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Risk factors for hypoglycemia in diabetes

Conventional risk factorsrelative or absolute insulin excess
1. Insulin or insulin secretagogue doses are excessive, ill-timed, or of the wrong type.
2. Exogenous glucose delivery is decreased (e.g. after missed meals and during the overnight fast).
3. Glucose utilization is increased (e.g. during exercise).
4. Endogenous glucose production is decreased (e.g. after alcohol ingestion).
5. Sensitivity to insulin is increased (e.g. after weight loss, an increase in regular exercise or improved
glycemic control, and in the middle of the night).
6. Insulin clearance is decreased (e.g. with renal failure).
Risk factors for hypoglycemia-associated autonomic failure
1. Absolute endogenous insulin deficiency.
2. A history of severe hypoglycemia, hypoglycemia unawareness, or both as well as recent antecedent
hypoglycemia, prior exercise, and sleep.
3. Aggressive glycemic therapy per se (lower HbA1C levels, lower glycemic goals, or both).
ADA Workgroup on Hypoglycemia classification of hypoglycemia in persons with diabetes (136 )
Severe hypoglycemia. An event requiring assistance of another person to actively administer carbohydrate,
glucagon, or other resuscitative actions. Plasma glucose measurements may not be available during such an
event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered
sufficient evidence that the event was induced by a low plasma glucose concentration.
Documented symptomatic hypoglycemia. An event during which typical symptoms of hypoglycemia are
accompanied by a measured plasma glucose concentration 70 mg/dl (3.9 mmol/liter).
Asymptomatic hypoglycemia. An event not accompanied by typical symptoms of hypoglycemia but with a
measured plasma glucose concentration 70 mg/dl (3.9 mmol/liter).
Probable symptomatic hypoglycemia. An event during which symptoms typical of hypoglycemia are not
accompanied by a plasma glucose determination (but that was presumably caused by a plasma glucose
concentration 70 mg/dl [3.9 mmol/liter]).
Relative hypoglycemia. An event during which the person with diabetes reports any of the typical symptoms of
hypoglycemia and interprets those as indicative of hypoglycemia, with a measured plasma glucose concentration
>70 mg/dl (3.9 mmol/liter) but approaching that level.
Thereare 3 categories of clinical hypoglycemia[13]: (1) fasting, (2) reactive or postprandial, and (3) drug-related.
Fasting hypoglycemia is defined as the inability to maintain glucose homeostasis in the postabsorptive, or fasting,
state.[13] An example is an insulinoma, an insulin-secreting tumor of the islets of Langerhans.

Reactive (postprandial) hypoglycemia occurs after ingesting food.[13] The 3 sub-types of reactive (postprandial)
hypoglycemia are: (1) alimentary; (2) associated with type 2 (noninsulin-dependent) diabetes mellitus; and (3)
idiopathic.[13] Patients who have undergone gastrointestinal surgery (eg, subtotal gastrectomy) experience
reactive hypoglycemia within 2 to 3 hours after eating.[11] Alimentary hypoglycemia occurs because an alteration
in the rate of nutrients that are delivered to the small intestine leads to excess and poorly timed release of insulin.
Patients with relatively mild noninsulin-dependent diabetes mellitus experience reactive hypoglycemia 3 to 5
hours after a meal.[13] The reactive hypoglycemia may be related to the late and extended second phase of insulin
secretion that is characteristic of type 2 diabetes mellitus. Idiopathic reactive hypoglycemia is a common cause of
nonspecific symptoms such as depression and mood swings.[13]
Drug-related hypoglycemiais related to accidental or intentional administration of a drug (eg, insulin,
sulfonylureas) that may occur in the both the fasting and postprandial states. [13
March 1, 2011 The American Academy of Pediatrics (AAP) Committee on Fetus and Newborn has waged an
opinion on neonatal hypoglycemia and produced a "practical guide and algorithm for the screening and

subsequent management of neonatal hypoglycemia." The guidelines recommend against routine glucose
monitoring except for "high-risk" infants.
The AAP guideline, reported in the March issue of Pediatrics by David H. Adamkin, MD, and colleagues, includes
which infants to screen, when to screen, laboratory data, clinical signs, and management.
Dr. Adamkin told Medscape Medical News, "We have no previous guidelines, so this represents the first document
on the subject with some guidance provided in a very controversial area. This algorithm will provide some
guidance in an area of medicine where evidence is lacking. The point is that babies will be screened, and
hopefully managed, to prevent any symptoms from developing. Those with symptoms will be treated promptly."
Dr. Adamkin is professor of pediatrics, director of the Division of Neonatal Medicine, director of the Neonatal
Fellowship Program, and director of Neonatal Nutrition Research at the University of Louisville, Kentucky.
William W. Hay, Jr, MD, told Medscape Medical News that the report "does represent the state of the art, as there
is very little science." Dr. Hay is professor of pediatrics; codirector, Colorado Clinical Translational Sciences
Institute; director, Child and Maternal Health Research; director of the Neonatal Clinical Research Center; and
scientific director of the Perinatal Research Center at the University of Colorado in Denver.
The process of weighing the evidence and writing the guidelines was far from smooth or simple.
"I was surprised at the degree of uncertainty and contentiousness that not only the topic had, but the experts and
other stakeholders had as we tried to develop these recommendations," Dr. Adamkin said.
No Simple Cut-Off for Safe vs Unsafe Glucose Levels
The AAP paper notes that "there has been no substantial evidence-based progress in defining what constitutes
clinically important [neonatal hypoglycemia (NH)], particularly regarding how it relates to brain injury, and that
monitoring for, preventing, and treating NH remain largely empirical." Other medical conditions are also a
complicating factor, as are differences between infants who are breastfed and those who are not.
Clinically significant NH is the result of an imbalance between glucose supply and other fuels such as ketone
bodies, which are released from fat. Blood glucose concentrations often dip to 30 mg/dL within 1 to 2 hours after
birth in healthy neonates, but they typically return to more than 45 mg/dL with normal feeding within 12 hours.
According to the guidelines, the infants at highest risk for clinically significant NH are small for gestational age,
large for gestational age, born to mothers who have diabetes, or late-preterm. Routine screening and monitoring
of blood glucose is recommended only for infants who have these risk factors or who have clinical manifestations
of NH such as jitteriness, cyanosis, seizures, an apneic episode, tachypnea, weak or high-pitched cry, floppiness,
or lethargy, poor feeding, or eye-rolling.
The guidelines call for immediate intravenous glucose for infants who are symptomatic and have glucose levels
lower than 40 mg/dL.
For asymptomatic at-risk infants, the initial feed should be within 1 hour of birth, with glucose screening 30
minutes after the first feed. Because there is no point-of-care screening method reliable enough to be used as the
sole method for screening for NH, the blood or plasma glucose concentration must be confirmed by laboratory
testing ordered stat.
If NH is suspected, the plasma or blood glucose level should be determined by a laboratory enzymatic method
such as glucose oxidase, hexokinase, or dehydrogenase.
Dr. Adamkin and colleagues wrote, "A long delay in processing the specimen can result in a falsely low
concentration as erythrocytes in the sample metabolize the glucose in the plasma. This problem can be avoided
by transporting the blood in tubes that contain a glycolytic inhibitor such as fluoride."
Early Treatment for Better Safety Margin
The guidelines warn that despite the lack of hard evidence that rapid treatment will prevent neurological damage,
"[t]reatment of suspected NH should not be postponed while waiting for laboratory confirmation."
If the initial screen is lower than 25 mg/dL, the guidelines call for feeding and checking again in 1 hour. If the level
remains lower than 25 mg/dL, intravenous glucose is called for. If it is 26 to 40 mg/dL, the guidelines call for
refeeding and/or intravenous glucose as needed. The target glucose level is 45 mg/dL or higher before routine
feeds. The recommended glucose dose is a minibolus 200 mg/kg (dextrose 10% at 2 mL/kg) and/or intravenous
infusion at 5 to 8 mg/kg per minute (80 - 100 mL/kg/day).
During the 4 to 24 hours after birth, feeds should be continued every 2 to 3 hours, with glucose screening taking
place before each feed. If a screen shows less than 35 mg/dL, the guideline is to feed and check again in 1 hour. If

the glucose levels remain lower than 35 mg/dL, the guideline calls for intravenous glucose. If the level is 35 to 45
mg/dL, the guideline calls for refeeding with intravenous glucose as needed to reach the target.
The screening schedule varies slightly. Late preterm (34- to 36-week) infants and small-for-gestational-age infants
should be fed every 2 to 3 hours and screened before each feeding for at least the first 24 hours after birth.
Infants born to mothers with diabetes and large-for-gestational-age infants with 34 weeks' gestation or more
should be screened for the first 12 hours after birth.
At-risk infants should maintain normal plasma glucose on a routine diet for at least 3 feedfast periods before
The authors note that plasma glucose levels tend to be lower in breastfed infants, whereas ketone body
concentrations tend to be higher than in formula-fed infants. They suggest that breastfed infants might tolerate
lower plasma glucose because of the increased ketone concentrations.
Hyperinsulinemic hypoglycemia is described as "the most common cause of severe persistent hypoglycemia in
the newborn period" and calls for measurement of blood insulin and glucose at a time when bedside blood
glucose is less than 40 mg/dL, as well as endocrinology consult.
Finally, the guidelines stress that managing neonatal hypoglycemia should "not unnecessarily disrupt the motherinfant relationship and breastfeeding."
Dr. Hay said that the recommendations reinforce the conclusions of the National Institute of Child Health and
Human Development Workshop on Neonatal Hypoglycemia, which have largely already become standard of care.
"So I would not expect this report to change practice, and I would only expect lawyers to really be interested in it,
trying as they do to find yet another wrinkle to support their cause," he said.
The guidelines process also threw into sharp focus the gaps in knowledge regarding management of neonatal
hypoglycemia. "We need evidence on outcomes of hypoglycemia and on the use of alternative fuels in these
patients that may protect them even when they are hypoglycemic," Dr. Adamkin said.
Pediatric endocrinologist Stuart Weinzimer, MD, who reviewed the study for Medscape Medical News, said that
new guidelines are likely both to increase clinicians' awareness of and testing for neonatal hypoglycemia and to
generate important data clarifying what is "normal."
"Any kind of standardization that will get people to test more is a good thing, since testing is not routinely done.
The testing is not difficult, and can even be done using a home blood glucose monitor. I am concerned that the
limit for hypoglycemia set by the guidelines for 4 to 24 hours of age (<35 mg/dL) might be too low. The fact that
these levels are common in babies does not mean that they are normal, and this points up the lack of data in this
area," Dr. Weinzimer said.
"One thing we do know is that unrecognized persistent neonatal hypoglycemia can be very dangerous and can
cause irreversible brain damage, although it is transient in most babies. I think these first guidelines will increase
awareness, lead to more testing, and encourage more aggressive management of persistent neonatal
hypoglycemia," Dr. Weinzimer added. He is associate professor of pediatrics at the Yale School of Medicine in New
Haven, Connecticut.
Short-term treatment of hypoglycemia consists of an intravenous (IV) bolus of dextrose 10% 2.5 mL/kg. The
critical sample should be drawn before the glucose is administered. After the bolus is administered, an IV infusion
that matches normal hepatic glucose production (approximately 5-8 mg/kg/min in an infant and about 3-5
mg/kg/min in an older child) should be continued. This should be adjusted to maintain the plasma glucose level at
more than 3 mmol/L