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Editor's Notes
Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS) are two acute complications of diabetes.
HHS used to be called hyperosmolar hyperglycaemic non-ketotic syndrome (HHNS or HONK).
There is a comprehensive review of the subject by Kitabchi et al in Diabetes Care 2009:
Kitabchi AE, Guillermo E, Umpierrez GE, Fisher JN. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
DKA occurs when a deficiency in insulin – either absolute or relative – prevents glucose from entering cells, which leads to increasing hyperglycaemia.
The secretion of counter-regulatory hormones (glucagon, epinephrine, growth hormone and cortisol) resulting in a massive release of glucose from the liver, contributes to this hyperglycaemia.
This is followed by the uncontrolled breakdown of adipose and muscle tissues (catabolism).
Fatty acids are released and are rapidly metabolized into ketones, which have strong acidity, to act as an alternative fuel in the absence of glucose and insulin.
The excessive production of ketones lowers the blood’s pH and leads to metabolic acidosis.
DKA is characterized as the biochemical triad involving:
Hyperglycaemia – usually blood glucose higher than 11mmol/L (191 mg/dL)
Excessive ketoacids in blood and urine
Metabolic acidosis – pH below 7.3.
Kitabchi AE, Guillermo E, Umpierrez GE, Fisher JN. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
The incidence of DKA varies across different communities depending to some extent on environment and people’s understanding of diabetes. Incidence varies geographically and in different ethnic populations. In the USA, there are about five to eight episodes per 1000 people with diabetes.
In some areas, the overall incidence appears to be increasing, especially in low-income communities.
Mortality due to DKA, usually through cerebral oedema, is thought to be less than 5% but this may be higher in some areas.
DKA usually occurs in people with type 1 diabetes either at onset (up to 40% of newly diagnosed people with type 1 diabetes are in DKA) or in people with established diabetes.
The average age of people with DKA is between 40 and 50 years; in 15% of people, there are recurrent episodes. When recurrent episodes occur, the underlying causes must be assessed. Recurrent episodes may be a sign of drug abuse or eating disorders.
DKA may occur in people with type 2 diabetes, sometimes at diagnosis. A person with type 2 diabetes with DKA can be treated initially as in type 1 diabetes until blood glucose levels drop and it becomes apparent that the person will be able to manage on diet and exercise and/or oral medication.
DKA in people with pre-existing type 2 diabetes often occurs in conjunction with an infection or other illness. People become unable to manage increasing hyperglycaemia and polyuria; dehydration and DKA may develop.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008. Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes, 32(suppl 1).
Kitabchi AE, Guillermo E, Umpierrez GE, Fisher JN. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
In the US it has been reported that over half of the unprovoked DKA in African or Hispanic people have type 2 diabetes. After a short period on insulin these people usually revert to management with lifestyle or oral medications.
It is important to look for the underlying causes or triggers of DKA. For example, if an illness or infection is the underlying cause, this must be treated.
Insulin omission or poor adherence to the insulin regimen are now recognized as common causes of DKA, especially when multiple admissions to hospital occur. This may be due to poor finances, the inability to acquire insulin or a lack of understanding of the critical need for insulin.
Insulin omission may also be intentional. This is most commonly found in younger females trying to lose weight. Inadequate insulin levels lead to glycosuria (excretion of blood glucose in the urine) and subsequent weight loss. Health care professionals must include psychosocial status as an essential component of assessment and intervene quickly in order to prevent further complications and risk to the individual.
A significant proportion of older people may have DKA as a complication of a heart attack, an infarction or other serious illness.
Kitabchi AE, Guillermo E, Umpierrez GE, Fisher JN. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
This diagram shows the pathways in the development of DKA. The influence of counterregulatory hormones on gluconeogenesis and ketogenesis is not shown but is important.
Note the osmotic diuresis that promotes the severe degree of electrolyte depletion and dehydration.
DKA is the combination of dehydration and acidosis, both of which require treatment.
Davidson MB. (2001). Hyperglycemia. In: Franz MJ, ed. A Core Curriculum for Diabetes Education: Diabetes and Complications. 4th ed. Chicago: American Association of Diabetes Educators, 23.
It is important to recognise the difference between mild physiological ketosis and the more serious pathological production of ketones in DKA.
All of us have ketosis at times of fasting or when we are losing weight. In fact, some diet programmes require people to test for ketones in their urine to determine whether they are burning fat. This ketosis is physiological, does not represent a problem and does not cause illness.
In DKA, insulin deficiency leads to hyperglycaemia and the release of fatty acids from the breakdown (lipolysis) of fat stores. This produces excess ketones which are acidic – hence ketoacidosis.
The three ketones produced are
Beta-hydroxybutyrate which is the major ketone in the blood (and there are newer bedside methods of measuring this)
Acetone (smelled on the breath and present in urine)
Acetoacetate (also excreted in the urine)
The usual practice is to test urine for ketones (acetone and acetoacetate). Urine testing does not recognize beta-hydroxybutyrate, which is the main ketoacid in DKA. By the time urine tests positive for ketones, the level of beta-hydroxybutyrate may be quite high. Therefore, it is possible for a person to have DKA when the urine shows negative for ketones.
It should be remembered that ketonuria takes many hours to clear and is not a good indicator of a person’s well-being in the recovery phase of DKA.
As blood ketones change more quickly, these enable the early detection of DKA and, compared to ketonuria, may be a better indicator of clinical progress as a person recovers from DKA. Meters are available that test blood for ketones but they are expensive and not available everywhere.
The early symptoms of DKA are the same as those for increasing levels of hyperglycaemia – increased thirst and urination and, often, an increased appetite – to cope with the catabolic phase of diabetes.
With regard to DKA, prevention is, of course, better than cure. The early recognition of these symptoms should alert us to a prompt diagnosis and urgent preventive treatment.
Use of a meter that tests blood for ketones results in earlier diagnosis.
If the early signs are ignored, rapid weight loss – often more than 5 kg – results from increased lipolysis and dehydration.
Acid-smelling breath (with acetone smell) occurs with the accumulation of CO2 due to shifts in acid base (very low pH and blood bicarbonate). At this stage, hospital treatment is urgently required.
These are the laboratory and other assessments which should be carried out. in underserved settings: high glucose with altered vital signs (pulse, BP, respiratory rate) and dehydration should be enough to begin treating for DKA.
Due to the metabolic acidosis, there is a shift of intra-cellular K+ to the extra-cellular fluid.
Osmotic diuresis results in the loss of potassium. Therefore, people with DKA usually have an overall deficit of potassium.
Cardiac monitoring is important in severe DKA to assess the possibility of heart attack as well as the ECG changes in hypoglycaemia or hyperkalaemia (excess potassium).
Blood cultures should be performed to exclude underlying infection.
These are the results of clinical tests that may be seen in a person with DKA. Although ketoacidosis may be present with blood glucose levels within the normal range, blood glucose is usually above 13.8 mmol/L (250 mg/dl).
As mentioned previously, there are total body deficits in potassium (K+). Sodium (Na+) will also be low. However, the lab results may be misleading because high lipid levels in a person with uncontrolled diabetes may spuriously lower sodium levels. Vascular dehydration plus the escape of potassium from cells often raises potassium levels.
Treatment with insulin results in the rapid movement of potassium and glucose from the extra-cellular fluid back into the cells, thus potentially causing dangerous falls in potassium levels.
In treatment, therefore, it is most important to correct shock and severe dehydration (with renal impairment in older people) before adding potassium and then insulin. Serum bicarbonate (HCO3) will be low. The lower the HCO3 or blood pH, the more severe the ketoacidosis.
Kitabchi AE, Guillermo E, Umpierrez GE, Fisher JN. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
It has been shown that the prognosis is improved if a written protocol is available and followed meticulously.
Managing DKA is a three pronged approach – IV fluids, Serum [K+] and insulin to correct the acidosis
Fluid is essential in the initial treatment of DKA. This helps to reverse dehydration, which in turn reduces production of counterregulatory hormones. It also lowers blood glucose by improving renal perfusion. Shock and severe dehydration must be corrected first with normal saline (NaCl 0.9%). The first litre of fluid is often delivered within the first 30 minutes.
After this phase of resuscitation, the volume of fluid and the speed at which the fluid is administered depends on the clinical status of the person, as well as their age and overall osmolality – the higher the osmolality, the greater the need for caution during rehydration. It is now agreed that full rehydration should take place steadily over 48 hours.
If vomiting persists (especially if consciousness is impaired) a nasogastric (NG) tube is advisable to empty and drain the stomach.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008. Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes, 32(suppl 1).
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008. Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes, 32(suppl 1).
NaHCO3 = sodium bicarbonate
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008. Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes, 32(suppl 1).
Although complications are not frequent, if these occur they are often serious and life-threatening.
With slower insulin infusions, hypoglycaemia is now much rarer; with careful potassium monitoring, cardiac arrhythmias with hypogycaemia or hyperkalaemia should be avoided.
The insertion of an NG tube to drain the stomach contents is very important in preventing continuing vomiting and aspiration pneumonia, especially in older people or those with impaired levels of consciousness.
If cerebral oedema is suspected, immediate Mannitol infusion is recommended before considering cerebral imaging.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008. Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes, 32(suppl 1).
Once treatment has been completed, people may show a rapid improvement, especially young children. It is important to maintain treatment while ketosis continues.
Once alert, people should be started on oral fluids and food.
Once ketosis is minimal, it is safe to start subcutaneous (s/c) short-/rapid-acting insulin. If using short acting it must be given 30-60 minutes before stopping the IV insulin infusion so that the s/c dose has time to be absorbed from the injection site.
After a few injections of this insulin the patient may be moved onto the preferred insulin regimen including a basal insulin.
Potassium-containing drinks and food (such as tea, fruit juices) may be helpful to complete the process of replacing the entire deficit – especially if there has been some degree of previous malnutrition.
Kalra S, Kalra B, Sharma A, Nanda G. (2007). Pre diabetes and ketosis: treatment with aspart insulin. Diabetes Vasc Dis Res ,4, S100.
Kalra S, Kalra B, Nanda G. (2006). OPD management of ketosis in pregnancy: aspart vs. regular insulin. Diabetic Medicine, 23 (Suppl 4), 504.
As mentioned in slide 1, hyperosmolar hyperglycaemic state (HHS) used to be called hyperosmolar hyperglycaemic non-ketotic syndrome (HHNS).
It has been renamed because ketosis may or may not be present to some degree. It is more of a state of altered consciousness when coma is not present.
HHS is another complication of steadily increasing hyperglycaemia and polyuria – often with a myocardial infarction or concurrent infection.
This usually occurs in older people, who are often unable to keep up with hydration and become progressively more confused and dehydrated.
Blood glucose rises sharply due to decreased renal perfusion and the inability to excrete excess glucose.
Kitabchi A.E., Guillermo E., Umpierrez, G.E., Fisher J.N. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
HHS is less common than DKA but the rate of mortality is much higher.
There is often a delay in recognising HHS because early symptoms may be mild. People do not reach the hospital until serious mental deterioration has already occurred.
HHS can occur in people with type 1 diabetes and in younger people if there is sufficient insulin to prevent ketosis but insufficient to prevent dehydration. HHS occurs more rarely in younger people but has similarly serious implications due to hyperosmolality.
Kitabchi A.E., Guillermo E., Umpierrez G.E., Fisher J.N. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
Blood glucose levels are sometimes very high. Because of this, coupled with serious dehydration, the blood becomes thicker and serum osmolality dangerously high.
Urine ketones are usually negative or only mildly positive.
Severely raised osmolality dehydrates the brain markedly and causes major changes in mental function.
It is these changes and the treatment with fluids that make this “syndrome” so dangerous.
Note that the precipitating factors for HHS are the same as for DKA.
Elderly people who are not known to have diabetes and who may not recognise hyperglycaemia are at particular risk of developing HHS.
Kitabchi A.E., Guillermo E., Umpierrez G.E., Fisher J.N. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
Initial symptoms include polyuria and polydipsia. Urine output drops as the person becomes more dehydrated. The ability to recognise thirst may also decrease with altered mental status.
In addition altered mental status can make it difficult to obtain the person’s history. Family and friends may be important in supplying information about the person’s health history over the previous few weeks.
Profound dehydration leads to hypotension and tachycardia.
It is important to recognise mental deterioration and dehydration in older people with type 2 diabetes.
There may be precipitating factors which require treatment, such as:
Infection
Heart attack
Stroke
Pancreatitis
These are the serious biochemical results one would expect in a person with HHS.
Although acidosis is not a typical feature, it does sometimes occur.
Kitabchi A.E., Guillermo E., Umpierrez G.E., Fisher J.N. (2009). Management of hyperglycemic crises in patients with diabetes. Diabetes Care, 32, 1335-1343.
In HHS, the first and foremost therapy is fluid replacement because of the severe dehydration.
However, the speed of rehydration has been the subject of great debate; generally it is believed that the process should be slow and steady, probably with normal saline, to avoid excess fluid crossing the blood-brain barrier, causing cerebral oedema.
There is also a risk of congestive heart failure. Therefore, fluid must be carefully replaced and monitored meticulously. Half-strength normal saline may be needed if sodium levels rise.
Potassium and insulin are usually – but not always – needed as blood glucose falls successfully with improved hydration.
Blood pressure and pulse should be monitored hourly to assess hydration.
Monitoring of cardiac or central vein pressure (CVP) may also be of value.
The treatment of both DKA and HHS have similar complications.
Hypokalaemia is more likely in older people with poor nutrition, and when insulin is administered.
Cerebral oedema is more of a risk in HHS than in DKA and carries a high risk of death.
Clinical monitoring is of the utmost importance when looking out for further mental deterioration and signs of cerebral oedema – such as a rise in blood pressure, slowing pulse, irritability and headache.
The incidence of DKA and HHS can be reduced through improved awareness of diabetes and its early symptoms, and early intervention.
All people with diabetes should be taught how to manage an episode of illness and to seek help if they are unable to manage their blood glucose levels.
Families of elderly people with diabetes should be made aware of the symptoms of deteriorating diabetes control and instructed to seek help if concerned, especially if changes in behaviour occur. These may be due to either low or high blood glucose levels.
When a person with diabetes develops an illness, and there is a risk of the serious complications that have just been discussed.
Therefore, it is very important that people with diabetes are well prepared to cope with illness.
If blood glucose levels are adequately managed, people with diabetes are no more likely to become sick than the general population.
However, if blood glucose levels are poorly controlled, people will have decreased immunity. The white cells do not work as effectively in the presence of high blood glucose levels, making people prone to infections.
Moreover if blood glucose levels are generally high, this is likely to cause some degree of polyuria and probably persistent levels of mild dehydration, making some people with diabetes more prone to DKA or HHS in the presence of further stress such as infections.
An illness occurring in people with diabetes can have three different effects on their glucose metabolism:
With some infectious illnesses, especially those which are systemic and cause fever (i.e. pneumonia, flu, tonsillitis), stress hormones are released, gluconeogenesis is increased. This results in greater insulin requirements and some degree of insulin insensitivity. As a result, hyperglycaemia occurs and ketosis can develop
Illness causing nausea, vomiting and/or diarrhoea, such as gastroenteritis, can lead to slow gastric emptying (but rapid intestinal transit), poor absorption of nutrients and hypoglycaemia
Some milder illnesses, such as colds, non-febrile chicken pox etc, may have little or no effect on blood glucose control
DKA and other complications are usually preventable if illness is managed appropriately.
If people do not know how to manage their diabetes during illness, they may run into problems at some stage.
Many people have been taught to always eat following administration of insulin. Therefore, when unwell and unable to eat, they think insulin should be omitted.
Most illness causes metabolic stress and increases blood glucose levels. Therefore, increased insulin is often required.
Prevention of dehydration is equally important. During illness, people should be instructed to drink more than usual – ideally a measured amount of sugar-free drinks each hour is recommended. If unable to retain fluids, they should seek medical help.
In contrast, gastroenteritis may cause hypoglycaemia. In this case, with decreased intake of carbohydrates, the instruction should be to consume carbohydrates by drinking sweetened drinks. Insulin doses may also need to be decreased.
Individual guidelines should be provided for those on blood glucose-lowering medications other than insulin.
It is important to identify the cause of the illness such as a viral infection (flu), a urinary tract infection, etc. This may need specific treatment such as antibiotics.
Symptoms such as headache or fever might be helped by specific treatment such as paracetamol.
Fluids are especially important if there is polyuria, fever, vomiting or diarrhoea to avoid dehydration.
More frequent testing of blood for glucose is required. As well testing for ketones is important in type 1 diabetes and type 2 when hyperglycaemic.
As discussed previously, insulin must never be discontinued.
Unless there is severe hypoglycaemia associated with serious gastrointestinal infection, the long- or intermediate-acting insulin is continued at the usual dose or sometimes higher.
Shorter acting insulin, either soluble or rapid acting should be adjusted according to blood glucose values. Some suggestions for how to do this are in the next slides. Rapid acting analogues may be safer when eating patterns are erratic during illness.
A person with type 2 diabetes not previously taking insulin may need short-term insulin treatment if a severe illness is present and blood glucose levels are inadequately controlled with oral glucose-lowering medication.
Hanas R. (2004). Type 1 diabetes in children, adolescents and young adults. 2nd edition. London: Publ Class Publishing.
This is an example of an algorithm that might be suggested for dealing with blood glucose control during different types of illness.
This is a suggested set of guidelines for problem solving where the usual dose of the rapid-acting insulin is increased or decreased according to the measured blood glucose.
If the blood glucose level is low (perhaps when there is vomiting and diarrhoea with gastroenteritis) the rapid-acting insulin will need to be decreased, sometimes by 50%.
On the other hand, if there is hyperglycaemia, the insulin dose will be increased. The exact dose may vary but this type of written guideline may be helpful to people with type 1 diabetes.
You will see that if blood glucose is higher than 18 mmol (325 mg/dl) there may be a 100% increase in insulin dosage for particular meals, but this will vary according to how much food is ingested during illness.
Meltzer, S. Yale, J.F. et al. (2007). Practical Diabetes Management: Clinical Support for Primary Care Physicians. Toronto, ON: Canadian Diabetes Association.
During periods of stress or illness, basal insulin rates can be increased (often between 25% to 100%).
Correction factors can be calculated using total daily insulin dose to determine how much the addition or subtraction of one unit of insulin will lower or raise the blood glucose level.
When unwell, this correction factor should be used to give bolus doses of insulin to correct high blood glucose levels.
If ketones are large in urine or >3mmol/L in blood, the correction dose may need to be doubled.
Correction doses should be repeated every 1 to 3 hours while hyperglycaemia and ketones persist. Therefore, close monitoring of blood glucose and ketones is required.
If hyperglycaemia persists, there may be reduced insulin absorption due to local inflammation. The site of the cannula should be changed.
If people are unable to tolerate food and blood glucose levels are below 12 mmol/L (216 mg/dl) they should be given about 150 ml of sweetened fluids each hour to avoid hypoglycaemia. Small sips may be necessary if they are nauseated.
In addition, if there is fever or diarhoea, additional sugar-free fluid may be required to replace lost fluid.
Sweetened fluids are not required if the blood glucose level is above 15 mmol/L (216 mg/dl). Sugar-free fluids should be given to replace fluid loss – often 150 ml to 300 ml per hour.
In hot climates fluid intake should be greater.
Canadian Diabetes Association, (2006). Beyond the Basics. Toronto, ON: Canadian Diabetes Association.
All people with diabetes should have guidelines on when to seek professional help.
It is important that people seek specialist care in hospital if illnesses become complicated or worsen over time.
Mild abdominal pain may be common in several illnesses. However, if it becomes more severe, this may be an indication that the person is developing DKA (gastritis/liver swelling/ileus) and may require urgent hospitalisation.
Similarly, if breathing has changed, the person may be developing pneumonia or, even more importantly, the acetone breath of ketoacidosis – requiring immediate attention.
Confusion or decreasing level of consciousness is another sign of their condition worsening. People with diabetes that are ill may need the assistance of their family or supports to recognize the symptoms and go to hospital. It is important that family are provided diabetes self-management education in order to respond.
Notes to the educator: This case study should be used to prompt a group discussion.
Nausea and gastrointestinal discomfort is a known side effect of metformin. Its use in a gastrointestinal illness is therefore contraindicated.
Short-term insulin therapy may be required if the person becomes severely hyperglycaemic.
Metformin should only be reintroduced once the person is able to tolerate a full diet.
Management of illnesses should be discussed with people before they get sick and, if possible (especially in people on insulin), written guidelines should be available. This must include guidance on when a healthcare professional should be contacted during illness.
The guidance should include the importance of regular urine and blood tests during illness and goals for blood glucose and ketones (urine or blood).
People should be given clear written guidelines about supplemental insulin if ketones are present, what fluids to drink if unable to eat and what equipment they should have on hand (i.e. calorie fluids, short- or rapid-acting insulin, methods to test glucose and ketones, etc).
Most references regarding sick days are found in the bigger or more practical text books (especially those dealing with children) or patient information packs published by ADA, CDA, DUK and pharmaceutical companies. A good exercise would be to design your own guidelines for practical, local use.
