1. Diabetic Ketoacidosis & Hyperosmolar Hyperglycemic State
Gita Majdi, M.D, MRCP(UK), FRCPC
PGY5 Endocrinology

2. DKA &HHS Epidemiology Causes Pthophysiology Management
DKA in Pregnancy & Childeren

3. Epidemiology
 Diabetic ketoacidosis (DKA) is characteristically associated with type 1 diabetes.
It also occurs in type 2 diabetes under conditions of extreme stress such as serious infection, trauma, cardiovascular or other emergencies, and, less often, as a presenting manifestation of type 2 diabetes, a disorder called ketosis-prone diabetes mellitus

5. Epidemiology Population-based data are not available for HHS.
The rate of hospital admissions for HHS is lower than the rate for DKA, and accounts for less than 1 percent of all primary diabetic admissions

6. The prognosis of hyperglycemic crisis is substantially worse at the extremes of age and in the presence of coma and hypotension 

8. Hyperglycemic crises in urban blacks.
Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE
Arch Intern Med Mar 24;157(6):669-75A
prospective evaluation was conducted of 144 consecutive patients with DKA and 23 patients with HHNS admitted to a large inner-city hospital between July 1993 and October 1994.
Conclusions:In urban black patients, poor compliance with insulin therapy was the main precipitating cause of acute metabolic decompensation, and substance abuse was a significant contributing factor for noncompliance.
-Obesity is common in black patients with DKA; it was present in more than half of those with newly diagnosed diabetes.
- Improved patient education and better access to medical care might reduce the development of these hyperglycemic emergencies.

9. ketosis-prone diabetes (KPD)
Since the mid-1990s increasing attention has been focused on a heterogeneous condition characterized by presentation with diabetic ketoacidosis (DKA) in patients who do not necessarily fit the typical characteristics of autoimmune type 1 diabetes.
KPD comprises a group of atypical diabetes syndromes characterized by severe beta cell dysfunction (manifested by presentation with diabetic ketoacidosis [DKA] or unprovoked ketosis) and a variable clinical course.

12. Pathogenesis:
 The extracellular concentration of glucose is primarily regulated by two hormones: insulin and glucagon.
As the serum glucose concentration rises after a glucose meal, glucose enters the pancreatic beta cells, initiating a sequence of events leading to insulin release.
Insulin restores normoglycemia by diminishing hepatic glucose production, via reductions in both glycogenolysis and gluconeogenesis, and by increasing glucose uptake by skeletal muscle and adipose tissue.
Insulin-induced inhibition of glucagon secretion contributes to the decline in hepatic glucose production; this effect is mediated by direct inhibition of glucagon secretion and of the glucagon gene in the pancreatic alpha cells.

14. Clinical Pearls:
Plasma Osmolality: 2[measured Na (mEq/L)] + glucose (mmol/lit)
Anion Gap : (Na+) - (Cl- + HCO3-) (mEq/L)
Sodium (NA) is the actual measured plasma sodium concentration and not the sodium concentration corrected for the simultaneous glucose concentration
Use of a simple ΔNa/ΔGlucose concentration ratio of 2.0 mEq/L decline in Na for each 100 mg/100 mL (5.5 mmol/L) increase in glucose concentration.

15. Hyponatremia: evaluating the correction factor for hyperglycemia
There are no controlled experimental data that assess the accuracy of the commonly used correction factor of a 1.6 meq/L decrease in serum sodium concentration for every 100mg/dl increase in plasma glucose concentration. The purpose of this study was to evaluate experimentally the hyponatremic response to acute hyperglycemia.
SUBJECTS AND METHODS:
Somatostatin was infused to block endogenous insulin secretion in 6 healthy subjects. Plasma glucose concentrations were increased to >600 mg/dL within 1 hour by infusing 20% dextrose. The glucose infusion was then stopped and insulin given until the plasma glucose concentration decreased to 140 mg/dL. Plasma glucose and serum sodium concentrations were measured every 10 minutes.
RESULTS:
Overall, the mean decrease in serum sodium concentration averaged 2.4 meq/L for every 100 mg/dL increase in glucose concentration. This value is significantly greater than the commonly used correction factor of 1.6 (P = 0.02). Moreover, the association between sodium and glucose concentrations was nonlinear. This was most apparent for glucose concentrations >400 mg/dL. Up to 400 mg/dL, the standard correction of 1.6 worked well, but if the glucose concentration was >400 mg/dL, a correction factor of 4.0 was better.
CONCLUSION:
These data indicate that the physiologic decrease in sodium concentration is considerably greater than the standard correction factor of 1.6 (meq/L Na per 100 mg/dL glucose), especially when the glucose concentration is >400 mg/dL. Additionally, a correction factor of a 2.4 meq/L decrease in sodium concentration per 100 mg/dL increase in glucose concentration is a better overall estimate of this association than the usual correction factor of 1.6.
Am J Med. 1999 Apr;106(4):

16. DEFINITIONS: American Diabetes Association (ADA)
In DKA:
metabolic acidosis is often the major finding
Serum glucose concentration is generally below 800 mg/dL (44.4 mmol/L) and often approximately 350 to 500 mg/dL (19.4 to 27.8 mmol/L).
In HHS:
there is little or no ketoacid accumulation,
Serum glucose concentration frequently exceeds 1000 mg/dL (56 mmol/L)
Plasma osmolality may reach 380 mosmol/kg, and neurologic abnormalities are frequently present (including coma in 25 to 50 percent of cases).
Significant overlap between DKA and HHS has been reported in more than one-third of patients.

22. Initial Evaluation
  The initial history and rapid but careful physical examination should focus on:
Airway, breathing, and circulation (ABC) status
Mental status
Possible precipitating events (eg, source of infection, myocardial infarction)
Volume status

23. Initial Investigation:
Serum glucose
Serum electrolytes (with calculation of the anion gap), blood urea nitrogen (BUN), and plasma creatinine
Complete blood count (CBC) with differential
Urinalysis and urine ketones by dipstick
Plasma osmolality
Serum ketones (if urine ketones are present)
Arterial blood gas if the serum bicarbonate is substantially reduced or hypoxia is suspected
Electrocardiogram
Additional testing, such as cultures of urine, sputum, and blood, serum lipase and amylase, and chest radiograph should be performed on a case-by-case basis

24. Ketones:
The term ‘ketone body’ refers to three molecules, acetoacetate, β-HB, and acetone.
Nitroprusside reacts with acetoacetate and, to a lesser degree, acetone (which is not an acid), but not with beta-hydroxybutyrte.
Beta-hydroxybutyrate is the predominant ketone, particularly in severe DKA.
The ratio of beta-hydroxybutyrate to acetoacetate, which is about 1:1 in normal subjects, can increase to as high as 10:1 in DKA .
False-positive nitroprusside urine ketone results can be generated by drugs containing free sulfhydryl groups that react with nitroprusside. Captopril, penicillamine, and mesna.
Serum nitroprusside test for ketone bodies has been largely replaced by direct assays for beta-hydroxybutyrate . Several beta-hydroxybutyrate assay instruments are commercially available

25. Treatment 1
The first step in the treatment of DKA or HHS is infusion of isotonic saline.
The next step is correction of the potassium deficit.
Low-dose intravenous (IV) insulin should be administered to all patients with moderate to severe DKA who have a serum potassium ≥3.3 mEq/L.
If the serum potassium is less than 3.3 mEq/L, insulin therapy should be delayed until potassium replacement has begun and the serum potassium concentration has increased.

26. Fluid Replacement 2 Isotonic saline (0.9 percent sodium chloride).
The optimal rate of isotonic saline infusion is dependent upon the clinical state of the patient.
Isotonic saline should be infused as quickly as possible in patients with hypovolemic shock.
In hypovolemic patients without shock (and without heart failure), isotonic saline is infused at a rate of 15 to 20 mL/kg lean body weight per hour (about 1000 mL/hour in an average-sized person), for the first couple hours, with a maximum of <50 mL/kg in the first four hours.

27. Fluid Replacement 3
After the second or third hour, the choice for fluid replacement depends upon the state of hydration, serum electrolyte levels, and the urine output.
The most appropriate IV fluid composition is determined by the “corrected” sodium concentration.
The “corrected” sodium concentration can be approximated by adding 2.0 mEq/L to the plasma sodium concentration for each 5.5 mmol/L increase above normal in glucose concentration.
If the “corrected” serum sodium concentration is less than 135 mEq/L, then isotonic saline should be continued at a rate of about 250 to 500 mL/hour.
If the “corrected” sodium concentration is normal or elevated, then the IV fluid is generally switched to one-half isotonic saline at a rate of 250 to 500 mL/hour in order to provide electrolyte-free water.
The timing of one-half isotonic saline therapy may also be influenced by potassium balance.
Potassium repletion affects the saline solution that is given, since potassium is as osmotically active as sodium. Thus, concurrent potassium replacement may be another indication for the use of one-half isotonic saline

28. Potassium Replacement
Add dextrose to the saline solution when the serum glucose reaches 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS.
If the initial serum potassium is below 3.3 mEq/L, IV potassium chloride (KCl 20 to 40 mEq/hour, which usually requires 20 to 40 mEq/L added to saline) should be given.
If the initial serum potassium is between 3.3 and 5.3 mEq/L, IV KCl (20 to 30 mEq) is added to each liter of IV replacement fluid and continued until the serum potassium (K) concentration has increased to the 4.0 to 5.0 mEq/L range.
If the serum potassium concentration is initially greater than 5.3 mEq/L, then potassium replacement should be delayed until its concentration has fallen below this level

29. Insulin Infusion 1
low-dose IV insulin in all patients with moderate to severe DKA or HHS who have a serum potassium ≥3.3 mEq/L.
IV regular insulin and rapid-acting insulin analogs are equally effective in treating DKA.
In HHS or moderate to severe DKA, treatment is initiated with an IV bolus of regular insulin (0.1 U/kg body weight) followed within 5 minutes by a continuous infusion of regular insulin of 0.1 U/Kg/.
Alternatively, the bolus dose can be omitted and a continuous IV infusion of regular insulin at a rate of 0.14 U/kg per hour (equivalent to 10 U/hour in a 70 kg patient) is initiated.

30. Insulin Infusion 2
These doses of regular insulin usually decrease the serum glucose concentration by about 2.8 to 3.9 mmol/L per hour.
If the serum glucose does not fall by at least 2.8 to 3.9 mmol/L from the initial value in the first hour, check the IV access to be certain that the insulin is being delivered and make sure that no IV line filters that may bind insulin have been inserted into the line.
After these possibilities are eliminated, the insulin infusion rate should be doubled every hour until a steady decline in serum glucose of this magnitude is achieved.

31. Monitoring
The serum glucose should initially be measured every hour until stable.
Serum electrolytes, blood urea nitrogen (BUN), creatinine, and venous pH (for diabetic ketoacidosis [DKA]) should be measured every two to four hours, depending upon disease severity and the clinical response.

32. Others:
No recommendation for the routine use of phosphate replacement in the treatment of DKA or HHS.
Phosphate replacement should be strongly considered if severe hypophosphatemia occurs ( below 1.0 mg/dL or 0.32 mmol/L), especially if cardiac dysfunction, hemolytic anemia, and/or respiratory depression develop.
Administering bicarbonate if the arterial pH is less than 6.90.
Give 100 mEq of sodium bicarbonate in 400 mL sterile water with 20 mEq of potassium chloride, if the serum potassium is less than 5.3 mEq/L, administered over two hours.

33. Resolution of Ketoacidosis
Accumulation of ketoacid anions increases the anion gap above its baseline.
Monitoring the anion gap will provide a reasonable estimate of changes in the serum ketoacid anion concentrations.
The anion gap returns to the normal range when ketoacid anions have disappeared from the serum.
If nitroprusside testing for ketones is utilized, ketonemia and ketonuria may persist for more than 36 hours due to the slow elimination of acetone, mainly via the lungs.
Direct measurement of beta-hydroxybutyrate in the blood is the preferred method for measuring the degree of ketonemia.
During insulin therapy, beta-hydroxybutyrate is converted to acetoacetate, resulting in an increasingly positive nitroprusside test for acetoacetate as ketosis is improving.

35. Resolution of ketoacidosis in DKA
Normalization of the serum anion gap (less than 12 mEq/L) and blood beta-hydroxybutyrate levels.
Patients with hyperosmolar hyperglycemic state (HHS) are mentally alert and the plasma effective osmolality has fallen below 315 mosmol/kg.
The patient is able to eat.

36. Bicarbonate therapy in severe diabetic ketoacidosis.
Morris LR, Murphy MB, Kitabchi AE. Ann Intern Med Dec;105(6):836-40
Twenty-one adult patients with severe diabetic ketoacidosis entered a randomized prospective protocol in which variable doses of sodium bicarbonate, based on initial arterial pH (6.9 to 7.14)
HCO3 were administered to 10 patients (treatment group) and were withheld from 11 patients (control group).
During treatment, there were no significant differences in the rate of decline of glucose or ketone levels or in the rate of increase in pH or bicarbonate levels in the blood or cerebrospinal fluid in either group.
Similarly, there were no significant differences in the time required for the plasma glucose level to reach 250 mg/dL, blood pH to reach 7.3, or bicarbonate level to reach 15 meq/L.
They conclude that in severe diabetic ketoacidosis (arterial pH 6.9 to 7.14), the administration of bicarbonate does not affect recovery outcome variables as compared with those in a control group.
Ann Intern Med Dec;105(6):836-40

37. Converting to subcutaneous insulin 1
The American Diabetes Association (ADA) guidelines for DKA recommend that IV insulin infusion be tapered and a multiple-dose SQ insulin schedule be started when the blood glucose is <200 mg/dL (11.1 mmol/L) and two of the following goals are met :
Serum anion gap <12 mEq/L (or at the upper limit of normal for the local laboratory)
Serum bicarbonate ≥15 mEq/L
Venous pH >7.30

38. Converting to subcutaneous insulin 2
Patients with known diabetes who were previously treated with insulin may be given insulin at the dose they were receiving before the onset of DKA or HHS.
In insulin-naive patients, a multi-dose insulin regimen should be started at a dose of 0.5 to 0.8 U/kg per day, including bolus and basal insulin until an optimal dose is established.
However, good clinical judgment and frequent glucose assessment is vital in initiating a new insulin regimen in insulin-naive patients.

46. Clinical Pearls:
Almost all patients with diabetic ketoacidosis who have relatively intact renal function will develop a hyperchloremic (normal AG) metabolic acidosis when they are treated with isotonic saline and insulin, due to the urinary loss of potential bicarbonate.
In contrast, patients with advanced chronic kidney disease will have limited or no excretion of ketoacid anions (potential bicarbonate) into the urine, and insulin therapy will return the serum HCO3 to values similar to those at baseline.

47. Clinical Pearls
When potassium salts are added to IV fluids, they have the same osmotic effect as sodium salts.
As an example, 40 mEq of KCl added to 1 L of fluid generates 80 mOsmol/L of electrolyte osmolality.
The addition of 40 mEq of potassium to 1 L of one-half isotonic saline creates a solution with an osmolality of 234 mOsmol/L (77 mEq sodium chloride [NaCl] and 40 mEq KCl), which is essentially three-quarters isotonic saline. (The osmolality of isotonic saline is 285 to 308 mOsmol/L).
If 40 mEq of KCl is added to isotonic saline, the final osmolality will be about 388 mOsmol/L. However, KCL will not have nearly the same extracellular fluid (ECF) expansion effect because most will shift into cells very rapidly.

48. COMPLICATIONS Hypoglycemia Hypokalemia Cerebral edema
The 2009 American Diabetes Association (ADA) guidelines on hyperglycemic crises in diabetes in adults suggested that the following preventive measures may reduce the risk of cerebral edema in high-risk patients:
Gradual replacement of sodium and water deficits in patients who are hyperosmolar. The usual regimen for the first few hours is isotonic saline at a rate of 15 to 20 mL/kg lean body weight per hour (about 1000 mL/hour in an average-sized person) with a maximum of <50 mL/kg in the first two to three hours .
The addition of dextrose to the saline solution once the serum glucose levels reach 200 mg/dL (11.1 mmol/L) in DKA or 250 to 300 mg/dL (13.9 to 16.7 mmol/L) in HHS.
In HHS, the serum glucose should be maintained at 250 to 300 mg/dL (13.9 to mmol/L) until the hyperosmolality and mental status improve and the patient is clinically stable.

49. DKA in Pregnancy 1
DKA occurs in approximately 1 to 3 percent of diabetic women who become pregnant.
The presentation of DKA is similar in pregnant and nonpregnant women, with symptoms of nausea, vomiting, thirst, polyuria, polydipsia, and a change in mental status.
Typical laboratory findings include acidemia, an elevated anion gap, renal dysfunction, and hyperglycemia (although as many as 36 percent of pregnant women may have blood glucose levels less than 200 mg/dL).

50. DKA in Pregnancy 2
Maternal hyperglycemia results in fetal hyperglycemia and fetal osmotic diuresis.
Maternal acidemia decreases uterine blood flow with a resultant decrease in placental perfusion leading to decreased oxygen delivery to the fetus.
Other than fetal heart rate monitoring, which is used to assess and monitor the fetus, DKA is treated similarly in pregnant and nonpregnant patients.
Plasma bicarbonate decreases during normal pregnancy. (NR 18-26).

51. Because the bicarbonate levels also decrease, pregnancy gives a state of COMPENSATED RESPIRATORY ALKOLOSIS
obstetrics-and-gynaecology/pregnancy-and- labour/normal-physiology- pregnancy#sthash.wWGxI0PL.dpuf

52. Sources: UP todate Chiasson J et al. CMAJ 2003;168:859-866
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycaemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335.
Hillier TA, Barrett E, AM Journal of Medicine. 1999 Apr;106(4):
Morris LR, Murphy MB, Kitabchi AE. Ann Intern Med Dec;105(6):836-40