Table of Contents

 

Hyperglycemic emergencies – diabetic ketoacidosis (DKA) and the hyperosmolar hyperglycemic state (HHS) – are common presentations in the ED that require swift, specialized management strategies. Uncovering the precipitating event is critical to management, as morbidity and mortality are related more to the trigger than the DKA/HHS itself.

What are the “five Is” triggers of DKA/HHS?

What causes abdominal pain in acidosis, and how will the presentation differ between DKA, HHS, and other causes (such as appendicitis)?

Why should volume resuscitation always be started before giving insulin?

What does the evidence show regarding aggressive versus nonaggressive dosing of IV fluids?

Why should you be especially cautious when giving fluids to patients with HHS?

When should you start adding dextrose to the IV fluid?

What is the latest evidence on the value of giving an insulin bolus?

What are the cautions that need to be observed when administering potassium?

Under what circumstances should sodium bicarbonate be administered?

Why is euglycemic diabetic ketoacidosis becoming increasingly common?

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Etiology and Pathophysiology
   1. Precipitating Causes
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. History
   2. Physical Examination
9. Diagnostic Studies
   1. Bedside Studies
      1. Point-of-Care Glucose
      2. Electrocardiogram
   2. Laboratory Testing
      1. Chemistry Panel
         • Anion Gap
         • Potassium
         • Sodium
      2. Blood Gas
      3. Serum Osmolality
      4. Ketones
      5. Complete Blood Cell Count
      6. Urinalysis
      7. Cultures
      8. Amylase and Lipase
   3. Imaging
10. Treatment
    1. Intravenous Fluids
       1. The First Hour
       2. Ongoing Rehydration
       3. Which Crystalloid is Best? Normal Saline Versus Balanced Crystalloids
       4. Adding Dextrose to Fluids
    2. Insulin
       1. Bolus Versus Drip
       2. Transitioning Off the Insulin Infusion
       3. Long-Acting Insulin
    3. Potassium
    4. Sodium Bicarbonate
    5. Phosphate
11. Special Populations and Circumstances
    1. Pediatric Patients
    2. Cerebral Edema
    3. Airway Management in Diabetic Ketoacidosis
    4. Euglycemic Diabetic Ketoacidosis
    5. Refractory Acidosis/Failure to Improve
    6. Dialysis Patients
12. Controversies and Cutting Edge
    1. Intravenous Versus Subcutaneous Insulin
    2. Thrombosis and Anticoagulation
13. Disposition
14. Summary
15. Time- and Cost-Effective Strategies
16. Risk Management Pitfalls for Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in the Emergency Department
17. Case Conclusions
18. Clinical Pathway for Emergency Department Management of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State
19. Tables
    1. Table 1. “Five Is” Precipitating Diabetic Ketoacidosis/Hyperosmolar Hyperglycemic State
    2. Table 2. Common Causes of Ketoacidosis
    3. Table 3. Differential Diagnosis of Wide Anion-Gap Metabolic Acidosis (“MUDPILES”)
    4. Table 4. Initial Diagnostic Workup for Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State
    5. Table 5. Diabetic Ketoacidosis Severity
    6. Table 6. Key Laboratory Findings in DKA Versus HHS
    7. Table 7. Five Treatments for Hyperglycemic Emergencies
    8. Table 8. Recommended Potassium Replacement in the First Hours of Diabetic Ketoacidosis
    9. Table 9. Subcutaneous Insulin Dosing
20. References

Abstract

For patients presenting with suspected diabetic ketoacidosis (DKA) and the hyperosmolar hyperglycemic state (HHS) understanding of the etiology and pathophysiology will ensure optimal emergency management. Morbidity and mortality is most often due to the underlying precipitating cause, which may include infection, infarction/ischemia, noncompliance with insulin therapy, pregnancy, and dietary indiscretion. Current guidelines are based primarily on expert opinion and consensus statements, but more recent evidence suggests that recommendations related to arterial blood gas, insulin bolus, and IV fluid replacement should be re-evaluated. This issue presents an approach to DKA and HHS management based on current evidence, with a simplified pathway for emergency department management.

Case Presentations

Midway through your shift, a 23-year-old woman arrives by EMS. She is ill-appearing, tachypneic, and has a distinct odor you recognize as ketones. Her bedside glucose is 680 mg/dL. You suspect DKA, but wonder what led to it. You know that starting insulin and fluids is indicated, but you wonder whether insulin should be administered as an IV bolus, whether insulin should be given before or after IV fluids, what fluids are most appropriate, or whether you should just proceed with subcutaneous insulin. As if these questions were not enough, your first-year resident tells you the patient has a pH of 7.1 and asks if she needs sodium bicarbonate. He also asks if she should be intubated, since she is breathing so hard…

A 76-year-old man arrives with his wife via EMS. He is slow to respond to you, and his wife says that over the past 10 days he has become increasingly weak, stopped walking, and this morning would not talk to her. His vital signs are: blood pressure, 90/60 mm Hg; pulse, 110 beats/min; and respiratory rate, 16 breaths/min. He is afebrile and has an oxygen saturation of 96% on room air. A fingerstick glucose reads high, and a venous pH is 7.38. You wonder whether his initial therapy should be similar to that for DKA, even with his normal pH, and whether 0.45% saline is the ideal fluid in his hyperosmolar state…

A 30-year-old man presents in DKA. He is a known type 1 diabetic and has an insulin pump that he says has been alarming. He is awake, alert, and his triage vital signs are: blood pressure, 110/60 mm Hg; pulse, 121 beats/min; respiratory rate, 26 breaths/min, temperature, 35.6°C (96°F); and oxygen saturation, 100% on room air. His fingerstick glucose reads high, and his venous pH is 7.12. You turn off his insulin pump and begin him on “standard therapy” of an IV fluid bolus of 20 mL/kg of normal saline followed by 500 mL/hr, 6 units of regular insulin IV, and put him on an insulin drip of 6 units/hr. The patient’s vital signs begin to stabilize, with his blood pressure rising and pulse and respirations slowing towards normal. Three hours after ED entry, the patient has a cardiac arrest and is defibrillated out of torsades de pointes. You wonder what went wrong …

Introduction

As the incidence of diabetes has risen over the past several decades, so too have the number of patients who present to the emergency department (ED) with diabetes-related emergencies, including diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS).¹ DKA alone is responsible for more than 140,000 hospital admissions per year in the United States, with an average length of stay of 3.4 days. This number has increased by 30% over the past decade.^2,3 In 2014, charges for DKA hospitalization amounted to $5.1 billion.⁴ The emergency clinician must be prepared to identify and promptly treat these conditions because, without intervention, morbidity and mortality are high. Being knowledgeable about common precipitants and rapidly identifying their presence is essential, as morbidity is primarily related to the triggering event. The metabolic derangements that occur in these conditions require careful treatment, but the treatment algorithms can seem overly complex. Having a simplified, systematic approach to patients with these conditions will improve efficiency in managing these emergencies.

Unfortunately, consensus statements and guidelines often lag behind recent data. Indeed, the most recent American Diabetes Association (ADA) consensus statement is over 10 years old and thus does not incorporate newer literature that supports changes in practice. This issue of Emergency Medicine Practice focuses on the management of the common diabetic hyperglycemic emergencies, DKA and HHS, and provides treatment strategies that are based on the best available evidence.

Critical Appraisal of the Literature

A literature search of PubMed was performed without any date filters using the search terms diabetic ketoacidosis, DKA, hyperosmolar hyperglycemic state, and HHS. The initial search produced over 2 million results. The majority of the results were review articles, case studies, and expert opinion. Results were narrowed by filtering for clinical trials published in the past 10 years and review articles published in the past 5 years. Consensus statements released by the ADA in 2009 and the International Society for Pediatric and Adolescent Diabetes (ISPAD) in 2018 were also reviewed.^1,5 The ADA and ISPAD guidelines are primarily expert opinion and were developed from studies through their publication years. References used by consensus statements were also evaluated. Final selections were made based on clinical relevance. During the literature search, particular attention was given to prospective studies; however, there are only a few randomized trials evaluating the treatment of DKA and HHS in the ED, and those that do exist tend to be quite small (approximately 50 patients or fewer).^6-8

Etiology and Pathophysiology

DKA and HHS are 2 distinct entities that exist on a spectrum of hyperglycemic emergencies. DKA typically occurs in younger patients, primarily those with type 1 diabetes (though type 2 diabetics can also develop DKA, particularly when concomitant illness is present). HHS is much more likely to occur in elderly patients with type 2 diabetes who have multiple underlying comorbidities, though it is being diagnosed increasingly in younger adults and even in children. In more than one-third of patients, these conditions overlap.¹

Although the exact pathophysiologic mechanisms of DKA and HHS are complex, in general, the pathogenesis begins with insufficient insulin and high levels of counterregulatory hormones (glucagon, cortisol, growth hormone, and catecholamines). This results in hyperglycemia, which promotes an osmotic diuresis, leading to dehydration and electrolyte loss. In both conditions, insulin levels are insufficient for peripheral tissue glucose utilization, resulting in hyperglycemia.

In DKA, there is an absolute insulin deficiency, in which glucose cannot be moved into the cell. To meet the body’s energy needs, fats are metabolized into free fatty acids that are then converted in the liver to ketone bodies. The 2 main ketones, beta-hydroxybutyrate and acetoacetate, are both strong acids, and their presence creates a significant metabolic acidosis in DKA.

Whereas there is an absolute insulin deficiency in DKA, in HHS, there is only a relative insulin deficiency. Endogenous insulin production is adequate to prevent a total catabolic state. Therefore, lipolysis, ketone body production, and significant acidosis do not occur; however, there is insufficient insulin to permit tissue utilization of glucose, and thus hyperglycemia still occurs.¹

In both states, the resultant hyperglycemia creates an osmotic diuresis in which tremendous amounts of water are lost through diuresis. It is estimated that there is a 3-L to 6-L fluid deficit in most adult cases of DKA and a 9-L to 12-L fluid deficit in HHS. In children, water loss is estimated to average 70 mL/kg in DKA and 12% to 15% of body weight in HHS.⁵ Fluid losses tend to be greater in HHS for several reasons, including the prolonged course of onset, delay in recognition, and the fact that many of these patients are elderly, bedridden patients with impaired thirst response. At least 20% of patients presenting with HHS have no documented history of diabetes.¹ In addition to fluid loss, osmotic diuresis also causes urinary wasting of electrolytes, resulting in large total body deficits of potassium, magnesium, and phosphate.

Counterregulatory hormones also play a key role in the development of the metabolic derangements seen in these conditions. In both states, there is an increase in cortisol, catecholamines, glucagon, and growth hormone. Together, they promote gluconeogenesis, glycogenolysis, and proteolysis, compounding the development of hyperglycemia.

Precipitating Causes

Both DKA and HHS are usually triggered by a precipitating cause. The major causes of DKA and HHS can be remembered as the “Five Is.” (See Table 1.)

Risk Management Pitfalls for Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in the Emergency Department

1. “He was very hyperglycemic, so I started insulin right away.”

Starting insulin before the potassium level is known can result in dangerous arrhythmias, such as torsades de pointes, as insulin drives potassium into cells, lowering potassium further. A smaller percentage of patients will present with hypokalemia on arrival. Additionally, initiating volume resuscitation before giving insulin has several benefits, including decreasing serum glucose and restoring renal perfusion.

3. “He was complaining of right-sided weakness, but I assumed it was from being so hyperglycemic.”

While hyperosmolarity can cause neurological deficits, including focal deficits, patients with focal deficits from hyperosmolarity should also have changes in mental status. Assume stroke until proven otherwise.

8. “He was breathing fast, so I intubated him to reduce his work of breathing and metabolic demands.”

DKA patients have a respiratory alkalosis to compensate for their metabolic acidosis. Intubating these patients can be dangerous. During periods of apnea, their pCO₂ can rise rapidly. Additionally, after intubation it can be difficult to match pre-intubation minute ventilation. Avoid intubation unless it becomes absolutely necessary; for example, for airway protection or in cases where extreme fatigue is interfering with the patient’s minute ventilation and ability to compensate for metabolic acidosis.

Tables

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.

1. Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343. (Review article, ADA consensus guidelines)
2. Fayfman M, Pasquel FJ, Umpierrez GE. Management of hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Med Clin North Am. 2017;101(3):587-606. (Review)
3. Nyenwe EA, Kitabchi AE. The evolution of diabetic ketoacidosis: an update of its etiology, pathogenesis and management. Metabolism. 2016;65(4):507-521. (Review)
4. Desai D, Mehta D, Mathias P, et al. Health care utilization and burden of diabetic ketoacidosis in the US. Over the past decade: a nationwide analysis. Diabetes Care. 2018;41(8):1631-1638. (National database review)
5. Wolfsdorf JI, Glaser N, Agus M, et al. ISPAD Clinical Practice Consensus Guidelines 2018: diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Pediatr Diabetes. 2018;19 Suppl 27:155-177. (ISPAD clinical practice guidelines)
6. Mahler SA, Conrad SA, Wang H, et al. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011;29(6):670-674. (Randomized controlled trial; 45 patients)
7. Van Zyl DG, Rheeder P, Delport E. Fluid management in diabetic-acidosis--Ringer’s lactate versus normal saline: a randomized controlled trial. QJM. 2012;105(4):337-343. (Randomized controlled trial; 57 patients)
8. Goyal N, Miller JB, Sankey SS, et al. Utility of initial bolus insulin in the treatment of diabetic ketoacidosis. J Emerg Med. 2010;38(4):422-427. (Prospective; 157 patients)
9. Padmanabhan S, Jiang S, McLean M, et al. Effect of pregnancy on insulin requirements differs between type 1 and type 2 diabetes: a cohort study of 222 pregnancies. Aust N Z J Obstet Gynaecol. 2016;56(4):352-357. (Retrospective cohort study; 222 pregnancies)
10. Marik PE, Bellomo R. Stress hyperglycemia: an essential survival response! Crit Care. 2013;17(2):305.
11. Khafaji HA, Suwaidi JM. Atypical presentation of acute and chronic coronary artery disease in diabetics. World J Cardiol. 2014;6(8):802-813. (Review)
12. 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(1):22-29. (Retrospective; 168 patients)
13. Peden NR, Braaten JT, McKendry JB. Diabetic ketoacidosis during long-term treatment with continuous subcutaneous insulin infusion. Diabetes Care. 1984;7(1):1-5. (Retrospective; 101 patients)
14. Dogan ADA, Jorgensen UL, Gjessing HJ. Diabetic ketoacidosis among patients treated with continuous subcutaneous insulin infusion. J Diabetes Sci Technol. 2017;11(3):631-632. (Retrospective; 205 patients)
15. Nyenwe EA, Razavi LN, Kitabchi AE, et al. Acidosis: the prime determinant of depressed sensorium in diabetic ketoacidosis. Diabetes Care. 2010;33(8):1837-1839. (Retrospective; 216 cases)
16. Fugate JE, Rabinstein AA. Absolute and relative contraindications to IV rt-PA for acute ischemic stroke. Neurohospitalist. 2015;5(3):110-121. (Review)
17. Tandberg D, Sklar D. Effect of tachypnea on the estimation of body temperature by an oral thermometer. N Engl J Med. 1983;308(16):945-946. (Prospective; 310 patients)
18. Barnett BJ, Nunberg S, Tai J, et al. Oral and tympanic membrane temperatures are inaccurate to identify fever in emergency department adults. West J Emerg Med. 2011;12(4):505-511. (Prospective; 457 patients)
19. Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care. 2002;17(1):63-67. (Prospective; 200 patients)
20. Campbell IW, Duncan LJ, Innes JA, et al. Abdominal pain in diabetic metabolic decompensation. Clinical significance. JAMA. 1975;233(2):166-168. (Retrospective; 211 patients)
21. Beigelman PM. Potassium in severe diabetic ketoacidosis. Am J Med. 1973;54(4):419-420. (Retrospective; 340 patients)
22. Penne EL, Thijssen S, Raimann JG, et al. Correction of serum sodium for glucose concentration in hemodialysis patients with poor glucose control. Diabetes Care. 2010;33(7):e91. (Restrospective; 208 patients)
23. Ma OJ, Rush MD, Godfrey MM, et al. Arterial blood gas results rarely influence emergency physician management of patients with suspected diabetic ketoacidosis. Acad Emerg Med. 2003;10(8):836-841. (Prospective observational study; 200 patients)
24. Slovis CM, Mork VG, Slovis RJ, et al. Diabetic ketoacidosis and infection: leukocyte count and differential as early predictors of serious infection. Am J Emerg Med. 1987;5(1):1-5. (Retrospective; 153 patients)
25. Yadav D, Nair S, Norkus EP, et al. Nonspecific hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities. Am J Gastroenterol. 2000;95(11):3123-3128. (Prospective; 150 patients)
26. Manikkan AT. Hyperlipasemia in diabetic ketoacidosis. Clinical Diabetes. 2013;31(1):31-32. (Case study)
27. Waldhausl W, Kleinberger G, Korn A, et al. Severe hyperglycemia: effects of rehydration on endocrine derangements and blood glucose concentration. Diabetes. 1979;28(6):577-584. (Observational; 10 patients)
28. Joint British Diabetes Societies Inpatient Care Group. The management of diabetic ketoacidosis in adults. 2013; 2nd. Accessed January 10, 2020. (Practice guidelines)
29. Adrogué HJ, Barrero J, Eknoyan G. Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis. Use in patients without extreme volume deficit. JAMA. 1989;262(15):2108-2113. (Prospective; 23 patients)
30. Chua HR, Venkatesh B, Stachowski E, et al. Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. J Crit Care. 2012;27(2):138-145. (Retrospective; 23 patients )
31. Bergmann KR, Abuzzahab MJ, Nowak J, et al. Resuscitation with Ringer’s lactate compared with normal saline for pediatric diabetic ketoacidosis. Pediatr Emerg Care. 2018 Jul 16. [Epub ahead of print] (Retrospective pediatric study; 49,000 patients)
32. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829-839. (Randomized controlled trial; 15,000 patients)
33. 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. (Prospective; 61 patients)
34. Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med. 1986;105(6):836-840. (Randomized controlled trial; 21 patients)
35. Hale PJ, Crase J, Nattrass M. Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis. Br Med J (Clin Res Ed). 1984;289(6451):1035-1038. (Prospective randomized trial; 38 patients)
36. Okuda Y, Adrogue HJ, Field JB, et al. Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis. J Clin Endocrinol Metab. 1996;81(1):314-320. (Prospective; 7 patients)
37. Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med. 1999;27(12):2690-2693. (Retrospective; 39 patients)
38. Gamba G, Oseguera J, Castrejon M, et al. Bicarbonate therapy in severe diabetic ketoacidosis. A double blind, randomized, placebo controlled trial. Rev Invest Clin. 1991;43(3):234-238. (Randomized controlled trial; 20 patients)
39. Duhon B, Attridge RL, Franco-Martinez AC, et al. Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother. 2013;47(7-8):970-975. (Retrospective; 86 patients)
40. Chua HR, Schneider A, Bellomo R. Bicarbonate in diabetic ketoacidosis - a systematic review. Ann Intensive Care. 2011;1(1):23. (Systematic review; 44 articles)
41. Glaser N, Barnett P, McCaslin I, et al. 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. 2001;344(4):264-269. (Retrospective; 61 patients )
42. Lindsay R, Bolte RG. The use of an insulin bolus in low-dose insulin infusion for pediatric diabetic ketoacidosis. Pediatr Emerg Care. 1989;5(2):77-79. (Randomized controlled trial; 56 cases)
43. Worly JM, Fortenberry JD, Hansen I, et al. Deep venous thrombosis in children with diabetic ketoacidosis and femoral central venous catheters. Pediatrics. 2004;113(1 Pt 1):e57-e60. (Retrospective; 113 patients)
44. Wolfsdorf JI, Allgrove J, Craig ME, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2014;15 Suppl 20:154-179. (ISPAD clinical practice guidelines)
45. Kuppermann N, Ghetti S, Schunk JE, et al. Clinical trial of fluid infusion rates for pediatric diabetic ketoacidosis. N Engl J Med. 2018;378(24):2275-2287. (Prospective; 1389 cases)
46. Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. Diabetes Care. 2014;37(11):3124-3131. (Review)
47. Mosier JM, Joshi R, Hypes C, et al. The physiologically difficult airway. West J Emerg Med. 2015;16(7):1109-1117. (Review)
48. Kum-Nji JS, Gosmanov AR, Steinberg H, et al. Hyperglycemic, high anion-gap metabolic acidosis in patients receiving SGLT-2 inhibitors for diabetes management. J Diabetes Complications. 2017;31(3):611-614. (5 cases of SGLT2 euglycemic DKA)
49. Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849-2852. (Review)
50. Gelaye A, Haidar A, Kassab C, et al. Severe ketoacidosis associated with canagliflozin (Invokana): a safety concern. Case Rep Crit Care. 2016;2016:1656182. (Case report)
51. Goldenberg RM, Berard LD, Cheng AYY, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clin Ther. 2016;38(12):2654-2664. (Review)
52. Blau JE, Tella SH, Taylor SI, et al. Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data. Diabetes Metab Res Rev. 2017;33(8). (Database review)
53. Kumar S, Costello AJ, Colman PG. Fournier’s gangrene in a man on empagliflozin for treatment of type 2 diabetes. Diabet Med. 2017;34(11):1646-1648. (Case report)
54. Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. 2014;7:255-264. (Review)
55. Tzamaloukas AH, Ing TS, Siamopoulos KC, et al. Pathophysiology and management of fluid and electrolyte disturbances in patients on chronic dialysis with severe hyperglycemia. Semin Dial. 2008;21(5):431-439. (Review)
56. Umpierrez GE, Cuervo R, Karabell A, et al. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care. 2004;27(8):1873-1878. (Randomized prospective; 45 patients)
57. Umpierrez GE, Latif K, Stoever J, et al. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. Am J Med. 2004;117(5):291-296. (Randomized prospective; 40 patients)
58. Keenan CR, Murin S, White RH. High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses. J Thromb Haemost. 2007;5(6):1185-1190. (Retrospective; 2859 patients)
59. Scott AR, Joint British Diabetes Societies (JBDS) for Inpatient Care, JBDS hyperosmolar hyperglycaemic guidelines group, et al. Management of hyperosmolar hyperglycaemic state in adults with diabetes. Diabet Med. 2015;32(6):714-724. (Joint British societies’ HHS guidelines)