Greet Van den Berghe, M.D., Ph.D., Alexander Wilmer, M.D., Ph.D., Greet Hermans, M.D., Wouter Meersseman, M.D., Pieter J. Wouters, M.Sc., Ilse Milants, R.N., Eric Van Wijngaerden, M.D., Ph.D., Herman Bobbaers, M.D., Ph.D., and Roger Bouillon, M.D., Ph.D.
Background Intensive insulin therapy reduces morbidity and mortalityin patients in surgical intensive care units (ICUs), but itsrole in patients in medical ICUs is unknown.
Methods In a prospective, randomized, controlled study of adultpatients admitted to our medical ICU, we studied patients whowere considered to need intensive care for at least three days.On admission, patients were randomly assigned to strict normalizationof blood glucose levels (80 to 110 mg per deciliter [4.4 to6.1 mmol per liter]) with the use of insulin infusion or toconventional therapy (insulin administered when the blood glucoselevel exceeded 215 mg per deciliter [12 mmol per liter], withthe infusion tapered when the level fell below 180 mg per deciliter[10 mmol per liter]). There was a history of diabetes in 16.9percent of the patients.
Results In the intention-to-treat analysis of 1200 patients,intensive insulin therapy reduced blood glucose levels but didnot significantly reduce in-hospital mortality (40.0 percentin the conventional-treatment group vs. 37.3 percent in theintensive-treatment group, P=0.33). However, morbidity was significantlyreduced by the prevention of newly acquired kidney injury, acceleratedweaning from mechanical ventilation, and accelerated dischargefrom the ICU and the hospital. Although length of stay in theICU could not be predicted on admission, among 433 patientswho stayed in the ICU for less than three days, mortality wasgreater among those receiving intensive insulin therapy. Incontrast, among 767 patients who stayed in the ICU for threeor more days, in-hospital mortality in the 386 who receivedintensive insulin therapy was reduced from 52.5 to 43.0 percent(P=0.009) and morbidity was also reduced.
Conclusions Intensive insulin therapy significantly reducedmorbidity but not mortality among all patients in the medicalICU. Although the risk of subsequent death and disease was reducedin patients treated for three or more days, these patients couldnot be identified before therapy. Further studies are neededto confirm these preliminary data. (ClinicalTrials.gov number,NCT00115479
[ClinicalTrials.gov]
.)
Hyperglycemia and insulin resistance are common in severe illnessand are associated with adverse outcomes.1,2,3,4 In a previousrandomized, controlled study conducted in a surgical intensivecare unit (ICU), strict control of blood glucose levels withinsulin reduced morbidity and mortality,5,6 significantly reducingin-hospital mortality from 11 to 7 percent in the entire studypopulation. In a subgroup of patients who stayed in the ICUfor three or more days, however, the benefit was much more pronounced,reducing mortality from 21 to 14 percent among patients treatedfor at least three days and from 26 to 17 percent among thosetreated for at least five days. Complications, such as severeinfections and organ failure, were reduced. Several potentialmechanisms may explain these benefits — prevention ofimmune dysfunction,7 reduction of systemic inflammation,8 andprotection of the endothelium9,10 and of mitochondrial ultrastructureand function.11
It remains unclear whether intensive insulin therapy also improvesthe prognosis of patients in a medical ICU, who often are moreseverely ill than are patients in a surgical ICU and have ahigher risk of death.4,12,13 The study in a surgical ICU,5 twostudies of patients with diabetes with acute myocardial infarction,14,15and observations in patients with diabetes undergoing coronary-bypasssurgery16 suggested that insulin-titrated blood glucose controlshould be continued for at least a few days to achieve a detectableoutcome benefit. We therefore conducted a randomized, controlledstudy of patients in a medical ICU, targeting those requiringintensive care for at least a third day.
Methods
Adult patients admitted to the medical ICU who were assumedto require at least a third day of intensive care were eligiblefor inclusion. We excluded surgical ICU patients and medicalpatients able to receive oral nutrition, because such patientsusually need less than three days of intensive care, and patientswith do-not-resuscitate orders on admission (Figure 1). Writteninformed consent was obtained from the closest family member,because patients were unable to give consent. The protocol andconsent forms were approved by the institutional review boardof the university. The study was carried out between March 2002and May 2005.
All adult patients admitted to the medical intensive care unit (ICU) from March 14, 2002, onward who were assumed to require at least a third day of intensive care were eligible for inclusion. Of those, 767 patients remained in the ICU for at least a third day. DNR denotes do not resuscitate.
Study Design
On admission to the ICU, patients were randomly assigned toreceive either intensive insulin treatment (intensive-treatmentgroup) or conventional insulin treatment (conventional-treatmentgroup). Treatment assignment was performed with the use of sealedenvelopes, stratified according to diagnostic category (Table 1),and balanced with the use of permuted blocks of 10. In theconventional-treatment group, continuous insulin infusion (50IU of Actrapid HM [Novo Nordisk]) in 50 ml of 0.9 percent sodiumchloride) with the use of a pump (Perfusor-FM pump, B. Braun),was started only when the blood glucose level exceeded 215 mgper deciliter (12 mmol per liter) and was adjusted to maintaina blood glucose level of between 180 and 200 mg per deciliter(10 and 11 mmol per liter). When the blood glucose level fellbelow 180 mg per deciliter, the insulin infusion was taperedand eventually stopped.
Table 1. Baseline Characteristics of the Patients.
In the intensive-treatment group, insulin infusion was startedwhen the blood glucose level exceeded 110 mg per deciliter (6.1mmol per liter) and was adjusted to maintain normoglycemia (80to 110 mg per deciliter [4.4 to 6.1 mmol per liter]). The maximalcontinuous intravenous insulin infusion was arbitrarily setat 50 IU per hour. At the patient's discharge from intensivecare, a conventional approach was adopted (maintenance of bloodglucose at 200 mg per deciliter or less).
The dose of insulin was adjusted according to whole-blood glucoselevels, measured at one-to-four-hour intervals in arterial bloodor, when an arterial catheter was not available, in capillaryblood, with the use of a point-of-care glucometer (HemoCue B-glucoseanalyzer, HemoCue). Adjustments were made by the nurses in theICU; the usual number of nurses (2.5 full-time-equivalent nursesper bed in the ICU) was not changed for the study. The nursesused titration guidelines that were adapted from the study inthe surgical ICU.5
When patients were hemodynamically stable, enteral feeding wasstarted according to routine guidelines. The guidelines aimedat a total of 22 to 30 kcal per kilogram of body weight per24 hours with balanced composition (0.08 to 0.25 g of nitrogenper kilogram of body weight per 24 hours and 20 to 40 percentof nonprotein kilocalories as lipids).17 Enteral feeding wasattempted as early as possible.
Data Collection
At baseline, data on demographic and clinical characteristicsof the patients were obtained, including information necessaryto determine the severity of illness and the use of intensivecare resources (Table 1). These data were scored according tothe Acute Physiology and Chronic Health Evaluation (APACHE II)18system and simplified Therapeutic Intervention Scoring System-28(TISS-28),19,20 with higher values indicating more severe illnessand more therapeutic interventions, respectively.
Blood was systematically sampled and blood glucose levels weremeasured on admission and subsequently every four hours in allpatients. More frequent blood glucose measurements were performedwhenever the attending nurse considered them necessary and wheneverthere had been a steep rise or fall in the blood glucose levelon the previous reading. Blood glucose levels that were measuredon admission and daily in the morning during the study, andhypoglycemic events (defined as blood glucose levels of 40 mgper deciliter [2.2 mmol per liter]) were analyzed.
According to clinical guidelines, blood cultures were obtainedwhenever the central body temperature exceeded 38.5°C orwhen other clinical signs of sepsis were present.21,22 Resultswere interpreted by an investigator blinded to the treatmentassignment. An episode of bacteremia was defined by the firstpositive culture in a series. To identify bacteremia with coagulase-negativestaphylococci, identical strains (compared by antibiogram) intwo or more positive blood cultures were required.21,22 A distinctionwas made between primary and secondary bacteremia, dependingon whether or not a focus could be identified.
The clinical cause of a death in the ICU was determined by asenior physician blinded to the treatment assignments. The causesof deaths occurring after discharge from the ICU could not beidentified.
Outcome Measures
The primary outcome measure was death from any cause in thehospital. Secondary, predefined outcome measures were mortalityin the ICU, 90-day mortality, days to weaning from mechanicalventilation, days in the ICU and in the hospital, the initiationof dialysis, new kidney injury during intensive care (definedas either a level of serum creatinine twice that present onadmission to the ICU23 or a peak level of serum creatinine of>2.5 mg per deciliter [220 µmol per liter]), days ofinotropic or vasopressor support, presence or absence of hyperinflammation(defined as a C-reactive protein level of >150 mg per deciliter),presence or absence of bacteremia, prolonged (i.e., more than10 days) use of antibiotics, and the presence or absence ofhyperbilirubinemia (defined as a bilirubin level of >3 mgper deciliter [51 µmol per liter]). Use of intensive careresources was assessed on the basis of cumulative TISS-28 scores(the sum of daily scores), indicating the total number of interventionsper patient.19 We performed a predefined subgroup analysis forpatients staying in the ICU for at least a third day. A posthoc exploratory mortality analysis was performed censoring patientsfor whom intensive care was limited or who were withdrawn fromintensive care by a senior attending physician within 72 hoursafter admission for reasons of futility.
To minimize the possibility of bias in assessing the ICU staycaused by delays in the transfer of patients to a regular wardbecause of the unavailability of beds, patients were consideredto be ready for discharge when they no longer needed vital-organsupport and were receiving at least two thirds of their caloricintake by the normal enteral route or when they were sent toa ward. Physicians on the general wards to which patients weretransferred from intensive care had no access to the resultsof blood glucose testing and were unaware of the study treatmentassignment.
Statistical Analysis
On the basis of data from our previous study,5 we hypothesizedan absolute reduction in the risk of death of 7 percent afterat least three days of intensive insulin therapy. Testing thishypothesis required a sample of 1200 patients for a two-sidedalpha level of less than 0.05 and a beta level of 0.2 in thetargeted group of patients staying in the ICU for three or moredays.
The baseline and outcome variables were compared with the useof Student's t-test, the chi-square test, and the Mann–WhitneyU test, as appropriate. The effect of the intervention on timeto death in the hospital was assessed with the use of Kaplan–Meierestimates and proportional-hazards regression analysis. Patientsdischarged alive from the hospital were considered survivors.The hazard ratios for death, calculated by proportional-hazardsregression analysis, were corrected for all well-known, clinicallyrelevant baseline risk factors. The effect on time to weaningfrom mechanical ventilation and time to discharge from the ICUand from the hospital was assessed by cumulative hazard estimatesand proportional-hazards regression analysis, with censoringfor early deaths.
The data are presented as means ±SD or medians (withinterquartile ranges), unless otherwise indicated. Separateanalyses were performed for the intention-to-treat group andfor the group staying in the ICU for three or more days. Forcomparison with the results of our previous study in the surgicalICU,5 the effects on patients in the ICU for at least a fifthday were also documented. P values were not adjusted for multiplecomparisons. The study sponsors were not involved in the designof the study, the collection, analysis, or interpretation ofthe data, or the preparation of the manuscript.
Results
Nutrition and Blood Glucose Control
Table 1 gives the baseline characteristics on admission of all1200 patients enrolled in the study, including the 767 patientswho stayed in the ICU for at least a third day. Nutritionalintake and blood glucose levels are shown in Figure 2 (for insulindoses, see Table A in the Supplementary Appendix, availablewith the full text of this article at www.nejm.org). Hypoglycemiaoccurred more often in the intensive-treatment group than theconventional-treatment group. Most patients who had hypoglycemiahad only one episode. The severity of hypoglycemia was similarin the two groups (Table A in the Supplementary Appendix). Nohemodynamic deterioration, convulsions, or other events werenoted in association with any hypoglycemic event. Mortalityamong patients in the ICU who had hypoglycemia was 66.7 percentin the conventional-treatment group, as compared with 46.4 percentin the intensive-treatment group (P=0.1); the in-hospital mortalitywas 73.3 percent and 61.9 percent, respectively (P=0.4). Twopatients in the conventional-treatment group and three in theintensive-treatment group died within 24 hours after havinga hypoglycemic event. Independent risk factors for hypoglycemia,aside from intensive insulin therapy (odds ratio, 7.50; 95 percentconfidence interval, 4.50 to 12.50; P<0.001), were a stayin the ICU for three or more days (odds ratio, 3.33; 95 percentconfidence interval, 1.95 to 5.70; P<0.001), renal failurerequiring dialysis (odds ratio, 1.94; 95 percent confidenceinterval, 1.19 to 2.84; P=0.006), and liver failure as definedby alanine aminotransferase levels above 250 U per liter (oddsratio, 1.62; 95 percent confidence interval, 1.01 to 2.60; P=0.04).
Figure 2. Nutrition Administered to All 1200 Patients during the First 14 Days of Intensive Care and Daily Morning Blood Glucose Levels during the First 10 Days of Intensive Care.
In Panel A, feeding at 0 represents the administration of nutrition to patients admitted to the intensive care unit (ICU) after midnight between admission and 7 a.m., and 1 represents feeding on the first day after admission, from 7 a.m. on. Nutrition in the two groups was similar. Total kilocalories are given as means ±SE. In Panel B, in the box plot the fraction of nutrition administered by the enteral route is expressed as medians (indicated by horizontal lines within the bars) and interquartile ranges (with the 90th percentile indicated by the I bar). In Panel C, among patients staying in the ICU for three or more days, intensive insulin treatment was continued until discharge from the ICU (mean, 12.5 days, with a range up to 65 days). P<0.001 for the comparison between the two groups. To convert values for glucose to millimoles per liter, multiply by 0.05551.
Morbidity
Intention-to-Treat Population
In the intention-to-treat population, there was no significantdifference between the two treatment groups in the use of medicationsother than insulin. Of 1200 patients in the intention-to-treatpopulation, 9 were treated for septic shock with activated proteinC, 5 in the conventional-treatment group and 4 in the intensive-treatmentgroup (P=0.8). Of 644 patients receiving corticosteroid therapy,327 were in the conventional-treatment group and 317 were inthe intensive-treatment group (P=0.8). The corticosteroid therapyconsisted largely of immunosuppressive or antiinflammatory treatmentwith methylprednisolone (at a median dose of 40 mg [interquartilerange, 24 to 75] per treatment day among 233 patients in theconventional-treatment group and a median dose of 40 mg [interquartilerange, 29 to 65] per day among 249 patients in the intensive-treatmentgroup; P>0.9). Hydrocortisone was given for presumed adrenalfailure at a median dose of 125 mg (interquartile range, 100to 193) per day to 129 patients in the conventional-treatmentgroup and at a median dose of 135 mg (interquartile range, 100to 240) per day to 118 patients in the intensive-treatment group(P=0.2). Five patients, two in the conventional-treatment groupand three in the intensive-treatment group, received a mediandaily dose of 10 mg of dexamethasone (P>0.9).
Morbidity was reduced in the intensive-treatment group, as reflectedby a reduction in newly acquired kidney injury (8.9 to 5.9 percent,P=0.04) and in earlier weaning from mechanical ventilation,as compared with the conventional-treatment group (hazard ratio,1.21; 95 percent confidence interval, 1.02 to 1.44; P=0.03),along with earlier discharge from the ICU (hazard ratio, 1.15;95 percent confidence interval, 1.01 to 1.32; P=0.04) and fromthe hospital (hazard ratio, 1.16; 95 percent confidence interval,1.00 to 1.35; P=0.05) (Figure 3). There was no significant effecton bacteremia (reduction, 7 to 8 percent; P=0.5), prolongedrequirement of antibiotic agents (reduction, 24 to 21 percent;P=0.2), hyperbilirubinemia (reduction, 27 to 25 percent; P=0.4),hyperinflammation (reduction, 61 to 56 percent; P=0.1), or cumulativeTISS-28 scores (reduction, 308±16 to 272±13; P=0.08).Rates of readmission to the ICU were similar (6.3 percent) inthe two groups.
Figure 3. Effect of Intensive Insulin Therapy on Morbidity.
The effect of intensive insulin therapy on time to weaning from mechanical ventilation, time to discharge from the intensive care unit (ICU), and time to discharge from the hospital is shown for all patients (intention-to-treat analysis, Panel A) and for the subgroup of 767 patients staying in the ICU for three or more days (Panel B). P values for the comparison between the two groups were calculated by proportional-hazards regression analysis with censoring for early deaths. Circles represent patients.
Stays in ICU Longer Than Three Days
Among the 767 patients who stayed for more than three days inthe ICU, there was no significant difference between the twogroups in the use of any medications other than insulin. Amongthe 386 patients in the intensive-treatment group, intensiveinsulin therapy for at least a third day, as compared with conventionaltherapy, accelerated weaning from mechanical ventilation (hazardratio, 1.43; 95 percent confidence interval, 1.16 to 1.75; P<0.001),discharge from the ICU (hazard ratio, 1.34; 95 percent confidenceinterval, 1.12 to 1.61; P=0.002), and discharge from the hospital(hazard ratio, 1.58; 95 percent confidence interval, 1.28 to1.95; P<0.001) (Figure 3).
In the conventional-treatment group, 28.6 percent of patientsreceived dialysis therapy, as compared with 27.2 percent ofthose in the intensive-treatment group (P=0.7). The use of dialysisin patients who did not require dialysis before admission tothe ICU was not significantly reduced (22.7 percent in the conventional-treatmentgroup and 20.8 percent in the intensive-treatment group, P=0.5).However, acquired kidney injury occurring after randomization,as defined by a serum creatinine level at least twice that presenton admission to the ICU (12.6 percent in the conventional-treatmentgroup and 8.3 percent in the intensive-treatment group, P=0.05)and the fraction of patients reaching a peak serum creatininelevel greater than 2.5 mg per deciliter (39.4 and 32.5 percent,respectively; P=0.04), was reduced. Hyperbilirubinemia was presentin 55.2 percent of patients in the conventional-treatment groupand 47.3 percent of those in the intensive-treatment group (P=0.04).The levels of alanine aminotransferase or aspartate aminotransferasewere similar in the two groups.
The proportion of patients who had bacteremia (11.3 percent)or secondary bacteremia (7.3 percent) or received prolongedantibiotic therapy (37.6 percent in the conventional-treatmentgroup and 31.9 percent in the intensive-treatment group, P=0.09)was not significantly reduced. However, intensive insulin therapyreduced the incidence of hyperinflammation from 74 percent inthe conventional-treatment group to 67 percent in the intensive-treatmentgroup (P=0.03).
Intensive insulin therapy reduced the cumulative TISS-28 scoresamong patients in the ICU by 20 percent (454±22 in theconventional-treatment group vs. 388±17 in the intensive-treatmentgroup, P=0.02), reflecting a reduction in the costs of intensivecare.19,20 Among patients who underwent randomization and stayedin the ICU less than three days, none of the morbidity end pointswere significantly different in the two treatment groups. Beyondthe fifth day of intensive insulin therapy, all the morbidityend points studied were also beneficially affected, with noeffect among those treated for less than five days.
Mortality
Among the 1200 patients included in the intention-to-treat analysis,ICU and in-hospital mortality were not significantly reducedby intensive insulin therapy (Table 2 and Figure 4). For allpatients, mortality in the ICU at day 3 (2.8 percent vs. 3.9percent, P=0.31) and in-hospital mortality at day 3 (3.6 percentvs. 4.0 percent, P=0.72) were not significantly different inthe two treatment groups. Beyond the third day of intensiveinsulin therapy, the in-hospital mortality was reduced from52.5 to 43.0 percent (Figure 4 and Table 2). Death from allcauses in the ICU appeared to be reduced. The effect on mortalityamong patients staying for more than three days in the ICU wasshown in most of the subgroups stratified according to diagnosticcategory, but it was much less pronounced in the highest APACHEII quartile (Table 2). Among the 433 patients who stayed inthe ICU less than three days and for whom data were censoredafter randomization, 56 of those in the intensive-treatmentgroup and 42 in the conventional-treatment group died, but thestatistical significance of this finding varied depending onthe analytical approach (P=0.05 with the chi-square test; hazardratio, 1.09; 95 percent confidence interval, 0.90 to 1.32; P=0.35by uncorrected proportional-hazards analysis; hazard ratio,1.09; 95 percent confidence interval, 0.89 to 1.32; P=0.41 aftercorrecting for baseline risk factors listed in Table 2).
Figure 4. Kaplan–Meier Curves for In-Hospital Survival.
The effect of intensive insulin treatment on the time from admission to the intensive care unit (ICU) until death is shown for the intention-to-treat group (Panel A) and the subgroup of patients staying in the ICU for three or more days (Panel B). Patients discharged alive from the hospital were considered survivors. P values calculated by the log-rank test were 0.40 for the intention-to-treat group and 0.02 for the subgroup staying in the ICU for three or more days. P values calculated by proportional-hazards regression analysis were 0.30 and 0.02, respectively.
Beyond the fifth day of intensive insulin therapy, mortalitywas reduced from 54.9 to 45.9 percent (P=0.03), with no significanteffect among patients staying less than five days in the ICU(P=0.50).
Post Hoc Exploratory Mortality Analysis
Of the 1200 patients in the total study group, a post hoc analysiscensored data on 65 patients for whom intensive care had beenlimited or withdrawn within 72 hours after admission to theICU (26 patients in the conventional-treatment group and 39in the intensive-treatment group). Of these 65 patients, 29had long stays in the ICU (16 in the conventional-treatmentgroup and 13 in the intensive-treatment group), and 36 had shortstays (10 and 26, respectively). After censoring, the in-hospitalmortality in the intention-to-treat population was 37.8 percentin the conventional-treatment group versus 33.5 percent in theintensive-treatment group (P=0.1); among those with long staysin the ICU, the in-hospital mortality was 50.9 percent versus41.5 percent (P=0.01); and among those with short stays, itwas 15.4 percent versus 16.9 percent (P=0.7).
Discussion
Intensive insulin therapy during intensive care prevented morbiditybut did not significantly reduce the risk of death among allpatients in the medical ICU included in the intention-to-treatpopulation. However, among those who stayed in the ICU for threeor more days, intensive insulin therapy reduced morbidity andmortality.
The reduced morbidity resulted from the prevention of acquiredkidney injury, earlier weaning from mechanical ventilation,and earlier discharge from the medical ICU and the hospitalin patients who received intensive insulin therapy as comparedwith those who did not. In contrast to patients in the surgicalICU,5 however, those in the medical ICU had no detectable reductionin bacteremia, which may be explained by the fact that amongmedical patients sepsis often triggers admission to the ICU,irrespective of the disease necessitating hospital admission.Although infections other than bacteremia were not analyzedfor our study and may have been missed, the antiinflammatoryeffect8 and the protection of organ function9 appeared to beindependent of prevention of infection. Possible mechanismsof action include the prevention of cellular hypoxia by meansof reduced endothelial damage10 and the prevention of cytopathichypoxia.11
Analysis of the subgroup treated in the ICU for three or moredays showed not only a beneficial effect on morbidity but alsoa reduction in mortality that was absent in the total studypopulation. However, since the length of stay in the ICU cannotbe predicted for an individual patient and therefore the analysisbased on length of stay inevitably requires post-randomizationstratification, there is a risk of bias. It is unclear whetherintensive insulin therapy received for less than three dayscaused harm, as might be inferred from the greater number ofdeaths among patients staying less than three days in the ICU.Post hoc exploratory analysis, with its inherent limitations,suggested that this apparent difference in mortality among thosestaying a shorter time in the ICU could be explained by thehigher number of patients in the intensive-treatment group forwhom intensive care was limited or withdrawn for reasons offutility within 72 hours after admission. In our previous study,brief exposure to insulin therapy had no significant effecton the risk of death.5 Why 48 hours or less of insulin therapywould cause harm, whereas sustained treatment would be beneficial,is unclear.
An alternative and more likely explanation for the differencein the effect of intensive insulin therapy in the intention-to-treatpopulation, as compared with patients staying in the ICU forat least three days, is that the benefit from intensive insulintherapy requires time to be realized. Indeed, the interventionis aimed not at curing disease but at preventing complicationsthat occur during and, perhaps in part as a result of, intensivecare. Prevention probably does not occur when the patient hasa high risk of death from the disease causing admission to theICU and when the intervention is administered for a relativelyshort time. However, among patients in whom complications resultingfrom intensive care contribute to an adverse outcome, such apreventive strategy, if continued long enough, is likely tobe effective. This would explain why patients with long staysin the medical ICU benefit more than those with short stays,as shown in a surgical ICU.5
Among patients staying for at least three days in the ICU, theabsolute reduction in in-hospital mortality associated withintensive insulin therapy was similar to that in our previousreport5 and exceeded the effect on mortality in the ICU, indicatingthat intensive insulin therapy during intensive care had a carryovereffect. Such a longer-term effect is in line with our previousfinding of superior long-term rehabilitation among patientswith brain injury who received intensive insulin therapy duringintensive care.24 Mortality in a subgroup with a diagnosis ofdiabetes appeared to be unaffected by intensive insulin therapy,although the numbers were small. This finding may be explainedin part by the fact that the target blood glucose level wasnot reached in this subgroup. Indeed, achieving normoglycemiaappears crucial to obtaining the benefit of intensive insulintherapy.6
In the present study, normoglycemia was achieved with insulintitrated by the attending nurses in the ICU. Despite the useof guidelines similar to those used in the surgical study,5an episode of biochemical hypoglycemia occurred more often amongthe patients in the medical ICU. Liver failure and kidney failure,which increase the vulnerability to hypoglycemia, may partlyexplain this observation. However, logistic-regression analysisidentified hypoglycemia as an independent risk factor for death.Hence, it is possible that hypoglycemia induced by intensiveinsulin therapy may have reduced a portion of the potentialbenefit.
This study has certain limitations. Like our previous studyof the surgical ICU,5 this was a single-center study; and asin previous studies in patients with diabetes mellitus,25,26it was not possible to achieve strict blinding, because safeinsulin titration requires monitoring of blood glucose levels.However, because physicians on the general wards were unawareof the treatment assignments of patients receiving intensivecare and had no access to the results of blood glucose testing,bias in the analysis of the effect on length of stay in thehospital and in the analysis of in-hospital mortality was prevented.Furthermore, since there was no survival benefit in the intention-to-treatgroup, as compared with the subgroup staying in the ICU forthree or more days, the use of intensive insulin therapy inall patients in the medical ICU, including those staying lessthan three days, could be questioned. Because patients who willhave a prolonged stay in the ICU cannot be identified with certaintyon admission, adequately powered trials are needed to addressthis important issue. On the basis of our current data, suchstudies would require at least 5000 patients in the medicalICU.
Thus, targeting blood glucose levels to below 110 mg per deciliterwith insulin therapy prevented morbidity but did not significantlyreduce mortality among all patients in our medical ICU. However,intensive insulin therapy in patients who stayed in the ICUfor at least three days was associated with reduced morbidityand mortality. Large multicenter trials are needed to confirmthese preliminary results.
Supported by grants from the Belgian Fund for Scientific Research(G.0278.03 and G.3C05.95N), the Research Council of the Universityof Leuven (OT/03/56), and the Belgian Foundation for Researchin Congenital Heart Diseases (to Dr. Van den Berghe).
Dr. Van den Berghe reports having received an unrestricted researchgrant from Novo Nordisk; and Dr. Bouillon, an unrestricted researchgrant from Servier. No other potential conflict of interestrelevant to this article was reported.
We are indebted to Mona Eerdekens, M.Sc., and Peggy Claes, R.N.,for assistance with blood samples and data collection; to theclinical fellows in the ICU for APACHE II scoring; to the nursesfor daily TISS-28 scoring and for excellent compliance withthe protocol; to Prof. Emmanuel Lesaffre for inspiring discussionsof the statistical analysis; and to HemoCue, Ängelholm,Sweden, for generously providing the equipment and reagentsfor point-of-care blood glucose measurements.
Source Information
From the Departments of Intensive Care Medicine (G.V.B., P.J.W., I.M.) and Medical Intensive Care Medicine (A.W., G.H., W.M., E.V.W., H.B.) and the Laboratory for Experimental Medicine and Endocrinology (R.B.), Catholic University of Leuven, Leuven, Belgium.
Address reprint requests to Dr. Van den Berghe at the Department of Intensive Care Medicine, Catholic University of Leuven, B-3000 Leuven, Belgium, or at greta.vandenberghe{at}med.kuleuven.be.
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Intensive Insulin Therapy in the Medical ICU
Hammer L., Dessertaine G., Timsit J.-F., Aberegg S. K., Tamler R., LeRoith D., Roth J., Van den Berghe G., Wilmer A., Bouillon R., Malhotra A.
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Lacherade, J.-C., Outin, H., De Jonghe, B., Bracco, D., Schricker, T., Carvalho, G., Muller, L., Jaber, S., Lefrant, J. Y., Van den Berghe, G., Wilmer, A., Bouillon, R., Ellger, B., van den Heuvel, I., Poelaert, J., Brunkhorst, F. M., Reinhart, K., Engel, C.
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40 mg per deciliter [2.2 mmol per liter]) were analyzed. 
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