# Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State

## Diabetic Ketoacidosis (DKA)

### Pathophysiology

Diabetic ketoacidosis represents the convergence of two fundamental metabolic derangements: absolute or relative insulin deficiency and a surge in counterregulatory hormones including glucagon, cortisol, catecholamines, and growth hormone. The interplay of these hormonal imbalances initiates a cascade of metabolic consequences that, if unchecked, can be rapidly fatal. Insulin deficiency releases adipose tissue from its normal inhibitory restraint, resulting in unrestrained lipolysis and a massive flux of free fatty acids (FFAs) to the liver. Concurrently, glucagon excess activates carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme governing mitochondrial fatty acid transport, thereby directing FFAs into beta-oxidation rather than re-esterification. The products of hepatic beta-oxidation are the ketone bodies acetoacetate and beta-hydroxybutyrate (BHB), along with acetone (a spontaneous decarboxylation product of acetoacetate). As ketoacid production overwhelms the body's buffering capacity, bicarbonate is consumed and an increased anion gap metabolic acidosis ensues. Simultaneously, insulin deficiency and counterregulatory hormone excess drive hyperglycemia through increased hepatic gluconeogenesis and glycogenolysis coupled with decreased peripheral glucose utilization. The resulting hyperglycemia produces an osmotic diuresis with glycosuria, causing profound fluid and electrolyte losses. On average, patients with DKA present with a free water deficit of 6-9 liters, sodium depletion of 7-10 mEq/kg, potassium depletion of 3-5 mEq/kg, and phosphate depletion of 1-1.5 mmol/kg.

### Precipitating Factors

Identification and treatment of the precipitating factor is as essential as correction of the metabolic derangement itself. Infection is the most common precipitant, accounting for 30-50% of DKA episodes, with pneumonia, urinary tract infections, and sepsis being the leading culprits. Insulin omission or nonadherence is the second most common trigger and encompasses a range of scenarios including deliberate insulin withholding (sometimes in the context of disordered eating or financial barriers to insulin access), insulin pump failure with interruption of continuous subcutaneous delivery, and inadvertent omission. New-onset type 1 diabetes accounts for 25-30% of initial presentations with DKA, particularly in children and adolescents. Acute physiological stressors such as myocardial infarction, stroke, pancreatitis, trauma, and surgery can precipitate DKA through counterregulatory hormone surges. Several medication classes are recognized precipitants, including corticosteroids, atypical antipsychotics (notably olanzapine and clozapine, which impair insulin secretion and sensitivity), SGLT2 inhibitors (which can cause euglycemic DKA), and immune checkpoint inhibitors (which can trigger autoimmune beta-cell destruction mimicking new-onset type 1 diabetes). Substance use including cocaine, alcohol, and cannabis hyperemesis (through severe dehydration) can also precipitate DKA. In pregnancy, the combination of accelerated starvation ketosis and the insulin resistance of the second and third trimesters creates particular vulnerability.

### Diagnostic Criteria (ADA)

| | Mild | Moderate | Severe |
|---|---|---|---|
| Glucose | >250 mg/dL | >250 mg/dL | >250 mg/dL |
| pH | 7.25-7.30 | 7.00-7.24 | <7.00 |
| Bicarbonate | 15-18 mEq/L | 10-14.9 mEq/L | <10 mEq/L |
| Anion gap | >10 | >12 | >12 |
| Mental status | Alert | Alert/drowsy | Obtunded/coma |
| Urine/serum ketones | Positive | Positive | Positive |
| BHB | >3.0 mmol/L | >3.0 mmol/L | >3.0 mmol/L |

### Euglycemic DKA

Euglycemic DKA is defined by the presence of ketoacidosis with blood glucose levels below 250 mg/dL, and in some cases below 200 mg/dL. This entity is most commonly associated with SGLT2 inhibitor use, but can also occur in the setting of pregnancy, starvation, partial treatment of DKA, and very low-carbohydrate diets. Euglycemic DKA is easily missed precisely because the hallmark feature of hyperglycemia is absent, and clinicians must maintain a high index of suspicion by checking ketones and obtaining blood gas analysis in any diabetic patient presenting with nausea, vomiting, or abdominal pain regardless of glucose level. The mechanism in SGLT2 inhibitor-associated euglycemic DKA involves ongoing glycosuria that lowers circulating glucose, leading to reduced insulin dosing and a relative insulin deficiency state, combined with increased glucagon secretion and enhanced renal ketone reabsorption, all of which favor ketogenesis while masking the typical hyperglycemic presentation.

<image>A pathophysiology diagram of diabetic ketoacidosis showing the metabolic cascade. Start with two inputs at top: absolute/relative insulin deficiency and counterregulatory hormone excess (glucagon, cortisol, catecholamines, GH). These lead to three parallel pathways: (1) Increased lipolysis from adipose tissue → FFA to liver → CPT-1 activation → mitochondrial beta-oxidation → ketone body production (acetoacetate, BHB, acetone) → metabolic acidosis. (2) Increased hepatic glucose output (gluconeogenesis + glycogenolysis) + decreased peripheral glucose uptake → hyperglycemia → osmotic diuresis → dehydration, electrolyte losses (Na, K, Mg, PO4). (3) Proteolysis → amino acid substrates for gluconeogenesis. Show clinical consequences at bottom: volume depletion, electrolyte derangements, acidosis, altered mental status. Use arrows showing feedback loops and interconnections. Medical textbook illustration style.</image>

### Management of DKA

#### Initial Assessment and Monitoring

The initial management of DKA demands rapid, systematic assessment and establishment of monitoring protocols. The ABCs of resuscitation are assessed first, followed by evaluation of hemodynamic status and establishment of two large-bore intravenous access sites. Stat laboratory studies should include a basic metabolic panel (glucose, potassium, sodium, BUN, creatinine, bicarbonate), venous or arterial blood gas, serum beta-hydroxybutyrate, complete blood count, urinalysis, and blood cultures if the patient is febrile. Critical calculations include the anion gap (sodium minus the sum of chloride and bicarbonate, with a normal value of approximately 12 plus or minus 4), corrected sodium (adding 1.6 mEq/L for every 100 mg/dL of glucose above 100, to account for the dilutional effect of hyperglycemia-induced water shifts), and effective osmolality (2 times the sodium concentration plus glucose divided by 18). An electrocardiogram should be obtained promptly to assess for signs of hyperkalemia (peaked T waves, widened QRS complexes) or concurrent myocardial infarction. A pregnancy test is indicated in all reproductive-age women. Ongoing monitoring includes hourly glucose measurements, basic metabolic panels every 2-4 hours, and continuous cardiac monitoring when potassium is abnormal.

#### Step 1: Fluid Resuscitation (Priority #1)

Fluid resuscitation is the single most important initial intervention in DKA management. Isotonic saline (0.9% NaCl) should be administered at a rate of 1-1.5 liters per hour (approximately 15-20 mL/kg/hr) for the first 1-2 hours, with a slower rate for patients with heart failure or the elderly. After the initial resuscitation bolus, the choice of subsequent fluids is guided by the corrected serum sodium: if the corrected sodium is low or normal, 0.9% NaCl is continued at 250-500 mL/hr; if the corrected sodium is elevated, the fluid is switched to 0.45% NaCl at 250-500 mL/hr. A critical management transition occurs when blood glucose reaches 200-250 mg/dL: dextrose 5% is added to the intravenous fluids (typically as D5-0.45% NaCl) to prevent hypoglycemia while allowing continuation of the insulin infusion needed to clear ketones. The total fluid deficit in DKA typically ranges from 6-9 liters, and the goal is to replace approximately 50% of this deficit within the first 8-12 hours, with the remainder corrected over the subsequent 24-36 hours.

#### Step 2: Potassium Replacement (Before or With Insulin)

Potassium management in DKA requires particularly careful attention because of the paradox between serum and total body potassium: despite the fact that total body potassium is invariably depleted (by 3-5 mEq/kg), the serum potassium at presentation may be normal, elevated, or low due to the extracellular shift of potassium caused by acidosis and insulin deficiency. When serum potassium is below 3.3 mEq/L, insulin must be held and potassium replaced aggressively at 20-40 mEq/hr until the level exceeds 3.3, because insulin administration in the setting of hypokalemia will further drive potassium intracellularly and can precipitate fatal cardiac arrhythmias. When potassium is between 3.3 and 5.3 mEq/L, 20-30 mEq of potassium should be added to each liter of intravenous fluid, targeting a serum level of 4.0-5.0 mEq/L. When potassium exceeds 5.3 mEq/L, supplementation should be withheld and levels rechecked in 2 hours, as the insulin infusion itself will drive potassium to lower levels.

#### Step 3: Insulin Therapy

The standard insulin protocol employs a continuous intravenous infusion of regular insulin. The initial approach is either a bolus of 0.1 units/kg followed by a continuous infusion of 0.1 units/kg/hr, or alternatively, no bolus with a starting infusion rate of 0.14 units/kg/hr. The target rate of glucose decline is 50-75 mg/dL/hr; if glucose is not falling at the expected rate, the infusion should be doubled. When glucose reaches 200-250 mg/dL, the drip rate is reduced to 0.02-0.05 units/kg/hr, and D5 is added to the intravenous fluids. It is essential to understand that the insulin drip must be continued until DKA has fully resolved, not merely until glucose has normalized; premature discontinuation of insulin while ketosis persists will result in rebound ketoacidosis. For patients with mild DKA (pH above 7.25 and alert mental status), subcutaneous insulin protocols using rapid-acting insulin at 0.2 units/kg initially followed by 0.1 units/kg every 1-2 hours have been shown to be non-inferior to intravenous insulin in several randomized controlled trials and may be appropriate in resource-limited settings.

#### Step 4: Bicarbonate (Controversial; Limited Indications)

Bicarbonate administration in DKA remains controversial and is reserved for severe acidosis. When pH is above 7.0, bicarbonate is not indicated, as the acidosis will correct with insulin therapy and fluid resuscitation alone. When pH is between 6.9 and 7.0, consideration may be given to administering 50 mEq of sodium bicarbonate in 200 mL of sterile water over 1 hour. When pH is below 6.9, 100 mEq of sodium bicarbonate in 400 mL of sterile water over 2 hours is recommended. The risks of bicarbonate administration are multiple and include paradoxical central nervous system acidosis (carbon dioxide crosses the blood-brain barrier more rapidly than bicarbonate, transiently worsening intracellular pH), exacerbation of hypokalemia, delayed clearance of ketones, and overshoot metabolic alkalosis.

#### Step 5: Phosphate Replacement

Routine phosphate replacement is not recommended in DKA, as randomized trials have not demonstrated a benefit on clinical outcomes. However, replacement should be considered in specific circumstances including severe hypophosphatemia (phosphate below 1.0 mg/dL), cardiac dysfunction, respiratory depression (diaphragmatic weakness from profound hypophosphatemia), or hemolytic anemia. When indicated, 20-30 mEq of potassium phosphate per liter of intravenous fluid provides both potassium and phosphate repletion simultaneously.

### Resolution Criteria for DKA

DKA is considered resolved when blood glucose falls below 200 mg/dL and at least two of the following criteria are met: serum bicarbonate is 15 mEq/L or higher, venous pH exceeds 7.3, or the anion gap has closed to 12 or less. Where available, serum BHB below 1.0 mmol/L is the most reliable marker of complete ketone clearance. Additionally, the patient should be able to tolerate oral intake before transitioning off intravenous therapy.

### Transition to Subcutaneous Insulin

The transition from intravenous to subcutaneous insulin requires careful timing to prevent rebound hyperglycemia and ketosis. The first dose of subcutaneous insulin (both long-acting and rapid-acting components) must be administered 1-2 hours before discontinuation of the intravenous insulin drip, because the half-life of intravenous insulin is only 5-7 minutes, and any gap in insulin coverage will rapidly result in recurrent ketogenesis. For patients with known type 1 diabetes, the home regimen should be resumed with adjustments as needed based on the total daily dose during the DKA episode. For new-onset type 1 diabetes, a starting dose of 0.5-0.6 units/kg/day divided as basal-bolus is appropriate. For patients with type 2 diabetes who developed DKA, the transition may be to subcutaneous insulin or oral agents depending on the clinical context and underlying etiology.

### Complications of DKA and Its Treatment

Cerebral edema is the most feared complication of DKA treatment, occurring primarily in the pediatric population (0.5-1% incidence) with a mortality rate of 20-25%. Risk factors include rapid fluid administration, rapid glucose reduction, young age, and new-onset type 1 diabetes. Treatment consists of mannitol 0.5-1 g/kg intravenously or hypertonic saline 3% at 5 mL/kg. Hypokalemia from insulin-mediated intracellular potassium shift without adequate replacement poses a significant arrhythmia risk. Hypoglycemia can result from excessive insulin administration or inadequate glucose supplementation when the drip rate is not reduced appropriately. A non-anion gap hyperchloremic metabolic acidosis commonly develops during recovery, resulting from large-volume normal saline administration and renal excretion of ketoanions; this explains why bicarbonate may not normalize immediately even after ketone clearance. Pulmonary edema can occur from aggressive fluid resuscitation, particularly in elderly patients or those with underlying cardiac disease. Venous thromboembolism is a recognized complication, as DKA induces a hypercoagulable state, and prophylactic anticoagulation should be considered.

<image>A step-by-step DKA management protocol flowchart. Start with DKA diagnosis confirmed (glucose >250, pH <7.3, bicarb <18, anion gap >10, ketones positive). Four parallel treatment tracks shown simultaneously: Track 1 (blue) - Fluids: NS 1-1.5 L/hr x 1-2 hours → assess corrected Na → NS or half-NS at 250-500 mL/hr → add D5 when glucose 200-250. Track 2 (red) - Potassium: check K first → if <3.3 hold insulin and replace K aggressively → if 3.3-5.3 add 20-30 mEq to each liter → if >5.3 hold K and recheck. Track 3 (green) - Insulin: IV regular 0.1 U/kg bolus then 0.1 U/kg/hr → target glucose drop 50-75/hr → reduce to 0.02-0.05 U/kg/hr when glucose 200-250 → continue until DKA resolved. Track 4 (yellow) - Bicarbonate: only if pH <7.0. End with resolution criteria box and transition to SC insulin protocol. Use clear color-coded parallel tracks with timing indicators.</image>

## Hyperosmolar Hyperglycemic State (HHS)

### Pathophysiology

Hyperosmolar hyperglycemic state is characterized by severe hyperglycemia (often exceeding 600 mg/dL), marked hyperosmolality, and profound dehydration in the absence of significant ketoacidosis. The key pathophysiological distinction from DKA lies in the presence of sufficient residual insulin to suppress lipolysis and ketogenesis, but not enough to prevent the progressive hyperglycemia driven by hepatic glucose output and impaired peripheral utilization. HHS develops insidiously over days to weeks, in contrast to the hours-to-days timeline of DKA, allowing a massive osmotic diuresis to produce extraordinary fluid losses averaging 8-12 liters. The resulting dehydration causes prerenal azotemia, which further impairs renal glucose excretion and creates a vicious cycle of worsening hyperglycemia and dehydration. The profound hyperosmolality directly causes altered mental status, with the severity of neurological impairment correlating closely with the degree of effective osmolality elevation.

### Epidemiology and Precipitants

HHS occurs predominantly in older adults with type 2 diabetes and carries a mortality rate of 5-20%, substantially higher than DKA, largely attributable to the advanced age and comorbidity burden of the affected population. Infection is the most common precipitant (40-60% of cases), followed by medication nonadherence, acute cardiovascular events (myocardial infarction, stroke), medications that impair glucose tolerance (glucocorticoids, thiazide diuretics, atypical antipsychotics), new-onset type 2 diabetes, and importantly, limited access to water, which is particularly common in nursing home residents and patients with dementia. A mixed presentation with features of both DKA and HHS occurs in 30-40% of hyperglycemic emergencies and should be treated according to DKA protocols when significant ketoacidosis is present.

### Diagnostic Criteria

The diagnostic criteria for HHS include blood glucose exceeding 600 mg/dL, effective osmolality greater than 320 mOsm/kg (calculated as 2 times the serum sodium plus glucose divided by 18), pH above 7.30 (indicating no significant ketoacidosis, though mild acidosis may be present from renal failure or lactic acidosis), bicarbonate above 18 mEq/L, and minimal ketonemia or ketonuria (although small amounts of ketones may be present from starvation). Altered mental status typically manifests when effective osmolality exceeds 320 mOsm/kg and progresses to coma when osmolality surpasses 340 mOsm/kg.

### Management of HHS

#### Fluid Resuscitation (Cornerstone of Therapy)

Fluid resuscitation is the most critical intervention in HHS management, even more so than in DKA, given the more profound dehydration (8-12 liter deficit). Initial resuscitation begins with 0.9% NaCl at 1-1.5 liters per hour for the first 1-2 hours. Subsequent fluid selection depends on the corrected sodium and hemodynamic status: when corrected sodium exceeds 145 mEq/L, half-normal saline (0.45% NaCl) at 250-500 mL/hr is used; when corrected sodium is below 145, isotonic saline continues at the same rate. When glucose reaches 250-300 mg/dL, fluids are switched to dextrose-containing solutions. It is important to recognize that fluid resuscitation alone will significantly lower blood glucose by reducing counterregulatory hormone levels and increasing renal glucose clearance, even before insulin is administered. A slower correction rate is recommended in elderly patients and those with cardiac comorbidities to avoid fluid overload.

#### Insulin Therapy

Insulin doses in HHS are generally lower than those used in DKA, typically 0.05-0.1 units/kg/hr, because the primary concern is the risk of rapid osmolality shifts that can precipitate cerebral edema. Insulin may be deferred initially until adequate fluid resuscitation is underway, particularly if potassium is low. The target glucose reduction rate is 50-75 mg/dL/hr, and rates exceeding 75 mg/dL/hr should be avoided. When glucose reaches 250-300 mg/dL, the insulin drip rate is reduced and D5 is added to intravenous fluids. If significant ketosis is present (consistent with a mixed DKA/HHS presentation), the DKA insulin protocol should be followed.

#### Potassium Management

Potassium management follows the same principles as in DKA, though total body potassium depletion may be even more profound given the longer duration of osmotic diuresis. Replacement should begin before or simultaneously with insulin administration.

#### Osmolality Monitoring

Effective osmolality should be calculated every 2-4 hours throughout treatment, with a target of gradual reduction at a rate of 3-8 mOsm/kg/hr. Overly rapid correction risks osmotic cerebral edema. Mental status should improve in parallel with osmolality normalization; failure of neurological improvement despite correcting osmolality should prompt investigation for alternative etiologies such as stroke or meningitis.

### Thromboprophylaxis

HHS carries a particularly high risk of venous thromboembolism due to hyperosmolality-induced hyperviscosity, immobility, and the prothrombotic state associated with severe illness. Prophylactic anticoagulation with low-molecular-weight heparin or unfractionated heparin is recommended unless contraindicated. Some guidelines, including those from the United Kingdom, recommend therapeutic-dose anticoagulation during HHS, though practice varies across institutions.

### Outcomes and Transition

Mortality from HHS ranges from 5-20% and is driven predominantly by the underlying precipitant and the comorbidity burden of the typically elderly affected population. Transition to subcutaneous insulin can be undertaken when osmolality is normalizing, glucose is controlled, mental status has improved, and the patient is tolerating oral intake. Many patients can ultimately be managed on oral hypoglycemic agents after the acute HHS episode resolves, though some will require ongoing insulin therapy.

## DKA vs HHS Comparison

| Feature | DKA | HHS |
|---------|-----|-----|
| Onset | Rapid (hours-days) | Insidious (days-weeks) |
| Glucose | >250 mg/dL (can be lower) | >600 mg/dL |
| pH | <7.30 | >7.30 |
| Ketones | Strongly positive | Minimal/absent |
| Osmolality | Variable (usually <320) | >320 mOsm/kg |
| Fluid deficit | 6-9 L | 8-12 L |
| Mental status change | Variable | Prominent |
| Mortality | 1-5% | 5-20% |
| Primary therapy | Insulin + fluids | Fluids + insulin |
| Typical diabetes type | T1D (can be T2D) | T2D |

## Special Situations

### Ketosis-Prone Type 2 Diabetes (KPD / "Flatbush Diabetes")

Ketosis-prone type 2 diabetes is a distinct clinical phenotype in which patients with phenotypic type 2 diabetes (often obese, with features of metabolic syndrome) present with DKA despite lacking autoimmune markers of type 1 diabetes. This entity is more prevalent in African American, Hispanic, and sub-Saharan African populations. The most common subtype follows the A-beta-negative classification (antibody-negative with recoverable beta-cell function), accounting for approximately 70% of cases. These patients characteristically achieve insulin independence within weeks to months as beta-cell function recovers following resolution of the acute glucotoxic and lipotoxic insult. Management involves standard DKA treatment during the acute episode, followed by cautious transition to oral agents as beta-cell function recovers, with close long-term follow-up for recurrence.

### DKA in Pregnancy

DKA in pregnancy presents unique challenges and carries grave fetal consequences. The threshold for DKA is lower during pregnancy due to the accelerated starvation ketosis of the fasting state and the progressive insulin resistance characteristic of the second and third trimesters; DKA can develop at glucose levels as low as 200-250 mg/dL. Fetal mortality during maternal DKA is alarmingly high, estimated at 30-50%, resulting from fetal acidosis, hypokalemia, and hypophosphatemia transmitted across the placenta. Management follows standard DKA protocols with several modifications: continuous fetal monitoring should be initiated, left lateral decubitus positioning should be employed to avoid aortocaval compression, and bicarbonate administration should generally be avoided due to the risk of worsening fetal acidosis.

### Pediatric DKA

Cerebral edema is the most feared and devastating complication of pediatric DKA, with an incidence of 0.5-1% and a mortality rate of 20-25%. Risk factors include new diagnosis of diabetes, younger age, higher blood urea nitrogen, greater severity of acidosis at presentation, and overly rapid fluid administration. Prevention strategies include limiting fluid replacement to 1.5-2 times maintenance rate, avoiding bolus fluid volumes exceeding 20 mL/kg, and targeting a glucose decline rate below 100 mg/dL/hr (slower than the adult target). When cerebral edema develops, treatment consists of mannitol 0.5-1 g/kg intravenously over 20 minutes or hypertonic saline 3% at 2.5-5 mL/kg over 10-15 minutes, elevation of the head of the bed, and avoidance of hypotonic fluids.

## Key Clinical Pearls

- Potassium replacement must precede insulin administration if K+ <3.3 mEq/L; insulin-driven hypokalemia can cause fatal cardiac arrhythmias
- Serum BHB is the preferred marker for monitoring DKA resolution over urine ketones; nitroprusside-based urine ketone tests detect acetoacetate (not BHB) and may paradoxically become "more positive" as DKA resolves (BHB converts to acetoacetate during treatment)
- The anion gap normalizes before bicarbonate in DKA recovery; a persistently positive anion gap indicates ongoing ketosis even if bicarbonate is improving
- Overlap DKA/HHS occurs in 30-40% of hyperglycemic emergencies; the presence of significant ketoacidosis mandates treatment as DKA regardless of glucose level
- Euglycemic DKA (especially SGLT2i-related) is frequently missed because glucose is near-normal; always check ketones and blood gas in diabetic patients with unexplained nausea, vomiting, or abdominal pain
- When transitioning from IV to SC insulin, the SC long-acting insulin must be given 1-2 hours BEFORE stopping the drip; the half-life of IV insulin is only 5-7 minutes

## References

1. Kitabchi AE, et al. "Hyperglycemic Crises in Adult Patients with Diabetes." Diabetes Care. 2009;32(7):1335-1343.
2. Umpierrez GE, et al. "Diabetic Emergencies: Ketoacidosis, Hyperglycaemic Hyperosmolar State and Hypoglycaemia." Nat Rev Endocrinol. 2016;12(4):222-232.
3. Dhatariya KK, et al. "Diabetic Ketoacidosis." Nat Rev Dis Primers. 2020;6(1):40.
4. Pasquel FJ, Umpierrez GE. "Hyperosmolar Hyperglycemic State: A Historic Review of the Clinical Presentation, Diagnosis, and Treatment." Diabetes Care. 2014;37(11):3124-3131.
5. Joint British Diabetes Societies Inpatient Care Group. "The Management of Diabetic Ketoacidosis in Adults." 2021.