EUGLYCEMIC DKA , The masquerading phenotype of DKA

Written By Darab Zohri



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Advancement in the treatment of diabetic mellitus with introduction of multiple new drugs and other therapeutic modalities is a double-edged sword. On one hand it has enabled us to choose appropriate therapeutic plan for selected patients; on the other hand we are faced with new picture of an old notoriously famous complication of diabetes mellitus, namely DKA.

Diagnostic criteria include high blood glucose, positive urinary or serum ketones, and increased blood acidity. But a relatively new challenge for us is a certain condition in which hyperglycemia is not clearly seen (i.e. there is a mild to moderate hyperglycemia), but there is an increase in acidity and the presence of ketones in the blood.

According to existing studies, this challenging condition, unlike known diabetic ketoacidosis, is more common in patients with type 2 diabetes. In a clinical study on 20 hospitalized diabetic patients (March 2013 to June 2014) who had mild to moderate hyperglycemia, acidosis and ketonemia were observed, which according to previous data did not meet the criteria for diabetic ketoacidosis. [1]

Diabetic ketoacidosis (DKA) has a diagnostic triad including metabolic acidosis, hyperglycemia, and increased body ketones in the blood and urine. Hyperglycemia is usually an important diagnostic hallmark of diabetic ketoacidosis, but there is a complication called Euglycemic Diabetic Ketoacidosis(EDKA) , which is characterized by a triad of high anion gap metabolic acidosis , ketonemia or ketonuria, and blood glucose less than 250 mg / dL.

This phenomenon was first described and introduced in 1973 by Munro et al.

This diagnosis is very challenging and requires high level of clinical suspicion since the hallmark of diabetic emergencies which include high blood glucose on the lab, is absent in this condition.

EDKA should be distinguished from other causes of ketoacidosis, such as ketoacidosis due to starvation and alcoholic ketoacidosis, which can be differentiated based on the patient’s history and bicarbonate level (bicarbonate in starvation ketoacidosis is usually above 18 meq / l.)


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Controlling blood sugar in our body is normally the result of balancing the function of insulin and counter regulatory hormones such as glucagon, growth hormone, glucocorticoids and epinephrine. DKA occurs when this balance is disturbed, which means that insulin levels decrease or counter-regulatory hormones increase, both of which result in high blood sugar.

Hyperglycemia in the absence of proper insulin function or lack of it, leads to inadequate utilization of glucose, increased lipolysis and the formation of ketone bodies. Ketone bodies are produced by the liver as an alternative energy source when sufficient glucose is not available to the tissues. [2], [3] , [4]

The New generation of drugs for diabetes mellitus (SGLT2 inhibitors), such as canagliflozin , dapagliflozin , empagliflozin , or ertugliflozin can directly cause EDKA.

It is more common in patients who consume these medications and have lower body mass index and lower glycogen stores.

The main mechanism of EDKA includes decreased production of glucose by the liver during prolonged fasting or increased urinary glucose secretion due to increased counter regulatory hormones. Therefore, when a diabetic patient is exposed to triggers of DKA and at the same time, is starving or fasting, or being treated with insulin at the usual dose, the liver is in a state of glycogen deficiency and produces less glucose. In other words, lipolysis and production of fatty acids and finally production of body ketones occurs in the liver.

Some common causes of this condition include anorexia, gastroparesis [5] , ketogenic diets, alcoholism, inadequate calorie intake, prolonged fasting or starvation, pregnancy [6] , pancreatitis [7] , [8] , cocaine poisoning, prolonged diarrhea or vomiting [9] , use an insulin pump [10] , glycogen storage diseases, surgery, use of SGLT2 inhibitors [10] , [11] and etc.

The mechanism of SGLT2 inhibitors is to increase excretion and prevent reabsorption of filtered glucose from the proximal tubule. Decreased glucose in the urine causes carbohydrate starvation and volume depletion. As a result, the ratio of glucagon to insulin increases, leading to severe dehydration and ketosis.

SGLT2 inhibitors also stimulate the secretion of glucagon directly from the pancreas, which impairs the balance of glucagon, insulin, and prevents the excretion of beta-hydroxybutyrate and acetoacetate by the kidneys .[11] , [12]


Dehydration usually causes hyperglycemia. However, it is interesting to know the different role of dehydration in pathogenesis of EDKA. Fasting causes the secretion of counter regulatory hormones, especially glucagon, resulting in a decrease in glycogen stores in the body, and dehydration acts as a stimulus for the secretion of more glucagon, which leads to lipolysis and the production of ketone bodies. This ultimately leads to the EDKA.

Pregnancy is one of the risk factors for EDKA due to its unique physiological status (hypoinsulinemia and starvation). Elevated levels of cortisol and placental lactogen increase insulin resistance, resulting in elevated post-prandial glucose. Multiple episodes of nausea and vomiting and oral intolerance lead to increased starvation-induced ketosis. Progesterone also reduces gastrointestinal motility and increases glucose reabsorption. On the other hand, respiratory alkalosis during pregnancy causes the excretion of bicarbonate through urine and exacerbates acidosis. [6]

Patients with alcoholic ketoacidosis can present with the same manifestations of EDKA, such as anorexia, nausea and vomiting, overt metabolic acidosis with high anion gap, and ketonemia.

Some experts consider alcoholic ketoacidosis, as a subtype of EDKA. (Due to the fact that the ratio of glucagon to insulin has increased in both diseases)

In distinguishing alcoholic ketoacidosis with EDKA, It is well worthy to mention that patients with the former condition have no history of using diabetes control medications, and symptoms of alcoholic ketoacidosis develop after an episode of alcohol abuse. In addition, patients with alcoholic ketoacidosis are usually hypoglycemic.

Similarly, excessive alcohol consumption in a diabetic person can destroy pancreatic beta cells, decrease gluconeogenesis and decrease glucose stores, and if nausea and vomiting and food intolerance occur, can accelerate the process of lipolysis, ketoacidosis and EDKA.

Diagnosis of EDKA is difficult and requires exclusion of other similar diagnoses and other causes of high anion gap metabolic acidosis with elevated ketone bodies such as toxic alcohol poisoning, lactic acidosis, drug poisoning and etc.

Signs and symptoms

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The clinical presentation of the disease may be different in patients. Similar manifestations of DKA such as nausea, vomiting, drowsiness, shortness of breath, generalized malaise, Fatigue and loss of appetite may be present. However, due to low blood glucose, symptoms such as polyuria, polydipsia, and changes in consciousness may not be very common.

The onset of the disease may be more subtle than DKA. Deep, rapid breathing (kussmaul respiration) with a compensatory respiratory mechanism may be present in severe metabolic acidosis. There may also be tachycardia, hypotension, altered mentation, increased skin turgor and delayed capillary refill , indicating a total body fluid depletion. In very severe cases, dehydration and severe metabolic disorders can lead to hypovolemic shock, lethargy, respiratory distress, coma, and even death.

Lab Evaluation

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In all ill-feeling diabetic patients with symptoms of dyspnea, nausea, vomiting, and malaise, screening for blood gases and blood or urine ketone testing should be performed.

Upon positive screening results; more comprehensive laboratory tests including electrolytes, glucose, renal function test, serum beta-hydroxybutyric acid, serum lactic acid, chest x-ray, and ECG should be requested.

Urine screening with nitroprusside reagent is not able to measure beta-hydroxybutyrate but can detect acetone and acetoacetate.

Serum levels of beta-hydroxybutyrate in EDKA are typically above 3 mmol / L (normal: less than 0.5 mmol / L)

If infection is suspected, a CBC diff, and blood, urine culture may be considered.

Measurement of serum osmolality, osmolar gap, serum ethanol level are also helpful.

As mentioned, EDKA diagnostic criteria include:

  1. glucose less than 250 mg / dL (normoglycemia)
  2. metabolic acidosis (pH less than 7.3)
  3. bicarbonate less than 18 meq / l.

The presence of ketone bodies in the blood and urine is essential for diagnosis.

Lactic acid may be high. Leukocytosis may occur due to infection, hemoconcentration, or stress, which is a nonspecific finding. Serum potassium may be high, low, or normal, but it is important to know the serum potassium level before starting treatment and to note that the total body potassium is usually low.

Hypomagnesemia and hypophosphatemia are seen in the state of starvation, which can be due to both decreased intake and increased excretion. Mild hyponatremia may be present as well.

Differential diagnosis of DKA

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Initial treatment should focus on patient resuscitation and appropriate fluid administration. IV Fluid choices include isotonic fluid such as plasmalyte or ringer`s lactate. 1 to 1.5 liters of isotonic fluid should be given within the first one to two hours, depending on the patient’s condition.

Normal saline reduces bicarbonate and is not recommended due to worsening acidosis (Normal saline infusion causes hyperchloremic metabolic acidosis).

This can be a problem, especially in patients with very low bicarbonate levels and failure of the potassium to decrease significantly despite insulin infusion may reflect potassium shifting out of the cells in response to the hyperchloremic metabolic acidosis. [17]

Insulin infusion is the second step of treatment, which should be started if K> 3.3 meq / l at a dose of 0.05 – 0.1 u / kg / hr.

Unlike DKA, since serum glucose is less than 250 mg / dl from the beginning in EDKA, D5W should be part of the fluid therapy protocol from the beginning (to prevent hypoglycemia and speed up the treatment of ketosis) and in the case of failure of treatment (resisistant-ketoacidosis) should be replaced with D10W.[13]

The proposed protocol is that isotonic fluid (ringer`s lactate or plasmalyte) is started at a rate of 1 to 1.5 liters in the absence of cardiovascular disease, renal failure (and other conditions which put limit on fluid administration) within the first one to two hours. Continuation of fluid therapy depends on the patient’s hydration status, electrolytes, serum glucose, and urinary output. D5W or D10W should be added to the prescribed fluid to maintain a serum glucose level of approximately 150-200 mg / dl in order to prevent hypoglycemia and to administer insulin to treat ketonemia and acidosis.

Normally, after infusion of a bolus dose of ringer`s lactate, depending on the patient’s dehydration and clinical evaluation, administration of D5W with ringer`s lactate at a rate of 200-400 cc / hr is appropriate at the beginning of treatment.

It is possible to make a fluid mixture of equal volume, including 5 or 10% dextrose and ringer`s lactate, as these liquids are compatible and can be infused through a vein (this solution which dose not exist in pre-mixed bags).

If serum sodium is low or is isotonic saline is needed for any reason, 5% dextrose with 0.9% saline can be prescribed. [14]

Frequent assessment of the patient’s fluid and electrolyte status, cardiovascular (e.g. with ultrasonography), renal, and mental status is especially important in the first few hours to prevent cerebral and pulmonary edema in all patients. [15]

Regular intravenous insulin should be started at a dose of 0.1 u / kg / hr (it is not necessary to give a bolus insulin dose.)

Note that the main problem in DKA and EDKA is not glucose levels, but is ketoacidosis, and the goal of insulin therapy is not to control blood glucose but to eliminate the ketosis.

Potassium levels should be monitored carefully, as the body’s total potassium levels are usually low and there may be a need for IV potassium replacement. Serum potassium levels should be maintained in the range of 4-5 meq / l. Normally adding 20-30 meq of potassium per liter of the prescribed fluid is sufficient to achieve this goal.

In the presence of obvious hypokalemia, the addition of potassium to the prescribed fluid is necessary and insulin administration should be delayed until potassium normalizes (above 3.3 meq / l).

The goal of DKA treatment is to achieve at least two of the following criteria: [14], [16]

  1. PH > 7.3
  2. Serum bicarbonate level > 15
  3. Anion gap < 12

Blood glucose should be checked every hour and electrolytes every four hours. Patients treated with SGLT2 inhibitors should stop taking the drug as soon as EDKA is diagnosed. Deciding to start the medication again will be considered in case following resolution of the disease. [14]

Bicarbonate is usually not useful, even in severe acidosis. The patient should be admitted to the ICU and careful monitoring of electrolytes and glucose should be performed and fluid therapy should be given carefully until the anion gap closes and acidosis resolves.

Intubating patients with DKA/EDKA is a risky procedure and should be considered as a last resort. Complications of intubation include hemodynamic disturbances, increased risk of vomiting and aspiration (most of these patients have gastroparesis and ileus), and worsening of acidosis (suppression of compensatory respiratory alkalosis) must be noted.

For the patient’s respiratory support, HFNC is a very suitable method as it also eliminates carbon dioxide. (The use of BIPAP is also not suitable because of the patient vomiting due to gastroparesis, etc.)


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EDKA is a diagnostic challenge, not only due to the absence of hyperglycemia, but also for its varied triggers.

Diagnosis is very challenging because normoglycemia masquerade the underlying ketoacidosis.

Unlike DKA, due to normoglycemia in EDKA, dextrose water should be added to the initial prescribed fluid ,to prevent the side effects of hypoglycemia.

Normal saline reduces bicarbonate and is not recommended due to worsening acidosis. Balanced crystalloid is preferred here (e.g. plasmalyte or Ringer`s lactate)

Avoid early intubation. Intubation can suppress the compensatory respiratory alkalosis of these patients.

Going further:

1.Anatomy of a DKA resuscitation (EMCrit)

2.Four DKA Pearls (EMCrit)

3.Euglycemic DKA : It`s not a Myth (REBELEM)

Post Peer Reviewed By: Shahriar Lahouti.MD ; Mojtaba Chardoli.MD



  1. Munro JF, Campbell IW, McCuish AC, Duncan LJ. 1973. Euglycaemic diabetic ketoacidosis. BMJ 2578–580. (10.1136/bmj.2.5866.578) 

  1. Modi A,Agrawal A,Morgan F, Euglycemic Diabetic Ketoacidosis: A Review. Current diabetes reviews. 2017;  

  1. Yu X,Zhang S,Zhang L, Newer Perspectives of Mechanisms for Euglycemic Diabetic Ketoacidosis. International journal of endocrinology. 2018;  

  1. Burge MR,Garcia N,Qualls CR,Schade DS, Differential effects of fasting and dehydration in the pathogenesis of diabetic ketoacidosis. Metabolism: clinical and experimental. 2001 Feb;

  1. Legaspi R,Narciso P, Euglycemic Diabetic Ketoacidosis Due to Gastroparesis, A Local Experience. The Journal of the Arkansas Medical Society. 2015 Sep;

  1. Guo RX,Yang LZ,Li LX,Zhao XP, Diabetic ketoacidosis in pregnancy tends to occur at lower blood glucose levels: case-control study and a case report of euglycemic diabetic ketoacidosis in pregnancy. The journal of obstetrics and gynaecology research. 2008 Jun;

  1. Nyenwe EA,Kitabchi AE, The evolution of diabetic ketoacidosis: An update of its etiology, pathogenesis and management. Metabolism: clinical and experimental. 2016 Apr;

  1. Prater J, Chaiban J. 2015. Euglycemic diabetic ketoacidosis with acute pancreatitis in a patient not known to have diabetes. Endocrine Practice 1 e88–e91. (10.4158/

  1.  Abdin AA, Hamza M, Khan MS, Ahmed A. 2016. Euglycemic diabetic ketoacidosis in a patient with cocaine intoxication. Case Reports in Critical Care 2016 Article ID: 4275651. (10.1155/2016/4275651) 

  1.  Modi A, Agrawal A, Morgan F. 2017. Euglycemic diabetic ketoacidosis. Current Diabetes Reviews 13315–321. (10.2174/1573399812666160421121307)

  1.  Qui H, Novikov A, Vallon V. 2017. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: basic mechanisms and therapeutic perspectives. Diabetes/Metabolism Research and Reviews 33 e2886 (10.1002/dmrr.2886)

  1.  Rosenstock J, Ferrannini E. 2015. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38 1638–1642. (10.2337/dc15-1380)

  1. Bader N,Mirza L, Euglycemic Diabetic Ketoacidosis in a 27 year-old female patient with type-1-Diabetes treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor Canagliflozin. Pakistan journal of medical sciences. 2016 May-June

  1. Goldenberg RM,Berard LD,Cheng AYY,Gilbert JD,Verma S,Woo VC,Yale JF, SGLT2 Inhibitor-associated Diabetic Ketoacidosis: Clinical Review and Recommendations for Prevention and Diagnosis. Clinical therapeutics. 2016 Dec;

  1. Joseph F,Anderson L,Goenka N,Vora J, Starvation-induced true diabetic euglycemic ketoacidosis in severe depression. Journal of general internal medicine. 2009 Jan;     

  1. Peters AL,Buschur EO,Buse JB,Cohan P,Diner JC,Hirsch IB, Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes care. 2015 Sep;     

  1. Chua HR, Venkatesh B, Stachowski E, et al. Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. J Crit Care. 2012;27(2):138-145. doi:10.1016/j.jcrc.2012.01.007


Darab Zohri

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