Glucose Control in ICU

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T h e n e w e n g l a n d j o u r n a l o f medicine

Glucose Control in the ICU — How Tight Is Too Tight?Silvio E. Inzucchi, M.D., and Mark D. Siegel, M.D.

For the past decade, hospitals have focused onthe inpatient management of hyperglycemia, par-ticularly in the intensive care unit (ICU). Extensiveobservational data have shown a consistent, al-most linear relationship between blood glucose

levels in hospitalized patients and adverse clinicaloutcomes, even in patients without establisheddiabetes.1 It has never been entirely clear, however, whether glycemia serves as a mediator of theseoutcomes or merely as a marker of the sickest pa-tients, who present with the well-known counter-regulatory stress response to illness. Several early studies suggested a clinical benefit from strict glu-cose control during critical care but were weakenedby a retrospective design or other methodologicconcerns.2 In the Journal in 2001, in a study froma single center in Leuven, Belgium, Van den Bergheet al.3 reported a dramatic 42% relative reductionin mortality in the surgical ICU when blood glu-cose was normalized to 80 to 110 mg per decili-ter (4.4 to 6.1 mmol per liter) by means of insu-lin infusion in a prospective, randomized fashion(Table 1). Five years later, the same investigatorsreported findings from their medical ICU, reveal-ing no mortality benefit from intensive glucosecontrol, except in a subgroup requiring critical carefor 3 or more days.4

Predominantly on the basis of the first of these

two trials, many hospitals identified an opportu-nity to improve the quality of care and sought toinstitute intensive glucose control measures. Key stakeholders were identified, protocols and algo-rithms created, working groups appointed, educa-tional programs developed, and consensus con-ferences held.8 Professional organizations joinedin this new, apparent mandate to reduce glucoselevels not just in the critically ill, but in all hospi-talized patients.8 Even the Joint Commission of-

fered commendation to hospitals demonstratingsuccess in certain process-performance measuresinvolving the care of inpatients with diabetes.9

Recently, two multicenter studies called intoquestion the Leuven findings.5,6 Both reported un-

acceptably high rates of hypoglycemia, and onetrial was prematurely terminated for this reason.6 By this time, an increasingly vocal chorus of criticshad emerged, raising concerns about how strin-gent glucose targets actually needed to be.10 Twometa-analyses on the subject reached disparateconclusions.11,12

Into this controversy comes the multinationalNormoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation(NICE-SUGAR) trial (ClinicalTrials.gov number,NCT00220987), reported on in this issue of the

Journal.7 Intensive and conventional glycemic con-trol were compared in a randomized, unblindedfashion in 6104 patients in the ICU, involving theuse of intravenous insulin to achieve a blood glu-cose level of 81 to 108 mg per deciliter (4.5 to6.0 mmol per liter) or a level of 144 to 180 mg perdeciliter (8.0 to 10.0 mmol per liter), respectively.The two treatment groups showed good glycemicseparation, with a mean absolute difference of 29 mg per deciliter in overall blood glucose levels(not as widely separated as in the Leuven studies

[47 mg per deciliter]).13

The results of NICE-SUGAR contrast starkly with those of preceding trials, with an absolute increase in the rate of the pri-mary end point, death at 90 days, with intensiveglucose control (27.5%, vs. 24.9% with convention-al control; odds ratio, 1.14; P = 0.02). Not sur-prisingly, severe hypoglycemia occurred in morepatients in the intensive-control group than inthe conventional-control group (6.8% vs. 0.5%,P<0.001).

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n engl j med 360;13 nejm.org march 26, 2009 1347

The strengths of the NICE-SUGAR trial includeits large, multicenter framework, robust statisti-cal analysis, use of a uniform and validated insulinprotocol applied consistently across sites with re-sultant low rates of hypoglycemia, the broad andprobably representative spectrum of critically illpatients, and use of a precise and clinically mean-

ingful primary outcome — death — that is resis-tant to the vagaries of adjudication. The trial’s weaknesses include its understandably open-labeldesign and a small imbalance between groups with respect to receipt of corticosteroid therapy.In addition, 10% of patients randomly assigned toundergo intensive glucose control had study treat-ment discontinued prematurely. Because they wereanalyzed in the customary intention-to-treat fash-ion, the extent to which these patients, essentially crossovers, contributed to the difference in mor-tality between the two groups is as yet unclear.

An additional unexplained and somewhat puzzlingaspect of the results of the NICE-SUGAR study isthe lack of any significant differences in the lengthsof stay in the ICU or hospital or in organ-dysfunc-tion rates between the two groups, despite thehigher mortality in the intensive-control group.

The many differences between the Leuventrials3,4 and the NICE-SUGAR trial may begin toexplain their divergent conclusions. In contrast tothe current multinational study, the Belgian in- vestigations were performed from a single center,raising the possibility that local features of that population of patients or the approach to caremight have influenced outcomes in ways that could not be replicated elsewhere. For example,parenteral hyperalimentation was the rule inLeuven, whereas enteral nutrition predominatedin the NICE-SUGAR study. Perhaps more impor-tantly, the Belgian studies compared intensiveglycemic management to standard management at the time — reduction of glucose level only if the level is markedly elevated (>215 mg per deci-liter [11.9 mmol per liter]). In contrast, the glu-

cose level in the conventional-control group of the NICE-SUGAR trial was targeted at only amildly elevated range — 144 to 180 mg per deci-liter — and more than two thirds of these pa-tients still received intravenous insulin to accom-plish this goal.

Accepting these differences, how might we ex-plain the surprising finding of a possible risk of death from intensive insulin therapy? Could in-sulin itself have direct deleterious effects (sym-

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T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 360;13 nejm.org march 26, 20091348

pathetic activation, sodium retention, or mitogenicactions)? Was the increased mortality simply re-lated to hypoglycemia and resultant neuroglyco-penia, which is difficult to detect in patients whoare intubated and sedated? Did the well-recog-nized complexities of intensive management of glucose distract from other, ostensibly more im-

portant management practices in the ICU? Is stresshyperglycemia the body’s proper response to ill-ness, an attempt to shunt energy from temporar-ily unessential skeletal muscle to critical organs?Do all measured biologic perturbations due to ill-ness require medical correction? For example, at-tempts to rectify elevated blood carbon dioxidelevels in patients with certain forms of respira-tory failure may actually increase the risk of adverse outcomes. This realization led to the now- widely-adopted therapeutic concept of permissivehypercapnia.14

The answer to these important questions must await post hoc analyses that the NICE-SUGAR study investigators are now obliged to conduct.Further exploration of the precise causes of deathin the patients may be helpful. A per-protocolanalysis (vs. intention-to-treat analysis) would beof great interest. Data inquiries stratified accord-ing to the development of hypoglycemia, durationof euglycemia, mean insulin dose received, andlength of stay in the ICU may shed further light on the provocative results of the NICE-SUGAR study. Moreover, which subgroups of patients, if any, might still benefit from the more stringent levels of glycemic control will most likely requirefurther study.

Clinicians, particularly those involved in criticalcare, are now left in something of a quandary. At many institutions, an infrastructure has emergedthat facilitates the automatic and seamless useof insulin infusion in patients in the ICU. Shouldthese efforts now be abandoned? Until further evi-dence becomes available, it would seem reason-able to continue our attempts to optimize the

management of blood glucose in our hospitalizedpatients, especially to avert the extremes of hyper-glycemia (which have acute effects on renal func-tion, hemodynamics, and immune defenses) andalso hypoglycemia (with its own, often more im-mediate and serious, consequences).

In retrospect, it may turn out that we have beenoverly enthusiastic in our attempts to attain eu-glycemia during critical care. (Similar and well-intentioned exuberance for rigid glucose targets

in outpatient care was challenged this past sum-mer by the jarring results from the Action to Con-trol Cardiovascular Risk in Diabetes [ACCORD]trial [NCT00000620].15) However, we would cau-tion against any overreaction to the NICE-SUGAR findings. As noted, many hospitals have imple-mented refined insulin-infusion protocols and are

achieving exemplary glucose control and clinicaloutcomes in their ICUs. The NICE-SUGAR study simply tells us that in cohorts of patients such asthose studied, there is no additional benefit fromthe lowering of blood glucose levels below therange of approximately 140 to 180 mg per deci-liter; indeed, for unclear reasons, there may besome risk that remains to be elucidated. Notwith-standing, it would be a disservice to our criti-cally ill patients to infer from the NICE-SUGAR data that neglectful glycemic control involvinghaphazard therapeutic approaches (e.g., use of

insulin “sliding scales”) — all too common adecade ago — is again acceptable practice inour ICUs.

Dr. Inzucchi reports receiving research funding from Eli Lilly.No other potential conflict of interest relevant to this article wasreported.

This article (10.1056/NEJMe0901507) was published at NEJM.orgon March 24, 2009.

From the Sections of Endocrinology (S.E.I.) and Pulmonary andCritical Care Medicine (M.D.S.), Department of Internal Medi-cine, Yale University School of Medicine and Yale–New HavenHospital, New Haven, CT.

Kosiborod M, Rathore SS, Inzucchi SE, et al. Admission glu-1.

cose and mortality in elderly patients hospitalized with acutemyocardial infarction: implications for patients with and with-out recognized diabetes. Circulat ion 2005;111:3078-86.

Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous2.

intravenous insulin infusion reduces the incidence of deep ster-nal wound infection in diabetic patients after cardiac surgicalprocedures. Ann Thorac Surg 1999;67:352-62.

Van den Berghe G, Wouters P, Weekers F, et al. Intensive3.

insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67.

Van den Berghe G, Wilmer A, Hermans G, et al. Intensive in-4.

sulin therapy in the medical ICU. N Engl J Med 2006;354:449-61.Devos P, Preiser JC, Melot C. Impact of tight glucose control5.

by intensive insulin therapy on ICU mortality and the rate of

hypoglycaemia: final results of the Glucontrol study. IntensiveCare Med 2007;33:Suppl 2:S189.Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin6.

therapy and pentastarch resuscitation in severe sepsis. N Engl JMed 2008;358:125-39.

The NICE-SUGAR Study Investigators. Intensive versus con-7.

ventional glucose control in critically ill patients. N Engl J Med2009;360:1283-97.

ACE/ADA Task Force on Inpatient Diabetes. American Col-8.

lege of Endocrinology and American Diabetes Association con-sensus statement on inpatient diabetes and glycemic control.Endocr Pract 2006;12:458-68.

Inpatient diabetes certification. Oakbrook Terrace, IL: The9.




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n engl j med 360;13 nejm.org march 26, 2009 1349

Joint Commission. (Accessed March 6, 2009, at http://www. jointcommission.org/CertificationPrograms/Inpatient+Diabetes/.)

Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and10.

mortalit y in critically ill patients. JAMA 2003;290:2041-7.Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill11.

hospitalized patients: a meta-analysis of randomized controlledtrials. Arch Intern Med 2004;164:2005-11.

Wiener RS, Wiener DC, Larson RJ. Benefits and risks of t ight 12.

glucose control in critically ill adults: a meta-analysis. JAMA

2008;300:933-44.

Van den Berghe G, Wilmer A, Milants I, et al. Intensive insu-13.

lin therapy in mixed medical/surgical intensive care units: ben-efits versus harm. Diabetes 2006;55:3151-9.

O’Croinin D, Ni Chonghaile M, Higgins B, Laffey JG. Bench-14.

to-bedside review: permissive hypercapnia. Crit Care 2005;9:51-9.

The Action to Control Cardiovascular Risk in Diabetes Study 15.

Group. Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med 2008;358:2545-59.

Copyright © 2009 Massachusetts Medical Society.

Prevention of Viral Sexually Transmitted Infections —Foreskin at the Forefront

Matthew R. Golden, M.D., M.P.H., and Judith N. Wasserheit, M.D., M.P.H.

Three landmark randomized, controlled trials con-ducted in South Africa, Uganda, and Kenya from2005 through 2007 demonstrated that adult male

circumcision reduced the acquisition of humanimmunodeficiency virus (HIV) by 50 to 60%.1-3 Complications associated with the procedure wererare and almost uniformly minor.4 These findings were largely consistent with those of observationaland ecologic studies in which adult male circum-cision was associated with a lower HIV risk at bothindividual and population levels,5 and mathemat-ical models suggest that widespread circumci-sion could substantially reduce the HIV epidem-ic in high-prevalence heterosexual populations.6 In 2007, the World Health Organization and theUnited Nations Programme on HIV/AIDS recom-mended that circumcision be promoted in areas with a high prevalence of heterosexually transmit-ted HIV, and donor agencies are now funding malecircumcision programs in Africa.

In this issue of the Journal, Tobian et al.7 report findings from the Ugandan trial on the effect of circumcision on the prevalence of human papillo-mavirus (HPV) infection and the incidence of herpes simplex virus type 2 (HSV-2) infection andsyphilis. They found that adult male circumcision

decreased the prevalence of HPV by 35%, reducedHSV-2 acquisition by 25%, and had no effect onthe incidence of syphilis (which probably reflect-ed a limited power to detect an effect). In previousreports from this trial, the Ugandan team report-ed that male circumcision reduced the occurrenceof genital ulcers in men and genital ulcers, bac-terial vaginosis, and trichomoniasis in femalepartners.8,9 These findings agree with two recent studies from South Africa showing that circum-

cision reduced the prevalence of high-risk HPVand the incidence of HSV-2 by one third.10,11 Theresults are also biologically plausible, since the

foreskin may increase susceptibility to micro-abrasion and allows prolonged contact time be-tween pathogens and nonkeratinized skin. Thesenew data should prompt a major reassessment of the role of male circumcision, not only in HIV prevention but also in the prevention of other sexu-ally transmitted infections.

Both HPV and HSV-2 infections are globalhealth problems that far outstrip HIV infectionin frequency and result in substantial morbidity and mortality. Roughly three quarters of U.S.adults have had at least one HPV infection. High-risk HPV types cause cervical cancer, the secondmost common cause of cancer deaths in womenglobally. In 2002, a total of 273,000 women world- wide died of cervical cancer, including 6500 inNorth America. Furthermore, approximately 536million people (16% of the world’s populationbetween the ages of 15 and 49 years) and morethan 25 million Americans (17% of the adult U.S.population) are infected with HSV-2. In adults,the infection is seldom fatal, but it is associated with substantial morbidity and is costly, gener-

ating almost $1 billion annually in direct medi-cal costs in the United States alone. HSV-2 infec-tion is associated with an increase in the risk of HIV infection by a factor of two to four, and upto 2800 neonatal herpes cases occur in the UnitedStates annually, often resulting in severe disabili-ty or death.

The data from these trials are consistent withthe majority of observational studies of male cir-cumcision and HPV infection. A meta-analysis


Glucose Control in ICU

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