17:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/3ykn5ops9bft5.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 18:T5139,## Summary **Hyperosmolar hyperglycemic state (HHS)** is a life-threatening hyperglycemic emergency characterized by severe hyperglycemia, hyperosmolality, and profound water/electrolyte depletion without the degree of ketonemia and metabolic acidosis required for diabetic ketoacidosis (DKA). The 2024 international consensus requires all four of the following: plasma glucose **≥600 mg/dL (33.3 mmol/L)**; effective serum osmolality **>300 mOsm/kg** or total serum osmolality **>320 mOsm/kg**; β-hydroxybutyrate **<3.0 mmol/L** or urine ketones below the DKA threshold; and venous pH **≥7.3** with bicarbonate **≥15 mmol/L**.[1] Altered cognition is common in severe HHS but is no longer required for diagnosis.[1] Treat HHS as a controlled correction of circulatory volume and hypertonicity, not simply as severe hyperglycemia. Initial priorities are airway and perfusion assessment, isotonic crystalloid, potassium surveillance, identification of the precipitant, and frequent monitoring of glucose, sodium, osmolality, kidney function, fluid balance, and neurologic status.[1,2] In adults without major cardiac or kidney compromise, the 2024 consensus supports isotonic saline or a balanced crystalloid at **500–1000 mL/h for the first 2–4 hours**, followed by individualized replacement.[1] Older adults, heart failure, advanced kidney disease, and frailty require smaller boluses and repeated reassessment. Correction must be gradual. During active treatment, glucose should generally fall no faster than **90–120 mg/dL/h (5–6.7 mmol/L/h)**, serum sodium no faster than **10 mmol/L in 24 hours**, and osmolality about **3–8 mOsm/kg/h**.[1,2] A rise in measured sodium as glucose falls is expected and does not by itself indicate a need for hypotonic fluid. For HHS without significant ketoacidosis, use IV insulin at **0.05 units/kg/h** once initial fluid replacement is underway and the treatment plan accounts for the rate of glucose/osmolality change.[1] The Joint British Diabetes Societies (JBDS) pathway is more explicit about delaying insulin until initial volume replacement has started and the response to fluid is known, unless substantial ketonemia requires earlier insulin.[2] Mixed DKA/HHS is treated with the DKA insulin rate of **0.1 units/kg/h**.[1] Potassium is depleted even when the presenting serum concentration is normal or high. Begin potassium replacement once serum potassium falls below **5.0 mmol/L**, aiming for about **4–5 mmol/L**. If potassium is **<3.5 mmol/L**, replace potassium first and defer insulin until the concentration is >3.5 mmol/L.[1] HHS is not resolved by a glucose threshold alone. The 2024 consensus defines resolution by **serum osmolality <300 mOsm/kg**, **glucose <250 mg/dL (13.9 mmol/L)**, **urine output >0.5 mL/kg/h**, and **improved cognition**.[1] The precipitating illness, hydration status, electrolyte stability, and transition plan must also be adequate before leaving monitored acute care. > **Caution:** Rapid reduction in tonicity can cause neurologic injury and circulatory instability. Follow the osmolality trajectory and clinical state, not the glucose value in isolation. ## Diagnostic criteria All four components should be present for pure HHS under the 2024 international consensus.[1] | Domain | HHS criterion | Bedside implication | |---|---:|---| | Hyperglycemia | Plasma glucose ≥600 mg/dL (33.3 mmol/L) | Severe glucose elevation alone is insufficient | | Hyperosmolality | Effective osmolality >300 mOsm/kg **or** total osmolality >320 mOsm/kg | Central diagnostic and monitoring variable | | Ketones | β-hydroxybutyrate <3.0 mmol/L or urine ketones below the DKA threshold | Greater ketonemia suggests mixed DKA/HHS | | Acid-base status | pH ≥7.3 and bicarbonate ≥15 mmol/L | More marked acidosis suggests DKA or another acid-base disorder | ### Osmolality calculations Use one formula consistently during treatment. When sodium and glucose are reported in mmol/L: - **Effective osmolality (mOsm/kg) ≈ 2 × sodium + glucose** - **Total osmolality (mOsm/kg) ≈ 2 × sodium + glucose + urea** When glucose and blood urea nitrogen are reported in mg/dL: - **Effective osmolality ≈ 2 × sodium + glucose/18** - **Total osmolality ≈ 2 × sodium + glucose/18 + BUN/2.8** Effective osmolality excludes urea because urea crosses cell membranes relatively freely and contributes less to acute transcellular water movement. ### HHS, DKA, and mixed crisis Overlap is common. Mixed DKA/HHS should be recognized early because insulin dosing and ketone clearance become DKA-directed.[1] | Feature | HHS | DKA | Mixed DKA/HHS | |---|---|---|---| | Glucose | ≥600 mg/dL for HHS definition | May be ≥200 mg/dL or lower with prior diabetes | Often very high | | Osmolality | Effective >300 or total >320 mOsm/kg | Variable | Hyperosmolar | | β-hydroxybutyrate | <3.0 mmol/L | ≥3.0 mmol/L | ≥3.0 mmol/L | | pH | ≥7.3 | <7.3 in acidotic DKA | Often <7.3 | | Bicarbonate | ≥15 mmol/L | <18 mmol/L supports DKA | Often <18 mmol/L | | IV insulin | 0.05 units/kg/h | 0.1 units/kg/h when IV infusion indicated | 0.1 units/kg/h | If a hyperosmolar patient has substantial ketonemia or DKA-range acidosis, manage the mixed syndrome rather than labeling the presentation pure HHS.[1] ## Pathophysiology Relative insulin deficiency permits severe hyperglycemia but usually retains enough insulin effect to suppress major lipolysis and ketogenesis. Hyperglycemia causes osmotic diuresis with large water and electrolyte losses. Progressive dehydration reduces renal perfusion, impairs glucose clearance, and amplifies hyperglycemia. Hypertonicity pulls water from intracellular to extracellular compartments, including brain tissue, and contributes to neurologic dysfunction. Total-body deficits often include: - many liters of free water; - sodium and chloride; - potassium despite normal or elevated initial serum potassium; - magnesium and phosphate to variable degrees. The physiologic target is therefore restoration of perfusion while allowing osmolality to normalize at a controlled rate. ## Precipitants and risk factors HHS occurs most often in adults with type 2 diabetes, particularly older or frail adults, but can occur with any diabetes phenotype.[1] Common precipitants include: - pneumonia, urinary infection, and other infections; - missed or inadequate glucose-lowering therapy; - newly recognized diabetes; - myocardial infarction, stroke, pancreatitis, trauma, or surgery; - glucocorticoids and other hyperglycemia-promoting medications; - enteral or parenteral nutrition without adequate glycemic management; - impaired thirst or restricted access to water; - cognitive impairment or dependence on caregivers; - chronic kidney disease or heart failure, which complicate replacement. A precipitant should be actively sought even when dehydration and hyperglycemia appear sufficient to explain the presentation. ## Clinical features HHS usually evolves over several days. Typical findings include: - polyuria and polydipsia early; - progressive weakness and poor oral intake; - marked dehydration; - tachycardia, orthostatic hypotension, or shock; - lethargy, confusion, focal neurologic findings, seizure, or coma; - manifestations of the precipitating illness. Absence of altered cognition does not exclude HHS. Conversely, profound neurologic dysfunction at a modest osmolality should prompt evaluation for stroke, infection, seizure, toxic exposure, or another metabolic disorder. ## Initial stabilization ### Immediate actions 1. Assess airway protection, ventilation, circulation, and level of consciousness. 2. Obtain continuous cardiac monitoring in severe disease or major electrolyte disturbance. 3. Establish IV access and begin isotonic crystalloid when hypovolemia is present. 4. Obtain bedside glucose, electrolytes, creatinine, venous blood gas, β-hydroxybutyrate, and osmolality. 5. Search for shock, sepsis, acute coronary syndrome, stroke, or another time-critical precipitant. 6. Measure urine output and begin strict fluid balance. 7. Escalate to a high-acuity setting when HHS is severe, organ failure is present, or correction cannot be monitored safely on a standard ward. The 2024 consensus recommends intensive-care management for HHS, severe DKA, or hyperglycemic crisis accompanied by critical illness.[1] ### Initial investigations | Test | Purpose | Action | |---|---|---| | Plasma glucose | Establish and follow hyperglycemia | Trend frequently during active correction | | Sodium, potassium, chloride, bicarbonate | Treatment safety and tonicity | Potassium determines when insulin can start | | Urea and creatinine | Kidney perfusion and total osmolality | Adjust fluid and potassium strategy | | Measured/calculated osmolality | Diagnostic and treatment target | Aim for fall about 3–8 mOsm/kg/h | | β-hydroxybutyrate | Identify mixed DKA/HHS | ≥3 mmol/L supports DKA physiology | | Venous pH | Detect acidemia | pH <7.3 requires explanation | | CBC, cultures, urinalysis, imaging as indicated | Identify infection | Leukocytosis alone is not proof of bacterial infection | | ECG ± troponin | Ischemia and potassium effects | Treat acute coronary syndrome in parallel | | Lactate | Shock or tissue hypoperfusion | Persistent elevation needs a cause beyond hyperglycemia | | HbA1c | Chronic glycemic context | Helps plan long-term therapy | ## Fluid therapy Fluid replacement is the first major intervention and often lowers glucose substantially before insulin has a large effect.[1,2] ### Initial fluid For adults without major cardiac or kidney compromise, start **0.9% sodium chloride or a balanced crystalloid at 500–1000 mL/h for the first 2–4 hours**.[1] Reassess frequently and then tailor the rate to: - blood pressure and perfusion; - heart rate; - urine output; - cumulative input/output; - sodium and osmolality trajectory; - heart failure, kidney disease, cirrhosis, pregnancy, or frailty. In older adults or those with heart failure or end-stage kidney disease, small boluses such as **250 mL** with serial reassessment can reduce iatrogenic fluid overload.[1] ### Correction targets During active treatment:[1,2] - glucose decline: generally no more than **90–120 mg/dL/h (5–6.7 mmol/L/h)**; - sodium decline: no more than **10 mmol/L in 24 hours**; - osmolality decline: about **3–8 mOsm/kg/h**. As glucose falls, water shifts intracellularly and measured sodium may rise. A glucose fall of 100 mg/dL (5.6 mmol/L) is commonly accompanied by an approximately 1.6 mmol/L rise in sodium.[1] This is expected if osmolality is falling appropriately. Do not switch automatically to 0.45% sodium chloride because sodium rises. Consider hypotonic saline only when the osmolality is not declining despite adequate fluid balance and after reassessing the entire biochemical trajectory.[1] > **Clinical pearl:** The safest fluid decision comes from the combination of perfusion, sodium trend, osmolality trend, urine output, and cumulative balance—not from a single sodium value. ## Insulin therapy ### Pure HHS For HHS without substantial ketoacidosis, use a fixed-rate IV insulin infusion of **0.05 units/kg/h**.[1] Ensure initial volume replacement is underway. The JBDS pathway emphasizes a fluid-led initial phase and generally delays insulin until the initial fall in glucose and osmolality with saline is established, unless clinically important ketonemia requires earlier insulin.[2] This difference is operational rather than conceptual: both strategies aim to avoid an overly rapid fall in tonicity. ### Mixed DKA/HHS If β-hydroxybutyrate is **≥3.0 mmol/L** or significant DKA-range acidosis is present, treat as mixed DKA/HHS with IV insulin at **0.1 units/kg/h**.[1] ### Dextrose during correction As glucose approaches the treatment threshold while hyperosmolality remains unresolved, add dextrose-containing fluid and continue insulin as needed to allow ongoing controlled metabolic correction without hypoglycemia. JBDS commonly introduces glucose-containing fluid when glucose falls below **14 mmol/L (252 mg/dL)**.[2] ## Potassium and other electrolytes ### Potassium Serum potassium may initially be normal or high even with severe total-body depletion.[1] | Serum potassium | Action | |---|---| | ≥5.0 mmol/L | Do not routinely replace initially; recheck frequently | | 3.5 to <5.0 mmol/L | Add potassium to replacement fluid to maintain about 4–5 mmol/L, individualized to kidney function and urine output | | <3.5 mmol/L | Replace potassium and **defer insulin until K >3.5 mmol/L** | | Severe disturbance or ECG change | Continuous monitoring and urgent senior/critical-care review | A common replacement requirement once potassium is below 5 mmol/L is **20–30 mmol/L** in IV fluid, adjusted to renal function, urine output, infusion limits, and local policy.[1] Marked hypokalemia may require more concentrated or separate replacement in a monitored setting. Measure potassium at baseline, about 2 hours after starting insulin, and at least every 4 hours during active treatment; check more often when unstable.[1] ### Phosphate Do not replace phosphate routinely. Consider replacement when severe hypophosphatemia causes respiratory weakness, cardiac dysfunction, or another clinically important manifestation. Rapid phosphate administration can precipitate hypocalcemia.[1] ### Magnesium Correct clinically significant hypomagnesemia, especially with arrhythmia or refractory hypokalemia. ## Monitoring HHS treatment requires trend-based monitoring.[1,2] | Variable | Typical active-treatment frequency | Main concern | |---|---|---| | Blood glucose | About hourly to every 1–2 h | Rate of fall and hypoglycemia | | Electrolytes/creatinine | About every 4 h, more often if unstable | Potassium, sodium, renal recovery | | Serum osmolality | About every 4 h | Fall 3–8 mOsm/kg/h | | Fluid balance/urine output | Hourly in severe disease | Perfusion and overload | | Cognition | Frequent bedside reassessment | Neurologic deterioration | | Cardiac rhythm | Continuous when severe electrolyte disturbance/cardiac disease | Arrhythmia and ischemia | ### When the course is not improving If glucose falls but osmolality, perfusion, or neurologic status does not improve, reassess: - circulating-volume replacement; - ongoing fluid losses; - sodium/free-water deficit; - kidney failure; - sepsis or other shock; - myocardial infarction or stroke; - mixed DKA/HHS; - insulin delivery; - medication-related hyperglycemia; - another cause of altered cognition. A plateau or rise in osmolality during apparently adequate treatment is a reason to reassess fluid delivery and calculations, not simply to increase insulin. ## Thrombosis prevention HHS is a prothrombotic state, but routine **therapeutic** anticoagulation is not indicated without another reason. Apply standard inpatient VTE risk assessment and prophylaxis unless contraindicated. JBDS specifically recommends prophylactic low-molecular-weight heparin during admission for HHS unless contraindicated.[2] Therapeutic anticoagulation is reserved for confirmed/suspected VTE, acute coronary syndrome, or another standard indication. ## Resolution and transition The 2024 consensus considers HHS resolved when all of the following are present:[1] - serum osmolality **<300 mOsm/kg**; - blood glucose **<250 mg/dL (13.9 mmol/L)**; - urine output **>0.5 mL/kg/h**; - cognition improved. Before transition out of acute monitored treatment, also ensure: - potassium and other electrolytes are stable; - the precipitating illness is controlled or has a defined treatment plan; - oral intake and hydration are adequate or supported; - a subcutaneous insulin/diabetes regimen is in place; - education and follow-up address the factor that precipitated the crisis. When IV insulin is being replaced by subcutaneous basal insulin, overlap the basal dose with the infusion for **1–2 hours** to prevent rebound hyperglycemia.[1] ## Special situations ### Older adults and frailty Older adults are at higher risk of HHS, acute kidney injury, thrombosis, delirium, and treatment-related fluid overload. Use smaller fluid aliquots, more frequent lung/perfusion reassessment, and a conservative transition plan that addresses access to water, medications, nutrition, and caregiver support. ### Heart failure The need for volume restoration remains, but rapid large-volume infusion can precipitate pulmonary edema. Use smaller boluses, frequent clinical reassessment, and bedside ultrasound or invasive monitoring when clinically necessary. Persistent shock despite cautious fluid replacement may require critical-care hemodynamic support. ### Advanced kidney disease Kidney failure reduces osmotic urinary losses but markedly complicates potassium and fluid management. Avoid formulaic replacement volumes. Hyperkalemia, pulmonary edema, or severe acid-base disturbance may require nephrology input and renal replacement therapy for standard indications. ### Pregnancy HHS in pregnancy is uncommon but high risk for parent and fetus. Manage jointly with critical care/endocrinology and obstetric medicine. Fluid, insulin, and electrolyte principles still apply, while fetal assessment and pregnancy-specific precipitants are addressed in parallel. ## Complications ### Treatment-related - hypoglycemia; - hypokalemia; - overly rapid decline in osmolality; - fluid overload; - hyperchloremic acidosis; - rare cerebral edema or osmotic neurologic injury. ### Disease-related - shock and acute kidney injury; - thrombosis; - rhabdomyolysis; - seizures; - myocardial ischemia; - aspiration; - infection-related organ failure. Worsening neurologic status during treatment is not an expected correction effect and requires immediate assessment for cerebral edema, stroke, seizure, excessive tonicity change, or another cause. ## Prevention after recovery Before discharge: - identify and treat the precipitant; - reconcile diabetes medications and insulin access; - provide a sick-day plan; - ensure glucose-monitoring supplies; - assess cognitive, functional, and social barriers to hydration and medication use; - arrange early diabetes follow-up; - address infection prevention and vaccination when relevant; - review medications that contributed to hyperglycemia; - document when to seek urgent care. Patients with newly diagnosed diabetes after HHS require a phenotype-directed plan once the acute crisis has resolved; the inpatient regimen should not be assumed to be the lifelong regimen. ## Acute management checklist - [ ] Confirm HHS criteria and assess for mixed DKA/HHS. - [ ] Stabilize airway, breathing, circulation, and shock. - [ ] Begin isotonic crystalloid with a rate appropriate to cardiac/kidney reserve. - [ ] Obtain glucose, electrolytes, creatinine, pH, β-hydroxybutyrate, and osmolality. - [ ] Identify and treat the precipitant. - [ ] Track glucose, sodium, osmolality, potassium, urine output, and cognition. - [ ] Keep osmolality fall near 3–8 mOsm/kg/h. - [ ] Replace potassium; withhold insulin if K <3.5 mmol/L. - [ ] Use insulin 0.05 units/kg/h for pure HHS; 0.1 units/kg/h for mixed DKA/HHS. - [ ] Add dextrose as glucose falls while ongoing insulin/correction is still required. - [ ] Provide VTE prophylaxis when indicated and not contraindicated. - [ ] Do not stop treatment on time or glucose alone; confirm resolution criteria. - [ ] Transition safely to subcutaneous therapy and address recurrence prevention. ## Related topics - [Diabetic Ketoacidosis](diabetic-ketoacidosis.md) - [Type 2 Diabetes Mellitus](type-2-diabetes-mellitus.md) - [Hyperkalemia](../nephrology/hyperkalemia.md) - [Hyponatremia](../nephrology/hyponatremia.md) - [Sepsis and Septic Shock](../critical-care/sepsis-and-septic-shock.md) ## References 1. Umpierrez GE, Davis GM, ElSayed NA, Fadini GP, Galindo RJ, Hirsch IB, et al. Hyperglycemic Crises in Adults With Diabetes: A Consensus Report. *Diabetes Care*. 2024;47(8):1257-1275. DOI: 10.2337/dci24-0032. PMID: 39052901. https://doi.org/10.2337/dci24-0032 2. Mustafa OG, Haq M, Dashora U, Castro E, Dhatariya KK; Joint British Diabetes Societies for Inpatient Care. Management of Hyperosmolar Hyperglycaemic State (HHS) in Adults: An updated guideline from the Joint British Diabetes Societies for Inpatient Care Group. *Diabetic Medicine*. 2023;40(3):e15005. DOI: 10.1111/dme.15005. https://doi.org/10.1111/dme.15005 3. Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. *Diabetes Care*. 2014;37(11):3124-3131. DOI: 10.2337/dc14-0984. PMID: 25342831. https://doi.org/10.2337/dc14-098419:T519f,## Summary **Hyperosmolar hyperglycemic state (HHS)** is a life-threatening hyperglycemic emergency characterized by severe hyperglycemia, hyperosmolality, and profound water/electrolyte depletion without the degree of ketonemia and metabolic acidosis required for [diabetic ketoacidosis](/library/diabetic-ketoacidosis) (DKA). The 2024 international consensus requires all four of the following: plasma glucose **≥600 mg/dL (33.3 mmol/L)**; effective serum osmolality **>300 mOsm/kg** or total serum osmolality **>320 mOsm/kg**; β-hydroxybutyrate **<3.0 mmol/L** or urine ketones below the DKA threshold; and venous pH **≥7.3** with bicarbonate **≥15 mmol/L**.[1] Altered cognition is common in severe HHS but is no longer required for diagnosis.[1] Treat HHS as a controlled correction of circulatory volume and hypertonicity, not simply as severe hyperglycemia. Initial priorities are airway and perfusion assessment, isotonic crystalloid, potassium surveillance, identification of the precipitant, and frequent monitoring of glucose, sodium, osmolality, kidney function, fluid balance, and neurologic status.[1,2] In adults without major cardiac or kidney compromise, the 2024 consensus supports isotonic saline or a balanced crystalloid at **500–1000 mL/h for the first 2–4 hours**, followed by individualized replacement.[1] Older adults, heart failure, advanced kidney disease, and frailty require smaller boluses and repeated reassessment. Correction must be gradual. During active treatment, glucose should generally fall no faster than **90–120 mg/dL/h (5–6.7 mmol/L/h)**, serum sodium no faster than **10 mmol/L in 24 hours**, and osmolality about **3–8 mOsm/kg/h**.[1,2] A rise in measured sodium as glucose falls is expected and does not by itself indicate a need for hypotonic fluid. For HHS without significant ketoacidosis, use IV insulin at **0.05 units/kg/h** once initial fluid replacement is underway and the treatment plan accounts for the rate of glucose/osmolality change.[1] The Joint British Diabetes Societies (JBDS) pathway is more explicit about delaying insulin until initial volume replacement has started and the response to fluid is known, unless substantial ketonemia requires earlier insulin.[2] Mixed DKA/HHS is treated with the DKA insulin rate of **0.1 units/kg/h**.[1] Potassium is depleted even when the presenting serum concentration is normal or high. Begin potassium replacement once serum potassium falls below **5.0 mmol/L**, aiming for about **4–5 mmol/L**. If potassium is **<3.5 mmol/L**, replace potassium first and defer insulin until the concentration is >3.5 mmol/L.[1] HHS is not resolved by a glucose threshold alone. The 2024 consensus defines resolution by **serum osmolality <300 mOsm/kg**, **glucose <250 mg/dL (13.9 mmol/L)**, **urine output >0.5 mL/kg/h**, and **improved cognition**.[1] The precipitating illness, hydration status, electrolyte stability, and transition plan must also be adequate before leaving monitored acute care. > **Caution:** Rapid reduction in tonicity can cause neurologic injury and circulatory instability. Follow the osmolality trajectory and clinical state, not the glucose value in isolation. ## Diagnostic criteria All four components should be present for pure HHS under the 2024 international consensus.[1] | Domain | HHS criterion | Bedside implication | |---|---:|---| | Hyperglycemia | Plasma glucose ≥600 mg/dL (33.3 mmol/L) | Severe glucose elevation alone is insufficient | | Hyperosmolality | Effective osmolality >300 mOsm/kg **or** total osmolality >320 mOsm/kg | Central diagnostic and monitoring variable | | Ketones | β-hydroxybutyrate <3.0 mmol/L or urine ketones below the DKA threshold | Greater ketonemia suggests mixed DKA/HHS | | Acid-base status | pH ≥7.3 and bicarbonate ≥15 mmol/L | More marked acidosis suggests DKA or another acid-base disorder | ### Osmolality calculations Use one formula consistently during treatment. When sodium and glucose are reported in mmol/L: - **Effective osmolality (mOsm/kg) ≈ 2 × sodium + glucose** - **Total osmolality (mOsm/kg) ≈ 2 × sodium + glucose + urea** When glucose and blood urea nitrogen are reported in mg/dL: - **Effective osmolality ≈ 2 × sodium + glucose/18** - **Total osmolality ≈ 2 × sodium + glucose/18 + BUN/2.8** Effective osmolality excludes urea because urea crosses cell membranes relatively freely and contributes less to acute transcellular water movement. ### HHS, DKA, and mixed crisis Overlap is common. Mixed DKA/HHS should be recognized early because insulin dosing and ketone clearance become DKA-directed.[1] | Feature | HHS | DKA | Mixed DKA/HHS | |---|---|---|---| | Glucose | ≥600 mg/dL for HHS definition | May be ≥200 mg/dL or lower with prior diabetes | Often very high | | Osmolality | Effective >300 or total >320 mOsm/kg | Variable | Hyperosmolar | | β-hydroxybutyrate | <3.0 mmol/L | ≥3.0 mmol/L | ≥3.0 mmol/L | | pH | ≥7.3 | <7.3 in acidotic DKA | Often <7.3 | | Bicarbonate | ≥15 mmol/L | <18 mmol/L supports DKA | Often <18 mmol/L | | IV insulin | 0.05 units/kg/h | 0.1 units/kg/h when IV infusion indicated | 0.1 units/kg/h | If a hyperosmolar patient has substantial ketonemia or DKA-range acidosis, manage the mixed syndrome rather than labeling the presentation pure HHS.[1] ## Pathophysiology Relative insulin deficiency permits severe hyperglycemia but usually retains enough insulin effect to suppress major lipolysis and ketogenesis. Hyperglycemia causes osmotic diuresis with large water and electrolyte losses. Progressive dehydration reduces renal perfusion, impairs glucose clearance, and amplifies hyperglycemia. Hypertonicity pulls water from intracellular to extracellular compartments, including brain tissue, and contributes to neurologic dysfunction. Total-body deficits often include: - many liters of free water; - sodium and chloride; - potassium despite normal or elevated initial serum potassium; - magnesium and phosphate to variable degrees. The physiologic target is therefore restoration of perfusion while allowing osmolality to normalize at a controlled rate. ## Precipitants and risk factors HHS occurs most often in adults with type 2 diabetes, particularly older or frail adults, but can occur with any diabetes phenotype.[1] Common precipitants include: - pneumonia, urinary infection, and other infections; - missed or inadequate glucose-lowering therapy; - newly recognized diabetes; - myocardial infarction, stroke, pancreatitis, trauma, or surgery; - glucocorticoids and other hyperglycemia-promoting medications; - enteral or parenteral nutrition without adequate glycemic management; - impaired thirst or restricted access to water; - cognitive impairment or dependence on caregivers; - chronic kidney disease or heart failure, which complicate replacement. A precipitant should be actively sought even when dehydration and hyperglycemia appear sufficient to explain the presentation. ## Clinical features HHS usually evolves over several days. Typical findings include: - polyuria and polydipsia early; - progressive weakness and poor oral intake; - marked dehydration; - tachycardia, orthostatic hypotension, or shock; - lethargy, confusion, focal neurologic findings, seizure, or coma; - manifestations of the precipitating illness. Absence of altered cognition does not exclude HHS. Conversely, profound neurologic dysfunction at a modest osmolality should prompt evaluation for stroke, infection, seizure, toxic exposure, or another metabolic disorder. ## Initial stabilization ### Immediate actions 1. Assess airway protection, ventilation, circulation, and level of consciousness. 2. Obtain continuous cardiac monitoring in severe disease or major electrolyte disturbance. 3. Establish IV access and begin isotonic crystalloid when hypovolemia is present. 4. Obtain bedside glucose, electrolytes, creatinine, venous blood gas, β-hydroxybutyrate, and osmolality. 5. Search for shock, sepsis, [acute coronary syndrome](/library/acute-coronary-syndrome), stroke, or another time-critical precipitant. 6. Measure urine output and begin strict fluid balance. 7. Escalate to a high-acuity setting when HHS is severe, organ failure is present, or correction cannot be monitored safely on a standard ward. The 2024 consensus recommends intensive-care management for HHS, severe DKA, or hyperglycemic crisis accompanied by critical illness.[1] ### Initial investigations | Test | Purpose | Action | |---|---|---| | Plasma glucose | Establish and follow hyperglycemia | Trend frequently during active correction | | Sodium, potassium, chloride, bicarbonate | Treatment safety and tonicity | Potassium determines when insulin can start | | Urea and creatinine | Kidney perfusion and total osmolality | Adjust fluid and potassium strategy | | Measured/calculated osmolality | Diagnostic and treatment target | Aim for fall about 3–8 mOsm/kg/h | | β-hydroxybutyrate | Identify mixed DKA/HHS | ≥3 mmol/L supports DKA physiology | | Venous pH | Detect acidemia | pH <7.3 requires explanation | | CBC, cultures, urinalysis, imaging as indicated | Identify infection | Leukocytosis alone is not proof of bacterial infection | | ECG ± troponin | Ischemia and potassium effects | Treat acute coronary syndrome in parallel | | Lactate | Shock or tissue hypoperfusion | Persistent elevation needs a cause beyond hyperglycemia | | HbA1c | Chronic glycemic context | Helps plan long-term therapy | ## Fluid therapy Fluid replacement is the first major intervention and often lowers glucose substantially before insulin has a large effect.[1,2] ### Initial fluid For adults without major cardiac or kidney compromise, start **0.9% sodium chloride or a balanced crystalloid at 500–1000 mL/h for the first 2–4 hours**.[1] Reassess frequently and then tailor the rate to: - blood pressure and perfusion; - heart rate; - urine output; - cumulative input/output; - sodium and osmolality trajectory; - heart failure, kidney disease, cirrhosis, pregnancy, or frailty. In older adults or those with heart failure or end-stage kidney disease, small boluses such as **250 mL** with serial reassessment can reduce iatrogenic fluid overload.[1] ### Correction targets During active treatment:[1,2] - glucose decline: generally no more than **90–120 mg/dL/h (5–6.7 mmol/L/h)**; - sodium decline: no more than **10 mmol/L in 24 hours**; - osmolality decline: about **3–8 mOsm/kg/h**. As glucose falls, water shifts intracellularly and measured sodium may rise. A glucose fall of 100 mg/dL (5.6 mmol/L) is commonly accompanied by an approximately 1.6 mmol/L rise in sodium.[1] This is expected if osmolality is falling appropriately. Do not switch automatically to 0.45% sodium chloride because sodium rises. Consider hypotonic saline only when the osmolality is not declining despite adequate fluid balance and after reassessing the entire biochemical trajectory.[1] > **Clinical pearl:** The safest fluid decision comes from the combination of perfusion, sodium trend, osmolality trend, urine output, and cumulative balance—not from a single sodium value. ## Insulin therapy ### Pure HHS For HHS without substantial ketoacidosis, use a fixed-rate IV insulin infusion of **0.05 units/kg/h**.[1] Ensure initial volume replacement is underway. The JBDS pathway emphasizes a fluid-led initial phase and generally delays insulin until the initial fall in glucose and osmolality with saline is established, unless clinically important ketonemia requires earlier insulin.[2] This difference is operational rather than conceptual: both strategies aim to avoid an overly rapid fall in tonicity. ### Mixed DKA/HHS If β-hydroxybutyrate is **≥3.0 mmol/L** or significant DKA-range acidosis is present, treat as mixed DKA/HHS with IV insulin at **0.1 units/kg/h**.[1] ### Dextrose during correction As glucose approaches the treatment threshold while hyperosmolality remains unresolved, add dextrose-containing fluid and continue insulin as needed to allow ongoing controlled metabolic correction without hypoglycemia. JBDS commonly introduces glucose-containing fluid when glucose falls below **14 mmol/L (252 mg/dL)**.[2] ## Potassium and other electrolytes ### Potassium Serum potassium may initially be normal or high even with severe total-body depletion.[1] | Serum potassium | Action | |---|---| | ≥5.0 mmol/L | Do not routinely replace initially; recheck frequently | | 3.5 to <5.0 mmol/L | Add potassium to replacement fluid to maintain about 4–5 mmol/L, individualized to kidney function and urine output | | <3.5 mmol/L | Replace potassium and **defer insulin until K >3.5 mmol/L** | | Severe disturbance or ECG change | Continuous monitoring and urgent senior/critical-care review | A common replacement requirement once potassium is below 5 mmol/L is **20–30 mmol/L** in IV fluid, adjusted to renal function, urine output, infusion limits, and local policy.[1] Marked hypokalemia may require more concentrated or separate replacement in a monitored setting. Measure potassium at baseline, about 2 hours after starting insulin, and at least every 4 hours during active treatment; check more often when unstable.[1] ### Phosphate Do not replace phosphate routinely. Consider replacement when severe hypophosphatemia causes respiratory weakness, cardiac dysfunction, or another clinically important manifestation. Rapid phosphate administration can precipitate hypocalcemia.[1] ### Magnesium Correct clinically significant hypomagnesemia, especially with arrhythmia or refractory hypokalemia. ## Monitoring HHS treatment requires trend-based monitoring.[1,2] | Variable | Typical active-treatment frequency | Main concern | |---|---|---| | Blood glucose | About hourly to every 1–2 h | Rate of fall and hypoglycemia | | Electrolytes/creatinine | About every 4 h, more often if unstable | Potassium, sodium, renal recovery | | Serum osmolality | About every 4 h | Fall 3–8 mOsm/kg/h | | Fluid balance/urine output | Hourly in severe disease | Perfusion and overload | | Cognition | Frequent bedside reassessment | Neurologic deterioration | | Cardiac rhythm | Continuous when severe electrolyte disturbance/cardiac disease | Arrhythmia and ischemia | ### When the course is not improving If glucose falls but osmolality, perfusion, or neurologic status does not improve, reassess: - circulating-volume replacement; - ongoing fluid losses; - sodium/free-water deficit; - kidney failure; - sepsis or other shock; - myocardial infarction or stroke; - mixed DKA/HHS; - insulin delivery; - medication-related hyperglycemia; - another cause of altered cognition. A plateau or rise in osmolality during apparently adequate treatment is a reason to reassess fluid delivery and calculations, not simply to increase insulin. ## Thrombosis prevention HHS is a prothrombotic state, but routine **therapeutic** anticoagulation is not indicated without another reason. Apply standard inpatient VTE risk assessment and prophylaxis unless contraindicated. JBDS specifically recommends prophylactic low-molecular-weight heparin during admission for HHS unless contraindicated.[2] Therapeutic anticoagulation is reserved for confirmed/suspected VTE, acute coronary syndrome, or another standard indication. ## Resolution and transition The 2024 consensus considers HHS resolved when all of the following are present:[1] - serum osmolality **<300 mOsm/kg**; - blood glucose **<250 mg/dL (13.9 mmol/L)**; - urine output **>0.5 mL/kg/h**; - cognition improved. Before transition out of acute monitored treatment, also ensure: - potassium and other electrolytes are stable; - the precipitating illness is controlled or has a defined treatment plan; - oral intake and hydration are adequate or supported; - a subcutaneous insulin/diabetes regimen is in place; - education and follow-up address the factor that precipitated the crisis. When IV insulin is being replaced by subcutaneous basal insulin, overlap the basal dose with the infusion for **1–2 hours** to prevent rebound hyperglycemia.[1] ## Special situations ### Older adults and frailty Older adults are at higher risk of HHS, [acute kidney injury](/library/acute-kidney-injury), thrombosis, delirium, and treatment-related fluid overload. Use smaller fluid aliquots, more frequent lung/perfusion reassessment, and a conservative transition plan that addresses access to water, medications, nutrition, and caregiver support. ### Heart failure The need for volume restoration remains, but rapid large-volume infusion can precipitate pulmonary edema. Use smaller boluses, frequent clinical reassessment, and bedside ultrasound or invasive monitoring when clinically necessary. Persistent shock despite cautious fluid replacement may require critical-care hemodynamic support. ### Advanced kidney disease Kidney failure reduces osmotic urinary losses but markedly complicates potassium and fluid management. Avoid formulaic replacement volumes. Hyperkalemia, pulmonary edema, or severe acid-base disturbance may require nephrology input and renal replacement therapy for standard indications. ### Pregnancy HHS in pregnancy is uncommon but high risk for parent and fetus. Manage jointly with critical care/endocrinology and obstetric medicine. Fluid, insulin, and electrolyte principles still apply, while fetal assessment and pregnancy-specific precipitants are addressed in parallel. ## Complications ### Treatment-related - hypoglycemia; - hypokalemia; - overly rapid decline in osmolality; - fluid overload; - hyperchloremic acidosis; - rare cerebral edema or osmotic neurologic injury. ### Disease-related - shock and acute kidney injury; - thrombosis; - rhabdomyolysis; - seizures; - myocardial ischemia; - aspiration; - infection-related organ failure. Worsening neurologic status during treatment is not an expected correction effect and requires immediate assessment for cerebral edema, stroke, seizure, excessive tonicity change, or another cause. ## Prevention after recovery Before discharge: - identify and treat the precipitant; - reconcile diabetes medications and insulin access; - provide a sick-day plan; - ensure glucose-monitoring supplies; - assess cognitive, functional, and social barriers to hydration and medication use; - arrange early diabetes follow-up; - address infection prevention and vaccination when relevant; - review medications that contributed to hyperglycemia; - document when to seek urgent care. Patients with newly diagnosed diabetes after HHS require a phenotype-directed plan once the acute crisis has resolved; the inpatient regimen should not be assumed to be the lifelong regimen. ## Acute management checklist - [ ] Confirm HHS criteria and assess for mixed DKA/HHS. - [ ] Stabilize airway, breathing, circulation, and shock. - [ ] Begin isotonic crystalloid with a rate appropriate to cardiac/kidney reserve. - [ ] Obtain glucose, electrolytes, creatinine, pH, β-hydroxybutyrate, and osmolality. - [ ] Identify and treat the precipitant. - [ ] Track glucose, sodium, osmolality, potassium, urine output, and cognition. - [ ] Keep osmolality fall near 3–8 mOsm/kg/h. - [ ] Replace potassium; withhold insulin if K <3.5 mmol/L. - [ ] Use insulin 0.05 units/kg/h for pure HHS; 0.1 units/kg/h for mixed DKA/HHS. - [ ] Add dextrose as glucose falls while ongoing insulin/correction is still required. - [ ] Provide VTE prophylaxis when indicated and not contraindicated. - [ ] Do not stop treatment on time or glucose alone; confirm resolution criteria. - [ ] Transition safely to subcutaneous therapy and address recurrence prevention. ## Related topics - [Diabetic Ketoacidosis](diabetic-ketoacidosis.md) - [Type 2 Diabetes Mellitus](type-2-diabetes-mellitus.md) - [Hyperkalemia](../nephrology/hyperkalemia.md) - [Hyponatremia](../nephrology/hyponatremia.md) - [Sepsis and Septic Shock](../critical-care/sepsis-and-septic-shock.md) ## References 1. Umpierrez GE, Davis GM, ElSayed NA, Fadini GP, Galindo RJ, Hirsch IB, et al. Hyperglycemic Crises in Adults With Diabetes: A Consensus Report. *Diabetes Care*. 2024;47(8):1257-1275. DOI: 10.2337/dci24-0032. PMID: 39052901. https://doi.org/10.2337/dci24-0032 2. Mustafa OG, Haq M, Dashora U, Castro E, Dhatariya KK; Joint British Diabetes Societies for Inpatient Care. Management of Hyperosmolar Hyperglycaemic State (HHS) in Adults: An updated guideline from the Joint British Diabetes Societies for Inpatient Care Group. *Diabetic Medicine*. 2023;40(3):e15005. DOI: 10.1111/dme.15005. https://doi.org/10.1111/dme.15005 3. Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. *Diabetes Care*. 2014;37(11):3124-3131. DOI: 10.2337/dc14-0984. PMID: 25342831. https://doi.org/10.2337/dc14-09847:["$","$L17",null,{"article":{"id":"medical-hyperosmolar-hyperglycemic-state","title":"Hyperosmolar Hyperglycemic State","slug":"hyperosmolar-hyperglycemic-state","description":"Hyperosmolar hyperglycemic state (HHS) is a life-threatening hyperglycemic emergency characterized by severe hyperglycemia, hyperosmolality, and profound water/electrolyte depletion without the degree of ketonemia and…","aliases":[],"category":"Endocrinology","tags":["Endocrinology","Emergency Medicine","Critical Care"],"updatedAt":"$undefined","body":"$18","headings":[{"id":"summary","text":"Summary","level":2},{"id":"diagnostic-criteria","text":"Diagnostic criteria","level":2},{"id":"osmolality-calculations","text":"Osmolality calculations","level":3},{"id":"hhs-dka-and-mixed-crisis","text":"HHS, DKA, and mixed crisis","level":3},{"id":"pathophysiology","text":"Pathophysiology","level":2},{"id":"precipitants-and-risk-factors","text":"Precipitants and risk factors","level":2},{"id":"clinical-features","text":"Clinical features","level":2},{"id":"initial-stabilization","text":"Initial stabilization","level":2},{"id":"immediate-actions","text":"Immediate actions","level":3},{"id":"initial-investigations","text":"Initial investigations","level":3},{"id":"fluid-therapy","text":"Fluid therapy","level":2},{"id":"initial-fluid","text":"Initial fluid","level":3},{"id":"correction-targets","text":"Correction targets","level":3},{"id":"insulin-therapy","text":"Insulin therapy","level":2},{"id":"pure-hhs","text":"Pure HHS","level":3},{"id":"mixed-dkahhs","text":"Mixed DKA/HHS","level":3},{"id":"dextrose-during-correction","text":"Dextrose during correction","level":3},{"id":"potassium-and-other-electrolytes","text":"Potassium and other electrolytes","level":2},{"id":"potassium","text":"Potassium","level":3},{"id":"phosphate","text":"Phosphate","level":3},{"id":"magnesium","text":"Magnesium","level":3},{"id":"monitoring","text":"Monitoring","level":2},{"id":"when-the-course-is-not-improving","text":"When the course is not improving","level":3},{"id":"thrombosis-prevention","text":"Thrombosis prevention","level":2},{"id":"resolution-and-transition","text":"Resolution and transition","level":2},{"id":"special-situations","text":"Special situations","level":2},{"id":"older-adults-and-frailty","text":"Older adults and frailty","level":3},{"id":"heart-failure","text":"Heart failure","level":3},{"id":"advanced-kidney-disease","text":"Advanced kidney disease","level":3},{"id":"pregnancy","text":"Pregnancy","level":3},{"id":"complications","text":"Complications","level":2},{"id":"treatment-related","text":"Treatment-related","level":3},{"id":"disease-related","text":"Disease-related","level":3},{"id":"prevention-after-recovery","text":"Prevention after recovery","level":2},{"id":"acute-management-checklist","text":"Acute management checklist","level":2},{"id":"related-topics","text":"Related topics","level":2},{"id":"references","text":"References","level":2}],"readingMinutes":13},"linkedMarkdown":"$19","backlinks":[],"related":[],"previewBySlug":{"abcde-approach":{"title":"ABCDE Approach","description":"The ABCDE approach is a structured method for the immediate assessment and treatment of a deteriorating or critically ill patient: Airway, Breathing, Circulation, Disability, Exposure. 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