Author: Ellen F Jones / Editor: Ellen F Jones / Reviewer: Sue Maurice / Codes: C3AP4 / Published: 25/09/2018 / Review Date: 25/09/2021
Hypoglycaemia occurs most commonly in diabetics, but can also occur in the absence of diabetes. Therefore, it must be considered in all cases of reduced conscious level, unusual behaviour and confusion. Hypoglycaemic patients may also present with seizures 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.
Basic science and pathophysiology
Metabolism of glucose in normal patients
In non-diabetics glucose levels are maintained within a small range. Glucose enters the blood from dietary carbohydrate, and as a result of insulin secretion is taken into the cells, in particular those of skeletal muscle and adipose. It can then be used directly by cells for energy via glycolysis and ultimately the Krebs cycle. When there is an excess of glucose, insulin triggers conversion of the excess initially to glycogen for storage in the liver and at higher levels of glucose to fatty acids in the liver, which are ultimately converted to triglycerides in adipocytes.
When the blood glucose level begins to fall, insulin levels also fall, and this process is reversed. This occurs initially via breakdown of glycogen (glycogenolysis) to release glucose from the liver, and once all the glycogen is utilised, by gluconeogenesis in which the hepatocytes produce glucose from non-carbohydrate substrates such as protein and fat. Therefore, during starvation or prolonged exercise gluconeogenesis maintains plasma glucose levels.
The pancreas secretes insulin at a background level and also in surges in response to rises in glucose in the portal system.
Insulin acts to suppress glucose production from the liver, and at higher levels stimulates glucose uptake by activating glucose transport into cells which is then converted to be stored in the liver as glycogen or fat.
Hepatocytes, skeletal myocytes, and adipocytes are the main targets for insulin action.
Brain, 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 the ability of liver cells to produce glucose through either glycogenolysis or gluconeogenesis increase the risk of hypoglycaemia. E.g. Alcoholic liver disease
Action of oral hypogly drugs
Mode of action
|Stimulate insulin secretion from the pancreas|
|Reduces gluconeogenesis and increases peripheral utilisation of glucose|
|Slows digestion of starch and sucrose|
|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.
However if the liver is unable to respond due to inadequate glycogen stores or liver cell disease, then glucagon will not be effective, and gluconeogenesis plays greater role.
Cortisol and growth hormone have a similar role in the later stages of hypogylcaemia.
In young healthy non diabetics counter regulatory hormones are released at blood glucose levels of 3.8 mmol/L, symptoms start around 3.0mmol/L with cognitive dysfunction at levels below 2mmol/L 5. However these effects occur at different levels in individuals with diabetes, partly dependent on their previous glycaemic control.
In type 1 diabetics 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
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
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 . 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].
|Adrenergic or Autonomic||Neuroglycopenic||Non Specific|
|Tremor or shaking||Convulsions||Nausea|
|Hunger||Focal neurological deficits|
|Tachycardia||Unusual behaviour including aggression|
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
- Other medication
- Awareness of warning signs
- Other illnesses
- Overall diabetic control
- Psychological and psychiatric causes
Two landmark trials, The Diabetes Control & Complications Trial (DCCT)  and the UK Prospective Diabetes Study , 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 .
Type 2 diabetics
In type 2 diabetics, advanced age and inadequate energy intake are the main risk factors for those patients on sulphonylureas .
In elderly patients, the main risk factors for severe hypoglycaemia are:
- Advanced age
- Recent hospitalisation/intercurrent illness
- Polypharmacy 
There are many different insulin types and regimes in use and each can produce a particular pattern of hypoglycaemia.
Other treatments; metformin and glitazones, only rarely cause hypoglycaemia on their own but they will exacerbate hypoglycaemia when used in combination with either insulin or sulphonylureas.
Insulin and sulphonylureas can both cause hypoglycaemia.
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 in Addisons disease and hypopituitarism exacerbate hypoglycaemia, as cortisol and growth hormone are both counter-regulatory hormones involved in the late recovery from hypoglycaemia.
Some drugs enhance the effect of insulin in both diabetics and non diabetics 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.
The risk factors for drug induced hypoglycaemia include: restricted carbohydrate intake, age the elderly and children, liver or renal impairment .
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
- 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
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.
In non diabetic patients hypoglycaemia should only be diagnosed on the basis of clinical symptoms and a serum or plasma glucose measured in the laboratory.
Treatment of Diabetic Emergency
There are no nationally agreed guidelines for the treatment of diabetic emergencies yet. Even within hospitals there is variation. The options are:
- Oral carbohydrate suitable for conscious cooperative patients
- Buccal glucose gels absorbed more quickly than complex carbohydrates, relatively easily administered, need to swallow to be fully effective
- Intravenous dextrose requires intravenous (IV) access, rapid response. Hypertonic solutions especially 50% dextrose, can cause inflammation, so rapid infusion of 100mls of 10% Dextrose is preferable.
- Glucagon Subcutaneous (SC), IV or Intramuscular (IM) routes Img IM used most frequently especially when behaviour, cooperation or other neuroglycopenic symptoms make oral or IV routes difficult
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.
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.
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:
- Myocardial infarction
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)  but the group receiving 50% dextrose received a larger total dose and had higher post treatment blood glucose levels .
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.
In severe or prolonged hypoglycaemia cerebral oedema can develop. Dexamethasone, mannitol or controlled ventilation may be required after CT scanning.
Flow Chart for Treatment
The flow chart is a guide to treatment for hypoglycaemia, it shows the levels of CBG and the levels of treatment required.
There are a number of further considerations to raise awareness of hypoglycaemia:
Patient education advice on hypoglycaemia how to recognise it and what to do, should be part of each diabetic review. It is important to check the patients understanding of the issues before discharge from the ED.
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 diabetic team or diabetic 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 and requires the close supervision of the diabetic team.
Hypoglycaemic unawareness poses a major risk to the patient and others. It is defined as lack of appropriate autonomic warning signals before the development of neuroglycopenia 14. The change to human insulin was widely thought to be a factor but has not been confirmed in trials although individual patients may use non human insulin for this reason.
Antecedent hypoglycaemia is thought to contribute, nocturnal hypoglycaemia may be an important aspect of this. Longer duration of diabetes, near normal HbA1c and intensive diabetes management are also implicated 15.
Awareness may also be impaired by alcohol and beta blockers.
Prognosis & Followup strategies:
Role of the diabetic 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 diabetic team.
Key Learning Points
- 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
- 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 non diabetics especially in association with certain drugs and alcohol. Grade D recommendation, level of evidence 5
- Most cases are managed in the community. Adults who come to the Emergency Department with hypoglycaemia should be advised to contact their diabetic team after treatment / discharge. Grade D recommendation, level of evidence 5
- Alcohol is a risk factor for hypoglycaemia in diabetics and non diabetics. Grade D recommendation, level of evidence 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
- 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
- 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
- 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
- Hypoglycaemic unawareness puts the patient and others at risk, urgent referral to the diabetic team is needed. Grade D recommendation, level of evidence 5
Safety pearls and Pitfalls:
The main pitfall in the treatment of hypoglycaemia is failing to consider it as a possible diagnosis. Remember it particularly in:
- Unconscious or drowsy patients
- Those with unusual behaviour
- Non cooperation or aggression
- Patients who have been drinking
- The malnourished
- Elderly patients who may present with non specific or neurological signs and symptoms
Capillary blood glucose tests may give inaccurate results if taken from an under perfused site, when dextrose has contaminated the skin, or if the instructions for the test strip and device are not used properly. If in doubt repeat, or send a sample to the laboratory for testing.
As mentioned above, in those patients who still produce insulin, treatment may cause rebound hypoglycaemia.
Hypoglycaemia caused by oral hypoglycaemics may recur unless monitored closely. Admission is usually required for these patients.
This is especially important in patients taking sulphonylureas, which stimulate insulin secretion and have a greater risk of recurrent hypoglycaemia
Diabetic patients will usually self treat hypoglycaemia, so always explore what was different on this occasion to make them come to hospital.
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