Advances in Surgery 45 (2011) 187–196

ADVANCES IN SURGERY

Glucose Elevations and Outcome inCritically Injured Trauma Patients

Joseph J. DuBose, MDa, Thomas M. Scalea, MDb,*aR Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore,MD 21201, USAbProgram in Trauma, R Adams Cowley Shock Trauma Center, University of Maryland School ofMedicine, Baltimore, MD 21201, USA

Stress hyperglycemia, defined as a transient plasma glucose level above200 mg/dL, is associated with adverse outcomes among the criticallyill, including increased mortality [1–7]. Since the landmark study con-

ducted by Van den Berghe and colleagues [8] in Leuven, Belgium, first demon-strated improved survival in ICU patients treated with intensive insulintherapy, there has been considerable attention dedicated toward defining theideal therapy required to optimize outcome for critically ill patients with hyper-glycemia. Although subsequent studies have failed to replicate the findings ofthe Leuven group, these investigations lacked the methodologic rigor of theinitial studies and have provided few data that can be effectively extrapolatedto the care of ICU populations, including victims of trauma. The largest bodyof work examining the risks and treatment of hyperglycemia after injury hasbeen conducted at the University of Maryland R Adams Cowley ShockTrauma Center [1,8–11]. Data from the authors’ group have demonstrated thathyperglycemia has a significant association with adverse outcomes after traumaand that intervention with insulin therapy may significantly improve outcomesfor these patients.

PATHOPHYSIOLOGY OF STRESS HYPERGLYCEMIAAlthough the precise cause of these glucose elevations has not been comprehen-sively defined, it has been postulated that they are the result of increased levelsof cortisol, glucagons, and epinephrine associated with critical illness [12,13].The action of these hormones results in increased gluconeogenesis in vivo.As a result of these hormones’ actions, there is also a decrease in peripheraluptake of glucose to insure substrate availability. These combined effects resultin high circulating levels of glucose during the physiologic response to criticalillness or trauma.

*Corresponding author. E-mail address: tscalea@umm.edu

0065-3411/11/$ – see front matterdoi:10.1016/j.yasu.2011.03.016 � 2011 Elsevier Inc. All rights reserved.

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There are several effects of hyperglycemia that have the potential tocontribute to associated adverse outcomes observed after acute illness ortrauma [7,14–17]. It has been suggested that hyperglycemia may be acutelytoxic in critically ill patients because of accentuated cellular glucose overloadand associated pronounced side effects of glycolysis and oxidative phosphory-lation [18]. Additionally, it has been hypothesized that after trauma or criticalillness, the expression of glucose transporters on the membranes of several celltypes may be up-regulated. During reperfusion after ischemia, this up-regulation may allow high circulating glucose levels to overload cellular metab-olism and cause irreversible damage to cellular function and structure. Otherproposed mechanisms of injury include increased generation and deficientscavenging systems for reactive oxygen species produced by the activatedglycolysis and oxidative phosphorylation associated with glucose toxicity[17]. All of these proposed mechanisms may contribute to the observeddysfunctions of liver, renal, cardiac, endothelial, and cellular immune functionsassociated with hyperglycemia in the setting of critical illness [19].

INSULIN THERAPY AND STRICT GLUCOSE CONTROLIN CRITICAL ILLNESSAs understanding of the adverse effects of hyperglycemia has expanded,considerable recent attention has been focused on the role of glycemic controlin mitigating the risks associated with this consequence of critical illness ortrauma.

In 2001, the first of 2 landmark randomized trials examining the effects ofinsulin therapy on outcome was reported by Van den Berghe and colleagues[8,20]. In the initial examination, reported in 2001, the investigators enrolled1548 patients requiring surgical ICU admission and mechanical ventilation.On admission, these patients were randomly assigned to receive intensiveinsulin therapy (maintenance blood glucose goal 80–110 mg/dL) or conven-tional glucose control therapy (infusion of insulin only if blood glucose ex-ceeded 215 mg/dL). At 12 months, they found that intensive insulin therapywas associated with reduced overall mortality (4.6% vs 8.0% for the conven-tional therapy group; P <.04). The researchers also found that the benefit ofintensive insulin therapy was most attributable to its effect on mortality inpatients who remained in an ICU for more than 5 days. The greatest reductionin mortality involved deaths due to multiple-organ failure with a proved septicfocus, with associated overall reductions in infections and renal failurerequiring dialysis [20].

A subsequent study conducted by the Leuven group examined the impact ofintensive glucose therapy in a population of medical ICU patients using thesame glucose control cohort arms [8]. In this study of 1200 patients, the inves-tigators found that the use of intensive insulin therapy significantly reducedblood glucose levels but did not significantly reduce in-hospital mortality(37.3% in the intensive therapy group and 40.0% in the conventional therapygroup; P ¼ .33). They did find, however, that for those patients staying in an

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ICU for more than 3 days, there was a reduction of in-hospital mortality(52.5% to 43.0%; P ¼ .009), with an associated reduction in all-causemorbidity. For those patients who required less than 3 days of admission,however, there was an increased mortality associated with intensive insulintherapy use. Based on these and subsequent post hoc analyses, the Leuvengroup concluded that intensive insulin therapy was beneficial for ICU patients,with the maximal benefit appreciated by surgical patients. The results of these 2studies prompted a significant shift in emphasis toward tight glucose controlpractices among ICU practitioners and were widely promoted as a standardof care practice by such groups as the Institute for Healthcare Improvement.

In the wake of the Leuven group findings, subsequent randomizedcontrolled trials were conducted in heterogeneous populations of ICU patients.The studies failed to achieve the same degree of glucose control as Van denBerghe and colleagues and also failed to support the subsequent benefit of theseintensive glucose control practices in this environment [21–24]. One of thelargest studies reported was conducted by the Normoglycaemia in IntensiveCare Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study group [23].

This multi-institutional, multinational collection of investigators conducteda study of 6104 patients from various ICU populations. These patients wererandomized to target glucose ranges of 81 to 108 mg/dL versus less than180 mg/dL using insulin therapy, with the primary endpoint death from anycause within 90 days after randomization. They failed to achieve the glucosecontrol success demonstrated by the initial studies of the Leuven group. The2 treatment groups had no differences in the median number of hospital orICU days, number of mechanical ventilation days, and the need for renalreplacement therapy. The use of intensive insulin therapy was associatedwith increased mortality (27.5% vs 24.9%; P ¼ .02). There were, however,important methodologic differences between NICE-SUGAR and the originalVan den Berghe studies, including the use of different target ranges for bloodglucose in the control and intervention groups, different routes for insulinadministration, and types of infusion systems used. Additionally, there weredifferences in sampling sites, glucometer devices used, nutritional strategies,and levels of expertise that may have contributed significantly to the observeddifferences between these investigations.

Meta-analyses of available prospective randomized controlled trials exam-ining intensive insulin therapy in the critical care environment have attemptedto provide answers regarding the role of this intervention in the setting of crit-ical illness [25,26]. In the largest meta-analysis of available data to date, Greis-dale and colleagues [26] evaluated 26 randomized controlled trials comparingintensive insulin therapy to conventional glucose control therapies, includingthe NICE-SUGAR study. They found that patients treated in a surgical ICUwere the only patients who seemed to benefit from intensive insulin therapycompared with those in the control group of patients undergoing conventionalinsulin therapy (P ¼ .02). Among all of these studies, however, there has been

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limited examination of the effect of glycemic control specifically on patientswho have required hospitalization or ICU admission after trauma.

HYPERGLYCEMIA RISK AND TREATMENT AMONGTRAUMA POPULATIONSThe largest studies of hyperglycemic effects and glucose control specifically fordedicated populations of critically ill trauma patients have been conducted atthe University of Maryland R Adams Cowley Shock Trauma Center. Theearliest of these investigations demonstrated that early hyperglycemia mightcontribute significantly to adverse outcome after trauma. In 2005, Sung andcolleagues [1] conducted a prospective examination of 1003 consecutive traumapatients admitted to the ICU at the Shock Trauma Center over a 2-year period.After excluding those patients with pre-existing diabetes, patients were stratifiedby serum glucose level (<200 mg/dL vs �200 mg/dL), demographics, severityof injury, and other pre-existing risk factors. The investigators found that 25%of patients were admitted with hyperglycemia over the study period and thatpatients with hyperglycemia had an overall greater infection rate and hospitallength of stay. Additionally, the hyperglycemic group had a 2.2-times greaterrisk of mortality after adjustment for age and Injury Severity Score, with hyper-glycemia proving an independent predictor of outcome and infection aftertrauma.

An additional examination conducted by Bochicchio and colleagues [10]prospectively examined the effects of hyperglycemia on patients requiringimmediate operative intervention after trauma. They evaluated 252 consecu-tive nondiabetic trauma patients who went directly to the operating roomfrom the resuscitation area, stratifying individuals by preoperative serumglucose level (<200 mg/dL vs �200 mg/dL), demographic data, severity ofinjury, and other pre-existing risk factors. Multiple linear regression analysis re-vealed patients with elevated serum glucose had a significantly higher incidenceof infection, longer hospital and ICU lengths of stay, and mortality whenmatched for age and Injury Severity Score. The investigators concluded thatelevated serum glucose on admission is an accurate predictor of postoperativemorbidity and mortality when found in the early phases after trauma.

Although the studies (discussed previously) at the authors’ institution estab-lished the risks of hyperglycemia in the early phases after trauma, subsequentstudy was required to better establish the potential adverse effects associatedwith persistent hyperglycemia after trauma. In 2005, Bochicchio and colleagues[11] collected prospective data on 942 consecutive trauma patients admitted toan ICU during a 2-year period. Patients were stratified by serum glucose levelfrom day 1 to day 7 of ICU stay using 3 different glucose levels (low ¼ 139 mg/dL; medium ¼ 140–219 mg/dL; and high >220 mg/dL). Patients with medium,high, worsening, and highly variable hyperglycemia were found to haveincreased ICU length of stay, hospital length of stay, and ventilator dayrequirements. Additionally, univariate analysis revealed higher infection andmortality rates in these same groups of patients. After controlling for age,

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Injury Severity Score, and glucose pattern, patients with high, worsening, andhighly variable hyperglycemia were most predictive of increased ventilatordays, ICU and hospital lengths of stay, infection, and mortality (P <.01) [10].

Finally, a study conducted by Scalea and colleagues [9] examined the impactof a tight glucose control policy (goal target 100 to 150 mg/dL) on outcomesassociated with hyperglycemia after trauma. The investigators performed a qua-siexperimental interrupted time-series design study to evaluate the impact oftight glucose control on a population of critically injured trauma patientsrequiring ICU admission. They compared outcomes from a 24-month periodbefore implementation of the tight glucose control protocol to a 24-month post-intervention phase. After comparing the more than 1000 patients in each arm,they found no significant difference in mechanism of injury, gender, age, orInjury Severity Score. They did find, however, that the tight glucose controlgroup was more likely in the all low or improving pattern of glucose control(P <.001). They also noted that the incidence of early infection (over the first2 weeks) was decreased from 29% to 21% after the introduction of their tightglucose control protocol (P <.001) (Fig. 1). After controlling for age, InjurySeverity Score, obesity, and pre-existing diabetes, the investigators discoveredthat the non–tight glucose control group required more ventilator days (oddsratio [OR] 3.9, class interval [CI ] 1.8–8.1), longer ICU stays (OR 4.3, CI2.1–7.5), and more hospital days (OR 5.5, CI 2.2–11.0) and were at higherrisk for in-hospital mortality (OR 1.4, CI 1.1–10.0) (Fig. 2) [8].

CONTROVERSIES AND FUTURE DIRECTIONSThe studies (discussed previously) as well as those of other investigators [27,28]have demonstrated both the adverse outcomes associated with hyperglycemiaafter trauma and the impact of intervention through effective glucose control.Several important questions still remain regarding the implementation of tightglucose control policies for these patients. Issues that require additional

Fig. 1. Incidence of infection stratified by site and study group before (Pre) and after (Post)implementation of a tight glucose control protocol among trauma patients requiring ICU admis-sion. (From Scalea TM, Bochicchio GV, Bochicchio KM, et al. Tight glycemic control in criti-cally injured trauma patients. Ann Surg 2007;246[4]:605–12; with permission.)

Fig. 2. All-cause mortality in a trauma ICU population with and without a tight glycemiccontrol protocol. (From Scalea TM, Bochicchio GV, Bochicchio KM, et al. Tight glycemiccontrol in critically injured trauma patients. Ann Surg 2007;246[4]:605–12; with permission.)

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clarification include the timing and mode of implementation for glucose controland the appropriate goal range that should be achieved. Additionally, theimpact of increased workload in the ICU that may be associated with tightglucose control policies must be better evaluated. Finally, potential complica-tions of insulin administration, in particular severe hypoglycemia, must befurther studied.

Timing of glucose control initiation

The question of the optimal time to initiate tight glucose control protocolsremains largely unanswered. The authors’ experiences at the University ofMaryland have demonstrated that hyperglycemia may have significant adverseimpact in the earliest phases after injury [1,10]. It is unknown, however, if theimplementation of intensive glucose control measures in emergency depart-ments or trauma resuscitation bays would significantly mitigate the subsequentassociated adverse outcomes. These early elevations in blood glucose may bemore reflective of the burden of injury response and, subsequently, may proveless amenable to effective manipulation during the most acute phases afterinjury. Further study of early intervention for posttraumatic hyperglycemiais required to better elucidate the approach required to optimize outcome.

What is the ideal goal range?

The ideal range of glucose control that should be used in the treatment ofhyperglycemia among the critically ill remains a matter of controversy. Theinitial clinical trials conducted by Van Den Berghe and colleagues [8,20]demonstrated a mortality benefit when a goal of 80 to 110 mg/dL was achievedin a population of predominantly surgical patients. None of the randomizedcontrolled trials completed after these investigations has succeeded in achievingsuch tight ranges of control. No subsequent randomized trial in any ICU pop-ulation achieved a median or mean blood glucose level in the interventiongroup below the upper normal target of blood glucose [17].

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The largest meta-analysis on the topic suggests that studies that managed toachieve their stated blood glucose target showed a reduced mortality, whereasrandomized studies that did not succeed in reaching the target reported nobenefit or even increased mortality [26]. The investigation of glucose controlfor trauma patients in the ICU conducted at the authors’ facility [9] demon-strated that the use of a tight glucose control protocol with goal range of 100to 150 mg/dL was associated with improved outcomes, including mortality.Whether this is the optimal goal glucose level for all trauma patients has notbeen established. Dedicated prospective randomized investigations in thisunique population are required to better determine the ideal range requiredto optimize outcome.

Increased ICU workload associated with tight glycemic control

There remain several potential challenges to the effective implementation oftight glycemic control policies in the ICU environment. Strict glycemic controlmandates frequent blood glucose measurements, which may be consideredlabor intensive among the other demands of the ICU staff. It has been sug-gested that the ability of nursing staff to obtain tight glycemic control mightbe hindered by various limitations, including time constraints and deficienciesin training [29]. These concerns can, however, be ameliorated by the effectiveincorporation and education of nursing staff as part of protocol developmentand implementation strategy [30]. The degree of training required to effectivelytrain staff for tight glycemic control policies as well as the workload associatedwith the active use of these policies in the conduct of care have not been wellstudied and require additional examination.

The risks of tight glycemic control

Hypoglycemia remains the most significant concern regarding implementationof strict glucose control policies. Reported incidences of severe hypoglycemia(blood glucose level <40 mg/dL) have been shown to rise by 5-fold to10-fold compared with conventional blood glucose control in previously con-ducted randomized controlled trials [17]. The true impact of these hypogly-cemic events, however, has not been definitively elucidated. It has beensuggested that hypoglycopenia may cause cerebral damage, epileptic insults,or even coma [31]. The duration and intensity of hypoglycemia required tocause these effects, however, is unknown [32]. Additionally, potential subsetsof patients at greatest risk for these potential consequences of hypoglycemiahave not been defined.

Currently available data preclude the definitive establishment of a correlationbetween severe hypoglycemia and harm in critically ill patients subjected tostrict glucose control. Two retrospective studies have previously identifiedsevere hypoglycemia as an independent predictor of mortality in the ICU envi-ronment [14,33]. In the larger of these 2 studies, however, 30% of patients werenot on insulin therapy in the 12 hours preceding severe hypoglycemic eventsand only a minority of patients were even receiving intravenous insulin therapy

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[33]. Therefore, this study fails to answer the question of whether severe hypo-glycemia with strict glucose control therapy actually influences outcome.

In both of these examinations, strict glycemic control practices were notroutinely used in the patient populations studied. In at least 1 initial study sug-gesting the benefits of glycemic control for critically ill patients, however,severe hypoglycemia was independently associated with mortality and mayhave diminished the benefit of intervention [8]. Although attempts to minimizethe occurrence of severe hypoglycemia during the employment of strict glucosecontrol should remain a concern, the true impact of these occurrences requiresadditional study.

Future directions

There remains a need for a prospective randomized trial on the effects of tightglucose control practices on outcome in critically ill trauma patients. To date,none of the conducted prospective randomized controlled trials have effectivelyexamined these patients. Currently available evidence from these studies doesnot permit practitioners to make conclusive recommendations on best practiceafter trauma. Although evidence from the University of Maryland suggests thattight glucose control practices are beneficial to outcome after trauma, a well-designed prospective randomized study is still required to substantiate theauthors’ findings. The development of such a study remains problematic,however, because the standard of care regarding glucose control in the ICUenvironment has certainly changed in the wake of the Van den Berghe studies[8,20]. As a result of these investigations, and their demonstrated mortalitybenefit, practice in most ICU environments has already been considerablyaltered. It is difficult to explain a trial design that requires deliberate exposureof critically ill patients to the hyperglycemia associated with conventionaltherapy, given this evidence and subsequent new standards of practice.

One promising option that could more readily be explored, however, is thatof the use of the next generation of glucose monitoring devices in the imple-mentation of tight glucose control strategies. These novel devices, whichprovide continuous or near-continuous monitoring capabilities, warrant exam-ination. Particularly when paired with treatment algorithm technology andpotential closed-loop control mechanisms, they may both alleviate the potentialworkload burden caused by implementation of tight glucose control policies inthe ICU and improve overall outcomes.

SUMMARYTight glucose control is associated with improved outcome among critically illtrauma patients. Further research is necessary, however, to better elucidate theetiology of this beneficial therapy. Additionally, future randomized trials onthis important topic are warranted, as are investigations of emerging technolo-gies that better facilitate tight glucose control in the ICU after trauma.

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