Glucose Control and Monitoring in the ICU C. De Block and P. Rogiers

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 hor- mones. In addition, several clinical interventions, such as administration of cortico- steroids, 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 nor- moglycemia 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 normoglyce- mia must be weighed against the increased risk of hypoglycemia.

Obtaining normoglycemia requires considerable nursing effort, including fre- quent 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 mon- itoring, 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

Table 1. Prevalence of stress hyperglycemia in the ICU

ICU type number

of patients

definition of hyperglycemia (mg/dl)

hyperglycemic patients (%)

Van den Berghe et al. [2] surgical ICU 1548

110 75

Egi et al. [3] surgical ICU 783

110 81

Van den Berghe et al. [4] medical ICU 1200

110

85

Ligtenberg et al. [5] medical ICU 1085

180 28

Cely et al. [6] medical ICU 100

110 64

De Block et al. [1] medical ICU 50

110 74

Finney et al. [7] mixed ICU 523

110

85

Freire et al. [8] mixed ICU 1185

110 59

Christiansen et al. [9] mixed ICU 135

110 100

Krinsley et al. [10] mixed ICU 1826

120 42

Umpierrez et al. [11] mixed ICU 239

126 56

Whitcomb et al. [12] mixed ICU 2713

200 27

Zimmerman et al. [13] cardiothoracic ICU 342

150 50

Latham et al. [14] cardiothoracic ICU 984

200 29

Swenne et al. [15] cardiothoracic ICU 374

120 95

Yendamuri et al. [16] trauma ICU 738

135 25

Laird et al. [17] trauma ICU 516

110 94

Sung et al. [18] trauma ICU 1003

200 25

Wintergerst et al. [19] pediatric ICU 980

110 87

Faustino and Apkon [20] pediatric ICU 942

120 75

Srinivasan et al. [21] pediatric ICU 152

126 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, gluco- corticoids) 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 hypo- thalamic-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 resis-

tance 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 aug-

mented more than two-fold in critical illness via increased gluconeogenesis and gly-

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, glyco- gen 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 electro- lyte abnormalities including hypokalemia, hypomagnesemia, and hypophosphate- mia. Hyperglycemia may also worsen catabolism in skeletal muscle. Other mecha- nisms 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 dys- function. Endothelial dysfunction may result in a compromised microcirculation.

Subsequent cellular hypoxia contributes to the risk of organ failure and death in crit- ically 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-

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 oxy- gen 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 myo- cytes 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 endo- thelium 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

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 insu- lin 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 A

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 syn- thase (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 cyto- kines (TNF- [ , IL-1, IL-6,) and adhesion molecules (soluble intercellular adhesion molecule-1), in addition to C-reactive protein [25]. TNF- [ causes endothelial dys- function and apoptosis, triggers procoagulant activity and fibrin deposition, and enhances NO synthesis in a variety of cells. Alternatively, prevention of hyperglyce- mia 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 ultrastruc- tural and functional abnormalities of hepatocytic mitochondria [36]. Mitochondrial dysfunction and the associated bioenergetic failure are regarded as factors contrib- uting 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 discus- sion. 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 poly- neuropathy), it appeared crucial to reduce glycemia to ‹ 110 mg/dl. For the preven- tion 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-

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-dia- betic 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 hyper- glycemia 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 out- come, lengthen in-hospital stay and increase hospital charges [41 – 43]. A meta-anal- ysis 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 associ- ated 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 con- tinuous glucose monitoring [42].

Trauma Patients

In trauma patients, hyperglycemia proved to be an independent predictor of mortal- ity and of in-hospital and ICU length of stay, when controlling for age, injury sever- ity score, and gender [16 – 18, 44]. In addition, infectious complications, including pneumonia, urinary tract infections, wound infections, and bacteremia, were signifi- cantly 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

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 regula- tion 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 num- ber 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 respira- tory 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 cardiotho- racic, 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 mortal- ity [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, sug- gested 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 in- hospital mortality was not uniform. Hyperglycemia was an independent risk factor only in patients without a history of diabetes in the cardiac, cardiothoracic, and neu- rosurgical 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].

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 hypergly- cemia on mortality was variable but was most pronounced in stroke patients (rela- tive 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 embo- lism. 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 Sur- vival Using Glucose Algorithm Regulation [NICE-SUGAR] enrolling 3,500 patients in Europe, and the Comparing the Effects of Two Glucose Control Regimens by Insu- lin in Intensive Care Unit Patients [GLUCONTROL] enrolling 1,500 pateints in Aus- tralia, 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 clini- cal 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 mor-

tality risk, length of stay and hyperglycemia [20]. Srinivasan et al. showed that peak

blood glucose and duration of hyperglycemia were independent predictors of mor-

tality in a group of pediatric ICU patients receiving vasoactive infusions or mechan-

ical ventilation [21].

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 man- agement of stress hyperglycemia is to identify and treat the most common precipi- tating 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, prefer- ably 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 gly- cemia 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 Col- lege 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 infu-

sions. 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 knowl-

edgeable about the optimal methods of administration of insulin (the endocrinolo-

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 hypoglyce- mia 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 effi- ciency and safety of glycemic control in critically ill adults, improved nursing accep- tance, 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 gly- cemic control without increasing the workload of the nursing staff. An accurate con- tinuous 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 gly- cemic 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 vaso- pressors, 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 addi- tion, 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 con-

centrations. However, previously published data on the reliability of continuous glu-

cose monitoring systems in diabetic patients cannot be automatically transferred to

a different situation like intensive care, where many variables can interfere with per-

formance of such systems (e.g., subcutaneous edema, hypotension, vasoactive

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 intersti- tial fluid. Under physiological conditions there is a free and rapid exchange of glu- cose 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/decre- ments in glycemia and insulin levels. In the ICU setting, the hemodynamic alter- ations encountered (hypotension, shock, vasopressor or inotropic need) did not affect accuracy [1, 57]. Such variables would rather affect the process of subcutane- ous glucose recovery, resulting in a calibration issue, rather than in a sensor perfor- mance 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, North- ridge, 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’ sen- sor, 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 microdialy- sis technique that measures glucose concentrations in the dialysate from subcutaneous interstitial fluid. It is approved by the European Community (CE). Glucose concentra- tions 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 applica- bility 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 mea- surements. 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 cur- rent insulin protocols and the potential of an accurate continuous glucose monitor- ing system in this setting. Similar results were reported by Goldberg et al. investigat- ing 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 Gluco- Day® 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].

Fig. 3. Examples of continuous glucose monitoring profiles in ICU patients. Top panel: A patient with brit- tle type 1 diabetes mellitus in cardiogenic shock; enteral feeding was started after 36 h; lower panel: A sta- ble 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.

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 dis- play 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. Sec- ond, 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 com- plex 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 fre- quency 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 devel- oped 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 SC- IV closed loop system.

Cost-effectiveness of Achieving Normoglycemia in the ICU

Controlling hyperglycemia in patients with either known diabetes or newly discov-

ered hyperglycemia in the hospital has been shown to be cost-effective in many set-

tings. Van den Berghe et al. showed that in her surgical ICU, the extra costs of inten-

sive insulin therapy, which were nearly double the cost of the conventional treat-

ment, 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 esti-

mated annual cost savings of $ 40,000 (31,400 c) per ICU bed. Intensive insulin ther-

apy 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-

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 medi- cally 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 associ- ated with adverse outcome, including increased mortality. Intensive insulin therapy to achieve normoglycemia may reduce mortality and morbidity, with a reduced inci- dence 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 nor- moglycemia is cost-effective. However, reaching and maintaining normoglycemia requires extensive efforts from the medical staff, including frequent glucose monitor- ing and adjustment of insulin dose. Current insulin titration is based upon intermit- tent glucose measurements, which may miss fast rises or falls in glycemia. Recent evi- dence suggests that continuous monitoring of glucose levels may help to signal glyce- mic excursions and eventually to optimize titration of insulin therapy in the ICU.

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