Hyperglycemic crises

Acute hyperglycemia, or high blood glucose, can be either the initial presentation of diabetes mellitus or a complication arising during the course of another disease. Inadequate insulin replacement (e.g., noncompliance with treatment) 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. Patients with HHS typically present with more extreme volume depletion than those with DKA. The mainstay of treatment for both DKA and HHS consists primarily of IV fluid resuscitation, electrolyte repletion, and insulin therapy.

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, noncompliance with insulin therapy
• Increased insulin demand
  • Stress: infections, surgery, trauma, myocardial infarction
  • 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 also increases fat breakdown (lipolysis).
• 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
• Tachycardia
• Recent weight loss
• Nausea and vomiting
• Signs of volume depletion (i.e., dry mucous membranes, decreased skin turgor), hypotension, circulatory collapse
• Neurological abnormalities
  • Altered mental status
  • Lethargy
  • Coma
  • Other neurological exam abnormalities, e.g., blurred vision and weakness

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

Known diabetics who present with nausea and vomiting should be immediately assessed for DKA/HHS. Because patients with type 2 diabetes can still produce small amounts of insulin in some cases, acute hyperglycemia progresses more slowly and serum glucose is significantly elevated compared with patients with type 1 diabetes in DKA (> 600 mg/dL in HHS versus > 250 mg/dL in DKA).

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

Overview of laboratory findings in hyperglycemic crises ^[2]

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

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!

Ketone levels should be ordered 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 falsely elevated despite a total body deficit.
• BUN and creatinine are often elevated. ^[6]

Additional diagnostic workup ^[2][3][7]

• HbA1c
• Urine pregnancy test ^[8]
• Identify the underlying cause.
  • Infection
    • CBC with differential
    • Urinalysis
    • Blood and/or urine cultures
    • Serum procalcitonin
    • Serum lactate
    • X-ray chest
  • Cardiac ischemia
    • 12-lead ECG
    • Serum troponin
  • Abdominal etiology
    • Serum lipase ^[9]
    • Serum transaminases
    • Abdominal ultrasound
  • Toxicology screen

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). ^[8][10].

Severity of DKA ^[2]

Approach

• IV access with two large-bore peripheral IV lines
• Assess the severity of DKA.
• Fluid resuscitation: initially with isotonic saline (0.9% NaCl), then 0.45% or 0.9% depending on corrected serum sodium
• Electrolyte repletion (especially potassium)
• Short-acting insulin (regular insulin) therapy
• IV bicarbonate (only in severe metabolic acidosis)
• Identify and treat the underlying cause.
• Consider admission to the ICU.

Initially treat DKA with normal saline and short-acting (regular) insulin.

Fluid resuscitation ^[2][7][11]

• First hour: isotonic saline solution (0.9% sodium chloride) at 15–20 mL/kg/hour (∼ 1000–1500 mL bolus) ^[2][7][11]
• 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
  • When serum glucose falls to < 200–250 mg/dL, add 5% dextrose to infusion.

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.

Insulin ^[2][11][13]

• 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
  • Both options listed are valid approaches with advantages and disadvantages. When in doubt, follow hospital standards.
• Check glucose level hourly and titrate as needed.
• The goal is to decrease blood glucose levels by 10% per hour (∼ 50–75 mg/dL/hour).
• Treatment with subcutaneous rapid-acting insulin analogues on a regular medical ward may be considered in cases of mild DKA.

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.

Monitoring ^{[2][11] [14]}

• Admission to the ICU or closely monitored setting ^[2]
• Consider endocrine consult.
• NPO status in patients with high anion gap metabolic acidosis on insulin infusion
• Hourly monitoring of 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.

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) ^{[15] [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 < 200–250 mg/dL.
• Identify and treat the underlying cause (e.g., medication noncompliance, infection).
• Order monitoring labs (e.g., BMP, serum osmolality, and blood gas every 2–4 hours).
• Consider endocrine consult.
• Admit to ICU (consider regular medical ward for mild cases).

All other etiologies that may cause 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.

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

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