Acute complications of Diabetes

Acute complications of Diabetes

1. School of Nursing & Midwifery Department of Adult Health Nursing P.by: Habtemariam Mulugeta College of Medicine & Health Sciences 1 Habtemariam M.

2. Prepared BY: HABTEMARIAM MULUGETA SGSR 398/12 2 ADULT HEALTH NURSING – II Acute Complications of Diabetes Habtemariam M.

3. Presentation Outline Habtemariam M. 3 Objectives Introduction Acute Complications of Diabetes Diabetic Ketoacidosis (DKA) Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) Insulin Shock (Hypoglycemia) Lactic acidosis Diabetic Comma Summary References Acknowledgment

4. Objectives Habtemariam M. 4 Within the entire sessions all learners will: Discuss the acute complications of diabetes Explain the different between DKA & HHNS Showcase the significance of Management of DM Complications Differentiate acute complications of diabetes prognosis Familiarize with management regimes of acute complications of diabetes

5. Introduction Habtemariam M. 5 Diabetes is a group of metabolic disease characterized by chronic hyperglycemia with disturbance in the carbohydrate, fat & protein metabolism resulting from defects in insulin secretion, insulin action or both. It can result abrupt or chronic complication and even death. All forms of diabetes increase the risk of long-term complications. The complications of diabetes mellitus are far less common and less severe in people who have well-controlled blood sugar levels. (Nathan DM, 2005)

6. Actions of Insulin Habtemariam M. 6 (Nathan DM, 2005)

7. Acute Complications of Diabetes Habtemariam M. 7 Health officers and nurses should provide screening, diagnosis, treatment and prevention of DM and its complications. If patients with acute complications like diabetic ketoacidosis, hyperosmolar hyperglycemic state and manifestations of chronic complications like proteinuria, neuropathy, and, cardiovascular symptoms present at the health centers, these cases should be referred to general hospitals. Guidelines on Clinical and Programmatic Management of Major Non Communicable Diseases, Ethiopian MoH , 2016

8. Acute Complications of Diabetes 8 Diabetic Ketoacidosis (DKA) Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) Insulin Shock (Hypoglycemia) Lactic acidosis Diabetic Comma Habtemariam M. "Diabetes Complications". Diabetes.co.uk. Retrieved 22 November 2012.

9. Diabetic Ketoacidosis (DKA) Habtemariam M. 9 It is an acute life threatening complication of DM that is always a medical emergency and requires prompt medical attention. characterized by hyperglycemia , ketoacidosis , and ketonuria . Occurs predominantly in type I DM though may occur in type II DM. ( Laffel , 1999)

10. Epidemiology Habtemariam M. 10 ¼ of hospital admissions for DM Incidence of DKA in diabetics 15 per 1000 patients 20-30% of cases occur in new-onset diabetes Mortality less than 5% Mortality higher in elderly due to underlying renal disease or coexisting infection Washington R.E., 2013

11. Definition Habtemariam M. 11 Williams textbook of endocrinology 10 th edition

12. Causes Habtemariam M. 12 Idiopathic (no identifiable cause) 25% of patient due to acute insulin deficiency Errors in insulin use, or Omission of daily insulin injections Bacterial infection and intercurrent illness (e.g. UTI) Klebsiella pneumoniae (the leading cause of bacterial infections precipitating DKA) Insulin infusion catheter blockage Mechanical failure of the insulin infusion pump Medical, surgical, or emotional stress Adams DD (June 2008).

13. Pathophysiology Habtemariam M. 13 (English P, 2004)

14. Cont. Habtemariam M. 14 Lack of insulin and excess counter regulatory hormones (glucagon, catecholamines, cortisol and growth hormone) results in: Hyperglycemia (due to excess production and underutilization of glucose) Osmotic diuresis Prerenal azotemia Ketone formation Wide anion-gap metabolic acidosis Clinical manifestations related to hyperglycemia, volume depletion and acidosis

15. Cont. Habtemariam M. 15 Free fatty acids released in the periphery are bound to albumin and transported to the liver where they undergo conversion to ketone bodies The metabolic acidosis in DKA is due to β-hydroxybutyric acid and acetoacetic acid which are in equilibrium Acetoacetic acid is metabolized to acetone, another major ketone body (English P, 2004)

16. Cont. Habtemariam M. 16 Depletion of baseline hepatic glycogen stores tends to favor ketogenesis Low insulin levels decrease the ability of the brain and cardiac and skeletal muscle to use ketones as an energy source, also increasing ketonemia Persistently elevated serum glucose levels eventually causes an osmotic diuresis Resulting volume depletion worsens hyperglycemia and ketonemia

17. Sign & Symptoms Habtemariam M. 17 Hyperglycemia Abnormal vital signs may be the only significant finding at presentation Initially polyuria and polydipsia are only symptoms until ketonemia and acidosis develop Mental confusion or coma may occur with serum osmolarity >340 mosm /L Tachycardia with orthostasis or hypotension are usually present Poor skin turgor Kussmaul respirations with severe acidemia Acetone - odor in some patients Abdominal pain and tenderness Williams textbook of endocrinology 10th edition

18. Cont. Habtemariam M. 18 Harrison’s Principle of internal medicine 18 th edition p2977

19. Cont. Habtemariam M. 19

20. Signs & symptoms of DKA associated with possible intercurrent infection Habtemariam M. 20 Fever Coughing Chills Chest pain Dyspnea Arthralgia Williams textbook of endocrinology 10th edition

21. Diagnosis Habtemariam M. 21 The cardinal biochemical features are: Hyperketonemia (> 3mmol/L) & Ketonuria (> 2+ on standard urine sticks) Hyperglycemia (blood glucose > 200mg/dL) Metabolic acidosis (venous bicarbonate <15mmol/L and/or venous pH<7.3) low bicarbonate (<15 mEq /L) Joint British Diabetes Societies Inpatient Care Group, 2013, 2 nd ed.

22. Investigations Habtemariam M. 22

23. Cont. Habtemariam M. 23 Harrison’s Principle of internal medicine 18th edition p2977

24. Cont. Habtemariam M. 24 Chest radiography - To rule out pulmonary infection such as pneumonia Head computed tomography (CT) scanning - To detect early cerebral edema ; use low threshold in altered mental status. Head magnetic resonance imaging (MRI) - To detect early cerebral edema (order only if altered consciousness is present)

25. Differential Diagnosis Habtemariam M. 25 Acute Pancreatitis Alcoholic Ketoacidosis Appendicitis UTI and Cystitis (Bladder Infection) in Females Hyperosmolar Coma Hypophosphatemia Hypothermia Lactic Acidosis Metabolic Acidosis Salicylate Toxicity Septic Shock (Newton CA, 2004)

26. Treatment Habtemariam M. 26 The Main goal of Therapy are: Reduction of hyperglycemia Rehydration Correction of electrolyte imbalance Correction of acid-base imbalance Investigation of precipitating factors, treatment of complications.

27. Cont. Habtemariam M. 27 Initial hospital management Replace fluid and electrolytes IV Insulin therapy Watch for complications Treat causes Once resolved Convert to home insulin regimen Prevent recurrence

28. Cont. Habtemariam M. 28 American Diabetes Association Dia Care 2018;27:s94-s102

29. Protocol for Management of Adult Patient with DKA Habtemariam M. 29 American Diabetes Association Dia Care 2018;27:s94-s102

30. Management of DKA at Health Center In Ethiopian Context Habtemariam M. 30 In case of hyperglycemic emergencies like DKA, if diagnosis can be made at least with marked elevation of blood glucose plus ketonuria of +2 or above at the health center level; start intravenous fluids with N/S, give the first dose of 10 units of regular insulin IV and 10 units IM and transfer to primary hospital. If basic diagnostic tests are not available for DKA but patient has significant hyperglycemia ; give the usual NPH or premixed insulin S.C or in case of a new type 1 diabetes diagnosis, initiate NPH insulin S.C at a dose of 0.4 to 0.5 U/KG and transfer to the nearest hospital as soon as possible. If blood glucose ≥18 mmol/l refer to hospital with i.v. drip 0.9% NaCl 1 litre in 2 hours, continue at 1 litre every 4 hours until hospital. Guidelines on Clinical and Programmatic Management of Major Non Communicable Diseases, Ethiopian MoH , 2016

31. Management of DKA at Primary Hospital In Ethiopian Context Habtemariam M. 31 An organized multidisciplinary team may best deliver care for patients with DM, establish chronic illness clinics in the center, Perform screening for DM and acute and chronic complications of DM, Register and set follow-up programs for patients. They should be able to manage acute complications of diabetes. They are also responsible to follow-up cases referred back from higher levels. Members of such a team can include a primary care physician, nurse practitioner, registered nurse, certified diabetes educator and mental healthcare professional. Guidelines on Clinical and Programmatic Management of Major Non Communicable Diseases, Ethiopian MoH , 2016

32. Management of DKA at Secondary Level Health Care Unit In Ethiopian Context Habtemariam M. 32 Diabetic clinics established in the center register and set follow-up programs for patients. Diabetic patients with evidence of chronic complication can be referred for evaluation at tertiary care level 1-2 times per year or as required. Patients will be referred back to primary healthcare for close follow-up at shorter intervals. Guidelines on Clinical and Programmatic Management of Major Non Communicable Diseases, Ethiopian MoH , 2016

33. Criteria for resolution of DKA Habtemariam M. 33 Glucose <200 mg/dl, Serum bicarbonate ≥18 mEq /l, and Venous pH of >7.3 Once DKA is resolved, if the patient is NPO, continue intravenous insulin and fluid replacement and supplement with subcutaneous regular insulin as needed every 4 h. American Diabetes Association Dia Care 2018;27:s94-s102

34. Cont. Habtemariam M. 34 Most patients require 0.5-0.6 units/kg/day highly insulin resistant patients 0.8-1.0 units/kg/day Give subcutaneous insulin at least 2 hours prior to weaning insulin infusion

35. Preventive Strategies of DKA Habtemariam M. 35

36. Prognosis Habtemariam M. 36 The overall mortality rate for DKA is 0.2-2%, with persons at the highest end of the range residing in developing countries. The presence of deep coma at the time of diagnosis, hypothermia , and oliguria are signs of poor prognosis . The prognosis of properly treated patients with diabetic ketoacidosis is excellent, especially in younger patients if intercurrent infections are absent. The worst prognosis usually is observed in older patients with severe intercurrent illnesses (e.g. myocardial infarction, sepsis, or pneumonia), especially when these patients are treated outside an intensive care unit. (Lin SF, 2005)

37. Clinical Errors Habtemariam M. 37 Fluid shift and shock Giving insulin without sufficient fluids Using hypertonic glucose solutions Hyperkalemia Premature potassium administration before insulin has begun to act Hypokalemia Failure to administer potassium once levels falling Recurrent ketoacidosis Premature discontinuation of insulin and fluid when ketones still present Hypoglycemia Insufficient glucose administration American Family Physician May 1, 2005, Volume 71, Number 9

38. Complications Habtemariam M. 38 Cerebral edema ARDS (Acute Respiratory Distress Syndrome) Thromboembolism DIC (Disseminated Intravascular Coagulation) Acute Circulatory Failure ( Wolfsdorf J, 2007)

39. Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) Habtemariam M. 39 It is a serious metabolic derangements that occur in patients with DM. It is a life-threatening emergency that, although less common than its counterpart, DKA. It was previously termed hyperosmolar hyperglycemic nonketotic coma (HHNC); however, the terminology was changed because coma is found in fewer than 20% of patients with HHS. ( Pasquel FJ, 2014)

40. Epidemiology Habtemariam M. 40 Mortality rate higher in HHNS 15-30 % for HHNS 5% for DKA Mortality for HHNS increases substantially with advanced age and concomitant illness The average age of patients with HHS is 60 years but it can also occur in younger people. Washington R.E., 2013

41. Definition Habtemariam M. 41 Defined by: Severe hyperglycemia With serum glucose usually > 600 mg/dL Elevated calculated plasma osmolality ( Hyperosmolality ) > 315 mOsm /kg Serum bicarbonate > 15 Dehydration Arterial pH > 7.3 Serum ketones that are negative to mildly positive Values are arbitrary Profound metabolic acidosis and even moderate degrees of ketonemia may be found in HHNS Williams textbook of endocrinology 10 th edition

42. Cont. Habtemariam M. 42 DKA HHS Ketonemia/Ketonuria + Ketonemia/Ketonuria - Serum Osmolality Normal Serum Osmolality >320mosm pH<7.3 pH>7.3 Serum Glucose >250mg/dL Serum Glucose >600mg/dL

43. Cause Habtemariam M. 43 HHS most commonly occurs in patients with type 2 DM who have some concomitant illness that leads to reduced fluid intake. The most at-risk population consists of the elderly or chronically ill, who in many cases have decreased thirst perception or limited free access to water. In general, any illness that predisposes to dehydration or to reduced insulin activity may lead to HHS. Adams DD (June 2008).

44. Cont. Habtemariam M. 44 Spontaneous occurrence in 5 – 7 % of patients. Infection: pneumonia, UTI, Gm - ve sepsis Drugs: steroids increase glucogenesis; potassium-wasting diuretics (hypokalemia decreases insulin secretion), e.g., thiazides, furosemide; other drugs, e.g., propranolol, azathioprine, diazoxide. Misc : CVA, acute pancreatitis, severe burns Use of conc. glucose solutions, such as used in peripheral hyperalimentation or renal dialysis Peritoneal or hemodialysis, tube feeding

45. Pathophysiology Habtemariam M. 45

46. Cont. Habtemariam M. 46 Three main factors: Decreased utilization of insulin Increased hepatic gluconeogenesis and glycogenolysis Impaired renal excretion of glucose Identification early of those at risk for HHNS is most effective means of preventing serious complications Must be vigilant on helping those who are non-ambulatory with inadequate hydration status Fundamental risk factor for developing HHNS is impaired access to water (English P, 2004)

47. Cont. Habtemariam M. 47 With poorly controlled DM II, inadequate utilization of glucose due to insulin resistance results in hyperglycemia Absence of adequate tissue response to insulin results in hepatic glycogenolysis and gluconeogenesis resulting in further hyperglycemia As serum glucose increases, an osmotic gradient is produced attracting water from the intracellular space and into the intravenous compartment

48. Cont. Habtemariam M. 48 Initial increase in intravascular volume is accompanied by a temporary increase in the GFR As serum glucose concentration exceeds 180 mg/dL, capacity of kidneys to reabsorb glucose is exceeded and glucosuria and a profound osmotic diuresis occurs Patients with free access to water are often able to prevent profound volume depletion by replacing lost water with large free water intake If water requirement is not met, volume depletion occurs (English P, 2004)

49. Cont. Habtemariam M. 49 During osmotic diuresis, urine produced is markedly hypertonic Significant loss of sodium and potassium and modest loss of calcium, phosphate, magnesium and urea also occur As volume depletion progresses, renal perfusion decreases and GFR is reduced Renal tubular excretion of glucose is impaired which further worsens the hyperglycemia A sustained osmotic diuresis may result in total body water losses that often exceeds 20-25% of total body weight or approximately 8-12 L in a 70 kg person Campanella LM., 2009

50. Cont. Habtemariam M. 50 Absence of ketosis in HHNS not clearly understood Some degree of starvation does occur but a clinically significant ketoacidosis does not occur Lack of ketoacidosis may be due to: Lower levels of counter regulatory hormones Higher levels of endogenous insulin that strongly inhibits lipolysis Inhibition of lipolysis by the hyperosmolar state

51. Sign & Symptoms Habtemariam M. 51 Polyuria, weight loss, and diminished oral intake Profound dehydration Hypotension, tachycardia and altered mental status Mental confusion, lethargy or coma Campanella LM., 2009

52. Diagnosis Habtemariam M. 52 It is characterized by: SEVERE hyperglycemia (>600mg/dL) Hyperosmolality (serum osmolality >320 mOsm /kg) Dehydration (in the ABSENCE of significant hyperketonemia or acidosis) Joint British Diabetes Societies Inpatient Care Group, 2013, 2 nd ed.

53. Cont. Habtemariam M. 53 Physical examination Severe dehydration is invariably present. Various neurologic deficits (such as coma, transient hemiparesis, and generalized areflexia) are commonly present. Altered states of consciousness from lethargy to coma are observed. Findings associated with coexisting medical problems (e.g., renal disease, cardiovascular disease) may be evident.

54. Investigations Habtemariam M. 54

55. Cont. Habtemariam M. 55 Harrison’s Principle of internal medicine 18th edition p2977

56. Differential Diagnoses Habtemariam M. 56 Diabetes Insipidus Diabetic Ketoacidosis (DKA) Myocardial Infarction Pulmonary Embolism (PE) Campanella LM., 2009

57. Treatment Habtemariam M. 57 This condition is a medical emergency and the patient should be placed in an intensive care unit. Many of the management techniques recommended for a patient with DKA are applicable here as well.

58. Cont. Habtemariam M. 58 The goals of therapy include: rehydration; reduction of hyperglycemia; electrolytes replacement; investigation of precipitating factors, treatment of complications.

59. Habtemariam M. 59 Normalize osmolality- 0.45% saline Replace fluid and electrolyte losses Normalize blood glucose Campanella LM., 2009

60. Protocol for Management of Adult Patient with HHNS Habtemariam M. 60 Joint British Diabetes Societies Inpatient Care Group, 2013, 2 nd ed.

61. DKA/HHS flowsheet Habtemariam M. 61 Joint British Diabetes Societies Inpatient Care Group, 2013, 2 nd ed.

62. Complications Habtemariam M. 62 Electrolyte Abnormalities Cerebral edema ARDS Vascular complications ( Wolfsdorf J, 2007)

63. Prognosis Habtemariam M. 63 Overall mortality for HHS is estimated at 5-20% and is usually due to the underlying illness that caused the hyperglycemic crisis. Prognosis is worse for elderly patients and patients in whom coma and hypotension are found. This is in contrast to the mortality rate of DKA, which is estimated to be about 1-5% (Lin SF, 2005)

64. DKA vs. HHS DKA HHS Age More in children More in elderly DM type More in type I More in type II Glucose > 250 > 600 Ketonuria/emia +++++ + or - pH <7.3 >7.3 HCO 3 <15 >15 S osmolarity Variable Hyperosmolarity Sensitivity to insulin Variable Sensitive to small dose Habtemariam M. 64

65. DKA Hypoglycemia Etiology Insulin deficiency or increased counter-reg hormones Insulin overdose or hyperinsulinemia Onset Gradual Acute Symptoms and signs Sign of hyperglycemia S of dehydration S of acidosis -S of Brain glucopenia - S of sympathetic overactivity RBS hyperglycemia hypoglycemia Ketonuria Yes No Ketonemia Yes No IV glucose No effect Rapidly recover if early DKA vs. HHS Habtemariam M. 65

66. Insulin Shock (Hypoglycemia) Habtemariam M. 66 Hypoglycemia (<63mg/dL) in DM occurs due to insulin overdose or hyperinsulinemia. Whipple’s triad- Symptoms consistent with HYPOGLYCEMIA Low plasma glucose conc . (measured with a precise method) Relief of symptoms after plasma glucose level is RAISED (Nathan DM., 2005)

67. Cause Habtemariam M. 67 Missed, delayed or inadequate meal Unexpected or unusual exercise Alcohol Errors in oral anti-diabetics or insulin dose/schedule/administration Poorly designed insulin regimen Lipoatrophy at injection sites Factitous (deliberately induced) Breasting feeding by DIABETIC mother Adams DD (June 2008).

68. Sign & Symptoms Habtemariam M. 68 Williams textbook of endocrinology 10th edition

69. Treatment Habtemariam M. 69

70. Management of Hypoglycemia In Ethiopian Context Habtemariam M. 70 Unconscious diabetic patients on hypoglycemic agents and/or blood glucose 70mg/dl should be given hypertonic glucose intravenously. Food should be provided as soon as the patient can ingest food safely. For unconscious diabetic patients on hypoglycemic agents and/or blood glucose<70mg/dl, administer intravenously 20 to 40 l of 40% or 50% glucose (dextrose) over 1 to 3 minutes. If not available, substitute with any hypertonic glucose solution. Food should be provided as soon as the patient can ingest food safely. Guidelines on Clinical and Programmatic Management of Major Non Communicable Diseases, Ethiopian MoH , 2016

71. Cont. Habtemariam M. 71 Oral treatment with glucose containing food, sweetened soft drinks 100-150 ml , 3-4 candy (candies), 1 tablespoonful of sugar or honey (equivalent to 15 gm-20 gm of glucose) If no response, try intravenous 40 % or 50% glucose 20 to 40ml iv stat, repeat the same in 15 minutes if there is no response. If still there is no response, start 10 % glucose solution in D/W at rate of 100 ml /hr. Emergency management should be followed by carbohydrate containing food, e.g. bread, fruits, Injera , etc. when patient is able to take food PO safely. Guidelines on Clinical and Programmatic Management of Major Non Communicable Diseases, Ethiopian MoH , 2016

72. Dawn phenomenon & Somogyi effect DAWN PHENOMENON occurs when endogenous insulin secretion decreases SOMOGYI EFFECT is seen in cases of excessive amounts of exogenous insulin Habtemariam M. 72 American Family Physician May 1, 2005, Volume 71, Number 9

73. SOMOGYI EFFECT TOO MUCH INSULIN HYPOGLYCEMIA GLUCAGON IS RELEASED LIPOLYSIS GLUCO N EO G EN E SIS GLYCOGENOLYSIS REBOUND HYPERGLYCEMIA + K E T O S IS Habtemariam M. 73 American Family Physician May 1, 2005, Volume 71, Number 9

74. DAWN PHENOMENON Body’s response to hormones released in early morning hours Counter-regulatory hormones are released Glucose level increases In DM, there is decrease in insulin levels So HIGH GLUCOSE levels in morning Habtemariam M. 74 American Family Physician May 1, 2005, Volume 71, Number 9

75. Cont. Habtemariam M. 75 Harrison’s Principle of internal medicine 18th edition p2977

76. Lactic acidosis  Habtemariam M. 76 It is a medical condition characterized by the buildup of  lactate  (especially  L-lactate ) in the body, with formation of an excessively low pH in the bloodstream. It is a form of  metabolic acidosis , in which excessive acid accumulates due to a problem with the body's oxidative  metabolism . Williams textbook of endocrinology 10th edition

77. Cont. Habtemariam M. 77 TYPE A Poor tissue perfusion Shock, Cardiac failure Severe anemia Mitochondrial enzyme defects Inhibitors (Cyanide, CO) TYPE B Aerobic disorders DM Malignancies NRTIs Renal or hepatic failure Thiamine deficiency Severe infections: cholera, malaria Drugs/toxins: Biguanides, ethanol, isoniazid, methanol

78. Clinical Manifestations Tachycardia & Hypotension. Poor skin turgor and dry skin Hypothermia Hyperpnea or Kussmaul breathing Findings associated with coexisting medical problems (e.g., renal disease, cardiovascular disease) Habtemariam M. 78 American Family Physician May 1, 2005, Volume 71, Number 9

79. Laboratory Diagnosis Arterial blood gas analysis : Metabolic acidosis with usually high anion gap. Normal anion gap lactic acidosis has also been reported. Blood lactate levels : >2 mEq/L : abnormal >4 mEq/L: more prognostic value in sepsis Habtemariam M. 79

80. Management Correct the underlying metabolic abnormality. Alkali therapy is of questionable value. HCO3 generates CO2 & lowers the intracellular & CSF pH Elevate blood lactate levels If pH < 7.1 & the patient deteriorating rapidly, a trial of bicarbonate therapy by administering 1/2 of the estimated bicarbonate deficit [= 0.6 x wt in kg (15- measured HCO3 )] Final aim: to maintain HCO3 level at 15 mEq/L by bicarbonate therapy Habtemariam M. 80 Williams textbook of endocrinology 10th edition

81. Diabetic coma Habtemariam M. 81 It is a medical emergency in which a person with DM is comatose (unconscious) because of one of the acute complications of diabetes: Severe diabetic hypoglycemia DKA advanced enough to result in unconsciousness from a combination of severe hyperglycemia, dehydration and shock, and exhaustion HHNS coma in which extreme hyperglycemia and dehydration alone are sufficient to cause unconsciousness. "Diabetes Coma". Cleveland Clinic (tertiary source). Retrieved 2019-06-21.

82. Summary Habtemariam M. 82 The  complications of diabetes mellitus  are far less common and less severe in people who have well-controlled  blood sugar  levels. Acute complications include  hypoglycemia ,  hyperglycemia ,  diabetic coma , and  nonketotic hyperosmolar coma . Chronic complications occur due to a mix of  microangiopathy ,  macrovascular disease  and immune dysfunction in the form of  autoimmune disease  or poor immune response, most of which are difficult to manage.

83. Reference Habtemariam M. 83 Nathan DM, Cleary PA, Backlund JY, et al. (December 2005).  "Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes" .  The New England Journal of Medicine .  353  (25): 2643–53. doi: 10.1056/NEJMoa052187 . PMC  2637991 . PMID  16371630 "Diabetes Complications". Diabetes.co.uk. Retrieved 22 November 2012. Washington R.E., Andrews R.M., Mutter R.L. Emergency Department Visits for Adults with Diabetes, 2010. HCUP Statistical Brief #167. November 2013. Agency for Healthcare Research and Quality, Rockville, MD. . Adams DD (June 2008). "Autoimmune destruction of pericytes as the cause of diabetic retinopathy". Clin Ophthalmol . 2 (2): 295–98. doi:10.2147/OPTH.S2629. PMC 2693966. PMID 19668719. Guidelines on Clinical and Programmatic Management of Major Non Communicable Diseases, Ethiopian MoH , 2016 English P, Williams G. Hyperglycaemic crises and lactic acidosis in diabetes mellitus. Postgrad Med J 2004; 80(943):253-261. "Diabetes Coma". Cleveland Clinic (tertiary source). Retrieved 2019-06-21. American Family Physician May 1, 2005, Volume 71, Number 9 Williams textbook of endocrinology 10th edition Harrison’s Principle of internal medicine 18th edition p2977 Joint British Diabetes Societies Inpatient Care Group, 2013, 2nd ed. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med. 2004 Sep 27. 164(17):1925-31. [Medline]. Lin SF, Lin JD, Huang YY. Diabetic ketoacidosis: comparisons of patient characteristics, clinical presentations and outcomes today and 20 years ago. Chang Gung Med J. 2005 Jan. 28(1):24-30. [Medline]. [Guideline] Wolfsdorf J, Craig ME, Daneman D, Dunger D, Edge J, Lee WR, et al. Diabetic ketoacidosis. Pediatr Diabetes. 2007 Feb. 8(1):28-43. [Medline]. Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. Diabetes Care. 2014 Nov. 37 (11):3124-31. [Medline]. [Full Text]. Campanella LM, Lartey R, Shih R. Severe hyperglycemic hyperosmolar nonketotic coma in a nondiabetic patient receiving aripiprazole. Ann Emerg Med. 2009 Feb. 53(2):264-6. [Medline].

84. Acknowledgment Habtemariam M. 84 First I would like to express my heartfelt gratitude to WU CMHS for giving me this chance to enhance my knowledge and skill. Secondly I would like to thank my instructor Dr. Prem Kumar for sharing me his deep knowledge, experience and expertise. Last but not least I would like to thank my family and friends in helping me in ideas and material during my entire work.

85. Thank You Habtemariam M. 85