Hyperosmolar hyperglycemic state in adults: Treatment

INTRODUCTION — 

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also known as hyperosmotic hyperglycemic nonketotic state [HHNK]) are two of the most serious acute complications of diabetes.

The treatment of HHS in adults will be reviewed here. The epidemiology, pathogenesis, clinical features, evaluation, and diagnosis of HHS and DKA are discussed separately. The treatment of DKA in adults and the clinical features, diagnosis, and treatment of DKA in children are also reviewed separately.

●(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis".)

●(See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis".)

●(See "Diabetic ketoacidosis in adults: Treatment".)

●(See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)

●(See "Diabetic ketoacidosis in children: Treatment and complications".)

DISTINGUISHING DKA FROM HHS — 

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) differ clinically according to the presence of ketoacidosis and, usually, the degree of hyperglycemia (table 1) [1-3]. However, approximately one-third of patients have a mixed presentation of DKA and HHS.

●In DKA, metabolic acidosis, ketonemia, and hyperglycemia are typically the major findings. The serum glucose concentration is generally below 800 mg/dL (44.4 mmol/L) and often in the 350 to 500 mg/dL (19.4 to 27.8 mmol/L) range [1-3]. However, serum glucose concentrations may exceed 900 mg/dL (50 mmol/L) in patients with DKA, usually in association with coma [2,4], or may be normal or minimally elevated (<200 mg/dL [11.1 mmol/L]) in patients with normoglycemic DKA. Normoglycemic DKA occurs more often in patients with poor oral intake, those treated with insulin prior to arrival in the emergency department, pregnant women, those who use sodium-glucose cotransporter 2 [SGLT2] inhibitors, and insulin pump-treated patients in whom insulin delivery is interrupted due to catheter or pump failure.

●In HHS, ketoacid accumulation is mild or absent, the serum glucose concentration frequently exceeds 1000 mg/dL (56 mmol/L), the plasma osmolality (Posm) may reach 380 mOsmol/kg, and neurologic abnormalities are frequently present (including coma in 25 to 50 percent of cases) [1,3,5].

The typical total body deficits of water and electrolytes in DKA and HHS are compared in the table (table 2). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Serum glucose' and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Diagnostic criteria'.)

TREATMENT

Overview and protocols — The treatment of hyperglycemic hyperosmolar state (HHS) (algorithm 1) includes correcting the fluid and electrolyte abnormalities that are typically present (hyperosmolality, hypovolemia, and potassium depletion) and administering insulin [3].

●Assess vital signs, cardiorespiratory status, and mental status – Initial evaluation should include assessment of the patient's cardiovascular, respiratory, and mental status. For patients who present with stupor or coma, a Glasgow Coma Scale score should be determined (table 3). In patients with a score ≤8, endotracheal intubation is usually required for airway protection. (See "Stupor and coma in adults", section on 'Management'.)

●Treat the volume depletion and electrolyte abnormalities – The first step in treating HHS is infusion of isotonic fluid (saline or buffered crystalloid) to expand extracellular volume and stabilize cardiovascular status. Volume expansion also increases insulin responsiveness by lowering the plasma osmolality (Posm), reducing vasoconstriction and improving perfusion, and reducing stress hormone levels [6,7]. Careful monitoring of Posm is required, and the target rate of decline should be 3 to 8 mOsm/L per hour.

The next step is correcting the potassium deficit if present. Potassium repletion may inform the choice of fluid replacement; the osmotic effect of potassium repletion must be considered since potassium is as osmotically active as sodium. (See 'Fluid replacement' below and 'Potassium replacement' below.)

●Administer insulin – Low-dose intravenous (IV) insulin should be administered to all patients with HHS with a serum potassium ≥3.5 mEq/L. If the serum potassium is <3.5 mEq/L, insulin therapy should be delayed until potassium replacement has increased the serum potassium concentration to >3.5 mEq/L. This delay in insulin initiation is necessary because insulin will drive potassium into cells and worsen hypokalemia, which can trigger cardiac arrhythmias. IV regular insulin and rapid-acting insulin analogs are equally effective in treating HHS. (See 'Insulin' below.)

Managing HHS requires frequent clinical and laboratory monitoring and the identification and treatment of any precipitating events, including infection. (See 'Monitoring' below and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Precipitating factors'.)

Our approach outlined below is based upon clinical experience and is largely in agreement with consensus guidelines from the American Diabetes Association (ADA), Joint British Diabetes Societies for Inpatient Care (JBDS), American Association of Clinical Endocrinology (AACE), and Diabetes Technology Society (DTS) for the management of hyperglycemic crises (algorithm 1) [3].

Fluid replacement — In patients with HHS, we recommend IV electrolyte and fluid replacement to correct both hypovolemia and hyperosmolality.

Goals for fluid management — Posm should not be reduced too rapidly, because this may cause cerebral edema. (See 'Cerebral edema' below.)

In patients with HHS, fluid and insulin therapy should be titrated to achieve the following goals:

●Decline in serum glucose level ≤90 to 120 mg/dL (5 to 6.7 mmol/L) per hour

●Decline in serum sodium ≤10 mmol/L in 24 hours

●Decline in Posm ≤3 to 8 mOsm/kg per hour

Choice of IV fluid — Isotonic saline (0.9 percent sodium chloride [NaCl]) or isotonic buffered crystalloid (eg, Lactated Ringer) should be used for volume repletion. Buffered crystalloid does not cause the hyperchloremic, non-anion gap metabolic acidosis that may result from isotone saline administration. No trials have directly compared saline with buffered crystalloid administration specifically in patients with HHS. (See 'Hyperchloremic acidosis' below.)

Initial rate of administration — The optimal rate of initial isotonic fluid infusion depends on the clinical state of the patient:

●In patients with hypovolemic shock, isotonic fluid should initially be infused as quickly as possible. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)

●In hypovolemic patients without shock or heart or kidney failure, isotonic fluid is infused at a rate of approximately 500 to 1000 mL/hour for the first few hours (algorithm 1) [8].

The goal is to correct estimated deficits within the first 24 to 48 hours. Osmolality should not be reduced too rapidly, because this may precipitate cerebral edema. Adequacy of fluid replacement is judged by frequent hemodynamic and laboratory monitoring. (See 'Monitoring' below and 'Cerebral edema' below.)

Subsequent fluid management

●Switching to hypotonic fluid – After the second or third hour of fluid administration, optimal fluid replacement depends upon the volume and hydration status, serum electrolyte levels, and urine output. The most appropriate IV fluid composition is determined by the sodium concentration "corrected" for the degree of hyperglycemia. The "corrected" sodium concentration can be approximated by adding 2 mEq/L to the plasma sodium concentration for each 100 mg/dL (5.5 mmol/L) increase above 100 mg/dL (5.5 mmol/L) (calculator 1).

If the "corrected" serum sodium concentration is [8]:

•<135 mEq/L, isotonic fluid infusion should be continued at a rate of approximately 250 to 500 mL/hour

•≥135 mEq/L, isotonic fluid infusion is generally switched to one-half isotonic saline at a rate of 250 to 500 mL/hour to provide electrolyte-free water

●Adding dextrose to IV fluids – When the serum glucose falls to <250 mg/dL (13.9 mmol/L), dextrose (5 or 10 percent) should be added to the IV fluids.

Special considerations

High-dose potassium replacement — The timing of one-half isotonic saline therapy may also be influenced by the need for potassium replacement. Potassium salts have an osmotic effect equivalent to sodium salts, and adding potassium to isotonic fluids generates a hypertonic solution. Major potassium replacement at rates >20 to 30 mEq/hour is rarely required. If such rates are needed, the potassium chloride (KCl) should be added to one-half isotonic (0.45 percent NaCl) rather than isotonic (0.9 percent NaCl) saline. (See 'Potassium replacement' below.)

Reduced kidney or cardiac function — In patients with reduced kidney or cardiac function, more frequent monitoring must be performed to avoid iatrogenic fluid overload [3,7,9]. Rather than continuous isotonic fluid infusion, such patients may be managed with repeated, small-volume fluid boluses (eg, 250 mL) [3].

Potassium replacement — Potassium replacement is initiated immediately if the serum potassium is ≤5.0 mEq/L, provided urine output is adequate (eg, approximately ≥50 mL/hour or 0.5 mL/kg/hour) (algorithm 1). Almost all patients with HHS have a substantial potassium deficit, usually due to urinary losses generated by the glucose-driven osmotic diuresis and secondary hyperaldosteronism. Despite the total body potassium deficit, the serum potassium concentration is usually normal or, in approximately one-third of cases, elevated at presentation. This is largely due to insulin deficiency and hyperosmolality, each of which causes potassium movement out of the cells [10].

Initial potassium repletion

●Serum potassium <3.5 mEq/L – If the initial serum potassium is <3.5 mEq/L, insulin should not be administered until the potassium has been raised above this threshold. IV KCl (10 to 20 mEq/hour, which usually requires 10 to 20 mEq added to each liter of IV fluid) should be given. Patients with marked hypokalemia may require more aggressive potassium replacement (eg, 30 mEq/hour) to raise the serum potassium concentration above 3.5 mEq/L [11-13]. If needed, potassium infusion rates >20 to 30 mEq/hour are highly irritating to peripheral veins and generally must be infused into a large central vein or via multiple peripheral veins. Such high infusion rates also usually require cardiac rhythm monitoring.

●Serum potassium 3.5 to 5.0 mEq/L – If the initial serum potassium is 3.5 to 5.0 mEq/L, IV KCl (10 to 20 mEq) is added to each liter of IV fluid. Adjust potassium replacement to maintain the serum potassium concentration in the range of 4 to 5 mEq/L.

●Serum potassium >5.0 mEq/L – If the initial serum potassium concentration is >5.0 mEq/L, potassium replacement should be delayed until the serum concentration has fallen below this level. Serum potassium should be monitored every two hours.

The altered potassium distribution is rapidly reversed with the administration of insulin and can result in an often dramatic fall in the serum potassium concentration, despite potassium replacement [11,12]. However, potassium replacement must be done cautiously, particularly if kidney function remains impaired and/or urine output remains <50 mL/hour. Careful monitoring of the serum potassium is essential. (See 'Monitoring' below and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis", section on 'Potassium'.)

Osmotic effect of potassium salts — Potassium salts added to IV fluids have the same osmotic effect as sodium salts, and this should be considered when determining the potential impact of IV fluid infusion on osmolality. As an example, 40 mEq of KCl added to 1 L of fluid generates 80 mOsmol/L of electrolyte osmolarity. The addition of 40 mEq of potassium to 1 L of one-half isotonic saline creates a solution with an osmolarity of 234 mOsmol/L (77 mEq NaCl and 40 mEq KCl), which is osmotically equal to three-quarters isotonic saline. (The osmolarity of isotonic saline is 308 mOsmol/L.) If 40 mEq of KCl is added to isotonic saline, the final osmolarity will be approximately 388 mOsmol/L. However, KCl will not have the same extracellular fluid (ECF) expansion effect as NaCl, because most of the potassium will shift into cells very rapidly. (See "Maintenance and replacement fluid therapy in adults", section on 'Choice of replacement fluid'.)

Insulin

Timing of insulin initiation

●Immediate initiation (preferred approach) – We recommend immediately initiating treatment with low-dose IV insulin in all patients with HHS who have a serum potassium ≥3.5 mEq/L. The only indication for delaying the initiation of insulin therapy is a serum potassium <3.5 mEq/L since insulin will worsen hypokalemia by driving potassium into cells. Patients with an initial serum potassium <3.5 mEq/L should receive fluid and potassium replacement prior to treatment with insulin. Insulin therapy should be delayed until the serum potassium is >3.5 mEq/L to avoid complications such as cardiac arrhythmias, cardiac arrest, and respiratory muscle weakness [3]. (See 'Fluid replacement' above and 'Potassium replacement' above.)

●Delayed initiation (alternative approach) – Some experts administer isotonic fluid alone initially and begin insulin treatment only after serum glucose stabilizes. Volume repletion alone can initially reduce the serum glucose by 35 to 70 mg/dL (1.9 to 3.9 mmol/L) per hour due to the combination of ECF expansion, reduction of Posm, increased urinary losses due to improved kidney perfusion, and a reduction in stress hormones, which oppose the effects of insulin [7,14]. The serum glucose levels often fall more rapidly in patients with HHS than in those with diabetic ketoacidosis (DKA) due to greater baseline volume depletion. (See 'Fluid replacement' above.)

Choice of IV insulin — The choice of IV insulin is based on institutional preferences, clinician experience, and cost concerns. We generally prefer regular insulin, rather than rapid-acting insulin analogs, due to its much lower cost. Rapid-acting or ultra rapid-acting insulin analogs do not provide any advantages over regular insulin. (See "General principles of insulin therapy in diabetes mellitus", section on 'Human insulins'.)

For acute management of HHS, long- or intermediate-acting insulin has no role. Subcutaneous insulin administration increases risk of excessively rapid fall in serum glucose.

Dosing — In HHS, optimal insulin dosing has not been well established. Initial dosing depends on whether the presentation is predominantly HHS or mixed HHS/DKA.

●HHS predominant – HHS is predominant if both of the following are true:

•Acidosis is absent (pH ≥7.3 and bicarbonate ≥18 mmol/L)

and

•Ketonemia is mild or absent (blood or serum beta-hydroxybutyrate <3 mmol/L or urine ketones <2+)

If HHS predominates, continuous infusion of regular insulin can be initiated at a rate of 0.05 units/kg body weight per hour (algorithm 1) [3,15-17].

●Mixed HHS/DKA – If acidosis or greater ketonemia is present, continuous infusion of regular insulin can be initiated at a rate of 0.1 units/kg body weight per hour [3]. (See "Diabetic ketoacidosis in adults: Treatment", section on 'Moderate to severe DKA'.)

Expected glucose response — This dose of IV regular insulin usually decreases the serum glucose concentration by approximately 50 to 70 mg/dL (2.8 to 3.9 mmol/L) per hour [16,18-20], in addition to the dilutional effects of volume repletion. Higher doses do not generally produce a more prominent glucose-lowering effect, probably because the insulin receptors are fully saturated by the lower doses [15]. However, if serum glucose does not fall by at least 50 to 70 mg/dL (2.8 to 3.9 mmol/L) from the initial value in the first hour, check the IV access to assess whether insulin is being delivered or if any IV line filters that may bind insulin have been inserted. After these possibilities are excluded, the insulin infusion rate should be doubled every hour until a steady decline in serum glucose of this magnitude is achieved.

The decline in serum glucose should not exceed 90 to 120 mg/dL (5 to 6.7 mmol/L) per hour.

Dose titration and IV dextrose — When the serum glucose is <250 mg/dL (13.9 mmol/L), do both of the following:

●Add dextrose (5 or 10 percent) to the IV fluids.

●Attempt to decrease the insulin infusion rate to 0.02 to 0.04 units/kg per hour (or to 0.05 units/kg per hour if a mixed HHS/DKA presentation) [3,7]. If possible, maintain serum glucose between 250 to 300 mg/dL (13.9 to 16.7 mmol/L) to reduce the risk of cerebral edema. (See 'Cerebral edema' below.)

The serum glucose should be maintained in this range until hyperosmolality improves and the patient is clinically stable. (See 'Resolution criteria' below.)

Method of glucose measurement — Serum glucose measurements should be done with hospital-approved bedside devices or in the chemistry laboratory and not with continuous glucose monitoring (CGM) devices. CGM devices measure interstitial rather than circulating glucose concentrations. As a result, if glucose is rapidly changing, changes in CGM-derived values may have a 10- to 15-minute delay relative to venous glucose levels. Further, CGM may be less accurate in the setting of severe hyper- or hypoglycemia, volume depletion, large volume shifts, and/or acidosis. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'CGM systems'.)

Bicarbonate repletion (rarely needed) — Metabolic acidosis is not a typical feature of HHS. However, it may be present in individuals with a mixed presentation of DKA and HHS. The management of metabolic acidosis in individuals with DKA is discussed separately. (See "Diabetic ketoacidosis in adults: Treatment", section on 'Bicarbonate and metabolic acidosis'.)

Phosphate repletion (rarely indicated) — We do not recommend the routine use of phosphate replacement in the treatment of HHS. However, phosphate replacement should be given if severe hypophosphatemia occurs (serum phosphate concentration <1 mg/dL [0.32 mmol/L]), especially if cardiac dysfunction, hemolytic anemia, and/or respiratory depression are present [21-25]. When needed, potassium or sodium phosphate 20 to 30 mEq can be added to 1 L of IV fluid.

Although whole-body phosphate depletion is common in uncontrolled diabetes mellitus, the serum phosphate concentration may initially be normal or elevated due to movement of phosphate out of the cells [22,26]. Like potassium, phosphate depletion and hypophosphatemia may be rapidly unmasked following the institution of insulin therapy and IV volume expansion. This frequently leads to asymptomatic hypophosphatemia, which gradually resolves. Phosphate replacement may have adverse effects, such as hypocalcemia and hypomagnesemia [27-30]. (See "Hypophosphatemia: Clinical manifestations of phosphate depletion".)

MONITORING

Monitoring schedule — A flow sheet of laboratory values and clinical parameters allows better visualization and evaluation of the clinical picture throughout treatment of hyperosmolar hyperglycemic state (HHS) (form 1).

●Hyperglycemia and electrolytes – The serum glucose should initially be measured every hour until stable, while serum electrolytes, blood urea nitrogen (BUN), phosphorus, and creatinine should be measured every two to four hours, depending upon disease severity and the clinical response [8,31]. Serum glucose measurement should be done with hospital-approved bedside devices or in the chemistry laboratory and not with continuous glucose monitoring (CGM) devices. (See 'Method of glucose measurement' above.)

For patients who present with mixed HHS/DKA, the approach to monitoring ketonemia and acidosis is reviewed in detail separately. (See "Diabetic ketoacidosis in adults: Treatment", section on 'Monitoring'.)

●Plasma osmolality (Posm) – Posm (reference range 275 to 295 mOsm/kg) should be calculated every two to four hours. The effective Posm can be estimated from the sodium and glucose concentrations using the following equations, depending on the units for serum glucose:

Effective Posm =  [2  x  Na (mEq/L)]  +  [glucose (mg/dL)  ÷  18]

Effective Posm =  [2  x  Na (mmol/L)]  +  glucose (mmol/L)

The Na in these equations is the actual measured plasma sodium concentration and not the "corrected" sodium concentration.

Resolution criteria — HHS may be considered resolved when all of the following criteria are met:

●Calculated effective Posm is <300 mOsmol/kg

●Serum glucose is <250 mg/dL (13.9 mmol/L)

●Urine output is >0.5 mL/kg per hour

●Cognitive status has returned to baseline

CONVERTING TO SUBCUTANEOUS INSULIN

Designing an insulin regimen — Irrespective of their preadmission glucose-lowering regimen, most patients require intensive insulin therapy at least transiently after an episode of hyperosmolar hyperglycemic state (HHS). We initiate a multiple-dose (basal-bolus), subcutaneous insulin schedule when the HHS has resolved and the patient is able to eat. (See 'Resolution criteria' above.)

In patients with type 2 diabetes, non-insulin therapies may be added to insulin treatment during hospital admission or upon discharge. Detailed discussions with the patient and/or caregivers (including nursing home care providers) are essential for designing practical treatment regimens that can be implemented in the outpatient setting.

●Insulin treatment prior to admission – For patients who were taking insulin prior to admission, their outpatient insulin regimen may be restarted if glycemia prior to the HHS episode was near or at target and the regimen was acceptable and manageable for the patient. For patients treated with continuous subcutaneous insulin infusion (insulin pump), the previous basal rate can be resumed. However, if the intravenous (IV) insulin requirements are significantly higher than their usual insulin requirements, it is reasonable to increase the basal rate temporarily.

●No insulin treatment prior to admission – For patients not taking insulin prior to admission, an initial total daily dose (TDD) of 0.5 to 0.8 units/kg of insulin per day is reasonable, until an optimal dose is established.

•Basal insulin – Approximately 40 to 60 percent of the TDD should be given as basal insulin, either as once- or twice-daily U-100 glargine or detemir (to be discontinued in the United States in 2024), or as twice-daily intermediate-acting insulin (neutral protamine Hagedorn [NPH]). The long-acting insulin can be given either at bedtime or in the morning; the NPH is usually given as approximately two-thirds of the dose in the morning and one-third at bedtime. In this setting, we do not use degludec or ultra long-acting U-300 insulin glargine, as these require at least three to four days to reach steady state due to their long half-life [32].

•Prandial insulin – The remainder of the TDD is given as short-acting or rapid-acting insulin, divided before meals. If NPH is the basal insulin used, a mid-day (pre-lunch) rapid-acting insulin may not be necessary. Frequent glucose monitoring or preferably continuous glucose monitoring (CGM) and comprehensive diabetes education are vital after initiating a new insulin regimen in treatment-naïve patients. (See "General principles of insulin therapy in diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus".)

Some patients who were not treated with insulin prior to admission can gradually (eg, over several weeks to months) resume their previous glucose-lowering regimen, depending on the inciting factors that led to the HHS episode.

Timing of initial dose — The IV insulin infusion should be continued for one to two hours after initiating subcutaneous rapid-acting insulin. The first dose of basal insulin also should be administered before IV insulin is discontinued. If short- or long-acting insulin is initiated without rapid-acting insulin, the IV insulin infusion should be continued for two to four hours after subcutaneous insulin administration. Abrupt discontinuation of IV insulin acutely reduces insulin levels and may result in recurrence of hyperglycemia and/or ketoacidosis.

Basal insulin (eg, NPH, U-100 glargine) can be administered either at the same time as the first injection of rapid-acting insulin (eg, in the morning before breakfast) or at bedtime the previous night.

COMPLICATIONS — 

Hypoglycemia and hypokalemia are the most common complications of treating hyperosmolar hyperglycemic state (HHS). These complications have become much less common since low-dose intravenous (IV) insulin treatment and careful monitoring of serum potassium have been implemented [33]. Hyperglycemia may recur from interruption or discontinuation of IV insulin without adequate overlap coverage with subcutaneous insulin.

Cerebral edema — Cerebral edema in uncontrolled diabetes mellitus is primarily a disease of children, and almost all affected patients are younger than 20 years old [34]. Symptoms typically emerge within 12 to 24 hours of treatment initiation but may exist prior to treatment.

●Clinical features – Headache is the earliest clinical manifestation, followed by lethargy and decreased arousal. Neurologic deterioration may be rapid. Seizures, incontinence, pupillary changes, bradycardia, and respiratory arrest can develop. Symptoms progress if brainstem herniation occurs, and the rate of progression may be so rapid that clinically recognizable papilledema does not develop. Thus, careful monitoring for changes in mental or neurologic status is essential to permit early detection and intervention.

●Preventive measures – The following preventive measures may reduce the risk of cerebral edema in high-risk patients [3]:

•Gradual replacement of sodium and fluid deficits (algorithm 1).

•Adding dextrose to IV fluids once the serum glucose level has fallen to <250 mg/dL (13.9 mmol/L).

●Management – Data evaluating the outcome and treatment of cerebral edema in adults are not available. Recommendations for treatment are based on clinical judgment and indirect evidence. Case reports and small series in children suggest benefit from prompt administration of mannitol (0.25 to 1 g/kg) and perhaps from hypertonic (3 percent) saline (5 to 10 mL/kg over 30 min) [34]. These interventions raise the plasma osmolality (Posm) and generate an osmotic movement of water out of brain cells and a reduction in cerebral edema.

Hyperchloremic acidosis — In the absence of severe kidney disease, most patients treated with isotonic saline develop a hyperchloremic, normal anion gap acidosis ("non-gap" or "hyperchloremic acidosis") during the resolution phase of ketoacidosis. This occurs for two reasons. First, IV volume expansion reverses volume contraction and improves kidney function, which accelerates the loss of ketoacid anions with sodium and potassium [35,36]. The loss of these ketoacid anion salts into the urine represents "potential" bicarbonate loss from the body. Second, isotonic saline has a chloride concentration of 154 mEq/L and does not contain any bicarbonate precursors. Therefore, volume expansion with isotonic saline generates an element of hyperchloremic metabolic acidosis. The hyperchloremic acidosis slowly resolves as the kidneys excrete ammonium chloride and regenerate bicarbonate. The risk of hyperchloremic acidosis is lower with buffered crystalloid than with isotonic saline because its chloride concentration is lower, and it contains "potential bicarbonate" (eg, acetate, lactate). There are generally no clinical sequelae of hyperchloremic acidosis in this setting.

Noncardiogenic pulmonary edema — Hypoxemia and rarely noncardiogenic pulmonary edema can complicate the treatment of diabetic ketoacidosis (DKA) or mixed DKA/HHS [37-40]. Hypoxemia is attributed to a reduction in colloid osmotic pressure that results in increased lung water content and decreased lung compliance [7]. Patients with DKA who are found to have a wide alveolar-arterial oxygen gradient and/or rales may be at higher risk for the development of pulmonary edema.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperglycemic emergencies".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Diabetic ketoacidosis (The Basics)" and "Patient education: Hyperosmolar hyperglycemic state (The Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles – The treatment of hyperosmolar hyperglycemic state (HHS) involves correction of the fluid and electrolyte abnormalities that are typically present, including hyperosmolality, hypovolemia, and potassium depletion, and the administration of insulin (table 1 and algorithm 1). Frequent monitoring is essential, and underlying precipitating events should be identified and corrected. (See 'Overview and protocols' above.)

●Fluid replacement – Individuals with HHS require intravenous (IV) fluid replacement to correct both hypovolemia and hyperosmolality. Isotonic saline and isotonic buffered crystalloid (eg, Lactated Ringer) are both reasonable options. The optimal rate is guided by clinical assessment. (See 'Fluid replacement' above.)

Fluid replacement should correct estimated volume deficits within the first 24 to 48 hours, with care to avoid an overly rapid reduction in the serum osmolality. (See 'Goals for fluid management' above.)

•Hypovolemia with shock – Isotonic fluid (saline or buffered crystalloid) should be infused as quickly as possible in patients with hypovolemic shock. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Nonhemorrhagic shock'.)

•Hypovolemia without shock – In hypovolemic patients without shock or heart failure, we suggest isotonic fluid (0.9 percent saline or buffered crystalloid) infused at a rate of 15 to 20 mL/kg per hour (approximately 1000 mL/hour in an average-sized person) for the first few hours (Grade 2C).

•Mild hypovolemia or euvolemia – Isotonic fluid is infused at a lower rate than in hypovolemic patients without shock, guided by clinical assessment.

●Subsequent fluid management – After the fluid deficit is corrected, one-half isotonic (0.45 percent) saline is administered at a rate of approximately 250 to 500 mL/hour if the serum sodium (corrected for hyperglycemia) is normal or elevated; isotonic saline is continued at a rate of approximately 250 to 500 mL/hour if the serum sodium (corrected for hyperglycemia) is low. (See 'Subsequent fluid management' above.)

●Potassium replacement – Most patients with HHS require IV potassium replacement. The dose depends on the initial serum potassium level (algorithm 1). In patients with high potassium (>5.0 mEq/L) and/or low urine output (eg, <50 mL/hour or 0.5 mL/kg/hour), potassium replacement should be delayed until potassium is ≤5.0 mEq/L and urine output ≥50 mL/hour.

Most patients with HHS have a substantial potassium deficit (due to urinary losses and secondary hyperaldosteronism) that may not be reflected in serum levels. (See 'Potassium replacement' above.)

●Insulin – In patients with initial serum potassium <3.5 mEq/L, insulin therapy should be delayed until the serum potassium is >3.5 mEq/L to avoid complications of hypokalemia. Aggressive potassium replacement is needed to avoid further delay in insulin therapy. (See 'Insulin' above.)

•Choice of IV insulin – We suggest IV regular insulin rather than rapid-acting insulin analogs (eg, insulin lispro, aspart, and glulisine) (Grade 2C), due to similar efficacy and much lower cost. (See 'Timing of insulin initiation' above and 'Choice of IV insulin' above.)

•Initial dosing and titration – If HHS predominates, continuous infusion of regular insulin can be initiated at a rate of 0.05 units/kg body weight per hour (algorithm 1). If acidosis or significant ketonemia is present (ie, mixed HHS/diabetic ketoacidosis [DKA]), continuous infusion of regular insulin can be initiated at a rate of 0.1 units/kg body weight per hour. Subsequent insulin dosing is titrated based on hourly glucose measurement. We add dextrose to the IV fluids when the serum glucose is <250 mg/dL (13.9 mmol/L). (See 'Dosing' above and "Diabetic ketoacidosis in adults: Treatment", section on 'Moderate to severe DKA'.)

●Indications for phosphate – For most patients, we suggest not administering phosphate (Grade 2B). Whole-body phosphate depletion is usually present, but routine phosphate administration does not appear to have clear benefit and can be associated with hypocalcemia and hypomagnesemia.

However, patients with severe hypophosphatemia (<1 mg/dL [0.32 mmol/L]) should receive phosphate. (See 'Phosphate repletion (rarely indicated)' above.)

●Monitoring – Serum glucose should initially be measured every hour until stable, while serum electrolytes, blood urea nitrogen (BUN), phosphorus, and creatinine should be measured every two to four hours, depending upon disease severity and the clinical response. Plasma osmolality (Posm) should be calculated based on sodium and glucose concentrations every two to four hours. (See 'Monitoring schedule' above.)

For patients who present with mixed HHS/DKA, the approach to monitoring ketonemia and acidosis is reviewed in detail separately. (See "Diabetic ketoacidosis in adults: Treatment", section on 'Monitoring'.)

●Converting to subcutaneous insulin – We initiate a multiple-dose (basal-bolus), subcutaneous insulin schedule when the HHS has resolved, serum glucose is <250 to 300 mg/dL (13.9 to 16.7 mmol/L), and the patient is able to eat. The IV insulin infusion should be continued for one to two hours after initiating subcutaneous rapid-acting insulin. The first dose of basal insulin also should be administered before IV insulin is discontinued. If short- or long-acting insulin is initiated without rapid-acting insulin, the IV insulin infusion should be continued for two to four hours after subcutaneous insulin administration. Abrupt discontinuation of IV insulin acutely reduces insulin levels and may result in recurrence of hyperglycemia and/or ketoacidosis.

When converting to subcutaneous insulin, we do not use ultra long-acting insulins (eg, degludec, U-300 glargine) as the basal insulin; these have a long half-life and require two to three days to reach steady state. (See 'Converting to subcutaneous insulin' above.)

●Potential complications – Cerebral edema is very rare in adults but is associated with high rates of morbidity and mortality. Possible preventive measures in high-risk patients include gradual rather than rapid correction of fluid and sodium deficits (maximum reduction in Posm of ≤3 to 8 mOsmol/kg per hour), and maintenance of a slightly elevated serum glucose until the patient is stable. (See 'Cerebral edema' above.)