Hyperosmolar Hyperglycemic State Treatment & Management

Author
Robin R Hemphill, MD, MPH Associate Professor, Director, Quality and Safety, Department
of
Emergency
Medicine,
Emory
University
School
of
Medicine
Robin R Hemphill, MD, MPH is a member of the following medical societies: American College
of Emergency Physicians and Society for Academic Emergency Medicine

Approach Considerations
Diagnosis and management guidelines for hyperglycemic crises are available from the American
Diabetes Association.[15, 16, 4]
The main goals in the treatment of hyperosmolar hyperglycemic state (HHS) are as follows:

To vigorously rehydrate the patient while maintaining electrolyte homeostasis

To correct hyperglycemia

To treat underlying diseases

To monitor and assist cardiovascular, pulmonary, renal, and central nervous system
(CNS) function

In an emergency situation, whenever possible, contact the receiving facility while en route to
ensure preparation for a comatose, dehydrated, or hyperglycemic patient. When appropriate,
notify the facility of a possible cerebrovascular accident. Initiation of insulin therapy in the
emergency department (ED) through a subcutaneous insulin pump may be an alternative to
intravenous (IV) insulin infusion.[17]
Airway management is the top priority. In comatose patients in whom airway protection is of
concern, endotracheal intubation may be indicated. Cervical spine immobilization is necessary if
head or neck injury is a possibility. In patients with HHS, consider other procedures, including
nasogastric tube placement, thoracentesis, paracentesis, and spinal tap, as appropriate.
Rapid and aggressive intravascular volume replacement is always indicated as the first line of
therapy for patients with HHS. Isotonic sodium chloride solution is the fluid of choice for initial
treatment because sodium and water must be replaced in these severely dehydrated patients.

Although many patients with HHS respond to fluids alone, IV insulin in dosages similar to those
used in diabetic ketoacidosis (DKA) can facilitate correction of hyperglycemia. [18] Insulin used
without concomitant vigorous fluid replacement increases the risk of shock. Adjust insulin or
oral hypoglycemic therapy on the basis of the patients insulin requirement once serum glucose
level has been relatively stabilized.
All patients diagnosed with HHS require hospitalization; virtually all need admission to a
monitored unit managed by medicine, pediatrics, or the intensive care unit (ICU) for close
monitoring. When available, an endocrinologist should direct the care of these patients.
Frequent reevaluation of the patients clinical and laboratory parameters is necessary. Recheck
glucose concentrations every hour. Electrolytes and venous blood gases should be monitored
every 2-4 hours or as clinically indicated.
When an underlying disease is responsible for HHS, it must be promptly identified and treated.
Resolution of HHS often lags while the underlying process remains to be resolved. Some authors
advocate prophylactic heparin treatment and broad-spectrum antibiotic coverage, but these
measures have not yet been studied thoroughly enough to allow recommendation of their use.
Standard Care for Dehydration and Altered Mental Status
Standard care for dehydration and altered mental status is appropriate, including airway
management, IV access, crystalloid fluid replacement, and administration of any medications
routinely given to coma patients.
Airway management
Protection of the airway is mandatory in patients with obtundation or unconsciousness. Many
patients present with respiratory failure and circulatory collapse and must be ventilated
mechanically.
Because of the underlying metabolic acidosis that is frequently present, take care to
hyperventilate patients when mechanical ventilation is instituted. Hyperventilation generates
respiratory alkalosis, which compensates for the metabolic acidosis and also decreases the risk of
cerebral edema.
Intravenous access
IV access, large bore if possible, or central venous access is useful, provided attempts to obtain it
do not significantly delay transfer to the nearest ED. Insertion of a central venous catheter is the
only procedure that should be considered routinely in patients with HHS. A centrally placed
catheter offers an avenue for vigorous rehydration. Findings from monitoring of the pulmonary
capillary wedge pressure or the central venous pressure may help guide intravenous rehydration
therapy.

Large-bore IV or central venous access may be especially helpful in cases in which hemorrhage
is a precipitant and blood products are likely to be required or when inotropic agents may be
necessary.
Fluid resuscitation
Fluid deficits in HHS are large; the fluid deficit of an adult may be 10 L or more. If a recent
record of the patients weight is available for comparison, the difference between the admission
weight and the preadmission weight may provide a rough estimate of the degree of dehydration.
Infuse enough volume to allow the perfusion of vital organs and the kidneys. A reasonable goal
of treatment is to replace half of the estimated volume deficit in the first 12 hours of therapy. The
remainder of the volume deficit may then be replaced over the second 12-hour period.
A 500-mL bolus of 0.9% isotonic saline is appropriate for nearly all adults who are clinically
dehydrated. Administer 1-2 L of isotonic saline in the first 2 hours. A higher initial volume may
be necessary in patients with severe volume depletion. Slower initial rates may be appropriate in
patients with significant cardiac or renal disease. Caution should be taken to not correct
hypernatremia too quickly, as this could lead to cerebral edema. As much as 2 L of 0.9% isotonic
saline may be infused safely over the first hour of treatment.
After the initial bolus, some clinicians recommend changing to half-normal saline, whereas
others continue with isotonic saline. Either fluid likely will replenish intravascular volume and
correct hyperosmolarity; a good standard is to switch to half-normal saline once blood pressure
and urine output are adequate.
At a serum osmolality below 320 mOsm/kg, the IV fluids may again be switched to 0.9%
isotonic saline. When the blood glucose concentration, initially checked hourly, reaches 300 (or,
as some prefer, 250) mg/dL, change the infusion to 5% dextrose in 0.9% isotonic saline again.
This helps prevent a precipitous fall of glucose, which may be associated with cerebral edema. [2]
In pediatric patients with suspected HHS, correcting fluid deficits over a longer period (48 h)
may help reduce the risk of cerebral edema.[8]
In most patients, adequately monitoring volume status entails the use of a urinary catheter. In
patients with preexisting or acute cardiac disease or with diseases in which third-spacing is a
problem, use findings from pulmonary capillary wedge pressure monitoring to guide rehydration
therapy. Patients with hypotension may require pressor support in the ICU while rehydration is
being accomplished.
Medications for coma patients
Basic medications given to coma patients in the field may include dextrose (50 mL of % dextrose
in water [D50]). This is of benefit to many comatose patients with few adverse effects.
When possible, fingerstick glucose measurement is obtained before dextrose administration.
Whenever fingerstick glucose measurement is unavailable or is likely to be delayed, D50 must

be administered to comatose patients on an empiric basis without delay. Undiagnosed and

untreated hypoglycemia, which may present with signs and symptoms very similar to those of
HHS, is readily reversible but can be rapidly lethal if not treated promptly.
Insulin Therapy for Correction of Hyperglycemia
All patients with HHS require IV insulin therapy; however, immediate treatment with insulin is
contraindicated in the initial management of patients with HHS. The osmotic pressure that
glucose exerts within the vascular space contributes to the maintenance of circulating volume in
these severely dehydrated patients. Institution of insulin therapy drives glucose, potassium, and
water into cells. This results in circulatory collapse if fluid has not been replaced first.
After the kidneys show evidence of being perfused, initiating insulin therapy is safe. This is
accomplished most effectively in the ICU, where cardiovascular and respiratory support is
available if needed. Infuse insulin separately from other fluids, and do not interrupt or suspend
the infusion of insulin once therapy is started.
The following steps may be used as a guideline for insulin infusion:

Begin a continuous insulin infusion of 0.1 U/kg/h

Monitor blood glucose by means of bedside testing every hour; if glucose levels are
stable for 3 hours, decrease the frequency of testing to every 2 hours

Set the target blood glucose level at 250-300 mg/dL; this target level may be adjusted
downward after the patient is stabilized

For a blood glucose concentration lower than 250 mg/dL, decrease the insulin infusion
rate by 0.5 U/h

For a blood glucose concentration of 250-300 mg/dL, do not change the insulin infusion
rate.

For a blood glucose concentration of 301-350 mg/dL, increase the insulin infusion rate by
0.5 U/h

For a blood glucose concentration higher than 350 mg/dL, increase the insulin infusion
rate by 1 U/h

Do not discontinue the insulin drip

If the blood glucose concentration decreases by more than 100 mg/dL between
consecutive readings, wait to increase the insulin infusion rate

When the glucose level has been between 200 and 300 mg/dL for at least 1 day and the patients
level of consciousness has improved, glycemic control may be tightened. The recommended
level of glycemia for most patients with type 2 diabetes mellitus (DM) is 80-120 mg/dL. This
correlates to the hemoglobin A1c value of 7% recommended by the American Diabetes
Association.
All patients who have experienced HHS will probably require intensive management of their
diabetes initially, and this includes insulin therapy. The severe hyperglycemia with which these
patients present implies profound beta cell dysfunction. In most instances, sufficient recovery of
endogenous insulin production is a reasonable expectation, with safe dismissal of the patient
from the hospital on oral therapy. After maintaining adequate glycemic control with insulin for
several weeks after HHS, consider switching patients to an oral regimen.
Initiation of insulin therapy in the ED via subcutaneous insulin pump may be an alternative to
intravenous insulin infusion.[17]
Electrolyte Replacement
Profound potassium depletion necessitates careful replacement. With rehydration, the potassium
concentration is diluted. With the institution of insulin therapy, potassium is driven into cells,
exacerbating hypokalemia. A precipitous drop in the potassium concentration may lead to cardiac
arrhythmia.
Potassium may be added to the infusion fluid and should be started at a level of 5 mEq/L or less.
Hypokalemia at the onset of rehydration requires up to 60 mEq/L to correct the serum potassium
concentration. Check the potassium level at least every 4 hours until the blood glucose
concentration is stabilized.
Phosphate, magnesium, and calcium are not replaced routinely, but a patient who is symptomatic
with tetany requires replacement therapy.
Monitoring During Treatment
The mortality associated with HHS remains high. The profound electrolyte and metabolic
abnormalities present during treatment warrant careful cardiorespiratory monitoring. When gas
exchange has been compromised, endotracheal intubation and mechanical ventilation are
indicated.
Neurologic monitoring is indicated in all patients with HHS who present with altered mental
status. Hyperosmolarity may trigger many neurologic syndromes. If a patient has seizures,
phenytoin is not the agent of choice, because it inhibits endogenous insulin secretion and
because, in general, it is ineffective in persons with HHS.
Diet

Provide adequate nutritional support for all patients. Most HHS patients with HNS are unable to
eat for several days as a consequence of the comorbidities with which they present.
Patients in the ICU who require prolonged mechanical ventilation, patients with impaired airway
defenses, and all patients with prolonged MS changes are candidates for enteral or parenteral
nutrition. The use of parenteral nutrition often induces insulin resistance and leads to increased
insulin requirements.
Once HHS is resolved, provide dietary counseling for all patients. This probably is most
effectively delivered by a registered dietitian who has expertise in counseling patients with
diabetes.
Consultations
Generally, no consultation is absolutely required to manage HHS in the ED; however, in
occasional cases, consultations may be useful.
A consultation with an endocrinologist is suggested for patients with HNS. Consider a
consultation with a neurologist for most patients with altered mental status. A neurologist should
monitor the cases of any patients with underlying neurologic disease (eg, cerebrovascular
accident or a history of seizures). A pulmonologist or critical care specialist should monitor the
cases of patients requiring intubation and mechanical ventilation. Other consultations (eg, with
infectious disease or psychiatry) may be obtained as appropriate.
Long-Term Monitoring
Primary care follow-up is necessary for additional diabetic teaching and any appropriate
immunizations. Visiting home nurse referral may be necessary to enhance compliance.
After any episode of HHS, enroll patients in a program of routine diabetes care. Adhere to
American Diabetes Association guidelines for the care of people with diabetes. For patients with
diabetes that was unrecognized before HHS, perform a dilated eye examination. Advise patients
treated with insulin to wear a bracelet or chain identifying them as having diabetes.

Medication Summary
Aggressive rehydration with intravenous (IV) fluids, including 0.9% isotonic saline, is indicated
in every patient with hyperosmolar hyperglycemic state (HHS). Insulin therapy and repletion of
electrolytes (especially potassium) are the other cornerstones of management. Antipyretics,
antiemetics, and antibiotics are added when appropriate to control fever and vomiting and to treat
an underlying infection if one is suspected.

Frequent monitoring of electrolyte concentrations is indicated when patients are treated with IV
fluids. Volume overload is the only other potential problem associated with IV fluid replacement;
therefore, regular assessment of the hydration state is indicated.
Antidiabetics, Insulins
Class Summary
Although many patients with hyperosmolar hyperglycemic state (HHS) respond to fluids alone,
intravenous (IV) insulin in dosages similar to those used in diabetic ketoacidosis (DKA) can
facilitate correction of hyperglycemia. Insulin used without concomitant vigorous fluid
replacement increases the risk of shock.
View full drug information
Regular insulin (Humulin R, Novolin R)

Regular insulin has a rapid onset of action (within 0.5-1 hours), and a short duration of action (46 hours). Peak effects occur within 2-4 hours. Insulin is used to reduce blood glucose levels and
decrease ketogenesis. Some authors favor lower bolus and infusion dosages, with the rationale
that fluids are the cornerstone of therapy and that HHS is more a disorder of insulin resistance
than it is one of insulin deficiency. Furthermore, lowering serum glucose and serum osmolarity
overly rapidly can result in complications.
View full drug information
Insulin aspart (NovoLog)

Insulin aspart has a rapid onset of action (5-15 minutes) and a short duration of action (3-5
hours). Peak effects occurs within 30-90 minutes.
View full drug information
Insulin glulisine (Apidra)

Insulin glulisine has a rapid onset of action (5-15 minutes) and a short duration of action (3-5
hours).
View full drug information

Insulin lispro (Humalog)

Insulin lispro has a rapid onset of action (5-15 minutes) and a short duration of action (4 hours).
Alkalizing agents
Class Summary
No evidence is found that sodium bicarbonate provides any benefit to patients with HHS. It may
be considered if a patient has significant acidosis (pH < 7.0), particularly if inotropic agents are
required to maintain blood pressure.
View full drug information
Sodium bicarbonate (NaHCO3)

Sodium bicarbonate neutralizes hydrogen ions and raises urinary and blood pH.
Electrolytes Supplements, Parenteral
Class Summary
Electrolytes are given to replenish electrolyte supplies depleted by the presence of a high blood
glucose level.
View full drug information
Potassium chloride (Klor-Con, K-Tab, Micro-K)

In virtually all cases of HHS, supplemental potassium is necessary because the serum level drops
secondary to insulin therapy and correction of metabolic acidosis. Do not start IV potassium until
the initial serum level is ascertained, as the initial level may be high related to
hemoconcentration. Administer it cautiously, with attention to proper dosing and concentration.
If the patient can tolerate oral medications or has a gastric tube in place, potassium chloride can
be given orally in doses of up to 60 mEq, with dosing based on frequently obtained laboratory
values.

insulin aspart (Rx) - NovoLog, NovoLog FlexPen, more..

Class: Antidiabetics, Insulins;

Antidiabetics, Rapid-Acting Insulins

Dosing Forms & Strengths

injectable solution

100 units/mL

prefilled syringe

100units/mL (3mL NovoLog FlexPen or FlexTouch)

Type 1 Diabetes Mellitus

Improvement of glycemic control in adults and children with diabetes mellitus
May administer 0.2-0.6 unit/kg/day in divided doses; conservative doses of 0.2-0.4 unit/kg/day
often recommended to reduce risk of hypoglycemia
Total maintenance daily insulin requirement may vary; it is usually between 0.5 and 1
unit/kg/day; nonobese may require 0.4-0.6 unit/kg/day; obese may require 0.6-1.2 units/kg/day
Type 2 Diabetes Mellitus
Diabetes inadequately controlled by diet, weight reduction, exercise, or oral medication
10 units/day SC (or 0.1-0.2 units/kg/day) in evening or divided q12hr of an intermediate (eg,
NPH) or long-acting insulin at bedtime recommended; conversely, regular insulin or rapid-acting
insulin (aspart insulin) before meals also recommended
Dosing Considerations
When used in a meal-related SC injection treatment regimen, 50-75% of total insulin
requirements may be provided by an intermediate-acting or long-acting insulin; the remainder is
divided and provided before or at mealtimes as a rapid-acting insulin, such as insulin aspart
Because of insulin asparts comparatively rapid onset and short duration of glucose-lowering
activity, some patients may require more basal insulin and more total insulin to prevent premeal
hyperglycemia than they would need when using human regular insulin
Dosage must be individualized; blood and urine glucose monitoring is essential in all patients
receiving insulin therapy

Insulin requirements may be altered during stress or major illness or with changes in exercise,
meal patterns, or coadministered drugs
SC injection

Administer within 5-10 minutes before a meal

When administered by SC injection, insulin aspart should generally be used in regimens

with an intermediate- or long-acting insulin

Injection sites should be rotated within the same region to reduce the risk of
lipodystrophy

As with all insulins, the duration of action will vary according to the dose, injection site,
blood flow, temperature, and level of physical activity

Continuous SC injection (insulin pump)

Divide the number of units by 24 to obtain the basal rate in units/hr

Change the NovoLog in the reservoir at least every 6 days

Change the infusion set and the infusion set insertion site at least every 3 days

Do not mix with other insulins or with a diluent when it is used in the pump

IV administration

IV use is at concentrations of 0.05-1 unit/mL in infusion systems using PVC infusion

bags

Stable in infusion fluids such as 0.9% NaCl

sodium bicarbonate (Rx)

Class: Alkalinizing Agents

Dosing Forms & Strengths

Cardiac Arrest
Initial: 1 mEq/kg/dose IV x1
Maintenance: 0.5 mEq/kg/dose q10min PRN

Hyperkalemia
50 mEq IV over 5 minutes
Metabolic Acidosis (Non-Life-Threatening)
2-5 mEq/kg IV infusion over 4-8 hr
Other Information
Urine Alkalinization: see sodium bicarbonate AD
Monitor: serum potassium
Other Indications & Uses
Severe metabolic acidosis (except hypercarbic acidosis)
Of little value in cardiopulmonary resuscitation before circulation has been restored
potassium chloride (Rx) - KDur, Slow K, more..

Class: Electrolyte Supplements, Parenteral;

Electrolytes

Dosing Forms & Strengths

Hypokalemia
20-40 mEq PO BID-QID
Hypokalemia Prophylaxis
Start: 20 mEq PO qDay
Dosing considerations

Dosing varies; adjust to serum potassium levels

insulin regular human (OTC) - Humulin R, Novolin R

Class: Antidiabetics, Insulins;

Antidiabetics, Short-Acting Insulins

Dosing Forms & Strengths

Type 1 Diabetes Mellitus
Initial: 0.2-0.4 units/kg/day SC divided q8hr or more frequently
Maintenance: 0.5-1 unit/kg/day SC divided q8hr or more frequently; in insulin-resistant patients
(eg, due to obesity), substantially higher daily insulin may be required
Approximately 50-75% of the total daily insulin requirements are given as intermediate- or longacting insulin administered in 1-2 injections; rapid- or short-acting insulin should be used before
or at mealtimes to satisfy the remainder balance of the total daily insulin requirements
Premixed combinations are available that deliver rapid- or short-acting components at the same
time as the intermediate- or long-acting component
Type 2 Diabetes Mellitus
Type 2 diabetes inadequately controlled by diet, exercise, or oral medication: Suggested
beginning dose of 10 units/day SC (or 0.1-0.2 unit/kg/day) in evening or divided q12hr
Morning

Give two thirds of daily insulin requirement

Ratio of regular insulin to NPH insulin 1:2

Evening

Give one third of daily insulin requirement

Ratio of regular insulin to NPH insulin 1:1

Severe Hyperglycemia (Diabetic Ketoacidosis)

0.1 unit/kg IV bolus (some argue against bolus), THEN
0.1 unit/kg/hr IV continuous infusion; if serum glucose does not fall by 50 mg/dL in the first
hour, check hydration status; if possible, double the insulin hourly until glucose levels fall at the
rate of 50-75 mg/dL/hr; decrease infusion to 0.05-0.1 unit/kg/hour when blood sugar reaches 250
mg/dL
Hyperkalemia

5-10 units IV insulin in 50 mL D50W (25 g) infused over 15-30 min

Administration
Administer within 15 minutes before a meal or immediately after a meal
Dosing Considerations
Dosage of human insulin, which is always expressed in USP units, must be based on the results
of blood and urine glucose tests and must be carefully individualized to optimal effect
Dose adjustments should be based on regular blood glucose testing
Adjust to achieve appropriate glucose control
Planning dose adjustments

Look for consistent pattern in blood sugars for >3 days

Same time each day: Compare blood glucose levels with previous levels found at that
time of day

For each time of day: Calculate blood glucose range

Calculate median blood glucose

Consider eating and activity patterns during day

Making dose adjustments

Adjust only 1 insulin dose at a time

Correct hypoglycemia first

Correct highest blood sugars next

If all blood sugars are high (within 2.75 mmol/L [50 mg/dL]): Correct morning fasting
blood glucose first

Change insulin doses in small increments: Type 1 diabetes (1-2 unit change); type 2
diabetes (2-3 unit change)

Sliding scales

Many sliding scales exist to determine exact insulin dose based on frequent blood glucose
monitoring

Commonly written for q4hr blood glucose test

Sliding scale coverage usually begins after blood glucose >11 mmol/L (200 mg/dL)

If coverage is needed q4hr for 24 hr, then base insulin dose is adjusted first; sliding scale
doses may be adjusted upwards as well

insulin glulisine (Rx) - Apidra, Apidra Solostar

Class: Antidiabetics, Insulins;

Antidiabetics, Rapid-Acting Insulins

Dosing Forms & Strengths

injectable solution (as 10 mL vial and 3 mL cartridge for OptiClick SC device)

100 units/mL

prefilled 3 mL pen (Solostar)

100 units/mL

Diabetes Mellitus Type I or II

Indicated to improve glycemic control in adults and children with diabetes mellitus
Dosing considerations

Equipotent to regular human insulin (ie, elicits same glucose lowering effects on unit per
unit basis) when administered IV

Insulin glulisine has a more rapid onset of action and a shorter duration of action than
regular human insulin

Dosage must be individualized; blood glucose monitoring is essential in all patients

receiving insulin therapy

Total daily insulin requirement may vary and is usually between 0.5-1 unit/kg/day

Insulin requirements may be altered during stress, major illness, or with changes in
exercise, meal patterns, or coadministered drugs

SC injection

Administer within 15 minutes before a meal or within 20 minutes after starting a meal

When administered by SC injection, insulin glulisine should generally be used in

regimens with an intermediate- or long-acting insulin

Administered by SC injection in the abdominal wall, thigh, or upper arm

Injection sites should be rotated within the same region (abdomen, thigh or upper arm)
from one injection to the next to reduce the risk of lipodystrophy

Continuous SC injection (insulin pump)

May be administered by continuous SC infusion in the abdominal wall

Do not dilute or mix with any other insulin

Infusion sites should be rotated within the same region to reduce the risk of lipodystrophy

Insulin in the reservoir must be changed at least q48hr

Do not expose to temeratures >98.6F (37C)

Initial programming of the external insulin infusion pump should be based on the total
daily insulin dose of the previous regimen

Malfunction of the insulin pump or infusion set, or handling errors or insulin degradation
can rapidly lead to hyperglycemia, ketosis and diabetic ketoacidosis

See prescribing information for compatible insulin pumps

IV administration

May be administered IV while under medical supervision for glycemic control with close
monitoring of blood glucose and serum potassium to avoid hypoglycemia and
hypokalemia

When administered IV, use concentrations of 0.05-1 unit/mL in infusion systems using
PVC bags

Stable only in 0.9% NaCl (normal saline)

Inspected visually for particulate matter and discoloration prior to administration

Do not administer insulin mixtures IV