Diabetic ketoacidosis

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This page is for adult patients. For pediatric patients, see: diabetic ketoacidosis (peds)

Background

  • Patients in DKA are almost always K+ depleted despite initially fairly normal K+.
    • This is due to extracellular shift of K+ due to acidosis as well as insulin infusion, which increases uptake of K+ intracellularly.


Epidemiology

  • Mortality rate approximately 2-5%[1]


Pathophysiology

Defining features include hyperglycemia (glucose > 200mg/dl), acidosis (pH < 7.3), and ketonemia


Hyperglycemia

  • Leads to osmotic diuresis and depletion of electrolytes including sodium, potassium, magnesium, calcium and phosphorus.
  • Further dehydration impairs glomerular filtration rate (GFR) and contributes to acute renal failure
  • Hypokalemia may inhibit insulin release


Acidosis

  • Due to insulin deficiency -> lipolysis / accumulation of of ketoacids (represented by increased anion gap)
  • Compensatory respiratory alkalosis (i.e. tachypnea and hyperpnea - Kussmaul breathing)
  • Breakdown of adipose creates first acetoacetate leading to conversion to beta-hydroxybutyrate


Dehydration

  • Causes activation of RAAS in addition to the osmotic diuresis
  • The initial serum values for electrolytes such as K+ may be higher than actual body stores
  • Cation loss (in exchange for chloride) worsens metabolic acidosis


Clinical Features

  • May be the initial presentation of unrecognized T1DM (6-21% of adults with T1D present with DKA as first diagnosis)
  • OR symptoms/signs of an inciting precipitant (e.g. medication/dietary nonadherence, signs/symptoms of infection, insulin pump malfunction)
  • Presenting features may include:

Constitutional

    • Generally ill-appearance
    • Fatigue, weakness, malaise
    • +/- Weight loss (may be significant in new-onset T1D)

Volume Depletion

    • Polydipsia, polyuria (initially) → decreased urine output (as volume depleted)
    • Signs of dehydration: dry mucous membranes, poor skin turgor, sunken eyes, delayed capillary refill
    • Hypotension, tachycardia
    • Most adults are 3-6 liters depleted at presentation

Gastrointestinal

    • Abdominal pain — present in up to 50% of DKA; can mimic an acute abdomen (appendicitis, pancreatitis, mesenteric ischemia)
      • ED Pearl: Abdominal pain that does not improve with correction of acidosis and hydration warrants further workup for intra-abdominal pathology — do not assume it is "just DKA"
      • Abdominal pain correlates with severity of acidosis; more common with pH <7.2
    • Nausea/vomiting (present in >75% of cases)
    • Anorexia
    • Ileus / decreased bowel sounds (from electrolyte derangements and acidosis)
    • Gastroparesis — increases aspiration risk, especially if intubation is being considered

Respiratory

    • Tachypnea — compensatory for metabolic acidosis
    • Kussmaul breathing (deep, labored breathing pattern) — classic finding in moderate-severe DKA; represents maximal respiratory compensation
    • Acetone / fruity smell on breath — from exhaled ketones; may be subtle or absent; not all clinicians can detect it
    • ED Pearl: A DKA patient who is no longer tachypneic despite persistent acidosis is decompensating — respiratory compensation is failing and the patient may need emergent airway management

Neurologic

    • Altered mental status — ranges from drowsiness and lethargy to confusion, stupor, and coma
      • Severity correlates with serum osmolality more than glucose level or pH
      • AMS is present in ~15-25% of DKA patients at presentation
    • Decreased reflexes
    • Headache
    • Seizures (uncommon; more frequent in pediatric DKA)
    • Cerebral edema — significantly increases mortality, especially in children; suspect if neurologic status worsens during treatment (see Cerebral edema in DKA)

Cardiovascular

Other

    • Hypothermia — DKA patients may be normothermic or hypothermic even in the presence of infection; absence of fever does NOT exclude infection as a precipitant
    • Blurred vision (from osmotic lens swelling)
    • Muscle cramps (from electrolyte derangements)
    • Deep vein thrombosis / pulmonary embolism — DKA is a hypercoagulable state; consider VTE in patients with unexplained tachycardia, hypoxia, or chest pain disproportionate to presentation


Differential Diagnosis

Causes of DKA

Hyperglycemia

Diabetic Emergencies

Diabetes Mellitus (New or Known)

Medication/Drug-Induced

Physiologic Stress Response

  • Sepsis / critical illness (stress hyperglycemia — very common in the ED)
  • Trauma / major surgery / burns
  • Acute coronary syndrome / myocardial infarction
  • Stroke (especially hemorrhagic)
  • Pancreatitis (both a cause and consequence)
  • Shock (any etiology)
  • Pain (catecholamine surge)
  • Seizure (postictal)
  • Physiologic stress alone rarely causes glucose >200 mg/dL in non-diabetics; glucose >200 in a "stress response" should prompt evaluation for undiagnosed diabetes or prediabetes

Endocrine

Pancreatic

  • Pancreatitis (acute or chronic — destruction of islet cells)
  • Pancreatic malignancy (adenocarcinoma, neuroendocrine tumors)
  • Post-pancreatectomy
  • Cystic fibrosis-related diabetes
  • Hemochromatosis (iron deposition in pancreas — "bronze diabetes")

Toxic/Overdose

Other

  • Renal failure (chronic kidney disease, acute kidney injury — impaired insulin clearance AND insulin resistance)
  • Cirrhosis / hepatic failure (impaired glycogenolysis regulation)
  • Pregnancy (gestational diabetes, steroid administration for fetal lung maturity)
  • Parenteral nutrition (TPN, dextrose-containing fluids)
  • Post-transplant diabetes (immunosuppressants)

Complications of Diabetes (Not Causes of Hyperglycemia)

These are associated conditions that may be present alongside hyperglycemia but do not themselves cause elevated glucose:


Evaluation

Workup

Workup to confirm diagnosis and search for possible inciting causes (e.g. infection, ACS)


Diagnosis

Diagnosis is made based on the presence of acidosis (e.g. venous pH < 7.3 or HCO3 <18) and ketonemia (e.g. >3mmol/L BOH or ketonuria) in the setting of diabetes (e.g. glucose >200mg/dl) [2]


Basic Laboratory Findings

  • Blood Glucose
    • Capillary blood sugar >200mg/dL
    • Blood sugar may not be very elevated if there is impaired gluconeogenesis (eg liver failure, severe alcoholism) or patient is taking a SGLT-2 Inhibitor [3]
  • Elevated Anion Gap
    • Bicarb may be normal due to compensatory and contraction alkalosis so the elevated anion gap or ketonuria may be the only clues to the DKA
  • Serum ketones
    • Beta hydroxybutyrate will be elevated


Blood Gas

No need to perform Arterial blood gas. Venous blood gas is sufficient[4]

  • Difference in pH from VBG vs ABG will be ±0.02pH units[5][6] [7][8]


Urinary analysis (ketonuria)

  • Urinalysis may be a useful screening test early in DKA, if serum ketones not available
    • However, may give a false negative for ketones later in DKA, as acetoacetate is converted to beta-hydroxybutyrate the urinary ketones may turn negative[9]


End Tidal CO2

Strongly consider capnography for respiratory distress[10]

  • ETCO2 can be used for bedside assessment of DKA in pts with glucose>550[11]
    • An ETCO2 of ≥35 is 100% sensitive to rule out DKA
    • An ETCO2 of ≤21 is 100% specific to diagnosis DKA


Management

Algorithm for the management of diabetic ketoacidosis
  • If the patient has an insulin pump, make sure it is shut off or disconnected


Volume Repletion

  • Administer 20-30cc/kg lactated ringers bolus during the first hour
    • Most important step in treatment since osmotic diuresis is the major driving force[7]
    • Most adult patients are 3-6L depleted
    • Increased systemic perfusion may transport insulin to previously unreached receptor sites, inhibiting ketogenesis
    • Increased renal perfusion promotes renal hydrogen ion loss
    • Use of LRs is preferred over NS [12],[13]
    • When blood sugar(BS) < 250-300 add a D10 infusion at an equal rate to the LR using a single IV line [14]
    • Patients can eat and drink if mental status is intact [15]


Electrolyte Repletion

  • Potassium (most important!)[16]
    • <3.5mEq/L:
      • Start potassium repleation: 20-30 mEq KCl to IVF/hr
      • Do not administer insulin (to avoid worsening of hypokalemia)
    • >3.5mEq/L and <5.5 mEq/L:
      • Start potassium repleation: 20-30 mEq KCl to IVF/hr
      • May start insulin (see below)
    • >5.5 mEq/L:
      • Hold potassium repletion and recheck electroltyes after initiaton of insulin (see below)
  • Sodium
    • Hyponatremia
      • Correct for hyperglycemia
        • Na+ decreases by 1.6mEq/L for every 100mg/dL increase in glucose (ie pseudohyponatremia)
      • If truly hyponatraemic, start NS 250-500ml/hr
    • Hypernatremia
      • Consider Lactated Ringers
  • Hypophosphatemia
    • <1.0 mEq/L, start repletion:
      • IV K2PO4 at 1mL/hour (contains 4.4meqK+ & 93mg phos)
      • Severe hypophosphatemia can cause cardiac and respiratory dysfunction
  • Hypomagnesemia
    • Mg<2.0mg/DL, start repletion:
      • 2g MgSO4 IV over 1h


Insulin Overview

  • Check potassium prior to insulin treatment (see above)! Do not administer insulin until potassium supplementation is underway.[17]
  • A bolus dose is unnecessary and may contribute to increased hypoglycemic episodes[18]
  • If the patient comes in wearing an insulin pump, turn off the pump and remove the subcutaneous catheter.
  • Expect BS to fall by 50-100mg/dL per hr if you administer 0.1units/kg/hr of insulin
  • Refractory hyperglycemia may be due to an associated infectious process contributing to the DKA


Long-Acting (Basal) Insulin

  • Two main practices exist: 1) Close the anion gap, then start basal insulin 2-3 hours before stopping insulin infusion, 2) Early basal insulin
    • Potential benefits of early basal insulin (glargine or detemir) include protecting against erroneously stopping insulin infusion prematurely and eliminating the 2-3 hour waiting period of starting basal insulin while on IV infusion
  • Early basal insulin:[19]
    • Glargine 0.30 U/kg SQ x 1[20][21], OR
    • Determine total 24 hour home dose of basal insulin and deliver that q24 hours (e.g. patient's normal home dose of glargine)[22]


Short-Acting Insulin

Intravenous Regimen (Short-Acting)

Do not stop insulin infusion until AG normalized AND bicarb normalized, despite resolution of blood sugar. Aim of insulin regime is to correct the acidosis, not merely the hyperglycemia.

  • Initial infusion 0.1 to 0.14 units/kg/hr of insulin (or 0.05units/kg/hr per local protocol)
    • Fixed Rate Insulin Infusion has improved outcomes over Variable Rate [23][24]
  • Maintain BS between 150 and 200mg/dL until resolution of acidosis
    • May require IV fluids to be switched to Dextrose 10% when BS <150mg/dL
  • Continue IV infusion for 2 hrs after subcutaneous insulin is begun
  • Subcutaneous route (appropriate only for mild DKA and if able to eat and void urine; poor perfusion may hamper its absorption)


Subcutaneous Regimen (Short-Acting)

A subcutaneous (SC) regimen must use short acting insulin and follow either a 1hr or 2hr dosing protocol. Regular insulin is not effective.[25] For patients who are euglycemic (glucose <250 mg/dl) at presentation (e.g. with mild gap), using standard insulin sliding scale instead of this regimen.[26] [27]

1hr Protocol

  • Initial dose SC short acting insulin (e.g. Aspart): 0.3 units/kg ideal body weight, followed by
    • 0.1 units/kg SC every hour
    • When blood glucose <250mg/dl (13.8 mmol/l), change IV fluids to D5<sub 0.45%NS and reduce SC aspart insulin to 0.05 units/kg/hr
    • Keep glucose at 150mg/dl (11 mmol/l) until resolution of DKA.

2hr Protocol

  • Initial dose SC short acting insulin (e.g. Aspart): 0.3 units/kg ideal body weight, followed by
    • 0.2 units/kg SC 1 hour later followed by Q2hr dosing
    • When blood glucose <250mg/dl (13.8 mmol/l), change IV fluids to D5 0.45% saline and reduce SC insulin to 0.1 units/kg/ 2hr
    • Keep glucose at 150mg/dl (11 mmol/l) until resolution of DKA.


Bicarbonate[28]

  • No evidence supports the use of sodium bicarb in DKA, with a pH >6.9
  • However, no studies have been performed for patients with pH <6.9 and the most recent ADA guidelines recommend it for patients with pH <7.1
  • Pitfalls of sodium bicarbonate therapy in DKA (outside of last ditch efforts in severe acidemia)[29]
    • Paradoxical CSF acidosis
    • Hypokalemia from H+ and K+ shifts
    • Large sodium bolus
    • Cerebral edema
    • Shifts oxygen-hemoglobin dissociation curve to left, decreasing O2 delivery to tissues


Subsequent Management

Labs/Monitoring

  • Glucose check Q1hr
  • Chem 10 Q2r (then move to Q4hr)
  • Check pH PRN based on clinical status (eval respiratory compensation)
  • Check appropriateness of insulin dose Q1hr (see below)
  • Corrected Electrolytes


Sliding Scale

  • Insulin Sliding Scale to be started once patient's DKA has resolved and eating a full diet.


Intubation

  • Avoid intubation unless patient cannot generate respiratory alkalosis compensation due to extreme fatigue[30]
  • Risks associated with intubation in DKA:
    • During sedation/paralysis, a rise in PaCO2 can decrease pH considerably
    • Severe gastroparesis in DKA creates a significant risk for aspiration
    • Strong DKA patients generally can achieve greater hyperventilation than mechanical ventilated patients
  • See Intubation for more information


Disposition

  • Admit to higher level care (usually ICU or step-down unit initially)
  • Subsequent hospital discharge requires closing on anion gap and resolution of symptoms.
  • Patients with mild DKA may be treated as outpatients if reliable, close follow-up available and underlying causes not requiring admission


Complications


See Also


External Links


References

  1. ↑ Lebovitz HE: Diabetic ketoacidosis. Lancet 1995; 345: 767-772.
  2. ↑ Glaser N, Fritsch M, Priyambada L, et al. ISPAD clinical practice consensus guidelines 2022: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes 2022; 23:835.
  3. ↑ Peters AL et al. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care 2015 Sep; 38(9): 1687-1693.
  4. ↑ Ma OJ, Rush MD, Godfrey MM, Gaddis G. Arterial blood gas results rarely influence emergency physician management of patients
  5. ↑ Kelly AM et al. Review Article – Can Venous Blood Gas Analysis Replace Arterial in Emergency Medical Care. Emery Med Australas 2010; 22: 493 – 498.
  6. ↑ Ma OJ et al. Arterial Blood Gas Results Rarely Influence Emergency Physician Management of Patients with Suspected Diabetic Ketoacidosis. Acad Emerg Med Aug 2003; 10(8): 836 – 41.
  7. ↑ 7.0 7.1 Savage MW, Datary KK, Culvert A, Ryman G, Rees JA, Courtney CH, Hilton L, Dyer PH, Hamersley MS; Joint British Diabetes Societies. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabet Med. 2011 May;28(5):508-15.
  8. ↑ Gokel Y, et al. Comparison of Blood Gas and Acid-Base Measurements in Arterial and Venous Blood Samples in Patients with Uremic Acidosis and Diabetic Ketoacidosis in the Emergency Room. American Journal of Nephrology 2000; 20:319-323.
  9. ↑ Stojanovic, V. Sherri Ihle. Role of beta-hydroxybutyric acid in diabetic ketoacidosis: A review. Can Vet J. 2011 Apr; 52(4): 426–430.
  10. ↑ Nagler J et al. Capnography: A valuable tool for airway management. Emerg Med Clin North Am, 26(4):881, Nov 2008.
  11. ↑ Chebl BR, Madden B, Belsky J, et al. Diagnostic value of end tidal capnography in patients with hyperglycemia in the emergency department. BCM Emerg Med. 2016; 16 (1).
  12. ↑ Carrillo et al. Balanced Crystalloid Versus Normal Saline as Resuscitative Fluid in Diabetic Ketoacidosis. https://pubmed.ncbi.nlm.nih.gov/34986659/
  13. ↑ Self et al. Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2772993/
  14. ↑ https://emcrit.org/ibcc/dka/
  15. ↑ Lipatov, K. et al. Early vs late oral nutrition in patients with diabetic ketoacidosis admitted to a medical intensive care unit. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347656/
  16. ↑ *http://emupdates.com/2010/07/15/correction-of-critical-hypokalemia/
  17. ↑ Aurora S, Cheng D, Wyler B, Menchine M. Prevalence of hypokalemia in ED patients with diabetic ketoacidosis. Am J Emerg Med 2012; 30: 481-4.
  18. ↑ Goyal N, Miller J, Sankey S, Mossallam U. Utility of Initial Bolus insulin in the treatment of diabetic ketoacidosis. Journal of Emergency Medicine, Vol 20:10, p30.
  19. ↑ Rao P, et al. Evaluation of Outcomes Following Hospital-Wide Implementation of a Subcutaneous Insulin Protocol for Diabetic Ketoacidosis. JAMA Netw Open. 2022;5(4):e226417. doi:10.1001/jamanetworkopen.2022.6417
  20. ↑ Hsia E, Seggelke S, Gibbs J, et al. Subcutaneous administration of glargine to diabetic patients receiving insulin infusion prevents rebound hyperglycemia. J Clin Endocrinol Metab. 2012;97(9):3132-3137.
  21. ↑ Doshi P, Potter A, De L, Banuelos R, Darger B, Chathampally Y. Prospective randomized trial of insulin glargine in acute management of diabetic ketoacidosis in the emergency department: a pilot study. Acad Emerg Med. 2015;22(6):657-662.
  22. ↑ Rappaport S, Endicott J, Gilbert M, Farkas J, Clouser R, McMillian W. A Retrospective Study of Early vs Delayed Home Dose Basal Insulin in the Acute Management of Diabetic Ketoacidosis. J Endocr Soc. 2019;3(5):1079-1086.
  23. ↑ Paranthaman, K & Srinivasan, B. Fixed Rate Insulin Infusion (FRII) vs Variable Rate Insulin Infusion (VRII) in Management of Patients with Diabetic Ketoacidosis (DKA). https://www.gavinpublishers.com/article/view/fixed-rate-insulin-infusion-frii-vs-variable-rate-insulin-infusion-vrii-in-management-of-patients-with-diabetic-ketoacidosis-dka
  24. ↑ Evans, K. Diabetic ketoacidosis: update on management. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771342/
  25. ↑ Umpierrez G. et al. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care. 2004 Aug;27(8):1873-8 [PDF http://care.diabetesjournals.org/content/27/8/1873.full.pdf]
  26. ↑ Rao P, et al. Evaluation of Outcomes Following Hospital-Wide Implementation of a Subcutaneous Insulin Protocol for Diabetic Ketoacidosis. JAMA Netw Open. 2022;5(4):e226417. doi:10.1001/jamanetworkopen.2022.6417
  27. ↑ Griffey R. et al. The SQuID protocol (subcutaneous insulin in diabetic ketoacidosis): Impacts on ED operational metrics. https://pubmed.ncbi.nlm.nih.gov/36775281/
  28. ↑ EBQ:Sodium Bicarbonate use in DKA
  29. ↑ Nickson C. Sodium Bicarbonate and Diabetic Ketoacidosis. Jan 28, 2014. http://lifeinthefastlane.com/ccc/sodium-bicarbonate-and-diabetic-ketoacidosis/.
  30. ↑ Four DKA Pearls. May 7, 2014. http://www.pulmcrit.org/2014/05/four-dka-pearls.html
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