presentation of euglycemic dka

Management of Euglycemic Diabetic Ketoacidosis

Daniya S. Mathew, PharmD Candidate 2022 St. John’s University College of Pharmacy and Health Sciences Queens, New York Kimberly E. Ng, PharmD, BCPS Associate Professor Department of Clinical Health Professions St. John’s University College of Pharmacy and Health Sciences Queens, New York Elsen C. Jacob, PharmD, MS, BCPS, BCGP, CPPS Assistant Professor Department of Clinical Health Professions St. John’s University College of Pharmacy & Health Sciences Queens, New York

US Pharm. 2021;46(11):HS1-HS6.

ABSTRACT: Euglycemic diabetic ketoacidosis (EDKA) is a rare, acute, life-threatening emergency that is characterized by euglycemia, metabolic acidosis, and ketoacidosis. Unlike DKA, the diagnosis of EDKA is often overlooked because of the absence of hyperglycemia. The mechanism behind EDKA involves a general state of starvation that results in ketosis while normoglycemia is maintained. EDKA may be associated with precipitating factors, including sodium-glucose cotransporter 2 inhibitors, starvation, pregnancy, alcohol use, surgery, and drug-induced intoxication. A stepwise approach is used in the management of EDKA. Pharmacists can assist the medical team in preventing EDKA and can play a role in the management of EDKA.

The management of type 1 and type 2 diabetes mellitus (T1DM, T2DM) has evolved with the availability of various antidiabetic agents. 1 Biguanides—most notably metformin—have been used in conjunction with sulfonylureas, thiazolidinediones, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors to treat T2DM. 2 Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the newest class of oral diabetes medications. 3 Besides maintaining glycemic control, SGLT2i also demonstrate cardiovascular and renal benefits. Therefore, SGLT2i have quickly become a mainstay of therapy in diabetes management. 4 However, euglycemic diabetic ketoacidosis (EDKA) has emerged as a rare but serious adverse effect associated with SGLT2i. The risk of EDKA from SGLT2i is increased sevenfold in patients with T2DM, with an estimated overall incidence of approximately 0.1%. 5,6 Pharmacists should be well versed in EDKA and its precipitating factors in order to educate patients and clinicians on the signs and management of EDKA in patients taking SGLT2i.

DKA, a life-threatening complication of diabetes, is characterized by the triad of hyperglycemia, metabolic acidosis, and ketoacidosis. Left untreated, DKA can lead to severe dehydration, cerebral edema, and coma. Hyperglycemia is a key criterion in the diagnosis of DKA; however, approximately 2.6% to 3.2% of DKA admissions are cases of EDKA, in which metabolic acidosis and ketoacidosis are accompanied by euglycemia. See TABLE 1 . 1,7-9

Pathophysiology

The mechanism behind EDKA involves a general state of starvation that results in ketosis while normoglycemia is maintained. 1 Simply put, EDKA is DKA in which normal glucose concentrations are present. Diabetic patients, especially those on insulin, may not recognize symptoms as DKA because the serum glucose is not elevated. 1 In the presence of a carbohydrate deficit due to precipitating factors, there is a reduction in serum insulin and an excess of glucagon, epinephrine, and cortisol. 9 The increase in glucagon and decrease in insulin shift the metabolism toward lipolysis, an increase in free fatty acids (FFAs), and ketoacidosis. 1 Ketone bodies—including acetoacetic acid, beta-hydroxybutyric acid, and acetone—are released, resulting in metabolic acidosis. 1 Other factors that can contribute to EDKA are 1) the decrease in hepatic glucose production during a fasting state when glycogen stores are already depleted and 2) the increased urinary excretion of glucose. 1

EDKA Precipitating Factors

SGLT2i: In the United States, SGLT2i (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) are currently approved to treat only T2DM, not T1DM. SGLT2i have demonstrated additional benefits for cardiovascular disease, chronic kidney disease, and heart failure. In fact, dapagliflozin is the only member of this class that has been approved for heart failure treatment regardless of a T2DM diagnosis. 10 In Europe, dapagliflozin is approved for use in T1DM patients with a BMI of 27 kg/m 2 or higher. 10 The FDA has yet to approve SGLT2i as an adjunct to insulin in T1DM patients, owing to the increased risk of fatal DKA. 11 Off-label use of SGLT2i has led to several documented cases of EDKA. 10 SGLT2i prevent reabsorption of glucose by blocking sodium-dependent glucose transporter 2 in the proximal convoluted tubule. This mechanism enhances urinary excretion of glucose, resulting in lower plasma glucose concentrations. 5 Low plasma glucose concentrations, in turn, create a carbohydrate deficit and volume depletion, stimulating glucagon secretion and suppressing insulin production. SGLT2i also directly stimulate the release of glucagon from the pancreas. The resulting lipolysis and ketogenesis are further worsened by the ability of SGLT2i to increase ketone reabsorption. The use of SGLT2i, combined with other precipitating factors, such as starvation (low-caloric diet), pregnancy, alcohol, acute infection, and procedures, can exacerbate EDKA. Reduced serum glucose, reduced insulin, increased glucagon release, and reduced clearance of ketones are contributors to EDKA in patients taking SGLT2i. Nondiabetic patients who are initiated on these medications may be at risk for developing EDKA. A study involving the administration of SGLT2i in healthy nondiabetic rats found that when they were exposed to volume-depleting stress, the rats developed EDKA. 12

On May 15, 2015, the FDA issued a warning that SGLT2i may cause DKA in T1DM and T2DM patients. 13 In the FDA Adverse Event Reporting System database, 73 cases of ketoacidosis in patients with T1DM or T2DM were reported from March 2013 to May 2015. 5,13 All patients required hospitalization or treatment in an emergency department (ED). 13 Treatment in these cases was delayed until the presentation of normal blood glucose (BG) concentrations. On March 19, 2020, the FDA issued an update regarding the risk of EDKA development after surgery in patients on SGLT2i. 13 Canagliflozin, dapagliflozin, and empagliflozin should be stopped at least 3 days prior to a procedure, and ertugliflozin should be stopped at least 4 days prior. 3,13

Low Caloric Intake or Starvation: A low-caloric diet or starvation in a patient with or without diabetes can trigger EDKA. 14 A reduction in dietary uptake, especially carbohydrates, leads to the use of FFAs and ketones as the primary source of energy. 8 Lipolysis and ketogenesis occur during prolonged fasting and lead to ketoacidosis. Glycogen stores are also entirely depleted, resulting in ketoacidosis with euglycemia. One case report described a 51-year-old female with no history of diabetes or excessive alcohol use who presented to the ED with altered general status, nausea, vomiting, deep asthenia, and articular pain after engaging in a 4-day restrictive diet followed by 48 hours of fasting. 15 Her laboratory tests indicated a pH of 7.2, BG of 8 mmol/L (160 mg/dL), anion gap of 23 mmol/L, and positive serum lactate and ketone bodies. The patient recovered from ketoacidosis within 48 hours of glucose infusion without the need for insulin. 15 In a similar case, a 24-year-old male without a history of diabetes or excessive alcohol use presented to the ED with shortness of breath, tachypnea, and sinus tachycardia after 3 days of fasting caused by nausea and vomiting. 16 His laboratory tests indicated a pH of 7.09, BG of 6 mmol/L (106 mg/dL), high anion gap, normal lactate, and positive urine ketones. The patient recovered from ketoacidosis within 12 hours of being started on IV dextrose with no insulin. 16

Pregnancy: Ketoacidosis in pregnancy is detrimental not only to the mother but also to the developing fetus, as it is linked to high fetal mortality rates. 17 Pregnancy creates intrinsic physiological changes that predispose those with T1DM, T2DM, or gestational diabetes mellitus (GDM) to ketoacidosis. 18 From 0.8% to 1.1% of DKA cases in pregnant women are EDKA. 18 Pregnancy creates an insulin-deficient state because of placentally derived hormones, including glucagon, cortisol, and human placental lactogen, which are produced during periods of stress. Decreased insulin sensitivity is considered a physiological mechanism for delivering glucose to the developing fetus and placenta, which in turn reduces maternal BG concentrations. 19 The insulin resistance increases with gestational age and may be exacerbated when coupled with prolonged fasting in the second and third trimesters. Maternal metabolism, as a result, is diverted to lipolysis for energy. 19 One study discovered significant production of FFAs and beta-hydroxybutyrate after 12 hours of fasting in pregnant women in their third trimester, compared with nonpregnant women. 20 Several cases of EDKA in pregnant women with T1DM, T2DM, or GDM have been reported in the third trimester (32-37 weeks’ gestation); patients had an average age of 30 years and BG of 110 mg/dL. 17

Acute Onset of Infection: An acute onset of infection in diabetic and nondiabetic patients may also cause EDKA. One case report described a nondiabetic female with a known history of alcoholism who presented with metabolic acidosis and acute pancreatitis. 21 The patient had not eaten for >1 week. The acidosis improved only after EDKA was suspected, insulin infusion dextrose was administered, and fluid/electrolyte abnormalities were addressed. 21 Another case report involved a 76-year-old nondiabetic female with a history of low caloric intake and alcohol abuse who presented with septic shock due to acute obstructive cholangitis and EDKA. 22 Sepsis can increase levels of counterregulatory hormones and insulin resistance, and these changes can induce ketogenesis in persons without diabetes. Septic shock can also induce renal dysfunction, leading to decreased excretion of ketones.

Drug-Induced Intoxication: Drug-induced intoxication, including that caused by cocaine, has been identified as a potential cause of EDKA. A case report described a 57-year-old female with T2DM who presented to the ED with altered mental status, nausea, vomiting, and abdominal pain. 23 The patient was nonadherent to insulin monotherapy and reported poor oral intake. Laboratory results indicated urine positive for ketones and cocaine, pH of 7.02, and anion gap of 46. 23 Cocaine has been reported to be a trigger for hyperglycemia because of its stimulatory effect on cortisol, epinephrine, and norepinephrine release from the adrenal gland. 23,24 Conversely, cocaine can suppress the feeding centers in the central nervous system, resulting in a state of anorexia. 24

Surgery: The American Association of Clinical Endocrinologists and the American College of Endocrinology recommend stopping SGLT2i at least 24 hours before an anticipated surgery, procedure, or stressful physical activity (e.g., marathon running). 25 However, several case reports suggest that the effects of SGLT2i persist beyond five half-lives of elimination (2-3 days), with glucosuria and ketonemia present even 8 to 10 days after discontinuation. 26 One case report described a 50-year-old female with T2DM who presented to the ED with constipation, fatigue, and reduced oral intake for 3 days prior to admission. 26 The patient discontinued her regimen of metformin and dapagliflozin 2 days prior to admission. Laboratory results revealed acidosis with a pH of 7.34, elevated anion gap, beta-hydroxybutyrate, severe hypokalemia, hypophosphatemia, and acute kidney injury. Despite discontinuation of dapagliflozin 2 days prior to admission, glucosuria and ketoacidosis were seen for 8 days after the last use of dapagliflozin. 26 In a review of nine cases of EDKA in both T1DM and T2DM patients, four patients in the T1DM subset had recurrent EDKA when restarted on SGLT2i and one patient presented with ketonuria 48 hours after discontinuation of canagliflozin. 27 In a T2DM patient taking canagliflozin prior to a scheduled surgery, metabolic recovery did not occur until 6 days following the last dose of canagliflozin. 27

TABLE 2 outlines a stepwise approach to the management of EDKA. 2,7,9,28-31

Step 1—Stop Inciting Agent, if Applicable: In the case of EDKA induced by SGLT2i or drug intoxication, the inciting agent(s) must be discontinued as soon as EDKA is diagnosed. 1,7 An appropriate medication reconciliation is important to assist in establishing differential diagnoses including EDKA as well as helping determine optimal management.

Step 2—Start Fluid Replacement With Monitoring of Electrolytes and Ketones: Fluid resuscitation should be the focus of initial management in EDKA. 28 Fluid loss due to EDKA can range from 6 L to 9 L, and rehydration is necessary for adequate tissue perfusion and resolution of metabolic abnormalities. 28 The American Diabetes Association recommends 1 L/hour to 1.5 L/hour of normal saline or lactated Ringer’s solution during the first 1 to 2 hours of fluid resuscitation. 28 Treatment with IV fluid supplementation should continue as appropriate based on patient factors until the anion gap closes and acidosis has resolved. 28 Ketones and electrolytes should be monitored hourly and every 2 hours, respectively, until blood ketones are <0.6 mmol/L and electrolytes are stabilized. 32

Step 3—Start Continuous Insulin Infusion: Despite the absence of hyperglycemia in EDKA, insulin plays an important role in the treatment and management of EDKA. 7 Insulin suppresses the formation of ketones by promoting utilization of glucose via decreasing gluconeogenesis and glycogenolysis. 28 Adequate fluid replacement should be followed by continuous insulin infusion, starting at a rate of 0.05 U/kg/hour to 0.1 U/kg/hour with serum potassium levels >3.3 mEq/L. 1,2,33 Insulin causes intracellular movement of potassium into muscle cells. Therefore, if hypokalemia is present, insulin therapy should be delayed until potassium normalizes. Adequate monitoring of potassium levels should be conducted every 2 hours until electrolyte stabilization. 32 Once EDKA has resolved, the patient may be started on SC long-acting insulin and premeal rapid-acting insulin to control BG. The insulin infusion should be continued for at least 1 hour after SC insulin is given. 28

Step 4—Start Dextrose Administration: EDKA treatment requires that dextrose 5% (D5W) be added to fluids because of BG concentrations <250 mg/dL. 1 Dextrose must be given to restore normal cellular utilization, resulting in enhanced clearance and reduced production of ketone bodies. 29 The addition of D5W to fluids also prevents hypoglycemia by serving as an exogenous source of glucose in the setting of insulin utilization. 1,29 If ketoacidosis persists despite administration of D5W, dextrose 10% may be used. 9,30,33

The Pharmacist’s Role

Discussion With the Medical Team: EDKA can be a diagnostic challenge for clinicians owing to the absence of hyperglycemia from the otherwise typical presentation of DKA. Failure to recognize EDKA can result in delayed treatment, leading to serious complications such as cerebral edema and coma. The incidence of EDKA has grown with the introduction of SGLT2i, but this condition can also be seen in pregnancy, starvation, infection, and surgery. EDKA must be suspected in any patient presenting with metabolic acidosis and ketoacidosis, even in the presence of euglycemia. Pharmacists must educate the medical team regarding preventive measures, such as withholding SGLT2i treatment prior to a procedure as well as managing EDKA. Pharmacists can also play a key role in conducting comprehensive medication reconciliations and educating providers about the risk of EDKA in patients on SGLT2i therapy.

Discussion With the Patient: Patients may not recognize EDKA because of the normal BG concentration. Pharmacists must counsel patients on the presentation of EDKA, including nausea, vomiting, shortness of breath, lethargy, loss of appetite, fatigue, and abdominal pain. 1 Patients with diabetes or with conditions predisposing them to EDKA should be educated about the signs and symptoms of ketoacidosis despite normal BG concentrations. To prevent EDKA, patients should be adherent to medications and consistently consume adequate meals throughout the day. Pharmacists must counsel patients about circumstances in which SGLT2i must be withheld, including prior to procedures, stressful physical activity (e.g., marathon running), acute illness, and low caloric intake.

EDKA is a high-risk yet obscure condition that can be challenging to diagnose and manage. As therapeutics experts, pharmacists are well suited to collaborate with other members of the healthcare team, as well as the patient, to identify risk factors for EDKA and to help appropriately manage this complex condition.

1. Plewa MC, Bryant M, King-Thiele R. Euglycemic diabetic ketoacidosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; January 2021. www.ncbi.nlm.nih.gov/books/NBK554570/. Accessed July 22, 2021. 2. American Diabetes Association. Standards of medical care in diabetes—2021. https://care.diabetesjournals.org/content/diacare/suppl/2020/12/09/44.Supplement_1.DC1/DC_44_S1_final_copyright_stamped.pdf. Accessed August 16, 2021. 3. Invokana (canagliflozin) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc; March 2016. 4. Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol . 2013;1(2):140-151. 5. Blau JE, Tella SH, Taylor SI, Rother KI. Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data. Diabetes Metab Res Rev . 2017;33(8):e2924. 6. Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care . 2015;38(9):1680-1686. 7. Bonora BM, Avogaro A, Fadini GP. Euglycemic ketoacidosis. Curr Diab Rep . 2020;20(7):25. 8. Rawla P, Vellipuram AR, Bandaru SS, Pradeep Raj J. Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma. Endocrinol Diabetes Metab Case Rep . 2017;2017:17-0081. 9. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care . 2015;38(9):1638-1642. 10. Farxiga (dapagliflozin) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; May 2020. 11. Nathan DM. Adjunctive treatments for type 1 diabetes. N Engl J Med . 2017;377:2390-2391. 12. Perry RJ, Rabin-Court A, Song JD, et al. Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats. Nat Commun . 2019;10(1):548. 13. FDA. FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. www.fda.gov/files/drugs/published/Drug-Safety-Communication--FDA-warns-that-SGLT2-inhibitors-for-diabetes-may-result-in-a-serious-condition-of-too-much-acid-in-the-blood.pdf. Accessed August 16, 2021. 14. Burge MR, Garcia N, Qualls CR, Schade DS. Differential effects of fasting and dehydration in the pathogenesis of diabetic ketoacidosis. Metabolism . 2001;50(2):171-177. 15. Larroumet A, Camoin M, Foussard N, et al. Euglycemic ketoacidosis induced by therapeutic fasting in a non-diabetic patient. Nutrition . 2020;72:110668. 16. Owen D, Little S, Leach R, Wyncoll D. A patient with an unusual aetiology of a severe ketoacidosis. Intensive Care Med . 2008;34(5):971-972. 17. Jaber JF, Standley M, Reddy R. Euglycemic diabetic ketoacidosis in pregnancy: a case report and review of current literature. Case Rep Crit Care . 2019;2019:e8769714. 18. Chauhan SP, Perry KG, McLaughlin BN, et al. Diabetic ketoacidosis complicating pregnancy. J Perinatol . 1996;16(3 Pt 1):173-175. 19. Sinha N, Venkatram S, Diaz-Fuentes G. Starvation ketoacidosis: a cause of severe anion gap metabolic acidosis in pregnancy. Case Rep Crit Care . 2014;2014:906283. 20. Metzger B, Ravnikar V, Vileisis R, Freinkel N. “Accelerated starvation” and the skipped breakfast in late normal pregnancy. Lancet . 1982;1(8272):588-592. 21. Prater J, Chaiban JT. Euglycemic diabetic ketoacidosis with acute pancreatitis in a patient not known to have diabetes. AACE Clin Case Rep . 2015;1(2):e388-e391. 22. Nakamura K, Inokuchi R, Doi K, et al. Septic ketoacidosis. Intern Med . 2014;53(10):1071-1073. 23. Abu-Abed Abdin A, Hamza M, Khan MS, Ahmed A. Euglycemic diabetic ketoacidosis in a patient with cocaine intoxication. Case Rep Crit Care . 2016;2016:4275651. 24. Sarnyai Z, Dhabhar FS, McEwen BS, Kreek MJ. 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Euglycemic diabetic ketoacidosis: Etiologies, evaluation, and management

Affiliations.

• 1 Department of Emergency Medicine, Brooke Army Medical Center, 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States of America. Electronic address: [email protected].
• 2 Division of Emergency Medicine, Department of Surgery, Larner College of Medicine, University of Vermont, Burlington, VT, United States of America.
• 3 The University of Texas Southwestern Medical Center, Department of Emergency Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390, United States of America.
• 4 Department of Emergency Medicine, Rush University Medical Center, Chicago, IL 60612, United States of America.
• PMID: 33626481
• DOI: 10.1016/j.ajem.2021.02.015

Introduction: Diabetic ketoacidosis is an endocrine emergency. A subset of diabetic patients may present with relative euglycemia with acidosis, known as euglycemic diabetic ketoacidosis (EDKA), which is often misdiagnosed due to a serum glucose <250 mg/dL.

Objective: This narrative review evaluates the pathogenesis, diagnosis, and management of EDKA for emergency clinicians.

Discussion: EDKA is comprised of serum glucose <250 mg/dL with an anion gap metabolic acidosis and ketosis. It most commonly occurs in patients with a history of low glucose states such as starvation, chronic liver disease, pregnancy, infection, and alcohol use. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which result in increased urinary glucose excretion, are also associated with EDKA. The underlying pathophysiology involves insulin deficiency or resistance with glucagon release, poor glucose availability, ketone body production, and urinary glucose excretion. Patients typically present with nausea, vomiting, malaise, or fatigue. The physician must determine and treat the underlying etiology of EDKA. Laboratory assessment includes venous blood gas for serum pH, bicarbonate, and ketones. Management includes resuscitation with intravenous fluids, insulin, and glucose, with treatment of the underlying etiology.

Conclusions: Clinician knowledge of this condition can improve the evaluation and management of patients with EDKA.

Keywords: Acidosis; Diabetes; Endocrinology; Euglycemic diabetic ketoacidosis.

Published by Elsevier Inc.

Publication types

• Diabetic Ketoacidosis / diagnosis*
• Diabetic Ketoacidosis / etiology*
• Diabetic Ketoacidosis / therapy*
• Diagnosis, Differential
• Emergency Service, Hospital*

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Euglycemic Ketoacidosis

• Other Forms of Diabetes and Its Complications (JJ Nolan and H Thabit, Section Editors)
• Published: 19 May 2020
• Volume 20 , article number  25 , ( 2020 )

Cite this article

• Benedetta Maria Bonora 1 ,
• Angelo Avogaro 1 &
• Gian Paolo Fadini   ORCID: orcid.org/0000-0002-6510-2097 1  

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Purpose of Review

Diabetic ketoacidosis is a life-threatening complication of diabetes characterized by hyperglycemia, acidosis, and ketosis. Ketoacidosis may occur with blood glucose level < 200 mg/dl (improperly defined as euglycemic ketoacidosis, euKA) and also in people without diabetes. The absence of marked hyperglycemia can delay diagnosis and treatment, resulting in potential serious adverse outcomes.

Recent Findings

Recently, with the wide clinical use of sodium glucose co-transporter 2 inhibitors (SGLT2i), euKA has come back into the spotlight. Use of SGLT2i use can predispose to the development of ketoacidosis with relatively low or normal levels of blood glucose. This condition, however, can occur, in the absence of diabetes, in settings such as pregnancy, restriction on caloric intake, glycogen storage diseases or defective gluconeogenesis (alcohol abuse or chronic liver disease), and cocaine abuse.

euKA is a challenging diagnosis for most physicians who may be misled by the presence of normal glycemia or mild hyperglycemia. In this article, we review pathophysiology, etiologies, clinical presentation and the management of euKA.

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Bonora, B.M., Avogaro, A. & Fadini, G.P. Euglycemic Ketoacidosis. Curr Diab Rep 20 , 25 (2020). https://doi.org/10.1007/s11892-020-01307-x

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Online Medical Education on Emergency Department (ED) Critical Care, Trauma, and Resuscitation

Diabetic Ketoacidosis (DKA)

August 6, 2021 by Josh Farkas

• Rapid Reference 🚀
• Evaluating anion gap & ketoacidosis
• Definition & severity of DKA
• Evaluating the cause of DKA
• Fluid administration
• Electrolyte management
• Insulin infusion
• Long-acting, basal insulin
• Management of severe or refractory ketoacidosis
• NAGMA management
• Monitoring & management of DKA recurrence
• DKA in a hemodialysis patient
• Euglycemic DKA
• DKA with an insulin pump
• Intubating a DKA patient
• Cerebral edema
• Questions & discussion

(back to contents)

DKA management checklist ✅

Diagnostic evaluation ( more ).

• Minimum evaluation for a patient with DKA: Electrolytes including Ca/Mg/Phos, complete blood count with differential, urinalysis, EKG, pregnancy test as appropriate.
• If unclear whether patient has DKA: beta-hydroxybutyrate & lactate levels.
• If the cause of DKA is unclear: blood cultures +/- urine culture, chest X-ray, perhaps CT abdomen/pelvis to evaluate for septic focus, possibly lipase (noting that DKA itself can increase lipase; 14578269 ) , troponin if genuine suspicion for ischemia.

crystalloid ( more )

• 1st : Bolus with lactated Ringers (LR) if substantial volume depletion (which is usually the case).
• 2nd : Infuse LR at ~150-200 ml/hr, until glucose <300 mg/dL (<16.6 mM).
• 3rd : When glucose <300 mg/dL, cut LR infusion in half and add a D10W infusion (e.g., 100 ml/hr D10W plus 100 ml/hr LR).

electrolyte repletion ( more )

• Check electrolytes q4hr ( including magnesium & phosphate).
• Target K>5.3 mM, if renal function preserved.
• Target Mg >2 mg/dL (>0.8 mM).
• Replete phosphate as needed.

insulin infusion ( more )

• Hold insulin if K <3.3 mM.
• Most patients: start insulin at 0.1 U/kg/hr (up to a max of 15 U/hr).
• For severe acidosis (e.g., bicarbonate <5 mM), consider a 10 unit IV insulin bolus followed by an infusion at 0.2 U/kg/hr.
• Resolution of ketoacidosis (anion gap <10-12 mM, in the absence of renal failure).
• Bicarbonate >18 mM.
• Patient received full dose of basal insulin >2 hours previously.
• Glycemic control is reasonable.
• Patient feels better & tolerating PO.

basal insulin ( more )

• Start basal insulin early (well before the anion gap has closed).
• New diagnosis of diabetes: start 0.25 U/kg glargine.
• Most patients: provide their entire daily requirement of basal insulin.
• Schedule basal glargine q24 hours .

management of non-anion-gap metabolic acidosis ( more )

• NAGMA often emerges during the course of a DKA resuscitation.
• Anion gap is falling, but bicarbonate is not rising appropriately.
• (Na – Cl – 10) << 20.
• NAGMA often requires treatment with IV bicarbonate to achieve a bicarbonate level >18 mM, to expedite discontinuation of the insulin infusion in a timely fashion.

three ways to evaluate for ketoacidosis

(#1) anion gap.

• Using this formula, an elevated anion gap is above 10-12 mEq/L. ( 23833313 )
• Please don't correct for albumin, glucose, or potassium. Don't make this unnecessarily complicated .
• Anion gap may be elevated due to a variety of causes (with the differential diagnosis explored here ). Therefore, an elevated anion gap does not necessarily imply DKA! This is especially true among patients with chronic renal failure, who may have a chronically elevated anion gap.

(#2) urinary dipstick for ketones

• The urinary ketone dipstick tests for acetoacetate .
• This test has a high sensitivity for DKA (98-99%), with urinary ketones are generally being ≧2+. ( 32771260 , 10459090 ) False negatives may occur in patients with highly acidic urine. ( 32409703 )
• The specificity of a positive measurement of urinary ketones is low, so a positive urinary measurement of ketones doesn't establish a diagnosis of DKA. ( 32763063 ) For example, starvation ketoacidosis is a more common cause of urinary ketones in most contexts.

(#3) blood beta-hydroxybutyrate level

• Beta-hydroxybutyrate level is the gold standard for defining the presence and extent of ketoacidosis in DKA.
• 0-0.6 mM: Normal
• 0.6-1 mM: Mild ketosis, may consider adjustment of insulin regimen. Among patients who initially presented with DKA, a reduction of the beta-hydroxybutyrate level below <1 mM indicates resolution of the DKA. ( 32409703 )
• 1-3 mM: Moderate ketosis, medical intervention is warranted. There is a risk of progression to DKA.
• >3 mM : Consistent with DKA. ( 10030312 , 18184896 , 32771260 )
• >6 mM: Severe DKA.

clinical approach to anion gap & ketoacidosis

• Obvious DKA : In some cases the history and physical examination are strongly suggestive of DKA. In this situation, an elevated anion gap with positive urinary ketones may be sufficient to reach a diagnosis of DKA.
• A strongly elevated beta-hydroxybutyrate level would support a diagnosis of DKA.
• A markedly elevated lactate level with mildly elevated beta-hydroxybutyrate level might suggest an underlying disease process (e.g., sepsis or shock) that may be causing a mild amount of ketoacidosis.
• An elevated anion gap with normal lactate and beta-hydroxybutyrate levels implies an alternative cause of the anion gap (e.g. certain intoxications).

definition of DKA

• Many definitions of DKA may be found in the literature, most of which are antiquated. The Canadian DKA guidelines are therefore correct in asserting that “there are no definitive criteria for the diagnosis of DKA.” ( 24070967 )
• My preferred definition of DKA is any patient with diabetes plus a significantly elevated serum beta-hydroxybutyrate level (>3 mM/L). ( 10030312 , 18184896 , 32771260 )
• DKA patients can have a normal glucose (euglycemic DKA, more on this below ).
• DKA patients can have a normal pH and a normal bicarbonate (this usually occurs due to a combination of ketoacidosis plus metabolic alkalosis from vomiting).

differential diagnosis of DKA

• Causes of ketoacidosis include starvation ketoacidosis, alcoholic ketoacidosis, and diabetic ketoacidosis.
• Clinical history is paramount in sorting these out. In patients with diabetes and alcoholism, it may be nearly impossible to sort out diabetic ketoacidosis versus alcoholic ketoacidosis (in this situation, the safest approach is often to treat the patient as if they have DKA).

severity of DKA

• Severe DKA: serum bicarbonate <5 mM (or pH < 7.0-7.1, or beta-hydroxybutyrate >6 mM).
• Moderate DKA: serum bicarbonate 5-10 mM (or pH ~7.1-7.2).
• Mild DKA: serum bicarbonate >10 mM (or pH >7.2).

precipitating cause

DKA is occasionally the initial manifestation of diabetes, but it usually occurs in the context of known diabetes plus a trigger. This is especially true of patients with type-II DM, who don't generally require exogenous insulin but may develop DKA in the context of physiologic stress. Most triggers of DKA are benign (e.g., nonadherence, viral gastroenteritis). However, DKA can be caused by any source of physiologic stress. Occasionally, DKA is the presentation of a serious underlying problem, especially sepsis. Common triggers of DKA include:

• Insulin nonadherence.
• Inadequate dosing of basal insulin.
• Insulin pump failure.
• New diagnosis of diabetes.
• Infection (e.g., gastroenteritis, pneumonia, urinary tract infection, diabetic foot infection).
• Pancreatitis.
• Trauma, surgery.
• Substance abuse or alcoholism.
• Sympathomimetics.
• SGLT-2 inhibitors.
• Atypical antipsychotics.
• HIV protease inhibitors.
• Checkpoint inhibitors (e.g., pembrolizumab, nivolumab).
• Pentamidine. ( 32409703 )
• Anti-calcineurin immunosuppressives. ( 10743693 )

evaluation for the cause of DKA

• History and physical examination are the key here. If there is clear history of nonadherence, a big workup isn't necessary.
• DKA itself may cause leukocytosis, so a WBC elevation alone is nonspecific.
• Infection is suggested by fever, marked left-shift, or severe leukocytosis (>20,000-25,000). ( 3101715 )
• DKA itself can cause abdominal pain. This creates diagnosis confusion – we must sort out whether the pain is due to DKA, or whether the pain represents an underlying problem (appendicitis, cholecystitis, etc). This may be sorted out in two ways:
• (#1) Severe pain with only mild ketoacidosis argues against DKA causing the pain. ( 12040551 )
• (#2) When in doubt about the need for an abdominal CT scan, aggressively treat the DKA and follow serial abdominal examinations. If the abdominal pain is due to DKA, it will resolve as the ketoacidosis improves. If pain fails to resolve or gets worse, then further investigation is warranted.
• DKA itself may cause mental status changes, but this usually occurs when the calculated serum osmolality is >320 mOsm/kg. Abnormal mental status despite normal serum osmolality should trigger suspicion for a primary neurologic problem (e.g., meningitis, intracranial hemorrhage). ( 25905280 )
• Another sign of a primary neurologic problem is if the mental status doesn't improve with treatment of the DKA. (Noting also that if mental status deteriorates during therapy, the possibility of cerebral edema should also be considered.)

#1) start with fluid boluses

• DKA patients are often profoundly volume depleted (e.g., due to vomiting, reduced oral intake, and osmotic diuresis). Hypovolemia triggers the release of stress hormones (e.g., catecholamines, cortisol) which cause insulin resistance and thereby exacerbate the DKA. So prompt reversal of hypovolemia is important.
• For young DKA patients with normal cardiorenal function, if the patient's heart rate is >100 b/m then they probably need more fluid.
• ⚠️ Ultrasound-guided fluid resuscitation is useful for patients with heart failure, or patients on hemodialysis.
• Balanced crystalloid is preferred here (e.g., LR or plasmalyte) if possible (further discussion below).

#2) initial maintenance fluid infusion (if glucose >300 mg/dL or >17 mM)

• Once the patient is approaching a euvolemic state, a maintenance fluid infusion is generally started.
• The usual choice is an isotonic balanced crystalloid (lactated Ringer's or plasmalyte) at ~150-200 ml/hr.
• ⚠️ Patients with heart failure may tend to become overloaded with standard DKA protocols, so follow volume status with ultrasonography and consider using less fluid.
• If the glucose level is <300 mg/dL or <17 mM already (e.g., in euglycemic DKA), then skip this step.

#3) after the glucose falls <300 mg/dL or <17 mM, add dextrose

• As the glucose falls, dextrose must be added to the IV fluid to allow for ongoing insulin administration (since ongoing insulin administration is needed to correct the ketoacidosis).
• Cut the LR rate in half (e.g., from 200 ml/hr to 100 ml/hr).
• Add a D10w infusion at an equal rate (e.g. 100 ml/hr LR plus 100 ml/hr D10W). Note that D10W is fine for peripheral IV infusion, it doesn’t require a central line. The D10W can actually be infused together with the LR using a single intravenous line, because these two fluids are compatible.
• Combining LR with an equal volume of D10W effectively creates a solution of “D5 1/2 LR” (a solution which doesn't exist in pre-mixed bags). The advantage of giving the components separately is that it provides you greater control with regards to adjusting the amount of sodium you are giving versus the amount of dextrose. For example, if you want to give additional dextrose you can up-tirate the D10W infusion (without giving the patient more sodium and causing volume overload).
• An alternative approach is to switch to D5 1/2 NS at ~200 ml/hr.

balanced crystalloid versus normal saline

• Balanced crystalloid is generally preferred (e.g. lactated Ringers), as this will avoid worsening the patient's acidosis. Evidence supports the ability of balanced crystalloid to accelerate resolution of DKA. ( 33196806 )
• The advantage of using normal saline is that it is available in preformulated bags containing potassium chloride. In some hospital units, this is a more convenient strategy for potassium repletion. Using normal saline for resuscitation is fine, particularly if this is the only way to appropriately replete the patient's potassium. However, clinicians should be aware that using saline will promote the development of NAGMA that may require active management with intravenous bicarbonate later on (as discussed below ).

hypokalemia

• Hypokalemia is extremely problematic , because insulin cannot be given to patients with significant hypokalemia (since insulin will exacerbate the hypokalemia). Thus, hypokalemia impairs our ability to treat DKA.
• (More on hypokalemia management here .)

hyperkalemia

• Hyperkalemia is less of a problem, because the usual DKA resuscitation will naturally reduce potassium.
• (More on hyperkalemia management here ).

ongoing potassium repletion

• DKA resuscitation will cause the potassium to fall over time.
• Aggressive potassium repletion is generally needed, usually with repeated doses of IV potassium. Oral potassium can be used, but patients are often nauseous and unable to tolerate this.
• In the absence of renal failure, shoot for a potassium >5.3 mM (to avoid falling behind).
• In renal failure, be more conservative with potassium repletion.
• Potassium chloride is generally used. However, oral potassium citrate or IV potassium acetate may offer the advantage of reducing the chloride load and thus decreasing the tendency to develop NAGMA. .

magnesium repletion

• (More on hypomagnesemia here ).

phosphate repletion

• Phosphate will drop during treatment, especially in patients with severe DKA.
• (More on hypophosphatemia here ).

general concepts of using insulin in DKA

• The primary problem with DKA is ketoacidosis (not hyperglycemia). Therefore, our overall goal is to titrate insulin as needed to treat the ketoacidosis (figure above).
• Unfortunately, it's a bit more complicated than this. Glucose levels are easier to repeat than measurements of ketoacidosis (e.g., the anion gap). Thus, glucose levels are often used as a surrogate measurement of the biological efficacy of insulin (for example, during the initial phase of resuscitation, if the glucose level isn't falling, that indicates that insulin isn't working and should be up-titrated).
• Every hospital will have a DKA protocol, which can generally be followed. However, it's still useful to understand the broad strokes of how insulin is utilized in DKA, as described below.

(#1) insulin infusion: getting started

• Unless the patient is hypokalemic (K <3.3 mM), insulin should be started immediately. ( 32409703 )
• (1) There is a delay in receiving an insulin infusion from the pharmacy. The main advantage of an insulin bolus is that this can usually be given immediately (most units have 10-unit insulin vials immediately available), whereas an insulin infusion needs to be mixed up in pharmacy).
• (2) For patients with severe acidosis (e.g., bicarbonate <5-10 mM), an insulin bolus will help immediately establish a therapeutic insulin level.
• An insulin infusion is usually started at 0.1 U/kg/hour (up to a max of 15 units/hour in morbid obesity). However, for patients with severe acidosis (e.g., bicarbonate <5 mEq/L) or marked insulin resistance (with high chronic insulin requirements), higher doses will often be needed (e.g. 0.2-0.3 U/kg/hr).

(#2) up-titration of insulin infusion, if needed

• The insulin infusion should be up-titrated as needed, with a goal of dropping the glucose by 50-70 mg/dL (2.8-3.9 mM) per hour.
• Occasionally, if the patient's anion gap isn't clearing, you might need to simultaneously increase both the insulin infusion rate and the glucose infusion rate. (Remember, the insulin is being used to clear the ketoacidosis.)

(#3) cut back on the insulin infusion, but don't stop it

• Once the glucose falls to ~250 mg/dL (14 mM) the insulin infusion rate is typically reduced considerably (to ~0.05 U/kg/hr). ( 32771260 , British guidelines )
• Avoid stopping the insulin infusion entirely, if possible. Hypoglycemia may generally be managed by the use of additional IV dextrose and down-titration of insulin (rather than shutting the insulin off entirely).

(#4) stop the insulin infusion only after the following criteria are met:

• An exception here is a patient with end-stage renal disease, who may chronically have an elevated anion gap due to uremia which never normalizes. In this situation, normalization of the beta-hydroxybutyrate level (<0.6 mM) is a more useful way to determine that ketoacidosis has resolved.
• Acidosis increases insulin resistance, so if the patient remains acidemic then there is an increased risk that the anion gap will open up.
• Many patients will develop a NAGMA, leading to a persistent acidosis that doesn't respond to insulin. This may be treated with IV bicarbonate as described below .
• (c) The patient has received the full daily dose of long-acting insulin >2 hours previously.
• (d) Glucose is reasonably well controlled (e.g., <250 mg/dL or <14 mM).
• If the insulin infusion is stopped and the patient doesn't eat anything or receive any IV glucose, this increases the risk of recurrent DKA.
• An exception can be made for patients with gastroenteritis or diabetic gastroparesis, who may not be hungry for several days. In this situation, the insulin infusion can be stopped, but patients should remain on low-dose intravenous glucose (e.g. D5W at 50-75 ml/hr). If the patient's glucose level increases, they should be treated with PRN short-acting insulin. Ongoing administration of carbohydrate plus PRN insulin will help prevent DKA recurrence.

(#5) start meal-associated & PRN insulin when the infusion is stopped

• If the patient isn't already on a prescribed regimen of meal-associated insulin, a dose of ~0.08 U/kg rapid-acting insulin per meal may be reasonable (i.e., about one third of the daily basal insulin requirement). Follow glucose carefully and titrate to effect.
• Encourage patients to eat . Carbohydrate intake (along with meal-associated and sliding-scale insulin) is important at this point, to prevent recurrent DKA.

concept of early basal insulin

• (More on the rationale & evidence for early insulin here .)

step #1: determine the total daily requirement of long-acting insulin

• For patients on once-daily long-acting insulin (e.g., glargine), that's their basal dose
• For patients on twice-daily basal insulin, add up all the basal doses given during a day.
• For patients naive to insulin, a starting dose of 0.25 units/kg daily of glargine (Lantus) may be used. ( B ritish guidelines )
• Some patients have a backup dosing regimen of long-acting insulin (e.g., a certain dose of s.q. long-acting insulin to use if their pump malfunctions). You can use that as their daily basal insulin dose.
• The basal insulin requirement may also be calculated from the pump's basal rate (e.g., multiply the basal rate times 24 hours to obtain the total daily basal requirement).
• Note that the patient's pump should be stopped and removed (more on this below )
• ⚠️ Don't calculate the patient's daily insulin requirement based on how much insulin they are receiving via the insulin infusion. Sick DKA patients are receiving lots of IV dextrose and they are acidotic , which will temporarily increase their insulin requirements.

step #2: give the full dose of basal insulin

• Provide the entire day's worth of basal insulin (typically in the form of glargine).
• If the glargine is given at an inopportune time (e.g. it’s given in the evening and the patient prefers taking it in the morning), the timing can be slowly shifted each day to meet the patient's preference.

common pitfalls with long-acting insulin

• Practitioners who are nervous about giving early glargine may sometimes give a reduced dose, which leads to tremendous confusion. Please give patients their full home-dose of basal insulin . Critical illness causes insulin resistance , so patients may have a tendency to require more insulin (not less).
• Some patients are on twice daily glargine (for reasons which aren't entirely clear to me). If such patients are continued on twice daily glargine, the insulin infusion shouldn't be stopped until after they receive their second dose of glargine. Alternatively, both doses can be compiled into a single daily dose (this is preferred as it may accelerate weaning off the insulin infusion).
• Glargine must be ordered “q24 hours,” rather than “daily.” If the glargine is electronically ordered as “daily,” then it may default to every morning at 9 AM – which will cause some patients to receive their daily dose in the evening, and then another dose the following morning. Please check and double-check the glargine dose and when it is scheduled to be delivered.

(#1) initial management of patients with severe ketoacidosis

• Some patients will present with profound ketoacidosis (e.g. pH<6.9 or bicarb <5 mM). Patients generally tolerate this surprisingly well.
• a) Don't wait for the insulin to arrive from pharmacy: bolus 10 units IV immediately.
• b) Consider starting an insulin infusion at 0.2 U/kg/hr in the sickest patients.
• High-flow nasal cannula is a safe way to support the patient's breathing (note that patients are not good BiPAP candidates, due to a tendency to vomit). High-flow nasal cannula may reduce the anatomic dead space, thereby reducing the work of breathing and avoiding respiratory fatigue.
• FiO2 titrated to achieve a saturation >92% (usually a low FiO2 will be needed e.g., 30-40%)
• Increase the flow rate as high as the patient can tolerate (e.g., 60 liters/minute). The flow rate is what does the work of reducing dead space and thereby blowing off CO2. If the patient is very sick and air-hungry, they will tolerate high flow rates.
• More on the management of severe acidosis here .

(#2) refractory ketoacidosis: if the anion gap is not closing

• Inadequate fluid resuscitation.
• Inadequately low insulin dose.
• Malfunction of insulin infusion (e.g., line infiltration or infusion pump error).
• Festering, underlying problem which hasn't been addressed.
• Evaluate fluid status (e.g. with ultrasonography), provide additional crystalloid resuscitation if necessary.
• Consider increasing the insulin infusion rate (which may require a simultaneous increase in dextrose administration).
• Reevaluate for a missed underlying problem.
• Consider checking beta-hydroxybutyrate & lactate levels (to exclude an occult lactic acidosis).
• Make sure the infusion pump and IV catheter are functioning properly.

the problem with non-anion-gap metabolic acidosis (NAGMA)

• NAGMA commonly develops in patients with DKA, often worsening during resuscitation.
• Resuscitation with normal saline or half-normal saline.
• Excretion of ketoacid in the urine (once ketoacid is in the sewer system, it can no longer be converted back into bicarbonate).
• A residual acidosis will increase insulin resistance, thereby increasing the risk of recurrent DKA after stopping the insulin infusion (more on this here ).
• If the NAGMA is severe, then it may delay the discontinuation of the insulin infusion entirely.

diagnosis of NAGMA

Predicted Final Bicarb = (Na – Cl – 10)

• The anion gap is closing, but the patient's bicarbonate remains low.
• The predicted final bicarbonate is a rough estimate of where the bicarbonate will end up after all the ketoacid is converted into bicarbonate (above). If the predicted final bicarbonate is falling over time to well under 20 mM, this suggests NAGMA.

management of NAGMA

• The bicarbonate deficit can be estimated using this formula . While the anion gap is still open, use the predicted final bicarbonate to get a rough concept of the bicarbonate deficit . Keep in mind, however, that you're only shooting for a bicarbonate of ~20 mEq/L (not 24 mEq/L). 100-150 mEq of bicarbonate is usually adequate.
• If the patient is hyponatremic, then a couple of hypertonic bicarbonate ampules can be used (each ampule contains 50 mEq sodium bicarbonate in 50 ml water).
• If the patient's sodium is normal or elevated, then isotonic bicarbonate may be used (e.g. one liter of D5W with three ampules of bicarbonate, to generate a 150 mEq/L bicarbonate solution, infused over 3-4 hours). This will cause the glucose to increase a bit, but that can actually be useful in closing the anion gap (because it will trigger an increase in the insulin infusion).
• The optimal time to treat NAGMA is often as the anion gap is beginning to close (e.g., when the anion gap is ~12-18 mEq/L). This facilitates prompt discontinuation of the insulin infusion (without needing to delay in order to separately treat the NAGMA).
• More on NAGMA and IV bicarbonate .

after the insulin infusion is stopped, patients should be monitored for recurrence of DKA:

• Development of progressively severe hyperglycemia may be an early sign of recurrent DKA.
• Since glucose levels are often checked frequently, skyrocketing glucose may pre-date the development of a widening anion gap by a few hours.
• A set of electrolytes ~6 hours after stopping the drip is a reasonable idea to make sure that the anion gap is remaining closed (if there is any doubt about this clinically).

management of recurrent DKA

• Insulin infusion was stopped despite not meeting all five of the criteria above.
• Inadequate long-acting insulin dose.
• Patient isn't eating enough (which causes insufficient meal-associated & PRN insulin doses)
• Ongoing systemic inflammation (e.g. DKA caused by infection, with persistent infection).
• Restart the insulin infusion.
• Continue long-acting insulin (consider up-titrating the dose).
• Address any reversible causes of DKA.
• Aggressively treat NAGMA to get the serum bicarb >20 mEq/L (this will improve insulin sensitivity).
• Sometimes patients just need a bit longer on the insulin infusion (especially if they were severely ill on admission).

key physiologic differences

• In some patients, hyperglycemia may osmotically pull water into the vasculature leading to hypervolemia! This can lead to volume overload with pulmonary edema, which may resolve following insulin administration (since the insulin causes a shift of glucose and water out of the vasculature and into the tissues).
• If you give excessive fluid or potassium, this will create a persistent problem that requires dialysis.
• Insulin clearance may be sluggish, so insulin may stick around longer than usual.

treatment pearls

• ⚠️ Standard DKA protocols will harm these patients.
• Many patients may be euvolemic or only mildly hypovolemic (e.g., due to emesis or poor oral intake). Other patients may be hypervolemic (if they have missed hemodialysis recently).
• There may be little or no need for volume resuscitation. Patients will inevitably get a couple liters of fluid with various drugs and infusions – this fluid alone may be adequate.
• 💡 Fluids administered to the patient will accumulate over time , so you don't want the patient to be euvolemic within the first couple hours of resuscitation. If the patient is slightly hypovolemic initially, then accumulation of fluid with various IV medications will eventually bring them to a euvolemic state.
• (2) Avoid aggressive potassium administration.
• For euvolemic patients, D10W may be superior to D5W to avoid causing hyponatremia. If central access happens to be available, then higher concentrations could be used (e.g., D20W). As discussed above, there is often no need for additional sodium administration (so there is no benefit from a fluid such as D5 half-normal saline).
• Be conservative with insulin administration , as it may be cleared slowly. For patients who aren't severely acidotic, it may be wise to start the insulin at a slower rate than usual (e.g., 0.05 units/kg/hour).
• Patients on dialysis will always have an elevated anion gap, due to uremia.
• If beta-hydroxybutyrate is available, this is arguably the best way to determine the severity of the ketoacidosis. DKA resolution may correlate with a beta-hydroxybutyrate level which is below ~1 mM. ( 32409703 )
• If beta-hydroxybutyrate is not available, look at the patients prior anion gap values to determine a sense of the patient's baseline (often around ~12-16 mM). If the patient's anion gap falls to within this range and remains stable over time despite insulin administration, then the ketoacidosis has likely resolved.

role of hemodialysis

• Hemodialysis will remove ketoacid, replace bicarbonate, and basically fix everything. However, hemodialysis often isn't required (e.g., insulin alone may be adequate to improve hyperkalemia and acidosis).
• The risk of hemodialysis is that it may cause rapid osmotic shifts. For patients with severe hypertonicity (serum osmolality >>330 mOsm/kg), this could theoretically carry a risk of causing cerebral edema.
• Even if hemodialysis fixes everything, don't forget the insulin – the patient still needs insulin to prevent slipping back into DKA.
• (#1) Ketoacidosis due to diabetes. The most unequivocal way to diagnose ketoacidosis is with a substantially elevated beta-hydroxybutyrate level (>3 mM). Alternatively, ketoacidosis may be inferred on the basis of urinary ketones, an elevated anion gap, and no alternative explanation for the anion gap elevation.
• (#2) “Euglycemia” is defined as a glucose <250 mg/dL (<13.9 mM). ( 28924481 ) Of course, this is not an entirely normal glucose level.
• The definition of DKA is discussed further above . Note that DKA does not require the presence of acid emia (low pH). For example, coexisting metabolic alkalosis due to vomiting plus DKA may leave the patient with a normal pH and normal bicarbonate level.
• 🤯 Euglycemic DKA can occur with a normal glucose and a stone-cold normal blood gas (e.g., normal pH, normal bicarbonate, and normal pCO2).

more common causes of euglycemic DKA

• SGLT2 inhibitors block glucose reabsorption in the proximal nephron, promoting glucosuria. This may tend to induce a physiologic state mimicking starvation, which promotes ketoacidosis.
• Starvation, prolonged nausea/vomiting.
• Abdominal pathology (e.g., pancreatitis, gastroenteritis).
• Intoxication (especially alcohol).
• Liver disease.
• Partial treatment with insulin before admission (either intentionally, or unintentionally via an insulin pump).
• Ketogenic diet.

clinical presentation

• Aside from the lack of hyperglycemia, patients present similarly to other DKA patients (e.g., with nausea, emesis, and abdominal discomfort).
• In situations where the DKA occurs in response to a primary stressor, clinical findings will reflect a melding of both conditions.
• Absence of hyperglycemia may cause both patients and clinicians alike to miss the diagnosis.

treatment: salient differences compared to the usual DKA resuscitation

• Treatment overall is very similar to DKA in general, with a few nuances:
• (1) Aggressive IV dextrose must be started immediately (e.g., D5 Lactated Ringers at ~250 ml/hr in mildly hypovolemic patients, or D10W at ~125 ml/hr in euvolemic patients).
• (2) Many patients weren't previously on insulin. Nonetheless, an insulin infusion is generally required to treat the DKA. ( 33626481 ) Additionally, early initiation of long-acting insulin is generally useful to prevent patients from slipping back into DKA (e.g., 0.25 units/kg glargine q24 hours).
• (3) Any SGLT2 inhibitors should be held until the DKA has resolved. These agents may be restarted later, at the discretion of the patient's endocrinologist.
• First, disconnect the insulin pump (including removal of the needle from the skin). ( 32763063 ) It's unclear whether the pump is working. The safest approach is to remove this variable from the equation until the patient is stabilized. ( British guidelines )
• Otherwise, the treatment of DKA is essentially as for any other patient.
• If the patient and their endocrinologist decide to resume pump therapy, the transition from glargine back onto the pump can be made at a later date (following stabilization and ICU discharge).

avoid intubation

• Whenever possible, avoid intubation .
• Intubating a patient due to altered mental status is usually a mistake. The mental status should improve over several hours, so careful observation is generally the best approach.
• Frank inability to protect airway (e.g. gurgling, inability to control secretions).
• Intubation needed to facilitate surgical procedure (e.g. patient has DKA plus perforated viscus).
• Respiratory arrest or impending arrest (e.g. patient in extremis).
• If intubation is necessary (e.g. for a surgical procedure), it may be wise to delay it for a few hours to allow vigorous treatment of DKA first.

risks involved with intubation

• Hemodynamic collapse: If hypovolemia isn't corrected prior to intubation
• Vomiting/aspiration: These folks often have gastroparesis and illeus.
• Decompensation of acidosis: Most patients have severe metabolic acidosis with a compensatory respiratory alkalosis. Paralysis takes away their respiratory compensation, potentially leading to profound acidosis.

mitigating the risks

• Volume resuscitate prior to intubation.
• If necessary start a vasopressor infusion to establish MAP >75-80mm before the procedure.
• Use hemodynamically stable induction drugs (e.g. ketamine).
• Visualize the stomach with ultrasound , if it's distended consider NG drainage prior to intubation.
• If the patient is intermittently vomiting, encourage them to vomit immediately before anesthetic induction (while they can still protect their airway).
• For example, slowly push 2-3 ampules (100-150 mEq) of bicarbonate over 10-15 minutes, at least ~10 minutes prior to intubation.
• Bicarbonate contains dissolved CO2, which the patient must blow off. In order to benefit from the bicarbonate, the patient should have enough time to blow off additional CO2 prior to intubation.
• Consider using mechanically controlled apneic ventilation (with BiPAP or a ventilator ) during induction of anesthesia if you're adept at this. If you're not, then it's probably best to perform pure RSI to minimize risk of regurgitation (without any breaths interposed between paralytic and intubation).
• Use a relatively large ETT to minimize airway resistance (ideally nothing smaller than a 7.5-mm ETT).
• Use rocuronium, so that after intubation the patient will be paralyzed and sync perfectly with the ventilator.
• Set the tidal volume at 8 cc/kg.
• Crank the respiratory rate as high as possible without causing autoPEEP (will often end up around ~24-28 breaths/minute).
• Shoot for a very high minute ventilation (e.g. 12-18 liters/minute).
• This is extraordinarily rare in the context of adult DKA (it's a much larger issue in pediatric DKA).
• Younger patients (almost all affected are <25 years old).
• Marked baseline hyperosmolarity (e.g., calculated serum osmolarity >~330 mOsm).
• Lack of the normal, expected rise in Na level during DKA treatment. ( 32409703 )

prevention of cerebral edema

• (1) Don't drop the glucose too fast or too low. Also avoid reducing the glucose below <200 mg/dL (<11 mM).
• (2) Avoid hypotonic fluids (there is no rush in reducing the tonicity). Note that the patient's sodium level will often initially increase during resuscitation, as glucose and water enter the cells. This doesn't reflect an increase in serum osmolality – and it shouldn't be a trigger to administer free water.
• (3) Avoid dropping the serum osmolality by more than 3 mOsm/kg/hour. ( 24070967 )
• A large pediatric study found no difference in cerebral edema when patients were randomized to hypotonic vs. isotonic fluid at various rates. ( 29897851 ) This suggests that cerebral edema is largely an idiosyncratic response, which may not be substantially impacted by our treatments.
• Consequently, there is no need to routinely take the above precautions to prevent cerebral edema in adults. ( British guidelines ) However, in selected patients who are at unusually high risk for cerebral edema, such precautions may remain reasonable.

diagnosis and treatment

• (1) Consider the diagnosis in at-risk patients, as described above.
• (2) Look for the emergence of headache, altered mental status, and emesis during treatment.
• Treatment involves the use of hypertonic fluid (e.g., hypertonic saline or hypertonic bicarbonate) to raise the serum tonicity. When the diagnosis of cerebral edema is suspected, the serum tonicity should be raised immediately, without delaying for neuroimaging. ( British guidelines )
• Neuroimaging should evaluate for alternative possibilities (including cerebral venous thrombosis or CVA).
• The vast majority of patients with DKA can be treated with peripheral IV access, but for the sickest patients central access may be needed.
• In a severely acidotic patient with respiratory compensation, a pneumothorax would be poorly tolerated.
• Patients may be delirious and unable to stay still enough to facilitate safe placement of a jugular/subclavian line.
• The line will only be needed for 24-48 hours (until DKA resolves), so infection risk is minimal.

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• Missing an underlying cause of DKA, especially sepsis. The primary cause of death among patients admitted with DKA isn't the DKA itself, but rather associated conditions.
• Bolusing large volumes of normal saline will make the patient more acidotic . This is generally not a major problem, but it can be for the sickest patients who present with severe acidosis.
• Avoid intubation of DKA patient if possible (it's a trap!). If you do need to intubate, proceed with extreme caution & preparation .
• BiPAP should be avoided as well, as patients will often vomit. To provide some additional respiratory support, consider high-flow nasal cannula .
• Please don't measure a troponin on every DKA patient (older DKA patients will usually have a measurable troponin level, which may trigger unnecessary and harmful workups). Be a doctor. Check a troponin if you are genuinely concerned about ischemia, based on symptoms and EKG evaluation.
• Don't stop the insulin infusion until the patient meets criteria to do so.
• Don't exclude the diagnosis of DKA because a patient has normal glucose, or normal bicarb/pH. Remember, instead, to mind the gap .

Guide to emoji hyperlinks

Going further.

• British guidelines (2021 update) – probably best guidelines currently available.
• Italian guidelines 2020 ( 32771260 )
• Canadian 2013 guidelines. ( 24070967 )
• American Diabetes Association 2009 guidelines – these are outdated and not recommended. ( 19564476 )
• DKA I: the pearls
• DKA II: Dominating the acidosis
• Why ABG & VBG are unhelpful in DKA
• REBEL EM : Euglycemic DKA isn't a myth
• EMDocs : Euglycemic DKA secondary to SGLT2 inhibitors
• Bicarb in DKA? See Chris Nickson on LITFL , Anand Swaminathan on EMDocs , Salim Rezai on RebelEM , Darrel Hughes on RebelEM .
• Insulin bolus? Darrel Hughes on RebelEM
• DKA myths by RebelEM, and also by Anand Swaminathan on EMDocs .
• More on DKA in ESRD: Great twitter thread by Jamie Willows here .
• 03101715 Slovis CM, Mork VG, Slovis RJ, Bain RP. Diabetic ketoacidosis and infection: leukocyte count and differential as early predictors of serious infection. Am J Emerg Med. 1987 Jan;5(1):1-5. doi: 10.1016/0735-6757(87)90280-4 [ PubMed ]
• 10030312 Fulop M, Murthy V, Michilli A, Nalamati J, Qian Q, Saitowitz A. Serum beta-hydroxybutyrate measurement in patients with uncontrolled diabetes mellitus. Arch Intern Med. 1999 Feb 22;159(4):381-4. doi: 10.1001/archinte.159.4.381 [ PubMed ]
• 10743693 Yoshida EM, Buczkowski AK, Sirrs SM, Elliott TG, Scudamore CH, Levin A, Tildesley HD, Landsberg DN. Post-transplant diabetic ketoacidosis–a possible consequence of immunosuppression with calcineurin inhibiting agents: a case series. Transpl Int. 2000;13(1):69-72. doi: 10.1007/s001470050011 [ PubMed ]
• 12040551 Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care. 2002 Mar;17(1):63-7. doi: 10.1053/jcrc.2002.33030 [ PubMed ]
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• 17403099 Keenan CR, Murin S, White RH. High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses. J Thromb Haemost. 2007 Jun;5(6):1185-90. doi: 10.1111/j.1538-7836.2007.02553.x [ PubMed ]
• 18184896 Sheikh-Ali M, Karon BS, Basu A, Kudva YC, Muller LA, Xu J, Schwenk WF, Miles JM. Can serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care. 2008 Apr;31(4):643-7. doi: 10.2337/dc07-1683 [ PubMed ]
• 19564476 Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009 Jul;32(7):1335-43. doi: 10.2337/dc09-9032 [ PubMed ]
• 23833313 Kraut JA, Nagami GT. The serum anion gap in the evaluation of acid-base disorders: what are its limitations and can its effectiveness be improved? Clin J Am Soc Nephrol. 2013 Nov;8(11):2018-24. doi: 10.2215/CJN.04040413 [ PubMed ]
• 24070967 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, Goguen J, Gilbert J. Hyperglycemic emergencies in adults. Can J Diabetes. 2013 Apr;37 Suppl 1:S72-6. doi: 10.1016/j.jcjd.2013.01.023 [ PubMed ]
• 25905280 Gosmanov AR, Gosmanova EO, Kitabchi AE. Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. 2021 May 9. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Grossman A, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. [ PubMed ]
• 28183452 Cardoso L, Vicente N, Rodrigues D, Gomes L, Carrilho F. Controversies in the management of hyperglycaemic emergencies in adults with diabetes. Metabolism. 2017 Mar;68:43-54. doi: 10.1016/j.metabol.2016.11.010 [ PubMed ]
• 28372715 Fayfman M, Pasquel FJ, Umpierrez GE. Management of Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. Med Clin North Am. 2017 May;101(3):587-606. doi: 10.1016/j.mcna.2016.12.011 [ PubMed ]
• 28659865 Tran TTT, Pease A, Wood AJ, Zajac JD, Mårtensson J, Bellomo R, Ekinci EII. Review of Evidence for Adult Diabetic Ketoacidosis Management Protocols. Front Endocrinol (Lausanne). 2017 Jun 13;8:106. doi: 10.3389/fendo.2017.00106 [ PubMed ]
• 28924481 Rawla P, Vellipuram AR, Bandaru SS, Pradeep Raj J. Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma. Endocrinol Diabetes Metab Case Rep. 2017 Sep 4;2017:17-0081. doi: 10.1530/EDM-17-0081 [ PubMed ]
• 32409703 Dhatariya KK, Glaser NS, Codner E, Umpierrez GE. Diabetic ketoacidosis. Nat Rev Dis Primers. 2020 May 14;6(1):40. doi: 10.1038/s41572-020-0165-1 [ PubMed ]
• 32763063 Long B, Willis GC, Lentz S, Koyfman A, Gottlieb M. Evaluation and Management of the Critically Ill Adult With Diabetic Ketoacidosis. J Emerg Med. 2020 Sep;59(3):371-383. doi: 10.1016/j.jemermed.2020.06.059 [ PubMed ]
• 32771260 Lapolla A, Amaro F, Bruttomesso D, Di Bartolo P, Grassi G, Maffeis C, Purrello F, Tumini S. Diabetic ketoacidosis: A consensus statement of the Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology and Pediatric Diabetoloy (SIEDP). Nutr Metab Cardiovasc Dis. 2020 Sep 24;30(10):1633-1644. doi: 10.1016/j.numecd.2020.06.006 [ PubMed ]
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• 33626481 Long B, Lentz S, Koyfman A, Gottlieb M. Euglycemic diabetic ketoacidosis: Etiologies, evaluation, and management. Am J Emerg Med. 2021 Jun;44:157-160. doi: 10.1016/j.ajem.2021.02.015 [ PubMed ]

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DYANNE P. WESTERBERG, DO

This is a corrected version of the article that appeared in print.

Am Fam Physician. 2013;87(5):337-346

Patient Information: A handout on this topic is available at https://familydoctor.org/familydoctor/en/diseases-conditions/diabetic-ketoacidosis.html .

Author disclosure: No relevant financial affiliations.

Diabetic ketoacidosis is characterized by a serum glucose level greater than 250 mg per dL, a pH less than 7.3, a serum bicarbonate level less than 18 mEq per L, an elevated serum ketone level, and dehydration. Insulin deficiency is the main precipitating factor. Diabetic ketoacidosis can occur in persons of all ages, with 14 percent of cases occurring in persons older than 70 years, 23 percent in persons 51 to 70 years of age, 27 percent in persons 30 to 50 years of age, and 36 percent in persons younger than 30 years. The case fatality rate is 1 to 5 percent. About one-third of all cases are in persons without a history of diabetes mellitus. Common symptoms include polyuria with polydipsia (98 percent), weight loss (81 percent), fatigue (62 percent), dyspnea (57 percent), vomiting (46 percent), preceding febrile illness (40 percent), abdominal pain (32 percent), and polyphagia (23 percent). Measurement of A1C, blood urea nitrogen, creatinine, serum glucose, electrolytes, pH, and serum ketones; complete blood count; urinalysis; electrocardiography; and calculation of anion gap and osmolar gap can differentiate diabetic ketoacidosis from hyperosmolar hyperglycemic state, gastroenteritis, starvation ketosis, and other metabolic syndromes, and can assist in diagnosing comorbid conditions. Appropriate treatment includes administering intravenous fluids and insulin, and monitoring glucose and electrolyte levels. Cerebral edema is a rare but severe complication that occurs predominantly in children. Physicians should recognize the signs of diabetic ketoacidosis for prompt diagnosis, and identify early symptoms to prevent it. Patient education should include information on how to adjust insulin during times of illness and how to monitor glucose and ketone levels, as well as information on the importance of medication compliance.

Diabetic ketoacidosis (DKA) continues to have high rates of morbidity and mortality despite advances in the treatment of diabetes mellitus. In a study of 4,807 episodes of DKA, 14 percent occurred in persons older than 70 years, 23 percent in persons 51 to 70 years of age, 27 percent in persons 30 to 50 years of age, and 36 percent in persons younger than 30 years. 1 In a second study of 28,770 persons younger than 20 years (mean age of 14 years) with diabetes, 94 percent had no episodes of DKA, 5 percent had one episode, and 1 percent had at least two episodes. 2 Additionally, DKA occurred more often in females, in persons with a migration background, and in persons 11 to 15 years of age. 2 DKA has a case fatality rate of 1 to 5 percent. 3 , 4 Although the highest rate of mortality is in older adults and persons with comorbid conditions, DKA is the leading cause of death in persons younger than 24 years with diabetes, most often because of cerebral edema. 1 , 4

Although persons with DKA typically have a history of diabetes, 27 to 37 percent have newly diagnosed diabetes. 5 , 6 This is especially true in young children. Most persons with DKA have type 1 diabetes. There is also a subgroup of persons with type 2 diabetes who have ketosis-prone diabetes; this subgroup represents 20 to 50 percent of persons with DKA. 7 Persons with ketosis-prone diabetes have impaired insulin secretion; however, with proper glucose management, beta cell function improves and the clinical course resembles that of type 2 diabetes. 8 These persons are often black or Latino, male, middle-aged, overweight or obese, have a family history of diabetes, and have newly diagnosed diabetes. 9

Pathophysiology

DKA results from insulin deficiency from new-onset diabetes, insulin noncompliance, prescription or illicit drug use, and increased insulin need because of infection ( Table 1 ) . 4 , 10 – 16 This insulin deficiency stimulates the elevation of the counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). Without the ability to use glucose, the body needs alternative energy sources. Lipase activity increases, causing a breakdown of adipose tissue that yields free fatty acids. These components are converted to acetyl coenzyme A, some of which enter the Krebs cycle for energy production; the remainder are broken down into ketones (acetone, acetoacetate, and β-hydroxybutyrate). Ketones can be used for energy, but accumulate rapidly. Glycogen and proteins are catabolized to form glucose. Together, these factors promote hyperglycemia, which leads to an osmotic diuresis resulting in dehydration, metabolic acidosis, and a hyperosmolar state ( eFigure A ) .

TYPICAL CLINICAL PRESENTATION

The presentation of DKA varies with severity and comorbid conditions. Polyuria with polydipsia is the most common presenting symptom and was found in 98 percent of persons in one study of childhood type 1 diabetes. Other common symptoms included weight loss (81 percent), fatigue (62 percent), dyspnea (57 percent), vomiting (46 percent), preceding febrile illness (40 percent), abdominal pain (32 percent), and polyphagia (23 percent). 17 Dehydration causes tachycardia, poor skin turgor, dry mucous membranes, and orthostatic hypotension. The metabolic acidosis may lead to compensatory deep (Kussmaul) respirations, whereas increased acetone can be sensed as a fruity smell on the patient's breath. Mental status can vary from somnolence to lethargy and coma. A detailed evaluation may reveal precipitating factors, especially nonadherence to medical regimens and infection, which are common causes of DKA.

DIFFERENTIAL DIAGNOSIS

Although hyperosmolar hyperglycemic state can be confused with DKA, ketone levels are low or absent in persons with hyperosmolar hyperglycemic state. Other causes of high anion gap metabolic acidosis, such as alcoholic ketoacidosis and lactic acidosis, must be ruled out. Table 2 provides the differential diagnosis of DKA. 14 , 18

DIAGNOSTIC TESTING

The diagnosis of DKA ( Table 3 ) is based on an elevated serum glucose level (greater than 250 mg per dL [13.88 mmol per L]), an elevated serum ketone level, a pH less than 7.3, and a serum bicarbonate level less than 18 mEq per L (18 mmol per L). 4 Although arterial blood gas measurement remains the most widely recommended test for determining pH, measurement of venous blood gas has gained acceptance. One review indicated that venous and arterial pH are clinically interchangeable in persons who are hemodynamically stable and without respiratory failure. 19 Traditionally, the severity of DKA is determined by the arterial pH, bicarbonate level, anion gap, and mental status of the patient ( Table 3 ) . 4 An anion gap greater than 16 mEq per L (16 mmol per L) confirms metabolic acidosis. Although persons with DKA usually have a glucose level greater than 250 mg per dL, a few case reports document DKA in pregnant women who were euglycemic. 20 , 21 Persons with hyperglycemia have pseudohyponatremia, and serum sodium concentration should be corrected. Table 4 provides formulas to calculate the anion gap, serum osmolality, osmolar gap, and serum sodium correction. 16 [ corrected ]

Urinalysis measures only acetone and acetoacetate, not β-hydroxybutyrate, which is the primary ketone in DKA. In one study, the urine dipstick test was negative for ketones in six of 18 persons. Ketonemia was defined as a ketone level greater than 0.42 mmol per L. 22 In a second study of point-of-care testing in the emergency department, urine dipstick testing for ketones had a sensitivity of 98 percent, specificity of 35 percent, and a positive predictive value of 15 percent. Serum testing for β-hydroxybutyrate had a sensitivity of 98 percent, a specificity of 79 percent, and a positive predictive value of 34 percent (using a cutoff of greater than 1.5 mmol per L), allowing for more accurate diagnosis of DKA. 23 The American Diabetes Association has revised its position on ketone analysis in favor of serum testing, and has concluded that capillary measurement is equivalent to venous measurement. 4 , 22 , 24

Further initial laboratory studies should include measurement of electrolytes, phosphate, blood urea nitrogen, and creatinine; urinalysis; complete blood count with differential; and electrocardiography ( Table 5 ) . 16 Potassium level is normal or low in persons with DKA, despite renal losses caused by the acidic environment. An initial potassium level less than 3.3 mEq per L (3.3 mmol per L) indicates profound hypokalemia. Amylase and lipase levels may be increased in persons with DKA, even in those without associated pancreatitis; however, 10 to 15 percent of persons with DKA do have concomitant pancreatitis. 18 , 25

Leukocytosis can occur even in the absence of infection; bandemia more accurately predicts infection. One study showed that an elevated band count in persons with DKA had a sensitivity for predicting infection of 100 percent (19 out of 19 cases) and a specificity of 80 percent. 26 Chest radiography and urine and blood cultures should be added for further evaluation of infection. An elevated hemoglobin level caused by dehydration may also exist. Elevated hepatic transaminase levels may occur, especially in persons with fatty liver disease. 27 Mild increases in creatine kinase and troponin levels may occur in the absence of myocardial damage; one study demonstrated that increased troponin levels occurred in 26 out of 96 persons with DKA without a coronary event. 28 Finally, the A1C level indicates the degree of glycemic control in persons known to have diabetes.

Figure 1 4 , 29 provides the treatment approach for DKA in adults, and Figure 2 24 , 30 provides the treatment approach for DKA in persons younger than 20 years. Both approaches are recommended by the American Diabetes Association. Specific issues for the adult patient are discussed in more detail below. For persons younger than 20 years, insulin should be administered gradually, and fluid and electrolyte replacement should be done cautiously because of limited data and concern for precipitating cerebral edema.

FLUID REPLACEMENT

After determining the level of dehydration, intravenous fluid replacement should be started. In most persons, saline 0.9% is started at 15 to 20 mL per kg per hour, or 1 L per hour initially. Fluid status, cardiac status, urine output, blood pressure, and electrolyte level should be monitored. As the patient stabilizes, fluids can be lowered to 4 to 14 mL per kg per hour, or 250 to 500 mL per hour. Once the corrected sodium concentration is normal or high (greater than 135 mEq per L [135 mmol per L]), the solution can be changed to saline 0.45%. Dextrose is added when the glucose level decreases to 200 mg per dL (11.10 mmol per L). 4

To further correct hyperglycemia, insulin should be added to intravenous fluids one to two hours after fluids are initiated. An initial bolus of 0.1 units per kg should be given with an infusion of 0.1 units per kg per hour. 4 Some believe this bolus is unnecessary as long as an adequate infusion of insulin is maintained. 31 An infusion of 0.14 units per kg per hour is recommended in the absence of a bolus. Glucose level should decrease by about 50 to 70 mg per dL (2.77 to 3.89 mmol per L) per hour, and the insulin infusion should be adjusted to achieve this goal. 4 Once the glucose level decreases to 200 mg per dL, the insulin infusion rate should be decreased to 0.05 to 0.1 units per kg per hour, and dextrose should be added to the intravenous fluids to maintain a glucose level between 150 and 200 mg per dL (8.32 and 11.10 mmol per L). 4 Subcutaneous insulin is an effective alternative to intravenous insulin in persons with uncomplicated DKA. 29 In one prospective randomized trial of 45 persons, 15 received insulin aspart (Novolog) hourly, 15 received insulin aspart every two hours, and 15 received standard intravenous infusion of regular insulin. Physiologic and clinical outcomes were identical in all three groups. 32 A meta-analysis supports subcutaneous administration of rapid-acting insulin analogues, such as lispro (Humalog), every hour (bolus of 0.3 units per kg, then 0.1 units per kg) or two hours (bolus of 0.3 units per kg, then 0.2 units per kg) as a reasonable alternative to intravenous regular insulin for treating uncomplicated DKA. 29

DKA is resolved when the glucose level is less than 200 mg per dL, the pH is greater than 7.3, and the bicarbonate level is 18 mEq per L or higher. 4

Once these levels are achieved and oral fluids are tolerated, the patient can be started on an insulin regimen that includes an intermediate- or long-acting insulin and a short- or rapid-acting insulin. When intravenous insulin is used, it should remain in place for one to two hours after subcutaneous insulin is initiated. Persons known to have diabetes can be started on their outpatient dose, with adjustments to improve control. Those new to insulin should receive 0.5 to 0.8 mg per kg per day in divided doses. 4

Although potassium is profoundly depleted in persons with DKA, decreased insulin levels, acidosis, and volume depletion cause elevated extracellular concentrations. Potassium levels should be monitored every two to four hours in the early stages of DKA. Hydration alone will cause potassium to drop because of dilution. Improved renal perfusion will increase excretion. Insulin therapy and correction of acidosis will cause cellular uptake of potassium. If the potassium level is in the normal range, replacement can start at 10 to 15 mEq potassium per hour. During treatment of DKA, the goal is to maintain serum potassium levels between 4 and 5 mEq per L (4 and 5 mmol per L). If the potassium level is between 3.3 and 5.2 mEq per L (3.3 and 5.2 mmol per L) and urine output is normal, replacement can start at 20 to 30 mEq potassium per hour. If the potassium level is lower than 3.3 mEq per L, insulin should be held and replacement should be started at 20 to 30 mEq potassium per hour. If the potassium level is greater than 5.2 mEq per L, insulin therapy without potassium replacement should be initiated, and serum potassium levels should be checked every two hours. When the potassium level is between 3.3 and 5.2 mEq per L, potassium replacement should be initiated. 4 Some guidelines recommend potassium replacement with potassium chloride, whereas others recommend combining it with potassium phosphate or potassium acetate. Clinical trials are lacking to determine which is best, although in the face of phosphate depletion, potassium phosphate is used.

BICARBONATE

Bicarbonate therapy in persons with DKA is somewhat controversial. Proponents believe that severe acidosis will cause cardiac and neurologic complications. However, studies have not demonstrated improved clinical outcomes with bicarbonate therapy, and treatment has been associated with hypokalemia. In one retrospective quasi-experimental study of 39 persons with DKA and a pH between 6.9 and 7.1, there was no difference in outcomes between those who received bicarbonate therapy and those who did not. 33 A second study of 106 adolescents with DKA showed no difference in outcomes in patients treated with and without sodium bicarbonate, but few had a pH below 7 and only one had a pH below 6.9. 34

Current American Diabetes Association guidelines continue to recommend bicarbonate replacement in persons with a pH lower than 6.9 using 100 mEq of sodium bicarbonate in 400 mL of sterile water with 20 mEq of potassium chloride at a rate of 200 mL per hour for two hours. This should be repeated every two hours until the patient's pH is 6.9 or greater. 4

PHOSPHATE AND MAGNESIUM

Phosphate levels may be normal to elevated on presentation, but decline with treatment as the phosphate enters the intracellular space. Studies have not shown a benefit from phosphate replacement, and it can be associated with hypocalcemia and hypomagnesemia. However, because phosphate deficiency is linked with muscle fatigue, rhabdomyolysis, hemolysis, respiratory failure, and cardiac arrhythmia, replacement is recommended when the phosphate level falls below 1.0 mg per dL (0.32 mmol per L) or when these complications occur. 4 Persons with anemia or respiratory problems and congestive heart failure may benefit from phosphate. This can be achieved by adding 20 to 30 mEq of potassium phosphate to the intravenous fluid. 4

DKA can cause a drop in magnesium, which can result in paresthesia, tremor, muscle spasm, seizures, and cardiac arrhythmia. It should be replaced if it falls below 1.2 mg per dL or if symptoms of hypomagnesemia develop. 35

Complications

Cerebral edema is the most severe complication of DKA. It occurs in 0.5 to 1 percent of all DKA cases, 36 , 37 and carries a mortality rate of 21 to 24 percent. 30 Survivors are at risk of residual neurologic problems. 38 Cerebral edema predominantly occurs in children, although it has been reported in adults. 39 Risk factors include younger age, new-onset diabetes, longer duration of symptoms, 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. 30 , 40 Signs of cerebral edema that require immediate evaluation include headache, persistent vomiting, hypertension, bradycardia, and lethargy and other neurologic changes.

Other complications of DKA include hypokalemia, hypoglycemia, acute renal failure, and shock. Less common problems can include rhabdomyolysis, 41 thrombosis and stroke, 42 pneumomediastinum, 43 prolonged corrected QT interval, 44 pulmonary edema, 45 and memory loss with decreased cognitive function in children. 46

Physicians should recognize signs of diabetes in all age groups, and should educate patients and caregivers on how to recognize them as well ( eTable A ) . In one study, persons with DKA had symptoms of diabetes for 24.5 days before developing DKA. 17 Persons with diabetes and their caregivers should be familiar with adjusting insulin during times of illness. This includes more frequent glucose monitoring; continuing insulin, but at lower doses, during times of decreased food intake; and checking urine ketone levels with a dipstick test if the glucose level is greater than 240 mg per dL (13.32 mmol per L). 47 More accessible home measurement of serum ketones with a commercial glucometer may allow for earlier detection of DKA and decreased hospital visits. 48 Persons with an insulin pump need to know their pump settings, and should maintain a prescription for basal insulin in case of pump failure.

Nonadherence to medical regimens is often the cause of recurrent DKA. Physicians need to recognize patient barriers to getting care, such as financial, social, psychological, and cultural reasons. Diabetes education with certified educators and pharmacists enhances patient care. 49 , 50 Other prevention techniques include group visits, telecommunication, web-based learning, and copay reduction for diabetes medications; however, evidence for their effectiveness is mixed. 51 – 55

Data Sources: In July 2010, an initially broad search of PubMed, Essential Evidence Plus, and sources such as the Cochrane database and Clinical Evidence was conducted using the key term diabetic ketoacidosis. In the fall of 2010, another search was conducted using additional key terms, such as incidence and prevalence. As information was collected, individual questions were then searched to add finer points to the documentation. The searches were repeated with each draft of the manuscript.

Henriksen OM, Røder ME, Prahl JB, Svendsen OL. Diabetic ketoacidosis in Denmark incidence and mortality estimated from public health registries. Diabetes Res Clin Pract. 2007;76(1):51-56.

Fritsch M, Rosenbauer J, Schober E, Neu A, Placzek K, Holl RW. German Competence Network Diabetes Mellitus and the DPV Initiative. Predictors of diabetic ketoacidosis in children and adolescents with type 1 diabetes. Experience from a large multicentre database. Pediatr Diabetes. 2011;12(4 pt 1):307-312.

Wang J, Williams DE, Narayan KM, Geiss LS. Declining death rates from hyperglycemic crisis among adults with diabetes, U.S., 1985–2002. Diabetes Care. 2006;29(9):2018-2022.

Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crisis in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343.

Schober E, Rami B, Waldhoer T Austrian Diabetes Incidence Study Group. Diabetic ketoacidosis at diagnosis in Austrian children in 1989–2008: a population-based analysis. Diabetologia. 2010;53(6):1057-1061.

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Kim MK, Lee SH, Kim JH, et al. Clinical characteristics of Korean patients with new-onset diabetes presenting with diabetic ketoacidosis. Diabetes Res Clin Pract. 2009;85(1):e8-e11.

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Umpierrez GE, Smiley D, Kitabchi AE. Narrative review: ketosis-prone type 2 diabetes mellitus. Ann Intern Med. 2006;144(5):350-357.

Wilson DR, D'Souza L, Sarkar N, Newton M, Hammond C. New-onset diabetes and ketoacidosis with atypical antipsychotics. Schizophr Res. 2003;59(1):1-6.

Ragucci KR, Wells BJ. Olanzapine-induced diabetic ketoacidosis. Ann Pharmacother. 2001;35(12):1556-1558.

Mithat B, Alpaslan T, Bulent C, Cengiz T. Risperidone-associated transient diabetic ketoacidosis and diabetes mellitus type 1 in a patient treated with valproate and lithium. Pharmacopsychiatry. 2005;38(2):105-106.

Nyenwe EA, Loganathan RS, Blum S, et al. Active use of cocaine: an independent risk factor for recurrent diabetic ketoacidosis in a city hospital. Endocr Pract. 2007;13(1):22-29.

Trachtenbarg DE. Diabetic ketoacidosis. Am Fam Physician. 2005;71(9):1705-1714.

Yan L. ‘Diabulimia’ a growing problem among diabetic girls. Nephrol News Issues. 2007;21(11):36.

Wilson JF. In clinic. Diabetic ketoacidosis. Ann Intern Med. 2010;152(1) ):ITC1-1-ITC1-15.

Xin Y, Yang M, Chen XJ, Tong YJ, Zhang LH. Clinical features at the onset of childhood type 1 diabetes mellitus in Shenyang, China. J Paediatr Child Health. 2010;46(4):171-175.

Nair S, Yadav D, Pitchumoni CS. Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA. Am J Gastroenterol. 2000;95(10):2795-2800.

Kelly AM. The case for venous rather than arterial blood gases in diabetic ketoacidosis. Emerg Med Australas. 2006;18(1):64-67.

Chico M, Levine SN, Lewis DF. Normoglycemic diabetic ketoacidosis in pregnancy. J Perinatol. 2008;28(4):310-312.

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. J Obstet Gynaecol Res. 2008;34(3):324-330.

Bektas F, Eray O, Sari R, Akbas H. Point of care blood ketone testing of diabetic patients in the emergency department. Endocr Res. 2004;30(3):395-402.

Arora S, Henderson SO, Long T, Menchine M. Diagnostic accuracy of point-of-care testing for diabetic ketoacidosis at emergency department triage: beta-hydroxbutyrate versus the urine dipstick. Diabetes Care. 2011;34(4):852-854.

Kitabchi AE, Umpierrez GE, Murphy MB, et al.; American Diabetes Association. Hyperglycemic crises in diabetes. Diabetes Care. 2004;27(suppl 1):S94-S102.

Yadav D, Nair S, Norkus EP, Pitchumoni CS. Nonspecific hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities. Am J Gastroenterol. 2000;95(11):3123-3128.

Slovis CM, Mork VG, Slovis RJ, Bain RP. Diabetic ketoacidosis and infection: leukocyte count and differential as early predictors of serious infection. Am J Emerg Med. 1987;5(1):1-5.

Takaike H, Uchigata Y, Iwamoto Y, et al. Nationwide survey to compare the prevalence of transient elevation of liver transaminase during treatment of diabetic ketosis or ketoacidosis in new-onset acute and fulminant type 1 diabetes mellitus. Ann Med. 2008;40(5):395-400.

Al-Mallah M, Zuberi O, Arida M, Kim HE. Positive troponin in diabetic ketoacidosis without evident acute coronary syndrome predicts adverse cardiac events. Clin Cardiol. 2008;31(2):67-71.

Mazer M, Chen E. Is subcutaneous administration of rapid-acting insulin as effective as intravenous insulin for treating diabetic ketoacidosis?. Ann Emerg Med. 2009;53(2):259-263.

Wolfsdorf J, Craig ME, Daneman D, et al. Diabetic ketoacidosis in children and adolescents with diabetes. Pediatr Diabetes. 2009;10(suppl 12):118-133.

Kitabchi AE, Murphy MB, Spencer J, Matteri R, Karas J. Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis?. Diabetes Care. 2008;31(11):2081-2085.

Umpierrez GE, Cuervo R, Karabell A, Latif K, Freire AX, Kitabchi AE. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care. 2004;27(8):1873-1878.

Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis?. Crit Care Med. 1999;27(12):2690-2693.

Green SM, Rothrock SG, Ho JD, et al. Failure of adjunctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emerg Med. 1998;31(1):41-48.

Chansky M, Haddad G. Acute diabetic emergencies, hypoglycemia, and glycemic control. In: Parrillo JE, Dellinger RP, eds. Critical Care Medicine: Principals of Diagnosis and Management in the Adult . 3rd ed. Philadelphia, Pa.: Mosby Elsevier; 2008:1245–1257.

Lawrence SE, Cummings EA, Gaboury I, Daneman D. Population-based study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis. J Pediatr. 2005;146(5):688-692.

Glaser N. Cerebral edema in children with diabetic ketoacidosis. Curr Diab Rep. 2001;1(1):41-46.

Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child. 2004;89(2):188-194.

Haringhuizen A, Tjan DH, Grool A, van Vugt R, van Zante AR. Fatal cerebral oedema in adult diabetic ketoacidosis. Neth J Med. 2010;68(1):35-37.

Carlotti AP, St George-Hyslop C, Guerguerian AM, Bohn D, Kamel KS, Halperin M. Occult risk factor for the development of cerebral edema in children with diabetic ketoacidosis: possible role for stomach emptying. Pediatr Diabetes. 2009;10(8):523-533.

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Diabetic ketoacidosis

On this page, when to see a doctor, risk factors, complications.

Diabetic ketoacidosis is a serious complication of diabetes.

The condition develops when the body can't produce enough insulin. Insulin plays a key role in helping sugar — a major source of energy for muscles and other tissues — enter cells in the body.

Without enough insulin, the body begins to break down fat as fuel. This causes a buildup of acids in the bloodstream called ketones. If it's left untreated, the buildup can lead to diabetic ketoacidosis.

If you have diabetes or you're at risk of diabetes, learn the warning signs of diabetic ketoacidosis and when to seek emergency care.

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Diabetic ketoacidosis symptoms often come on quickly, sometimes within 24 hours. For some, these symptoms may be the first sign of having diabetes. Symptoms might include:

• Being very thirsty
• Urinating often
• Feeling a need to throw up and throwing up
• Having stomach pain
• Being weak or tired
• Being short of breath
• Having fruity-scented breath
• Being confused

More-certain signs of diabetic ketoacidosis — which can show up in home blood and urine test kits — include:

• High blood sugar level
• High ketone levels in urine

If you feel ill or stressed or you've had a recent illness or injury, check your blood sugar level often. You might also try a urine ketone test kit you can get at a drugstore.

Contact your health care provider right away if:

• You're throwing up and can't keep down food or liquid
• Your blood sugar level is higher than your target range and doesn't respond to home treatment
• Your urine ketone level is moderate or high

Seek emergency care if:

• Your blood sugar level is higher than 300 milligrams per deciliter (mg/dL), or 16.7 millimoles per liter (mmol/L) for more than one test.
• You have ketones in your urine and can't reach your health care provider for advice.
• You have many symptoms of diabetic ketoacidosis. These include excessive thirst, frequent urination, nausea and vomiting, stomach pain, weakness or fatigue, shortness of breath, fruity-scented breath, and confusion.

Remember, untreated diabetic ketoacidosis can lead to death.

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Sugar is a main source of energy for the cells that make up muscles and other tissues. Insulin helps sugar enter the cells in the body.

Without enough insulin, the body can't use sugar to make the energy it needs. This causes the release of hormones that break down fat for the body to use as fuel. This also produces acids known as ketones. Ketones build up in the blood and eventually spill over into the urine.

Diabetic ketoacidosis usually happens after:

• An illness. An infection or other illness can cause the body to make higher levels of certain hormones, such as adrenaline or cortisol. These hormones work against the effects of insulin and sometimes cause diabetic ketoacidosis. Pneumonia and urinary tract infections are common illnesses that can lead to diabetic ketoacidosis.
• A problem with insulin therapy. Missed insulin treatments can leave too little insulin in the body. Not enough insulin therapy or an insulin pump that doesn't work right also can leave too little insulin in the body. Any of these problems can lead to diabetic ketoacidosis.

Other things that can lead to diabetic ketoacidosis include:

• Physical or emotional trauma
• Heart attack or stroke
• Pancreatitis
• Alcohol or drug misuse, particularly cocaine
• Certain medicines, such as corticosteroids and some diuretics

The risk of diabetic ketoacidosis is highest if you:

• Have type 1 diabetes
• Often miss insulin doses

Sometimes, diabetic ketoacidosis can occur with type 2 diabetes. In some cases, diabetic ketoacidosis may be the first sign of having diabetes.

Diabetic ketoacidosis is treated with fluids, electrolytes — such as sodium, potassium and chloride — and insulin. Perhaps surprisingly, the most common complications of diabetic ketoacidosis are related to this lifesaving treatment.

Possible complications of the treatments

Treatment complications include:

• Low blood sugar, also known as hypoglycemia. Insulin allows sugar to enter cells. This causes the blood sugar level to drop. If the blood sugar level drops too quickly, the drop can lead to low blood sugar.
• Low potassium, also known as hypokalemia. The fluids and insulin used to treat diabetic ketoacidosis can cause the potassium level to drop too low. A low potassium level can affect the heart, muscles and nerves. To avoid this, potassium and other minerals are usually given with fluid replacement as part of the treatment of diabetic ketoacidosis.
• Swelling in the brain, also known as cerebral edema. Adjusting the blood sugar level too quickly can cause the brain to swell. This appears to be more common in children, especially those with newly diagnosed diabetes.

Untreated, diabetic ketoacidosis can lead to loss of consciousness and, eventually, death.

There are many ways to prevent diabetic ketoacidosis and other diabetes complications.

• Manage your diabetes. Make healthy eating and physical activity part of your daily routine. Take diabetes medicines or insulin as directed.
• Monitor your blood sugar level. You might need to check and record your blood sugar level at least 3 to 4 times a day, or more often if you're ill or stressed. Careful monitoring is the only way to make sure that your blood sugar level stays within your target range.
• Adjust your insulin dosage as needed. Talk to your health care provider or diabetes educator about how to make your insulin dosage work for you. Consider factors such as your blood sugar level, what you eat, how active you are, and whether you're ill. If your blood sugar level begins to rise, follow your diabetes treatment plan to return your blood sugar level to your target range.
• Check your ketone level. When you're ill or stressed, test your urine for excess ketones with a urine ketones test kit. You can buy test kits at a drugstore. If your ketone level is moderate or high, contact your health care provider right away or seek emergency care. If you have low levels of ketones, you may need to take more insulin.
• Be prepared to act quickly. If you think you have diabetic ketoacidosis because your blood sugar is high and you have too many ketones in your urine, seek emergency care.

Diabetes complications are scary. But don't let fear keep you from taking good care of yourself. Follow your diabetes treatment plan carefully. Ask your diabetes treatment team for help when you need it.

Oct 06, 2022

• DKA (ketoacidosis) and ketones. American Diabetes Association. https://diabetes.org/diabetes/dka-ketoacidosis-ketones. Accessed Sept. 17, 2022.
• Diabetic ketoacidosis (DKA). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka?query=Diabetic ketoacidosis (DKA). Accessed Sept. 17, 2022.
• Hirsch IB, et al. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis. https://www.uptodate.com/contents/search. Accessed Sept. 17, 2022.
• Hirsch IB, et al. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment. https://www.uptodate.com/contents/search. Accessed Sept. 17, 2022.
• Ferri FF. Diabetic ketoacidosis. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Sept. 17, 2022.
• Evans K. Diabetic ketoacidosis: Update on management. Clinical Medicine. 2019; doi:10.7861/clinmed.2019-0284.
• Diseases & Conditions
• Diabetic ketoacidosis symptoms & causes

Associated Procedures

• Chest X-rays
• Electrocardiogram (ECG or EKG)

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A Can’t Miss ED Diagnosis: Euglycemic DKA

Which home medication is likely responsible for this presentation?

• Liraglutide
• Canagliflozin

Canagliflozin: An SGLT2 Inhibitor

The patient’s presentation is consistent with diabetic ketoacidosis (DKA) in the absence of hyperglycemia. This entity is known at euglycemic DKA and it is increasingly recognized for an association with a newer oral diabetic medication class, SGLT2 inhibitors. Examples include:

• Empagliflozin
• Dapagliflozin

The FDA has approved these three SGLT2 inhibitors for Type 2 diabetics, and at times, they are prescribed off-label for Type 1. The mechanism involves decreasing glucose reabsorption in the nephron’s proximal tubule (via inhibition of the sodium-glucose linked cotransporter-2 protein). This results in increased urinary excretion of glucose that is independent of the body’s insulin secretion. 1

Other potential benefits of this class of medications include: 1–3

• Weight loss
• Blood pressure reduction
• Few reported hypoglycemic events

In 2015 the FDA issued a warning, however, that SGLT2 inhibitors may cause ketoacidosis, urinary tract infections, and urosepsis. 4 Since then, multiple case reports have been published showing an association between SGLT2 inhibitors and the development of euglycemic DKA.

Euglycemic DKA

Euglycemic DKA is an uncommon and likely under-diagnosed phenomenon, best defined as DKA with a lower than expected blood glucose (less than 250 mg/dL according to the American Diabetes Association). 4–6

Potential precipitants, in addition to SGLT2 inhibitors, include: 7

• Carbohydrate restriction
• Dehydration
• Partial treatment of hyperglycemic DKA

EPs may delay diagnosis, given the modest glucose levels at the time of presentation. This, however, is false reassurance because DKA is not defined by an absolute blood glucose . Interestingly, patients with euglycemic DKA may have a normal mental status despite marked ketoacidosis, and vomiting seems to be a common complaint. 5

Euglycemic DKA treatment is the same as traditional DKA, and includes hydration, insulin, and supportive care. Patients with euglycemic DKA may also need a dextrose infusion given the lower glucose levels.

SGLT2 Inhibitors and Euglycemic DKA: Mechanism

The mechanisms by which SGLT2 inhibitors cause or predispose to euglycemic DKA are unclear and likely complex. SGLT2 inhibitors may lead to a decrease in either endogenous or exogenous insulin, and an increase in glucagon production. 8  This insulin deficiency or resistance may be mild in Type 2 diabetics, however, preventing the profound spike in blood glucose seen in traditional DKA. 7

SGLT2 Inhibitors and Euglycemic DKA: Evidence

The evidence suggesting a link between SGLT2 inhibitors and euglycemic DKA remains limited to case reports. Both the FDA and the European Medicine Agency have reported cases of DKA with unusually low glucose levels. 4,9  Peters et al. reported 13 episodes euglycemic DKA in patients taking SGLT2 inhibitors, though most were Type 1 diabetics. 10 In Japan, 28 cases of DKA or ketoacidosis in patients taking SGLT2 inhibitors have been reported as of 2015. Of these, the initial blood glucose is known in only 14 cases, but in 9 cases, it was <300 mg/dL. 8

Take-Home Points

• DKA is not defined by an absolute blood glucose.
• Obtaining a urine sample for ketones and a blood gas early in the ED course is extremely important in all diabetics, especially those who are Type 1 and those on SGLT2 inhibitors.
• The treatment of euglycemic DKA is essentially the same as traditional DKA: hydration, replace electrolytes, insulin.
• Cefalu W, Leiter L, Yoon K, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet . 2013;382(9896):941-950. [ PubMed ]
• Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care . 2015;38(3):420-428. [ PubMed ]
• Handelsman Y, Henry R, Bloomgarden Z, et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF SGLT-2 INHIBITORS AND DIABETIC KETOACIDOSIS. Endocr Pract . 2016;22(6):753-762. [ PubMed ]
• FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. U.S. Food and Drug Administration: Drug and Safety Availability. https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm . Published January 19, 2018. Accessed March 18, 2018.
• Munro J, Campbell I, McCuish A, Duncan L. Euglycaemic diabetic ketoacidosis. Br Med J . 1973;2(5866):578-580. [ PubMed ]
• Kitabchi A, Umpierrez G, Miles J, Fisher J. Hyperglycemic crises in adult patients with diabetes. Diabetes Care . 2009;32(7):1335-1343. [ PubMed ]
• Rosenstock J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care . 2015;38(9):1638-1642. [ PubMed ]
• Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig . 2016;7(2):135-138. [ PubMed ]
• European Medicines Agency. SGLT2 Inhibitors-Scientific Conclusions . European Medicines Agency; 2016:2-4. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors__20/European_Commission_final_decision/WC500206487.pdf . Accessed February 1, 2018.
• Peters A, Buschur E, Buse J, Cohan P, Diner J, Hirsch I. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care . 2015;38(9):1687-1693. [ PubMed ]
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Euglycemic Diabetic Ketoacidosis

Introduction.

Euglycemic diabetic ketoacidosis (DKA, EDKA) is a clinical syndrome occurring both in type 1 (T1DM) and type 2 (T2DM) diabetes mellitus characterized by euglycemia (blood glucose less than 250 mg/dL) in the presence of severe metabolic acidosis (arterial pH less than 7.3, serum bicarbonate less than 18 mEq/L) and ketonemia. DKA is one of the most severe and life-threatening complications of diabetes mellitus and can be seen in a variety of conditions. However, the incidence of EDKA has grown with the introduction of sodium-glucose transporter 2 (SGLT2) inhibitors. [1] It also presents a diagnostic challenge for physicians due to the variety of etiologies and normal blood glucose levels, often resulting in delayed diagnosis. [2] [3] [4]

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There are many known causes of EDKA in patients with diabetes. The overall mechanism is based on a general state of starvation, resulting in ketosis while maintaining normoglycemia. Therefore, conditions like anorexia, gastroparesis, fasting, use of a ketogenic diet, and alcohol use disorder can lead to states of carbohydrate starvation and subsequent ketosis. Additional triggers for EDKA include pregnancy, pancreatitis, glycogen storage disorders, surgery, infection, cocaine toxicity, cirrhosis, and insulin pump use. [5] [6] [7] T1DM who underwent bariatric surgery patients experience DKA in over 20% of postoperative cases and may be especially prone to EDKA. [8]

The newer oral antidiabetic medication category of SGLT2 inhibitors, including canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin, can also directly result in EDKA. [2] [3] [9] [10] [11] [12] [13]  EDKA may be more common in patients with diabetes on SGLT2 inhibitors with lower body mass index and decreased glycogen stores. [1]  Episodes can be triggered by surgery, infection, trauma, a major illness, reduced food intake, persistent vomiting, gastroparesis, dehydration, and reduced insulin dosages. [14]

On rare occasions, a patient in DKA may receive enough extra insulin to bring the blood sugar under 250 mg/dL.

Epidemiology

Approximately 2.6% to 3.2% of DKA admissions are euglycemic. [9] [15] DKA-associated with the use of SGLT2 inhibitors has rates ranging from 0.16 to 0.76 events per 1000 patient-years in patients with type 2 diabetes. Blau et al. estimate that the SGLT2 inhibitors increase the risk of DKA in T2D patients by 7-fold. [16]  

Erondu et al. estimate an overall incidence of DKA from SGLT2 inhibitor use of approximately 0.1%. [17]  Data on patients with type 1 diabetes who presented with DKA associated with SGLT2 inhibitors showed rates varying from 5 to 12%; however, euglycemia was not present in all cases. [10]  SGLT2 inhibitors are not approved for use in patients with type 1 diabetes. Data associated with other causes of euglycemic DKA is scarce.

Pathophysiology

The underlying mechanism of EDKA is secondary to a carbohydrate deficit resulting in generalized decreased serum insulin and excess counter-regulatory hormones like glucagon, epinephrine, and cortisol. The increased glucagon/insulin ratio leads to increased lipolysis, increased free fatty acids, and ketoacidosis. [2] [9] [12] Ketone body production in EDKA is similar to DKA with acetoacetic acid, beta-hydroxybutyric acid (after acetoacetic acid reduction), and acetone (after acetoacetic acid decarboxylation). The resulting anion gap metabolic acidosis triggers respiratory compensation and the sensation of dyspnea, as well as nausea, anorexia, and vomiting. Volume depletion resulting from decreased oral intake, vomiting, and osmotic diuresis from glucosuria further exacerbates elevations in glucagon, cortisol, and epinephrine, worsening lipolysis and ketogenesis. Additionally, decreased gluconeogenesis by the liver occurs in fasting where hepatic glycogen is already depleted, or increased glucosuria by the kidneys contributes to EDKA. [3]  

Often the insulin-using patients do not recognize their symptoms as DKA because serum glucose is not elevated and may maintain or decrease their insulin dose. [1]  If insulin dosing is adequate for glucose levels, it will prevent gluconeogenesis, resulting in euglycemia. EDKA can be considered a “partially treated DKA” in this setting. [9]

SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) are a newer class of antidiabetic drugs that increase the risk of EDKA unrelated to the duration of exposure. [16] [18] [19]  The use of SGLT2 inhibitors in T1DM is not recommended by the U.S. Food and Drug Administration and is discouraged because the risk of ketone-associated effects can be as high as 9%. [1] [20] [21] The risk of EDKA among T2DM patients on SGLT2 inhibitors may be higher in patients with beta-cell insufficiency and perhaps predict those at greater risk for evolving to T1DM. [20] The mechanism of action of SGLT2 inhibitors is to enhance excretion and block reabsorption of filtered glucose from the proximal convoluted tubule. [22]  The loss of urinary glucose again creates a state of carbohydrate starvation and volume depletion, increasing the glucagon/insulin ratio and resulting in a state of severe dehydration and ketosis. [1]

Additionally, SGLT2 inhibitors have been found to directly stimulate the release of glucagon from the pancreas, further worsening the glucagon/insulin imbalance, as well as suppressing the removal of beta-hydroxybutyrate and acetoacetate by the kidneys. [22] [23] [24] Euglycemia is maintained due to the loss of urinary glucose  [2] [9] [10] [25] [26]  and SGLT2 inhibitor-triggered hypoinsulinemia. [27]  SGLT2 inhibitors also increase ketone reabsorption, such that ketosis is common in patients taking SGLT2 inhibitors after a trigger such as pregnancy, alcohol, surgery, infection, or starvation. [9] [18]

Pregnancy is a risk factor for EDKA because of the physiologic state of hypoinsulinemia and increased starvation. Increased levels of cortisol and placental lactogen result in insulin resistance, and episodes of vomiting or fasting can lead to exaggerated starvation ketosis. [28] Respiratory alkalosis leading to bicarbonate loss in the urine exacerbates the acidosis. [29] These factors, taken together, can result in starvation, euglycemia, and ketoacidosis by the previous mechanisms described. [2]

Alcoholic ketoacidosis may have a similar presentation to EDKA, with anorexia, vomiting, dyspnea, and significant anion gap metabolic acidosis and ketonemia. Some consider alcoholic ketoacidosis a subtype of euglycemic DKA, and both are associated with increased glucagon/insulin ratio. [1] [9] [15] The differentiating factors are that alcoholic ketoacidosis patients do not have diabetes or use diabetic medications and are more commonly present with hypoglycemia or after a severe alcohol binge. [26] Similarly, excessive alcohol consumption in a person with diabetes can destroy pancreatic beta cells, decrease gluconeogenesis, and decrease glycogen stores. Coupled with vomiting and carbohydrate starvation results in accelerated lipolysis, ketoacidosis, and EDKA. [2] [9]

History and Physical

Signs and symptoms will vary on a case-by-case basis but will be similar in presentation to hyperglycemic DKA, although perhaps without polyuria, polydipsia, or severe mental status changes. EDKA patients can present with nausea, vomiting, shortness of breath, generalized malaise, lethargy, loss of appetite, fatigue, or abdominal pain. Patients may not have polydipsia or polyuria since serum glucose is normal. The onset can be more insidious compared to hyperglycemic DKA due to the mechanism of subacute starvation required to induce ketosis and dehydration. There may or may not be an inciting infection or stressors, such as pregnancy, surgery, pancreatitis, alcohol use, or fasting. [30]

Patients may present with deep, rapid breathing, known as Kussmaul respiration, which represents respiratory compensation for severe metabolic acidosis. They may have a fruity odor to their breath due to the loss of acetone. Tachycardia, hypotension, altered mentation, increased skin turgor and delayed capillary refill are all signs of total body fluid loss. In severe cases, severe dehydration and metabolic derangement can lead to hypovolemic shock, lethargy, respiratory failure, coma, and death.

An ill-feeling patient with diabetes with symptoms such as malaise, dyspnea, nausea, or vomiting should undergo screening with serum pH and blood or urine ketone testing. [3] [31] [32] [33]

The initial laboratory evaluation of EDKA includes basic electrolytes, glucose, calcium, magnesium, creatinine, BUN, serum and urine ketones, beta-hydroxybutyric acid, arterial or venous blood gas analysis, lactic acid, chest radiograph, and electrocardiogram. Urine screening for ketones with nitroprusside reagent does not measure beta-hydroxybutyrate but detects acetone and acetoacetate. Serum levels of beta-hydroxybutyrate are typically greater than 3 mmol/L in EDKA (normal values less than 0.5 mmol/L). If an infection is on the differential, consider CBC with differential white blood cell count and blood cultures. Serum osmolality, to assess for an osmolar gap, and toxic alcohols should be sent to rule out toxic alcohol ingestion when suspected in any patient with severe, unexplained anion gap metabolic acidosis. Close attention should be paid to the anion gap to help narrow direct diagnosis, workup, and management.

As described previously, the patient will have normoglycemia (capillary blood glucose less than 250 mg/dL) in the presence of metabolic acidosis (pH less than 7.3) and a total decreased serum bicarbonate (less than 18 mEq/L). Serum and urine ketones must be elevated to make the diagnosis of EDKA. Lactic acid may be elevated but should not account entirely for the elevation in the anion gap. Leukocytosis may be present in the case of a concurrent infection; however, it is nonspecific and could also be due to hemoconcentration or stress, among other causes. Potassium levels will vary, but great attention should be paid to the level before starting therapy, as total body potassium is usually depleted. Hypomagnesemia and hypophosphatemia can be seen in starvation due to decreased total intake and increased losses. Mild hyponatremia may also be seen but is generally less severe than the “pseudo-hyponatremia” seen in profound hyperglycemic states.

Treatment / Management

Initial management should be directed toward fluid resuscitation, as patients usually present as profoundly dehydrated. Begin with the administration of isotonic saline or lactated ringers solution. The American Diabetes Association (ADA) recommends 1 to 1.5 L/hr isotonic fluids during the first 1 to 2 hours. Continuous insulin infusion should follow fluid replacement, contingent on serum potassium levels greater than 3.3 mEq/L, starting at a rate of 0.05 to 0.1 U/kg/hr. In contrast to DKA management, since serum glucose in EDKA is less than 250 mg/dL, dextrose 5% should initially be added to the fluids to avoid hypoglycemia and hasten clearance of ketosis. [34] Consider increasing the amount of dextrose to 10% if ketoacidosis persists on D5%. [27] [35] [27] (B3)

Potassium should also be carefully monitored as total body potassium levels will likely be depleted, and IV supplementation of potassium and other electrolytes may be needed. Blood glucose levels should be checked hourly, and electrolytes every four hours at a minimum, as is the standard for treating DKA. Patients taking SGLT2 inhibitors should have these medications discontinued as soon as the diagnosis is recognized and held until recovery from the acute illness. [10] Sodium bicarbonate infusions are not indicated, and even use in the setting of severe acidemia of pH less than 6.9 is controversial. Patients will generally require ICU admission for close hemodynamic and laboratory monitoring as well as frequent titration of insulin infusion. [2] [36] [37]  

Treatment with IV fluid resuscitation should continue until the anion gap closes and acidosis has resolved.

Differential Diagnosis

In patients presenting with anion gap metabolic acidosis, clinicians must consider a variety of possibilities early on. Infections, including pneumonia, genitourinary infection, and bacteremia, must be ruled out early in the diagnostic algorithm. In patients presenting with abdominal pain, consider intraabdominal infection and pancreatitis. Consider toxic alcohol (methanol, ethylene glycol) or paraldehyde ingestion, salicylate overdose, lactic acidosis, starvation ketosis, and pregnancy in the appropriate clinical setting.

Note that patients may have also recently administered insulin, contributing to the euglycemic presentation. The presentation is very similar to alcoholic ketoacidosis (AKA), except EDKA patients have diabetes, and AKA patients present after an alcohol binge more commonly have hypoglycemia and can be successfully resuscitated with crystalloid and dextrose without the requirement for insulin.

Most patients with EDKA recover well with prompt recognition and treatment. Delayed diagnosis and inadequate treatment, especially hydration without dextrose/insulin infusion, can lead to persistent acidosis, vomiting, and prolonged hospitalization. Prognosis is worse for small children and pregnant women. Rarely, severe cases of respiratory failure, hypovolemic shock, coma, and death. Death is rare in most EDKA cases; however, pregnant women are at greater mortality risk than the general population.

Complications

Euglycemic DKA can result in persistent vomiting, dehydration, hypoglycemia, hypovolemic shock, respiratory failure, cerebral edema, coma, seizures, infection, thrombosis, myocardial infarction, and death. [38]  Maternal EDKA can increase the rate of fetal (up to 9%) and maternal mortality. [39] [40]

Consultations

Consider consultation with a critical care intensivist and endocrinologist for severe cases. Pregnant women suffering from EDKA benefit from involvement with obstetric and maternal-fetal medicine consultants.

Deterrence and Patient Education

Vigilant monitoring of capillary or urine ketones by patients with diabetes, especially during episodes of nausea or illness, can diagnose EDKA before it becomes severe.

Although the SGLT2 inhibitors have been shown to have extra benefits on cardiovascular and kidney health, they are not recommended to be used in managing patients with T1DM because of the high risk of EDKA. [41] [42] [43]

Pearls and Other Issues

• Successful diagnosis is dependent on early screening with serum or urine ketones, even when serum glucose is normal, whenever EDKA is suspected.
• After volume expansion with crystalloid, the foundation of therapy is a combination of dextrose (5 to 10%) and insulin (0.05 to 0.1 u/kg/hr) infusion until acidosis resolves.
• Insulin infusion should not be avoided due to normal glucose levels but instead is essential to successful treatment.
• Ketosis does not resolve with intravenous crystalloid hydration alone.
• SGLT2 inhibitor treatment should be discontinued as soon as EDKA is diagnosed.
• Sodium bicarbonate infusion is not indicated.

Enhancing Healthcare Team Outcomes

Euglycemic DKA is becoming more prevalent with the appearance of the new SGLT2 inhibitors. However, it is important to recognize the variety of etiologies of a potentially fatal condition. Early diagnosis and initiation of treatment can significantly improve morbidity and mortality. In patients presenting with euglycemic anion gap acidosis, great care is necessary to rule out other causes, including sepsis, toxic alcohol ingestion, and alcoholic ketoacidosis, among others. Early IV crystalloid and prompt initiation of insulin and dextrose infusion are the primary treatment.

Treatment requires a team of interprofessional healthcare workers consisting of clinicians (MDs, DOs, NPS, or PAs), possibly including consultation with a critical care intensivist as well as an endocrinologist. Emergency and critical care nurses monitor patients, administer ordered treatments, and report changes to physicians so treatment can be optimized. The clinicians can also consult with the pharmacy regarding appropriate interventions and have them run a full medication reconciliation to check for drug interactions or agents that may contribute to EDKA. ALl interprofessional team members must be prepared to communicate with the rest of the team as they note any changes in patient status, including therapeutic failure. The observations must also be documented in the patient's health record so all interprofessional team members can access the same accurate patient data. In this way, appropriate corrective actions can be implemented. These interprofessional interventions are crucial to achieving better patient outcomes. [Level 5]

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INTRODUCTION

The precipitating factors, clinical features, evaluation, and diagnosis of DKA and HHS in adults will be reviewed here. The epidemiology, pathogenesis, and treatment of these disorders are discussed separately. DKA in children is also reviewed separately.

● (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Epidemiology and pathogenesis" .)

● (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment" .)

● (See "Diabetic ketoacidosis in children: Clinical features and diagnosis" .)

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Euglycemic Diabetic Ketoacidosis

Modified: May 9, 2022 by John Coleman · This post may contain affiliate links ·

Diabetes is a lifelong condition that can cause serious health problems if it's not managed well. One of the most serious diabetes-related health problems is a condition called euglycemic diabetic ketoacidosis (DKA).

What is euglycemic diabetic ketoacidosis?

What are the symptoms of euglycemic diabetic ketoacidosis, what causes euglycemic diabetic ketoacidosis, how is euglycemic diabetic ketoacidosis treated, what are the complications of euglycemic diabetic ketoacidosis, how can euglycemic diabetic ketoacidosis be prevented.

In this article, we'll explain what EDKA is, what causes it, and how to treat it.

Euglycemic diabetic ketoacidosis (EDKA) is a rare but serious complication of diabetes. When you have a high blood sugar level, your body produces ketones, which are acidic compounds that can build up in the blood and cause serious health problems.

EDKA is most often seen in people with type 1 diabetes , but it can also occur in people with type 2 diabetes and can be caused by several things such as fasting, surgery, pregnancy, or the use of SGLT2 inhibitors.

This complication is usually due to an imbalance between insulin and counter-regulatory hormones. Or in other words, it happens when your blood sugar gets too high, and your body starts to produce ketones that then build up in your body.

Without proper treatment, it can lead to coma and death. If you have diabetes, it's important to know the signs and symptoms of EDKA so you can get treatment right away.

People with EDKA can have different symptoms, such as feeling sick and vomiting, having trouble breathing, feeling generally bad, being very tired, not wanting to eat, and having pain in their stomach. People with EDKA may also have a normal blood sugar level. This can make it hard for diabetic patients to recognize the symptoms.

The symptoms of EDKA can be more gradual than the symptoms of DKA (diabetic ketoacidosis), which happens when someone's blood sugar level is high because they are not taking enough insulin. Sometimes there is an infection or other stressor that causes EDKA.

Some patients may have a fast, deep breathing pattern called Kussmaul respiration. This happens when the body is trying to compensate for a severe case of acidosis. The patient's breath may also smell fruity because of the loss of acetone. They may also have a fast heart rate, low blood pressure, confusion, increased skin turgor and delayed capillary refill.

If someone has diabetes and feels sick, has trouble breathing, feels sick in their stomach, or vomits, they should have a blood and urine test to see if they have ketones. The blood tests will check for electrolytes, glucose, creatinine, and BUN. And the urine tests will check for ketones, beta-hydroxybutyric acid, acetone, and acetoacetate.

Euglycemic diabetic ketoacidosis (EDKA) is a relatively rare complication that can occur when blood sugar levels are not tightly controlled.

When the body doesn't have enough glucose to use for energy, it starts to break down fatty acids for fuel. This process, called ketogenesis, produces a ketone called acetoacetate.

Acetoacetate then can build up in the body and cause diabetic ketoacidosis (EDKA) – a life-threatening condition that also can result in coma or death.

It's not clear what causes euglycemic diabetic ketoacidosis .

Euglycemic diabetic ketoacidosis is not clearly understood. However, some experts believe that it's caused by a combination of factors, including a build-up of ketones in the body, stress, and infection.

It's also thought that people with type 1 diabetes may be more susceptible to euglycemic diabetic ketoacidosis because their bodies are unable to produce insulin.

It may be related to changes in insulin levels .

As mentioned before, the exact cause of EDKA is not known, but it is thought to be related to changes in insulin levels. This can happen if you miss a dose of insulin, have an infection, or are under stress. But the most common cause of euglycemic diabetic ketoacidosis is an infection, such as pneumonia, urinary tract infection, or sepsis.

Other possible triggers include certain medications, such as corticosteroids or octreotide; alcohol abuse; and underlying conditions, such as heart failure or cancer. Euglycemic diabetic ketoacidosis can also occur in people without diabetes who have had a recent surgery or who have been fasting for a prolonged period of time.

Treatment for euglycemic diabetic ketoacidosis usually involves hospitalization and close monitoring by a team of healthcare professionals. Your blood sugar levels will be closely managed, and you may be given insulin to bring your blood sugar levels down to a safe range.

Fluids will also be administered through an IV to help correct the dehydration that often accompanies this condition. If your potassium (important minerals in your body) levels are low, you may also be given potassium supplements.

Euglycemic diabetic ketoacidosis is then treated with insulin therapy. Insulin therapy is used to lower blood sugar and stop ketone production. The goal of treatment is to bring blood sugar levels into a normal range and to correct the electrolyte imbalance.

Treatment usually requires a hospital stay so that fluids and insulin can be given intravenously. Most people with euglycemic diabetic ketoacidosis make a full recovery with treatment. The key to preventing these complications is recognizing EDKA early and treating it with fluids, dextrose, and insulin.

Complications of euglycemic diabetic ketoacidosis can be very serious and even life-threatening. Some of the most common complications include:

• Respiratory failure – occurs when the lungs can't provide enough oxygen to the body.

This can occur when the body's tissues and organs are unable to get enough oxygen from the blood. This, in turn, happens when the body's tissues cannot use glucose for energy, and the body starts to break down fat for energy.

This process produces ketones, which can build up in the blood and cause a dangerous condition called ketoacidosis.

Ketones that are built up in the blood can cause an acidic environment that can cause damage to the lungs and make it difficult for you to breathe.

The body will try to compensate by breathing faster, but this can lead to a build-up of carbon dioxide in the blood. This can cause the blood pH to become too low, which then can lead to coma and death.

• Cerebral edema – this is a dangerous accumulation of fluid in the brain.

Cerebral edema, or swelling of the brain, is a serious complication of euglycemic diabetic ketoacidosis. Increased pressure inside the skull can cause headaches, seizures, and even comas.

• Heart failure – this is a condition in which the heart can't pump enough blood to meet the body's needs.

Euglycemic diabetic ketoacidosis can cause heart failure for a few reasons.

• The lack of insulin can cause the body to break down fat for energy, which produces ketones, which then can build up in the blood and make the blood more acidic. This acidity can damage the heart muscle and lead to heart failure.
• The dehydration that often occurs with euglycemic diabetic ketoacidosis can also lead to heart failure. When the body is dehydrated, it doesn't have enough fluid to pump through the heart properly, which can cause the heart to fail.
• The electrolyte imbalance that occurs with euglycemic diabetic ketoacidosis can also lead to heart failure. An imbalance in the body's electrolytes can cause irregular heart rhythms, which can eventually cause heart failure.
• Gastrointestinal haemorrhage – this is a loss of blood from the stomach or intestines.

Euglycemic diabetic ketoacidosis can cause gastrointestinal haemorrhage due to the increase in ketone levels in the blood. When the ketones level gets too high in the blood, they can create an acidic environment that can break down blood vessels.

This can lead to bleeding in the gastrointestinal tract. In severe cases, this can lead to death.

• Septicemia – this is a serious infection in the bloodstream.

Septicemia is a potentially life-threatening complication of euglycemic diabetic ketoacidosis. It occurs when the infection that caused the ketoacidosis spreads through the bloodstream. Septicemia can lead to organ failure and death.

It's important to know how to prevent EDKA so that you can avoid this potentially life-threatening condition. Several things can be done to reduce your risk of EDKA.

Recognize the symptoms of euglycemic diabetic ketoacidosis

The best way to prevent euglycemic diabetic ketoacidosis is to recognize the symptoms and get treatment right away.

If you are a diabetes type 1 patient and observe symptoms that include nausea, vomiting, abdominal pain, shortness of breath, and fatigue, call your doctor or go to the emergency room immediately.

Test your blood sugar regularly

One of the best ways to prevent euglycemic diabetic ketoacidosis is to test your blood sugar regularly.

If you are a diabetes patient, it's important to ask your doctor how often you should check your blood sugar and what to do if it gets too low. This way, you can catch any changes in your blood sugar levels early and take steps to correct them.

Adjust your insulin doses as needed

The best way to prevent euglycemic diabetic ketoacidosis is to adjust your insulin doses.

If you are sick or have a fever, you may need to increase your insulin doses. If you exercise more, you may need to decrease your insulin dosage.

Take insulin as prescribed by your doctor, and always speak with your doctor before making any changes.

Follow a healthy diet and exercise regularly.

A diet high in fibre and low in sugar can help regulate your blood sugar levels and prevent spikes. Exercise helps to promote insulin sensitivity and can also help to prevent ketoacidosis.

Following a healthy lifestyle is the best way to prevent this condition.

Stay hydrated and avoid alcohol.

Euglycemic diabetic ketoacidosis can be prevented by staying hydrated and avoiding alcohol. Alcohol consumption can lead to dehydration, which can in turn trigger euglycemic diabetic ketoacidosis.

It is therefore important to drink enough - not alcohol but water or other fluids.

Monitor Your ketone level

You should also check your ketone levels regularly, and if they become high, contact your doctor right away.

Euglycemic diabetic ketoacidosis, though rare, is a serious complication of diabetes that can result in coma or death if not treated.

So it's essential to be aware of the signs and symptoms and to seek medical help right away. And be sure to carry an ID card or wear a medical bracelet that indicates you have diabetes in case of an emergency.

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Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma

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Euglycemic diabetic ketoacidosis (EDKA) is a clinical triad comprising increased anion gap metabolic acidosis, ketonemia or ketonuria and normal blood glucose levels <200 mg/dL. This condition is a diagnostic challenge as euglycemia masquerades the underlying diabetic ketoacidosis. Thus, a high clinical suspicion is warranted, and other diagnosis ruled out. Here, we present two patients on regular insulin treatment who were admitted with a diagnosis of EDKA. The first patient had insulin pump failure and the second patient had urinary tract infection and nausea, thereby resulting in starvation. Both of them were aggressively treated with intravenous fluids and insulin drip as per the protocol for the blood glucose levels till the anion gap normalized, and the metabolic acidosis reversed. This case series summarizes, in brief, the etiology, pathophysiology and treatment of EDKA.

• Learning points:

Euglycemic diabetic ketoacidosis is rare.

Consider ketosis in patients with DKA even if their serum glucose levels are normal.

High clinical suspicion is required to diagnose EDKA as normal blood sugar levels masquerade the underlying DKA and cause a diagnostic and therapeutic dilemma.

Blood pH and blood or urine ketones should be checked in ill patients with diabetes regardless of blood glucose levels.

Diabetic ketoacidosis (DKA) is defined as a clinical triad comprising metabolic acidosis, hyperglycemia and increased ketone bodies in the blood and urine. Hyperglycemia is usually the hallmark for the diagnosis of DKA ( 1 ). However, there is a subset of patients in whom the serum glucose levels are within the normal limits, and this condition is termed as euglycemic DKA (EDKA). This phenomenon was first described by Munro et al. where 37 out of 211 DKA patients had normal sugar levels (<300 mg/dL) along with a plasma bicarbonate level of <10 mmol/L at presentation ( 2 ). Later, normoglycemia was redefined as <250 mg/dL. Thus, EDKA is defined as a triad comprising high anion gap metabolic acidosis with positive serum and urine ketones when serum glycemic levels are <250 mg/dL ( 3 ). In this case series, we report two patients with type I diabetes mellitus (T1DM) who were diagnosed with EDKA. We believe that this case series would serve as a reminder to all practitioners across the world to consider ketosis in a diabetic patient despite their serum glucose levels being within the normal range. This case series summarizes, in brief, the etiology, pathophysiology and treatment of EDKA.

• Case presentation 1

A 21-year-old female with T1DM diagnosed five years back and on an insulin pump for the last two years was admitted with complaints of weakness and inability to eat for the past one day. Patient’s insulin pump had stopped working two days before visiting the hospital. There was no history of any fever, nausea, vomiting, diarrhea or other symptoms suggestive of any infective pathology. On examination, the patient had moderate dehydration with loss of skin turgor.

• Investigation

Patient’s blood glucose levels were checked, and she was found to be normoglycemic. An arterial blood gas analysis revealed metabolic acidosis and low carbon dioxide values. This was followed by a complete blood work-up that included a hemogram, electrolytes and renal function tests, the results of which along with reference values are given in Table 1 . The patient’s urine was positive for ketone bodies with increased ketonemia. There was evidence of dehydration and resulting hemoconcentration along with features suggestive of pre-renal failure. The arterial blood gas (ABG) revealed a partially compensated increased anion gap metabolic acidosis. Thus, a diagnosis of EDKA was made.

Laboratory investigations of patient 1.

She was treated with 4L bolus of IV normal saline and an insulin drip as per the protocol based on her glucose levels. She was also started on dextrose 5% ½ normal saline. The basic metabolic profile was monitored every 4 h, and serum glucose levels were checked every hour. When her serum carbon dioxide levels were greater than or equal to 18 and her anion gap was less than 12, her insulin drip was switched off, and she was placed on long-acting insulin.

• Outcome and follow-up

Patient was discharged to home on long-acting and short-acting insulin and was advised to get her insulin pump fixed on her next appointment with her endocrinologist.

• Case presentation 2

25-year-old female diagnosed with T1DM 10 years back, on regular treatment with insulin glargine at bedtime and insulin aspart at sliding scale as needed before meals, came with complaints of burning while urinating and high-grade intermittent fever of up to 101 F associated with chills and rigors. She also complained of nausea since last 12 h and was therefore unable to eat meals adequately. On physical examination at the time of admission, she had mild suprapubic tenderness, and her mucous membranes were dry. There was no renal angle tenderness, and the rest of the physical examination was normal.

A working diagnosis of urinary tract infection was made, and a routine blood work-up was done, the results of which are given in Table 2 . Since clinical dehydration was out of proportion to the symptoms, based on our previous experiences with T1DM patients, we decided to evaluate the patient for DKA, and this revealed the patient to be suffering from concomitant EDKA secondary to urinary tract infection, starving and severe dehydration. The urine analysis confirmed urinary tract infection, and the blood investigations revealed hemoconcentration, pre-renal failure, sepsis and partially compensated increased anion gap metabolic acidosis.

Laboratory investigations of patient 2.

In both our patients, other causes of metabolic acidosis were excluded by testing for urine toxicology screen, blood salicylate, acetaminophen, lactic acid and alcohol levels, which were all within the normal limits. There was no known ingestion of toxic substances in these patients. No history of SGLT-2 inhibitors usage in the above patients.

She was treated with 5L of bolus IV normal saline to reverse the dehydration and was started on insulin drip according to the protocol for her blood glucose levels. She was also started on dextrose 5% ½ normal saline IV. She was treated with IV ceftriaxone for her UTI. Her anion gap closed slowly and her acidosis resolved.

Patient was started back on her regular insulin regimen with insulin glargine and insulin aspart and was discharged home.

The American Diabetes Association defines DKA as having a combination of hyperglycemia (serum glucose >250 mg/dL), acidosis (arterial pH <7.3 and bicarbonate <15 mEq/L) and ketosis (moderate ketonuria or ketonemia) ( 1 ). Glycemic control is achieved in our human body using a balance between the insulin levels and the levels of counter-regulatory hormones like glucagon, growth hormone, glucocorticoids and epinephrine. DKA occurs when there is either a decrease in insulin or when there is an excess of counter-regulatory hormones both of which causes hyperglycemia. Though there is hyperglycemia, the end organs are unable to utilize the available glucose due to the comparative lack of insulin, and this leads to lipolysis thereby leading to excessive production of ketone bodies ( 4 ). However, in this case series, we have reported 2 cases where there is DKA but no hyperglycemia.

The underlying mechanism of EDKA is either due to decreased hepatic production of glucose during fasting state or enhanced urinary excretion of glucose induced by an excess of counter-regulatory hormones, the former being the most common reason. Thus, when a diabetic patient is exposed to any triggering factor for DKA and is fasting or starving while continuing the insulin treatment regularly, the liver will be in a state of glycogen depletion, thereby producing a lesser amount of glucose. On the other hand, there will be lipolysis and fatty acid production, which finally leads to excessive ketone body production ( 3 ). Some of the common causes of EDKA that have been reported in literature so far are low caloric intake, fasting or starvation ( 5 ), pregnancy ( 6 ), pancreatitis ( 7 ), cocaine intoxication, prolonged vomiting or diarrhea ( 8 ), insulin pump use ( 9 ) and of late use of SGLT2 inhibitors like empagliflozin, canagliflozin and so forth ( 10 ).

Both our patients were type 1 diabetes mellitus patients on insulin therapy. The first patient had a history of failed insulin pump two days before admission and decreased food intake in the past 24 h. Burge et al had reported in their study that short-term fasting is a well-known mechanism of developing euglycemic ketoacidosis when there is insulin deficiency in type I diabetic patients ( 11 ). They also subsequently went ahead to describe how dehydration can accelerate the development of DKA during periods of insulin deficiency. Dehydration usually promotes the development of hyperglycemia. However, it is interesting to note its differential role in EDKA. Fasting primarily increases the secretion of counter-regulatory hormones especially the glucagon, which depletes the glycogen stores in the liver. Dehydration acts as a stimulus for further glucagon secretion, which results in lipolysis and ketone body production in the background of decreased glucose production leading to EDKA. During insulin deficiency, dehydration also increases the secretion of other counter-regulatory hormones like catecholamines and cortisol, which further worsens EDKA ( 12 ). In the case of our second patient, urinary tract infection in conjunction with nausea due to the infection caused a decreased calorie intake and led to ketoacidosis with euglycemia. This is a classic presentation of EDKA.

Diagnosis of EDKA is difficult as it is primarily a diagnosis of exclusion. Other forms of ketoacidosis like starvation ketoacidosis has to be ruled out. Also, other causes of increased anion gap metabolic acidosis like lactic acidosis, increased toxic serum alcohols (methanol, ethylene glycol, etc.), drug toxicity, paraldehyde ingestion and renal failure have to be excluded ( 8 ). Once diagnosed, management of EDKA is simple and is almost similar to the management of DKA. The mainstay of treatment involves rapid correction of dehydration using intravenous fluids ( 13 ). The second most important step in the management is the use of insulin drip along with a dextrose containing solution until the anion gap, and bicarbonate levels normalize ( 14 ). Periodic checking of urine for ketones and arterial blood gas analysis to estimate anion gap are warranted till the values normalize ( 13 ).

Here, we presented two patients diagnosed with euglycemic diabetic ketoacidosis both of whom were on regular insulin therapy. Early detection and management are warranted as this condition may else prove fatal. High clinical suspicion is required to diagnose EDKA as normal blood sugar levels masquerade the underlying DKA and cause a diagnostic and therapeutic dilemma. It is best advised that the clinicians are aware of the possible etiological triggers of EDKA in susceptible patients and actively rule out other differentials thereby minimizing the time required for diagnosing EDKA. If diagnosed early and management aggressively with fluids and insulin drip, EDKA may be easily reversed, thus minimizing morbidity and mortality.

• Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

• Patient consent

Written informed consent has been obtained from the patients for publication of this article.

• Author contribution statement

Study design, drafting by P R, critical revisions and final approval by P R, A R V, S S B and J P R.

Nyenwe EA & Kitabchi AE 2016 The evolution of diabetic ketoacidosis: an update of its etiology, pathogenesis and management . Metabolism 65 507 – 521 . ( doi:10.1016/j.metabol.2015.12.007 )

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Munro JF , Campbell IW , McCuish AC & Duncan LJ 1973 Euglycaemic diabetic ketoacidosis . BMJ 2 578 – 580 . ( doi:10.1136/bmj.2.5866.578 )

Kitabchi AE , Umpierrez GE , Miles JM & Fisher JN 2009 Hyperglycemic crises in adult patients with diabetes . Diabetes Care 32 1335 – 1343 . ( doi:10.2337/dbib9-9032 )

Laffel L 1999 Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes . Diabetes/Metabolism Research and Reviews 15 412 – 426 . ( doi:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8 )

Joseph F , Anderson L , Goenka N & Vora J 2009 Starvation induced true diabetic euglycemic ketoacidosis in severe depression . Journal of General Internal Medicine 24 129 – 131 . ( doi:10.1007/s11606-008-0829-0 )

Chico M , Levine SN & Lewis DF 2008 Normoglycemic diabetic ketoacidosis in pregnancy . Journal of Perinatology 28 310 – 312 . ( doi:10.1038/sj.jp.7211921 )

Prater J & Chaiban J 2015 Euglycemic diabetic ketoacidosis with acute pancreatitis in a patient not known to have diabetes . Endocrine Practice 1 e88 – e91 . ( doi:10.4158/ep14182.cr )

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. ( doi:10.1155/2016/4275651 )

Modi A , Agrawal A & Morgan F 2017 Euglycemic diabetic ketoacidosis . Current Diabetes Reviews 13 315 – 321 . ( doi:10.2174/1573399812666160421121307 )

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 . ( doi:10.1002/dmrr.2886 )

Burge MR , Hardy KJ & Schade DS 1993 Short-term fasting is a mechanism for the development of euglycemic ketoacidosis during periods of insulin deficiency . Journal of Clinical Endocrinology and Metabolism 76 1192 – 1198 . ( doi:10.1210/jc.76.5.1192 )

Burge MR , Garcia N , Qualls CR & Schade DS 2001 Differential effects of fasting and dehydration in the pathogenesis of diabetic ketoacidosis . Metabolism 50 171 – 177 . ( doi:10.1053/meta.2001.20194 )

Gelaye A , Haidar A , Kassab C , Kazmi S & Sinha P 2016 Severe ketoacidosis associated with canagliflozin (Invokana): a safety concern. Case Reports in Critical Care 2016 Article ID: 1656182. ( doi:10.1155/2016/1656182 )

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

• Diabetes mellitus type 1
• Diabetic ketoacidosis
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• Haemoglobin
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• Urea and electrolytes
• White blood cell count
• Fluid repletion
• Ceftriaxone
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Diabetic ketoacidosis with SGLT2 inhibitors

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• Peer review
• Giovanni Musso , consultant and clinical researcher 1 ,
• Francesca Saba , research fellow 2 ,
• Maurizio Cassader , professor 3 ,
• Roberto Gambino , professor 3
• 1 Emergency and Intensive Care Medicine, HUMANITAS Gradenigo Hospital; Laboratory of Diabetology and Metabolism, Department of Medical Sciences, Città della Salute, University of Turin, Italy
• 2 Laboratory of Diabetology and Metabolism, Department of Medical Sciences, University of Turin
• 3 Clinical Biochemistry, Laboratory of Diabetology and Metabolism, Department of Medical Sciences, University of Turin
• Correspondence to: G Musso giovanni_musso{at}yahoo.it

What you need to know

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are relatively new drugs approved for diabetes, but they increase the risk for diabetic ketoacidosis, particularly in patients with type 1 diabetes and those with certain high risk conditions

In some cases blood glucose levels are normal or only mildly elevated, a condition known as euglycaemic ketoacidosis, which can delay the diagnosis

Check ketones in patients taking SGLT2 inhibitors with symptoms or precipitating factors for ketoacidosis regardless of blood glucose levels

A 45 year old woman with type 2 diabetes complains of malaise, shortness of breath, and nausea for two days. She has been taking metformin and insulin. She was started on canagliflozin six weeks earlier to improve glycaemic control. Over the previous week she has halved the insulin dose. On examination, she is drowsy. Her respiratory rate is 28 breaths/min with a deep breathing pattern. A random blood glucose test shows 8 mmol/L (144 mg/dL). Blood tests reveal metabolic acidosis with an increased anion gap of 23 mmol/L (reference range 8-12 mmol/L), pH 7.18, and bicarbonate 14 mmol/L. Urine dipstick showed ketones +++.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, used in patients with diabetes, can cause diabetic ketoacidosis. This is rare but can be serious and life threatening. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) warn about possible “atypical” presentation of diabetic ketoacidosis with SGLT2 inhibitors 1 2 : instead of having hyperglycaemia, patients may have normal or only mildly elevated blood glucose levels (<13.9 mmol/L, <250 mg/dL). This may delay diagnosis. In 2020, the FDA and EMA updated guidance to interrupt SGLT2 inhibitors and monitor ketosis in patients scheduled for surgery or hospitalised. 3 4

What are SGLT2 inhibitors?

SGLT2 inhibitors, also called gliflozins, lower blood sugars by causing kidneys to remove glucose from the body in urine. 5 Figure 1 depicts their actions. They are used as second or third line therapy in type 2 diabetes along with metformin, sulfonylurea, or insulin to improve glycaemic control. 6 In 2019, consensus guidelines in the US and Europe further recommended their use in patients with type 2 diabetes and established cardiovascular disease or chronic kidney disease. 5 7 SGLT2 inhibitors represented 14% of new second line prescriptions and 27% of new third line prescriptions for type 2 diabetes in primary care in the UK in 2016. 8

Actions of SGLT2 inhibitors in ketoacidosis. SGLT2 inhibitors inhibit SGLT2 on pancreatic islet α-cells and directly stimulate glucagon secretion, which up-regulates endogenous glucose production, ketogenesis, and lipolysis. In the kidney, SGLT2 inhibition increases ketone reabsorption. SGLT2 inhibition-induced glycosuria lowers blood glucose, thereby allowing insulin dose reduction. Insulin reduction further reduces the insulin:glucagon ratio, a critical factor in inhibiting hepatic ketogenesis and lipolysis of free fatty acids. Glycosuria also induces osmotic diuresis and dehydration, which triggers the synthesis of glucagon, cortisol, and adrenaline, further contributing to lipolysis and ketogenesis

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Few SGLT2 inhibitors have been approved for type 1 diabetes in Europe and Japan as an adjunct to insulin to improve glycaemic control. The FDA has rejected their use in type 1 diabetes because of a higher risk of diabetic ketoacidosis in these patients. 9 10 Supplementary table 1 on bmj.com lists indications and licensing for SGLT2 inhibitors.

How do patients with this adverse reaction present?

Symptoms of diabetic ketoacidosis include excessive thirst, frequent urination, dehydration, nausea, vomiting, abdominal pain, shortness of breath, and altered sensorium. 11 12 13 14 Patients may report malaise, dizziness, and syncope, with or without fever, which are non-specific. 15

Diabetic ketoacidosis is typically characterised by hyperglycaemia. Over a third of patients with ketoacidosis associated with SGLT2 inhibitor have normal or only mildly elevated blood glucose levels (<13.9 mmol/L, <250 mg/dL), also referred to as euglycaemic diabetic ketoacidosis. 16 17 In such cases, the absence of hyperglycaemia and the less severe polyuria polydipsia, owing to the milder degree of hyperglyacemia-induced osmotic diuresis, can delay diagnosis. 1 15 18

How common is this adverse reaction?

The relative risk of diabetic ketoacidosis is higher in patients with type 1 diabetes. Observational studies with SGLT2 inhibitors suggest an incidence of 1.3-8.8 ketoacidosis events per 1000 patient-years in type 2 diabetes 19 20 21 22 and 7.3 events per 1000 patients-years in type 1 diabetes. 23 The risk is higher in the first few months of initiating treatment. Between 76.8% and 85.2% of ketoacidosis events occur within 180 days of starting SGLT2 inhibitors in observational studies and pharmacovigilance reports. 15 22 24

What is the evidence?

Supplementary table 2 on bmj.com lists epidemiological evidence linking diabetic ketoacidosis to SGLT2 inhibitors. In an analysis of 487 cases of ketoacidosis from the WHO pharmacovigilance database, ketoacidosis was more frequently reported with gliflozins than with other glucose-lowering drugs (adjusted reporting odds ratio 15.5 (95% confidence interval 12.8 to18.7). 25

A meta-analysis of 13 randomised controlled trials (5397 patients) found that SGLT2 inhibitors increased the risk of diabetic ketoacidosis in type 1 diabetes (risk ratio 4.49 (95% CI 2.88 to 6.99)) 15 in a dose dependent manner, with a 4.9-fold higher rate at high doses of SGLT2 inhibitors (34 events per 1000 patient-years) than with low doses (7 events per 1000 patient-years). Sotagliflozin was associated with an increased risk of ketoacidosis in type 1 diabetes (relative risk 3.93 (1.94 to 7.96)) compared with placebo in a meta-analysis (6 RCTs, 3238 patients) 16 : higher baseline HbA 1c was associated with a lower risk of diabetic ketoacidosis, and the magnitude of basal insulin dose reduction was associated with an increased risk of diabetic ketoacidosis.

High quality evidence from a systematic review and meta-analysis (39 RCTs, 60 580 patients) suggests an increased risk of diabetic ketoacidosis with SGLT2 inhibitors in type 2 diabetes compared with placebo or other antidiabetic drugs (relative risk 2.13 (1.38 to 3.27)), with an absolute rate of 3 events per 1000 patient-years. 26

What factors increase the risk?

Certain conditions predispose to diabetic ketoacidosis ( box 1 , supplementary table 3). Over two thirds of patients who develop diabetic ketoacidosis are noted to have one of these factors in observational studies of SGLT2 inhibitors. 20 24 27

Predisposing conditions and precipitating factors of diabetic ketoacidosis in patients taking SGLT2 inhibitors

Predisposing condition.

Inability or unwillingness to monitor ketone bodies

Excessive alcohol use or illicit drug use

Very low carbohydrate or ketogenic diet

Pregnancy (ongoing or planned)

Previous diabetic ketoacidosis

Inappropriate insulin dose reduction

SGLT2 inhibitor dose

Insulin pump use

Late-onset autoimmune diabetes of adulthood (LADA)

Precipitating factor

Volume depletion or dehydration

Acute infection or illness of any sort

Hospitalisation for surgery or acute serious medical illness

Acute volume depletion or dehydration

Vigorous or prolonged exercise

Insulin pump or infusion site failure

Travel with disruption in usual schedule or insulin regimen

How is it diagnosed?

Test patients with signs and symptoms of metabolic acidosis for ketoacidosis regardless of blood glucose level. 1 2 3 The following findings indicate ketoacidosis 11 12 13 14 :

Increased ketones in blood (β-hydroxybutyrate ≥3 mmol/L) or urine (ketonuria ++ or higher on urine dipsticks). Blood ketone testing is preferred over urine test strips as it is more accurate for detecting onset and resolution of ketosis 28

Acidosis— serum bicarbonate <15 mmol/L and/or blood pH <7.3. An elevated serum anion gap (sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration) >10 mmol/L may help rule out other causes of metabolic acidosis if blood ketone testing is unavailable. 7

Once ketoacidosis is diagnosed, other conditions that can cause it, usually in the form of euglycaemic ketoacidosis, should be excluded. These conditions and hints for differential diagnosis are listed in supplementary table 4.

How is it managed?

In patients with suspected or confirmed ketoacidosis, stop SGLT2 inhibitors immediately. International consensus guidelines for type 1 diabetes recommend the STICH protocol (stop SGLT2 inhibitor, inject bolus insulin, consume 30 g carbohydrates, hydrate) 29 and the STOP diabetic ketoacidosis protocol (stop SGLT2 inhibitor, test ketones, oral ingestion of fluid and carbohydrates, protocol instructions for supplemental insulin and carbohydrates) 30 (see supplementary table 5 for details). Early initiation of these measures can reverse ketosis and prevent progression to diabetic ketoacidosis. 16 24

Avoid restarting SGLT2 inhibitors after an episode of ketoacidosis unless another cause is clearly identified and resolved. 2 Even so, patients remain at risk of recurrence with SGLT2 inhibitors, and other antidiabetic drugs are preferred. 17 24

How can the risk of harm be minimised?

Assess patients for risk factors for ketoacidosis and avoid prescribing SGLT2 inhibitors in these patients ( box 1 , supplementary table 3). 6 13 Explain the risk of ketoacidosis to patients before starting treatment. Start with the lowest dose required for clinical benefit. Explain when and how to measure ketones and actions to take if ketones are elevated. Patients must regularly monitor ketones in the initial weeks of therapy, regardless of symptoms. 18 SGLT2 inhibitors are better avoided in patients unable to monitor ketones. Later, individualise the frequency of ketone testing according to each patient’s lifestyle and risk factors. Avoid insulin dose reduction and ask patients to check ketones with every change in insulin pump set and insulin dose. Stop SGLT2 inhibitors during acute serious medical illness and at least three days before scheduled surgery and monitor ketones after drug interruption (supplementary table 3).

Ask the patients to check ketones if they develop symptoms or precipitating factors for ketoacidosis. If ketones are elevated, they should hold the medication and promptly consult their doctor. 29 30

Sources and selection criteria

We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews, international trial registries, and drug regulatory agencies’ websites up to 15 July 2020 using the search terms “ketoacidosis, diabetic, DKA, euglycemic diabetic ketoacidosis, euDKA, ketone, ketosis, acidosis, sodium glucose cotransporter 2 (SGLT2) inhibitors.” We prioritised articles on humans, scientific society guidelines (ADA, EASD, ESC, NICE, British Diabetes Societies), expert reviews, and articles providing mechanistic insights into diabetic ketoacidosis. We included in our analysis 307 records (13 systematic reviews, 161 RCTs, 30 records from regulatory agencies,13 consensus/guidelines 59 case series, and 31 reviews on SGLT2 inhibitor-associated diabetic ketoacidosis).

Education into practice

When do you start a patient on sodium-glucose cotransporter-2 (SGLT2) inhibitors? What factors do you consider when choosing these drugs?

How would you discuss the risk of diabetic ketoacidosis with a patient when starting SGLT2 inhibitors and strategies to minimise the risk?

How do patients at your practice prescribed SGLT2 inhibitors adhere to measuring ketones?

How patients were involved in the creation of this article

We arranged a live Tweet chat with 12 patients with type 2 diabetes taking SGLT2 inhibitors for their views on an initial draft of this article. Patients emphasised that general physicians educate patients on strategies to minimise the risk for diabetic ketoacidosis and the need for providing a blood ketone meter to patients taking SGLT2 inhibitors. Based on their feedback we now highlight the importance of checking ketone levels if patients have predisposing conditions and precipitating factors for diabetic ketoacidosis, irrespective of symptoms. We are grateful for their input.

This is one of a series of occasional articles to help doctors prevent, diagnose, and respond to adverse drug reactions that may be serious if not recognised. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and City Hospital Birmingham, and Patricia McGettigan, reader in clinical pharmacology and medical education, Queen Mary University of London.

Contributors: All authors made substantial contributions to the text and were involved in drafting and revision of the work and in final approval. All authors accept responsibility for the accuracy and integrity of the work. GM is the guarantor.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: no competing interests to declare

Patient consent: Not required (patient anonymised, dead, or hypothetical).

Provenance and peer review: Commissioned, based on an idea from the author; externally peer reviewed.

• ↵ US Food and Drug Administration. FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. 2015. https://www.fda.gov/media/92185/download .
• ↵ European Medicines Agency. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes. 2016. https://www.ema.europa.eu/en/documents/referral/sglt2-inhibitors-article-20-procedure-ema-confirms-recommendations-minimise-ketoacidosis-risk-sglt2_en.pdf .
• ↵ US Food and Drug Administration. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious .
• ↵ Health Products Regulatory Authority. SGLT2 inhibitors – Updated advice on monitoring ketone bodies in patients hospitalised for major surgical procedures or acute serious medical illnesses. 2019. https://www.hpra.ie/docs/default-source/default-document-library/hpra-article-in-mims-supplement_november-2019.pdf .
• Wexler DJ ,
• ↵ National Institute for Health and Care Excellence. Type 2 diabetes in adults: management (NICE guideline NG28): 1.6 Blood glucose management. 2019. https://www.nice.org.uk/guidance/ng28/chapter/1-Recommendations#blood-glucose-management-2 .
• Cosentino F ,
• Aboyans V ,
• ESC Scientific Document Group
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• Dennis JM ,
• Shields BM ,
• ↵ Sanofi. FDA issues complete response letter for Zynquista (sotagliflozin). 2019. http://www.news.sanofi.us/2019-03-22-FDA-issues-Complete-Response-Letter-for-Zynquista-TM-sotagliflozin
• ↵ AstraZeneca. Update on US regulatory decision for Farxiga in type-1 diabetes. 2019. https://www.astrazeneca.com/media-centre/press-releases/2019/update-on-us-regulatory-decision-for-farxiga-in-type-1-diabetes-15072019.html
• Agiostratidou G ,
• ↵ Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis in adults. 2nd ed. 2013. http://www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_DKA_Adults_Revised.pdf .
• Handelsman Y ,
• Bloomgarden ZT ,
• ↵ National Institute for Health and Care Excellence. Diabetes (type 1 and type 2) in children and young people: diagnosis and management (NICE guideline NG18): 1.4 Diabetic ketoacidosis. 2016. https://www.nice.org.uk/guidance/ng18/chapter/1-Recommendations#diabetic-ketoacidosis-2 .
• Gambino R ,
• Cassader M ,
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• ↵ US Food and Drug Administration. Material for FDA presentations for the January 17, 2019 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. https://www.fda.gov/advisory-committees/endocrinologic-and-metabolic-drugs-advisory-committee/2019-meeting-materials-endocrinologic-and-metabolic-drugs-advisory-committee .
• ↵ European Medicines Agency. Forxiga (dapagliflozin): Product information. www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf .
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Euglycemic DKA as an Initial Presentation of Immunotherapy-Induced Insulin-Dependent Diabetes

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PRIYANKA IYER , SONALI N. THOSANI; Euglycemic DKA as an Initial Presentation of Immunotherapy-Induced Insulin-Dependent Diabetes. Diabetes 1 July 2018; 67 (Supplement_1): 1195–P. https://doi.org/10.2337/db18-1195-P

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• Ris (Zotero)
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New onset insulin dependent diabetes (DM) has been reported in cancer patients (pts) receiving immunotherapy (IO). Typically, pts have Grade 3 hyperglycemia (CTCAE) and sometimes DKA. Euglycemic DKA has been reported in pts on empagliflozin (Empa). We present a unique case of euglycemic DKA as initial presentation for immunotherapy induced insulin dependent DM. Pt is a 68 year old man without preexisting DM started on nivolumab for metastatic prostate cancer. Following 2 doses of nivolumab, he developed fatigue, weight loss and Grade 2 hyperglycemia for which he was started on metformin, glipizide, and Empa by his outside physician. His BG levels ranged from 130-200 mg/dL on these therapies. Nivolumab treatment was stopped due to significant adverse effects. On return visit to our clinic, approximately 3 months after initial hyperglycemia, pt complained of persistent fatigue, weight loss and a new fruity odor in his breath. Labs revealed BG of 134mg/dl, bicarb of 19 mEq/L (23-30mEq/L), anion gap (AG) of 17mEq/L (4-14mEq/L). Urine ketones were positive and c-peptide level was 0.3ng/ml (0.8- 3.85ng/ml). Pt was advised to immediately stop Empa and follow-up with local ER. When he presented to local ER, approximately 4 days later, he was hyperglycemic with glucose 316 mg/dL, and labwork consistent with classic DKA. Pt was initiated on basal bolus insulin regimen and had resolution of DKA.IO mediated DM results from immune mediated islet cell destruction leading to rapidly progressive insulin deficiency. When suspected, these pts should be evaluated for beta cell dysfunction and insulin should be used for glycemic control. This case highlights that SGLT2 therapy should be used with caution in patients with hyperglycemia on immunotherapy as it could mask the diagnosis of DKA. In addition, this case shows that patients taken off of immunotherapy may develop delayed glycemic complications and may need long term monitoring.

P. Iyer: None. S.N. Thosani: Consultant; Spouse/Partner; Boston Scientific Corporation, Medtronic. Speaker's Bureau; Spouse/Partner; AbbVie Inc..

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Euglycemic Diabetic Ketoacidosis in the ICU: 3 Case Reports and Review of Literature

Pablo lucero.

1 Hospital Británico de Buenos Aires, Intensive Care Services, Argentina

Sebastián Chapela

2 Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquimica Humana, Argentina

Diabetic ketoacidosis (DKA) is an acute complication of diabetes mellitus, both type I and type II, as well as other types with diabetes such gestacional diabetes mellitus. It is characterized by blood glucose levels greater than 250 mg/dL and metabolic acidosis (pH < 7.3 and serum bicarbonate < 15 mEq/dL) with an increased anion gap and the presence of ketone bodies in the blood or urine. Within this pathology, there is a subgroup of pathologies which are characterized by being present with no signs of hyperglycemia, posing a diagnostic challenge due to the absence of the main sign of the pathology and the diversity of their pathophysiology. In this article, we will present 3 clinical cases with 3 different forms of clinical presentation: a case of DKA in pregnancy, a case of DKA associated with the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and a third case related to sepsis, together with a narrative review of the literature on the topic.

1. Introduction

Diabetic ketoacidosis is an acute complication of diabetes. It is diagnosed through laboratory results showing metabolic acidosis with an increased gap and evidence of ketone bodies in the blood or urine. Most of the time, it is present with hyperglycemia. The clinical presentation of this pathology is diverse, going from abdominal pain to sensory deterioration and coma [ 1 ].

The pathophysiology of hyperglycemia in diabetic ketoacidosis has 3 cornerstones: an increase in gluconeogenesis, an increase in glycogenolysis and a decrease in peripheral glucose uptake due to a decrease in insulin action in the receptors or a decrease in insulin levels [ 1 ]. This prevents glucose from being transported inside the cells and being used as metabolic fuel. On the other hand, there is an increase in lipolysis and fatty acids start being used in the liver, where they are metabolized into ketone bodies, which can be absorbed by most cells [ 1 ].

Diabetic ketoacidosis is defined by the presence of blood glucose levels greater than 250 mg/dL, being this the main finding, associated with metabolic acidosis (pH < 7.3 and serum bicarbonate < 15 mEq/dL) with an increased anion gap and the presence of ketone bodies in the blood and/or urine [ 1 ]. There are different forms of presentation which differ from the usual presentation described in literature, such as the case of normoglycemic diabetic ketoacidosis. This pathology was first described by Munro in 1973 [ 2 ] but, in his work, he studied patients with blood glucose levels under 300mg/dL. Currently, the definition is in line with blood glucose levels under 250mg/dL [ 1 ]. 6% of patients show blood glucose levels under 300 mg/dL and around 1% of patients show levels under 180 mg/dL. The most common causes are insulin administration on the way to the hospital and fasting [ 1 ]. The diagnosis and treatment of this pathology require a deep pathophysiological knowledge, since it can be triggered by different etiologies. In this review, we will present 3 completely different cases of normoglycemic diabetic ketoacidosis.

2. Clinical Case 1

A 22-year-old woman with a history of diabetes mellitus (diagnosed at 7 years old) is treated with insulin glargine and with good adherence to treatment, with hypothyroidism and 2 previous ICU admissions due to diabetic ketoacidosis in which blood glucose levels were greater than 300 mg/dL.

The patient sought consultation due to vomiting and abdominal pain 12 hours after onset. Upon physical examination, the abdomen was distended with diffuse pain and no signs of peritoneal irritation. Laboratory results showed the following values: pH: 7.25; bicarbonate: 10 mEq/dL; BE: -14.9; blood glucose: 153 mg/dL and positive ketonemia. Admission laboratory results are shown in Table 1 . Upon diagnosis of normoglycemic diabetic ketoacidosis, in the context of menstrual cycle alterations and with the aim of studying the trigger, beta subunit of human chorionic gonadotropin levels was requested: 98.928 IU/L. A transvaginal ultrasound was performed and showed a gestational sac with an embryo inside. Reanimation was started with parenteral crystalloids administered at 250 mL/h during 24 hrs. It was interspersed isotonic saline solutions and polyelectrolyte solutions. Total income is 7000 ml / 24 hs. Urinary volume is 2750 ml / 24 hs. Positive balance is 4250 ml/24 hs. Continuous insulin infusion was started, as described in literature (receiving a total of 100 IU in 48 hrs). Progress was shown with improvement of the clinical condition and lab monitoring every 8 hours: pH 7.47; bicarbonate of 22 mEq/dL with blood glucose levels in the normal range (< 200 mg/dl). The usual insulin glargine dose was restored and the patient was discharged.

Patients' laboratory results upon admission to the ICU.

3. Clinical Case 2

A 50-year-old woman, former smoker, with a history of arterial hypertension, dyslipidemia, left side breast cancer which required chemotherapy, radiation therapy and surgery, hypothyroidism, and diabetes mellitus type II, is treated with 10 mg/day of Dapagliflozin, 1000 mg of Metformin every 12 hours, and NPH insulin at 40 and 60 IU. The patient sought consultation due to abdominal pain, diarrhea and fever. Upon admission, the patient was alert, tachypneic, and being with diffuse abdominal pain with no sign of peritoneal irritation. An abdominal ultrasound was requested and showed the gallbladder with multiple gallstones. The complete laboratory results are shown in Table 1 . In the context of leukocytosis, acute kidney failure, and severe metabolic acidosis, the patient was admitted to the ICU with a diagnosis of sepsis. Due to the presence of metabolic acidosis with a gap of 32, a ketonemia test was requested. The result was positive and the patient was diagnosed with euglycemic diabetic ketoacidosis.

After starting treatment with a continuous insulin infusion pump and the administration of water, the patient was discharged from the hospital after 5 days.

4. Clinical Case 3

A 74-year-old male patient with a history of arterial hypertension, noninsulin dependent diabetes mellitus medicated with oral hypoglycemic agents, ischemic cardiopathology with stent placement, nonoliguric chronic kidney failure, and cryptogenic liver cirrhosis required a liver transplant and subsequently suffered portal vein thrombosis requiring anticoagulation. The patient sought consultation after 3 days of passing liquid stools, together with emesis. He denied having fever spikes and, on that date, consulted the emergency ward of this institution, to which he was admitted feeling alert, with AT: 130/64, heart rate: 108 beats per minute, and SO2: 97% on room air. Upon physical examination, the patient was alert, tachypneic, and being with dry mucous membranes. Admission laboratory results are shown in Table 1 . A ketonemia test was requested and the result was positive. The clinical presentation was interpreted as dehydration secondary to gastrointestinal losses and euglycemic diabetic ketoacidosis. Reanimation was started with crystalloids, a continuous insulin infusion pump, and the administration of intravenous bicarbonate. After 48 hrs, the patient presented DKA resolution criteria.

5. Discussion

Euglycemic diabetic ketoacidosis is a diagnostic challenge for treating physicians, since there is no hyperglycemia. On the other hand, there are many causes of metabolic acidosis in patients in the intensive care unit, although, when analyzing the gap, high gap metabolic acidosis is less frequent than hyperchloremic acidosis [ 14 ]. Therefore, knowing this pathology is key when treating patients with diabetes. Moreover, the triggers are varied and, in this study, we presented 3 cases with two different pathophysiological causes.

This pathology is triggered by multiple causes ( Table 2 ). The following pathophysiological mechanisms are common to all causes: a decrease in insulin action or secretion with a decrease in total glucose uptake at a cellular level, an increase in the production of counterregulatory hormones, and a decrease in glucose production by the liver or an increase in the excretion of glucose in the urine [ 11 , 12 ].

Causes of euglycemic diabetic ketoacidosis.

SGLT-2: type 2 sodium-glucose cotransporter.

The first case deals with a diabetic patient who is pregnant. The reason that normal pregnancy increases blood glucose levels is based on the progressive insulin resistance, which normally occurs. This resistance also explains the worsening of pregestational diabetes during pregnancy. The exogenous insulin loses its effect as the pregnancy progresses. These effects are attributable to the destruction of insulin by the kidney and the action of placental insulinases.

At the beginning of pregnancy, insulin maintains its activity, and its concentration increases due to the hyperplasia of the Beta cells of the pancreatic islets, induced by the high concentrations of placental steroids. As a result of these changes, fasting glycemia decreases. The main effect of insulin in the body is to allow the storage of nutritious substrates to meet energy needs. The provision of food is intermittent while the consumption of energy is constant from where the need for storage arises. The maternal organism stores energies in the form of glucose and fats. In addition, human chorionic gonadotropin causes vomiting, which causes fasting, dehydration, and metabolic acidosis [ 15 ].

As pregnancy progresses, the activity of the usual counterregulatory hormones such as human placental lactogen, which is synthesized by the trophoblast and released into the circulation, reduces maternal sensitivity to insulin, increasing postprandial blood glucose levels [ 10 ]. Progesterone reduces gastrointestinal motility, increasing glucose uptake [ 10 ]. In addition, there is a decrease in insulin sensitivity, particularly in the third trimester, caused by hormonal changes that occur during pregnancy like an increase in estrogen, progestogens, human placental lactogen, and secretion of TNF- α [ 15 ]. All these mechanisms induce hyperglycemia in pregnancy. On the other hand, the placenta and the fetus absorb large amounts of glucose, decreasing blood levels when fasting. This leads to an increase in the secretion of maternal fatty acids and their subsequent metabolization in ketone bodies [ 12 ].

During late pregnancy, the fetus dramatically increases its glucose-based metabolism and accentuates its anabolic process by growth. On the other hand, the maternal metabolism enters a catabolic process in order to send all the glucose to the fetus through the placenta, using fat as the primary fuel. In the diabetic patient, the decrease in insulin intake profoundly affects the general metabolism, particularly at the level of liver, muscle, and adipose tissue, which are insulin essential action points. The absence of this hormone causes distortion of homeostasis. Plasma levels of glucose, free fatty acids and ketones rise to extreme figures, plasma pH and bicarbonate fall dangerously and there is marked loss of fatty tissue and body mass. If insulin levels are not restored, this case can lead to death.

Finally, the respiratory alkalosis that occurs during pregnancy increases the urinary excretion of bicarbonate, reducing the ability to buffer pH changes caused by the increase in body ketone production [ 16 ]. This leads to euglycemic diabetic ketoacidosis in pregnancy.

The incidence rate of diabetic ketoacidosis in all pregnant women with diabetes varies between 0.5 and 3%, being more common in patients with type I diabetes. However, there are more and more cases of patients with type II and gestational diabetes [ 17 , 18 ]. In a unicentric study in which 223,000 deliveries were analyzed, 14,532 (6.5%) were complicated due to diabetes, just 33 patients presented 40 diabetic ketoacidosis episodes with average blood glucose levels of 380 mg/dL on admission, whereas only 3 cases presented euglycemic diabetic ketoacidosis [ 18 ]. The different cases of euglycemic diabetic ketoacidosis in pregnancy, their initial diagnosis, and clinical presentations are analyzed in Table 3 . In contrast to most of the cases described in literature, our patient presented with DKA during the first trimester.

Cases of euglycemic DKA in pregnancy reported in literature.

The harmful effects of ketoacidosis on the fetus are caused by ketone bodies and glucose passing the placental barrier, dehydration, which leads to decreased placental perfusion and electrolyte imbalance [ 18 ]. Fetal acidosis is caused by hyperglycemia, which leads to osmotic diuresis and fetal intravascular volume depletion. Fetal hyperinsulinemia increases oxygen uptake. A decrease in 2,3-DPG increases oxygen affinity for hemoglobin, reducing the amount of oxygen available to the fetus and generating hypoxia [ 17 ]. The electrolyte disturbance can not only generate maternal arrhythmias with a subsequent decrease in placental perfusion, but also generate fetal arrhythmias and risk of cardiorespiratory arrest [ 18 ]. Although there are no studies that show the long-term consequences for the fetuses born alive, neurodevelopmental alterations were observed. In contrast to other pregnancy complications, a hasty delivery with DKA would be harmful to the fetus. Therefore, it is recommended to stabilize the mother first [ 19 ]. Some studies state that fetal mortality in patients with DKA can reach 9% [ 15 ] and perinatal mortality is between 9 and 35% [ 17 ]. However, there are also authors who argue that ketoacidosis is not associated with a higher mortality rate during the first trimester, nor with a higher rate of malformations [ 20 ].

The mainstay of treatment does not differ from the treatment for hyperglycemic ketoacidosis, that is, hydration and insulin. The difference is that, in order to maintain blood glucose levels, the amount of glucose administered must be higher and, in the case of pregnant patients, care should be taken to maintain blood glucose levels suitable for fetal welfare. There is evidence in literature showing that a value of 250 mg/dL (Baha M. 2014) or values between 100 and 150 mg/dL would accomplish this [ 20 ].

The second case is associated with the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors. The incidence rate of diabetic ketoacidosis in patients treated with SGLT-2 inhibitors varies between 0.16 and 0.76 cases per 1000 patients per year [ 21 , 22 ]. In a review of literature, 46 cases of diabetic ketoacidosis associated with the use of SGLT-2 were found and, in 70% of the cases, the ketoacidosis was euglycemic [ 23 ]. The main mechanism of action is the inhibition of glucose uptake in proximal tubules, increasing glycosuria [ 24 ]. In addition, SGLT-2 inhibitors significantly increase plasma glucagon levels through a decrease in paracrine inhibition of insulin and possibly due to the inhibition of glucose transport into pancreatic α cells by SGLT-2 [ 22 ]. At the same time, they decrease 3-hydroxybutyrate and acetoacetate elimination at the kidney level [ 24 – 28 ]. Moreover, when blood glucose levels decrease, patients that are being treated with insulin decrease its administration. Therefore, counterregulatory hormone effects predominate, resulting in a lower inhibition of lipolysis and lipogenesis and, thereby, triggering euglycemic ketoacidosis [ 29 – 31 ]. Case reports include the 3 drugs of the gliflozin class: Dapagliflozin [ 24 , 25 , 29 – 35 ], Canagliflozin [ 26 – 28 , 31 – 33 , 36 , 37 ], and Empagliflozin [ 38 – 40 ].

The last case deals with a patient with diabetic ketoacidosis associated with dehydration. During fasting, when hepatic glycogen is consumed, there is no source of glucose release into the bloodstream; however, lipolysis and the generation of ketone bodies are increased [ 41 ]. Dehydration is also a factor that contributes to the development of euglycemia [ 42 ].

Luethi et al. [ 43 ] analyzed blood glucose levels, arterial blood gases, and ketonemia and ketonuria in 60 critically ill patients. 63% of the patients developed some degree of ketosis ( β -hydroxybutyric levels greater than 0.6 mmol/L). In 12% of the patients, it was severe (greater than 3 mmol/L), and 33 % developed ketonuria (which was only severe in 2% of the patients). The prevalence of ketosis was the same in those who presented glucose peaks greater than 180 mg/dL and those who did not [ 1 ]. It is interesting to observe that, in this study [ 44 ], only 2 patients out of the 60 developed ketoacidosis based on the criteria set forth by the Joint British Diabetes Society [ 45 ] and none of them did, based on the ADA's criteria [ 11 ].

Finally, another possible cause of euglycemic ketoacidosis is the administration of insulin before being admitted to the hospital [ 42 ]. Other causes are pancreatic lesions developed during pancreatitis due to alcohol consumption, associated with the fasting required by this condition, which would explain the development of euglycemic ketoacidosis [ 42 ]. Furthermore, cocaine abuse causes an increase in the secretion of cortisol and noradrenaline by the adrenal gland, in addition to the anorexigenic effects of this drug, which lead to fasting [ 46 ].

6. Conclusion

Euglycemic diabetic ketoacidosis is a diagnostic challenge, not only due to the absence of its most important sign, which is hyperglycemia, but also due to its varied triggers. Knowing the different contexts in which it can occur will allow us to suspect euglycemic diabetic ketoacidosis and begin rapid and adequate treatment of the precipitating cause, as well as aggressive hydration, glucose homeostasis through insulin administration, and the adjustment of electrolyte imbalances. A delay results in serious complications both in the fetus (in the case of gestational diabetes) and in the patient, increasing in-hospital morbidity and mortality.

Conflicts of Interest

The authors declare that they have no conflicts of interest.