Pathophysiology of diabetic ketoacidosis (DKA)

Diabetic ketoacidosis is most often found in patients with Type I Diabetes Mellitus (DM). Insulin deficiency is the hallmark of DKA pathophysiology. Insufficient insulin presence leads to increased hepatic glucose production and decreased peripheral glucose uptake, both of which lead to elevated blood glucose. The lack of sufficient circulating insulin drives fatty acid oxidation, which results in the accumulation of acetoacetate and beta-hydroxybutyrate, called ketone bodies. This leads to significant metabolic acidosis with an anion gap, which is a cardinal feature of DKA. This can result in:

• Critical electrolyte abnormalities
• Worsening volume depletion
• End-organ damage.

Pathophysiology of hyperosmolar hyperglycemic state (HHS)

HHS is more commonly seen in patients with Type II DM. In addition to high blood glucose levels, HHS represents a state of increased plasma osmolality, along with severe hyperglycemia, yet without significant ketone production. There is a relative insulin deficiency, inadequate to control blood glucose levels, yet not severe enough to lead to ketosis. The hyperosmolar state results from osmotic diuresis, leading to profound volume depletion and elevated plasma osmolality. One of the hallmark features of HHS vs. DKA is that HHS does not cause an anion gap metabolic acidosis. Severe hyperglycemia, critical electrolyte abnormalities, and progressive volume depletion must be corrected in tandem to prevent long-term complications.

Pathogenesis of severe hyperglycemia

Critical glucose dysregulation, as seen in DKA and HHS, involves complex interplays between metabolic and hormonal milieu. The pathophysiologic stress response in DKA and HHS leads to elevated counterregulatory hormones for plasma glucose, including glucagon, cortisol, catecholamines, and growth hormone. These hormones worsen hyperglycemia by increasing hepatic glucose production and causing impaired glucose utilization. The resulting hyperglycemic crises lead to worsened insulin resistance.

Risk factors of DKA and HHS

There are a number of precipitating factors of DKA and HHS, all of which result in insulin deficiency, volume depletion, or both.

Infections

Infections are the most common causes of hyperglycemic crises, with as many as 50% of cases of DKA being caused by infections. Bacterial infections can cause metabolic decompensation, especially urinary tract infections and pneumonia, which are frequently identified with cases of DKA. DKA and HHS often lead to sepsis, which exacerbates hypovolemia and end-organ damage.

Acute illnesses

Other acute illnesses with physiologic stress, such as myocardial infarction, cerebrovascular accident, pancreatitis, trauma, major surgery, starvation ketosis, or eating disorders, can lead to DKA or HHS.

Inadequate treatment with insulin

New-onset type 1 diabetes mellitus

Diabetic ketoacidosis is a common manifestation of new-onset type 1 diabetes mellitus, leading to an initial diagnosis of diabetes mellitus.

Medication non-adherence

Insulin omission is a common cause of DKA or HHS. In patients who do not take insulin as prescribed, for reasons like an inadequate supply, unaffordability, or missed insulin doses, DKA or HHS can occur.  Often patients will have a gastrointestinal illness which limits oral intake, as a result a patient may skip their insulin which in concert with the stress of the illness will precipitate DKA.

Insulin pump malfunction

Malfunctions of an insulin pump can deliver insufficient insulin doses, causing severe hyperglycemia and requiring prompt correction to avoid life-threatening complications. Something as simple as a kink in the tubing from the pump can cause this malfunction.

Medications

Diabetes medications and other medications that affect carbohydrate metabolism and blood glucose levels can predispose to diabetes mellitus. Examples of medications that can predispose to severe hyperglycemia include:

• glucocorticoids
• antipsychotics
• sympathomimetics
• and sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Clinical manifestations of DKA and HHS

Shared signs and symptoms

DKA and HHS present with some of the same overall signs and symptoms as a result of volume depletion and severe hyperglycemia. Dry mucosa, decreased skin turgor, tachycardia, hypotension, and kidney injury are common objective findings as a result of profound dehydration. Severe hyperglycemia often leads to polyuria, polydipsia, fatigue, and anorexia. However, some signs and symptoms will differ between DKA and HHS, as a result of the underlying pathophysiology.

DKA presentation

In DKA, anion gap metabolic acidosis and ketosis are primary factors, and they often cause characteristic findings, like abdominal pain, nausea, vomiting, breath with a fruity odor, and Kussmaul respirations (deep compensatory hyperventilation). In addition, because DKA can cause significant electrolyte imbalances (especially potassium), patients often have signs related to cardiac dysrhythmias, renal dysfunction, and muscle weakness.

In severe cases, patients may present with:

• Multiorgan system failure
• Sepsis
• Altered mental status, or
• Coma
• Respiratory failure

HHS presentation

Neurologic dysfunction is even more common in HHS, as a result of severe dehydration and high serum osmolality, with signs and symptoms like confusion, altered mental status, somnolence, or coma. Severe volume depletion can lead to signs of end-organ damage, and electrolyte abnormalities can cause cardiac or kidney complications. However, the evolution of HHS can take several days to a week, the signs and symptoms of HHS can be less specific, both of which can lead to a delay in diagnosis.

Diagnostic Criteria of DKA and HHS

Making the correct severe hyperglycemic crisis diagnosis requires an ability to compare DKA vs HHS, knowing what diagnostic criteria to anticipate for each. This table illustrates the similarities and differences between DKA and HHS.

Other Considerations

Both DKA and HHS typically present with elevated blood urea nitrogen (BUN) and serum creatinine levels as a result of severe dehydration. Sodium, potassium, magnesium, and phosphorus levels are usually all low. Other signs of end-organ damage and profound volume depletion often include a lactic acidosis, increased troponin, leukocytosis, and others, depending on the underlying etiology.

Euglycemic diabetic ketoacidosis represents a phenomenon in which ketoacidosis is present, but blood glucose levels are normal or close to normal. Euglycemic DKA can occur when patients receive insulin treatment prior to the time of drawing laboratory testing or in patients taking SGLT2 inhibitors. The treatment of euglycemic diabetic ketoacidosis usually requires using both insulin and glucose to resolve the acidosis while preventing dangerous hypoglycemia.

Management of DKA and HHS

Initial Measures

Fluid Resuscitation

The first step in managing DKA and HHS is aggressive fluid resuscitation. Rehydration resolves volume depletion, improves serum osmolality, and restores hemodynamic stability. Isotonic saline or crystalloid is preferred initially, including several liters over the first two hours, based on the degree of volume depletion and hemodynamic status. As volume status improves, treatment often shifts to hypotonic fluids (often with glucose and potassium), depending on blood glucose, sodium, potassium, and osmolality. Improved fluid status and osmolality leads to improved insulin utilization and lower blood glucose.

Electrolyte corrections

Electrolyte imbalances, especially potassium, must be carefully monitored and promptly corrected to avoid life-threatening complications. In DKA, serum potassium concentration may be initially normal or elevated to extracellular potassium shifts; however, total body potassium is usually low, which becomes evident as potassium levels decrease with fluid resuscitation. In addition, insulin administration can lead to a rapid drop in serum potassium because insulin drives potassium from the extracellular to the intracellular space. Potassium repletion should always occur at the start of the insulin infusion in patients will a low serum potassium level. For these reasons, it is vital to carefully monitor and adequately supplement potassium intravenously.

In HHS, common electrolyte imbalances include sodium, potassium, and phosphate. While hypophosphatemia may occur with DKA, it is more common with HHS because HHS typically develops over several days to one week, allowing time for phosphate depletion (compared to DKA, which develops over hours to days). The admission serum sodium should be calculated as a corrected value, depending on the degree of hyperglycemia, and the corrected sodium concentration, along with the serum osmolality, should be used to help determine the type of intravenous fluids that are given.

Gradual reduction of osmolality and glucose

Gradual osmolality reduction is critical to avoid too rapid of correction, which can cause cerebral edema and osmotic demyelination syndrome. Frequent, serial monitoring of blood glucose levels and serum osmolality helps prevent overcorrection and hypoglycemia.

Insulin Therapy

Intravenous insulin infusion

Insulin should be given after potassium is administered and fluid resuscitation has begun. Intravenous insulin infusion is preferred over subcutaneous injections in the acute management of DKA and HHS. Regular insulin is favored because of its rapid onset and short duration of action. A bolus of insulin dosed at 0.1 units/kg of body weight is usually given first, followed by a maintenance insulin infusion rate starting at 0.1 units/kg/hour, which is then titrated to facilitate a gradual reduction in blood glucose levels and osmolality and to achieve adequate plasma insulin levels. The goal of blood glucose reduction is usually 50-75 mg/dL/hour. Too rapid of correction of glucose and osmolality could precipitate cerebral edema.

Transition to subcutaneous insulin

Once blood glucose levels have stabilized, the ketosis has resolved in DKA, the hyperosmolarity has improved in HHS, and patients are able to tolerate oral intake, they can be transitioned to subcutaneous insulin, usually as intravenous fluids are adjusted as well.

In DKA, when the blood glucose level reaches about 250 mg/dL, intravenous insulin is usually transitioned to subcutaneous insulin, and intravenous fluids are switched to hypotonic saline or crystalloid with dextrose added to prevent hypoglycemia.  Discontinuation of IV insulin should not occur until the anion gap has normalized.  In HHS, this change is usually made at a serum glucose of about 300 mg/dL.

EndoTool insulin dosing software provides patient-specific dosing using a controlled reduction in blood glucose levels to prevent complications from rapid correction in intravenous insulin dosing. When using EndoTool subcutaneous insulin dosing mode, the preferred subcutaneous insulin dose usually includes basal insulin, bolus rapid-acting insulin, and correction doses as needed.

Other Considerations

Severe acidosis

Bicarbonate treatment is not used universally for the metabolic acidosis in DKA. However, in patients who have a severe acidosis (pH < 6.9) or critical hyperkalemia, bicarbonate therapy can be given to help resolve the acidosis.

Hypophosphatemia

Routine phosphate supplementation is not recommended in DKA or HHS. However, phosphate therapy should be given in cases of severe hypophosphatemia to prevent cardiac or respiratory complications.

Hypomagnesemia

While magnesium levels may initially be high in DKA or HHS, the lack of insulin may lead to excess magnesium losses in the urine during fluid resuscitation. As a result, hypomagnesemia often occurs, which is alongside the hypokalemia that is common. If hypomagnesemia is present, adequate correction of hypokalemia requires correcting hypomagnesemia concurrently.

Pseudohyponatremia

Serum sodium concentrations are usually low in DKA and HHS as a result of the degree of hyperglycemia, occurring from fluid and electrolyte shifts between the extracellular and intracellular spaces. In HHS, with higher serum osmolality, hyponatremia is typically more severe. Because glucose drives water into the intravascular and intracellular spaces, leading to a decrease in extracellular sodium, sodium levels should be corrected for glucose because correction of volume depletion and restoration of intracellular and extracellular fluid will help restore sodium balance.

Addressing underlying causes

Identifying and treating underlying causes of DKA and HHS are important in managing them effectively. If bacterial infection is present, prompt treatment with antibiotics is critical to improve outcomes. In the presence of acute illness, like myocardial infarction or stroke, stabilization and treatment to avoid further organ damage is crucial. If inadequate medication treatment from non-adherence, insulin pump failure, expired medication, or other lack of access is behind the severe hyperglycemia, mitigating the cause can prevent recurrent episodes.

Potential Complications

Measures to avoid severe acute complications of DKA and HHS should be integrated in their treatment strategies because the potential immediate complications can significantly increase mortality.

DKA

DKA is an emergency, necessitating prompt, appropriate treatment because it can lead to a number of potential complications.

• Organ failure is a frequent complication, as severe diabetic ketoacidosis can cause hypoperfusion and circulatory dysfunction.
• Profound hypokalemia and hypoglycemia increase the risk of cardiac and neurologic complications.
• Hypokalemia raises the risk of fatal cardiac dysrhythmias, and severe hypoglycemia can cause irreversible cognitive damage or coma.

• Rebound hyperglycemia is possible when insulin infusions are discontinued prematurely, allowing the acidosis to worsen and hyperglycemia to increase.
• Aggressive fluid resuscitation can cause flash pulmonary edema and respiratory compromise.
• Cerebral edema is a rare complication, seen primarily in pediatric patients, but it denotes a poor prognosis.

HHS

Like DKA, HHS can cause potential complications.

• Organ dysfunction (kidneys, liver, heart) as a result of volume depletion and impaired circulation.
• Severe volume depletion results in blood that is thick and more viscous, which can cause thromboembolic complications.
• Osmotic demyelination syndrome can be a complication of correcting sodium levels and serum osmolality too rapidly.

Monitoring sodium, glucose, and osmolality during fluid resuscitation and insulin treatment is imperative to improve patient outcomes.

Mortality and prognosis

The prognosis for DKA and HHS depends on the severity of the condition, the underlying etiology, the promptness and effectiveness of treatment, and the presence of any comorbidities. While the mortality rate for DKA has improved over the last few decades, it still remains as high as 5% in the immediate treatment period. However, the mortality rate of HHS is often higher than that of DKA, with HHS having a >10% mortality rate in the immediate treatment period and rates higher in elderly patients who have other comorbidities. Appropriately managing diabetes mellitus after DKA and HHS episodes in order to prevent recurrence is imperative to improving prognosis.

Conclusion

DKA and HHS are severe hyperglycemic complications of diabetes mellitus, with some similarities, yet also with significant differences in their underlying pathophysiology. By understanding the differences between DKA and HHS, making an accurate diagnosis, promptly initiating treatment, and monitoring patients appropriately, healthcare practitioners can improve patient outcomes and prevent life-threatening complications.

About EndoTool

Made by Monarch Medical Technologies, EndoTool is the only patient-specific insulin dosing system which simplifies the complex task of glycemic management in hospitals environments. The recommended dosing is different for each patient based on multiple clinical characteristics. The FDA-cleared platform is utilized in hundreds of hospitals across the United States and is fully integrated with all major electronic medical records. To see how EndoTool can support your health system, get in touch today.