Hyperglycemia: occurs due to decreased glucose utilization in peripheral tissues (adipocytes, muscles), decreased glycogen storage in muscles and hepatocytes, and glucagon-mediated stimulation of hepatocyte gluconeogenesis
Glycosuria/Hyperosmolarity-Associated Osmotic Diuresis Leads to Renal Loss of Sodium and Potassium
Normally, All Glucose Filtered by the Kidney is Reabsorbed
However, When Glucose Reaches 180 mg/dL, Renal Proximal Tubular Reabsorption of Glucose (from Tubular Lumen Back into the Renal Interstititium) is Overwhelmed and Glycosuria Occurs
Hyperglycemia Further Inhibits Insulin Release by Pancreatic β-Cells
Ketogenesis: with resulting accumulation of ketones/acids
Acetoacetate: this is the only true ketoacid
Acetone: this is a ketone (not an acid) derived from the decarboxylation of acetoacetate
ß-Hydroxybutyrate: this is a hydroxyacid formed from the reduction of acetoacetate
Fate of Ketoacids (Acetoacetate, ß-Hydroxybutyrate) During Treatment of DKA
Urinary Excretion of Ketoacids (30% of ketoacids are excreted in urine with normal renal function)
Ketoacids Excreted in Urine with Hydrogen or Ammonium: results in loss of protons and correction of acidosis and anion gap
Ketoacids Excreted in Urine in form of Potassium/Sodium salts: results in the effective loss of these bicarbonate precursors
Conversion of Ketoacids to Acetone: approximately 15-25% of ketoacids are converted to acetone, neutralizing the ketoacid
Hyperosmolar Hyperglycemic State (HHS)
Acute Illness-Associated Absolute/Relative Decrease in Insulin Synthesis
Hyperglycemia: occurs due to decreased glucose utilization in peripheral tissues (adipocytes, muscles), decreased glycogen storage in muscles and hepatocytes, and glucagon-mediated stimulation of hepatocyte gluconeogenesis
Glycosuria/Hyperosmolarity-Associated Osmotic Diuresis Leads to Renal Loss of Sodium and Potassium
Normally, All Glucose Filtered by the Kidney is Reabsorbed
However, When Glucose Reaches 180 mg/dL, Renal Proximal Tubular Reabsorption of Glucose (from Tubular Lumen Back into the Renal Interstititium) is Overwhelmed and Glycosuria Occurs
Hyperglycemia Further Inhibits Insulin Release by Pancreatic β-Cells
Concomitant Increase in Counter-Regulatory Hormones (Epinephrine, Glucagon, Growth Hormone, Cortisol): high levels of these hormones cause insulin resistance
Possible Explanations for Observation That Patients with HHS Do Not Develop Significant Ketonemia
Sufficient Insulin is Present to Prevent Ketogenesis, But Not Enough to Prevent Hyperglycemia
Presence of Higher Portal Vein Insulin Levels
Hyperosmolarity May Decrease Lipolysis (Which Limits the Free Fatty Acids Available for Ketogenesis)
The Levels of Counter-Regulatory Hormones are Lower in HHS (as Compared to Patients with DKA)
Euglycemic Diabetic Ketoacidosis (DKA) Has Been Described in the Following Settings (Br Med J, 1973) [MEDLINE] (J Clin Endocrinol Metab, 1993) [MEDLINE] (J Clin Endocrinol Metab, 2015) [MEDLINE] (Diabetes Metab Res Rev, 2017) [MEDLINE]
Poor Oral Intake
Prior Treatment with Insulin Before Arrival in the Emergency Department
Inhibition of Sodium-Glucose Cotransporter 2 Results in Glucosuria, Which Minimize the Development of Hyperglycemia (Despite Very Low Insulin Levels/Activity and the Development of Ketoacidosis)
Hyperglycemia May Be Severe and Result in Lipemic Serum
Due to Lipolysis Associated with Insulin Deficiency (as Insulin is a Potent Anti-Lipolytic Hormone) and Elevated Lipolytic Hormones (Catecholamines, Glucagon, Growth Hormone, Corticotropin)
To Calculate the True Serum Sodium, Need to Correct Sodium Upward by 2 mEq/L for Each 100 mg/dL of Glucose Above 100 to Account for the Component of Hyperglycemia-Associated Pseudohyponatremia
Normal Serum Beta Hydroxybutyrate Level: <0.6 mmol/L
Serum Beta Hydroxybutyrate Level in DKA: usually ranges from 3 to >8 mmol/L
Serum Beta Hydroxybutyrate Level is the Preferred Test in DKA (Especially for Monitoring the Therapeutic Response), Since this is the Predominant Ketone Present in Severe DKA
Epidemiology: occurs as part of initial presentation
Physiology: the degree of anion gap elevation depends on the rate/duration of ketoacid production, rate of metabolism of ketoacids, degree of urinary ketoacid loss, and volume of distribution of the ketoacids
Diagnosis
Anion gap is usually >20
Delta Gap/Delta Bicarbonate Ratio: usually 1.1
pH is variable (depending on severity of DKA), but pH can be <7.0 in severe cases
Epidemiology: occurs during the course of DKA therapy in almost all patients who have relatively intact renal function (due to the urinary excretion of ketoacids)
Mechanism: urinary excretion of ketoacids (acetoacetate, ß-hydroxybutyrate) in the form of potassium/sodium salts -> this represents an effective loss of bicarbonate precursors
Resolution: resolves as kidneys excrete ammonium chloride (NH4Cl) and regenerate bicarbonate
Due to Lipolysis Associated with Insulin Deficiency (as Insulin is a Potent Anti-Lipolytic Hormone) and Elevated Lipolytic Hormones (Catecholamines, Glucagon, Growth Hormone, Corticotropin)
Hyperkalemia (see Hyperkalemia): occurs in 33% of cases
Mechanism: due to insulin deficiency and hyperosmolality (but is not believed to be due to the ketoacidosis) -> both drive potassium out of the cells
Hypokalemia (see Hypokalemia): occurs in only 5% of cases
Mechanism: due to urinary potassium loss (due to osmotic diuresis and excretion of potassium ketoacid salts)
Abnormal Serum Sodium
Hyponatremia (see Hyponatremia): usually mild hyponatremia
To Calculate the True Serum Sodium, Need to Correct Sodium Upward by 2 mEq/L for Each 100 mg/dL of Glucose Above 100 to Account for the Component of Hyperglycemia-Associated Pseudohyponatremia
Diagnosis: effective serum osmolality at least 320 mOsm/kg
Effective Plasma Osmolality Includes Sodium and Glucose Only, Since Urea is Freely Permeable Across Most Membranes and its Accumulation Does Not Induce Water Shifts Between the Intracellular Spaces (Including the Brain) and the Extracellular Space
Protocol-Driven Care for Adult Patients with DKA Decreases ICU and Hospital Length of Stay, Time to Anion Gap Closure, and Time to Ketone Clearance (Crit Care Med, 2007) [MEDLINE]
Compliance with the 2006 ADA Hyperglycemic Crises in Adult Patients with Diabetes Clinical Guidelines for DKA was Low (Am J Health Syst Pharm, 2015) [MEDLINE]
Intravenous Fluid Resuscitation
General Comments
Volume Repletion Alone May Initially Reduce the Serum Glucose by 35-70 mg/dL Per Hour (Due to Expansion of Extracellular Fluid, Dilution, and Increased Urinary Elucose Excretion Resulting from Improved Renal Perfusion)
Bolus with 1L Per Hour of 0.9% Normal Saline (Max: <50 mL/kg in First 2-3 hrs) Before Insulin is Administered (see Normal Saline)
This is Critical Since Insulin Therapy Will Drive Glucose Out of Vascular Space (and Into the Cell), Dropping Serum Osmolality
Normal Saline Infusion at 200 mL/hr (see Normal Saline)
If the Glucose-Corrected Serum Sodium is Normal or High, 0.45% Saline Can Be Alternately Administered (Based on Volume Status) During the Next Few Hours of Therapy
Once Blood Glucose Reaches 200 mg/dL: change IV fluid to D5/0.45% saline at 200 mL/hr
Continue D5/0.45% saline + insulin drip together (titrating only the insulin drip up/down based on blood glucose) until the anion gap clears
Insulin Therapy Should Not Be Started Until Potassium and Fluid Deficits are Repleted
Insulin Infusion Will Be Expected to Decrease Serum Glucose by Approximately 50-75 mg/dL Per Hour (Higher Insulin Infusion Rates Likely Will Not Lower Serum Glucose Faster Than This, Due to Probable Saturation of the Insulin Receptors)
Effects of Insulin Therapy
Inhibition of Hepatic Gluconeogenesis
Increase in Peripheral Glucose Utilization: to a lesser extent
Decrease in Ketone Production: due to inhibition of lipolysis and glucagon secretion (amti-lipolytic effect of insulin occurs at lower doses than that required to decrease the serum glucose)
Enhancement of ketone utilization
Dosing
Bolus (optional): regular insulin 10U IV (or 0.1 U/kg IV)
Insulin Infusion: run per insulin drip protocol (usually start at 0.5-0.1 U/kg/hr)
Titrate Insulin to Maintain Blood Glucose Between 150-200 mg/dL (Avoid Decreasing the Serum Glucose Below This to Avoid Inducing Cerebral Edema)
Continue D5/0.45% Saline + Insulin Drip Together (Titrating Only the Insulin Drip Up/Down Based on Blood Glucose) Until the Anion Gap Clears
Once Anion Gap Clears (and Patient is Able to Tolerate Oral Intake), Administer Long-Acting Insulin (Lantus, etc) and Then Stop Both the D5/0.45% Saline + Insulin Drip Together 1 hr After the Long-Acting Insulin is Given
Clinical Data
Addition of Glargine Insulin to Standard Therapy within 3 hrs of Presentation for DKA Decreased the Average Recovery Time from DKA without Incurring Episodes of Hypoglycemia or Hypokalemia (J Clin Diagn Res, 2015) [MEDLINE]: small trial (n = 40), requires validation in larger trials
Repletion of Serum Phosphate
Indications: hypophosphatemia in the setting of myocardial dysfunction, hemolytic anemia, or respiratory depression (note that routine phosphate replacement is not recommended)
Randomized Trials Have Not Demonstrated a Benefit of Phosphate Replacement in DKA: replacement does not change the duration of ketoacidosis, dose of insulin required, the rate of fall of serum glucose, or morbidity/mortality
Potential Harmful Effects of Phosphate Replacement in DKA
Hypocalcemia
Hypomagnesemia
Monitoring (at least q4 hrs): critical since insulin therapy can cause a decrease in the serum phosphate
Repletion of Serum Potassium
Indications: serum potassium between <5 mEq/L
Monitoring (at least q4 hrs): critical since insulin therapy can cause a marked decrease in the serum potassium
Indications: serum pH <6.9-7.0 (although randomized trials supporting this are lacking)
Patients with Hemodynamic Compromise (Due to Impaired Myocardial Contractility and Vasodilation) or Life-Threatening Hyperkalemia May Particularly Benefit from Bicarbonate Administration to Correct the pH
Potential Adverse Effects of Bicarbonate in DKA
Hypokalemia (see Hypokalemia): sodium bicarbonate drives potassium intracellularly -> close monitoring of potassium is required when bicarbonate therapy is used (see Hypokalemia)
Post-Treatment Metabolic Alkalosis (see Metabolic Alkalosis): due to fact that insulin induces metabolism of ketoacid anions with generation of bicarbonate
Paradoxical Decrease in Cerebral pH: due to fact that bicarbonate administration decreases ventilatory drive, increasing pCO2 -> increased pCO2 is more quickly reflected across the blood-brain barrier than increased bicarbonate
Slowed Rate of Ketone Clearance
Cautions: when the bicarbonate concentration increases, the serum potassium may decrease -> close monitoring of potassium is required when bicarbonate therapy is used
Monitoring of Diabetic Ketoacidosis Therapy
Serial Serum Glucose: q1hr serum glucose monitoring is standard while on an insulin drip
Serum Electrolytes: q4hrs is standard
Follow the Anion Gap: anion gap returns to normal when ketoacids have disappeared from the serum
If Serum or Urine Testing is Done During Insulin Therapy with a Nitroprusside Reaction Method (Only Detects Acetoacetate and, to a Far Lesser Extent, Acetone), Ketonemia/Ketonuria May Appear to Persist for >36 hrs Due to the Slow Elimination of Acetone via the Lungs (However, Since Acetone is Not an Acid, it Does Not Cause Acidosis)
During Insulin Therapy, ß-Hydroxybutyrate is Converted to Acetoacetate, Resulting in an Increasingly Positive Nitroprusside Test for Acetoacetate as the Degree of Ketosis is Improving
Serial Serum ß-Hydroxybutyrate Level (see Serum β-Hydroxybutyrate): this is the best test to follow ketoacids during insulin therapy
Complications of Diabetic Ketoacidosis Therapy
Development of Non-Anion Gap Metabolic Acidosis During the Course of DKA Therapy
Incidence: occurs in almost all patients with relatively intact renal function
Mechanism: urinary excretion of ketoacids (acetoacetate, ß-hydroxybutyrate) in the form of potassium/sodium salts -> this represents an effective loss of bicarbonate precursors
Resolution: resolves as kidneys excrete ammonium chloride (NH4Cl) and regenerate bicarbonate
Clinical: symptoms typically emerge within 12-24 hrs of the initiation of DKA treatment, but may be present prior to the onset of therapy in some cases
Gradual Replacement of Sodium and Water Deficits in Patients with Hyperosmolarity: bolus with 1L per hour of normal saline in first few hrs (Max: <50 mL/kg in first 2-3 hrs)
Addition of Dextrose to IV Fluids Once Serum Glucose Reaches 200 mg/dL in DKA or 250-300 mg/dL in HHS
Treatment
Mannitol (0.25 to 1.0 g/kg) or Hypertonic (3%) Saline (5 to 10 mL/kg over 30 min): although data is from case reports only, these measures increase plasma osmolality, resulting in osmotic movement of water out of the brain and a decrease in cerebral edema
Prognosis: 20-40% mortality rate
Hypoxemia/Noncardiogenic Pulmonary Edema: may result from excessive IV fluid administration
Hypoxemia May Occur Due to a Decrease in Colloid Osmotic Pressure that Results in Increased Lung Water Content and Decreased Lung Compliance
Patients with DKA Who Have a Widened A-a Oxygen Gradient on Initial ABG or Rales on Physical Examination Appear to Be at Higher Risk for the Development of Pulmonary Edema
Hyperosmolar Hyperglycemic State
Intravenous Fluid Resuscitation
General Comments
Volume Repletion Alone May Significantly Reduce the Serum Glucose (Often faster than that Observed in DKA, Due to a Greater Degree of Hypovolemia Present in HHS
Bolus with 1L Per Hour of 0.9% Normal Saline (Max: <50 mL/kg in First 2-3 hrs) Before Insulin is Administered (see Normal Saline)
This is Critical Since Insulin Therapy Will Drive Glucose Out of Vascular Space (and Into the Cell), Dropping Serum Osmolality
Normal Saline (0.9%) Infusion at 200 mL/hr (see Normal Saline)
If the Glucose-Corrected Serum Sodium is Normal or High, 0.45% Saline Can Be Alternately Administered (Based on Volume Status) During the Next Few Hours of Therapy
Once Blood Glucose Reaches 250 mg/dL: change IV fluid to D5/0.45% saline at 200 mL/hr
Continue D5/0.45% Saline + Insulin drip together (titrating only the insulin drip up/down based on blood glucose) until the anion gap clears
Variably Necessary, as Many Patients with HHS May Respond to IV Fluids Alone
Dosing
Bolus (optional): regular insulin 10U IV (or 0.1 U/kg IV)
Insulin Infusion: run per insulin drip protocol (usually start at 0.5-0.1 U/kg/hr)
Titrate Insulin to Maintain Blood Glucose Between 250-300 mg/dL (Avoid Decreasing the Serum Glucose Below This to Avoid Inducing Cerebral Edema)
Continue D5/0.45% Saline + Insulin Drip Together (Titrating Only the Insulin Drip Up/Down Based on Blood Glucose) Until the Anion Gap Clears
Once Anion Gap Clears (and Patient is Able to Tolerate Oral Intake), Administer Long-Acting Insulin (Lantus, etc) and Then Stop Both the D5/0.45% Saline + Insulin Drip Together 1 hr After the Long-Acting Insulin is Given
Repletion of Serum Phosphate
Indications: hypophosphatemia in the setting of myocardial dysfunction, hemolytic anemia, or respiratory depression (note that routine phosphate replacement is not recommended)
Randomized Trials Have Not Demonstrated a Benefit of Phosphate Replacement in DKA: replacement does not change the duration of ketoacidosis, dose of insulin required, the rate of fall of serum glucose, or morbidity/mortality
Potential Harmful Effects of Phosphate Replacement
Clinical: symptoms typically emerge within 12-24 hrs of the initiation of DKA treatment, but may be present prior to the onset of therapy in some cases
Gradual Replacement of Sodium and Water Deficits in Patients with Hyperosmolarity: bolus with 1L per hour of normal saline in first few hrs (Max: <50 mL/kg in first 2-3 hrs)
Addition of Dextrose to IV Fluids Once Serum Glucose Reaches 200 mg/dL in DKA or 250-300 mg/dL in HHS
Treatment
Mannitol (0.25 to 1.0 g/kg) or Hypertonic (3%) Saline (5 to 10 mL/kg over 30 min) (see Mannitol and Hypertonic Saline): although data is from case reports only, these measures increase plasma osmolality, resulting in osmotic movement of water out of the brain and a decrease in cerebral edema
Pulmonary edema; a complication of diabetic ketoacidosis. Chest. 1980 May;77(5):687-8 [MEDLINE]
Recurrent high-permeability pulmonary edema associated with diabetic ketoacidosis. Crit Care Med. 1985 Jan;13(1):55-6 [MEDLINE]
Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19 Suppl 1:1-93 [MEDLINE]
Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2006 Dec;29(12):2739-48 [MEDLINE]
Postgrad Med J. Feb 2007; 83(976): 79–86. doi: 10.1136/pgmj.2006.049445 [MEDLINE]
Mandatory protocol for treating adult patients with diabetic ketoacidosis decreases intensive care unit and hospital lengths of stay: results of a nonrandomized trial. Crit Care Med. 2007 Jan;35(1):41-6 [MEDLINE]
Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009 Jul;32(7):1335-43. doi: 10.2337/dc09-9032 [MEDLINE]
Diabetes: Advances in Diagnosis and Treatment. JAMA. 2015 Sep 8;314(10):1052-62. doi: 10.1001/jama.2015.9536 [MEDLINE]
Effectiveness of Insulin Glargine on Recovery of Patients with Diabetic Ketoacidosis: A Randomized Controlled Trial. J Clin Diagn Res. 2015 May;9(5):OC01-5. doi: 10.7860/JCDR/2015/12005.5883. Epub 2015 May 1 [MEDLINE]
Evaluation of the treatment of diabetic ketoacidosis in the medical intensive care unit. Am J Health Syst Pharm. 2015 Dec 1;72(23 Suppl 3):S177-82. doi: 10.2146/sp150028 [MEDLINE]
Clinical
Euglycemic Diabetic Ketoacidosis
Euglycaemic diabetic ketoacidosis. Br Med J. 1973;2(5866):578 [MEDLINE]
Short-term fasting is a mechanism for the development of euglycemic ketoacidosis during periods of insulin deficiency. J Clin Endocrinol Metab. 1993;76(5):1192 [MEDLINE]
SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849 [MEDLINE]
Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives. Diabetes Metab Res Rev. 2017;33(5) [MEDLINE]
Prognosis
Mortality Due to Hyperglycemic Crises in the US, 1999-2022. JAMA. 2024 Jan 11:e2326174. doi: 10.1001/jama.2023.26174 [MEDLINE]
