Adult Diabetic Ketoacidosis

Etiology

Diabetic ketoacidosis more commonly occurs in patients with type 1 diabetes, though it can also occur in patients with type 2 diabetes. Patients with type 2 diabetes are also at risk. In both populations, catabolic stress of acute illness or injuries such as trauma, surgery, or infections may be a trigger. Common precipitating factors for DKA are non-compliance, new-onset diabetes, and other acute medical illness. The most common types of infections are pneumonia and urinary tract infections. Other conditions like alcohol abuse, trauma, pulmonary embolism, and myocardial infarction can also precipitate DKA. Drugs that affect carbohydrate metabolisms, such as corticosteroids, thiazides, sympathomimetic agents, and pentamidine, may precipitate DKA. Conventional, as well as atypical antipsychotic drugs, may also cause hyperglycemia and rarely DKA.[1]

SGLT2 inhibitors can predispose to diabetic ketoacidosis via multiple mechanisms. When SGLT2 inhibitors are used together with insulin, insulin doses are often decreased to avoid hypoglycemia. A lower dose of insulin may not be sufficient to suppress lipolysis and ketogenesis. SGLT2 is also expressed in pancreatic α-cells. SGLT2 inhibitors promote glucagon secretion and may decrease urinary excretion of ketone bodies, leading to an increase in plasma ketone body levels as well as hyperglycemia and DKA.[2] While hyperglycemia is typically the hallmark of DKA, a small subset of patients may experience euglycemic DKA. Euglycemic DKA results in a high anion gap metabolic acidosis with positive serum and urine ketones when serum glycemic levels are less than 250 mg/dL. SGLT-2 inhibitors may precipitate euglycemic DKA.[3]

One of the major causes of recurrent DKA in the inner-city population in the United States is non-compliance with insulin. Socioeconomic and educational factors play a significant role in poor adhesion to medications, including insulin. A recent report suggests that cocaine abuse is an independent risk factor associated with DKA recurrence.[4]

Epidemiology

Diabetic ketoacidosis incidence ranges from 0 to 56 per 1000 person-years, shown in different studies from different geographic areas. DKA has a higher prevalence rate among women and non-Whites. Incidence is higher among patients using injectable insulin compared to the subcutaneous insulin infusion pumps.[5]

Rates of DKA among children varies widely from country to country. The lowest incidence was found in Nigeria (2.9 cases per 100,000). The highest incidence rate was found in Sweden and Finland, with 41.0 and 37.4 per 100,000.[6] In the United States, one study reported nursing home residents accounted for 0.7% of DKA. Increased mortality was associated with nursing home residence among patients with DKA.[7] Mortality rate greater than 5% has been reported in the elderly and patients with concomitant life-threatening illnesses. Death in these conditions is rarely because of the metabolic complications of hyperglycemia or ketoacidosis alone.

The prognosis substantially worsens at the extremes of age in the presence of coma, hypotension, and severe comorbidities.[1] In urban Black patients, poor compliance with insulin was the leading precipitating cause of DKA. Substance abuse is a major contributing factor for non-adherence to therapies. Obesity is common in Blacks with DKA; it is found in more than half of those with newly diagnosed diabetes mellitus. Enhanced patient education and better access to medical care help in reducing the development of these hyperglycemic emergencies.[8]  

Diabetic ketoacidosis (DKA) is one of the life-threatening but preventable complications of diabetes. CDC's United States Diabetes Surveillance System (USDSS) indicated an increase in hospitalization rates for DKA from 2009 to 2014, most notably in persons aged less than 45 years.[9] However, overall mortality due to hyperglycemic crisis among adults with diabetes has declined in the U.S. Scope for further improvement remains, especially to further reduce death rates among Black men and to prevent deaths occurring at home.[10] 

The geriatric population is at particular risk for developing hyperglycemic crises with the development of diabetes. Some of the causes are increased insulin resistance and a decrease in the thirst mechanism. The elderly are particularly vulnerable to hyperglycemia and dehydration, the critical components of hyperglycemic emergencies. With increased diabetes surveillance and aggressive early treatment of hyperglycemia and its complications, morbidity, and mortality from acute diabetic crises in the geriatric population can be significantly reduced.[11]

Pathophysiology

Diabetes mellitus is characterized by insulin deficiency and increased plasma glucagon levels, which can be normalized by insulin replacement.[12] Normally, once serum glucose concentration increases, it enters pancreatic beta cells and leads to insulin production. Insulin decreases hepatic glucose production by inhibiting glycogenolysis and gluconeogenesis. Glucose uptake by skeletal muscle and adipose tissue is increased by insulin. Both of these mechanisms result in the reduction of blood sugar. In diabetic ketoacidosis, insulin deficiency and increased counter-regulatory hormones can lead to increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization. This will ultimately cause worsening hyperglycemia.

Insulin deficiency and increased counterregulatory hormones also lead to the release of free fatty acids into circulation from adipose tissue (lipolysis), which undergo hepatic fatty acid oxidation to ketone bodies (beta-hydroxybutyrate and acetoacetate), resulting in ketonemia and metabolic acidosis.[1] Glucagon is not crucial for the development of ketoacidosis in diabetes mellitus, as has previously been mentioned; however, it may accelerate the onset of ketonemia and hyperglycemia in situations of insulin deficiency.[13] Patients treated with SGLT2 are at increased risk of developing euglycemic DKA.

Diuresis induced by hyperglycemia, dehydration, hyperosmolarity, and electrolyte imbalance results in a decrease of glomerular filtration. Due to worsening renal function, hyperglycemia/hyperosmolality worsens. Potassium utilization by skeletal muscle is also impaired by hyperosmolality and impaired insulin function. This results in intracellular potassium depletion. Osmotic diuresis also leads to loss of potassium resulting in low total body potassium. The potassium level in patients with DKA varies, and a patient's normal plasma potassium level might indicate low total body potassium.[4] Hyperosmolarity appears to be the main factor responsible for the lowering of consciousness in patients with diabetic ketoacidosis.[14] 

New data suggests that hyperglycemia leads to a severe inflammatory state and an increase in proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-beta, -6, and -8), C-reactive protein, lipid peroxidation, and reactive oxygen species, as well as cardiovascular risk factors, plasminogen activator inhibitor-1 and free fatty acids in the absence of apparent infection or cardiovascular pathology. After insulin therapy and IV fluid hydration, the pro-inflammatory cytokines return to normal values within 24 hours.[1]

History and Physical

The patient with diabetic ketoacidosis may present with a myriad of symptoms and physical exam findings. Patients may have symptoms of hyperglycemia like polyphagia, polyuria, or polydipsia. As patients become more volume-depleted, they may experience decreased urine output, dry mouth, or decreased sweating indicative of dehydration. They may complain of many other symptoms, including anorexia, nausea, vomiting, abdominal pain, and weight loss.

If there is a superimposed infection that triggered the episode of DKA, the patient may have other infectious symptoms like fever, cough, or other urinary symptoms. In patients who may be developing cerebral edema, headache, or confusion may be present. Medication history should also be elicited, including what medications the patient is prescribed and how the patient has been using them. Substance use (drug and alcohol) should be ascertained.[15] 

On examination, vital signs typically reveal tachycardia and tachypnea. Due to the possibility of an infectious trigger for DKA, the patient may be febrile or hypothermic. Blood pressure may also vary, though hypotension is possible and indicative of a more severe disease process. Patients are often ill-appearing. Kussmaul breathing, which is labored, deep, and tachypneic, may occur. Some providers may appreciate a fruity scent to the patient's breath, indicative of the presence of acetone. Patients may have signs of dehydration, including poor capillary refill, skin turgor, and dry mucous membranes. Abdominal tenderness is possible. In the most severe cases, altered mental status, general drowsiness, and focal neurologic deficits can be appreciated and are signs of cerebral edema. If found, this needs to be treated immediately.[16]

Evaluation

Commonly accepted criteria for diabetic ketoacidosis are blood glucose greater than 250 mg/dl, arterial pH less than 7.3, serum bicarbonate less than 15 mEq/l, and the presence of ketonemia or ketonuria. The normal anion gap is 12 mEq/l. Anion gap greater than 14-15 mEq/l indicates the presence of an increased anion gap metabolic acidosis.[17] Arterial pH may be normal or even raised if other types of metabolic or respiratory alkalosis coexist. Typical examples are vomiting or diuretic use.[18] Blood glucose may be normal or minimally elevated in patients with DKA (<300 mg/dl), where the underlying risk of hypoglycemia preexists, such as in patients with alcohol use disorder or patients receiving insulin or SGLT2 inhibitors. 

The majority of patients with DKA who present to the hospital are found to have leukocytosis. Serum sodium in the lab report is falsely low in DKA and can be corrected by adding 1.6 mEq to the measured serum sodium for each 100 mg/dl of glucose above 100 mg/dl. Serum potassium is usually elevated because of a shift of potassium from the intracellular to the extracellular space caused by acidosis and insulin deficiency. However, total body potassium may be depleted or may quickly become depleted with insulin administration. Magnesium is often low and requires repletion as well. The serum phosphate level in DKA may be elevated despite total-body phosphate depletion.[19] 

Other tests like cultures of urine, sputum, and blood, serum lipase, and chest radiograph may need to be performed depending upon the case. Pneumonia and urinary tract infections are the most common infections precipitating DKA. Measurement of glycated hemoglobin (A1C) provides information about glucose trends over months.

In acute DKA, the ketone body ratio (3-beta-hydroxybutyrate:acetoacetate) rises from normal (1:1) to as high as 10:1. In response to insulin therapy, 3-beta-hydroxybutyrate (3-HB) levels commonly decrease long before acetoacetate (AcAc) levels. The frequently employed nitroprusside test only detects acetoacetate in blood and urine. This test provides only a semiquantitative assessment of ketone levels and is associated with false-positive results. Recently, inexpensive quantitative tests of 3-HB levels have become available for common use, and these tests offer options for monitoring and treating diabetes and other states characterized by the abnormal metabolism of ketone bodies.[20]

The serum level of pancreatic enzymes is elevated in DKA due to disorder in carbohydrate metabolism.[21] In DKA, patients presenting with abdominal pain and elevated pancreatic enzymes should not be diagnosed with acute pancreatitis promptly.[22] In the case of a dilemma, imaging like a CT scan would help in distinguishing mild to moderate elevation of enzymes due to DKA from acute pancreatitis. Lipid derangement is commonly seen in patients with DKA. In one study, before insulin treatment, mean plasma triglyceride and cholesterol levels were 574 mg/dl (range 53 to 2355) and 212 mg/dl (range 118 to 416), respectively. Insulin therapy resulted in rapid decreases in plasma triglyceride levels below 150 mg/dl at 24 hours. Plasma apoprotein (apo) B levels were in the normal upper range (101 mg/dl) before treatment and decreased with therapy due to significant decreases in VLDL, but not IDL or LDL apoB.[23]

An ECG will help detect ischemic changes or signs of hypokalemia or hyperkalemia. Peaked T waves can signal hyperkalemia, and low T waves with U wave indicating hypokalemia.

Imaging: A chest X-ray may be done to rule out consolidation. MRI, and to some degree, CT imaging of the head can detect cerebral edema, but imaging should not delay treatment if cerebral edema is suspected.

Treatment / Management

Fluid resuscitation and maintenance, insulin therapy, electrolyte replacement, and supportive care are the mainstays of management in diabetic ketoacidosis. 

Hydration

In patients with DKA, the fluid deficit could be up to 10-15% of the body weight.[1] Immediate fluid resuscitation is vital to correct hypovolemia, restore tissue perfusion, and to clear ketones. Hydration improves glycemic control independent of insulin. 

Choice of Fluids 

Isotonic fluids have been well established for more than 50 years as preferred fluids. Colloids vs. crystalloids were compared for critically ill patients, in a 2013 meta-analysis, and crystalloid was found to be non-inferior.[24] Traditionally, 0.9% normal saline has been used. There has been a concern that normal saline may contribute to hyperchloremia and hyperchloremic metabolic acidosis; however, this typically occurs when it is used for large volumes. There have been small studies comparing normal saline with other solutions like Ringer lactate. These studies did not show differences in clinical outcomes.[25][26][27] Normal saline continues to be used for initial hydration. (A1)

Infusion Rate

Initial:

Infusion of 15-20 ml per Kg body weight in the first 1 hour is typically appropriate. Aggressive hydration with 1 liter/hour for 4 hours has been compared in a study to a slower rate of hydration at half the rate. Slower hydration was found to be equally effective.[28] However, in critically ill patients, including those with hypotension, aggressive fluid therapy is preferred. There has been extensive debate regarding the risk of cerebral edema in patients with aggressive early volume resuscitation. There are studies that have demonstrated rates of increased cerebral edema with aggressive volume, particularly in the pediatric population. Yet other studies show no difference in outcome and theorize that patients at greatest risk from cerebral edema present at a later stage and are the most severe volume depleted.[29](B2)

Maintainance:

The subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels, and urinary output.[1] In patients who have high serum sodium level, 0.45% NaCl infused at 4–14 ml/kg/hour or 250–500 mL/hr is appropriate, and for patients with hyponatremia, 0.9% NaCl at a similar rate is preferred.[30] Maintenance fluids may need to be adjusted if hyperchloremic metabolic acidosis becomes a concern, then you can switch to the Ringer lactate solution.

Insulin Therapy

The discovery of insulin, along with the antibiotics, has led to a drastic decrease in mortality with DKA, down to 1%. Intravenous insulin by continuous infusion is the standard of care. Previous treatment protocols have recommended the administration of an initial bolus of 0.1 U/kg, followed by the infusion of 0.1 U/kg/h. A more recent prospective randomized trial demonstrated that a bolus is not necessary if patients are given hourly insulin infusion at 0.14 U/kg/hr.[31] When the plasma glucose reaches 200-250 mg/dl, and if the patient still has an anion gap, then dextrose containing fluids should be initiated, and the insulin infusion rate may need to be reduced. (A1)

Treatment of adult patients who have uncomplicated, mild diabetic ketoacidosis can be treated with subcutaneous insulin lispro hourly in a non-intensive care setting may be safe and cost-effective as opposed to treatment with intravenous regular insulin in the intensive care setting as shown in many studies.[32] In one of these studies, the patients received subcutaneous insulin lispro at a dose of 0.3 U/kg initially, followed by 0.1 U/kg every hour until blood glucose was less than 250 mg/dl. Then insulin dose was decreased to 0.05 or 0.1 U/kg given every hour until the resolution of DKA.[32] Similarly, insulin aspart has been used and found to be similar in efficacy.[33](A1)

Patients with DKA should be treated with insulin until resolution. Criteria for resolution of ketoacidosis include blood glucose less than 200 mg/dl and two of the following criteria: a serum bicarbonate level >=more than 15 mEq/l, a venous pH more than 7.3, or a calculated anion gap equal or less than 12 mEq/l. Patients can be transitioned to subcutaneously administered insulin when DKA has resolved, and they are able to eat. Those previously treated with insulin might be recommended on their home dose if they had been well controlled.

Insulin-naive patients should receive a multi-dose insulin regimen beginning at a dose of 0.5 to 0.8 U/kg/day. To prevent the recurrence of ketoacidosis in the transition period, insulin infusion should be continued for 2 hrs after the starting of subcutaneous insulin and check blood sugar and complete metabolic profile again before stopping the insulin drip. If the patient cannot tolerate oral intake, intravenous insulin, and fluids may be continued. The use of long-acting insulin analogs during the initial management of DKA may facilitate the transition from intravenous to subcutaneous insulin therapy.[34] 

Electrolyte Replacement

Potassium

Patients with DKA are often found to initially have mild to moderate hyperkalemia, despite a total body deficit of potassium. The initiation of insulin causes an intracellular shift of potassium and lowers the potassium concentration, potentially resulting in severe hypokalemia.[35][36] Hence patients with serum potassium levels of less than 3.3 mmol/L need initial management with fluid resuscitation and potassium replacement while delaying commencement of insulin until after potassium levels are above 3.3 mmol/L, to avoid cardiac arrhythmias, arrest, and respiratory muscle weakness.[34] In other patients, potassium replacement should be started when the serum concentration is less than 5.2 mEq/L to maintain a level of 4 to 5 mEq/L. The administration of 20 to 30 mEq of potassium per liter of fluids is sufficient for most patients; however, lower doses are required for patients with acute or chronic renal failure.[37] (B3)

Magnesium

Hypokalemia is commonly associated with hypomagnesemia. Repletion of both potassium and magnesium may need to be done, and it may be difficult to improve potassium levels until magnesium levels are repleted.

Bicarbonate

Bicarbonate replacement does not appear to be beneficial. In one study, the difference in time to resolution of acidosis (8 hours vs. 8 hours; p = 0.7) and time to hospital discharge (68 hours vs. 61 hours; p = 0.3) was found to be statistically insignificant between patients who received intravenous bicarbonate (n = 44) compared with those who did not (n = 42).[38] In another pediatric study, children with diabetic ketoacidosis who have low PaCO2 and high BUN concentrations at presentation and those treated with bicarbonate were at increased risk for cerebral edema.[39] Proposed pitfalls of the use of sodium bicarbonate therapy in DKA may include paradoxical CSF acidosis, hypokalemia, large sodium bolus, and cerebral edema. However, it may be used in patients with severe acidemia. The most recent ADA guidelines do recommend the use of sodium bicarbonate therapy in patients with pH less than 7.1.[38](B2)

Phosphate

The role of phosphate replacement in DKA has been looked at in different studies. In one randomized study with 44 patients, phosphate therapy did not alter the duration of DKA, insulin dosage required to correct the acidosis, abnormal muscle enzyme levels, glucose disappearance, or morbidity and mortality. Although theoretically appealing, phosphate therapy is not an essential part of the treatment for DKA in most patients, an unusual case of severe hypophosphatemia (1.0 mg/dl) related seizure in a child with diabetic ketoacidosis (DKA) has been described in the literature.[40](B3)

Laboratory Monitoring

• Hourly point-of-care testing (POCT) glucose should be performed

• Serum glucose and electrolyte levels may need to be done every 2 hours until the patient is stable, then every 4 hours

• Initial blood urea nitrogen (BUN)

• Initial VBG or ABG monitoring, followed by as-needed precipitating events

Intubation

There are multiple risks associated with intubation in patients with DKA. Intubation should be avoided if at all possible. Treating as above with a focus on administering fluids and insulin will almost always lead to an improvement in acidosis and overall clinical presentation. Patients attempt to compensate for severe acidosis by creating a compensatory respiratory alkalosis that manifests via tachypnea and Kussmaul breathing. If patients are no longer able to generate respiratory alkalosis due to comatose state or severe fatigue, intubation should be considered. However, the risks of intubation in DKA include a rise in PaCO2 during sedation and/or paralysis, which can decrease pH further, increasing the risk of aspiration due to gastroparesis, and difficulty matching the degree of respiratory compensation once the patient is on a ventilator. If a patient is intubated and placed on a ventilator, it is essential to attempt to match the patient's minute ventilation such that respiratory alkalosis is created to compensate for the metabolic acidosis of DKA. If not, there will be worsening acidosis, which can ultimately lead to cardiac arrest. It is reasonable to start with a tidal volume of 8 ml/kg based on ideal body weight and respiratory rate, similar to the patient's compensating respiratory rate. However, care should be taken that auto-PEEP is not occurring due to the rapid respiratory rate.[41]

Cerebral Edema

Mental status and neurologic exam should be monitored in all patients with DKA. In any patient who is severely obtunded or comatose or who has declining mental status despite treatment or focal neurologic deficits, there should be a very low threshold to treat for cerebral edema. Mannitol is typically the first-line agent, though there are also studies in both TBI literature and DKA literature regarding the use of 3% saline. 

Precipitating Events

Infection is a very common trigger for DKA in patients who have new-onset diabetes and previously established diabetes. If there is any suspicion of infection, antibiotics should be administered promptly. As discussed, there can be other events that trigger DKA as well. Treating both DKA and any other underlying etiologies should be done.

Differential Diagnosis

Diabetic ketoacidosis has a diverse presentation, and this is why several other common pathologies may mimic this diagnosis. It is imperative for the providers to consider the following differential diagnoses when the diagnosis of DKA is suspected:

• Hyperosmolar hyperglycemic nonketotic syndrome
• Starvation ketosis
• Myocardial infarction
• Pancreatitis
• Alcoholic ketoacidosis
• Lactic acidosis
• Sepsis 
• Toxicologic exposure (ethylene glycol, methanol, paraldehyde, salicylate)
• Diabetic medication overdose
• Uremia

Prognosis

Diabetic ketoacidosis still carries a mortality rate of 0.2 to 2.5% in developing countries. Patients who present in a comatose state, hypothermia, and oliguria tend to have the worst outcomes. For most patients treated promptly, the outcomes are good, especially if the trigger is not an infection. Elderly patients with concurrent illnesses such as myocardial infarction, pneumonia, or sepsis tend to have long hospital stays and high mortality.

The most important cause of mortality is cerebral edema, usually seen in younger patients. The cerebral edema is primarily due to the intracellular shifts. Another important cause of morbidity is renal dysfunction. A recent study has noted that among patients with type-2 diabetes mellitus who develop DKA, there is a high risk of stroke within the first six months after the event.

Complications

Hypoglycemia is the most common complication of diabetic ketoacidosis while being treated, occurring in an estimated 5–25% of patients with DKA.[37] Acute adverse outcomes of hypoglycemia include seizures, arrhythmias, and cardiovascular events. Hourly blood sugar monitoring is needed in the acute phase of treatment. 

Hypokalemia is common. Severe hypokalemia can cause muscle weakness, cardiac arrhythmias, and cardiac arrest.[8] Monitoring and management are described in this article under the DKA management section in detail. Other possible electrolyte disturbances are hyperchloremia, which can occur in up to 1/3rd of patients, and hypomagnesemia, and hyponatremia.[42]

Cerebral edema is less common in adults than in children. Risk factors include younger age, new-onset diabetes, longer duration of symptoms, the lower partial pressure of carbon dioxide, severe acidosis, low initial bicarbonate level, low sodium level, high glucose level at presentation, rapid hydration, and retained fluid in the stomach.[39]

Rhabdomyolysis may occur in patients with DKA though it occurs more commonly with HHS. It may result in acute kidney failure. Severe hypophosphatemia in relation to DKA can also cause rhabdomyolysis.[43]

Acute respiratory failure could be associated with DKA. Causes could be pneumonia, ARDS, or pulmonary edema. Two varieties of pulmonary edema in DKA have been recognized, secondary to elevated pulmonary venous pressure, and because of increased pulmonary capillary permeability.[44]

TTP and myocarditis have also been described with DKA.