YAJEM-55541; No of Pages 5

American Journal of Emergency Medicine xxx (2016) xxxxxx

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

journal homepage: www.elsevier.com/locate/ajem

1 Original Contribution

2 Higher serum level of myoglobin could predict more severity and poor
3 outcome for patients with sepsis,

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4Q1 Liqiong Yao a,, Zhiwu Liu a, Jinhong Zhu a, Bin Li b, Chen Chai c, Yunlin Tian d

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5 a
Department of Medical Laboratory center, the First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
6 b
Department of Intensive Care Unit, the First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
7 c
Department of general surgery, the First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China

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8 d
Department of endocrinology, the First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China

a r t i c l e i n f o a b s t r a c t

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10 Article history: Background: There have been sporadic case reports published focusing on myoglobin and sepsis. However, there 16

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11 Received 14 June 2015 are no systematic studies evaluating the correlation between myoglobin level and sepsis. This study investigated 17
12 Received in revised form 6 January 2016 the correlation between the serum myoglobin level and the severity of septic patients. Next, we assessed the pre- 18
13 Accepted 7 January 2016 dictive value of the serum myoglobin level for the prognosis of septic patients. 19
14 Available online xxxx
Methods: Seventy septic patients were included and subdivided into the following 3 groups: sepsis group, severe
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sepsis group, and septic shock group. We collected blood samples at 0, 6, 12, 18, and 24 hours after admission. The 21
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serum levels of myoglobin, C-reactive protein, and procalcitonin were analyzed. We also evaluated the levels of 22
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malondialdehyde, which is a biomarker for oxidative stress.
Results: The data indicate that the myoglobin level increased gradually within 24 hours after admission. The me- 24
dian myoglobin levels of the sepsis, severe sepsis, and septic shock groups were 635.7, 903.6, and 1094.8 g/L, re- 25
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spectively (P b .05). The elevated myoglobin level was positively correlated with Sequential Organ Failure 26
Assessment score, C-reactive protein, and procalcitonin level in septic patients. The increased myoglobin level 27
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was also associated with the mortality of septic patients. The Kaplan-Meier survival curves indicated that patients 28
with high myoglobin levels had an elevated mortality rate. Moreover, an elevated myoglobin level indicated 29
more oxidative stress. 30
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Conclusions: The myoglobin level can be detected in the early stage of sepsis and may serve as a potential bio- 31
marker for evaluating sepsis severity and further prognosis. 32
33 2016 Published by Elsevier Inc.
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34 1. Introduction endotoxin, and other pathogenic factors. In addition, excessive inam- 46

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matory responses may induce the secretion of cytokines and elevate re- 47
35 Myoglobin is a heterodimer composed of a peptide chain and a heme active oxygen species, which leads to oxidative stress [56]. Oxidative 48
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36 group. The molecular weight is approximately 17.9 kDa. The protein is stress causes a positive feedback loop by aggravating tissue injury and 49
37 found in the cytoplasm of myocardial and skeletal muscle cells [1]. causing further myoglobin outow into the bloodstream. Therefore, el- 50
38 When muscle tissue damage occurs, the cytosolic myoglobin is rapidly evated myoglobin levels in critical diseases indicate widespread and se- 51
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39 released into the blood circulation [2]. Thus, myoglobin is often used vere injury [78]. The myoglobin protein catalyzes oxidation reactions 52
40 as a biomarker in the diagnosis of myocardial injury in clinical settings and hydrogen oxidation reactions in conditions of oxidative stress. The 53
41 54
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[3]. Recent studies have shown that, in addition to myocardial and skel-
42 etal muscle injury, there are also elevated serum myoglobin levels in the
43 following diseases: severe infection, systemic inammation, organ fail-
44 ure, severe trauma, gastrointestinal bleeding, and severe pancreatitis
45 [4]. Critical diseases may cause ischemia, hypoxia, local hypoperfusion,
This study was supported by grants from the National High Technology Research and
Development Program of China (863 Program) (no. 2011AA02A111).
Declaration of interest: We declare that we have no conict of interest.
Corresponding author.
E-mail address: medyaoliq@sina.com (L. Yao).
peroxidase-like activity of myoglobin may be involved in oxidative
stress and promotes the generation of ferroferric oxide, lipid peroxides, 55
isoprostanes, and other cytotoxic products. Excessive myoglobin levels 56
may aggravate the injury caused by oxidative stress [911]. Therefore, 57
monitoring serum myoglobin levels may facilitate our understanding 58
of critical disease progression and may be used to evaluate the severity 59
of critical diseases or multiple organ injury. Although sporadic case re- 60
ports have been published, there are no systematic studies examining 61
the correlation between serum myoglobin level and sepsis. Therefore, 62
this study investigated the correlation between the serum myoglobin 63
level and severity of septic patients. We also determined the clinical 64
prognostic value of myoglobin as a potential biomarker. 65

http://dx.doi.org/10.1016/j.ajem.2016.01.009
0735-6757/ 2016 Published by Elsevier Inc.

Please cite this article as: Yao L, et al, Higher serum level of myoglobin could predict more severity and poor outcome for patients with sepsis, Am J
Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.01.009
 2 L. Yao et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx

66 2. Materials and methods 2.3. Statistical analysis 102

67 2.1. Patient selection The data analyses were performed using SPSS18.0 software (SPSS 103
Inc, Chicago, IL). The data with a normal distribution were expressed 104
68 The study population consisted of 70 consecutive septic patients as the mean SD, and data with a nonnormal distribution were 105
69 who were admitted to the First Hospital of Lanzhou University between expressed as the median. A 1-way analysis of variance was performed 106
70 April 2013 and May 2014. The diagnosis of sepsis was based on the to compare multiple groups and was followed by the least signicant 107
71 guideline of American College of Chest Physicians and the American So- difference test for parametric data. The nonparametric data were ana- 108
72 ciety of Critical Care Medicine. Sepsis was dened as the presence of sys- lyzed using the Mann-Whitney test to compare groups. The difference 109
73 temic inammatory response syndrome (SIRS) associated with in frequency distribution between groups was determined using the 110
74 infection. SIRS was further dened as the presence of 2 or more of the 2 test. A Spearman correlation analysis was also performed. The 28- 111
75 following criteria: temperature b 36.8C or N38.8C, heart rate N 90 day survival was calculated using the Kaplan-Meier curves and the 112
76 beats per minute in the absence of a pacemaker, respiratory rate N 20 log-rank test. A P value b .05 was considered statistically signicant. 113
77 times per minute or PaCO2 less than 4.3 kPa (32 mm Hg), and white

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78 blood cell count N2 10 9/L or b4 10 9/L, or N 10% immature band 3. Results 114
79 cells. The patients included in the study were subdivided into the fol-

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80 lowing 3 groups: sepsis group, severe sepsis group, and septic shock The demographic characteristics of all included patients are shown 115
81 group. Sepsis complicated with organ dysfunction was dened as severe in Table. There were 20, 35, and 15 patients in the sepsis, severe sepsis, 116
82 sepsis in accordance with the criteria of the 2001 American Society of and septic shock groups, respectively. The age, sex, site of infection, and 117

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83 Critical Care Medicine/European Society of Intensive Care Medicine/ pathogen culture results were comparable among groups (P N .05). The 118
84 American Thoracic Society/Surgical Infection Society International Sep- SOFA score, serum CRP, and PCT levels (at 24 hours after admission) 119
85 sis Denitions Conference. In addition, sepsis complicated with hypo- were higher in the septic shock group than in the sepsis and severe sep- 120

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86 tension refractory to adequate volume resuscitation in the absence of sis groups (P b .05). The sepsis group had the lowest SOFA score, CRP, 121
87 an alternate cause is termed septic shock. The exclusion criteria in this and PCT level (P b .05). 122

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88 study were the following: (1) age b18 years; (2) coronary heart disease,
89 myocardial infarction, or coronary syndrome; (3) malignant tumors; 3.1. The serum myoglobin level is elevated in septic patients 123
90 (4) rhabdomyolysis; (5) pregnancy; and (6) autoimmune disease.
Fig. 1 shows the blood samples collected from patients at the indicat- 124
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ed time points after admission. The data demonstrate that the median 125
91 2.2. Study design myoglobin level increased signicantly with time (510.6 g/L at 126
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0 hour vs 541.5 g/L at 6 hours vs 673.4 g/L at 12 hours vs 764.2 g/L 127
92 The patients' age, sex, Sequential Organ Failure Assessment (SOFA) at 18 hours vs 886.5 g/L at 24 hours, all Ps b .05). 128
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93 score, and other clinical information were recorded. The patients re-
94 ceived routine vital sign monitoring, breathing and blood gas parameter 3.2. The elevated myoglobin level is correlated with the severity of sepsis 129
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testing, and pathogen cultures at admission. The blood samples were

96 collected at 0, 6, 12, 18, and 24 hours after admission. The serum myo- At 24 hours after admission, the median levels of myoglobin in pa- 130
97 globin, C-reactive protein (CRP) and procalcitonin (PCT) levels were tients with sepsis, severe sepsis, and septic shock were 635.7, 903.6, 131
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98 also analyzed. The malondialdehyde (MDA) level was evaluated as a and 1094.8 g/L, respectively (P b .05, Fig. 2). As shown in Fig. 3, the sep- 132
99 biomarker for oxidative stress. All patients provided informed consents, tic shock group displayed higher SOFA score, CRP, and PCT levels than 133
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100 and the protocol was approved by the Ethics Committee of the First the sepsis and severe sepsis groups (P b .05). The correlation analysis 134
101 Hospital of Lanzhou University. (Fig. 4) showed that the myoglobin level (at 24 hours after admission) 135
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t1:1 Table
t1:2 Clinical characteristics of the subjects enrolled
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t1:3 Sepsis patients (n = 70) P value

Sepsis subgroup (n = 20) Server subgroup (n = 35) Septic shock subgroup (n = 15)
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t1:4 Median age (y) 52 (36-62) 55 (40-71) 54 (42-69) NS

t1:5 Sex
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Male 9 20 7 NS
t1:7 Female 11 15 8
t1:8 Blood culture
t1:9
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Negative 2 2 3 NS
t1:10 Bacterial (G+) 6 10 3
t1:11 Bacterial (G) 10 20 8
t1:12 Fungi 2 3 1
t1:13 Primary infection site
t1:14 Lower respiratory tract 2 5 4 NS
t1:15 upper respiratory tract 3 3 2
t1:16 Urinary tract 4 8 3
t1:17 Abdomen 11 19 6
t1:18 SOFA score 6 (4-8) 7 (5-10) 9 (6-11) b.05
t1:19 CRP (mg/L) 72.3 (53.2-91.3) 95.5 (57.5-119.9) 135.7 (100.1-158.3) b.05
t1:20 PCT (g/L) 2.9 (0.9-5.7) 6.8 (3.4-11.6) 12.8 (9.9-18.3) b.05
t1:21 Median ICU stay (d) 10 (6-18) 15 (15-22) 20 (18-27) b.05
t1:22 28-d survival
t1:23 Yes 15 25 5 b.05
t1:24 No 5 10 10

t1:25 Abbreviations: ICU, intensive care unit; NS, no signicance.

Please cite this article as: Yao L, et al, Higher serum level of myoglobin could predict more severity and poor outcome for patients with sepsis, Am J
Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.01.009
 L. Yao et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx 3

Fig. 1. An increased serum myoglobin level of a patient with sepsis was observed within
24 hours after admission. *P b .05 compared with 0 hour; #P b .05 compared with

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24 hours.

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136 in all included patients was proportional to their SOFA score (r = 0.641,
137 P b .05) and was positively related to serum CRP and PCT levels (r =
138 0.733 and 0.721, P b .05). These results suggest that the serum myoglo-

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139 bin level is correlated with sepsis severity.

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140 3.3. Relationship between serum myoglobin level and patient outcome

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141 There were 70 patients enrolled in this study, and 25 patients died
142 within 28 days. The remaining 45 patients survived 28 days after ICU
143 admission. The myoglobin levels of the surviving the patients were sig-
nicantly lower than the levels in deceased patients (733.9 g/L vs
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145 1041.1 g/L, P b .05, Fig. 5). We then assessed the clinical value of myo-
146 globin level for predicting 28-day mortality using as receiver operating
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147 characteristic (ROC) curve. As shown in Fig. 6, the area under the ROC
148 curve was 0.824 (95% condence interval, 0.728-0.920; P b .05), and
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149 the cutoff value was 922.4 g/L. The Kaplan-Meier survival curve
150 (Fig. 7) showed that the patients with a myoglobin level N922.4 g/L
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151 had a decreased 28-day survival rate compared with patients with
152 a myoglobin level 922.4 g/L (26.3% vs 76.0%, P b .05). These
153 results suggest that the myoglobin level can predict the prognosis of
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154 septic patients.

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155 3.4. An increased myoglobin level is correlated with oxidative stress in

156 septic patients Fig. 3. The SOFA score, CRP, and PCT level of patients with different severities of sepsis.
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157 Fig. 8 shows that higher MDA levels were found in more severe sep- 4. Discussion 165
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158 tic patients. At 24 hours after admission, the median MDA levels in the
159 sepsis group, severe sepsis group, and septic shock group were 8.9, Sepsis is a systemic inammatory response caused by infection and 166
160 15.1, and 22.9 nmol/mL, respectively (P b .05). A correlation analysis may result in multiple organ dysfunction syndrome and a high mortal- 167
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161 (Fig. 9) showed that the myoglobin level (at 24 hours after admission) ity rate [12]. Multiple studies have focused on the prevention and treat- 168
162 in all included patients was proportional to the MDA level (r = 0.768, ment of sepsis during the past decade. However, sepsis remains a major 169
163 P b .05). This nding indicates that the myoglobin level is correlated 170
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cause of death in the ICU [13]. Thus, additional studies are needed to im-
164 with oxidative stress. prove the prognosis (or outcomes) of severe sepsis and septic shock pa- 171
tients using early treatments. Therefore, it is critical to quickly diagnose 172
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and accurately assess patients with sepsis. Recent advances in molecular 173
and biological techniques will improve the role of biomarkers in the 174
early diagnosis, state of illness, prognosis, and evaluation of response 175
to sepsis [14]. Biomarkers including CRP, interleukin, PCT, and B-type 176
natriuretic peptide are currently used in the early diagnosis of sepsis 177
[1516]. However, these biomarkers have specic limitations or rela- 178
tively low accuracy. For example, CRP has a high sensitivity but low 179
specicity for the diagnosis of sepsis and is not suitable for individual di- 180
agnosis. Furthermore, PCT has a higher specicity than CRP but is affect- 181
ed by bacterial infections [1718]. Several studies have shown that PCT 182
cannot be used to distinguish sepsis from SIRS not caused by bacterial 183
infection because it has an inadequate diagnostic efcacy in severe sep- 184
sis patients when used alone. Thus, a combination of biomarkers associ- 185
Fig. 2. The myoglobin levels of patients with different severities of sepsis. ated with predictive systems such as SOFA or APACHE is required. 186

Please cite this article as: Yao L, et al, Higher serum level of myoglobin could predict more severity and poor outcome for patients with sepsis, Am J
Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.01.009
 4 L. Yao et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx

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Fig. 6. Receiver operating characteristic curve for myoglobin as a predictor of 28-day sur-
vival in patients with sepsis.

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Fig. 7. Kaplan-Meier survival curves show that patients with high myoglobin levels had an
increased mortality compared with patients with low myoglobin level.
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Fig. 4. The increased myoglobin was positively associated with SOFA score, CRP, and PCT
level in patients with sepsis.
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187 The majority of biomarkers require a minimum of 24-hour hospitaliza-

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188 tion to be specic, so it is necessary to develop new biomarkers for

189 early diagnosis.
190 Myoglobin is commonly used for the diagnosis of myocardial injury
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191 in clinical settings [3]. However, recent studies have shown that critical-
192 ly ill patients with severe infection, burns, shock, and multiple traumas
193 display elevated myoglobin levels. Similar to the Acute Physiology and
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194 Chronic Health Evaluation II score, the myoglobin level reects the se-
Fig. 8. The malondialdehyde level of patients with different severities of sepsis.
195 verity of illness and can predict the survival rate and patient outcome
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Fig. 5. The increased myoglobin level was associated with mortality of septic patients. Fig. 9. The increased myoglobin was positively associated with malondialdehyde level.

Please cite this article as: Yao L, et al, Higher serum level of myoglobin could predict more severity and poor outcome for patients with sepsis, Am J
Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.01.009
 L. Yao et al. / American Journal of Emergency Medicine xxx (2016) xxxxxx 5

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Please cite this article as: Yao L, et al, Higher serum level of myoglobin could predict more severity and poor outcome for patients with sepsis, Am J
Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.01.009