Diabetic ketoacidosis (DKA) is the most common acute complication of diabetes. It is a severe metabolic disorder syndrome caused by a combination of insulin deficiency and an excess of insulin-antagonistic hormones. Its main characteristics include hyperglycemia, ketosis, and high anion gap metabolic acidosis. Ketone bodies consist of β-hydroxybutyrate, acetoacetate, and acetone. Insulin deficiency leads to three major metabolic disturbances: it not only causes significant hyperglycemia but also promotes increased fat breakdown. Fatty acids undergo β-oxidation in the liver, producing large amounts of acetyl-CoA. Due to the disruption in glucose metabolism and a shortage of oxaloacetate, acetyl-CoA cannot enter the tricarboxylic acid cycle for energy production and is instead converted into ketone bodies. At the same time, increased protein breakdown leads to a rise in gluconeogenic and ketogenic amino acids in the blood, further exacerbating hyperglycemia and ketosis.
DKA progresses through several stages:
- Ketosis: Elevated blood ketones are referred to as ketonemia, while increased urinary ketone excretion is known as ketonuria. Together, these are collectively termed ketosis.
- Acidosis: Among the ketone bodies, β-hydroxybutyrate and acetoacetate are acidic metabolic products that consume alkaline reserves in the body. In the early stages, blood pH may remain normal (compensated ketoacidosis). In the later stages, blood pH decreases (decompensated ketoacidosis).
- Coma: As the condition progresses further, alterations in consciousness can occur, leading to diabetic ketoacidosis coma. Delayed diagnosis and improper management can result in patient mortality.
Triggers
Patients with type 1 diabetes mellitus (T1DM) are inherently inclined to develop DKA, while patients with type 2 diabetes mellitus (T2DM) can also develop DKA under certain triggers. Infection is the most common precipitating factor for DKA. Other triggers include interruptions or improper reductions in insulin therapy, various stressors, excessive alcohol consumption, and the use of certain medications (e.g., glucocorticoids, immune checkpoint inhibitors, antipsychotic drugs, and SGLT-2 inhibitors). Additionally, 2–10% of cases have unknown causes.
Pathophysiology
Acidosis
Acidosis results from increased levels of β-hydroxybutyrate, acetoacetate, and organic acids produced during protein breakdown. Circulatory failure and reduced renal excretion of acidic metabolic products further contribute to acidosis. Acidosis can reduce insulin sensitivity, increase tissue breakdown, and cause potassium (K+) to move out of cells. It may also impair oxygen utilization and energy metabolism. Severe acidosis worsens microcirculatory function, reduces myocardial contractility, and can lead to hypothermia and hypotension. When blood pH drops below 7.2, the respiratory center becomes stimulated, leading to deep and rapid breathing. If the pH falls to 7.0–7.1, central respiratory and nervous system functions may be suppressed, and cardiac arrhythmias may develop.
Severe Dehydration
Hyperglycemia, high blood ketone levels, and various acidic metabolic products result in osmotic diuresis. Ketone excretion through the lungs also leads to substantial water loss. Anorexia, nausea, and vomiting reduce fluid intake, collectively causing extracellular dehydration. Increased plasma osmolality drives water from intracellular to extracellular spaces, resulting in intracellular dehydration. Severe dehydration, reduced blood volume, and microcirculatory dysfunction can lead to hypovolemic shock. Decreased renal perfusion may result in oliguria or anuria, and in severe cases, acute renal failure may develop.
Electrolyte Imbalance
Osmotic diuresis causes significant losses of sodium (Na+), potassium (K+), chloride (Cl-), and phosphate. Decreased electrolyte intake due to anorexia, nausea, and vomiting further contributes to electrolyte disturbances. Although total body sodium is depleted in DKA, water loss and blood concentration may lead to normal, decreased, or increased serum sodium levels upon hospital admission. Insufficient insulin action causes potassium to move out of cells, resulting in intracellular potassium depletion, even though serum potassium levels may initially appear normal or elevated due to dehydration, reduced renal function, and potassium shifts from cells to the extracellular space during acidosis. During treatment, fluid replacement (which dilutes potassium levels), increased urinary potassium excretion, correction of acidosis, and insulin administration may cause potassium to shift back into cells, potentially leading to severe hypokalemia.
Dehydration, severe acidosis, and circulatory dysfunction can result in brain cell dehydration and central nervous system dysfunction. Moreover, improper treatment (such as excessive or rapid administration of bicarbonate) may exacerbate paradoxical cerebrospinal fluid acidosis. Rapid declines in blood glucose, excessive or rapid fluid infusion, and osmotic imbalances may also worsen cerebral hypoxia and secondary cerebral edema.
Clinical Manifestations
In the early stages, symptoms such as polyuria, polydipsia, polyphagia, and weight loss tend to worsen. After the onset of decompensated acidosis, patients may experience fatigue, loss of appetite, nausea, emesis, dry mouth, polyuria, headache, and drowsiness. Rapid and deep breathing (Kussmaul respiration) often develops, and the breath may have a fruity odor due to acetone. In later stages, signs of severe dehydration can emerge, including reduced urine output, sunken eyes, dry skin and mucous membranes, decreased blood pressure, increased heart rate, and cold extremities. In advanced stages, various degrees of altered consciousness and even coma may occur. A minority of patients present with abdominal pain that mimics an acute abdomen, leading to potential misdiagnosis. Although infections are common in such patients, their symptoms may be masked by the manifestations of DKA. Additionally, peripheral vascular dilation often results in normal or even low body temperature, which is considered a poor prognostic indicator.
Laboratory Examinations
Blood glucose levels are often elevated, typically ranging from 11.1 to 33.3 mmol/L. When levels are ≥33.3 mmol/L, this is usually accompanied by hyperosmolar hyperglycemic state or renal dysfunction. However, some patients with DKA present with blood glucose levels <11.1 mmol/L. This can occur due to prior insulin use, reduced nutritional intake, pregnancy, advanced liver disease, or the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i).
Measurement of serum β-hydroxybutyrate can aid in diagnosis, and urine ketones can also be tested. One of the key diagnostic criteria for DKA includes blood ketone levels ≥3 mmol/L or urine ketones being positive at a level of ++ or higher.
Actual bicarbonate (AB) and standard bicarbonate (SB) levels in the blood are typically <18 mmol/L. Carbon dioxide binding capacity decreases, and blood pH drops below 7.3 during decompensated acidosis. There is an increase in base deficit and anion gap, roughly corresponding to the decrease in HCO3- levels.
Serum potassium levels before treatment may be normal, slightly decreased, or elevated. Decreases in serum sodium and chloride are also observed. Blood urea nitrogen and creatinine levels are usually elevated, and plasma osmolality may show a mild increase.
Serum amylase and lipase levels can become elevated in the absence of pancreatitis, typically returning to normal within days after treatment. Even without concurrent infection, white blood cell count and the proportion of neutrophils may be increased.
Diagnosis and Differential Diagnosis
Early diagnosis is essential for successful treatment. In clinical practice, for patients with unexplained nausea, vomiting, acidosis, dehydration, shock, or coma—especially those with fruity (acetone) breath, low blood pressure, and increased urine output—the possibility of DKA should be considered, even if there is no prior history of diabetes. Diagnosis should be supported by immediate testing of capillary blood glucose, blood ketones, urine glucose, and urine ketones, along with laboratory analysis of blood glucose, serum β-hydroxybutyrate, blood urea nitrogen, creatinine, electrolytes, and arterial blood gas to confirm or exclude DKA. DKA can be diagnosed with a blood glucose level >11 mmol/L, ketonuria and/or ketonemia, arterial blood pH <7.3, and/or serum bicarbonate (HCO3-) concentration <18 mmol/L.
Patients taking SGLT-2 inhibitors may develop DKA without significant hyperglycemia, making a detailed medication history critical for diagnosis in these cases.
Once DKA is identified, the severity of acidosis must be assessed. Mild acidosis is defined by pH <7.3 or serum bicarbonate concentration <18 mmol/L. Moderate acidosis is characterized by pH <7.25 or bicarbonate <15 mmol/L. Severe acidosis is indicated by pH <7.0 or bicarbonate <10 mmol/L. The degree of acidosis is an important marker for determining the severity of DKA.
The differential diagnosis includes:
- Other types of diabetic coma, such as hypoglycemic coma, hyperosmolar hyperglycemic syndrome, or lactic acidosis.
- Coma caused by other diseases, such as uremia or cerebrovascular accidents.
In some patients, DKA may be the first clinical presentation of diabetes. Additionally, some patients may present with other diseases or triggering factors as the primary concern. In cases where DKA coexists with uremia or stroke, the clinical complexity increases, necessitating careful differentiation.
Treatment
For patients with ketosis, adequate insulin therapy and fluid replacement are typically sufficient, along with identification and resolution of underlying triggers. Close monitoring of the condition with regular assessments of blood glucose and ketone levels is necessary, and insulin dosage adjustments are made until ketosis resolves. For those with acidosis or even coma, prompt diagnosis necessitates immediate and proactive resuscitation efforts.
General Principles of Treatment
Treatment is aimed at promptly restoring blood volume, correcting dehydration, reducing blood glucose levels, balancing electrolytes and acid-base disturbances, identifying and addressing precipitating factors, preventing complications, and lowering mortality.
Fluid Replacement
Fluid replacement is a critical component of DKA management. Establishing a timely intravenous access is essential since the biological effects of insulin can only be fully realized after effective tissue perfusion has been restored. Patients with mild dehydration and no acidosis may undergo oral rehydration, while those with moderate to severe DKA require intravenous fluid replacement.
The fluid deficit in DKA can exceed 10% of body weight, making precise control of fluid volume and infusion rate highly important. The basic principle of rehydration is "initially fast, then slower; saline first, then glucose." Normal saline is typically used first, with an initial infusion rate of 1,000–2,000 mL of 0.9% sodium chloride solution in the first 1–2 hours. During the first four hours, about one-third of the calculated fluid deficit should be replaced to quickly restore blood volume, improve peripheral circulation, and protect kidney function.
If the patient presents with pre-existing hypotension or shock and fails to respond adequately to rapid infusion, colloid solutions and other anti-shock measures may be necessary. Subsequent fluid volume and infusion rate is determined based on blood pressure, heart rate, hourly urine output, peripheral circulation, and the presence of fever, vomiting, or diarrhea. For older adults and patients with cardiac or renal disease, central venous pressure may guide fluid therapy.
Total fluid volume over 24 hours should include the estimated deficit and ongoing fluid losses. When blood glucose falls to approximately 13.9 mmol/L, fluids containing glucose should be administered, with 1 unit of short-acting insulin added for every 2–4 grams of glucose. Monitoring for improvements in both blood glucose and ketone levels is recommended during this stage.
Encouragement of oral water intake is suggested when appropriate. For those without vomiting, gastrointestinal distention, or upper gastrointestinal bleeding, warm 0.9% saline solution or warm water may be administered via nasogastric tube in divided, incremental, and slow doses to avoid aspiration caused by vomiting. For patients with impaired cardiac or renal function, plasma osmolality, and heart, lung, kidney, and neurological functions require close monitoring, and adjustments to fluid volume and infusion rate should follow accordingly.
Insulin Therapy
For mild DKA, subcutaneous insulin therapy combined with aggressive fluid management may suffice. For moderate or severe DKA, small-dose intravenous infusions of short-acting insulin are recommended. Insulin at a dosage of 0.1 U/kg body weight per hour is used to maintain serum insulin levels between 100–200 mU/L, thereby achieving maximum inhibition of lipolysis, ketone production, and potent glucose-lowering effects while exerting limited influence on potassium transport.
Typically, short-acting insulin is mixed into normal saline and administered as a continuous intravenous infusion (via a separate infusion channel). For critically ill patients, an initial dose of 0.1 U/kg insulin can be administered intravenously, followed by a continuous infusion at 0.1 U/kg/hour, targeting a blood glucose reduction of 2.8–4.2 mmol/L per hour.
If blood glucose does not decrease by at least 10% in the first hour of treatment, or if blood ketones decline at a rate of less than 0.5 mmol/L per hour despite adequate hydration, an increase in insulin dosage may be considered. When blood glucose reaches about 13.9 mmol/L, an infusion of 5% glucose (or glucose-saline solution) should be started, with insulin added proportionately. Blood glucose levels will inform adjustments to the insulin-to-glucose infusion ratio. If the patient begins oral intake, subcutaneous insulin administration should be initiated.
DKA may recur, and rebound hyperglycemia can occur, requiring continued monitoring for changes and timely adjustments to the treatment plan. Once the condition is stabilized, the patient can transition to routine subcutaneous insulin therapy.
Correction of Electrolyte and Acid-Base Imbalances
Potassium supplementation is crucial in DKA treatment. Pre-treatment serum potassium levels may not accurately reflect the extent of total body potassium depletion, necessitating supplementation based on serum potassium levels and urinary output.
When serum potassium is below normal, potassium supplementation should begin immediately upon initiation of insulin and fluid therapy. For serum potassium levels <3.3 mmol/L, potassium correction must take priority, and insulin therapy should only commence once potassium levels reach ≥3.3 mmol/L, in order to avoid life-threatening arrhythmias, cardiac arrest, or respiratory muscle paralysis.
When serum potassium is normal, and urine output is >40 mL/hour, potassium supplementation should begin concurrently with insulin and fluid therapy. For normal potassium levels but a urine output <30 mL/hour, potassium supplementation is delayed until urine output increases. When pre-treatment potassium levels are elevated, potassium supplementation is postponed. Regular monitoring of serum potassium and urine output during treatment is critical for dosage and infusion rate adjustments. Oral potassium salt supplementation is often continued for several days after recovery.
Acid-base imbalances in DKA are primarily caused by acidic metabolic products from ketone bodies. Acidosis generally resolves with fluid and insulin therapy, making bicarbonate administration unnecessary in most cases. However, severe acidosis with pH ≤6.9 warrants appropriate intervention. Bicarbonate replacement should avoid excessive or rapid administration. Isotonic bicarbonate solutions (1.25–1.4%) are recommended, such as a solution prepared by mixing 84 mL of 5% bicarbonate with sterile water to produce 300 mL of 1.4% isotonic solution, administered slowly over one hour or more.
Typically, only 1–2 doses are needed, and blood pH is measured every two hours until it stabilizes above 7.0. Hypokalemia should be corrected before bicarbonate administration. Excessive or overly rapid bicarbonate replacement may lead to serum potassium depletion, paradoxical cerebrospinal fluid acidosis, exacerbation of tissue hypoxia, or increased risk of cerebral edema.
Management of Triggering Factors and Prevention of Complications
Coordination among treatment measures is essential during resuscitation efforts, with a particular focus on the prevention and management of critical complications such as cerebral edema and renal failure, while maintaining the function of vital organs.
Shock
For patients with severe shock that fails to resolve after rapid fluid resuscitation, thorough examination and analysis of potential causes, such as infection or acute myocardial infarction, is necessary to guide appropriate interventions.
Severe Infections
Severe infection is both a common precipitating factor for DKA and a potential secondary complication. Because DKA can cause hypothermia and an increase in white blood cell count, the presence or absence of fever or changes in blood cell levels may not reliably indicate infection. Infection should be actively managed.
Heart Failure and Arrhythmias
Excessive fluid administration in elderly patients or those with coexisting coronary artery disease may lead to heart failure or pulmonary edema, requiring attention to prevention. Fluid volume and infusion rate may be adjusted based on blood pressure, heart rate, central venous pressure, and urine output, with consideration for the use of diuretics or positive inotropic agents. Both hypokalemia and hyperkalemia can precipitate serious arrhythmias, necessitating enhanced monitoring and timely intervention.
Renal Failure
Renal failure is one of the leading causes of mortality in DKA and is influenced by pre-existing kidney disease, the degree and duration of dehydration and shock, and delays in treatment. Close monitoring of urine output during treatment is critical for early detection and management.
Cerebral Edema
Cerebral edema has a high fatality rate and requires an emphasis on prevention, early detection, and timely treatment. Cerebral edema may be associated with factors such as cerebral hypoxia, improper bicarbonate replacement or fluid administration, and overly rapid reductions in blood glucose. Indications of cerebral edema may include worsening coma despite improvements in blood glucose and acidosis, reemergence of coma after a brief period of consciousness, irritability, bradycardia accompanied by elevated blood pressure, or increased muscle tone. In such cases, dexamethasone, furosemide, or albumin may be used. Caution is advised with the use of mannitol.
Hypoglycemia
Enhanced blood glucose monitoring is necessary, and when blood glucose levels decrease to approximately 13.9 mmol/L, intravenous fluids should be replaced with glucose-containing solutions.
Nursing
Proper nursing care plays a vital role in the management of DKA. Preventing pressure ulcers and secondary infections is critically important. Careful and continuous observation of the patient’s condition is required, including accurate documentation of vital signs and fluid input/output balance.
Managing severe DKA involves a level of expertise akin to art. Adhering to treatment principles while personalizing therapy based on the patient’s evolving clinical status is the key to successful resuscitation.
Prevention
Emphasis is placed on a prevention-first approach. Effective blood glucose control and strong communication between healthcare providers and patients are crucial to preventing DKA. Proactive measures to manage infections and other precipitating factors are also emphasized. During periods of physical discomfort or illness, monitoring of blood glucose, blood ketones, or urine ketones supports the early identification and management of DKA. Early medical attention is encouraged in such cases.