Hyperglycemic Crises

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperosmolar hyperglycemic state occurs due to a relative deficiency of insulin or insulin resistance, leading to severe hyperglycemia and elevated serum osmolality. Triggering factors include inadequate insulin therapy, underlying infection, concurrent medical illness, or drug side effects. Diabetic ketoacidosis patients tend to be younger, with type 1 diabetes, who present with acute symptoms, including abdominal pain, nausea, and vomiting. On the other hand, HHS patients are generally older, with type 2 diabetes, and will have gradual onset of symptoms, including altered mental status and neurologic changes. Both sets of patients will have polyuria, polydipsia, and evidence of severe dehydration. Diagnosis is based on laboratory values demonstrating hyperglycemia with ketoacidosis or hyperosmolality. Management involves aggressive fluid rehydration, insulin therapy, and correction of electrolyte abnormalities.

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Overview

Definition

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. 

  • Both DKA and HHS are characterized by: 
    • Hyperglycemia 
    • Dehydration
    • Hyperosmolality
    • Electrolyte abnormalities
  • Patients with DKA will have ketoacidosis.
  • Patients with HHS have more severe hyperglycemia and hyperosmolality.
  • Both of these diagnoses can run on a spectrum, and patients may present with features of both DKA and HHS.

Epidemiology

  • DKA
    • More frequently seen in younger patients 
    • Mostly seen in patients with type 1 diabetes
    • Accounts for approximately 14% of all hospital admissions for diabetics
    • Mortality rate: 0.2%–2% (increased mortality in patients with coma, hypothermia, and oliguria)
  • HHS
    • Usually associated with older individuals (≥ 65 years)
    • Patients will usually have type 2 diabetes.
    • Accounts for fewer hospitalizations than DKA (< 1%)
    • Mortality rate: 10%–20%
      • 10 times higher than DKA
      • Usually due to the precipitating cause
      • Increased mortality in patients with coma and hypotension

Etiology

  • Both HHS and DKA:
    • Infections (most common)
    • Inadequate or noncompliance with insulin treatment
    • Acute illnesses (e.g., stroke, myocardial infarction, pancreatitis, surgery, trauma)
    • Medications
      • Corticosteroids
      • Olanzapine
      • Lithium
      • Clozapine
    • Drugs
      • Alcohol
      • Cocaine
  • HHS:
    • Dehydration
    • Medications
      • Diuretics
      • Beta blockers
      • Calcium channel blockers
      • Total parenteral nutrition
    • Endocrine disorders
      • Cushing’s syndrome
      • Acromegaly
      • Thyrotoxicosis
  • DKA:
    • New-onset diabetes
    • Medications
      • SGLT2 inhibitors
      • Terbutaline

Pathophysiology

Normal physiology

The normal response to increased serum glucose involves the release of insulin by pancreatic beta cells. This leads to:

  •  ↓ glucagon secretion in pancreatic alpha-cells → ↓ gluconeogenesis and glycogenolysis in the liver → ↓ glucose production
  • ↑ glucose uptake by muscle and adipose cells

Pathophysiology of DKA

  • Hormone abnormalities:
    • Absolute insulin deficiency
    • ↑ glucagon
    • Additional hormone changes, which oppose insulin:
      • ↑ cortisol
      • ↑ growth hormone
      • ↑ catecholamines
  • Hyperglycemia results from:
    • ↓ glucose utilization by peripheral tissues
    • ↑ glycogenolysis
    • ↑ gluconeogenesis
      • ↑ amino acid delivery from muscle
      • ↑ glycerol delivery from adipose tissue
  • Severe hyperglycemia leads to: 
    • ↑ osmolality → draws water out of cells → dilutes sodium concentrations
    • Glucosuria → osmotic diuresis, resulting in:
      • Water and electrolyte loss (sodium and potassium) 
      • Dehydration  
      • ↑ osmolality
      • Impaired renal function
  • Ketoacidosis results from:
    • ↑ lipolysis → ↑ free fatty acids → ↑ ketone production (ketogenesis)
    • ↓ bicarbonate → consumed as a buffer → ↑ anion gap
  • Acidosis and hyperosmolality results in:
    • Potassium shifts out of cells → ↑ extracellular potassium, ↓ intracellular potassium
    • Potassium is then excreted in the urine → ↓ total body potassium
Insufficient or absent insulin

Pathophysiology of diabetic ketoacidosis

Image by Lecturio.

Pathophysiology of HHS

  • Hormone abnormalities:
    • ↓ insulin or insulin resistance
    • Other similar hormone changes of DKA
  • Hyperglycemia occurs through the same process as DKA.
  • Since some insulin is present, ketogenesis is prevented → no acidosis
  • Severe hyperglycemia leads to the same osmotic diuresis and sodium changes.
  • Hyperglycemia will be more severe than DKA → more severe hyperosmolar state
  • Despite the lack of acidosis, the hyperosmolar state will still lead to similar shifts in potassium.

Clinical Presentation

Clinical presentation of DKA

  • Rapid onset of symptoms (over 24 hours)
    • Polyuria
    • Polydipsia
    • Nausea and vomiting
    • Diffuse abdominal pain
    • Weakness
    • History of weight loss → common with a new diagnosis of type 1 diabetes
  • Physical exam findings:
    • Vitals:
      • Tachycardia
      • Hypotension
      • Hypothermia
      • Rapid, deep respirations (Kussmaul respirations) → compensatory hyperventilation
    • Fruity breath → exhaled acetone
    • Evidence of severe dehydration:
      • Dry mucous membranes
      • Sunken eyes
      • Decreased skin turgor
      • Anhidrosis
      • Decreased urine output

Clinical presentation of HHS

  • Gradual development of symptoms (over days to weeks)
    • Polyuria 
    • Polydipsia
    • Nausea and vomiting
    • Neurologic changes
      • Lethargy
      • Delirium
      • Coma (in severe disease)
      • Seizures
      • Sensory deficits
      • Vision changes
  • Physical exam findings:
    • Vitals:
      • Similar to DKA
      • Kussmaul respirations are not usually seen
    • Altered mental status, lethargy, or coma
    • Similar findings of severe dehydration to DKA
    • Transient focal neurologic changes may be seen in some patients
      • Hemiparesis
      • Hemianopsia

Diagnosis

Initial findings

Table: Main differences between DKA and HHS on workup
Laboratory testDiabetic ketoacidosisHyperosmolar hyperglycemic state
Serum glucose> 250 mg/dL> 600 mg/dL
Serum bicarbonate↓↓> 18 mEq/L
Anion gapGenerally normal
Serum osmolalityVariable> 320 mOsm/L
Serum ketones (beta-hydroxybutyrate, acetone)PositiveSmall or negative
Urine ketonesPositiveSmall or negative
Arterial blood gas
  • pH: ↓
  • pCO2: ↓
pH: > 7.3

Other findings

  • Sodium (Na):
    • Generally ↓ due to sodium loss, extracellular dilution, and pseudohyponatremia
      • Corrected sodium = measured serum sodium +  (2 mEq/L for each 100 mg/dL of glucose above 100 mg/dL)
    • May be normal or ↑ in HHS → significant osmotic diuresis and dehydration
      • Associated with neurologic symptoms
  • Potassium (K):
    • Normal or ↑ (despite an actual potassium deficit)
    • Will start to ↓ with correction of acidosis and insulin administration
  • Creatinine: ↑ due to hypovolemia and acute kidney injury
  • Complete blood count:
    • Leukocytosis → not necessarily related to infection
    • Bandemia → should be concerning for infection
  • Lipid panel:
    • ↑ cholesterol
    • ↑ triglycerides
    • Will ↓ with insulin therapy
  • Brain imaging (computed tomography (CT) or magnetic resonance imaging (MRI)):
    • For patients with altered mental status
    • Evaluates for cerebral edema, especially in children

General workup for precipitating factors

  • Myocardial infarction:
    • Electrocardiogram (ECG)
    • Troponin
  • Infection:
    • Urinalysis → rule out urinary tract infection
    • Blood cultures
    • Chest radiograph → rule out pneumonia
  • Toxicology:
    • Drug screen
    • Alcohol level

Management and Complications

Management of DKA

  • Admit patient to the intensive care unit (ICU).
  • Aggressive intravenous (IV) fluid administration: Begin with normal saline.
    • If corrected Na is < 135 mEq/L, continue normal saline.
    • If corrected Na remains normal or elevated, consider changing to 0.45% saline.
    • Monitor urine output and hemodynamics.
    • Add dextrose to the fluids once the glucose reaches 200 mg/dL.
  • IV insulin infusion (K must be > 3.3 mEq/L)
    • Hourly serum glucose monitoring
    • Close monitoring of serum electrolytes and anion gap (every 2–4 hours)
    • Provide potassium supplementation to maintain a K of 4–5 mEq/L.
    • Mild DKA may be managed with frequent subcutaneous (SC) insulin administration
  • Sodium bicarbonate (NaHCO3) can be given if the patient’s pH is < 6.9.
  • Identify and treat the underlying cause.
  • DKA has resolved once the serum anion gap has normalized (< 12 mEq/L) and glucose is 150–200 mg/dL.
    • Can initiate SC insulin if the patient is tolerating oral intake
    • Overlap with the IV insulin infusion for 2–4 hours to prevent recurrence of hyperglycemia and acidosis.
Treatment algorithm diagram for diabetic ketoacidosis

Treatment algorithm for diabetic ketoacidosis

Image by Lecturio.

Management of HHS

  • Admit patient to the ICU.
  • Aggressive intravenous (IV) fluid administration:
    • HHS patients typically have a fluid deficit of approximately 7–12 L.
    • Begin with normal saline.
      • If the corrected Na is < 135 mEq/L, continue normal saline.
      • If the corrected Na remains normal or elevated, consider changing to 0.45% saline.
    • Add dextrose to fluids once the glucose reaches 300 mg/dL.
    • Monitor urine output and hemodynamics.
  • IV insulin infusion (K must be > 3.3 mEq/L)
    • Hourly serum glucose monitoring
    • Close monitoring of serum electrolytes (every 2–4 hours)
    • Provide potassium supplementation to maintain K at 4–5 mEq/L.
  • Identify and treat the underlying cause.
  • HHS is resolved when the patient’s mental status has improved, serum osmolality is < 315 mOsmol/kg, and glucose is 250–300 mg/dL.
    • Can initiate subcutaneous (SC) insulin if the patient is tolerating oral intake
    • Continue the IV insulin infusion for 2–4 more hours to minimize the recurrence of hyperglycemia
Treatment algorithm hyperosmolar hyperglycemic state

Treatment algorithm hyperosmolar hyperglycemic state

Image by Lecturio.

Complications

  • Cerebral edema
    • Due to rapid reduction in the serum osmolality during treatment of DKA and HHS
    • Patients can develop headache, altered level of consciousness, or respiratory arrest.
  • Cardiac arrhythmia: from electrolyte abnormalities
  • Noncardiogenic pulmonary edema
    • Due to changes in osmolality
    • Patients will become dyspneic and hypoxic.
  • Thromboembolic disease
    • Severe dehydration may lead to blood hyperviscosity.
    • Can involve the coronary, cerebral, pulmonary, and mesenteric vessels
  • Mucormycosis
    • An opportunistic rhino-cerebral infection that may occur due to immunosuppression in DKA
    • Patients will have symptoms of acute sinusitis, fever, and headache.

Differential Diagnosis

  • Alcoholic ketoacidosis: a complication of alcohol use and starvation for > 24 hours, resulting in ketosis and high anion gap acidosis without hyperglycemia. Patients will present with nausea, vomiting, and abdominal pain. Diagnosis is made through the history and laboratory findings suggesting ketoacidosis with a normal glucose, which helps differentiate this condition from DKA. Treatment includes IV fluid hydration with saline, dextrose, thiamine, and vitamins.
  • Fasting and starvation ketoacidosis: low-carbohydrate intake leading to hepatic ketone production. Ketone levels are mildly elevated and serum bicarbonate remains > 17 mEq/L. Glucose levels are typically normal, but hypoglycemia can occur with starvation, which differs from DKA. In starvation ketoacidosis, patients may have fatigue, vomiting, altered mental status, evidence of dehydration, and tachypnea. Intravenous fluids and electrolyte correction may be required.
  • Toxic-metabolic encephalopathy: a disruption of normal physiologic functions in the brain caused by other conditions, such as infection, renal dysfunction, electrolyte abnormalities, and medications.  Patients present with somnolence, disorientation, motor abnormalities, or seizure. Laboratory tests can help distinguish the cause and differentiate this condition from HHS. Treatment focuses on the underlying cause.
  • Salicyclate poisoning: toxicity due to a large ingestion of salicylates. Patients will have confusion, vomiting, fever, and seizures. Laboratory evaluation will show an anion gap acidosis, respiratory alkalosis, elevated salicylate level, negative ketones, and normal glucose. This evaluation will differentiate the condition from DKA. Treatment includes activated charcoal, sodium bicarbonate, and potential hemodialysis to enhance salicylate elimination.
  • Methanol poisoning: toxicity due to ingestion of methanol. Patients may have blurry vision or blindness, seizures, appear inebriated or comatose, and have Kussmaul respirations. Workup will show an anion gap acidosis, osmolar gap, respiratory alkalosis, and negative ketones, which differs from DKA. A high degree of suspicion is required, and a volatile alcohol test can establish the diagnosis. Treatment includes fomepizole, ethanol, or hemodialysis.

References

  1. Brutsaert, E.F. (2020). Hyperosmolar hyperglycemic state (HHS) [online]. MSD Manual Professional Version. https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hyperosmolar-hyperglycemic-state-hhs
  2. Brutsaert, E.F. (2020). Diabetic ketoacidosis (DKA) [online]. MSD Manual Professional Version. https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka
  3. Avichal, D., and Blocher, N.C. (2019). Hyperosmolar hyperglycemic state. In Griffing, G.T. (Ed.), Medscape. Retrieved November 16, 2020, from https://emedicine.medscape.com/article/1914705-overview
  4. Hamdy, O. (2019). Diabetic ketoacidosis (DKA). In Khardori, R. (Ed.), Medscape. Retrieved November 17, 2020, from https://emedicine.medscape.com/article/118361-overview
  5. Hirsch, I.B., and Emmett, M. (2020). Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis. In Mulder, J.E. (Ed.), UpToDate. Retrieved November 16, 2020, from https://www.uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-epidemiology-and-pathogenesis
  6. Hirsch, I.B., and Emmett, M. (2020). Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis. In Mulder, J.E. (Ed.), UpToDate. Retrieved November 16, 2020, from https://www.uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-clinical-features-evaluation-and-diagnosis
  7. Hirsch, I.B., and Emmett, M. (2020). Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment. In Mulder, J.E. (Ed.), UpToDate. Retrieved November 16, 2020, from https://www.uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-treatment

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