DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1254 new cases of pediatric diabetes may in fact be type 2 diabetes; rates
vary by ethnicity, with disproportionately high rates in Native
Americans, African Americans, and Latinos. Because of a paucity of
clinical trials performed in children, there is only limited information
on which to base decisions for appropriate therapy. Thus the results
in the Diabetes Control and Complications Trial with young and
middle-aged adults have been extrapolated to the pediatric population
such that current practice is for more intensive, physiologically
based insulin replacement with a goal of tight glucose control
(Diabetes Control Complications Trial Research Group, 1993).
This is achieved with combinations of basal and prandial insulin
replacement. The primary limiting factor of more aggressive insulin
therapy is hypoglycemia, a problem with special concerns in young
children. Diabetic patients <5 years old are at greater risk for hypoglycemia,
have increased rates of severe hypoglycemia with seizures
and coma, and may suffer permanent cognitive dysfunction as a
result of repeated episodes of low blood glucose. Older children and
adolescents do not seem to have demonstrable cognitive impairment
related to hypoglycemia; good glycemic control is associated with
better mental function (Kodl and Seaquist, 2008).
The treatment of type 1 diabetes in children and adolescents
has changed with the availability of newer technologies. The standard
for insulin treatment now includes multiple dose regimens with
three to five injections per day or CSII. Split/mixed regimens using
NPH and regular insulin have been increasingly supplanted by regimens
using insulin analogs because they offer more flexibility in
dosing and meal patterns. Similarly, CSII is used with increasing
frequency in the pediatric diabetic population. Moreover, recent
studies show that this approach is applicable to young children as
well as older children and adolescents.
Because of the nearly uniform association of type 2 diabetes
with obesity in the pediatric age group, lifestyle management is the
recommended first step in therapy. Goals of reducing body weight
while maintaining normal linear growth, and increasing physical
activity, are broadly recommended and can be effective when patients
are compliant. There have been few clinical trials of glucose lowering
therapy in pediatric type 2 diabetes. The only medication currently
approved by the FDA specifically for medical treatment of
type 2 diabetes is metformin. Metformin is approved for children as
young as 10 years of age and is available in a liquid formulation
(100 mg/mL). Results from clinical trials have shown that both metformin
and glimepiride effectively lower blood glucose in affected
patients. Insulin is the typical second line of therapy after metformin;
basal insulin can be added to oral agent therapy or multiple daily
injections can be used when simpler regimens are not successful.
Weight gain is a more significant problem than hypoglycemia with
insulin treatment in pediatric type 2 diabetes. Other diabetes medications,
such as thiazolidinediones, α-glucosidase inhibitors, DPP-4
inhibitors, and exenatide, have been tried empirically in type 2 diabetic
adolescents, but there is no systematically collected data on efficacy
or safety of these agents in the pediatric population.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Management of Diabetes in Hospitalized Patients. Hyperglycemia
is common in hospitalized patients. Depending on how hyperglycemia
is defined, prevalence estimates of elevated blood glucose
among inpatients with and without a prior diagnosis of diabetes range
between 20% and 100% for patients treated in intensive care units
(ICUs) and 30% and 83% outside the ICU. Although most of these
individuals will have known diabetes, ~30% of hospitalized patients
will have elevated blood glucose levels without a prior diagnosis of
diabetes (Falciglia, 2007). Patients admitted to the hospital often have
a number of challenges to glucose regulation in addition to those
faced by diabetic outpatients (Donner and Flammer, 2008). Stress of
illness has been associated with insulin resistance, possibly the result
of counterregulatory hormone secretion, cytokines, and other inflammatory
mediators. Food intake is often variable due to concurrent
illness or preparation for diagnostic testing. Medications used in the
hospital, such as glucocorticoids or dextrose-containing intravenous
solutions, can exacerbate tendencies toward hyperglycemia. Finally
fluid balance and tissue perfusion can affect the absorbance of
subcutaneous insulin and the clearance of glucose. Therapy of
hyperglycemia in hospitalized patients needs to be adjusted for these
variables.
There is an emerging body of information indicating that
hyperglycemia portends poor outcomes in hospitalized patients,
most notably in the critically ill, and that this effect is independent
of severity of illness (Finfer et al., 2009; van den Berghe et al., 2001).
The mechanisms for this association have not been fully explained,
and controversy persists about the optimal level of glycemia in hospitalized
patients. The ADA currently suggests these blood glucose
targets: 140-180 m/dL (7.8-10.0 mM) in critically ill patients and random
glucose of 180 mg/dL (10 mM) or pre-meal glucose of 140 mg/dL
(7.8 mM) in noncritically ill patients. Great emphasis should be
placed on steps taken to minimize hypoglycemia in both settings.
Insulin is the cornerstone of treatment of hyperglycemia in
hospitalized patients (Moghissi et al., 2009). For critically ill patients
and those with variable blood pressure, edema, and tissue perfusion,
intravenous insulin is the treatment of choice. This method of insulin
administration has been firmly established in the care of critically
ill patients with elevated blood glucose and provides the most flexible
and precise means of treatment. A number of algorithms have
been adapted to allow rapid titration with adjustments to maintain
blood glucose in a target range. For patients who are more stable,
subcutaneous insulin regimens using combinations of basal and
prandial insulin is the standard. There is considerable evidence that
reactive treatment, using sliding scale regimens, is inferior and associated
with wider fluctuations in blood glucose and greater rates of
both hyper- and hypoglycemia. Oral agents have a limited place in
treatment of hyperglycemic patients in the hospital because of slow
onset of action, insufficient potency, need for intact GI function,
and side effects. In general, oral glucose-lowering medications
should be discontinued on hospital admission and can be restarted at
discharge.
Intravenous administration of insulin also is well suited to the
treatment of diabetic patients during the perioperative period and
during childbirth. There is debate, however, about the optimal route
of insulin administration during surgery. Although some clinicians
advocate subcutaneous insulin administration, most recommend
intravenous insulin infusion. Some physicians give patients half their
normal daily dose of insulin as long-acting insulin subcutaneously on
the morning of an operation and then administer 5% dextrose infusions
during surgery to maintain glucose concentrations. This
approach provides less minute-to-minute control than is possible
with intravenous regimens and also may increase the likelihood of
hypoglycemia. For patients with type 1 diabetes, failure to provide
some basal insulin at all times can precipitate diabetic ketoacidosis.