The primary cause of diabetic ketoacidosis (DKA) is absolute or relative insulin deficiency:

• Absolute - e.g. previously undiagnosed type 1 diabetes mellitus (T1DM) or patient with known T1DM who does not take their insulin
• Relative - stress causes a rise in counter-regulatory hormones with relative insulin deficiency

Pathophysiology¹

• 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.

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.

Epidemiology

The incidence of diabetic ketoacidosis (DKA) at diagnosis in children with T1DM in Europe is approximately 23 per 100,000 children, whereas that of T2DM is estimated at 1.52 per 100,000.³ T2DM probably only accounts for 5% of all diabetic children, although this number is on the rise.⁴ DKA is more commonly found at diagnosis of T1DM in children aged <4 years old, children from families with low socioeconomic standing and children with no first-degree relative with T1DM. In children with established T1DM the risk of an episode of DKA is in the region of 1-10% per child per year and many of these will occur as a result of poor adherence to a therapeutic regime.⁵

Presentation

Young children (under 4 years) are more likely to have T1DM and present with atypical symptoms. They are more likely to have diabetic ketoacidosis (DKA) and thus a high index of suspicion is required. Other children with DKA may present with any or all of the following common features of the condition:

• Dehydration
• Lethargy
• Confusion
• Polyuria ± polydypsia
• Weight loss
• Abdominal pain ± vomiting (may mimic a surgical abdomen)
• Rapid respiratory rate (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
• Also look for any evidence of cerebral oedema (see below), ileus or infection

Differential diagnosis

Other causes of metabolic acidosis:

• Overdose, e.g. salicylates, iron, ethylene glycol, ethanol
• Lactic acidosis
• Inborn errors of metabolism such as ethylmalonic acidaemia
• Renal failure
• Gram-negative septicaemia

Investigations

Investigations should include:

• Capillary blood glucose - can be performed but the glucose level must be confirmed on plasma samples
• Renal function - may reveal a pattern consistent with dehydration; potassium may also be abnormal
• Venous pH and bicarbonate
• Near patient testing for ketones - this is superior to testing for urinary ketones⁶
• Urine dipstick - looking for ketones and infection
• FBC - leukocytes increased with left shift (not necessarily caused by infection) - but fever is not normal in diabetic ketoacidosis (DKA)
• Liver function tests
• Amylase - may be nonspecifically raised
• If indicated, consider - blood cultures, CXR, CSF, throat swab and other appropriate samples

Always look for precipitating causes, e.g. urinary tract infection, chest infection, etc.

Severity of DKA

This can be divided according to the acidosis:

• Mild - pH <7.3 or bicarbonate <15 mmol/L
• Moderate - pH <7.2 or bicarbonate <10 mmol/L
• Severe - pH <7.1 or bicarbonate <5 mmol/L

Management

The following is based on British Society for Paediatric Endocrinology and Diabetes (BSPED) recommended diabetic ketoacidosis (DKA) guidelines which were recently updated:⁶

Correct dehydration⁷

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.

Patients with <5% dehydration who are not clinically unwell, i.e. mild acidosis and no nausea or vomiting, can be given oral rehydration with subcutaneous insulin.

Assessing dehydration

Assess the severity of dehydration using a combination of the following:

• Capillary refill time
• 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

Degree of dehydration

Overestimation is dangerous and must be avoided, and it is advised not to use >8% in calculations when estimating.

Fluid replacement

• If the patient is severely dehydrated or shocked (quite rare): 10 ml/kg 0.9% normal saline as a bolus (may be repeated if necessary up to a maximum of 30 ml/kg).
• Calculate the deficit (by weight or, less accurately, by clinical assessment) and replace over 48 hours along with usual maintenance requirements using 500 ml of 0.9% saline, initially containing 20 mmol KCl, which can later be changed to 0.45% saline with 5% glucose and 20 mmol KCl when the blood glucose (BG) has fallen to 12-15 mmol/L.
• Because the severity of dehydration may be overestimated, it is important to know that the rate required will rarely exceed 1.5-2.0 times the usual daily requirement based on age, weight, or body surface area.
• Neonatal patients may require larger volumes, e.g. 100-150 ml/kg/24 hours.
• Fluid replacement must be monitored, as some patients may experience a massive diuresis and this volume may need to be incorporated in to the ongoing infusions.

Oral fluids should only be started once there is clinical improvement with no vomiting. This may precede the end of the 48-hour period; if so, then adjust the rate of IV infusion.

Replace insulin

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:^2,6,7

• IV fluids and potassium replacement should occur for one hour before starting insulin, by which point the BG 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 dose of 0.1 U/kg/hour (some favour 0.05 U/kg/hour especially in younger children). An initial bolus is not usually recommended.⁸
• After an initial, often sizable, drop in BG from rehydration the aim is to reduce the BG by <= 4 mmol/L/hr.
• When the BG falls to 12-15 mmol/L change fluids to 0.45% saline with 5% glucose. If the BG drops below 8 mmol/L, add a sideline of 10% glucose and titrate the BG to 8-12 mmol/L. Do not decrease the insulin infusion.
• If the BG rises, reduce the amount of glucose infused and, if necessary, increase the insulin infusion.
• If the pH and anion gap ( [Na+] ) - ( [Cl-]+[HCO3-] )(normal range 10-18 mmol/L) fail to improve, review the insulin therapy and consider other causes, e.g. infection, errors in insulin preparation, adhesion of insulin to tubing in dilute solutions.
• In the rare event that IV administration cannot be used, insulin may be given intramuscularly or subcutaneously, although absorption may be variable due to poor perfusion.
• Once pH is >7.3 and BG <14 mmol/L, the insulin dose can be reduced but not <0.05 U/kg/hour and it should not be stopped until the patient is clinically well.
• In some centres, if the patient is on long-acting insulin, this may be continued (deal with the consultant in charge) but continuous subcutaneous insulin pumps should be discontinued temporarily.⁶

Replace potassium²

• 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.
• Potassium replacement therapy should be started immediately if the patient is hypokalaemic, but should otherwise be started when insulin therapy is begun.
• If the patient is hyperkalaemic, do not give potassium therapy until urine output has been documented.
• Potassium replacement therapy should continue until IV fluids are no longer necessary.

Phosphate replacement²

• Although serum phosphate levels fall as a result of the osmotic diuresis, and this fall is further aggravated by insulin therapy which encourages phosphate to enter cells, there is no evidence that replacement has clinical benefit.^6,9
• If severe and associated with neurology, hypophosphatemia may be treated using potassium phosphate salts as an alternative to, or combined with, potassium chloride/acetate.
• Replacement of phosphate may induce hypocalcaemia.

Bicarbonate infusion is rarely needed and should be considered jointly by the intensive care team, paediatricians and possibly the resuscitation team.

Anticoagulation

• Femoral line insertion is associated with femoral vein thrombosis and these patients must be anticoagulated.
• Anticoagulation may also be considered in other patients, e.g. those who are significantly hyperosmolar, and this should be discussed with senior colleagues.

Where should the patient be managed?²

• Children who have long duration of symptoms, any element of confusion or a compromised circulation should be admitted to a children's unit or high dependency unit where staff have considerable experience in treating children with diabetic ketoacidosis (DKA).
• Children aged less than 5 and new-onset T1DM are at high risk of developing cerebral oedema and should be referred for consideration for treatment in an intensive care unit.⁷
• The following are recommended criteria for admission to PICU/HDU:⁶
  • Severe acidosis (pH <7.1) with marked hyperventilation
  • Severe dehydration or shock
  • Depressed consciousness with risk of aspiration from vomiting
  • Very young (i.e. <2 years)
  • Insufficient staffing on wards

Once ketoacidosis has resolved

• Continue IV fluids until the patient is drinking and tolerating food.
• Only change to subcutaneous insulin once blood ketones are <1.0 mmol/L (note urine ketones may still be present).
• Stop insulin infusion 60 minutes after soluble or long-acting insulin or 10 minutes after rapid-acting insulin to avoid rebound hyperglycaemia.

Cerebral oedema^2,6

• 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
• Patients develop:
  • Headache
  • Vomiting
  • Confusion or irritability
  • Rising blood pressure and bradycardia
  • Decreased oxygen saturation
  • Focal neurology, e.g. cranial nerve palsies
  • Papilloedema - a late sign
• Treatment:
  • Exclude hypoglycaemia
  • Mannitol 0.5-1 g/kg IV should be given immediately over 20 minutes - this may need to be repeated after 2 hours
  • Reduce rate of fluid administration - halve the maintenance dose and replace the deficit over 72 hours rather than 48 hours
  • Elevate head of bed
  • Transfer to ICU - may need intubation and ventilation
  • 5-10 ml/kg of 3% saline is an alternative
  • Alternative diagnoses may need to be considered, e.g. thrombosis, haemorrhage, infection, and a CT brain scan will help delineate the cause

One core issue in cerebral oedema is early identification. Major and minor criteria have been put forth with improved detection rates.¹⁰

Complications

• Hypoglycaemia
• Hypokalaemia
• Systemic infections
• Aspiration pneumonia
• Appendicitis - consider if there is ongoing abdominal pain
• Others, e.g. pneumothorax, interstitial pulmonary oedema, hyperosmolar hyperglycaemia nonketotic coma

Prognosis

The mortality rate of children with diabetic ketoacidosis (DKA) in the United Kingdom is approximately 0.31%, with the majority of these deaths occurring as a result of cerebral oedema.¹¹

Document references

1. Wolfsdorf J, Glaser N, Sperling MA; Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care. 2006 May;29(5):1150-9.
2. Diabetic ketoacidosis; ISPAD Clinical Practice Consensus Guidelines 2006?2007
3. Ehtisham S, Kirk J, McEvilly A, et al; Prevalence of type 2 diabetes in children in Birmingham. BMJ. 2001 Jun 9;322(7299):1428.
4. Williams R, and Farrar H. Diabetes mellitus in Health Care Needs Assessment: the epidemiologically based Needs Assessment Reviews. 3rd series. Oxford: Radcliffe Medical Press.
5. Morris AD, Boyle DI, McMahon AD, et al; Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus. The DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside Scotland. Medicines Monitoring Unit. Lancet. 1997 Nov 22;350(9090):1505-10. [abstract]
6. Guidelines for the management of diabetic ketoacidosis, British Society of Paediatric Endocrinology (2009)
7. Dunger DB, Sperling MA, Acerini CL, et al; European Society for Paediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society consensus statement on diabetic ketoacidosis in children and adolescents. Pediatrics. 2004 Feb;113(2):e133-40.
8. Lindsay R, Bolte RG; The use of an insulin bolus in low-dose insulin infusion for pediatric diabetic ketoacidosis. Pediatr Emerg Care. 1989 Jun;5(2):77-9. [abstract]
9. Wilson HK, Keuer SP, Lea AS, et al; Phosphate therapy in diabetic ketoacidosis. Arch Intern Med. 1982 Mar;142(3):517-20. [abstract]
10. Muir AB, Quisling RG, Yang MC, et al; Cerebral edema in childhood diabetic ketoacidosis: natural history, radiographic findings, and early identification. Diabetes Care. 2004 Jul;27(7):1541-6. [abstract]
11. Edge JA, Ford-Adams ME, Dunger DB; Causes of death in children with insulin dependent diabetes 1990-96. Arch Dis Child. 1999 Oct;81(4):318-23. [abstract]

Acknowledgements