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Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis

Irl B Hirsch, MD
Michael Emmett, MD
Section Editor
David M Nathan, MD
Deputy Editor
Jean E Mulder, MD


Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also known as hyperosmotic hyperglycemic nonketotic state [HHNK]) are two of the most serious acute complications of diabetes. DKA is characterized by ketoacidosis and hyperglycemia, while HHS usually has more severe hyperglycemia but no ketoacidosis (table 1). Each represents an extreme in the spectrum of hyperglycemia.

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 "Clinical features and diagnosis of diabetic ketoacidosis in children and adolescents".)

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Literature review current through: Nov 2017. | This topic last updated: Dec 07, 2016.
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  1. Kitabchi AE, Razavi L.Hyperglycemic Crises: Diabetic Ketoacidosis (DKA), And Hyperglycemic Hyperosmolar State (HHS). In: http://www.endotext.org/diabetes/diabetes24/diabetesframe24.htm (Accessed on January 30, 2013).
  2. Randall L, Begovic J, Hudson M, et al. Recurrent diabetic ketoacidosis in inner-city minority patients: behavioral, socioeconomic, and psychosocial factors. Diabetes Care 2011; 34:1891.
  3. Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med 1991; 6:495.
  4. Wachtel TJ. The diabetic hyperosmolar state. Clin Geriatr Med 1990; 6:797.
  5. Wachtel TJ, Silliman RA, Lamberton P. Prognostic factors in the diabetic hyperosmolar state. J Am Geriatr Soc 1987; 35:737.
  6. Kitabchi AE, Murphy MB. Consequences of insulin deficiency. In: Atlas of Diabetes, 4th, Skyler J (Ed), Springer US, New York 2012. p.39.
  7. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19 Suppl 1:1.
  8. Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab 2015; 100:2849.
  9. Warner EA, Greene GS, Buchsbaum MS, et al. Diabetic ketoacidosis associated with cocaine use. Arch Intern Med 1998; 158:1799.
  10. 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; 13:22.
  11. Polonsky WH, Anderson BJ, Lohrer PA, et al. Insulin omission in women with IDDM. Diabetes Care 1994; 17:1178.
  12. Peden NR, Braaten JT, McKendry JB. Diabetic ketoacidosis during long-term treatment with continuous subcutaneous insulin infusion. Diabetes Care 1984; 7:1.
  13. Pańkowska E, Błazik M, Dziechciarz P, et al. Continuous subcutaneous insulin infusion vs. multiple daily injections in children with type 1 diabetes: a systematic review and meta-analysis of randomized control trials. Pediatr Diabetes 2009; 10:52.
  14. Daugirdas JT, Kronfol NO, Tzamaloukas AH, Ing TS. Hyperosmolar coma: cellular dehydration and the serum sodium concentration. Ann Intern Med 1989; 110:855.
  15. Fulop M, Tannenbaum H, Dreyer N. Ketotic hyperosmolar coma. Lancet 1973; 2:635.
  16. Kitabchi AE, Fisher JN. Insulin therapy of diabetic ketoacidosis: Physiologic versus pharmacologic doses of insulin and their routes of administration. In: Handbook of Diabetes Mellitus, Brownlee M (Ed), Garland ATPM Press, New York 1981. p.95.
  17. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995; 79:39.
  18. Maccario M. Neurological dysfunction associated with nonketotic hyperglycemia. Arch Neurol 1968; 19:525.
  19. Guisado R, Arieff AI. Neurologic manifestations of diabetic comas: correlation with biochemical alterations in the brain. Metabolism 1975; 24:665.
  20. Lavin PJ. Hyperglycemic hemianopia: a reversible complication of non-ketotic hyperglycemia. Neurology 2005; 65:616.
  21. Harden CL, Rosenbaum DH, Daras M. Hyperglycemia presenting with occipital seizures. Epilepsia 1991; 32:215.
  22. Nyenwe EA, Razavi LN, Kitabchi AE, et al. Acidosis: the prime determinant of depressed sensorium in diabetic ketoacidosis. Diabetes Care 2010; 33:1837.
  23. Malone ML, Gennis V, Goodwin JS. Characteristics of diabetic ketoacidosis in older versus younger adults. J Am Geriatr Soc 1992; 40:1100.
  24. Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care 2002; 17:63.
  25. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335.
  26. Barrett EJ, DeFronzo RA. Diabetic ketoacidosis: diagnosis and treatment. Hosp Pract (Off Ed) 1984; 19:89.
  27. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001; 24:131.
  28. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine (Baltimore) 1972; 51:73.
  29. Munro JF, Campbell IW, McCuish AC, Duncan LJ. Euglycaemic diabetic ketoacidosis. Br Med J 1973; 2:578.
  30. Burge MR, Hardy KJ, Schade DS. Short-term fasting is a mechanism for the development of euglycemic ketoacidosis during periods of insulin deficiency. J Clin Endocrinol Metab 1993; 76:1192.
  31. Eisenbarth GS, Polonsky KS, Buse JB. Type 1 diabetes mellitus: Acute diabetic emergencies: Diabetic ketoacidosis. In: Williams Textbook of Endocrinology, Larsen PR, Kronenberg HM, Melmed S, Polonsky KS (Eds), Elsevier Science, Philadelphia 2003. p.1500.
  32. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999; 15:412.
  33. Sheikh-Ali M, Karon BS, Basu A, et al. Can serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 2008; 31:643.
  34. Wiggam MI, O'Kane MJ, Harper R, et al. Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study. Diabetes Care 1997; 20:1347.
  35. Porter WH, Yao HH, Karounos DG. Laboratory and clinical evaluation of assays for beta-hydroxybutyrate. Am J Clin Pathol 1997; 107:353.
  36. Fulop M, Murthy V, Michilli A, et al. Serum beta-hydroxybutyrate measurement in patients with uncontrolled diabetes mellitus. Arch Intern Med 1999; 159:381.
  37. Smith SW, Manini AF, Szekely T, Hoffman RS. Bedside detection of urine beta-hydroxybutyrate in diagnosing metabolic acidosis. Acad Emerg Med 2008; 15:751.
  38. Bektas F, Eray O, Sari R, Akbas H. Point of care blood ketone testing of diabetic patients in the emergency department. Endocr Res 2004; 30:395.
  39. DeFronzo RA, Matzuda M, Barret E. Diabetic ketoacidosis: a combined metabolic-nephrologic approach to therapy. Diabetes Rev 1994; 2:209.
  40. Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore) 1986; 65:163.
  41. Khardori R, Soler NG. Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases and brief review. Am J Med 1984; 77:899.
  42. Phillips PA, Bretherton M, Johnston CI, Gray L. Reduced osmotic thirst in healthy elderly men. Am J Physiol 1991; 261:R166.
  43. Kaminska ES, Pourmotabbed G. Spurious laboratory values in diabetic ketoacidosis and hyperlipidemia. Am J Emerg Med 1993; 11:77.
  44. Rumbak MJ, Hughes TA, Kitabchi AE. Pseudonormoglycemia in diabetic ketoacidosis with elevated triglycerides. Am J Emerg Med 1991; 9:61.
  45. Emmett M. Case 6: Diabetes and Acidosis. In: NephSAP: Nephrology Self-Assessment Program: Fluid, Electrolyte, and Acid-Base Disturbances, Sterns RH, Emmett M (Eds), The American Society of Nephrology 2013. Vol 12, No 3, p.191.
  46. Graber ML, Quigg RJ, Stempsey WE, Weis S. Spurious hyperchloremia and decreased anion gap in hyperlipidemia. Ann Intern Med 1983; 98:607.
  47. Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann Intern Med 1978; 88:681.
  48. Abramson E, Arky R. Diabetic acidosis with initial hypokalemia. Therapeutic implications. JAMA 1966; 196:401.
  49. Murthy K, Harrington JT, Siegel RD. Profound hypokalemia in diabetic ketoacidosis: a therapeutic challenge. Endocr Pract 2005; 11:331.
  50. Arora S, Cheng D, Wyler B, Menchine M. Prevalence of hypokalemia in ED patients with diabetic ketoacidosis. Am J Emerg Med 2012; 30:481.
  51. Atchley DW, Loeb RF, Richards DW, et al. ON DIABETIC ACIDOSIS: A Detailed Study of Electrolyte Balances Following the Withdrawal and Reestablishment of Insulin Therapy. J Clin Invest 1933; 12:297.
  52. Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus levels in diabetic ketoacidosis. Am J Med 1985; 79:571.
  53. Shen T, Braude S. Changes in serum phosphate during treatment of diabetic ketoacidosis: predictive significance of severity of acidosis on presentation. Intern Med J 2012; 42:1347.
  54. Molitch ME, Rodman E, Hirsch CA, Dubinsky E. Spurious serum creatinine elevations in ketoacidosis. Ann Intern Med 1980; 93:280.
  55. Kemperman FA, Weber JA, Gorgels J, et al. The influence of ketoacids on plasma creatinine assays in diabetic ketoacidosis. J Intern Med 2000; 248:511.
  56. 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; 95:3123.
  57. Warshaw AL, Feller ER, Lee KH. On the cause of raised serum-amylase in diabetic ketoacidosis. Lancet 1977; 1:929.
  58. Vinicor F, Lehrner LM, Karn RC, Merritt AD. Hyperamylasemia in diabetic ketoacidosis: sources and significance. Ann Intern Med 1979; 91:200.
  59. Vantyghem MC, Haye S, Balduyck M, et al. Changes in serum amylase, lipase and leukocyte elastase during diabetic ketoacidosis and poorly controlled diabetes. Acta Diabetol 1999; 36:39.
  60. Kjaergaard JJ, Salling N, Magid E, Ditzel J. Serum amylase during recovery from diabetic ketoacidosis. Diabete Metab 1984; 10:25.
  61. Nair S, Yadav D, Pitchumoni CS. Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA. Am J Gastroenterol 2000; 95:2795.
  62. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 2004; 53:2079.
  63. Nematollahi LR, Taheri E, Larijani B, et al. Catecholamine-induced leukocytosis in acute hypoglycemic stress. J Investig Med 2007; 55:S262.
  64. 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.
  65. Weidman SW, Ragland JB, Fisher JN Jr, et al. Effects of insulin on plasma lipoproteins in diabetic ketoacidosis: evidence for a change in high density lipoprotein composition during treatment. J Lipid Res 1982; 23:171.
  66. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th, McGraw-Hill, New York 2001. p.809-815.
  67. Morris LR, Kitabchi AE. Efficacy of low-dose insulin therapy for severely obtunded patients in diabetic ketoacidosis. Diabetes Care 1980; 3:53.
  68. Szeto CC, Li KY, Ko GT, et al. Acromegaly in a woman presenting with diabetic ketoacidosis and insulin resistance. Int J Clin Pract 1997; 51:476.
  69. Shah P, Isley WL. Ketoacidosis during a low-carbohydrate diet. N Engl J Med 2006; 354:97.
  70. Reichard GA Jr, Owen OE, Haff AC, et al. Ketone-body production and oxidation in fasting obese humans. J Clin Invest 1974; 53:508.
  71. Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006; 26:1.
  72. Mahoney CA. Extreme gestational starvation ketoacidosis: case report and review of pathophysiology. Am J Kidney Dis 1992; 20:276.
  73. Wrenn KD, Slovis CM, Minion GE, Rutkowski R. The syndrome of alcoholic ketoacidosis. Am J Med 1991; 91:119.