Clinical implications of serum myoglobin in trauma patients: A retrospective study from a level 1 trauma center.

BACKGROUND: We aimed to study the clinical implication of high serum myoglobin levels in trauma patients.
METHODS: A retrospective analysis was conducted on data from trauma patients who were admitted to a level 1 trauma center between January 2012 and December 2015. A receiver operating characteristic (ROC) curve analysis was performed for the optimum myoglobin cutoff plotted against hospital length of stay of >1 week. Patients were divided into two groups (Group 1; low vs. Group 2; high myoglobin), and a comparative analysis was performed.
RESULTS: There were 898 patients who met the inclusion criteria with a mean age of 35.9 ± 14.6 years. Based on ROC, the myoglobin optimum cutoff was 1000 ng/ml (64% of patients were in Group 1 and 36% in Group 2). The mean myoglobin level was 328 ng/ml in patients with the Injury Severity Score (ISS) <15 versus 1202 ng/ml in patients with ISS ≥15 (P < 0.001). Patients in Group 2 had higher ISS (22.2 ± 10 vs. 18.8 ± 10), more musculoskeletal injuries (18.3% vs. 4.2%), more blood transfusion (74% vs. 39%), intubation (57% vs. 46.5%), and sepsis (12% vs. 7.3%). The length of hospital stays was significantly higher in Group 2, but mortality was comparable. High myoglobin levels had a crude odd ratio 2.41; 95% confidence interval (1.470-3.184) for a longer hospital stay with a positive predictive value of 89% and a specificity of 77%.
CONCLUSIONS: One-third of the admitted trauma patients have elevated serum myoglobin level, which is associated with the prolonged hospital stay. The discriminatory power of myoglobin value of 1000 in trauma is fair, and further prospective assessments are needed. Copyright:

INTRODUCTION

Myoglobin is a muscle protein released into circulation due to damage to the muscles following either by inherited causes or by acquired etiology, mainly trauma.[1] Rhabdomyolysis is a serious syndrome in which muscle fiber lysis occurs, and their contents are released into the bloodstream, often diagnosed with elevated creatine kinase (CK) and myoglobin levels. Disproportionately higher burden of traumatic injuries among males puts them at high risk of high serum myoglobin level and its complications. The main sources for higher myoglobin release into circulation are extremities and trunk. Although there is no guideline yet, delayed diagnosis and treatment of patients with elevated myoglobin level may result in high morbidity and mortality since it causes acute kidney injury (AKI), compartment syndrome, sepsis, acute respiratory distress syndrome (ARDS), or pneumonia.[1]

The clinical consequences of high serum myoglobin are not well defined due to the lack of clinical diagnostic criteria and prognostic indicators and well-established treatment guidelines. Treatment of rhabdomyolysis associated high serum myoglobin varies considerably depending on the clinical scenario from close observation to active interventions such as dialysis and treatment of complications. However, the distinction between cases who will recover quickly and uncomplicated and those who will have prolonged hospital stay due to significant myoglobin level may be difficult early in the management. Since every injury is unique with different degrees of associated muscle damage; it is difficult to develop appropriate precise decision-making algorithm for treatment, and therefore, risks of rhabdomyolysis often remain unidentified on the initial presentation. Interestingly, there is a paucity of information in the literature on cutoff levels of myoglobin to determine significant muscle damage. In this study, we retrospectively reviewed the injury characteristics, complications, and outcome of trauma patients based on myoglobin level from a single institute over 4 years. We hypothesized that a high myoglobin level is associated with the prolonged hospital stay. The study aims to identify patients' characteristics, complications associated with elevated serum myoglobin level and in-hospital outcomes.

METHODS

Following required institutional approval, data were acquired retrospectively for all trauma patients identified from the trauma registry database who were admitted to the Hamad Trauma Center (HTC) between January 2012 and December 2015. The HTC is the national Level 1 trauma center facility in Qatar, which admits and treats all patients with traumatic injury in the country. Serum myoglobin was checked for trauma patients on admission to our center, based on the physician's discretion; however, there is no institutional protocol for that.

There is a lack of specific criteria to diagnose rhabdomyolysis in trauma settings, and therefore, a combination of clinical and laboratory data is used. Serum CK levels exceeding five times the upper limit of normal levels are often used for the diagnosis. However, in our patient population, CK level was not routinely requested along with myoglobin, and the diagnosis usually relied on the combination of clinical signs and symptoms and myoglobin level. Only the maximum or peak CK levels were reported in this study because of the lack of availability of data. AKI was defined as an increase in serum creatinine of ≥0.3 mg/dL or ≥50% within 48 h or urine output of <0.5 mL/kg/h for >6 h. Our study included trauma patients (14 years and above) with serum myoglobin level order written with admission order. Children (<14 years) and those who do not have a test for serum myoglobin on admission were excluded. If the myoglobin level was above the normal range (reference range was 72 ng/mL), it was checked every 8 h until it was normalized. On arrival, all trauma patients underwent a thorough clinical assessment and resuscitation according to advanced trauma life support guidelines.[2] Collected data included demographic information (age, gender, and nationality); injury characteristics such as the mechanism of injury, injured body sites; injury characteristics Glasgow Coma Score (GCS), Abbreviated Injury Score (AIS), and Injury Severity Score (ISS); management (blood transfusion, Open Reduction and Internal Fixation Surgery [ORIF], hemodialysis and intubation); complications such as compartment syndrome, sepsis, ARDS, pneumonia, and AKI; relevant laboratory findings and outcomes including intensive care unit (ICU) days, ventilator days, hospital length of stay (LOS), and mortality.

Statistical analysis

Data were expressed as proportions, medians, or mean ± standard deviation, as appropriate. A receiver operating characteristic (ROC) curve analysis was performed for the optimum myoglobin cutoff plotted against hospital LOS (<7 vs. >7 days). The cutoff value of 1000 ng/mL in this study was based on the ROC curve analysis, which correlated myoglobin level and the length of hospital stay for >7 days. Discriminatory power was determined using sensitivity, specificity, and positive and negative likelihood ratio (LR). Patients were divided into two groups based on the myoglobin cutoff (low vs. high myoglobin group), and comparative analysis was performed. Differences in categorical variables between respective comparison groups were analyzed using the Chi-square test or Fisher exact. Continuous variables were analyzed using the Student's t-test or ANOVA test. The correlation coefficient was performed for the relation between myoglobin, ISS, and hospital stay days. A subanalysis was performed to look for the association between hospital course and complications in different myoglobin levels (<200, 200–400, 400–600, 600–800, 800–1000, and > 1000 ng/mL). Two-tailed P < 0.05 was considered to be statistically significant. Data analysis was carried out using the Statistical Package for the Social Sciences IBM® SPSS version 18 (IBM Inc., Armonk, USA). This manuscript adheres to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.[3]

RESULTS

A total of 898 patients met the inclusion criteria; the mean age of patients was 35.9 ± 14.6 years with male predominance (n = 837, 93%). A ROC curve analysis for the optimum myoglobin cutoff plotted against prolonged hospital LOS revealed a myoglobin cutoff 1000 ng/mL. Patients were divided into two groups based on the myoglobin level; <1000 ng/mL (Group 1; 64%) and ≥1000 ng/ml (Group 2; 36%). The age and male predominance were comparable between the 2 groups.

The main mechanism of injury was road traffic-related (n = 500, 56%), followed by falls (n = 235, 26%) and hit by heavy objects (n = 78, 9%). Mechanisms of injuries in both groups showed significant differences; road traffic-related was mainly associated with Group 2, whereas falls were significantly higher in Group 1.

Head injuries were more frequent in Group 1 when compared to Group 2, whereas chest, abdomen, pelvic, and solid organ injuries were more common in Group 2. Eighty-three patients (9%) had musculoskeletal injuries, more frequently reported in Group 2 patients.

The mean ISS score was higher in Group 2 (22.2 ± 10.4 vs. 18.8 ± 9.6, P < 0.001). The mean myoglobin level was 328 ng/ml in patients with ISS <15 versus 1202 ng/ml in patients with ISS ≥15 (P < 0.001). Serum myoglobin was correlated with ISS (r = 0.12, P = 0.001). Figure 1 shows that ISS was not directly increasing as the myoglobin levels increases; however, it was significantly higher in patients with myoglobin values between 400 and 600 and in those with values >1000 ng/mL. The mean GCS and AIS score for anatomical regions (head, chest, and abdomen) were comparable; however, pelvis AIS was higher in Group 2 [Table 1].

Figure 1

Injury severity score in different serum myoglobin levels

Table 1

Characteristics of trauma patients based on the myoglobin level

Variables	Overall (n=898)	Myoglobin <1000 ng/mL (n=576, 64.1%)	Myoglobin ≥ 1000 ng/mL ;(n=322, 35.9%)	P
Mean age	35.9±14.6	37.8 ± 15.0	36.0±13.7	0.84
Males	837 (93.2)	532 (92.4)	305 (94.7)	0.18
Mechanism of injuryRTAFallsHit by heavy objectsATVAssaultOther	500 (55.7)235 (26.2)78 (8.7)23 (2.6)22 (2.4)40 (4.4)	289 (50.2)182 (31.6)43 (7.5)18 (3.1)20 (3.5)24 (4.1)	211 (65.5)53 (16.5)35 (10.9)5 (1.6)2 (0.6)16 (5.0)	0.001
Injury sitesHeadChestAbdomen PelvisSolid organSpineMusculoskeletal	421(46.9)410 (45.7)297 (33.1)227 (25.3)181 (20.2)340 (37.9)83 (9.2)	309 (53.6)210 (36.5)153 (26.6)85 (14.8)100 (17.4)168 (29.2)24 (4.2)	112 (34.8)200 (62.1)144 (44.7)142 (44.1)81 (25.2)172 (53.4)59 (18.3)	0.0010.0010.0010.0010.0050.0010.001
Injury characteristicsED GCSHead AISChest AISAbdomen AISPelvis AISISS	13.6±2.63.7 ±0.92.8 ±0.72.7±0.92.5±0.820.0±10.0	13.6±2.53.8±0.92.7±0.82.7±0.92.3±0.518.8±9.6	13.7±2.73.6±1.02.9±0.72.6±0.92.6±0.922.2±10.4	0.750.100.160.980.0090.001

Data were expressed as n (%), mean±SD or median (range). RTA: Road traffic accidents, ATV: All-terrain vehicle, ED: Emergency department, AIS: Abbreviated. injury scale, ISS: Injury severity score, SD: Standard deviation, GCS: Glasgow Coma Score

Baseline laboratory findings in the two groups are given in Table 2. Hemoglobin, hematocrit, urea, creatinine, and CK values showed significant differences across the study groups; all except hemoglobin and hematocrit were higher for Group 2 (P < 0.05). Sodium or potassium levels showed no significant difference (P > 0.05).

Table 2

Laboratory parameters based on the myoglobin level

Variables	Myoglobin <1000 ng/mL (n=576, 64.1%)	Myoglobin ≥ 1000 ng/mL ;(n=322, 35.9%)	P
Hemoglobin	13.3±2.1	12.4±2.2	0.001
Hematocrit	40.2±6.7	37.7±7.4	0.001
INR	1.1±0.3	1.2±0.2	0.001
Urea	4.7±2.1	5.4±23.0	0.001
Creatinine	86.1±52.5	101.5±50.3	0.001
Sodium	140.1±5.2	140.4±11.5	0.63
Potassium	4.0±0.6	4.0±0.8	0.50
Creatinine Kinase (CK) [median,range]	584 (1-3765)	2436 (25-23115)	0.001
Lactate	2.9±1.9	4.0±2.3	0.001

Data are expressed as mean±SD or median (range) whenever appropriate. INR: International normalized ratio, CK: Creatinine kinase, SD: Standard deviation

Based on the nature of injuries, blood transfusion was given in nearly half of the patients (n = 465, 52%) with a median of four units. Interventions included intubation (n = 451, 50%), ORIF of fractures (n = 225, 25%), and hemodialysis (n = 18, 2%). Blood transfusion, ORIF and intubation were performed more frequently in group 2 patients (P < 0.05). Hemodialysis was comparable in the two groups.

Complications included pneumonia (17%), sepsis (9%), ARDS, (3.2%), AKI (3%), and compartment syndrome (1%). Complications in both study groups were comparable [Table 3] except for sepsis and compartment syndrome that were more evident in Group 2. Figures 2 and 3 demonstrate the comparison of interventions and complications among six groups of myoglobin levels (ranging from <200 to >1000 ng/mL). It shows no significant statistical differences among different myoglobin levels regarding pneumonia, sepsis, ARDS, AKI, and mortality. However, the proportions of blood transfusion, intubation, compartment syndrome, and hospital stay were significantly higher in groups with higher myoglobin. The median ICU LOS was 5 days, and the median hospital LOS was 16 (1–232) days. Group 2 patients had a longer duration of ICU and hospital stay when compared to Group 1 patients. A large majority of the study cohort stayed in the hospital for more than 7 days (n = 740, 82%). Of these, Group 2 patients were larger in proportion than Group 1 (89% vs. 79%, P = 0.001). The overall in-hospital mortality was 7% (n = 58); comparable among the two groups.

Table 3

Management, complications and outcomes based on the myoglobin level

Variables	Overall (n=898)	Myoglobin <1000 ng/mL (n=576, 64.1%)	Myoglobin ≥ 1000 ng/mL ;(n=322, 35.9%)	P
ManagementBlood transfusionBlood units (median)ORIFHemodialysisIntubation	465 (51.8)4 (1-79)225 (25.1)18 (2.0)451 (50.2)	227 (39.4)4 (1-79)104 (18.1)12 (2.1)268 (46.5)	238 (73.9)6 (1-42)121 (37.6)6 (1.9)183 (56.8)	0.0010.0020.0010.820.003
ComplicationsCompartment syndromeSepsisARDSPneumoniaAKI	8 (0.9)81 (9.0)29 (3.2)156 (17.4)23 (2.6)	042 (7.3)22 (3.8)95 (16.5)13 (2.3)	8 (2.5)39 (12.1)7 (2.2)61 (18.9)10 (3.1)	0.001*0.020.200.350.44
OutcomesICU days (median)Ventilator daysHospital LOS≤7 days (%)>7 days (%)Mortality	5 (1-124)5 (1-63)16 (1-232)158 (17.6)740 (82.4)58 (6.5)	5 (1-124)6 (1-53)14 (1-232)122 (21.2)454 (78.8)37 (6.4)	6 (1-82)5 (1-63)22 (2-218)36 (11.2)286 (88.8)21 (6.5)	0.0090.590.0010.0010.95

Data are expressed as n (%), mean±SD or median (range) whenever appropriate. ORIF: Open reduction internal fixation, ARDS: Acute respiratory distress syndrome, AKI: Acute kidney injury, ICU: Intensive care unit, LOS: Length of stay, SD: Standard deviation

Figure 2

Hospital complications in different myoglobin levels (P > 0.05 for all)

Figure 3

Hospital course and interventions in different myoglobin levels (P < 0.005 for all)

Serum myoglobin was correlated with hospital LOS (r = 0.20, P = 0.001). High myoglobin levels had a crude odd ratio 2.1; 95% confidence interval (1.40–3.18) for longer hospital LOS (>1 week). The myoglobin cutoff 1000 ng/ml for longer hospital LOS had a sensitivity 39%, specificity 77%, positive predictive value 89%, negative predictive value 21%, −LR 0.79 and +LR 1.69 [Figure 4].

Figure 4

Receiver operating characteristic for hospital length of stay: myoglobin cutoff value 1000 ng/mL area under the curve 0.63; 95% confidence interval 0.58–0.67, P < 0.001

DISCUSSION

The present descriptive study revealed that one-third of the patients admitted to the trauma center had high serum myoglobin level (>1000 ng/ml). These elevated serum myoglobin levels are associated with injury severity, sepsis, and prolonged hospital stay. However, there were no statistically significant differences in mortality based on serum myoglobin level. Patients with higher myoglobin levels often required blood transfusion and mechanical ventilation. Myoglobin value of 1000 ng/ml in trauma settings has fair discriminatory power to identify patients at higher risk.

This is a unique study with a large sample size from the Arab Middle Eastern region, which provides an insight on the injury characteristics, management, complications, and outcome of trauma patients based on myoglobin level. The study was based on data obtained from the only national trauma registry present in a level 1 trauma center in the country, and therefore, it is nationally representative.

Most of the current literature on rhabdomyolysis is mainly based on retrospective studies and case series or case reports. However, Sousa et al. conducted a prospective study of small sample size (n = 57) to assess the risk factors and incidence of rhabdomyolysis in polytrauma patients and showed that many factors are implicated in CK and myoglobin variations.[4] The authors found that CK alone was not correlated with the incidence of acute renal failure (ARF) and therefore myoglobin level should be considered in these patients. Hackl et al. studied 34 polytrauma patients prospectively and demonstrated that although the myoglobin concentration increased over the period of study, there was no correlation with the creatinine clearance.[5] In our study, AKI was found not associated with increased levels of myoglobin; this could be related to the early, effective fluid resuscitation. Previous studies also demonstrated elevated myoglobin levels in crush injuries.[6] Unlike these patients, the majority of our patients were younger and victims of road traffic injuries. It was already shown that myoglobin can be used as a biomarker to evaluate the severity of critically ill patients and guide the treatment, especially in the ICU settings.[7]

Early diagnosis of rhabdomyolysis is challenging as the initial clinical evaluation in polytrauma patients cannot predict the severity of future complications. Prompt recognition is crucial as treatment should be initiated early to reduce the risk of complications. The severity of complications due to rhabdomyolysis mainly depends on the mechanism of injury, comorbidities, concomitant injuries, and anatomic site. It also shows that the greater the number of body sites involvement, the higher will be myoglobin level, as evident from the high ISS score of the group with a high myoglobin level.[8]

Due to the lack of specific criteria to diagnose rhabdomyolysis in the trauma setting, a combination of clinical and laboratory data is usually used to predict the outcome. Serum CK levels exceeding five times the upper limit of normal is often used for diagnosing rhabdomyolysis; however, in our patient population, CK level was not routinely requested along with myoglobin, and the diagnosis usually relied on the combination of clinical signs and symptoms and myoglobin level. Only a few studies put forwarded cutoffs for myoglobin level, which varies from 25 μg/ml to 5197 UI/L.[9] Studies did not mention the reason for selecting these cutoff values and the population in each of these group are different with more focus on ARF as an indicator of the severity of rhabdomyolysis. Second, different units were used for the measurement of myoglobin in different studies. In short, research studies regarding the use of a cutoff value of myoglobin as a predictor for diagnosis remains inconclusive. In our study, we selected a cut off value of 1000 ng/mL based on the ROC curve analysis correlating myoglobin level and the length of hospital stay for >7 days.

The clinical consequences of high myoglobin level in trauma patients are multifactorial, taking into account the injuries of the involved organs. A study focusing on the rhabdomyolysis induced ARF showed a prevalence of 8.6% with hypovolemia as a leading cause for ARF.[10] While another study concluded that elevated myoglobin level was likely resulted from muscle damage rather than from dehydration.[11] Supportive measures, including early intravenous infusion therapy and correction of dehydration, remain as the mainstay of treatment.[1213] Administration of both blood products and normal saline may be necessary for the effective treatment of hypovolemia in trauma patients; more than half of the patients in our study received blood products as a part of their resuscitation.

ARF develops in 33% of patients and is the most serious complication in the days following the initial presentation.[14] However in the absence of hypovolemia, myoglobin has less nephrotoxic effect, and as it can be seen in our study that only 2.6% of the elevated myoglobin level patient develop ARF due to better resuscitation and hydration.[1415]

A combination of high myoglobin and CK are good biological markers for muscle injury.[16] Prognostic value and kinetics of serum myoglobin level and CK in critically ill patients showed that myoglobin peaked earlier than the CK and has a better prognostic tool than the CK; however, myoglobin has a wide inter-individual range.[17] Consensus criteria for rhabdomyolysis are the elevation of serum CK activity of at least ten times the upper limit of normal, followed by a rapid decrease to (near) normal.[18] Only 8 cases were documented to have rhabdomyolysis/compartment syndrome. CK level in our patients was not repeatedly followed up.

Our study showed that baseline reading for troponin is statistically significant in high myoglobin level, but the level of troponin was not clinically significant for the diagnosis of acute myocardial infarction. A study by Li et al. found a false-positive troponin with rhabdomyolysis in up to 17% of cases.[19] None of the patients in our study developed acute myocardial infarction.

A number of cytokines are increased in septic patients such as plasma calcitonin gene-related peptides, and myoglobin was found to be significantly higher in this group of patients.[20] High myoglobin level was associated with sepsis, as shown in our study, in 9.0% of the study population. Yao et al. studied the relationship between serum myoglobin level and sepsis and assessed the predictive value of the serum myoglobin level for the prognosis in 70 septic patients.[21] They concluded that myoglobin level can be detected in the early stage of sepsis and may serve as a potential biomarker for evaluating sepsis severity and further prognosis. This association of high myoglobin level in septic shock trauma patients.[2223] has demonstrated that the early recognition of high myoglobin level and early management would result in a better outcome. Moreover, the elevated myoglobin level was found to correlate with the Sequential Organ Failure Assessment score, C-reactive protein, and procalcitonin level in septic patients.[21]

The outcomes of a patient with elevated myoglobin depend on the nature of injuries and how aggressively these injuries are treated. The mortality rate of rhabdomyolysis with high myoglobin level was reported as 8%–10%.[1824]

Limitations

The retrospective nature of the study is one of the limitations. Selection bias cannot be ruled out since serum myoglobin was checked for trauma patients on admission were based on the physician's discretion, and there was no institutional protocol. The study does not address the crush syndrome or rhabdomyolysis in detail as a direct complication of elevated myoglobin. However, there is no well-defined cutoff of serum myoglobin in trauma patients in these regards. As CK testing was not routinely requested in trauma patients, the diagnosis of rhabdomyolysis was not perfectly available in most of cases. Only the maximum or peak CK levels were reported in this study. The timing and frequency of serum myoglobin testing still need further assessment. In addition, several variables, including activated partial thromboplastin time, platelets, phosphate, calcium, liver function tests, lactate dehydrogenase were not available because of the retrospective design of the study. Surgical interventions such as ORIF were recorded from the operating room notes; however, complete records of nonoperative management were not available. Further studies are needed for much better discriminatory power and accuracy of the selected cut-off.

CONCLUSIONS

One-third of admitted trauma patients have elevated serum myoglobin levels, which is associated with prolonged hospital stay. Level of myoglobin should be checked on admission of polytrauma patients and if it is higher, it should be followed up to avoid complications. The discriminatory power of myoglobin value of 1000 in trauma is fair and therefore, further assessment in prospective studies is needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

This study was approved by the local Institutional Review Board / Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines, during the conduct of this research project.