Download Glucose Control and Monitoring in the ICU

Glucose Control and Monitoring in the ICU
C. De Block and P. Rogiers
Introduction
Recently, stress hyperglycemia, occurring in the vast majority of critically ill
patients, has become a major therapeutic target in the intensive care unit (ICU).
Stress associated with critical illness induces the release of counter-regulatory hormones. In addition, several clinical interventions, such as administration of corticosteroids, enteral or parenteral nutrition, or dialysis, further predispose patients to
hyperglycemia. Moreover, in critical illness, changes in carbohydrate metabolism
occur resulting in insulin resistance and relative insulin deficiency.
Hyperglycemia is associated with adverse outcomes, not only after myocardial
infarction, cardiothoracic surgery, and stroke, but also in the ICU. Achieving normoglycemia appears crucial to obtaining the benefits of insulin therapy, which
include a reduced incidence of acute renal failure, accelerated weaning from
mechanical ventilation, and accelerated discharge from the ICU and hospital. In
addition, it is a cost-effective intervention. However, the advantages of normoglycemia must be weighed against the increased risk of hypoglycemia.
Obtaining normoglycemia requires considerable nursing effort, including frequent glucose monitoring and adjustment of insulin dose. Moreover, the inherent
clinical perturbations of critically ill patients (fluctuating severity of illness, changes
in nutritional delivery, off-unit visits to diagnostic imaging) produce frequent
changes in insulin requirements. Current insulin titration is based on discontinuous
glucose measurements, which may miss fast changes in glycemia. In a pilot study
using continuous glucose monitoring, we observed that insulin therapy based on
discontinuous glucose measurements failed to maintain normoglycemia in most
subjects [1]. Similar to the continuous, online display of blood pressure and cardiac
output for optimal titration of inotropes and vasopressors, continuous glucose monitoring, using a well-tolerated and accurate device, may help to signal changes in
glycemia and to optimize titration of insulin therapy in the ICU.
Prevalence of Stress Hyperglycemia
Stress-induced hyperglycemia is very common in the ICU, being present in 50 – 85 %
of critically ill patients (Table 1) [1 – 22]. However, true prevalence of stress-induced
hyperglycemia is difficult to assess because there are discrepancies in definitions,
particularly regarding the cut-off level by which one defines hyperglycemia, in the
homogeneity of study populations with in/exclusion of diabetic patients, in severity
of illness, and in the timing of blood glucose sampling. In general, up to 25 – 30 % of
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Table 1. Prevalence of stress hyperglycemia in the ICU
Van den Berghe et al. [2]
Egi et al. [3]
Van den Berghe et al. [4]
Ligtenberg et al. [5]
Cely et al. [6]
De Block et al. [1]
Finney et al. [7]
Freire et al. [8]
Christiansen et al. [9]
Krinsley et al. [10]
Umpierrez et al. [11]
Whitcomb et al. [12]
Zimmerman et al. [13]
Latham et al. [14]
Swenne et al. [15]
Yendamuri et al. [16]
Laird et al. [17]
Sung et al. [18]
Wintergerst et al. [19]
Faustino and Apkon [20]
Srinivasan et al. [21]
ICU type
number
of
patients
surgical ICU
surgical ICU
medical ICU
medical ICU
medical ICU
medical ICU
mixed ICU
mixed ICU
mixed ICU
mixed ICU
mixed ICU
mixed ICU
cardiothoracic ICU
cardiothoracic ICU
cardiothoracic ICU
trauma ICU
trauma ICU
trauma ICU
pediatric ICU
pediatric ICU
pediatric ICU
1548
783
1200
1085
100
50
523
1185
135
1826
239
2713
342
984
374
738
516
1003
980
942
152
definition of hyperglycemic
hyperglycemia patients (%)
(mg/dl)
8 110
8 110
8 110
8 180
8 110
8 110
8 110
8 110
8 110
8 120
8 126
8 200
8 150
8 200
8 120
8 135
8 110
8 200
8 110
8 120
8 126
75
81
8 85
28
64
74
8 85
59
100
42
56
27
50
29
95
25
94
25
87
75
86
patients admitted to the ICU have diabetes, and up to one third of critically ill
patients present with previously unrecognized diabetes or glucose intolerance [23].
Etiology of Stress Hyperglycemia (Fig. 1)
The onset of stress hyperglycemia in critical illness is driven by excessive release of
counter-regulatory hormones (glucagon, growth hormone, catecholamines, glucocorticoids) and cytokines (interleukin [IL]-1, IL-6 and tumor necrosis factor [TNF]- [ )
[24 – 26]. Counter-regulatory hormones inhibit hepatic glycogenesis and peripheral
glycolysis while promoting gluconeogenesis, hepatic and muscle glycogenolysis, and
peripheral lipolysis. Pro-inflammatory cytokines such as TNF- [ , IL-1, and IL-6 may
induce a state of peripheral and hepatic insulin resistance, and stimulate the hypothalamic-pituitary-adrenal axis.
In addition, several conditions may promote hyperglycemia during stress. These
include diabetes, obesity, cirrhosis (which impairs glycogen storage), pancreatitis
(insulin deficiency), increasing severity of illness, hypokalemia (impairs insulin
secretion), bed rest and advancing age. Bed rest leads to peripheral insulin resistance via impaired skeletal muscle glucose uptake combined with increased fasting
plasma insulin concentrations. In addition, several clinical interventions can worsen
this picture, including administration of dextrose, enteral or parenteral nutrition, or
drugs (corticosteroids, thiazide diuretics, phenytoin, phenothiazines, vasopressors),
and dialysis [26, 27]. Moreover, alterations in carbohydrate metabolism contribute to
the development of stress hyperglycemia [25, 28]. Hepatic glucose output is augmented more than two-fold in critical illness via increased gluconeogenesis and gly-
Glucose Control and Monitoring in the ICU
Fig. 1. Etiology of stress hyperglycemia – IL: interleukin; TNF: tumor necrosis factor
cogenolysis. Insulin resistance is characterized by increased hepatic glucose output,
less insulin action in muscle (reduction of glucose uptake, glucose oxidation, glycogen synthesis and protein anabolism) and in adipocytes (increased lipolysis rate
with consequently higher availability of free fatty acids and glycerol) and impaired
insulin secretion.
Adverse Effects of Hyperglycemia
Manifest hyperglycemia promotes osmotic diuresis with hypovolemia and electrolyte abnormalities including hypokalemia, hypomagnesemia, and hypophosphatemia. Hyperglycemia may also worsen catabolism in skeletal muscle. Other mechanisms to explain the relationship between stress hyperglycemia and morbidity
include an attenuated host defence, increased inflammatory cytokines, increased
coagulability, endothelial dysfunction, increased oxidative stress, and changes in
myocardial metabolism due to altered substrate availability [26 – 30].
Hyperglycemia adversely affects immune function and increases susceptibility to
infection [31]. Hyperglycemia may also impair fibrinolysis and platelet function,
which lead to hypercoagulability and an increased risk of thrombotic events [28, 29].
Moreover, glucose causes abnormalities in vascular reactivity and endothelial dysfunction. Endothelial dysfunction may result in a compromised microcirculation.
Subsequent cellular hypoxia contributes to the risk of organ failure and death in critically ill patients [32].
In addition to cellular glucose overload, vulnerability to glucose toxicity may be
due to increased generation and deficient scavenging of reactive oxygen species
(ROS) produced by glycolysis and oxidative phosphorylation. Hyperglycemia-
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induced mithochondrial overproduction of superoxide activates the four pathways
(polyol pathway, protein kinase C activation, production of advanced glycation
products, increased hexosamine pathway) involved in the pathogenesis of diabetic
complications [33]. Hyperglycemia is also associated with increased levels of free
fatty acids (FFA) which may 1) affect endothelial nitric oxide (NO) production,
thereby impairing endothelium-dependent vasodilation; 2) increase myocardial oxygen requirements and thus ischemia; 3) decrease myocardial contractility; and 4)
induce cardiac arrhythmias [30, 34]. Furthermore high FFA concentrations may
increase ROS generation in mononuclear cells and induce insulin resistance in myocytes and hepatocytes. FFA excess has numerous consequences, called lipotoxicity,
which is a critical feature of multi-organ failure (MOF) [35].
Beneficial Effects of Insulin and of Normoglycemia (Fig. 2)
The multiple potential benefits of insulin infusion during acute illness include a
reduction in hyperglycemia via enhanced insulin-mediated glucose transport and
via decreased hepatic glucose production, anabolic effects, positive influences on
immune function, suppression of ROS generation, and positive effects on the endothelium and on hepatocytic mitochondrial ultrastructure and function [23].
First, insulin lowers blood glucose predominantly by increasing glucose uptake in
insulin-sensitive tissues, particularly skeletal muscle [28]. Insulin also decreases
hepatic glucose production by stimulating glycogen synthesis and by suppressing
gluconeogenesis [25, 29]. Second, insulin has anabolic actions; it promotes muscle
protein synthesis and inhibits lipolysis. Insulin may also provide myocardial protec-
Fig. 2 Beneficial effects of insulin. Tx: thromboxane; HDL: high density lipoprotein; IL: interleukin; TNF: tumor
necrosis factor; NOS: nitric oxide synthase; CRP: c-reactive protein; PAI: plasminogen activator inhibitor
Glucose Control and Monitoring in the ICU
tion during ischemia by suppressing FFAs and increasing availability of glucose as a
myocardial substrate. In addition, insulin itself has direct cardioprotective effects
during reperfusion, mainly via anti-apoptotic properties [28]. Third, intensive insulin therapy partially restores the dyslipidemia present in critically ill patients, which
explains part of the beneficial effect on mortality and organ failure [35]. Fourth,
insulin has a key inhibitory role in the regulation of inflammatory growth factors,
which are central to atherogenesis, plaque rupture, and thrombosis, the final events
which precipitate acute myocardial or cerebral ischemia and infarction. Insulin also
reduces thromboxane A2 production and plasminogen activator inhibitor-1 (PAI-1)
activity, thereby decreasing platelet aggregation and increasing fibrinolysis [28, 29].
Fifth, insulin protects the endothelium via inhibition of excessive inducible NO synthase (iNOS)-generated release of NO [32]. Low NO concentrations generated by
endothelial NOS are beneficial for the endothelium and organ function, whereas
high NO levels, generated via iNOS may lead to endothelial dysfunction and tissue
injury. On platelets, insulin exerts an anti-aggregatory action via induction of NO.
Sixth, in euglycemic conditions, insulin appears to inhibit pro-inflammatory cytokines (TNF- [ , IL-1, IL-6,) and adhesion molecules (soluble intercellular adhesion
molecule-1), in addition to C-reactive protein [25]. TNF- [ causes endothelial dysfunction and apoptosis, triggers procoagulant activity and fibrin deposition, and
enhances NO synthesis in a variety of cells. Alternatively, prevention of hyperglycemia may contribute. Insulin also enhances the production of the anti-inflammatory
cytokines, IL-10 and IL-4. Seventh, insulin suppresses ROS generation [25]. Finally,
strict glycemic control with intensive insulin therapy prevents or reverses ultrastructural and functional abnormalities of hepatocytic mitochondria [36]. Mitochondrial
dysfunction and the associated bioenergetic failure are regarded as factors contributing to MOF, the most common cause of death in the ICU.
Whether achieving strict normoglycemia or the administration of insulin is the
decisive factor explaining the wide range of clinical benefits is still open to discussion. Strict control of hyperglycemia seems to be of paramount importance [2, 4, 7,
10]. A post hoc analysis of the Leuven study [2] revealed a linear correlation
between the degree of hyperglycemia and the risk of death, which persisted after
correction for insulin dose and severity of illness [27]. Patients in the conventional
insulin treatment group who showed only moderate hyperglycemia (110 – 150 mg/dl
or 6.1 – 8.3 mmol/l) had a lower risk of death than those with frank hyperglycemia
(150 – 200 mg/dl) but a higher risk of death than those who were intensively treated
with insulin to restore blood glucose levels to below 110 mg/dl. Similarly, for the
prevention of morbidity (bacteremia, anemia, and particularly critical illness polyneuropathy), it appeared crucial to reduce glycemia to ‹ 110 mg/dl. For the prevention of acute renal failure, insulin dose was an independent determinant. From all
these data it is clear that the clinical benefits seen in critically ill patients are not just
due to one single phenomenon. Many pathways may play a role; some of them being
more dependent on achieving normoglycemia, whereas others are likely to be
affected by non-glycemic, and even non-metabolic, effects of insulin.
Clinical Evidence for Achieving Normoglycemia in the ICU
In a variety of clinical settings, stress hyperglycemia has been shown to negatively
affect patient morbidity and mortality. Even without a prior diagnosis of diabetes
mellitus, hyperglycemia independently predicted poor outcome for patients sustain-
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ing myocardial infarction [37 – 39], cardiothoracic surgery [2, 13, 22, 31, 40], stroke
[41 – 43], or trauma [16 – 18].
Patients undergoing Cardiovascular and Cardiothoracic Surgery
Following acute myocardial infarction, hyperglycemia predicted increased rates of
congestive heart failure, cardiogenic shock, and death [37 – 39]. A meta-analysis of
15 studies including over 6,000 patients, showed that among critically ill non-diabetic patients sustaining myocardial infarction, those with glucose levels in the
range of 110 – 140 mg/dl had an almost 4-fold higher risk of death than patients who
had lower glucose values [37].
Patients undergoing cardiothoracic surgery with concurrent perioperative hyperglycemia have increased morbidity rates including wound and sternal infection,
pneumonia and urinary tract infection, and perioperative mortality rates [2, 13 – 15,
22, 31]. Insulin therapy to maintain blood glucose ‹ 150 – 200 mg/dl halved the rate
of deep surgical site infections (mediastinitis, deep sternal, vein donor site) [22, 31].
Continuous insulin infusion therapy reduced absolute mortality by 57 % [22]. In
another study, tight glycemic control in diabetic patients undergoing coronary
artery bypass grafting (CABG) lowered the incidence of atrial fibrillation, decreased
recurrent ischemic events, and shortened postoperative length of stay [40].
Stroke Patients
Hyperglycemia has been reported to increase infarct size, worsen functional outcome, lengthen in-hospital stay and increase hospital charges [41 – 43]. A meta-analysis of 32 observational studies found that after stroke of either subtype (ischemic or
hemorrhagic), admission glycemia of 110 – 144 mg/dl (6.1 – 8.0 mmol/l) was associated with a 3-fold increased risk of in-hospital 30-day mortality in non-diabetic
patients and a 1.3-fold increased risk in diabetic patients [41]. Acute and final
infarct volume change and outcome were negatively affected in patients with mean
blood glucose levels & 126 mg/dl (7 mmol/l) as measured by conventional and continuous glucose monitoring [42].
Trauma Patients
In trauma patients, hyperglycemia proved to be an independent predictor of mortality and of in-hospital and ICU length of stay, when controlling for age, injury severity score, and gender [16 – 18, 44]. In addition, infectious complications, including
pneumonia, urinary tract infections, wound infections, and bacteremia, were significantly increased in hyperglycemic patients [16, 18, 44]. Ventilator days were also
higher in patients with hyperglycemia [44].
Critically Ill Patients Admitted to the Intensive Care Unit
The landmark study of Van den Berghe et al. [2] in a surgical ICU (n = 1,548),
mainly composed of cardiothoracic surgery patients, showed that intensive insulin
therapy aimed at maintaining glycemia between 80 – 110 mg/dl reduced the overall
in-hospital mortality by 34 %, blood stream infections by 46 %, acute renal failure
requiring dialysis or hemofiltration by 41 %, critical illness polyneuropathy by 44 %,
and transfusion requirements by 50 %. It also reduced the need for prolonged
Glucose Control and Monitoring in the ICU
mechanical ventilatory support, and the length of ICU stay. The benefit of intensive
insulin therapy was particularly apparent among patients requiring intensive care
for more than 5 days [2].
In the medical ICU study by the same group, comprising 1,200 patients, intensive
insulin therapy significantly reduced the incidence of newly acquired renal failure,
accelerated weaning from mechanical ventilation, and accelerated discharge from
the ICU and the hospital [4]. In contrast to patients in the surgical ICU, those in the
medical ICU had no significant reduction in bacteremia, which may be explained by
the fact that among medical ICU patients sepsis often triggers admission to the ICU.
In addition, in-hospital mortality was only reduced among patients staying in the
ICU for & 3 days. Most likely, the beneficial effects of intensive insulin therapy
require time to be realized. Indeed, the intervention is not aimed at curing disease,
but at preventing complications. In addition, the potential benefit of glucose regulation may be small because of the high mortality caused by the underlying diseases.
In a retrospective review of 1,826 critically ill medical and surgical patients,
the lowest hospital mortality occurred in patients with mean glycemia between
80 – 99 mg/dl [10]. Importantly, there was no difference in mortality based on the
presence or absence of diabetes. Independent predictors of mortality were APACHE
II score and glycemia. In an extension study including 1,600 patients, Krinsley noted
a 75 % reduction in newly acquired renal insufficiency, a 19 % reduction in the number of patients undergoing transfusion of packed red blood cells, a 11 % decreased
length of stay in the ICU and a 29 % reduction in mortality in patients treated with
intensive insulin therapy [45]. Insulin therapy in this study aimed to reach glucose
values ‹ 140 mg/dl. However, no mortality benefit of intensive insulin therapy was
apparent in patients with APACHE II scores & 35 [45]. In patients with acute respiratory distress syndrome (ARDS), hyperglycemia was associated with critical illness
polyneuropathy and myopathy, causing prolonged mechanical ventilation and ICU
stay [46].
In another prospective ICU single center study including 531, mainly cardiothoracic, patients, Finney et al. observed a mortality benefit with a speculative upper
limit of 145 mg/dl for the target blood glucose level [7]. In a retrospective study of
7,049 critically ill patients, not only mean glycemia, but also the variability of blood
glucose concentration, were independent predictors of ICU and in-hospital mortality [47]. The authors, therefore, suggested that reducing the variability of glycemia
might be an important aspect of glucose management.
It is not clear whether the relation between acute hyperglycemia and increased
mortality risk is consistent for all critically ill patients. In the study by Umpierrez et
al. the mortality rate for newly hyperglycemic patients in the ICU approached one in
three [11]. Freire et al., studying 1,185 medical ICU patients, did not find admission
hyperglycemia to independently predict in-hospital mortality [8]. Ligtenberg et al.,
retrospectively studying 1,085 consecutive patients admitted to a mixed ICU, suggested that higher glucose levels reflect disease severity, but are not an independent
risk factor for mortality [5]. Whitcomb et al., reviewing records from 2,713 ICU
patients, concluded that the association between admission hyperglycemia and inhospital mortality was not uniform. Hyperglycemia was an independent risk factor
only in patients without a history of diabetes in the cardiac, cardiothoracic, and neurosurgical ICUs [12]. In a retrospective study of 783 surgical ICU patients, Egi et al.
calculated that the number needed to treat to prevent an ICU death varied between
38 and 125, at the cost of approximately 9 cases of hypoglycemia. This wide variation
in number needed to treat depended on baseline mortality and case selection [3].
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At the latest Scientific Sessions of the American Diabetes Association, Falciglia et
al. presented data on 216,775 critically ill patients and confirmed that hyperglycemia
was an independent predictor of mortality in the medical, surgical and cardiac ICU,
starting at 1 mg/dl above normal glucose levels (111 mg/dl). The impact of hyperglycemia on mortality was variable but was most pronounced in stroke patients (relative risk 3.4 – 15.1), followed by acute myocardial infarction patients (relative risk
1.6 – 5.0). A weaker impact was seen in sepsis, pneumonia, and pulmonary embolism. However, in some conditions such as chronic obstructive pulmonary disease
and liver failure, glycemia seemed not to affect mortality. The effects seen were also
greatest in patients without diagnosed diabetes.
In contrast to the above-mentioned trials, the multicenter German study (the
VISEP trial), designed to randomize 600 subjects with medical or surgical severe
sepsis to conventional or intensive insulin therapy, was stopped after recruitment of
488 subjects because of no difference in mortality and frequent hypoglycemia in the
intensive insulin therapy arm (12.1 vs 2.1 %) [48]. However, the experimental design
failed to exclude confounding variables by not controlling for conventional aspects
of sepsis care (antibiotics, resuscitation, mechanical ventilation). The results of
ongoing multicenter studies (Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation [NICE-SUGAR] enrolling 3,500 patients
in Europe, and the Comparing the Effects of Two Glucose Control Regimens by Insulin in Intensive Care Unit Patients [GLUCONTROL] enrolling 1,500 pateints in Australia, New Zealand and Canada) are anticipated in 2007.
Aggressive treatment of hyperglycemia with insulin may, however, be limited by
an increased risk of hypoglycemia. Recognition of hypoglycemia in a patient who is
receiving sedatives and analgesics with or without neuromuscular blocking agents in
the ICU is problematic, potentially leaving the hypoglycemic state unappreciated for
a critical period before treatment. In addition, the response to hypoglycemia may be
blunted in critical illness. The reported rates of hypoglycemia vary between 0 – 30 %,
but differences as to its precise definition make comparisons difficult. The VISEP
study was stopped prematurely because of this increased hypoglycemia risk [48].
Interestingly, despite the obvious increase in hypoglycemic events, no adverse clinical outcomes associated with hypoglycemia have been reported in any of the studies.
Hemodynamic deterioration, convulsions, or other events were not noted during
hypoglycemic episodes. Independent risk factors for hypoglycemia, aside from
intensive insulin therapy, include a prolonged ICU stay ( 8 3 days), renal failure
requiring dialysis, and liver failure [4]. In addition, there is always the possibility of
the occasional human error. Insufficient frequency of glucose monitoring may also
contribute.
Pediatric ICU
In the retrospective study of Wintergerst et al. including 980 non-diabetic pediatric
ICU patients, 87 % of subjects had blood glucose levels 8 110 mg/dl. In their study,
not only hyperglycemia, but also increased glucose variability and hypoglycemia
were associated with increased length of stay and mortality [19]. Faustino and
Apkon, studying 942 non-diabetic PICU patients, found a correlation between mortality risk, length of stay and hyperglycemia [20]. Srinivasan et al. showed that peak
blood glucose and duration of hyperglycemia were independent predictors of mortality in a group of pediatric ICU patients receiving vasoactive infusions or mechanical ventilation [21].
Glucose Control and Monitoring in the ICU
Management of Hyperglycemia
The preponderance of stress-hyperglycemia has encouraged intensivists to apply
early, tight glycemic control without a complete understanding of when (threshold),
in whom (population), and how early (timing), this intervention should be started.
Also the optimal level of glycemic control is not known. The first step in the management of stress hyperglycemia is to identify and treat the most common precipitating causes. Second, the patient population in which insulin therapy might benefit,
should be clearly defined. Third, consensus should be obtained regarding the target
level of glycemia. Fourth, glycemic excursions should be carefully monitored, preferably on a continuous base, and a comprehensive, validated, easily implementable
insulin infusion protocol should be provided.
In which Patients should Intensive Insulin Therapy be Applied
and What is the Target Glycemic Level?
The risk/benefit ratio for intensive insulin therapy may change according to baseline
mortality, patient selection, and ICU type (e.g., post-cardiac surgery ICU, neurologic
ICU, trauma ICU, medical ICU) as shown by Whitcomb et al. [12]. Thus, different
ICUs should carefully consider formal decision analysis of the possible benefits and
risks of intensive insulin therapy before implementing such a protocol.
The Surviving Sepsis Campaign guidelines recommend maintaining a blood
glucose level of ‹ 150 mg/dl in patients with severe sepsis [49]. Finney et al.
observed the best survival when mean glycemia was between 110 – 145 mg/dl [7],
whereas Krinsley observed the lowest hospital mortality in patients with mean glycemia between 80 – 99 mg/dl [10]. The target glycemia in the Leuven studies was
80 – 110 mg/dl [2, 4]. The American Diabetes Association and the American College of Endocrinology have issued guidelines recommending in-hospital intensive
insulin therapy to maintain preprandial blood glucose levels at e 110 mg/dl and
postprandial glycemia ‹ 180 mg/dl in critical care patients [50]. The preferred
method of insulin administration in critical illness is continuous insulin infusion
using a dynamic scale protocol with frequent blood glucose measurements. Data are
difficult to interpret because of the diverse clinical settings, the varying methods of
insulin administration, and the different targets and timing of glycemic control.
While any single cut-off value by definition is arbitrary, we and others believe that
we should aim for a blood glucose that is as near to normal as is safe and practical.
The potential for improvement in ICU patient outcomes, combined with a low-cost
drug, make intensive insulin therapy an attractive option.
Glucose Control and Monitoring in the ICU
Insulin requirements vary widely in patients depending on insulin production
reserves, insulin sensitivity, caloric intake in the ICU, the nature and fluctuating
severity of the underlying illness and the administration of medications. The need
for a protocol to guide the prescribing and monitoring of insulin infusions is evident
due to the significant heterogeneity and dissatisfaction with current insulin infusions. The analysis of the correct amount of insulin to be administered requires a
relatively high degree of skill, and this expert assessment will need frequent revision
as the clinical situation changes. Therefore, the physician who may be most knowledgeable about the optimal methods of administration of insulin (the endocrinolo-
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gist) should be a member of the team caring for a critically ill patient. Goldberg et
al. proposed an insulin infusion protocol that was based primarily on the velocity of
glycemic change rather than on absolute blood glucose levels, and on the current
insulin infusion rate [51]. The complexity of an insulin infusion protocol requires at
least a 2-to-1 patient-to-nurse ratio.
There are many obstacles to implementing insulin infusion protocols in an ICU.
Insulin infusion protocols add significantly to the work of managing ICU patients.
Every hour, the nurse must perform a glucose measurement, document the results,
and make the necessary adjustments to the insulin drip. This process may take up to
3 – 5 minutes every hour (2 hours per day). Moreover, a prevalent fear of hypoglycemia may hinder the widespread acceptance of intensive insulin infusion protocols.
Training, education and continuing feedback is necessary to motivate ICU nurses.
Kanji et al. showed that standardization of i.v. insulin therapy improved the efficiency and safety of glycemic control in critically ill adults, improved nursing acceptance, but also increased the workload as 35 % more glucose measurements were
required with the intensive insulin protocol [52].
In the future, the development of a closed-loop control system that automatically
regulates the dose of insulin based on glucose measurements could permit tight glycemic control without increasing the workload of the nursing staff. An accurate continuous glucose monitoring system combined with an algorithm for calculation of
the appropriate insulin infusion rate are pre-requisites for the establishment of such
an automated glycemic control system. Plank et al. observed that compared with
routine protocols, treatment according to a fully automated model predictive control
algorithm resulted in a significantly higher percentage of time within the target glycemic range (80 – 110 mg/dl) [53].
How to Evaluate Glycemic Control in the ICU?
An objective measure of hyperglycemia for assessing glucose control in acutely ill
patients should reflect the magnitude and duration of hyperglycemia. In studies of
acutely ill patients, regular indices of glucose regulation that have been used are
admission glucose, maximum glucose, and mean glucose. However, they are based
on either a single measurement or on a subset of measurements, and, therefore, they
are not indicative of overall glycemia. Just as we prefer continuous, online display of
blood pressure and/or cardiac output for optimal titration of inotropes and vasopressors, a continuous display of blood glucose levels seems mandatory for optimal
titration of insulin therapy in the ICU [54, 55].
Continuous Glucose Monitoring in the ICU
Strict glycemic control improves clinical outcomes in critically ill patients. In addition, reducing variability in blood glucose concentrations might be an important
aspect of glucose management [47]. Implementation of strict glycemic control in
daily ICU practice may be facilitated by a continuous glucose monitor.
Current continuous glucose monitoring systems measure interstitial glucose concentrations. However, previously published data on the reliability of continuous glucose monitoring systems in diabetic patients cannot be automatically transferred to
a different situation like intensive care, where many variables can interfere with performance of such systems (e.g., subcutaneous edema, hypotension, vasoactive
Glucose Control and Monitoring in the ICU
drugs). A precise evaluation of the accuracy of the system and the quality of sensor
performance in the ICU setting is necessary, and must represent the premise of
every clinical or research utilization of these devices. The following requirements
have to be met by continuous glucose monitoring systems: 1) immediate availability
of the measurement result, 2) high frequency of measurements, 3) fast sensor signal
stability after application and over time [56].
Current continuous glucose monitoring systems measure glucose in the interstitial fluid. Under physiological conditions there is a free and rapid exchange of glucose molecules between blood plasma and interstitial fluid and, for this reason,
changes in blood glucose and interstitial fluid glucose are strongly correlated [56].
Nevertheless, changes of glucose concentrations in interstitial fluid lag behind those
in the blood. The lag time seems to be consistent, irrespective of increments/decrements in glycemia and insulin levels. In the ICU setting, the hemodynamic alterations encountered (hypotension, shock, vasopressor or inotropic need) did not
affect accuracy [1, 57]. Such variables would rather affect the process of subcutaneous glucose recovery, resulting in a calibration issue, rather than in a sensor performance issue. This could be solved by frequent calibration [1]. Calibration should be
performed in times of glucose stability [56]. In any case, a lag time of ‹ 10 min is
clinically acceptable since online adjustment of insulin dose should be based on
immediate detection of unacceptable rates of change ( 8 25 mg/dl/h).
The Continuous Glucose Monitoring System® (CGMS, Medtronic Minimed, Northridge, CA, USA) is currently approved by the U.S. Food and Drug Administration (FDA)
as a ‘retrospective’ Holter-style glucose monitor. It is a percutaneous ‘needle-type’ sensor, measuring glucose in the interstitial fluid every 5 minutes for up to 72 hours. The
GlucoDay® device (A. Menarini Diagnostics, Florence, Italy) is based on the microdialysis technique that measures glucose concentrations in the dialysate from subcutaneous
interstitial fluid. It is approved by the European Community (CE). Glucose concentrations are measured every 3 min by the glucose sensor over a 48-h period [1].
Only a few studies have used continuous glucose monitoring systems in critically
ill patients [1, 42, 57, 58]. In a pilot study, we investigated the accuracy and applicability of the GlucoDay® continuous glucose monitoring device in the medical ICU
[1]. Fast changes in glycemia were noted immediately (Fig. 3), whereas this was
noted much later ( ' 1 – 3 hours) when only using intermittent blood glucose measurements. Hyperglycemia was present in 74 % of MICU patients and target glycemia
(80 – 110 mg/dl) was reached only 22 % of the time, revealing the inadequacy of current insulin protocols and the potential of an accurate continuous glucose monitoring system in this setting. Similar results were reported by Goldberg et al. investigating the use of the CGMS® device in the medical ICU [57]. No adverse events were
noted in either study [1, 57]. Vriesendorp et al. investigated the use of the GlucoDay® device during and after surgery and encountered a high technical failure rate
[58], which was mainly attributed to breaking of the microdialysis fiber during
transfer from the surgical bench to the ICU bed. In our study, only one fiber broke.
Baird et al. using the GlucoDay®, observed that acute and final infarct volume
change and outcome were negatively affected in patients with mean blood glucose
levels & 126 mg/dl (7 mmol/l) [42].
Javid et al. have tested the Extracorporeal Glucose Monitoring System (EGMS®,
Medtronic Minimed, Northridge, CA) in patients on extracorporeal bypass. This
pilot study suggested that the EGMS is a reliable tool for continuous blood glucose
monitoring in critically ill patients on extracorporeal life support, cardiopulmonary
bypass, and renal replacement therapy [59].
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Fig. 3. Examples of continuous glucose monitoring profiles in ICU patients. Top panel: A patient with brittle type 1 diabetes mellitus in cardiogenic shock; enteral feeding was started after 36 h; lower panel: A stable non-diabetic patient admitted due to respiratory insufficiency; total parenteral nutrition (TPN) was
started after 30 h. Little squares are arterial blood glucose readings.
Chee et al. conducted a study to determine if continuous subcutaneous glucose
monitoring using the CGMS® could be used in real-time to control glycemia in five
critically ill patients [55]. They concluded that the automatic sliding scale approach
of closed-loop glycemic control is feasible in patients in ICU, but more work is
needed in the refinement of the algorithm and the improvement of real-time sensor
accuracy.
Glucose Control and Monitoring in the ICU
How to Use Data Obtained with Continuous Glucose Monitoring?
The presentation of the vast amount of data collected during continuous glucose
monitoring must be made in an easy to understand fashion so that the physician can
interpret it adequately. First, the continuous glucose monitoring system should display the actual glucose measurement and in the future a warning alarm should be
available if the actual glucose value is below or above a predefined target value. Second, continuous glucose monitoring provides trend information. By presenting the
direction of glucose changes, this trend analysis may provide additional information
to take preventative actions in time. It might be possible in the future, using complex mathematical trend analysis, to predict the course of glucose changes for longer
time periods ahead. Third, continuous glucose monitoring data provide an accurate
impression of the blood glucose profile over 24 hours a day, thereby detecting many
glucose fluctuations. Fourth, the profiles of several days can be superimposed to
detect specific glucose patterns in specific time periods. Thus, continuous glucose
monitoring provides information about the direction, magnitude, duration, and frequency of glycemic fluctuations. Continuous glucose monitoring will permit
smoother, timelier adjustments in insulin infusions to more quickly achieve target
glycemia and it will provide early warning about incipient hypoglycemia.
In conclusion, our data and those of Goldberg et al. suggest that using continuous
glucose monitoring in critically ill patients looks promising [1, 57]. If further developed as a ‘real-time’ glucose sensor, continuous glucose monitoring technology
could ultimately prove clinically useful in the ICU, by providing alarm signals for
impending glycemic excursions, rendering intensive insulin therapy easier and safer.
Closed loop systems, with computer-assisted titration of insulin dose, will go a step
further and will reduce nursing workload and lower the risk of hypoglycemia. The
European community-funded CLINICIP (Closed Loop Insulin Infusion for Critically
Ill Patients) project aims to develop a low-risk monitoring and control system that
allows health care providers to maintain strict glycemic control in ICUs using a SCIV closed loop system.
Cost-effectiveness of Achieving Normoglycemia in the ICU
Controlling hyperglycemia in patients with either known diabetes or newly discovered hyperglycemia in the hospital has been shown to be cost-effective in many settings. Van den Berghe et al. showed that in her surgical ICU, the extra costs of intensive insulin therapy, which were nearly double the cost of the conventional treatment, were more than offset by a 25 % reduction in the total hospitalization costs
[60]. Intensive insulin therapy resulted in improved medical outcomes, and a
reduced length of stay in the ICU and in the hospital, thereby resulting in an estimated annual cost savings of $ 40,000 (31,400 c) per ICU bed. Intensive insulin therapy proved to be cost-effective, saving $ 3,360 (2,638 c) per patient [60]. The cost
savings occurred because of reductions in ICU length of stay and several morbid
events such as renal failure, sepsis, blood transfusions, and mechanical ventilation
dependency. Krinsley et al. also found intensive insulin therapy to be cost-effective
in their mixed medical-surgical ICU, with a net annualized decrease in costs of $
1,580 (1,240 c) per patient [61]. The savings associated with the intensive glucose
management program were, however, not shared equally among the different patient
groups. The largest net savings occurred among surgical, cardiac, and gastrointesti-
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nal patients. Due to a reduction in hospital length of stay, intensive glycemic control
allowed the hospital to serve more patients per bed and generated further income
from new patient groups. Thus optimizing glycemic management is not only medically effective, saving lives and reducing morbidity, but also cost-effective to health
care systems.
Conclusion
Recently, stress hyperglycemia has become a major therapeutic target in the ICU.
Stress hyperglycemia affects the vast majority of critically ill patients and is associated with adverse outcome, including increased mortality. Intensive insulin therapy
to achieve normoglycemia may reduce mortality and morbidity, with a reduced incidence of acute renal failure, accelerated weaning from mechanical ventilation, and
accelerated discharge from the ICU and hospital. Optimal benefits appear to be
achieved with a maintenance of glycemia ‹ 110 mg/dl. In addition, achieving normoglycemia is cost-effective. However, reaching and maintaining normoglycemia
requires extensive efforts from the medical staff, including frequent glucose monitoring and adjustment of insulin dose. Current insulin titration is based upon intermittent glucose measurements, which may miss fast rises or falls in glycemia. Recent evidence suggests that continuous monitoring of glucose levels may help to signal glycemic excursions and eventually to optimize titration of insulin therapy in the ICU.
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