- Open Access
The effect of diabetes mellitus on the association between measures of glycaemiccontrol and ICU mortality: a retrospective cohort study
Critical Care volume 17, Article number: R52 (2013)
In critical illness, four measures of glycaemic control are associated with ICUmortality: mean glucose concentration, glucose variability, the incidence ofhypoglycaemia (≤ 2.2 mmol/l) or low glucose (2.3 to 4.7 mmol/l). Underlyingdiabetes mellitus (DM) might affect these associations. Our objective was to studywhether the association between these measures of glycaemic control and ICUmortality differs between patients without and with DM and to explore the cutoffvalue for detrimental low glucose in both cohorts.
This retrospective database cohort study included patients admitted betweenJanuary 2004 and June 2011 to a 24-bed medical/surgical ICU in a teachinghospital. We analysed glucose and outcome data from 10,320 patients: 8,682 withoutDM and 1,638 with DM. The cohorts were subdivided into quintiles of mean glucoseand quartiles of glucose variability. Multivariable regression models were used toexamine the independent association between the four measures of glycaemic controland ICU mortality, and for defining the cutoff value for detrimental lowglucose.
Regarding mean glucose, a U-shaped relation was observed in the non-DM cohort withan increased ICU mortality in the lowest and highest glucose quintiles (odds ratio= 1.4 and 1.8, P < 0.001). No clear pattern was found in the DMcohort. Glucose variability was related to ICU mortality only in the non-DMcohort, with highest ICU mortality in the upper variability quartile (odds ratio =1.7, P < 0.001). Hypoglycaemia was associated with ICU mortality inboth cohorts (odds ratio non-DM = 2.5, P < 0.001; odds ratio DM = 4.2,P = 0.001), while low-glucose concentrations up to 4.9 mmol/l wereassociated with an increased risk of ICU mortality in the non-DM cohort and up to3.5 mmol/l in the DM cohort.
Mean glucose and high glucose variability are related to ICU mortality in thenon-DM cohort but not in the DM cohort. Hypoglycaemia (≤ 2.2 mmol/l) wasassociated with ICU mortality in both. The cutoff value for detrimental lowglucose is higher in the non-DM cohort (4.9 mmol/l) than in the DM cohort (3.5mmol/l). While hypoglycaemia (≤ 2.2 mmol/l) should be avoided in bothgroups, DM patients seem to tolerate a wider glucose range than non-DMpatients.
Hyperglycaemia, hypoglycaemia and increased glucose variability in critically illpatients are independently associated with ICU mortality [1–6]. In the last decade many clinical triallists have attempted to improvemortality rates through intensive insulin therapy. Unfortunately, these trials haveproduced conflicting data, with some of the studies showing lower and others highermortality with strict glucose control, the latter possibly due to an increased incidenceof hypoglycaemia [7–12]. There is consensus about the importance to avoid hypoglycaemia and many ICUshave therefore increased their lower glucose limit . However, there is no consensus about the optimal target glucose range. In aprevious database cohort study, we found an optimal mean glucose range of 6.7 to 8.4mmol/l in a medical cohort and 7.0 to 9.4 mmol/l in a surgical cohort . We additionally found that glucose concentrations that were low but abovehypoglycaemic levels (between 2.3 and 4.7 mmol/l) were associated with increased ICUmortality . Thus, in addition to the mean glucose concentration, glucose variability andhypoglycaemia, a fourth measure of glycaemic control - low glucose (2.3 to 4.7 mmol/l) -is associated with ICU mortality in the critically ill.
Underlying diabetes mellitus (DM) might affect the abovementioned associations. In arecent review we examined the current literature on glycaemic control and mortality indiabetic ICU patients and we found that, despite patients with DM having an increasedrisk of developing complications when admitted to the ICU, their risk of mortality isnot increased . In addition, ICU patients with DM have lower mortality in the higher meanglucose range compared with those without DM, although varying cutoff values were used [16–19]. Some studies found the opposite, with higher mortality rates for DM patientsin the low-normal mean glucose range. However, these findings were unadjusted resultsonly [18, 20] and this relation was not significant after adjustment for severity ofdisease . Furthermore, high glucose variability in ICU patients with DM seems to beless harmful than in patients without DM [21, 22] although data are limited. Lastly, hypoglycaemia is associated with mortalityin patients with and without DM [3, 4, 23], while the risk of hypoglycaemia is higher in patients with DM [4, 24]. Altogether, some of the abovementioned findings are inconsistent and none ofthe reviewed studies evaluated all four measures of glycaemic control concomitantly.
The objective of this study was to determine whether the association between measures ofglycaemic control - mean glucose, glucose variability (measured as the mean absoluteglucose (MAG) change), the occurrence of hypoglycaemia (≤ 2.2 mmol/l) or lowglucose (2.3 to 4.7 mmol/l) - and ICU mortality differs between patients without andwith underlying DM in a large cohort of critically ill patients admitted to a generalICU of a teaching hospital in the Netherlands. We also explored the cutoff value fordetrimental low glucose in both populations.
Materials and methods
Design and setting
The current study was conducted as a single-centre retrospective database cohortstudy in a 24-bed mixed surgical/medical ICU in a teaching hospital (Onze LieveVrouwe Gasthuis, Amsterdam, the Netherlands). All data were collected prospectively.All beds were equipped with a clinical information system (MetaVision;i MDsoft, Tel Aviv, Israel) from which clinical and laboratorydata were extracted. The nurse-to-patient ratio was on average 1:2, depending on theseverity of disease. According to national guidelines this research is exempt fromethical approval because it is a retrospective study. The requirement for informedconsent was waived because all data were anonymous and collected retrospectively.
Glucose regulation protocol
A glucose regulation protocol, with a target blood glucose concentration of 4.0 to7.0 mmol/l, was implemented in 2001 after the publication of the study by van denBerghe and colleagues . The glucose regulation sliding scale algorithm was connected to theclinical information system and fully computerised with an integrated decisionsupport module controlling the algorithm . The glucose regulation protocol has been reported previously [2, 3, 14]. In April 2009, following the publication of the Normoglycaemia inIntensive Care Evaluation - Survival Using Glucose Algorithm Regulation investigatorsin 2009 , a new target blood glucose concentration of 5.0 to 9.0 mmol/l wasinstituted. To date, this new target blood glucose range is maintained in routineintensive care management.
Cohort and data collection
Relevant data were extracted from the clinical information system concerning patientsadmitted to the ICU between January 2004 and June 2011. Readmissions, patients with awithholding care policy, and patients with < 3 glucose values during ICU admissionwere excluded. The assignment of each patient's diabetic status on ICU admission wasbased on the use of oral glucose-lowering drugs and/or insulin therapy. Demographicvariables, admission diagnosis, glucose values, the occurrence of hypoglycaemia andICU and hospital mortality rates were assessed. Severity of disease was assessedusing the Acute Physiology and Chronic Health Evaluation (APACHE) II score onadmission . For each subsequent day of ICU admission, the Sequential Organ FailureAssessment score was assessed as a measurement of severity of disease . The maximal Sequential Organ Failure Assessment score was determined forthe patient's entire stay in the ICU .
Glucose was measured from blood samples obtained from an arterial catheter using theAccu-chek (Roche/Hitachi, Basel, Switzerland). Results were automatically stored inthe clinical information system. For each patient, mean glucose during admission wascalculated from all glucose values measured during ICU admission. As markers forglucose variability, the MAG change  and the standard deviation were calculated per patient. Hypoglycaemia wasdefined as one or more glucose values ≤ 2.2 mmol/l, which is in accordance withprevious trials [7, 11]. Although our blood glucose target range in the initial years was between4.0 and 7.0 mmol/l, we later found an association between the presence of a glucosevalue ≤ 4.7 mmol/l and ICU mortality . Low glucose was therefore defined as the presence of at least one glucosevalue between 2.3 and 4.7 mmol/l.
Continuous data are presented as mean (standard deviation) or median (interquartilerange), as appropriate, and compared using Student's t test or theMann-Whitney rank-sum test, respectively. Categorical data are presented aspercentages and compared using the chi-square test. In accordance with our previousstudies, mean glucose and glucose variability (MAG change) were categorised intoequally sized quintiles  and quartiles  and were plotted against ICU mortality for the DM and non-DM cohortsseparately.
The independent association between mean glucose and ICU mortality was examined usingmultivariable logistic regression analysis calculating odds ratios (ORs) with 95%confidence intervals (CIs). The quintile with the lowest mortality incidence was usedas a reference. Based on clinical relevance and prognostic scoring, we adjusted fordemographics (age, sex), severity of disease (using the APACHE II score),hypoglycaemia (≤ 2.2 mmol/l) and cardiothoracic surgery as the admissioncategory. Cardiothoracic surgery was included as a covariate for several reasons: agenerally lower mortality in this group compared with other surgical patients, arelatively low APACHE II score, a relatively short length of ICU stay and severaldifferent demographic and physiological characteristics of this group from thegeneral ICU population, which could be reflected in differences in mean glucoseconcentration and glucose variability . In an alternative model, adjustment was made for the occurrence ofglucose values ≤ 4.7 mmol/l, which is also independently associated withmortality [3, 30].
A second multivariable regression model was used to assess the independentassociation between glucose variability (MAG change) and ICU mortality, the quartilewith lowest mortality incidence used as a reference. In this model the same potentialconfounders were used including the variable mean glucose. Furthermore, to assess theassociation between hypoglycaemia (≤ 2.2 mmol/l) and low glucose (2.3 to 4.7mmol/l) and ICU mortality, unadjusted and adjusted ORs with 95% CIs were calculated,the latter using a third multivariable regression model adjusted for age, sex,severity of disease, cardiothoracic surgery and sepsis as admission diagnoses.
In both cohorts, we also assessed the cutoff value for detrimental low glucose, byperforming the latter analysis for different blood glucose cutoff values.Additionally, when we adjusted the logistic regression models for the change intarget glucose range in the studied period, no change in our results was observed(data not shown). All statistical analyses were performed in SPSS 18.0 (SPSS Inc,Chicago, IL, USA).
From 11,901 ICU admissions, 10,320 patients were selected for analyses after excluding842 readmissions, 105 patients with a withholding care policy, and 714 patients with< 3 glucose measurements. The remaining cohort consisted of 8,682 (84.2%) patientswho did not have DM at the time of ICU admission (non-DM cohort) and 1,638 (15.8%)patients who had DM at the time of ICU admission (DM cohort). The percentage of medicaland surgical ICU admissions in the entire cohort was 26% and 74%. The non-DM:DM ratiowithin these groups was 9:1 in patients with a medical ICU admission diagnosis and 4:1in patients with a surgical ICU admission diagnosis. Table 1illustrates patient characteristics of the entire study population as well as thedifferences between the non-DM cohort and the DM cohort.
Association between mean glucose concentration and ICU mortality
Figure 1 demonstrates the quintiles of mean glucose ranges percohort (non-DM cohort: < 6.8, 6.8 to 7.3, 7.3 to 7.9, 7.9 to 8.9, > 8.9 mmol/l; DMcohort: < 6.9, 6.9 to 7.4, 7.4 to 8.0, 8.0 to 8.9, > 8.9 mmol/l) and correspondingICU mortality rates. This resulted in a U-shaped relationship between mean glucoseand ICU mortality in the non-DM cohort, with high ICU mortality in the lowest andhighest glucose quintile (11.8% and 7.7%). Multivariable logistic regression analysisin the non-DM cohort showed that mean glucose values in the lowest and highestquintiles were associated with a significantly higher OR for ICU mortality comparedwith the quintile with the lowest ICU mortality (Figure 2).This was supported by a significant nonlinear relationship between mean glucose andICU mortality (P for trend < 0.001). When we adjusted the logisticregression model for the occurrence of glucose values ≤ 4.7 mmol/l, the OR forICU mortality in the lowest quintile no longer reached significance in the non-DMcohort (OR = 1.3, 95% CI = 0.9 to 1.8, P = 0.17). The increased ICUmortality in the non-DM cohort in the lower part of the U-curve therefore seems to bedue to the relation between glucose values ≤ 4.7 mmol/l and ICU mortality. Incontrast, no clear pattern was found in the DM cohort in unadjusted (Figure 1B) or multivariate analysis (data not shown).
Association between glucose variability and ICU mortality
The ranges of MAG change per quartile (non-DM cohort: < 0.37, 0.37 to 0.56, 0.56to 0.82, > 0.82 mmol/l/hour; DM cohort: < 0.56, 0.56 to 0.76, 0.76 to 1.03, > 1.03mmol/l/hour) and corresponding ICU mortality per cohort are shown in Figure 3. This resulted in a linear relationship in the non-DM cohort,with the highest mortality rate seen in the upper MAG quartile (13.4%). Multivariablelogistic regression analysis for the non-DM cohort is displayed in Figure 4; the OR for ICU mortality was highest in the upper MAG changequartile (OR = 1.69, P = 0.001). This was supported by a significantrelationship between MAG quartiles and ICU mortality (P for trend = 0.004).In contrast, in the DM cohort no clear pattern was found in unadjusted (Figure 3B) or multivariate analysis (data not shown).
Association between hypoglycaemia and low glucose and ICU mortality
The percentage of patients who experienced at least one episode of hypoglycaemia(≤ 2.2 mmol/l) was similar in both cohorts (Table 1). Lowglucose (2.3 to 4.7 mmol/l) occurred more frequently in the DM cohort. The increasein glucose target range as introduced in 2009 decreased the percentage of patientswho experienced both hypoglycaemia (before 3.3%; after 0.3%) and low glucose (before36.3%; after 8.4%).
ICU mortality rates for hypoglycaemia were 29.7% and 21.1% in the non-DM and DMcohorts, respectively. Unadjusted ORs of hypoglycaemia (≤ 2.2 mmol/l) for ICUmortality in the occurrence of hypoglycaemia were 6.2 (95% CI = 4.8 to 8.1, P < 0.001) in the non-DM cohort and 6.6 (95% CI = 3.3 to 13.1, P <0.001) in the DM cohort. In logistic regression analysis, adjusted for potentialconfounders (see above), the OR of hypoglycaemia for ICU mortality was stillsignificant in both cohorts (non-DM cohort: OR = 2.5, 95% CI = 1.8 to 3.4, P < 0.001; DM cohort: OR = 4.2, 95% CI = 1.8 to 10.1, P = 0.001).
ICU mortality rates for low glucose (2.3 to 4.7 mmol/l) were 13.1% and 5.2% in thenon-DM and DM cohorts, respectively. The OR of low glucose for ICU mortality wassignificant in the non-DM cohort (unadjusted OR = 5.3, 95% CI = 4.4 to 6.4, P < 0.001; adjusted OR = 1.5, 95% CI = 1.2 to 1.9, P < 0.001). Whenexploring the cutoff value for detrimental low glucose in the non-DM cohort, we foundthat lowest blood glucose concentrations up to 4.9 mmol/l were associated with anincreased risk for ICU mortality (adjusted OR = 1.3, 95% CI = 1.1 to 1.7, P = 0.01). In contrast, when exploring the cutoff value for detrimental lowglucose in the DM cohort, we found that lowest blood glucose concentrations up to 3.5mmol/l were associated with an increased risk of ICU mortality (adjusted OR = 2.1,95% CI = 1.2 to 3.7, P = 0.01). With glucose values between 3.5 and 4.7mmol/l, no significant effect on the OR for ICU mortality was found. Poissonregression analysis, which we used in a previous study to adjust for daily SequentialOrgan Failure Assessment score over time , amounted to similar results (data not shown).
In this retrospective database cohort study evaluating the association of four measuresof glycaemic control and ICU mortality concomitantly, we found striking differencesbetween the non-DM cohort and the DM cohort. In the non-DM cohort, ICU mortality wassignificantly related to all four measures of glycaemic control: mean glucose, glucosevariability, the occurrence of hypoglycaemia (≤ 2.2 mmol/l) and low glucoseconcentrations up to 4.9 mmol/l. In contrast, in the DM cohort, only the occurrence ofhypoglycaemia (≤ 2.2 mmol/l) and low-glucose concentrations up to 3.5 mmol/l weresignificantly associated with ICU mortality, while mean glucose and glucose variabilitywere not. The presence of DM thus seems to affect the association between glucosecontrol and ICU mortality.
Our findings support the results of previous studies that have focused on understandingthe association between the presence of DM at ICU admission, glycaemia, and ICUmortality [7, 8, 16–19, 31, 32]. In all these studies, a stronger association between hyperglycaemia and ICUmortality was found in patients without DM, in comparison with patients with DM.
Hypoglycaemia has been found to be a risk factor of mortality in patients without andwith DM in the literature [3, 4, 7, 8, 30, 33, 34]. Of note, different cutoff values were used to define hypoglycaemia, rangingfrom ≤ 2.2 mmol/l [4, 35] up to ≤ 4.7 mmol/l [3, 33]. We also found a significant independent association between hypoglycaemia(≤ 2.2 mmol/l) and ICU mortality, in both the non-DM and DM cohorts. However, theassociation between low glucose (2.3 and 4.7 mmol/l) and ICU mortality was onlysignificant in the non-DM cohort, not in the DM cohort. When exploring the cutoff valuefor detrimental low glucose in the present cohort, we found that lowest blood glucoseconcentrations up to 4.9 mmol/l were associated with an increased risk of ICU mortalityin the non-DM cohort, and 3.5 mmol/l in the DM cohort. The cutoff value in the non-DMcohort is in line with our previous study, in which we found that lowest glucose valuesup to 4.7 mmol/l were associated with significant increased ICU mortality . Furthermore, this cutoff value is supported by the finding that the highermortality in the lower half of the U-shaped curve (< 6.8 mmol/l) in the non-DM cohortis mainly determined by the occurrence of glucose values ≤ 4.7 mmol/l and less bythe glucose range between 4.7 and 6.8 mmol/l. The cutoff value for detrimental lowglucose we found in our DM cohort (≤ 3.5 mmol/l) is also in line with theliterature [23, 30]. Both studies found that glucose concentrations ≤ 3.9 mmol/l weresignificantly associated with mortality in a subgroup of DM patients. Altogether, we canconclude that the cutoff value for detrimental low glucose is lower in the DM populationthan in the non-DM population.
The association between glucose variability and ICU mortality in patients without andwith DM was studied previously . In this observational study of 4,084 patients (including 942 DM patients), astrong association of glucose variability - expressed as the coefficient of variation(standard deviation/mean glucose level) - with mortality was found in patients withoutDM, while, in concordance with our study, no association was found in patients with DM . Of note, this measure of glucose variability does not take order and timeinto account.
Several explanations can be considered for the different associations between glycaemiccontrol and ICU mortality in patients without and with pre-existing DM. We previouslysuggested that adaptation to hyperglycaemia might be a key mechanism . Acute hyperglycaemia and inflammation induce oxidative stress, which causesendothelial damage . In patients without DM, cellular adaptation mechanisms will be activated forthe first time in the acute care setting, whereas patients with DM could already haveadapted to these insults during their years with DM and therefore better tolerateepisodes of hyperglycaemia in an acute care setting. In addition, cellular adaptation torecurrent hypoglycaemia is also a well-established phenomenon [37–39]. Although speculative, adaptation to low glucose will already be present inpatients with DM and might explain why patients with DM can withstand relatively lowglucose values better.
Our results should be viewed in light of the study's strengths and limitations.Strengths of our study include the large number of ICU patients and that glucose valueswere captured automatically, which prevents transcription errors. Furthermore, this isthe first study examining all four markers of glycaemic control in a non-DM cohort and aDM cohort simultaneously. Also, we used a time-based metric for glucose variability andwe explored multiple cutoff values for hypoglycaemia. Potential limitations of the studyare that it is a single-centre study and retrospective in design, and thus ispotentially subject to systematic error and bias. However, all data were prospectivelycollected and independently measured. Moreover, the findings are robust and internallyconsistent.
As in all studies in this field, our definition for a patient's diabetic status may benonrepresentative. Unfortunately, glycosylated haemoglobin testing was not performedbefore ICU admission and we were unable to make a distinction between type 1 and type 2DM patients. In addition, we were not able to distinguish between diabetes patients withgood and poor chronic control, who may become hyperglycaemic due to acute illness.Whether this might affect the optimal glucose target for the DM cohort remainsunknown.
Another limitation was that we were not able to distinguish between spontaneous(illness-related) and treatment-induced hypoglycaemia or variability. However, otherstudies could make this distinction. Finfer and colleagues reported that patients whohad encountered severe or moderate hypoglycaemia while not being treated with insulinwere at an increased mortality risk . But they also demonstrated that, although to a lesser extent,insulin-induced hypoglycaemia was associated with an increased risk for ICU death. Incontrast, Kosiborod and colleagues only reported a high risk for mortality in patientshospitalised with acute myocardial infarction who developed hypoglycaemia spontaneously.Iatrogenic hypoglycaemia after insulin therapy was not associated with higher mortalityrisk .
Furthermore, in our cohort, most patients were admitted for cardiothoracic surgery; wecorrected for this potential confounder in our regression analyses and still foundsignificantly increased ICU mortality in the lowest and highest mean glucose quintilesand in the highest glucose variability quartile in the non-DM cohort. Moreover, the highamount of cardiothoracic surgery patients in the studied cohort may also havecontributed to the high administration level of corticosteroids. In our hospital, as inmany European hospitals (but not in most North American cardiac surgical centres),corticosteroid administration during cardiac surgery is part of routine care. Allpatients who were in shock or had sepsis or systemic inflammatory response syndrome alsoreceived corticosteroids. This could possibly limit the external validity of thissingle-centre study.
In our analyses of glucose variability, we did not correct for the frequency of glucosemeasurements during ICU admission. However, we did correct for severity of disease,which in itself is clearly correlated with the frequency of glucose measurements and ICUmortality. Furthermore, the concern that the frequency of blood glucose measurements mayinfluence the relation between the MAG and ICU mortality has been previously discussed . MAG is independent of the number of measurements, as long as blood glucosekeeps changing at a constant rate. The MAG only increases when there is actually moreglucose variability. The possibility to capture variability, if there is any, increaseswhen the number of glucose measurements is increased. However, this can be said for allmeasures of glucose variability and this is not unique for the MAG change.
A limitation of our correction for severity of disease is the use of the APACHE IIscore. Although the validation of the use of APACHE II score to predict mortality incardiac surgery patients is lacking, this adjustment is the best available method . Finally, because of the observational nature of the study, no proof ofcausation can be derived from the abovementioned associations between glycaemic controland ICU mortality.
This retrospective database cohort study shows that the presence of DM affects theassociation between three out of four measures of glycaemic control and ICU mortality.Mean glucose and high glucose variability were associated with ICU mortality in thenon-DM cohort but not in the DM cohort, whereas hypoglycaemia (≤ 2.2 mmol/l) wasassociated with ICU mortality in both. We additionally found a higher cutoff value fordetrimental low glucose in our non-DM cohort (4.9 mmol/l) than the DM cohort (3.5mmol/l). Glucose concentrations ≤ 4.9 mmol/l should therefore be avoided in thenon-DM cohort, while DM patients seem to tolerate a wider glucose range. Further studiesshould examine whether new technologies - that is, continuous glucose monitoringtechnology - could be of use for clinicians to improve glycaemic control.
The presence of DM affects the association between three out of fourmeasures of glycaemic control and ICU mortality.
Mean glucose relates to ICU mortality by a U-shaped curve in thenon-DM population, whereas no clear association was found in the DM population.
High glucose variability is only related to ICU mortality in thenon-DM cohort.
The occurrence of hypoglycaemia (≤ 2.2 mmol/l) is related toICU mortality in both populations and should undoubtedly be avoided.
The cutoff value for detrimental low glucose in the non-DM population(4.9 mmol/l) seems to be higher than in the DM population (3.5 mmol/l).
Acute Physiology and Chronic Health Evaluation
mean absolute glucose
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The authors declare that they have no competing interests.
MKS participated in the design of the study, performed the statistical analysis, andwrote the manuscript. HMO-vS, SES, JH and JBLH participated in the design of the study,contributed to the interpretation of the data, and revised the manuscript critically forimportant intellectual content. RJB participated in the design of the study, performedacquisition of the data, contributed to the interpretation of the data, and revised themanuscript for important intellectual content. JHDV participated in the design of thestudy, contributed to the interpretation of the data, and participated in the writing ofthe manuscript. All authors read and approved the final manuscript.
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Sechterberger, M.K., Bosman, R.J., Oudemans-van Straaten, H.M. et al. The effect of diabetes mellitus on the association between measures of glycaemiccontrol and ICU mortality: a retrospective cohort study. Crit Care 17, R52 (2013). https://doi.org/10.1186/cc12572
- Glycaemic Control
- Diabetes Mellitus Patient
- Clinical Information System
- Glucose Variability
- Glucose Range