Background

Sepsis is a common complication in patients with diabetes mellitus. In a Western population, risk of respiratory dysfunction was lower in diabetic patients with sepsis.

Objective

To compare organ dysfunction, particularly respiratory dysfunction, between sepsis patients with and without diabetes mellitus in an Asian population.

Method

Hospital discharge data were collected for the period 2004 through 2008. Patients with sepsis, diabetes mellitus, and organ dysfunction were identified by using the International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Australian Modification codes.

Results

Of the 383 238 patients hospitalized during the 5 years, 2943 of the 9221 who had sepsis also had diabetes (31.9%).The most common organ dysfunctions in patients with sepsis were renal (31.5%), cardiovascular (19.2%), and respiratory (10.9%). Among patients with sepsis, respiratory dysfunction was less likely in patients with diabetes (9.4%) than in those without (11.6%; P = .002), but renal dysfunction was more likely in patients with diabetes (46.5%) than in those without (24.4%; P < .001). However, only 27.6% of patients with diabetes had a respiratory source of sepsis compared with 33.4% in patients without diabetes (P < .001). Among patients with sepsis, diabetes mellitus was a significant and independent predictor of respiratory dysfunction (odds ratio, 0.80; 95% confidence interval, 0.66–0.98) after adjustments for age, sex, ethnicity, admission to intensive care, number of comorbid conditions, and other infection sources.

Conclusion

Among an Asian population, respiratory dysfunction in patients with sepsis is less likely to develop in those with diabetes than in those without diabetes.

Epidemiological studies have shown that sepsis is a common health care problem. In the United States, approximately 700000 cases occur each year, and the cost of care is almost US$17 billion.1,2  In Singapore, sepsis has accounted for about 2.3% of all hospital admissions.3  Sepsis often occurs in patients with diabetes mellitus, and diabetes mellitus is associated with marked morbidity and mortality.1,2,4  Sepsis complicated by acute organ system dysfunction accounts for almost half of intensive care unit (ICU) resources and is associated with a higher morbidity and mortality than sepsis without acute organ system dysfunction.2,5,6  Thus, accurate identification of populations at risk for acute organ dysfunction is crucial to improve understanding of the mechanisms involved in the risk and to develop novel therapies for these patients.

Clinical and epidemiological studies69  have indicated that respiratory dysfunction is less likely in patients who have both sepsis and diabetes mellitus than in patients who have sepsis but no diabetes. Possible explanations for this difference include the effects of hyperglycemia on the inflammatory response, metabolic abnormalities in diabetes, and interactions of agents used to treat diabetes mellitus.7,9  Compared with other ethnic groups, Asian patients, especially those from South Asian countries, have a 4- to 6-fold greater risk for type 2 diabetes mellitus and a higher risk for renal, cardiovascular, and cerebrovascular complications.10  Knowledge of differences in the pattern of organ failure would be useful in monitoring and managing patients with diabetes mellitus in whom sepsis develops. However, little information is available on sepsis and organ dysfunction in Asian patients with diabetes.

The purpose of the study reported in this article was to compare the patterns of organ dysfunction, particularly respiratory dysfunction, between Asian patients with sepsis who did or did not have diabetes mellitus.

Methods

Data Collection

Singapore General Hospital is the largest acute tertiary care hospital in Singapore. With 1600 beds, it serves approximately one-fourth of Singapore’s population of 4.98 million people.11  Each year the hospital handles approximately 80 000 patient discharges. Data on all hospitalized patients 18 years or older, from January 1, 2004, to December 31, 2008, were collected from the hospital’s data warehouse, Information Technology Department, Singhealth Group. The data included demographic information such as ethnicity, sex, age, and marital status and clinical characteristics such as dates of admission and discharge, dates of ICU admission and discharge, up to 10 International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Australian Modification (ICD-9-AM) diagnosis codes, up to 10 ICD-9-AM procedure codes, discharge status, and disposition at discharge. The research protocol was approved by the ethics committee of Singapore General Hospital, and no informed consent was required.

Patients from South Asian countries have a 4–6 times greater risk of type 2 diabetes mellitus.

Case Definition

Sepsis was defined1,3  as the presence of any of the ICD-9-AM codes listed in Table 1. In previous validation studies,1,12  this method had positive predictive values of 88.7% to 99.8% for identifying true cases of sepsis. Diabetes mellitus was defined by ICD-9-AM code 250, which has a positive predictive value of 95%.13 

Organ dysfunctions, type of organ dysfunction, source of infection (ie, the anatomical site of infection, which included respiratory; genitourinary; skin, soft tissue, or bone; gastrointestinal; central nervous system; cardiovascular; and others), and associated surgical and medical conditions were defined by using a combination of ICD-9-AM diagnosis, diagnostic codes and procedure codes1,2,14  (Table 2). Chronic comorbid conditions were identified and were used to calculate the well-established adaptation of the Charlson Comorbidity Index by Deyo et al.15 

Statistical Analysis

Categorical variables were reported as percentages and continuous variables as means with standard deviations. Because of their skewed distribution, length of hospital stay and the number of comorbid conditions were summarized by using geometric means with 95% confidence intervals. Among patients with sepsis, variables were compared between those with and without diabetes mellitus by using χ2 tests, 2-tailed t tests, and Mann-Whitney tests as appropriate. Logistic regression was used to assess the association of respiratory dysfunction with diabetes mellitus, and adjustments were made for age, sex, ethnicity, ICU admissions, number of comorbid conditions, and the source of infection. The Hosmer-Lemeshow χ2 goodness-of-fit test was used to exclude nonsignificant variables and to identify clinically plausible interaction terms. The area under the receiver operating characteristic curve was also presented for the regression model. All P values were 2 sided. The level of significance was set at the conventional level of α=.0 5. STATA, version 10.0 (StataCorp LP, College Station, Texas) was used for all data analysis.

Presence of diabetes mellitus was negatively associated with respiratory dysfunction.

Results

Of the 383 238 patients 18 years and older hospitalized during the period 2004 through 2008, a total of 9221 (2.4%) met the criteria used to define sepsis. Among the patients with sepsis, 2943 (31.9%) had diabetes mellitus. The patients with diabetes were generally older (mean 65.5 years; SD, 12.4) than those without diabetes (59.8 years; SD, 17.4; P < .001) and were predominately women (53% vs 48.5%; P < .001). The percentage of patients managed medically did not differ significantly (P = .87) between those with both sepsis and diabetes (66.5%) and those with sepsis only (66.7%). The percentage of patients who received ICU care also did not differ significantly (P = .28) between those with both sepsis and diabetes (16.5%) and those with sepsis only (17.4%). Patients with both sepsis and diabetes had significantly more comorbid conditions than did patients with sepsis only (geometric mean, 1.9 vs 1.3; P < .001). The demographic profile, clinical characteristics, and outcomes of patients with sepsis are given in Table 3.

Patients with both sepsis and diabetes had a significantly lower frequency than did patients with sepsis only for respiratory (27.6% vs 33.4%), gastrointestinal (25.5% vs 29.3%), cardiovascular (0.7% vs 1.9%), and neurological (0.8% vs 1.4%) sources of infection (Figure 1). However, patients with both sepsis and diabetes had an increased frequency of renal (32.6% vs 26.2%); skin, soft tissue, or bone (15.6% vs 13.1%); and other (19% vs 15.1%) sources of infection.

Among all patients with sepsis, 10.9% had respiratory dysfunction, 31.5% had renal dysfunction, 19.2% had cardiovascular dysfunction, 11.8% had hematological dysfunction, and 7.6% had other organ dysfunction (Figure 2). Patients with both sepsis and diabetes were more likely than those with sepsis only to have renal (46.5% vs 24.4%) and metabolic (4.7% vs 3.6%) dysfunction and less likely to have respiratory (9.4% vs 11.6%), hepatic (1.1% vs 1.7%), and hematologic (9.4% vs 12.9%) dysfunction. The occurrence of other organ dysfunctions differed little between the 2 groups.

Multivariate logistic regression analysis showed that diabetes mellitus was significantly negatively associated with respiratory dysfunction (adjusted odds ratio, 0.80; 95% confidence interval, 0.66–0.98; P = .03) after adjustments were made for age, sex, ethnicity, ICU admission, number of comorbid conditions, and infection sources, including respiratory; genitourinary; skin, soft tissue, or bone; and gastrointestinal sources (Table 4). The goodness of fit of the regression model was assessed by using the Hosmer-Lemeshow test (χ82  =8.3; P =.4 0). The area under the receiver operating characteristic curve was 0.92 (P < .001).

Evaluation of hospital mortality and length of stay (Table 3) indicated that sepsis patients with and without diabetes mellitus had comparable hospital mortality (19.2% vs 20.0%; P = .37). This finding was evident in the subgroup of patients with respiratory dysfunction as well (56.7% vs 52.9%; P = .29). Similarly, the hospital length of stay did not differ significantly between the 2 groups (geometric mean, 12.1 days vs 12.2 days; P = .53) or in the subgroup of patients with respiratory dysfunction (15.9 days vs 17.8 days: P = .21).

Discussion

In this study of 5 years of discharge data from a major tertiary acute care hospital, we found that respiratory dysfunction was less likely to develop in patients with both sepsis diabetes mellitus than in patients with sepsis only. This difference persisted even after adjustments were made for age, sex, ethnicity, ICU admission, the number of comorbid conditions, and the source of infection.

Our study was the first on the effect of diabetes mellitus on respiratory dysfunction in an Asian population, and our results confirm and extend the previous published results for a Western population.9  In an observational cohort study6  of 375 patients treated with mechanical ventilation for more than 48 hours, higher glucose levels in the first 24 hours of respiratory failure were associated with a decreased risk for acute respiratory distress syndrome (ARDS; P = .025). In another large cohort of 688 critically ill patients at risk for ARDS from sepsis, trauma, massive transfusion, and aspiration, diabetes protected against the development of ARDS, even after adjustments for potential confounders such as age, clinical risk for ARDS, severity of illness, and transfusion (adjusted odds ratio, 0.58; 95% confidence interval, 0.36–0.92).16  In a third independent cohort study17  of 160 patients with sepsis, diabetes mellitus was detected in only 24% of patients with acute lung injury, the less severe form of ARDS, and in 43% of patients without acute lung injury (P = .01). Investigators in other clinical trials8,18  have also reported reduced occurrence of ARDS or acute lung injury in sepsis patients with diabetes mellitus. Furthermore, in a large epidemiological study involving 12.5 million sepsis cases from the US National Hospital Discharge Survey from 1979 to 2003, Esper et al7  found that patients with diabetes mellitus were less likely to have acute respiratory failure than were patients without diabetes (9% vs 14%; P < .05) and were more likely to have acute renal failure (13% vs 7%; P<.05). The reduced likelihood of respiratory dysfunction in the patients with diabetes mellitus occurred irrespective of the source of infection.

Patients with sepsis and diabetes mellitus are less likely to develop respiratory dysfunction than those without diabetes mellitus.

Our results and these published findings support the view that respiratory dysfunction is less likely to develop in patients with sepsis and diabetes mellitus than in patients with sepsis only. Nevertheless, the results of 2 studies contradict this finding. In a large population-based case-control study19  and a cohort study,20  the risk of pneumonia-related hospitalizations and deaths was increased in patients with type 2 diabetes. These contradicting study results emphasize that the underlying mechanism for the effect between diabetes mellitus and respiratory dysfunction is still not well understood.

Neutrophils play an essential role in the host inflammatory response against infection.21  Neutrophils from patients with diabetes can have impaired biological responses, including reduced bactericidal activity and impaired chemotaxis.22,23  Compared with neutrophils from age and sex-matched controls, neutrophils from patients with diabetes adhere with less affinity to endothelial cell monolayers.24,25  In addition, neutrophils from diabetic patients produce 40% less leukotriene B4 than do neutrophils from healthy volunteers.26  Also, neutrophils from uninfected patients with poorly controlled diabetes did not have the same bactericidal activity as did neutrophils from healthy volunteers or patients with well-controlled diabetes.23  Furthermore, defects of neutrophil chemotactic, phagocytic, and microbicidal activities in experimental studies in diabetic rats and mice have been reported.21,27  These abnormalities in neutrophil function may protect the lungs by decreasing the ability of the neutrophils to migrate into the organ and to produce oxidant damage. Impaired neutrophil function or altered neutrophil-endothelial interactions have been proposed as a possible mechanisms for reduced incidence of respiratory dysfunction.22,23 

Likewise, hyperglycemia can have immunomodulatory effects. Hyperglycemia in itself has an independent effect on neutrophil and endothelial properties, resulting in decreased injury in response to endotoxin.22  In an in vitro study,28  hyperglycemia increased production of anti-inflammatory cytokines such as interleukin 10 and promoted mitochondrial dysfunction. Impaired neutrophil function resulting in decreased intracellular bactericidal activity, opsonic activity, and innate immunity has also been reported.29  Such effects could theoretically modulate the intense inflammation associated with respiratory organ dysfunction and may explain the decrease in respiratory dysfunction, but what the effects contribute to the increased incidence of other organ dysfunctions, such as renal failure, is not known. Further studies on these differential effects are needed.

From the clinical perspective, the development of organ failures determines the course and prognosis of most sepsis patients. Patients who usually die of sepsis in the course of different comorbid conditions have their deaths attributed to these conditions rather than to sepsis. Among specific organ dysfunctions, respiratory dysfunction is the most common, and then, in order, cardiovascular and renal failure.

The finding that patients with both sepsis and diabetes are less likely than patients with sepsis only to have respiratory dysfunction and more likely to have renal failure will have a significant impact on the management of sepsis patients. The effect of diabetes in patients with sepsis will be augmented by the increasing incidence of diabetes among Asian patients.30  It would affect the need of support systems and equipment resource in ICUs and high-dependence units where sepsis patients receive care. The effect of diabetes could also be a prognostic indicator in patients with sepsis.

Our study had several limitations. The advantages of hospital discharge data are well known. The data are relatively inexpensive to obtain and use, are more reliable than other sources of data, cover a large population over multiple years, and are being used extensively in health services and health policy research.31  Nevertheless, hospital discharge data are administrative and are not intended for research purposes. The data are subject to coding errors and omissions of important diagnoses and complications, conditions that could have affected our results.32  However, the coding errors might occur across all patient groups, a possibility that offsets the possible impact of the errors. Although detailed chart reviews could provide more reliable data, chart reviews are time-consuming and labor intensive.33 

The data we used were generated from a single, large acute care tertiary hospital, a situation that limits the generalizability of our results. Furthermore, lack of data on patients’ medication history and/or duration of existing comorbid conditions might affect the interpretation of the results. Another possible confounding variable is chronic alcohol abuse, which may increase the incidence of ARDS in critically ill patients.23  Unfortunately, we do not have the alcohol intake history of all patients whose data were used in our study.

In conclusion, our results confirm and extend the results of other studies done in Western populations, suggesting that in this group of Asian patients, respiratory dysfunction is also less likely to develop in patients with both sepsis and diabetes mellitus than in patients with sepsis only.

ACKNOWLEDGMENTS

Y. Yang designed and performed the study and contributed to the analysis of data, interpretation of data, and writing of the final draft of the manuscript. Z.H. Abdul-Salam contributed to the study design, the analysis of data, and contributed to the manuscript. B.C. Ong contributed to the study design, the analysis of data, and the writing of the manuscript. K.S. Yang contributed to the study design, the analysis of data, and the manuscript. We acknowledge Mr Jeffrey Fong, Mrs Bessie Ang, and Mrs LiSee Lou for their assistance in database preparation.

REFERENCES

REFERENCES
1
Martin
GS
,
Mannino
DM
,
Eaton
S
,
Moss
M
.
The epidemiology of sepsis in the United States from 1979 through 2000
.
N Engl J Med.
2003
;
348
(
16
):
1546
1554
.
2
Angus
DC
,
Linde-ZwirbleW
T
,
Lidicker
J
,
Clermont
G
,
Carcillo
J
,
Pinsky
MR
.
Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care
.
Crit Care Med.
2001
;
29
(
7
):
1303
1310
.
3
Yang
Y
,
Yang
KS
,
Hsann
YM
,
Lim
V
,
Ong
BC
.
The effect of comorbidity and age on hospital mortality and length of stay in patients with sepsis
.
J Crit Care.
2010
;
25
(
3
):
398
405
.
4
Alberti
C
,
Brun-Buisson
C
,
Chevret
S
, et al
.
Systemic inflammatory response and progression to severe sepsis in critically ill infected patients
.
Am J Respir Crit Care Med.
2005
;
171
(
5
):
461
468
.
5
Esper
AM
,
Martin
GS
.
Extending international sepsis epidemiology: the impact of organ dysfunction
.
Crit Care.
2009
;
13
(
1
):
120
.
6
Yilmaz
M
,
Keegan
MT
,
Iscimen
R
, et al
.
Toward the prevention of acute lung injury: protocol-guided limitation of large tidal volume ventilation and inappropriate transfusion
.
Crit Care Med.
2007
;
35
(
7
):
1660
1666
.
7
Esper
AM
,
Moss
M
,
Martin
GS
.
The effect of diabetes mellitus on organ dysfunction with sepsis: an epidemiological study
.
Crit Care.
2009
;
13
(
1
):
R18
.
8
Moss
M
,
Guidot
DM
,
Steinberg
KP
, et al
.
Diabetic patients have a decreased incidence of acute respiratory distress syndrome
.
Crit Care Med.
2000
;
28
(
7
):
2187
2192
.
9
Honiden
S
,
Gong
MN
.
Diabetes, insulin, and development of acute lung injury
.
Crit Care Med.
2009
;
37
(
8
):
2455
2464
.
10
Chowdhury
TA
,
Hitman
GA
.
Diabetes care for south Asian patients: a special case
.
Lancet.
2008
;
371
(
9626
):
1728
1730
.
11
Statistics Singapore
.
Time series on population (mid-year estimates)
.
Singapore Department of Statistics Web site
. . Updated August 31, 2010. Accessed December 19, 2010.
12
Eaton
S
,
Burnham
E
,
Martin
GS
,
Moss
M
.
The ICD-9 code for septicemia maintains a high positive predictive value for clinical sepsis [abstract]
.
Am J Respir Crit Care Med.
2002
;
165
:
A471
.
13
Zgibor
JC
,
Orchard
TJ
,
Saul
M
, et al
.
Developing and validating a diabetes database in a large health system
.
Diabetes Res Clin Pract.
2007
;
75
(
3
):
313
319
.
14
Esper
AM
,
Moss
M
,
Lewis
CA
,
Nisbet
R
,
Mannino
DM
,
Martin
GS
.
The role of infection and comorbidity: factors that influence disparities in sepsis
.
Crit Care Med.
2006
;
34
(
10
):
2576
2582
.
15
Deyo
RA
,
Cherkin
DC
,
Ciol
MA
.
Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases
.
J Clin Epidemiol.
1992
;
45
(
6
):
613
619
.
16
Gong
MN
,
Thompson
BT
,
Williams
P
,
Pothier
L
,
Boyce
PD
,
Christiani
DC
.
Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion
.
Crit Care Med.
2005
;
33
(
6
):
1191
1198
.
17
Iscimen
R
,
Cartin-Ceba
R
,
Yilmaz
M
, et al
.
Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study
.
Crit Care Med.
2008
;
36
(
5
):
1518
1522
.
18
Frank
JA
,
Nuckton
TJ
,
Matthay
MA
.
Diabetes mellitus: a negative predictor for the development of acute respiratory distress syndrome from septic shock
.
Crit Care Med.
2000
;
28
(
7
):
2645
2646
.
19
Kornum
JB
,
Thomsen
RW
,
Riis
A
,
Lervang
HH
,
Schonheyder
HC
,
Sorensen
HT
.
Type 2 diabetes and pneumonia outcomes: a population-based cohort study
.
Diabetes Care.
2007
;
30
(
9
):
2251
2257
.
20
Kornum
JB
,
Thomsen
RW
,
Riis
A
,
Lervang
HH
,
Schonheyder
HC
,
Sorensen
HT
.
Diabetes, glycemic control, and risk of hospitalization with pneumonia: a population-based case-control study
.
Diabetes Care.
2008
;
31
(
8
):
1541
1545
.
21
Alba-Loureiro
TC
,
Munhoz
CD
,
Martins
JO
, et al
.
Neutrophil function and metabolism in individuals with diabetes mellitus
.
Braz J Med Biol Res.
2007
;
40
(
8
):
1037
1044
.
22
Alexiewicz
JM
,
Kumar
D
,
Smogorzewski
M
,
Klin
M
,
Massry
SG
.
Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: abnormalities in metabolism and function
.
Ann Intern Med.
1995
;
123
(
12
):
919
924
.
23
Repine
JE
,
Clawson
CC
,
Goetz
FC
.
Bactericidal function of neutrophils from patients with acute bacterial infections and from diabetics
.
J Infect Dis.
1980
;
142
(
6
):
869
875
.
24
Andersen
B
,
Goldsmith
GH
,
Spagnuolo
PJ
.
Neutrophil adhesive dysfunction in diabetes mellitus; the role of cellular and plasma factors
.
J Lab Clin Med.
1988
;
111
(
3
):
275
285
.
25
Delamaire
M
,
Maugendre
D
,
Moreno
M
,
Le Goff
MC
,
Allannic
H
,
Genetet
B
.
Impaired leucocyte functions in diabetic patients
.
Diabet Med.
1997
;
14
(
1
):
29
34
.
26
Jubiz
W
,
Draper
RE
,
Gale
J
,
Nolan
G
.
Decreased leukotriene B4 synthesis by polymorphonuclear leukocytes from male patients with diabetes mellitus
.
Prostaglandins Leukot Med.
1984
;
14
(
3
):
305
311
.
27
Alba-Loureiro
TC
,
Hirabara
SM
,
Mendonca
JR
,
Curi
R
,
Pithon-Curi
TC
.
Diabetes causes marked changes in function and metabolism of rat neutrophils
.
J Endocrinol.
2006
;
188
(
2
):
295
303
.
28
Vanhorebeek
I
,
DeVos
R
,
Mesotten
D
,
Wouters
PJ
,
De Wolf-Peeters
C
,
Van den Berghe
G
.
Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients
.
Lancet.
2005
;
365
(
9453
):
53
59
.
29
Perner
A
,
Nielsen
SE
,
Rask-Madsen
J
.
High glucose impairs superoxide production from isolated blood neutrophils
.
Intensive Care Med.
2003
;
29
(
4
):
642
645
.
30
Chan
JC
,
Malik
V
,
Jia
W
, et al
.
Diabetes in Asia: epidemiology, risk factors, and pathophysiology
.
JAMA.
2009
;
301
(
20
):
2129
2140
.
31
Schoenman
JA
,
Sutton
JP
,
Kintala
S
,
Love
D
,
Maw
R
.
The value of hospital discharge databases: final report
.
NORC at the University of Chicago, The National Association of Health Data Organizations
. . Published May 2005. Accessed December 19, 2010.
32
Gedeborg
R
,
Furebring
M
,
Michaelsson
K
.
Diagnosis-dependent misclassification of infections using administrative data variably affected incidence and mortality estimates in ICU patients
.
J Clin Epidemiol.
2007
;
60
(
2
):
155
162
.
33
Ernst
FR
,
Malatestinic
WN
,
Linde-ZwirbleW
T
.
Evaluating the clinical and financial impact of severe sepsis with Medicare or other administrative hospital data
.
Am J Health Syst Pharm.
2006
;
63
(
6
):
575
581
.

Footnotes

We also thank all other staff of the Epidemiology Department, Singapore General Hospital, for logistical support, and the patients who made the study possible.

FINANCIAL DISCLOSURES

None reported.

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