Can J Diabetes 38 (2014) 144e150

Contents lists available at ScienceDirect

Canadian Journal of Diabetes

journal homepage:
www.canadianjournalofdiabetes.com

Review

Insulin Infusion Therapy in Critically Ill Patients

Jean-Marie Boutin MD, PhD a, *, Lyne Gauthier BScPhm, MSc b
a
Département de Médecine, Service d’endocrinologie, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada
b
Département de Pharmacie, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada

a r t i c l e i n f o a b s t r a c t

Article history: While dysglycemia (hyperglycemia, hypoglycemia and glucose variability) is clearly associated with
Received 9 December 2013 increased mortality in critically ill patients, target range of blood glucose control remains controversial.
Received in revised form Standardized insulin infusion protocols constitute the basis of treatment of these patients. The choice of
28 January 2014
protocol and its implementation is a great challenge. In this article, we review the published data to help
Accepted 29 January 2014
define the essential elements that compose a good protocol and apply the right conditions to make it safe
and effective.
Keywords:
Ó 2014 Canadian Diabetes Association
computer-base protocol
critical care
hyperglycemia
r é s u m é
intravenous insulin protocol
Bien que la dysglycémie (hyperglycémie, hypoglycémie et variabilité glycémique) soit de toute évidence
Mots clés :
associée à l’augmentation de la mortalité chez les patients gravement atteints, l’intervalle cible de la
protocole informatisé
maîtrise de la glycémie demeure controversé. Les protocoles standardisés de perfusion d’insuline con-
soins aux patients gravement atteints
hyperglycémie stituent la base du traitement de ces patients. Le choix du protocole et sa mise en œuvre constituent un
protocole d’insuline par voie intraveineuse défi majeur. Dans cet article, nous passons en revue les données publiées pour aider à définir les élé-
ments essentiels qui composent un bon protocole et à appliquer les bonnes conditions pour le rendre sûr
et efficace.
Ó 2014 Canadian Diabetes Association

Introduction
Dysglycemia in the intensive care unit
Dysglycemia, which refers to hyperglycemia, hypoglycemia and
glucose variability (GV), frequently occurs in critically ill patients
regardless of their diabetes status (1). The association between
these glucose dysregulations and morbidity and mortality in
intensive care units (ICUs) is well documented, but there is still a
great deal of debate about their involvement as biomarkers rather
than causative factors of adverse outcomes (2).
The landmark study by van den Berghe and colleagues in
2001 (3), referred to as the surgical Leuven 1 study, brought
about a major shift in our approach to hyperglycemia in criti-
cally ill patients. It was the first evidence that demonstrated a
mortality benefit of tight glycemic control (TGC) in the ICU. New
guidelines for treatment of hyperglycemia in the ICU targeting
the “normal range” of blood glucose (BG) of 4.4 to 6.1 mmol/L
* Address for correspondence: Jean-Marie Boutin, MD, PhD, Hôtel-Dieu du
CHUM, 3840 rue Saint-Urbain, Montreal, Quebec H2W 1T8, Canada.
E-mail address: jm.boutin@umontreal.ca.
1499-2671/$ e see front matter Ó 2014 Canadian Diabetes Association
http://dx.doi.org/10.1016/j.jcjd.2014.01.016
followed that study (4). Prior to that publication, the treatment
of hyperglycemia in ICUs was not considered a priority and was
often initiated only when BG values exceeded the renal
threshold for glycosuria (5).
It is well established that hyperglycemia is associated with
increased morbidity and mortality in ICUs (6). The prevalence of
diabetes in ICUs is probably 25% or higher, but most cases of
hyperglycemia in this setting occur in patients without known
diabetes (1). These hyperglycemic patients have stress-induced
hyperglycemia or undiagnosed diabetes and have higher
in-hospital mortality than patients with known diabetes (7).
Since studies by the Leuven group showed positive results for
TGC in surgical (3) (Leuven 1), medical (8) (Leuven 2) and pediatric
ICUs (9) (Leuven 3), several attempts to reproduce those results
have failed to show any benefits. Hypoglycemia appeared to be
problematic, and 2 trials were terminated prematurely due to an
unacceptable rate of hypoglycemia (10,11). The larger of these
attempts, the Normoglycemia in Intensive Care Evaluation and
Surviving Using Glucose Algorithm Regulation (NICE-SUGAR)
Study, is another landmark randomized controlled trial (RCT) that
was conducted in 41 multinational mixed medical/surgical ICUs,
aiming at the tight target range of 4.5 to 6.0 mmol/L and resulting in
an increased mortality rate in the TGC group (12). In a recent
 J.-M. Boutin, L. Gauthier / Can J Diabetes 38 (2014) 144e150
analysis of the hypoglycemic events in this study, the authors
showed a correlation between the severity of the hypoglycemia and
the risk for death, but causality could not be proved (13). The fear of
iatrogenic hypoglycemia brought about by this study was instru-
mental in changing recent guidelines for hyperglycemia in the
ICU (14).
Iatrogenic hypoglycemia must be distinguished from sponta-
neous hypoglycemia because the latter is more clearly associated
with mortality (15). Despite the increased rate of hypoglycemia in
the TGC groups in the Leuven studies, there was a decrease in
mortality. The NICE-SUGAR study was the only TGC RCT in which
there was an increase in mortality. Moreover, the greatest hazard
ratio for death in this study was observed in patients with severe
hypoglycemia in the absence of insulin treatment (13).
Glucose variability (GV) is the third aspect of dysglycemia that
has been shown to correlate with mortality in the ICU (16).
Different glucometrics have been used, such as standard deviation
(SD) of the mean BG level (17) and mean absolute glucose change
(18), to demonstrate that GV is an independent predictor of mor-
tality in critically ill patients. Two recent large retrospective ana-
lyses have shown that high GV was independently associated with
higher mortality in the non-diabetes mellitus cohort but not in the
diabetes cohort, although severe hypoglycemia correlated with
increased mortality in both cohorts of patients (19,20). Also, an
analysis of the Leuven studies revealed that the decline in mortality
in the TGC group was associated with decreased mean BG levels,
but there was no decrease in GV (21).
Optimal target range for blood glucose in ICUs
The optimal target range for BG in the treatment of hypergly-
cemia in critically ill patients has shifted markedly over the past
15 years; the changes have been driven mainly by the landmark
studies mentioned above. Retrospective studies have shown that
the relation between mean BG values and mortality and post-
operative infections follows a U-shaped curve in hospitalized
patients (22e24), and a safe range of BG in ICUs has been defined as
being between 7 and 9 mmol/L (24). Interestingly, patients with
established diabetes have a curve slightly shifting to the right, with
a blunted relationship between hyperglycemia and death (5).
Several meta-analyses of the effects of TGC in the ICU have been
published over the past 5 years (25e32). None found a significant
benefit in terms of mortality. Of these 8 analyses, 4 found a
decreased risk for morbidity in surgical patients (26,29,31,32).
However, in all settings, TGC increased hypoglycemia by 3 to 8
times compared with conventional controls. Substantial disparities
exist among these studies, and much has been written in an
Table 1
Differences between the Leuven I and NICE-SUGAR studies
Feature
Number of sites
Number of subjects
ICU admission type
Protocol type
Nurses expertise
Source of blood
Device used to measure BG
Main feeding route
Administration route of the insulin infusion
BG target range in mmol/L (intensive group/control)
Mean BG in mmol/L (intensive group/control)
BG in target range
Overlap between intensive and control groups
Patients with at least one severe hypoglycemia (intensive group/control)
BG, blood glucose; ICU, intensive care unit.
145
attempt to reconcile the results, especially when comparing the
landmark studies of Leuven and NICE-SUGAR (2,5,33).
As illustrated in Table 1, several methodological differences are
present between the first Leuven study and the NICE-SUGAR study,
which resulted in opposite conclusions concerning the benefit of
targeting normal values of BG in ICUs. The first major difference
concerns the environment of the studies. The Leuven 1 study was
performed in a single centre in Leuven (Belgium) with experienced
nurses who were well versed in the use of their intuitive paper
protocol. In the NICE-SUGAR study, the cases were spread over 41
centres and treated by a heterogeneous group of nurses who had
had much less exposure to a new computerized protocol. Surgical
patients were studied in the Leuven 1 trial, compared to a mixed
population of surgical and medical patients in the NICE-SUGAR
study. It is interesting to note that in the Leuven 2 trial, in which
medical patients were studied, TGC significantly reduced morbidity
but reduced mortality only in a subset of subjects treated for 3 days
or more in ICUs (8). Less than 50% of patients in the TGC group in
the NICE-SUGAR study reached the target, compared to 70% in the
Leuven trial. Also, the target range for the control group was higher
in the Leuven trial (10 to 11.1 mmol/L) than in the NICE-SUGAR trial
(8 to 10 mmol/L). The resulting gap in BG values for the treated and
control groups was narrower in the NICE-SUGAR trial, with >50%
overlap between the 2 groups compared to <10% in the Leuven
study. Consequently, this study cannot be considered to replicate
the Leuven study (5).
The ways in which the BG levels were measured in both studies
constitute another major difference. Indeed, a blood-gas analyzer
was used with arterial blood samples in Leuven, while various
blood glucose meters were used in NICE-SUGAR, with samples from
a mixture of arterial, venous and capillary sites. Point-of-care (POC)
glucose meters are not accurate enough and are not designed to
cope with the numerous interferences affecting the measurement
of BG in the ICU (33,34). Major inaccuracies in BG values in the
NICE-SUGAR trial have subsequently been reported at a partici-
pating site in Canada that could result in unacceptable glucose
fluctuations and hypoglycemia (35). Moreover, BG levels can vary
quite significantly if measured by finger-stick capillary specimens
compared with arterial or venous specimens, especially during a
hypoperfusion state in an ICU (34). A recent systematic review
confirmed that BG measures were more accurate using arterial
blood than using capillary blood (36).
Feeding strategies in the ICU reveal a third major difference
between these 2 broad trials. In the Leuven study, early parenteral
nutrition was used in most patients, whereas feeding relied almost
exclusively on the enteral route in the NICE-SUGAR study (37). To
explore the best feeding strategy in the ICU, van den Berghe’s group
designed a multicentre trial with patients randomly assigned to
Leuven I study (3) NICE-SUGAR study (12)
1 41
1548 6104
Surgical Surgical and medical
Intuitive, paper Computerized
Experimented nurses Heterogeneous group
Arterial Capillary, arterial, venous
Blood gas analyzer Multiple; all types of meters
Early parenteral nutrition Enteral
Central intravenous Peripheral intravenous
4.4e6.1/10e11.1 4.5e6/8e10
5.7/8.5 6.4/8
70% <50%
<10% >50%
5.2%/0.8% 6.8%/0.5%
146 J.-M. Boutin, L. Gauthier / Can J Diabetes 38 (2014) 144e150
either early (<48h) or late initiation (>7 days) of parenteral nutrition
and treated with Leuven’s usual TGC protocol (38). The results
indicated that postponing parenteral nutrition for 1 week did not
affect mortality but markedly reduced morbidity and accelerated
recovery. Surprisingly, this study suggests that patients were not
treated optimally from a nutrition standpoint in the Leuven studies,
and the resulting morbidities could have been reduced, causing an
even more positive outcome compared to the outcome of the NICE-
SUGAR study. On the other hand, early feeding in the NICE-SUGAR
context could possibly decrease the risk for hypoglycemia and GV
and the associated morbidities. Therefore, the interplay between
feeding strategies and BG control is complex and requires further
studies to determine the best overall protocol to follow in the ICU.
As we can see from these analyses, it is difficult to determine
optimal targets of treatment in view of such disparities. Targeting
normal values of 4.4 to 6.1 mmol/L was proven to be effective in
reducing morbidity and mortality in the unique context of the
Leuven studies. However, these conditions have been very difficult
to reproduce, for the various reasons explained. The NICE-SUGAR
settings correspond more closely to real-life experience in our
institutions, with practical shortcomings related to inaccurate tools
for monitoring BG and deficiencies in the design and imple-
mentation of the intensive insulin protocol (IIT). In this context, it
seems more reasonable to aim for a moderate target range of BG
similar to the range for the conventional group in the NICE-SUGAR
trial (8 to 10 mmol/L) as a compromise, to avoid the deleterious
effects of hypoglycemia and GV (5).
Most medical organizations have adopted this target for glucose
control in ICUs in their most recent guidelines (14,39e42). Two of
these guidelines also propose more stringent BG control in certain
subpopulations. The Society of Thoracic Surgeons proposes a more
stringent upper limit of 8.3 mmol/L following 3 days in an ICU after
cardiac surgery for patients with comorbidities (40). For the
American Diabetes Association, lower BG targets (6.1 to 7.8 mmol/L)
may be appropriate in selected patients, but strong evidence is
lacking (14). Guidelines from the Society of Critical Care Medicine
also reached a consensus glycemic goal range of 5.6 to 8.3 mmol/L
to avoid excursion of BG >10 mmol/L, which has been clearly
associated with an increased risk for death, length of stay and
infection in an ICU (16,34). They set their upper limit at 8.3 mmol/L,
particularly for patients with cardiac surgery and patients with
trauma, based on evidence of morbidities in these patients (34). In a
recent international multicentre cohort study of patients admitted
to 23 ICUs, BG >7.8 mmol/L was associated with an increased risk
for mortality in patients without diabetes but not in patients with
diabetes, where even values of BG >10 mmol/L were not related to
increased mortality (19). Moreover, diabetes was independently
associated with decreased mortality in the entire cohort. Therefore,
patients with diabetes seem to behave differently from patients
without diabetes and may benefit from higher target ranges of BG.
Despite the controversy, there is general consensus that a BG level
of 10 mmol/L constitutes the absolute upper limit and that hypo-
glycemia (BG <4 mmol/L) should be avoided. The upper limit could
be lowered in certain subpopulations if the adjustments are made
safely without hypoglycemia.
The ideal insulin protocol in ICUs
The disparities in the results of the TGC trials have demon-
strated abundantly that an effective and safe IIT is much more than
a simple order set. There are many practical elements involved,
including existing local technical and human resources that can
make or break an insulin infusion protocol and its implementation.
Failure to implement the protocol and replicate the results of the
Leuven group at other medical centres is a good example. Because
the Leuven protocol is based on simple rules with a high level of
intuitive decision making by users, it is difficult to reproduce.
Recently, a group from the Netherlands (8 ICUs) undertook to
reproduce the Leuven protocol closely by investing heavily in
training their staffs, with visits to Leuven and gradual imple-
mentation (43). They succeeded in obtaining a median BG level of
5.8 mmol/L with an initial increase in the hypoglycemia rate that
improved over time, confirming the importance of the environ-
ment and well-trained staff when implementing a protocol.
The Society of Critical Care Medicine did an extensive review of
the literature to draw up recommendations concerning the essen-
tial components of an insulin infusion system (34). Likewise, the
Society of Hospital Medicine offers its recommendations with ex-
amples of insulin infusion protocols on its website (http://www.
hospitalmedicine.org/ResourceRoomRedesign/GlycemicControl.cfm).
A proper protocol should make it possible to set different BG target
ranges. As discussed previously, a range of 8 to 10 mmol/L may be
appropriate in most situations in an ICU, but tighter ranges may be
considered for certain situations, such as after cardiac surgery. If the
protocol is to be used outside an ICU, different target ranges can be
used for pregnancy, diabetic ketoacidosis or other settings,
according to the pathology or the local resources available. There
should be clear instructions about the BG threshold for initiating
insulin infusion and the initial rate. A validated algorithm for sub-
sequently adjusting the rate should be based not only on the cur-
rent BG level but also on the dynamic change of BG levels over time.
This makes it possible to reach the target faster if correction of
hyperglycemia is too slow or to avoid hypoglycemia if the correc-
tion is too fast. A concentration of 1 unit/mL of insulin for the
infusion is recommended to limit volume intake in an ICU along
with priming new tubing with at least 20 mL of waste volume to
avoid adsorption of insulin to the IV tubing (34). Accurate insulin
administration requires a reliable infusion pump that can deliver
insulin dose in increments of 0.1 unit per h.
Monitoring BG during IIT is crucial, especially with tight BG
target ranges. It is suggested that BG levels be monitored every 1 to
2 h, with more frequent readings in unstable patients. Many pro-
tocols allow testing every 4 h once BG values have been stabilized
in the target range, but routine monitoring at a frequency of 4 h is
discouraged because the rates of hypoglycemia increase above 10%
in many of these protocols (34). Studies have shown the superi-
ority of blood gas analyzers compared to POC glucose meters for
measuring BG levels in the ICU (33,34,44). The 1987 Clarke error
grid, used to describe the clinical accuracy of glucometers in
outpatient settings, is unsuitable in an ICU. The US Food and Drug
Administration is currently establishing tighter performance
requirements for BG monitors used in hospitals (33). However, POC
glucose meters remain the most popular instruments for moni-
toring BG levels in ICUs in terms of time and money. Additional
consideration should also be given to the sampling site of the
blood. As mentioned previously, arterial blood from indwelling
catheters should be the primary source of samples for measuring
glucose levels, and venous blood should be used as an alternative
source. Capillary samples should be used only in patients whose
severity of illness does not justify invasive vascular monitoring
(33,34,44).
Frequent BG monitoring according to the recommendations is
time-consuming for nurses and constitutes a major barrier in the
proper implementation of an insulin infusion protocol. For this
reason, continuous glucose monitoring (CGM) has been explored to
reduce the burden and increase the safety of IIT (44). Initial reports
of continuous monitoring with interstitial glucose sensors have
shown acceptable accuracy (33,44). Intravascular BG monitoring by
devices using various techniques based on microdialysis,
absorption spectroscopy, optical scattering or fluorescence is
currently being studied in ICUs. The first studies involving the Eirus
microdialysis system (Maquet Critical Care, Solna, Sweden) and the
 J.-M. Boutin, L. Gauthier / Can J Diabetes 38 (2014) 144e150 147

OptiScanner (Optiscan Biomedical, Hayward, CA), based on infrared
spectroscopy, have shown very promising results, with superior
accuracy compared to interstitial CGM (45, 46). These CGM systems
have potential for avoiding hypoglycemia by trend detection,
optimizing insulin titration, reducing nurses’ workloads and mak-
ing it possible to analyze new parameters of glucose regulation
such as GV and glucose complexity.
Procedures for treating hypoglycemia are an important
component of insulin infusion protocols. Clear indications should
be given to stop the infusion when BG <4 mmol/L and to administer
50% dextrose intravenously, titrated according to the hypoglycemic
value, in order to avoid rebound hyperglycemia and a rise in GV
(34). BG testing should be repeated every 15 m, with further
dextrose administration until hypoglycemia is corrected. Nutri-
tional considerations can have an important effect on glycemic
control and can have a major influence in terms of insulin
requirements. Providing constant carbohydrate calories simplifies
glycemic management. Guidance for handling situations in which
caloric intake could be interrupted, such as “field trips” to the
operating room or for imaging studies, should be incorporated
into the order set to avoid hypoglycemia. The transition from
insulin infusion when patients are stable and start eating deserves
special instructions in the protocol. It is suggested that all patients
with type 1 diabetes, patients with type 2 diabetes who have an
insulin infusion rate >0.5 unit/h and patients without diabetes
who have an insulin infusion rate >1 unit/h would benefit from
transition to a basal-nutritional-correction subcutaneous insulin
regimen (34). Insulin infusion should be stopped only after the
initiation of subcutaneous insulin to avoid rebound hyperglyce-
mia. There are various ways to determine the total daily dose of
insulin necessary for the transition based on the last hours of IV
insulin infusion, and guidance should be given in the protocol to
this effect (47).
An excellent validated insulin titration program is no guarantee
of effective and safe control of glycemia in the ICU unless imple-
mentation is carefully planned. The insulin infusion system must be
tailored to local resources and the subset of patients treated. The
availability of appropriate hospital staff, accurate monitoring
technology and continuous assessment of glucometrics are essen-
tial aspects of successful implementation (34). Team education is of
paramount importance, and great efforts should be invested in
teaching the nurses, who bear the burden of carrying out the
protocol (43). Explaining the rationale behind the importance of
glycemic control, the practicalities of the protocol, the situations
that demand drastic changes in insulin requirements, and when
alerting a physician is appropriate should help in overcoming bar-
riers to executing the protocol. It is also essential to get feedback
from the staff and organize regular sessions during the early phase
of implementation so as to clarify and adjust the protocol
accordingly.
Types of insulin infusion protocols
There are many published insulin infusion protocols, and the
adoption of protocols with demonstrated safety and efficacy is
highly recommended (14). However, there is not a single proven
ideal protocol that would fit every ICU. As explained above, a vali-
dated protocol should be chosen and customized according to local
resources and patient characteristics. Protocols vary in insulin
dosing intensity and complexity, and comparison is made more
difficult by differing glucometrics, BG target ranges, monitoring
methodologies and the populations studied. There are currently no

Table 2
Comparative summary of some insulin infusion protocols used in ICUs

Type of Type of protocol Protocol Type of admission BG target range Mean BG BG in target Hypoglycemia
algorithm range
IR Paper Leuven (3) Surgical 4.4e6.1 5.7 5.1% of patients
n¼765 (BG <2.2)
Portland (51) Surgical 5.6e8.3 0.5% of patients
n¼4864 (BG <3.3)
Yale (52) Medical 5.5e7.7 6.9 diabetes; 6.7 52% of BG (once 0.3% of BG <3.3;
n¼52 no diabetes BG <7.8) 0.05% of BG <2.2
Computerized LOGIC (58) Mainly surgical 4.4e6.1 5.6 68.6% of time 14.1% of patients, 0.6%
(eMPC) of BG (BG <3.3); 0% (BG <2.2)
n¼149
Agus (57) Surgical 4.4e6.1 6.2 median of time- 50% of time 19% of patients (BG <3.3);
PID weighted BG average 3% of patients (BG <2.2)
n¼444
Commercial Dumont (59) Surgical 4.4e8.3 8.6 70.4% of BG 7 cases (BG <3.3);
software EndoTool 0 (BG <2.2)
n¼141
Marvin (60) Mixed 5.5e7.8 6.9 92.4% of patients 17.6% of patients, 1.1%
GlucoCare of BG (BG 2.2e3.9); 0.3%
n¼1657 of patients, 0.01% of BG
(BG <2.2)
MR Paper Markovitz (54) Surgical 6.7e11 1.4% of days (BG <3.9)
n¼29
Braithwaite (55) Trauma <6.1 6.3 2,4% of BG < 3.9; 0%
n¼27 of BG <2.8
Computerized Davidson (61) Surgical 5e6.7 5.9 7.7% (BG <3.3); 0%
Glucommander (BG <2.2)
n¼457
Yamashita (62) Surgical 5.1e8 7.9 53% of time 3.7% of BG <4; 0%
Glucommander of BG <2.2
n¼50
Commercial Jujena (63) Mixed 4.4e6.1 5.4 73.4% of time 4.25% of patients, 0.1%
software GlucoStabilizer of BG (BG <2.2)
n¼4588

BG, blood glucose; IR, infusion rate; MR, maintenance rate; n, number of patients under the protocol; PID, proportional integral derivative.
All BG values are in mmol/L.
148 J.-M. Boutin, L. Gauthier / Can J Diabetes 38 (2014) 144e150
data from a prospective RCT comparing the impact of various types
of glucose control protocols on morbidity and mortality. However,
available evidence indicates that static control algorithms dictating
insulin delivery rate based solely on the last glucose measurement
should be discouraged (48). Dynamic-control algorithms, based on
the last 2 BG levels and rate-of-change of BG levels, can be classified
in 2 broad categories: infusion rate (IR) algorithms and mainte-
nance rate (MR) algorithms (49,50).
In IR algorithms, the new insulin infusion rate is the result of a
direct adjustment of the previous IR and sometimes requires
additional calculations or qualitative assessments by the nursing
staff. These are often referred to as learning algorithms and are
possibly more flexible (50). The Leuven (3,8), Portland (51) and Yale
(52) protocols belong to this class of algorithms. Table 2 shows
characteristics and some glucose metrics from these studies. The
Leuven protocol, discussed above, includes a high level of intuitive
decision making by users. The Portland protocol, used for patients
after cardiac surgery and revised many times since 1992, is a
complex protocol with a combination of fixed and relative adjust-
ments of the IR. The most recent versions with various target
ranges can be downloaded from the Portland Diabetic Project site.
The Yale protocol has been published, showing results in both
medical and surgical ICUs, and has also been revised to adapt the
BG target range as the guidelines continue to evolve (53). It uses 2
tables to help the nurse identify the desired change of IR and
convert the change into a new IR.
The MR algorithms seek to define a maintenance rate, also
referred as a multiplier or column, according to the patient’s insulin
sensitivity. The paper-based protocols use multiple columns
(sliding scales) corresponding to different multipliers or levels of
sensitivity to insulin. The designation of the multiplier (column)
used to calculate the new IR is determined according to the rate of
change in BG levels (49). These algorithms have potential for
improved adaptation to insulin resistance, making it possible to
achieve target BG levels rapidly for all levels of insulin sensitivity
(50). Moreover, the burden of interpretation of these protocols by
nursing staff may be less than that of the IR protocols (49). The first
published paper based on this concept used 5 columns of
increasing insulin resistance in cardiac surgery patients (54). In the
North Carolina protocol, Braithwaite et al pushed the concept with
a 6-columns algorithm for trauma patients (55). Details of these 2
protocols are shown in Table 2.
These paper-based protocols are quite complex, and they are
nurse-dependent for interpretation and application. Both types of
algorithms have been translated into mathematical equations, with
several benefits. Indeed, they reduce the number of parameters
needed to determine the IR of insulin, from more than 50 in certain
paper-based protocols to 5 or fewer in computer-based protocols
(50). With fewer parameters, they are more adaptable to differing
subsets of patients in an ICU and to local resources. Simplicity of use
makes them less prone to error. In a crossover study in which a
computer-based protocol was compared to the same paper-based
protocol in simulated scenarios for ICU nurses, there were signifi-
cantly fewer errors in the titration and transition phases of the
protocol (56).
The IR algorithms have been translated into various equations. The
proportional integral derivative computer protocol has only 4
parameters to define basic responses. It was used recently in an RCT
targeting normoglycemia in a pediatric cardiac ICU compared to
standard care (57). TGC was achieved with low hypoglycemia, but
neither morbidity nor mortality changed significantly (Table 2). The
enhanced Model Predictive Control (eMPC) is another computerized
protocol of the IR type that uses advanced control algorithms
designed by the Closed Loop Insulin Infusion for Critically Ill Patients
(CLINICIP) consortium. That protocol was compared to the Leuven
protocol in a recent RCT that also targeted normoglycemia in a mixed
ICU. The eMPC improved efficacy of TGC without increasing the
hypoglycemia rate (58). There are also 2 commercial electronic pro-
tocols based on IR algorithms: the EndoTool from Monarch Health-
Care (Irvine, CA) and the GlucoCare from Pronia Medical Systems
(Louisville, KY). In an RCT including 300 patients in an ICU, the
EndoTool protocol was compared with the Portland protocol and
resulted in a higher percentage of BG levels in the target range,
reduced GV and produced higher satisfaction rates for nurses (59).
The computerization of the Yale protocol within the GlucoCare sys-
tem produced a very low incidence of hypoglycemia, and those epi-
sodes that were reported were caused mainly by the decreased
frequency of BG testing and by staff failing to comply with the protocol
(60).
Paul Davidson translated the MR algorithm into a simple
equation: Insulin/Hour ¼ Multiplier  (BGe60), where BG is in
mg/dL and Multiplier is the factor of insulin resistance. He devised
the Glucommander computer program, which adjusts the multi-
plier to reach target glucose. This program has been tested exten-
sively in differing environments with excellent results, and many
centres have adapted the original equation in their hospital infor-
matics systems to achieve BG control. As shown in Table 2, the
implementation of the Glucommander in a cardiac surgery ICU was
highly effective in normalizing glucose without hypoglycemia (61).
However, the adaptation of this protocol at the Sunnybrook Health
Sciences Centre in Toronto produced a reduction in mean BG levels
with an increase in hypoglycemic episodes compared to a paper-
based protocol (62). Two commercial computer programs based
on this algorithm are available. Since 2006, the Glucommander
protocol has been marketed by Glytec (Greenville, SC), which has
extended the use of the protocol far beyond the ICU to include
many areas where IV insulin infusion is advised. The GlucoStabil-
izer program from Alere Informatics Solution (Waltham, MA) like
the Glytec solution, covers not only IV insulin infusion but also
subcutaneous insulin treatments. Using this IV protocol, Juneja et al
were able to reach the normoglycemia target in nearly all patients
and with a low incidence of hypoglycemia (Table 2). The delay in
measuring BG was a contributing factor in 67% of episodes of hy-
poglycemia (63).
There is currently no direct comparison study of the effectiveness,
nursing errors or hypoglycemic risks involved in the use of either
type of algorithm. However, systematic reviews of the computerized
protocols indicate that their implementation improves BG control
while keeping the rate of hypoglycemia stable or reducing the rate
(64,65). Although staff adherence to the protocol is easier with
computerized programs, delays in BG measurements remain a
potential problem. The recent use of accurate CGM and the devel-
opment of sophisticated mathematical algorithms for delivering IV
insulin make the fully automated closed-loop glucose control a
reality. Leelarathna et al demonstrated the feasibility of such a
system, based on a subcutaneous CGM and the MPC algorithm, in an
RCT of 24 patients in the ICU, comparing the closed-loop system with
the local paper-based protocol. They proved that the closed-loop
system, without nurse intervention, was efficacious and hypoglyce-
mia free, improving on the results of the usual therapy (66).
Complexity is unavoidable in flexible and efficient paper-based
IV insulin protocols, making them difficult to use in the busy
environment of the ICU. Computerization of these protocols, com-
bined with the use of CGM, appears to be the solution for optimal
management of hyperglycemia in ICUs in the future.
Conclusion
There is no doubt that dysglycemia is detrimental for patients in
ICUs or that it is necessary to treat it. However, there clearly are few
data on which to base firm conclusions concerning glucose levels to
target and algorithms to use for insulin infusion therapy. Despite
 J.-M. Boutin, L. Gauthier / Can J Diabetes 38 (2014) 144e150
controversies concerning the target ranges of blood glucose control
in ICUs, treatment of hyperglycemia in a safe fashion is essential,
and insulin infusion therapy should be tailored to match local
resources and subtypes of critically ill patients. The development of
accurate monitoring techniques and computerized algorithms of
insulin delivery should facilitate the achievement of this goal.
Acknowledgements
JMB received speaker fees and consulting fees from AstraZeneca,
Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, NovoNordisk
and Sanofi Aventis and consulting fees from Janssen. LG received
honoraria, speaker fees and consulting fees from Eli Lilly and
NovoNordisk and speaker fees from AstraZeneca, Bayer, Boehringer
Ingelheim, Bristol-Myers Squibb and Sanofi Aventis.
Author Contributions
JMB contributed to the literature review and wrote and edited
the manuscript. LG contributed to the literature review, produced
the tables and reviewed the manuscript.
References
1. Smith FG, Sheehy AM, Vincent JL, Coursin DB. Critical illness-induced dysgly-
caemia: diabetes and beyond. Crit Care 2010;14:327.
2. Wagstaff AE, Cheung NW. Diabetes and hyperglycemia in the critical care
setting: has the evidence for glycemic control vanished? (Or.is it going
away?). Curr Diab Rep 2014;14:444.
3. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in
critically ill patients. N Engl J Med 2001;345:1359e67.
4. Garber AJ, Moghissi ES, Bransome Jr ED, et al. American College of Endocri-
nology position statement on inpatient diabetes and metabolic control. Endocr
Pract 2004;10:77e82.
5. van den Berghe G. Intensive insulin therapy in the ICU: reconciling the
evidence. Nat Rev Endocrinol 2012;8:374e8.
6. Falciglia M, Freyberg RW, Almenoff PL, et al. Hyperglycemia-related mortality
in critically ill patients varies with admission diagnosis. Crit Care Med 2009;37:
3001e9.
7. Egi M, Bellomo R, Stachowski E, et al. Blood glucose concentration and outcome
of critical illness: the impact of diabetes. Crit Care Med 2008;36:2249e55.
8. van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the
medical ICU. N Engl J Med 2006;354:449e61.
9. Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in
paediatric intensive care: a prospective, randomised controlled study. Lancet
2009;373:547e56.
10. Preiser JC, Devos P, Ruiz-Santana S, et al. A prospective randomised multi-
centre controlled trial on tight glucose control by intensive insulin therapy
in adult intensive care units: the Glucontrol study. Intensive Care Med 2009;
35:1738e48.
11. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and penta-
starch resuscitation in severe sepsis. N Engl J Med 2008;358:125e39.
12. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control
in critically ill patients. N Engl J Med 2009;360:1283e97.
13. Finfer S, Liu B, Chittock DR, et al. Hypoglycemia and risk of death in critically ill
patients. N Engl J Med 2012;367:1108e18.
14. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of
Clinical Endocrinologists and American Diabetes Association consensus state-
ment on inpatient glycemic control. Diabetes Care 2009;32:1119e31.
15. Carey M, Boucai L, Zonszein J. Impact of hypoglycemia in hospitalized patients.
Curr Diab Rep 2013;13:107e13.
16. Bilotta F, Rosa G. Glycemia management in critical care patients. World J
Diabetes 2012;3:130e4.
17. Krinsley JS. Glycemic variability: a strong independent predictor of mortality in
critically ill patients. Crit Care Med 2008;36:3008e13.
18. Hermanides J, Vriesendorp TM, Bosman RJ, et al. Glucose variability is associ-
ated with intensive care unit mortality. Crit Care Med 2010;38:838e42.
19. Krinsley JS, Egi M, Kiss A, et al. Diabetic status and the relation of the three
domains of glycemic control to mortality in critically ill patients: an interna-
tional multicenter cohort study. Crit Care 2013;17:R37.
20. Sechterberger MK, Bosman RJ, Oudemans-van Straaten HM, et al. The effect of
diabetes mellitus on the association between measures of glycaemic control
and ICU mortality: a retrospective cohort study. Crit Care 2013;17:R52.
21. Meyfroidt G, Keenan DM, Wang X, et al. Dynamic characteristics of blood
glucose time series during the course of critical illness: effects of intensive
insulin therapy and relative association with mortality. Crit Care Med 2010;38:
1021e9.
149
22. King Jr JT, Goulet JL, Perkal MF, Rosenthal RA. Glycemic control and infections
in patients with diabetes undergoing noncardiac surgery. Ann Surg 2011;253:
158e65.
23. Kosiborod M, Inzucchi SE, Krumholz HM, et al. Glucose normalization and
outcomes in patients with acute myocardial infarction. Arch Intern Med 2009;
169:438e46.
24. Siegelaar SE, Hermanides J, Oudemans-van Straaten HM, et al. Mean glucose
during ICU admission is related to mortality by a U-shaped curve in surgical
and medical patients: a retrospective cohort study. Crit Care 2010;14:R224.
25. Friedrich JO, Chant C, Adhikari NK. Does intensive insulin therapy really reduce
mortality in critically ill surgical patients? A reanalysis of meta-analytic data.
Crit Care 2010;14:324.
26. Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and
mortality among critically ill patients: a meta-analysis including NICE-SUGAR
study data. CMAJ 2009;180:821e7.
27. Kansagara D, Fu R, Freeman M, et al. Intensive insulin therapy in hospitalized
patients: a systematic review. Ann Intern Med 2011;154:268e82.
28. Kramer AH, Roberts DJ, Zygun DA. Optimal glycemic control in neurocritical
care patients: a systematic review and meta-analysis. Crit Care 2012;16:
R203.
29. Ling Y, Li X, Gao X. Intensive versus conventional glucose control in critically ill
patients: a meta-analysis of randomized controlled trials. Eur J Intern Med
2012;23:564e74.
30. Marik PE, Preiser JC. Toward understanding tight glycemic control in the ICU: a
systematic review and metaanalysis. Chest 2010;137:544e51.
31. Ooi YC, Dagi TF, Maltenfort M, et al. Tight glycemic control reduces infection
and improves neurological outcome in critically ill neurosurgical and neuro-
logical patients. Neurosurgery 2012;71:692e702. discussion 702.
32. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in
critically ill adults: a meta-analysis. JAMA 2008;300:933e44.
33. Klonoff DC. Intensive insulin therapy in critically ill hospitalized patients:
making it safe and effective. J Diabetes Sci Technol 2011;5:755e67.
34. Jacobi J, Bircher N, Krinsley J, et al. Guidelines for the use of an insulin infusion
for the management of hyperglycemia in critically ill patients. Crit Care Med
2012;40:3251e76.
35. Cembrowski GS, Tran DV, Slater-Maclean L, et al. Could susceptibility to low
hematocrit interference have compromised the results of the NICE-SUGAR
trial? Clin Chem 2010;56:1193e5.
36. Inoue S, Egi M, Kotani J, Morita K. Accuracy of blood-glucose measurements
using glucose meters and arterial blood gas analyzers in critically ill adult
patients: systematic review. Crit Care 2013;17:R48.
37. van den Berghe G, Schetz M, Vlasselaers D, et al. Clinical review: intensive
insulin therapy in critically ill patients: NICE-SUGAR or Leuven blood glucose
target? J Clin Endocrinol Metab 2009;94:3163e70.
38. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition
in critically ill adults. N Engl J Med 2011;365:506e17.
39. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: interna-
tional guidelines for management of severe sepsis and septic shock: 2012. Crit
Care Med 2013;41:580e637.
40. Lazar HL, McDonnell M, Chipkin SR, et al. The Society of Thoracic Surgeons
practice guideline series: blood glucose management during adult cardiac
surgery. Ann Thorac Surg 2009;87:663e9.
41. Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest care:
2010 American Heart Association guidelines for cardiopulmonary resuscitation
and emergency cardiovascular care. Circulation 2010;122:S768e86.
42. Houlden R, Capes S, Clement M, Miller D. In-hospital management of diabetes.
Can J Diabetes 2013;37:S77e81.
43. Schultz MJ, Harmsen RE, Korevaar JC, et al. Adoption and implementation of
the original strict glycemic control guideline is feasible and safe in adult crit-
ically ill patients. Minerva Anestesiol 2012;78:982e95.
44. Finfer S, Wernerman J, Preiser JC, et al. Clinical review: consensus recom-
mendations on measurement of blood glucose and reporting glycemic control
in critically ill adults. Crit Care 2013;17:229.
45. Krinsley J, Bochicchio K, Calentine C, Bochicchio G. Glucose measurement of
intensive care unit patient plasma samples using a fixed-wavelength mid-
infrared spectroscopy system. J Diabetes Sci Technol 2012;6:294e301.
46. Schierenbeck F, Owall A, Franco-Cereceda A, Liska J. Evaluation of a continuous
blood glucose monitoring system using a central venous catheter with an
integrated microdialysis function. Diabetes Technol Ther 2013;15:26e31.
47. O’Malley CW, Emanuele M, Halasyamani L, Amin AN. Society of Hospital
Medicine Glycemic Control Task Force. Bridge over troubled waters: safe and
effective transitions of the inpatient with hyperglycemia. J Hosp Med 2008;3:
55e65.
48. Meijering S, Corstjens AM, Tulleken JE, et al. Towards a feasible algorithm for
tight glycaemic control in critically ill patients: a systematic review of the
literature. Crit Care 2006;10:R19.
49. Braithwaite SS, Clement S. Algorithms for intravenous insulin delivery. Curr
Diabetes Rev 2008;4:258e68.
50. Steil GM, Deiss D, Shih J, et al. Intensive care unit insulin delivery algorithms:
why so many? how to choose? J Diabetes Sci Technol 2009;3:125e40.
51. Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intra-
venous insulin infusions on outcomes of cardiac surgical procedures: the
Portland Diabetic Project. Endocr Pract 2004;10(Suppl 2):21e33.
52. Goldberg PA, Siegel MD, Sherwin RS, et al. Implementation of a safe and
effective insulin infusion protocol in a medical intensive care unit. Diabetes
Care 2004;27:461e7.
150 J.-M. Boutin, L. Gauthier / Can J Diabetes 38 (2014) 144e150
53. Shetty S, Inzucchi SE, Goldberg PA, et al. Adapting to the new consensus
guidelines for managing hyperglycemia during critical illness: the updated Yale
insulin infusion protocol. Endocr Pract 2012;18:363e70.
54. Markovitz LJ, Wiechmann RJ, Harris N, et al. Description and evaluation of a
glycemic management protocol for patients with diabetes undergoing heart
surgery. Endocr Pract 2002;8:10e8.
55. Braithwaite SS, Edkins R, Macgregor KL, et al. Performance of a dose-defining
insulin infusion protocol among trauma service intensive care unit admis-
sions. Diabetes Technol Ther 2006;8:476e88.
56. Lee A, Faddoul B, Sowan A, et al. Computerisation of a paper-based
intravenous insulin protocol reduces errors in a prospective crossover
simulated tight glycaemic control study. Intensive Crit Care Nurs 2010;26:
161e8.
57. Agus MS, Steil GM, Wypij D, et al. Tight glycemic control versus standard care
after pediatric cardiac surgery. N Engl J Med 2012;367:1208e19.
58. Van Herpe T, Mesotten D, Wouters PJ, et al. LOGIC-insulin algorithm-guided
versus nurse-directed blood glucose control during critical illness: the
LOGIC-1 single-center, randomized, controlled clinical trial. Diabetes Care
2013;36:188e94.
59. Dumont C, Bourguignon C. Effect of a computerized insulin dose calculator on
the process of glycemic control. Am Crit Care 2012;21:106e15.
60. Marvin MR, Inzucchi SE, Besterman BJ. Computerization of the Yale insulin
infusion protocol and potential insights into causes of hypoglycemia with
intravenous insulin. Diabetes Technol Ther 2013;15:246e52.
61. Davidson PC, Steed RD, Bode BW, et al. Use of a computerized intravenous
insulin algorithm within a nurse-directed protocol for patients undergoing
cardiovascular surgery. J Diabetes Sci Technol 2008;2:369e75.
62. Yamashita S, Ng E, Brommecker F, et al. Implementation of the glucommander
method of adjusting insulin infusions in critically ill patients. Can J Hosp Pharm
2011;64:333e9.
63. Juneja R, Roudebush CP, Nasraway SA, et al. Computerized intensive insulin dosing
can mitigate hypoglycemia and achieve tight glycemic control when glucose
measurement is performed frequently and on time. Crit Care 2009;13:R163.
64. Eslami S, Abu-Hanna A, de Jonge E, de Keizer NF. Tight glycemic control and
computerized decision-support systems: a systematic review. Intensive Care
Med 2009;35:1505e17.
65. Hoekstra M, Vogelzang M, Verbitskiy E, Nijsten MW. Health technology
assessment review: computerized glucose regulation in the intensive care unit:
how to create artificial control. Crit Care 2009;13:223.
66. Leelarathna L, English SW, Thabit H, et al. Feasibility of fully automated closed-
loop glucose control using continuous subcutaneous glucose measurements in
critical illness: a randomized controlled trial. Crit Care 2013;17:R159.