571

The Long and Winding Road to Personalized

Glycemic Control in the Intensive Care Unit
Mayanka Tickoo, MD, MS1

1 Section of Pulmonary and Critical Care Medicine, Department of
Internal Medicine, Yale University School of Medicine, New Haven,
Connecticut
Semin Respir Crit Care Med 2019;40:571–579.
Address for correspondence Mayanka Tickoo, MD, MS, Pulmonary
and Critical Care Medicine, Department of Internal Medicine,
Yale School of Medicine, New Haven, CT 06510
(e-mail: Mayanka.tickoo@yale.edu).

Abstract In the critically ill adult, dysglycemia is a marker of disease severity and is associated
with worse clinical outcomes. Close monitoring of glucose and use of insulin in critically
ill patients have been done for more than 2 decades, but the appropriate target
glycemic range in critically ill patients remains controversial. Physiological stress
Keywords response, levels of inflammatory cytokines, nutritional intake, and level of mobility

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► hyperglycemia
► hypoglycemia
► glycemic variability
► critical illness
► insulin
affect glycemic control, and a more personalized approach to patients with dysglyce-
mia is warranted in critically ill intensive care unit (ICU) patients. We discuss the
pathophysiology and downstream effects of altered glycemic response in critical
illness, management of glycemic control in the ICU, and future strategies toward
personalization of critical care glycemic management.

In the critically ill adult, dysglycemia is a marker of disease
severity and is associated with worse clinical outcomes.1 The
common practice of close monitoring of glucose in critical
illness and management using insulin finds its roots in the
seminal randomized study by van den Berghe and colleagues
in 20012 which showed a 42% decrease in mortality with
tight glucose control (TGC; 80–110 mg/dL) in patients who
remained in the surgical critical care unit for a period over
5 days. However, a similar trial by the authors in the medical
intensive care unit (ICU) did not replicate the same mortality
benefit.3 Intensive glucose control was associated with
higher incidence of hypoglycemia in the treatment arm in
both studies. Brunkhorst and colleagues4 also found an
increase in the incidence of severe hypoglycemia and serious
adverse events in the intensive treatment arm in their study
in critically ill patients with sepsis. In the past two decades,
multiple studies have tried to assess the appropriate target
glycemic range in critically ill patients in a myriad of clinical
settings while minimizing the risk of hypoglycemia. There is
in addition debate around techniques of glucose monitoring
and administration of insulin as well as consideration of
liberalization of glycemic targets based on pre-existing
diabetes mellitus (DM) in the critically ill adult. These factors
along with nuances in physiological stress response, levels of
inflammatory cytokines, nutritional intake, and effect of
mobility, all of which affect glycemic control in the ICU,
indicate the need for a more personalized approach to
patients with dysglycemia. The aim of this review is to
discuss the domains of dysglycemia, the pathophysiology
and downstream effects of altered glycemic response in
critical illness, review the evolution of evidence in the
strategies and management of glycemic control in the ICU,
and establish future strategies toward personalization of
critical care glycemic management.
Dysglycemia is a commonly encountered issue in the
critically ill population and comprises four states of altered
glucose control—hyperglycemia, increased glycemic vari-
ability (GV), hypoglycemia, and time outside the normal
range. Compared with the initial debates in the management
of glycemic control in critically ill patients which focused on
decision models favoring “TGC 80 to 110 mg/dL” versus
liberal glucose control (140–180 mg/dL), the concept of
dysglycemia encompasses management focused on hyper-
glycemia, GV, hypoglycemia, and time in target range (TITR)
as individual and independent predictors of outcomes in
critical illness (►Fig. 1).

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572 Glycemic Control in the ICU Tickoo
Hyperglycemia
Hyperglycemia is defined as fasting blood sugar >126 mg/dL
or random blood sugar >200 mg/dL. Stress hyperglycemia,
defined as transient hyperglycemia >180 mg/dL during
severe illness5 in patients without known history of diabetes,
is very common (incidence 50–80%) especially in the initial
48 hours of illness.6,7 Unlike traditional insulin deficiency in
diabetes, the pathophysiology of stress hyperglycemia
revolves around insulin resistance. In normal glucose
metabolism, release of insulin causes activation of glucose
transporter 4 (GLUT-4) channels on adipocytes, skeletal
muscle, and cardiac muscle membrane, which promotes
glucose uptake into the above (insulin-mediated glucose
uptake [IMGU]) tissues.8 In addition, insulin also promotes
uptake of glucose via GLUT-2 channels in hepatocytes, with
the downstream effect of decreasing endogenous glucose
production by inhibiting gluconeogenesis and glycogenoly-
sis. As a result, insulin released by pancreatic islet cells in
response to a meal, will establish normoglycemia under
homeostatic conditions. However, during critical illness,
counter-regulatory hormones including glucagon, epineph-
rine, cortisol, and inflammatory cytokines like tumor necro-
sis factor-α (TNFα) cause excessive hepatic glucose release
(from gluconeogenesis as well as glycogenolysis9) as well as
increased insulin resistance.10 The combination of these
effects diverts glucose away from IMGU tissues, and in
combination with de novo glucose synthesis from hepato-
cytes as well as central insulin resistance (decreased down-
regulation of endogenous glucose production by existing
insulin) produces a “glucose overload” in non-IMGU tissues
including the brain, erythrocytes, immune cells like macro-
phages, endothelial cells, and renal medullary cells. Several
downstream effects associated with hyperglycemia have
been reported including mitochondrial toxicity associated
with multiorgan dysfunction, generation of reactive oxygen
species, an increase in expression of inflammatory media-
tors, a decrease in complement levels, a diminished innate
immunity, and abolishment of ischemic preconditioning.8
Effective removal of damaged mitochondria via mitophagy
has been associated with improved outcomes in critical
illness11 and hyperglycemia is known to worsen this core
cellular homeostatic process12 thereby contributing to wors-
ened clinical outcomes. Hyperglycemia has been indepen-
dently associated with increased mortality and morbidity in
multiple clinical settings including in patients with acute
stroke13,14 and infections15 as well as increased length of
stay in the ICU.16
In addition to the neurohormonal dysregulation during
critical illness, iatrogenic causes including dextrose-contain-
ing fluids, exogenous steroids, and catecholamines, as well as
continuous nutrition, increase the incidence of hyperglyce-
mia in the ICU.
Hypoglycemia
Hypoglycemia is defined as blood glucose (BG) level below
70 mg/dL with severe hypoglycemia defined as occurring
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 5/2019
below 40 mg/dL.2 Both severe17,18 and mild19,20 hypoglyce-
mia have been shown to be strongly associated with
increased mortality in a variety of patients with critical
illness. In a study of more than 6,000 critically ill adults,
the NICE-SUGAR investigators showed that the adjusted
hazard ratio for death among patients with moderate or
severe hypoglycemia was 1.41 and 2.10 respectively,
compared with those without hypoglycemia.21 Mild hypo-
glycemia in the critically ill has also been associated with
increased length of stay22 in the ICU. Targeting TGC has been
well established as the most prominent risk factor for
precipitating hypoglycemia4,23,24 with a recent network
meta-analysis25 showing a fivefold increase in incidence of
hypoglycemia in patients undergoing TGC. Other common
factors associated with increased risk of hypoglycemia
include use of bicarbonate-containing fluids in patients on
continuous venovenous hemofiltration, interruption of
nutritional support, sepsis, DM, use of vasopressors, female
gender as well as octreotide use.26,27 While the exact thresh-
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old for duration and degree of hypoglycemia that cause
worse outcomes are not clearly defined, there does appear
to be a clear relationship between severity of hypoglycemia
and increase in poor patient outcomes including mortality.20
Patients with the abovementioned factors need to be identi-
fied as being at high risk for hypoglycemia and associated
poor outcomes that perhaps require closer monitoring in the
ICU to avoid the adverse risks of hypoglycemia. While
initially, the evidence pointed to spontaneous hypoglyce-
mia28 in the ICU predicting worse outcomes in patients
with advanced illness like adrenal insufficiency, renal
failure, and liver failure, newer studies are starting to recog-
nize iatrogenic or medication-induced hypoglycemia to be
equally hazardous in the critically ill.29 The mechanisms by
which hypoglycemia causes worsened clinical outcomes are
not entirely clear. The neurons utilize glucose as an obliga-
tory metabolic fuel, and at extreme hypoglycemia, in addi-
tion to a state of energy failure, profound and prolonged
hypoglycemia is also associated with release of excitatory
neurotransmitters that cause neuronal cell damage and
death.30 Additionally, the myocardium is also predisposed
to rhythm abnormalities with sinus tachycardia,31 sinus
bradycardia, ventricular repolarization abnormalities, and
prolonged QT dispersion32 described in nocturnal hypogly-
cemia. It is important to note that routine neuroglycopenic
symptoms including lightheadedness, sweating, and altered
mentation can easily be masked in a critically ill patient who
is sedated and on vasoactive medications. As such, early
detection of hypoglycemia with close and accurate monitor-
ing of blood sugar, as well as early and appropriate inter-
ventions, becomes critical in avoiding deleterious effects.
Glycemic Variability
The third domain in the management of glycemia in the
critically ill is the role of GV. High GV was conceptually
defined by Braithwaite33 as the propensity of a patient to
develop repeated excursions of plasma glucose over a rela-
tively short period of time that exceeds the expected range
 Glycemic Control in the ICU Tickoo 573

Table 1 Review of randomized control trials in critical care glycemic management

Study van den Van den Arabi Finfer De La Rosa Kalfon Preiser
Berghe et al2 Berghe et al3 et al88 et al51 Gdel et al50 et al52 et al46
Patient population Surgical Medical Mixed Mixed Mixed Mixed Mixed
No. of patients 1,548 1,200 523 6,104 504 2,684 1,101
Blood glucose Control 180–200 <200 180–200 <180 180–200 <180 140–180
target
IIT 80–110 80–110 80–110 81–108 80–110
80–110
80–110
Mortality significantly IIT No No Control No No No
lower (control vs. IIT) difference difference difference difference difference
Hypoglycemia Control 0.7% 3.1% 3.1% 0.5% 1.7% 6.2% 2.1%
rate
IIT 5% 18.7% 28.6% 6.8% 8.5% 13.2% 8.7%
Percentage of patients 13 17 40 20 12 20 18
with preexisting DM

Abbreviations: DM, diabetes mellitus; IIT, intensive insulin therapy.

ranging from 5.9 in the least GV quartile to 30.1 in the highest

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Fig. 1 The domains of dysglycemia during critical illness. Each
domain is independently associated with poor clinical outcomes.
for a normal physiological response. Measures of GV include
but are not limited to the magnitude of glycemic excursion
over a given time interval in relation to mean plasma glucose
and the frequency with which a critical value (hypo or
hyperglycemia) is exceeded in a certain time period.34
In their initial study in 2006, Egi and colleagues described
high GV as an independent predictor of ICU and hospital
mortality.35 High GVcorrelated better with increased mortality
compared with the average BG level. This correlation was
further established in a mixed ICU population of over 3,000
patients where GV was shown to confer a strong independent
risk of mortality.36 The authors found successive increase in
mortality rate with increasing quartile of GV (from 12.1 in the
lowest quartile to 37.8 in the highest quartile). The highest
correlation between GV and mortality also occurred in the
patients in the “euglycemic” range of blood sugars; patients
with mean glucose level of 70 to 99 mg/dL had mortality
GV quartile. The corresponding range was 9.7% to as high as 31%
for patients with mean glucose in the 100 to 119 mg/dL range.36
In another larger database of more than 66,000 critically ill
adults, Bagshaw and colleagues described that GV was associ-
ated with higher odds of ICU and hospital mortality compared
with hypoglycemia.37
The clinical significance of GV as a marker of severity of
illness in complex critically ill patients who require multiple
interventions to maintain “euglycemia” versus as an indepen-
dent predictor of mortality in various clinical settings remains
to be fully elucidated.38 While the concept of iatrogenic GV—a
product of overcorrection of BG levels upon administration of
dextrose to correct episodes of hypoglycemia—has been
brought up in the past, newer protocols have been described
to minimize GV while allowing for appropriate management of
hypoglycemia in critical illness.39 Mechanistically, in vitro
studies have linked marked fluctuations in BG level with
increase in oxidative stress and downstream endothelial dys-
function and cellular apoptosis.40,41 Additional in vivo studies
have also shown that glucose variability exerts a stronger
influence as a cause of oxidative stress compared with sustained
hyperglycemia.42 Indeed, in the critically ill patient, endothelial
dysfunction could only be accelerated by hyperactive inflam-
matory cells potentiated by marked glucose variation. Like other
domains of glycemic management, variability in glucose does
not affect all patient subpopulations equally. GV in the ICU is a
more common occurrence in patients with the classic type 1
DM than type 2,43 and has been associated with worse out-
comes in patients without a history of diabetes compared with
those with diabetes.44
Time in Target Range
The fourth and more recently described concept in glycemic
control is TITR and is aimed at establishing a more compre-
hensive and yet individualized approach to managing all
three domains—hyperglycemia, hypoglycemia, and GV—in
an individual patient. TITR expresses the percentage of time
in which a patient’s glycemic level remains within the target

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574 Glycemic Control in the ICU Tickoo
range. It can thus vary significantly from patient to patient
even if the same glucose target is set for them, and has been
postulated as a possible explanation of variable outcomes in
the initial randomized studies using TGC strategies.45 One of
the earliest randomized control trials to report TITR with
intensive insulin therapy (IIT) was the Glucontrol trial46 that
demonstrated a TITR >50% was independently associated
with an increased rate of survival in both the intensive
glucose target (80–110 mg/dL) and the moderate target
arm (140–180 mg/dL). As part of a series of studies utilizing
their Specialized Relative Insulin Nutrition Tables (SPRINT)
protocol for IIT, Chase and colleagues have shown less organ
failure with TITR >50%47 and increased survival48 in patients
who achieved TITR >70% in a critically ill, mixed ICU popu-
lation. Further refining this concept, and in an attempt to
delineate the concomitant effect of pre-existing diabetes on
ICU outcomes, Krinsley and Preiser recently published that
TITR with a range of 70 to 140 mg/dL for BG was strongly
associated with survival among patients without diabetes,49
but not with known diabetes. Additionally, TITR >80% has
also been associated with better outcomes including fewer
ICU days, shorter mechanical ventilation time, and reduced
surgical site infections in patients undergoing cardiac sur-
gery, whether or not they carried a presurgical diagnosis of
diabetes.
A low TITR has been invoked as a potential reason for lack
of benefit for IIT49 in initial randomized glucose control
studies. While this evidence is certainly promising in terms
of establishing TITR as an independent target in glycemic
management, most guidelines are yet to incorporate this
domain in usual care of the dysglycemic patient in the ICU.
Summation of Major Studies in
Management of Critical Care Glycemia
The sentinel study looking at glycemic control in the criti-
cally ill adult was the Leuven trial published in 2001 by Van
den Berghe et al (►Table 1). The authors compared IIT
targeting TGC in a ventilated, surgical critical care population
with standard care and showed a 3.4% absolute reduction in
ICU mortality compared with controls. This effect was am-
plified in patients who remained in the ICU for more than
5 days (9.6% absolute reduction, relative risk 48%, number
needed to treat
10).2 This mortality benefit, however, could
not be replicated in a medical ICU at the same center by the
same authors.3 Follow-up studies in mixed ICUs by Brunk-
horst et al4 in a sepsis cohort (VISEP) and De La Rosa et al50
did not show any significant reduction in mortality and
morbidity but did show increased adverse events related
to hypoglycemia in their study groups. The Glucontrol
study46 also attempted to define the best target for glucose
management in a mixed medical and surgical cohort over 21
participating sites using IIT. The study had to be terminated
early due to a high number of protocol violations, but of the
1,101 patients studied, there were no significant mortality
benefits in the intensive insulin arm, but the rate of hypo-
glycemia was significantly higher. This body of evidence was
further strengthened by the largest randomized controlled
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 5/2019
trial to date in management of ICU glycemia: the NICE-
SUGAR trial.51 This was a trial involving more than 6,000
mixed medical and surgical patients in the ICU and compared
the outcomes between TGC (80–110 mg/dL) and more liberal
glucose control (below 180 mg/dL). This study actually
showed a higher mortality in the tight glucose arm in
addition to higher hypoglycemia rates. There were no differ-
ences in outcomes in terms of medical versus surgical
patients, median number of days in ICU, median days on
mechanical ventilation, or rate of renal replacement therapy
in the two groups. At this point, the trends in management of
glucose control in the ICU had started to swing toward more
liberal glucose targets in the critically ill adult due to unclear
benefit, if not adverse outcomes and high antecedent hypo-
glycemia risk, of IIT and TGC. Attempts at integrating com-
puterized decision support models for IIT to achieve TGC
with decreased incidence of hypoglycemia have also yielded
mixed results and not shown a major mortality benefit52 for
TGC. A recently concluded network meta-analysis by Yamada
and colleagues25 compared four consecutive glycemic tar-
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gets in critically ill patients with hyperglycemia: tight con-
trol (80–110 mg/dL), moderate (110–140 mg/dL), mild
(140–180 mg/dL), and very mild control (180–220 mg/dL).
A total of 17,996 patients were studied, and mortality was
comparable in the mild glycemic control group compared
with the tight, moderate, and very mild control groups,
respectively (no significant difference in the cause of death,
ICU type, time period in ICU, or diabetes). Incidence of
hypoglycemia was, as expected, higher in the tight control
group.
Guidelines on Management of Critical Care
Glycemia
Based on this body of evidence, most current guideline
statements favor somewhat liberal glycemic control in the
critically ill adult. The American College of Physicians53
clinical guidelines committee recommends a target blood
sugar of 140 to 200 mg/dL in the surgical as well as medical
ICU patient on insulin therapy. The American Diabetes
Association (ADA) in the most recent iteration of standards
of diabetes care in the hospital54 recommends a BG target of
140 to 180 mg/dL in the majority of critical care patients.
More stringent goals (110–140 mg/dL) may be appropriate
for selected patients, as long as these can be achieved
without significant hypoglycemia. The ADA recommends
administration of intravenous insulin using a validated
written or computerized protocol in the ICU that allows for
predefined adjustments in the infusion rate, accounts for
glycemic fluctuations and glycemic dose. In addition, if a
patient with BG 140 mg/dL has not had an HbA1c checked
in the preceding 3 months, this should be sent irrespective of
the patient’s status in terms of known diabetes. Similarly, the
most recent iteration of the surviving sepsis (European
Society of Intensive Care Medicine [ESICM] and Society of
Critical Care Medicine [SCCM]) guidelines recommends ini-
tiation of insulin dosing when two consecutive BG levels are
>180 mg/dL using a protocolized approach that targets an

upper BG level <180 mg/dL rather than <110 mg/dL. Close
BG monitoring every 1 to 2 hours till infusion rates are stable
followed by checks at 4-hour intervals are recommended.
The authors do caution regarding interpretation of point-of-
care capillary glucose levels in critically ill patients which
may not reflect true arterial BG concentration,55 and deci-
sion making including use and dosing of insulin based on
potentially inaccurate BG assessment.
The data on noninsulin antihyperglycemic therapies in
the ICU are not well established. Metformin has been used in
the ICU given its low risk of hypoglycemia; however, it needs
to be used very cautiously in patients with metabolic acidosis
and renal impairment.56,57 While dipeptidyl peptidase 4
inhibitors58 have been shown to have similar glucose control
and frequency of hypoglycemia in the noncritical care
setting, saxagliptin and alogliptin carry a U.S. Food and
Drug Administration warning against use in patients with
heart failure. GLP-1 antagonists are associated with gastro-
intestinal side effects, whereas SGLT-2 inhibitors have been
associated with increased risk of renal failure as well as
ketosis. In the absence of rigorous data in the critically ill
patient, the noninsulin antihyperglycemic agents are not
currently recommended in the ICU.
The vast majority of the data regarding ICU glycemic
management stem from medical literature. However, glycemic
control can also have far reaching consequences in terms of
wound healing and rate of postoperative infections in postop-
erative patients in the surgical or cardiothoracic ICU. Surgical
stress causes release of counter-regulatory hormones that are
associated with dysglycemia, in addition to starvation in the
fasting state preoperatively, that is associated with increased
insulin resistance. The degree of glycemic dysregulation is
affected both by surgical59 (anatomic location of surgery,
laparoscopic vs. open surgery) and anesthetic factors60 (gen-
eral vs. loco-regional anesthesia, use of volatile anesthetics).
The Society of Thoracic Surgeons (STS) practice guidelines in
2009 for patients undergoing cardiac surgery recommend
strict glucose control <180 mg/dL throughout the ICU stay
unless the patient is expected to have an ICU stay >3 days. In
case a patient is ventilator-dependent, or requires inotrope
mechanical circulator support or renal replacement therapy,
the STS guidelines recommend even tighter glycemic control
with a target glucose level of <150 mg/dL.61 While studies in
the surgical ICU have shown reduced surgical site infections
with intensive glucose control (80–110 mg/dL) compared with
intermediate control,62 the current Centers for Disease Control
and Preventions guidelines for the prevention of surgical site
infection recommend a glycemic range of <200 mg/dL both in
patients with and without diabetes,63 giving due credence to
risk of hypoglycemia with tight glucose strategies.
In patients admitted to the ICU following acute coronary
syndrome, the American Heart Association recommends use of
intravenous insulin to maintain BG <180 mg/dL. Stricter glu-
cose targets of 90 to 140 mg/dL have not been associated with a
clear benefit in the post-myocardial infarction setting, and,
while they may be a reasonable target, should not be aimed
for at the cost of causing hypoglycemia.64 These recommenda-
tions were reinforced by the European Society for Cardiology
Glycemic Control in the ICU Tickoo 575
guidelines which recommend glucose targets of <200 mg/dL in
the acute phase post-STEMI with strict avoidance of hypo-
glycemia which has been associated with increased mortality
in the postischemic setting.65 Patients who are maintained
for >50% of time in the appropriate glycemic range in the
cardiac ICU have been shown to have improved 30-day as well as
1-year mortality.16 Strict avoidance of hypoglycemia (glucose
<70 mg/dL)66 is also of paramount importance in the neurolog-
ical ICU given the preferential utilization of glucose as a neuro-
nal metabolic fuel. On the other hand, hyperglycemia (glucose
>200 mg/dL) has been associated with poor neurological out-
comes (mortality at 6 months, level of neurological recovery)
and therefore, should be avoided. Current recommendations
are using low-dose insulin infusion as needed to maintain BG in
the 110 to 180 mg/dL range along with adequate nutritional
support in the neurocritical care unit.67
Toward Personalization of Glycemic
Management in ICU—A Long and Winding
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Road
Research in recent years in the field of glycemic management
in the ICU has focused on trying to identify potential factors
that could have contributed to the inconsistent results of the
sentinel interventional studies in the field. From van den
Berghe’s initial Leuven study showing mortality benefit with
tight glycemic control to NICE-SUGAR demonstrating the
complete opposite results with TGC, the recommendations
over the past two decades have become far more liberal in
terms of BG “targets.” However, we now know that hyper-
glycemia is not the only factor associated with poorer clinical
outcomes, but even mild hypoglycemia is independently
associated with increased mortality among other outcomes.
GV and time outside target range have been identified as
important and independent determinants of clinical out-
comes fairly recently. With the focus on just defining the
target “acceptable hyperglycemic range,” we were likely
using an extremely blunt approach to what we now know
to be an extremely complex issue in the critically ill patient,
affected by multiple domains, type of critical care needs of
the patient and multiple other metabolic factors as discussed
below. In the fast changing world of personalized medicine,
evidence is pointing rapidly toward the need for a more
nuanced approach and not the “one size fits all” umbrella to
manage glycemia in the ICU. Various areas have been delin-
eated that are the subject of intense investigation, and might
finally change the way we approach comprehensive glycemic
management in the ICU.
Role of Pre-Existing Diabetes Mellitus
One of the major factors that have been the subject of
rigorous investigation is the role of pre-existing diabetes
and its influence on the various domains of dysglycemia in
the ICU. Two recently published studies by Sechterberger and
colleagues68 (retrospective, single center study) as well as
Krinsley and colleagues44 provide great insights into the
above question. Sechterberger et al retrospectively studied
more than 10,000 critically ill medical and surgical patients
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 5/2019
576 Glycemic Control in the ICU Tickoo
(1,638 with DM and 8,682 without) and analyzed mean
glucose, GV, and hypoglycemia vis a vis clinical outcomes
in the diabetic and nondiabetic groups. Nondiabetic patients
had increased ICU mortality in the lowest as well as the
highest glucose quintiles (odds ratio ¼ 1.4 and 1.8, p < 0.001)
as well as with higher GV (odds ratio ¼ 1.7, p < 0.001). There
was no significant association with mean glucose or GV in the
diabetic group. Hypoglycemia was associated with ICU
mortality in both groups; however, diabetic patients seemed
to tolerate a wider glucose range than non-DM patients.68 In
a multicenter study, Krinsley et al retrospectively studied
44,964 patients admitted to 23 ICUs across nine centers
and compared the domains of dysglycemia stratified by
diabetes status. The authors found that in nondiabetic
patients, mortality was lowest for the “tight” BG group
(80–110 mg/dL). This was different in patients with
diabetes, where a lower band of glucose (mean BG from
80 to 110 mg/dL) was associated with increased risk of
mortality and a more liberal target (mean BG from 110 to
180 mg/dL) with decreased risk of mortality. Similar to the
Sechterberger study, GV was associated with increased mor-
tality in the nondiabetic group, while hypoglycemia had
worse outcomes in both the diabetic and nondiabetic
cohorts.44 Patients with an unknown diagnosis of diabetes
at the time of critical illness (HbA1c > 6.5%, without history
of diabetes) have been identified as not only having signifi-
cantly worse dysglycemia but also an increased mortality
risk (13.8 vs. 11.4%; p ¼ 0.01) compared with those without
diabetes.69 It is not only the history of diabetes (diagnosed or
undiagnosed) but also the metabolic control prior to critical
illness that seems to affect outcomes in the ICU. In a critically
ill cohort, Plummer and colleagues6 showed that in patients
with DM and very good (HbA1c < 6%) and adequate prior
metabolic control (HbA1c between 6 and 7%), an increase in
peak BG in the first 48 hours of critical illness was associated
with increased mortality, whereas patients with poor
baseline control tolerated higher peak BG better. Based on
these findings, interventional studies have started to evalu-
ate use of newer insulin protocols that allow for “permissive
hyperglycemia” with more liberal BG targets (>180 mg/dL)
and reduce hypoglycemia as well as GV in patients with
diabetes in the ICU. In a small exploratory study, Kar and
colleagues recently reported70 that in patients with type 2
diabetes and chronic hyperglycemia, liberal glucose control
(180–250 mg/dL) appeared to attenuate GV and reduces the
prevalence of moderate–severe hypoglycemia. However,
glucose levels in excess of 200 mg/dL are associated with
increased risk of surgical-site infections due to low intracel-
lular phagocytosis and opsonization, high prevalence of
glycosuria with resultant intravascular volume depletion,
and to prevent the polyneuropathy in critically ill patients.71
Thus, while there is a strong case to be made for different
glycemic targets in patients with and without diabetes, the
burden of evidence for permissive hyperglycemia in diabetic
patients has not been well established. The LUCID (liberal BG
in critically ill patients with pre-existing type 2 diabetes)
trial is currently underway to assess the effects of permissive
hyperglycemia on outcomes including hypoglycemia, GV,
Seminars in Respiratory and Critical Care Medicine Vol. 40 No. 5/2019
time-weighted mean glucose, and 90-day mortality in the
ICU. Till the results of this trial are available, glucose control
in the ICU should be maintained <180 mg/dL while avoiding
hypoglycemia and decreasing GV as much as possible,1 in
accordance with current guidelines.
Role of Feeding and Mobility in Critically Ill Patients
In addition to pre-existing glycemic stress, variation in glucose
control is also associated with nutritional status, especially in
the ICU. The usual process of nutrition in mammals is bolus
feeding, and following a meal, there is a complex neurohor-
monal release of enteric peptides including glucose-like pep-
tide-1 (GLP-1), gastric inhibitory peptide, cholecystokinin,
ghrelin, and peptide Y. This array of hormones causes a wide
variety of responses including potentiation of β-cell-mediated
insulin release and suppression of glucagon release which in
turn inhibits endogenous glucose production, with the end
result of maintaining physiologic glucose control. During
critical illness, several of these entero-hormonal responses
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are impaired. Additionally, the common practice of continuous
tube feeds in the ICU also dampens these responses which
results in increased insulin resistance.72 Acute hyperglycemia
is associated with delayed gastric emptying73,74 and the
resultant decreased nutrient absorption can independently
predispose the patient to increased rates of hypoglycemia as
well as GV75 only worsened in the setting of frequent discon-
tinuation of feeds in the ICU for procedures, increased gastric
residuals, and risk for aspiration, etc.
We also know that exercise stimulates IMGU into muscle
cells. Patients who are bed bound in the ICU often lose this
stimulus76 and are at risk of worsened hyperglycemia. Exercise
and early mobilization have both been shown to be associated
with decreased insulin resistance77 and could potentially
mitigate some of the dysglycemia in the critically ill patient.
Practical Management in the ICU
With current evidence, approach to glycemic management has
to evolve form a “one size fits all target” blood sugar range to a
more comprehensive assessment of a patient’s diagnosis of
diabetes, premorbid glycemic state, and degree of metabolic
control using HbA1c, critical clinical scenario as well as their
risk of developing glycemic derangements related to nutritional
and ambulatory status in the ICU. As critical care providers, we
will need to formulate an individualized therapeutic range for
each patient with due consideration to the above factors. The
crux of the management paradigm should focus equally on
minimizing significant hyperglycemia (BG > 180 mg/dL), hypo-
glycemia (BG < 70 mg/dL), and GV as it should on trying to
maximize time in the range. To a modified approach consider-
ing premorbid metabolic status, Aramendi and colleagues1
recommend using a glycemic range of 140 to 180 mg/dL in
hyperglycemic patients with an HbA1c <7% as well as surgical
ICU patients with an A1c >7%, but favor a more liberal target of
180 to 220 mg/dL in patients in medical ICUs with A1c >7% who
likely have developed modifications in homeostatic responses
as a result of chronic hyperglycemia. Similar recommendations
are made by Krinsley78 albeit for a narrower glycemic range of
80 to 140 mg/dL in patients without diabetes or with excellent

metabolic control prior to critical illness (HbA1c < 7%). While
these recommendations appear in line with emerging evidence
in the field, we are still awaiting randomized studies looking at
specific glycemic ranges in various critically ill cohorts based on
the above factors before universal guidelines can be
recommended.
In line with developing personalized glycemic control
plans, redefining accurate measurement of glucose levels
in the ICU is another area of intense investigation. The gold
standard in the inpatient setting is the laboratory measure-
ment of plasma glucose. This can be affected by the source of
the sample with arterial blood samples being approximately
10 to 20 mg/dL higher than laboratory samples based on the
point-of-care system used.79 Venous blood samples showed
the poorest correlation with plasma laboratory levels.79
Routine practice in most ICUs is to use capillary (fingerstick)
blood samples using various point-of-care devices given
convenience of use. While commonly practiced over much
of the United States, this practice does not withstand strin-
gent tests for evidence-based practice. In fact, studies have
often shown greatest disagreement from gold standard
laboratory measures when using point-of-care capillary
blood samples80 to estimate BG. This presents a challenge
applicable to each patient encounter in daily workflow
because critically ill patients will often have peripheral
hypoperfusion, acidosis, anemia, and hypothermia, all of
which can increase the discordance between actual labora-
tory plasma measures and bedside capillary BG measure-
ments. Given our realization of how dynamic glucose levels
in the critically ill can be, and how often they can change with
potentially wide swings in multiple domains of dysglycemia,
our routine practice of estimation of capillary BG really does
not give an accurate assessment of the 24-hour glycemic
milieu in a patient. The major risk of intermittent capillary
glucose assessment is that we might be missing periods of
intense dysglycemia, especially episodes of hypoglycemia,
which could critically affect patient outcomes. This stream of
thought has led to consideration of continuous glucose
monitoring (CGM) in the ICU.
CGM works on the basis of a sensor that is inserted
subcutaneously (or intravenously in some platforms) and
measures the interstitial glucose concentration via a redox
reaction and transmits the data to a device interface that is
updated every 3 to 5 minutes (no longer than 15-minute
intervals per Clinical and Laboratory Standards Institute
[CLSI] guidelines).81 Most CGMs can provide 3 to 5 days of
continuous information and can pave the way for better
glucose control and fewer hypoglycemic episodes in the
critically ill.82 The OptiScanner 5000 (OptiScan Biomedical
Corporation, Hayward, CA) is a CGM system that has recently
been approved for use in the ICU.83 While interstitial glucose
levels often closely reflect true plasma glucose levels84 with
less aberrancy despite changes in electrolytes and acid–base
milieu, the limitation of CGM systems is still housed in
accuracy, especially in the setting of hypoglycemia.85 Other
considerations include cost of care, as well as risk of throm-
bus or biofilm formation, occlusion, and catheter-related
infections if intravascular systems are used. Despite these
Glycemic Control in the ICU Tickoo 577
limitations, CGM systems certainly seem to be the path
forward in terms of glucose monitoring in the ICU.86
With increasing accuracy of CGM systems, the next step is
combining CGM data with feedback or predictive automated
algorithms that can potentially mimic an artificial pancreas
providing continuous adjustment in insulin administration,
and allow for the ultimate personalization of glycemic
management in the critically ill.87 The essential components
of establishing a system like this would include accurate real-
time CGM, continuous intravenous insulin infusion, and a
well-established algorithm that automatically adjusts the
dosing in the insulin pump. Such a closed loop system
with CGM and a computer-based algorithmic approach could
potentially manage all the facets of dysglycemia, focusing on
minimizing hypoglycemic events in our patients. The devel-
opment of these systems is well underway, but the real test
will have to again be subjecting them to real-life scenarios
across a breadth of critically ill patients.
Downloaded by: University of Connecticut. Copyrighted material.
Conclusion
This is indeed an exciting time in the field of glycemic
management in the critically ill. Our knowledge has become
more nuanced in terms of multiple domains of dysglycemia
and how each of these needs to be managed independently to
allow for the best possible clinical outcomes for our patients.
And while we are not quite at the point where machine
learning and automated systems have become part of routine
practice in the ICU, this is likely fast approaching and will
allow for a more personalized approach to glycemic man-
agement rather than a current “one size fits all” paradigm.
Disclosures
None.
Conflicts of Interest
The author does not have any relevant conflicts of interest.
Acknowledgments
None.
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