Hyperosmolar Hyperglycemic State

Aka: Hyperosmolar Hyperglycemic State, Hyperosmolar Hyperglycemic Syndrome, Hyperosmolar Hyperglycemic Nonketotic Coma, Hyperglycemic Hyperosmolar Nonketotic Coma, Hyperglycemic Dehydration Syndrome, Hyperosmolar Nonketotic Diabetic Syndrome, Diabetic Hyperosmolar Non-Ketotic State

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II. Definitions

  1. Hyperosmolar Hyperglycemic Syndrome
    1. Severe Hyperglycemia resulting in increased Serum Osmolality and secondary Altered Mental State

III. Pathophysiology

  1. HHS Occurs in patients still able to produce Insulin (contrast with Diabetic Ketoacidosis)
    1. However, DKA and HHS findings coexist in the same patient presentation in up to one third of patients
  2. Very high Blood Glucose
    1. Insufficient Insulin decreases peripheral Glucose uptake and utilization
      1. However Insulin is often sufficient to prevent lipolysis and Ketogenesis (contrast with DKA)
    2. However Glucose is not accessible for energy source utilization due to insufficient Insulin
      1. Results in inappropriate reflex responses intended for true Hypoglycemia
      2. Glucose increase mediated by Glucagon, Catecholamines, Cortisol, Growth Hormone
      3. Hepatic Glucose production via Gluconeogenesis and glycogenolysis
  3. Glucosuria results in significant osmotic diuresis and marked Dehydration
    1. Water loss exceeds Sodium loss
    2. Results in hyperosomality and Hypernatremia
  4. Acute Kidney Injury on Chronic Kidney Disease with decreased Glomerular Filtration Rate
    1. Decreased Glucose clearance and further increased Blood Glucose
  5. Proinflammatory Cytokine release in first 24 hours creates a prothrombotic environment
    1. Proinflammatory Cytokines include TNFa, IL-B, IL-6, IL-8, PAI-1
    2. Associated prothrombotic complications include CVA, DIC, MI (see complications below)

IV. Epidemiology

  1. Primarily has affected adults with Type II Diabetes Mellitus
  2. Increasing Incidence among children
    1. Morbid Obesity
    2. Chronic Corticosteroids
    3. Gastroenteritis
    4. Black race
    5. Acanthosis Nigricans
    6. Family History of Diabetes Mellitus

V. Risk Factors

  1. Uncontrolled or undiagnosed Type II Diabetes Mellitus (accounts for >20% of cases)
  2. Advanced age
    1. Decreased thirst response and cognitive deficits interfere with free water loss replacement
  3. Infection
    1. Causes more than 50% of hyperosmolar Hyperglycemia
    2. Pneumonia, often Gram Negative (most common)
    3. Urinary Tract Infection
    4. Cellulitis
    5. Sepsis
    6. Dental Infection
  4. Medications
    1. See Medication Causes of Hyperglycemia
    2. Atypical Antipsychotic Medications are among the most common causes
    3. Diuretic use (esp. in elderly) compounds the level of Dehydration
  5. Vascular event
    1. Cerebrovascular Accident
    2. Pulmonary Embolism
    3. Myocardial Infarction
    4. Mesenteric Artery Thrombosis
  6. Endocrine Disease
    1. Acromegaly
    2. Cushing's Disease or ACTH producing tumors
    3. Thyrotoxicosis
  7. Comorbid illness
    1. Subdural Hematoma
    2. Acute Pancreatitis
    3. Severe Burn Injury
    4. Hypothermia or hyperthermia
    5. Substance Abuse (Alcohol Abuse or Cocaine use)
    6. Renal Insufficiency

VI. Symptoms

  1. Insidious onset of symptoms over days to weeks (contrast with hours for DKA development)
    1. Non-specific presentations in children (e.g. Headache, weakness, Vomiting)
  2. Symptoms related to Hyperglycemia
    1. Polyuria
    2. Polydipsia
    3. Weight loss
  3. Symptoms common at presentation
    1. Weakness
    2. Visual changes
    3. Leg Cramps
  4. Neurologic changes occur later
    1. Progressive Decreased Level of Consciousness (50%)
    2. Seizures (5%)

VII. Signs

  1. Low-grade Fever
  2. Severe Dehydration
    1. Dry mucous membranes
    2. Poor skin turgur
    3. Cool extremities
    4. Weak, rapid pulses
  3. Neurologic deficit (related to hyperosmolality)
    1. Decreased Level of Consciousness (Coma in 30%)
    2. Transient Hemiparesis (corrects with rehydration)
    3. Hyperreflexia or areflexia
    4. Seizures occur in 25%

VIII. Differential Diagnosis

  1. Diabetic Ketoacidosis
    1. Metabolic Acidosis with Anion Gap (arterial pH <7.30 with Ketosis)
    2. DKA often presents with Vomiting, Abdominal Pain, periodic breathing (Kussmaul Respirations)
    3. Contrast with Altered Mental Status in HHS
  2. Myxedema Coma

IX. Diagnosis

  1. Severe Dehydration with Serum Osmolality >320
  2. Neurologic deficit (e.g. Altered Level of Consciousness, focal weakness or sensory deficit, Seizure, coma)
  3. Hyperglycemia with Serum Glucose >600 mg/dl
  4. Minimal to no Ketosis
    1. Minimal acidosis (arterial pH >7.30)
    2. Contrast the Ketosis in DKA with Metabolic Acidosis with Anion Gap (arterial pH <7.30)

X. Labs

  1. Blood Glucose 600-2000 mg/dl
  2. Serum Osmolarity >320 mOsm/L
    1. See Calculated Serum Osmolality
    2. Often > 350 mOsm/L
    3. Coma is associated with Serum Osmolality >340 mOsm/L
    4. Water deficit 100-200 ml/kg
  3. Prerenal Azotemia
    1. Blood Urea Nitrogen (BUN) markedly elevated (70-90 mg/dl)
    2. Serum Creatinine increased
  4. Serum Ketones
    1. Typically not detected in HHS (contrast with DKA)
    2. However HHS and DKA may coexist in up to one third of patients
  5. Minimal to no Metabolic Acidosis
    1. Arterial Blood Gas with arterial pH > 7.30
    2. Serum bicarbonate >15 meq/L
    3. Anion Gap is typically normal
    4. Consider Lactic Acidosis or combined HHS-DKA if Metabolic Acidosis with Anion Gap
  6. Creatine Phosphokinase (CPK)
    1. Rhabdomyolysis with CPK >10 fold normal may occur
    2. Consider Malignant Hyperthermia in children with DKA (related to m-cresol Insulin preservative)
  7. Electrolytes
    1. Serum Sodium is signficantly elevated in HHS
      1. See Corrected Serum Sodium for Glucose
      2. Serum Sodium decreases 1.6 meq/L (up to 2.4 meq/L) for each 100 mg/dl Glucose rise
      3. Corrected normal or Low Serum Sodium suggests cause other than HHS
    2. Potassium deficit: 5-15 meq/kg
    3. Calcium deficit 50-100 meq/kg
    4. Magnesium deficit 50-100 meq/kg
    5. Phosphorus may be chronically depleted in uncontrolled Diabetes Mellitus
  8. Other labs and studies
    1. Evaluate for underlying cause of HHS (e.g. Sepsis, Acute Coronary Syndrome)

XI. Approach: Monitoring

  1. Bedside fingerstick Glucose every 30-60 minutes
  2. Recheck labs every 2-4 hours until stable
    1. Electrolytes
    2. Blood Urea Nitrogen and Serum Creatinine
    3. Serum Glucose

XII. Management: Fluid Replacement

  1. Background
    1. Most critical initial step in HHS
    2. Overall fluid deficit is often >9 Liters in adults (100-200 ml/kg) and 12-15% in children
  2. Initial
    1. Lactated Ringers 1 Liter/hour
    2. Run Lactated Ringers until
      1. Stable Vital Signs (Heart Rate, Blood Pressure)
      2. Improved mental status
      3. Adequate Urine Output
      4. Exercise caution with Fluid Overload (esp. older patients with Chronic Kidney Disease)
      5. Avoid lowering Serum Sodium too quickly (risk of cerebral edema)
      6. Consider Inferior Vena Cava Ultrasound for Volume Status
      7. Expect Serum Glucose to improve 75-100 mg/dl/hour with IV hydration alone
  3. Later
    1. Fluid
      1. Hypernatremia: 1/2LR
      2. Hyponatremia (uncommon): LR
    2. Rate
      1. Estimate: 150 to 500 cc/hour
      2. Calculation: 4-14 cc/kg/hour
      3. Do not drop mOsm more than 3 mOsm/hour in children (risk of cerebral edema)
  4. Overall
    1. 50% of loss replaced in first 18-24 hours
    2. 50% of loss replaced over next 24 hours

XIII. Management: Serum Potassium

  1. Serum Potassium <3.3
    1. Hold Insulin until Serum Potassium >3.3
    2. Replace Potassium with 20-30 meq/hour until Serum Potassium >3.3
  2. Serum Potassium >5.2
    1. Hold Potassium Replacement in IV Fluids
    2. Recheck Serum Potassium every 2 hours
  3. Serum Potassium >3.3 and <5.2
    1. Keep Serum Potassium >4.0 and <5.2
    2. Add 20-30 meq of Potassium to each liter of IV fluid

XIV. Management: Phase 3 - Blood Glucose Control

  1. Precautions
    1. Hypokalemia must be corrected prior to Insulin
    2. Hold Insulin until Serum Potassium >3.5 meq/L
      1. Start Potassium Replacement concurrent with Insulin if Serum Potassium <5.5 mEq/L
  2. Adult IV Insulin administration
    1. Initial
      1. Preferred non-bolus protocol (but must flush IV line with Insulin)
        1. Start Regular Insulin 0.14 units/kg/hour
      2. Bolus protocol (older method, do NOT Use in children due to cerebral edema risk)
        1. Start with Regular Insulin 0.1 unit/kg IV bolus, AND
        2. Next, start 0.1 units/kg/hour Regular Insulin drip
    2. Maintenance
      1. If Serum Glucose does NOT drop at least 50-70 mg/dl/hour (or 10% drop in first hour)
        1. Option 1: Insulin bolus
          1. Give Regular Insulin 0.14 units/kg IV AND
          2. Next, resume prior Insulin rate
        2. Option 2: Increase drip
          1. Increase Insulin Infusion rate by 50-100%
          2. Continue at increased rate until adequate Glucose drop
      2. When Serum Glucose <300 mg/dl
        1. Keep Serum Glucose at 200 to 300 mg/dl until
          1. Serum Osmolality <315 mOsm/kg
          2. Alert mental status
        2. Decrease rate by 50% (to 0.02 to 0.05 units/kg) or
        3. Discontinue Insulin Drip and start SC dosing
    3. Transition to subcutaneous Insulin once HHS resolves and patient able to eat
      1. Continue IV Insulin for 1-2 hours after initiating subcutaneous Insulin
      2. In Insulin naive patients, start Insulin SC at 0.5 to 0.8 units/kg/day divided
  3. Glucose monitoring
    1. Glucose monitoring every 30 minutes to 1 hour
    2. Target Glucose decrease 50-70 mg/dl/hour
  4. Dextrose Administration
    1. Add 5% Dextrose to fluids when Glucose < 300 mg/dl

XV. Management: Additional measures

  1. Identify underlying precipitating factors (esp. infection, ischemia, Medication Noncompliance)
    1. Evaluate and treat for underlying infection (esp. Sepsis)
    2. Consider withdrawing medications causing Hyperglycemia
  2. Other Electrolytes
    1. Phosphorus Replacement indications in Hypophosphatemia
      1. Precaution: If Phosphorus is replaced, monitor Serum Calcium closely for Hypocalcemia risk
      2. Serum Phosphate <1.0 mEq/L
      3. Muscle Weakness (e.g respiratory compromise, Heart Failure)
    2. Magnesium Replacement indications in Hypomagnesemia (common)
      1. Precaution: Exercise caution in Renal Failure
      2. Consider in all patients (except Renal Failure) with Hypokalemia or Hypomagnesemia
      3. When Serum Potassium is depleted, Serum Magnesium is likely also depleted
      4. May stabilize Arrhythmias, and improve weakness, Seizures, and mental status

XVI. Complications

  1. Seizures
  2. Pancreatitis
  3. Acute Kidney Injury (Acute Renal Failure)
  4. Rhabdomyolysis
  5. Prothrombotic complications with vascular Occlusion (HHS is a Hypercoagulable state)
    1. Venous Thromboembolism (Pulmonary Embolism, Deep Vein Thrombosis)
    2. Mesenteric Artery Thrombosis
    3. Myocardial Infarction
    4. Disseminated Intravascular Coagulopathy (DIC)
    5. Cerebrovascular Accident
    6. Bilateral Femoral Artery Thrombosis
  6. Overhydration in acute management
    1. Adults
      1. Respiratory distress syndrome
      2. Congestive Heart Failure
    2. Children
      1. Cerebral Edema

XVII. Prognosis: Mortality

  1. Mortality: 10-40% (up to 60% in children)
    1. HHS mortality is as much as 10x higher than DKA mortality (1-9%)
  2. Predictors of mortality
    1. Extremes of age
    2. Dehydration Severity
    3. Hemodynamic instability
    4. Decreased Level of Consciousness
    5. Concurrent infection
    6. Cancer history

XVIII. Prevention

  1. See Diabetes Sick Day Management
  2. Maximize Glucose control and compliance
  3. Ensure adequate hydration
  4. Monitor for Dehydration, infection, and Hyperglycemia

XIX. References

  1. Chiasson (2003) CMAJ 168:859-66 [PubMed]
  2. Kitabchi (2009) Diabetes Care 32(7): 1335-43 [PubMed]
  3. Stoner (2017) Am Fam Physician 96(11):729-36 [PubMed]
  4. Stoner (2005) Am Fam Physician 71:1723-30 [PubMed]
  5. Trence (2001) Endocrinol Metab Clin North Am 30:817-31 [PubMed]

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