Diabetic Ketoacidosis (DKA)
“Cerebral injury occurs more commonly in children than adults. The frequency of clinically significant CI may be as high as 1%,”
Diabetic Ketoacidosis (DKA) remains one of the most serious acute complications of diabetes mellitus, characterised by significant metabolic derangement secondary to insulin deficiency and counter-regulatory hormone excess. While modern care has dramatically reduced its mortality to below 1% in developed health systems, DKA still represents a medical emergency requiring prompt recognition and multidisciplinary management. This article explores the underlying pathophysiology, clinical features, differential considerations, and management strategies in both adult and paediatric patients, integrating current evidence and pre-hospital considerations.
Pathophysiology of DKA
The defining feature of DKA is a profound insulin deficiency coupled with excess of counter-regulatory hormones, including glucagon, cortisol, catecholamines, and growth hormone. These hormones stimulate gluconeogenesis (the generation of glucose from non-carbohydrate substrates) and glycogenolysis (the breakdown of glycogen into glucose). However, in the absence of sufficient insulin, peripheral tissues cannot utilise this rising glucose concentration. The result is persistent hyperglycaemia and cellular starvation despite abundant circulating glucose [1].
To compensate, the body mobilises free fatty acids (FFAs) from adipose tissue via lipolysis. Within the liver, these FFAs undergo β-oxidation, forming acetyl-CoA, which is converted into the ketone bodies—acetoacetate and β-hydroxybutyrate. Both are organic acids; as they accumulate, metabolic acidosis develops. The presence of acetoacetate may produce a characteristic acetone odour on the breath, often described as “pear drops” or nail-polish-like, though not universally detected [1].
Hyperglycaemia increases plasma osmolality, drawing water from intracellular to extracellular compartments. As filtered glucose exceeds renal reabsorption thresholds, osmotic diuresis ensues, leading to polyuria, electrolyte loss, and progressive dehydration. The ensuing hypovolaemia stimulates thirst and polydipsia, though as shock develops, oliguria may follow [2].
Diagnostic criteria for DKA, as set by the Association of British Clinical Diabetologists, require all three of the following [3]:
Blood glucose >11 mmol/L
Ketonemia >3 mmol/L or urine ketones ≥2+
Metabolic acidosis: pH <7.3 and/or bicarbonate <15 mmol/L
The resultant acid-base disturbance triggers compensatory hyperventilation to “blow off” CO₂ (carbonic acid), known as Kussmaul respiration—deep, laboured breathing indicative of respiratory compensation for metabolic acidosis [4].
Clinical Manifestations
The clinical picture of DKA evolves through the interplay of hyperglycaemia, dehydration, and acidosis.
Common symptoms include:
Polyuria and polydipsia
Nausea, vomiting, and abdominal pain
Fatigue and malaise
Kussmaul breathing
Ketotic (fruity) breath odour
Altered level of consciousness, ranging from lethargy to coma in severe cases
Abdominal pain in DKA is multifactorial—ketone-induced irritation, smooth muscle dysfunction due to hypokalaemiaand hypophosphataemia, and mesenteric hypoperfusion all contribute. In severe dehydration, splanchnic hypoperfusion may cause visceral ischaemia and worsening pain. These features often mimic intra-abdominal pathology; hence, clinicians should remain vigilant for concurrent causes such as appendicitis, cholecystitis, or bowel obstruction.
Neurological Implications
The central nervous system depends almost exclusively on glucose as its energy substrate. In DKA, relative cerebral energy deprivation, compounded by dehydration and electrolyte imbalance, may manifest as reduced consciousness. Cerebral oedema—although rare in adults—remains a leading cause of mortality in paediatric DKA [5]. Risk factors include:
New-onset diabetes
Age <5 years
Severe acidosis (pH <7.1)
Rapid or excessive fluid resuscitation
Use of sodium bicarbonate
Early or bolus insulin administration
Failure of serum sodium to rise during treatment
Warning signs of cerebral injury include headache, deteriorating GCS, vomiting, bradycardia, hypertension, and respiratory depression. Prompt recognition and critical care involvement are essential [5][6].
Counter-Regulatory Hormones and Hyperglycaemia
Cortisol, glucagon, and catecholamines are central to the hyperglycaemic drive in DKA. These hormones promote hepatic glucose production and oppose insulin-mediated uptake. This understanding is critical in clinical practice—steroid therapy (e.g. dexamethasone or prednisolone) can induce hyperglycaemia or precipitate DKA in susceptible individuals, underscoring the need for glucose monitoring in diabetic patients receiving corticosteroids.
Differentiating DKA from Hyperosmolar Hyperglycaemic State (HHS)
While both DKA and HHS share the hallmark of insulin deficiency, the latter typically occurs in type 2 diabetes and involves partial insulin function sufficient to suppress lipolysis. Consequently, ketogenesis is minimal or absent, but hyperglycaemia is often more severe (>30 mmol/L), producing marked osmotic diuresis and dehydration. HHS thus presents with profound hypovolaemia, electrolyte imbalance, and neurological compromise, but without significant acidosis [1].
Euglycaemic DKA (EDKA)
An important modern variant, Euglycaemic DKA (EDKA), is characterised by ketonaemia and metabolic acidosis with normal or mildly elevated glucose levels (<11 mmol/L). It typically arises when carbohydrate availability is reduced while lipolysis and ketogenesis persist.
Common precipitating factors include:
SGLT-2 inhibitors (e.g. empagliflozin, dapagliflozin, canagliflozin), which enhance urinary glucose excretion
Pregnancy, due to increased glucose utilisation by the fetus
Prolonged fasting or bariatric surgery
Chronic pancreatitis
Patients on SGLT-2 inhibitors presenting with nausea, vomiting, or breathlessness should be screened for DKA even if blood glucose is normal. Early intravenous fluids with dextrose may be necessary to prevent further ketosis [1].
Triggers and Precipitating Factors
DKA is rarely idiopathic. Common precipitating events include:
Physiological stress (≈30% of cases):
Infection is the predominant trigger—particularly lower respiratory tract infections, urinary tract infections, and skin sepsis. The inflammatory response induces cortisol and adrenaline release, driving hepatic glycogenolysis and insulin resistance.
Other triggers include myocardial infarction, surgery, and major trauma.Insulin omission or delivery failure (≈20%):
This may occur due to non-compliance, insulin pump malfunction, self-neglect, or improper insulin storage.Alcohol misuse:
Acute ethanol consumption suppresses gluconeogenesis and may initially cause hypoglycaemia; however, excessive intake, particularly in poorly controlled diabetics, can lead to erratic insulin use and subsequent DKA.New-onset diabetes (≈25%):
Undiagnosed type 1 diabetes remains a frequent first presentation.No identifiable cause (≈25%) [7].
Pre-Hospital Assessment and Management
From a pre-hospital perspective, the emphasis is on ABC assessment, recognition of metabolic derangement, and early fluid resuscitation.
Airway and Breathing
Reduced GCS and vomiting are common—patients should be positioned laterally where possible to reduce aspiration risk.
Breathing is classically deep and laboured (Kussmaul), reflecting respiratory compensation for metabolic acidosis. Despite the profound respiratory effort, oxygenation is usually adequate unless the underlying precipitant (e.g. pneumonia) causes hypoxia.
Circulation
Due to osmotic diuresis, patients may be up to 8–10 litres fluid-depleted, presenting with tachycardia, hypotension, dry mucous membranes, and poor capillary refill. Severe dehydration or electrolyte imbalance may precipitate arrhythmias, including atrial fibrillation or bradycardia.
Disability
Assess GCS and capillary glucose. Note that normal glucose readings do not exclude DKA (as in EDKA). If available, capillary ketone testing should be performed pre-hospitally.
Exposure
Perform a full examination for underlying causes: look for fever, jaundice, abdominal tenderness, or localised infection.
Principles of DKA Management
The overarching goals in DKA management are:
Rehydration
Correction of electrolyte imbalance
Insulin therapy to suppress ketogenesis and restore euglycaemia
Identification and treatment of the underlying cause
In pre-hospital or initial ED settings, fluid resuscitation is paramount. Isotonic crystalloids (e.g. 0.9% sodium chloride) are administered to restore circulating volume, improve renal perfusion, and enhance ketone clearance. Early insulin therapy without adequate hydration may worsen circulatory collapse, so fluids should precede insulin administration[8][9].
Rehydration also dilutes plasma ketones and aids correction of acidosis. Electrolyte monitoring is essential—potassiummust be maintained between 4–5 mmol/L. Insulin promotes intracellular potassium shift, risking hypokalaemia if not supplemented appropriately.
Cerebral Oedema: A Paediatric Concern
Cerebral oedema occurs in approximately 0.3–0.9% of paediatric DKA cases and accounts for most DKA-related deaths in children [5][10]. The precise mechanism remains uncertain but likely involves rapid osmotic shifts during rehydration.
Current guidelines recommend cautious rehydration—10 mL/kg isotonic bolus over 15–30 minutes in shocked children, followed by slower replacement [11]. Avoid hypotonic fluids and bicarbonate therapy, both of which increase cerebral injury risk.
Hospital and Critical Care Management
While many DKA cases are managed successfully on acute medical wards, certain criteria mandate high-dependency or intensive care admission, including:
Age <25 or elderly
Pregnancy
Severe metabolic derangement (pH <7.0, HCO₃⁻ <5 mmol/L, ketones >6 mmol/L)
Hypoxaemia or persistent hypotension
GCS <12
Renal or cardiac failure
Fixed-rate intravenous insulin infusion (FRIII) is commenced at 0.1 units/kg/hour, aiming to reduce ketones by 0.5 mmol/L/hour and glucose by 3 mmol/L/hour. Adjustments are made based on response. Potassium supplementation is administered via IV fluids, and central access may be required for higher concentrations.
Notably, mechanical ventilation is rarely indicated—intubation may worsen acidosis by interrupting spontaneous respiratory compensation. If necessary (e.g. for surgery), high minute ventilation strategies are required to maintain pH.
With appropriate treatment, DKA typically resolves within 24 hours, though the underlying cause (e.g. infection, MI) must also be addressed to prevent recurrence.
Outcomes and Prognosis
In the UK and other developed healthcare systems, mortality from DKA is now <1%, largely due to standardised care pathways and early recognition. In children and adolescents, morbidity and mortality are most commonly linked to cerebral oedema. Among adults, deaths are more often attributable to the precipitating illness rather than DKA itself.
Conclusion
DKA represents a dynamic interplay between endocrine failure, metabolic compensation, and systemic physiological stress. For clinicians across all care settings, a clear understanding of its pathophysiology underpins effective and safe management. Early recognition, prompt rehydration, appropriate insulin therapy, and attention to underlying causes remain the cornerstone of care. As pharmacological therapies such as SGLT-2 inhibitors become more prevalent, awareness of euglycaemic DKA and its atypical presentation is essential. Above all, vigilance and a structured, physiology-based approach continue to save lives in this critical metabolic emergency.
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