reduces some symptoms such as tremor.
Effect of alcohol in people with diabetes

Treating hypoglycaemia

You should confirm hypoglycaemia by a finger prick blood glucose test.
The management of hypoglycaemia depends on the patient's level of consciousness and cooperation.
If the patient is conscious and cooperative:
Give a glass of water with four teaspoons of glucose or six glucose sweets.

Small cartons of apple juice could also be used

Follow this with a snack of medium or low glycaemic index carbohydrates of 10-20 g, for example two digestive biscuits. The patient should wait for about five minutes before taking this snack to avoid the fat content in the biscuits delaying the absorption of the glucose .
Check the blood glucose again to ensure it has returned to normal about 15 minutes after treatment.

If the patient is conscious but uncooperative:

Insert dextrose gel (Glucogel) into the mouth, using about a third of the bottle. Massage gently around the cheeks to aid absorption of the gel through the buccal mucosa. This will usually raise blood glucose within a few minutes
Recheck the blood glucose.
If the patient is now cooperative:
If blood glucose is <4.0 mmol/l, repeat steps 1-3 under "if the patient is conscious and cooperative"
If blood glucose is >4.0 mol/l, repeat steps 2 and 3 under "if the patient is conscious and cooperative


If the patient remains uncooperative:
Give Glucogel again.
If the patient is unconscious:
Inject glucagon either subcutaneously or intramuscularly. Intramuscular injection is preferable because it is more likely to be absorbed quickly
Place the person in the recovery position and wait for the return of consciousness, which usually occurs in 15 to 20 minutes
Repeat the blood glucose test and give a medium or low glycaemic index carbohydrate.

Give an intravenous injection of glucose, usually in the form of 25 ml of 25% or 50% glucose solution. Give this into a large vein through a wide bore needle over 15 to 20 minutes.
You should be cautious when giving intravenous glucose because solutions of concentrated glucose can damage tissue if they leak out of a vein. Flushing with saline may reduce the risk of thrombophlebitis.
Fifty per cent glucose is banned in certain trusts but there are no national guidelines on this.
If glucagon doesn't work:

Diagnosing the cause of recurrent hypoglycaemia and advising about reducing doses

If hypoglycaemia is recurring at a particular time of day it can be useful to plot when tablets or insulin are being taken and food consumed. Frequent self monitoring of blood glucose or the use of a 72 hour continuous blood glucose monitoring device may be needed to understand the pattern of the recurrent hypoglycaemia. You may need to reduce the dose of the injection thought to be causing the hypoglycaemia by about 10%. If recurrent hypoglycaemia is occurring in a person treated with sulphonylureas, you should reduce the dose of tablets.

If you think that exercise is the main cause of recurrent hypoglycaemia you should give the patient the following advice:
If the exercise is planned and the patient wants to lose weight they should reduce their insulin
If they do not need to lose weight they can either reduce their insulin or eat some carbohydrates before the exercise.
If the exercise is unplanned, the patient should eat some carbohydrates.

Hypoglycaemia can occur during, one to two hours after, or up to 18 to 24 hours after exercise while the body is replacing its used energy stores. The diabetes team may therefore advise the patient to reduce their insulin doses (both basal and pre-meals) for the next 12 to 24 hours.
Severe recurrent hypoglycaemia occuring in someone on insulin injection therapy may be an indication for a trial of insulin pump therapy and it is also one of the indications for consideration for entry into the research programme of islet cell transplantation in people with type 1 diabetes.


Hypoglycaemia caused by treatment with sulphonylureas
This is mainly associated with longer acting sulphonylureas (particularly glibenclamide, which is now used sparingly in the UK).
Patients with severe hypoglycaemia caused by a long acting sulphonylurea may need admission to hospital. The bolus of glucose to treat the hypoglycaemia results in further release of insulin in people with type 2 diabetes who have some preservation of beta cell function. This consequence of treatment combined with the long duration of action of glibenclamide is why the hypoglycaemia often returns in such patients. A continuous dextrose infusion is often needed.

Effect of education on rates of hypoglycaemia in people with type 1 diabetes

The Diabetes Control and Complications Trial compared the effects of two regimens - standard therapy and intensive control - on the complications of diabetes. It showed the long term benefits of strict glycaemic control in reducing complications. But the rates of hypoglycaemia increased in proportion to the reduction in HbA1c and the intensive treatment group had a threefold increased rate of severe hypoglycaemia.

Training programmes developed in Germany used the principles of adult education group techniques. The modified programme in the UK is called Dose Adjustment For Normal Eating (DAFNE). The principle of the programme is that people with type 1 diabetes should adjust their insulin to whatever they want to eat rather than adjust their diet to fit in with set amounts of prescribed insulin.

The published data from the initial trials in Germany showed improvement in glycaemic control with low rates of severe hypoglycaemia.13 Results from a six month trial of the DAFNE programme also showed improvement in glycaemic control but did not show any significant difference in rates of severe hypoglycaemia.

Some situations where you might miss hypoglycaemia

When it is mistaken for drunkenness in a young person who has been out for the night and who has slurred speech, becomes aggressive, and then becomes unconscious.
In an older person when it may be mistaken for memory loss and early dementia.

Hypoglycaemia and cognitive dysfunction

Good control reduces the risk of complications but intensive control in people using insulin increases the risk of hypoglycaemia. The possibility that hypoglycaemia, especially recurrent hypoglycaemia, may damage the brain and cause cognitive dysfunction has been a concern for many years.

In the Diabetes Control and Complications Trial a battery of cognitive tests was used to evaluate the effect of diabetes treatment and recurrent hypoglycaemia on cognitive ability. At an average of 6.5 years of follow up no effect on cognitive function was found. But the study involved short follow up of mainly young adult patients who had relatively few hypoglycaemic events.

The cohort of patients in the Diabetes Control and Complications Trial study has been followed up in the Epidemiology of Diabetes Interventions and Complications study. At a mean of 18 years later they were subjected to a similar battery of cognitive tests. A recently published report has shown no evidence of substantial long term decline in cognitive function in a large group of people with type 1 diabetes who were followed for 18 years, despite relatively high rates of recurrent severe hypoglycaemia.


Learning bite
When someone on insulin has an episode of hypoglycaemia, you should consider reducing the dose of insulin that they took prior to the episode. It is a common error to reduce the dose of insulin immediately after the episode.

Hypoglycaemia and driving

People on insulin therapy are advised to check their blood glucose levels before starting to drive and ensure that they take snacks to eat. They are advised to pull over and stop driving if any symptoms suggestive of impending hypoglycaemia occur.
Loss of hypoglycaemic awareness and frequent hypoglycaemic episodes should lead to cessation of driving until the problem is resolved. People on insulin therapy can hold a normal driving licence (group 1) but will not be eligible for a group 2 (large goods vehicles and passenger carrying vehicles)