L6 Hyperglycemic Crises in Adults: Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS)

Overview of Hyperglycemic Crises

• Hyperglycemic crises in adults primarily manifest as Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS).

• DKA is typically associated with Type 1 Diabetes Mellitus (T1DM) but can rarely occur in Type 2 Diabetes Mellitus (T2DM).

• HHS is primarily associated with Type 2 Diabetes Mellitus (T2DM).

• DKA is characterized by a severe lack of insulin, whereas HHS involves a relative lack of insulin.

• The onset of DKA is rapid, occurring over hours to days.

• The onset of HHS is insidious, occurring over days to weeks.

• The one-year age-corrected mortality rate for these crises is $13 \times$ higher than that of the general population.

• Current mortality rates for both DKA and HHS in patients are approximately $1\%$.

• Historical mortality for DKA: $~5\% \text{ (4–10\%)}$.

• Historical mortality for HHS: $~15\% \text{ (10–50\%)}$.

• Approximately $1/3$ of hyperglycemic emergencies present as a hybrid DKA/HHS case.

Diagnostic Criteria and Acid-Base Chemistry

• Anion Gap Calculation: $\text{Anion gap} = \text{measured } \text{Na}^+ - (\text{Cl}^- + \text{HCO}_3^-)$

• Definition: Extracellular cation ($\text{Na}^+$) minus extracellular anions ($\text{Cl}^-$ and $\text{HCO}_3^-$).

• Normal Anion Gap: $\text{7-9 mmol/dm}^3$.

• High Anion Gap Metabolic Acidosis (HAGMA) in DKA: >12\text{ mmol/dm}^3.

• Causes of Anion Gap Metabolic Acidosis (MUDPILES):

  • M: Methanol

  • U: Uremia

  • D: Diabetic ketoacidosis

  • P: Paraldehyde, phenformin, propylene glycol

  • I: Infection, iron, isoniazid, inhalants

  • L: Lactic acidosis

  • E: Ethylene glycol, ethanol (alcoholic ketoacidosis)

  • S: Salicylates, solvents, starvation

• Ketogenesis:

  • Definition: The production of ketoacids (ketone bodies).

  • Purpose: Ketone bodies serve as metabolic fuels for peripheral tissues (heart, brain, skeletal muscle) when glucose is unavailable (e.g., starvation).

  • Important Note: The body is NOT able to synthesize glucose from fatty acids.

  • Types of Ketone Bodies:

  • $\beta\text{-Hydroxybutyrate}$ ($78\%$): Measured via standard serum blood tests.

  • $\text{Acetoacetate}$ ($20\%$): Measured via the nitroprusside reaction method.

  • $\text{Acetone}$ ($2\%$): Measured via the nitroprusside reaction method.

Precipitating Factors for Hyperglycemic Crises

• General Causes (The 5 I's): Iatrogenic, Ingestion, Infection, Infarction, Indiscretion.

• Specific Causes for DKA:

  • New onset Diabetes Mellitus ($17\%-24\%$).

  • Insulin omission ($40\%-69\%$).

  • Acute infection ($14\%-58\%$).

  • Acute myocardial infarction.

  • Drugs:

  • Atypical antipsychotics / antimanics: e.g., olanzapine (ZYPREXA), Lithium (LITHOBID).

  • Sympathomimetics: e.g., terbutaline, dobutamine.

  • SGLT2 inhibitors (SGLT2i): e.g., dapagliflozin (FARXIGA), ertugliflozin (STEGLATRO), empagliflozin (JARDIANCE), canagliflozin (INVOKANA). Associated with EUglycemic DKA.

  • Glucocorticoids: e.g., prednisone, methylprednisolone (SOLUMEDROL). Associated with steroid-induced hyperglycemia.

  • Immune checkpoint inhibitors: e.g., pembrolizumab (KEYTRUDA), "-mabs". Associated with autoimmune diabetes.

• Specific Causes for HHS:

  • Insulin omission (<40\%).

  • Volume depletion: caused by polyuria, age-related thirsty mechanism impairment, or limited access to fluids.

  • Acute pancreatitis.

  • Surgery.

  • Acute infection ($30\%-60\%$), such as Pneumonia (PNA) or Urinary Tract Infection (UTI).

  • Acute myocardial infarction / acute cerebrovascular events.

  • Drugs:

  • Sympathomimetics: terbutaline, dobutamine.

  • Glucocorticoids: prednisone, methylprednisolone.

  • Atypical antipsychotics: olanzapine (ZYPREXA).

  • Diuretics: hydrochlorothiazide, chlorthalidone (THALITONE), ethacrynic acid (EDECRIN).

  • Total Parenteral Nutrition (TPN).

Physiology and Pathophysiology

• Balance of Hormones:

  • The body relies on counterregulatory hormones from the pancreas with opposite actions to maintain blood glucose.

  • Regulated processes include: Gluconeogenesis, Glycogenolysis, and Glucose utilization by peripheral tissues.

  • Insulin: Primary glucose-lowering hormone.

  • Glucagon: Stimulates glycogenolysis in the liver and muscles; stimulates gluconeogenesis in the liver and kidneys.

  • Cortisol: Induces proteolysis.

  • Catecholamines (Norepinephrine, Epinephrine): Increase access to gluconeogenic substrates, including amino acids.

  • Growth Hormone: Activates hormone-sensitive lipase to break down adipose tissue into free fatty acids.

  • Pathophysiology core: Reduction (absolute or relative) in the net effective concentration of circulating Insulin.

Clinical Features and Risk Markers

• Common Features for DKA and HHS:

  • Polyuria, polydipsia, weight loss, and dehydration.

• DKA Specific Features:

  • Patient usually alert (in mild/moderate cases).

  • Nausea, vomiting, abdominal pain.

  • Kussmaul respiration: Deep, rapid, labored breathing.

  • Fruity odor to breath (due to acetone).

• HHS Specific Features:

  • Change in cognitive state is common.

  • Often co-presenting with other acute illnesses.

• Risk Markers for Worse Outcomes:

  • Severity of dehydration.

  • Presence of comorbidities.

  • Age >60 years.

  • Positive diagnosis for HHS.

Diagnostic Criteria and Classification

• DKA Diagnostic Criteria:

  • Diabetes/Hyperglycemia: Glucose $\ge 200\text{ mg/dL}$ OR prior history of diabetes.

  • Ketosis: $\beta\text{-Hydroxybutyrate}$ concentration $\ge 3.0\text{ mmol/dm}^3$ OR urine ketone strip $2+$ or greater.

  • Metabolic Acidosis: \text{pH} < 7.3 and/or bicarbonate concentration <18\text{ mmol/dm}^3.

• DKA Classification by Severity:

  • Mild: \text{pH } >7.25 \text{ to } <7.30, Bicarbonate $\text{15–18 mmol/dm}^3$, Alert.

  • Moderate: $\text{pH } 7.0–7.25$, Bicarbonate \text{10 to } <15\text{ mmol/dm}^3, Alert/Drowsy.

  • Severe: \text{pH } <7.0, Bicarbonate <10\text{ mmol/dm}^3, Stupor/Coma.

  • Care Level: Mild (Regular/Observation unit), Moderate (Step-down/Intermediate unit), Severe (Intensive Care Unit).

• HHS Diagnostic Criteria:

  • Hyperglycemia: Plasma glucose $\ge 600\text{ mg/dL}$.

  • Hyperosmolarity: Effective serum osmolality >300\text{ mOsm/kg} or Total serum osmolality >320\text{ mOsm/kg}.

  • Absence of significant ketonemia: \beta\text{-Hydroxybutyrate} < 3.0\text{ mmol/dm}^3 or urine ketone < 2+.

  • Absence of acidosis: $\text{pH} \ge 7.3$ and bicarbonate $\ge 15\text{ mmol/dm}^3$.

Baseline Assessments and Fluid Distribution

• Serum Chem-7 / BMP Assessments:

  • Identifies hyperglycemia and allows calculation of anion gap, corrected Na, and effective serum osmolality.

  • Assesses renal function (BUN/Cr) and electrolytes (K).

  • Blood gases for acidity ($\text{pH}$ normal range: $7.35-7.45$).

  • Blood ketone levels ($\beta\text{-hydroxybutyrate}$ normal: < 3.00).

  • Volume status monitoring via Heart Rate (Tachycardia indicates depletion) and Blood Pressure (Hypovolemia indicated by low BP).

• Fluid Compartments (70-kg Man):

  • Total Body Water (TBW) = $42\text{ dm}^3$ ($60\%$ of weight).

  • Intracellular Fluid (ICF): $2/3$ of TBW. Dominant electrolytes: $K^+$, $Mg^{++}$, $Phos^-$.

  • Extracellular Fluid (ECF): $1/3$ of TBW. Dominant electrolytes: $\text{Na}^+$, $\text{Cl}^-$, $\text{HCO}_3^-$.

  • Interstitial Fluid: $3/4$ of ECF ($80\%$ of non-solid/extracellular space).

  • Intravascular Fluid (Plasma): $1/4$ of ECF ($20\%$ of non-solid/extracellular space).

• Typical Total Body Deficits:

  • DKA: Water ($6\text{ dm}^3$), $\text{Na}^+$ ($7-10\text{ mEq/kg}$, $\text{K}^+$ ($3-5\text{ mEq/kg}$).

  • HHS: Water ($9\text{ dm}^3$), $\text{Na}^+$ ($5-13\text{ mEq/kg}$, $\text{K}^+$ ($4-6\text{ mEq/kg}$).

Osmolality and Sodium Correction Formulas

• Effective Serum Osmolality Calculation: $\text{Effective serum osmolality} = 2 \times (\text{measured } \text{Na}^+) + \frac{\text{Glucose}}{18}$

• Total Serum Osmolality Calculation: $\text{Total serum osmolality} = 2 \times \text{Na}^+ + \text{Glucose} + \text{Urea}$

• Corrected Serum Sodium: $\text{Corrected Na} = \text{Measured Na} + 1.6 \times \frac{(\text{Glucose} - 100)}{100}$

• A reduction of $100\text{ mg/dL}$ of glucose results in a $1.6\text{ mmol/dm}^3$ rise in sodium concentration.

Therapeutic Goals and Treatment Principles

• Fact 1: The entire body is fluid and electrolyte depleted during DKA/HHS.

• Fact 2: Rehydration with isotonic crystalloid fluids is first-line to restore total body water and ensure tissue perfusion.

• Fact 3: Potassium management is critical. Both hypo- and hyperkalemia can induce cardiac arrhythmias, heart block, and sudden death.

• Fact 4: Marked hyperglycemia results in hyponatremia; water follows glucose from the ICF to the ECF, diluting sodium.

• Fact 5: Crises are acute, life-threatening decompensations requiring inpatient admission.

• Management Goals:

  • Correction of dehydration.

  • Correction of electrolyte imbalances and acidosis.

  • Correction of hyperglycemia and osmolality.

  • Identification of precipitating events.

  • Prevention of treatment complications (Hypoglycemia, Hypokalemia, AKI, Thrombosis, Cerebral Edema).

Specific Treatment Protocols

• IV Fluids Strategy:

  • Start with $\text{0.9\% NaCl (NS)}$ or Lactated Ringer’s ($\text{LR}$) $1000\text{ cm}^3$ IV bolus over 1 hour ($1000\text{ cm}^3/\text{hr}$).

  • Followed by continuous infusion of NS or LR at $500\text{ cm}^3/\text{hr}$.

  • When Blood Glucose reach $250\text{ mg/dL}$, switch to $5\% \text{ dextrose in 0.45\% NaCl (D5 1/2 NS)}$ at $250\text{ cm}^3/\text{hr}$.

• Insulin Therapy:

  • Titrate insulin to achieve a Blood Glucose drop of $50-75\text{ mg/dL}$ per hour.

  • Regular insulin dose: $0.1\text{ units/kg}$ IV bolus, followed by $0.1\text{ units/kg/hr}$ continuous infusion.

  • Double the infusion rate if glucose fails to decrease by $50-70\text{ mg/dL/hr}$.

• Potassium Supplementation:

  • If \text{K} < 3.5: Give $20\text{ mEq}$ potassium chloride IV @ $10\text{ mEq/hr}$. Hold insulin until $\text{K} \ge 3.5$.

  • If $\text{K } 3.5-5.0$: Add $20\text{ mEq}$ per liter of IV fluid to maintain levels.

  • If \text{K} > 5.0: Hold potassium supplementation. Give insulin to drive potassium into cells.

• Ancillary Treatments:

  • Bicarbonate: Only if arterial \text{pH} < 6.9.

  • Phosphate: Only if \text{Phos} < 1.0\text{ mmol/dm}^3 or presence of muscle weakness/respiratory compromise.

Monitoring and Resolution Criteria

• Monitoring Frequency:

  • Blood Glucose: Q1hr initially, then Q2-4hrs.

  • Electrolytes, BUN/Cr, pH: Baseline, then Q2-4hrs.

• Resolution Criteria for DKA:

  • Glucose trending <200\text{ mg/dL}.

  • Bicarbonate > 18\text{ mEq/dm}^3 or venous \text{pH} > 7.3.

  • Ketone < 0.6.

• Resolution Criteria for HHS:

  • Serum osmolality < 300.

  • Urine output > 0.5\text{ cm}^3/\text{kg/hr}.

  • Glucose < 250\text{ mg/dL}.

• Complications:

  • Cerebral Edema: Rare but fatal. May result from declining plasma osmolality too rapidly. Prevent via gradual replacement of sodium and water.

Transitioning from IV to Subcutaneous (SC) Insulin

• VIP #1 (Overlap): Continue IV insulin infusion for $1–2$ hours after the first dose of SC basal insulin is started to prevent rebound hyperglycemia.

• VIP #2: Verify that a hypoglycemia protocol is ordered.

• SC basal/bolus regimen should be initiated once the patient is able to tolerate a diet.

Role of the Pharmacist

1. Verify type of hyperglycemic crisis (DKA vs HHS) to align protocol goals.

2. Start IV fluids ASAP and verify floor stock.

3. Verify electrolyte (Potassium) replacement protocols.

4. Prepare and dispense insulin infusion bags ASAP.

5. Ensure hypoglycemia protocol is ordered.

6. Evaluate patient for medication-induced hyperglycemia.

7. Suspect euglycemic DKA in metabolic acidosis cases even with regular glycemia, especially if patient is on SGLT2i.

8. Verify transition from IV to SC insulin (ensuring diet and proper timing).

9. Provide comprehensive medication education on adherence.