HYPEROSMOLAR

HYPERGLYCEMIC STATE
(HHS)

Kimaiga H.O, MBChB (University of Nairobi)

Hyperosmolar Hyperglycemic state (HHS)
• Hyperosmolar hyperglycaemic nonketotic coma is usually a complication of
type 2 DM.
• It is caused by severe dehydration resulting from sustained hyperglycaemic
diuresis.
• HHS is characterized by hyperglycemia, hyperosmolarity, and severe
dehydration without significant ketoacidosis
• The loss of glucose in urine is so intense that the patient is unable to drink
sufficient water to maintain urinary fluid loss.
• The usual clinical features of ketoacidosis are absent but prominent central
nervous signs are present.
• Blood sugar is extremely high and plasma osmolality is high.
• Thrombotic and bleeding complications are frequent due to high viscosity of
blood.
• The mortality rate in hyperosmolar nonketotic coma is high.
• The contrasting features of diabetic ketoacidosis and hyperosmolar non-
ketotic coma are summarised in
Kimaiga H.O, MBChB (University of Nairobi)
• An acute metabolic complication of diabetes mellitus
(DM) characterized by:
– Impaired mental status (MS)
– Elevated plasma osmolality
– Hyperglycemia.
– Dehydration (volume deletion)
– Absence of significant ketosis.
– Pro-thrombotic state
• Despite the name, coma is present in fewer than 10% of
cases.
• In many cases, the clinical features of HONC and diabetic
ketoacidosis (DKA) overlap and these may be observed
simultaneously.
Kimaiga H.O, MBChB (University of Nairobi)
Criteria for HONC include
• Serum osmolality > 320 mOsm/kg
• Plasma glucose level greater than >33.3 mmol/L
• Profound dehydration, up to an average of 9L
• PH of 7.3 and HCO3- of about 15 mEq/L
• Absence of severe ketosis.
• Bicarbonate concentration greater than 15 mEq/L
• Small ketonuria and absent-to-low ketonemia
• Some alteration in consciousness
• HONC is the initial presentation of DM for 30-40% of patients.
• Most cases of occur in patients with type 2 DM, characterized by insulin
resistance and defective insulin secretion.
• Also occur in type 1 DM, in whom diabetic ketoacidosis (DKA) is more
common.
• Both HNS and DKA may occur in the same individual, which suggests these 2
states of uncontrolled DM differ only in the magnitude of dehydration and the
severity Diabetes
American of acidosis
Association consesus statement:
Kimaiga H.O, MBChB (University of Nairobi)
Case
• 78 year old woman living on her own
– Type 2 diabetes for 12 years on metformin and glibenclamide
– CVA with R hemiparesis
– Discovered in bed by her daughter semi conscious and
incapacitated
• Admission to emergency ward:
Lab bloods:
Random blood glucose 810 mg/dl
Na+ 150 mmol/L Hb 14.6 g/dL
K+ 5.0 mmol/L WBC 16 x 108/L
Creatinine 192 µmol/L Neutrophils 92%
Urea 20 mmol/L
Osmolality: 370 mosm/L
Kimaiga H.O, MBChB (University of Nairobi)
Etiology
• Commonly occurs in T2DM who have some concomitant illness that leads to
reduced fluid intake.
• Acute febrile illnesses, including infections, account for the largest proportion of
HHS cases. A preceding or intercurrent infection (in particular, pneumonia or
UTI).
• The stress response to any acute illness tends to increase hormones that favor
elevated glucose levels. Cortisol, catecholamines, glucagon, and many other
hormones have effects that tend to counter those of insulin. Examples of such
acute conditions are as follows:
• Stroke
• Intracranial hemorrhage
• Silent MI – Consider MI in all patients with HHS until it is excluded
• Pulmonary embolism
• Patients with underlying renal dysfunction
• congestive heart failure.
• Drugs that raise serum glucose levels, inhibit insulin, or cause dehydration may
cause HHS.
Kimaiga H.O, MBChB (University of Nairobi)
Pathophysiology
• Same as DKA. Unlike patients with DKA, patients do not develop ketoacidosis, but the reason for this is not known.
• Contributing factors include the limitation on ketogenesis by hyperosmolarity, the lower levels of free fatty acids available for
ketogenesis, the availability of insulin in amounts sufficient to inhibit ketogenesis but not sufficient to prevent hyperglycemia,
and the hepatic resistance to glucagons in these patients.

• Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS.
• Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose
utilization in skeletal muscle
• Hyperglycemia induces an osmotic diuresis that leads to intravascular volume depletion, which is exacerbated by inadequate
fluid replacement.
• The absence of ketosis in HHS is not completely understood.
• Presumably, the insulin deficiency is only relative and less severe than in DKA.
• Lower levels of counterregulatory hormones and free fatty acids have been found in HHS than in DKA in some studies.
• It is also possible that the liver is less capable of ketone body synthesis or that the insulin/glucagon ratio does not favor
ketogenesis

• Underlying mechanism of HHS is a relative or absolute reduction in effective circulating insulin with a concomitant elevation
of counterregulatory hormones.
• Decreased renal clearance and decreased peripheral utilization of glucose lead to hyperglycemia.
• Hyperglycemia and hyperosmolarity result in an osmotic diuresis and an osmotic shift of fluid to the intravascular space,
resulting in further intracellular dehydration.
• This diuresis also leads to loss of electrolytes, such as sodium and potassium.
• Unlike patients with DKA, patients with HHS do not develop significant ketoacidosis, but the reason for this is not known.
– May be availability of insulin in amounts sufficient to inhibit ketogenesis but insufficient to prevent hyperglycemia.
– Additionally, hyperosmolarity may decrease lipolysis, limiting the amount of free fatty acids available for ketogenesis.
– In addition, levels of counterregulatory hormones are found to be lower in patients with HHS than in those with DKA.

Kimaiga H.O, MBChB (University of Nairobi)

• Hyperglycemia and the rise in the plasma protein concentration
after intravascular water loss cause a hyperosmolar state.
• The hyperosmolarity of the plasma triggers release of antidiuretic
hormone, which ameliorates renal water loss.
• Hyperosmolarity also stimulates thirst, a defense mechanism that
is impaired in people dependent on others for care.
• In the presence of HHS, if the renal water loss is not compensated
for by oral water intake, dehydration →hypovolemia →
hypotension → hypotension → impaired tissue perfusion → →
Coma
• Hypotension causes a massive stimulation of the renin-
angiotensin-aldosterone system → renal shutdown. Oliguria
precludes further excretion of glucose from the kidneys, which
conserves circulating volume but exacerbates hyperglycemia.
Kimaiga H.O, MBChB (University of Nairobi)
Pathway to HHS:
• low insulin concentrations, but sufficient to
suppress lipolysis -> hyperglycaemia
• Inability to hydrate or excrete glucose
particularly due to a disabling primary
condition
– serious acute infection, overwhelming infection,
stroke, MI, debility, etc

Kimaiga H.O, MBChB (University of Nairobi)

• Morbidity and mortality
• Cerebral edema-With rapid rehydration
• ARDS
– ARDS may develop in association with underlying diseases, such as pancreatitis and
MI.
– May also occur rapid rehydration causing pulmonary edema.
• Vascular complications:
– The severe dehydration leads to hypotension and hyperviscosity of the blood, both of
which predispose patients to thromboembolic disease of the coronary, cerebral,
pulmonary, and mesenteric beds. DIC may also occur.
– Low-dose subcutaneous heparin is advisable for all patients without a
contraindication.
• Age:
– The average age of patients with HNS is 60 years. Underlying comorbidities that
prevent adequate hydration, including immobility, advanced age, debility, dementia,
agitation, and restraint use, place these patients at risk. Impaired senses, such as
deafness and blindness, may lead to social isolation and also increase the risk of HNS

Kimaiga H.O, MBChB (University of Nairobi)

Clinical presentation
HISTORY:
• Most patients with HHNC have a known history of diabetes, which is
usually adult onset.
• 1/3 patients with HHNC do not have a prior diagnosis of diabetes.
• Often, a preceding illness results in several days of increasing
dehydration.
• Oral hydration usually is impaired by concurrent acute illness or
chronic co morbidity (eg, dementia, immobility, vomiting).
• A wide variety of focal and global neurologic changes may be present,
including the following:
– Drowsiness,lethargy,Delirium, Coma
– Focal or generalized seizures
– Visual changes or disturbances
– Hemiparesis
– Sensory deficits
Kimaiga H.O, MBChB (University of Nairobi)
PHYSICAL
• Signs of dehydration-dry mucous membranes and reduced skin tugour.
• Vital signs: Tachycardia is an early indicator of dehydration; hypotension is a later
sign suggestive of profound dehydration.
• Tachypnea may result from respiratory compensation for metabolic acidosis.
• Hypoxemia can be a concurrent problem affecting mentation. Administer
supplemental oxygen if the patient has any degree of desaturation.
• Perform a thorough skin examination including a search for sources of infection,
such as cellulitis or abscess.
• Examination of the head, eyes, ears, nose, and throat (HEENT) may reveal altered
hydration status (eg, sunken eyes, dry mouth) or potential foci of infection (eg,
middle ear, sinuses, oropharynx). Cranial neuropathies may be appreciated.
• CVS examination-CCF,MI
• Visual field losses and nystagmus sometimes are observed in HONC.
• The neck exam may reveal enlarged lymph nodes or meningismus. Palpation of the
thyroid may reveal evidence consistent with thyrotoxicosis as a cause for
tachycardia, fever, and dehydration.
Kimaiga H.O, MBChB (University of Nairobi)
Clinical Features
• The prototypical patient with HHS is an elderly individual with type 2 DM,
with a several week history of polyuria, weight loss, and diminished oral
intake that culminates in mental confusion, lethargy, or coma
• The physical examination reflects profound dehydration and hyperosmolality
and reveals hypotension, tachycardia, and altered mental status.
• Notably absent are symptoms of nausea, vomiting, and abdominal pain and
the Kussmaul respirations characteristic of DKA.
• HHS is often precipitated by a serious, concurrent illness such as myocardial
infarction or stroke.
• Sepsis, pneumonia, and other serious infections are frequent precipitants and
should be sought.
• In addition, a debilitating condition (prior stroke or dementia) or social
situation that compromises water intake usually contributes to the
development of the disorder
• Finally, the development of HHS can be associated with the use of certain
medications (thiazide diuretics, glucocorticoids, and phenytoin).
Kimaiga H.O, MBChB (University of Nairobi)
Complications
• Cerebral edema is rare in HHS and is usually observed in patients
much younger than the average age of 60 years. However, it may occur
from rapid lowering of glucose levels and an ensuing rapid drop in
plasma osmolarity.
• Acute respiratory distress syndrome- Although the precise
mechanism by which ARDS develops in persons with HHS remains
unclear, a likely scenario is that rapid correction of hyperglycemia and
hyperosmolarity gives rise to pulmonary edema in much the same
manner as it gives rise to cerebral edema. To compensate for hypoxia
and mild acidosis, an increase in the minute ventilation with tachypnea
develops. Continuing pulmonary disease may lead to acute respiratory
failure that necessitates full respiratory support, including mechanical
ventilation.
• Vascular complications-hypotension and hyperviscosity of the blood→
thromboembolic disease of the coronary, cerebral, pulmonary, and
mesenteric beds.
Kimaiga H.O, MBChB (University of Nairobi)
Investigations
• Hyperglycemia [plasma glucose may be >55.5 mmol/L (1000mg/dL)]
• Hyperosmolality (>350 mosmol/L)
• Prerenal azotemia.
• The measured serum sodium may be normal or slightly low despite
the marked hyperglycemia.
• The corrected serum sodium is usually increased [add 1.6 meq to
measured sodium for each 5.6 mmol/L (100 mg/dL) rise in the serum
glucose].
• In contrast to DKA, acidosis and ketonemia are absent or mild.
• Potassium: normal
• A small anion gap metabolic acidosis may be present secondary to
increased lactic acid.
– The calculated anion gap is usually less than 12 mmol/L.
• Moderate ketonuria, if present, is secondary to starvation.

Kimaiga H.O, MBChB (University of Nairobi)

• Serum ketones- A mild degree of ketosis is usually observed
in any patient who is dehydrated. In those with HHS, despite
the significant degree of dehydration, ketosis is mild and
responds readily to treatment.
• BUN and creatinine- Patients with HNS present with prerenal
azotemia. Initially, BUN and creatinine concentrations are
likely to be elevated, and the BUN-to-creatinine ratio may
exceed 30:1.
– When possible, these values should be compared with previous
values; many patients with diabetes have baseline renal insufficiency.
• Blood culture- bacteremia.
• Urine cultures
• ECG,

Kimaiga H.O, MBChB (University of Nairobi)

Prognosis
• Longer duration of disease
• More pronounced fluid deficit
• Older patients with comorbidities
• Higher risk population of life threatening
precipitating event
• Higher Mortality: up to 15% in some
prospective cohorts

Kimaiga H.O, MBChB (University of Nairobi)

Treatment
• Careful monitoring of the patient's fluid status, laboratory values, and insulin infusion rate is
crucial.
1. Resuscitation: ABC, ? N.G. Tube, C.V.P. Line
2. Anticoagulate with heparin
3. Rehydrate with normal saline – but extreme caution if chance not to overload with fluid (CVP line)
4. I.V. Insulin to reduce the glucose slowly:
N.B. the danger of rapid correction of hyperosmosis is cerebral oedema
5. Treat the underlying cause
6. Return to maintenance care (often just tablet treatment)

• Underlying or precipitating problems should be aggressively sought and treated.

• In HHS, fluid losses and dehydration are usually more pronounced than in DKA due to the longer
duration of the illness.
• The patient with HHS is usually older, more likely to have mental status changes, and more likely to
have a life-threatening precipitating event with accompanying comorbidities.
• Short acting Insulin: regular
• Fluid replacement with ½ NS
• Follow electrolytes: K/Mg/PO4
• BG <300mg/dl either add D5 to IVF or convert to SC insulin depending on nutrition

Kimaiga H.O, MBChB (University of Nairobi)

• Even with proper treatment, HHS has a substantially higher
mortality than DKA (up to 15% in some clinical series).
• Fluid replacement should initially stabilize the hemodynamic status
of the patient (1–3 L of 0.9% normal saline over the first 2–3 h).
• Because the fluid deficit in HHS is accumulated over a period of
days to weeks, the rapidity of reversal of the hyperosmolar state
must balance the need for free water repletion with the risk that too
rapid a reversal may worsen neurologic function.
• If the serum sodium > 150 mmol/L (150 meq/L), 0.45% saline
should be used.
• After hemodynamic stability is achieved, the IV fluid
administration is directed at reversing the free water deficit using
hypotonic fluids (0.45% saline initially then 5% dextrose in water,
D5W).

Kimaiga H.O, MBChB (University of Nairobi)

• Fluid deficits in HHS are large; the fluid deficit of an adult may be 10 L or more
• 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.
• 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
<16mmol/l, change the infusion to 5% dextrose in 0.9% isotonic saline again.
• In most patients, adequately monitoring volume status entails the use of a urinary catheter.

Kimaiga H.O, MBChB (University of Nairobi)

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 14mmol/l; this target level may be adjusted
downward after the patient is stabilized
Kimaiga H.O, MBChB (University of Nairobi)