Foundational Principles and Epidemiology of Hyperglycemic Crises (DKA & HHS)
Lesson Objective
Provide a framework for understanding the global trends, pathophysiology, and risk factors that underlie diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS).
1. Epidemiology and Incidence
Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are acute, life-threatening complications of diabetes. Their prevalence is rising globally, driven by the increasing incidence of diabetes itself, with distinct demographic patterns and significant health disparities influenced by socioeconomic factors.
- DKA Incidence: Hospitalizations for DKA have increased by approximately 30–55% over the last two decades in high-income nations. Fortunately, with modern management, in-hospital mortality has fallen to less than 1%.
- HHS Incidence: While less common than DKA, HHS is far more lethal, carrying a mortality rate of 10–15%. It predominantly affects older adults who often have multiple comorbidities that complicate their presentation and treatment.
- Age Distribution: DKA is most common in younger individuals, with a peak incidence between 18 and 44 years, often as the first presentation of type 1 diabetes. HHS typically occurs in older patients, aged 45 to 64 years and beyond, usually in the context of uncontrolled type 2 diabetes.
- Geographic Variation: In resource-limited settings, mortality from hyperglycemic crises remains high (5–10% or more) due to challenges such as delayed diagnosis, limited access to insulin and intravenous fluids, and inadequate laboratory monitoring.
- Socioeconomic Disparities: In the United States, African American and Hispanic patients, as well as those who are uninsured or underinsured, have a nearly two-fold higher rate of DKA admissions and experience longer hospital stays compared to other groups.
Clinical Pearl: The Power of Multidisciplinary Support
Integrating clinical pharmacy support with comprehensive diabetes education and social work services can be highly effective. Such programs have been shown to reduce 30-day readmissions for DKA by up to 25% in vulnerable populations by addressing root causes like medication affordability, health literacy, and access to follow-up care.
2. Pathophysiology of DKA
DKA is defined by the triad of hyperglycemia, ketonemia, and metabolic acidosis. It is caused by an absolute or near-absolute deficiency of insulin, coupled with an excess of counterregulatory hormones (glucagon, cortisol, catecholamines, and growth hormone).
DKA Pathophysiology
+ ↑ Counterregulatory Hormones
(β-hydroxybutyrate & Acetoacetate)
- Ketogenesis: The combination of insulin lack and glucagon excess activates hormone-sensitive lipase, releasing free fatty acids (FFAs) from fat stores. The liver takes up these FFAs and, through β-oxidation, converts them into ketone bodies: β-hydroxybutyrate and acetoacetate. In severe acidosis, the metabolic environment favors the production of β-hydroxybutyrate.
- Metabolic Acidosis: The accumulation of these keto-acids consumes bicarbonate, leading to a high-anion-gap metabolic acidosis, typically defined by a pH < 7.3 and serum bicarbonate < 18 mEq/L. The body attempts to compensate for the acidemia through deep, rapid breathing known as Kussmaul respirations.
- Hyperglycemia and Dehydration: Unopposed gluconeogenesis and glycogenolysis lead to hyperglycemia (usually >250 mg/dL). This high glucose level creates an osmotic gradient, pulling water into the urine (osmotic diuresis) and causing significant losses of water and electrolytes, including sodium, potassium, and phosphate. Critically, total body potassium is severely depleted, even if the initial serum potassium level is normal or elevated due to acidosis-induced extracellular shifting.
Clinical Pearl: Interpreting Ketone Ratios
The ratio of β-hydroxybutyrate to acetoacetate is a marker of redox state and acidosis severity. A ratio greater than 3:1 indicates more severe acidosis and often predicts a slower resolution of ketosis with treatment. Standard urine ketone strips only detect acetoacetate and can be misleadingly negative or low in early, severe DKA.
3. Pathophysiology of HHS
HHS is characterized by extreme hyperglycemia and hyperosmolarity without significant ketoacidosis. It develops because there is enough residual insulin to suppress lipolysis and ketogenesis, but not enough to control hepatic glucose production or facilitate glucose uptake by peripheral tissues.
HHS Pathophysiology
(Enough to suppress ketosis)
(Often >600 mg/dL)
+ Profound Dehydration
- Severe Hyperglycemia and Hyperosmolarity: Plasma glucose levels are typically extreme, often exceeding 600 mg/dL. This, combined with significant dehydration, leads to a markedly elevated effective serum osmolality (>320 mOsm/kg). This hypertonic state pulls water out of cells, including brain cells, leading to intracellular dehydration and the characteristic neurologic manifestations of HHS.
- Minimal Ketosis: The small amount of circulating insulin is sufficient to prevent the runaway activation of hormone-sensitive lipase, thereby limiting the production of ketone bodies. As a result, the acid-base status is usually near normal (pH > 7.3), although a mild lactic acidosis may develop from hypoperfusion.
- Profound Dehydration: The prolonged osmotic diuresis leads to massive total body water deficits, often estimated at 8–12 liters. This severe volume contraction results in hypotension, tachycardia, acute kidney injury, and an increased risk of thromboembolic events and other ischemic injuries.
- Electrolyte Disturbances: As in DKA, there are significant total body deficits of potassium and phosphate. Sodium levels may appear falsely low (pseudohyponatremia) due to the dilutional effect of hyperglycemia.
Clinical Pearl: Controlled Correction of Osmolality
During fluid resuscitation for HHS, a rapid decrease in serum osmolality can cause a fluid shift back into brain cells, creating a risk for cerebral edema. The therapeutic goal is a slow, controlled reduction in effective serum osmolality by no more than 3–5 mOsm/kg per hour to minimize this risk.
4. Precipitating Factors and Comorbid Conditions
Both DKA and HHS are typically triggered by an underlying physiological stressor that increases counterregulatory hormones, increases insulin resistance, or directly interferes with insulin administration.
- Infections: The most common precipitant, accounting for up to 50% of cases. Urinary tract infections (UTIs) and pneumonia are classic triggers that elevate stress hormones and drive hyperglycemia.
- Insulin Nonadherence: Omission of insulin doses is a major cause, particularly in DKA, and is responsible for about 30% of crises. This can be due to cost, lack of education, psychosocial issues, or equipment failure (e.g., insulin pump malfunction).
- Acute Medical Illnesses: Major cardiovascular events like acute myocardial infarction or stroke, as well as pancreatitis, can precipitate a hyperglycemic crisis through profound stress hormone release.
- Comorbid Organ Dysfunction: Chronic kidney disease alters insulin clearance and can mask the severity of hyperglycemia. Hepatic dysfunction can impair both gluconeogenesis and ketone metabolism, altering the typical presentation.
- Medications: SGLT2 inhibitors are a well-recognized cause of euglycemic DKA, where patients present with significant ketosis and acidosis but with a blood glucose level often below 200 mg/dL. Other drugs like corticosteroids and atypical antipsychotics can also trigger crises.
Clinical Pearl: The Euglycemic DKA Trap
Always maintain a high index of suspicion for euglycemic DKA. In any patient with unexplained metabolic acidosis or ketosis, especially if they have symptoms like nausea or vomiting, inquire about recent SGLT2 inhibitor use, regardless of their blood glucose level. Patients should be educated on “Sick-Day Rules,” which include holding their SGLT2 inhibitor during acute illness.
5. Clinical Presentation and Differential Features
While both are hyperglycemic crises, DKA and HHS have distinct clinical presentations. DKA typically evolves rapidly over hours to a day, whereas HHS develops more insidiously over several days to weeks.
- DKA Presentation: Patients often present with a rapid onset of polyuria, polydipsia, significant nausea/vomiting, and diffuse abdominal pain. The classic signs of metabolic acidosis are prominent: Kussmaul respirations (deep, sighing breaths) and a fruity or acetone-like odor on the breath.
- HHS Presentation: The onset is gradual. Polyuria and polydipsia are present but may be less prominent or missed in older adults. The defining features are profound dehydration and significant neurologic changes, ranging from confusion and lethargy to focal deficits (mimicking a stroke) or coma.
| Laboratory Feature | Diabetic Ketoacidosis (DKA) | Hyperosmolar Hyperglycemic State (HHS) |
|---|---|---|
| Plasma Glucose | >250 mg/dL | >600 mg/dL |
| Arterial pH | <7.30 | >7.30 |
| Serum Bicarbonate | <18 mEq/L | >18 mEq/L |
| Anion Gap | >12 | Variable (Normal) |
| Serum Ketones | Positive (Moderate to Large) | Minimal or Negative |
| Serum Osmolality | Variable | >320 mOsm/kg |
Clinical Pearl: Look Beyond the Glucose Threshold
Do not rely solely on hyperglycemia thresholds to rule out a crisis. Remember that “euglycemic DKA” can occur in patients on SGLT2 inhibitors, during pregnancy, or in those with prolonged poor oral intake. If the clinical picture suggests DKA (acidosis, ketosis), initiate treatment even if the glucose is not dramatically elevated.
6. Special Populations and Prevention Strategies
Certain patient populations have unique risks and require tailored approaches for both management and prevention of hyperglycemic crises.
- Pregnancy: Pregnant women are in a state of “accelerated starvation” and have increased insulin resistance, making them prone to DKA at lower glucose levels. DKA poses a high risk to both mother and fetus, so close monitoring for ketosis is essential during any illness.
- Pediatric Patients: Children are at a significantly higher risk of developing cerebral edema during DKA treatment, a rare but devastating complication. Fluid resuscitation must be more cautious (e.g., limiting initial boluses to ≤40 mL/kg in the first 4 hours), and frequent neurologic monitoring is mandatory.
- Geriatric Patients: Older adults are predisposed to HHS due to an impaired thirst mechanism, age-related decline in renal function, and polypharmacy. Comorbid conditions like dementia and social isolation can increase the risk of insulin omission and delay seeking care.
- Psychosocial Factors: Recurrent DKA is often driven by underlying psychosocial challenges, including depression, eating disorders (diabulimia), food insecurity, and low health literacy. Addressing these factors is key to breaking the cycle of readmissions.
- Prevention Strategies: Effective prevention is multimodal and patient-centered. It includes structured diabetes self-management education, using teach-back methods to ensure comprehension, connecting patients to insulin assistance programs, and leveraging telemedicine and community health workers for proactive follow-up.
Clinical Pearl: Address Social Determinants of Health
Clinical interventions alone are often insufficient. Multimodal programs that explicitly address social determinants of health—such as providing transportation vouchers, connecting patients to food banks, and offering mental health support—have been shown to reduce DKA recurrence by 20–30%.
References
- Umpierrez GE, Davis GM, ElSayed NA, et al. Hyperglycaemic crises in adults with diabetes: A consensus report. Diabetologia. 2024;67(7):1455–1479.
- Fayfman M, Pasquel FJ, Umpierrez GE. Management of hyperglycemic crises: DKA and HHS. Med Clin North Am. 2017;101(3):587–606.
- Aldhaeefi M, Aldardeer NF, Alkhani N, et al. Updates in the management of hyperglycemic crisis. Front Clin Diabetes Healthc. 2022;2:820728.
- Benoit SR, Zhang Y, Geiss LS, et al. Trends in DKA hospitalizations and mortality—United States, 2000–2014. MMWR Morb Mortal Wkly Rep. 2018;67(12):362–365.
- Zhong VW, Juhaeri J, Mayer-Davis EJ, et al. Trends in DKA admissions in type 1 and type 2 diabetes, England 1998–2013. Diabetes Care. 2018;41(9):1870–1877.
- Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and DKA: data from FDA. Diabetologia. 2017;60(8):1385–1389.
- Ehrmann D, Kulzer B, Roos T, et al. Risk factors and prevention strategies for DKA in type 1 diabetes. Lancet Diabetes Endocrinol. 2020;8(5):436–446.
