Hyperosmolar hyperglycemic syndrome (HHS) represents another clinical subtype of acute metabolic disturbance in diabetes and is characterized by severe hyperglycemia, high plasma osmolality, and dehydration, without significant ketosis. Patients may exhibit varying degrees of altered consciousness or coma. In some cases, mild ketosis may also be present. HHS primarily occurs in elderly patients with type 2 diabetes mellitus (T2DM), and over 2/3 of affected individuals have no prior history of diabetes.
Etiology
The precipitating factors for HHS include conditions that increase blood glucose levels and cause dehydration, such as acute infections, trauma, surgeries, cerebrovascular events, or other stress states. Use of medications like glucocorticoids, diuretics, or mannitol, insufficient water intake, fluid loss, dialysis, and intravenous parenteral nutrition are recognized triggers. Misdiagnosis resulting in the infusion of large amounts of glucose solutions or excessive intake of sugary beverages to alleviate thirst may also precipitate HHS or worsen its severity.
Clinical manifestations
HHS has an insidious onset. Initial symptoms include polyuria and polydipsia, while polyphagia is often absent, and appetite may instead diminish. These early symptoms can easily go unnoticed. Over time, severe dehydration and neurological symptoms develop, manifesting as lethargy, irritability, apathy, or drowsiness that progressively worsen into coma or seizures. In the late stages, patients may experience oliguria or even anuria. Upon presentation, patients are frequently severely dehydrated and may show neurological signs indicative of localized damage, which may lead to misdiagnosis as stroke. Compared to diabetic ketoacidosis (DKA), HHS is associated with more pronounced dehydration and neurological symptoms, but it lacks the characteristic Kussmaul breathing seen in acidosis.
Laboratory Findings
Diagnosis of HHS is generally confirmed when blood glucose levels reach or exceed 33.3 mmol/L and effective plasma osmolality measures 320 mOsm/(kg·H2O) or higher. Effective plasma osmolality can be calculated using the formula:
Effective plasma osmolality [mOsm/(kg·H2O)] = 2 × (serum Na+ + serum K+) + blood glucose (all in mmol/L).
Serum sodium is either normal or elevated. Urine ketone levels are negative or weakly positive, and pronounced acidosis is typically absent, distinguishing HHS from DKA. However, DKA and HHS may occasionally coexist.
HHS is a serious and life-threatening condition with a higher mortality rate than DKA, largely due to its severe complications. Early diagnosis and treatment are critical. Clinicians should consider HHS in cases of unexplained dehydration, shock, altered consciousness, or coma, particularly in patients with low blood pressure despite high urinary output, irrespective of their diabetes history. Relevant diagnostic tests should be performed to confirm the condition.
Treatment
The treatment principles for HHS are similar to those for DKA. However, the severity of dehydration in HHS is greater, involving fluid loss that may reach 10–15% of body weight. Aggressive and careful fluid replacement is required, with a total fluid volume of 6,000–10,000 mL administered over 24 hours.
The fluid administration rate parallels that of DKA treatment, with 1.0–1.5 L given in the first hour and subsequent adjustments based on the degree of dehydration improvement, plasma osmolality (monitored hourly at the beginning of treatment), and urine output. An effective plasma osmolality reduction rate of 3–8 mOsm/(kg·H2O) per hour is typically achieved.
Isotonic solutions, such as 0.9% sodium chloride, are preferred at the start of treatment to restore blood volume, correct shock, improve renal blood flow, and recover kidney function, as the administration of large volumes of isotonic saline reduces the risk of hemolysis. For patients in shock, plasma or whole blood may be considered. In cases where shock is absent or already corrected, and plasma osmolality exceeds 350 mOsm/(kg·H2O) with serum sodium levels above 155 mmol/L after normal saline infusion, a low-osmolality solution such as 0.45% sodium chloride may be used. Oral rehydration via the gastrointestinal tract may also be an option depending on the clinical situation.
It is important to note that elevated blood glucose contributes to maintaining blood volume. A rapid decrease in blood glucose levels combined with insufficient fluid replacement may lead to further reductions in blood volume and blood pressure.
Insulin therapy follows a protocol similar to that for DKA, although lower doses of insulin are required due to greater insulin sensitivity in HHS patients. Insulin is typically administered as an intravenous infusion at a rate of 0.05–0.1 U/(kg·h). When blood glucose levels decrease to 16.7 mmol/L, glucose-containing fluids are introduced, with 1 unit of short-acting insulin added for every 2–4 g of glucose. Blood glucose levels are monitored, and the insulin-to-glucose infusion ratio is adjusted to maintain blood glucose levels at 13.9–16.7 mmol/L until HHS resolves.
Potassium replacement follows the same principles as in DKA therapy, while bicarbonate treatment is generally not required.
Potential Complications During Treatment
Dehydration of brain cells may transition into cerebral edema during treatment. Patients may remain in a coma or experience a return to coma after initial improvement. Continuous monitoring of the clinical status is essential for early identification and management of complications.
Continuous renal replacement therapy (CRRT) may reduce the risk of multiple organ dysfunction syndrome in severe HHS cases, thereby improving survival rates.
Prevention
The prevention principles for HHS are consistent with those for DKA. Prevention focuses on effective blood glucose management, patient education, and timely intervention for precipitating factors.