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A diabetic patient with blood glucose reaching 101.7 mmol/L and blood osmotic pressure reaching 427 mOsm/kg.H2O was hospitalized and diagnosed with hyperosmolar nonketotic diabetic syndrome. After full rescue efforts, the patient was almost out of danger.
However, when it comes to hyperosmolar nonketotic diabetic syndrome, its high mortality rate is almost universally known. Therefore, overall control of this disease, especially familiarity with treatment, becomes more important.
I. Overview
Hyperosmolar Nonketotic Diabetic Syndrome (hyperosmolar nonketotic diabetic syndrome, HNDS) is characterized by severe hyperglycemia, dehydration, and elevated plasma osmotic pressure without ketosis or acidosis. Clinically, patients present with impaired consciousness or coma; those who do not fall into a coma are referred to as being in a hyperosmolar state. HNDS predominantly occurs in elderly diabetic patients, most of whom are older than 60 years of age; there is no gender difference. Approximately 50% of patients may have no history of diabetes before onset, or they may be mild type 2 diabetics. Notably, it also occurs in young type 1 diabetic patients, either coexisting with or sequentially developing from DKA. The incidence of HNDS is lower than that of DKA, with an approximate ratio of 1:6~1:10 between the two conditions, but the mortality rate of HNDS is higher. In recent years, due to advances in diagnostic and therapeutic techniques, the mortality rate of this condition has significantly decreased, yet it still remains at 15%~20%.
Normal plasma osmotic pressure is maintained between 280 mOsm/kg.H2O and 320 mOsm/kg.H2O, mainly supplied by blood Na+. When blood glucose significantly increases, plasma osmotic pressure can also rise. Patients with HNDS already have varying degrees of carbohydrate metabolism disorders. Under the influence of certain precipitating factors, these existing carbohydrate metabolism disorders worsen, leading to reduced insulin secretion and sensitivity, which causes significant elevation of blood glucose levels. High urinary glucose leads to osmotic diuresis, resulting in substantial water loss. Hyperglycemia and dehydration progressively exacerbate high plasma osmotic pressure, eventually leading to a hyperosmolar state, with severe cases presenting as coma. Clinically, almost all HNDS patients have obvious precipitating factors, including:
1. Infection and stress: Respiratory tract, gastrointestinal, and urinary system infections are the most common precipitating factors. Cerebrovascular accidents, acute myocardial infarction, acute pancreatitis, severe trauma, surgery, heatstroke, etc., under stress states, are also important precipitating factors.
2. Excessive intake or infusion of glucose: Large consumption of sugary beverages and foods, intravenous infusion of large amounts of glucose solution, or use of glucose-containing solutions for hemodialysis and peritoneal dialysis.
3. Excessive water loss: Severe vomiting and diarrhea patients, extensive burn victims, neurosurgical and neurosurgical patients receiving dehydration therapy, improperly administered dialysis treatment, etc.
4. Insufficient water intake: Elderly diabetic patients have a reduced response of the thirst center, mental or conscious impairment, and other patients unable to actively hydrate themselves.
5. Medications: Use of propranolol, phenytoin sodium, chlorpromazine, cimetidine, large doses of corticosteroids, azathioprine, and other immunosuppressants can cause increased blood glucose levels. Thiazide and loop diuretics exacerbate dehydration and can also induce HNDS.
6. Others: Some endocrine diseases such as hyperthyroidism, acromegaly, hypercortisolism, pheochromocytoma, etc., can lead to carbohydrate metabolism disorders, making them more susceptible to inducing HNDS.
II. Diagnostic Approach
(A) Clinical Characteristics
1. Medical History: Common among individuals aged 50-70 years, with similar male and female prevalence rates. Half of the patients already have diabetes.
2. Diabetes Type: Type 2 diabetes is more common; Type 1 diabetes is less common and can coexist with DKA; occasionally seen in secondary diabetic patients with hypercortisolism, acromegaly, etc.
3. Onset: Days to weeks before onset, patients often experience gradually worsening symptoms of polydipsia, polyuria, fatigue, dizziness, lack of appetite, and vomiting.
4. Symptoms: Patients show signs of dehydration, such as dry skin, reduced elasticity, sunken eyes, a dry tongue with longitudinal cracks. Severe cases exhibit signs of circulatory failure such as weak and rapid pulse, orthostatic hypotension, and even shock. Some patients, despite severe dehydration, maintain normal blood pressure because the high plasma osmotic pressure causes extracellular fluid to seep into cells, masking the severity of dehydration. Patients may exhibit psychiatric symptoms such as apathy and somnolence. About half of HNDS patients develop confusion or coma when plasma osmotic pressure exceeds 350 mOsm/kg.H2O. The presence of consciousness impairment depends on the speed and degree of increase in plasma osmotic pressure.
5. Signs: Transient hemiplegia, muscle relaxation or involuntary twitching, hemianopia, visual disturbances, nystagmus, aphasia, hallucinations, and central fever suggest possible cortical or subcortical damage due to dehydration, hemodilution, or vascular thrombosis. These manifestations are mostly reversible, but some patients may retain certain neurological or psychiatric symptoms.
6. Others: Some patients may have concurrent infections such as pneumonia, urinary tract infections, pancreatitis, etc., or complications such as cerebral edema and thrombus formation.
(B) Routine Examination
1. Blood Glucose: Patient's blood glucose is significantly elevated, usually exceeding 33mmol/L (600mg/dL).
2. Urine Sugar: Most patients have strongly positive urine sugar. If renal glycosuria threshold is raised, urine sugar may be weakly positive.
3. Electrolytes: Serum sodium may be normal, elevated, or reduced; serum potassium may be normal, reduced, or elevated. Changes in serum sodium and potassium depend on the total loss, distribution inside and outside cells, and the severity of dehydration.
4. Urea Nitrogen and Creatinine: Normal or significantly elevated, reflecting the degree of dehydration and renal insufficiency. Patient's urea nitrogen can reach 21mmol/L~36mmol/L, creatinine can reach 163mmol/L~600mmol/L, BUN/Cr ratio can exceed 30:1 (normal people generally range from 10:1~20:1). Significant elevation in plasma osmotic pressure is an important characteristic and diagnostic basis of this condition. Plasma osmotic pressure can be directly measured, or calculated using the formula: Plasma osmotic pressure (mOsm/kg.H2O) = 2([Na+] + [K+]) + glucose + BUN (all units in mmol/L). Since BUN freely crosses cell membranes and does not contribute to effective extracellular osmotic pressure, many experts advocate omitting BUN in calculations. Effective osmotic pressure exceeding 320 mOsm/kg.H2O indicates hyperosmolality.
5. Acid-base Imbalance: About half of patients have mild to moderate metabolic acidosis with a high anion gap. Anion gap increases approximately twofold, serum [HCO3-] is mostly above 15mmol/L, pH is mostly above 7.3. Elevated anions primarily include lactate and keto acids, and also small amounts of sulfate and phosphate.
6. Blood Ketones and Urine Ketones: Blood ketones are normal or mildly elevated, generally not exceeding 50mg/dL, urine ketones are negative or weakly positive.
7. Others: White blood cell count in patients is often elevated, hematocrit is elevated, reflecting dehydration and blood concentration. Some patients have abnormal urinalysis, suggesting urinary tract infection. Chest X-ray examination reflects pulmonary infection status.
(C) Diagnostic Thinking and Differential Diagnosis
1. Key Diagnostic Points
(1) More common in elderly individuals aged 50~70 years.
(2) Type 2 diabetes is more common.
(3) Prominent symptoms of dry mouth, polydipsia, polyuria, and fatigue, evident dehydration, no deep breathing.
(4) Blood glucose usually ≥33mmol/L (600mg/dL).
(5) Serum sodium markedly elevated ≥155 mmol/L.
(6) Effective plasma osmotic pressure ≥320 mOsm/kg.H2O.
(7) Strongly positive urine sugar, urine ketone bodies negative or weakly positive.
(8) Serum HCO3- ≤15mmol/L, arterial blood gas pH ≤7.30.
2. Indicators Suggesting Severe DKA
(1) Clinical presentation includes severe dehydration, shock, or coma.
(2) Blood glucose ≥33mmol/L (600mg/dL).
(3) Electrolyte imbalance signs such as excessively high or low potassium.
(4) Persistent elevation of blood urea nitrogen and creatinine.
(5) Combined with ketoacidosis or moderate lactic acidosis.
(6) Combined with cardiovascular or cerebrovascular accidents.
3. Differential Diagnosis
HNDS may simultaneously occur with DKA or lactic acidosis. All HNDS patients exhibit significant hyperosmolality; if the patient's plasma effective osmotic pressure is below 320 mOsm/kg.H2O, other causes of coma should be considered. Some patients have very high blood glucose but low serum sodium, so the effective osmotic pressure does not reach 320mmol/L. Although HNDS cannot be diagnosed, treatment should follow HNDS protocols.
(1) Cerebrovascular accident: Patient’s blood glucose is often not elevated or slightly increased due to stress, but does not exceed 33.3mmol/L, HbA1C is normal.
(2) HNDS and poorly controlled diabetes with anuric renal failure: Both may have severe hyperglycemia and elevated blood BUN and Cr levels, but their treatments differ greatly. The former requires large fluid replacement and appropriate insulin; the latter uses only insulin to lower blood glucose and should not receive large fluid input.
(3) Differentiate between ketoacidosis, lactic acidosis, or hypoglycemic coma.
III. Treatment Methods
The basic treatment principles are the same as for DKA, implementing individualized and effective treatment plans. The key is active fluid replacement and small-dose insulin to correct severe dehydration, restore blood volume, correct hyperosmolality, and correct electrolyte imbalances.
(A) General Treatment
1. Bed rest, provide oxygen if arterial PO2 150mmol/L, start with hypotonic fluids immediately. If the patient is in shock or systolic blood pressure remains persistently below 80mmHg, besides isotonic fluids, colloid fluids such as plasma or whole blood should be intermittently infused.
(1) 0.9% Normal Saline is an isotonic solution that can rapidly replenish blood volume, improve kidney function, and lower blood glucose. However, attention should be paid to the increase in serum sodium and chloride during treatment. If the patient’s blood pressure is low and serum sodium is 150mmol/L, use half-normal solutions. However, excessive hypotonic solutions can excessively lower plasma osmotic pressure, making it difficult to effectively maintain blood volume, and may lead to hemolysis, cerebral edema, and delayed shock correction. Therefore, half-normal solutions should be used cautiously. They can be moderately used in patients without obvious hypotension. Once plasma osmotic pressure drops to 330mmos/L, switch back to normal saline. When blood glucose drops to around 13.9 mmol/L, switch to 5% glucose solution or 5% glucose saline based on serum sodium levels. If plasma osmotic pressure is too low at the same time, 5% glucose saline can also be used.
(3) For patients with severe hypotension (SBP below 80mmHg) or shock, plasma or physiological saline containing 10% dextran can be used. If serum sodium >150mmol/L, plasma and 5% glucose can be combined. If heart failure, pulmonary edema, and renal failure are induced, dextran should be used cautiously for fluid replacement.
3. Fluid Infusion Rate
The principle is to start fast and then slow down. Infuse 2L in the first 2 hours, then 0.5L every 2 hours thereafter. In the first 8 hours, infuse half of the total fluid volume (approximately 3000ml~4000ml), and complete the remaining amount within 24 hours (approximately 4000 ml~8000ml). To avoid complications such as congestive heart failure, pulmonary edema, and cerebral edema caused by excessive fluid, monitor the patient's urine output, jugular vein filling, lung auscultation during fluid administration. Central venous pressure and hematocrit can be measured if necessary to guide fluid replacement. Elderly and heart dysfunction patients should try to replace fluids via oral or nasogastric tube, given warm water at 1L/h~2L/h to reduce adverse reactions caused by large intravenous infusions.
(C) Insulin Therapy
HNDS patients have good insulin sensitivity, and the dose of insulin used for treatment should be small, with close monitoring of blood glucose changes to adjust dosage in a timely manner. Intravenous infusion of insulin is preferred due to its convenience, rapid and stable reduction in blood glucose, and good controllability. If blood glucose exceeds 33.3mmol/L, a bolus injection of 10U~16U of regular insulin can be given intravenously, followed by continuous intravenous infusion at 0.1U.kg-1.h-1. When blood glucose drops to 13.9mmol/L, the insulin dose can be reduced to 0.05 U.kg-1.h-1. The ideal rate of blood glucose decrease is 3.3mmol/L.h~6.1mmol/(L.h). If after 2 hours of treatment, blood glucose decreases by less than 2mmol/(L.h) or instead increases under conditions where fluid volume has been adequately replaced, the insulin dose should be increased by 0.5 to 1 times. Blood glucose should be measured every 1 hour~2 hours in the first 12 hours. Rapid blood glucose reduction is not conducive to correcting low blood volume and can easily lead to hypoglycemia. After the condition stabilizes, subcutaneous insulin injections multiple times daily can be used, gradually returning to the treatment plan prior to HNDS onset.
(D) Correcting Electrolyte Imbalance
Imbalances in serum sodium can be corrected while replacing normal saline. Potassium supplementation commonly uses potassium chloride solution, preferably supplemented orally with potassium citrate solution for safety and convenience. Initial high potassium and oliguria patients should temporarily withhold potassium supplementation; patients with normal or low potassium levels and urine output exceeding 40ml/h should begin potassium supplementation immediately upon initiation of treatment. For patients with potassium levels between 3.5mmol/L~5.5mmol/L, add 1.0g~1.5g potassium chloride per liter of fluid; for patients with potassium levels 5.5mmol/L, pause potassium supplementation. After HNDS correction, continue oral potassium supplementation at 3g/d~6g/d for at least one week. During potassium supplementation, monitor serum potassium to guide the amount and rate of supplementation.
(E) Correcting Acidosis
Acidosis associated with HNDS may be related to elevated levels of ketones or lactate in the blood. If blood gas analysis shows pH > 7.1, sufficient fluid replacement and insulin treatment will correct acidosis without the need for alkaline drugs. If pH < 7.1 (equivalent to CO2CP 4.5mmol/L~