Diabetic Emergencies: New Strategies For An Old Disease

Table of Contents

 

1. Abstract
2. Case Presentations
3. Introduction for Diabetic Emergencies
4. Critical Appraisal Of The Literature for Diabetic Emergencies
5. Etiology And Pathophysiology for Diabetic Emergencies
   1. Diabetes Mellitus Type 1
   2. Diabetes Mellitus Type 2
   3. Diabetic Ketoacidosis
   4. Hyperosmolar Hyperglycemic State
6. Differential Diagnosis for Diabetic Emergencies
7. Prehospital Care for Diabetic Emergencies
   1. Hypoglycemia
   2. Hyperglycemia
8. Emergency Department Evaluation for Diabetic Emergencies
   1. History
   2. Physical Examination
9. Diagnostic Studies for Diabetic Emergencies
   1. Hypoglycemia
   2. Hyperglycemia
      1. Sodium And Serum Osmolality
      2. Serum Potassium
      3. Serum Phosphate
      4. Serum pH And Anion Gap
      5. Serum Glucose
      6. Serum Ketones
      7. Urine Ketones
10. Treatment for Diabetic Emergencies
    1. Diabetic Ketoacidosis
       1. Rehydration
       2. Insulin
          • Subcutaneous Insulin
       3. Correction Of Potassium
       4. Sodium Bicarbonate
    2. Hyperosmolar Hyperglycemic State
    3. Hypoglycemia
       1. Refractory Hypoglycemia
11. Special Circumstances for Diabetic Emergencies
    1. Cardiac Arrest
    2. Metformin-Induced Lactic Acidosis
    3. Management Of New-Onset Diabetes
12. Controversies And Cutting Edge
    1. New Oral Hypoglycemic Agent
13. Disposition for Diabetic Emergencies
    1. Diabetic Ketoacidosis
    2. Hyperosmolar Hyperglycemic State
    3. Hypoglycemia
14. Summary for Diabetic Emergencies
15. Clinical Pathway For Management Of Diabetic Ketoacidosis In The Emergency Department
16. Risk Management Pitfalls For Diabetic Emergencies
17. Time- And Cost-Effective Strategies For Diabetic Emergencies
18. Case Conclusions
19. Tables and Figures
    1. Table 1. Etiologies Of Hyperglycemia
    2. Table 2. Etiologies Of Hypoglycemia
    3. Table 3. Common Drugs And Their Effects On Serum Glucose
    4. Table 4. Diagnostic Testing Considerations In Hypoglycemia And Hyperglycemia
    5. Figure 1. Electrocardiogram In A Patient With Hyperkalemia, Showing A Sine Wave Pattern
    6. Figure 2. Electrocardiogram In The Same Patient After Administration Of Calcium Gluconate
20. References

Abstract

Diabetic emergencies are common presentations to the emergency department. It is estimated that diabetes affects 25.8 million people in the United States, at an annual total cost of over $174 billion. There are 2 general categories of diabetic emergencies: hyperglycemic and hypoglycemic. The hyperglycemic emergencies include diabetic ketoacidosis and hyperosmolar hyperglycemic state. Management of these conditions requires a careful hydration strategy to restore volume and improve perfusion, intravenous insulin therapy, and electrolyte monitoring. Management of hypoglycemia includes identification of the underlying etiology, oral food and/or glucose, intravenous dextrose, and consideration of glucagon. This review evaluates the current strategies for management of diabetic emergencies and offers new information regarding effective diagnostic strategies, selection of fluids for rehydration, correction of potassium, the use of subcutaneous insulin for mild hyperglycemia, and management of metformin-induced lactic acidosis.

Case Presentations

You walk into a busy Monday evening shift, and one of the nurses asks you to see a patient who has been waiting for several hours. The nurse states that the 26-year-old woman is sleepy, with a heart rate of 126 beats/min. He advises you that the patient has diabetes, for which she has been medically compliant by taking her insulin. The patient stated that she had not been feeling well for a few days, after which she developed fever, nausea, and vomiting. As you enter the room, you observe the patient retching. You note her respiratory rate is 32 breaths/min, her heart rate is 124 beats/min, and that her blood pressure is 88/50 mm Hg. You start considering your differential and wonder if this presentation is due to her diabetes or if there is something else you might be missing.

After giving your orders on the first patient, a nurse requests that you see a 56-year-old man who is unresponsive. You enter the room and note that the patient's blood pressure is 110/60 mm Hg, respiratory rate is 16 breaths/ min, and heart rate is 110 beats/min. He also appears mildly diaphoretic. As you glance though the patient’s chart, you note that he has a history of diabetes. There are no family or friends in the patient’s room, and EMS has already departed to another call. Since the airway is always your first priority in unresponsive patients, you begin to prepare for intubation when a medical student asks what the patient’s finger-stick glucose was.

Your next patient is an 87-year-old man with diabetes who has been compliant with his medicines and is being treated for pneumonia that developed about a week ago. His primary care physician started him on an oral antibiotic and sent him home with strict instructions to return if his symptoms worsened. He has been taking his antibiotics as prescribed; however, he continues to have fevers, and today he felt progressive, generalized weakness with malaise. His family notes that he has also been getting more confused over the last few days. You request a STAT finger-stick glucose and realize that this Monday shift is going to be a long one!

Introduction for Diabetic Emergencies

Diabetes is estimated to affect 6% of the world’s population, with more than 97% having type 2 diabetes.¹ The prevalence of diabetes has increased almost 700% in the United States since 1958. In 2010, diabetes affected the lives of 25.8 million people in the United States, which is about 8.3% of the United States population. Of those affected, about 18.8 million carry the diagnosis of diabetes, with 7 million people later being diagnosed as diabetic.¹

According to the Centers for Disease Control and Prevention (CDC), diabetes carried an annual cost of about $174 billion in 2007, with approximately $116 billion for direct medical costs and $58 billion for indirect costs (such as loss of wages, disability, and mortality). The cost to society is substantial, since patients with diabetes have twice the medical expenses compared to patients of a similar age without diabetes. In terms of mortality, the CDC recognizes diabetes as the seventh leading cause of death, and patients with diabetes have death rates 2 to 4 times higher than those without diabetes.¹ The morbidity associated with diabetes is also substantial. The risk for stroke is 2 to 4 times higher than for those without diabetes. Diabetes is the primary etiology of vision loss and blindness among adults in the United States.¹ Similarly, diabetes is the primary etiology of kidney failure. In 2008, 44% of all new cases of renal failure were attributable to diabetes.¹ Recent data estimate that 60% to 70% of people with diabetes also have nervous system injury from their disease.¹ Examples of nervous system injury include neuropathy of the hands and/or feet, erectile dysfunction, and gastroparesis. Neuropathy, combined with poor wound healing, contribute to lower-extremity amputation. About 60% of nontraumatic lower-extremity amputations are sequelae of diabetes.¹

With these financial and health impacts, diabetes carries substantial costs to both society and the individual. In the emergency department (ED), successful management of these patients reduces mortality and morbidity. This issue of Emergency Medicine Practice examines the best evidence available on the evaluation and management diabetic emergencies and provides best-practice management recommendations.

Critical Appraisal Of The Literature for Diabetic Emergencies

A literature review was conducted utilizing MEDLINE ® and PubMed. The following keywords were used for the MEDLINE® search; the number of articles that were identified are presented in parentheses: diabetic emergencies (73), diabetic ketoacidosis and treatment and hyperosmolar hyperglycemia (3), sulfonylurea and hypoglycemia (932), potassium and diabetic ketoacidosis (75), fluids and diabetic ketoacidosis (51), fluids and hyperosmolar hyperglycemia (0), diabetic ketoacidosis treatment (11), hyperosmolar hyperglycemia treatment (0), hypoglycemia treatment (30), sodium bicarbonate and diabetic ketoacidosis (95), and factitious hypoglycemia (67). The following keywords were used for the PubMed search: diabetic emergencies (421), diabetic ketoacidosis and treatment and hyperosmolar hyperglycemia (112), sulfonylurea and hypoglycemia (2099), potassium and diabetic ketoacidosis (78), fluids and diabetic ketoacidosis (65), fluids and hyperosmolar hyperglycemia (34), diabetic ketoacidosis treatment (3876), hyperosmolar hyperglycemia treatment (302), hypoglycemia treatment (18), sodium bicarbonate and diabetic ketoacidosis (131), and factitious hypoglycemia (129). Each of these articles was evaluated further only if written in English and based upon human studies. Once these criteria were applied, the articles were examined for relevance. The pertinent studies were then used as part of the review for this article.

In addition to these databases, the American College of Emergency Physicians clinical policies were reviewed, but no articles were found. Additionally, the Cochrane Library was searched for the following terms: DKA (36), diabetic ketoacidosis (3), hyperglycemia (15), and hyperosmolar hyperglycemia (0). Finally, the National Guideline Clearinghouse (www.guideline.gov) was searched for the following terms: DKA (18), diabetic ketoacidosis (19), hyperglycemia (88), and hyperosmolar hyperglycemia (12). Only articles written in English and based upon human studies were reviewed. Once these criteria were applied, the articles were examined for relevance.

There are many articles related to diabetic emergencies; however, most of these articles are reviews, and there are few well-designed studies to provide a high level of evidence on which to base clinical practice. Overall, the literature is based more upon consensus than on objective studies, with many of the evaluation and management strategies based more upon previous practice than on science. Recently, there have been several new research articles discussing evaluation and management strategies.^2-7

Risk Management Pitfalls For Diabetic Emergencies

1. “I ordered a serum ketone, and it was mildly elevated. I was told later that the patient was in severe DKA.” The preferred laboratory value to examine for DKA is beta-hydroxybutyrate. In DKA, the ratio of the beta-hydroxybutyrate to acetoacetate or acetone changes in response to the increased ketones. Instead of 1:1, it increases to as much as 5:1 of beta-hydroxybutyrate to acetoacetate. Beta-hydroxybutyrate will more accurately reflect whether the patient is in DKA.
2. “The elderly patient had HHS, but I thought the floor could handle him.” In patients with HHS, admission to the intensive care unit is prudent, given that they will be on insulin drips and because of their underlying medical conditions. If a patient has few or no underlying medical conditions and responds well to management in the ED as observed through laboratory tests and vital signs, then it may be reasonable to admit the patient to a step-down unit.
3. “The patient had family members with nausea, vomiting, and diarrhea. I didn’t think that his diabetes was the cause of his nausea and vomiting.” Have a low threshold for checking blood sugar and a basic metabolic profile. The etiology of the diabetic emergency can be from a viral illness or some other physiologic stressor.
4. “The patient had HHS, but also a history of congestive heart failure, so I started him on an insulin infusion but held back the fluids. I thought treating the hyperglycemia alone would help resolve the patient’s tachycardia.” Patients with HHS have an average deficit of 8 to 10 liters of fluid. Rehydration is a key initial management strategy in treating this ailment. Both hydration and insulin would have helped manage this patient’s pathology.
5. “The patient who had DKA received 9 liters of fluid and then started to develop mental status changes.” Although rare, cerebral edema does develop in adults. Using the correct rehydration may reduce the risk of this devastating illness.68 Mannitol may be considered once neurological symptoms occur.31,99 Additionally, fluid infusion rates should be decreased and the head of the bed should be elevated. An alternative to mannitol is hypertonic saline, which can be given at a dose of 5 to 10 mL/kg of 3% saline over 30 minutes.100,101 Risk Management Pitfalls For Diabetic Emergencies
6. “The patient’s potassium was elevated and he was in DKA, so I gave him kayexalate.” In DKA, the serum potassium may be elevated, but unless there are ECG changes, the management for the elevated potassium is to manage the DKA. The insulin infusion will allow the potassium to transition intracellularly, thereby decreasing the serum potassium. If the potassium is decreased prior to the insulin infusion, the patient may become hypokalemic and develop life-threatening dysrhythmias.
7. “The patient was diabetic, and I checked his serum glucose and it was not elevated; therefore, he could not be in DKA.” A patient may have DKA with a normal blood sugar. This pathology is referred to as euglycemic DKA. Typically, the patient has vomiting, but continues to use his/her insulin. In this situation, the beta-hydroxybutyrate levels will be crucial to the successful diagnosis of DKA.
8. “I knew the patient was in DKA, so I started the insulin infusion. I did not know that his potassium of 2.8 mEq/L was going to be problematic.” Patients in DKA tend to have a normal to low body potassium level. If the serum potassium is < 3.3 mEq/dL, then the initial management strategy is to administer fluids with potassium intravenously; once the serum potassium is ≥ 3.3 mEq/dL, then the insulin infusion can be initiated. If this is not done, the patient may develop life-threatening dysrhythmias from the hypokalemia. Repletion of potassium can be achieved by infusing potassium at 20 to 30 mEq/h, usually mixing 40 to 60 mEq of potassium in a liter of half-normal saline.67,68
9. “The patient’s blood sugar improved and she was tolerating food, so I discharged her. She was on a sulfonylurea, but her vitals looked fine.” In diabetics who are using sulfonylureas, admission is generally advisable due to the high risk of recurrence of hypoglycemia. This is especially true with the longer-acting sulfonylureas.
10. “There were no intensive care unit beds and the ED was very busy. I kept the patient with DKA on the normal saline infusion and insulin, but I didn't expect him to become so hypoglycemic.” When the serum glucose is 200 mg/dL, consider decreasing the insulin infusion rate from 0.1 or 0.14 units/kg/h to 0.02 to 0.05 units/kg/h and adding dextrose to the infusing fluids. If this is not done, the patient’s glucose can drop too rapidly and hypoglycemia may ensue.

Tables and Figures

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 will be included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, will be noted by an asterisk (*) next to the number of the reference.

1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: Centers for Disease Control and Prevention; 2011.
2. Graz B, Dicko M, Willcox ML, et al. Sublingual sugar for hypoglycaemia in children with severe malaria: a pilot clinical study. Malar J. 2008;7:242. (Randomized nonblinded trial; 151 patients)
3. Barennes H, Valea I, Nagot N, et al. Sublingual sugar administration as an alternative to intravenous dextrose administration to correct hypoglycemia among children in the tropics. Pediatrics. 2005;116(5):e648-e653. (Randomized nonblinded trial; 69 patients)
4. Arora S, Henderson SO, Long T, et al. Diagnostic accuracy of point-of-care testing for diabetic ketoacidosis at emergencydepartment triage: beta-hydroxybutyrate versus the urine dipstick. Diabetes Care. 2011;34(4):852-854. (Prospective observational study; 516 patients)
5. 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 observational cohort chart review; 157 patients)
6. * Kitabchi AE, Murphy MB, Spencer J, et al. Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis? Diabetes Care. 2008;31(11):2081-2085. (Randomized prospective study; 47 patients)
7. 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 controlled trial; 40 patients)
8. Ganong WF. Review of Medical Physiology. 22nd ed. New York: The McGraw-Hill Companies; 2005.
9. Ganong WF. Ganong’s Review of Medical Physiology. 24th ed. New York: The McGraw Hill Companies; 2012.
10. Lin MV, Bishop G, Benito-Herrero M. Diabetic ketoacidosis in type 2 diabetics: a novel presentation of pancreatic adenocarcinoma. J Gen Intern Med. 2010;25(4):369-373. (Case report)
11. Welch BJ, Zib I. Case study: diabetic ketoacidosis in type 2 diabetes: “look under the sheets.” Clinical Diabetes. 2004;22(4):198-200. (Case reports)
12. Rewers A, Klingensmith G, Davis C, et al. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the search for diabetes in youth study. Pediatrics. 2008;121(5):e1258-e1266. (Retrospective chart review; 2824 patients)
13. Chaithongdi N, Subauste JS, Koch CA, et al. Diagnosis and management of hyperglycemic emergencies. Hormones (Athens). 2011;10(4):250-260. (Review)
14. Graffeo CS. Hyperosmolar hyperglycemic state. In: Tintinalli's Emergency Medicine. Tintinalli JE, Stapczynski JS, Cline DM, et al, eds. 7th ed. New York: McGraw-Hill Companies, Inc. 2011. (Textbook)
15. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am. 1995;79(1):39-52. (Review)
16. Arieff AI. Cerebral edema complicating nonketotic hyperosmolar coma. Miner Electrolyte Metab. 1986;12(5-6):383-389. (Case reports; 5 patients)
17. Maccario M, Messis CP, Vastola EF. Focal seizures as a manifestation of hyperglycemia without ketoacidosis. A report of seven cases with review of the literature. Neurology. 1965;15:195-206. (Case report)
18. Maccario M. Neurological dysfunction associated with nonketotic hyperglycemia. Arch Neurol. 1968;19(5):525-534. (Case report)
19. Guisado R, Arieff AI. Neurologic manifestations of diabetic comas: correlation with biochemical alterations in the brain. Metabolism. 1975;24(5):665-679. (Review)
20. * Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343. (Guidelines)
21. Ha WC, Oh SJ, Kim JH, et al. Severe hypoglycemia is a serious complication and becoming an economic burden in diabetes. Diabetes Metab J. 2012;36(4):280-284. (Retrospective analysis; 320 patients)
22. McCoy RG, Van Houten HK, Ziegenfuss JY, et al. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care. 2012;35(9):1897-1901. (Retrospective study; 1020 patients)
23. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94(3):709-728. (Review)
24. Graveling AJ, Frier BM. Review: does hypoglycaemia cause cardiovascular events? The British Journal of Diabetes & Vascular Disease. 2010;10(1):5-13. (Review)
25. Svensson AM, McGuire DK, Abrahamsson P, et al. Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J. 2005;26(13):1255-1261. (Retrospective analysis of prospectively collected data; 713 consecutive patients)
26. Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract. 2010;16(2):244-248. (Case report)
27. Kosiborod M, Inzucchi SE, Krumholz HM, et al. Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk. Circulation. 2008;117(8):1018-1027. (Retrospective cohort; 16,871 patients)
28. Prakash S, Galluccio S. Three strikes and you’re out: unanticipated hyperkalaemic cardiac arrest following rapid sequence intubation. Anaesth Intensive Care. 2012;40(1):187- 188. (Case report)
29. Jackson MA, Lodwick R, Hutchinson SG. Hyperkalaemic cardiac arrest successfully treated with peritoneal dialysis. BMJ. 1996;312(7041):1289-1290. (Case report)
30. Ritchie JV, Juliano ML, Thurman, RJ. ECG Abnormalities. In: The Atlas of Emergency Medicine. 3rd edition. New York: The McGraw Hill Companies; 2009. (Textbook)
31. Chansky MEL, C. L. Diabetic Ketoacidosis. In: Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. New York: The McGraw Hill Companies; 2011. (Textbook)
32. Newton CR, Delgado JH, Gomez HF. Calcium and beta receptor antagonist overdose: a review and update of pharmacological principles and management. Semin Respir Crit Care Med. 2002;23(1):19-25. (Review)
33. Levine M, Boyer EW, Pozner CN, et al. Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med. 2007;35(9):2071-2075. (Retrospetive chart review; 40 patients)
34. Gangji AS, Cukierman T, Gerstein HC, et al. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30(2):389-394. (Metaanalysis)
35. Agarwal DK, Jeloka T, Sharma A, et al. Steroid-induced diabetes mellitus presenting as diabetic ketoacidosis. Indian Journal of Nephrology. 2002;12(4):122. (Case report)
36. Alavi IA, Sharma BK, Pillay VK. Steroid-induced diabetic ketoacidosis. Am J Med Sci. 1971;262(1):15-23. (Case reports; 13 patients)
37. Alavi IA, Pillay VKG. Steroid-induced diabetic ketoacidosis. Ann Intern Med. 1970;72(5):787-787. (Case reports; 4 patients)
38. Kang SH, Lee JY, Park HS, et al. Hyperglycemic hyperosmolar syndrome caused by steroid therapy in a patient with lupus nephritis. J Korean Med Sci. 2011;26(3):447-449. (Case report)
39. Warner EA, Greene GS, Buchsbaum MS, et al. Diabetic ketoacidosis associated with cocaine use. Arch Intern Med. 1998;158(16):1799-1802. (Retrospective case-control study; 720 patients)
40. 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 cohort analysis; 168 patients)
41. Kearney T, Dang C. Diabetic and endocrine emergencies. Postgrad Med J. 2007;83(976):79-86. (Review)
42. Umpierrez G, Freire AX. Abdominal pain in patients with hyperglycemic crises. J Crit Care. 2002;17(1):63-67. (Prospective evaluation; 200 consecutive patients)
43. Yong AW, Morris Z, Shuler K, et al. Acute symptomatic hypoglycaemia mimicking ischaemic stroke on imaging: a systematic review. BMC Neurol. 2012;12:139. (Systematic review; 42 papers)
44. Chang Y, Zhang MC, Wan HH, et al. Magnetic resonance imaging features in seizures associated with nonketotic hyperglycemia. Neurol India. 2013;61(5):528-530.
45. Aquino A, Gabor AJ. Movement-induced seizures in nonketotic hyperglycemia. Neurology. 1980;30(6):600-604. (Case reports; 2 patients)
46. Hoizey G, Lamiable D, Trenque T, et al. Identification and quantification of 8 sulfonylureas with clinical toxicology interest by liquid chromatography-ion-trap tandem mass spectrometry and library searching. Clin Chem. 2005;51(9):1666- 1672. (Laboratory analysis; 134 cases)
47. Walfish PG, Feig DS, Bauman WA. Factitious hyperinsulinemic hypoglycemia: confirmation of the diagnosis by a species-specific insulin radioimmunoassay. J Endocrinol Invest. 1987;10(6):601-604. (Case report)
48. Andersen L, Jorgensen PN, Jensen LB, et al. A new insulin immunoassay specific for the rapid-acting insulin analog, insulin aspart, suitable for bioavailability, bioequivalence, and pharmacokinetic studies. Clin Biochem. 2000;33(8):627- 633. (Laboratory analysis)
49. Moriyama M, Hayashi N, Ohyabu C, et al. Performance evaluation and cross-reactivity from insulin analogs with the ARCHITECT insulin assay. Clin Chem. 2006;52(7):1423-1426. (Laboratory analysis of ARCHITECT assay)
50. Neal JM, Han W. Insulin immunoassays in the detection of insulin analogues in factitious hypoglycemia. Endocr Pract. 2008;14(8):1006-1010. (Case report)
51. Grunberger G, Weiner JL, Silverman R, et al. Factitious hypoglycemia due to surreptitious administration of insulin. Diagnosis, treatment, and long-term follow-up. Ann Intern Med. 1988;108(2):252-257. (Follow-up study; 10 patients)
52. Murray BJ. Hypoglycemia secondary to factitious hyperinsulinism. Postgrad Med. 1981;69(2):237, 240-231. (Case report)
53. Lupsa BC, Chong AY, Cochran EK, et al. Autoimmune forms of hypoglycemia. Medicine (Baltimore). 2009;88(3):141-153. (Case report)
54. Cheuvront SN, Ely BR, Kenefick RW, et al. Biological variation and diagnostic accuracy of dehydration assessment markers. Am J Clin Nutr. 2010;92(3):565-573.
55. Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999;106(4):399-403.
56. Kitabchi AE. Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults. 2013. Available at: http://www.uptodate.com/contents/ clinical-features-and-diagnosis-of-diabetic-ketoacidosis-andhyperosmolar- hyperglycemic-state-in-adults?source=previe w&anchor=H12&selectedTitle=1~150#H12. Accessed March 2, 2013.
57. Lin CJ, Chen YC, Chen HH, et al. Life-threatening ventricular arrhythmia induced by hypokalemia during sodium bicarbonate infusion. South Med J. 2008;101(2):215-216. (Case report)
58. Cortesi C, Bettinelli A, Emma F, et al. Severe syncope and sudden death in children with inborn salt-losing hypokalaemic tubulopathies. Nephrol Dial Transplant. 2005;20(9):1981- 1983. (Chart analysis; 249 patients)
59. Facchini M, Sala L, Malfatto G, et al. Low-K+ dependent QT prolongation and risk for ventricular arrhythmia in anorexia nervosa. Int J Cardiol. 2006;106(2):170-176. (Evaluation of 29 patients with anorexia nervosa compared to 29 controls)
60. Maeder M, Rickli H, Sticherling C, et al. Hypokalaemia and sudden cardiac death--lessons from implantable cardioverter defibrillators. Emerg Med J. 2007;24(3):206-208. (Case reports; 4 patients)
61. Fisher JN, Kitabchi AE. A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab. 1983;57(1):177-180. (Randomized control study; 30 patients)
62. Wilson HK, Keuer SP, Lea AS, et al. Phosphate therapy in diabetic ketoacidosis. Arch Intern Med. 1982;142(3):517-520. (Randomized control study; 44 patients)
63. Wallace TM, Matthews DR. Recent advances in the moni3oring and management of diabetic ketoacidosis. QJM. 2004;97(12):773-780. (Review)
64. Gennis PR, Skovron ML, Aronson ST, et al. The usefulness of peripheral venous blood in estimating acid-base status in acutely ill patients. Ann Emerg Med. 1985;14(9):845-849. (Prospective pilot study; 183 patients)
65. * Kelly AM, Kyle E, McAlpine R. Venous pCO(2) and pH can be used to screen for significant hypercarbia in emergency patients with acute respiratory disease. J Emerg Med. 2002;22(1):15-19. (Prospective study; 196 patients)
66. * MacGillivray MH, Li PK, Lee JT, et al. Elevated plasma beta-hydroxybutyrate concentrations without ketonuria in healthy insulin-dependent diabetic patients. J Clin Endocrinol Metab. 1982;54(3):665-668. (Case control study; 30 subjects)
67. Kitabchi AE. Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults. 201. Available at: http://www.uptodate.com/contents/treatment-of-diabeticketoacidosis- and-hyperosmolar-hyperglycemic-state-inadults? source=search_result&search=diabetic+ketoacidos is+. Accessed March 3, 2013.
68. Hoorn EJ, Carlotti AP, Costa LA, et al. Preventing a drop in effective plasma osmolality to minimize the likelihood of cerebral edema during treatment of children with diabetic ketoacidosis. J Pediatr. 2007;150(5):467-473. (Retrospective study; 79 patients)
69. Haringhuizen A, Tjan DH, Grool A, et al. Fatal cerebral oedema in adult diabetic ketoacidosis. Neth J Med. 2010;68(1):35-37. (Case report)
70. Troy PJ, Clark RP, Kakarala SG, et al. Cerebral edema during treatment of diabetic ketoacidosis in an adult with new onset diabetes. Neurocrit Care. 2005;2(1):55-58. (Case report)
71. Hiller KM, Wolf SJ. Cerebral edema in an adult patient with diabetic ketoacidosis. Am J Emerg Med. 2005;23(3):399-400. (Case report)
72. Abramson E, Arky R. Diabetic acidosis with initial hypokalemia. Therapeutic implications. JAMA. 1966;196(5):401-403. (Case report)
73. Tillman CR. Hypokalemic hypoventilation complicating severe diabetic ketoacidosis. South Med J. 1980;73(2):231-233. (Case report)
74. * Chua HR, Schneider A, Bellomo R. Bicarbonate in diabetic ketoacidosis - a systematic review. Ann Intensive Care. 2011;1(1):23. (Systematic review)
75. Darby TD, Aldinger EE, Gadsden RH, et al. Effects of metabolic acidosis on ventricular isometric systolic tension and the response to epinephrine and levarterenol. Circ Res. 1960;8:1242-1253. (Prospective animal study; 78 dogs)
76. Monroe RG, French G, Whittenberger JL. Effects of hypocapnia and hypercapnia on myocardial contractility. Am J Physiol. 1960;199:1121-1124. (Prospective animal study; 15 dogs)
77. Ng ML, Levy MN, Zieske HA. Effects of changes of pH and of carbon dioxide tension on left ventricular performance. Am J Physiol. 1967;213(1):115-120. (Prospective animal study; 74 dogs)
78. Wildenthal K, Mierzwiak DS, Myers RW, et al. Effects of acute lactic acidosis on left ventricular performance. Am J Physiol. 1968;214(6):1352-1359. (Prospective animal study; 15 dogs)
79. Cryer PE. Management of hypoglycemia during treatment of diabetes mellitus. 2014. Available at: http://www.uptodate. com/contents/management-of-hypoglycemia-during-treatment- of-diabetes-mellitus?source=search_result&search=ma nagement+of+hypoglycemia&selectedTitle=1~150. Accessed March 3, 2013.
80. Bloomfield HE, Greer N, Newman D, et al. Predictors and consequences of severe hypoglycemia in adults with diabetes - a systematic review of the evidence. VA-ESP Project #09-009. Minneapolis, MN; 2012. (Government report)
81. Dougherty PP, Klein-Schwartz W. Octreotide’s role in the management of sulfonylurea-induced hypoglycemia. J Med Toxicol. 2010;6(2):199-206. (Review)
82. Hanchard B, Boulouffe C, Vanpee D. Sulfonylureainduced hypoglycaemia: use of octreotide. Acta Clin Belg. 2009;64(1):56-58. (Case report)
83. Carr R, Zed PJ. Octreotide for sulfonylurea-induced hypoglycemia following overdose. Ann Pharmacother. 2002;36(11):1727-1732. (Case report)
84. Glatstein M, Scolnik D, Bentur Y. Octreotide for the treatment of sulfonylurea poisoning. Clin Toxicol (Phila). 2012;50(9):795-804. (Case series review; 53 patients)
85. Fasano CJ, O’Malley G, Dominici P, et al. Comparison of octreotide and standard therapy versus standard therapy alone for the treatment of sulfonylurea-induced hypoglycemia. Ann Emerg Med. 2008;51(4):400-406. (Prospective doubleblind placebo controlled trial; 40 patients)
86. Sargent AI, Overton CC, Kuwik RJ, et al. Octreotide-induced hyperkalemia. Pharmacotherapy. 1994;14(4):497-501. (Case report)
87. Brown RO, Hamrick KD, Dickerson RN, et al. Hyperkalemia secondary to concurrent pharmacotherapy in a patient receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 1996;20(6):429-432. (Case report)
88. Sharma AM, Thiede HM, Keller F. Somatostatin-induced hyperkalemia in a patient on maintenance hemodialysis. Nephron. 1991;59(3):445-448. (Case report)
89. Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18 Suppl 3):S729-S767. (Review)
90. Alivanis P, Giannikouris I, Paliuras C, et al. Metformin-associated lactic acidosis treated with continuous renal replacement therapy. Clin Ther. 2006;28(3):396-400. (Case report)
91. Bruijstens LA, van Luin M, Buscher-Jungerhans PM, et al. Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment. Neth J Med. 2008;66(5):185-190. (Case reports; 3 patients)
92. No authors listed. Standards of medical care in diabetes-- 2011. Diabetes Care. 2011;34 Suppl 1:S11-S61. (Consensus document)
93. Wing RR, Blair EH, Bononi P, et al. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Diabetes Care. 1994;17(1):30-36. (Prospective; 93 patients)
94. Kirwan JP, Solomon TP, Wojta DM, et al. Effects of 7 days of exercise training on insulin sensitivity and responsiveness in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2009;297(1):E151-E156. (Prospective; 14 patients)
95. Winnick JJ, Sherman WM, Habash DL, et al. Short-term aerobic exercise training in obese humans with type 2 diabetes mellitus improves whole-body insulin sensitivity through gains in peripheral, not hepatic insulin sensitivity. J Clin Endocrinol Metab. 2008;93(3):771-778. (Prospective; 18 patients)
96. Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care. 2007;30(6):1374-1383. (Prospective randomized controlled trial; 5145 patients)
97. 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. (Case control; 416 patients)
98. Lawrence SE, Cummings EA, Gaboury I, et al. Populationbased study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis. J Pediatr. 2005;146(5):688- 692. (Case control; 39 patients)
99. Rosenbloom AL. The management of diabetic ketoacidosis in children. Diabetes Ther. 2010;1(2):103-120. (Review)
100. Kamat P, Vats A, Gross M, et al. Use of hypertonic saline for the treatment of altered mental status associated with diabetic ketoacidosis. Pediatr Crit Care Med. 2003;4(2):239-242. (Case series; 4 patients)
101. Curtis JR, Bohn D, Daneman D. Use of hypertonic saline in the treatment of cerebral edema in diabetic ketoacidosis (DKA). Pediatr Diabetes. 2001;2(4):191-194. (Case report)
102. Davis SN. Canagliflozin versus glimepiride treatment in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU trial). Expert Rev Clin Pharmacol. 2014;7(1):21-23. (Randomized double-blind phase 3 noninferiority trial)
103. Song JC, Kaubisch S, Doan T, et al. Canagliflozin--an emerging treatment option for type 2 diabetes mellitus. 2013. Available at: http://formularyjournal.modernmedicine.com/ formulary-journal/news/user-defined-tags/canagliflozin/ canagliflozin-emerging-treatment-option-type-. Accessed March 3, 2013. (Review)