Leanna R. Miller, RN, MN, CCRN-CSC, PCCN-CMC, CEN, CNRN, NP
Education Specialist
LRM Consulting
Nashville, TN

Behavioral Objectives
Describe the etiology of hyperglycemia
in critical illness.
 Discuss the most common
complications associated with glucose
abnormalities in the ICU.
 Identify an algorithm for monitoring
glucose levels and managing insulin
therapy in the ICU.


Case Study
42 – year old man
 acute exacerbation of asthma
associated with community –
acquired pneumonia
 he has no history of diabetes
or other chronic diseases


Case Study

Medications
 Cefotaxime
 Azithromycin
 Nebulized albuterol
 IV hydrocortisone

Case Study
His blood glucose on
admission is 105 mg/dL
 On the next day his blood
glucose is 195 mg/dL and
HA1C of 5.3%
 Should his glucose be treated?


Incidence

Hyperglycemia is exceedingly common
in critical illness and may be seen in
virtually all adult medical ICU patients
when the threshold blood glucose (BG)
value is set at >110 mg/dL

Overview

van den Berghe and coworkers in 2001
directly addressed this question and
demonstrated that targeting strict
euglycemia (80 to 110 mg/dL) can lead
to meaningful morbidity and mortality
reductions among surgical ICU patients
supported by mechanical ventilation

Pathophysiology
 stress hyperglycemia was considered
adaptive, providing vital fuel to organs
that rely largely on glucose for energy
 only excessive glucose excursions,
generally above the renal threshold of
220 mg/dL (known to induce osmotic
diuresis and infectious complications),
were treated with insulin.

Overview
 recent research has highlighted the
association between hyperglycemia
and increased morbidity and mortality
in a number of disease states, including
critical illness

Overview
 hyperglycemia has been shown to
correlate with development of
congestive heart failure, cardiogenic
shock, and hospital mortality among
patients admitted for acute myocardial
infarction

Overview
 after an ischemic stroke, the degree of
hyperglycemia appears to
independently
predict infarct
expansion and
neurologic outcome

Hyperglycemia & Critical Illness

Hyperglycemia during critical illness
can be best characterized as a state of
insulin resistance that develops in the
context of:
 increased hepatic gluconeogenesis and
glycogenolysis
 impaired peripheral glucose uptake
 and higher circulating levels of insulin

Hyperglycemia & Critical Illness

Counterregulatory hormones, such as
glucagon, cortisol, growth hormone,
and catecholamines, as well as elevated
levels of cytokines play an important
role in up-regulating hepatic glucose
production

Hyperglycemia & Critical Illness

Some of these hormones and cytokines
have also been shown to directly
oppose insulin, resulting in increased
lipolysis and proteolysis, which serve
to provide substrates for further
gluconeogenesis

Hyperglycemia & Critical Illness

As patients become bed-bound in the
ICU, exercise-stimulated uptake in
skeletal muscle disappears

Hyperglycemia & Critical Illness

the increased counterregulatory
environment of critical illness and the
impairments in glycogen synthase
activity compromise glucose uptake in
the heart, skeletal muscle, and adipose
tissue

Hyperglycemia & Critical Illness

insulin-stimulated uptake by carriers
such as GLUT-4 (solute carrier family 2,
facilitated glucose transporter member
4) is decreased

Hyperglycemia and Its Biologic Effects
 number of important biologic effects
that may explain the apparent
association between glucose excursions
and poor outcomes in the ICU

Hyperglycemia and Its Biologic Effects
 the higher risk of organ failure seen in
patients with hyperglycemia, likely in
part arises from alterations in
microcirculation that lead to
inadequate oxygen delivery as a result
of endothelial dysfunction

Hyperglycemia and Its Biologic Effects
 even when oxygen delivery is
adequate, certain types of tissue appear
to be at risk for bioenergetic failure and
cellular death resulting from
mitochondrial dysfunction when faced
with persistent hyperglycemia

Hyperglycemia and Its Biologic Effects
 hyperglycemia has a number of
immunomodulatory effects
 can compromise innate immunity by:
 impairing polymorphonuclear
neutrophil function
 intracellular bactericidal activity, &
 opsonic activity

Hyperglycemia and Its Biologic Effects
 high glucose levels can promote
excessive inflammation as evidenced
by increasing proinflammatory
cytokines (such as tumor necrosis
factor-α and interleukins 1β, 6, 8, and
18), inducing nuclear factor-κB, and upregulating leukocyte adhesion
molecules

Hyperglycemia and Its Biologic Effects
 Hyperglycemia additionally induces
formation of advanced glycation end
products, which is now recognized to
promote inflammation and endothelial
dysfunction.
 high BG levels lead to oxidative stress
and promote a procoagulant state
Clement S et al. Dia Care 2004;27:553-591

Insulin Administration
 normalizes blood sugar levels
 prevents endothelial dysfunction
 preserves mitochondrial structure
 improves innate immunity
 modulates excessive inflammation
 regulates apoptosis

Insulin Administration
 reverses the state of dyslipidemia in
critical illness
 normalizes the procoagulant state
 regulates oxidative stress
 attenuates the catabolic state of critical
illness

Review of Available RCTs
 In the original single-center surgical
ICU study from Belgium(2001)
 a BG target of 80 to 110 mg/dL
 absolute risk reduction in ICU mortality
of 3.4%
 relative risk reduction of 42%

Review of Available RCTs
 meaningful morbidity benefits –
reductions in:
 ventilator days
 development of infection
 acute kidney injury

Review of Available RCTs
 mortality improvements were further
amplified (to an ARR of 9.6%) among
the subset of patients who required
ICU-level care for more than 5 days

Review of Available RCTs
 VISEP (2008)targeted patients with
severe sepsis or septic shock
 designed as a four-arm study to assess
two concurrent interventions
 glycemic control (BG targets 80 – 110
mg/dl)
 fluid resuscitation

Review of Available RCTs
 insulin arm of the study was
prematurely terminated due to
excessive hypoglycemia (defined as BG
<40 mg/dL) in 12.1% of patients

Review of Available RCTs
 later, the fluid resuscitation arms of the
study were also stopped early owing to
concerns about increased organ failure
in the 10% pentastarch arm

Review of Available RCTs
 Glucontrol enrolled a mixed ICU
population investigated whether IIT
(defined as BG of 80 to 110 mg/dL) led
to better outcomes compared with a
control group with moderate
hyperglycemia ranging between 140
and 180 mg/dL

Review of Available RCTs
 Glucontrol study also terminated early,
this time because of excessive protocol
violations and hypoglycemia
 No difference in hospital or 28-day
mortality was observed

Review of Available RCTs
 NICE-SUGAR, enrolled 6,100 patients
and confirmed that the tightest glucose
control was not necessary—and that it
may even lead to potential harm
 NICE-SUGAR assumed a 3% to 4%
absolute risk reduction in death

Safe Glycemic Management in ICU
 Sampling
 Blood (vascular catheter) – danger of
contamination with IV fluids
 Fingerstick – inaccurate in patients with
edema or anemia

Safe Glycemic Management in ICU
 Measurements
 Glucometer – fastest, least accurate
 Blood gas machine – fast, accurate
 Laboratory analysis – slowest, most
accurate

Safe Glycemic Management in ICU
 Interpretation
 < 140 mg/dL – consider context -
monitoring less frequent
 140 – 180 mg/dL -  HA1C – frequent
monitoring
 > 180 mg/dL -  HA1C , consider
insulin – monitor per algorithm

Safe Glycemic Management in ICU
 Insulin Use
 Choose an insulin algorithm
 Validate algorithm
 Develop criteria for insulin use (upper &
lower limits)
 Develop safety procedure
 Develop quality – assurance process

Glycemic Variability
wide fluctuations in glucose levels induce
apoptosis, endothelial activation, and
oxidative stress more than sustained
hyperglycemia
 glycemic variability has been shown to be a
more powerful predictor of mortality than
mean BG values among a heterogenous
group of ICU patients


Glycemic Variability
 In one study, for the same degree of
glucose control (mean BG ranging
between 80 and 110 mg/dL), mortality
ranged from 4.2% to 27.5% depending
on the degree of glucose variability
Krinsley JS. Glycemic variability: a strong independent predictor of mortality
in critically ill patients. Crit Care Med. 2008;36(11):3008-3013

Hypoglycemia
 All insulin infusion protocols, no
matter how well executed, almost
always lead to some increase in
hypoglycemic events

Hypoglycemia
 hypoglycemia rates in study settings,
where significant hypoglycemia is
defined as a BG level <40 mg/dL may
range from approximately 5% to nearly
19%

Hypoglycemia
 some conditions commonly
encountered in the ICU are associated
with an increased risk of hypoglycemia
 knowledge of these conditions may
help identify subgroups that require
closer monitoring

Hypoglycemia – High Risk
 patients receiving bicarbonate-based
fluid during CVVHD
 hemodynamically unstable patients in
need of inotropic support
 women
 patients with known diabetes

Hypoglycemia – High Risk
 septic patients
 patients taking octreotide
 patients with interruptions in or
intolerance to nutritional support

Hypoglycemia
 no studies to date that have definitively
demonstrated the dangers of
hypoglycemia
 it is well established that prolonged
and severe hypoglycemia can deplete
astrocyte glycogen stores and lead to
cell death and brain injury

Hypoglycemia
 Those already brain injured, such as
neurosurgical patients, or who have
prolonged hypoxemia from refractory
respiratory failure may be at higher
risk for accelerated astrocyte store
depletion
 may constitute a particularly
vulnerable subset that requires special
attention.

Recommentations
 enthusiasm for rigid glycemic control
has waned
 accepting markedly elevated BG values
should remain a relic of the past

Recommentations
 Based on the best available evidence,
an approach targeting a moderate BG
value between 140 and 180 mg/dL, as
endorsed by the American Association
of Clinical Endocrinologists and the
American Diabetes Association, seems
most prudent

Recommentations
 Wide fluctuations in glucose values
should also be avoided, given
increasing data pointing to the
detrimental effects of glycemic
variability

Case Study
42 – year old man
 acute exacerbation of asthma
associated with community –
acquired pneumonia
 he has no history of diabetes
or other chronic diseases


Case Study
His blood glucose on
admission is 105 mg/dL
 On the next day his blood
glucose is 195 mg/dL and
HA1c of 5.3%
 Should his glucose be treated?
