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iabetic ketoacidosis (DKA) and the rapid than the overall increase in the di-
hyperosmolar hyperglycemic state agnosis of diabetes (1). Most patients with combination of insulin deficiency and in-
(HHS) are the two most serious acute DKA were between the ages of 18 and 44 creased counterregulatory hormones in
metabolic complications of diabetes. DKA is years (56%) and 45 and 65 years (24%), DKA also leads to the release of free fatty
responsible for more than 500,000 hospital with only 18% of patients ⬍20 years of acids into the circulation from adipose tis-
days per year (1,2) at an estimated annual age. Two-thirds of DKA patients were sue (lipolysis) and to unrestrained hepatic
DKA HHS
Mild (plasma glucose Moderate (plasma glucose Severe (plasma glucose Plasma glucose
⬎250 mg/dl) ⬎250 mg/dl) ⬎250 mg/dl) ⬎600 mg/dl
Arterial pH 7.25–7.30 7.00 to ⬍7.24 ⬍7.00 ⬎7.30
Serum bicarbonate (mEq/l) 15–18 10 to ⬍15 ⬍10 ⬎18
Urine ketone* Positive Positive Positive Small
Serum ketone* Positive Positive Positive Small
Effective serum osmolality† Variable Variable Variable ⬎320 mOsm/kg
Anion gap‡ ⬎10 ⬎12 ⬎12 Variable
Mental status Alert Alert/drowsy Stupor/coma Stupor/coma
*Nitroprusside reaction method. †Effective serum osmolality: 2关measured Na⫹ (mEq/l)兴 ⫹ glucose (mg/dl)/18. ‡Anion gap: (Na⫹) ⫺ 关(Cl⫺ ⫹ HCO3⫺ (mEq/l)兴.
(Data adapted from ref. 13.)
Table 2—Admission biochemical data in patients with HHS or DKA who complain of abdominal pain on pre-
sentation because the symptoms could be
HHS DKA either a result of the DKA or an indication
of a precipitating cause of DKA, particu-
Glucose (mg/dl) 930 ⫾ 83 616 ⫾ 36 larly in younger patients or in the absence
Na⫹ (mEq/l) 149 ⫾ 3.2 134 ⫾ 1.0 of severe metabolic acidosis (34,35). Fur-
K⫹ (mEq/l) 3.9 ⫾ 0.2 4.5 ⫾ 0.13 ther evaluation is necessary if this com-
BUN (mg/dl) 61 ⫾ 11 32 ⫾ 3 plaint does not resolve with resolution of
Creatinine (mg/dl) 1.4 ⫾ 0.1 1.1 ⫾ 0.1 dehydration and metabolic acidosis.
pH 7.3 ⫾ 0.03 7.12 ⫾ 0.04
Bicarbonate (mEq/l) 18 ⫾ 1.1 9.4 ⫾ 1.4 Laboratory findings
3--hydroxybutyrate (mmol/l) 1.0 ⫾ 0.2 9.1 ⫾ 0.85 The diagnostic criteria for DKA and HHS
Total osmolality* 380 ⫾ 5.7 323 ⫾ 2.5 are shown in Table 1. The initial labora-
IRI (nmol/l) 0.08 ⫾ 0.01 0.07 ⫾ 0.01 tory evaluation of patients include deter-
C-peptide (nmol/l) 1.14 ⫾ 0.1 0.21 ⫾ 0.03 mination of plasma glucose, blood urea
Free fatty acids (nmol/l) 1.5 ⫾ 0.19 1.6 ⫾ 0.16 nitrogen, creatinine, electrolytes (with
bolic acidosis. The anion gap is calculated major changes in intracellular volume contracted patients, plasma lactate should
by subtracting the sum of chloride and or osmotic gradient across the cell be measured on admission.
bicarbonate concentration from the so- membrane (4). A clinical history of previous drug
dium concentration: [Na ⫺ (Cl ⫹ Serum potassium concentration may abuse should be sought. Measurement of
HCO3)]. A normal anion gap is between 7 be elevated because of an extracellular serum salicylate and blood methanol level
and 9 mEq/l and an anion gap ⬎10 –12 shift of potassium caused by insulin defi- may be helpful. Ethylene glycol (anti-
mEq/l indicate the presence of increased ciency, hypertonicity, and acidemia (43). freeze) is suggested by the presence of cal-
anion gap metabolic acidosis (4). Patients with low normal or low serum cium oxalate and hippurate crystals in the
Hyperglycemia is a key diagnostic cri- potassium concentration on admission urine. Paraldehyde ingestion is indicated
terion of DKA; however, a wide range of have severe total-body potassium defi- by its characteristic strong odor on the
plasma glucose can be present on admis- ciency and require careful cardiac moni- breath. Because these intoxicants are low–
sion. Elegant studies on hepatic glucose toring and more vigorous potassium molecular weight organic compounds,
production rates have reported rates replacement because treatment lowers they can produce an osmolar gap in addi-
ranging from normal or near normal (38) potassium further and can provoke car- tion to the anion gap acidosis (14). A re-
to elevated (12,15), possibly contributing diac dysrhythmia. Pseudonormoglycemia cent report states that active cocaine use is
to the wide range of plasma glucose levels (44) and pseudohyponatremia (45) may an independent risk factor for recurrent
of cardiac, renal, and mental status must lin via continuous intravenous infusion or dose of insulin is not necessary if patients
be performed during fluid resuscitation to by frequent subcutaneous or intramuscu- receive an hourly insulin infusion of 0.14
avoid iatrogenic fluid overload (4,10, lar injections (4,56,57). Randomized units/kg body wt (equivalent to 10 units/h
15,53). Aggressive rehydration with sub- controlled studies in patients with DKA in a 70-kg patient) (59). In the absence of
sequent correction of the hyperosmolar have shown that insulin therapy is effec- an initial bolus, however, doses ⬍0.1
state has been shown to result in a more tive regardless of the route of administra- units 䡠 kg⫺1 䡠 h⫺1 resulted in a lower in-
robust response to low-dose insulin ther- tion (47). The administration of sulin concentration, which may not be
apy (54). continuous intravenous infusion of regu- adequate to suppress hepatic ketone body
During treatment of DKA, hypergly- lar insulin is the preferred route because production without supplemental doses
cemia is corrected faster than ketoacido- of its short half-life and easy titration and of insulin (15).
sis. The mean duration of treatment until the delayed onset of action and prolonged Low-dose insulin infusion protocols
blood glucose is ⬍250 mg/dl and ketoac- half-life of subcutaneous regular insulin decrease plasma glucose concentration at
idosis (pH ⬎7.30; bicarbonate ⬎18 (36,47,58). a rate of 50 –75 mg 䡠 dl⫺1 䡠 h⫺1. If plasma
mmol/l) is corrected is 6 and 12 h, respec- Numerous prospective randomized glucose does not decrease by 50 –75 mg
tively (9,55). Once the plasma glucose studies have demonstrated that use of from the initial value in the first hour, the
is ⬃ 200 mg/dl, 5% dextrose should be low-dose regular insulin by intravenous insulin infusion should be increased ev-
added to replacement fluids to allow con- infusion is sufficient for successful recov- ery hour until a steady glucose decline is
tinued insulin administration until ke- ery of patients with DKA. Until recently, achieved (Fig. 2). When the plasma glu-
tonemia is controlled while at the same treatment algorithms recommended the cose reaches 200 mg/dl in DKA or 300
time avoiding hypoglycemia. administration of an initial intravenous mg/dl in HHS, it may be possible to de-
dose of regular insulin (0.1 units/kg) fol- crease the insulin infusion rate to 0.02–
Insulin therapy lowed by the infusion of 0.1 units 䡠 kg⫺1 䡠 0.05 units 䡠 kg⫺1 䡠 h⫺1, at which time
The mainstay in the treatment of DKA in- h⫺1 insulin (Fig. 2). A recent prospective dextrose may be added to the intravenous
volves the administration of regular insu- randomized study reported that a bolus fluids (Fig. 2). Thereafter, the rate of in-
sulin administration or the concentration lead to impaired myocardial contractility, erally regarded as safe to treat severe
of dextrose may need to be adjusted to cerebral vasodilatation and coma, and hypophosphatemia is 4.5 mmol/h (1.5
maintain glucose values between 150 and several gastrointestinal complications ml/h of K2 PO4) (69). No studies are avail-
200 mg/dl in DKA or 250 and 300 mg/dl (63). A prospective randomized study in able on the use of phosphate in the treat-
in HHS until they are resolved. 21 patients failed to show either beneficial ment of HHS.
Treatment with subcutaneous rapid- or deleterious changes in morbidity or
acting insulin analogs (lispro and aspart) mortality with bicarbonate therapy in Transition to subcutaneous insulin
has been shown to be an effective alterna- DKA patients with an admission arterial Patients with DKA and HHS should be
tive to the use of intravenous regular in- pH between 6.9 and 7.1 (64). Nine small treated with continuous intravenous
sulin in the treatment of DKA. Treatment studies in a total of 434 patients with di- insulin until the hyperglycemic crisis is
of patients with mild and moderate DKA abetic ketoacidosis (217 treated with bi- resolved. Criteria for resolution of
with subcutaneous rapid-acting insulin carbonate and 178 patients without alkali ketoacidosis include a blood glucose
analogs every 1 or 2 h in non–intensive therapy [62]) support the notion that bi- ⬍200 mg/dl and two of the following cri-
care unit (ICU) settings has been shown carbonate therapy for DKA offers no ad- teria: a serum bicarbonate level ⱖ15
to be as safe and effective as the treatment vantage in improving cardiac or mEq/l, a venous pH ⬎7.3, and a calcu-
with intravenous regular insulin in the neurologic functions or in the rate of re- lated anion gap ⱕ12 mEq/l. Resolution of
bonate, respectively, but these complica- sulin during an illness and the reasons experiencing multiple episodes (77).
tions have occurred less often with the never to discontinue without contacting Based on an annual average of 135,000
low-dose insulin therapy (4,56,57). Fre- the health care team. hospitalizations for DKA in the U.S., with
quent blood glucose monitoring (every 3) Review of blood glucose goals and an average cost of 17,500 USD per pa-
1–2 h) is mandatory to recognize hypo- the use of supplemental short- or rapid- tient, the annual hospital cost for patients
glycemia because many patients with acting insulin. with DKA may exceed 2.4 billion USD per
DKA who develop hypoglycemia during 4) Having medications available to year (3). A recent study (2) reported that
treatment do not experience adrenergic suppress a fever and treat an infection. the cost burden resulting from avoidable
manifestations of sweating, nervousness, 5) Initiation of an easily digestible liq- hospitalizations due to short-term uncon-
fatigue, hunger, and tachycardia. Hyper- uid diet containing carbohydrates and salt trolled diabetes including DKA is sub-
chloremic non–anion gap acidosis, which when nauseated. stantial (2.8 billion USD). However, the
is seen during the recovery phase of DKA, 6) Education of family members on long-term impact of uncontrolled diabe-
is self-limited with few clinical conse- sick day management and record keeping tes and its economic burden could be
quences (43). This may be caused by loss including assessing and documenting more significant because it can contribute
of ketoanions, which are metabolized to temperature, blood glucose, and urine/ to various complications. Because most
bicarbonate during the evolution of DKA blood ketone testing; insulin administra- cases occur in patients with known diabe-
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