Diabetic ketoacidosis medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]
Overview
Diabetic ketoacidosis (DKA) is a medical emergency. The mainstay of therapy for DKA is medical therapy including intravenous insulin, fluids, potassium replacement and bicarbonate therapy in case of severe acidosis (pH <6.9). The basic principles guiding therapy include rapid restoration of adequate circulation and perfusion, insulin to reverse ketosis and lower glucose levels, and close monitoring to prevent and treat complications if they develop. There are minor differences in the management of DKA in U.S.A. and U.K. which are opinion based and depend on the healthcare setting.
Medical Therapy
The United States (US) and United Kingdom (UK) follow slightly different guidelines for the management of diabetic ketoacidosis (DKA) but the basic principles are same.
Basic principles
The basic principles of diabetic ketoacidosis treatment (DKA) are:
- Rapid restoration of adequate circulation and perfusion with intravenous fluids.
- Gradual rehydration and restoration of depleted electrolytes (especially sodium and potassium), even if serum levels appear adequate.
- Insulin to reverse ketosis and lower glucose levels.
- Careful monitoring to detect and treat complications.
ADA guidelines
The American Diabetes Association (ADA) recommends the following therapy for diabetic ketoacidosis (DKA):[1][2][3]
Fluid therapy
- Initial fluid therapy is aimed towards expansion of the intravascular, interstitial, and intracellular volume, all of which are reduced in hyperglycemic crises.
- Fluid restoration also leads to increased renal perfusion and improves renal function.
- The following options may be used for fluid restoration:
- Isotonic saline (0.9% NaCl) is infused at a rate of 15–20 ml/kg/h or 1–1.5 L during the first hour. It may also be infused at a rate of 250-500 ml/h if serum sodium is low.
- Subsequent choice for fluid replacement depends on hemodynamics, the volume status of the body (signs and symptoms of dehydration), serum electrolyte levels, and urinary output.[4]
- Half normal saline (0.45% NaCl ) infused at 250–500 ml/h is beneficial if the corrected serum sodium is normal or increased.[4][5]
- Successful progress with fluid replacement is judged by, blood pressure monitoring, measurement of fluid input/output, laboratory values, and clinical examination.
- Fluid replacement usually leads to successful treatment of volume deficit within the first 24 hours.
- In patients with renal or cardiac compromise, monitoring of serum osmolality and frequent assessment of cardiac, renal, and mental status must be performed during fluid resuscitation to avoid iatrogenic fluid overload.
- Aggressive rehydration with subsequent resolution of the hyperosmolar state has been shown to be linked to a better response to low dose insulin.
- Once the plasma glucose is ∼ 200 mg/dl, 5% dextrose should be added to replacement fluids to allow continued insulin administration.
Insulin therapy
- Insulin therapy helps control hyperglycemia, hyperkalemia and ketosis.[6]
- The following routes and rates of insulin administration may be used:
- Route: Intravenous route is preferred because of rapid onset of action, although subcutaneous route can also be used.
- Rate of administration: An initial intravenous dose of regular insulin (0.1 units/kg) followed by infusion of 0.1 units/kg/h insulin.[2]
- The initial bolus of insulin may be skipped, if patients receive an hourly insulin infusion of 0.14 units/kg body weight.
- Low-dose insulin infusion protocols decrease plasma glucose concentration at a rate of 50–75 mg/dl/h.[2]
- Titration:If plasma glucose does not decrease by 50–75 mg from the initial value in the first hour, the insulin infusion should be increased every hour until a steady glucose decline is achieved.
- When the blood glucose level reaches 200 mg/dl, the rate of insulin infusion should be changed to 0.02 units/kg/h - 0.05 units/kg/h and dextrose may be added to the IV fluids.[7]
Potassium replacement
- Potassium replacement is started when the levels fall below the upper limit of normal (5.0-5.2 mEq/L).[8]
- Goal is to maintain serum potassium levels within the normal range of 4–5 mEq/L.
Bicarbonate
- The use of bicarbonate in DKA is controversial. It lacks evidence-based prospective clinical trials (especially in patients with pH <6.85 and pediatric population), and there has been no proven clinical efficacy of bicarbonate use.[9][10][11][12][13][2]
- The use of bicarbonate in emergent settings depends on the clinical judgment, opinion, and expertise. The perceived benefit in acute reversal of severe acidemia is only based on animal and experimental studies.
- According to ADA guidelines, bicarbonate is administered if arterial pH is < 6.9 to prevent acidotic complications.
- 100 mmol sodium bicarbonate (two ampules) in 400 ml sterile water (an isotonic solution) with 20 mEq KCI administered at a rate of 200 ml/h for 2 h until the venous pH is >7.0.
- Bicarbonate use may be associated with a higher risk of developing cerebral edema in patients with high blood urea nitrogen levels.[14]
Phosphate
- Phosphate therapy may be given to avoid potential cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia.[7]
- Phosphate replacement may sometimes be indicated in patients with cardiac dysfunction, anemia, or respiratory depression and when serum phosphate concentration is <1.0 mg/dl.
- Aggressive phosphate replacement may lead to hypocalcemia.
Criteria for resolution
- According to American Diabetes Association, the following criteria must be met for labeling resolution of DKA:
- Blood glucose <200mg/dl
PLUS
- Any two of the following:
- Bicarbonate greater than equal to 15 mEq/L
- Venous pH > 7.3
- Anion gap less than equal to 12 mEq/L
- Bicarbonate level should not be relied upon to assess the resolution of DKA. This is because high volumes of 0.9 % saline (NaCl) may lead to hyperchloremia in patients. The hyperchloremic acidosis will lower the bicarbonate and thus lead to difficulty is assessing whether the ketosis has resolved. The hyperchloremic acidosis may cause renal vasoconstriction and be a cause of oliguria.
- DKA usually resolves in 24 hours with appropriate treatment.
Differences in management between US and UK
- American Diabetes Association guidelines recommend treating DKA based on the severity.
- Joint British Diabetes Societies in the UK recommend treating DKA based on rate of fall of glucose and serum ketones, with a corresponding rise in bicarbonate.
The following are differences in management of DKA between the US and UK:[1][11][15][16][17]
| Region | Treatment | ||
|---|---|---|---|
| Insulin | Intravenous fluids | Bicarbonate | |
| United states |
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| United Kingdom |
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Step-wise approach to management of diabetic ketoacidosis
| DKA treatment protocol according to ADA guidelines | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fluids | Bicarbonate | Insulin | Potassium | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydration status | pH greater than equal to 6.9 | pH less than 6.9 | 0.1 u/kg/B.WT. as IV bolus | 0.14 u/kg/B.WT/hr as continous IV infusion | K < 3.3 mEq/L | K = 3.3 - 5.2 mEq/L | K > 5.2 mEq/L | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe hypovolemia | Mild dehydration | Cardiogenic shock | 0.1 u/kg/B.WT. as IV continous infusion | Hold insulin and give 20-30mEq/L of potassium until K+ > 3.3mEq/L | Give 20-30mEq/L in each liter of IV fluids to maintain serum K 4-5mEq/L | Do not give potassium but check serum potassium every 2 hours | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 0.9% Nacl (1L/hr) as IV infusion | Check corrected serum sodium | Hemodynamic monitoring and add pressors accordingly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| If serum glucose does not fall by 10 % within one hour of therapy then give 0.14 U/Kg as IV bolus and continue previous regimen | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| High serum Na (>145 mEq/L) | Normal serum Na (135-145 mEq/L) | Low serum Na (< 135 mEq/L) | When serum glucose drops to 200 mg/dl, reduce regular insulin to 0.02-0.05 U/Kg/hour, or give rapid-acting insulin at 0.1 U/kg SC every 2 hours, maintain serum glucose between 150 mg/dl to,200 mg/dl until resolution | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 0.45% NaCl (250-500 ml per hour depending on hydration status | 0.9% NaCl (200-500 ml per hour) depending on hydration status | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| When serum glucose decreases to 200 mg/dl, switch to 5% dextrose with 0.45% NaCl at 150-250 ml/hour | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Contraindicated medications
Diabetic ketoacidosis is considered an absolute contraindication to the use of the following medications:
- Glipizide
- Glyburide
- Glyburide and Metformin
- Linagliptin and Metformin hydrochloride
- Repaglinide
- Saxagliptin hydrochloride and Metformin hydrochloride
References
- ↑ 1.0 1.1 Radhakrishna Pillai M, Balaram P, Bindu S, Hareendran NK, Padmanabhan TK, Nair MK (1989). "Interleukin 2 production in lymphocyte cultures: a rapid test for cancer-associated immunodeficiency in malignant cervical neoplasia". Cancer Lett. 47 (3): 205–10. PMID 2699725.
- ↑ 2.0 2.1 2.2 2.3 "Diabetes Care".
- ↑ Nyenwe EA, Kitabchi AE (2011). "Evidence-based management of hyperglycemic emergencies in diabetes mellitus". Diabetes Res. Clin. Pract. 94 (3): 340–51. doi:10.1016/j.diabres.2011.09.012. PMID 21978840.
- ↑ 4.0 4.1 "Diabetic Ketoacidosis: Evaluation and Treatment - American Family Physician".
- ↑ Kageyama Y, Kawamura J, Ajisawa A, Yamada T, Iikuni K (1988). "A case of pseudohypoparathyroidism type 1 associated with gonadotropin resistance and hypercalcitoninaemia". Jpn. J. Med. 27 (2): 207–10. PMID 3138479.
- ↑ "Management of Diabetic Ketoacidosis - American Family Physician".
- ↑ 7.0 7.1 Gosmanov AR, Gosmanova EO, Dillard-Cannon E (2014). "Management of adult diabetic ketoacidosis". Diabetes Metab Syndr Obes. 7: 255–64. doi:10.2147/DMSO.S50516. PMC 4085289. PMID 25061324.
- ↑ Beigelman PM (1973). "Potassium in severe diabetic ketoacidosis". Am. J. Med. 54 (4): 419–20. PMID 4633105.
- ↑ Chua HR, Schneider A, Bellomo R (2011). "Bicarbonate in diabetic ketoacidosis - a systematic review". Ann Intensive Care. 1 (1): 23. doi:10.1186/2110-5820-1-23. PMC 3224469. PMID 21906367.
- ↑ Hale PJ, Crase J, Nattrass M (1984). "Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis". Br Med J (Clin Res Ed). 289 (6451): 1035–8. PMC 1443021. PMID 6091840.
- ↑ 11.0 11.1 Morris LR, Murphy MB, Kitabchi AE (1986). "Bicarbonate therapy in severe diabetic ketoacidosis". Ann. Intern. Med. 105 (6): 836–40. PMID 3096181.
- ↑ Munk P, Freedman MH, Levison H, Ehrlich RM (1974). "Effect of bicarbonate on oxygen transport in juvenile diabetic ketoacidosis". J. Pediatr. 84 (4): 510–4. PMID 4209917.
- ↑ Latif KA, Freire AX, Kitabchi AE, Umpierrez GE, Qureshi N (2002). "The use of alkali therapy in severe diabetic ketoacidosis". Diabetes Care. 25 (11): 2113–4. PMID 12401775.
- ↑ Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, Kuppermann N (2001). "Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics". N. Engl. J. Med. 344 (4): 264–9. doi:10.1056/NEJM200101253440404. PMID 11172153.
- ↑ Fleming TN, Runge PE, Charles ST (1992). "Diode laser photocoagulation for prethreshold, posterior retinopathy of prematurity". Am. J. Ophthalmol. 114 (5): 589–92. PMID 1443021.
- ↑ Chua HR, Schneider A, Bellomo R (2011). "Bicarbonate in diabetic ketoacidosis - a systematic review". Ann Intensive Care. 1 (1): 23. doi:10.1186/2110-5820-1-23. PMC 3224469. PMID 21906367.
- ↑ Dhatariya KK, Vellanki P (2017). "Treatment of Diabetic Ketoacidosis (DKA)/Hyperglycemic Hyperosmolar State (HHS): Novel Advances in the Management of Hyperglycemic Crises (UK Versus USA)". Curr. Diab. Rep. 17 (5): 33. doi:10.1007/s11892-017-0857-4. PMC 5375966. PMID 28364357.