Diabetic ketoacidosis (DKA)

Common Precipitating Factors

1. Infection (40%)
   Infection remains the most common trigger for DKA. It increases counter-regulatory hormones like glucagon, adrenaline, and cortisol, leading to insulin resistance and enhanced lipolysis. Common infections associated with DKA include:
   • Urinary tract infections (UTIs)
   • Pneumonia
   • Bacterial infections such as those caused by Klebsiella pneumoniae
2. Missed or Disrupted Insulin Treatment (25%)
   • Non-compliance with prescribed insulin therapy is a frequent cause of DKA, often due to:
     • Psychological stress (e.g., fear of weight gain, needle phobia)
     • Mismanagement or omission of doses
     • Mechanical issues, such as infusion catheter blockages or insulin pump failures
   • Vomiting or poor oral intake may also lead to disrupted insulin administration.
3. Newly Diagnosed Diabetes (15%)
   • In type 1 diabetes, DKA may present at the time of diagnosis, particularly when acute insulin deficiency remains undetected.
     
     

Causes in Type 1 Diabetes

• Acute Insulin Deficiency: Occurs in approximately 25% of cases at the time of diagnosis.
• Poor Compliance: Common in adolescents and younger adults due to psychological stress, lack of education, or socioeconomic challenges.
• Brittle Diabetes: Frequent fluctuations in blood glucose levels increase the risk of DKA.
• Idiopathic Causes: Cases with no identifiable cause.
• Mechanical Failures: Blockages in insulin infusion catheters or pump malfunctions are additional factors.
  
  

Causes in Type 2 Diabetes

• Intercurrent Illness: Conditions such as myocardial infarction, pneumonia, prostatitis, or other severe infections.
• Medications: Certain drugs can precipitate DKA, including:
  • Corticosteroids
  • Thiazides
  • Second-generation antipsychotics (e.g., clozapine)
  • Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which may cause euglycemic DKA by promoting ketogenesis.
• Physiological Stressors: Surgery, trauma, or severe dehydration may act as triggers.
  
  

DKA in Special Populations

1. Pregnancy
   • Physiological changes during pregnancy, such as increased insulin resistance, predispose individuals to DKA.
   • DKA in pregnancy is a medical emergency with potential morbidity and mortality risks for both mother and fetus.
2. COVID-19
   • The COVID-19 pandemic has been linked to increased rates of DKA, potentially due to:
     • Direct beta-cell destruction by SARS-CoV-2
     • Exacerbation of systemic inflammation and insulin resistance
   • SGLT2 inhibitors combined with COVID-19 infection may further elevate the risk of euglycemic DKA.
     
     

Role of Counter-Regulatory Hormones

• Enhancing hepatic gluconeogenesis and glycogenolysis
• Promoting lipolysis and subsequent ketogenesis
• Reducing glucose uptake in peripheral tissues
  
  

Drug-Induced DKA

• Corticosteroids: Increase insulin resistance and gluconeogenesis.
• Thiazides: Alter glucose uptake and release.
• Sympathomimetics: Enhance glycogenolysis and lipolysis.
• SGLT2 Inhibitors: Associated with both hyperglycemic and euglycemic DKA due to decreased renal glucose reabsorption and enhanced ketogenesis.
• Immune Checkpoint Inhibitors: Can precipitate autoimmune-related insulin deficiency.
  
  

Key Mechanisms in DKA

1. Insulin Deficiency
   • Insulin deficiency is central to DKA pathophysiology. Normally, insulin suppresses hepatic gluconeogenesis and glycogenolysis while promoting glucose uptake by skeletal muscle and adipose tissue.
   • In DKA, insulin deficiency results in:
     • Increased gluconeogenesis.
     • Accelerated glycogenolysis.
     • Impaired glucose uptake by peripheral tissues.
   • This leads to hyperglycemia, which further exacerbates osmotic diuresis and dehydration.
2. Counter-Regulatory Hormones
   • Elevated levels of glucagon, cortisol, catecholamines, and growth hormone promote hepatic gluconeogenesis, lipolysis, and glycogenolysis.
   • These hormones contribute to the mobilisation of free fatty acids from adipose tissue into circulation.
3. Ketogenesis
   • Free fatty acids undergo hepatic oxidation to form ketone bodies, including beta-hydroxybutyrate and acetoacetate.
   • Ketone body accumulation causes metabolic acidosis (ketoacidosis) and ketonemia.
   • The resultant acidosis leads to compensatory respiratory alkalosis, manifested as Kussmaul respiration (deep and labored breathing).
4. Electrolyte Disturbances
   • Potassium:
     • Insulin deficiency and acidosis cause a shift of potassium from intracellular to extracellular spaces.
     • Osmotic diuresis leads to urinary potassium losses, resulting in severe total-body potassium depletion, despite normal or elevated plasma potassium levels.
   • Sodium:
     • Osmotic diuresis induces significant sodium loss, contributing to hyponatremia.
   • Other Electrolytes:
     • Magnesium and phosphate depletion are also common and can exacerbate neuromuscular and cardiac dysfunction.
5. Hyperosmolarity and Dehydration
   • Severe hyperglycemia leads to osmotic diuresis, dehydration, and hyperosmolarity.
   • Hyperosmolarity is a primary contributor to altered consciousness in DKA.
     
     

Impact of Pro-Inflammatory and Oxidative Stress States

1. Inflammatory Markers
   • Hyperglycemia triggers a pro-inflammatory state, characterised by increased levels of tumor necrosis factor-alpha, interleukin-beta, interleukin-6, interleukin-8, and C-reactive protein.
   • These inflammatory markers return to baseline within 24 hours following insulin therapy and hydration.
2. Oxidative Stress
   • Elevated reactive oxygen species and lipid peroxidation are associated with DKA, further contributing to cellular damage and cardiovascular risk.
     
     

Molecular and Cellular Mechanisms

1. Mitochondrial Dysfunction in Hepatocytes
   • Insulin deficiency promotes beta-oxidation of free fatty acids in the liver, leading to the production of acetyl-CoA.
   • Excess acetyl-CoA is diverted to ketogenesis due to inhibition of the citric acid cycle.
   • Elevated nicotinamide adenine dinucleotide (NADH) levels further inhibit the citric acid cycle, exacerbating ketone body production.
2. Buffering Systems
   • Early ketonemia is mitigated by extracellular and intracellular buffers, such as bicarbonate and hemoglobin.
   • As ketone levels rise, buffering capacity is overwhelmed, resulting in frank metabolic acidosis.
     
     

Clinical Correlations of Pathophysiology

1. Ketonemia and Ketonuria
   • Ketone bodies overflow into the urine when their serum concentrations exceed the renal threshold.
   • Urinary ketones, along with glucosuria, contribute to further osmotic diuresis and electrolyte losses.
2. Neurological Impairment
   • Hyperosmolarity, acidosis, and severe electrolyte disturbances lead to altered mental status and, in severe cases, coma.
3. Respiratory Compensation
   • The metabolic acidosis triggers hyperventilation (Kussmaul breathing) to reduce carbon dioxide levels, partially compensating for acidosis.
4. Nausea and Vomiting
   • Elevated ketone levels, particularly beta-hydroxybutyrate, induce nausea and vomiting, worsening dehydration and electrolyte imbalance.

   • 
     

Severe DKA Classification

• Blood ketones >6 mmol/L.
• Serum bicarbonate <5 mmol/L.
• Venous or arterial pH <7.0.
• Hypokalemia (<3.5 mmol/L).
• Glasgow Coma Scale score <12.
• Systolic blood pressure <90 mmHg.
• Oxygen saturation <92% on room air.
• Anion gap >16.
  
  

Global Incidence and Demographics

• The incidence of DKA varies widely:
  • In developed countries, rates range from 0 to 56 per 1,000 person-years.
  • In Sweden and Finland, the incidence is among the highest globally, at 41.0 and 37.4 cases per 100,000, respectively.
  • In Nigeria, the incidence is markedly lower at 2.9 per 100,000.
• DKA is more common in women and non-White populations, with higher prevalence noted among those using injectable insulin compared to subcutaneous insulin infusion pumps.
• The condition is frequently observed at the time of type 1 diabetes diagnosis, with rates reported at 32.8% in Brazil and significant occurrences in younger age groups and adolescents.
  
  

Trends in Developed Countries

• England:
  • Among adults with type 2 diabetes, hospital admissions for DKA increased annually by 4.24% between 1998 and 2013.
  • Hospitalisations for adults with type 1 diabetes rose between 1998 and 2007, then plateaued.
• United States:
  • From 2000 to 2009, hospitalisations for DKA decreased from 21.9 to 19.5 per 1,000 persons with diabetes but rose again from 2009 to 2014, reaching 30.2 per 1,000 persons.
  • DKA hospitalisations were highest in individuals aged <45 years, with rates declining with increasing age.
  • The overall in-hospital mortality for DKA fell from 1.1% in 2000 to 0.4% in 2014, reflecting improved care.
• Denmark:
  • The annual incidence of DKA was 12.6 per 100,000 from 1996 to 2002, with men experiencing higher rates (14.4 vs. 11.4 per 100,000 for women).
  • Mortality stood at 4%, with a higher prevalence of type 2 diabetes among those aged >50 years.
    
    

Developing Countries

• The incidence of DKA in developing nations remains poorly defined but is presumed to be higher than in industrialised countries due to limited access to healthcare and diabetes management resources.
• In urban Black populations in the United States, poor compliance with insulin therapy and substance abuse have been identified as significant contributors to recurrent DKA episodes.
  
  

Age-Related and Vulnerable Populations

• Among children and adolescents with type 1 diabetes, DKA is a frequent complication, particularly in newly diagnosed cases.
• The elderly population is at increased risk due to:
  • Declining thirst mechanisms.
  • Increased insulin resistance.
  • Dehydration and comorbidities such as myocardial infarction or infections, which exacerbate hyperglycemic crises.
• In nursing home residents in the United States, DKA accounted for 0.7% of cases and was associated with higher mortality rates (>5%).
  
  

Ethnic and Socioeconomic Factors

• Higher incidence rates of DKA are observed in non-White populations and individuals with lower socioeconomic status.
• Ethnic minorities, lack of health insurance, and delayed treatment contribute to higher risks in children and young adults.
  
  

Hospitalisation and Mortality Trends

• Hospitalisation rates for DKA are significant, representing 14% of all diabetes-related hospital admissions and 16% of diabetes-related fatalities.
• Approximately 50% of diabetes-related admissions in young individuals are due to DKA.
• Enhanced patient education and improved access to healthcare have the potential to reduce the frequency of hyperglycemic emergencies and associated fatalities.
  
  

Impact of Co-Morbidities

• The prognosis of DKA worsens with the presence of severe comorbidities, particularly in the elderly.
• Factors such as coma, hypotension, and concurrent infections significantly increase mortality risk.
• Specific comorbid conditions, such as substance abuse and obesity, exacerbate the risk and outcomes of DKA in vulnerable populations.
  
  

Early Symptoms

1. Polydipsia and Polyuria:
   • Insidious onset of excessive thirst (polydipsia) and increased urination (polyuria) are among the earliest symptoms of DKA.
2. Generalised Malaise:
   • Patients often report fatigue, generalised weakness, and reduced energy levels.
3. Nausea and Vomiting:
   • These symptoms may occur with or without diffuse abdominal pain, reduced appetite, or anorexia.
4. Weight Loss:
   • Rapid, unintentional weight loss is a common presenting symptom, especially in patients newly diagnosed with type 1 diabetes.
     
     

Signs of Metabolic Derangement

1. Altered Mental Status:
   • Mild disorientation or confusion may occur early.
   • Severe cases may progress to stupor or coma if untreated.
2. Dehydration Symptoms:
   • History of dry mouth, reduced sweating, and decreased urine output often suggests significant volume depletion.
3. Breath Odor:
   • Patients may exhibit a characteristic fruity odor of breath due to acetone production from ketosis.
     
     

Associated and Triggering Factors

1. Insulin Therapy Issues:
   • Non-compliance with insulin therapy is a frequent contributing factor. Patients may omit insulin doses due to:
     • Psychological stress (e.g., fear of weight gain or hypoglycemia).
     • Technical issues such as malfunctioning insulin pumps or degraded insulin from improper storage.
2. Infections:
   • Infections, especially urinary tract infections and pneumonia, are common triggers of DKA.
   • Symptoms of fever, chills, cough, or dysuria may indicate an infection.
3. Acute Illness or Stress:
   • Events such as myocardial infarction, sepsis, or physical trauma can precipitate DKA.
4. Drug Use:
   • Certain medications, including corticosteroids, thiazides, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, are implicated in triggering DKA.
   • Substance abuse, particularly alcohol or cocaine use, is also a contributing factor.
     
     

Medication and Past Medical History

1. Medication History:
   • A detailed review of medications can identify potential contributors, such as:
     • Corticosteroids and thiazides (which impair glucose metabolism).
     • Immune checkpoint inhibitors (which may cause insulin deficiency).
   • Use of SGLT2 inhibitors may increase the risk of euglycemic DKA.
2. History of Diabetes:
   • DKA is most common in patients with type 1 diabetes but may also occur in type 2 diabetes during periods of stress or insulin deficiency.
   • Newly diagnosed type 1 diabetes frequently presents with DKA.
     
     

Psychosocial and Lifestyle Factors

1. Psychological and Social Stressors:
   • Non-compliance with insulin therapy may stem from psychological factors such as needle phobia, stress, or eating disorders.
   • Financial or logistical barriers may hinder access to insulin or healthcare.
2. Substance Use:
   • A history of drug or alcohol use, particularly binge drinking or cocaine use, may precipitate DKA.
     
     

Paediatric Considerations

• In children with type 1 diabetes, factors like a recent emergency department visit or delayed endocrinologist follow-up increase the risk of DKA development.
• Younger children are also at higher risk of complications like cerebral Oedema during DKA episodes.
  
  

Special Populations

1. Pregnancy:
   • Pregnant women with diabetes are at increased risk for DKA, particularly in the second and third trimesters due to heightened insulin resistance.
   • DKA in pregnancy may present with abdominal pain and may mimic pre-term labor.
2. Elderly Patients:
   • Older adults are at heightened risk due to reduced thirst mechanisms, increased insulin resistance, and comorbid conditions that may exacerbate hyperglycemia and dehydration.
     
     

General Appearance and Initial Observations

• Appearance:
  • Patients often appear unwell, with signs of systemic distress.
• Dehydration:
  • Common findings include dry mucous membranes, decreased skin turgor, and delayed capillary refill.
  • Tachycardia and hypotension are common indicators of hypovolemia.
    
    

Vital Signs

• Heart Rate:
  • Tachycardia is frequently observed due to dehydration and compensatory mechanisms.
• Respiratory Rate:
  • Tachypnea, often associated with Kussmaul respiration (deep, labored breathing), reflects metabolic acidosis.
• Blood Pressure:
  • Hypotension, when present, suggests severe dehydration or shock.
• Temperature:
  • Fever may indicate an infectious trigger, whereas hypothermia can reflect peripheral vasodilation or advanced disease.
    
    

Respiratory Findings

• Kussmaul Respiration:
  • This late sign of DKA occurs due to severe acidosis, characterised by deep, sighing respirations at a slow or normal rate.
• Acetone Breath:
  • A fruity odor of the breath, caused by the presence of acetone, may be noted by the clinician.
    
    

Neurological Findings

• Altered Mental Status:
  • Patients may present with confusion, drowsiness, or even coma in severe cases.
  • A reduced Glasgow Coma Scale (GCS) score may indicate cerebral Oedema or other complications.
• Focal Neurological Deficits:
  • These can occur in severe cases due to cerebral Oedema and must be addressed urgently.
• Signs of Cerebral oedema:
  • Symptoms may include headache, irritability, bradycardia, rising blood pressure, or a declining level of consciousness. Immediate treatment with mannitol is required if cerebral oedema is suspected.
    
    

Abdominal Examination

• Tenderness:
  • Abdominal pain is common and can mimic or coexist with other acute abdominal conditions, such as pancreatitis.
• Acute Abdomen:
  • Although DKA itself may cause diffuse tenderness, rebound tenderness or guarding should prompt investigation for potential peritonitis or bowel obstruction.

Other Findings

• Skin:
  • Dry skin and poor peripheral perfusion are common due to dehydration.
• Reflexes:
  • Decreased reflexes may be noted, reflecting electrolyte imbalances.
• Signs of Infection:
  • Signs such as fever, localised pain, or inflammation should prompt an evaluation for infections such as pneumonia, urinary tract infections, or sepsis.
    
    

Common Differential Features on Examination

1. Myocardial Infarction:
   • Patients may present with atypical symptoms such as chest pain or palpitations, particularly in the elderly or those with autonomic dysfunction.
   • Maintain a high index of suspicion for silent myocardial infarction.
2. Acute Illness:
   • Pancreatitis, sepsis, or other stressors may present similarly to or trigger DKA.
3. Infection:
   • Pneumonia, urinary tract infections, or abscesses may complicate or precipitate DKA.
     
     

Initial Investigations

• Purpose: Assess acid-base status and severity of DKA.
  • pH:
    • ≥7.0: Mild or moderate DKA.
    • <7.0: Severe DKA (requires critical care input).
  • Potassium:
    • Hyperkalemia is common initially due to acidosis and insulin deficiency.
    • Hypokalemia (<3.5 mmol/L) indicates severe total-body potassium depletion.
  • Plasma Osmolality:
    • Elevated plasma osmolality (>320 mmol/kg) indicates significant dehydration.

• Purpose: Assess ketosis severity.
  • Blood ketones >3.0 mmol/L confirm ketonemia.
  • If bedside testing is unavailable, urinary ketone testing can be used (though it primarily detects acetoacetate, which may not fully reflect metabolic status).
  • Certain medications, such as captopril, can cause false-positive results in nitroprusside-based ketone tests.

• Purpose: Identify hyperglycemia or euglycemic DKA.
  • Hyperglycemia (>11 mmol/L or >250 mg/dL) is typical.
  • Normal blood glucose may indicate euglycemic DKA, particularly in patients using sodium-glucose cotransporter-2 (SGLT2) inhibitors.
  • Blood glucose must be interpreted alongside pH and ketone levels.
    
    

• Key findings:
  • Hyponatremia: Common due to osmotic shifts; hypernatremia indicates severe dehydration.
  • Hyperkalemia: Due to extracellular potassium shift.
  • Hypokalemia: Indicates severe DKA and total-body potassium depletion.
  • Hypomagnesemia and Hypophosphatemia: May also be present due to osmotic diuresis.
    
    

• Key findings:
  • Leukocytosis is common and correlates with ketone levels.
  • Leukocytosis >25 × 10⁹/L may suggest infection and warrants further evaluation.
    
    

Additional Investigations

• Findings:
  • Ketonuria (2+ or more) and glucosuria are typical.
  • Leukocytes and nitrites suggest urinary tract infection.
  • Myoglobinuria or hemoglobinuria may indicate rhabdomyolysis.
    
    

• Purpose: Detect cardiac precipitants (e.g., myocardial infarction) and electrolyte disturbances.
  • Findings:
    • Hypokalemia: U waves.
    • Hyperkalemia: Peaked T waves.
    • ST-segment changes or Q waves may indicate myocardial infarction.

• Amylase may be elevated in DKA, while lipase is usually normal, helping differentiate DKA from pancreatitis.

• Plasma osmolality >290 mOsm/L confirms hyperosmolarity.
• Comatose patients typically have osmolality >330 mOsm/L.
  
  

• Purpose: Identify pulmonary infections or complications.
  • Findings may include consolidation (pneumonia) or signs of pulmonary edema.
    
    

• Indicated if infection is suspected based on clinical presentation or leukocytosis.

• Elevated troponin T or I may indicate myocardial infarction as a trigger for DKA.

• Perform in all women of childbearing age to identify pregnancy as a potential precipitant.

• Elevated in rhabdomyolysis, which occurs in approximately 10% of DKA cases.
  
  

Advanced Monitoring and Considerations

• Serum Beta-Hydroxybutyrate:
  • Provides a direct measure of ketonemia and is useful for monitoring response to treatment.
  • Levels >3 mmol/L confirm significant ketonemia.
• Arterial vs. Venous Blood Gas:
  • Venous pH is a reliable substitute for arterial pH in most cases, with a consistent difference of ~0.03 units.
• Bicarbonate:
  • Used to assess acidosis severity and calculate the anion gap.
  • Elevated anion gap (>12 mEq/L) confirms metabolic acidosis.
    
    

Key Indicators of Severe DKA

• Blood ketones >6 mmol/L.
• Venous bicarbonate <5 mmol/L.
• pH <7.0.
• Potassium <3.5 mmol/L.
• Glasgow Coma Scale <12.
• Oxygen saturation <92% on room air.
• Persistent hypotension or oliguria.
• Anion gap >16.
  
  

Hyperosmolar Hyperglycemic State (HHS)

• Clinical Features:
  • More common in older adults with type 2 diabetes, particularly nursing home residents with poor fluid intake.
  • Symptoms develop insidiously over days to weeks.
  • Altered mental status, coma, and focal neurological deficits (e.g., hemiparesis, seizures) are frequent.
• Investigations:
  • Serum glucose >33.3 mmol/L (>600 mg/dL).
  • Serum osmolality >320 mOsm/kg.
  • ABG: pH >7.30 and bicarbonate >15 mmol/L.
  • Ketones: Absent or mildly positive.
  • Anion gap: Normal or mildly elevated.
    
    

Lactic Acidosis

• Clinical Features:
  • Symptoms resemble DKA, including acidosis, but without hyperglycemia or significant ketonemia.
• Investigations:
  • Serum lactate >5 mmol/L.
  • Normal serum glucose and ketones.
  • Anion gap metabolic acidosis.
    
    

 Starvation Ketosis

• Clinical Features:
  • Results from prolonged fasting or inadequate carbohydrate intake, triggering physiologically appropriate lipolysis and ketone production.
• Investigations:
  • Normal blood glucose levels.
  • Urine may contain significant ketones, but blood ketone levels are usually mild.
  • Normal arterial pH or mildly elevated anion gap.
    
    

Alcoholic Ketoacidosis

• Clinical Features:
  • Common in individuals with chronic alcohol use who reduce caloric intake suddenly.
  • Symptoms include abdominal pain, nausea, and vomiting.
• Investigations:
  • Elevated anion gap metabolic acidosis.
  • Positive serum and urine ketones.
  • Hypoglycemia or normoglycemia.
  • Blood alcohol level may be undetectable.
    
    

Salicylate Toxicity

• Clinical Features:
  • Symptoms include nausea, vomiting, and tinnitus, alongside altered mental status.
  • May cause mixed metabolic acidosis and respiratory alkalosis.
• Investigations:
  • Elevated anion gap.
  • Normal or low glucose, negative ketones.
  • Positive serum and/or urine salicylates.
    
    

Toxic Alcohol Ingestion (Ethylene Glycol or Methanol)

• Clinical Features:
  • Severe metabolic acidosis with an elevated anion gap.
  • Symptoms may include visual disturbances (methanol) or renal failure (ethylene glycol).
• Investigations:
  • High measured serum osmolality.
  • Positive methanol or ethylene glycol serum levels.
  • No hyperglycemia or ketonemia.
    
    

Uremic Acidosis

• Clinical Features:
  • Occurs in patients with advanced renal failure.
  • Symptoms may include fatigue, nausea, and altered mental status.
• Investigations:
  • Markedly elevated serum urea (>71.4 mmol/L or >200 mg/dL) and creatinine (>884 µmol/L or >10 mg/dL).
  • Normal glucose, mild acidosis, and mildly elevated anion gap.

Pancreatitis

• Clinical Features:
  • Abdominal pain, nausea, and vomiting that mimic symptoms of DKA.
• Investigations:
  • Elevated serum amylase and lipase.
  • Imaging (e.g., CT scan) may confirm pancreatic inflammation.
    
    

Myocardial Infarction

• Clinical Features:
  • Common precipitant of DKA in adults; symptoms may include chest pain, dyspnea, or asymptomatic presentation in diabetic patients.
• Investigations:
  • ECG: ST-segment changes or Q waves.
  • Elevated troponin or CK-MB.

Sepsis

• Clinical Features:
  • Fever, hypotension, and altered mental status.
  • Common infections include pneumonia, urinary tract infections, or intra-abdominal infections.
• Investigations:
  • Elevated white blood cell count and procalcitonin.
  • Positive blood, urine, or sputum cultures.
    
    

Metabolic Acidosis (Non-DKA Causes)

• Conditions to Consider:
  • Hypophosphatemia.
  • Hypothermia.
  • Other toxic exposures (e.g., paraldehyde, carbon monoxide).
• Investigations:
  • Review of specific metabolic markers (e.g., phosphate levels, carboxyhemoglobin for carbon monoxide poisoning).
    
    

Treatment Goals

1. Restore circulatory volume.
2. Correct electrolyte imbalances.
3. Suppress ketogenesis.
4. Normalise blood glucose levels.
5. Identify and address the precipitating cause.
   
   

Initial Management Priorities

1. Determine the Site of Care:
   • Most patients require inpatient management.
   • Outpatient treatment may be considered for selected cases of mild DKA with a clear, reversible cause (e.g., insulin pump occlusion) and adequate support systems.
2. Evaluate Clinical Status:
   • Assess vital signs, cardiorespiratory function, and mental status.
   • Perform Glasgow Coma Scale (GCS) scoring for stupor or coma. Patients with GCS ≤8 may require endotracheal intubation.
     
     

Fluid Replacement

• Isotonic Crystalloids:
  • Use 0.9% saline or isotonic buffered crystalloids (e.g., Lactated Ringer’s solution).
  • Buffered crystalloids may reduce time to DKA resolution and prevent hyperchloremic non-anion gap acidosis.

• Hypovolemic Shock:
  • Infuse isotonic saline as rapidly as possible.
• Hypovolemia Without Shock:
  • Start at 15-20 mL/kg/hour (approximately 1 L/hour in an average adult).
  • Avoid exceeding 50 mL/kg in the first 4 hours to minimise the risk of cerebral edema.
• Mild Hypovolemia or Euvolemia:
  • Use lower rates guided by clinical assessment.

• Switch to hypotonic fluids (e.g., 0.45% saline) if the corrected sodium level is ≥135 mEq/L.
• Add dextrose (5-10%) when blood glucose falls below 250 mg/dL (13.9 mmol/L) to prevent hypoglycemia while continuing insulin therapy.
  
  

Potassium Replacement

• Potassium <3.5 mEq/L:
  • Delay insulin therapy until potassium levels are corrected above this threshold.
  • Replace with IV potassium chloride (10-20 mEq/hour).
• Potassium 3.5-5.0 mEq/L:
  • Add 10-20 mEq of potassium chloride to each liter of IV fluids to maintain serum potassium between 4.0-5.0 mEq/L.
• Potassium >5.0 mEq/L:
  • Delay potassium replacement but monitor levels frequently.
    
    

 Insulin Therapy

• Timing:
  • Initiate insulin therapy only if serum potassium is ≥3.5 mEq/L.
• Intravenous Insulin:
  • Moderate to severe DKA: Start with a fixed-rate infusion of regular insulin (0.1 units/kg/hour).
  • Expected glucose reduction: 50-70 mg/dL (2.8-3.9 mmol/L) per hour.
• Subcutaneous Insulin:
  • For mild DKA, subcutaneous rapid-acting insulin analogs (e.g., lispro or aspart) may be used, typically every 1-2 hours.
    
    

Titration and Glucose Management

• Reduce insulin infusion to 0.05 units/kg/hour when glucose falls below 250 mg/dL.
• Maintain glucose levels between 150-200 mg/dL (8.3-11.1 mmol/L) until DKA resolution.
  
  

Correction of Acidosis

• Acidosis generally resolves with insulin therapy and volume expansion.
• Sodium Bicarbonate:
  • Consider only in patients with pH <7.0 and severe cardiovascular compromise.
  • Administer 100 mmol bicarbonate in 400 mL sterile water over 2 hours, with careful monitoring.
    
    

Phosphate Replacement

• Routine phosphate replacement is not recommended.
• Replace phosphate if levels fall below 1 mg/dL and are associated with hemolytic anemia, respiratory failure, or cardiac dysfunction.
  
  

Monitoring During Treatment

• Hourly assessments of vital signs, mental status, and fluid balance.
• Watch for complications, including cerebral edema, pulmonary edema, and hypoglycemia.

• Every 1-2 Hours:
  • Blood glucose.
• Every 2-4 Hours:
  • Serum electrolytes, BUN, creatinine, bicarbonate, and venous pH.
• Every 2 Hours:
  • Beta-hydroxybutyrate or anion gap (if beta-hydroxybutyrate testing is unavailable).
    
    

Criteria for DKA Resolution

1. Blood beta-hydroxybutyrate <0.6 mmol/L or anion gap ≤12 mEq/L.
2. Venous pH ≥7.3 or bicarbonate ≥18 mmol/L.
3. Blood glucose <200 mg/dL (11.1 mmol/L).
   
   

Transition to Subcutaneous Insulin

• Begin subcutaneous insulin when DKA has resolved, and the patient can tolerate oral intake.
• Overlap IV and subcutaneous insulin by 1-2 hours to prevent recurrence of hyperglycemia or ketoacidosis.

Addressing Precipitating Factors

• Identify and treat underlying causes such as infection, myocardial infarction, or medication errors.
• Discontinue SGLT2 inhibitors if implicated in the development of DKA.
  
  

Complications to Monitor

1. Cerebral Oedema:
   • Symptoms include headache, irritability, altered mental status, and bradycardia.
   • Treat with mannitol and seek immediate critical care input.
2. Pulmonary Oedema:
   • Associated with fluid overload, especially in patients with cardiac or renal dysfunction.
3. Hypoglycemia and Hypokalemia:
   • Avoid rapid reductions in glucose or potassium levels.
     
     

Mortality Rates

• Global Trends:
  • Overall mortality rates for DKA range from 0.2% to 2%, with higher rates seen in developing countries.
  • In developed nations, mortality has decreased significantly over the last 30 years, from 7.96% to 0.67%.
• Historical Perspective:
  • Before the discovery of insulin in 1922, the mortality rate for DKA was 100%.
    
    

Prognostic Factors

1. Age and Comorbidities:
   • Elderly patients, particularly those with concurrent illnesses such as myocardial infarction, pneumonia, or sepsis, tend to have worse outcomes, longer hospital stays, and higher mortality rates.
   • Children under 10 years account for 70% of diabetes-related deaths due to DKA, primarily from complications like cerebral edema.
2. Severe Presentations:
   • Signs of poor prognosis include:
     • Deep coma at presentation.
     • Hypothermia.
     • Oliguria (indicative of severe dehydration and kidney injury).
   • Pregnant women with DKA face a fetal mortality rate of up to 30%, with rates as high as 60% in cases of DKA-induced coma.
3. Complications:
   • Cerebral Oedema:
     • The most common cause of mortality in younger patients, especially children and adolescents.
     • Caused by rapid shifts in intracellular fluid during treatment.
   • Renal Dysfunction:
     • Acute kidney injury (AKI) is common in pediatric DKA, with up to 64% of hospitalised children developing some degree of AKI. Severe AKI is associated with lower bicarbonate levels and higher sodium concentrations at presentation.
   • Stroke:
     • In type 2 diabetes, patients who experience DKA have a 1.55 times greater risk of stroke, particularly within the first six months after the event.
       
       

Improved Outcomes

1. Early Diagnosis and Treatment:
   • Prompt management significantly improves outcomes, particularly in patients without intercurrent infections.
   • Emergency room protocols like the Emergency Valuable Approach and Diabetes Education (EVADE) have shown success in managing mild cases of DKA outside of intensive care settings.
2. Advancements in Care:
   • A better understanding of DKA pathophysiology and diligent monitoring of electrolyte imbalances have led to marked reductions in mortality.
3. Intensive Care Settings:
   • Best outcomes are observed in patients managed in intensive care during the first 1-2 days of hospitalization.
   • Non-hospitalized patients with delayed treatment continue to have higher mortality rates, highlighting the importance of prevention and early recognition.
     
     

Key Studies and Findings

1. Severe Acidosis and AKI:
   • A study by Hursh et al found that severe acidosis (serum bicarbonate <10 mEq/L) increases the risk of AKI fivefold in pediatric patients.
   • Higher corrected sodium levels (>145 mEq/L) also increase the likelihood of AKI.
2. Stroke Risk in Type 2 Diabetes:
   • Chen et al reported a significantly increased stroke risk in patients with type 2 diabetes who experienced DKA, particularly in those with hypertension and hyperlipidemia.
3. Serum Potassium and pH:
   • Lee et al demonstrated that higher potassium levels and lower pH at admission are independent predictors of prolonged DKA resolution times.
     
     

Factors That Worsen Prognosis

1. Extremes of Age:
   • Both very young and elderly patients face higher morbidity and mortality due to limited physiological reserves and higher rates of complications.
2. Comorbid States:
   • Conditions like pneumonia, sepsis, and myocardial infarction significantly worsen outcomes, particularly when patients are treated outside of intensive care units.
3. Delayed Treatment:
   • Lack of early diagnosis or mismanagement increases the risk of complications, including cerebral Oedema and renal failure.
     
     

Long-Term Outlook

• When treated promptly and effectively, DKA rarely leads to long-term sequelae.
• Comprehensive follow-up and patient education significantly reduce the risk of recurrence, particularly in patients with type 1 diabetes or those newly diagnosed with diabetes.
  
  

Hypoglycemia

• Incidence:
  • Occurs in 5–25% of patients during DKA treatment.
• Cause:
  • Iatrogenic due to excessive insulin therapy or inadequate glucose supplementation.
• Clinical Implications:
  • May lead to seizures, arrhythmias, or cardiovascular events.
• Prevention and Management:
  • Frequent blood glucose monitoring during treatment.
  • Use of glucose-containing intravenous fluids as glucose levels normalise.
    
    

Hypokalemia

• Incidence:
  • Common due to potassium shifts and osmotic diuresis, especially during insulin therapy.
• Cause:
  • Insulin drives potassium into cells, exacerbating total body potassium depletion.
• Clinical Implications:
  • Severe hypokalemia can cause muscle weakness, cardiac arrhythmias, and cardiac arrest.
• Prevention and Management:
  • Frequent potassium monitoring and replacement according to serum levels.
  • Avoid insulin administration if potassium is <3.5 mEq/L until corrected.
    
    

Cerebral Oedema

• Incidence:
  • Rare but the most common cause of DKA-related mortality, especially in children and adolescents.
• Risk Factors:
  • Younger age, new-onset diabetes, severe acidosis, rapid rehydration, and high initial glucose levels.
• Clinical Features:
  • Symptoms include headache, irritability, altered mental status, cranial nerve dysfunction, and recurrent vomiting.
• Management:
  • Hourly Glasgow Coma Scale monitoring.
  • Administer mannitol and seek critical care support immediately.
  • Consider CT imaging for persistent or worsening symptoms.
    
    

Pulmonary Oedema and Acute Respiratory Distress Syndrome (ARDS)

• Incidence:
  • Rare but significant complication, occurring due to fluid overload.
• Cause:
  • Excessive fluid administration or increased pulmonary capillary permeability.
• Clinical Features:
  • Low oxygen saturations, fluid overload, and crepitations on auscultation.
• Management:
  • Monitor oxygen saturation and consider chest X-ray or arterial blood gas analysis.
  • Adjust fluid replacement cautiously, especially in patients with cardiac or renal dysfunction.
    
    

Non-Anion Gap Hyperchloremic Acidosis

• Cause:
  • Occurs due to urinary loss of ketoanions required for bicarbonate regeneration and excessive administration of chloride-containing fluids.
• Clinical Features:
  • Typically resolves with continued treatment.
• At-Risk Groups:
  • More likely in pregnant women.
    
    

Rhabdomyolysis

• Cause:
  • Rare but may occur due to severe hypophosphatemia or hyperosmolar states.
• Clinical Features:
  • Muscle weakness, elevated creatine kinase, and potential acute kidney injury.
• Management:
  • Monitor phosphate levels and provide replacement if serum phosphate <1 mg/dL.
    
    

Acute Respiratory Failure

• Causes:
  • Pneumonia, ARDS, or pulmonary edema.
• Clinical Features:
  • May include hypoxia and respiratory distress.
• Management:
  • Address underlying conditions and provide supportive care, including oxygen therapy.
    
    

Arterial or Venous Thromboembolic Events

• Incidence:
  • Medium likelihood in DKA due to hypercoagulable states.
• Management:
  • Prophylactic low-dose heparin for patients at high risk.
  • Full anticoagulation is not routinely recommended without clinical evidence of thrombosis.
    
    

Hypophosphatemia

• Cause:
  • Rapid insulin administration and rehydration may uncover underlying phosphate depletion.
• Clinical Features:
  • Severe cases can lead to respiratory depression, hemolytic anemia, and rhabdomyolysis.
• Management:
  • Replace phosphate if levels are <1 mg/dL and symptoms are present.
    
    

Other Rare Complications

• TTP (Thrombotic Thrombocytopenic Purpura):
  • Rarely reported in association with DKA.
• Myocarditis:
  • An uncommon but severe complication requiring cardiac monitoring.
    
    

Prevention and Monitoring

• Frequent Monitoring:
  • Hourly glucose and ketone levels.
  • Serum electrolytes every 2–4 hours, adjusted based on clinical stability.
• Avoid Rapid Correction:
  • Gradual reduction of hyperglycemia and osmolality to minimise risks of cerebral and pulmonary edema.
• Special Considerations:
  • Use cautious fluid replacement in children, elderly patients, and those with cardiac or renal dysfunction.
    
    

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