Hyperosmolar hyperglycemic state (HHS) is a serious, acute complication of type 2 diabetes mellitus. HHS is characterized by elevated serum glucose, increased serum osmolality, dehydration, and no or minimal ketoacidosis. Triggering factors are related to increased levels of counter-regulatory hormones notably due to inadequate insulin therapy, underlying infection, concurrent medical illness, or drug side effects. Management involves rapid fluid replacement with normal saline, insulin therapy, correction of electrolyte abnormalities, and treating the underlying etiology.

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Introduction

Definition

  • Serious, acute complication of diabetes mellitus type 2 marked by 
    • Hyperglycemia 
    • Hyperosmolarity
    • Dehydration 
    • Minimal or no ketoacidosis

Epidemiology

  • Usually associated with older individuals with
    • Gradual onset of symptoms (over days to weeks)
    • Previous diabetes diagnosis
    • Recent triggering event (discussed below)

Pathophysiology

Precipitating causes

Triggering events for HHS are associated with increased levels of counter-regulatory hormones.

  • Infections (most common)
  • Discontinuation of, or inadequate, insulin therapy
  • Conditions resulting in inadequate fluid intake
    • Stroke
    • Acute myocardial infarction
    • Trauma
  • Medications
    • Corticosteroids
    • Thiazide diuretics

Pathophysiology

HHS is a state of severe hyperglycemia-induced dehydration and increased serum osmolality. It occurs due to relative insulin deficiency. 

  • Decreased glucose entry into cells → increase of counter-regulatory hormones
    • Glucagon
    • Cortisol
    • Growth hormone
    • Catecholamines
  • These counter-regulatory hormones cause
    • Increased gluconeogenesis and glycogenolysis
    • Decreased glucose utilization by peripheral tissues
  • This results in severe hyperglycemia leading to
    • Osmotic diuresis
    • Water and electrolyte loss (polyuria)
    • Dehydration → hyperosmolar state
    • Impaired renal function

Diagnosis

Clinical presentation

  • Gradual development of (over days to weeks):
    • Polyuria, polydipsia
    • Severe dehydration:
      • Decreased skin turgor
      • Sunken eyes
      • Dry mucous membranes
      • Weakness
    • Altered mental status, seizures
  • Nausea, vomiting, and abdominal pain are less commonly associated with HHS (typically associated with DKA).

Diagnostic criteria

  • Glucose > 600 mg/dl
  • Osmolality > 320 mOsm/L
  • Arterial pH > 7.3
  • Bicarbonate > 18 mEq/L
  • Little or no ketonemia/ketonuria
  • Anion gap is usually normal.

Video Gallery

Hyperglycemic Hyperosmolar State (HHS) by Sharon Bord, MD

Differential Diagnosis

The following table summarizes the important differences between HHS and DKA.

DKA HHS
Pathophysiology: Insulin deficiency → ketosis, acidosis, dehydration Relative insulin deficiency → hyperosmolarity, osmotic diuresis, profound dehydration
Patient status:
  • Affect DM type 1 patients
  • Younger age
  • Affect DM type 2 patients
  • Older age
Signs and symptoms:
  • Main symptoms are abdominal pain and hyperventilation
  • Symptoms develop rapidly over hours
  • Main symptoms are dehydration and mental status change
  • Symptoms develop gradually (over days to weeks)
Laboratory findings: Diagnostic criteria:

  • Glucose > 250-300 mg/dl
  • Osmolality < 320 mOsm/L
  • Arterial pH < 7.3
  • Bicarbonate < 18 mEq/L
  • Positive urine and serum ketones
  • Increased anion gap (>10-12)
Diagnostic criteria: 

  • Glucose > 600 mg/dl
  • Osmolality > 320 mOsm/L
  • Arterial pH > 7.3
  • Bicarbonate > 18 mEq/L
  • Little or no ketonemia/ketonuria
  • Anion gap is usually normal.

Management

Initial workup

  • Serum glucose
  • CBC, BMP, BUN, Cr
    • Calculate total serum osmolality 
      • 2(Na⁺) + 18/glucose + BUN/2
    • Calculate anion gap 
      • Na⁺ – (Cl⁻ + HCO₃⁻)
    • Calculate corrected sodium
      • Add 1.6 mg/dL to the measured serum sodium for each 100mg/dL of glucose above 100 mg/dL.
  • ABG
  • ECG
  • Urine dipstick/urinalysis for ketones 
  • Urine, blood, and/or sputum Gram stain and culture if infection is suspected.
  • Chest X-ray if pneumonia is suspected.

Management

  • Admit patient to the ICU
    • Hourly serum glucose
    • Q2-4hr serum electrolytes
      • Provide potassium supplementation to maintain Kᐩ 4-5 mEq/L
    • Monitor urine output
    • Low dose IV insulin (Kᐩ must be >3.3 mEq/L)
  • Aggressive IV fluid administration 
    • HHS patients are estimated to require ~7-12L of fluid replacement.
    • Begin with normal saline, 
      • If corrected sodium is <135 mEq/L, continue normal saline.
      • If corrected sodium remains normal or elevated, consider changing to 0.45% saline.
  • Identify and treat the underlying cause.
    • Often associated with an infectious cause
  • Provide patient education on diabetes self-management.

Clinical Relevance

The following are clinically relevant conditions associated with HHS.

Diabetic Ketoacidosis
Diabetic ketoacidosis is the acute state of severe uncontrolled diabetes characterized by hyperglycemia (> 250-300 mg/dl), ketonemia (>31 mg/ml)/ketonuria (3+) and acidosis (pH <7.3). The condition requires treatment with insulin and intravenous fluids. Along with the symptoms of HHS, DKA usually presents with abdominal pain, nausea, and vomiting. 

Diabetes mellitus type 1
Diabetes mellitus describes a heterogeneous group of metabolic diseases whose basic characteristic is chronic hyperglycemia with subsequent glucosuria. Type 1 DM results from autoimmune destruction of beta cells in the pancreas.
Diabetes mellitus type 2
Diabetes mellitus describes a heterogeneous group of metabolic diseases whose basic characteristic is chronic hyperglycemia with subsequent glucosuria. Type 2 DM results from insulin resistance of the target tissue.

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