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{{Adult top}} [[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%<ref>Lebovitz HE: Diabetic ketoacidosis.  Lancet 1995; 345: 767-772.</ref>

===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==
{{DKA clinical features}}

==Differential Diagnosis==
===Causes of DKA===
*[[Insulin]] or oral hypoglycemic medication non-compliance (or insulin pump malfunction)
*Infection 
*[[Cardiac Ischemia]] 
*Intra-abdominal infections
*[[Steroid]] use
*[[ETOH Abuse]] 
*[[Toxicologic exposure]]
*[[Pregnancy]] 
*[[Hyperthyroidism]] 
*[[GI Hemorrhage]]
*[[CVA]]
*[[PE]]
*[[Pancreatitis]]
*[[Renal Failure]]
*[[GI Bleed]]
*[[Alcoholic Ketoacidosis]]
*[[SGLT-2 inhibitors]] (euglycemic DKA)

{{Hyperglycemia DDX}}

==Evaluation==
===Workup===
''Workup to confirm diagnosis and search for possible inciting causes (e.g. infection, [[ACS]])''
*CBC
*BMP
*Blood glucose
*Serum ketones (e.g. beta-hydroxybutyrate and/or acetone)
*Mag
*Phos
*[[VBG]]/[[ABG]]
*Consider [[ECG]], [[urinalysis]], [[chest X-ray]], [[blood cultures]]

===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)'' <ref>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.</ref>

====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]] <ref>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.</ref>
*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<ref>Ma OJ, Rush MD, Godfrey MM, Gaddis G. Arterial blood gas results rarely influence emergency physician management of patients</ref>''
*Difference in pH from VBG vs ABG  will be ±0.02pH units<ref>Kelly AM et al. Review Article – Can Venous Blood Gas Analysis Replace Arterial in Emergency Medical Care. Emery Med Australas 2010; 22: 493 – 498.</ref><ref>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. </ref> <ref name="British DKA">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.</ref><ref>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.</ref>

====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<ref>Stojanovic, V. Sherri Ihle. Role of beta-hydroxybutyric acid in diabetic ketoacidosis: A review. Can Vet J. 2011 Apr; 52(4): 426–430. </ref>

====End Tidal CO2====
''Strongly consider capnography for respiratory distress<ref>Nagler J et al. Capnography: A valuable tool for airway management. Emerg Med Clin North Am, 26(4):881, Nov 2008.</ref>''
*ETCO2 can be used for bedside assessment of DKA in pts with glucose>550<ref>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).</ref>
**An ETCO2 of ≥35 is 100% sensitive to rule out DKA
**An ETCO2 of ≤21 is 100% specific to diagnosis DKA

==Management==
[[File:DKA management.png|thumb|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<ref name="British DKA"></ref>
**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 <ref>Carrillo et al. Balanced Crystalloid Versus Normal Saline as Resuscitative Fluid in Diabetic Ketoacidosis. https://pubmed.ncbi.nlm.nih.gov/34986659/</ref>,<ref>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/</ref>
**When blood sugar(BS) < 250-300 add a D10 infusion at an equal rate to the LR using a single IV line <ref>https://emcrit.org/ibcc/dka/</ref>
**Patients can eat and drink if mental status is intact <ref>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/</ref>

===[[Electrolyte Repletion]]===
*Potassium (most important!)<ref>*http://emupdates.com/2010/07/15/correction-of-critical-hypokalemia/</ref>
**<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.'''<ref>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.</ref>
*A bolus dose is unnecessary and may contribute to increased hypoglycemic episodes<ref>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.</ref>
*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:<ref>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</ref>
**Glargine 0.30 U/kg SQ x 1<ref>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.</ref><ref>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.</ref>, '''OR'''
**Determine total 24 hour home dose of basal insulin and deliver that q24 hours (e.g. patient's normal home dose of glargine)<ref>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.</ref>

===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 <ref>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</ref><ref>Evans, K. Diabetic ketoacidosis: update on management. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771342/</ref>
*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.<ref>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]</ref>'' '''For patients who are euglycemic (glucose <250 mg/dl) at presentation (e.g. with mild gap), using standard [[Insulin#Insulin_Sliding_Scale|insulin sliding scale]] instead of this regimen.<ref>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</ref>''' <ref>Griffey R. et al. The SQuID protocol (subcutaneous insulin in diabetic ketoacidosis): Impacts on ED operational metrics. https://pubmed.ncbi.nlm.nih.gov/36775281/</ref>

'''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%</sub>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]]<ref>[[EBQ:Sodium Bicarbonate use in DKA]]</ref>===
{{EBQ Sodium Bicarbonate use in DKA conclusion}}
*Pitfalls of sodium bicarbonate therapy in DKA (outside of last ditch efforts in severe acidemia)<ref>Nickson C. Sodium Bicarbonate and Diabetic Ketoacidosis. Jan 28, 2014. http://lifeinthefastlane.com/ccc/sodium-bicarbonate-and-diabetic-ketoacidosis/.</ref>
**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<ref>Four DKA Pearls. May 7, 2014. http://www.pulmcrit.org/2014/05/four-dka-pearls.html</ref>
*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#Severe_Metabolic_Acidosis|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==
*[[Cerebral Edema in DKA]]

==See Also==
*[[Diabetes mellitus (main)]]
*[[EBQ:Sodium_Bicarbonate_use_in_DKA|Evidence Review Sodium Bicarbonate in DKA]]
*[[Diabetic ketoacidosis (peds)]]
*[[Ketonemia]]
*[[Cerebral edema in DKA]]

==External Links==
*[http://www.bsped.org.uk/clinical/docs/DKAcalculator.pdf British Society for Paediatric Endocrinology and Diabetes - Paediatric Diabetic Ketoacidosis]
*[http://ddxof.com/diabetic-ketoacidosis/ DDxOf: Management of DIabetic Ketoacidosis]

==References==
<references/>

[[Category:Endocrinology]]