07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

Hyperglycemic hyperosmolar state in adults

Overview and Recommendations
Background

Hyperglycemic hyperosmolar state (HHS) is a metabolic emergency occurring in patients with

diabetes mellitus.
It is characterized by extremely elevated serum glucose, increased osmolality, significant dehydration,
and minimal ketoacidosis.
Both HHS and diabetic ketoacidosis (DKA) are often precipitated by medication noncompliance in
patients with known diabetes, concurrent infection, other underlying medical illness such as
pancreatitis, acute myocardial infarction or stroke, or drugs that affect carbohydrate metabolism.
Compared with DKA, HHS:
occurs more often in patients with type 2 diabetes
is characterized by relative insulin deficiency, but insulin levels are usually sufficient to prevent
ketogenesis
is associated with higher morbidity and mortality

Evaluation

Suspect hyperglycemic hyperosmolar state (HHS) in patients with gradual development (over days to
weeks) of polyuria, polydipsia, weight loss, weakness, and mental status changes.
Initial testing should include:
serum glucose, electrolytes, blood urea nitrogen (BUN), creatinine, beta-hydroxybutyrate
(ketones), and complete blood count with differential
arterial (or venous) blood gas
urine dipstick and urinalysis
urine, blood, or sputum culture if infection is suspected
electrocardiogram
chest x-ray if pulmonary or cardiac involvement is suspected
Diagnostic criteria for HHS include glucose > 540-600 mg/dL (30-33.3 mmol/L), effective serum
osmolality > 320 mOsm/kg, arterial pH > 7.3, serum bicarbonate > 15-18 mEq/L (15-18 mmol/L),
little or no ketonemia and ketonuria, and stupor or coma.

Relevant DynaMed calculators

Anion Gap Calculator
Osmolar Gap Calculator
Osmolality Estimator (serum)
Sodium Correction in Hyperglycemia

Management

Admit the patient to intensive care. Initial monitoring includes hourly glucose, electrolytes, calculated
osmolality, blood urea nitrogen (BUN), and pH.
Provide fluid resuscitation.
Begin with 0.9% saline IV at 1-1.5 L/hour (15-20 mL/kg/hour) for the first hour.

1/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

If not severely dehydrated, reduce the infusion rate to 250-500 mL/hour.

If not hyponatremic (correcting for hyperglycemia), change fluids to 0.45% saline.
Once serum glucose falls to 300 mg/dL (16.7 mmol/L), change fluids to 5% dextrose with
0.45% saline IV at 150-250 mL/hour.
Give potassium 20-30 mEq/hour IV (and withhold insulin) until potassium level is ≥ 3.3 mEq/L, then
give 20-30 mEq/L of IV fluid to maintain serum potassium level of 4-5 mEq/L; do not give potassium
if serum potassium level is ≥ 5.2 mEq/L.
Consider limiting phosphate replacement to persistent hypophosphatemia and magnesium replacement
to symptomatic hypomagnesemia.
Consider giving IV insulin (for example 0.05-0.14 units/kg/hour and adjust to maintain glucose 200-
300 mg/dL [11.1-16.7 mmol/L]) until patient is mentally alert; exceptions to starting insulin vary
according to guideline but include:
ketonemia < 1 mmol/L
serum potassium < 3.3 mEq/L (3.3 mmol/L)
Unless contraindicated, administer low-molecular-weight heparin to all patients throughout
hospitalization.
Once the hyperglycemic hyperosmolar state is resolved, consider:
transitioning to subcutaneous insulin therapy
prevention measures with attention to diabetes management and patient education on sick day
measures

Related Summaries
Hyperglycemic hyperosmolar state in children
Diabetic ketoacidosis (DKA) in adults
Diabetes (list of topics)

General Information
Description
metabolic emergency occurring mainly in patients with diabetes mellitus and characterized by
dehydration, extremely elevated serum glucose, increased osmolality, and no significant ketoacidosis(1,
2)

may occur as a mixed syndrome with diabetic ketoacidosis(1, 2)

Also called

hyperosmolar hyperglycemic crisis

hyperglycemic hyperosmolar syndrome
HHS
hyperglycemic hyperosmolar nonketotic syndrome
hyperosmolar hyperglycemic nonketotic coma

Epidemiology
Who is most affected

older patients with type 2 diabetes(1, 2)

Incidence/Prevalence

2/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

5-year incidence of hyperglycemic crises in adults with diabetes may be 7.5% (1.7% for
hyperglycemic hyperosmolar state and 4.7% with diabetic ketoacidosis)
based on retrospective cohort study
83 adults (mean age 55 years) with diabetes mellitus hospitalized for diabetic ketoacidosis
(DKA) or hyperglycemic hyperosmolar state (HHS) were evaluated
87% had type 2 diabetes, 13% had type 1 diabetes
precipitating factors included infections in 74% and noncompliance with treatment in 42%
Reference - J Med Assoc Thai 2012 Aug;95(8):995

Etiology and Pathogenesis

Causes

precipitating causes include(1, 3)

infection (major precipitating cause, occurring in 30–60% of patients)
noncompliance with treatment for previously diagnosed diabetes
other concomitant illnesses, including
pancreatitis
myocardial infarction
cerebrovascular accident
trauma
conditions resulting in dehydration
restricted water intake in bedridden patients
decreased thirst response in older patients
medications that affect carbohydrate metabolism, including
corticosteroids
thiazides
sympathomimetic agents
pentamidine
first- and second-generation antipsychotic drugs
gatifloxacin associated with hyperosmolar nonketotic hyperglycemia in 2 adults with liver disease in
case report (Ann Intern Med 2004 Dec 21;141(12):968)

Pathogenesis

physiologic stress results in elevation of counter-regulatory hormones, including(1)

catecholamines
glucagon
cortisol
growth hormone
relative insulin deficiency combined with increased counter-regulatory hormone levels lead to(1)
acceleration of gluconeogenesis and glycogenolysis, and decrease in glucose utilization by
peripheral tissues results in hyperglycemia, which in turn results in
glycosuria and resulting osmotic diuresis, water and electrolyte loss, dehydration (fluid
losses estimated to be between 100 and 220 mL/kg), and impaired renal function
increased intravascular osmolarity and resulting extravascular dehydration
increased proinflammatory cytokine and procoagulation factor levels
endogenous insulin levels are higher than in diabetic ketoacidosis (DKA); while inadequate to enable
normal glucose utilization, insulin levels are sufficient to prevent lipolysis (which in DKA results in
increased free fatty acid production and conversion to ketone bodies, leading to ketoacidosis)(1)
causes of altered mental status include(2)
changes in osmolality
electrolyte disturbances
dehydration
infection and sepsis
3/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

hypoglycemia during treatment

renal failure

History and Physical

Clinical presentation

slow onset (many days) compared with diabetic ketoacidosis (DKA) (hours), which results in more
severe manifestations of hyperglycemia, dehydration, and hyperosmolality(2, 3)
older patients often have multiple comorbidities(2)
may be the initial presentation of type 2 diabetes mellitus, especially in young adults and even
children(2)
typical symptoms include(1)
polyuria
polydipsia
weight loss
weakness
mental status changes
nausea, vomiting, and abdominal pain less common than in DKA(1)
findings of encephalopathy are usually present when serum sodium > 160 mmol/L and when
calculated effective osmolality > 320 mmol/kg(3)

History

History of present illness (HPI)

ask about preexisting diabetes diagnosis (present in 60%-70% of adults with hyperglycemic
hyperosmolar state [HHS]) (J Pediatr 2010 Feb;156(2):180)
ask about recent symptoms of infection (may precipitate HHS)(1)
ask about typical symptoms of HHS

Medication history

ask about medications that may precipitate HHS, such as(1)

corticosteroids
thiazides
sympathomimetic agents
pentamidine
first- and second-generation antipsychotic drugs
if preexisting diabetes, ask about usual medications and compliance

Family history (FH)

ask about family history of diabetes

Physical

General physical

tachycardia(1, 2)
hypotension(1, 2)

4/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

fever may occur with or without infection and patients with infection may be normothermic or
hypothermic due to peripheral vasodilation(1)
examine for possible infective source(2)

Skin

poor skin turgor(1)

assess for acanthosis nigricans - hyperpigmented, hyperkeratotic, often verrucous velvety plaques,
especially on neck, flexural, and anogenital areas

HEENT

signs of dehydration may include(2)

sunken eyes
longitudinal furrows on tongue
dry mucous membranes

Neuro

findings may include(1)

lethargy
coma (consider use of coma assessment scale such as Glasgow Coma Scale)
focal or generalized seizures
hemianopia
hemiparesis

Diagnosis
Making the diagnosis

ADA Consensus Statement Diagnostic Criteria for Hyperglycemic Hyperosmolar State:

Plasma glucose > 600 mg/dL (33.3 mmol/L)
Arterial pH > 7.3
Serum bicarbonate > 18 mEq/L (18 mmol/L)
Urine ketones Small
Serum ketones Small
Effective serum osmolality > 320 mOsm/kg
Anion gap Variable
Alteration in sensorium or mental obtundation Stupor/coma
Dehydration Severe
Abbreviation: ADA, American Diabetes Association.

Reference - (1)

Joint British Diabetes Societies Inpatient Care Group statement for adults with hyperglycemic
hyperosmolar state (HHS)(2)
precise definition and diagnosis do not exist
HHS should not be diagnosed based on biochemical parameters alone
characteristic features include
hypovolemia
5/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

marked hyperglycemia (≥ 30 mmol/L [540.5 mg/dL]) without significant hyperketonemia

(< 3.0 mmol/L) or acidosis (pH > 7.3, bicarbonate > 15 mmol/L)
high osmolality (usually ≥ 320 mOsm/kg)

Differential diagnosis
transient elevations of blood glucose in patients with diabetes; distinguished from hyperglycemic
hyperosmolar state by short duration of hyperglycemia and lack of accompanying dehydration(2)
diabetic ketoacidosis (DKA) (1, 2)
Common Findings with DKA and HHS:
Hyperglycemic Hyperosmolar
Parameter Diabetic Ketoacidosis
State
Serum glucose > 250 mg/dL (13.9 mmol/L) > 600 mg/dL (33.3 mmol/L)
Arterial pH < 7-7.3 > 7.3
Serum bicarbonate < 15-18 mEq/L (18 mmol/L) > 18 mEq/L (18 mmol/L)
Serum and urine ketones Positive Small
Effective serum osmolality Variable > 320 mOsm/kg (320 mmol/kg)
Anion gap > 10-12 mEq/L (10-12 mmol/L) Variable
Alteration in sensorium or mental
Variable Stupor/coma
obtundation
Abbreviations: DKA, diabetic ketoacidosis; HHS, hyperglycemic hyperosmolar state.

Reference - (1)
mixed hyperglycemic hyperosmolar state and diabetic ketoacidosis may occur in ≥ 30% of adults with
hyperglycemic crisis(1, 2)

Testing overview

initial laboratory evaluation includes(1, 2)

blood tests
glucose
electrolytes with calculated anion gap
osmolality
blood urea nitrogen (BUN)
creatinine
beta-hydroxybutyrate (serum ketones if unavailable)
complete blood count with differential
arterial or venous blood gas
complete blood count with differential
serum lactate
urine tests - ketones, urinalysis
cultures of urine, blood, or sputum
electrocardiogram
chest x-ray (if suspected pulmonary or cardiac involvement)

Blood tests

Relevant DynaMed calculators

Anion Gap Calculator

Osmolar Gap Calculator
6/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

Osmolality Estimator (serum)

Sodium Correction in Hyperglycemia

Serum metabolic analysis

glucose > 600 mg/dL (33.3 mmol/L) (severe hyperglycemia)(1, 2)

bicarbonate > 15-18 mEq/L (15-18 mmol/L)(1, 2)
serum osmolality
formulas for calculating serum osmolality vary
calculate effective serum osmolality as (2 × Na) + (glucose/18)(1)
Na = serum sodium in mEq/L or mmol/L
glucose = plasma glucose in mg/dL (if mmol/L, do not divide by 18)
calculate effective serum osmolality as 2 Na+ + glucose (urea is omitted from the equation
since it is an ineffective osmolyte and does not contribute to tonicity)(2, 3)
serum osmolality in hyperglycemic hyperosmolar state (HHS) usually > 320 mOsm/kg(1, 2)
beta-hydroxybutyrate or serum ketones(1, 2)
usually minimal (beta-hydroxybutyrate < 1 mmol/L, ketonuria < 2+)
significant ketosis suggests diabetic ketoacidosis (DKA) or mixed HHS and DKA
arterial blood gas
pH > 7.3(1, 2)
mild acidosis common (usually hypoperfusion-related lactic acidosis)(1)
significant acidosis suggests DKA or mixed HHS and DKA(1, 2)
serum sodium(1)
initial measured sodium may be low due to osmotic flow of water from extravascular to
intravascular space
increased or normal sodium indicates significant water loss
serum sodium is falsely lowered by 1.6 mEq/L for every 100 mg/dL (5.55 mmol/L) increase in
blood glucose
calculate corrected serum sodium by adding 1.6 mg/dL to measured serum sodium for each 100
mg/dL of glucose above 100 mg/dL
serum electrolytes(1)
potassium may be elevated, usually due to extracellular shift caused by insulin deficiency,
hypertonicity, and acidemia
phosphate may be elevated without body deficit, usually due to intra/extracellular shifts
severe hypocalcemia may occur with phosphate replacement
lactate levels recommended on admission because lactic acidosis may occur in severely volume-
contracted patients(1, 2)
anion gap metabolic acidosis reported to be present in 20–30% of patients due to concomitant
ketoacidosis with or without increased serum levels of lactate(3)

Other blood tests

complete blood count with differential (leukocytosis 10-15 × 109/L appears common and associated
with stress in DKA but > 25 × 109/L may suggest infection)(1)
C-reactive protein may suggest likelihood of infection(2)
C-peptide levels (reflecting endogenous insulin secretion) higher in hyperglycemic hyperosmolar state
than in diabetic ketoacidosis(1)

Urine studies

initial testing should include urine ketones, urinalysis, and urine culture(1, 2)

7/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

Electrocardiography (ECG)

cardiac monitoring indicated for patients with hyperglycemic hyperosmolar state (HHS) and low
normal or low serum potassium levels(1, 2)
electrocardiogram findings associated with electrolyte abnormalities seen in HHS
hypokalemia - ST depression, decreased amplitude or inverted T wave, increased amplitude of U
wave, apparent prolongation of QT interval
hyperkalemia - tall, narrow, or tent-shaped T wave, decreased or absent P waves, short QT,
widened QRS
hypomagnesemia - flattened T waves, U waves, prolonged QT interval, widened QRS
complexes, and atrial and ventricular arrhythmias
hypocalcemia - QT or ST prolongation, 2:1 heart block

Treatment
Treatment overview

goals of treatment are to(2)

normalize osmolality
replace fluid and electrolyte losses
normalize blood glucose
prevent complications such as arterial or venous thrombosis, cerebral edema and central pontine
myelinolysis
admit to intensive care, especially if hemodynamic, metabolic, cardiorespiratory, or neurologic
instability
initial monitoring may include hourly glucose, electrolytes, calculated osmolality, blood urea nitrogen
(BUN), and pH
fluid resuscitation
0.9% saline IV at 1-1.5 L/hour (15-20 mL/kg/hour) for first hour
may reduce infusion rate to 250-500 mL/hour in absence of severe dehydration
after initial 1-2 liters of 0.9% saline, may switch to 0.45% saline IV if high or normal corrected
serum sodium level without severe dehydration
once serum glucose falls to 300 mg/dL (16.7 mmol/L), change to 5% dextrose with 0.45%
sodium chloride IV at 150-250 mL/hour
give potassium 20-30 mEq/hour IV (and withhold insulin) until potassium level ≥ 3.3 mEq/L, then 20-
30 mEq per L of IV fluid to maintain serum potassium level 4-5 mEq/L; do not give potassium if
serum potassium level ≥ 5.2 mEq/L
consider limiting phosphate replacement to persistent hypophosphatemia and magnesium replacement
to symptomatic hypomagnesemia
bicarbonate infusion not recommended(3)
insulin protocols vary
using American Diabetes Association (ADA) protocol
continuous IV infusion of regular insulin is treatment of choice with either of
insulin 0.1 units/kg IV bolus followed by continuous infusion at 0.1 units/kg/hour
insulin 0.14 units/kg/hour IV by continuous infusion (no bolus)
if serum glucose does not fall by at least 10% in first hour, give 0.14 units/kg as IV bolus
once serum glucose falls to 300 mg/dL (16.7 mmol/L), reduce infusion rate to 0.02-0.05
units/kg/hour and maintain serum glucose 200-300 mg/dL (11.1-16.7 mmol/L) until
patient is mentally alert
when hyperglycemic hyperosmolar state (HHS) resolves (osmolality and mental status
normal), and when patient able to eat, transition to subcutaneous insulin therapy
continue IV insulin for 1-2 hours after initiation of subcutaneous insulin to prevent
recurrence of hyperglycemia
Joint British Diabetes Societies Inpatient Care Group suggests limiting insulin to patients with
significant ketonemia, and then using fixed-rate infusion of 0.05 units/kg/hour, but may increase
by 1 unit/hour to achieve glucose reduction ≤ 5 mmol/L (90.1 mg/dL) per hour
8/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

Joslin Diabetes Center uses protocol based on patient's blood glucose level, but notes lower
insulin levels may be needed in HHS compared to diabetic ketoacidosis
once HHS is resolved, consider prevention measures with attention to diabetes management and
patient education for sick day management

Treatment setting and monitoring

Indications for intensive care

management in intensive care unit recommended(1)

admission to level 2 (high-dependency) unit suggested for hyperglycemic hyperosmolar state if(2)
osmolality > 350 mOsm/kg, sodium > 160 mmol/L, potassium < 3.5 mmol/L or > 6 mmol/L,
serum creatinine > 200 mcmol/L, venous or arterial pH < 7.1
systolic blood pressure < 90 mm Hg, heart rate > 100 beats per minute (bpm) or < 60 bpm,
hypothermia
oxygen saturation < 92% on room air (assuming normal baseline respiratory function)
urine output < 0.5 mL/kg/hour
Glasgow Coma Scale (GCS) < 12 or abnormal Alert, Voice, Pain, Unresponsive (AVPU) scale
macrovascular event such as myocardial infarction or stroke, other serious comorbidity

Monitoring

American Diabetes Association (ADA) consensus statement(1)

once glucose falls to 300 mg/dL, check glucose, electrolytes, blood urea nitrogen (BUN), venous
pH every 2-4 hours until stable
cardiac monitoring for patients with low or low normal serum potassium
in addition to laboratory values, assess adequacy of rehydration with hemodynamic monitoring
(blood pressure), measuring urine output, clinical exam
Joint British Diabetes Societies Inpatient Care Group statement(2)
first hour
continuous pulse oximetry
consider continuous cardiac monitoring
insert urinary catheter to monitor urine output
first 24 hours
blood glucose hourly
sodium, potassium, urea, and calculated osmolality hourly for first 6 hours, then
(assuming continued improvement) sodium and calculated osmolality every 2 hours for 6
more hours, then every 4 hours for next 12 hours
resolution of hyperglycemic hyperosmolar state is indicated by effective serum osmolality < 310
mmol/kg and plasma glucose level ≤ 13.8 mmol/L in a patient whose mental status has recovered (3)

Fluid and electrolytes

Fluid resuscitation

DynaMed commentary -- limited evidence to guide specific approach to fluid resuscitation, guidelines
provide varied protocols
goal of initial therapy is expansion of the intravascular and extravascular volume and to restore
peripheral perfusion(2)
fluid therapy also reduces the level of counter-regulatory hormones and hyperglycemia(3)
American Diabetes Association (ADA) consensus statement for adults with hyperglycemic
hyperosmolar state (HHS)(1)
give 0.9% sodium chloride at 1-1.5 L/hour (15-20 mL/kg/hour) IV during first hour
determine hydration status
9/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

if cardiogenic shock, use hemodynamic monitoring to guide fluid management and

pressors
if severe dehydration (hypovolemic shock), continue 0.9% sodium chloride IV at 1 L/hour
if mild dehydration, reduce infusion rate to 250-500 mL/hour and calculate corrected
serum sodium (see DynaMed calculator for Sodium Correction in Hyperglycemia)
if low sodium, continue 0.9% sodium chloride IV
if high or normal sodium, switch to 0.45% sodium chloride IV
once serum glucose falls to 300 mg/dL (16.7 mmol/L), change to 5% dextrose with 0.45%
sodium chloride IV at 150-250 mL/hour
Joint British Diabetes Societies Inpatient Care Group statement(2)
ideally water deficit may be replaced by patient taking fluids orally
initial therapy with 0.9% sodium chloride solution (with potassium added as needed) to restore
circulating volume and reverse dehydration
avoid rapid changes in
osmolality, adjust fluids as needed for gradual decline in osmolality
calculate osmolality often (initially hourly), using the Worthley formula in which
osmolality = (2 × Na+) + glucose (mmol/L) + blood urea nitrogen
recommended decline in osmolality between 4 and 6 mmol/hour
serum sodium - decline should not exceed 10 mmol/L (180.2 mg/dL) in 24 hours
serum glucose - reduction of 4-6 mmol/hr is recommended
substitute with 0.45% sodium chloride solution if osmolality no longer declining despite
adequate fluid replacement with 0.9% sodium chloride AND adequate plasma glucose reduction
is not achieved
no experimental evidence to suggest using hypotonic fluids < 0.45% sodium chloride solutions
replace approximately 50% of estimated fluid loss within first 12 hours and remainder in the
following 12 hours (though speed of correction may be limited by the presence of renal
dysfunction or comorbidities such as heart failure)(2)
other formulas for calculation of serum osmolality may be more accurate than formulas noted above if
data linked to computer for processing (Clin Chem Lab Med 2005;43(6):635)

Potassium

American Diabetes Association (ADA) consensus statement(1)

establish adequate renal function (urine output ≥ 50 mL/hour) before giving potassium
if serum potassium < 3.3 mEq/L (3.3 mmol/L)
give potassium 20-30 mEq (20-30 mmol) per hour IV until ≥ 3.3 mEq/L (3.3 mmol/L)
do not start insulin until potassium replaced
if serum potassium 3.3-5.2 mEq/L (3.3-5.2 mmol/L)
give potassium 20-30 mEq (20-30 mmol) in each L of IV fluid
maintain level at 4-5 mEq/L (4-5 mmol/L)
if serum potassium ≥ 5.2 mEq/L (5.2 mmol/L)
do not give supplemental potassium
check level every 2 hours
Joint British Diabetes Societies Inpatient Care Group statement (based on potassium level in first 24
hours)(2)
if potassium level < 3.5 mmol/L (3.5 mEq/L), give potassium 40 mmol/L (40 mEq/L) in
infusion solution and additional potassium required via central line in high-dependency unit
(consult with senior clinician familiar with hyperosmotic hyperglycemic state treatment)
if potassium level 3.5-5.5 mmol/L (3.5-5.5 mEq/L), give potassium 40 mmol/L (40 mEq/L) in
infusion solution
if potassium level > 5.5 mmol/L (5.5 mEq/L), do not give supplemental potassium
see also Hypokalemia

Magnesium and phosphate

10/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

hypophosphatemia and hypomagnesemia common in hyperglycemic hyperosmolar state, but no

evidence for benefit with replacement during acute management(2)
consider oral or IV phosphate replacement if hypophosphatemia persists beyond acute phase(2)
consider magnesium replacement only for symptomatic hypomagnesemia or symptomatic
hypocalcemia(2)
see also Hypophosphatemia - approach to the patient and Hypomagnesemia - approach to the patient

Medications

Insulin

DynaMed commentary -- limited evidence to guide specific approach to insulin use and initiation in
hyperglycemic hyperosmolar state (HHS), guidelines provide varied protocols
Joint British Diabetes Societies Inpatient Care Group statement(2)
if ketonemia < 1 mmol/L do not start insulin
fluid replacement (with 0.9% sodium chloride solution) associated with reduction in blood
glucose
risk of cardiovascular collapse if insulin treatment started before adequate fluid
replacement
lowering osmolality may occur rapidly as patients with HHS are insulin sensitive
if ketonemia significant (3-beta hydroxybutyrate > 1 mmol/L) (indicates relative
hypoinsulinemia)
start insulin after glucose has stopped falling after initial fluid resuscitation
recommend fixed rate IV infusion of insulin 0.05 units/kg/hour
ideal glucose reduction ≤ 5 mmol/L (90.1 mg/dL) per hour
may increase infusion rate by 1 unit/hour after reassessing fluid intake and evaluating
renal function
target blood glucose 10-15 mmol/L
American Diabetes Association (ADA) consensus statement(1)
if serum potassium < 3.3 mEq/L (3.3 mmol/L), do not start insulin until potassium replaced
continuous IV infusion of regular insulin is treatment of choice, options include
insulin 0.1 units/kg IV bolus followed by continuous infusion at 0.1 units/kg/hour
insulin 0.14 units/kg/hour IV by continuous infusion (no bolus)
if serum glucose does not fall by at least 10% in first hour, give 0.14 units/kg as IV bolus, then
continue infusion at previous rate
once serum glucose falls to 300 mg/dL (16.7 mmol/L), reduce infusion rate to 0.02-0.05
units/kg/hour
maintain serum glucose 200-300 mg/dL (11.1-16.7 mmol/L) until patient is mentally alert
upon resolution of HHS (normal osmolality and mental status), and when patient able to eat,
transition to subcutaneous insulin therapy
multiple dose schedule should be started with combination short or rapid-acting and
intermediate or long-acting insulin subcutaneously
in patients with known diabetes, restart insulin at prior dosing if this was controlling
glucose levels
if new to insulin, start multidose regimen at 0.5-0.8 units/kg/day and adjust as
needed
IV insulin should continue for 1-2 hours after initiation of subcutaneous insulin to prevent
recurrence of hyperglycemia
Joslin Diabetes Center and Beth Israel Deaconess Medical Center guideline for management of
uncontrolled glucose in the hospitalized adult states for treatment of HHS (in contrast to diabetic
ketoacidosis)
more fluids may be required (patients may be more dehydrated)
lower doses of insulin may be required (patients may be more sensitive to insulin)
Reference - Joslin 2013 May 20 PDF
maintaining blood glucose > 250 mg/dL for first 24 hours reported to decrease risk of cerebral edema
in 2 case series (Miner Electrolyte Metab 1986;12(5-6):383, Diabetes 1974 Jun;23(6):525)
11/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

Heparin

Joint British Diabetes Societies Inpatient Care Group statement for adults with HHS(2)
unless contraindicated, give prophylactic low molecular weight heparin (LMWH) to all patients
throughout hospitalization
consider extending prophylaxis beyond hospitalization in patients with risk factors for venous
thromboembolism
consider full anticoagulation for suspected acute coronary syndrome or thrombosis

Antibiotics

antibiotics may be indicated if clinical, laboratory, or imaging findings suggest infection(2)

Follow-up

most patients should be discharged on subcutaneous insulin(2)

if stable for weeks to months on subcutaneous insulin, consider transitioning to oral hypoglycemic
agent(2)
reinforce sick day measures to prevent hyperglycemic crises in patients with diabetes(1)
see also
Diabetes mellitus type 2 or Diabetes mellitus type 1
Diabetes (list of topics)

Complications and Prognosis

Complications

complications may include(2)

peripheral arterial or venous thrombosis
myocardial infarction
stroke
seizure
cerebral edema
central pontine myelinosis
epilepsia partialis continua as a rare complication of nonketotic hyperglycemia in case presentation of
61-year-old man (CMAJ 2005 Sep 27;173(7):754 full-text)

Prognosis

5%-20% mortality reported(1, 2)

estimated 10-fold higher mortality compared to diabetic ketoacidosis(3)
overall mortality rate of hyperglycemic crises may be 8.4% (15.8% with hyperglycemic
hyperosmolar state, 5.8% with diabetic ketoacidosis, 8.3% with overlap of both conditions) (level
2 [mid-level] evidence)
based on retrospective cohort study
83 adults (mean age 55 years) with diabetes mellitus hospitalized for diabetic ketoacidosis
(DKA) or hyperglycemic hyperosmolar state (HHS) were evaluated
87% had type 2 diabetes, 13% had type 1 diabetes
precipitating factors included infections in 74% and noncompliance with treatment in 42%
mean plasma glucose level on admission was 741.3 mg/dL (41.1 mmol/L)
serum sodium level on admission independently associated with mortality (adjusted odds
ratio 1.08, 95% CI 1.01-1.16, p = 0.03)
treatment complications included
recurrent hyperglycemia in 70%
12/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

hypokalemia in 48%
hypernatremia in 22%
hypoglycemia in 16%
Reference - J Med Assoc Thai 2012 Aug;95(8):995
factors affecting prognosis
worse prognosis with coma, hypotension, severe hypothermia, and severe comorbidities(1)
comorbid myocardial infarction or pneumonia may increase risk of death in patients with
hyperglycemic hyperosmolar state (HHS) (level 2 [mid-level] evidence)
based on retrospective cohort study evaluating 28-day case fatality rates in 1,083 children
and adults admitted with HHS or diabetic ketoacidosis (DKA) between 1991 and 2005 in
Taiwan
394 patients (36%) had HHS
overall 28-day case fatality rate was 18.8% for HHS vs. 6.1% for DKA (p < 0.0001)
28-day case fatality in patients with HHS
associated with
comorbid myocardial infarction (adjusted hazard ratio [HR] 2.92, 95% CI
1.22-6.97)
comorbid pneumonia (adjusted HR 2.08, 95% CI 1.23-3.52)
not associated with age, gender, stroke, or urinary tract infection
rate decreased from 27.4% in 1991-1995 to 11.6% in 2001-2005
Reference - Intern Med 2010;49(8):729 PDF

Prevention and Screening

Prevention

sick day measures to prevent hyperglycemic crises in patients with diabetes include
early contact with healthcare provider
emphasizing importance of insulin during an illness
emphasizing reasons to never discontinue insulin without contacting the healthcare team
reviewing blood glucose goals and use of supplemental short- or rapid-acting insulin, especially
if pump failure
having medications available to suppress a fever and treat infection
initiating an easily digestible liquid diet containing carbohydrates and salt if patient has nausea
educating family members on sick day management
assessing and documenting temperature, blood glucose, and urine/blood ketone
insulin administration
oral intake and weight measurement
educating staff in long-term facilities to prevent dehydration
Reference - Diabetes Care 2009 Jul;32(7):1335 full-text, commentary can be found in Diabetes
Care 2009 Dec;32(12):e157

Guidelines and Resources

Guidelines

United States guidelines

Joslin Diabetes Center and Beth Israel Deaconess Medical Center guideline on management of
uncontrolled glucose in the hospitalized adult can be found in Joslin 2013 May 20 PDF

American Diabetes Association (ADA)

American Diabetes Association (ADA) standards of medical care in diabetes can be found in
Diabetes Care 2018 Jan; 41(Suppl 1):S1 PDF
introduction (Diabetes Care 2018 Jan;41(Suppl 1):S1)
13/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

professional practice committee (Diabetes Care 2018 Jan;41(Suppl 1):S3)

summary of revisions (Diabetes Care 2018 Jan;41(Suppl 1):S4)
1. improving care and promoting health in populations (Diabetes Care 2018 Jan;41(Suppl
1):S7)
2. classification and diagnosis of diabetes (Diabetes Care 2018 Jan;41(Suppl 1):S13)
3. comprehensive medical evaluation and assessment of comorbidities (Diabetes Care
2018 Jan;41(Suppl 1):S28)
4. lifestyle management (Diabetes Care 2018 Jan;41(Suppl 1):S38)
5. prevention or delay of type 2 diabetes (Diabetes Care 2018 Jan;41(Suppl 1):S51)
6. glycemic targets (Diabetes Care 2018 Jan;41(Suppl 1):S55)
7. obesity management for the treatment of type 2 diabetes (Diabetes Care 2018
Jan;41(Suppl 1):S65)
8. pharmacologic approaches to glycemic treatment (Diabetes Care 2018 Jan;41(Suppl
1):S73)
9. cardiovascular disease and risk management (Diabetes Care 2018 Jan;41(Suppl 1):S86)
10. microvascular complications and foot care (Diabetes Care 2018 Jan;41(Suppl 1):S105)
11. older adults (Diabetes Care 2018 Jan;41(Suppl 1):S119)
12. children and adolescents (Diabetes Care 2018 Jan;41(Suppl 1):S126)
13. management of diabetes in pregnancy (Diabetes Care 2018 Jan;41(Suppl 1):S137)
14. diabetes care in the hospital (Diabetes Care 2018 Jan;41(Suppl 1):S144)
15. diabetes advocacy (Diabetes Care 2018 Jan;41(Suppl 1):S152)
ADA consensus statement on hyperglycemic crisis in adult patients with diabetes can be found
in Diabetes Care 2009 Jul;32(7):1335 full-text, commentary can be found in Diabetes Care 2009
Dec;32(12):e157 (DynaMed commentary -- footnote states "An American Diabetes Association
consensus statement represents the authors' collective analysis, evaluation, and opinion at the
time of publication and does not represent official association opinion.")

Endocrine Society clinical practice guideline on management of hyperglycemia in hospitalized patients

in non-critical care setting can be found in J Clin Endocrinol Metab 2012 Jan;97(1):16

United Kingdom guidelines

Joint British Diabetes Societies Inpatient Care Group statement on management of hyperosmolar
hyperglycaemic state (HHS) in adults with diabetes can be found at Joint British Diabetes Societies
2012 Aug PDF

Review articles

review of hyperglycemic hyperosmolar state can be found in Am Fam Physician 2017 Dec
1;96(11):729
review of hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic
hyperosmolar state can be found in Endocrinol Metab Clin North Am 2006 Dec;35(4):725
review of presentation, diagnosis, and treatment of hyperosmolar hyperglycemic state can be found in
Diabetes Care 2014 Nov;37(11):3124 full-text
review of diabetic ketoacidosis and hyperglycemic hyperosmolar state can be found in Med Klin
(Munich) 2006 Mar 22;101 Suppl 1:100

MEDLINE search
to search MEDLINE for (hyperosmolar hyperglycemia) with targeted search (Clinical Queries), click
therapy, diagnosis, or prognosis

ICD-9/ICD-10 Codes
ICD-9 codes

14/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

250.20 diabetes mellitus with hyperosmolar coma, type II or unspecified type, not stated as
uncontrolled
250.21 diabetes mellitus with hyperosmolar coma, type I not stated as uncontrolled
250.22 diabetes mellitus with hyperosmolar coma, type II or unspecified type, uncontrolled (blood
glucose > 200)
250.23 diabetes mellitus with hyperosmolar coma, type I, uncontrolled (blood glucose > 200)
249.2 secondary diabetes mellitus with hyperosmolarity
249.20 secondary diabetes mellitus with hyperosmolarity, not stated as uncontrolled, or
unspecified
249.21 secondary diabetes mellitus with hyperosmolarity, uncontrolled

ICD-10 codes
E10.0 insulin-dependent diabetes mellitus with coma [use for hyperosmolar coma]
E10.6 insulin-dependent diabetes mellitus with other specified complications
E11.0 non-insulin-dependent diabetes mellitus with coma [use for hyperosmolar coma]
E11.6 non-insulin-dependent diabetes mellitus with other specified complications

References
General references used

1. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with
diabetes. Diabetes Care. 2009 Jul;32(7):1335-43 full-text, commentary can be found in Diabetes Care
2009 Dec;32(12):e157 full-text (DynaMed commentary -- footnote states "An American Diabetes
Association consensus statement represents the authors' collective analysis, evaluation, and opinion at
the time of publication and does not represent official association opinion.")
2. Scott A, Claydon A. Joint British Diabetes Societies Inpatient Care Group. The management of
hyperosmolar hyperglycaemic state (HHS) in adults with diabetes. Joint British Diabetes Societies
2012 Aug PDF
3. Umpierrez G, Korytkowski M. Diabetic emergencies - ketoacidosis, hyperglycaemic hyperosmolar
state and hypoglycaemia. Nat Rev Endocrinol. 2016 Apr;12(4):222-32

Synthesized Recommendation Grading System for DynaMed Plus

DynaMed systematically monitors clinical evidence to continuously provide a synthesis of the most
valid relevant evidence to support clinical decision-making (see 7-Step Evidence-Based
Methodology).
Guideline recommendations summarized in the body of a DynaMed topic are provided with the
recommendation grading system used in the original guideline(s), and allow DynaMed users to quickly
see where guidelines agree and where guidelines differ from each other and from the current evidence.
In DynaMed Plus (DMP), we synthesize the current evidence, current guidelines from leading
authorities, and clinical expertise to provide recommendations to support clinical decision-making in
the Overview & Recommendations section.
We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to
classify synthesized recommendations as Strong or Weak.
Strong recommendations are used when, based on the available evidence, clinicians (without
conflicts of interest) consistently have a high degree of confidence that the desirable
consequences (health benefits, decreased costs and burdens) outweigh the undesirable
consequences (harms, costs, burdens).
Weak recommendations are used when, based on the available evidence, clinicians believe that
desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists
about the magnitude of expected consequences (benefits and harms). Weak recommendations
are used when clinicians disagree in judgments of relative benefit and harm, or have limited
confidence in their judgments. Weak recommendations are also used when the range of patient
values and preferences suggests that informed patients are likely to make different choices.
15/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

DynaMed Plus (DMP) synthesized recommendations (in the Overview & Recommendations section)
are determined with a systematic methodology:
Recommendations are initially drafted by clinical editors (including ≥ 1 with methodological
expertise and ≥ 1 with content domain expertise) aware of the best current evidence for benefits
and harms, and the recommendations from guidelines.
Recommendations are phrased to match the strength of recommendation. Strong
recommendations use "should do" phrasing, or phrasing implying an expectation to perform the
recommended action for most patients. Weak recommendations use "consider" or "suggested"
phrasing.
Recommendations are explicitly labeled as Strong recommendations or Weak
recommendations when a qualified group has explicitly deliberated on making such a
recommendation. Group deliberation may occur during guideline development. When group
deliberation occurs through DynaMed-initiated groups:
Clinical questions will be formulated using the PICO (Population, Intervention,
Comparison, Outcome) framework for all outcomes of interest specific to the
recommendation to be developed.
Systematic searches will be conducted for any clinical questions where systematic
searches were not already completed through DynaMed content development.
Evidence will be summarized for recommendation panel review including for each
outcome, the relative importance of the outcome, the estimated effects comparing
intervention and comparison, the sample size, and the overall quality rating for the body
of evidence.
Recommendation panel members will be selected to include at least 3 members that
together have sufficient clinical expertise for the subject(s) pertinent to the
recommendation, methodological expertise for the evidence being considered, and
experience with guideline development.
All recommendation panel members must disclose any potential conflicts of interest
(professional, intellectual, and financial), and will not be included for the specific panel if
a significant conflict exists for the recommendation in question.
Panel members will make Strong recommendations if and only if there is consistent
agreement in a high confidence in the likelihood that desirable consequences outweigh
undesirable consequences across the majority of expected patient values and preferences.
Panel members will make Weak recommendations if there is limited confidence (or
inconsistent assessment or dissenting opinions) that desirable consequences outweigh
undesirable consequences across the majority of expected patient values and preferences.
No recommendation will be made if there is insufficient confidence to make a
recommendation.
All steps in this process (including evidence summaries which were shared with the panel,
and identification of panel members) will be transparent and accessible in support of the
recommendation.
Recommendations are verified by ≥ 1 editor with methodological expertise, not involved in
recommendation drafting or development, with explicit confirmation that Strong
recommendations are adequately supported.
Recommendations are published only after consensus is established with agreement in phrasing
and strength of recommendation by all editors.
If consensus cannot be reached then the recommendation can be published with a notation of
"dissenting commentary" and the dissenting commentary is included in the topic details.
If recommendations are questioned during peer review or post publication by a qualified
individual, or reevaluation is warranted based on new information detected through systematic
literature surveillance, the recommendation is subject to additional internal review.

DynaMed editorial process

DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
All editorial team members and reviewers have declared that they have no financial or other competing
interests related to this topic, unless otherwise indicated.

16/17
07/07/2018 DynaMed Plus: Hyperglycemic hyperosmolar state in adults

DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster
University and F1000.

Special acknowledgements
Samir Malkani, MBBS, MD, MRCP (Clinical Professor of Medicine, University of Massachusetts
Medical School; Physician Leader, Diabetes Services, UMassMemorial Health Care; Massachusetts,
United States)
Dr. Malkani has declared that he has no financial conflicts of interest.

Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS (Director of Bahrain Branch of the United Kingdom
Cochrane Center, The Cochrane Collaboration; Awali, Bahrain)
Dr. Fedorowicz has declared that he has no financial conflicts of interest.

William Aird, MD (Deputy Editor of Hematology, Endocrinology, and Nephrology; Professor of

Medicine, Harvard Medical School; Massachusetts, United States)
Dr. Aird declares no relevant financial conflicts of interest.

DynaMed Plus topics are written and edited through the collaborative efforts of the above individuals.
Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice.
Recommendations Editors are actively involved in development and/or evaluation of guidelines.

Editorial Team role definitions

Topic Editors define the scope and focus of each topic by formulating a set of clinical questions and
suggesting important guidelines, clinical trials, and other data to be addressed within each topic.
Topic Editors also serve as consultants for the internal DynaMed Plus Editorial Team during the
writing and editing process, and review the final topic drafts prior to publication.
Section Editors have similar responsibilities to Topic Editors but have a broader role that includes the
review of multiple topics, oversight of Topic Editors, and systematic surveillance of the medical
literature.
Recommendations Editors provide explicit review of DynaMed Plus Overview and
Recommendations sections to ensure that all recommendations are sound, supported, and evidence-
based. This process is described in "Synthesized Recommendation Grading."
Deputy Editors are employees of DynaMed and oversee DynaMed Plus internal publishing groups.
Each is responsible for all content published within that group, including supervising topic
development at all stages of the writing and editing process, final review of all topics prior to
publication, and direction of an internal team.

How to cite

National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal

Editors):
DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No.
115340, Hyperglycemic hyperosmolar state in adults; [updated 2018 Feb 20, cited place cited
date here]; [about 8 screens]. Available from http://www.dynamed.com/login.aspx?
direct=true&site=DynaMed&id=115340. Registration and login required.

17/17