Management of Hypoglycaemia

While hypoglycaemia occurs most commonly in patients with diabetes, it can occur in the absence of diabetes. Consequently, it must be considered in cases of unusual or bizarre behaviour, confusion, lethargy, and reduced conscious level. Patient with hypoglycaemia may also present with seizure or neurological symptoms and signs.

Hypoglycaemia can be fatal and even repeated mild episodes can lead to cumulative brain damage. Most episodes are managed in the community but it is the most frequent complication of diabetes seen in the ED².

Metabolism of glucose in normal patients

In patients without diabetes glucose levels are maintained within a small range.

When there is an excess of glucose, insulin triggers conversion of this excess initially to glycogen, which is stored in the liver. At higher levels of glucose, insulin converts to fatty acids in the liver these are ultimately converted to triglycerides in adipocytes.

The pancreas secretes insulin at a background level but also surges in response to rises in glucose within the portal system.

Brain, Liver, Retina, and Pancreatic B cells have glucose transport which functions independently of insulin.

Role of the Liver in Hypoglycaemia

• Liver cells are vital for storage of glycogen and subsequent production of glucose via glycogenolyisis.
• Gluconeogenesis is the process by which glucose is produced from non-carbohydrate substrates including protein and lipids.
• Diseases which reduce ability of liver cells to produce glucose through either glycogenolysis or gluconeogenesis increase the risk of hypoglycaemia e.g. alcoholic liver disease, cirrhosis, hepatitis.

Action of Hypoglycaemic Drugs

Drug	Mode of action
Insulin	Replacement therapy
Sulphonylureas	Stimulate insulin secretion from the pancreas
Metformin	Reduces gluconeogenesis and increases peripheral utilisation of glucose
Acarbose	Slows digestion of starch and sucrose
Thiazolidinediones (glitazones)	Increases sensitivity of cells to insulin

Action of other hormones

When hypoglycaemia is present the body protects itself by:

• Suppressing endogenous insulin secretion
• A sequence of counter-regulatory effects

In the acute phase, release of counter regulatory hormones glucagon (from the pancreas), and catecholamines (from the adrenals) stimulate glycogenolysis and gluconeogenesis.

If the liver is unable to response, due to inadequate glycogen stores or liver cell disease, then glucagon is ineffective, and gluconeogenesis will play a greater role.

Young healthy persons (without diabetes) release counter-regulatory hormones are released at blood glucose levels of 3.8 mmol/L, symptoms start usually around 3.0 mmol/L with cognitive dysfunction at levels below 2 mmol/L [5]. However these effects occur at different levels in individuals with diabetes, partly dependent on their previous glycaemic control.

In type 1 diabetes the endogenous glucagon response to hypoglycaemia reduces or is absent within a few years of diagnosis. However they continue to respond to exogenous glucagon, hence its role in treatment. The catecholamine response may also be attenuated or occur at a lower glucose level producing fewer warning signs and less time to take corrective action.

In type 2 diabetes glucose counter regulatory mechanisms are usually preserved during the early years, as is insulin secretion. As insulin deficiency develops, and the patient needs insulin treatment, counter regulatory mechanisms are impaired. Hypoglycaemia is usually said to be more frequent in type 1 diabetes than type 2, but in patients treated with insulin the rates may be similar.5

Somogyi effect

The counter-regulatory hormones cause transient insulin resistance. This results in post hypoglycaemic hyperglycaemia known as the Somogyi effect. The duration of the effect is different for each of the main hormones:

• Glucagon <2 h
• Epinephrine 4-6 h
• Cortisol and Growth hormone up to 12 h

Common presentations

There is considerable variation in symptoms associated with hypoglycaemia, although individuals may recognise their own pattern from repeated episodes.

Symptoms are classically divided into two groups; adrenergic or autonomic, and neuroglycopenic, some add a third group of non specific symptoms. In type 1 DM adrenergic and non specific symptoms start at blood glucose levels of approximately 3.8 mmol/L [6]. These are the symptoms most frequently identified as warning symptoms, and give time for action to be taken before the neuroglycopenic symptoms develop.

Significant pathologies may present in association with severe hypoglycaemia presenting to the ED. It is not clear whether these conditions are cause or effect of hypoglycaemia. In a US study of diabetic patients aged over 65 treated with insulin or oral hypoglycaemics, 5% of episodes of severe hypoglycaemia were associated with catastrophic complications e.g. stroke, TIA, MI, injury or death [7,9].

Table 1: Symptoms associated with hypoglycaemia

Adrenergic or Autonomic	Neuroglycopenic	Non Specific
Sweating	Confusion	Hunger
Hunger	Coma	Headache
Tremor or shaking	Convulsions	Nausea
Hunger	Focal neurological deficits
Nausea	Speech difficulties
Pallor	Incoordination
Tachycardia	Unusual behaviour including aggression

Causes

The majority of episodes of hypoglycaemia will be dealt with in the community by the patient themselves. When patients present to the ED with hypoglycaemia it is important to explore the circumstances and reasons for hospital attendance. In many cases a clear cause is not found.

Possible causes include:

• Use of insulin and oral hypoglycaemics
• Meals and snacks
• Exercise
• Other medication
• Awareness of warning signs
• Other illnesses
• Overall diabetic control
• Alcohol
• Psychological and psychiatric causes

Two landmark trials, The Diabetes Control & Complications Trial (DCCT) [4] and the UK Prospective Diabetes Study [8], reported increased incidence of hypoglycaemia with intensive therapy. HbA1c levels within the normal range are associated with increased risk of hypoglycaemia.

Type 1 diabetics

In type 1 diabetics, insulin errors, missed meals and excessive exercise were important causes of hypoglycaemia [9].

Type 2 diabetics

In type 2 diabetics, advanced age and inadequate energy intake are the main risk factors for those patients on sulphonylureas [10].

Elderly patients

In elderly patients, the main risk factors for severe hypoglycaemia are:

• Advanced age
• Recent hospitalisation/intercurrent illness
• Polypharmacy [7]

Diabetes treatment

People with Type 1 diabetes experience around two episodes of mild hypoglycaemia per week[18]. The estimated annual prevalence of severe hypoglycaemia is 30-40%.

In type one diabetes insulin errors, missed meals and excessive exercise are important causes of hypoglycaemia (9).

Type Two Diabetes

While the oral hypoglycaemic agents used mainly for type two diabetes (metformin, thiolidinediones, sulphonylureas and meglitinides) rarely cause hypoglycaemia on their own, combination therapy increases this risk. Having that said, Sulphonylureas do carry an increased risk of hypoglycaemia above that of metformin. (Odds ration 3.73 versus 1.42) Furthermore due to its long duration of action the risk of recurrent hypoglycaemia persists for hours after the initial treatment[19].

Advanced age, polypharmacy and inadequate energy intake remain important risk factors in those with type two diabetes.

Learning Bite

Insulin and sulphonylureas can both cause hypoglycaemia.

Other factors

There are other factors that need to be considered:

Chronic kidney disease

In chronic kidney disease insulin clearance is reduced and excretion of some medications is slower.

Hormone deficiency

Hormone deficiency in Addisons disease and hypopituitarism exacerbate hypoglycaemia, as cortisol and growth hormone are both counter-regulatory hormones involved in the late recovery from hypoglycaemia.

Drugs

Some drugs enhance the effect of insulin in both patients with diabetes and those without e.g. quinine, quinolones, pentamidine. Beta blockers may mask warning symptoms and non selective beta blockers also block the actions of glucagon in the liver. Longer acting oral hypoglycaemics continue to cause problems especially in the elderly with the added risk of polypharmacy.

Learning Bite

The risk factors for drug induced hypoglycaemia include: restricted carbohydrate intake, age the elderly and children, liver or renal impairment [10].

Alcohol

Alcohol blunts the appreciation of some of the warning signs in hypoglycaemia e.g. tremor, anxiety, and may be mistaken as the cause of neuroglycopenic effects. It also inhibits gluconeogenesis.

Exercise and heat

Exercise and heat may increase absorption of insulin from injection sites.

Nocturnal hypoglycaemia & glycaemic threshold

It classically occurs around 2am. It may be caused by:

• Early or no evening snack
• Alcohol
• Inappropriate insulin dose or timing

Nocturnal hypoglycaemia is thought to play a part in the development of hypoglycaemic unawareness due to changes in the glycaemic threshold.

The glycaemic threshold is the plasma glucose level at which counter-regulatory hormones, such as glucagon, are activated and can move higher or lower depending on the usual glycaemic control of the individual

Learning Bite

If blood sugars are usually high the patient may feel hypoglycaemic (hypo) even when the plasma glucose level is in the normal range.

There are minor differences in arterial, venous and capillary blood glucose(CBG) levels but these do not cause practical treatment difficulties in the ED.

Capillary blood samples are not reliable when the circulation to the area is impaired e.g. in shock, and when the haematocrit is low. In these circumstances venous or arterial samples are preferable.

If there is any doubt, or the result does not fit with the clinical picture, the test should be repeated and a laboratory sample sent.

In patients with normal circulation, point of care capillary blood glucose measurements are reliable, providing the equipment is used according to the instructions, within the approximate range 4-10 mmol/L. In the setting of diabetes this provides results we can act upon as glucose levels below 4 mmol/L indicate hypoglycaemia and need treatment.

Learning Bite

In patients without diabetes hypoglycaemia should only be diagnosed on the basis of clinical symptoms and a serum or plasma glucose measured in the laboratory.

Management

Treatment of hypoglycaemic emergency

Variability exists between hospitals and jurisdictions over the treatment and management of diabetic and glycaemic emergencies. When treating hypoglycaemia, consideration needs to be given to potential for prolonged susceptibility. While normal glucose levels for those without diabetes are 3.5-7.0mmol/L, Diabetes UK recommends a lower limit and treatment of 4.0mmol/L for those with diabetes.

• Oral carbohydrate 15-20g of a quick acting carbohydrate (e.g. orange juice) should be followed by a long acting carbohydrate (e.g. toast/banana/two biscuits). With the recent introduction of the sugar tax it is important to check the carbohydrate content if administering a soft drink (e.g Lucozade)
• Buccal Glucose Gel This is absorbed more quickly than complex carbohydrates and is easily administered. The patient should be able to swallow in order for it to be fully effective.
• Glucagon Can be administered via IV, IM or SC routes. Useful in situations where behaviour, co-operation or other neuroglycopenic symptoms make oral or IV routes difficult. Repeated doses are not advised. It is important to appreciate the cohort of patients for whom glucagon will be less effective (those with depleted glycogen reserves e.g. sulphonylurea treatment, malnourished, or excessive alcohol consumption)
• Dextrose using 10% dextrose results in lower post treatment hyperglycaemia. Given the risk of extravasation and phlebitis from 50% dextrose, 10% dextrose is the preferred option. 150-200mls of 10% dextrose is usually sufficient to correct hypoglycaemia for most patients.[17]

When dextrose or glucagon are given recovery is quick, but hypoglycaemia may recur if complex carbohydrates are not also given to provide continued glucose supply. This is particularly important after glucagon as it uses up liver glycogen stores.

Learning Bite

In patients who remain unconscious from another cause or who are unable to eat, frequent monitoring of glucose levels is required and dextrose infusions may be needed.

Learning Bite

Do not omit next insulin dose. Dose modification may be required but the next dose should be given.

Overtreatment

Overtreatment, leading to hyperglycaemia should be avoided as this can make glycaemic control difficult for the patient to manage over the following hours.

Hyperglycaemia also has a deleterious effect in many conditions:

• Sepsis
• Myocardial infarction
• Stroke

In most cases capillary blood glucose in the range 5-10 mmol/L are appropriate after treatment for hypoglycaemia.

Glucagon stimulates insulin secretion as well as glycogenolysis so is less useful in type 2 diabetes when there is still insulin secretion.

Intravenous dextrose also stimulates insulin release, which can then cause rebound hypoglycaemia, this is particularly important in hypoglycaemia associated with sulphonylureas.

There are few studies comparing different concentrations of intravenous dextrose. In a randomised controlled trial (RCT) of pre-hospital treatment of adults unable to take oral carbohydrate, two concentrations of IV dextrose (10% and 50%) given in 5 g aliquots were compared.

There was no significant difference in time to return to Glasgow Coma Score (GCS) [11] but the group receiving 50% dextrose received a larger total dose and had higher post treatment blood glucose levels [7].

Two studies comparing IV dextrose with glucagon [12,13] by intramuscular and intravenous injection are often quoted in recommendations for the treatment of hypoglycaemia. However the dose of dextrose (50 ml of 50%) was higher than is commonly used now. The return to normal consciousness was slower for glucagon (IM more so than IV) than dextrose.

Glucagon tended to produce a steady rise in plasma glucose from low to the normal range, whereas IV dextrose produced high levels at 5 min which settled to normal by 30 min.

Learning Bite

In severe or prolonged hypoglycaemia cerebral oedema can develop. Dexamethasone, mannitol or controlled ventilation may be required after CT scanning.

Flow Chart for Treatment

*Lucozade – Recent changes in sugar content means clinicians should check carbohydrate content carefully prior to administration.

The flow chart is a guide to treatment for hypoglycaemia, it shows the levels of CBG and the levels of treatment required.

Other Considerations

There are a number of further considerations when a patient presents with hypoglycaemia:

Cause

It is important to establish why this episode of hypoglycaemia occurred and why the patient ended up in the emergency department. Clinicians should be satisfied they have addressed the cause in order to prevent recurrence (Does the patient need prolonged observation eg hypoglycaemia caused by sulphonlyurea)

Patient education

Patient education how to recognise it and what to do, should be part of each diabetes review. It is important to check the patients understanding of the issues before discharge from the ED.

Driving

Patients with a loss of warning symptoms should not drive. It is the doctors duty to inform the patient of this and to explain their responsibility to notify the DVLA. This should be documented in the patient notes and wherever possible, written advice should be provided and the patients GP informed.

Patients who have attended hospital following hypoglycaemia should have OP follow up with diabetes team or diabetes liaison nurse arranged prior to discharge. Changes to treatment and patient education may prevent future episodes. This is particularly important for those who have hypoglycaemic unawareness. Awareness may be restored by meticulous avoidance of hypoglycaemia requires the close supervision by the diabetes team.

Role of the diabetes team

Patients who have attended hospital following hypoglycaemia should be advised to contact their diabetic team. Changes to treatment and patient education may prevent future episodes. This is particularly important for those who have hypoglycaemic unawareness. Awareness may be restored by meticulous avoidance of hypoglycaemia and requires the close supervision of the diabetes team.

1. Hypoglycaemia is the main obstacle to good glycaemic control in people with diabetes. It can be unsafe and causes concern to the patient and relatives. (Grade D recommendation, level of evidence 5)
2. The main pitfall in the management of hypoglycaemia is failure to consider its presence. Most cases of hypoglycaemia occur as a result of treatment for diabetes, but it can also occur in those without diabetes especially in association with certain drugs and alcohol. (Grade D recommendation, level of evidence 5)
3. Most cases are managed in the community. Adults who come to the Emergency Department with hypoglycaemia should be advised to contact their diabetes team after treatment / discharge. (Grade D recommendation, level of evidence 5)
4. Alcohol is a risk factor for hypoglycaemia in those with and without diabetes. (Grade D recommendation, level of evidence 5)
5. Adults with hypoglycaemia who are able to swallow safely should take oral glucose or sucrose. Glucose tablets or gels also require swallowing to be effective. (Grade A recommendation for type 1 diabetes, level of evidence 1a)
6. Intramuscular glucagon is useful treatment for uncooperative hypoglycaemic patients or when intravenous access is not possible. Some patients given im glucagons will require additional intravenous dextrose. (Grade C recommendation, level of evidence 4)
7. Concentrated dextrose solutions are inflammatory especially if extravasation occurs, less concentrated solutions should be used when available eg10% dextrose, 20% dextrose. (Grade D recommendation, level of evidence 5)
8. Hypoglycaemia secondary to oral hypoglycaemics has high morbidity and mortality. Close monitoring, a dextrose infusion and admission, is required. (Grade D recommendation, level of evidence 5)
9. Hypoglycaemic unawareness puts the patient and others at risk, urgent referral to the diabetic team is needed. (Grade D recommendation, level of evidence 5)

The main pitfall in the treatment of hypoglycaemia is not considering it as a diagnosis. Check a glucose early in;

• Unconscious or drowsy patients
• Unusual or bizarre behaviour
• Agitated or aggressive patients
• Patients after alcohol consumption
• Patients at risk of malnourishment or prolonged vomiting (e.g. hyperemesis)
• Elderly patients with vague or non-specific neurological signs or symptoms.

Capillary blood glucose testing may give inaccurate results if taken from poorly perfused sites or in patients with profound hypoxia or shock. If in doubt check a venous blood gas and send a serum sample to the lab for analysis.

Be careful in patients treated for hypoglycaemia -some will develop rebound hypoglycaemia. Those who have hypoglycaemia secondary to oral hyperglycaemic agents will likely require a prolonged observation period.

Patients with diabetes are usually well able to self-treat hypoglycaemia remember to explore what was different on this occasion. Address this (where possible) prior to discharge.

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