Glycated hemoglobin at admission in the intensive care unit: Clinical implications and prognostic relevance

    Glycated hemoglobin at admission in the ICU: clinical implications and prognostic relevance Maria Kompoti, Martha Michalia, Vaia Salma, Evangelia Diogou, Anthi Lakoumenta, Phyllis-Maria Clouva-Molyvdas PII: DOI: Reference:

S0883-9441(14)00343-8 doi: 10.1016/j.jcrc.2014.08.014 YJCRC 51619

To appear in:

Journal of Critical Care

Please cite this article as: Kompoti Maria, Michalia Martha, Salma Vaia, Diogou Evangelia, Lakoumenta Anthi, Clouva-Molyvdas Phyllis-Maria, Glycated hemoglobin at admission in the ICU: clinical implications and prognostic relevance, Journal of Critical Care (2014), doi: 10.1016/j.jcrc.2014.08.014

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Glycated hemoglobin at admission in the ICU: clinical implications and

T

prognostic relevance

RI P

Maria Kompoti1, Martha Michalia1, Vaia Salma1, Evangelia Diogou1, Anthi

1

MA NU

SC

Lakoumenta2, Phyllis-Maria Clouva-Molyvdas1

Intensive Care Unit, Thriassio General Hospital of Eleusis, Athens, Greece

2

Department of Laboratory Hematology, Thriassio General Hospital of Eleusis,

ED

Athens, Greece

PT

Correspondence: Maria Kompoti, Vithinias 18, Nea Smirni, 17123 Athens, Greece

CE

Tel: +30.210.9318700

AC

Email: [email protected]

1

ACCEPTED MANUSCRIPT

2

INTRODUCTION

T

Glycated hemoglobin (HbA1c), a marker of long-term glycemic control in patients

RI P

with diabetes mellitus (DM), is formed by non-enzymatic glycation of valine and lysine residues in the hemoglobin molecule. Its concentration depends on the

SC

lifespan of erythrocytes and on plasma glucose concentration [1]. HbA1c reflects the

MA NU

glycemic state of the previous three to four months, but it is weighted to more recent values, with approximately half of its value being determined by the plasma glucose level in the last month and the remainder over the previous two months [2]. Guidelines of diabetes management recommend an HbA1c target below 7% as an

ED

indicator of adequate glycemic control in diabetic patients [3].

PT

Recently, the American Diabetes Association introduced HbA1c as a diagnostic criterion for diabetes, suggesting that a level of ≥6.5% is consistent with a diagnosis

CE

of diabetes and a level of 5.7% to 6.4% with a diagnosis of prediabetes [4]. These

AC

cutoff values are based mostly on outpatient populations, not acutely ill at the time of testing [5]. A limited number of studies, mainly in cardiosurgical patients, have implicated HbA1c as a tool for identifying previously undiagnosed DM in acute care setting and reported a prognostic significance of HbA1c for morbidity and mortality, not only in-hospital but long-term as well [6]. However, the clinical significance of HbA1c in critically ill patients, particularly those with previously undiagnosed DM, has not been adequately explored. A recent study in diabetic patients with sepsis has shown that the HbA1c level on admission in the intensive care unit (ICU) was an independent predictor of ICU mortality [7].

ACCEPTED MANUSCRIPT

3

Additionally, another study investigating the impact of chronic and acute hyperglycemia in critically ill diabetic patients showed an interaction between

RI P

T

admission HbA1c and glucose levels and mortality [8].

Our study investigated the clinical significance of HbA1c levels on admission in the

MA NU

admitted in a multidisciplinary ICU.

SC

ICU as a prognostic marker for morbidity and mortality in critically ill patients

METHODS

ED

Patients-Data

PT

The study was performed in an 8-bed medical/surgical intensive care unit (ICU) of a tertiary hospital during the period between July 1, 2006 and April 1, 2013). All

CE

patients admitted in the ICU were prospectively followed until the ICU outcome

AC

(discharge from the ICU or death in the ICU). Patients with length of stay (LOS) shorter than 48h, and readmissions were excluded from the study. Data recorded were: patient demographics, medical history, admission category (medical, elective surgical, emergency surgical, trauma), APACHE II and SOFA scores at admission in the ICU, Charlson’s comorbidity index [9], number of packed red blood cell units transfused before admission in the ICU, HbA1c and blood glucose at admission in the ICU, ward hospitalization before admission in the ICU, ICU-acquired infections, ICU day of the first infectious episode, need for continuous renal replacement therapy (CRRT) in the ICU, duration of mechanical ventilation, LOS in

ACCEPTED MANUSCRIPT

4

the ICU, ICU outcome (death/discharge). In trauma patients, the Injury Severity Score (ISS) was calculated by taking the highest Abbreviated Injury Scale (AIS)

RI P

T

severity code in each of the three most severely injured ISS body regions (head or neck, face, chest, abdominal or pelvic contents, extremities or pelvic girdle,

SC

external), squaring each AIS code and adding the three squared numbers [10]. A prior diagnosis of DM was recorded, if at least one prescription for insulin or an oral

MA NU

antidiabetic agent had been handled and/or there had been a hospital discharge diagnosis or a family doctor diagnosis of type 1 or type 2 diabetes recorded before the date of admission in the ICU. Patients not fulfilling either of the above criteria

PT

HbA1c measurement

ED

were classified as not having a known history of diabetes.

The determination of HbA1c was obtained by the Variant TM HbA1c /HbA2 Dual Kit

CE

(BIO-RAD Laboratories GmbH, München, Germany). The analyzer utilizes the

AC

principles of ion exchange high performance liquid chromatography (HPLC) for the automatic separation of normal and abnormal hemoglobin and the accurate determination of hemoglobins A1c, F and A2 in whole blood samples. Normal range is 4.4 -6.4%. The method has been certified by the National Glycohemoglobin Standardization Program (http://www.ngsp.org/). Patient groups To account for potential misclassification of a previously undiagnosed abnormal glycemic status (diabetes, prediabetes), patients without prior diagnosis of diabetes mellitus were classified according to the admission HbA1c as diabetic (HbA1c ≥

ACCEPTED MANUSCRIPT

5

6.5%), having prediabetes (HbA1c within the range 5.7–6.4%) and normal (HbA1c ≤ 5.6%), based on the American Diabetes Association criteria [4]. Subsequently,

RI P

T

according to glycemic status, patients of the study formed four groups: N (normal), PD (prediabetes), UD (previously undiagnosed diabetes) and DM (known diabetes

MA NU

SC

mellitus).

The protocol was approved by the Institutional Review Board and Ethics Committee of the hospital. Patients or their closest relatives gave informed consent prior to

PT

Statistical analysis

ED

inclusion in the study.

CE

Categorical variables were analyzed with Fisher’s exact test. Normality of continuous

AC

variables was assessed with Kolmogorov-Smirnov test. Normally distributed data were analyzed with Student’s t-test. Skewed data were analyzed with Mann-Whitney test. Survival analysis was performed with Kaplan-Meier procedure, and survival rates were compared with log-rank test. Logistic regression models were fitted with ICU mortality as the dependent variable and baseline characteristics (age, sex, admission category, APACHE II score at admission, SOFA score at admission, Charlson’s comorbidity index, HbA1c at admission, ISS only in trauma patients) as explanatory (independent) variables. Entry criterion in the models was set at p<0.1. Model fitting was assessed with plots of residuals. Calibration was assessed with Hosmer-Lemeshow’s test. Autocorrelation was assessed using residuals, with

ACCEPTED MANUSCRIPT

6

calculation of first-order autocorrelation coefficient and the Dubin-Watson test. Discrimination ability of the models was assessed with c index, expressed as the area

RI P

T

under the receiver operating curve (ROC) of the model-predicted probability against the dependent variable (ICU mortality).

MA NU

analyses, alpha was set at 0.05 (2-sided).

SC

Data analysis was performed with SPSS 17.0 (IBM Corporation, NY, 2008). For all

RESULTS

During the study period, 1095 patients were admitted in the ICU and 555

ED

consecutive patients (376 males and 179 females) fulfilled the study criteria and were included in the analysis. Characteristics of patients are shown in table 1. One

PT

hundred one patients had a prior diagnosis of DM (18.2%-DM group). HbA1c at

CE

admission in the ICU (mean ± SD) was 7.3±1.7% vs. 5.4±0.7% in patients with and without prior diagnosis of DM, respectively (p<0.001). HbA1c had an excellent

AC

discriminating ability (AUC=0.892, p<0.001) for known DM history. HbA1c above 6.5% discriminated patients with DM history with 99% specificity and 70% sensitivity. Among patients without known history of DM, prediabetes was diagnosed in 106 patients (19.1%-PD group), diabetes in 33 (5.9%-UD group), while 315 patients (56.8%) were classified as having a normal glycemic status (N group). UD group did not differ significantly in healthcare exposure prior to admission in the ICU compared with DM group. Characteristics of patients according to glycemic status are shown in table 2. N group had significantly lower blood glucose levels at admission in the ICU

ACCEPTED MANUSCRIPT

7

compared with UD and DM groups, while they did not differ significantly compared

T

with PD group (table 2).

RI P

Crude mortality was 20.3% (95% confidence interval 17.0–23.7). Mortality was significantly higher in patients with a prior diagnosis of DM compared with patients

SC

who without prior diagnosis of DM (31.7% vs. 17.8%, respectively, p=0.002).

MA NU

Mortality rate throughout the years of the study fluctuated between 12.6% and 26.7%, but did not differ significantly. No cases of severe or complicated hypoglycemia were recorded.

Mortality in the ICU was significantly higher in patients with increasing levels of

ED

HbA1c (figure 1). The difference persisted after adjustment for admission blood

PT

glucose levels. Mortality was significantly higher in UD and DM groups compared with N and PD groups (figure 2). UD group had a significantly higher ICU mortality

CE

compared with N group (39.4% vs. 15.9%, respectively, p<0.001). Noticeably,

group.

AC

mortality in this subgroup of patients tended to exceed even the mortality of DM

Subgroup analyses i.

Patients without a prior diagnosis of DM

In this subgroup of patients, a cutoff of 6.5% for HbA1c (which is the diagnostic cutoff for DM) predicted a lower ICU survival (figure 3). In the above subgroup, patients with HbA1c ≥ 6.5% (UD group) were significantly older with higher Charlson’s comorbidity index and had higher APACHE II and SOFA scores at admission in the ICU compared with patients with HbA1c < 6.5% (age: 63.0 ± 15.1 vs.

ACCEPTED MANUSCRIPT

8

50.0 ± 19.8 years, p<0.001; Charlson’s comorbidity index: 1.4 ± 1.4 vs. 0.9 ± 1.4, p<0.001; APACHE II score: 22.7 ± 6.0 vs. 19.4 ± 6.2, p<0.001; SOFA score: 12.5 ± 4.0

RI P

T

vs. 9.5 ± 3.4, p<0.001, respectively). In a logistic regression model, HbA1c≥6.5% was independently associated with ICU mortality (table 3). Model fitting was adequate,

SC

no autocorrelation was detected (ρ=0.001, p=0.493) and discrimination ability of the model was satisfactory (c=0.7, p<0.001). Calibration was also satisfactory (Hosmer-

MA NU

Lemeshow’s chi-square=9.74, p=0.284).

Additionally, in the same subgroup of patients, HbA1c ≥6.5 was independently associated with increased probability of continuous renal replacement therapy

ED

(CRRT) implementation (adjusted OR 2.2, 95% confidence interval 1.3–3.9), increased ICU LOS compared with patients with HbA1c<6.5 (27.0±20.0 vs. 22.5±17.9,

PT

respectively, p=0.023) and longer duration of mechanical ventilation (23.3±19.4 vs.

AC

CE

17.8±15.1, respectively, p=0.008).

ii. Patients with a prior diagnosis of DM (DM group) In the subgroup of patients (DM group), a cutoff of 7% for HbA1c, which is the target indicating an adequate glycemic control, had no predicting ability for ICU mortality and displayed no significant association with the probability of CRRT implementation, duration of mechanical ventilation or ICU LOS. DM group did not display significant differences in APACHE II score at admission, ICU LOS, duration of mechanical ventilation, probability of CRRT implementation or ICU mortality compared with patients with UD group. However, patients of UD group

ACCEPTED MANUSCRIPT

9

were admitted in the ICU with a significantly higher SOFA score at admission

RI P

T

compared with patients of DM group (12.5±4.0 vs. 10.8±3.7, respectively, p=0.048).

SC

DISCUSSION

Our findings show that in critically ill patients with previously undiagnosed DM,

MA NU

HbA1c levels at admission in the ICU are significantly associated with severity of disease and, thus, duration of mechanical ventilation, ICU LOS, CRRT implementation and ICU mortality.

ED

In order to clarify the observed association between HbA1c and ICU mortality and further explore the potentially confounding role of DM, we investigated the clinical

PT

implications of HbA1c in two separate subgroups: a) patients without a prior

AC

CE

diagnosis of DM and b) patients with a prior diagnosis DM.

Patients without a prior diagnosis of DM Based on HbA1c level ≥ 6.5% as a diagnostic criterion for DM, the diagnosis of DM can be established upon admission in the ICU if the level of HbA1c exceeds this cutoff. Additionally, HbA1c within the range 5.7 – 6.4% indicates prediabetes. This increased level of HbA1c accounts for periods of hyperglycemia within the previous three months, of which the patient has been partly or totally unaware. In our study 5.9% of patients without a prior diagnosis of DM were first diagnosed with DM and a

ACCEPTED MANUSCRIPT

10

further 19.1% were diagnosed with prediabetes by the HbA1c level at admission in

T

the ICU.

RI P

Patients with elevated HbA1c are more likely to have comorbid conditions and complications associated with DM, even if a prior diagnosis of DM had not been

SC

established [8]. In our study group of no prior DM diagnosis, patients with HbA1c

MA NU

≥6.5% (UD group) had a significantly higher Charlson’s comorbidity index with the most prevalent comorbidities being coronary artery disease and cerebrovascular disease. Noticeably, these patients had significantly higher APACHE II and SOFA scores at admission in the ICU compared with patients with HbA1c <6.5%, adjusted

ED

for age and admission category, a finding that could imply a deleterious effect of micro- and macroangiopathy associated with long-term hyperglycemia [11].

PT

Hyperglycemia causes vascular damage that occurs many years prior to the

CE

development of clinically overt diabetes [12]. Timmer et al have shown that in nondiabetic patients with ST segment-elevation myocardial infarction, increasing

AC

levels of HbA1c (even within the nondiabetic range) were significantly associated with lower estimated glomerular filtration rates and higher proportion of multivessel coronary disease, findings that probably confirm the above hypothesis of angiopathy [13]. However, well-designed studies assessing micro- and macroangiopathy in nondiabetic patients with respect to HbA1c could further explore this potential association.

ACCEPTED MANUSCRIPT

11

Patients with a prior diagnosis of DM (DM group)

T

In the subgroup of patients (DM group), although crude mortality was significantly

RI P

higher compared with N group, a cutoff of 7% for HbA1c, which is the target indicating an adequate glycemic control, had no predicting ability for ICU mortality.

SC

The existing literature depicts conflicting results. A recent systematic review and

MA NU

meta-analysis concluded that diabetes mellitus confers an increased risk of death in the ICU only in cardiac surgery patients, while no effect could be established in the other patient subgroups [14]. However, apart from the reported heterogeneity of the included studies, there is no information about the way diagnosis of DM was

ED

established, and the authors themselves comment on the possibility that patients

PT

with previously undiagnosed diabetes or diabetic patients treated with diet alone

CE

(without glucose-lowering agents or insulin) may have been misclassified. The results of a recent large cohort study, investigating 1-year mortality in ICU

AC

patients, are quite similar to our results, showing an increased 30-day mortality of diabetic patients compared with normal subjects, and finding no association between HbA1c and 30-day mortality of ICU patients with DM. However, in this study, the HbA1c measurement could date even within a year before the recorded hospital admission [15]. Considering our findings, a reasonable question would be why an HbA1c cutoff of 6.5% is of clinical importance in UD group, while the 7.0% cutoff in N group has no similar importance. In our opinion, this finding underlines the impact of uncontrolled hyperglycemia, which remains unperceived for months or years, exerting its

ACCEPTED MANUSCRIPT

12

deleterious effect on the micro- and macrovasculature and developing a serious clinical burden in patients with undiagnosed diabetes, which becomes apparent

RI P

T

during critical illness, particularly when compared with patients with normal glycemic status or even with patients with prediabetes. On the other hand, most

SC

patients with known DM history make efforts towards glycemic control under treatment with agents modifying cardiovascular risk, and are followed up by a

MA NU

physician, so that HbA1c near the glycemic target of 7.0% seems to be of no clinical importance for the setting of critical illness. However, this finding needs further external validation in other populations of ICU patients and should not be

ED

extrapolated for long-term outcomes in patients with DM. Our findings are in accordance with the results of a prospective observational study

PT

in trauma patients [16], which showed that admission HbA1c is a more useful

CE

predictor of ICU outcome compared with admission blood glucose. Furthermore, it has been shown that HbA1c is an independent predictor of ICU morbidity, being

AC

significantly associated with repeated episodes of ICU-acquired bloodstream infections [17] and prolonged hospital and ICU LOS [18].

Limitations of our study Our study has certain limitations. First, although glycemic control in the ICU was closely inspected in all patients with a strict protocol, data concerning glycemic variability, episodes of hypoglycemia and daily requirements of insulin were not recorded in all patients and therefore could not be analyzed. The impact of glycemic

ACCEPTED MANUSCRIPT

13

variability and hypoglycemia on morbidity and mortality of critically ill patients and the optimal glycemic control in the ICU have been widely disputed during the last

RI P

T

few years, with concerns arising about the potential of different glycemic targets with regard to glycemic status [19, 20]. In similar studies, apart from the reported

SC

medical history, HbA1c at admission in the ICU would be a useful marker in

MA NU

discriminating diabetic, prediabetic and nondiabetic patients. Second, although HbA1c is not substantially affected by acute illness and can be safely implemented as a screening assay in the acute care setting [21], its levels can be influenced by certain factors [1]. In particular, red blood cell (RBC) transfusion

ED

may complicate the interpretation of HbA1c, since it introduces hemoglobin molecules that may have been exposed to different levels of glycemia from those of

PT

the transfusion recipient [22]. To control for that potential confounder, we

CE

performed a sensitivity analysis in the group of patients who had not received RBC transfusion before admission in the ICU (n=297): a) in patients without history of

AC

DM, an HbA1c level >=6.5% was persistently associated with lower survival rate, however of borderline significance (log rank p=0.097) since the patient sample was smaller and b) in patients with known DM, an HbA1c cutoff of 7% had no predicting ability for death in the ICU. Consequently, after elimination of the potentially confounding effect of RBC transfusions, our main results persisted relatively unchanged. Noticeably, a similar trend, i.e. lower survival rate in patients with previously undiagnosed DM and HbA1c level >=6.5%, was recorded in the subgroup of patients (n=121) which had received RBC transfusion before admission in the ICU. CONCLUSIONS

ACCEPTED MANUSCRIPT

14

HbA1c is a useful tool for assessing prior glycemic status in critically ill patients admitted in the ICU, particularly in cases with incomplete self-reported medical

RI P

T

history. In patients without prior diagnosis of DM, an admission HbA1c ≥6.5% was significantly associated with higher severity of disease and increased ICU mortality.

SC

In patients with a prior diagnosis of DM, no association between HbA1c and ICU

MA NU

mortality was recorded. Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest. Acknowledgment

ED

The authors thank Nikoletta A. Antonakos, Department of Social Studies, Deerfield

AC

CE

PT

High-School, Deerfield, IL, USA, for text editing.

REFERENCES

1. Higgins T. HbA(1c)-An analyte of increasing importance. Clin Biochem 2012;45:1038-1045 2. Tahara Y, Shima K. Kinetics of HbA1c, glycated albumin, and fructosamine and analysis of their weight functions against preceding plasma glucose level. Diabetes Care 1995;18:440-447 3. Standards of medical care in diabetes, 2011. Diabetes Care 2011;34 (suppl I):S11-S61

ACCEPTED MANUSCRIPT

15

4. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36 Suppl 1:S67-S74

RI P

T

5. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care

SC

2009;32:1327-1334

6. Letourneau J, Bui H, Schricker T, Hatzakorzian R. HbA1c: A prognostic

MA NU

biomarker in the surgical and critically ill patient population. J Cardiothor Vasc Anesth 2013;27:760-764

7. Gornik I, Gornik O, Gasparović V. HbA1c is outcome predictor in diabetic

ED

patients with sepsis. Diabetes Res Clin Pract 2007;77:120-125 8. Egi M, Bellomo R, Stachowski E, French CJ, Hart GK, Taori G, Hegarty C, Bailey

PT

M. The interaction of chronic and acute glycemia with mortality in critically

CE

ill patients with diabetes. Crit Care Med 2011;39:105-111 9. Charlson ME, Pompei P, Ales KL, MacKenzie RC. A new method of classifying

AC

prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987;40:373-383

10. Abbreviated Injury Scale 2005. Association for the Advancement of Automotive Medicine, IL 60011, USA 11. Brownrigg JRW, Davey J, Holt PJ, Davis W a, Thompson MM, Ray KK, Hinchliffe RJ. The association of ulceration of the foot with cardiovascular and all-cause mortality in patients with diabetes: a meta-analysis. Diabetologia 2012;55:2906-2912

ACCEPTED MANUSCRIPT

16

12. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4 – 7 years before clinical diagnosis. Diabetes Care 1992;5:815-819

RI P

T

13. Timmer JR, Hoekstra M, Nijsten MWN, Van der Horst ICC, Ottervanger JP, Slingerland RJ, Dambrink JE, Bilo HJG, Zijlstra F, van’t Hof AWJ. Prognostic

SC

value of admission glycosylated hemoglobin and glucose in nondiabetic patients with ST-segment-elevation myocardial infarction treated with

MA NU

percutaneous coronary intervention. Circulation 2011;124:704-711 14. Siegelaar SE, Hickmann M, Hoekstra JBL, Holleman F, DeVries JH. The effect of diabetes on mortality in critically ill patients: a systematic review and

ED

meta-analysis. Crit Care 2011;15:R205

15. Christiansen CF, Johansen MB, Christensen S, O’Brien JM, Tønnesen E,

PT

Sørensen HT. Type 2 diabetes and 1-year mortality in intensive care unit

CE

patients. Eur J Clin Invest 2013;43:238-247 16. Lionel KR, John J, Sen N. Glycated hemoglobin: a predictor of outcome in

AC

trauma admissions to the intensive care unit. Indian J Crit Care Med 2014;18:21-25

17. Tsakiridou E, Makris D, Chatzipantazi V, Vlachos O, Xidopoulos G, Charalampidou O, Moraitis G, Zakynthinos E. Diabetes and hemoglobin A1c as risk factors for nosocomial infections in critically ill patients. Crit Care Res Pract 2013 (Epub); doi: 10.1155/2013/279479 18. Tennyson C, Lee R, Attia R. Is there a role for HbA1c in predicting morbidity and mortality outcomes after coronary artery bypass graft surgery? Interact Cardiovasc Thorac Surg 2013;17:1000-1008

ACCEPTED MANUSCRIPT

19. Klonoff DC. Intensive insulin therapy in critically ill hospitalized patients: making it safe and effective. J Diabetes Sci Technol 2011;5:755-767

RI P

T

20. Lanspa MJ, Hirshberg EL, Phillips GD, Holmen J, Stoddard G, Orme J. Moderate glucose control is associated with increased mortality compared

SC

to tight glucose control in critically ill non-diabetics. Chest 2012;143:12261234

MA NU

21. Thakker U, Magleby R, Graff K, Kelson J, Silverman RA. The impact of acute illness on HbA 1c determination of undiagnosed diabetes. Diabetes Metab Res Rev 2012;28:603-607

ED

22. Spencer DH, Grossman BJ, Scott MG. Red cell transfusion decreases

AC

CE

PT

haemoglobin A1C in diabetic patients. Clin Chem 2011;57:344-345

17

ACCEPTED MANUSCRIPT

RI P

T

FIGURE LEGENDS

18

SC

Figure 1. Mortality according to HbA1c levels at admission in the ICU (n=555).

MA NU

Figure 2. Mortality in the ICU according to glycemic status: normal (n=315), prediabetic (n=106), previously undiagnosed diabetic (n=33) and diabetic (n=101).

ED

Figure 3. Kaplan-Meier curves of survival in the ICU stratified by HbA1c levels (<6.5% and >=6.5%) in patients without known history of diabetes mellitus (n=454). In this graph, patient censoring is equivalent with release from the ICU.

AC

CE

PT

DM: diabetes mellitus; ICU: intensive care unit; LOS length of stay

ACCEPTED MANUSCRIPT

19

Table 1. Patient characteristics overall and according to ICU outcome (n=555)*

Variable

Overall

Survivors

(n=555)

(n=442)

Nonsurvivors

p value**

Male gender (%)

53.0±19.8

51.0±19.1

60.7±19.0

<0.001

376 (67.7%)

306 (69.2%)

70 (61.9%)

0.144

Admission category (%) 

Medical



Elective surgical



Emergency surgical



Trauma

SC

Age (years)

RI P

T

(n=113)

0.001

177 (40.0%)

61 (54.0%)

36 (6.5%)

34 (7.7%)

2 (1.8%)

89 (16.0%)

65 (14.7%)

24 (21.2%)

192 (34.6%)

166 (37.6%)

26 (23.0%)

20.1±6.3

19.1±5.9

23.9±6.4

<0.001

9.8±3.6

9.3±3.2

12.3±4.1

<0.001

23.5±8.3

23.6±8.3

23.1±8.3

0.793

Charlson’s comorbidity index

1.1±1.5

1.0±1.4

1.5±1.6

0.004

Diabetes mellitus history (%)

101 (18.2%)

69 (15.6%)

32 (28.3%)

0.002

HbA1c at admission in the ICU (%)

5.7±1.2

5.7±1.2

6.0±1.3

0.003

Blood glucose at admission in the ICU (mg.dl)

156±73

153±73

170±69

0.027

pRBC units transfused before admission

1.2±3.0

1.2±2.6

1.4±4.0

0.508

ICU-acquired infection (%)

202 (36.4%)

158 (35.7%)

44 (38.9%)

0.584

CRRT implementation (%)

95 (17.1%)

39 (8.8%)

56 (49.6%)

<0.001

Duration of mechanical ventilation (days)

18.8±16.1

19.7±16.2

21.2±19.2

0.132

ICU LOS (days)

23.4±18.4

23.8±18.0

21.4±19.6

0.217

SOFA score at admission

AC

CE

PT

ISS***

ED

APACHE II score at admission

MA NU

238 (42.9%)

ICU: intensive care unit; APACHE: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment; ISS: Injury Severity Score; CRRT: continuous renal replacement therapy; LOS: length of stay. *Data are mean±SD, unless else is indicated. ** p value stands for significant difference in comparisons of survivors and non-survivors. ***Applicable only in trauma patients.

ACCEPTED MANUSCRIPT

20

Table 2. Patient characteristics according to glycemic status* (n=555)** Prediabetes (PD)

(n=315)

(n=106)

Variable

Previously undiagnosed diabetes (UD)

RI P

(n=33)

Diabetes (DM)

T

No diabetes (N)

p value***

(n=101)

45.4±18.9

59.1±17.9

63.0±15.1

67.0±13.5

<0.001

Male gender (%)

210 (66.7%)

78 (73.6%)

26 (78.8%)

62 (61.4%)

0.137

Admission category (%) 111 (35.2%)

47 (44.3%)

Elective surgical

14 (4.4%)

12 (11.3%)

Emergency surgical

37 (11.7%)

Trauma

<0.001

24 (72.7%)

56 (55.4%)

1 (3.0%)

9 (8.9%)

22 (20.8%)

5 (15.2%)

25 (24.8%)

153 (48.6%)

25 (23.6%)

3 (9.1%)

11 (10.9%)

APACHE II score at admission

18.6±6.1

21.1±6.2

22.7±6.0

22.8±6.1

<0.001

SOFA score at admission

9.2±3.4

9.9±3.1

12.5±4.0

10.8±3.7

<0.001

ISS****

23.7±8.3

22.2±8.3

25.7±5.8

23.7±8.3

0.845

1.1±1.4

1.4±1.4

2.4±1.7

<0.001

ED

PT 0.7±1.2

CE

Charlson’s comorbidity index

MA NU

Medical

SC

Age (years)

5.0±0.5

5.9±0.2

7.0±0.7

7.4±1.8

<0.001

Blood glucose at admission in the ICU (mg/dl)

134±39

147±50

178±48

229±123

<0.001

pRBC units transfused before admission

1.6±3.4

0.8±1.8

0.2±0.5

0.9±2.8

<0.001

ICU-acquired infection (%)

117 (37.1%)

38 (35.8%)

13 (39.4%)

34 (33.7%)

0.909

CRRT implementation (%)

41 (13.0%)

10 (9.4%)

10 (30.3%)

34 (33.7%)

<0.001

Duration of mechanical ventilation (days)

17.1±14.5

18.7±16.0

21.2±15.0

23.9±20.1

0.003

23.1±18.4

26.2±17.1

26.9±20.1

0.101

AC

HbA1c at admission in the ICU (%)

ICU LOS (days)

22.0±17.8

ICU: intensive care unit; APACHE: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment; ISS: Injury Severity Score; CRRT: continuous renal replacement therapy; LOS: length of stay *Normal (N): HbA1c≤5.6%; prediabetes (PD): HbA1c 5.7 – 6.4%; previously undiagnosed diabetes (UD): diabetes first diagnosed at ICU admission with HbA1c≥6.5%; diabetes (DM): diagnosis of diabetes prior to ICU admission. **Data are mean±SD, unless else is indicated. ***p value stands for significant difference arising in comparisons of the four groups. ****Applicable only in trauma patients.

ACCEPTED MANUSCRIPT

22

Table 3. Logistic regression models for ICU mortality (n=555)

RI P

SC

0.001 0.423 0.023

ED

PT

CE

AC

Multivariable analysis Odds 95% p ratio confidence value interval

T

p value

MA NU

Patients without prior history of DM Univariable analysis Variable Odds 95% ratio confidence interval Age (years) 1.02 1.01 – 1.04 Sex 0.81 0.49 – 1.35 Admission category 2.02 1.17 – 3.50  Medical 0.25 0.03 – 1.94  Elective surgical 1.67 0.79 – 3.51  Emergency 1.00 surgical  Trauma Charlson’s comorbidity 1.17 0.99 – 1.38 index HbA1c ≥6.5% 3.37 1.60 – 7.11 Blood glucose at 1.91 1.13 – 3.22 admission (per 100 mg/dl increase) APACHE II score at 1.11 1.07 – 1.16 admission SOFA score at admission 1.25 1.15 – 1.36 Patients with prior history of DM Univariable analysis Variable Odds 95% ratio confidence interval Age (years) 1.04 1.00 – 1.08 Sex 0.60 0.26 – 1.42 Admission category 2.13 0.42 – 10.90  Medical 0.5 0.04 – 7.44  Elective surgical 3.54 0.63 – 19.82  Emergency 1.00 surgical  Trauma Charlson’s comorbidity 1.11 0.87 – 1.42 index HbA1c ≥7.0% 0.82 0.76 – 1.26 Blood glucose at 0.86 0.58 – 1.29 admission (per 100 mg/dl increase) APACHE II score at 1.20 1.10 – 1.32 admission SOFA score at admission 1.42 1.17 – 1.73

0.071 0.001 0.016

2.43

1.11 – 5.33

0.027

<0.001

1.09

1.05 – 1.15

<0.001

<0.001

P value 0.032 0.247 0.254

Multivariable analysis Odds 95% P ratio confidence value interval 1.06 1.00 – 1.12 0.058

0.392 0.856 0.470

<0.001 <0.001

1.33

1.06 – 1.67

0.016

ICU: intensive care unit; DM: diabetes mellitus; APACHE: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment.

PT

ED

MA NU

SC

RI P

T

ACCEPTED MANUSCRIPT

AC

CE

Fig. 1

23

AC

Fig. 2

CE

PT

ED

MA NU

SC

RI P

T

ACCEPTED MANUSCRIPT

24

PT

ED

MA NU

SC

RI P

T

ACCEPTED MANUSCRIPT

AC

CE

Fig. 3

25