Definition and Overview

Diabetic ketoacidosis is defined by a biochemical triad: hyperglycaemia (blood glucose >11 mmol/L or 200 mg/dL, though may be lower in euglycemic DKA), ketonaemia (blood ketones ≥3.0 mmol/L or urinary ketones ≥2+), and metabolic acidosis (pH <7.3 and/or bicarbonate <15 mmol/L). It represents a state of absolute or relative insulin deficiency combined with excess counter-regulatory hormones — glucagon, cortisol, catecholamines, and growth hormone — resulting in uncontrolled lipolysis, ketogenesis, and gluconeogenesis.

DKA is most commonly encountered in type 1 diabetes mellitus but can occur in type 2 diabetes, particularly under conditions of physiological stress. The condition exists on a spectrum of severity — mild, moderate, and severe — stratified by the degree of acidosis and alteration in consciousness, as outlined in joint guidelines from the American Diabetes Association (ADA) and summarised in contemporary reviews published in Nature Reviews Disease Primers and the BMJ.

Epidemiology and Burden of Disease

DKA accounts for approximately 500,000 hospital days annually in the United States alone, with incidence rising globally in parallel with the increasing prevalence of type 1 diabetes. According to data reviewed in Disease Monthly (2023), DKA-related hospitalisation rates have increased over recent decades, driven by rising diabetes prevalence, increased SGLT-2 inhibitor use, and delayed insulin initiation in newly diagnosed patients. Mortality from DKA in high-income countries now sits below 1% in adults when managed in experienced centres, but in resource-limited settings and in extremes of age — particularly children — mortality can be considerably higher, largely due to cerebral oedema and delayed presentation. The economic burden is substantial: hospitalisation costs, critical care utilisation, and long-term complications all contribute to DKA’s status as a major public health concern.

Aetiology and Risk Factors

Precipitating Factors

The most common precipitants of DKA follow the mnemonic 6 I’s: Infection (most common, particularly urinary tract infections and pneumonia), Insulin omission or inadequacy, Ischaemia (myocardial infarction, stroke), Intoxication (alcohol, cocaine), Iatrogenic causes (corticosteroids, atypical antipsychotics), and Initial presentation of new-onset diabetes. In up to 25% of cases, no clear precipitant is identified.

SGLT-2 Inhibitors and Euglycemic DKA

An increasingly recognised aetiology is the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors — a drug class including empagliflozin, dapagliflozin, and canagliflozin. These agents paradoxically reduce glucosuria-driven hyperglycaemia while simultaneously promoting ketogenesis via increased glucagon secretion, reduced insulin levels, and enhanced free fatty acid oxidation. The result is euglycemic DKA (euDKA), where blood glucose may be only mildly elevated (typically <14 mmol/L), posing a significant diagnostic trap for unwary clinicians. This phenomenon is extensively reviewed in a 2023 BMJ Open Diabetes Research and Care publication and a 2021 American Journal of Emergency Medicine study.

Patient-Related Risk Factors

Young age, female sex, psychiatric comorbidity (associated with insulin omission), eating disorders, limited access to healthcare, and poor diabetes self-management education all independently elevate DKA risk. Recurrent DKA is a red flag for psychosocial complexity requiring multidisciplinary input.

Pathophysiology

The Insulin Deficiency Cascade

At the molecular core of DKA lies absolute or relative insulin deficiency. Without insulin, glucose transport into peripheral tissues is impaired. Concurrently, counter-regulatory hormones — predominantly glucagon — activate hepatic glycogenolysis and gluconeogenesis, driving blood glucose upward. The resultant hyperglycaemia exceeds the renal threshold (approximately 10 mmol/L), leading to osmotic diuresis, polyuria, dehydration, and electrolyte depletion. This sequence is elegantly detailed in the Nature Reviews Disease Primers overview of DKA pathophysiology (Rawshani et al., 2020).

Ketogenesis and Acidosis

In the absence of insulin, hormone-sensitive lipase is uninhibited, promoting lipolysis of adipose tissue and releasing free fatty acids (FFAs) into the circulation. FFAs are transported to the liver, where they undergo beta-oxidation and are converted to acetyl-CoA. Overwhelmed mitochondrial capacity diverts acetyl-CoA into ketone body synthesis — acetoacetate, beta-hydroxybutyrate (the predominant ketone in DKA), and acetone. Ketone bodies are organic acids; their accumulation overwhelms the bicarbonate buffering system, producing a high anion-gap metabolic acidosis. The body compensates via Kussmaul breathing — deep, sighing respirations that blow off CO₂ — and renal bicarbonate reclamation, both of which are clinically identifiable at the bedside.

Electrolyte Derangements

DKA causes profound total-body potassium depletion through osmotic diuresis, vomiting, and transcellular shifts. However, measured serum potassium at presentation may be normal or even elevated due to acidosis-driven extracellular shift of K⁺ in exchange for H⁺ ions. This creates a dangerous clinical situation: as insulin is administered and acidosis corrects, potassium re-enters cells rapidly, risking life-threatening hypokalaemia if replacement is delayed. Similarly, sodium, phosphate, and magnesium are depleted, though routine phosphate replacement is not currently recommended unless severe.

Clinical Presentation

DKA presents across a spectrum from subtle to florid. Classic symptoms include polyuria, polydipsia, nausea, vomiting, and diffuse abdominal pain — the latter a result of gastric dysmotility and splanchnic vasoconstriction. Examination may reveal signs of dehydration (dry mucous membranes, reduced skin turgor, tachycardia, hypotension in severe cases), Kussmaul respirations, and the distinctive fruity or acetone breath odour from exhaled acetone. Altered consciousness and frank coma are markers of severe DKA, correlating with degree of hyperosmolality and acidosis. It is vital to remember that fever may be absent even in infectious precipitants due to peripheral vasodilation from acidosis, masking the severity of underlying infection.

⚠️ Emergency Warning Signs: GCS <13, pH <7.0, bicarbonate <5 mmol/L, potassium <3.5 mmol/L on arrival, blood ketones >6 mmol/L, oxygen saturation <92%, or systolic BP <90 mmHg should prompt immediate senior review and consideration of HDU/ICU-level care.

Diagnosis

Diagnosis is clinical and biochemical. Investigations should be obtained urgently and simultaneously with initial resuscitation:

• Capillary blood glucose and ketones — bedside, immediate
• Venous blood gas (VBG) — pH, bicarbonate, lactate, pCO₂
• Full blood count — leucocytosis common even without infection
• Urea and electrolytes — note corrected sodium, potassium (critical before insulin)
• Calculated anion gap = Na⁺ − (Cl⁻ + HCO₃⁻); normal 8–12 mEq/L; elevated in DKA
• HbA1c — guides chronicity
• Blood cultures, urinalysis, CXR, ECG — to identify precipitants
• Urine or serum β-hydroxybutyrate — quantitative ketone measurement preferred over urinalysis
• Phosphate, magnesium, LFTs, amylase/lipase — abdominal pain can mimic pancreatitis (amylase non-specifically elevated in DKA)

Severity is classified as: Mild (pH 7.25–7.30, HCO₃ 15–18, alert); Moderate (pH 7.00–7.24, HCO₃ 10–14, drowsy); Severe (pH <7.0, HCO₃ <10, stupor/coma). The ISPAD 2022 consensus guidelines provide a similar framework for paediatric DKA stratification.

Management

Initial Assessment and Resuscitation (0–60 Minutes)

Adopt an ABCDE approach. Secure IV access — two wide-bore cannulae. Apply continuous cardiac monitoring (hypokalaemia causes arrhythmias), pulse oximetry, and hourly urine output monitoring via urinary catheter if obtunded. Weigh the patient if possible to guide fluid calculations. Inform the senior clinician and diabetes specialist team early.

Fluid Resuscitation

Intravenous fluid replacement is the cornerstone of initial DKA management. The average fluid deficit in DKA is 3–6 litres. Current UK guidelines (JBDS, endorsed by NHS England) and evidence from Medical Clinics of North America (2017) recommend 0.9% sodium chloride as the initial resuscitation fluid. A typical regimen begins with 1 litre of 0.9% NaCl over the first hour, followed by further 0.9% NaCl over subsequent hours titrated to haemodynamic response and urine output. When blood glucose falls to ≤14 mmol/L (252 mg/dL), switch to 5% glucose-saline to prevent hypoglycaemia while continuing insulin infusion to clear ketones. Over-aggressive fluid resuscitation increases the risk of cerebral oedema — particularly in children — and hyperchloraemic acidosis, underscoring the importance of careful, monitored replacement rather than bolus flooding.

Insulin Therapy

Insulin is the definitive treatment for ketogenesis suppression. Crucially, insulin should NOT be started until serum potassium is ≥3.5 mmol/L — if potassium is below this threshold, replace first, then start insulin. A fixed-rate intravenous insulin infusion (FRIII) at 0.1 units/kg/hour is the current standard of care in the UK, replacing previous variable-rate regimens. The therapeutic target is ketone clearance of ≥0.5 mmol/L/hour (or bicarbonate rise of ≥3 mmol/L/hour if ketones unavailable). Blood glucose reduction should not exceed 5 mmol/L/hour to avoid precipitous osmotic shifts. Once DKA has resolved (pH >7.3, ketones <0.6 mmol/L, bicarbonate >18 mmol/L) and the patient can eat and drink, transition to subcutaneous insulin while maintaining IV insulin overlap for at least 30 minutes to avoid rebound ketosis.

Potassium Replacement

Potassium management requires vigilance. As noted, total body K⁺ is invariably depleted. Add potassium chloride to IV fluids as per measured serum levels: if K⁺ is 3.5–5.5 mmol/L, add 40 mmol KCl per litre; if K⁺ >5.5 mmol/L, withhold until K⁺ falls; if K⁺ <3.5 mmol/L, senior review and enhanced replacement before insulin. Monitor potassium every 1–2 hours in the critical phase.

Bicarbonate Therapy

Routine bicarbonate administration is not recommended and may paradoxically worsen intracellular acidosis and hypokalaemia. It may be considered in life-threatening hyperkalaemia (K⁺ >6.5 mmol/L) or severe acidosis (pH <6.9) refractory to fluids and insulin, and only after senior/ICU consultation, in line with guidance from the BMJ review of hyperglycaemic crises (Dhatariya et al., 2019).

Monitoring and Resolution Criteria

Monitoring should include hourly capillary blood glucose and ketones, VBG every 1–2 hours until pH >7.3, and electrolytes every 2–4 hours. Clinical resolution of DKA is defined by: blood ketones <0.6 mmol/L, venous pH >7.3, and bicarbonate >18 mmol/L. Do not use blood glucose normalisation alone as a resolution criterion — ketosis may persist with near-normal glucose.

Complications and Prognosis

Cerebral oedema is the most feared complication, occurring predominantly in children and adolescents and carrying a mortality of 20–25%. Risk factors include younger age, new-onset diabetes, rapid osmotic shifts from aggressive fluid or insulin administration, and low pCO₂ at presentation. It typically manifests 4–12 hours into treatment with headache, altered behaviour, bradycardia, and deteriorating GCS. Management involves immediate IV mannitol (0.5–1 g/kg) or hypertonic saline, reduction in fluid rate, and urgent neuroimaging.

Other complications include hypoglycaemia and hypokalaemia from over-treatment, aspiration pneumonia in obtunded patients, venous thromboembolism (VTE prophylaxis is recommended), acute kidney injury, and ARDS (rare). With modern management in experienced centres, adult mortality is <1%, but outcomes worsen significantly with delayed diagnosis, extremes of age, and resource-limited settings.

Prevention and Emerging Research

Prevention centres on structured diabetes self-management education, clear “sick day rules” (never stop insulin, increase monitoring, seek early medical advice), and access to specialist diabetes teams. Technology — including continuous glucose monitoring (CGM) and insulin pump therapy — has demonstrably reduced DKA rates in type 1 diabetes. Emerging evidence supports closed-loop insulin delivery systems (“artificial pancreas”) as a significant preventive strategy.

In the SGLT-2 inhibitor space, euDKA prevention strategies include patient education regarding sick-day insulin adjustment, withholding SGLT-2 inhibitors 24–72 hours before planned surgery or major illness (“hold for procedures” guidance), and heightened clinical suspicion when ketosis symptoms arise despite near-normal glucose. Research into novel biomarkers for earlier DKA detection and into immune-modulating therapies to preserve beta-cell function continues to evolve.

Clinical Pearls

• 🩺 Never start insulin before checking potassium. A potassium below 3.5 mmol/L mandates replacement before insulin infusion to avoid fatal arrhythmias from hypokalaemia.
• 🩺 Normal glucose does not exclude DKA. Euglycemic DKA occurs in SGLT-2 inhibitor users, fasting patients, and pregnant women — always check ketones in acidotic patients regardless of glucose level.
• 🩺 Treat to ketone clearance, not glucose normalisation. Adding 5% dextrose when glucose reaches ≤14 mmol/L allows continued insulin infusion to clear ketones without causing hypoglycaemia.
• 🩺 Abdominal pain in DKA can be a red herring. It is common in DKA itself; however, if it persists after DKA resolution, investigate for a primary abdominal precipitant (e.g., pancreatitis, appendicitis).
• 🩺 A “normal” or low temperature may mask infection. Vasodilation from acidosis blunts the febrile response — have a low threshold for broad-spectrum antibiotics pending cultures.

Key Takeaways

• ✅ DKA is defined by hyperglycaemia, ketonaemia, and metabolic acidosis — the triad must be assessed simultaneously, not sequentially.
• ✅ Fluid resuscitation is the immediate priority; 0.9% NaCl is the first-line choice with transition to glucose-containing solution when blood glucose reaches ≤14 mmol/L.
• ✅ Fixed-rate IV insulin at 0.1 units/kg/hour is the standard; always confirm potassium ≥3.5 mmol/L before initiation.
• ✅ SGLT-2 inhibitors cause euglycemic DKA — a diagnostic trap that demands ketone testing in any patient on these agents presenting with acidosis, nausea, or malaise.
• ✅ Resolution criteria are biochemical (ketones <0.6 mmol/L, pH >7.3, HCO₃ >18 mmol/L), not solely clinical or glucometric.
• ✅ Cerebral oedema is a life-threatening complication, especially in children; avoid over-rapid fluid administration and monitor neurological status closely.
• ✅ Structured diabetes education, sick-day rules, and emerging technologies (CGM, closed-loop systems) are the pillars of DKA prevention.

Frequently Asked Questions

Q1: Can DKA occur in type 2 diabetes?

Yes. While DKA is classically associated with type 1 diabetes, it can occur in type 2 diabetes under conditions of severe physiological stress — infection, surgery, myocardial infarction — when counter-regulatory hormone surges overwhelm remaining beta-cell capacity. It is also increasingly seen in type 2 diabetes patients prescribed SGLT-2 inhibitors, manifesting as euglycemic DKA.

Q2: What is euglycemic DKA and why does it matter clinically?

Euglycemic DKA (euDKA) refers to DKA where blood glucose is below the classical threshold (typically <14 mmol/L or even lower). It is most commonly associated with SGLT-2 inhibitor use, pregnancy, starvation, or partial insulin treatment. It matters because the absence of marked hyperglycaemia can delay or prevent diagnosis if clinicians do not check ketones and blood gas in at-risk patients presenting with non-specific symptoms.

Q3: When should I consider ICU admission for a DKA patient?

ICU or HDU admission is warranted for severe DKA (pH <7.0, GCS <12, persistent haemodynamic instability despite initial resuscitation), inability to maintain airway, requirement for >2 litres fluid bolus, suspected or confirmed cerebral oedema, or significant comorbidities such as acute coronary syndrome precipitating DKA.

Q4: How do I transition a patient from IV insulin to subcutaneous insulin?

Ensure DKA resolution criteria are met and the patient is able to eat and drink. Administer the first dose of subcutaneous (SC) basal insulin and continue IV insulin for at least 30–60 minutes afterwards to avoid a gap in insulin coverage. For patients with new-onset diabetes, a diabetes specialist should guide the initial SC regimen. Restarting the patient’s prior regimen is appropriate for those with known diabetes and an identifiable precipitant.

Q5: Why is bicarbonate not routinely given in DKA despite severe acidosis?

Bicarbonate administration carries risks of paradoxical CNS acidosis (CO₂ crosses the blood-brain barrier more rapidly than bicarbonate), hypokalaemia, sodium overload, and a left shift of the oxyhaemoglobin dissociation curve impairing tissue oxygen delivery. Clinical trials have not demonstrated mortality benefit from routine bicarbonate use in DKA, and it is therefore reserved for extreme, refractory cases (pH <6.9 or life-threatening hyperkalaemia) under senior supervision.

References

1. Rawshani A et al. Diabetic ketoacidosis. Nat Rev Dis Primers. 2020. https://pubmed.ncbi.nlm.nih.gov/32409703/
2. Dhatariya KK et al. Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ. 2019. https://pubmed.ncbi.nlm.nih.gov/31142480/
3. Fayfman M et al. Management of Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. Med Clin North Am. 2017. https://pubmed.ncbi.nlm.nih.gov/28372715/
4. Milder DA et al. Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors. BMJ Open Diabetes Res Care. 2023. https://pubmed.ncbi.nlm.nih.gov/37797963/
5. Plewa MC et al. Euglycemic diabetic ketoacidosis: Etiologies, evaluation, and management. Am J Emerg Med. 2021. https://pubmed.ncbi.nlm.nih.gov/33626481/
6. Stojanovic M et al. Diabetic ketoacidosis. Dis Mon. 2023. https://pubmed.ncbi.nlm.nih.gov/35577617/
7. Rosenbloom AL et al. ISPAD clinical practice consensus guidelines 2022: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2022. https://pubmed.ncbi.nlm.nih.gov/36250645/
8. Nasa P et al. Euglycemic Diabetic Ketoacidosis: A Review. Curr Diabetes Rev. 2017. https://pubmed.ncbi.nlm.nih.gov/27097605/

Medical Disclaimer: This article is intended for educational purposes for medical students and healthcare professionals. It does not constitute individualised medical advice and should not replace clinical judgement, local institutional protocols, or specialist consultation. Management of DKA should always follow current local and national guidelines and be supervised by appropriately trained clinical teams. Always refer to your institution’s DKA pathway and involve senior clinicians when managing critically unwell patients.