• Clinical science
  • Clinician

Hyperglycemic crises

Summary

Acute hyperglycemia, or high blood glucose, may be either the initial presentation of diabetes mellitus or a complication arising during the course of another disease. Inadequate insulin replacement (e.g., noncompliance with treatment) or increased insulin demand (e.g., during times of acute illness, surgery, or stress) may lead to acute hyperglycemia. In diabetic ketoacidosis (DKA), which is more common in patients with type 1 diabetes, no insulin is available to suppress lipolysis, resulting in ketone formation and acidosis. In a hyperosmolar hyperglycemic state (HHS), which is more common in patients with type 2 diabetes, there is still some insulin available and so there is minimal or no ketone formation. Clinical features of both DKA and HHS include polyuria, polydipsia, nausea and vomiting, volume depletion (e.g., dry oral mucosa, decreased skin turgor), and eventually mental status changes and coma. Features unique to DKA include a fruity odor to the breath, hyperventilation, and abdominal pain. Patients with HHS typically present with more extreme volume depletion than those with DKA. The mainstay of treatment for both DKA and HHS consists primarily of IV fluid resuscitation, electrolyte repletion, and insulin therapy.

Etiology

DKA, oftentimes precipitated by infection (e.g., pneumonia, urinary tract infection), is often the initial manifestation of type 1 diabetes mellitus (∼ 30% of cases)!

References:[1]

Pathophysiology

Diabetic ketoacidosis (DKA)

Primarily affects patients with type 1 diabetes

Osmotic diuresis and hypovolemia

Hypovolemia resulting from DKA can lead to acute kidney injury (AKI) due to decreased renal blood flow! Hypovolemic shock may also develop.

Metabolic acidosis with increased anion gap

DKA is an important cause of anion gap metabolic acidosis with respiratory compensation.

Intracellular potassium deficit

  • As a result of hyperglycemic hyperosmolality, potassium shifts along with water from inside cells to the extracellular space and is lost in the urine.
  • Insulin normally promotes cellular potassium uptake but is absent in DKA, compounding the problem.
  • A total body potassium deficit develops in the body, although serum potassium may be normal or even paradoxically elevated.
  • Insulin deficiency → hyperosmolality K+ shift out of cells + lack of insulin to promote K+ uptake → intracellular K+depleted → total body K+ deficit despite normal or even elevated serum K+

There is a total body potassium deficit in DKA. This becomes important during treatment, when insulin replacement leads to rapid potassium uptake by depleted cells and patients may require potassium replacement.

Hyperosmolar hyperglycemic state (HHS)

  • Primarily affects patients with type 2 diabetes
  • The pathophysiology of HHS is similar to that of DKA.
  • However, in HHS, there are still small amounts of insulin being secreted by the pancreas, and this is sufficient to prevent DKA by suppressing lipolysis and, in turn, ketogenesis.
  • HHS is characterized by symptoms of marked dehydration (and loss of electrolytes) due to the predominating hyperglycemia and osmotic diuresis.

References:[1][2]

Clinical features

  • Signs and symptoms of both DKA and HHS
  • Signs and symptoms specific to DKA
Clinical findings of DKA versus HHS
DKA HHS
Diabetes Type 1 Type 2
History of severe stress, illness, hospitalization + +
Polyuria, polydipsia + +
Nausea, vomiting + +/-
Dehydration + ++ (Profound)
Altered mental status Possible Possible
Hyperventilation + -
Fruity breath + -
Severe abdominal pain + -
Onset Rapid (< 24 h) Insidious (days)

Known diabetics who present with nausea and vomiting should be immediately assessed for DKA/HHS! Because patients with type 2 diabetes can still produce small amounts of insulin in some cases, acute hyperglycemia progresses more slowly and serum glucose is significantly elevated compared with patients with type 1 diabetes in DKA (> 600 mg/dL versus > 250 mg/dL).

References:[1][2][3][4]

Diagnostics

Approach [5][6]

Overview of laboratory findings in hyperglycemic crises [5]

Laboratory test DKA HHS
BMP Glucose
  • < 600 mg/dL (< 33.3 mmol/L)
  • About 10% of patients with DKA will be euglycemic (e.g., glucose ≤ 250 mg/dL) [5]
  • > 600 mg/dL (> 33.3 mmol/L)
Bicarbonate
  • < 18 mEq/L (< 18 mmol/L)
  • > 18 mEq/L (> 18 mmol/L)
Anion gap
  • Elevated anion gap > 10 mEq/L (> 10 mmol/L)
Urinalysis
  • Negative or small ketones
  • Glucosuria
Serum β-hydroxybutyrate
  • Elevated
  • Normal
Blood gas
  • pH < 7.30
  • pH > 7.30
Serum osmolality
  • Normal
  • Elevated > 320 mosm/kg (> 320 mmol/kg)

DKA is the diagnosis in patients with type 1 diabetes who have hyperglycemia, ketonuria, and high anion gap metabolic acidosis with decreased bicarbonate!

HHS is the diagnosis in patients with type 2 diabetes who have hyperglycemia and hyperosmolality!

Ketone levels should be ordered in all patients with high anion gap metabolic acidosis to evaluate for euglycemic DKA.

Electrolytes and renal function [5][6]

  • Sodium:
  • Potassium in DKA: normal or elevated (despite a total body deficit)
  • Magnesium levels are typically low.
  • Phosphorus levels may be falsely elevated despite a total body deficit.
  • BUN and creatinine are often elevated. [9]

Additional diagnostic workup [5][10][6]

Infection, myocardial infarction, and pancreatitis should be ruled out in all patients presenting with a hyperglycemic crisis.

Severity of DKA [5]

Arterial pH Serum bicarbonate Anion gap Mental status
Mild > 7.24 15–18 mEq/L > 10 mEq/L Alert
Moderate 7.0–7.24 10–15 mEq/L > 12 mEq/L Alert or drowsy
Severe < 7.0 < 10 mEq/L > 12 mEq/L Stuporous

Management

Approach

Initially treat DKA with normal saline and short-acting (regular) insulin.

Fluid resuscitation [5][10][13]

  • First hour: isotonic saline solution (0.9% sodium chloride) at 15–20 mL/kg/hour (∼ 1000–1500 mL bolus) [5][10][13]
  • Next 48 hours: Adjust IV fluid rate and composition according to CVP, urine output, blood glucose, and corrected sodium levels.
    • Check corrected sodium for hyperglycemia.
      • If corrected serum sodium ≥ 135 mmol/L: 0.45% NaCl
      • If corrected serum sodium < 135 mmol/L: 0.9% NaCl
    • When serum glucose falls to < 200–250 mg/dL, add 5% dextrose to infusion.

Electrolyte repletion [5]

Serum K+ Recommended dose [14]
< 3.3 mEq/L

3.3–5.2 mEq/L

> 5.2 mEq/L

  • No repletion recommended

It is critical that potassium levels are confirmed to be > 3.3 mEq/L before administering insulin, as insulin will lower serum potassium and potentially cause severe hypokalemia.

Insulin [5][13][15]

  • The administration of insulin is essential in halting lipolysis and ketoacidosis in patients with DKA.
  • Recommended regimens [5]
    • IV regular insulin bolus , followed by continuous regular insulin IV infusion
    • Or regular insulin continuous IV infusion without a bolus
    • Both options listed are valid approaches with advantages and disadvantages. When in doubt, follow hospital standards.
  • Check glucose level hourly and titrate as needed.
  • The goal is to decrease blood glucose levels by 10% per hour (∼50–75 mg/dL/hour).
  • Treatment with subcutaneous rapid-acting insulin analogues on a regular medical ward may be considered in cases of mild DKA.

Acid-base status [5]

  • Acidosis usually resolves with fluids and insulin therapy and the use of IV bicarbonate is usually not necessary
  • If pH < 6.9 despite adequate IV fluid resuscitation, administer IV sodium bicarbonate.

Monitoring [5][13] [16]

  • Admission to the ICU or closely monitored setting [5]
  • Consider endocrine consult.
  • NPO status in patients with high anion gap metabolic acidosis on insulin infusion
  • Hourly monitoring of vitals and mental status and hydration status
  • POC glucose every 1–2 hours until blood glucose < 250 mg/dL and hourly blood glucose readings are stable for at least 3 hours; then decrease monitoring to every 2–4 hours
  • Serum osmolality every 1–4 hours
  • Blood gas and BMP with electrolytes every 2–4 hours

Monitoring of volume status, serum glucose, serum electrolytes, and acid-base status at regular intervals is essential.

Resolution and transition to subcutaneous insulin [5]

Criteria for the resolution of hyperglycemic crises [5][6]
DKA HHS
  • Glucose < 200 mg/dL
  • PLUS at least two of the following:
    • Venous pH > 7.30
    • Serum bicarbonate ≥ 15 mEq/L
    • Anion gap ≤ 12 mEq/L
  • Normalization of serum osmolality (i.e., < 320 mOsm/kg)
  • Normal mental status
  • Criteria for transitioning to subcutaneous insulin:
    • Resolution of hyperglycemic crisis
    • Precipitating factor identified and treated
    • Patient tolerating oral nutrition and eating consistently
  • Procedure for transitioning to subcutaneous insulin:

Acute management checklist

  • ABCDE survey
  • Establish IV access with two large-bore peripheral IV lines.
  • Confirm diagnosis with blood gas, BMP, serum osmolality, serum ketones, and urine ketones.
  • Identify and treat life-threatening causes (e.g., MI, sepsis).
  • Assess severity of DKA.
  • Begin fluid resuscitation with 0.9% NaCl.
  • Replete potassium and maintain K+ levels at 4–5 mEq/L.
  • Replete other electrolytes (see electrolyte repletion).
  • Start continuous insulin IV infusion with hourly POC glucose checks once serum potassium is confirmed > 3.3 mEq/L.
  • Consider bicarbonate if pH < 6.9 despite adequate fluid therapy.
  • Adjust fluid resuscitation based on corrected sodium for hyperglycemia, serum glucose, and clinical response.
    • Corrected serum sodium ≥ 135 mmol/L: 0.45% NaCl
    • Corrected serum sodium < 135 mmol/L: 0.9% NaCl
    • Add dextrose once POC glucose < 200–250 mg/dL.
  • Identify and treat the underlying cause (e.g., medication noncompliance, infection).
  • Order monitoring labs (e.g., BMP, serum osmolality, and blood gas every 2–4 hours).
  • Consider endocrine consult.
  • Admit to ICU (consider regular medical ward for mild cases).

Differential diagnoses

All etiologies of altered mental status must be considered in the differential diagnosis of DKA/HHS! Intoxication and other endocrine disorders, as well as gastroenteritis, myocardial infarction, pancreatitis, and other causes of high anion gap metabolic acidosis, should all be excluded.

Differential diagnosis of DKA/HHS and hypoglycemia
DKA/HHS Hypoglycemia
Onset Hours to days Minutes
Appetite ∅ (unchanged) ↑↑↑↑
Thirst ↑↑↑↑ ∅ (unchanged)
Muscle tone ↓↓ ↑↑ (tremor)
Skin turgor ↓↓ (dry skin) ↑↑ (moist skin)
Respirations ↑↑ (Kussmaul respirations with DKA) ∅ (unchanged)

Complications

We list the most important complications. The selection is not exhaustive.

  • 1. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. New York, NY: McGraw-Hill Education; 2015.
  • 2. Agabegi SS, Agabegi ED. Step-Up To Medicine. Baltimore, MD, USA: Wolters Kluwer Health; 2015.
  • 3. Westerberg DP. Diabetic Ketoacidosis: Evaluation and Treatment. Am Fam Physician. 2013; 87(5): pp. 337–346. pmid: 23547550.
  • 4. Hirsch IB, Emmett M. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-clinical-features-evaluation-and-diagnosis?source=see_link. Last updated December 7, 2016. Accessed February 14, 2017.
  • 5. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic Crises in Adult Patients With Diabetes. Diabetes Care. 2009; 32(7): pp. 1335–1343. doi: 10.2337/dc09-9032.
  • 6. Westerberg D. Diabetic Ketoacidosis: Evaluation and Treatment. Am Fam Physician. 2013. url: https://www.aafp.org/afp/2013/0301/p337.html#afp20130301p337-b19.
  • 7. Trachtenbarg DE. Diabetic ketoacidosis. Am Fam Physician. 2005; 71(9): pp. 1705–14. pmid: 15887449.
  • 8. Kelly A-M. The case for venous rather than arterial blood gases in diabetic ketoacidosis. Emergency Medicine Australasia. 2006; 18(1): pp. 64–67. doi: 10.1111/j.1742-6723.2006.00803.x.
  • 9. Orban JC, Maizière EM, Ghaddab A, Van Obberghen E, Ichai C. Incidence and characteristics of acute kidney injury in severe diabetic ketoacidosis. PLoS ONE. 2014; 9(10): p. e110925. doi: 10.1371/journal.pone.0110925.
  • 10. Gosmanov AR, Gosmanova EO, Kitabchi AE, et al. Hyperglycemic Crises: Diabetic Ketoacidosis (DKA), And Hyperglycemic Hyperosmolar State (HHS). endotext.org. 2018. pmid: 25905280.
  • 11. Kamalakannan D. Diabetic ketoacidosis in pregnancy. Postgrad Med J. 2003; 79(934): pp. 454–457. doi: 10.1136/pmj.79.934.454.
  • 12. 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): pp. 3123–3128. doi: 10.1111/j.1572-0241.2000.03279.x.
  • 13. Van Ness-Otunnu R, Hack JB. Hyperglycemic Crisis. J Emerg Med. 2013; 45(5): pp. 797–805. doi: 10.1016/j.jemermed.2013.03.040.
  • 14. Cardoso L, Vicente N, Rodrigues D, Gomes L, Carrilho F. Controversies in the management of hyperglycaemic emergencies in adults with diabetes. Metabolism. 2017; 68: pp. 43–54. doi: 10.1016/j.metabol.2016.11.010.
  • 15. Kitabchi AE, Umpierrez GE, Fisher JN, Murphy MB, Stentz FB. Thirty Years of Personal Experience in Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. The Journal of Clinical Endocrinology & Metabolism. 2008; 93(5): pp. 1541–1552. doi: 10.1210/jc.2007-2577.
  • 16. Savage MW, Dhatariya KK, Kilvert A, et al. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabetic Medicine. 2011; 28(5): pp. 508–515. doi: 10.1111/j.1464-5491.2011.03246.x.
  • 17. American Diabetes Association. Diabetes Care in the Hospital: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2017; 41(Supplement 1): pp. S144–S151. doi: 10.2337/dc18-s014.
  • Avichal A. Hyperosmolar Hyperglycemic State. In: Griffing GT. Hyperosmolar Hyperglycemic State. New York, NY: WebMD. https://emedicine.medscape.com/article/1914705. Updated March 26, 2017. Accessed October 25, 2018.
  • Matz R. Management of the hyperosmolar hyperglycemic syndrome. Am Fam Physician. 1999; 60(5): pp. 1468–1476. url: https://www.aafp.org/afp/1999/1001/p1468.html.
  • Crum-Clanflone NF. Mucormycosis. In: Mucormycosis. New York, NY: WebMD. http://emedicine.medscape.com/article/222551-overview#showall. Updated April 3, 2015. Accessed February 14, 2017.
  • Kitabchi AE, Wall BM. Management of diabetic ketoacidosis. Am Fam Physician. 1999; 60(2): pp. 455–64. pmid: 10465221.
  • Hamdy O. Diabetic Ketoacidosis. In: Diabetic Ketoacidosis. New York, NY: WebMD. http://emedicine.medscape.com/article/118361-overview. Updated January 25, 2017. Accessed February 14, 2017.
  • Blouin D. Too much of a good thing: Management of diabetic ketoacidosis in adults. Can Fam Physician. 2012; 58(1): pp. 55–7. pmid: 22267622.
  • Brunzel NA. Fundamentals of Urine and Body Fluid Analysis. Amsterdam, The Netherlands: Elsevier Health Sciences; 2016.
  • Handelsman Y, Henry RR, Bloomgarden ZT, et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF SGLT-2 INHIBITORS AND DIABETIC KETOACIDOSIS. Endocrine Practice. 2016; 22(6): pp. 753–762. doi: 10.4158/ep161292.ps.
  • Mehta A, Emmett M. Fasting Ketosis and Alcoholic Ketoacidosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/fasting-ketosis-and-alcoholic-ketoacidosis. Last updated November 1, 2016. Accessed October 28, 2017.
  • Hirsch IB, Emmett M. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic-state-in-adults-treatment?source=search_result&search=treatment+of+dka&selectedTitle=1~150. Last updated January 13, 2017. Accessed February 14, 2017.
last updated 06/29/2020
{{uncollapseSections(['_I052h', '0r0efh', 'Yr0nfh', 'br0Hfh', '1r02Th', '8m1Ohh0', 'fT1kJT0', 'um1phh0', 'yVcdCY0'])}}