DIABETIC KETOACIDOSIS

Diabetic ketoacidosis (DKA) occurs in a setting of absolute or relative insulin deficiency. Estimated
annual incidence is 4 to 8 episodes per 1000 patients with diabetes. Specific clinical settings should
generate a high index of suspicion for the disorder. Interruptions of normal insulin delivery due to
purposeful reduction in insulin dosage or interference with the delivery system (eg, kinking in pump
tubing) are frequent precipitating events, as are reduced insulin sensitivity in the setting of systemic
infection, myocardial infarction, burns, trauma, or pregnancy. In a significant percentage of patients,
DKA is the presenting feature of diabetes. In these instances, clinical suspicion and accurate
interpretation of the initial laboratory studies will usually lead to the correct diagnosis. Measurement of
HbA1C (hemoglobin A1C) levels may help in assessing the chronicity of the diabetes. Mortality in DKA is
less than 5% in experienced centers. Prognosis worsens at the extremes of age and in the presence of
coma or hypotension.

Diagnosis

DKA is characterized metabolically by two prominent features: hyperglycemia and ketoacidosis. Patients
with DKA present with evidence of volume contraction (eg, dry mucous membranes, thirst, orthostatic
hypotension) and labored breathing (Kussmaul respiration) related to the underlying acidosis. The
breath often has a fruity odor, reflecting the presence of acetone. Patients may have abdominal pain
mimicking an acute abdomen, nausea, and vomiting. The latter symptoms may be related to elevated
gastrointestinal prostaglandins that accrue in the presence of insulin deficiency. Presentation may be
dominated by symptoms of the precipitating illness (eg, urinary tract infection, pneumonia, or
myocardial infarction). Plasma glucose levels are elevated, usually to over 250 mg/dL. This reflects
impairment in glucose utilization (see discussed earlier), increased gluconeogenesis and glycogenolysis,
and reduced renal clearance of glucose in the setting of decreased glomerular filtration rate (GFR).
Osmotic diuresis related to glucose excretion results in reduction in intravascular volume and depletion
of total body water, sodium, potassium, phosphate, and magnesium. In general, the relative depletion
of water is roughly twice that of the solutes it contains. Hypertonicity in the extracellular fluid
compartment, although typically not as severe as that seen in hyperosmotic nonketotic coma (see later),
can be significant. Calculated plasma osmolalities greater than 340 mOsm/kg are associated with coma.
Plasma osmolality—rather than acidemia—correlates most closely with state of consciousness in DKA.
Arterial blood pH is low and, in the absence of coexistent respiratory disease, is partially compensated
by a reduction in PCO2. The acidosis is metabolic in origin and accompanied by an anion gap that is
calculated by subtracting the combined concentrations of chloride and bicarbonate from serum sodium
concentration. Anion gaps greater than 12 mEq/L are considered abnormal. Keto acids account for most
of the unmeasured anions that generate the abnormal gap, although under conditions of extreme
volume contraction and hypoperfusion, lactate accumulation may also contribute. Levels of serum and
urinary ketones (measured using the nitroprusside reagent) are typically high in DKA. It should be
recalled, however, that this reagent reacts strongly only with acetoacetate, less strongly with acetone
(which is not a keto acid and does not contribute to the anion gap), and not at all with β
hydroxybutyrate. Thus, paradoxically, the most extreme levels of ketoacidosis may be accompanied by
relatively modest levels of ketones measured by this method. As a corollary between state of
consciousness and plasma osmolality in diabetic ketoacidosis. Note that the state of consciousness
correlates with plasma osmolality rather than blood pH of this, resolution of severe DKA may be linked
to transient increases in measurable ketone levels as β-hydroxybutyrate is converted to the more readily
detectable acetoacetate. Serum sodium levels may be high, normal, or low, but in all instances total
body sodium is depressed. Estimates of depletion range from 7 to 10 mEq/kg body weight. As blood
glucose levels rise in DKA, they create an osmotic gradient that draws water, as well as intracellular
solutes, into the extracellular space. This results in moderate hyponatremia, which can be corrected to
account for the dilutional effect of the transmembrane flux of water by adding 1.6 mEq/L (more recent
studies suggest that the correction factor is closer to 2.4 mEq/L) to the sodium concentration for every
100 mg/dL increment in plasma glucose above a basal concentration of 100 mg/dL (see below). The
decrease in serum sodium partially offsets the increase in tonicity that accompanies the elevation in
plasma glucose. This results in a net increase in plasma osmolality of 2 mOsm/kg H2O per 100 mg/dL
elevation in plasma glucose:

Corrected Na+ + = Measured Na

Total body potassium levels are also severely depleted in DKA to an average of 5 to 7 mEq/kg body
weight. This results from a number of factors, including exchange of intracellular potassium for
extracellular hydrogen ion, impaired movement of K+ into cells in the insulinopenic state, increased
urinary potassium excretion secondary to the osmotic diuresis and, in those instances where
intravascular volume contraction is present, secondary hyperaldosteronism. Serum potassium levels
may be high, normal, or low depending on the severity and duration of DKA, the status of extracellular
fluid volume, and the adequacy of renal perfusion and excretory function. A low serum potassium at
presentation generally indicates severe potassium deficiency and, in the presence of adequate renal
function, is an indication for early and aggressive repletion (see below). Potassium depletion can result
in muscle weakness and cardiac arrhythmias, including ventricular fibrillation. The H+ excess in DKA
titrates endogenous buffer systems including serum bicarbonate, resulting in reduction in
concentrations of the latter. Chloride levels may also be low, reflecting the osmotic diuresis alluded to
above. Ketone bodies have been estimated to account for one-third to one-half of the osmotic dieresis
seen in DKA. Electrolyte depletion is further aggravated by the obligate cation (eg, sodium) excretion
required to maintain electrical neutrality. In patients who have maintained adequate hydration during
the development of DKA or in those who are aggressively resuscitated with normal saline, chloride levels
may be elevated and the anion gap narrowed. This reflects the enhanced clearance of the keto anions in
the kidney, converting the system from an anion gap acidosis to a hyperchloremic, nongap acidosis (ie,
the hydrogen ion excess persists despite clearance of the anion). Because the excreted keto anions
represent a lost source of bicarbonate regeneration, correction of the hyperchloremic acidosis may
proceed slowly. The hyperchloremic acidosis is inconsequential from a clinical standpoint. Total body
magnesium and phosphate levels are also depleted by the osmotic diuresis in DKA. Phosphate depletion
is amplified by diffusion of the anion from the intracellular to the extracellular compartment in the
absence of insulin. Phosphate depletion can result in muscle weakness, rhabdomyolysis, hemolytic
anemia, respiratory distress, and altered tissue oxygenation (due to reduction in 2,3-diphosphoglycerate
levels in the red blood cell).
Management

Treatment of DKA is focused on two major objectives. The first is restoration of normal tonicity,
intravascular volume, and solute homeostasis. The second is correction of the insulinopenic state with
suppression of counterregulatory hormone secretion, glucose production, and ketogenesis and
improved utilization of glucose in target tissues. The steps outlined in Table 24–7 provide a general
approach to the management of this disorder. Because depletion of intracellular and extracellular fluids
may be severe in DKA (typically in the range of 5-10 L), early and aggressive resuscitation with fluids is
mandatory. This is usually initiated with administration of 1 to 2 L of isotonic normal saline (0.9% NaCl)
over the first hour of therapy. As intravascular volume is restored, renal perfusion increases, with a
consequent increase in renal clearance of glucose and a fall in plasma glucose levels. If volume
contraction is severe, a second liter of normal saline can be administered. If not, half-normal saline
(0.45% NaCl) can be initiated at a rate of 250 to 500 mL/h

Management of diabetic ketoacidosis.

Fluid administration

(1) 1-2 L of normal saline over the first hour. Repeat if clinically significant volume contraction persists
after the first hour.

(2) Change to half-normal saline, 500-1000 mL/h, depending on volume status. Continue for about 4 h.
Decrease rate to 250 mL/h as intravascular volume returns to normal.

(3) Convert fluids to D5W when plasma glucose falls to 250 mg/dL.

Insulin

(1) Administer 10-20 U of regular insulin IV.

(2) Mix 50 U of regular insulin in 500 mL of normal saline (1 U/10 mL).

Discard first 50 mL of infusion to accommodate insulin binding to tubing. Administer through piggyback
line along with parenteral fluids at a rate of 0.1 U/kg/h.

3. Double the infusion rate after 2 h if there is no improvement in plasma glucose levels.

Potassium

(1) Administer supplemental potassium chloride once renal function is established; provide 20 mEq/L of
fluids for patients who are initially normokalemic, 40 mEq/L for those who are hypokalemic at
presentation. In the latter case, hold insulin until serum potassium levels begin to increase.

(2) Gauge subsequent replacement based on serum K+ measurements at 2-h intervals.

Bicarbonate
(1) Sodium bicarbonate only for patients with blood pH less than 7.0.

(2) Add 1 ampule of sodium bicarbonate (44 mEq) to 500 mL of D5W or half-normal saline. Administer
over 1 h. depending on intravascular volume status. Because water is typically lost in excess of solute in
DKA, half-normal saline addresses both the volume depletion and the hypertonicity. It has been
suggested that approximately half of the total fluid deficit should be corrected within the first 5 hours of
therapy. Half-normal saline can be continued until intravascular volume has been restored or plasma
glucose levels fall to 250 mg/dL, at which point D5W should be started. The latter maneuver reduces the
likelihood of insulin-induced hypoglycemia and avoids the theoretical complication of cerebral edema
due to osmotically induced fluid shifts from plasma into the central nervous system. This complication is,
in fact, seen rarely in adults and uncommonly in children with DKA. It is important to account for
ongoing urinary volume and electrolyte losses in assessing fluid requirements. Once fluid resuscitation
has been initiated, insulin should be administered. Only short-acting insulin should be used. A number of
different insulin regimens have demonstrated efficacy in the treatment of DKA; however, a commonly
used regimen includes a loading dose (10-20 U) of regular insulin intravenously followed by a continuous
infusion at a rate of 0.1 U/kg/h. The need for a loading dose is controversial and may not be required in
the majority of cases. It is not recommended for children with ketoacidosis. If intravenous access is
problematic, maintenance insulin can be given intramuscularly (0.1 U/kg/h). This regimen provides
plasma insulin levels in a physiologic range (100-150 mU/mL) with minimal risk of hypoglycemia or
hypokalemia. It restores plasma glucose levels at rates equivalent to those obtained with regimens using
higher insulin doses. Plasma glucose levels should fall at a rate of 50 to 100 mg/dL/h. Failure to achieve
this end point over a 2-hour period should lead to doubling of the infusion rate with reevaluation an
hour later. When plasma glucose concentrations reach 250 mg/dL, D5W is begun to prevent
hypoglycemia (see above). Some diabetologists recommend a coincident reduction in insulin dose (to
0.05-0.1 U/kg/h) at this point. The insulin infusion is continued to suppress ketogenesis and allow
restoration of normal acid-base balance. As noted above, total body potassium stores are depleted in
DKA (∼3-4 mEq/kg), and plasma K+ levels fall with treatment. Repletion of K+ is almost always indicated
in management of DKA (one notable exception being DKA that occurs in the setting of chronic renal
insufficiency); however, the timing of repletion varies as a function of the plasma K+ level. If the initial
K+ level is less than 4 mEq/L, K+ depletion is severe, and repletion should begin with the first
administration of parenteral fluids if renal function is adequate. Twenty milliequivalents of potassium
chloride can be added to the first liter of normal saline if the serum K+ is in the 3.5 to 4 mEq/L range; 40
mEq should be added for K+ levels less than 3.5 mEq/L. Particular attention should be devoted to
patients in this latter state, because K+ levels may plummet to very low levels with initiation of insulin
therapy. To avoid this, insulin therapy should be postponed in this group until K+ repletion has begun
and serum K+ levels are on the rise. The general goal of therapy should be to keep the K+ in a near-
normal range. This may require several hundred milliequivalents of potassium chloride administered
over several days. The administration of bicarbonate in the setting of DKA hasbeen controversial.
Acidosis, in addition to increasing ventilator work (Kussmaul respiration), may also suppress cardiac
contractile function. Therefore, restoration of normal pH would seem to make sense in the setting of
DKA. However, there is considerable risk associated with the use of sodium bicarbonate in this setting,
including paradoxical acidification of the central nervous system due to the selective diffusion of CO2
versus HCO3− across the blood–brain barrier and an increase in intracellular acidosis, which may worsen
rather than ameliorate cardiac function. Volume overload related to the high tonicity (44.6-50 mEq/50
mL) of the bicarbonate solution, hypokalemia resulting from overly rapid correction of the acidosis,
hypernatremia, and rebound alkalosis are also potential complications of bicarbonate therapy. In
general, pH of 7.0 or greater is not life-threatening to the average patient with DKA and will resolve with
appropriate volume expansion and insulin therapy. For pH less than 7.0, many clinicians would argue for
a limited administration of sodium bicarbonate. If bicarbonate is used, careful patient monitoring
looking for alterations in mental status or cardiac decompensation is indicated. The goal of therapy
should be to maintain pH greater than 7.0, not to return pH to normal. Similarly, phosphate
administration, once considered a key component in the management of DKA (estimated deficit ∼5-7
mmol/kg), has come under closer scrutiny. Phosphate depletion definitely occurs in DKA for the reasons
outlined above, and in the past repletion of phosphate (much of it as potassium phosphate salts) had
been advocated to forestall the development of muscle weakness and hemolysis and to promote tissue
oxygenation through generation of 2,3-diphosphoglycerate in erythrocytes. However, the administration
of phosphate salts has been associated with the development of hypocalcemia and deposition of
calcium phosphate precipitates in soft tissues, including the vasculature. Thus, in general, parenteral
phosphate repletion is not routinely provided for patients with DKA unless plasma phosphate falls to
very low levels (<1 mmol/L). In this case, 2 mL of a mixture of KH2PO4 and K2HPO4 solution, containing
3 mmol of elemental phosphorus and 4 mEq of potassium, may be added to 1 L of fluids and introduced
over 6 to 8 hours. In no instance should all K+ repletion be in the form of potassium phosphate salts. In
general, renewal of food ingestion and insulin therapy complete restoration of total body phosphate
stores and return plasma phosphate levels to normal over a period of several days. In pediatric patients
(age <20 years) the need for volume expansion needs to be weighed against the potential risk of
cerebral edema secondary to aggressive fluid administration, although this is controversial (see below).
A recent recommendation suggests 10 to 20 mL/kg/h of normal saline during the first 1 to 2 hours with
limitation of total fluid administration to 50 mL/kg over the first 4 hours. The remaining fluid deficit is
corrected over the next 48 hours. Normal saline or half-normal saline (depending on serum Na+ levels)
usually accomplishes this with a rate of 5 mL/kg/h. The decrease in serum osmolality should not exceed
3 mOsm/kg H2O/h. An insulin bolus prior to initiating the insulin infusion (0.1 U/kg/h) is usually not
required in children. Finally, it is necessary to actively seek out and treat the precipitants of DKA when
they are identified. This includes appropriate cultures of urine and blood (and cerebrospinal fluid, if
indicated) and empiric antibiotic therapy directed against the most likely pathogenic organisms (pending
the results of the cultures). The presence of fever is typically a good marker for infection or other
inflammatory process because it is not a feature of DKA per se. Elevated white blood cell counts, on the
other hand, are frequently seen with DKA alone. Hyper-amylasemia is common but rarely reflects
pancreatitis—the amylase is usually of salivary origin. Other precipitants should also be sought.
Myocardial infarction, which is often clinically silent in diabetic patients, is an uncommon but life-
threatening precipitant of DKA in patients with established diabetes.

Complications
Aggressive resuscitation with isotonic or hypotonic fluids is a theoretical but uncommon cause of fluid
overload during management of DKA. Careful attention to the cardiovascular examination, chest x-ray,
and urine output should aid in preventing this complication.

Hypoglycemia is relatively rare in the current era given the low doses of insulin used in management and
appropriate initiation of glucose-containing fluids as plasma glucose levels fall below 250 mg/dL.

Cerebral edema due to rapid correction of plasma hypertonicity has usually been reported with plasma
glucose levels below 250 mg/dL. Clinically significant cerebral edema is relatively uncommon in adult
patients. Milder forms of cerebral edema have been noted in many patients being treated for DKA but
have not been strongly correlated with changes in extracellular tonicity. At present, in a symptomatic
adult patient, it would appear prudent to treat hypertonicity exceeding 340 mOsm/kg aggressively
withhypotonic fluids to avoid complications related to plasma hyperviscosity. Further correction from
that point to normal plasma osmolality (about 285 mOsm/kg) can probably be accomplished in slower
fashion over several days. Cerebral edema occurs in 1% to 2% of children with DKA, frequently with
devastating results. Approximately one-third of children with clinically significantcerebral edema die
during the acute illness, and another third sustain permanent neurologic impairment. The predilection
for young children may reflect, in part, immaturity of the autoregulatory mechanism that governs
cerebral blood flow. There is increased risk in children less than 5 years of age, and those with low PCO2
or high blood urea nitrogen at presentation. Cerebral edema in children may be associated with high
initial rates of fluid resuscitation (>4 L/m2/d) and rapid falls in plasma sodium (or corrected sodium)
concentration, although it can occur in clinical settings without an apparent cause, and mild degrees of
cerebral edema have been noted in DKA even prior to initiation of therapy. In the absence of definitive
trial data to guide therapy, lower rates of fluid administration (<2.5 L/m2/d) with volume resuscitation
spread over a longer time interval would seem appropriate if the clinical situation permits. When signs
of cerebral edema appear— deterioration in level of consciousness, focal neurologic signs, hypotension
or bradycardia, sudden decline in urine output after an initial period of apparent recovery following
treatment for DKA—fluid administration should be reduced and mannitol (0.2-1 g/kg given
intravenously over 30 minutes) should be administered with repetition at hourly intervals based on
response. CT or MRI scan of the brain can be done once therapy has been initiated to confirm the
diagnosis. Hyperventilation has not been shown to alter the course of this complication once it
develops.

Patients with DKA are also prone to develop acute respiratory distress syndrome, presumably reflecting
the sequelae of a damaged pulmonary endothelium and elevated capillary hydrostatic pressures
following fluid resuscitation. Patients who present with rales at the time of initial diagnosis may be at
higher risk for the development of this complication. Patients may also be at increased risk for
development of pancreatitis as well as systemic infection, including fungal infections (eg,
mucormycosis).

Abdominal pain and gastric stasis seen in DKA may put a semi-stuporous patient at risk for aspiration.
Up to 25% of patients with DKA have emesis that may be guaiac positive. The latter finding appears to
result from hemorrhagic gastritis. Patients who are believed to be at risk with regard to airway
protection should have a nasogastric tube in place for evacuation of stomach contents. Finally, patients
with DKA are at risk for recurrence of the disorder if insulin is withdrawn prematurely. The current
infusion protocols, because they raise plasma insulin only to physiologic levels, have a very short half-life
for control of blood glucose and ketogenesis. Premature cessation of insulin therapy before depot
insulin (eg, NPH or glargine insulin) can exert its effect may allow the patient to regress into
ketoacidosis. To preclude this possibility, subcutaneous regular and intermediate-acting insulin should
be provided on the morning when feeding is to be resumed. The insulin drip should be continued for 1
hour following this injection to provide coverage until the depot insulin becomes effective.