Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—A retrospective study

Weining Yan; Felix Bläsius; Tabea Wahl; Frank Hildebrand; Elizabeth Rosado Balmayor; Johannes Greven; Klemens Horst

doi:10.1371/journal.pone.0308228

. 2024 Aug 1;19(8):e0308228. doi: 10.1371/journal.pone.0308228

Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—A retrospective study

Weining Yan ^1,^2,^*,^#, Felix Bläsius ^1,^#, Tabea Wahl ², Frank Hildebrand ¹, Elizabeth Rosado Balmayor ², Johannes Greven ^2,^‡,^*, Klemens Horst ^1,^‡

Editor: Zsolt J Balogh³

PMCID: PMC11293635 PMID: 39088425

Abstract

Background

Chest injury is an important factor regarding the prognosis of patients with polytrauma (PT), and the rapid diagnosis of chest injury is of utmost importance. Therefore, the current study focused on patients’ physiology and laboratory findings to quickly identify PT patients with chest injury.

Method

Data on 64 PT patients treated at a trauma center level I between June 2020 and August 2021 were retrospectively collected. The patients were divided into a PT group without chest injury (Group A) and a PT group including chest injury (Group B). The relationship between chest injury and the patients’ baseline characteristics and biochemical markers was analyzed.

Results

Heart rate, respiration rate, Sequential Organ Failure Assessment (SOFA) score, glutamate oxaloacetate aminotransferase (GOT), glutamate pyruvate transaminase (GPT), creatine kinase MB (CK-MB), leucocytes, hemoglobin (Hb), platelets, urine output, lactate, and lactate dehydrogenase (LDH) in groups A and B exhibited statistically significant differences at certain time points. Multifactorial analysis showed that blood LDH levels at admission were associated with chest injury (P = 0.039, CI 95% 1.001, 1.022).

Conclusion

LDH may be a promising indicator for screening for the presence of chest injury in patients with severe polytrauma.

Introduction

Trauma is considered one of the most important public health problems worldwide, accounting for approximately 5.8 million deaths per year, reflecting 10% of the global mortality rate [1]. Thereby patients with polytrauma (PT) represent a challenging population due to the complexity of their injuries [2]. Chest injuries occur commonly in this population and are considered to have a high priority in primary care because of the respiratory or circulatory complications they can cause. Furthermore, aside from severe traumatic brain injury, lethal hemorrhage, and abdominal injuries, chest trauma is a common cause of death in PT patients [3]. In patients with PT, assessing the presence of chest trauma and its severity therefore has a significant influence on the further treatment strategy [4]. The commonly used tools currently available for the assessment of chest trauma are physical examination, computed tomography (CT), and ultrasound [5, 6]. These tests rely heavily on patient feedback and examination facilities, so having a reliable predictive model to quickly and accurately screen patients with severe polytrauma for the presence of chest injuries remains a necessity for current emergency and clinical care. Although, lactate levels can reflect tissue hypoxia and be used as a prognostic indicator in trauma patients [7], lactate’s significance for the diagnosis of chest injury is unclear. Lactate dehydrogenase (LDH) however, also can be used as a marker of cellular damage for the diagnosis of severe tissue injury [8, 9]. Yet, due to its lack of tissue specificity, there are no reports of its use in the diagnosis of chest injury.

Method

Research population and ethical permission

Data were retrospectively collected on all patients with PT who were treated for severe trauma at the RWTH Aachen University Hospital Trauma Surgery Department (Trauma Level Center I) between June 2020 and August 2021. Data collection was approved by the Ethical Committee of RWTH Aachen University Hospital (no. EK 401–19, the original document has been submitted). Clinical data were collected and anonymized by specialized person (TW, and TW was not involved in the analysis of the data or the interpretation of the results). The inclusion criteria were patients diagnosed with severe PT. The following exclusion criteria were applied: age <18 years, diagnosis of PT not fulfilled (see below), patient discharged from the emergency room, death on arrival at the hospital or within the first 24 h, participation in other studies, radiation or chemotherapy within the last 3 months, immunosuppression, kidney dialysis, reanimation at place of injury, pregnancy, or incomplete medical data. A total of 64 patients were included in the study (Fig 1).

Fig 1 — This figure shows the source of the study population, the inclusion and exclusion criteria, and the grouping of patients in this study.

Definitions

Trauma severity was rated using the abbreviated injury scale (AIS) and the ISS, an internationally accepted scoring system. Severe polytrauma is defined as significant injuries of three or more points in two or more different anatomic AIS regions [10, 11]. Chest injury is defined as a patient with a chest AIS ≥1. The AIS score (0–5) is assigned to 6 body regions: head, face, chest, abdomen, the distal region (including the pelvis), and the body surface. The scores of the 3 most severely injured body regions are squared and summed to obtain an ISS score (0–75). If the AIS for any area is 6 (unsurvivable injury), the ISS is automatically scored as 75 [12].

Data collection

The following information was extracted from the medical records and electronic laboratory results of the included patients: heart rate (HR), respiration rate (RR), age, time in hospital, Injury Severity Score (ISS), Glasgow Coma Scale (GCS) score, Sequential Organ Failure Assessment (SOFA) score, presence of organ failure, volume of blood transfused, urine output, hemoglobin (Hb), leucocytes, platelets, hematocrit, C-reactive protein (CRP), potassium ions (K⁺), calcium ions (Ca²⁺), cholesterol, glutamate oxaloacetate aminotransferase (GOT), glutamate pyruvate transaminase (GPT), creatinine, creatine kinase (CK), creatine kinase MB (CK-MB), pH, lactate, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), carbon dioxide partial pressure (PCO₂), oxygen partial pressure/fraction of inspired oxygen (PO₂/FiO₂), bicarbonate (HCO₃^-), partial prothrombin time (PPT), and international normalized ratio (INR). The assessment scores and biochemical results were available on admission (0 h/shock room), 8 h post admission, and on the first to the tenth day (every 24 h) for a total of 12 time points (Table 1).

Table 1. Summary of patient information data.

Variable
HR^*	Ca²⁺^*
RR^*	Cholesterol^*
age	GOT^*
time in hospital	GPT^*
ISS^*	Creatinine^*
GCS^*	CK^*
SOFA^*	CK-MB^*
presence of organ failure	pH^*
volume of blood transfused	Lactate^*
urine output^*	LDH^*
Hb^*	ALP^*
Leucocyte^*	PCO₂^*
Platelet^*	PaO₂/FiO₂^*
Hematocrit^*	HCO₃^-^*
CRP^*	PPT^*
K⁺^*	INR^*

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This table shows all the clinical and laboratory information that was collected on the study population and the point in time at which the information was collected.

* Data collected corresponded to admission (0h/shock room), 8h post admission and, first to tenth day (every 24h) for a total of 12 time points.

HR: Heart rate; RR: Respiration rate; ISS: Injury Severity Score; GCS: Glasgow Coma Scale; SOFA: Sequential Organ Failure Assessment; Hb: Hemoglobin; CRP: C-reactive protein; K⁺: Potassium ions; Ca²⁺: Calcium ions; GOT: Glutamate oxaloacetate aminotransferase; GPT: Glutamate-pyruvate transaminase; CK: Creatine kinase; CK-MB: Creatine Kinase-MB; LDH: Lactate dehydrogenase; ALP: Alkaline phosphatase; PO₂: Oxygen partial pressure; PCO₂: Carbon dioxide partial pressure; FiO₂: Fraction of inspiration Oxygen; HCO₃^-: Bicarbonate; PPT: Partial prothrombin time; INR: International normalized ratio.

Statistical approaches and data analysis

The continuous variables that followed normal distribution after the Shapiro-Wilk test were used to calculate p-values using Student’s t-test and the T-test. Among the nonnormally distributed continuous variables, the ordinal variables were subjected to the Wilcoxon rank sum test, and Fisher’s exact test or Pearson’s chi-square test were used for the categorical variables. Significance was set at p<0.05. We used binary logistic regression analysis to assess the correlation of the clinical data with chest trauma injuries. Furthermore, the statistically significant correlated variables in the univariate analysis were included to determine the efficacy of the various assessment scores and biochemical parameters analyzed in this study for predicting chest injury. For the same parameter at different time points, we selected the time point with the best univariate analysis results. We calculated the associations between the variables included in the multivariate analyses, with significance set at p <0.05. Sensitivity and specificity tests were defined using receiver operating characteristic (ROC) curves to test the feasibility of screening variables for prediction. The statistical analyses were performed using IBM SPSS software v. 25.0 (IBM Corp., Armonk, NY, USA).

Results

A total of 64 patients with severe PT (ISS = 30.71 [range 17–57]) were included in this study, of whom 29 were without chest injury (Group A) and 35 were with chest injury (Group B, mean chest AIS = 3.14 [range 3–4]). Demographic results are depicted in Table 1. After comparing all the data between the groups, heart rate, respiration rate, SOFA score, GOT, GPT, CK-MB, leucocytes, Hb, platelets, urine output, lactate, and LDH exhibited statistically significant differences at certain time points (Table 2). Other indicators including age, time in hospital, and ISS, did not differ significantly between the two groups of patients (S1 Table).

Table 2. Comparison of biochemical markers between patients with severe polytrauma without chest injury (Group A) and with chest injury (Group B).

Variable	A Group	B Group	P value
Variable	n = 29	n = 35	P value
HR d6 (beats/min)	77.86±15.08	68.2±10.44	0.034^*
RR d1 (times/min)	14.43±3.56	17.41±4.53	0.017^*
SOFA d1	7.05±3.69	9.35±3.55	0.041^*
Output Urine d3(ml)	2357.33±622.2	3102.17±1172.67	0.030^*
GOT 8h(U/l)	73.61±65.04	187.91±252.14	0.015^*
GOT d1(U/l)	76.96±70.85	198.15±314.56	0.036^*
GOT d7(U/l)	52.16±29.52	82.62±64.42	0.019^*
GOT d8(U/l)	48.16±21.33	70.35±47.73	0.020^*
GPT d1(U/l)	37±22.27	143.85±289.56	0.039^*
GPT d7(U/l)	43.64±35.71	81.65±87.42	0.027^*
CK-MB d1(U/l)	90.63±70.82	152.95±121.04	0.046^*
Leucocyte d3 (U/nl)	10.54±3.85	8.01±2.88	0.010^*
Hb d5 (g/dl)	9.75±2.24	8.67±1.35	0.036^*
Platelet d3(U/nl)	182.2±81.78	139.26±44.77	0.023^*
Platelet d4(U/nl)	191.88±65.82	151.79±53.69	0.012^*
Lactate d1[mg/dl]	23.88±15.57	36.58±26.03	0.034^*
LDH 0h[U/l]	358.29±191.29	533.06±247.23	0.004^*
LDH d1[U/l]	308.89±72.03	466.17±176.94	0.014^*

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This table shows all the biomarkers that are significantly different between Group A and Group B.

*: P-value<0.05. Data shown as mean ± standard deviation.

0h: on admission; 8h: 8 hours post admission; dx: x days post admission.

HR: Heart rate; RR: Respiration rate; GOT: Glutamate oxaloacetate aminotransferase; GPT: Glutamate-pyruvate transaminase; CK-MB: Creatine Kinase-MB; Hb: Hemoglobin; LDH: Lactate dehydrogenase.

From the obtained data of the 64 patients (Table 1), a logistic regression analysis was performed (Table 3). We first performed correlation analyses on all the indicators to filter the covariates for the logistic regression analysis (S2 Table). The results showed that HR, RR, GCS score, SOFA score, urine output, CRP, K⁺, GOT, GPT, CK-MB, leucocytes, Hb, platelets, lactate, LDH, and ALP were associated with the presence of chest injuries in the polytrauma patients. We performed univariate binary logistic regression analyses of these factors and selected significant factors as covariates in the multivariate logistic regression analyses (Table 3). For the multifactor binary logistic regression analysis, we used the stepwise forward method for regression analysis. Variables not included in the equation are shown by score (residuals/degrees of freedom). The only variable left in the final equation was LDH (OR = 1.011) (Table 3).

Table 3. Logistic regression analysis of factors associated with the presence or absence of chest injury in patients with severe polytrauma.

Risk factors	Univariate		Multivariate
Risk factors	OR (95% CI)	p-value	Score/OR (95% CI)	p-value
HR d6 (beats/min)	0.938(0.881,0.999)	0.047 ^*	0.926	0.336
RR d1 (beats/min)	1.197(1.023,1.399)	0.025 ^*	2.869	0.09
GCS d1	0.896(0.782,1.028)	0.117
SOFA d1	1.2(1.001,1.439)	0.049 ^*	0.084	0.772
Output Urine d3(ml)	1.001(1,1.002)	0.038 ^*	0.608	0.435
CRP d6 (mg/dl)	1.056(0.986,1.131)	0.121
K⁺ d10	0.611(0.242,1.544)	0.297
GOT 8h(U/l)	1.008(1.001,1.016)	0.034 ^*	0.001	0.979
GOT d1(U/l)	1.007(1,1.015)	0.046 ^*
GOT d7(U/l)	1.014(1,1.027)	0.047 ^*
GOT d8(U/l)	1.017(1,1.035)	0.047 ^*
GPT d1(U/l)	1.024(1.003,1.046)	0.024 ^*	0.011	0.916
GPT d7(U/l)	1.015(0.999,1.031)	0.066
CK-MB d1(U/l)	1.007(1,1.015)	0.067
Leucocyte d3 (U/nl)	0.79(0.647,0.964)	0.020 ^*	1.226	0.268
Hb d5 (g/dl)	0.714(0.525,0.97)	0.031 ^*	2.583	0.108
Lactate d1[mg/dl]	1.031(1,1.062)	0.048 ^*	1.028	0.311
LDH 0h[U/l]	1.005(1.001,1.008)	0.011 ^*	1.011(1.001,1.022)	0.039 ^*
LDH d1[U/l]	1.010(1.000,1.021)	0.047 ^*
ALP d8[U/l]	1.007(0.989,1.025)	0.438

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This table presents the outcomes of binary logistic regression analyses, identifying severe polytrauma with concurrent chest injury as the outcome of interest. Initially, a binary logistic univariate analysis was conducted on all variables correlated with the outcome, as determined by correlation tests. Subsequently, variables that demonstrated significance in the univariate analyses were incorporated into a binary logistic multivariate analysis, employing a forward stepwise selection method. The findings highlight LDH as an independent risk factor for the presence of concurrent chest injuries in severe polytrauma patients.

*: P-value<0.05.

0h: on admission; 8h: 8 hours post admission; dx: x days post admission.

ROC curves were used to examine the sensitivity, specificity, and threshold values of LDH for screening patients with severe multiple injuries accompanied by chest injury (Fig 2). ROC curves were drawn considering polytrauma with chest injury as a positive result and polytrauma without chest injury as a negative result to obtain the optimal cutoff point of LDH = 365 U/l (p<0.001). Table 4 presents the sensitivity, specificity, positive predictive value, and negative predictive value of LDH as a predictor of the presence of concomitant chest injury in patients with multiple injuries when the LDH threshold is set at 365 U/L.

Fig 2 — This is an ROC curve figure with LDH as a variable using sever polytrauma patients with concomitant chest injuries as a positive result and polytrauma patients without concomitant chest injuries as a negative result. AUC (= 0.771, p<0.001) provides a measure of the overall diagnostic accuracy of LDH in identifying sever polytrauma patients with chest injurie. LDH: Lactate dehydrogenase. AUC: Area Under Curve.

Table 4. Sensitivity, specificity, PPV and NPV of LDH for screening patients with severe polytrauma for the presence of chest injury.

Variable	LDH>365U/l
Sensitivity	80.65%
Specificity	67.86%
PPV	73.53%
NPV	76.00%

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This table shows the sensitivity, specificity, positive predictive value, and negative predictive value for predicting the presence or absence of comorbid chest injuries in patients with severe polytrauma using LDH = 365 U/L as the threshold value.

LDH: Lactate dehydrogenase. PPV: positive predictive value; NPV: negative predictive value.

Subsequently, to identify the source of chest injuries associated with elevated LDH levels, we stratified the patients into two cohorts using an LDH threshold of 365 U/l and examined the differences in the incidence of various chest injuries. Due to the complexity of the diagnoses, we categorized the injuries as follows: fractures of the chest wall (including ribs, sternum, and thoracic vertebrae), extra-thoracic wall fractures (including scapula and clavicle), pulmonary contusion, pleural diseases (including pneumothorax, haemothorax, and pleural effusion), pneumonia, and cardiovascular diseases (including blunt aortic injury, myocardial contusion, pericardial effusion, and mediastinal haematoma). Our results indicated that elevated LDH levels were more frequently observed in patients with fractures of the chest wall (6/27 vs. 24/37, p = 0.001), pulmonary contusion (0/27 vs. 18/37, p<0.001), and cardiovascular diseases (0/27 vs. 6/37, p = 0.035) (Table 5).

Table 5. Comparison of diagnostic results of chest injuries in patients with different LDH.

Diagnosis of chest injuries	LDH<365 U/L n = 27	LDH≥365 U/L n = 37	P value
Fractures of the chest wall: ribs, sternum, thoracic vertebrae	6	24	0.001^**
Extra-thoracic wall fractures: scapula, clavicle	0	3	0.257
Pulmonary contusion	0	18	<0.001^**
Pneumothorax, haemothorax, pleural effusion	4	13	0.089
Pneumonia	1	7	0.124
Cardiovascular diseases: aortic dissection, myocardial contusion, pericardial effusion, mediastinal haematoma	0	6	0.035^*
Blunt aortic injury	0	2	0.504
Myocardial contusion	0	2	0.504
Pericardial effusion, mediastinal haematoma	0	3	0.257

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This table shows the distribution of different chest injuries in different LDH patients.

Results are shown in the number of patients.

*: P-value<0.05;

**: P-value<0.001.

Discussion

This study aimed to find clinical indicators that could quickly and accurately screen patients with PT for the presence of chest injury using multifactorial analysis modeling. The thoracic cavity contains life-sustaining organs, such as the heart and lungs, and chest injuries are of particular concern in the assessment and treatment of patients with PT [13].

LDH is an enzyme found in many body tissues, including the heart, lungs, liver, kidneys, skeletal muscle, and blood cells. When cells are damaged by injury, LDH is released into the bloodstream. Therefore, systemically elevated levels of LDH might be seen as an indicator of tissue damage [14]. The physiological role of LDH is to catalyze the reversible reaction of pyruvate with lactate [15] and previous studies have already shown that lactate, the substrate of LDH, can be an excellent prognostic indicator for trauma patients [1, 16, 17]. Against this background, Régnier, M.A., et al. [18] showed that elevated levels of lactate were strongly correlated with trauma severity. Furthermore, Park, H.O., et al. [1] and Parsikia, A., et al [16]. found that elevated lactate concentrations were associated with post-traumatic respiratory failure, and death. Data from the present study revealed that lactate, however, does not identify site-specific injuries, specifically chest injuries, in patients with PT. This may be because lactate, as a biomarker of inadequate tissue perfusion, is highly correlated with the overall burden of trauma in PT patients. In addition, the included patients presented with a very high ISS compared to other studies that investigated the role of lactate in PT [1, 7, 16, 19]. However, the present study demonstrated that serum LDH levels exhibited a correlation with the occurrence of concomitant chest injuries among patients afflicted with PT. LDH has been used as an aid in the diagnosis of many diseases, such as cancer, thyroid disease, and tuberculosis [8], and its diagnostic value for lung injury caused by 2019-nCoV has received widespread attention [9, 20]. LDH levels may also rise due to injuries to organs, such as the liver and kidneys [21, 22]. However, elevations in LDH levels have been observed in a broad spectrum of chest injuries, including those affecting the lungs and myocardium [14, 23, 24]. Thus, LDH could serve as a viable biomarker for the identification of individuals suffering from PT with concomitant chest injuries. As the concentration of LDH in tissues is approximately 500-fold greater than that in serum [25], LDH from the affected tissues is liberated into the bloodstream, culminating in an increase in serum LDH levels. This mechanism might even be enhanced by the fact that thoracic organs are very susceptible to hypoperfusion and hypoxemia, thereby precipitating more widespread tissue damage and an augmented serum LDH level. Although, the ubiquitous elevation in serum LDH levels is frequently regarded as lacking tissue specificity, none of the other organ specific laboratory results within this study cohort presented with significant changes [26]. Thus, this study demonstrated that elevated LDH levels at the time of admission in PT may serve as a reliable indicator of chest injury, a finding which has not been previously reported in the literature. The implications of these findings are significant for enhancing clinical diagnosis and treatment strategies. As a consequence of the presented findings, additional investigation of the thoracic organs in PT with increased LDH could be promptly initiated [13, 27]. The finding that LDH directly correlates with chest injury patterns opens new possibilities for small hospitals that may not have direct access to high-resolution CT scanners in their shock rooms. This could also be an on-scene option using a “lab on a chip” [28], so that blood samples could be evaluated before arriving at a hospital or in situations where the patient cannot be transported (e.g., natural disasters or battlefields). In addition, it might reduce the overall costs associated with this diagnosis.

Additionally, through an analysis of the diagnoses of patients with varying LDH levels, we identified that fractures of the chest wall, pulmonary contusions, and cardiovascular diseases may contribute to elevated LDH. This finding suggests a potential direction for subsequent diagnostic tests in polytrauma patients with concomitant chest injuries as identified by elevated LDH levels. It is important to note that due to the small sample size in this study and the low incidence of certain injuries (e.g., blunt aortic injury, myocardial contusion), it is challenging to conduct specific analyses for each individual condition. Therefore, we do not advocate for LDH to completely replace other investigations such as ultrasound, CT, etc., as they are necessary to confirm the diagnosis and clarify the progression of the disease. Nonetheless, our current results provide valuable insights into the direction of further examinations, which can aid in optimizing the diagnostic process and allocating medical resources more effectively.

The fact that a wide variety of easily available and inexpensive methods exist for the detection of LDH (e.g., colorimetric, spectrophotometric, and fluorescence methods) confers further attractiveness on LDH as a marker to use in the fast diagnosis of chest injury in patients with polytrauma [29]. Combined with the predictive model of this study, it provides a convenient and inexpensive new method for the diagnosis of patients with multiple injuries accompanied by chest damage.

Conclusion

LDH may be a promising indicator for screening for the presence of chest injury in patients with polytrauma. Although the presented findings delineate an association between LDH levels and PT accompanied by chest injuries, the precise underlying mechanism warrants additional exploration.

Strengths & limitations

Our study is characterized by several notable strengths: the trauma severity of the subjects investigated was comparably high and the comprehensiveness of our patient data is significantly enhanced by the advanced degree of digital integration within our clinical operations, thereby enabling more exhaustive analyses. Yet, this is a single-center, small sample study with a retrospective design, which may introduce selection bias. Due to the limited sample size, subgroup analyses for specific chest injuries like lung contusions and rib fractures were not feasible. Consequently, while our study’s capacity to advance treatment modalities is restricted, it proves invaluable for early diagnosis and triage of patients.

Considering the variety of comorbidities that could influence the levels of LDH in patients, further research is imperative. The objective of such studies would be to discern additional comorbidities impacting LDH levels, thereby facilitating the classification of patients with severe polytrauma into subgroups based on their specific comorbid conditions. This stratification would enable more precise evaluation of the efficacy of LDH in detecting the occurrence of chest injuries within this patient cohort.

Supporting information

S1 Table. All results of comparison of biochemical markers between patients with severe polytrauma without chest injury (Group A) and with chest injury (Group B).

This table shows the results of the comparison between Group A and Group B for all biomarkers.

(DOCX)

pone.0308228.s001.docx^{(52.2KB, docx)}

S2 Table. All results of the correlation analysis of various biochemical parameters with chest injury in polytrauma patients.

This table delineates the findings from an analysis examining the correlation of all variables with the presence or absence of concurrent chest injuries in individuals suffering from severe polytrauma, wherein the presence of such injuries is denoted as a positive outcome.

(DOCX)

pone.0308228.s002.docx^{(42.9KB, docx)}

Acknowledgments

The authors would like to express their appreciation to the medical and nursing teams of Department of Orthopaedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, who helped with this study. We would like to mention the convenient service of the proof-reading company Scribendi.

Data Availability

All relevant data are within the manuscript and its Supporting information files. Corresponding author can be contacted for any other requirements.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0308228.r001

Decision Letter 0

Zsolt J Balogh

13 May 2024

PONE-D-24-08209Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—a retrospective studyPLOS ONE

Dear Dr. Yan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Kind regards,

Zsolt J. Balogh, MD, PhD, FRACS

Academic Editor

PLOS ONE

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Dear Authors,

Our reviewers identified some major concerns related to your submission.

I would like to provide the opportunity to address these and have a chance for them to reconsider their position.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have presented a well written and reasoned article outlining the clinical relevance and

implication of their hypothesis and results. There are some issues that I think would benefit from

addressing to clarify the results and utilise current validated definitions.

Issues

1. The authors use ISS>16 as a definition for polytrauma, without justification. This justification

is required as it is not consistent with the current validated “Newcastle definition”. Two

options are suggested to address this:

a. Change the inclusion criteria to match the validated “Newcastle definition” (AIS > 2

in 2 body regions)

b. Change the nomenclature to “multiple trauma” or “major trauma” depending on the

number of body regions involved

2. The authors use the term “severe polytrauma” when describing patients with chest injury,

but do not clarify what constitutes “severe polytrauma”.

3. The threshold for patients having a chest injury is not articulated – was it AIS ≥1, another

cutoff, or based on clinical/radiological findings.

4. Whether the patient groups are matched in other variables, injuries and demographics was

not outlined. With a small sample size there are many possible confounders. For example the

ISS or presence of solid organ injury were not included. Such confounding factors need to be

addressed.

Reviewer #2: The authors present an interesting set of data, albeit small.

The structures actually injured in the chest are not described.

they do not describe how to use these data to change treatment.

i would add CXR to the modalities available to quickly determine cheat injury.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2024 Aug 1;19(8):e0308228. doi: 10.1371/journal.pone.0308228.r002

Author response to Decision Letter 0

21 May 2024

Dear Editor and Reviewers,

Thank you very much for your time and effort in reviewing our manuscript titled " Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—a retrospective study" We greatly appreciate your valuable comments and suggestions. The feedback provided has been instrumental in enhancing the quality and clarity of our manuscript. We have carefully considered each point raised and have made corresponding revisions to address these concerns.

We are resubmitting our manuscript after incorporating the changes suggested by you and hope that the revised manuscript meets the esteemed standards of PlosOne. Below, we provide detailed responses to each of the comments and outline the modifications we have made to the manuscript. Thank you once again for the opportunity to improve our work.

Response to Reviewer #1

1. In response to the first and second comments. Thank you for your suggestion, as you said, there is a descriptive problem with the definitions here, now we have defined polytrauma, severe trauma and severe polytrauma more accurately based on your suggestions and have added references to support the basis of our definitions. Changes are made on lines 79 to 83 of the manuscript.

2. In response to the third comment. Yes, the threshold for patients having a chest injury is chest AIS ≥1. Thank you very much for the reminder, we have added a description on line 83 of the manuscript.

3. In response to the fourth comment.

In this study, we analyzed patients by indicators such as age, gender, and Injury Severity Score (ISS), observing no significant differences in outcomes among the groups; detailed results are provided in the Supporting Materials. Our patient cohort consisted of individuals suffering from severe polytrauma. We categorized these patients based on the presence or absence of chest injuries. It is important to note that while other parenchymal organ injuries such as liver, kidney, and spleen were identified, their incidence did not differ between our two groups of patients (6/29 vs. 8/35, P=0.835). Our findings revealed no differences in ISS scores between groups, indicating a uniform severity of trauma across the cohort. This suggests that the presence of chest injuries does not correlate with a higher overall injury severity under the conditions of this study.

Moreover, we addressed potential confounding factors using a multifactorial logistic regression model. This analysis helped to clarify the impact of variables that appeared significant in univariate analyses, such as glutamic-pyruvic transaminase (GPT) and lactate levels, which ultimately did not affect the outcomes related to the diagnosis of chest injuries. Our results highlight that lactate dehydrogenase (LDH) levels at admission are significantly associated with the differential diagnosis of chest injuries in cases of severe polytrauma.

Given the limited sample size of our study, it was not feasible to perform subgroup analyses for multiple organ injuries comprehensively. Therefore, our laboratory is committed to expanding the sample size in future studies. This expansion will allow us to explore additional biomarkers and potentially introduce new screening indicators for other organ injuries. We trust that our rigorous approach to eliminating confounding factors meets your standards and contributes to the robustness of our findings.

Response to Reviewer #2

1. Thank you very much for your insightful comments and for highlighting the limitations of our study. In our analysis, the categorization of chest injuries included various conditions such as lung contusion, rib fractures, sternal fractures, pneumothorax, among others. Due to the limited sample size, detailed subgroup analyses within these categories were not feasible. Consequently, we grouped these conditions under a general category of "chest injuries," defined as chest AIS (Abbreviated Injury Scale) ≥ 1.

As a result, our study primarily demonstrates the utility of lactate dehydrogenase (LDH) as a diagnostic biomarker for detecting chest injuries in patients with severe polytrauma. We acknowledge, as you pointed out, that this classification approach limits our study’s implications for enhancing specific treatment strategies for distinct injuries such as rib fractures or lung contusions. However, the accessibility and rapidity of LDH testing can significantly aid prehospital diagnosis. This is particularly beneficial in scenarios where immediate access to well-equipped medical facilities is not possible or during large public events that necessitate quick triage of patients.

We have also taken your advice into consideration and have included a detailed description of these limitations in the Limitations section of our manuscript. We appreciate your rigorous review and valuable suggestions, which have undoubtedly improved the manuscript.

2. Thank you very much for your suggestion regarding the inclusion of chest X-ray (CXR) as part of the screening criteria. Indeed, in our study, CXR was utilized as one of the foundational diagnostic tools for patients with chest injuries. We acknowledge that incorporating CXR into the screening protocol can enhance the accuracy of injury detection.

However, the primary focus of our study was to evaluate the effectiveness of a rapid hematological screening method as a standalone diagnostic tool, particularly in scenarios where radiological facilities, such as CXR, are not readily accessible—such as at the scene of a natural disaster. The intent was to provide a feasible alternative for initial assessment in severe polytrauma patients, both with and without apparent chest injuries, when traditional radiological diagnostics are unavailable.

Therefore, while CXR results were considered in the patient assessment, our manuscript emphasizes the utility and applicability of hematological screening in resource-limited settings. We believe this focus is crucial for advancing pre-hospital care in less equipped environments, and it complements existing diagnostic protocols that rely on imaging technologies.

We are deeply grateful for the detailed and constructive feedback provided by the reviewers and the editor. Your insights have significantly contributed to refining our manuscript and ensuring that it meets the rigorous standards of PlosOne. We have endeavored to address all the points raised in a comprehensive manner and have made revisions that we believe enhance the value and clarity of our work.

We hope that the changes we have implemented are satisfactory and meet the expectations of the review committee. We are committed to making any further modifications if needed and are looking forward to your suggestions and final decision.

Thank you once again for your guidance and support throughout the review process. We appreciate the opportunity to contribute to PlosOne and eagerly anticipate the possibility of our work being published.

Sincerely yours,

Weining Yan

Attachment

Submitted filename: Response to Reviewers.docx

pone.0308228.s003.docx^{(20.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0308228.r003

Decision Letter 1

Zsolt J Balogh

14 Jun 2024

PONE-D-24-08209R1Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—a retrospective studyPLOS ONE

Dear Dr. Yan,

Please submit your revised manuscript by Jul 29 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Zsolt J. Balogh, MD, PhD, FRACS

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: No

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Thanks for the responses and clarifications from the authors.

I have one further suggestion. I do not understand the distinction between "severe polytrauma" and "polytrauma" and suggest removing it from the article. By the 2xAIS>2 definition now used by the authors, the minimum ISS is 18. Therefore the distinction of severe polytrauma as 2xAIS>2 + "severe trauma" as ISS of ≥16 shouldn't be required.

Reviewer #2: the authors have addressed the reviewers comments within the limitations of their very small dataset. I remain unconvinced that LDH is a useful tool in this situation. the authors need to describe what chest injuries injuries cause this elevation. Rib fractures do not need immediate treatment, neither does a pulmonary contusion. what about pericardial tamponade? myocardial contusion? pneumothorax?

this is a a very preliminary finding that should be explored to see what injury its associated with.

why wouldn't a pulse oximeter and US just be as useful in a mass casualty situation?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

PLoS One. 2024 Aug 1;19(8):e0308228. doi: 10.1371/journal.pone.0308228.r004

Author response to Decision Letter 1

20 Jun 2024

Dear Editor and Reviewers,

We sincerely appreciate the time and effort you have invested in reviewing our manuscript titled "Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—a retrospective study." Your insightful comments and constructive feedback have been invaluable in refining and improving the quality of our work.

Following your recommendations from the initial review, we have undertaken a thorough revision of our manuscript. Your detailed and thoughtful suggestions have significantly contributed to the enhancement of the clarity, robustness, and overall scientific merit of our study. We are deeply grateful for your guidance.

In this second round of revisions, we have meticulously addressed each of the points you raised. We believe the changes we have implemented strengthen the manuscript and align it more closely with the high standards of PlosOne. We have summarized our responses to each comment below, detailing the modifications made to the manuscript to address your concerns.

Thank you once again for providing us with this invaluable opportunity to further improve our work. We hope that the revised manuscript meets your expectations and the esteemed standards of PlosOne.

Response to Reviewer #1

Thank you very much for your insightful comments. As you rightly pointed out, the original description was overly cumbersome. In accordance with your suggestion, I have retained only the definition of 'Severe polytrauma' and have revised the description of the inclusion criteria (lines 66, 79-81). I trust these modifications address your concerns and enhance the clarity and precision of the manuscript.

Response to Reviewer #2

1. Thank you for your constructive feedback regarding the need for a deeper analysis of the sources of elevated LDH levels, which could indeed enhance the credibility and practical value of our study. In response to your suggestion, we conducted a detailed examination of the specific injuries contributing to elevated LDH levels. Given the complexity of these diagnoses, we categorized the injuries as follows: fractures of the chest wall (including ribs, sternum, and thoracic vertebrae), extra-thoracic wall fractures (scapula and clavicle), pulmonary contusion, pleural diseases (pneumothorax, haemothorax, pleural effusion), pneumonia, and cardiovascular diseases (aortic dissection, myocardial contusion, pericardial effusion, mediastinal haematoma).

Our results indicate significant associations between elevated LDH levels and the following conditions: fractures of the chest wall (p=0.001), pulmonary contusion (p<0.001), and cardiovascular diseases (p=0.035). These findings provide valuable guidelines for directing further diagnostic examinations in patients.

In our manuscript, we have elaborated on the significance of these findings and discussed the limitations arising from the low incidence of certain conditions, such as myocardial contusion and aortic coarctation, which prevented a more detailed disease-specific analysis. These changes have been incorporated into lines 198-211 and 260-269 of the revised manuscript. I trust these amendments address your concerns and contribute positively to the manuscript.

2. Thank you for your suggestion regarding the use of pulse oximetry and ultrasound in our study. Our investigation did include an analysis of the partial pressure of blood oxygen; however, we found that it does not reliably indicate chest injuries. This may be due to its insensitivity to injuries that do not directly impact ventilation and gas exchange, noting that chest injuries can extend beyond the lungs and airways.

While we agree that comprehensive diagnostic tools like ultrasound or X-ray can enhance diagnostic accuracy, the primary goal of our study was to develop a rapid screening method for chest injuries in polytrauma patients. This approach is intended to streamline patient triage and optimize the allocation of healthcare resources. LDH testing, which can be performed concurrently with routine blood gas analyses, offers a quick and readily available diagnostic measure without the need for additional equipment or specialized personnel such as ultrasonographers.

We have detailed the benefits of using LDH as a diagnostic tool in the sections on lines 48-53, 252-258, and 266-275 of our manuscript. These sections explain how LDH integrates into clinical protocols to provide effective, efficient care in emergency settings. I appreciate your comments and hope that the revisions and clarifications meet the article's aims and your expectations.

3. Thank you for your insightful comments. As you noted, our study is a preliminary investigation with a limited sample size. Despite these constraints, our methodology—which includes controlling for confounders—has successfully demonstrated a rapid screening technique for chest injuries. This method also aims to guide clinical examinations and optimize the allocation of healthcare resources effectively.

However, we acknowledge several limitations, particularly concerning the specificity of our screening for individual organs and distinct pathologies. In response to these limitations and guided by your valuable suggestions, our laboratory is committed to expanding the sample size in future studies. This expansion will enable us to explore additional biomarkers and potentially develop new screening metrics for other organ injuries.

We appreciate your guidance, which has been instrumental in refining our research approach. We trust that the revisions and future study directions outlined here meet your expectations and contribute meaningfully to the field.

We extend our deepest gratitude to the reviewers and the editor for their detailed and constructive feedback. Your insights have been instrumental in refining our manuscript and ensuring it adheres to the rigorous standards of PlosOne. We have diligently addressed all the points raised, implementing revisions that we believe significantly enhance the clarity, robustness, and overall value of our work.

We sincerely hope that the changes we have made meet your expectations and are satisfactory to the review committee. We remain fully committed to making any further modifications if needed and greatly value your continued guidance and support.

Thank you once again for this opportunity to improve our manuscript. We appreciate the chance to contribute to PlosOne and eagerly anticipate the possibility of our work being published.

Sincerely yours,

Weining Yan

Attachment

Submitted filename: Response to Reviewers.docx

pone.0308228.s004.docx^{(20.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0308228.r005

Decision Letter 2

Zsolt J Balogh

24 Jun 2024

PONE-D-24-08209R2Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—a retrospective studyPLOS ONE

Dear Dr. Yan,

Please submit your revised manuscript by Aug 08 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Zsolt J. Balogh, MD, PhD, FRACS

Academic Editor

PLOS ONE

Additional Editor Comments:

Dear Dr. Yan,

I appreciate your revision efforts and providing more information.

One of our reviewers still has major concerns and I have some questions to clarify:

- You need to rationalise pragmatism for using LDH as a diagnostic tool in acute trauma. What are you diagnosing with it. The clinical examination within minutes identifies if we need to decompress the chest or we need to do ED thoracotomy or to start haemostatic resuscitation with coagulation factors and packed red blood cells. in 3 minutes we have a chest x-ray, which excludes almost all immediately life-threatening conditions in the chest and raises suspicion for others. We have CT scan with contrast within 15 minutes in any patients who had an injury mechanism, which can cause major chest injury and had polytrauma. What additional benefit LDH add during this early phase of rapid work-up? I doubt that it would prevent some imaging and I would doubt that it would indicate earlier intervention than based on clinical exam, chest x-ray and panscan.

- Aortic dissection is a medical condition not traumatic, I assume you are referring to torn thoracic aorta or in other words blunt aortic injury.

- LDH is a cell necrosis marker (that's it), to make your conclusions you need to convince that it is a better cell necrosis marker than others and also specific to chest injuries

- Your study does not include an essential chest (cardiac) injury marker, which is routinely used in most trauma centres: Troponin. Is LDH better than troponin? is it more specific? I doubt.

- the ~75% NP and PPV is not stellar, I am sure clinical exam/chest x-ray/CT and overall pattern recognition by clinicians will beat it.

- Please address the potential of Type2 error in your manuscript from the fact that you evaluate a bunch of variables and by chance one popping up just significant.

- Please provide convincing information that LDH is specific to chest injury and not just a marker of overall severe tissue disruption.

- your analysis does not address the treatment factors, which can have an effect on LDH (resuscitation blood products and surgical interventions).

- I am sure you agree that LDH is unlikely to be a single marker for diagnosing chest injury, could you please elaborate how much better is it with addition to our existing ones? You do not have ROCs for clinical exam, chest x-ray and CT scan or echocardiography, ECG etc.

I appreciate your work on this manuscript and its revisions. My questions are merely pragmatic clarifications as we have not find yet a single laboratory test in trauma care identifying region specific injuries and the current data available about LDH is not convincing to me based on 64 patients.

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PLoS One. 2024 Aug 1;19(8):e0308228. doi: 10.1371/journal.pone.0308228.r006

Author response to Decision Letter 2

27 Jun 2024

Dear Reviewers and Editor,

We would like to express our sincere gratitude for the continued time and effort you have dedicated to reviewing our manuscript titled "Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—a retrospective study." Your ongoing insightful comments and valuable suggestions have been crucial in further refining and enhancing the quality of our work.

Following your detailed feedback from the second review, we have once again undertaken a revision of our manuscript. We greatly appreciate the constructive guidance provided, which has significantly contributed to the robustness and clarity of our study. Each point raised has been carefully considered, and corresponding revisions have been made to address these concerns thoroughly.

We are resubmitting our manuscript after incorporating these additional changes and hope that the revised version meets the high standards of PlosOne. If you believe that incorporating our detailed responses directly into the body of the manuscript would be beneficial, we would be more than happy to do so. Below, we provide detailed responses to each of the comments and outline the modifications made to the manuscript. Thank you once again for this invaluable opportunity to improve our work.

Responses to Reviewer Comments

1. Rationalization of LDH as a Diagnostic Tool in Acute Trauma

Thank you for your detailed and insightful comments regarding the limitations of LDH as a diagnostic reference marker in well-resourced medical environments. We fully acknowledge that our study has limited utility in guiding the diagnosis and treatment of specific diseases under such conditions. However, the primary aim of our research was to facilitate the rapid screening of polytrauma patients for chest injuries, thereby providing a basis for the necessity of further chest examinations.

In scenarios where medical resources are severely constrained—such as during natural disasters (earthquakes, tsunamis), conflicts, or widespread epidemics—conducting comprehensive examinations on all potentially injured patients within a short timeframe is unfeasible. In these situations, any tool that aids in patient triage can significantly improve the allocation of medical resources and potentially save lives. Thus, our study highlights the utility of LDH in identifying patients with potential chest injuries, allowing healthcare providers to prioritize their evaluations more effectively during periods of resource scarcity, as detailed in lines 252-258 of the manuscript.

Regarding your concern that the use of LDH may deter some imaging tests, we believe our findings will instead assist physicians in determining when imaging is warranted. For instance, a patient with an LDH level exceeding 365 U/L would prompt increased vigilance for chest injuries, thereby reducing the risk of missed diagnoses, even if the primary injury is elsewhere, such as an open fracture of the lower extremity with hemorrhagic shock.

Moreover, our study aimed to identify patients who are "more likely" to have chest injuries, allowing for prioritized treatment and avoiding unnecessary delays for those less likely to have such injuries. This stratification is crucial for the rational allocation of limited healthcare resources, enabling more efficient and targeted patient care.

We hope this clarifies the scope and significance of our study in contexts with limited medical resources.

2. Clarification on Aortic Dissection

Thank you for your correction. We indeed referred to aortic tears resulting from trauma. We have updated the description in the manuscript to "blunt aortic injury."

3. LDH as a Cell Necrosis Marker

Thank you for your insightful comments. Lactate dehydrogenase (LDH) is recognized as a marker of cellular necrosis, and our findings suggest that it can be effectively used for the differential diagnosis of chest injuries in polytrauma patients. However, we did not evaluate LDH in comparison to other markers of cellular necrosis, such as TNFα, because these are not commonly assessed in routine clinical practice. This approach allows our results to be more directly applicable to everyday clinical settings.

While it is acknowledged that LDH lacks tissue specificity, displaying only a 1.5-fold difference in activity between tissues with the highest (e.g., liver) and lowest (e.g., kidney) LDH levels, our study still observed elevated LDH levels in patients with chest injuries, despite having similar overall trauma severity scores (ISS=30.43 ± 9.28 vs. 30.88 ± 10.24, P=0.894). This elevation likely reflects the involvement of organs within the chest that are critical to respiratory and circulatory functions, resulting in greater cellular necrosis and subsequent release of LDH into the bloodstream.

We have detailed this rationale in lines 237-252 of the manuscript. If LDH can demonstrate significant differences between groups, the utility of other markers, even if potentially more specific, becomes less critical in the context of routine clinical assessments. We hope this clarification meets your requirements and enhances the manuscript.

4. Comparison with Troponin

Thank you for your insights regarding the use of cardiac troponins (cTnI and cTnT) as specific markers of myocardial injury. We recognize that troponins are superior to lactate dehydrogenase (LDH) in identifying cardiac damage. However, the primary diagnostic aim of our study was not solely to detect cardiac injury but to ascertain the presence of any chest injury in polytrauma patients. Since the chest includes a variety of tissues, such as the lungs and chest wall, normal troponin levels do not necessarily exclude the presence of non-cardiac chest injuries. Our results support the utility of LDH as a broader marker in this context, providing a simple and routinely available diagnostic option that can indicate a range of chest injuries during initial patient evaluations.

Additionally, we also analyzed creatine kinase (CK) and CK-MB in our study. Despite the high cardiac specificity of CK-MB, it did not show potential in identifying general chest injuries among polytrauma patients, further highlighting LDH’s broader applicability for this purpose. These findings reinforce the importance of LDH in the initial assessment of polytrauma patients, where a comprehensive evaluation of all possible chest injuries is critical.

We trust this explanation clarifies the rationale behind our focus on LDH and its role in our study. We appreciate your valuable feedback and hope that our findings contribute meaningfully to the field.

5. Positive and Negative Predictive Values

Thank you for your pertinent and insightful comments. It is generally accepted that NPV and PPV values above 80% are ideal for clinical diagnosis. While our results are very close to this threshold, we acknowledge that the diagnosis of specific chest injuries ultimately relies on targeted tests such as ultrasound, CT, and other imaging modalities.

The significance of our study lies in the potential of LDH to aid physicians in pre-screening patients who are likely to have chest injuries. This preliminary screening can guide clinicians to perform more targeted and efficient examinations, optimizing the use of diagnostic resources and potentially improving patient outcomes.

6. Addressing Type 2 Error

Thank you for your attention to the details of our study. We validated our data through efficacy analysis. In our binary logistic regression analysis, we achieved an acceptable result with N=64, α=0.05, and a power of 0.83 (a power of 0.8 is usually acceptable in scientific research). We have prepared the test report in PDF format and are ready to provide it for your review. Please advise on the preferred method for submission if submission is required, as the manuscript submission guidelines do not specify where such documents should be uploaded or sent.

7. Specificity to Chest Injury

As discussed in response to question No. 3, our statistical analysis clearly demonstrates that elevated LDH levels correlate significantly with additional chest trauma in severely injured patients. This correlation is mathematically significant, reinforcing LDH's utility as a biomarker in this context.

Although LDH is not tissue-specific—studies indicate only about a 1.5-fold difference between the tissues with the highest LDH values (e.g., liver) and those with the lowest (e.g., kidney)—we observed a notable increase in LDH levels in patients with chest injuries, despite comparable overall trauma levels (ISS=30.43 ± 9.28 vs. 30.88 ± 10.24, P=0.894). This observation may be attributed to the involvement of organs within the chest that are essential to the respiratory and circulatory systems, which could lead to increased cellular necrosis and subsequent LDH release into the bloodstream, as detailed in lines 237-252 of the manuscript.

It is important to recognize that elevated LDH levels in patients with chest injuries may not solely arise from the factors described. The underlying mechanisms remain a subject for further investigation, a direction we have committed to pursuing in future research, as outlined in our article.

8. Influence of Treatment Factors on LDH

Thank you for your suggestion. In our analysis, we considered the effect of blood transfusion by examining the transfusion of red cells, plasma, and platelets in patients with and without chest injuries. Our results, presented in S1 Table, indicate no significant difference between the groups.

Surgery may indeed affect LDH levels, which could explain why the between-group differences in LDH became non-significant at subsequent observation time points. However, our findings demonstrate that LDH levels at admission can be used to identify the presence of chest injury in polytrauma patients. At the time of admission, none of the patients had undergone surgery, so the LDH levels were not influenced by surgical intervention.

9. Addition to Existing Diagnostic Methods

Thank you for your insights regarding the reliability of using elevated LDH levels as a sole diagnostic marker. I concur that a definitive diagnosis of specific diseases based solely on LDH levels would be unreliable. However, our findings suggest that LDH can serve effectively as an indicative marker for potential concomitant chest injuries in polytrauma patients. It is important to clarify that our study does not advocate for the abandonment of established diagnostic tests such as X-rays, CT scans, and ultrasounds; rather, we propose that LDH can be used to guide more targeted diagnostic efforts.

To prevent any potential misunderstandings, we have included a clarifying note in lines 266-268 of the manuscript, emphasizing that LDH should not replace more comprehensive diagnostic methods like ultrasound or CT scans. These tools are indispensable for confirming disease diagnoses and monitoring disease progression.

In resource-constrained settings, such as during natural disasters or conflicts, the ability to quickly classify patients using basic laboratory tests like LDH can be invaluable. This method enables a more efficient allocation of limited medical resources by prioritizing the examination of patients most likely to have significant injuries. Additionally, detecting elevated LDH levels can raise awareness among physicians of possible underlying injuries that may not be immediately apparent from the patient's primary complaints.

We hope this explanation addresses your concerns and clarifies the intent and scope of our research.

We are deeply grateful for the detailed and constructive feedback provided by the reviewers and the editor throughout this review process. Your insights have been instrumental in refining our manuscript and ensuring it meets the rigorous standards of PlosOne. We have endeavored to address all the points raised in a comprehensive manner, and we believe the revisions we have implemented significantly enhance the value and clarity of our work.

We sincerely hope that the changes made are satisfactory and meet the expectations of the review committee. Should you find it advantageous for our responses to be integrated into the manuscript itself, we are more than willing to make such modifications. We remain committed to making any further adjustments if needed and greatly value your continued guidance and support.

Thank you once again for your assistance and for providing us with this opportunity to improve our manuscript. We appreciate the chance to contribute to PlosOne and eagerly anticipate the possibility of our work being published.

Sincerely yours,

Weining Yan

Attachment

Submitted filename: Response to Reviewers.docx

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PLoS One. doi: 10.1371/journal.pone.0308228.r007

Decision Letter 3

Zsolt J Balogh

19 Jul 2024

Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—a retrospective study

PONE-D-24-08209R3

Dear Dr. Yan,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Additional Editor Comments (optional):

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PLoS One. doi: 10.1371/journal.pone.0308228.r008

Acceptance letter

Zsolt J Balogh

23 Jul 2024

PONE-D-24-08209R3

PLOS ONE

Dear Dr. Yan,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. All results of comparison of biochemical markers between patients with severe polytrauma without chest injury (Group A) and with chest injury (Group B).

This table shows the results of the comparison between Group A and Group B for all biomarkers.

(DOCX)

pone.0308228.s001.docx^{(52.2KB, docx)}

S2 Table. All results of the correlation analysis of various biochemical parameters with chest injury in polytrauma patients.

(DOCX)

pone.0308228.s002.docx^{(42.9KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

pone.0308228.s003.docx^{(20.3KB, docx)}

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pone.0308228.s004.docx^{(20.2KB, docx)}

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pone.0308228.s005.docx^{(23.1KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting information files. Corresponding author can be contacted for any other requirements.

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Lactate dehydrogenase can be used for differential diagnosis to identify patients with severe polytrauma with or without chest injury—A retrospective study

Weining Yan

Felix Bläsius

Tabea Wahl

Frank Hildebrand

Elizabeth Rosado Balmayor

Johannes Greven

Klemens Horst

Roles

Abstract

Background

Method

Results

Conclusion

Introduction

Method

Research population and ethical permission

Fig 1. Inclusion and exclusion criteria for the study population.

Definitions

Data collection

Table 1. Summary of patient information data.

Statistical approaches and data analysis

Results

Table 2. Comparison of biochemical markers between patients with severe polytrauma without chest injury (Group A) and with chest injury (Group B).

Table 3. Logistic regression analysis of factors associated with the presence or absence of chest injury in patients with severe polytrauma.

Fig 2. Receiver operating characteristic curves for LDH for screening patients with severe polytrauma for the presence of chest injury.

Table 4. Sensitivity, specificity, PPV and NPV of LDH for screening patients with severe polytrauma for the presence of chest injury.

Table 5. Comparison of diagnostic results of chest injuries in patients with different LDH.

Discussion

Conclusion

Strengths & limitations

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

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Zsolt J Balogh

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Author response to Decision Letter 0

Decision Letter 1

Zsolt J Balogh

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Author response to Decision Letter 1

Decision Letter 2

Zsolt J Balogh

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Author response to Decision Letter 2

Decision Letter 3

Zsolt J Balogh

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Acceptance letter

Zsolt J Balogh

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Associated Data

Supplementary Materials

Data Availability Statement

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