Hyperglycemic crises

Hyperglycemic crises can be the initial presentation of diabetes mellitus or complications due to other diseases. Inadequate insulin replacement (e.g., due to poor adherence) or increased insulin demand (e.g., during times of acute illness, surgery, or stress) may lead to acute hyperglycemia. In diabetic ketoacidosis (DKA), which is more common in patients with type 1 diabetes, no insulin is available to suppress lipolysis, resulting in ketone formation and acidosis. In a hyperosmolar hyperglycemic state (HHS), which is more common in patients with type 2 diabetes, there is still some insulin available, so there is minimal or no ketone formation. Clinical features of both DKA and HHS include polyuria, polydipsia, nausea and vomiting, volume depletion (e.g., dry oral mucosa, decreased skin turgor), and eventually mental status changes and coma. Features unique to DKA include a fruity odor to the breath, hyperventilation, and abdominal pain. DKA typically has an acute onset (e.g., within hours) while HHS usually develops insidiously (e.g., within days) and manifests with more extreme volume depletion. The mainstay of treatment for both DKA and HHS consists of IV fluid resuscitation, electrolyte repletion, and insulin therapy.

For patients with hyperglycemia without DKA or HHS, see also “Inpatient management of hyperglycemia.”

The most important findings of diabetic ketoacidosis (DKA) are: Delirium/psychosis, Dehydration, Kussmaul respirations, Abdominal pain/nausea/vomiting, fruity (Acetone) breath odor.

• Lack of or insufficient insulin replacement therapy
  • Undiagnosed, untreated diabetes mellitus
  • Treatment failure in known diabetics:
    • Insulin pump failure
    • Forgotten insulin injection
    • Poor adherence to insulin therapy
    • Inability to afford treatment
• Increased insulin demand
  • Stress: infections, surgery, trauma, myocardial infarction, burns, heatstroke
  • Drugs: glucocorticoid therapy, cocaine use, alcohol abuse

DKA, often precipitated by infection (e.g., pneumonia, urinary tract infection), is a common initial manifestation of type 1 diabetes mellitus (∼ 30% of cases).

Diabetic ketoacidosis (DKA)

DKA primarily affects patients with type 1 diabetes.

Osmotic diuresis and hypovolemia

• Insulin normally elevates cellular uptake of glucose from the blood.
• In the insulin-deficient state of DKA, hyperglycemia occurs.
• Hyperglycemia, in turn, leads to progressive volume depletion via osmotic diuresis.
• Insulin deficiency → hyperglycemia → hyperosmolality → osmotic diuresis and loss of electrolytes → hypovolemia

Hypovolemia resulting from DKA can lead to acute kidney injury (AKI) due to decreased renal blood flow! Hypovolemic shock may also develop.

Metabolic acidosis with increased anion gap

• Insulin deficiency increases fat breakdown (lipolysis) through increased activity of hormone-sensitive lipase.
• Metabolic acidosis develops as the free fatty acids generated by lipolysis become ketones, two of which are acidic (acetoacetic acid and beta-hydroxybutyric acid).
• Serum bicarbonate is consumed as a buffer for the acidic ketones. Metabolic acidosis with an elevated anion gap is therefore characteristic of DKA.
• Insulin deficiency → ↑ lipolysis → ↑ free fatty acids → hepatic ketone production (ketogenesis) → ketosis → bicarbonate consumption (as a buffer) → anion gap metabolic acidosis

DKA is an important cause of anion gap metabolic acidosis with respiratory compensation.

Intracellular potassium deficit

• As a result of hyperglycemic hyperosmolality, potassium shifts along with water from inside cells to the extracellular space and is lost in the urine.
• Insulin normally promotes cellular potassium uptake but is absent in DKA, compounding the problem.
• A total body potassium deficit develops in the body, although serum potassium may be normal or even paradoxically elevated.
• Insulin deficiency → hyperosmolality → K⁺ shift out of cells + lack of insulin to promote K⁺ uptake → intracellular K⁺depleted → total body K⁺ deficit despite normal or even elevated serum K⁺

There is a total body potassium deficit in DKA. This becomes important during treatment, when insulin replacement leads to rapid potassium uptake by depleted cells and patients may require potassium replacement.

Hyperosmolar hyperglycemic state (HHS)

• Primarily affects patients with type 2 diabetes
• The pathophysiology of HHS is similar to that of DKA.
• However, in HHS, there are still small amounts of insulin being secreted by the pancreas, and this is sufficient to prevent DKA by suppressing lipolysis and, in turn, ketogenesis.
• HHS is characterized by symptoms of marked dehydration (and loss of electrolytes) due to the predominating hyperglycemia and osmotic diuresis.

Signs and symptoms of both DKA and HHS

• Polyuria
• Polydipsia
• Recent weight loss
• Nausea and vomiting
• Signs of significant dehydration
• Neurological abnormalities
  • Altered mental status
  • Lethargy
  • Coma
  • Other neurological examination abnormalities, e.g., blurred vision and weakness

Patients with known diabetes who present with nausea and/or vomiting should be immediately assessed for DKA/HHS.

Specific findings in DKA ^[1]

• Rapid onset (< 24 h) in contrast to HHS
• Abdominal pain
• Fruity odor on the breath (from exhaled acetone)
• Hyperventilation: long, deep breaths (Kussmaul respirations)

Comparison: DKA vs. HHS

In DKA, absolute insulin deficiency leads to the rapid development of symptomatic acidosis and an early presentation (within hours) with only moderate hyperglycemia (> 250 mg/dL).

In HHS, residual insulin production prevents significant ketoacidosis leading to insidious progression (days to weeks) and profound hypovolemia and hyperglycemia (> 600 mg/dL).

Approach ^[2][3]

• Check serum glucose to confirm hyperglycemia.
• Check BMP for serum bicarbonate, anion gap, electrolytes, and renal function.
• Check for the presence of ketones.
  • Urine ketones: Standard urine dipstick assays detect acetoacetate and acetone but not beta-hydroxybutyrate.
  • Serum beta-hydroxybutyrate ^[4]
• Check blood gas analysis for pH. ^[5]
• Diagnostic workup to evaluate the underlying cause: HbA1c, CBC, ECG, infectious workup

DKA is the diagnosis in patients with type 1 diabetes who have hyperglycemia, ketonuria, and high anion gap metabolic acidosis with decreased bicarbonate!

HHS is the diagnosis in patients with type 2 diabetes who have hyperglycemia and hyperosmolality!

Overview of laboratory findings in hyperglycemic crises ^[2]

• DKA: hyperglycemia, high anion gap metabolic acidosis, ketonuria/ketonemia
• HHS: hyperglycemia, hyperosmolality, and dehydration without ketonuria

Normal serum osmolality in a stuporous patient rules out HHS and should prompt investigation for other causes of altered mental status.

Euglycemia does not rule out DKA! Assess ketone levels in all patients with high anion gap metabolic acidosis to evaluate for euglycemic DKA.

Electrolytes and renal function ^[2][3]

• Sodium:
  • Hyponatremia is common in both DKA and HHS, due to hypovolemic hyponatremia ; and hypertonic hyponatremia
  • Always check corrected sodium for hyperglycemia.
• Potassium in DKA: normal or elevated (despite a total body deficit)
• Magnesium levels are typically low.
• Phosphorus levels may be elevated despite a total body deficit.
• BUN and creatinine are often elevated. ^[6]

For anion gap calculation, use the measured serum sodium concentration rather than the corrected serum sodium concentration. ^[7]

Additional diagnostic workup ^[2][3][8]

Additional diagnostics are indicated depending on suspected precipitating causes and differential diagnoses.

• HbA1c
• Urine pregnancy test ^[9]
• Diagnostics for AMS, e.g.:
  • CT head
  • Toxicology screen
• Diagnostics for sepsis, e.g.:
  • CBC with differential
  • Serum lactate
• Diagnostics for myocardial infarction, e.g., 12-lead ECG
• Diagnostics for acute abdomen, e.g.:
  • Abdominal imaging
  • Serum lipase ^[10]
  • Serum transaminases

Infection, myocardial infarction, and pancreatitis should be ruled out in all patients presenting with a hyperglycemic crisis.

Pregnancy and SGLT2-inhibitors can cause euglycemic DKA (i.e., high anion gap metabolic acidosis with normal or near-normal glucose). ^[9][11]

Severity of DKA ^[2]

DKA and HHS are both managed by restoring intravascular volume, repleting water and electrolyte deficits, repleting insulin, and treating the underlying cause.

Approach ^[2][8][12]

• Initial steps
  • ABCDE approach
  • Urgent diagnostics, e.g., POC glucose, BMP, blood gas analysis
  • Volume status assessment
• Principal interventions
  • Fluid resuscitation: initially with isotonic saline (0.9% NaCl)
  • Potassium repletion: for potassium level < 5.3 mEq/L
  • Insulin therapy: initiate short-acting insulin once potassium level is > 3.3 mEq/L
  • IV sodium bicarbonate: only for severe refractory metabolic acidosis ^[13]
  • Identify and treat precipitating causes (e.g., sepsis).
  • Consider endocrine consult and admission to the ICU.

The goal of therapy is the resolution of ketonemia and acidosis (i.e., closure of the anion gap) in DKA and of hyperglycemia and hyperosmolarity in HHS.

Monitoring ^[2][14][15]

• Hourly vitals and mental status and hydration status
• POC glucose every 1–2 hours until blood glucose < 250 mg/dL and hourly blood glucose readings are stable for at least 3 hours; then decrease monitoring to every 2–4 hours
• Serum osmolality every 1–4 hours
• Blood gas and BMP with electrolytes every 2–4 hours

Monitoring of volume status, serum glucose, serum electrolytes, and acid-base status at regular intervals is essential.

Disposition ^[2][12][16]

• Admission
  • Indicated for all patients with HHS and most patients with DKA ^[17]
  • Consider ICU admission for patients with any of the following:
    • Persistently altered mental status or hemodynamic instability
    • Severe electrolyte imbalance or persistent acidosis
    • Underlying critical illness (e.g., sepsis, MI)
• Discharge may be considered for patients with mild DKA and all of the following:
  • Resolved anion gap acidosis
  • No concerning precipitating cause
  • Toleration of oral hydration and nutrition
  • Ability to adhere to discharge instructions, including outpatient follow-up

Pregnant patients with DKA should be assessed by an endocrinologist and obstetrician because of the potential for a high-risk pregnancy.

Fluid resuscitation ^[2][8][14]

• First hour: isotonic saline solution (0.9% sodium chloride) at 15–20 mL/kg/hour (∼ 1000–1500 mL bolus) ^[2][8][14]
• Next 24–48 hours: Adjust IV fluid rate and composition according to CVP, urine output, blood glucose, and corrected sodium levels.
  • Check corrected sodium for hyperglycemia.
    • If corrected serum sodium ≥ 135 mmol/L: 0.45% NaCl
    • If corrected serum sodium < 135 mmol/L: 0.9% NaCl
• Switch to a solution containing dextrose (e.g., D5NS) when glucose falls to ∼ 200 mg/dL (DKA) or 300 mg/dL (HHS).

Carefully monitor for signs of fluid overload during fluid resuscitation, especially in patients with comorbidities (e.g., CHF, CKD). ^[12]

Electrolyte repletion ^[2]

• Potassium
  • Potassium levels must be ≥ 3.3 mEq/L before insulin therapy is initiated
  • If potassium level is < 3.3 mEq/L, potassium should be repleted and rechecked prior to giving any insulin.
  • If potassium level is < 5.3 mEq/L, the patient will likely require potassium repletion once insulin therapy is started
  • Maintain serum potassium between 4–5 mEq/L.
  • Use extreme caution with potassium repletion in anuric patients.
  • Monitor potassium levels every 2 hours while administering insulin infusion.
  • See also repletion regimens for hypokalemia.

• Phosphorus: See repletion regimens for hypophosphatemia.
• Magnesium: See repletion regimens for hypomagnesemia.

It is critical that potassium levels are confirmed to be > 3.3 mEq/L before administering insulin, as insulin will lower serum potassium and potentially cause severe hypokalemia.

Acid-base status ^[2]

• Acidosis usually resolves with fluids and insulin therapy and the use of IV bicarbonate is usually not necessary
• If pH < 6.9 despite adequate IV fluid resuscitation, administer IV sodium bicarbonate.

General principles ^[2][14][19]

• The administration of insulin is essential in halting lipolysis and ketoacidosis in patients with DKA.
• Recommended regimens ^[2]
  • IV regular insulin bolus , followed by continuous regular insulin IV infusion
  • OR regular insulin continuous IV infusion without a bolus
  • Treatment with subcutaneous rapid-acting insulin analogues may be considered for mild DKA.
• The initial goal is to decrease blood glucose levels by 10% per hour (∼ 50–75 mg/dL/hour).
• Check glucose level hourly and titrate as needed.
• In patients requiring ongoing insulin infusion:
  • Switch IV fluids to D5NS or D5½NS infusion when serum glucose falls to ∼ 200 mg/dL (DKA) or 300 mg/dL (HHS).
  • Titrate insulin to a goal serum glucose of 150–200 mg/dL (DKA) or 200–300 mg/dL (HHS).

Resolution and transition to subcutaneous insulin ^[2]

• Criteria for transitioning to subcutaneous insulin:
  • Resolution of hyperglycemic crisis
  • Precipitating factor identified and treated
  • Patient tolerating oral nutrition and eating consistently
• Procedure for transitioning to subcutaneous insulin:
  • Stop dextrose infusion.
  • Administer long-acting insulin dose.
    • Patients who were on insulin may resume their normal regimen.
    • In insulin-naive patients, initiate subcutaneous insulin at a total daily dose of ∼ 0.6 units/kg/day (see also insulin regimens) ^{[20] [2]}
  • Continue IV insulin for 1–2 hours after initiating SQ insulin.

• ABCDE survey
• Establish IV access with two large-bore peripheral IV lines.
• Confirm diagnosis with blood gas, BMP, serum osmolality, serum ketones, and urine ketones.
• Identify and treat life-threatening causes (e.g., MI, sepsis).
• Assess severity of DKA.
• Begin fluid resuscitation with 0.9% NaCl.
• Replete potassium and maintain K+ levels at 4–5 mEq/L.
• Replete other electrolytes (see electrolyte repletion).
• Start continuous insulin IV infusion with hourly POC glucose checks once serum potassium is confirmed > 3.3 mEq/L.
• Consider bicarbonate if pH < 6.9 despite adequate fluid therapy.
• Adjust fluid resuscitation based on corrected sodium for hyperglycemia, serum glucose, and clinical response.
  • Corrected serum sodium ≥ 135 mmol/L: 0.45% NaCl
  • Corrected serum sodium < 135 mmol/L: 0.9% NaCl
  • Add dextrose once POC glucose is below 250–300 mg/dL.
• Identify and treat the underlying cause (e.g., medication nonadherence, infection).
• Order monitoring labs (e.g., BMP, serum osmolality, and blood gas every 2–4 hours).
• Consider endocrine consult.
• Hospital admission; consider ICU admission.

• Other causes of anion gap metabolic acidosis, e.g.:
  • Alcoholic ketoacidosis
  • Lactic acidosis
  • Starvation ketoacidosis
  • Toxin ingestion
• Other causes of hyperglycemia and hypovolemia (e.g., sepsis, acute pancreatitis)
• Other causes of AMS, e.g., hypoglycemia

All other causes of altered mental status must be considered in the differential diagnosis of DKA/HHS. Intoxication and other endocrine disorders, as well as gastroenteritis, myocardial infarction, pancreatitis, and other causes of high anion gap metabolic acidosis, should all be excluded.

• Cerebral edema
• Cardiac arrhythmias
• Heart failure, respiratory failure
• Mucormycosis (Mucor and Rhizopus species)
• Hypoglycemia
• Hypokalemia

We list the most important complications. The selection is not exhaustive.