Hypoglycemia: is a clinical syndrome with diverse causes in
which low plasma glucose concentrations lead to symptoms and
signs, and there is resolution of the symptoms/signs when the
plasma glucose concentration is raised .
In patients with Diabetes, hypoglycemia is defined as :
All episodes of an abnormally low plasma glucose concentration
(with or without symptoms) that expose the individual to harm.
The diagnosis of hypoglycemia is not based on an absolute blood
glucose level; it requires fulfillment of the Whipple triad:
I ) Signs and symptoms consistent with hypoglycemia
2) Associated low glucose level
3) Relief of symptoms with supplemental glucose
People with diabetes should become concerned about the
possibility of hypoglycemia at a self-monitored blood glucose
(SMBG) level ≤70 mg/dL (3.9 mmol/L).
This cut-off value has been debated, with some favoring a
value of <63 mg/dL .
While this value is higher than the value used to diagnose
hypoglycemia in people without diabetes ≤55 mg/dL .
The primary task in a patient without diabetes is to make an
accurate diagnosis, whereas the primary task in a patient with
diabetes is to alter or adjust therapy in an attempt to minimize
or eliminate hypoglycemia .
Hypoglycemia is common in type 1 diabetes, especially in
patients receiving intensive therapy, in whom the risk of severe
hypoglycemia is increased more than threefold.
They suffer an average of two episodes of symptomatic
hypoglycemia per week, thousands of such episodes over a
lifetime of diabetes, and one episode of severe, at least
temporarily disabling hypoglycemia per year.
• Incidence :
• 3.14% in the intensive treatment group
• 1.03% in the standard group
• Increased risk among women, African Americans, those with
less than high school education, aged participants .
Hypoglycemia is less frequent in type 2 diabetes than it is in
Hypoglycemia was reported in 38% of patients with T2DM who
added a sulfonylurea or meglitinide to metformin therapy.
Over time, the frequency of hypoglycemia in patients with type
2 diabetes approaches that in type 1 diabetes as patients with
type 2 diabetes approach the insulin deficient end of the
spectrum of the disease and require aggressive treatment with
In contrast to patients with diabetes, hypoglycemia is
uncommon in individuals who do not have drug-treated
Physiologic response to hypoglycemia in normal
subjects and patients with diabetes mellitus
The brain uses glucose as its preferred fuel. When a person's
plasma glucose level is less than 70 mg/dL (3.9 mmol/L),
signals are sent from the brain to the pancreas, liver, and
adrenal glands that collectively raise the plasma glucose level.
The hormones involved are insulin, glucagon, epinephrine,
norepinephrine, Cortisol, and growth hormone .
RESPONSE TO HYPOGLYCEMIA IN NORMAL
As plasma glucose levels decline within the physiologic range
in the fasting state, pancreatic beta-cell insulin secretion
decreases, thereby increasing hepatic glycogenolysis and
hepatic (and renal) gluconeogenesis.
Low insulin levels also reduce glucose utilization in peripheral
tissues, inducing lipolysis and proteolysis, thereby releasing
Thus, a decrease in insulin secretion is the first defense
As plasma glucose levels decline just below the physiologic
range, counterregulatory (plasma glucose–raising) hormones
are released Among these, pancreatic α-cell glucagon, which
stimulates hepatic glycogenolysis, plays a primary role.
Glucagon is the second defense against hypoglycemia.
Adrenomedullary Epinephrine , which stimulates hepatic
glycogenolysis and gluconeogenesis, renal gluconeogenesis),
is not normally critical. However, it becomes critical when
glucagon is deficient.
Epinephrine has similar hepatic effects as glucagon. It also
increases the delivery of gluconeogenic substrates from the
periphery, inhibits glucose utilization by several tissues ,and
inhibits insulin secretion.
As with glucagon, a normally functioning liver is necessary for
an adequate response. Epinephrine is the third defense against
When hypoglycemia is prolonged beyond 4 hours, cortisol and
growth hormone also support glucose production and limit
As plasma glucose levels fall to lower levels, symptoms prompt
the behavioral defense against hypoglycemia, including the
ingestion of food.
RESPONSE TO HYPOGLYCEMIA IN
Insulin : The protective response to hypoglycemia is impaired in
many diabetic patients . The first defense, the ability to suppress
insulin release, cannot occur in patients with absolute beta-cell
failure ( those with type 1 diabetes and long-standing type 2
diabetes). Therefore, inhibition of hepatic glucose production
Thus, the main defense against hypoglycemia is increased
release of counter regulatory hormones (glucagon and
epinephrine), which raise plasma glucose concentrations by
stimulating glucose production and by antagonizing the insulin-
induced increase in glucose utilization.
Glucagon :The glucagon response to hypoglycemia, although
normal at the onset of diabetes, is lost in parallel with that of insulin
in type 1 diabetes and more slowly in type 2 diabetes . This may be
the result of beta-cell failure and subsequent loss of the
hypoglycemia-induced decline in intra islet insulin that normally
signals increased glucagon secretion during hypoglycemia .
Epinephrine : In the setting of absent insulin and glucagon
responses, patients are dependent upon epinephrine to protect
against hypoglycemia. However, the epinephrine response to
hypoglycemia also becomes attenuated in many patients, at least in
part because of recent antecedent hypoglycemia .
The concept of hypoglycemia-associated autonomic failure (HAAF) in
type 1 diabetes and long-standing (absolute endogenous insulin
deficient) type 2 diabetes posits that recent antecedent iatrogenic
hypoglycemia causes both defective glucose counterregulation and
hypoglycemia unawareness and thus a vicious cycle of recurrent
It does so by shifting the glycemic threshold for the sympathoadrenal
response to subsequent hypoglycemia to a lower plasma glucose
This shift causes defective glucose counterregulation by reducing
epinephrine responses in the setting of absent insulin and glucagon
responses at a given level of hypoglycemia.
It also causes hypoglycemia unawareness by reducing neurogenic
• Mechanism — The precise mechanism(s) of the key feature of
HAAF, the attenuated sympathoadrenal response to falling
plasma glucose concentrations, is unknown .
1) One hypothesis is that hypoglycemic episodes lead to up
regulation of glucose transport in the brain, resulting in the
maintenance of glucose uptake and therefore the prevention
of warning symptoms of hypoglycemia.
2) Another is that an increase in cortisol during hypoglycemia
causes a reduced sympathoadrenal response to subsequent
3) A third is that hypoglycemia-induced alterations in hypothalamic
functions, or even a cerebral network, reduce the sympathoadrenal
response to subsequent hypoglycemia.
Classifications of Hypoglycemia
• In diabetes mellitus the hypoglycemia is classified as :
1) Severe hypoglycemia
2) Documented symptomatic hypoglycemia
3) Probable symptomatic hypoglycemia
4) Asymptomatic hypoglycemia(or hypoglycemic Unawareness)
5) Relative hypoglycemia
• Without diabetes mellitus the hypoglycemia is classified as:
1) reactive(sometimes called "postprandial")
2) and nonreactive(sometimes called "fasting").
Severe hypoglycemia: which requires the assistance of
another person to administer a carbohydrate (preferably glucose
sublingually or intravenously) or subcutaneous glucagon
Documented symptomatic hypoglycemia : which occurs
when a patient feels typical hyperadrenergic hypoglycemic
symptoms and verifies the blood glucose level is less than 70
mg/dL (3.9 mmol/L) before self treating with 15 grams of a
Probable symptomatic hypoglycemia : Typical hypoglycemia
symptoms not accompanied by plasma glucose determination
but likely caused by plasma glucose ≤70 mg/dL (≤3.9 mmol/L)
Asymptomatic hypoglycemia (or hypoglycemic unawareness):
in which a patient does not develop typical hyperadrenergic
symptoms but has a measured plasma glucose level of less
than 70 mg/dL (3.9mmol/L).
this situation occurs most often in type 1 diabetes in patients
striving for excellent glycemic control (hemoglobin A1c value
<7.0%) who have chronic, frequent episodes of hypoglycemia.
The body's ability to recognize hypoglycemia and secrete
counterregulatory hormones in response to hypoglycemia
deteriorates and leaves these patients vulnerable to further
episodes of severe hypoglycemia.
In diabetic patients, if severe neuropathy is present, the
autonomic response (epinephrine) to hypoglycemia is not
activated. This leads to neuroglycopenic symptoms.
Relative hypoglycemia: in which a patient experiences
hyperadrenergic hypoglycemic symptoms but has a measured
plasma glucose level greater than 70 mg/dL (3.9 mmol/L).
• this situation occurs most often in patients who have had months (or
longer) of hyperglycemia (plasma glucose levels >200 mg/dL
[11.1mmol/L] at all times) whose plasma glucose levels are then
lowered by medication or lifestyle changes closer to the normal
• Hyperadrenergic hypoglycemic symptoms can occur when the
plasma glucose level in these patients is 120 mg/dL (6.7 mmol/L) or
• If these patients continue to keep their plasma glucose level
substantially less than 200 mg/dL (11.1 mmol/L), the threshold at
which they manifest hypoglycemic symptoms will fall to more typical
levels (<70 mg/dL [3.9mmol/L]).
Reactive or postprandial hypoglycemia :
develops in response to a nutrient challenge. see it in some
post-GI surgical patients, when gastric contents get dumped into
the small intestine too quickly.
• Idiopathic reactive hypoglycemia requires fulfillment of the
Whipple triad to be a true diagnosis.
• Some patients have symptoms but normal blood glucoses; they
need no further workup, in spite of their insistence.
Nonreactive or fasting hypoglycemia
can be further subdivided into:
1) iatrogenic (most common overall cause)
2) and fasting/factitious.
• In the fasting/factitious type, the patient is unable to maintain
glucose levels with fasting.
• Most common causes: alcohol abuse, drugs (oral
hypoglycemics, pentamidine), sepsis, and renal failure.
CAUSES OF HYPOGLYCEMIA
• Drugs are the most common cause of hypoglycemia , Hypoglycemia is
common in type 1 diabetes, especially in patients receiving intensive
therapy in whom the risk of severe hypoglycemia is increased more
• Less commonly, hypoglycemia may also affect patients with type 2
diabetes who take either insulin secretagogues or insulin.
• In contrast, hypoglycemia is uncommon in individuals who do not have
drug-treated diabetes mellitus.
• In such patients, hypoglycemia may be caused by a variety of other
drugs, including :
alcohol, and common critical illnesses such as hepatic, renal, or
cardiac failure, sepsis, or inanition. It may be due to adrenal
insufficiency, an insulinoma, or an IGF-secreting tumor. In addition,
hypoglycemia can be factitious, accidental, or even malicious
Hypoglycemia in Diabetes
Exogenous insulin and insulin secretagogue (eg, Glyburide ,
Glipizide , Glimepiride , Repaglinide , Nateglinide ) stimulated
endogenous insulin secretion suppress hepatic (and renal)
glucose production and stimulate glucose utilization and, thus,
can cause hypoglycemia, particularly in the setting of
Even in the setting of intact defenses, these drugs can cause
hypoglycemia when given in sufficient doses.
Among the commonly used sulfonylureas, Glimepiride and
Glyburide (Glibenclamide) are more often associated with
hypoglycemia than glipizide because of the longer duration of
Among the drugs used to treat type 2 diabetes early in its
course, insulin sensitizers ( metformin , Glitazones), glucosidase
inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists,
and dipeptidyl peptidase IV inhibitors should not cause
These drugs rely on residual endogenous insulin secretion for
efficacy, and insulin secretion should decrease appropriately as
plasma glucose concentrations decline into the normal range.
However, all of these drugs can increase the risk of
hypoglycemia when combined with administration of insulin
secretagogues or insulin.
Hypoglycemia in patients without Diabetes
• Drugs : In addition to insulin, sulfonylureas, and meglitinides,
other drugs, including alcohol, may also cause hypoglycemia.
• Excluding drugs used to treat diabetes and alcohol 164 different
drugs were associated with hypoglycemia .
• The drugs most commonly associated with hypoglycemia were
quinolones, pentamidine , quinine , beta blockers, angiotensin-
converting enzyme inhibitors, and IGF-1.
Ethanol: inhibits gluconeogenesis but not glycogenolysis. Thus
alcohol-induced hypoglycemia typically follows a several day
alcohol binge with limited ingestion of food resulting in hepatic
Sepsis: is a relatively common cause of hypoglycemia.
Cytokine accelerated glucose utilization and induced inhibition
of gluconeogenesis in the setting of glycogen depletion .
chronic kidney disease: The mechanism of hypoglycemia is
less clear. It likely involves impaired gluconeogenesis, reduced
renal clearance of insulin, and reduced renal glucose
severe liver failure: gluconeogenesis and glycogenolysis are
cardiac failure: The mechanism of hypoglycemia is unknown,
It may involve hepatic congestion and hypoxia.
Malnourishment: Malnutrition can cause hypoglycemia as a
result of substrate limitation of gluconeogenesis and
glycogenolysis in the setting of glycogen depletion.
Hypoglycemia has been reported in patients with anorexia
Hormone deficiencies :Cortisol deficiency (adrenal
insufficiency ) growth hormone deficiency (hypopituitrism).
Nonislet cell tumors hypoglycemia(NICTH) :
usually large tumors of mesenchymal or epithelial cell types
(hepatomas, adrenocortical carcinomas, carcinoids).
Hypoglycemia usually occurs as a result of tumor production of
incompletely processed insulin-like growth factor II IGF-II . but
insulin secretion is suppressed appropriately.
During hypoglycemia plasma IGF-II to IGF-I ratios are high and
free IGF-II levels and levels of pro-IGF-II are elevated.
Curative surgery is seldom possible, but reduction of tumor bulk
may ameliorate hypoglycemia.
Therapy with a glucocorticoid, growth hormone, or both has also
been reported to alleviate hypoglycemia.
Endogenous hyperinsulinism: is more likely in an otherwise
overtly well individual with no clinical clues to the common
causes of hypoglycemia.
• In adults, hypoglycemia due to endogenous hyperinsulinism
can be caused by the following :
1) A beta cell secretagogue, such as a sulfonylurea
2) A beta cell tumor (Insulinoma)
3) A functional beta cell disorder, often termed nesidioblastosis, that
can occur as a feature of the noninsulinoma pancreatogenous
hypoglycemia syndrome (NIPHS)
4) Insulin autoimmune hypoglycemia an antibody to insulin or to
the insulin receptors
Accidental, surreptitious, or malicious hypoglycemia:
should be considered when the cause of a hypoglycemic
disorder is not apparent .
• Hypoglycemia can result from medical, pharmacy, or patient
errors, such as the mistaken use of a hypoglycemic tablet by the
elderly spouse of a patient with diabetes. It may also occur after
ingestion of herbal products contaminated with sulfonylureas or
after covert self-administration of a hypoglycemic tablet or insulin
by a patient with or without diabetes.
Malicious hypoglycemia : Involves administration of an insulin
secretogogue or insulin to another person with the intent to
SYMPTOMS AND SIGNS OF HYPOGLYCEMIA
Symptoms of hypoglycemia have been classified into two major
Autonomic Symptoms (Adrenergic And Cholinergic).
Autonomic symptoms are recognized at a threshold of
approximately 60 mg/dL
Neuroglycopenic symptoms occurs at a threshold of
approximately 50 mg/dL
Neurogenic (or autonomic) symptoms of hypoglycemia are the
result of the perception of physiologic changes caused by the
CNS-mediated sympathoadrenal discharge triggered by
1. adrenergic symptoms (mediated largely by norepinephrine
released from sympathetic postganglionic neurons but perhaps
also by epinephrine released from the adrenal medullae) such
as palpitations, tremor, and anxiety are usually experienced
2. cholinergic symptoms (mediated by acetylcholine released
from sympathetic postganglionic neurons) such as sweating,
hunger, and paresthesias.
Neuroglycopenic symptoms of hypoglycemia are the direct
result of central nervous system (CNS) glucose deprivation.
They include behavioral changes, confusion, fatigue, loss of
consciousness , cognitive impairment, somnolence, dizziness,
slurred speech .
If these signs and symptoms are not recognized and treated
and the plasma glucose level continues to decrease , the
patient may develop focal neurologic signs such as
hemiparesis, or have seizures and death
Signs of hypoglycemia
• Common signs of hypoglycemia include :
1. diaphoresis and pallor.
2. Heart rate and systolic blood pressure are typically increased
but may not be raised in an individual who has experienced
repeated, recent episodes of hypoglycemia.
3. Transient focal neurologic deficits occur occasionally.
4. Permanent neurologic deficits are rare.
1) General : confusion, lethargy
2) HEENT: diplopia
3) CVS : tachycardia
4) Neurologic: tremulousness, weakness, paresthesias , stupor,
seizure, or coma
5) Mental status: irritability, inability to concentrate, or short-term
6) Skin: pale, diaphoresis
Who should be evaluated?
• Only those patients in whom Whipple's triad is documented
require evaluation and management of hypoglycemia.
• In patients with symptoms of hypoglycemia but normal plasma
glucose concentrations at the same time, no further evaluation
The first step is to review the patient's history in detail, including
the nature and timing of symptoms (particularly in relationship to
meals), existence of underlying illnesses or conditions, surgical
history ,medications taken by the individual and by family
members, and social history.
In a patient with documented hypoglycemia, the cause may be
apparent from the history and physical examination.
In a seemingly well individual, the cause is less apparent and
may be due to hyperinsulinism or factitious hypoglycemia.
When the cause of hypoglycemia is not evident, detailed
laboratory evaluation is needed.
Fasting evaluation: There are patients in whom symptoms
occur after only a short period of food withdrawal. Plasma
glucose should be measured repeatedly during the period of
• If symptoms occur and hypoglycemia is documented (plasma
glucose <55 mg/dL [3 mmol/L]), the other tests should be
performed( Insulin, C-peptide,Beta-hydroxybutyrate,Proinsulin
Sulfonylurea and meglitinide screen)
• If this approach causes neither symptoms nor hypoglycemia
and if clinical suspicion remains high, the patient should
undergo a 72-hour fast.
Postprandial evaluation: If symptoms of hypoglycemia
typically occur within five hours after eating, patients should be
evaluated in the postprandial state (mixed meal test).
mixed meal diagnostic test: the patient consumes a meal
that usually leads to symptoms and is then observed for up to
five hours .
• Samples are collected for plasma glucose, insulin, C-peptide,
and proinsulin prior to ingestion of the meal and every 30
minutes thereafter for five hours.
• If severe symptoms occur prior to five hours, samples for the
above lab tests should be collected before the administration
of carbohydrates (to assess for correction of symptoms). All
glucose samples are sent for analysis.
• The samples for insulin, C-peptide, and proinsulin should be
analyzed only in those samples in which plasma glucose is
<60 mg/dL (3.3 mmol/L).
• If Whipple's triad is demonstrated, sulfonylureas, meglitinides,
and antibodies to insulin should also be measured.
72-hour fast :
• Normal subjects do not have symptomatic hypoglycemia after
a prolonged fast because of a hormonally mediated increase
in glucose production.
• Gluconeogenesis accounts for approximately 50% of glucose
production after an overnight fast and for almost all glucose
production after 42 hours or more of fasting .
• The prolonged fast will result in hypoglycemia only if there is
a defect in the ability to maintain normoglycemia due, for
example, to an excess of insulin.
1) Date the onset of the fast at the time of the last intake of
calories. Discontinue all nonessential medications.
2) Allow the patient to drink beverages that are calorie and
3) Ensure that the patient is active during waking hours.
4) Collect blood specimens for measurement of plasma glucose,
insulin, C-peptide, proinsulin, and beta hydroxybutyrate
(BHOB) every six hours until the glucose concentration is
below 60 mg/dL (3.3 mmol/L); at this point, the frequency of
sampling should be increased to every one to two hours.
Although blood is collected repeatedly, we measure insulin, C-
peptide, and proinsulin only in those specimens in which the
plasma glucose concentration is ≤60 mg/dL (3.3 mmol/L).
Test end points and duration :
1) when the plasma glucose concentration is ≤45 mg/dL
2) the patient has symptoms or signs of hypoglycemia,
3) 72 hours have elapsed,
4) or when the plasma glucose concentration is ≤55 mg/dL
if Whipple's triad was documented on a prior occasion
Ending the fast: Three steps are performed at the end of the
1) Collect samples for plasma glucose, insulin, C-peptide,
proinsulin, BHOB, and oral hypoglycemic agents
2) 1 mg of glucagon is given intravenously and the plasma
glucose measured 10, 20, and 30 minutes later
3) The patient is fed
7) Antibodies for insulin and its receptors
8) Sulfonylurea and meglitinide screen
9) Electrolytes, BUN/Cr, UA
10) liver function tests, cortisol and thyroid levels , growth
11) Other tests: ECHO, ECG, CXR , CT and MRI
Management of Hypoglycemia
The management of hypoglycaemia can be divided into three
1. acute intervention to prevent and minimize neurological
2. maintenance therapy to prevent recurrence of hypoglycemia .
3. subsequent measures to search for and treat the underlying
it is important if possible to obtain a blood sample for
laboratory glucose measurement before glucose administration
and to save serum for more sophisticated investigation if the
cause of hypoglycaemia is not obvious (i.e. hypoglycaemia in a
seemingly healthy, nondiabetic patient).
If the patient has a history of malnutrition or chronic alcohol
abuse, intravenous (IV) thiamine at a bolus dose of 12 mg/kg
should be given before initiation of glucose treatment, to avoid
precipitating Wernicke’s encephalopathy.
The treatment for all hypoglycaemia events is the
administration of glucose.
The route and amount of administration will depend on the
glucose level as well as the patient’s level of consciousness
and available access.
Where possible an oral carbohydrate load should be
administered urgently, followed by careful blood glucose
Consider the ‘rule of 15s’ during therapy (i.e. 15 g of
carbohydrate will raise the glucose level about 15 mg/dl in
about 15 minutes).
If the oral route is not possible, such as in cases of impaired
consciousness or an uncooperative patient, IV glucose
intramuscular (IM) or subcutaneous (SC) glucagon can be
Oral carbohydrate is ideally provided in the form of 15-20 g (or
20-30 g if blood glucose 50 mg/dl) glucose tablets.
However, any form of carbohydrate that contains glucose can
This dose of glucose will typically maintain euglycaemia for up
to 2 hours, and therefore a complex carbohydrate (e.g. snack
or meal) should be administered as soon as it is safe to do so.
Failure of the hypoglycaemia to correct within 15 minutes
following one dose of glucose should lead to administration of
a second dose, and occasionally a third, But failure thereafter
should prompt the clinician to consider other interventions ??
The patient should be warned not to drive for at least 45
minutes after correction of hypoglycaemia.
Oral treatments are clearly inappropriate in the unresponsive
patient or those who are unable to take oral medications.
In this situation, the presence of IV access allows 25-50 ml
(i.e.12.5-25 g) 50% dextrose (D50) to be administered and is
adequate in most circumstances.
D50 is highly irritating and should be administered through a
large gauge needle into a large vein if possible and followed by a
Larger volumes of less concentrated dextrose in IV infusions
(e.g. 125 ml of 20% dextrose D20 or 250 ml of 10% dextrose
[D10]) may be used to minimize irritation.
For inpatients with hypoglycaemia, D50 mixed with equal parts
of water can also be given through a feeding tube if available.
If IV access is not available, or is delayed, glucagon 1mg IM
(or SC) can be administered, but its action is short lived.
However, glucagon may not be effective in cases where
gluconeogenesis is defective, such as in cases of extreme
fasting, liver failure, alcohol induced hypoglycaemia or adrenal
insufficiency because of glycogen depletion.
Glucocorticoid replacement (after plasma is saved for cortisol
testing) is required for patients with suspected adrenal
Owing to these various issues, IV glucose remains the
treatment of choice for severe hypoglycaemia.
The clinical response of hypoglycaemia to IV glucose administration
should be rapid and dramatic.
Patients with hypoglycaemic coma are expected to regain
consciousness and become coherent within 5-10 minutes.
However, complete cognitive recovery may be delayed for 30-60
minutes after restoration of normoglycaemia.
If there is no obvious improvement in symptoms or consciousness
within 10-15 minutes, alternative diagnoses (e.g. stroke or drug
overdose) should be reconsidered.
A common mistake is to assume that once the glucose has been
corrected, it will maintain itself.
Depending on the initial cause for hypoglycaemia, a concurrent
source of glucose may need to be administered for some time.
As the effect of IV glucose is relatively transient, patients should
receive an additional form of glucose along with protein (e.g.
milk, cheese and crackers) to replenish hepatic glycogen stores.
If the hypoglycaemic episode is expected to be prolonged or
recurrent (e.g. due to long acting insulin or sulfonylurea), an IV
infusion of 5-10% dextrose (D5 or D10) should be commenced
and continued as necessary.
For example sulfonylurea-induced hypoglycaemia, which due
to long duration of action can cause prolonged hypoglycaemic
events (especially in the elderly or in patients with renal
Octreotide, a synthetic somatostatin analogue, inhibits insulin
release and has been used to treat hypoglycaemia in this
Various regimens are described but 50 mcg 6-8 hourly administered
IV or SC are commonly used
The use of this agent should be considered in any situation where
endogenous hyperinsulinaemia is apparent.
After initial stabilization, subsequent management should be
directed at searching for the underlying etiology of
hypoglycemia and preventing further attacks .
Once the underlying cause is established, definitive therapy
should be offered.
Repeated hypoglycemia in an otherwise stable diabetic
patient should alert the healthcare provider of the onset of
nephropathy, concomitant Addison’s disease, hypothyroidism,
hypopituitarism or interfering medications
Treatment of Non-Diabetes Related
Non diabetic hypoglycemia definitive management depends
on the underlying etiology.
Hypoglycemia induced by medications improves promptly
once the medication is removed.
Correction of sepsis and improvement in hepatic and renal
function improves hypoglycemia of the critical illness.
Deficiencies of counterregulatory hormones can be corrected
with replacement of relevant hormone.
Dietary changes are importance in the context of hyperinsulinaemic
hypoglycemia, and the frequency and severity of episodes can be
significantly reduced with frequent smaller volume meals.
Complex carbohydrates such as bread, rice and pasta should be
Wherever possible, surgery to remove an insulinoma should be
employed, although patient preference and significant comorbidities
may preclude the use of surgery.
In these cases and in the context of NIPHS (where partial
pancreatectomy can also be offered if diet and/or medical treatment
fails, although may be ineffectual if diffuse nesidioblastosis is
present), medical therapies should be used in the knowledge that
each has significant limitations or side effects
Diazoxide is a potassium channel activator, first developed as an
antihypertensive agent, but now more commonly used in the
context of hypoglycaemia due to inhibition of insulin secretion.
It is administered at a dose of 5 mg/kg/day (with higher doses in
refractory cases up to 15 mg/kg/day) in two or three divided oral
doses (e.g. 200-1200 mg/day) .
somatostatin inhibits insulin production, and analogues can be
used in any state of chronic hyperinsulinaemia.
Octreotide therapy is effective in reducing hypoglycaemia in over
50% of patients with an insulinoma and can be administered as
a long-acting formulation.
Octreotide is commenced at a dose of 50 mcg three times daily
by SC injection, and can be titrated to a maximum dose of 500
mcg three times daily.
Many other medications have been used in the management of
hyperinsulinaemic hypoglycemia including:
1. verapamil (i.e. because calcium influx is required for insulin
secretion, calcium channel blockers have been tried for
treatment of hyperinsulinaemia),
2. a-glucosidase inhibitors (e.g. acarbose or miglitol) and
glucocorticoids, but evidence supporting their efficacy is
based primarily on case reports only
3. Glucocorticoid and/or GH therapy have been used with some
success in patients with NICTH, for tumors which cannot be
Treatment Of Diabetes Related
Evaluation of hypoglycemia in a diabetic patient is focused on
intensity of glycemic control and the treatment regimen.
If hypoglycemic agents (e.g. insulin, sulfonylureas or
meglitinides) are prescribed, adjustments may be required to
prevent further episodes.
Patient education is vital with respect to diet, exercise, timing of
medications, insulin injection sites and frequent self-monitoring
of blood glucose (SMBG) or continuous glucose monitoring
(CGM), to try to avoid hypoglycemia.
The patient should be concerned about the possibility of
developing hypoglycaemia when the SMBG is falling rapidly or
is ≤70 mg/dl.
In the UK, it has been recommended that ‘four is the floor’ for
blood glucose targets in order to limit hypoglycaemia frequency.
For non critically ill patients, glycemic goals are premeal and
random blood glucose levels <140 mg/dl and<180 mg/dl
If intensive insulin therapy is used in ICU patients a target
blood glucose range of 140-200 mg/dl
Summary Of Management
Obtain blood glucose concentration as soon as possible (usually with
a meter and strips, if available):
For symptomatic patient known to have diabetes and with a low
glucose value, <70 mg/dL, administer treatment. If a glucose test
cannot be performed, do not delay. Treat as if hypoglycemia has been
If the glucose is low (<55 mg/dL) and the patient is a not a diabetic,
draw blood for glucose, insulin, C-peptide, and an oral hypoglycemic
agent screen and then treat
Do not delay treatment if symptomatic hypoglycemia is suspected but
rapid blood glucose measurement is not available or blood for
diagnostic studies cannot be collected
If the patient is conscious and able to drink and swallow safely (ie,
alert enough to do so and with gag reflex intact), administer a rapidly-
absorbed carbohydrate (eg, 3 to 4 glucose tablets or a tube of gel
with 15 grams, 4 to 6 oz. fruit juice or non-diet soda, or a teaspoon of
honey or table sugar).
If the patient has altered mental status, is unable to swallow, or does
not respond to oral glucose administration within 15 minutes, give an
IV bolus of 12.5 to 25 g of glucose (25 to 50 mL of 50 percent
Measure a blood glucose 10 to 15 minutes after the IV bolus.
Readminister 12.5 to 25 grams of glucose as needed to maintain the
blood glucose above 80 mg/dL.
If glucose cannot be given by parenteral or oral routes, give glucagon
1 mg IM or SQ. Response may be transient and should be followed
by careful glucose monitoring and oral or intravenous glucose
• Give additional maintenance glucose by mouth or IV. IV
dextrose infusion should ensure delivery of 6 to 9 mg/kg per
minute of glucose.
• Amounts needed vary depending upon the cause and severity
of the symptomatic hypoglycemia. Once the patient is able to
ingest carbohydrate safely, providing a mixed meal (including
carbohydrates, such as a sandwich) is the preferred means of
maintaining glucose levels.
• Measure a blood glucose 10 to 15 minutes after the initial IV
bolus and monitor every 30 to 60 minutes thereafter until stable
(minimum of 4 hours).
1) Any doubt of cause
2) Expectation of prolonged hypoglycemia (e.g., caused by
3) Inability to drink or eat
4) Treatment has not resulted in prompt sensory recovery.
5) Seizures, coma, or altered behavior (e.g., ataxia,
disorientation, unstable motor coordination, dysphasia)
secondary to documented or suspected hypoglycemia
6) recurrent hypoglycemia during observation
1. Normoglycemia and risk of severe hypoglycemia is
In a retrospective review of 37,898 non-diabetic, non-critical care hospital admissions, the estimated frequency of hypoglycemia (≤55 mg/dL [3.0 mmol/L]) was 36 per 10,000 admissions .
Sleep and prior exercise can cause a similar phenomenon
Treatment for this hypoglycemic unawareness is to reduce the insulin dosage and eat more carbohydrates both at meals and between meals to ensure a blood glucose level of 150 to 200 mg/dL (8.3-11.1 mmol/L) at all times for several weeks.
. Never order an OGTT to work up this entity
and thereby raises blood glucose in 5-10 minutes Glucagon in these situations may paradoxically aggravate the hypoglycaemia by stimulating insulin secretion.
The response to IM (or SC) glucagon is slightly slower, with an average time difference of 2-3 minutes when compared with IV glucose.
Diazoxide has numerous side effects including peripheral oedema, nausea, vomiting, hypotension and arrhythmias. Of concern, particularly to females, is the tendency for diazoxide to promote hypertrichosis, whilst pancytopaenia is occasionally seen in an idiosyncratic manner. Thiazide diuretics synergise the hyperglycaemic effect of diazoxide as well as reduce the fluid retention, and can be used in addition. However, a paradoxical fall in blood glucose levels can occur in approximately 50% of patients because of suppression of counterregulatory hormones such as glucagon. Patients are usually stabilized with short-acting octreotide for 10-28 days before converting them to long acting somatostatin analogues. Sandostatin LAR, administered as an IM depot, given at an initial dose of 20mg every 4 weeks and adjusted after 3 months to a maximal dose of 40 mg every 4 weeks Lanreotide LA, administered as an IM depot 30mg every 2 weeks and can be increased to 30 mg every 7 days Lanreotide Autogel, administered as a deep SC injection of 60mg every 4 weeks and increased after 3 months to 120mg every 4 weeks if needed