Archives of Academic Emergency Medicine. 2023; 11(1): e29 OR I G I N A L RE S E A RC H Association Between Neutrophil Density and Survival in Trauma Patients Admitted to the Intensive Care Unit; a Retrospective Cohort Study Mohebat Vali1, Shahram Paydar2, Mozhgan Seif3, Maryam Hosseini2, Pardis Basiri5, Golnar Sabetian6, Haleh Ghaem3∗ 1. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran. 2. Trauma Research Center, Shahid Rajaee (Emtiaz) Trauma Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. 3. Non-Communicable Diseases Research Center, Department of Epidemiology, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran. 4. Trauma Research Center, Shahid Rajaee (Emtiaz) Trauma Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. 5. Department of Computer Science and Engineering and IT School of Electrical Engineering and Computer, Shiraz University, Shiraz, Iran. 6. Anesthesiology and Critical Care Trauma Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Received: January 2023; Accepted: February 2023; Published online: 3 April 2023 Abstract: Introduction: Altered immune responses, in particular neutrophil changes, are perceived to play a key role in immune responses to trauma. This study aimed to evaluate the association of neutrophil changes with patients’ survival in severe trauma cases. Methods: The current retrospective cohort study was conducted using data from patients admitted in the intensive care unit (ICU) of a trauma center in Shiraz, Iran, between 2016 and 2021. Patients were divided into three groups (i.e., normal, neutropenia, and neutrophilia) based on neutrophil count at the time of ICU admission, and the association of neutrophil count with in-hospital mortality was analyzed. Results: 2176 patients with the mean age of 37.90 ± 18.57 years were evaluated (84.04% male). The median trauma severity based on injury severity score (ISS) in this series was 9 (4 -17). Patients were divided in to three groups of neutrophilia (n = 1805), normal (n = 357), and neutropenia (n = 14). There were not any significant differences between groups regarding age distribution (p = 0.634), gender (p = 0.544), and trauma severity (p = 0.197). The median survival times for the normal, neutropenia, and neutrophilia groups were 49 (IQR: 33 -47) days, 51 (IQR: 8- 51) days, and 38 (IQR: 26 - 52) days, respectively (p = 0.346). The log-rank test showed a statistically significant difference between the three groups adjustment for ISS (p ≤ 0.001). For each unit increase in ISS, the hazard ratio increased by 2%. In ISS 9-17, the hazard ratio increased by 11% compared to ISS<4. Also, in ISS>17, the hazard ratio increased by 76% compared to ISS<4 in ICU-hospitalized patients. Conclusion: In general, the findings of the present study showed that the survival rate of patients in the normal group after ISS adjustment was higher than the other two groups. Also, the Cox model showed that the mortality risk ratio in the neutropenia group was 15 times higher than the normal group. Keywords: Neutrophils; Survival; Neutropenia; Wounds and Injuries; Multiple trauma; Trauma Severity Indices Cite this article as: Vali M, Paydar S, Seif M, Hosseini M, Basiri P, Sabetian G, Ghaem H. Association Between Neutrophil Density and Survival in Trauma Patients Admitted to the Intensive Care Unit; a Retrospective Cohort Study. Arch Acad Emerg Med. 2023; 11(1): e29. https://doi.org/10.22037/aaem.v11i1.1990. ∗Corresponding Author: Haleh Ghaem; Department of Epidemiology, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran. Tel: +98 71 37256007, Email: ghaemh@sums.ac.ir, ORCID: https://orcid.org/0000-0001- 9564-392X. 1. Introduction Recently, WHO has estimated that trauma accounts for 5.8 million mortalities, annually (1, 2). In recent years, trauma- caused mortalities have substantially declined owing to ad- vances in treatment approaches, particularly in patients un- der blood clot and blood loss treatments. However, sec- ondary complications such as sepsis, multiple organ fail- ure (MOF), and nosocomial infections may harm trauma pa- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index M. Vali et al. 2 tients or even cause death (3). Neutrophils constitute 60-70% of circulatory leukocytes in the body, playing a key role in innate immunity and host defense against invading pathogens, as well as elic- iting inflammation-induced tissue damage (4). In healthy individuals, circulatory neutrophils are primarily naïve cells, which are subsequently activated by recognizing damage-associated molecular patterns (DAMPs) through their pathogen-associated molecular patterns (PAMPs), thereby maintaining the immune system homeostasis (5). Upon inflammation, neutrophils properly respond to mi- croenvironmental signals and obtain distinct functional phe- notypes, commonly referred to as neutrophil heterogene- ity (6, 7). Besides, trauma can affect neutrophils (8). In- deed, neutrophils are the first line of defense against micro- bial pathogens and trauma and commence inflammatory re- sponses. Trauma-induced modulations in neutrophils, ul- timately lead to post-traumatic complications e.g., multiple organ failure and acute respiratory distress syndrome (8). At a wide range of time points after traumatic injury, ex vivo studies have reported significant changes in many neutrophil functions (9-14) that probably contribute to the development of secondary complications. Experimental studies indicate a direct relationship between trauma severity and the consequent tissue impairment and/or neutrophil dysfunction (15). In addition, depending on the stage of injury, neutrophils can contribute to repair mechanisms or exacerbate the pathophysiology of trauma (16). A retrospective study (17) explored neutrophils’ involvement in severe trauma to uncover the link between trauma severity and neutrophils’ phenotype/function. However, given that we only obtained the basic blood test information on neu- trophils’ percentage from patients at the time of admission, we were encouraged to investigate the impact of neutrophil density on trauma patients’ survival. For this purpose, we at- tempted to evaluate neutrophil counts in patients with ad- justed injury severity to determine neutrophils’ overall ef- fects. As mentioned, there is an important balance between pro- inflammatory and anti-inflammatory systems in the im- mune response to trauma. The imbalance between these systems plays an important role in the post-injury outcomes of critically ill patients (18, 19). Understanding the link be- tween neutrophil dysfunction (neutropenia, or neutrophilia) and patients’ survival may yield appropriate early biomark- ers for clinical applications and treatment of trauma patients. Therefore, this study aimed to evaluate the association of neutrophil changes with patients’ survival in severe trauma cases admitted to intensive care unit (ICU). 2. Methods 2.1. Study design and setting The current retrospective cohort study was carried out us- ing data from trauma patients admitted to ICU of Shahid Ra- jaee Hospital (Imtiaz), Shiraz, Iran, between 2016 and 2021. Patients were divided into three groups (i.e., normal, neu- tropenia, and neutrophilia) based on neutrophil count at the time of ICU admission and the association of neutrophil count with in-hospital mortality were analyzed. The Ethics Committee approved this study at Shiraz University of Med- ical Sciences (IR.SUMS.SCHEANUT.REC.1400.006). This in- formation was collected for the purpose of research by the Trauma Research Center of Shahid Rajaei Hospital using the patients’ files; therefore, due to the nature of the research, in- formed consent was obtained from the patients themselves or their legal guardians upon the arrival of the patients. In addition, the private medical information of the patients re- mained confidential, and the researchers were not provided with the name, surname, and national code for the confiden- tiality of the patients’ information 2.2. Participants All trauma patients over 18 years old, who presented to the ICU of the mentioned hospital were enrolled. Patients who were transferred to another hospital or whose final outcomes regarding in-hospital mortality or survival was not available were exclude. Additionally, all women regardless of preg- nancy status were included in the study, but those who died in the emergency department and patients who died within 6 hours of hospital admission were excluded from the study. Also, patients were followed for the duration of their hospital stay or at subsequent hospital visits, but were not specifically followed for post-discharge trauma deaths. 2.3. Data gathering The variables included the demographic information (age and gender), hospitalization information (date and time of ICU admission and discharge), patients’ outcome at the time of discharge from ICU (in-hospital mortality), injury mecha- nism (accidents or others), patients’ consciousness status at the time of ICU admission (Glasgow coma scale (GCS), Pupil 1 and 2), the injury severity score )ISS), patients’ vital signs (heart rate [HR], respiratory rate [RR], systolic blood pressure [SBP], and diastolic blood pressure [DBP]), and arterial blood gas analysis (blood acidity [PH], arterial blood carbon dioxide [PCO2], arterial blood oxygen [PAO2] levels and using artifi- cial respiration device, FiO2), as well as laboratory informa- tion (blood sugar [BS], blood urea nitrogen [BUN], creatinine [Cr], sodium [Na], potassium [K], prothrombin time PT], par- tial thromboplastin time [PTT], international normalized ra- tio [INR], hemoglobin, lymphocyte, fibrinogen, white blood This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 3 Archives of Academic Emergency Medicine. 2023; 11(1): e29 Table 1: Patients’ baseline characteristics Characteristic Neutropenia N = 14 Normal N = 357 Neutrophilia N =1805 Pa Age (year) Mean ± SD 33.50 ± 15.35 38.21 ± 18.43 38.26 ± 18.68 0.634 Gender Female 1 (0.29) 61 (17.63) 284 (82.08) 0.544 Male 13 (0.71) 296 (16.17) 1521 (83.11) Cause of injury Accidentsd 10 (0.61) 261 (16.00) 1360 (83.38) 0.610 Othere 4 (0.74) 96 (17.71) 442 (81.55) Length of stay, Median (IQR) ICU 3 (0.75 - 8.25) 3 (1 - 9) 6 (2 - 12) 0.0001 Hospital 2.5 (1.75 - 6.25) 7 (2 - 17) 10 (4 - 38) 0.0001 Vital signs on arrival, Median (IQR) O2 saturation (%) 93 (90.75 - 96.25) 93 (89 - 96) 93 (90 - 96) 0.917 SBP (mmHg) 116.5 (103 - 137.75) 123 (107 - 138.75) 127 (110 - 139) 0.037 DBP (mmHg) 75 (59.5 - 87.5) 78 (65.5 - 87) 80 (70 - 88) 0.063 GCS 13 (7 - 15) 13 (7 - 15) 12 (7 - 15) 0.318 RR (/minute) 19.5 (17.75 - 21.25) 20 (17 - 22) 20 (17 - 22) 0.974 PR (/minute) 104.14 (21.73) 104.04 (23.64) 101.45 (24.42) 0.174 Pupils (first hour) Responsive 13 (0.71) 314 (17.05) 1515 (82.25) 0.314 Unresponsive 0 (0.00) 24 (14.04) 147 (85.96) ISS Median (IQR) 9 (8 - 16.5) 9 (4 - 17.25) 12 (5 - 18) 0.197 Intubated Yes 4 (0.54) 113 (15.13) 630 (84.34) 0.863 No 8 (0.71) 175 (15.57) 941 (83.72) a: comparison of the three groups (One-way ANOVA or Kruskal–Wallis) or Chi square d: Traffic accidents and accidents include: pedestrian accident, motorcyclist accident, and car accident. e: Others include: falling from a height, being hit by a sharp object, being hit by a bullet, assault, falling to the ground, continuing treatment, suicide, and self-mutilation. IQR: interquartile range; ISS: Injury severity score; SBP: systolic blood pressure, DBP: diastolic blood pressure; GCS: Glasgow coma scale; RR: Respiratory rate; PR: pulse rate; ICU: intensive care unit; SD: standard deviation. For neutrophils, 45-75% of white blood cell count was considered normal, while less than 4% and more than 75% were considered neutropenia and neutrophilia, respectively. Table 2: Multiple Cox regression of survival in trauma patient Variable Hazard ratio 95% CI P value Injury severity score 1.02 (1.00,1.05) 0.042 pH 0.42 (0.21,0.82) 0.011 O2 saturation 0.990 (0.982,0.999) 0.044 Groups Normal (Ref ) - - - Neutropenia 15.06 (1.809,125.40) 0.012 Neutrophilia 0.92 (0.42, 2.00) 0.843 CI: confidence interval. Test of proportional hazards assumption based on Schoenfeld residuals (phtest) = 0.726. count [WBC], and neutrophils count) based on patients’ pro- file. Patients were divided into three groups based on their circulatory neutrophil count. For neutrophils, 45-75% of WBC was considered normal, while less than 45% and more than 75% were considered neutropenia and neutrophilia, re- spectively. To determine the final status of the patients as our preferred outcome, the patients were followed up until the last day of hospitalization and if the patients were discharged from the hospital alive, we considered them "alive" and if the doctor diagnosed and issued a death certificate, we consid- ered them "dead". In addition, we excluded the patients who were transferred to another treatment center due to the in- ability to follow up their condition. MV, in collaboration with Trauma Research Center, was responsible for data gathering. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index M. Vali et al. 4 Figure 1: Kaplan-Meier diagram in trauma patients adjusted for injury severity score (ISS) in three groups of neutropenia, normal and neu- trophilia. AIS: Abbreviated Injury Scale. 2.4. Statistical analysis We analyzed the data normality using the Kolmogorov- Smirnov test and related graphs. For quantitative variables with normal distribution, mean and standard deviation (SD) were employed, and for non-normal data, the median and percentiles were reported. Besides, for qualitative variables, frequency and percentage were utilized. Analysis of variance (ANOVA) or Kruskal–Wallis test was also exploited to com- pare quantitative variables between the normal, neutrope- nia, and neutrophilia groups. Furthermore, Sidak post hoc or Mann–Whitney U test was used for subsequent comparison between the groups. In addition, the Chi-square test was uti- lized to compare qualitative variables between the groups. To draw graphs. In addition, for survival analysis, Kaplan-Meier adjusted for the ISS and log-rank were employed to compare the groups. Finally, both simple and multiple Cox regres- sion analyses were utilized to explore factors associated with the survival of ICU-hospitalized trauma patients. Then, the proportional hazards assumption test based on the Schoen- feld residuals (phtest) was utilized to determine the propor- tional hazards assumption. All analyses were performed us- ing STATA 12 software with a significance level of P ≤ 0.05. 3. Results 3.1. Baseline characteristics of studied cases Data was collected from 3782 trauma patients hospitalized in the intensive care unit. After the exclusion of patients un- der 18 years of age, patients transferred to another hospi- tal, patients whose final status (death or aliveness) was not known, and patients with missing data, 2176 patients were finally evaluated. Table 1 depicts the participants’ character- istics. Patients’ average age was 37.90±18.57 (range 18-100) years (84.04% male). The Median trauma severity based on ISS in this series was 9 (4 -17) and the main cause of hospital- ization in more than 70% of the patients was traffic accidents (pedestrian, motorcyclist, and car accidents). Patients were divided in to three groups of neutrophilia (n = 1805), normal (n = 357), and neutropenia (n = 14) based on total neutrophil count at the time of admission to ICU. There were not any significant differences between groups regarding age distribution (p = 0.634). gender (p = 0.544), and trauma severity (p = 0.197). In laboratory data, a statistically significant difference was observed between the groups only regarding the amount of K (p = 0.002), PTT (p = 0.0022), WBC (p ≤ 0.001), Hb (p = 0.0026), and lymphocytes (p ≤ 0.001). 3.2. Survival analysis The median overall survival time was 40 (IQR: 22-51) days. Also, the median survival time for the normal, neutrope- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 5 Archives of Academic Emergency Medicine. 2023; 11(1): e29 nia, and neutrophilia groups was 49 (IQR: 33 -47) days, 51 (IQR: 8- 51) days, and 38 (IQR: 26 - 52) days, respectively (p = 0.346). Figure 1 shows the Kaplan-Meier diagram for the groups adjusted for the ISS. Also, the log-rank test did not exhibit a statistically significant difference between the nor- mal and neutropenia groups (p = 0.581). Likewise, no statis- tically significant difference was shown between the normal and neutrophilia groups (p = 0.437). However, the log-rank test showed a statistically significant difference between the three groups despite adjustment for ISS (p ≤ 0.001). Multiple Cox analysis results are shown in Table 2. As the table de- picts, for each unit increase in ISS, the hazard ratio increased by 2%. In ISS 9-17, the hazard ratio increased by 11% com- pared to ISS<4. Also, in ISS>17, the hazard ratio increased by 76% compared to ISS<4 in ICU-hospitalized patients. In addition, for each unit increase in blood pH, the hazard ratio decreased by 58%. In this sense, neutropenia had 15.06 times higher hazard ratio than the normal group. 4. Discussion This retrospective study evaluated trauma patients’ survival rate based on their neutrophil count (i.e., normal, neutrope- nia, and neutrophilia). Our findings denoted that after ad- justment for ISS, the normal group’s survival rate is greater than the neutropenia and neutrophilia groups. Furthermore, the Cox model revealed that each unit increase in the ISS in- creases the hazard ratio. Consistently, this model revealed that neutropenia increases the hazard ratio up to 15 times. Neutrophils play a major role in inflammatory responses upon the occurrence or following traumatic injuries. Ensu- ing the trauma, neutrophils undergo significant functional changes, causing a rapid efflux of neutrophils from the bone marrow into the circulation (20). In compliance with pre- vious studies, we showed that neutrophilia is more preva- lent in the first 24 hours’ post-trauma compared to neutrope- nia. Indeed, neutrophilia is the first post-trauma event due to the endogenous release of cortisol and catecholamine, resulting in neutrophil production and subsequent release from the bone marrow (21, 22). However, numerous stud- ies have proposed that the increased release of neutrophils into the circulation may lead to the emergence of imma- ture and dysfunctional neutrophil s(21-25), ultimately, re- sulting in peripheral tissue damage and multiple organ dys- functions (MODS) (26-29). Hence, neutrophilia might not be correlated with the improved survival of traumatic pa- tients as it was revealed that the normal group patients lived much longer than the neutrophilia group patients. On the other hand, neutropenia increased mortality more than 15 times in critical trauma patients. The low survival of neu- tropenia patients could be attributed to neutrophil dysfunc- tion, thereby enhancing hospitalized trauma patients’ sen- sitivity to healthcare-associated infections (30). Also, in a previous review study, by investigating the effect of trauma on neutrophil phenotype with the main purpose of using this knowledge to investigate the predictive potential of neu- trophil changes on secondary complications in patients with traumatic injuries, they came to the same conclusion that changes in the markers and functions of neutrophils may be potential biomarkers that predict the outcome of trauma pa- tients (17). In this sense, manipulating neutrophil frequency to improve patients’ survival might be controversial. How- ever, boosting neutrophils’ germicidal and anti-infective ca- pacity could be quite appealing. Of note, uncontrolled neu- trophil hyperactivation may lead to significant tissue impair- ment, thereby contributing to development of acute respi- ratory distress syndrome (ARDS) and MOF. On the contrary, suppressing neutrophils’ inflammatory response shortly af- ter a traumatic insult to reduce immunity-induced tissue im- pairment may predispose patients to microbial infections. Therefore, developing strategies to create an equilibrium be- tween these issues is urgently required to assist patients’ re- covery by modifying the immune response. 5. Limitations The current study has several strengths such as including a large number of trauma patients. In addition, this study was conducted in the largest trauma center in southern Iran, which is a specialized center for trauma. Taking potential confounders into account (e.g., the ISS), as well as using lab- oratory information and ABG are other advantages of the current study. Nonetheless, the shortcomings of the current study should not also be neglected. For example, the retro- spective design of study has its limitations. In this regard, we suggest the prospective investigation of neutrophils’ effects on patients’ survival in future studies. Also, we were not able to study neutrophil phenotypes, therefore, investigating their phenotypes is encouraged. Furthermore, our data on neu- trophils was based on WBC percentages, hence, we suggest these data to be analyzed based on WBC number/L. Also, we reported neutrophils’ normal range from different sources, which might have affected the results. However, we chose neutrophils’ normal range based on hospital kits, which are used for correcting differential reports. Also, for neutrophil measurement, we did not have data on neutrophil counts at different time points after trauma, which should be taken into account in future studies. Finally, neutrophil changes in ICU-hospitalized patients also require further investigation. 6. Conclusion Overall, the findings of the current study revealed that pa- tients’ survival rate in the normal group after adjustment for ISS was higher than the neutropenia and neutrophilia This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index M. Vali et al. 6 groups. Also, the Cox model showed that the hazard ratio in the neutropenia group was 15 times higher than that of the normal group. Hence, fixing neutrophil disorder may plummet the hazard ratio in trauma patients. Indeed, one of the core findings of the current review is that the survival rate can be predicted using neutrophil count, which can be measured using a simple blood sample. In addition, neu- trophil count could have a predictive value for the risk assess- ment of trauma patients. Moreover, we suggest neutrophil changes during patients’ ICU hospitalization to be further in- vestigated. 7. Declarations 7.1. Acknowledgments This article was a part of Mohebat Vali’s Ph.D. the- sis, approved and financially supported by the Research Vice-chancellor of Shiraz University of Medical Sciences (grant No. 1400-10-5-23391). The Ethics Committee ap- proved this study at Shiraz University of Medical Sciences (IR.SUMS.SCHEANUT.REC.1400.006). We would also like to express our special thanks to the efforts and cooperation of the staff of Rajaei Hospital, including Mrs. Mrs. Saadat Jo, Mrs. Shayan, and Mrs. Mohammadi who helped us a lot in collecting data. 7.2. Competing Interests Statement The authors of this study declared no competing interests. 7.3. Fundings and supports This article was a part of Mohebat Vali’s Ph.D. thesis, ap- proved and financially supported by the Research Vice- chancellor of Shiraz University of Medical Sciences (grant No. 1400-10-5-23391). 7.4. Authors’ contribution HG is the lead author and guarantor and contributed to in- terpreting the data and revising the manuscript. MV and SHP planned the study and led the drafting and revising of the manuscript. MV, MS, MH, SHP, PB and GS con- tributed to interpreting the data and drafting and revising the manuscript. All authors approved the submitted ver- sion of the manuscript. All authors have contributed to the preparation of the manuscript, have read, and approved the submitted manuscript. All authors listed meet the author- ship criteria according to the latest guidelines of the Interna- tional Committee of Medical Journal Editors and agree with the manuscript. The work is original and not under consid- eration by any other journal. 7.5. Data Availability The data that support the findings of this study are available from the corresponding author, [HGH], upon reasonable re- quest. 7.6. Ethics approval and consent to participate The Ethics Committee approved this study at Shiraz University of Medical Sciences (IR.SUMS.SCHEANUT.REC.1400.006). Informed consent was obtained from all subjects or their legal guardians to use their data for research. References 1. Lord JM, Midwinter MJ, Chen Y-F, Belli A, Brohi K, Ko- vacs EJ, et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014;384(9952):1455-65. 2. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, et al. Management of bleeding following major trauma: an updated European guideline. Crit Care. 2010;14:R52. 3. Glance LG, Stone PW, Mukamel DB, Dick AW. Increases in mortality, length of stay, and cost associated with hospital-acquired infections in trauma patients. Arch Surg. 2011;146(7):794-801. 4. Kobayashi SD, DeLeo FR. Role of neutrophils in innate immunity: a systems biology-level approach. Wiley In- terdiscip Rev Syst Biol Med. 2009;1(3):309-33. 5. Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33(5):657-70. 6. Hellebrekers P, Hietbrink F, Vrisekoop N, Leenen LPH, Koenderman L. Neutrophil functional heterogeneity: identification of competitive phagocytosis. Front Im- munol. 2017;8:1498. 7. Tak T, Wijten P, Heeres M, Pickkers P, Scholten A, Heck AJR, et al. Human CD62Ldim neutrophils identified as a separate subset by proteome profiling and in vivo pulse- chase labeling. Blood. 2017;129(26):3476-85. 8. Hazeldine J, Hampson P, Lord JM. The impact of trauma on neutrophil function. Injury. 2014;45(12):1824-33. 9. Junger WG, Rhind SG, Rizoli SB, Cuschieri J, Shiu MY, Baker AJ, et al. Resuscitation of traumatic hem- orrhagic shock patients with hypertonic saline-without dextran-inhibits neutrophil and endothelial cell activa- tion. Shock. 2012;38(4):341. 10. Junger WG, Rhind SG, Rizoli SB, Cuschieri J, Baker AJ, Shek PN, et al. Pre-hospital hypertonic saline resuscita- tion attenuates the activation and promotes apoptosis of neutrophils in patients with severe traumatic brain in- jury. Shock. 2013;40(5):366. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 7 Archives of Academic Emergency Medicine. 2023; 11(1): e29 11. Kanyilmaz S, Hepguler S, Atamaz FC, Gokmen NM, Ard- eniz O, Sin A. Phagocytic and oxidative burst activity of neutrophils in patients with spinal cord injury. Arch Phys Med Rehabil. 2013;94(2):369-74. 12. Kinoshita M, Miyazaki H, Ono S, Inatsu A, Nakashima H, Tsujimoto H, et al. Enhancement of neutrophil function by interleukin-18 therapy protects burn-injured mice from methicillin-resistant Staphylococcus aureus. Infect Immun. 2011;79(7):2670-80. 13. Kurihara T, Jones CN, Yu Y-M, Fischman AJ, Watada S, Tompkins RG, et al. Resolvin D2 restores neutrophil di- rectionality and improves survival after burns. FASEB J. 2013;27(6):2270. 14. Liao Y, Liu P, Guo F, Zhang Z-Y, Zhang Z. Oxidative burst of circulating neutrophils following traumatic brain injury in human. PloS one. 2013;8(7):e68963. 15. Wang X, Li Z-Y, Zeng L, Zhang A-Q, Pan W, Gu W, et al. Neutrophil CD64 expression as a diagnostic marker for sepsis in adult patients: a meta-analysis. Crit Care. 2015;19:245. 16. Morganti-Kossmann MC, Rancan M, Stahel PF, Koss- mann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care. 2002;8(2):101-5. 17. Mortaz E, Zadian SS, Shahir M, Folkerts G, Garssen J, Mumby S, et al. Does neutrophil phenotype pre- dict the survival of trauma patients? Front Immunol. 2019;10:2122. 18. Robertson CM, Coopersmith CM. The systemic in- flammatory response syndrome. Microbes Infect. 2006;8(5):1382-9. 19. Tschoeke SK, Hellmuth M, Hostmann A, Ertel W, Ober- holzer A. The early second hit in trauma management augments the proinflammatory immune response to multiple injuries. J Trauma. 2007;62(6):1396-404. 20. Botha AJ, Moore FA, Moore EE, Peterson VM, Goode AW. Base deficit after major trauma directly relates to neutrophil CD11 b expression: a proposed mecha- nism of shock-induced organ injury. Intensive Care Med 1997;23(5):504-9. 21. Hazeldine J, Naumann DN, Toman E, Davies D, Bishop JRB, Su Z, et al. Prehospital immune responses and devel- opment of multiple organ dysfunction syndrome follow- ing traumatic injury: A prospective cohort study. PLoS Med. 2017;14(7):e1002338. 22. Spijkerman R, Hesselink L, Bongers S, van Wessem KJP, Vrisekoop N, Hietbrink F, et al. Point-of-Care Analysis of Neutrophil Phenotypes: A First Step Toward Immuno- Based Precision Medicine in the Trauma ICU. Crit Care Explor. 2020;2(7):e0158. 23. Finlay LD, Conway Morris A, Deane AM, Wood AJ. Neu- trophil kinetics and function after major trauma: A sys- tematic review. World J Crit Care Med. 2021;10(5):260-77. 24. Hesselink L, Spijkerman R, de Fraiture E, Bongers S, Van Wessem KJP, Vrisekoop N, et al. New automated analysis to monitor neutrophil function point-of-care in the in- tensive care unit after trauma. Intensive Care Med Exp. 2020;8:12. 25. Hesselink L, Spijkerman R, van Wessem KJP, Koenderman L, Leenen LPH, Huber-Lang M, et al. Neutrophil hetero- geneity and its role in infectious complications after se- vere trauma. World J Emerg Surg. 2019;14:24. 26. Hazeldine J, Hampson P, Lord JM. The impact of trauma on neutrophil function. Injury. 2014;45(12):1824-33. 27. Lord JM, Midwinter MJ, Chen YF, Belli A, Brohi K, Ko- vacs EJ, et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014;384(9952):1455-65. 28. Botha AJ, Moore FA, Moore EE, Sauaia A, Banerjee A, Pe- terson VM. Early neutrophil sequestration after injury: a pathogenic mechanism for multiple organ failure. J Trauma. 1995;39(3):411-7. 29. Visser T, Pillay J, Koenderman L, Leenen LP. Postinjury immune monitoring: can multiple organ failure be pre- dicted? Curr Opin Crit Care. 2008;14(6):666-72. 30. Papia G, McLellan BA, El-Helou P, Louie M, Rachlis A, Szalai J-P, et al. Infection in hospitalized trauma patients: incidence, risk factors, and complications. J Trauma. 1999;47(5):923. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index Introduction Methods Results Discussion Limitations Conclusion Declarations References