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Diabetic ketoacidosis (DKA) is the leading cause of mortality in childhood diabetes. The primary cause of DKA is absolute or relative insulin deficiency:
- Absolute - eg, previously undiagnosed type 1 diabetes mellitus or a patient with known type 1 diabetes who does not take their insulin.
- Relative - stress causes a rise in counter-regulatory hormones with relative insulin deficiency.
DKA can be fatal
The usual causes of death are:
- Cerebral oedema - has a mortality of 25% and is more common in younger children.
- Hypokalaemia - which is preventable with good monitoring.
- Aspiration pneumonia - thus, use of a nasogastric tube in the semi-conscious or unconscious is advised.
- Deficiency of insulin.
- Rise in counter-regulatory hormones, including glucagon, cortisol, growth hormone, and catecholamines.
- Thus, inappropriate gluconeogenesis and liver glycogenolysis occur compounding the hyperglycaemia, which causes hyperosmolarity and ensuing polyuria, dehydration and loss of electrolytes.
- Accelerated catabolism from lipolysis of adipose tissue leads to increased free fatty acid circulation, which on hepatic oxidation produces the ketone bodies (acetoacetic acid and beta-hydroxybutyric acid) that cause the metabolic acidosis.
- Potassium moves from the intracellular to the extracellular space in a switch with hydrogen ions that accumulate. Much of this extracellular potassium is then eliminated in urine, creating total body hypokalemia.
A vicious circle is usually set up as vomiting usually occurs compounding the stress and dehydration; the cycle can only be broken by providing insulin and fluids; otherwise, severe acidosis occurs and can be fatal.
- Acidosis - indicated by blood pH of <7.3 or bicarbonate <18 mmol/L:
- pH ≥7.1 indicates mild or moderate DKA.
- pH <7.1 indicates severe DKA.
- Ketonaemia (indicated by blood beta-hydroxybutyrate above 3 mmol/L) or ketonuria (indicated by ++ or more on urine dipstick).
There is usually raised blood glucose >11 mmol/L. However, children and young people with normal blood sugar levels can develop DKA.
- There is wide geographic variation in the frequency of DKA at onset of type 1 diabetes; rates inversely correlate with the regional incidence of type 1 diabetes.
- Frequencies range from 15% to 70% in Europe and North America.
- DKA at diagnosis is more common in children aged under 5 years, and in children whose families do not have ready access to medical care for social or economic reasons.
- The risk of DKA in established type 1 diabetes is 1-10% per per year. The risk is increased in:
- Children with poor metabolic control or previous episodes of DKA.
- Peripubertal and adolescent girls.
- Children with psychiatric disorders, including those with eating disorders.
- Children with difficult or unstable family circumstances.
- Children who omit insulin.
- Children with limited access to medical services.
- Insulin pump therapy (as only rapid- or short-acting insulin is used in pumps, interruption of insulin delivery for any reason rapidly leads to insulin deficiency).
Children with DKA may present with any or all of the following common features of the condition:
- Lethargy, confusion.
- Polyuria ± polydypsia.
- Weight loss.
- Abdominal pain ± vomiting (may mimic a surgical abdomen).
- Rapid, deep sighing (Kussmaul's respirations).
- Ketotic breath - fruity, pear drops smell.
- Fever - this is not normal for DKA and a source of sepsis must be sought.
- Shock, coma (assess Glasgow Coma Scale (GCS)).
- Also look for any evidence of cerebral oedema (see 'Cerebral oedema', below), ileus or infection.
Other causes of metabolic acidosis:
- Overdose - eg, salicylates, iron, ethylene glycol, ethanol.
- Lactic acidosis.
- Inborn errors of metabolism such as ethylmalonic acidaemia.
- Acute kidney injury.
- Gram-negative septicaemia.
On arrival in hospital, a child or young person with suspected DKA should have immediate:
- Capillary blood glucose.
- Capillary blood ketones (beta-hydroxybutyrate) if near-patient testing is available, urinary ketones if not.
- Capillary or venous pH and bicarbonate.
Further investigations should include:
- Plasma blood glucose.
- Renal function - may reveal a pattern consistent with dehydration; potassium may also be abnormal (If laboratory measurement of serum potassium is delayed, perform an ECG for baseline evaluation of potassium status).
- Venous pH, bicarbonate and blood gases.
- Repeated monitoring of near-patient testing for blood ketones - this is superior to testing for urinary ketones, which are unhelpful for ongoing monitoring.
- Urine dipstick - looking for ketones and infection.
- FBC - leukocytes increased with left shift (not necessarily caused by infection) - but fever is not normal in DKA.
- Consider blood and urine cultures, CXR, CSF, throat swab and other appropriate samples if there is any indication of possible infection. Always look for precipitating causes - eg, urinary tract infection, chest infection, etc.
- Assessment and monitoring of conscious level.
The following is based on National Institute for Health and Care Excellence (NICE) and British Society for Paediatric Endocrinology and Diabetes (BSPED) DKA guidelines.
- Airway - check the airway is patent, attempt to open it if not. Seek urgent anaesthetic review and discuss with paediatric critical care specialist if airway is not protected due to a reduced level of consciousness as intubation may be indicated. Consider need for nasogastric tube to decompress and empty the stomach and lower the risk of aspiration, particularly if there is reduced consciousness. Once placed, aspirate and leave on free drainage.
- Breathing - consider need for oxygen -eg, if altered level of consciousness (if necessary 6-10L/min via Hudson mask)
- Circulation - insert two intravenous (IV) cannulae if possible, one for fluid and medications and one as a blood sampling line. Attach cardiac monitor. Assess cardiovascular status and only give a fluid bolus (10 ml/kg 0.9% sodium chloride) if there is hypotensive shock. Discuss any further bolus and the use of inotropes with a paediatric critical care specialist.
- Disability - assess conscious level early on. All patients should have GCS assessment, or a modification of the verbal response score for younger children, and one-hourly neurological observations. If the patient is comatose or semi-conscious, consider cerebral oedema and institute treatment and arrange transfer to PICU/HDU (but do not delay therapy).
Ideally, weigh the patient to calculate exact fluid replacement. However, this may not be possible and either a recent weight can be used or an estimated weight. Weight can be estimated by calculating for the child's age or surface area. Serial weights may also help chart the child's progress.
Treat DKA with oral fluids (and subcutaneous insulin - see below) only if the child or young person is alert, not nauseated or vomiting, and not clinically dehydrated. Signs of dehydration include:
- Increased capillary refill time.
- Reduced skin turgor.
- Abnormal respiratory pattern.
- Dry mucous membranes.
- Sunken eyes.
- Weak pulse.
- Cool peripheries.
- Hypotension and oliguria, which are late signs in children and indicate severe dehydration.
However, latest guidelines state that it is not possible to accurately assess the degree of dehydration; therefore advise the clinician to:
- Assume a 5% fluid deficit in mild or moderate DKA (ie blood pH of 7.1 or above).
- Assume a 10% fluid deficit in severe DKA (ie a blood pH below 7.1).
A fluid bolus is not advised routinely. If the child was in hypotensive shock with severe DKA, this would have been discussed with a senior paediatrician as above at immediate assessment/resuscitation stage, and a single bolus of 10 ml/kg 0.9% sodium chloride given.
Fluid maintenance requirements are calculated as follows (comparatively low rate of replacement to avoid cerebral oedema):
- If weight is less than 10 kg, give 2 ml/kg/hour.
- If weight is between 10 and 40 kg, give 1 ml/kg/hour.
- If weight is more than 40 kg, give a fixed volume of 40 ml/hour.
To calculate overall fluid need, add together the fluid maintenance requirement above with the fluid deficit assumed (5 or 10%), and aim to provide this evenly distributed over the first 48 hours. (So hourly rate = deficit/48 hours + maintenance per hour.) Note also:
- Use 0.9% sodium chloride with 20 mmol potassium chloride in 500 ml (40 mmol per litre) until blood glucose levels are less than 14 mmol/L.
- If more than 20 ml/kg of fluid has been given by IV bolus, subtract any additional bolus volumes from the total fluid calculation for the 48‑hour period.
- Neonatal DKA will require special consideration and larger volumes of fluid than those quoted may be required, usually 100-150 ml/kg/24 hour.
- Don't give oral fluids to a child or young person who is receiving IV fluids for DKA until ketosis is resolving and there is no nausea or vomiting. If this occurs before the 48-hour period ends, the rate of IV infusion will need adjustment.
- The BSPED guidelines give worked examples of these calculations, and the BSPED site hosts a fluid calculator.
Treatment with insulin is essential to return the blood sugar level to normal limits, and to prevent further lipolysis and ketogenesis. The current recommendations for insulin therapy are as follows:
- IV fluids and potassium replacement should occur for one to two hours before starting insulin, by which point the blood glucose should have started falling.
- Early insulin has been associated with an increased chance of developing cerebral oedema.
- Insulin should be given as an IV infusion at a dosage between 0.05 and 0.1 units/kg/hour. Use pre-filled syringes containing 50 Units of soluble insulin in 50 ml 0.9% sodium chloride. An initial bolus is not recommended. Continuous subcutaneous insulin pumps should be stopped while the IV infusion is given, but long-acting insulin treatment may be continued.
- Subcutaneous insulin may only be used along with oral fluids where the child or young person is alert, not nauseated or vomiting, and not clinically dehydrated.
- There is always depletion in total body potassium; however the initial serum K values may not be low; instead, they can be normal-to-high, reflecting the transcellular shift caused by the ketoacidosis.
- This masks the deficit which is uncovered once insulin has commenced.
- Ensure that all fluids (except any initial bolus) contain 40 mmol/L potassium chloride, unless there is evidence of renal failure.
- Femoral line insertion is associated with femoral vein thrombosis and these patients need to be considered for anticoagulation.
- Anticoagulation may also be considered in other patients (eg, those who are significantly hyperosmolar) and this should be discussed with senior colleagues.
MonitoringChildren admitted with DKA must be monitored closely until their biochemistry has normalised. Monitoring should include:
- Measurements of pulse, respiratory rate and blood pressure - at least hourly.
- Accurate fluid input/output documentation (catheterisation may be required) - at least hourly.
- ECG monitoring - due to potential potassium imbalance.
- Capillary blood glucose - hourly, but it must be checked regularly against venous glucose, as capillary levels may be inaccurate in DKA.
- 1- to 2-hourly capillary blood ketones (if available); if not, test urine for ketones. Near-patient ketone testing is a fairly new addition to the guidelines. This will help confirm that the blood ketones are falling adequately. If it does not fall then check infusion lines, calculations and the dose of insulin. If these are all fine then consider sepsis or inadequate fluid replacement.
- Twice-daily weights may be helpful
- U&Es, BG, FBC, venous blood gas and osmolality - every 2-4 hours.
- Hourly assessments of conscious level including the modified GCS.
- Half-hourly neurological investigations in children under 2 years or those with severe DKA including using the modified GCS and looking for indications of cerebral oedema, such as headache, vomiting, rising blood pressure, confusion or irritability, slow heart rate, decreased oxygen saturation.
Where should the patient be managed?
All children with DKA require a high level of nursing care and should be considered high-dependency patients. Those aged under 2 years or with severe DKA, require one-to-one nursing, ideally on a high-dependency unit.
Once ketoacidosis has resolved
- Continue IV fluids until the patient is drinking and tolerating food.
- When the blood glucose has fallen to 14 mmol/L, add glucose to the fluid. When pH is above 7.3, ketones are below 3, the blood glucose is down to 14 mmol/L, and a glucose-containing fluid has been started, the insulin infusion rate can be reduced to 0.05 units/kg/hour.
- Only change to subcutaneous insulin once blood ketones are <1.0 mmol/L (note urine ketones may still be present) and once the child or young person is alert, tolerating oral fluids and not vomiting.
- Start subcutaneous insulin at least half an hour before stopping the insulin infusion.
- Cerebral oedema is associated with nearly 25% mortality and usually manifests within the first 12 hours.
- Risk factors include:
- Younger age.
- New-onset diabetes mellitus.
- Longer duration of symptoms.
- Use of bicarbonate in management of ketoacidosis (now rarely used).
- Patients develop:
- Confusion or irritability.
- Rising blood pressure and bradycardia.
- Decreased oxygen saturation.
- Papilloedema - a late sign.
- Other later features include deterioration in conscious level, pauses in breathing, oculomotor palsies, pupillary inequality or dilation.
- Exclude hypoglycaemia.
- If cerebral oedema is suspected or any typical late features develop, treat immediately with the most readily available of mannitol (20%, 0.5-1 g/kg over 10-15 minutes) or hypertonic sodium chloride (2.7% or 3%, 2.5-5 ml/kg over 10-15 minutes).
- Mannitol may need to be repeated after two hours.
- Reduce rate of fluid administration - halve the maintenance dose and discuss with a senior clinician.
- Transfer to ICU may be appropriate - may need intubation and ventilation, which should only be performed by an experienced clinician.
- Alternative diagnoses may need to be considered (eg, thrombosis, haemorrhage, infection) and a CT brain scan will help delineate the cause.
- Systemic infections.
- Aspiration pneumonia.
- Venous thromboembolism.
- Appendicitis - consider if there is ongoing abdominal pain.
- Others - eg, pneumothorax, interstitial pulmonary oedema, hyperosmolar hyperglycaemic non-ketotic coma.
Prevention of recurrence
After recovery, discuss the factors which might have led to the episode. Educate the patient and/or care-givers on the management of diabetes, and prevention of DKA, including:
- Adherence to therapy.
- Early symptoms of DKA.
- Managing intercurrent illnesses (sick day rules).
- Sources of support and advice.
When DKA is recognised and treated immediately, the prognosis is excellent. However, when a patient has prolonged or multiple courses of DKA or if DKA is complicated by cerebral oedema then the prognosis can be very poor.
The mortality rate of children with DKA in the UK is approximately 0.31%, with the majority of these deaths occurring as a result of cerebral oedema.
Cerebral oedema associated with DKA is more common in children than in adults. In the UK around 70-80% of diabetes-related deaths in children under 12 years of age are caused as a result of cerebral oedema[4, 9].
DKA at the time of diagnosis of type 1 diabetes may be associated with poor long-term metabolic regulation and residual beta cell function.
Further reading and references
Management of Type 1 Diabetes Mellitus during illness in children and young people under 18 years (Sick Day Rules); Association of Children's Diabetes Physicians, BSPED, Children and Young People's National Diabetes Network
Lokulo-Sodipe K, Moon RJ, Edge JA, et al; Identifying targets to reduce the incidence of diabetic ketoacidosis at diagnosis of type 1 diabetes in the UK. Arch Dis Child. 2014 Jan 6. doi: 10.1136/archdischild-2013-304818.
Recommended Guideline for the Management of Children and Young People under the age of 18 years with Diabetic Ketoacidosis; British Society for Paediatric Endocrinology and Diabetes (BSPED), 2015
EL-Mohandes N, Huecker MR; Diabetic Ketoacidosis, Pediatric
Diabetes (type 1 and type 2) in children and young people: diagnosis and management; NICE Guidelines (Aug 2015 - updated Nov 2016)
Global Guideline for Diabetes in Childhood and Adolescence; International Diabetes Federation and International Society for Pediatric and Adolescent Diabetes, 2011
de Vries L, Oren L, Lazar L, et al; Factors associated with diabetic ketoacidosis at onset of Type 1 diabetes in children and adolescents. Diabet Med. 2013 Nov30(11):1360-6. doi: 10.1111/dme.12252. Epub 2013 Jul 9.
Yau M, Sperling M; Treatment of Diabetes mellitus in Children and Adolescents
Olivieri L, Chasm R; Diabetic ketoacidosis in the pediatric emergency department. Emerg Med Clin North Am. 2013 Aug31(3):755-73. doi: 10.1016/j.emc.2013.05.004. Epub 2013 Jul 6.
Management of Diabetic Ketoacidosis in Adults; Joint British Diabetes Societies Inpatient Care Group (March 2010)
Fredheim S, Johannesen J, Johansen A, et al; Diabetic ketoacidosis at the onset of type 1 diabetes is associated with future HbA1c levels. Diabetologia. 2013 May56(5):995-1003. doi: 10.1007/s00125-013-2850-z. Epub 2013 Feb 7.