Diabetic ketoacidosis and hyperosmolar hyperglycaemic state: quick reference

About this quick reference

Treatment protocols differ between regions. Always follow the local protocol for exact infusion rates, electrolyte concentrations and level of care. This quick reference is intended primarily for adults and summarises the order in which measures are taken and the principles that are common to all protocols.

Children, pregnant women and patients with advanced renal failure, marked heart failure or circulatory shock require a specific protocol and early specialist involvement. DKA and HHS are dynamic conditions. Treatment must be guided by the clinical response and by repeated laboratory measurements, not by the values on admission alone.

Diagnosis

Current diagnostic criteria

According to the international consensus report of 2024, the diagnosis of DKA requires three components: diabetes or hyperglycaemia, ketosis and metabolic acidosis. A very high glucose value is no longer required [1].

Blood ketones are preferable to urine ketones. The principal ketone body in DKA is beta-hydroxybutyrate, whereas ordinary urine dipsticks mainly measure acetoacetate. Urine ketones may therefore underestimate the ketosis early on and remain positive after the clinically relevant ketosis has resolved. Capillary measurement of beta-hydroxybutyrate has high diagnostic accuracy [2].

A venous blood gas is generally sufficient for the assessment of pH and bicarbonate. An arterial blood gas is needed mainly when concomitant respiratory failure or an exact assessment of oxygenation requires it [3].

Calculation of osmolality

Use the same formula throughout treatment:

Effective osmolality, tonicity:

2 × plasma sodium + plasma glucose

Total calculated osmolality:

2 × plasma sodium + plasma glucose + plasma urea

All concentrations are given in mmol/L and the result in mosm/kg. Urea is included in the total osmolality but not in the effective osmolality, because urea crosses cell membranes relatively freely and therefore does not produce the same sustained shift of water [3].

Severity of DKA

The classification helps in choosing the level of care. The clinical state, the circulation, comorbidity and the precipitating cause carry at least as much weight as the laboratory values [1].

Mixed picture of DKA and HHS

Overlap is common. Treat as mixed DKA and HHS if the patient has marked hyperosmolality together with significant ketosis and acidosis. With blood ketones ≥ 3 mmol/L and acidosis, the ketosis must be treated immediately with DKA-dose insulin, while the osmolality is corrected cautiously [1,3].

Euglycaemic DKA

Euglycaemic DKA means ketosis and metabolic acidosis despite a normal or only moderately raised glucose, often below 13.9 mmol/L. The condition occurs above all in:

• treatment with SGLT2 inhibitors
• pregnancy
• prolonged fasting or a very low carbohydrate intake
• excessive alcohol consumption
• vomiting or other restriction of energy intake
• partially treated DKA
• marked liver disease.

A normal or low plasma glucose therefore does not exclude DKA. In nausea, vomiting, abdominal pain, tachypnoea or an unexplained high anion gap acidosis, blood ketones and a venous blood gas must be checked even if the glucose value is not particularly high [4].

In patients taking SGLT2 inhibitors the typical rise in glucose may be absent. In a large compilation of reported cases the median glucose was about 10.6 mmol/L despite clear acidosis and ketosis [5]. The SGLT2 inhibitor must be stopped immediately when DKA is suspected. The question of restarting it is decided later, after assessment of the precipitating factors and of the future risk.

Clinical presentation

DKA

Common findings:

• polyuria and polydipsia
• dehydration and tachycardia
• nausea, vomiting and abdominal pain
• Kussmaul respiration
• the smell of acetone
• weakness and weight loss
• impaired consciousness in severe acidosis, hyperosmolality or concomitant critical illness.

Abdominal pain may be caused by DKA, but may equally signal pancreatitis, ileus, ischaemia or another acute abdominal condition. If the abdominal pain persists as the acidosis improves, another cause must be actively investigated.

HHS

HHS usually develops over several days or weeks. Common findings:

• marked dehydration, sometimes without dramatic external signs
• polyuria and polydipsia early in the course
• hypotension, tachycardia and acute kidney injury
• lethargy, confusion, focal neurological signs, seizures or coma
• concomitant infection, stroke, myocardial infarction or drug effect.

Cognitive impairment becomes more common at an osmolality above about 330 mosm/kg, but impaired consciousness is not an absolute diagnostic requirement. A patient with HHS therefore need not be unconscious [3].

Always look for a precipitating cause

Common precipitating factors are:

• infection
• missed insulin doses or other interruption of diabetes treatment
• insulin pump failure, a kinked cannula or an empty insulin reservoir
• newly diagnosed diabetes
• myocardial infarction
• stroke
• pancreatitis
• surgery or trauma
• pregnancy
• glucocorticoids
• thiazide diuretics, sympathomimetics or certain antipsychotics
• SGLT2 inhibitors
• alcohol or other drugs
• fasting, vomiting or marked dehydration
• psychosocial difficulties, poor access to insulin or recurrent interruptions of treatment.

Take a history covering insulin and other diabetes drugs, the most recent dose, technical problems with the pump or sensor, signs of infection, chest pain, neurological symptoms, the possibility of pregnancy, alcohol, drugs and nutritional intake.

The investigation is adapted to the clinical picture but usually includes full blood count, CRP, electrolytes, creatinine, liver tests, blood gas, blood ketones, glucose, osmolality, ECG and urine dipstick. Consider troponin, lipase, cultures, chest radiography, a pregnancy test and targeted imaging. Leucocytosis may be caused by the stress response in DKA and does not prove infection.

Immediate measures

1. Carry out an ABCDE assessment and decide the level of care.
2. Insert at least one large-bore peripheral cannula, often two in severe DKA or HHS.
3. Take a venous blood gas, blood ketones, glucose, sodium, potassium, chloride, creatinine, urea and other targeted tests.
4. Attach cardiac monitoring in significant potassium disturbance, severe acidosis, circulatory compromise or a high rate of replacement.
5. Start an isotonic crystalloid.
6. Check the potassium before starting insulin.
7. Start intravenous insulin when the potassium and the clinical situation permit. In pure HHS without significant ketosis, insulin is given later than in DKA.
8. Identify and treat the precipitating cause.
9. Contact the diabetes consultant, the general medical consultant or intensive care early in severe illness.

Order of treatment

Fluid therapy

DKA

In DKA there is often a fluid deficit of several litres, frequently around 5 to 10 litres. In an adult without heart or renal failure, international consensus generally recommends an isotonic crystalloid at approximately 500 to 1,000 mL per hour during the first 2 to 4 hours, with faster initial administration in shock and slower administration when there is a risk of fluid overload [1].

The practical sequence is:

1. Usually give about 1,000 mL in the first hour if the circulation and comorbidity permit.
2. Assess pulse, blood pressure, peripheral perfusion, chest findings, sodium, urine output and fluid balance.
3. Continue according to the local protocol and the individual fluid requirement.
4. Replace the remaining deficit gradually, usually over about 24 to 48 hours.

In older patients and in patients with heart failure, advanced renal failure or on dialysis, smaller boluses are used, for example 250 mL, with frequent reassessment. Standardised administration of several litres may be dangerous in these groups.

Isotonic sodium chloride and balanced crystalloid are both possible initial solutions in DKA. Balanced crystalloids produce less hyperchloraemia. A meta-analysis of 11 randomised trials with 753 patients found a lower chloride after resuscitation but no definite difference in time to resolution of DKA, serious renal events or hypokalaemia [6]. Another meta-analysis in adults and a randomised subgroup analysis suggest somewhat faster resolution of DKA with balanced solutions, but the evidence is heterogeneous and at risk of bias [7,8]. The choice should therefore follow the local protocol, but a balanced crystalloid is a reasonable alternative.

HHS

The fluid deficit in HHS is often larger than in DKA, approximately 100 to 220 mL/kg. At the same time many patients are elderly and have cardiac or renal disease. Correction must therefore be slow and guided by the osmolality [3].

Important targets:

• the osmolality should fall by approximately 3 to 8 mosm/kg per hour
• glucose should not fall faster than about 5 mmol/L per hour
• sodium should not fall by more than about 10 mmol/L over 24 hours
• approximately half of the fluid deficit is replaced during the first 12 hours and the remainder during the following 12 to 24 hours, if comorbidity permits.

In HHS the glucose often falls with fluid alone. Insulin given too early can produce a rapid fall in osmolality, hypokalaemia and a reduced intravascular volume. In pure HHS without significant ketosis, insulin is therefore started only when adequate fluid has been given and glucose or osmolality is no longer falling adequately [3].

Insulin therapy

DKA

Standard treatment is a continuous intravenous infusion of rapid-acting or short-acting insulin:

• the usual initial rate is 0.1 units/kg/hour
• a routine intravenous bolus of insulin is not needed if the infusion can be started without delay
• when the plasma glucose has fallen below about 13.9 mmol/L, a glucose infusion is added and the insulin rate is usually reduced according to the local protocol
• insulin is continued until the ketosis and the acidosis have resolved, not merely until the glucose value is normal [1].

In euglycaemic DKA a glucose infusion is often needed as soon as the insulin is started. Insulin is required to stop lipolysis and ketone production even when the patient is not hyperglycaemic.

In carefully selected, haemodynamically stable patients with mild or moderate uncomplicated DKA, subcutaneous rapid-acting insulin according to a structured protocol may be an alternative. The Cochrane review found no clear difference from intravenous insulin, but the evidence was of low or very low certainty and the method requires close monitoring [9]. Intravenous infusion remains the standard in severe DKA, HHS, pregnancy, circulatory failure or impaired consciousness.

HHS

In pure HHS a lower insulin dose than in DKA is usually used:

• start only after initial fluid therapy, unless significant ketosis or a mixed picture is present
• the usual initial infusion is 0.05 units/kg/hour
• in mixed DKA and HHS, the DKA dose of 0.1 units/kg/hour is used [1,3].

Insulin pump and basal insulin

In DKA in a pump user, insulin delivery by the pump must be stopped and the infusion set disconnected. Document and investigate the possible cause, for example a kinked cannula, leakage, an empty reservoir, a pump that has been switched off, or a technical fault. The pump must not be used for the acute treatment of DKA.

Long-acting basal insulin already prescribed, for example NPH, glargine, detemir or degludec, can as a rule be continued during intravenous treatment. This reduces the risk of insulin deficiency when the infusion is stopped. The dose must however be individualised in, for example, renal failure, repeated hypoglycaemia or a changed nutritional state [1]. A small randomised trial suggests that early glargine may shorten the time to resolution of DKA without an increase in hypoglycaemia, but this does not replace the local protocol [10].

Potassium

Basic principle

Total body potassium is almost always depleted in DKA and HHS because of osmotic diuresis, vomiting and secondary hyperaldosteronism. At the same time, acidosis and insulin deficiency shift potassium out of the cells. The plasma potassium may therefore be high on arrival despite a substantial total deficit. When insulin and fluid are given, the plasma potassium falls rapidly [1,3].

International consensus generally recommends that potassium replacement be started when the plasma potassium falls below 5.0 mmol/L, with a target of about 4 to 5 mmol/L. A common principle is 20 to 30 mmol of potassium per litre of infusion fluid, but the concentration, the route of access and the maximum rate must follow local safety procedures [1].

At a plasma potassium below 3.5 mmol/L, potassium takes priority over insulin. Insulin in this situation can precipitate severe hypokalaemia, muscle weakness and life-threatening arrhythmia. A high rate of replacement requires cardiac monitoring and often central venous access according to the local protocol.

Glucose infusion

When the plasma glucose has fallen to around 13.9 mmol/L, glucose, usually 5 or 10 per cent, is added to the infusion regimen. The purpose is not to correct hypoglycaemia after the event but to prevent it, and at the same time to allow insulin treatment to continue until the ketosis has resolved [1].

In HHS a reasonable initial glucose target is often 10 to 15 mmol/L during the first 24 hours. Full normalisation should not be forced [3].

In euglycaemic DKA a glucose infusion is often started at the same time as the insulin, since ketone production cannot otherwise be treated safely.

Bicarbonate and phosphate

Bicarbonate

Routine bicarbonate treatment is not recommended. Studies have not shown improved survival, faster clinical recovery or better glycaemic control. Possible disadvantages are hypokalaemia, increased carbon dioxide production, paradoxical worsening of ketosis and neurological complications [11].

In extreme acidaemia, usually a pH below 7.0, bicarbonate may be considered after senior assessment and according to the local protocol. The evidence at the very lowest pH values is very limited, because such patients have hardly been included in randomised trials [1,11].

Phosphate

Phosphate often falls during treatment, but routine replacement has not been shown to be of clinical benefit. Check the phosphate in:

• a protracted or severe course
• muscle weakness or respiratory failure
• cardiac compromise
• haemolysis
• malnutrition or excessive alcohol consumption.

Replace in marked or symptomatic hypophosphataemia according to the local protocol. Bear in mind the risk of hypocalcaemia.

Monitoring

Follow the change over time. A single laboratory value may be misleading.

The desired treatment response in DKA is:

• blood ketones fall by at least about 0.5 mmol/L per hour
• bicarbonate rises by about 3 mmol/L per hour
• glucose falls by approximately 3 mmol/L per hour.

If the response fails to appear, check the venous access, the insulin pump, the preparation of the infusion, the infusion rate, the fluid administration, and whether an untreated precipitating cause persists.

Sodium and osmolality

Hyperglycaemia draws water from the intracellular to the extracellular compartment and lowers the measured sodium value. This is primarily a translocational or dilutional hyponatraemia, not classical pseudohyponatraemia.

As the glucose falls, the plasma sodium normally rises. In HHS a fall in glucose of 5.5 mmol/L often corresponds to a rise in sodium of about 2.4 mmol/L. Such a rise is not in itself an indication for hypotonic fluid if the osmolality is at the same time falling at the desired rate [3].

Assess sodium, glucose and osmolality together. A rising sodium is worrying above all if the osmolality is not falling, or if the sodium rises considerably more than expected, which may indicate inadequate fluid administration.

When should intensive care or a higher level of care be considered?

Consider intensive care or the equivalent in:

• severe DKA, particularly pH < 7.0 or bicarbonate < 10 mmol/L
• circulatory shock
• markedly impaired consciousness or seizures
• osmolality > 350 mosm/kg
• plasma sodium > 160 mmol/L
• plasma potassium < 3.5 or ≥ 6.0 mmol/L
• significant arrhythmia
• severe acute kidney injury or oliguria
• respiratory failure
• pregnancy
• concomitant myocardial infarction, stroke, sepsis or other critical illness
• a need for high-rate potassium replacement or other treatment that cannot be monitored safely on a general ward.

Criteria for resolution of DKA

The insulin infusion must not be stopped merely because the glucose value has normalised.

DKA is regarded as resolved when:

• blood ketones are < 0.6 mmol/L
• the venous pH is ≥ 7.3 or the bicarbonate ≥ 18 mmol/L
• the glucose is preferably < 11.1 mmol/L [1].

The anion gap must not be used as the sole criterion for stopping treatment. Large volumes of sodium chloride can produce a hyperchloraemic metabolic acidosis with a persistently low bicarbonate even though the ketosis has resolved. Direct measurement of blood ketones is more specific [1,6].

The patient does not necessarily have to be able to eat for DKA to be biochemically resolved, but a safe plan for continued insulin and glucose administration must be in place.

Criteria for resolution of HHS

HHS is judged to have resolved when all of the following conditions are met:

• osmolality < 300 mosm/kg
• the hypovolaemia has been corrected
• urine output at least 0.5 mL/kg/hour
• cognitive function has returned to the patient's previous level
• plasma glucose < 15 mmol/L [3].

A normalised glucose is not sufficient on its own. Electrolytes, osmolality and the fluid deficit may require treatment for up to 72 hours.

Transition to subcutaneous insulin

Plan the transition before the insulin infusion is switched off.

• Give long-acting basal insulin at least 1 to 2 hours before the intravenous infusion is stopped, if effective basal insulin is not already in place.
• In patients who have already received their usual long-acting insulin, a further basal dose does not automatically need to be given.
• Ensure that mealtime insulin and correction insulin are prescribed once the patient is eating.
• Subcutaneous rapid-acting insulin alone does not provide sufficient overlap if the patient has no active basal insulin.
• In pump therapy, the pump is restarted only once DKA has resolved, the patient can manage the equipment, and a new infusion set, a new cannula and new insulin have been provided.

Insufficient overlap between intravenous and subcutaneous insulin can rapidly produce renewed insulin deficiency and recurrent ketosis.

Thromboprophylaxis in HHS

HHS is associated with an increased risk of both venous and arterial thrombosis. The JBDS recommends prophylactic low-molecular-weight heparin throughout the admission if there is no contraindication [3]. Follow local procedures and make the usual assessment of bleeding risk and renal function.

Therapeutic anticoagulation is not given routinely, but only in confirmed or strongly suspected thrombosis, pulmonary embolism or acute coronary syndrome.

Red flags and pitfalls

• Stopping insulin when the glucose has normalised. Ketones and acidosis govern the treatment of DKA.
• Starting insulin in marked hypokalaemia. The potassium must be corrected first.
• Giving insulin too early in pure HHS. Begin with fluid and follow the osmolality.
• Missing euglycaemic DKA. Check blood ketones and a blood gas when there are symptoms, particularly in patients taking SGLT2 inhibitors.
• Using urine ketones to decide when to stop. Urine ketones may remain positive after DKA has resolved.
• Using the anion gap as the sole criterion for stopping. A hyperchloraemic acidosis may persist after the ketosis has resolved.
• Interpreting a rising sodium as treatment failure without checking the osmolality. The sodium normally rises as the glucose falls.
• Giving standardised large fluid volumes to patients with heart or renal failure. Give smaller boluses and reassess frequently.
• Assuming that all abdominal pain is caused by DKA. Investigate persistent or atypical abdominal pain.
• Giving antibiotics on the basis of leucocytosis alone. Look for clinical, microbiological or radiological evidence of infection.
• Giving bicarbonate or phosphate routinely. Both must be reserved for particular situations.
• Missing mixed DKA and HHS. Marked hyperosmolality together with ketosis requires both immediate insulin treatment and cautious correction of the osmolality.
• Forgetting the precipitating cause. Fluid and insulin treat the metabolic crisis, but not infection, infarction, stroke, pump failure or psychosocially determined insulin omission.
• Having no plan for basal insulin. Intravenous insulin must not be switched off without sufficient overlap.

Cerebral oedema and osmotic demyelination syndrome are rare in adults but serious. New headache, vomiting, a falling level of consciousness, seizures, bradycardia or focal neurological signs require immediate assessment, adjustment of treatment and contact with intensive care. Cerebral oedema is considerably more common in children and adolescents, who must be treated according to a paediatric protocol.

Before discharge

Before discharge, every patient should receive:

• a review of the precipitating cause
• assured access to insulin, needles, measuring equipment and prescriptions
• an updated insulin prescription
• sick-day rules and instructions for ketone measurement
• information on when to contact the emergency department
• a review of the pump or other technical equipment
• a medication review, particularly of SGLT2 inhibitors
• planned diabetes follow-up
• assessment of psychosocial, financial and addiction-related factors in recurrent DKA.

Patients on an SGLT2 inhibitor must know that the drug should normally be paused during acute serious illness, fasting and dehydration, and before major surgery, in accordance with the current product information and local procedures. Initiation or reinstitution after DKA requires an individual risk assessment.

References

1. Umpierrez GE et al. Hyperglycemic Crises in Adults With Diabetes: A Consensus Report. Diabetes Care 2024. PMID: 39052901
2. Brooke J et al. Evaluation of the Accuracy of Capillary Hydroxybutyrate Measurement Compared with Other Measurements in the Diagnosis of Diabetic Ketoacidosis: A Systematic Review. International Journal of Environmental Research and Public Health 2016. PMID: 27563914
3. Mustafa OG et al. Management of Hyperosmolar Hyperglycaemic State in Adults: An updated guideline from the Joint British Diabetes Societies for Inpatient Care Group. Diabetic Medicine 2023. PMID: 36370077
4. Long B et al. Euglycemic diabetic ketoacidosis: Etiologies, evaluation, and management. American Journal of Emergency Medicine 2021. PMID: 33626481
5. Sharma AM et al. Clinical characteristics and outcomes of diabetes-related ketoacidosis in sodium-glucose co-transporter-2 inhibitor users with type 2 diabetes. Diabetes, Obesity and Metabolism 2025. PMID: 40919651
6. Liu Y et al. Comparison of balanced crystalloids versus normal saline in patients with diabetic ketoacidosis: a meta-analysis of randomized controlled trials. Frontiers in Endocrinology 2024. PMID: 38836222
7. Szabó GV et al. Fluid resuscitation with balanced electrolyte solutions results in faster resolution of diabetic ketoacidosis than with 0.9% saline in adults: A systematic review and meta-analysis. Diabetes/Metabolism Research and Reviews 2024. PMID: 38925619
8. Self WH et al. Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials. JAMA Network Open 2020. PMID: 33196806
9. Andrade-Castellanos CA et al. Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis. Cochrane Database of Systematic Reviews 2016. PMID: 26798030
10. Thammakosol K, Sriphrapradang C. Effectiveness and safety of early insulin glargine administration in combination with continuous intravenous insulin infusion in the management of diabetic ketoacidosis: A randomized controlled trial. Diabetes, Obesity and Metabolism 2023. PMID: 36479786
11. Chua HR et al. Bicarbonate in diabetic ketoacidosis: a systematic review. Annals of Intensive Care 2011. PMID: 21906367