55

Advances in Pediatrics

Hyperglycemic Hyperosmolar Nonketotic Syndrome

R. Venkatraman and Sunit C. Singhi
Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research
Center, Chandigarh, India

Abstract. Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) was infrequently diagnosed till recently. Now it is
being diagnosed with increasing frequency in obese children with type 2 diabetes mellitus (T2 DM) and its incidence is likely
to go up, given global increase in incidence of childhood obesity, increased insulin resistance, and T2 DM. The syndrome
is characterized by severe hyperglycemia, a marked increase in serum osmolality and dehydration without accumulation of
-hydroxybutyric or acetoacetic ketoacids. Significant ketogenesis is restrained by the ability of the pancreas to secrete
small amount of insulin. Prolonged phase of osmotic diuresis leads to severe depletion of body water, which excees that
of sodium, resulting in hypertonic dehydration. These children, usually obese adolescents with T2 DM, present with signs
of severe dehydration and depressed mental status but continue to have increased rather than decreased urine output and
are at increased risk of developing rhabdomyolysis and malignant hyperthermia. Emergency treatment is directed at
restoration of the intravascular volume, followed by correction of deficits of fluid and electrolyte (Na +, K+, Ca++, Mg++, PO4++),
hyperglycemia and serum hyperosmolarity, and a thorough search for conditions that may lead to this metabolic
decompensation and their treatment. Use of iso-osomolar isotonic fluid (0.9% saline) until hemodynamic stabilization
initially, followed by 0.45% saline with insulin infusion at the rate of 0.1 units/kg/hour, addition of 5% dextrose in fluids and
reduction of insulin infusion once the blood glucose is 250 to 300 mg/dl is generally recommended. However, evidence
based guidelines about composition and tonicity of fluids and electrolyte solutions for early resuscitation and rehydration,
the rate of infusionrapid vs slow, and insulin doselow vs normal, in treatment of HHNS in children are awaited. Careful
monitoring of glucose levels and ensuring adequate hydration in patients at risk of HHNS, including those receiving
medications that interfere with the secretion or effectiveness of insulin should decrease the risk of HHNS.
[Indian J Pediatr 2006; 73 (1) : 55-60] E-mail: drsinghi@glide.net.in, dr_singhi@yahoo.com
Key words : Hyperglycemic hyperosmolar nonketotic syndrome; Hyperglycemia; Fluid therapy; Electrolyte imbalance;
Hypertonic dehydration

Hyperglycemic hyperosmolar nonketotic syndrome

(HHNS) is a life-threatening complication commonly
associated with uncontrolled type 2 diabetes mellitus
(T2 DM). It was first recognized over a century ago but
was infrequently diagnosed until the report by Sament
and Schwartz in 1957 1. New HHNS accounts for
between 5 and 15 percent of all adult and pediatric
diabetic hyperglycemic emergencies. 2 In adults HHNS
occurs at a frequency of 17.5 cases/100,000 persons /
year. 3 Populationbased data for children are not
available. A recent estimate suggests in USA that nearly
4% of newly diagnosed pediatric T2 DM patients will
have HHNS with a case fatality of 12%. 4 T2 DM
accounts for as much as half of newly diagnosed DM in

children between 12-21 years in USA. 2 Similar trends

are beginning to appear in adolescents in U.K. 5 More
recently the syndrome has been recognized with
increasing frequency in obese adolescents and children
with T2 DM. 6-8 The incidence is therefore likely to
increase with global increase in incidence of obesity9-11,
increased insulin resistance and T2 DM. 10,12,13 HHNS
may rarely occur in younger patients14 and following
acute stress of sepsis or trauma, use of several drugs,
and other conditions without underlying T2DM 15
(Table 1). In this review, we discuss issues in diagnosis
and management of this resurgent problem with a
pediatric perspective.
PATHOGENESIS

Correspondence and Reprint requests : Dr. Sunit Singhi,

Professor, Head, Pediatric Emergency and Intensive CareUnits,
Advanced Pediatrics Center, PGIMER, Chandigarh 160012. Fax
No. 91-172-2744401, 2745078

Indian Journal of Pediatrics, Volume 73January, 2006

The syndrome is characterized by severe

hyperglycemia, a marked increase in serum osmolality
and clinical evidence of dehydration without the
accumulation of -hydroxybutyric or acetoacetic
ketoacids (Fig. 1). Hyperglycemia results from either an
absolute or relative deficiency of insulin or due to
decreased tissue responsiveness to insulin (Increased
55

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R. Venkatraman and Sunit Singhi

TABLE 1. Common Diseases and Drugs Associated with
Hyperglycemic Hyperosmolar Non-ketotic Syndrome

Infections pneumonia, UTI, Sepsis

Trauma,
Drugs: Diuretics, Corticosteroids, -blockers, Phenytoin,
diazoxide, - L-asperginase, Calcium channel blockers,
Chlorpromazine, Cimetidine and Immunosuppressive
agents
Renal failure, Dialysis,
Hyper-alimentation,
Endocrine: Acromegaly, Thyrotoxicosis, Cushing's
syndrome
Myocardial infarction
Pancreatitits
Thromboembolism
Gastrointestinal hemorrhage

insulin resistance). This results in increased

gluconeogenesis and glycogenolysis,2 reduced rate of
glucose uptake and utilization by peripheral tissues 16,
and thus a rise in blood glucose level. Glycogenolysis,
however, contributes much less to the severity of
hyperglycemia as these patients are usually quite ill
and may not have eaten for several days, thus
depleting their hepatic glycogen stores. HHNS evolves
when insulin resistance permits development of
hyperglycemia in the absence of significant ketone
production and limited ability of the kidney to excrete
large quantities of glucose. HHNS therefore is more
likely to occur in children with renal disease associated
with increased renal threshold for the excretion of
glucose.17
A rise in osmolality in the extracellular fluid causes
a shift of water from the intracellular to the extracellular
space resulting in intracellular dehydration. Initially,
this redistribution of water causes a slight expansion of
the extracellular fluid volume and lowers the serum
sodium, but the effect is transient. 18 Glycosuria and
osmotic diuresis ensue once the blood glucose exceeds
the renal threshold (normal range 180-250 mg/dl). The
initial glycosuria temporarily protects the patients from
hyperglycemia, but as the osmotic diuresis continues
profound depletion of intravascular volume occurs,
decreasing renal perfusion and the ability of the
kidneys to excrete large quantities of glucose.19 At this
point, profound hyperglycemia and a further increase
in plasma osmolality occur. The stress of profound
hyperglycemia and resultant hyperosmolarity and
dehydration, as well as the precipitating illness,
contributes to increased production of counter
regulatory hormones like cortisol, catecholamines and
glucagon. The increased secretion of the counter
regulatory hormones further accentuates the degree of
hyperglycemia.2
In addition to glucose, electrolytes such as sodium,
potassium, phosphate and magnesium are also lost
during the osmotic diuresis. Sodium depletion leads to
further decrease in intravascular volume but urinary
56

Initiating / Precipitating event

Insulin (relative insulin deficiency)

Counter regulatory Hormones (cortisol,
glucagon, epinephrine, growth hormone)

Glucose uptake

Hyperglycemia
Absence or minimal
ketogenesis

Hyperosmolarity

Osmotic diuresis
Pre renal azotemia
Volume depletion

Dehydration

Electrolyte depletion
Fig. 1. Pathogenesis of HHNS
losses of water always exceeds that of sodium leading
to development of hypertonic dehydration.
The mechanisms responsible for limiting significant
accumulation of ketoacidosis in HHNS have been a
subject of debate. 20 Most data support the hypothesis
that significant ketogenesis is restrained by the ability
of the pancreas to secrete small amount of insulin.21
Inhibition of lipolysis and stimulation of lipogenesis
occurs at much lower concentrations, while glucose
uptake and inhibition of gluconeogenesis require
considerably greater concentration of insulin. 16
Hyperosmolality and dehydration have also been
reported to inhibit release of free fatty acids from
adipose tissue.
DIAGNOSIS
HHNS is a medical emergency that requires prompt
recognition and treatment. Delayed diagnosis and
treatment is one of the important factors responsible for
the high mortality associated with HHNS. 7,22 There is
no symptom or sign specific of HHNS and hence there
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Hyperglycemic Hyperosmolar Nonketotic Syndrome

is often a delay in seeking medical care. Patients
typically have no prior knowledge of glucose
intolerance, and experiences polyuria, polydipsia and
weight loss as osmotic diuresis sets in. The lack of
significant ketonaemia and acidosis and absence of
Kussumal breathing and fruity scent in breath usually
allows patients with HHNS to lapse into prolonged
phase of osmotic diuresis and a greater degree of
dehydration compared to patients with diabetic
ketoacidosis (DKA) before presenting for medical
attention.17
Usually, these patients at presentation have poor
skin turgour, dry mucus membrane, tachycardia, low
jugular venous pressure and may be hypotensive. The
sensorium may vary from normal to profound coma. In
some patients focal neurological signs (hemiparesis or
hemianopsia) and seizures may be the dominant
clinical features 23. The physical findings of fluid
depletion in a patient who continues to have increased
rather than decreased urine output, especially in the
presence of depressed mental status, should lead the
physician to strongly consider a diagnosis of HHNS. In
some instances HHNS was not suspected even when
the patients presented with neurological signs and
symptoms associated with glycosuria18 . Hence, a high
index of suspicion for HHNS should be maintained,
especially in obese adolescents at risk of T2 DM or in
children who are on drugs known to precipitate
hyperglycemia. Due to severe dehydration, patients
with HHNS are at increased risk of developing
vascular thrombosis including cerebral and mesenteric
artery occlusions. 24
Rhabdomyolysis and malignant hyperthermia have
been reported in HHNS, especially in obese adolescents
with T2 DM. 7,25 It is believed that defects in the fatty
acid oxidation in the skeletal muscles of such
individuals lead to excess lipid deposition in their
muscles and predisposes them to rhabdomyolysis.7
Laboratory Findings
Diagnostic criteria for HHNS are summarized in table
2. The initial laboratory evaluation of patients with
suspected HHNS should include immediate
determination of blood glucose, blood urea and
creatinine, serum electrolytes, osmolality and ketones
and arterial blood gases. Urine analysis and blood
counts with differentials should be done. Bacterial
cultures of urine, blood and other tissues should be
obtained and appropriate antibiotics should be
administered if infection is suspected. Approximately,
50% of the patients with HHNS have an increased
anion gap metabolic acidosis because of increased
serum lactate level18.
Sodium: All patients with HHNS, regardless of the
initial serum sodium concentration from low to high,
are in a state of hypertonic dehydration. It must be
Indian Journal of Pediatrics, Volume 73January, 2006

TABLE 2. Laboratory Criteria for Diagnosis of Hyperosmolar

Hyperglycemic Non-Ketotic Syndrome (HHNS) and
its Differentiation from Diabetic Ketoacidosis
(DKA) (Kitabchi 2001 2 )
___________________________________________________________________________
Laboratory criteria
DKA
HHNS
___________________________________________________________________________
Glucose (serum), mg/dl
>250
>600
Arterial pH
<7.3
>7.3
Bicarbonate (serum), mEq/dl
<15
<20
BUN (serum) mEq/dl
<25
>30
Osmolality, mosm/kg
<320
>330
Urine Ketones
> +3
nil or small
Plasma Ketones
Positive >1:2 dilution nil or small
Anion gap
>10
variable

appreciated that due to transcellular shifts of water, the

serum sodium concentration decreases approximately
1.6 mEq/l for every 100 mg/dl increment in blood
glucose.26 Reduction of the blood glucose concentration
following administration of fluids and insulin causes
an increase in serum sodium levels as water is
transported back into the intracellular space.
Potassium : Its depletion results from the osmotic
diuresis and poor oral intake and in some case due to
vomiting and kaliuretic drugs. However, insulin
deficiency causes a shift of potassium to the
extracellular fluid, and the initial serum potassium
values may be normal or elevated. With fluid and
insulin therapy there is a danger of rapid fall in serum
potassium.
Dehydration also causes an elevation in serum urea
and creatinine, and these parameters may not
normalize in patients with renal disease. Leucocytosis
may be observed due to increased levels of
catecholamines and glucocorticoids, but it should be
remembered that even sepsis could raise the levels of
white cell count. Normal hemoglobin at presentation
may indicate an underlying anemia, which will
manifest after rehydration.
Elevation of muscle enzymes such as creatinine
phosphokinase and lactic dehydrogenase aid in the
diagnosis of rhabdomyolysis.
MANAGEMENT
Total body water deficit in HHNS may range from 100
200 ml/kg. The early objective of management of HHNS
is therefore rapid restoration of circulatory volume,
replacement of fluid and electrolyte deficits and
correction of hyperglycemia and hyperosmolarity
(Table 3).
Fluid therapy: The principal objective at the outset is
restoration of the intravascular volume to assure
adequate perfusion of the brain, heart and kidneys. 27
However, evidencebased guidelines to achieve the
above treatment objectives in children are not available.
57

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R. Venkatraman and Sunit Singhi

TABLE 3. Objectives of Acute Management of HHNS
1.
2.
3.
4.

Restoration of circulatory volume and tissue perfusion.

Replacement of fluid loses and correction of total fluid
deficits.
Correction of hyperglycemia and serum hyperosmolarity
Replacement of electrolyte losses.

Note-All of these objectives are approached simultaneously and

are best achieved in an intensive care unit20.

The issues about composition and tonicity of fluid and

electrolyte solutions for early resuscitation and
rehydration, the rate of infusionrapid vs slow, insulin
doseearly high dose for rapid lowering of glucose etc.
remain unresolved in the absence of studies in children.
One of the reasons for the controversy is fear of cerebral
edema with rapid fluid correction as seen in patients
with diabetic ketoacidosis. A rapid decline in blood
glucose concentration after initiation of treatment with
insulin might decrease brain/blood glucose ratio
resulting in fluid shift to the brain28.
Rapid restoration of circulating volume using iso
osomolar isotonic fluid (0.9% saline) until stabilization
of pulse, blood pressure and other vital signs, followed
by 0.45% saline with insulin infusion at the rate of 0.1
units/kg/hour is recommended 2,18. The decrease in
plasma glucose level should be 75 to 100mg/dl (4.0 to
5.5 mmol/l). Once the blood glucose is in the range of
250 to 300 mg/dl, 5% dextrose may be added to the
fluids and insulin infusion reduced. The fluid,
electrolyte and glucose therapy should be directed at a
gradual decrease in plasma osmolality and corrected
serum sodium levels28. Rapid corrections of metabolic
abnormality and hyperosmolarity by administration of
hypotonic fluids and insulin should be avoided in
younger patients to decrease the risk of cerebral
edema 29. American Diabetic Association guidelines
recommend slower correction of fluid deficit (over 48
hours) in patients below 20 years than in adults.2
Insulin Therapy: The intravenous route of insulin
administration is preferred in dehydrated patients in
whom the absorption of insulin from subcutaneous or
even intramuscular sites may not be predictable. A
lower dose of insulin (0.1 unit/kg/hour without an
initial loading dose) is required to correct the metabolic
abnormalities in children with HHNS in comparison to
those used in DKA.2,29 This is also expected to prevent
cerebral edema and hypotension, which develop
because of rapid shift of extracellular fluid into
intracellular compartment due to lowering of blood
sugar, and worsening of hypokalemia and
hypophostemia because of rapid insulin therapy.
Potassium therapy: Potassium deficits in HHNS
approximate those seen in diabetic ketoacidosis (5 to 15
mEq/kg). The initial serum potassium levels may be
low or normal, or occasionally elevated due to a shift of
58

intracellular potassium to extracellular fluid. Treatment

with insulin and fluid will cause a further decline in
potassium level due to its ingress into the cells.
Potassium replacement, 0.2 to 0.3 mEq/kg/hour,
should therefore be started early, once oliguria is ruled
out. Subsequent adjustments of potassium infusion rate,
which may go upto 0.5-0.75 mEq/kg/hour, is made
according to serum K+ levels. 2,18 Potassium phosphate
may be used instead of potassium chloride if
concomitant hypophosphatemia is present.
Phosphate therapy: Hypophosphatemia is uncommon.
It can lead to respiratory and skeletal muscle weakness,
hemolytic anemia and systolic cardiac dysfunction. 30
Phosphate depletion is believed to lead to decreased
2,3-diphosphoglycate, shifting of the oxygen
dissociation curve to the left. Phosphate replacement
(0.2-0.3 mEq/kg by infusion over several hours) is
indicated at a serum phosphate concentration < 1 mg/
dl or in patients with moderate hypophosphatemia and
concomitant hypoxia, anemia or cardio-respiratory
compromise. 2 The serum calcium and magnesium
concentration should be checked at the time of
presentation and during therapy: repletion is instituted
if levels fall below the normal range. Low dose infusion
of dopamine (1 to 5 g/kg/min) in neurosurgical
patients with HHNS has been associated with reduced
incidence of cerebral edema, renal failure and cardiac
failure31.
Immediate post-hyperglycemic care: Low dose insulin
therapy provides a circulating insulin concentration of
60-100 g/ml. However, because of the short half-life of
intravenous regular insulin, sudden interruption of
insulin infusion can lead to rapid lowering of insulin
concentration resulting in a relapse of HHNS. 2
Subcutaneous insulin can be started once the patients
intravenous volume has been corrected; sensorium
improves and is able to accept fluids orally.2
Treatment of precipitating causes and complications:
Optimal management of patients with HHNS requires a
thorough search for conditions that may lead to this
metabolic decompensation and their treatment (Table
1). Some authors recommend institution of empiric
broad-spectrum antibiotics particularly for Gram
negative organisms pending the results of bacterial
cultures.24
Thromboembolic events are frequently reported in
patients with HHNS and may in part be responsible for
the high mortality rate associated with this condition.32
Low-dose subcutaneous heparin is advised for
prophylactic anticoagulant administration in older
patients24,32; however, guidelines for its use in children
with HHNS are not available.
Fatal cases of cerebral edema have been reported
with HHNS. Clinically, cerebral edema is characterized
by deterioration in the level of consciousness, lethargy,
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Hyperglycemic Hyperosmolar Nonketotic Syndrome

decrease in arousal and headache. These symptoms
progress rapidly as brainstem herniation occurs, to
pupillary changes, bradycardia and respiratory arrest;
the progression may be so rapid that papilledema may
not be found. To avoid cerebral edema the blood
glucose level should be maintained between 250
300mg/dl until hyperosmolarity and mental status
improve and the patient becomes clinically stable.
Rhabdomyolysis has been observed frequently with
HHNS and is often associated with high mortality 7,25,
whether it is related to hyperosmolality or metabolic
disturbances associated with HHNS or their treatment
is not clear. No proven therapy exists for
rhabdomyolysis, although therapy with carnitine and
dantrolene has been tried. 7,25
MONITORING
Rapid changes in volume status and fluid and
electrolyte
balance
necessitate
meticulous
documentation of the therapeutic actions taken, as well
as the patients response to such therapy. Volume of
fluid administered, urine output, blood glucose
concentration, serum electrolyte levels, including
sodium, potassium, magnesium, calcium and
phosphate, blood urea, nitrogen (BUN) and creatinine
must be monitored and recorded hourly initially. 28 It
may be useful to monitor glucose corrected sodium
level to minimize the consequences of rapid decrease in
serum osmolality. 28 The brain/subcutaneous glucose
monitoring using the microdialysis may be helpful in
guiding the insulin and fluid therapy as any rapid
increase in the above ratio can forewarn the clinician
about the risk of impending cerebral edema.33
PREVENTION
Careful monitoring of glucose levels and ensuring
adequate hydration in patients at risk of HHNS
including those receiving medications that interfere
with the secretion or effectiveness of insulin should
decrease the risk of HHNS. Screening programmes
directed at identifying T2 DM in the community will
help identify patients at risk for HHNS.
CONCLUSION
Life-threatening hyperglycemic hyperosmolar
syndrome, which is characterized by severe
hyperglycemia without ketoacidosis, and very high
serum osmolality and dehydration, appears to be on
rise in adolescents with extreme obesity and T2 DM.
Population-based estimates of the magnitude of the
problem are needed. High index of suspicion in
dehydrated patients who continue to have increased
rather than decreased urine output may help in early
Indian Journal of Pediatrics, Volume 73January, 2006

diagnosis. Although the emergency treatment

guidelines recommend early restoration of the
intravascular volume, correction of fluid and electrolyte
deficits, hyperglycemia and hyperosmolarity,
prospective studies are needed to resolve controversy
surrounding tonicity and electrolyte composition of the
resuscitation and rehydration fluids, the rate of fluid
infusion and insulin doses in children. 34
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Indian Journal of Pediatrics, Volume 73January, 2006