Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State: Pharmacotherapy and Acute Management

Distinguish DKA, HHS, and mixed presentations

Apply the complete adult HHS diagnostic criteria

The 2024 international consensus and 2026 ADA inpatient standards require all four components for HHS: plasma glucose at least 600 mg/dL; effective calculated osmolality above 300 mOsm/kg or total osmolality above 320 mOsm/kg; absence of significant ketonemia (beta-hydroxybutyrate below 3.0 mmol/L or urine ketones below 2+); and absence of acidosis (pH at least 7.3 and bicarbonate at least 15 mmol/L). Evaluate mixed DKA/HHS when ketosis or acidosis accompanies hyperosmolality. These criteria are diagnostic boundaries, not a substitute for evaluating acuity or selecting an institution-approved treatment protocol (Umpierrez et al., 2024; American Diabetes Association Professional Practice Committee for Diabetes, 2026).

The 2024 international consensus defines DKA by three elements: diabetes or hyperglycemia (glucose at least 200 mg/dL or a prior diabetes diagnosis), significant ketosis (blood beta-hydroxybutyrate at least 3.0 mmol/L or urine ketones at least 2+ when blood ketones unavailable), and metabolic acidosis (pH below 7.3 or bicarbonate below 18 mmol/L). Thus DKA can occur without marked hyperglycemia, particularly with SGLT2 inhibitor exposure. HHS predominantly involves severe hyperglycemia, hyperosmolality and dehydration without substantial ketosis or acidosis; mixed presentations occur. Assess glucose, ketones, pH/bicarbonate, osmolality, volume status and mental status together rather than applying a single glucose cutoff (Umpierrez et al., 2024).

SGLT2 inhibitor exposure and prolonged carbohydrate restriction can cause ketoacidosis with less pronounced hyperglycemia. Consequently, nausea, abdominal pain, tachypnea, or otherwise unexplained metabolic acidosis warrants ketone assessment even without marked hyperglycemia. The glucose threshold in older diagnostic frameworks must not be applied as the sole rule for excluding ketoacidosis; confirm the current institutional diagnostic approach (Sease & Blake, 2026).

Feature	DKA predominant	HHS predominant
Core problem	Insulin deficit with ketogenesis and metabolic acidosis	Extreme water deficit and hyperosmolality
Key measurements	Beta-hydroxybutyrate, pH, bicarbonate, electrolytes, glucose	Osmolality, corrected sodium, glucose, hydration, neurologic status
Priority nuance	Potassium safety before insulin; continue insulin until ketonemia resolves	Careful rehydration and controlled change in osmolality; assess mixed DKA
Important exception	Glucose need not be markedly elevated in SGLT2-associated ketoacidosis	Ketones/acidosis may coexist in mixed presentations

Initial resuscitation and diagnostic assessment

Obtain bedside glucose, vital signs, mental status, cardiac monitoring when indicated, venous or arterial acid-base assessment, electrolytes, bicarbonate, kidney function, serum beta-hydroxybutyrate, and a calculated anion gap. Consider serum osmolality, corrected sodium, magnesium, phosphate, ECG, urinalysis, and testing for infection or ischemia based on symptoms. Measure intake and output to follow renal perfusion and the response to treatment. A delayed or abbreviated laboratory evaluation can miss dangerous potassium shifts or progressive hyperosmolarity.

Give isotonic crystalloid in a volume and rate appropriate to hemodynamics, comorbid heart or kidney disease, sodium, and the degree of dehydration. Rapid early isotonic fluid replacement may be appropriate in otherwise appropriate adults; frail patients, HF, and reduced renal reserve need individualized rates and close reassessment. Isotonic saline and balanced crystalloids are potential institutional choices; the referenced treatment approach describes saline-based pathways. Reassess blood pressure, perfusion, urine output, corrected sodium, and pulmonary findings rather than using a fixed rate for every patient (Sease & Blake, 2026).

Insulin and potassium: the sequencing decision

Electrolytes and volume status determine whether insulin can start safely

For adult DKA/HHS, insulin shifts potassium intracellularly even when total-body potassium is depleted. The 2024 consensus recommends delaying insulin when serum potassium is below 3.5 mmol/L, replacing potassium first, and beginning insulin after potassium exceeds 3.5 mmol/L. Recheck potassium about two hours after insulin starts and every four hours thereafter until DKA resolves; target potassium is approximately 4–5 mmol/L during treatment. ECG, renal impairment, urinary output and institutional replacement procedures govern individual execution. Do not use the older 3.3 mmol/L insulin-hold threshold as a current general rule (Umpierrez et al., 2024).

Routine bicarbonate is not recommended in DKA; the 2024 consensus reserves consideration for profound acidemia (pH below 7.0), with individualized critical-care and electrolyte management. During HHS, avoid overly rapid correction of serum osmolality (the consensus describes a decline of about 3–8 mOsm/kg/hour) and assess heart failure or advanced kidney disease before large crystalloid boluses. These are adult consensus recommendations, not standing medication orders (Umpierrez et al., 2024).

After initial assessment and volume resuscitation, continuous IV regular insulin may be used according to the local DKA/HHS protocol. An educational adult DKA infusion example uses approximately 0.1 unit/kg/hour; this is illustrative and does not supersede the active protocol. Do not initiate insulin before addressing clinically significant hypokalemia: insulin moves potassium intracellularly and can precipitate dangerous dysrhythmias when potassium is already depleted. Reassess potassium, renal function, volume replacement, beta-hydroxybutyrate or other relevant metabolic indices, and glucose during treatment. A source-described starting rate is not a universal order for mixed DKA/HHS, severe renal impairment, or a patient with a changing potassium concentration (Sease & Blake, 2026).

Example: a 70-kg adult given a protocol rate of 0.1 unit/kg/hour would receive 7 units/hour initially (70 × 0.1 = 7). That arithmetic must be paired with a current potassium result, planned monitoring, and a rate-adjustment algorithm. It is not appropriate to initiate an infusion solely from the calculation.

When glucose improves before ketosis resolves

Glucose often falls before acidosis and ketonemia fully resolve. Adding dextrose-containing IV fluid as glucose approaches the protocol threshold allows continuation of insulin to suppress ketogenesis without causing hypoglycemia. Stopping insulin just because plasma glucose reaches a desired number risks rebound ketosis. Follow beta-hydroxybutyrate, bicarbonate/pH, and the anion gap when appropriate to the local resolution criteria, in addition to glucose (Sease & Blake, 2026).

Dextrose and insulin are not opposing treatments in this situation: dextrose prevents treatment-induced hypoglycemia while insulin addresses the metabolic mechanism. Phosphate and bicarbonate are not routinely required for every DKA presentation; bicarbonate consideration is restricted to selected patients with profound acidemia and emphasizes monitoring and selective electrolyte replacement.

HHS: avoid rapid osmotic shifts

HHS often involves a larger water deficit and greater hyperosmolality than uncomplicated DKA. Initial management prioritizes fluids, electrolytes, mentation, kidney function, and identification of the precipitant; insulin timing and dose must reflect osmolality and potassium as well as glucose. The degree and pace of osmolality correction matters because overly rapid shifts can cause neurologic harm. Mixed DKA/HHS presentations require treating ketosis and acidosis while simultaneously limiting unsafe fluid and osmotic changes. Assess effective osmolality and neurologic status repeatedly and use a protocol that avoids overly rapid changes. Mixed DKA/HHS presentations cannot be treated as purely hyperglycemic dehydration if clinically significant ketonemia and acidosis are also present (Sease & Blake, 2026).

Older age, heart failure, kidney impairment, infection, and impaired access to water create special risk. An older patient with marked hyperglycemia and confusion may have a concomitant stroke, infection, or medication-related delirium; do not assume all neurologic symptoms are solely metabolic. Reassess clinical and laboratory status frequently (Sease & Blake, 2026).

Monitor for treatment complications and endpoints

Laboratory trajectories that demand a change in the plan

During DKA treatment, monitor beta-hydroxybutyrate clearance, venous pH or bicarbonate, glucose, potassium, renal function, and clinical perfusion; the anion gap can help characterize acid–base changes but should not serve as the primary DKA resolution endpoint. No single improved value establishes resolution. Careful monitoring emphasizes repeated electrolyte and acid–base assessment during IV insulin and fluid therapy. Serum potassium may appear initially normal or high despite a substantial total-body deficit and can fall rapidly when insulin and rehydration begin.

If glucose normalizes while ketonemia or acidosis persists, the patient may still require insulin with appropriately adjusted dextrose-containing fluids under the active institutional protocol. Prematurely stopping insulin risks persistent ketosis. Conversely, marked hypokalemia requires potassium correction before insulin because insulin moves potassium intracellularly and can precipitate dysrhythmia.

During active resuscitation, record glucose hourly when on IV insulin; reassess potassium, sodium, bicarbonate, acid-base status, renal function, and other electrolytes at protocol-specified intervals. Evaluate ECG changes, urine output, neurologic status, hemodynamics, hypoglycemia, pulmonary edema, and persistent acidosis. A source-described approach repeats chemistries about every two to four hours until stable; monitoring may be more frequent in unstable or high-risk patients (Sease & Blake, 2026).

The 2024 consensus defines DKA resolution by blood beta-hydroxybutyrate below 0.6 mmol/L plus venous pH at least 7.3 or bicarbonate at least 18 mmol/L; ideally glucose is also below 200 mg/dL. Do not rely on glucose alone, the anion gap as the primary resolution criterion, or urinary ketones for clearance. Proposed HHS recovery criteria include osmolality below 300 mOsm/kg, glucose below 250 mg/dL, urine output above 0.5 mL/kg/hour, improved cognition and corrected hyperglycemia. Assess metabolic and clinical stability together, following the institution’s approved protocol (Umpierrez et al., 2024).

Transition from IV to subcutaneous insulin and oral intake

Close the treatment loop after DKA/HHS

The 2026 ADA inpatient standards emphasize a timely, bridged transition to maintenance subcutaneous insulin and treatment of the precipitating cause. Discharge planning should document insulin and supply access, a feasible glucose and ketone-monitoring plan, recognition of recurring DKA/HHS symptoms, sick-day instructions, and a named follow-up clinician. Medication changes or unmet glucose targets support earlier follow-up, rather than relying on discharge instructions alone (American Diabetes Association Professional Practice Committee for Diabetes, 2026).

Before stopping IV insulin, confirm metabolic-resolution endpoints, hemodynamic and electrolyte stability, and the ability to provide a reliable subcutaneous regimen and nutrition plan. Subcutaneous basal insulin must be given before the infusion ends to avoid an insulin-free gap. The 2024 hyperglycemic-crises consensus describes a one- to two-hour overlap, whereas the DKA-specific discussion in the 2026 ADA inpatient standards describes administering basal insulin two to four hours before ending the infusion. These recommendations agree that an overlap is necessary but differ in timing; apply the institution’s active transition protocol, the specific basal product, and patient factors such as kidney impairment or hypoglycemia risk. Reconcile the home regimen, glucose and ketone supplies, follow-up access, and the precipitating cause before handoff (Umpierrez et al., 2024; American Diabetes Association Professional Practice Committee for Diabetes, 2026).

At transfer and discharge, reconcile long-acting and mealtime insulin, correction instructions, CGM or glucometer supplies, needles or pump consumables, ketone testing, follow-up access, and the precipitating cause. Explain whether any SGLT2 inhibitor remains on hold and under what circumstances it may be reconsidered by the treating clinician. A discharge plan is incomplete if patients cannot obtain or safely administer their prescribed regimen.

A safe handoff contains more than an insulin order

Before discharge, use teach-back to confirm that the patient can obtain and administer the insulin regimen, monitor glucose, recognize recurrent ketosis or dehydration, and identify the responsible follow-up clinician. Medication access, pump or injection supplies, and a practicable rescue plan are part of preventing readmission, not administrative afterthoughts.

Case: glucose is not markedly elevated, but ketones are

A patient taking an SGLT2 inhibitor presents with vomiting, tachypnea, reduced intake, elevated serum ketones, and an anion-gap metabolic acidosis, but the plasma glucose is only moderately elevated. This presentation must not be excluded from ketoacidosis assessment because the glucose value is below a traditional threshold. Evaluate for euglycemic DKA, address the precipitating illness and medication exposure, and apply institutional fluid, potassium, insulin, and dextrose protocols with appropriate monitoring. A safe discharge plan must specify when to withhold and reassess the implicated medicine (Sease & Blake, 2026).

Applied clinical reasoning

Case 1: A 23-year-old with type 1 diabetes presents with vomiting, tachypnea, elevated beta-hydroxybutyrate, and potassium 2.9 mEq/L. The prescribing priority is to begin volume resuscitation and urgently correct potassium with cardiac/electrolyte monitoring while withholding the insulin infusion until potassium is safe under the applicable protocol. Insulin cannot be treated as an isolated first step because its potassium-shifting effect can provoke dangerous arrhythmia (Sease & Blake, 2026).

Case 2: A 76-year-old with type 2 diabetes, CKD, confusion, profound hyperglycemia, and severe dehydration may have HHS. Determine osmolality, volume deficit, serum sodium, and cardiac/renal reserve before aggressive fixed-rate fluid replacement. Monitor neurologic recovery and investigate infection or another precipitant. The appropriate treatment sequence prioritizes controlled correction of fluid and electrolyte derangements.

Case 3: After several hours of treatment for DKA, glucose is 190 mg/dL but serum ketones remain elevated and acidosis persists. Stopping insulin would leave the pathophysiologic mechanism active; instead, follow the appropriate dextrose-containing fluid and insulin-adjustment protocol, continuing close potassium and glucose monitoring until the metabolic endpoint is reached.

High-yield distinctions

In DKA/HHS, falling glucose does not by itself establish resolution. Safe management requires repeated reassessment of potassium, acid-base status, volume, osmolality, and the criteria for transition to subcutaneous therapy.

Related YourDNP Resources

Pharmacology hub · Diabetes mellitus · ABG interpretation · Insulin therapy · Diabetes monitoring

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References

American Diabetes Association Professional Practice Committee for Diabetes. (2026). 16. Diabetes care in the hospital: Standards of Care in Diabetes—2026. Diabetes Care, 49(Supplement 1), S339–S355. https://doi.org/10.2337/dc26-S016

Sease, J. M., & Blake, E. W. (2026). Diabetes mellitus. In M. A. Chisholm-Burns, P. M. Malone, J. M. Kolesar, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed., pp. 1372–1419). McGraw Hill.

Umpierrez, G. E., Davis, G. M., ElSayed, N. A., Fadini, G. P., Galindo, R. J., Hirsch, I. B., Klonoff, D. C., McCoy, R. G., Misra, S., Gabbay, R. A., Bannuru, R. R., & Dhatariya, K. K. (2024). Hyperglycaemic crises in adults with diabetes: A consensus report. Diabetologia, 67(8), 1455–1479. https://doi.org/10.1007/s00125-024-06183-8