Acute Complications of Diabetes

1. Acute Complications of Diabetes

2. Diabetic Ketoacidosis

3. Introduction • DKA is an acute life threatening complication of DM • ¼ of hospital admissions for DM • Occurs predominantly in type I though may occur in II • 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

4. Definition • Exact definition is variable • Most consistent is: • Blood glucose level greater than 250 mg/dL • Bicarbonate less than 15 mEq/L • Arterial pH less than 7.3 • Moderate ketonemia

5. Pathophysiology • Body’s response to cellular starvation • Brought on by relative insulin deficiency and counter regulatory or catabolic hormone excess • Insulin is responsible for metabolism and storage of carbohydrates, fat and protein • 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

6. Pathophysiology • 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 • 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

7. Electrolytes • Renal potassium losses already occurring from osmotic diuresis worsen due to renin-angiotensin-aldosterone system activation by volume depletion • In the kidney, chloride is retained in exchange for the ketoanions being excreted • Loss of ketoanions represents a loss of potential bicarbonate • In face of marked ketonuria, a superimposed hyperchloremic acidosis is also present • Presence of concurrent hyperchloremic metabolic acidosis can be detected by noting a bicarbonate level lower than explainable by the amount the anion gap has increased • As adipose tissue is broken down, prostaglandins PGI2 and PGE2 are produced • This accounts for the paradoxical vasodilation that occurs despite the profound levels of volume depletion

8. DKA in Pregnancy • Physiologic changes in pregnancy makes more prone to DKA • Maternal fasting serum glucose levels are normally lower • Leads to relative insulin deficiency and an increase in baseline free fatty acid levels in the blood • Pregnant patients normally have increased levels of counter regulatory hormones • Chronic respiratory alkalosis • Seen in pregnancy • Leads to decreased bicarbonate levels due to a compensatory renal response • Results in a decrease in buffering capacity

9. DKA in Pregnancy • Pregnant patients have increased incidence of vomiting and infections which may precipitate DKA • Maternal acidosis: • Causes fetal acidosis • Decreases uterine blood flow and fetal oxygenation • Shifts the oxygen-hemoglobin dissociation curve to the right • Maternal shifts can lead to fetal dysrhythmia and death

10. Causes of DKA • 25% have no precipitating causes found • Errors in insulin use, especially in younger population • Omission of daily insulin injections • Stressful events: • Infection • Stroke • MI • Trauma • Pregnancy • Hyperthyroidism • Pancreatitis • Pulmonary embolism • Surgery • Steroid use

11. Clinical Features • Hyperglycemia • Increased osmotic load • Movement of intracellular water into the vascular compartment • Ensuing osmotic diuresis gradually leads to volume loss and renal loss of sodium, chloride, potassium, phosphorus, calcium and magnesium • Patients initially compensate by increasing their fluid intake • Initially polyuria and polydipsia are only symptoms until ketonemia and acidosis develop

12. Clinical Features • As acidosis progresses • Patient develops a compensatory augmented ventilatory response • Increased ventilation is stimulated physiologically by acidemia to diminish PCO2 and counter the metabolic acidosis • Peripheral vasodilation develops from prostaglandins and acidosis • Prostaglandins may contribute to unexplained nausea, vomiting and abdominal pain • Vomiting exacerbates the potassium losses and contributes to volume depletion, weakness and weight loss

13. Clinical Features • Mental confusion or coma may occur with serum osmolarity greater than 340 mosm/L • Abnormal vital signs may be the only significant finding at presentation • Tachycardia with orthostasis or hypotension are usually present • Poor skin turgor • Kussmaul respirations with severe acidemia

14. Clinical Features • Acetone presents with odor in some patients • Absence of fever does not exclude infection as a source of the ketoacidosis • Hypothermia may occur due to peripheral vasodilatation • Abdominal pain and tenderness may occur with gastric distension, ileus or pancreatitis • Abdominal pain and elevated amylase in those with DKA or pancreatitis may make differentiation difficult • Lipase is more specific to pancreatitis

15. Clinical Suspicion • If suspect DKA, want immediately: • Acucheck • Urine dip • ECG • Venous blood gas • Normal Saline IV drip • Almost all patients with DKA have glucose greater than 300 mg/dL

16. Acidosis • Elevated serum β-hydroxybutyrate and acetoacetate cause acidosis and ketonuria • Elevated serum ketones may lead to a wide-anion gap metabolic acidosis • Metabolic acidosis may occur due to vomiting, osmotic diuresis and concomitant diuretic use • Some with DKA may present with normal bicarbonate concentration or alkalemia if other alkalotic processes are severe enough to mask acidosis • In which case the elevated anion gap may be the only clue to the presence of an underlying metabolic acidosis

17. ABGs • Help determine precise acid-base status in order to direct treatment • Venous pH is just as helpful • Studies have shown strong correlation between arterial and venous pH in patients with DKA • Venous pH obtained during routine blood draws can be used to avoid ABGs • Decreased PCO2 reflects respiratory compensation for metabolic acidosis • Widening of anion gap is superior to pH or bicarbonate concentration alone • Widening is independent of potentially masking effects concurrent with acid base disturbances

18. Potassium • Total body potassium is depleted by renal losses • Measured levels usually normal or elevated

19. Sodium • Osmotic diuresis leads to excessive renal losses of NaCl in urine • Hyperglycemia artificially lowers the serum sodium levels • Two corrections: • Standard-1.6 mEq added to sodium loss for every 100 mg of glucose over 100 mg/dL • True-2.4 mEq added for blood glucose levels greater than 400 mg/dL

20. Electrolyte Loss: • Osmotic diuresis contributes to urinary losses and total body depletion of: • Phosphorus • Calcium • Magnesium

21. Other values elevated: • Creatinine • Some elevation expected due to prerenal azotemia • May be factitiously elevated if laboratory assays for Cr and Acetoacetate interfere • LFTs • Due to fatty infiltration of the liver which gradually corrects as acidosis is treated • CPK • Due to volume depletion • Amylase • WBCs • Leukocytosis often present due to hemoconcentration and stress response • Absolute band count of 10,000 microL or more reliably predicts infection in this population

22. ECG changes • Underlying rhythm is sinus tachycardia • Changes of hypo/hyperkalemia • Transient changes due to rapidly changing metabolic status • Evaluate for ischemia because MI may precipitate DKA

23. Differential Diagnosis • Any entity that causes a high-anion-gap metabolic acidosis • Alcoholic or starvation ketoacidosis • Uremia • Lactic acidosis • Ingestions (methanol, ethylene glycol, aspirin) • If ingestion cannot be excluded, serum osmolarity or drug-level testing is required • Patients with hyperosmolar non-ketotic coma tend to: • Be older • Have more prolonged course and have prominent mental status changes • Serum glucose levels are generally much higher (>600 mg/dL) • Have little to no anion-gap metabolic acidosis

24. Studies • Diagnosis should be suspected at triage • Aggressive fluid therapy initiated prior to receiving lab results • Place on monitor and have one large bore IV with NS running • Rapid acucheck, urine dip and ECG • CBC • Electrolytes, phosphorus, magnesium, calcium • Blood cultures • ABG optional and required only for monitoring and diagnosis of critically ill • Venous pH (0.03 lower than arterial pH) may be used for critically ill

25. Treatment Goals: • Volume repletion • Reversal of metabolic consequences of insulin insufficiency • Correction of electrolyte and acid-base imbalances • Recognition and treatment of precipitating causes • Avoidance of complications

26. Treatment • Order of therapeutic priorities is volume first, then insulin and/or potassium, magnesium and bicarbonate • Monitor glucose, potassium and anion gap, vital signs, level of consciousness, volume input/output until recovery is well established • Need frequent monitoring of electrolytes (every 1-2 hours) to meet goals of safely replacing deficits and supplying missing insulin • Resolving hyperglycemia alone is not the end point of therapy • Need resolution of the metabolic acidosis or inhibition of ketoacid production to signify resolution of DKA • Normalization of anion gap requires 8-16 hours and reflects clearance of ketoacids

27. Fluid Administration • Rapid administration is single most important step in treatment • Restores: • Intravascular volume • Normal tonicity • Perfusion of vital organs • Improve glomerular filtration rate • Lower serum glucose and ketone levels • Average adult patient has a 100 ml/Kg (5-10 L) water deficit and a sodium deficit of 7-10 mEq/kg • Normal saline is most frequently recommended fluid for initial volume repletion

28. Fluid Administration • Recommended regimen: • First L of NS within first 30 minutes of presentation • First 2 L of NS within first 2 hours • Second 2 L of NS at 2-6 hours • Third 2 L of NS at 6-12 hours • Above replaces 50% of water deficit within first 12 hours with remaining 50% over next 12 hours • Glucose and ketone concentrations begin to fall with fluids alone

29. Fluid Administration • Add D5 to solution when glucose level is between 250-300 mg/dL • Change to hypotonic ½ NS or D5 ½ NS if glucose below 300 mg/dL after initially using NS • If no extreme volume depletion, may manage with 500 ml/hr for 4 hours • May need to monitor CVP or wedge pressure in the elderly or those with heart disease and may risk ARDS and cerebral edema

30. Insulin • Ideal treatment is with continuous IV infusion of small doses of regular insulin • More physiologic • Produces linear fall in serum glucose and ketone body levels • Less associated with severe metabolic complications such as hypoglycemia, hypokalemia and hypophosphatemia

31. Insulin • Recommended dose is 0.1 unit/kg/hr • Effect begins almost immediately after initiation of infusion • Loading dose not necessary and not recommended in children

32. Insulin • Need frequent glucose level monitoring • Incidence of non-response to low-dose continuous IV administration is 1-2% • Infection is primary reason for failure • Usually requires 12 hours of insulin infusion or until ketonemia and anion gap is corrected

33. Potassium • Patients usually with profound total body hypokalemia • 3-5 mEq/kg deficient • Created by insulin deficiency, metabolic acidosis, osmotic diuresis, vomiting • 2% of total body potassium is intravascular • Initial serum level is normal or high due to: • Intracellular exchange of potassium for hydrogen ions during acidosis • Total body fluid deficit • Diminished renal function • Initial hypokalemia indicates severe total-body potassium depletion and requires large amounts of potassium within first 24-36 hours

34. Potassium • During initial therapy the serum potassium concentration may fall rapidly due to: • Action of insulin promoting reentry into cells • Dilution of extracellular fluid • Correction of acidosis • Increased urinary loss of potassium • Early potassium replacement is a standard modality of care • Not given in first L of NS as severe hyperkalemia may precipitate fatal ventricular tachycardia and ventricular fibrillation

35. Potassium • Fluid and insulin therapy alone usually lowers the potassium level rapidly • For each 0.1 change in pH, serum potassium concentration changes by 0.5 mEq/L inversely • Goal is to maintain potassium level within 4-5 mEq/L and avoid life threatening hyper/hypokalemia • Oral potassium is safe and effective and should be used as soon as patient can tolerate po fluids • During first 24 hours, KCl 100-200 mEq usually is required

36. Phosphate • Roll of replacement during treatment of DKA is controversial • Recommended not treating until level less than 1 mg/dL • No established roll for initiating IV potassium phosphate in the ED

37. Magnesium • Osmotic diuresis may cause significant magnesium depletion • Symptomatic hypomagnesemia in DKA is rare as is need of IV therapy

38. Bicarbonate • Role in DKA debated for decades • No clinical study indicates benefit of treating DKA with bicarbonate • Routine use of supplemental bicarbonate in DKA is not recommended • Routine therapy works well without adding bicarbonate

39. Complications and Mortality • Complications related to acute disease • Main contributors to mortality are MI and infection • Old age, severe hypotension, prolonged and severe coma and underlying renal and cardiovascular disease • Severe volume depletion leaves elderly at risk for vascular stasis and DVT • Airway protection for critically ill and lethargic patients at risk for aspiration

40. Complications related to therapy • Hypoglycemia • Hypophosphatemia • ARDS • Cerebral edema

41. Complications related to therapy • Cerebral edema • Occurs between 4 and 12 hours after onset of therapy but may occur as late as 48 hours after start treatment • Estimated incidence is 0.7 to 1.0 per 100 episodes of DKA in children • Mortality rate of 70% • No specific presentation or treatment variables predict development of edema • Young age and new-onset diabetes are only identified potential risk factors

42. Cerebral edema • Symptoms include: • Severe headache • Incontinence • Change in arousal or behavior • Pupillary changes • Blood pressure changes • Seizures • Bradycardia • Disturbed temperature regulation • Treat with Mannitol • Any change in neurologic function early in therapy should prompt immediate infusion of mannitol at 1-2 g/kg

43. Disposition • Most require admission to ICU: • Insulin drips • If early in the course of disease and can tolerate oral liquids, may be managed in ED or observation unit and discharged after 4-6 hours of therapy • Anion gap at discharge should be less than 20

44. Alcoholic Ketoacidosis

45. Alcoholic Ketoacidosis • Wide anion gap acidosis • Most often associated with acute cessation of alcohol consumption after chronic alcohol abuse • Metabolism of alcohol with little or no glucose sources results in elevated levels of ketoacids that typically produce metabolic acidosis present in the illness • Usually seen in chronic alcoholics but may be seen in first time drinkers who binge drink, especially in those with volume depletion from poor oral intake and vomiting

46. Epidemiology • No gender difference • Usually presents between age 20 to 60 • Many with repeated episodes of ketoacidosis • Incidence is unknown but mirrors incidence of alcoholism • Usually self-limited • Poor outcomes may occur • 7-25% of deaths of known alcoholics due to AKA

47. Pathophysiology • Key features • Ingestion of large quantities of alcohol • Relative starvation • Volume depletion

48. Pathophysiology • Pathophysiologic state occurs with: • Depletion of NAD • Aerobic metabolism in the Krebs cycle is inhibited • Glycogen stores are depleted and lipolysis is stimulated • Occurs in patients with: • Recently intoxicated • Volume-contraction • Poor nutrition • Underlying liver disease

49. Pathophysiology • Insulin secretion is suppressed • Glucagon, catecholamines, and growth hormone are all stimulated • Aerobic metabolism is inhibited and anaerobic metabolism causes lipolysis and ketones are produced • β-hydroxybutyrate is increased • More ketones are produced with malnourishment and vomiting or with hypophosphatemia

50. Clinical Features • Usually occurs after episode of heavy drinking followed by decrease in alcohol and food intake and vomiting • Nausea, vomiting and abdominal pain of gastritis and pancreatitis may exacerbate progression of illness • With anorexia continuing, symptoms worsen leading to seeking medical help • Symptoms are nonspecific and diagnosis is difficult without labs • No specific physical findings solely with AKA • Most commonly tachycardia, tachypnea, diffuse mild to moderate abdominal tenderness • Volume depletion resulting from anorexia, diaphoresis and vomiting may explain the tachycardia and hypotension