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## Complete Summary

#### GUIDELINE TITLE

Hyperglycemic crises in diabetes.

#### BIBLIOGRAPHIC SOURCE(S)

Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone
JI, Wall BM. Hyperglycemic crises in diabetes. Diabetes Care 2004
Jan;27(Suppl 1):S94-102. \[38 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14693938)

#### GUIDELINE STATUS

This is the current release of the guideline.

The guideline was originally approved in October 2000; the most recent
review/revision was completed in 2001.

American Diabetes Association (ADA) position statements are reissued
annually.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   Type 1 diabetes mellitus

-   Type 2 diabetes mellitus

-   Diabetic ketoacidosis (DKA)

-   Hyperosmolar hyperglycemic state

#### GUIDELINE CATEGORY

Diagnosis\
Evaluation\
Management\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Emergency Medicine\
Endocrinology\
Family Practice\
Internal Medicine\
Pediatrics

#### INTENDED USERS

Advanced Practice Nurses\
Nurses\
Physician Assistants\
Physicians

#### GUIDELINE OBJECTIVE(S)

To outline precipitating factors and recommendations for the diagnosis,
treatment, and prevention of diabetic ketoacidosis and hyperosmolar
hyperglycemic state

#### TARGET POPULATION

-   Adults and children with type 1 diabetes mellitus

-   Adults and children with type 2 diabetes mellitus

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis**

1.  Rapid, careful history and physical examination, with special
    attention to:

    -   Patency of airway

    -   Mental status

    -   Cardiovascular and renal status

    -   Sources of infection

    -   State of hydration

2.  Diagnostic tests:

    -   Plasma glucose

    -   Blood urea nitrogen (BUN)/creatinine

    -   Serum ketones

    -   Electrolytes (with calculated anion gap)

    -   Osmolality

    -   Urinalysis, urine ketones by dipstick

    -   Initial arterial blood gases

    -   Complete blood count with differential

    -   Bacterial cultures of urine, blood, and throat, etc. (if
        infection is suspected)

    -   Glycated hemoglobin

    -   Chest x-ray (if indicated)

    -   Electrocardiogram

**Treatment and Management**

1.  Fluid therapy

2.  Insulin therapy

3.  Potassium

4.  Bicarbonate

5.  Phosphate

**Prevention**

1.  Education of patients and caregivers:

    -   Knowledge regarding conditions, procedures, and medications that
        worsen diabetes control

    -   Glucose monitoring

2.  Sick-day management:

    -   When to contact the health care provider

    -   Blood glucose goals and use of supplemental short-acting insulin
        during illness

    -   Means to suppress fever and treat infection

    -   Initiation of an easily digestible liquid diet containing
        carbohydrates and salt

    -   Patient advisement never to discontinue insulin and to seek
        professional advice early in the course of the illness

    -   Involvement by the patient and/or a family member

    -   Accurate measurement and recording of blood glucose and urine or
        blood ketone

    -   Measurement of temperature, respiratory and pulse rate, and body
        weight and communication to a health care professional

#### MAJOR OUTCOMES CONSIDERED

-   Incidence rates of diabetic ketoacidosis and hyperosmolar
    hyperglycemic state

-   Morbidity and mortality associated with diabetic ketoacidosis and
    hyperosmolar hyperglycemic state

-   Efficacy of treatment

-   Health care costs

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Recommendations have been assigned ratings of A, B, or C, depending on
the quality of evidence (see table below). Expert opinion (E) is a
separate category for recommendations in which there is as yet no
evidence from clinical trials, in which clinical trials may be
impractical, or in which there is conflicting evidence. Recommendations
with an \"A\" rating are based on large, well-designed clinical trials
or well done meta-analyses. Generally, these recommendations have the
best chance of improving outcomes when applied to the population to
which they are appropriate. Recommendations with lower levels of
evidence may be equally important but are not as well supported.

American Diabetes Association\'s evidence grading system for clinical
practice recommendations:

**A**

Clear evidence from well-conducted, generalizable, randomized controlled
trials that are adequately powered including:

-   Evidence from a well-conducted multicenter trial

-   Evidence from a meta-analysis that incorporated quality ratings in
    the analysis

-   Compelling non-experimental evidence, i.e., \"all or none\" rule
    developed by the Center for Evidence Based Medicine at Oxford\*

Supportive evidence from well-conducted randomized trials that are
adequately powered including:

-   Evidence from a well-conducted trial at one or more institutions

-   Evidence from a meta-analysis that incorporated quality ratings in
    the analysis

*\*Either all patients died before therapy and at least some survived
with therapy, or some patients died without therapy and none died with
therapy. Example: use of insulin in the treatment of diabetic
ketoacidosis*.

**B**

Supportive evidence from well-conducted cohort studies, including:

-   Evidence from a well-conducted prospective cohort study or registry

-   Evidence from a well-conducted meta-analysis of cohort studies

Supportive evidence from a well-conducted case-control study

**C**

Supportive evidence from poorly controlled or uncontrolled studies:

-   Evidence from randomized clinical trials with one or more major or
    three or more minor methodological flaws that could invalidate the
    results

-   Evidence from observational studies with high potential for bias
    (such as case series with comparison with historical controls)

-   Evidence from case series or case reports

Conflicting evidence with the weight of evidence supporting the
recommendation

**E**

Expert consensus or clinical experience

#### COST ANALYSIS

Significant resources are spent on the cost of hospitalization. Based on
an annual average of 100,000 hospitalizations for diabetic ketoacidosis
in the U.S., with an average cost of \$13,000 per patient, the annual
hospital cost for patients with diabetic ketoacidosis may exceed \$1
billion per year.

#### METHOD OF GUIDELINE VALIDATION

Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

This document was peer-reviewed, modified, and approved by the
Professional Practice Committee and the Executive Committee, October
2000. The paper was most recently revised in 2001.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

*Excerpted by the National Guideline Clearinghouse (NGC)*

The evidence grading system (A through C, E) is defined at the end of
the \"Major Recommendations\" field.

**[Diagnosis]{.underline}**

**History and Physical Examination**

The first approach to patients suspected of diabetic ketoacidosis (DKA)
or hyperosmolar hyperglycemic state (HHS) consists of a rapid but
careful history and physical examination with special attention to (1)
patency of airway, (2) mental status, (3) cardiovascular and renal
status, (4) sources of infection, and (5) state of hydration. These
steps should allow determination of the degree of urgency and priority
with which various laboratory results should be obtained so that
treatment can start without delay. Please refer to the original
guideline document for signs and symptoms associated with diabetic
ketoacidosis and hyperosmolar hyperglycemic state.

**Laboratory Evaluation**

The initial laboratory evaluation of patients with suspected DKA or HHS
should include determination of plasma glucose, blood urea
nitrogen/creatinine, serum ketones, electrolytes (with calculated anion
gap), osmolality, urinalysis, urine ketones by dipstick, as well as
initial arterial blood gases, complete blood count with differential,
and electrocardiogram. Bacterial cultures of urine, blood, and throat,
etc., should be obtained and appropriate antibiotics given if infection
is suspected. Glycated hemoglobin (HbA~1c~) may be useful in determining
whether this acute episode is the culmination of an evolutionary process
in previously undiagnosed or poorly controlled diabetes or a truly acute
episode in an otherwise well-controlled patient. A chest x-ray should
also be obtained if indicated. Table 1 (reproduced below) and Table 2
titled \"Typical Total Body Deficits of Water and Electrolytes in DKA
and HHS\" in the original guideline document depict typical laboratory
findings in patients with DKA or HHS.

**Table 1. Diagnostic Criteria for DKA and HHS**

  --------------------------------------------------------------------------------
  ** **                      **DKA**                                 ** **
  -------------------------- ---------- -------------- ------------- -------------
  ** **                      **Mild**   **Moderate**   **Severe**    **HHS**

                                                                     

  Plasma glucose (mg/dL)     \>250      \>250          \>250         \>600

  Arterial pH                7.25 to    7.00 to 7.24   \<7.00        \>7.30
                             7.30                                    

  Serum bicarbonate (mEq/L)  15 to 18   10 to \<15     \<10          \>15

  Urine ketones\*            Positive   Positive       Positive      Small

  Serum ketones\*            Positive   Positive       Positive      Small

  Effective serum osmolality Variable   Variable       Variable      \>320
  (mOsm/kg)\*\*                                                      

  Anion gap\*\*\*            \>10       \>12           \>12          Variable

  Alteration in sensorium or Alert      Alert/drowsy   Stupor/coma   Stupor/coma
  mental obtundation                                                 
  --------------------------------------------------------------------------------

\*Nitroprusside reaction method

\*\*Calculation: 2\[measured Na (mEq/)\] + glucose (mg/dL)/18

\*\*\*Calculation: (Na^+^) -- (Cl^-^ -- HCO~3~^-^) (mEq/L). See the text
of the original guideline document for details.

The majority of patients with hyperglycemic emergencies present with
leukocytosis proportional to blood ketone body concentration. Serum
sodium concentration is usually decreased because of the osmotic flux of
water from the intracellular to the extracellular space in the presence
of hyperglycemia, and less commonly, serum sodium concentration may be
falsely lowered by severe hypertriglyceridemia. Serum potassium
concentration may be elevated because of an extracellular shift of
potassium caused by insulin deficiency, hypertonicity, and acidemia.
Patients with low-normal or low serum potassium concentration on
admission have severe total-body potassium deficiency and require very
careful cardiac monitoring and more vigorous potassium replacement,
because treatment lowers potassium further and can provoke cardiac
dysrhythmia. The occurrence of stupor or coma in diabetic patients in
the absence of definitive elevation of effective osmolality
([\>]{.underline}320 mOsm/kg) demands immediate consideration of other
causes of mental status change. Effective osmolality may be calculated
by the following formula: 2\[measured Na (mEq/L)\] + glucose (mg/dL)/18.
Amylase levels are elevated in the majority of patients with DKA, but
this may be due to nonpancreatic sources, such as the parotid gland. A
serum lipase determination may be beneficial in the differential
diagnosis of pancreatitis. However, lipase could also be elevated in
DKA. Abdominal pain and elevation of serum amylase and liver enzymes are
noted more commonly in DKA than in HHS.

**Differential Diagnosis**

Not all patients with ketoacidosis have DKA. Starvation ketosis and
alcoholic ketoacidosis are distinguished by clinical history and by
plasma glucose concentrations that range from mildly elevated (rarely
\>250 mg/dL) to hypoglycemia. In addition, although alcoholic
ketoacidosis can result in profound acidosis, the serum bicarbonate
concentration in starvation ketosis is usually not lower than 18 mEq/L.
Diabetic ketoacidosis must also be distinguished from other causes of
high-anion gap metabolic acidosis, including lactic acidosis, ingestion
of drugs such as salicylate, methanol, ethylene glycol, and paraldehyde,
and chronic renal failure (which is more typically hyperchloremic
acidosis rather than high-anion gap acidosis). Clinical history of
previous drug intoxications or metformin use should be sought.
Measurement of blood lactate, serum salicylate, and blood methanol level
can be helpful in these situations. Ethylene glycol (antifreeze) is
suggested by the presence of calcium oxalate and hippurate crystals in
the urine. Paraldehyde ingestion is indicated by its characteristic
strong odor on the breath. Because these intoxicants are low-molecular
weight organic compounds, they can produce an osmolar gap in addition to
the anion gap acidosis.

**[Treatment]{.underline}**

Successful treatment of DKA and HHS requires correction of dehydration,
hyperglycemia, and electrolyte imbalances; identification of comorbid
precipitating events; and above all, frequent patient monitoring.
Guidelines for the management of patients with DKA and HHS follow and
are summarized in Figures 1, 2, and 3 of the original guideline
document. Table 3 in the original guideline document includes a summary
of major recommendations and evidence gradings.

**Fluid Therapy**

Initiate fluid replacement therapy based on recommendations in the
original guideline document. (*Grade A*)

**Adult patients**. Initial fluid therapy is directed toward expansion
of the intravascular and extravascular volume and restoration of renal
perfusion. In the absence of cardiac compromise, isotonic saline (0.9%
sodium chloride) is infused at a rate of 15 to 20 mL/kg body weight per
hour or greater during the 1st hour (approximately 1 to 1.5 liters in
the average adult). Subsequent choice for fluid replacement depends on
the state of hydration, serum electrolyte levels, and urinary output. In
general, 0.45% sodium chloride infused at 4 to 14 mL/kg per hour is
appropriate if the corrected serum sodium is normal or elevated; 0.9%
sodium chloride at a similar rate is appropriate if corrected serum
sodium is low. Once renal function is assured, the infusion should
include 20 to 30 mEq/L potassium (2/3 potassium chloride and 1/3
potassium phosphate) until the patient is stable and can tolerate oral
supplementation. Successful progress with fluid replacement is judged by
hemodynamic monitoring (improvement in blood pressure), measurement of
fluid input/output, and clinical examination. Fluid replacement should
correct estimated deficits within the first 24 hours. The induced change
in serum osmolality should not exceed 3 mOsm/kg H~2~O per hour. In
patients with renal or cardiac compromise, monitoring of serum
osmolality and frequent assessment of cardiac, renal, and mental status
must be performed during fluid resuscitation to avoid iatrogenic fluid
overload.

**Pediatric patients (\<20 years of age)**. Initial fluid therapy is
directed toward expansion of the intravascular and extravascular volume
and restoration of renal profusion. The need for vascular volume
expansion must be offset by the risk of cerebral edema associated with
rapid fluid administration. The first hour of fluids should be isotonic
saline (0.9% sodium chloride) at the rate of 10 to 20 mL/kg per hour. In
a severely dehydrated patient, this may need to be repeated, but the
initial reexpansion should not exceed 50 mL/kg over the first 4 hours of
therapy. Continued fluid therapy is calculated to replace the fluid
deficit evenly over 48 hours. In general, 0.45 to 0.9% sodium chloride
(depending on serum sodium levels) infused at a rate of 1.5 times the
24-hour maintenance requirements (approximately 5 mL/kg per hour) will
accomplish a smooth rehydration, with a decrease in osmolality not
exceeding 3 mOsm/kg H~2~O per hour. Once renal function is assured and
serum potassium is known, the infusion should include 20 to 40 mEq/L
potassium (2/3 potassium chloride or potassium-acetate and 1/3 potassium
phosphate). Once serum glucose reaches 250 mg/dL, fluid should be
changed to 5% dextrose and 0.45 to 0.75% sodium chloride, with potassium
as described above. Therapy should include monitoring mental status to
rapidly identify changes that might indicate iatrogenic fluid overload,
which can lead to symptomatic cerebral edema.

**Insulin Therapy**

Initiate insulin therapy according to the recommendations in the
original guideline document. (*Grade A*)

Unless the episode of DKA is mild (see Table 1, above), regular insulin
by continuous intravenous infusion is the treatment of choice (*Grade
B*). In adult patients, once hypokalemia (K^+^ \<3.3 mEq/L) is excluded,
an intravenous bolus of regular insulin at 0.15 units/kg body weight,
followed by a continuous infusion of regular insulin at a dose of 0.1
unit/kg per hour (5 to 7 units per hour in adults), should be
administered. An initial insulin bolus is not recommended in pediatric
patients; a continuous insulin infusion of regular insulin at a dose of
0.1 unit/kg per hour may be started in these patients. This low dose of
insulin usually decreases plasma glucose concentration at a rate of 50
to 75 mg/dL per hour, similar to a higher-dose insulin regimen. If
plasma glucose does not fall by 50 mg/dL from the initial value in the
first hour, check hydration status; if acceptable, the insulin infusion
may be doubled every hour until a steady glucose decline between 50 and
75 mg/hour is achieved. When the plasma glucose reaches 250 mg/dL in DKA
or 300 mg/dL in HHS, it may be possible to decrease the insulin infusion
rate to 0.05 to 0.1 unit/kg per hour (3 to 6 units per hour), and
dextrose (5 to 10%) may be added to the intravenous fluids. Thereafter,
the rate of insulin administration or the concentration of dextrose may
need to be adjusted to maintain the above glucose values until acidosis
in DKA or mental obtundation and hyperosmolarity in HHS are resolved.

Ketonemia typically takes longer to clear than hyperglycemia. Direct
measurement of beta-hydroxybutyric acid in the blood is the preferred
method for monitoring DKA. The nitroprusside method only measures
acetoacetic acid and acetone. However, beta-hydroxybutyric acid, the
strongest and most prevalent acid in DKA, is not measured by the
nitroprusside method. During therapy, beta-hydroxybutyric acid is
converted to acetoacetic acid, which may lead the clinician to believe
that ketosis has worsened. Therefore, assessments of urinary or serum
ketone levels by the nitroprusside method should not be used as an
indicator of response to therapy. During therapy for DKA or HHS, blood
should be drawn every 2 to 4 hours for determination of serum
electrolytes, glucose, blood urea nitrogen, creatinine, osmolality, and
venous pH (for DKA). Generally, repeat arterial blood gases are
unnecessary; venous hydrogen ion concentration (which is usually 0.03
units lower than arterial pH) and anion gap can be followed to monitor
resolution of acidosis. With mild DKA, regular insulin given either
subcutaneously or intramuscularly every hour is as effective as
intravenous administration in lowering blood glucose and ketone bodies.
Patients with mild diabetic ketoacidosis should first receive a
\"priming\" dose of regular insulin of 0.4 to 0.6 units/kg body weight,
half as an intravenous bolus and half as a subcutaneous or intramuscular
injection. Thereafter, 0.1 unit/kg per hour of regular insulin should be
given subcutaneously or intramuscularly.

Criteria for resolution of DKA includes a glucose \<200 mg/dL, serum
bicarbonate [\>]{.underline}18 mEq/L, and a venous pH of \>7.3. Once DKA
is resolved, if the patient is nothing by mouth, continue intravenous
insulin and fluid replacement and supplement with subcutaneous regular
insulin as needed every 4 hours. In adult patients, this can be given in
5-unit increments for every 50 mg/dL increase in blood glucose above 150
mg/dl for up to 20 units for blood glucose of [\>]{.underline}300 mg/dl.
When the patient is able to eat, a multiple-dose schedule should be
started that uses a combination of short-or rapid-acting and
intermediate- or long-acting insulin as needed to control plasma
glucose. Continue intravenous insulin infusion for 1 to 2 hours after
the split-mixed regimen is begun to ensure adequate plasma insulin
levels. An abrupt discontinuation of intravenous insulin coupled with a
delayed onset of a subcutaneous insulin regimen may lead to worsened
control; therefore, some overlap should occur in intravenous insulin
therapy and initiation of the subcutaneous insulin regimen. Patients
with known diabetes may be given insulin at the dose they were receiving
before the onset of DKA or HHS and further adjusted as needed for
control. In patients with newly diagnosed diabetes, the initial total
insulin dose should be approximately 0.5 to 1.0 units/kg per day,
divided into at least two doses in a regimen including short- and
long-acting insulin until an optimal dose is established. Finally, some
type 2 diabetes patients may be discharged on oral antihyperglycemic
agents and dietary therapy.

**Potassium**

Despite total-body potassium depletion, mild to moderate hyperkalemia is
not uncommon in patients with hyperglycemic crises. Insulin therapy,
correction of acidosis, and volume expansion decrease serum potassium
concentration. To prevent hypokalemia, potassium replacement is
initiated after serum levels fall below 5.5 mEq/L, assuming the presence
of adequate urine output. Generally, 20 to 30 mEq potassium (2/3
potassium chloride and 1/3 potassium phosphate) in each liter of
infusion fluid is sufficient to maintain a serum potassium concentration
within the normal range of 4 to 5 mEq/L. Rarely, DKA patients may
present with significant hypokalemia. In such cases, potassium
replacement should begin with fluid therapy, and insulin treatment
should be delayed until potassium concentration is restored to \>3.3
mEq/L to avoid arrhythmias or cardiac arrest and respiratory muscle
weakness.

**Bicarbonate**

Assess need for bicarbonate therapy and, if necessary, follow treatment
recommendations in the original guideline document: bicarbonate may be
beneficial in patients with a pH \<6.9; no bicarbonate is necessary if
pH is \>7.0. (*Grade C*)

No prospective randomized studies concerning the use of bicarbonate in
DKA with pH values \<6.9 have been reported. Given that severe acidosis
may lead to a myriad of adverse vascular effects, it seems prudent that
for adult patients with a pH \<6.9, 100 mmol sodium bicarbonate be added
to 400 mL sterile water and given at a rate of 200 mL/hour. In patients
with a pH of 6.9 to 7.0, 50 mmol sodium bicarbonate is diluted in 200 mL
sterile water and infused at a rate of 200 mL/hour. No bicarbonate is
necessary if pH is \>7.0.

Insulin, as well as bicarbonate therapy, lowers serum potassium;
therefore, potassium supplementation should be maintained in intravenous
fluid as described above and carefully monitored. (See Figure 1 in the
original guideline document.) Thereafter, venous pH should be assessed
every 2 hours until the pH rises to 7.0, and treatment should be
repeated every 2 hours if necessary.

In the pediatric patient, there are no randomized studies in patients
with pH \<6.9. If the pH remains less than 7.0 after the initial hour of
hydration, it seems prudent to administer 1 to 2 mEq/kg sodium
bicarbonate over the course of one hour. This sodium bicarbonate can be
added to sodium chloride, with any required potassium, to produce a
solution that does not exceed 155 mEq/L sodium. No bicarbonate therapy
is required if pH is [\>]{.underline}7.0.

**Phosphate**

Prospective randomized studies have failed to show any beneficial effect
of phosphate replacement on the clinical outcome in DKA, and overzealous
phosphate therapy can cause hypocalcemia with no evidence of tetany.
However, to avoid cardiac and skeletal muscle weakness and respiratory
depression due to hypophosphatemia, careful phosphate replacement may
sometimes be indicated in patients with cardiac dysfunction, anemia, or
respiratory depression and in those with serum phosphate concentration
less than 1.0 mg/dL. (*Grade A*) When needed, 20 to 30 mEq/L potassium
phosphate can be added to replacement fluids. No studies are available
on the use of phosphate in the treatment of hyperosmolar hyperglycemic
state. Continuous monitoring using a flowsheet (see Figure 4 in the
original guideline document) aids in the organization of recovery
parameters and treatment interventions.

**[Complications]{.underline}**

Complications of DKA and HHS, including hypoglycemia, hypokalemia,
hyperglycemia, hyperchloremia, cerebral edema, hypoxemia, and
non-cardiogenic pulmonary edema are discussed in the original guideline
document.

Studies of cerebral edema in DKA are limited in number. Therefore, to
avoid the occurrence of cerebral edema, follow the recommendations in
the original guideline document regarding a gradual correction of
glucose and osmolality as well as the judicious use of isotonic or
hypotonic saline, depending on serum sodium and the hemodynamic state of
the patient. (*Grade C*)

Prevention measures that might decrease the risk of cerebral edema in
high-risk patients are gradual replacement of sodium and water deficits
in patients who are hyperosmolar (maximal reduction in osmolality 3
mOsm/kg H~2~O per hour) and the addition of dextrose to the hydrating
solution once blood glucose reaches 250 mg/dL. In HHS, a glucose level
of 250 to 300 mg/dL should be maintained until hyperosmolarity and
mental status improves and the patient becomes clinically stable.

**Prevention**

Many cases of DKA and HHS can be prevented by better access to medical
care, proper education, and effective communication with a health care
provider during an intercurrent illness. The observation that stopping
insulin for economic reasons is a common precipitant of DKA in urban
African-Americans is disturbing and underscores the need for health care
delivery systems to address this problem, which is costly and clinically
serious.

Sick-day management should be reviewed periodically with all patients.
It should include specific information on (1) when to contact the health
care provider, (2) blood glucose goals and use of supplemental
short-acting insulin during illness, (3) means to suppress fever and
treat infection, and (4) initiation of an easily digestible liquid diet
containing carbohydrates and salt. Most importantly, the patient should
be advised to never discontinue insulin and to seek professional advice
early in the course of the illness. Successful sick-day management
depends on involvement by the patient and/or a family member. The
patient/family member must be able to accurately measure and record
blood glucose, urine or blood ketone determination when blood glucose is
\>300 mg/dL, insulin administered, temperature, respiratory and pulse
rate, and body weight and must be able to communicate this to a health
care professional. Adequate supervision and help from staff or family
may prevent many of the admissions for hyperosmolar hyperglycemic state
due to dehydration among elderly individuals who are unable to recognize
or treat this evolving condition. Better education of care givers as
well as patients regarding signs and symptoms of new-onset diabetes;
conditions, procedures, and medications that worsen diabetes control;
and the use of glucose monitoring could potentially decrease the
incidence and severity of hyperosmolar hyperglycemic state.

Because repeated admissions for DKA are estimated to drain approximately
one out of every two health care dollars spent on adult patients with
type 1 diabetes, resources need to be redirected toward prevention by
funding better access to care and educational programs tailored to
individual needs, including ethnic and personal health care beliefs. In
addition, resources should be directed toward the education of primary
care providers and school personnel so that they can identify signs and
symptoms of uncontrolled diabetes and new-onset diabetes can be
diagnosed at an earlier time. This has been shown to decrease the
incidence of DKA at the onset of diabetes.

**[Definitions]{.underline}**:

American Diabetes Association\'s evidence grading system for clinical
practice recommendations:

**A**

Clear evidence from well-conducted, generalizable, randomized controlled
trials that are adequately powered including:

-   Evidence from a well-conducted multicenter trial

-   Evidence from a meta-analysis that incorporated quality ratings in
    the analysis

-   Compelling non-experimental evidence, i.e., \"all or none\" rule
    developed by the Center for Evidence Based Medicine at Oxford\*

Supportive evidence from well-conducted randomized trials that are
adequately powered including:

-   Evidence from a well-conducted trial at one or more institutions

-   Evidence from a meta-analysis that incorporated quality ratings in
    the analysis

*\*Either all patients died before therapy and at least some survived
with therapy, or some patients died without therapy and none died with
therapy. Example: use of insulin in the treatment of diabetic
ketoacidosis*.

**B**

Supportive evidence from well-conducted cohort studies, including:

-   Evidence from a well-conducted prospective cohort study or registry

-   Evidence from a well-conducted meta-analysis of cohort studies

Supportive evidence from a well-conducted case-control study

**C**

Supportive evidence from poorly controlled or uncontrolled studies:

-   Evidence from randomized clinical trials with one or more major or
    three or more minor methodological flaws that could invalidate the
    results

-   Evidence from observational studies with high potential for bias
    (such as case series with comparison with historical controls)

-   Evidence from case series or case reports

Conflicting evidence with the weight of evidence supporting the
recommendation

**E**

Expert consensus or clinical experience

#### CLINICAL ALGORITHM(S)

The original guideline document contains clinical algorithms for:

-   Management of Adult Patients with Diabetic Ketoacidosis

-   Management of Adult Patients with Hyperosmolar Hyperglycemic State

-   Management of Pediatric Patients (\<20 years) with Diabetic
    Ketoacidosis or Hyperosmolar Hyperglycemic State

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for select
recommendations (see the \"Major Recommendations\" field).

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Appropriate management (diagnosis, treatment, and prevention) of
    hyperglycemic crises in patients with diabetes

-   Decreased incidence and severity of diabetic ketoacidosis and
    hyperosmolar hyperglycemic state

-   Decreased morbidity and mortality associated with diabetic
    ketoacidosis and hyperosmolar hyperglycemia

-   Decreased health care costs

#### POTENTIAL HARMS

-   Severe hypocalcemia is associated with phosphate therapy.

-   Hypoglycemia or hypokalemia are associated with insulin
    administration.

-   Hypokalemia is associated with bicarbonate.

-   Hyperchloremia and transient non-anion gap metabolic acidosis are
    associated with saline for fluid and electrolyte replacement. These
    biochemical abnormalities are transient and are not clinically
    significant except in cases of acute renal failure or extreme
    oliguria.

-   Fatalities can be associated with the treatment of diabetic
    ketoacidosis or hyperosmolar hyperglycemic state. Cerebral edema is
    a rare but frequently fatal complication of diabetic ketoacidosis.
    Fatal cases of cerebral edema have also been reported with
    hyperosmolar hyperglycemic state. Although the mechanism of cerebral
    edema is not known, it likely results from osmotically driven
    movement of water into the central nervous system when plasma
    osmolality declines too rapidly with the treatment of diabetic
    ketoacidosis or hyperosmolar hyperglycemic state.

**Subgroups Most Likely to be Harmed**

Patients with acute renal failure or extreme oliguria are most likely to
be harmed by saline for fluid and electrolyte replacement.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   Bicarbonate use in diabetic ketoacidosis remains controversial. At a
    pH \>7.0, reestablishing insulin activity blocks lipolysis and
    resolves ketoacidosis without any added bicarbonate. Prospective
    randomized studies have failed to show either beneficial or
    deleterious changes in morbidity or mortality with bicarbonate
    therapy in diabetic ketoacidosis patients with pH between 6.9 and
    7.1. No prospective randomized studies concerning the use of
    bicarbonate in diabetic ketoacidosis with hydrogen ion concentration
    values \<6.9 have been reported. In the pediatric patient, there are
    no randomized studies in patients with pH \<6.9.

-   No studies are available on the use of phosphate in the treatment of
    hyperosmolar hyperglycemic state.

-   There is a lack of information on the morbidity associated with
    cerebral edema in adult patients; therefore, any recommendations for
    adult patients are clinical judgments, rather than scientific
    evidence.

-   Evidence is only one component of clinical decision-making.
    Clinicians care for patients, not populations; guidelines must
    always be interpreted with the needs of the individual patient in
    mind. Individual circumstances, such as comorbid and coexisting
    diseases, age, education, disability, and above all, patient\'s
    values and preferences, must also be considered and may lead to
    different treatment targets and strategies. Also, conventional
    evidence hierarchies, such as the one adapted by the American
    Diabetes Association, may miss some nuances that are important in
    diabetes care. For example, while there is excellent evidence from
    clinical trials supporting the importance of achieving glycemic
    control, the optimal way to achieve this result is less clear. It is
    difficult to assess each component of such a complex intervention.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Clinical Algorithm

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone
JI, Wall BM. Hyperglycemic crises in diabetes. Diabetes Care 2004
Jan;27(Suppl 1):S94-102. \[38 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14693938)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2000 Oct (revised 2001; republished 2004 Jan)

#### GUIDELINE DEVELOPER(S)

American Diabetes Association - Professional Association

#### SOURCE(S) OF FUNDING

The American Diabetes Association (ADA) received an unrestricted
educational grant from LifeScan, Inc., a Johnson and Johnson Company, to
support publication of the 2004 Diabetes Care Supplement.

#### GUIDELINE COMMITTEE

Professional Practice Committee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Authors of Position Statement, Initial Draft*: Abbas E. Kitabchi, PhD,
MD; Guillermo E. Umpierrez, MD; Mary Beth Murphy, RN, MS, CDE, MBA;
Eugene J. Barrett, MD, PhD; Robert A. Kreisberg, MD; John I. Malone, MD;
Barry M. Wall, MD

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

The guideline was originally approved in October 2000; the most recent
review/revision was completed in 2001.

American Diabetes Association (ADA) position statements are reissued
annually.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [American Diabetes Association
(ADA) Web
site](http://care.diabetesjournals.org/cgi/content/full/27/suppl_1/s94).

Print copies: Available from American Diabetes Association, 1701 North
Beauregard Street, Alexandria, VA 22311.

#### AVAILABILITY OF COMPANION DOCUMENTS

The recommendations in this paper are based on the evidence reviewed in
the following publication:

-   Management of hyperglycemic crises in patients with diabetes
    (Technical Review). Diabetes Care 2001:24:131-53.

In addition, a description of the American Diabetes Association (ADA)
clinical practice recommendations and reports and evidence grading
system is available in the introduction to the 2003 compilation
(Diabetes Care 2003 Jan;25\[Suppl 1\]:S1-S2).

Print copies: Available from the American Diabetes Association, 1701
North Beauregard Street, Alexandria, VA 22311.

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on April 2, 2001. The information was
verified by the guideline developer on August 24, 2001. This summary
updated by ECRI on March 14, 2002, April 21, 2003, and March 24, 2004.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is
copyrighted by the American Diabetes Association (ADA).

For information on guideline reproduction, please contact Alison Favors,
Manager, Rights and Permissions by e-mail at <permissions@diabetes.org>.

For information about the use of the guidelines, please contact the
Clinical Affairs Department at (703) 549-1500 ext. 1692.

### DISCLAIMER

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