University of Groningen
New insights in outcome after major trauma
Nijboer, Johanna Maria Margaretha
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HYPERGLYCEMIA HAS A
STRONGER RELATION WITH
OUTCOME IN TRAUMA
PATIENTS THAN IN OTHER
CRITICALLY ILL PATIENTS
Mathijs Vogelzang
Johanna M.M. Nijboer
Iwan C.C. van der Horst
Felix Zijlstra
Hendrik-Jan ten Duis
Maarten W.N. Nijsten
J Trauma. 2006;60(4):873-7;
discussion 878-9.
7
ABSTRACT
Background
Acute hyperglycemia is associated with adverse outcome in critically ill patients. Glucose
control with insulin improves outcome in surgical intensive care unit (SICU) patients, but
the effect in trauma patients is unknown. We investigated hyperglycemia and outcome
in SICU patients with and without trauma.
Methods
A 12-year retrospective study was performed at a 12-bed SICU. We collected the reason for
admission, Injury Severity Scores (ISS), and 30-day mortality rates. Glucose measurements
were used to calculate the hyperglycemic index (HGI), a measure indicative of overall
hyperglycemia during the entire SICU stay.
Results
84
In all, 5234 nontrauma and 865 trauma patients were studied. Trauma patients were
younger, more frequently male, and had both lower median admission glucose (123
versus 133 mg/dL) and HGI levels (8.9 vs. 18.4 mg/dL) than nontrauma patients (p <
0.001). Mortality was 12% in both groups. Area under the receiver-operator characteristic
for HGI and mortality was 0.76 for trauma patients and 0.58 for nontrauma patients (p
< 0.001). In multivariate analysis, HGI correlated better with mortality in trauma patients
than in nontrauma patients (p < 0.001). Head-injury and nonhead-injury trauma patients
showed similar glucose levels and relation between glucose and mortality.
Conclusions
The relation of hyperglycemia and mortality is more pronounced in trauma patients than
in SICU patients admitted for other reasons. The different behavior of hyperglycemia in
these patients underscores the need for evaluation of intensive insulin therapy in these
patients.
INTRODUCTION
Patients and Treatment
Our study retrospectively analyzed all patients over 15 years of age admitted from 1990
through 2001 to the surgical intensive care unit (SICU) of the Groningen University
Hospital, a tertiary teaching hospital and Level I trauma center. Patients with no glucose
measurements were excluded. Enteral nutrition was started as soon as possible after
admission, whereas parenteral nutrition was infrequently used. Insulin treatment was
conservative, as insulin administration was only started when glucose levels reached
180 mg/dL; insulin was never administered above 10 IU/h. Except for liver transplant
patients, steroids were not routinely used.
85
Hyperglycemia
MATERIALS AND METHODS
Chapter 7
Acute hyperglycemia caused by acute disease is associated with adverse outcome. This
association has been demonstrated in patients suffering from trauma1–3, myocardial
infarction4, and stroke5, as for both general ICU patients6 and patients admitted to the
hospital ward7. Numerous reports have documented the relation of early hyperglycemia
with outcome in trauma patients8–16. Numerous studies have concentrated on early
hyperglycemia (i.e., hyperglycemia at admission or during the first 24 hours) in head injury
patients. Although glucose levels after the first day have been studied in conjunction with
hormone levels or with age17–20, their relation with outcome has not been previously
extensively studied, as all prior studies included less than 50 patients. Similarly, although
some investigators have compared hormonal levels in trauma patients with and without
head injury18,20, no study compared the association between hyperglycemia and
outcome directly in these two patient groups. Two intervention studies have showed
improvement in outcome after strict treatment of hyperglycemia in the intensive care
unit21,22. However, trauma patients only made up 4.4%21 and 5.4%22 of the study
subjects and therefore the effect of this intervention on trauma patients remains unclear.
To elucidate the possible value of intensive insulin therapy in trauma patients, we
performed a retrospective study to analyze how changes in glucose relate to mortality
in subgroups of ICU patients with various reasons for admission, focusing especially on
differences between trauma patients and nontrauma patients. To assess overall glucose
control during a longer period than 1 or 2 days, we have developed the hyperglycemic
index (HGI). HGI is calculated from all the glucose measurements taken during the entire
length of stay at the ICU for a single patient23. In contrast to admission glucose, HGI
reflects hyperglycemia that is amenable to insulin therapy. Within the trauma group, we
also analyzed the difference between patients with and patients without head injury.
Age, sex, reason for admission and all glucose measurements taken during the ICU stay
were retrieved from the central hospital information database. The Injury Severity Score
(ISS)24 as well as International Classification of Diseases (ICD)-9 codes were recorded for
trauma patients. ICD diagnoses for closed or penetrating skull or cerebral injuries were
used to categorize these patients as suffering from head injury or not. Admission glucose
was defined as the first glucose measurement upon arrival at the ICU. See Vogelzang
et al.23 for the exact calculation of HGI. The hyperglycaemic index corrects for irregular
sampling intervals and is not erroneously lowered by hypoglycemic episodes, as HGI only
measures levels higher than 108 mg/dL (6.0 mmol/L). HGI can be viewed as the mean
glucose level above 108 mg/dL. Therefore, the HGI yields a better estimate of overall
glucose control than a single value at admission or the highest value during the first day.
Mean glucose levels of all patients were calculated at fixed intervals of 12 hours after
admission by linearly interpolating glucose measurements. Hypoglycemia was defined as
a measurement lower than 54 mg/dL (3.0 mmol/L). The primary endpoint of this study
was 30-day mortality.
Statistical analysis
86
Data are presented as medians and interquartile range (IQR) for both continuous and
ordinal variables. When comparing groups, Student’s t test, the Mann-Whitney U
test, or Fisher’s exact test were used when appropriate. Univariate analysis of glucose
parameters and mortality was performed by calculating receiver-operator characteristics
(ROC) curves. Multivariate analysis was performed by means of binary logistic regression
that controlled for age, sex, and ISS (for trauma patients). All evaluated parameters were
entered in the model. Odds ratios for glucose-related parameters were calculated for
increases of 10 mg/dL. Significance of differences between odds ratios was calculated
as described by Altman and Bland25. Statistics were performed with the SPSS statistical
package (version 10.0.7, SPSS Inc, Chicago, IL) and Excel (version 97-SR 2, Microsoft
Corporation. Redmond, WA).
RESULTS
During the study period, 6,099 out of 6,307 admissions (97%) met the inclusion criteria.
Overall mortality was 12%. The reasons for admission were trauma (N = 865, mortality
12.4%), abdominal surgery (N = 2256, mortality 10.8%), liver transplantation (N = 552,
mortality 9.1%), vascular surgery (N = 921, mortality 13.5%), and miscellaneous (N =
1505, mortality 14.2%). As trauma patients were the focus of our study, and as univariate
correlation between hyperglycemia and outcome was similar for all nontrauma groups
(see Fig. 2), we will present only differences between trauma patients and nontrauma
patients.
Trauma patients significantly differed from those without trauma in several demographics:
age, length of stay, admission glucose, and HGI (all p < 0.001, Table 1). The median
(IQR) ISS for all trauma patients was 21 (13 – 29). Hypoglycemia occurred in 14 trauma
patients (1.6%) and in 190 patients without trauma (3.5%, p = 0.001). Of the trauma
patients, 402 (46%) had head injury. Patients with head injury were younger, had higher
ISS scores, and stayed longer at the ICU, and died of different causes than those without
head injury (Table 2). Mortality in patients without head injury was 11% compared with
14% in patients with head injury (p = 0.01).
Figure 1, A and B shows mean glucose levels from admission to 5 days after admission
for patients with and without trauma. As demonstrated by HGI levels in Table 1,
patients without trauma had higher overall mean glucose levels than trauma patients.
Chapter 7
87
Hyperglycemia
Figure 1. Mean glucose level from
admission to 5 days after admission
for survivors (continuous line, filled
symbols) and non-survivors (dotted
line, empty symbols) of non-trauma
patients and trauma patients.
The error bars depict 1 standard
error of the mean. Stars denote a
significant difference (p < 0.05) after
Bonferroni’s correctionfor multiple
testing. The shaded area represents
the normal range for glucose.
Table 1. General characteristics of patients studied
N
Male N (%)
Mortality N (%)
Age (years)1
Length of stay (days)1
Number of glucose measurements /
Admission glucose (mg/dL)1
Hyperglycemic index
1
(mg/dL)1
day1
Nontrauma
Trauma
5234
865
3204 (61)
642 (74)
P-value
< 0.001
631 (12)
107 (12)
0.78
62 (49 – 71)
38 (25 – 57)
< 0.001
1.6 (0.9 – 4.6)
2.6 (1.1 – 7.5)
< 0.001
2.3 (1.7 – 3.6)
1.7 (1.3 – 2.6)
< 0.001
133 (106 – 171)
123 (103 – 151)
< 0.001
18.4 (4.6 – 44.2)
8.9 (1.8 – 26.5)
< 0.001
median (interquartile range)
Nonsurvivors displayed higher glucose values than survivors in the trauma group as well
as in the group with other conditions (Figure 1). Moreover, the trauma group showed a
greater difference in mean glucose levels between survivors and nonsurvivors than the
nontrauma group. A selection effect could play a role in this kind of figure as a large
number of patients left the ICU during the first 5 days. However, the same analysis of
patients who stayed 5 days or longer displayed a similar pattern.
88
Figure 2 shows ROC curves of HGI and mortality in all subgroups. The area under
the curve for nontrauma patients was low (0.56 for abdominal surgery, 0.61 for liver
transplantation, 0.62 for vascular surgery, and 0.57 for miscellaneous). All nontrauma
groups together had an area under the curve of 0.58 versus 0.76 for trauma patients (p
< 0.001). For head injury patients, the area under the ROC was 0.79 and trauma patients
without head injury had an area of 0.72 (p = 0.20). The area under the curve for HGI was
Figure 2. Receiver-operator characteristics
for 30-day mortality and Hyperglycemic index
in ICU patients with different reasons for
admission, Areas under the curve are 0.76 for
trauma, 0.56 for abdominal surgery, 0.61 for
liver transplant, 0.62 for vascular surgery and
0.57 for miscellaneous.
Table 2. Characteristics of trauma patients with and without head injury
Non-head injury
Head injury
463
402
Male sex N (%)
327 (71)
315 (78)
0.10
Mortality N (%)
49 (11)
58 (14)
0.01
42 (27 – 68)
32 (23 – 50)
< 0.001
N
Age (years)1
Length of stay
(days)1
Admission glucose (mg/dL)1
Hyperglycemic index
(mg/dL)1
Injury Severity Score1
P-value
2.1 (1.0 – 6.3)
3.0 (1.5 – 10.0)
< 0.001
119 (101 – 150)
124 (104 – 155)
0.07
8.2 (1.12 – 2.7)
9.8 (2.4 – 29.0)
0.02
16 (9 – 25)
25 (18 – 34)
< 0.001
Cause of death N (%)
9 (18)
46 (79)
19 (39)
6 (10)
Respiratory failure
5 (10)
3 (5)
Sepsis/multiple organ failure
12 (24)
1 (2)
Pulmonary embolism
2 (4)
1 (2)
Unknown
2 (4)
1 (2)
< 0.001
Chapter 7
1
Neurological
Circulatory failure
median (interquartile range)
Table 3. Results of binary logistic regression analysis of factors influencing 30-day mortality
Age
Nontrauma
patients
Trauma
patients
P-value for
difference
1.03 (1.02 – 1.04)*
1.03 (1.02 – 1.04)*
0.74
Male
1.16 (0.97 – 1.38)
0.96 (0.57 – 1.61)
0.49
Admission glucose (per increase of 10 mg/dL)
0.99 (0.97 – 1.00)
0.98 (0.89 – 1.08)
0.99
Hyperglycemic index (per increase of 10 mg/dL)
1.10 (1.07 – 1.13)*
1.46 (1.29 – 1.65)*
< 0.001
-
1.09 (1.07 – 1.12)*
Injury Severity Score
Data are odds ratios (95% CI) * Significant, p < 0.001
89
Hyperglycemia
bigger compared with admission glucose in all subgroups. The area under the ROC for
ISS in all trauma patients was 0.66.
Multivariate analysis revealed that HGI correlated significantly better with mortality in
patients with trauma than in patients without trauma (Table 3, p < 0.001). Of admission
glucose and HGI, only HGI is a significant parameter in the multivariate model (p < 0.001).
Further analysis of the trauma group showed no significant differences in odds ratios of
measured variables between head injury and non-head injury patients, apart from age,
for which the odds ratio (95% confidence interval) was 1.01 (1.00 – 1.03) in head injury
patients and 1.05 (1.03 – 1.07) in patients without head injury (p = 0.006).
DISCUSSION
The relation between hyperglycemia and outcome depended upon reason of admission
and was stronger in trauma patients than in other types of critically ill patients, regardless
of the presence of head injury. Nonsurviving trauma patients showed marked early
hyperglycemia, whereas surviving trauma patients sustained only minor hyperglycemia.
Remarkably, glucose levels and their relation with outcome were similar in trauma patients
with and without head injury. The hyperglycemic index was superior to admission glucose
in discriminating survivors and nonsurvivors in all subgroups.
It must be noted that this study was conducted at an SICU and not at an emergency
department. Therefore, patients might already have undergone surgery or other therapy
before the admission glucose level was recorded. This may explain why admission
glucose and ISS were not as strongly correlated with outcome as in studies that utilize
glucose levels from the emergency department2,9,10,12–16. However, this does not affect
the relevance of this study, as intensive insulin therapy is mostly advocated while patients
are treated at an ICU. Another limitation is that we did not include confounding factors
such as caloric intake, steroid use, history of diabetes, and insulin use.
90
Injury-induced hyperglycemia was already recognized by Claude Bernard. Injury causes
an immediate surge of catecholamines in the blood26. The stress response to trauma
or surgery causes a hypermetabolic state, characterized by protein and fat catabolism,
negative nitrogen balance, hyperglycemia, and insulin resistance27,28. Although
peripheral uptake of glucose as well as cellular glucose utilization is enhanced, increased
gluconeogenesis and insulin resistance may prevail, leading to hyperglycemia29. The
stress response provides a plausible link between injury and the rise in glucose. Glucose
levels have been shown to correlate with catecholamine levels in general trauma patients
and patients with head injury12,18,20,26.
Previously a causal relation has been suggested between glucose and outcome in head
injury patients. Assuming hyperglycemia increases anaerobic metabolism and subsequently
higher intracerebral lactate levels, low pH levels causing secondary brain damage may
result9–14. However, De Salles and colleagues have found that cerebrospinal fluid lactate
levels stayed high for more than 5 days after trauma, when blood glucose had already
normalized30, obscuring a direct relation. Recently, Diaz-Parejo and colleagues have
measured intracerebral lactate levels during both normoglycemia and hyperglycemia.
They found that intracerebral lactate concentration only increased when blood glucose
values were over 270 mg/dL, and thus is less likely to play a role at more modest levels
of hyperglycemia31. Our finding of similarity in the relation between hyperglycemia
and mortality in head injury and non-head injury patients could also indicate that other
mechanisms, common to both patient groups, are present.
We think the notably different glucose profiles of trauma patients and other ICU
patients can be explained by their different baseline characteristics. Trauma patients
are significantly younger than other ICU patients and suffer only from trauma, whereas
general ICU patients are often older, and more often than not suffer from multiple
conditions. Injury drives the stress response, and young trauma patients are able to
build up a powerful reaction. Therefore, hyperglycemia might reflect severity of illness
better in trauma patients than in general ICU patients. Previous investigators have found
that adding additional severity of illness scores into their multivariate model diminishes
the role of glucose in predicting outcome9,11. Whether the strong correlation between
hyperglycemia and outcome is caused by confounding factors like severity of illness or
by a causal relation cannot be concluded from this or any other retrospective study. We
think that the differences found in this retrospective study justify the conclusion that
regarding hyperglycemia, trauma patients differ from other ICU patients. Furthermore,
even with our very conservative insulin protocol, surviving trauma patients only had very
modest hyperglycemia as shown in Figure 1 and reflected in their HGI of only 9 mg/dL,
which is equivalent to a mean glucose level of 117 mg/dL.
Chapter 7
91
Hyperglycemia
Thorell and colleagues recently investigated how intensive insulin therapy leads to
normoglycemia in critically ill trauma patients. They showed that insulin reduces
endogenous glucose production, whereas whole-body glucose disposal is not
increased32. The mechanism behind the impressive results of intensive insulin therapy
in the study by van den Berghe and colleagues is still largely unknown21. Multiple
theories have been proposed, including a decreased infection rate due to improved
macrophage function, reduced endothelial dysfunction, improvement of lipid disorders,
and reduced hyperglycaemic axonal damage33. These general mechanisms may apply to
every critically ill patient and, therefore, proponents advocate intensive insulin therapy
in all critically ill patients, regardless of underlying illness34,35. However, retrospective
data incompatible with this theory is available; Laird and colleagues did not find a
significant relation between infection and hyperglycemic levels on day 1 or 2 in trauma
patients3. Yendamuri and colleagues did find a significant relation between admission
glucose and urinary tract infection and a borderline significant trend toward increased
incidence of pneumonia, but no increased rate of bacteremia or wound infection2.
More important, few trauma patients were included in the two intervention studies that
actually implemented strict glucose control by intensive insulin therapy. In the Leuven
study (a randomized controlled trial), the mortality in the trauma group was 8.6% in
the conventional group (N = 35) and 12.1% in the intervention group (N = 33)21. In
the study by Krinsley (a “before - after” study), the mortality rates were 17.8% and
19.5%, respectively (N = 48 and 38)22. The trend toward higher mortality is remarkable
regarding the Acute Physiology and Chronic Health Evaluation (APACHE-II) scores, which
were significantly lower in the intervention group.
CONCLUSIONS
Our results show that trauma patients differ from patients with other reasons for
admission. It is likely that different mechanisms play a role in glucose homeostasis in
patient groups with different baseline characteristics. Caution is to be exercised when
implementing insulin therapy in trauma patients. A randomized controlled trial in a large
group of trauma patients is needed to bring the value of glucose control in trauma
patients to light.
ACKNOWLEDGEMENTS
The authors want to thank Rob Kolstad for critical reading of the manuscript.
92
REFERENCES
Chapter 7
93
Hyperglycemia
1. McNamara JJ, Molot M, Stremple JF, et al. Hyperglycemic response to trauma in combat
casualties. J Trauma. 1971;11:337–339.
2. Yendamuri S, Fulda GJ, Tinkoff GH. Admission hyperglycemia as a prognostic indicator in
trauma. J Trauma. 2003;55:33–38.
3. Laird AM, Miller PR, Kilgo PD, et al. Relationship of early hyperglycemia to mortality in trauma
patients. J Trauma. 2004;56:1058–1062.
4. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycaemia and increased risk of death after
myocardial infarction in patients with and without diabetes: a systematic overview. Lancet.
2000;355:773–778.
5. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and prognosis of stroke in nondiabetic
and diabetic patients: a systematic overview. Stroke. 2001;32:2426–2432.
6. Lind L, Lithell H. Impaired glucose and lipid metabolism seen in intensive care patients is related
to severity of illness and survival. Clin Intensive Care. 1994;5:100–105.
7. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital
mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87:978–982.
8. Merguerian PA, Perel A, Wald U, et al. Persistent nonketotic hyperglycemia as a grave prognostic
sign in head-injured patients. Crit Care Med. 1981;9:838–840.
9. Young B, Ott L, Dempsey R, et al. Relationship between admission hyperglycemia and neurologic
outcome of severely brain-injured patients. Ann Surg. 1989;210:466–472.
10. Lam AM, Winn HR, Cullen BF, et al. Hyperglycemia and neurological outcome in patients with
head injury. J Neurosurg.1991;75:545–551.
11. Margulies DR, Hiatt JR, Vinson DJ, et al. Relationship of hyperglycemia and severity of illness to
neurologic outcome in head injury patients. Am Surg. 1994;60:387–390.
12. Yang SY, Zhang S, Wang ML. Clinical significance of admission hyperglycemia and factors
related to it in patients with acute severe head injury. Surg Neurol. 1995;44:373–377.
13. Rovlias A, Kotsou S. The influence of hyperglycemia on neurological outcome in patients with
severe head injury. Neurosurgery. 2000;46:335–342.
14. Walia S, Sutcliffe AJ. The relationship between blood glucose, mean arterial pressure and
outcome after severe head injury: an observational study. Injury. 2002;33:339–344.
15. Jeremitsky E, Omert L, Dunham CM, et al. Harbingers of poor outcome the day after severe
brain injury: hypothermia, hypoxia, and hypoperfusion. J Trauma. 2003;54:312–319.
16. Rovlias A, Kotsou S. Classification and regression tree for prediction of outcome after severe
head injury using simple clinical and laboratory variables. J Neurotrauma. 2004;21:886–893.
17. Desai D, March R, Watters JM. Hyperglycemia after trauma increases with age. J Trauma.
1989;29:719–723.
18. Chiolero R, Schutz Y, Lemarchand T, et al. Hormonal and metabolic changes following severe
head injury or noncranial injury. JPEN J Parenter Enteral Nutr. 1989;13:5–12.
19. Jeevanandam M, Petersen SR, Shamos RF. Protein and glucose fuel kinetics and hormonal
changes in elderly trauma patients. Metabolism. 1993;42:1255–1262.
20. Petersen SR, Jeevanandam M, Harrington T. Is the metabolic response to injury different with
or without severe head injury? Significance of plasma glutamine levels. J Trauma. 1993;34:653–
660.
21. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients.
N Engl J Med. 2001;345:1359–1367.
22. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill
adult patients. Mayo Clin Proc. 2004;79:992–1000.
23. Vogelzang M, van der Horst ICC, Nijsten MWN. Hyperglycaemic index as a tool to assess glucose
control: a retrospective study. Crit Care. 2004;8:R122–R127.
94
24. Baker SP, O’Neill B, Haddon WJ, et al. The injury severity score: a method for describing patients
with multiple injuries and evaluating emergency care. J Trauma. 1974;14:187–196.
25. Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ.
2003;326:219.
26. Heath DF. Glucose, insulin and other plasma metabolites shortly after injury. J Accid Emerg Med.
1994;11:67–77.
27. Chiolero R, Revelly JP, Tappy L. Energy metabolism in sepsis and injury. Nutrition. 1997;13:45S–
51S.
28. Thorell A, Nygren J, Ljungqvist O. Insulin resistance: a marker of surgical stress. Curr Opin Clin
Nutr Metab Care. 1999;2:69–78.
29. Mizock BA. Blood glucose management during critical illness. Rev Endocr Metab Disord.
2003;4:187–194.
30. De Salles AA, Muizelaar JP, Young HF. Hyperglycemia, cerebrospinal fluid lactic acidosis, and
cerebral blood flow in severely head-injured patients. Neurosurgery. 1987;21:45–50.
31. Diaz-Parejo P, Stahl N, Xu W, et al. Cerebral energy metabolism during transient hyperglycemia
in patients with severe brain trauma. Intensive Care Med. 2003;29:544–550.
32. Thorell A, Rooyackers O, Myrenfors P, et al. Intensive insulin treatment in critically ill trauma
patients normalizes glucose by reducing endogenous glucose production. J Clin Endocrinol
Metab. 2004;89:5382–5386.
33. Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J
Clin Invest. 2004;114:1187–1195.
34. Preiser J, Devos P, Van den Berghe G. Tight control of glycaemia in critically ill patients. Curr
Opin Clin Nutr Metab Care. 2002;5:533–537.
35. Van den Berghe G. Tight blood glucose control with insulin in “real-life” intensive care. Mayo
Clin Proc. 2004;79:977–978.