Diabetic ketoacidosis (DKA)

Common Precipitating Factors

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

Missed or Disrupted Insulin Treatment (25%)

• Non-compliance with prescribed insulin therapy is a frequent cause of DKA.
  • 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.

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

• While less common than in type 1 diabetes, DKA in type 2 diabetes is often associated with:
  • Intercurrent Illness: Conditions such as myocardial infarction, pneumonia, prostatitis, or other severe infections.
  • Medications:
    • 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

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.

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

• Elevated counter-regulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) play a central role in the pathophysiology of DKA by:
  • 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

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.

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.

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).

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.

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

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.

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

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.

Buffering Systems

• Early ketonemia is mitigated by extracellular and intracellular buffers, such as bicarbonate and haemoglobin.
• As ketone levels rise, buffering capacity is overwhelmed, resulting in frank metabolic acidosis.

Clinical Correlations of Pathophysiology

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.

Neurological Impairment

• Hyperosmolarity, acidosis, and severe electrolyte disturbances lead to altered mental status and, in severe cases, coma.

Respiratory Compensation

• The metabolic acidosis triggers hyperventilation (Kussmaul breathing) to reduce carbon dioxide levels, partially compensating for acidosis.

Nausea and Vomiting

• Elevated ketone levels, particularly beta-hydroxybutyrate, induce nausea and vomiting, worsening dehydration and electrolyte imbalance.

Severe DKA Classification

• The presence of one or more of the following parameters indicates severe DKA:
  • 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.
• Higher prevalence is 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 hyperglycaemic 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 hyperglycaemic 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

 Polydipsia and Polyuria

• Insidious onset of excessive thirst (polydipsia) and increased urination (polyuria) are among the earliest symptoms of DKA.

Generalised Malaise

• Patients often report fatigue, generalised weakness, and reduced energy levels.

Nausea and Vomiting

• These symptoms may occur with or without diffuse abdominal pain, reduced appetite, or anorexia.

Weight Loss

• Rapid, unintentional weight loss is a common presenting symptom, especially in patients newly diagnosed with type 1 diabetes.

Signs of Metabolic Derangement

 Altered Mental Status

• Mild disorientation or confusion may occur early.
• Severe cases may progress to stupor or coma if untreated.

Dehydration Symptoms

• History of dry mouth, reduced sweating, and decreased urine output often suggests significant volume depletion.

Breath Odor

• Patients may exhibit a characteristic fruity odor of breath due to acetone production from ketosis.

Associated and Triggering Factors

 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 hypoglycaemia)
  • Technical issues such as malfunctioning insulin pumps or degraded insulin from improper storage

Infections

• Infections, especially urinary tract infections and pneumonia, are common triggers of DKA.
• Symptoms of fever, chills, cough, or dysuria may indicate an infection.

Acute Illness or Stress

• Events such as myocardial infarction, sepsis, or physical trauma can precipitate DKA.

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

 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 euglycaemic DKA

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

 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.

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

 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 labour.

Elderly Patients

• Older adults are at heightened risk due to reduced thirst mechanisms, increased insulin resistance, and comorbid conditions that may exacerbate hyperglycaemia 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.
• 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 evaluation for infections such as pneumonia, urinary tract infections, or sepsis.

Common Differential Features on Examination

 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.

Acute Illness

• Pancreatitis, sepsis, or other stressors may present similarly to or trigger DKA.

Infection

• Pneumonia, urinary tract infections, or abscesses may complicate or precipitate DKA.

Initial Investigations

 Venous Blood Gas (VBG)

• 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.

Blood Ketones

• 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.

Blood Glucose

• 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.

Urea and Electrolytes

• 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.

Full Blood Count (FBC)

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

Additional Investigations

 Urinalysis

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

Electrocardiogram (ECG)

• 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 and Lipase

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

Serum Osmolality

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

Chest X-Ray

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

Blood, Urine, and Sputum Cultures

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

Cardiac Enzymes

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

Pregnancy Test

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

Creatinine Kinase (CK)

• 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)

• 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.

• 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

• Symptoms resemble DKA, including acidosis, but without hyperglycemia or significant ketonemia.

• Serum lactate >5 mmol/L.
• Normal serum glucose and ketones.
• Anion gap metabolic acidosis.

Starvation Ketosis

• Results from prolonged fasting or inadequate carbohydrate intake, triggering physiologically appropriate lipolysis and ketone production.

• 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

• Common in individuals with chronic alcohol use who reduce caloric intake suddenly.
• Symptoms include abdominal pain, nausea, and vomiting.

• Elevated anion gap metabolic acidosis.
• Positive serum and urine ketones.
• Hypoglycemia or normoglycemia.
• Blood alcohol level may be undetectable.

Salicylate Toxicity

• Symptoms include nausea, vomiting, and tinnitus, alongside altered mental status.
• May cause mixed metabolic acidosis and respiratory alkalosis.

• Elevated anion gap.
• Normal or low glucose, negative ketones.
• Positive serum and/or urine salicylates.

Toxic Alcohol Ingestion (Ethylene Glycol or Methanol)

• Severe metabolic acidosis with an elevated anion gap.
• Symptoms may include visual disturbances (methanol) or renal failure (ethylene glycol).

• High measured serum osmolality.
• Positive methanol or ethylene glycol serum levels.
• No hyperglycemia or ketonemia.

Uremic Acidosis

• Occurs in patients with advanced renal failure.
• Symptoms may include fatigue, nausea, and altered mental status.

• 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

• Abdominal pain, nausea, and vomiting that mimic symptoms of DKA.

• Elevated serum amylase and lipase.
• Imaging (e.g., CT scan) may confirm pancreatic inflammation.

Myocardial Infarction

• Common precipitant of DKA in adults; symptoms may include chest pain, dyspnea, or asymptomatic presentation in diabetic patients.

• ECG: ST-segment changes or Q waves.
• Elevated troponin or CK-MB.

Sepsis

• Fever, hypotension, and altered mental status.
• Common infections include pneumonia, urinary tract infections, or intra-abdominal infections.

• Elevated white blood cell count and procalcitonin.
• Positive blood, urine, or sputum cultures.

Metabolic Acidosis (Non-DKA Causes)

• Hypophosphatemia.
• Hypothermia.
• Other toxic exposures (e.g., paraldehyde, carbon monoxide).

• Review of specific metabolic markers (e.g., phosphate levels, carboxyhemoglobin for carbon monoxide poisoning).

Treatment Goals

• Restore circulatory volume.
• Correct electrolyte imbalances.
• Suppress ketogenesis.
• Normalise blood glucose levels.
• Identify and address the precipitating cause.

Initial Management Priorities

 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.

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

•  Fluid resuscitation is the cornerstone of DKA management and addresses dehydration and hyperosmolality.

Initial Choice of Fluid

 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.

Rate of Administration

•  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 oedema.
• Mild Hypovolemia or Euvolemia:
  • Use lower rates guided by clinical assessment.

Subsequent Fluid Adjustments

• 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 hypoglycaemia 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 litre 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 analogues (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

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 haemolytic anaemia, respiratory failure, or cardiac dysfunction.

Monitoring During Treatment

 Clinical Monitoring

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

Laboratory Monitoring

 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

• Blood beta-hydroxybutyrate <0.6 mmol/L or anion gap ≤12 mEq/L.
• Venous pH ≥7.3 or bicarbonate ≥18 mmol/L.
• 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 hyperglycaemia 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

 Cerebral Oedema

• Symptoms include headache, irritability, altered mental status, and bradycardia.
• Treat with mannitol and seek immediate critical care input.

Pulmonary Oedema

• Associated with fluid overload, especially in patients with cardiac or renal dysfunction.

Hypoglycaemia and Hypokalaemia

• 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

 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 oedema.

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.

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 paediatric 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

 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.

Advancements in Care

• A better understanding of DKA pathophysiology and diligent monitoring of electrolyte imbalances have led to marked reductions in mortality.

Intensive Care Settings

• Best outcomes are observed in patients managed in intensive care during the first 1–2 days of hospitalisation.
• Non-hospitalised patients with delayed treatment continue to have higher mortality rates, highlighting the importance of prevention and early recognition.

Key Studies and Findings

 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 paediatric patients.
• Higher corrected sodium levels (>145 mEq/L) also increase the likelihood of AKI.

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 hyperlipidaemia.

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

 Extremes of Age

• Both very young and elderly patients face higher morbidity and mortality due to limited physiological reserves and higher rates of complications.

Comorbid States

• Conditions like pneumonia, sepsis, and myocardial infarction significantly worsen outcomes, particularly when patients are treated outside of intensive care units.

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.

Hypoglycaemia

• 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.

Hypokalaemia

• 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 hypokalaemia 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 overall
  • Most common cause of DKA-related mortality in children and adolescents
• Risk Factors
  • Younger age
  • New-onset diabetes
  • Severe acidosis
  • Rapid rehydration
  • High initial glucose levels
• Clinical Features
  • Headache
  • Irritability
  • Altered mental status
  • Cranial nerve dysfunction
  • Recurrent vomiting
• Management
  • Hourly Glasgow Coma Scale monitoring
  • Administer mannitol and seek critical care input immediately
  • Consider CT imaging for persistent or worsening symptoms

Pulmonary Oedema and ARDS

• Incidence
  • Rare but clinically significant in fluid-overloaded patients
• Cause
  • Excessive fluid administration
  • Increased pulmonary capillary permeability
• Clinical Features
  • Low oxygen saturation
  • Crepitations on auscultation
  • Signs of fluid overload
• Management
  • Monitor oxygen saturation
  • Chest X-ray or ABG as indicated
  • Adjust fluid replacement cautiously

Non-Anion Gap Hyperchloraemic Acidosis

• Cause
  • Loss of ketoanions via urine
  • Excess chloride-containing fluids
• Clinical Features
  • Typically self-limiting with continued DKA treatment
• At-Risk Groups
  • More common in pregnant women

Rhabdomyolysis

• Cause
  • Severe hypophosphataemia
  • Hyperosmolar states
• Clinical Features
  • Muscle weakness
  • Elevated creatine kinase
  • Possible AKI
• Management
  • Monitor phosphate levels
  • Replace if <1 mg/dL

Acute Respiratory Failure

• Causes
  • Pneumonia
  • ARDS
  • Pulmonary oedema
• Clinical Features
  • Hypoxia
  • Respiratory distress
• Management
  • Treat underlying cause
  • Provide oxygen and supportive care

Thromboembolic Events

• Incidence
  • Moderate risk due to hypercoagulable state
• Management
  • Prophylactic low-dose heparin in high-risk patients
  • Full anticoagulation only with confirmed thrombosis

Hypophosphataemia

• Cause
  • Insulin and fluid replacement uncover underlying phosphate depletion
• Clinical Features
  • Respiratory depression
  • Haemolytic anaemia
  • Rhabdomyolysis
• Management
  • Replace phosphate if <1 mg/dL and symptomatic

Other Rare Complications

• TTP: Rarely reported
• Myocarditis: Uncommon, requires monitoring

Prevention and Monitoring

• Hourly glucose and ketone monitoring
• Electrolytes every 2–4 hours
• Gradual correction of hyperglycaemia
• Cautious fluids in at-risk groups (children, elderly, cardiac/renal patients)

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