A. Characteristics

1. Usually occurs in Type 1 Diabetes with insufficient insulin
2. DKA is often the initial presentation of DM Type 1
   1. DKA less common but may occur in Type 2 DM
   2. About 20% of DM2 in African-American and Hispanic persons includes ketosis and may present with diabetic ketoacidosis (DKA) [2]
3. Diagnostic Criteria for Diabetic Ketoacidosis (DKA)
   1. Glucose >250mg/dL
   2. pH <7.35
   3. Low bicarbonate (<18mM)
   4. High anion gap
   5. Positive serum ketones
4. Symptoms
   1. Volume Loss: Polyuria, Polydipsia, Weakness, Tachycardia
   2. Acidosis: Tachypnea (Kussmaul Respiration), drowsiness, nausea (with vomiting), coma
   3. Inefficient glucose utilization: drowsiness, tachycardia, diaphoresis
5. Differential of Ketoacidosis
   1. Urinary ketones found in diabetes mellitus, alcoholism and starvation
   2. Serum ketones usually not seen in starvation unless very severe
   3. Always consider underlying alcohol abuse in new DKA

B. Precipitants of DKA

1. Always evaluate patients for underlying precipitant of DKA
   1. In many cases, poor compliance with insulin therapy leads to DKA [3,4]
   2. Other precipitants cause an increase in counter-regulatory hormones
   3. These stress hormones are released in infection, hypovolemia, diet changes, etc.
   4. Stress hormones include epinephrine, cortisol, glucagon, norepinephrine, growth hormone
2. Classes of Precipitants
   1. Noncompliance with insulin - often associated with substance abuse [3]
   2. Infection - most commonly of urinary tract in women (UTI)
   3. Ischemia - particularly with longstanding diabetes
3. Myocardial Infarction
   1. Common precipitant and/or complication of DKA or hyperosmolar glycemic episode
   2. All DKA patients should have an ECG, most should be ruled out by serum enzymes

C. Pathophysiology of DKA

1. Lack of insulin with increased glucagon leads to decreased glucose utilization
   1. This causes serum hyperglycemia with renal losses as glucosuria
   2. Low insulin and high glucagon fail to suppress lipolysis
   3. This leads to elevated fatty acids in blood with conversion to ketones and ketoacids
2. The ketoacids cause an anion gap acidosis which leads to compensitory tachypnea
3. Glucosuria causes an osmotic diuresis leading to hypovolemia
4. The combination of acidosis and hypovolemia causes worsening tissue perfusion
5. Acidosis, hypoperfusion eventually cause shock and hyperosmolar, ketotic, acidotic state
6. Hypersecretion of glucagon now thought to potentiate each of these problems

D. Initial Evaluation

1. Rapid history
2. Fingerstick glucose
3. Urinalyses
   1. Dipstick urine for glucose and ketones
   2. Urine specific gravity, sodium and creatinine levels for volume evaluation
4. Serum Analyses
   1. Electrolytes and renal function (BUN, Creatinine)
   2. Calcium, Phosphorus and Mg2+
   3. Albumin
   4. Acetone
   5. Serum pH (arterial or venous)
   6. Serum Na+ levels are not reflected accurately in presence of hyperglycemia
5. Evaluation of Serum Sodium (Na+) [5]
   1. High levels of glucose induce hyponatremia
   2. This is due primarily to extracellular shift of water since glucose is extracellular
   3. Laboratory results for serum Na+ levels with hyperglycemia should be adjusted to reflect these fluid shifts (which will reverse as glucose levels drop)
   4. Classically, adjustment of 1.6 meq/L decrease in Na+ for every 100mg/dL increase in serum glucose (above baseline 100mg/dL) was used
   5. However, likely that adjustment factor of 2.4meq/L is more appropriate
   6. For example, if serum glucose is 800mg/dL and reported serum Na+ is 132meq/L, then the corrected serum Na+ level is {(800-100)/100} x 2.4 + 132 = 149meq/L
   7. The corrected serum Na+ level reflects the true state of hypovolemia
6. Evaluation of Hypovolemia [4]
   1. Physical exam is not sensitive for hypovolemia
   2. Orthostatic vital sign changes are somewhat helpful
   3. Pulse increase >30 beats/min is specific but not very sensitive
   4. Capillary refill time and skin turgor are of no use in adults
   5. Serum electrolytes, renal function tests, and urine studies are most helpful
   6. Corrected serum Na+ levels as described above can be used to guide fluid treatment
7. Electrocardiogram (ECG)
   1. Initial evaluation of serum K+ prior to SMA7 data and to rule out cardiac ischemia
   2. Hyperkalemia due to acidosis and dehydration
   3. Hypokalemia due to volume (with electrolyte) depletion
8. Rule out myocardial infarction and other stresses as precipitant
9. Rule out infection as the underlying precipitant
   1. Chest Radiography
   2. Urinalysis - UTI is very common in diabetics
   3. Blood cultures as warranted
10. Begin Flow chart of progress

E. Therapeutic Overview

1. Replete Intravascular Volume
2. Correct Acidosis - insulin and fluids, possible bicarbonate
3. Lower Glucose - insulin
4. Maintain normal potassium and phosphorus
5. Attention to other electrolytes
6. Maintain suppression of ketosis - continued insulin ± glucose

F. Intravenous Fluid (IVF)

1. Assume hypovolemia deficit 60-70cc/kg (average 3-5 liters deficit; mostly water)
2. 1 liter/hr x 2-3 hrs Lactated Ringers or 0.9% (normal) Saline
3. Consider addition of Bicarbonate to IVF if pH <7.20
4. Monitor FS glucose q hr; when glucose < 300, add D5 (or D10) to IVF
5. Serum Na+ results must be corrected for level of hyperglycemia (see above)

G. Insulin [6]

1. Given to lower sugar but primarily to suppress ketogenesis
2. Initial Dosing
   1. Bolus of regular insulin 0.1-0.2U/kg intravenously (IV) initially
   2. Followed by regular insulin 0.1U/kg/hr IV, that is, 5-10U/hr IV (SC is not effective)
   3. Insulin Lispro can be used subcutaneously (SC)
   4. Lispro dose is 0.3U/kg SC initially then 0.1U/kg/hour sc until glucose <250mg/dL [8]
3. When glucose <250-300, consider starting sc normal insulin <0.25U/kg q4-6 hours or lispro insulin 0.05-0.1 U/kg/hr until resolution of acidosis [8]
4. There must be a 60-90 minute overlap between IV and sc insulin (qhr glucose checks)
5. If no response to insulin, consider resistance to insulin and increase dose
6. Stopping Insulin
   1. Insulin should be stopped only when pH>7.3, bicarbonate >18mEq/L, acetone is gone
   2. Monitor serum ketones, but note that ketone test only measures acetoacetate, not ßHB
7. Special Settings
   1. Insulin requirements are much reduced in renal failure (bolus low dose only)
   2. Insulin requirements are very high in setting of infection, MI, others

H. Potassium

1. Average deficit ~4 mmol/kg
2. May be elevated initially due to acidosis
3. ECG must be obtained early in course
   1. If ECG shows flat T waves or prominant U waves, add 40mEq/L K+ to initial IVF
   2. K+ will fall rapidly when pH and volume status are corrected
   3. Calcium iv should be given in setting of severe hyperkalemia, when ECG changes present

I. Phosphate

1. Average deficit ~1mmol/kg
2. Hypophosphatemia can cause changed MS, rhabdomyolysis, weakness, hemolysis
3. Respiratory failure has also been reported
4. Replete very slowly (3-5mmol / hour) iv
5. Rapid infusion can cause tonus, vasospasm and arrhythmias (due to Ca2+ binding)

J. Acidosis

1. Insulin + fluids will allow body to convert ketoacids to energy forms
2. Bicarbonate usually given for pH < 7.20 (controversial as HCO3- may worsen cell acidosis)
3. Acidosis with pH < 7.2 can cause respiratory problems and circulatory collapse
4. Consider 1 Liter of 1/2NS with 2 Amps sodium bicarbonate added

K. Complications of DKA

1. Shock
2. Infection: mucormyces is not uncommon following DKA
3. Thrombosis
4. Respiratory Distress
5. Arrhythmias: secondary to electrolyte and acid/base perturbations
6. Cerebral Edema (see below)
7. Death

L. Cerebral Edema

1. Epidemiology
   1. Rare but dreaded complication of treatment for DKA
   2. More commonly seen in pediatric than adult patients
   3. Sub-clinical cerebral edema occurs in majority of patients
   4. 0.7%-1.0% of pediatric cases develop clinically significant cerebral edema
2. Morbidity and Mortality
   1. Significant morbidity in survivors
   2. Only 7-14% of patients recover without permanent impairment
   3. Mortality approaches 50% of symptomatic patients
3. Likely present before the initiation of therapy
4. Risk Factors [7]
   1. Aggravated during aggressive rehydration
   2. Low partial pressures of arterial carbon dioxide (pCO2)
   3. Elevated serum urea nitrogen (BUN) concentrations
   4. Treatment with bicarbonate
5. Pathophysiology
   1. Brain cells enzymatically produce idiogenic osmoles in response to hyperosmolar state
   2. Thus, response to hyperglycemia is to protect against cell shrinkage
   3. Tight junctions between CNS endothelial cells permit instantaneous water diffusion
   4. But these junctions retard the rate of solute (Na+, Cl-) diffusion (blood-brain barrier)
   5. Cerebral edema develops after the initiation of rehydration therapy
   6. This occurs when serum biochemical indices suggest improvement
   7. Rapid serum glucose correction decreases serum osmolarity
   8. Plasma solute becomes lower than spinal fluid solute concentration
   9. Water without solute diffuses easily into cerebral spinal space
   10. Intracellular osmoles do not diffuse outward easily and must be enzymatically degraded
   11. Brain cells accumulate intracellular water (edema) to equalize osmolarity
   12. Rigid skull results in increased intracranial pressure as volume expands
   13. Significant cerebral edema can result in herniation of brain stem and cerebral tonsils
6. Symptoms
   1. Related to elevated intracranial pressure
   2. Headache
   3. Change in level of consciousness
   4. Papilledema or unequal dilated pupils
   5. Vomiting
   6. Neurological deterioration progresses rapidly if not treated
   7. Progresses to brain herniation with Cushing Triad:
   8. Bradycardia
   9. Elevated blood pressure
   10. Bradypnea and Respiratory arrest
   11. New onset polyuria (diabetes insipidus from pituitary necrosis)
7. Diagnosis
   1. Head CT confirms cerebral edema
   2. Radiologic confirmation of clinical diagnosis not needed to initiate therapy
8. Treatment
   1. Immediate therapy after earliest symptoms maximizes treatment efficacy
   2. Reduce rate of IVF to about maintenance rates
   3. Mannitol 1 g/kg IV infusion
   4. Intubation with hyperventilation
   5. Note risk factors for cerebral edema above
9. Prevention
   1. Cerebral edema more likely when serum Na+ fails to rise as serum glucose falls
   2. Use of NS rather than 0.5 NS replacement fluids prevent downward trend in serum Na+
   3. Correcting total fluid deficits over 48 hour period
   4. Correct hyperglycemia slowly (< 100 mg/hour)
   5. Prospective trial showed reduced risk of cerebral edema with slower therapy
   6. Risk factors suggest minimizing bicarbonate use

M. Hyperosmolar, Hypokalemic, Nonketotic Coma

1. Usually occurs in DM2 (and not in Type I DM)
2. Enough insulin will lead to suppression of ketolysis
   1. Failure of sufficient insulin can lead to frank diabetic ketoacidosis
   2. Patients with DM2 may secrete insulin intermittantly
3. However, hyperosmolar state (serum glucose may be >1000mg/dL) develops
4. Effects of Hyperosmolarity
   1. Osmotic diuresis ensues due to high glucose, leading to dehydration
   2. Potassium and magnesium are lost along with body water and sodium
   3. Severe dehydration will compromise cardiac perfusion
   4. High Cardiac Risks: tachycardia from dehydration, low cardiac perfusion, low K+, Mg+
   5. Impaired cerebral perfusion leads to coma
5. Typically triggered by underlying stress
   1. Infection appears to be most common
   2. MI or ischemia also not uncommon
   3. Dietary indiscretion, especially with failure to take medications
   4. Pancreatitis may precipitate hyperosmolar coma as well
6. Treatment
   1. Fluids usually with insulin as for diabetic ketoacidosis (DKA)
   2. Very high volumes of fluid usually required (with sodium)
   3. Fill intravascular space with saline, then correct free water deficit (see below)
   4. Attention to potassium and phosphate deficit
   5. Rarely need bicarbonate to reduce acidosis
7. Intravenous Fluid Replacement in Hyerosmolar Coma
   1. Dehydration is the major problem in this state
   2. Average deficit is 8-10Liters total body fluid depletion; give 1/4 to 1/3 in first 24 hrs
   3. Calculate fluid deficit based on osmolality of serum
   4. Correction of problem should begin with >2L of Normal Saline (~2L in first 18-24 hours)
   5. Calculation of free water deficit: Deficit = BW·[(Na-140)÷ 140] where BW= Body water
   6. BW = FF·Wt(Kg) where FF= fluid fraction, 0.6 for men, 0.5-0.45 for women, and elderly
   7. Na (sodium concentration) must be corrected for glucose value (as described above)
   8. In general, Na drops ~1.6mM for each 100mg/dL glucose value above 100mg/dL

References

1. Fleckman AM. 1993. Endocrin Metab Clin N Amer. 22(2):181
2. Umpierrez GE, Smiley D, Kitabchi AE. 2006. Ann Intern Med. 144(5):350
3. Umpierrez GE, Kelly JP, Navarrete JE, et al. 1997. Arch Intern Med. 157(6):669
4. Morris AD, Boyle DIR, McMahon AD, et al. 1997. Lancet. 350(9090):1505
5. Hillier TA, Abbott RD, Barrett EJ. 1999. Am J Med. 106(4):399
6. Metchick LN, Petit WA Jr, Inzucchi SE. 2002. Am J Med. 113(4):317
7. Glaser N, Barnett P, McCaslin I, et al. 2001. NEJM. 344(4):264
8. Umpierrez GE, Latif K, Stoever J, et al. 2004. Am J Med. 117(5):291