ORIGINAL ARTICLE Year : 2022  |  Volume : 55  |  Issue : 5  |  Page : 177-183

Change of neutrophil-to-monocyte ratio to stratify the mortality risk of adult patients with trauma in the intensive care units

Ching-Hua Tsai1, Hang-Tsung Liu1, Ting-Min Hsieh1, Chun-Ying Huang1, Sheng-En Chou1, Wei-Ti Su1, Chi Li1, Shiun-Yuan Hsu1, Ching-Hua Hsieh2
1 Department of Trauma Surgery, Chang Gung University College of Medicine, Kaohsiung City, Taiwan
2 Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City, Taiwan

Date of Submission14-Apr-2022Date of Decision20-Jun-2022Date of Acceptance23-Jun-2022Date of Web Publication26-Sep-2022

Correspondence Address:
Ching-Hua Hsieh
Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University Col-lege of Medicine, No. 123, Ta-Pei Road, Niao-Song District, Kaohsiung City 83301
Taiwan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/fjs.fjs_88_22

Background: The subtypes of circulating white blood cells undergo relative changes under systemic inflammation; thus, the derived ratio may reflect patients' immunoinflammatory status. Under the hypothesis that change in segmented neutrophil-to-monocyte (SeMo) ratio, delta-SeMo ratio, may reflect the host's immunoinflammatory response against illness, this study aims to investigate the effectiveness of using delta-SeMo ratio to assess the mortality risk of patients with trauma and critical illness.
Materials and Methods: A total of 1476 adult patients with trauma admitted to the intensive care unit (ICU) between January 1, 2009, and December 31, 2020, were enrolled in this study. Delta-SeMo ratio was defined using the following formula: SeMo ratio at day 3 (72–96 h after admission into ICU) – SeMo ratio at admission (at admission into ICU). The primary outcome was inhospital mortality.
Results: There was no significant difference in the SeMo ratio at admission between death and survival patients (18.7 ± 11.0 vs. 18.7 ± 18.4, P = 0.974); however, SeMo ratio at day 3 (20.3 ± 15.5 vs. 15.7 ± 16.0, P = 0.002) and delta-SeMo ratio (1.6 ± 19.5 vs.–3.0 ± 24.2, P = 0.034) of the patients who died were significantly higher than those of the patients who survived. The patients with delta-SeMo ratio ≥1.038, an estimated cutoff value for best predicting mortality by the plotted receiver operating characteristic curve, sustained an approximately 2-fold adjusted mortality (adjusted odds ratio [AOR]: 1.84, 95% confidence interval [CI]: 1.27–2.66, P = 0.001) than those with a delta-SeMo ratio <1.038. Furthermore, when the delta-SeMo ratio was set at 0, a threshold value indicating a condition with an increase or decrease in the SeMo ratio at day 3 than the SeMo ratio at admission, there was a 1.7-fold higher adjusted mortality (AOR: 1.70, 95% CI: 1.18–2.46, P = 0.004) of the patients with delta-SeMo ratio ≥0 than those with delta-SeMo ratio <0.
Conclusion: Following trauma injury, critically ill patients with an increased SeMo ratio present with a higher rate of mortality and longer stay in the hospital and ICU than those with a decreased SeMo ratio. The use of the delta-SeMo ratio may help physicians quickly identify patients at higher risk of inhospital mortality.

Keywords: Delta-segmented neutrophil-to-monocyte, immune, mortality, segmented neutrophil-to-monocyte, trauma

How to cite this article:
Tsai CH, Liu HT, Hsieh TM, Huang CY, Chou SE, Su WT, Li C, Hsu SY, Hsieh CH. Change of neutrophil-to-monocyte ratio to stratify the mortality risk of adult patients with trauma in the intensive care units. Formos J Surg 2022;55:177-83
How to cite this URL:
Tsai CH, Liu HT, Hsieh TM, Huang CY, Chou SE, Su WT, Li C, Hsu SY, Hsieh CH. Change of neutrophil-to-monocyte ratio to stratify the mortality risk of adult patients with trauma in the intensive care units. Formos J Surg [serial online] 2022 [cited 2022 Sep 27];55:177-83. Available from: https://www.e-fjs.org/text.asp?2022/55/5/177/356986   Introduction 

In patients with trauma, complete blood count is one of the most frequent examinations to provide information on the distribution of hemograms, including red blood cells, white blood cells (WBC), platelets, and information on subtypes of WBCs. Several studies have suggested that circulating WBC subtypes undergo relative changes under systemic inflammation, and thus, the derived ratio could reflect the change in patients' immunoinflammatory status as well as patient outcomes in various diseases.[1],[2] For example, the monocyte-to-lymphocyte ratio in osteoporosis patients,[3] platelet-to-lymphocyte ratio in patients with cancer,[4],[5],[6] neutrophil-to-lymphocyte ratio in patients with cancer,[4],[5],[6] and hip fracture[7] have been reported to predict mortality in specific patient populations.

Among the subtypes of WBC, neutrophils are the most abundant, with prominent functions in the acute inflammatory response. Neutrophils migrate toward injured tissues in response to chemoattractant signals, such as interleukin (IL) 8,[8] and act as one of the most important immune cells in response to infection by producing IL-1 β, IL-6, tumor necrosis factor-alpha (TNF-α), and reactive oxygen species species.[9] Paradoxically, hyperactivation and recruitment of neutrophils can intensify the acute inflammatory response and worsen tissue damage, resulting in the progression of the illness.[9],[10] In addition, under stressful conditions, such as major trauma, macrophages, and monocytes are triggered to produce PGE2, resulting in a hypoinflammatory state.[1] Monocytes can differentiate into alternatively activated macrophages and prevent inflammatory responses by promoting tissue repair via IL-10 and transforming growth factor β1 production, which also plays a key role in the regulation of hyperactivation of the inflammatory response.[11] The deactivation of monocytes leads to conditions of immunoincompetence, which is characterized by a profound loss of antigen-presenting capacity, reduced expression of human leukocyte antigen receptors, and lack of ability to produce TNF-α.[12],[13]

The neutrophil-to-monocyte ratio, or segmented neutrophil-to-monocyte (SeMo) ratio, can serve as potential markers for skin cancer,[14] breast cancer,[15] pancreatic cancer,[16] severity of knee osteoarthritis,[17] and differentiation of infection from flare in patients with lupus nephritis.[18] The SeMo ratio is independently associated with 30-day all-cause mortality in patients with acute kidney injury after presentation to the emergency department.[19] In patients with severe COVID-19, a value ≥17.75 at admission was an independent risk factor for inhospital mortality.[20] In addition, the SeMo ratio helps predict the 28-day mortality in patients with sepsis.[21] Furthermore, the delta-SeMo ratio measurement can be applied in risk stratification of patients with sepsis in medical intensive care units (ICU).[22]

Under the hypothesis that changes in the SeMo ratio may reflect the host immunoinflammatory response against illness, this study aimed to investigate the effectiveness of using the delta-SeMo ratio to assess the mortality risk of patients with trauma in the ICU.

  Materials and Methods 

Study population

This study was approved by the Institutional Review Board (IRB) of Chang Gung Memorial Hospital (approval number: 202100936B0). Due to the retrospective nature of the study, the need for informed consent was waived by IRB regulations. As shown in [Figure 1], of the 43,114 hospitalized patients with trauma registered in the Trauma Registry System of the hospital between January 1, 2009, and December 31, 2020, 6519 ages older than years were admitted to the ICU. After excluding patients with burns (n = 733), hang injuries (n = 14), drowns (n = 5), and incomplete data on neutrophils and monocytes (n = 4291), 1476 patients were enrolled in the study.

Figure 1: Study flowchart illustrating the inclusion of patients with trauma and critical illness and stay in the ICU. ICU: Intensive care unit

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Data collection

Clinical information was extracted from the registered data in the trauma registry system, including sex, age, neutrophil and monocyte counts at admission to ICU and 72–96 h later, preexisting comorbidities (cerebrovascular accident, hypertension, coronary artery disease, congestive heart failure, diabetes mellitus, and end-stage renal disease), Glasgow Coma Scale (GCS), and injury severity score (ISS). The SeMo ratio was calculated by dividing the segmented neutrophil count by the mature monocyte count. The SeMo ratio at admission indicates the ratio calculated at admission into ICU, and the SeMo ratio at day 3 indicates the ratio calculated at 72–96 h after admission into ICU. Therefore, the delta-SeMo ratio was defined using the following formula: SeMo ratio at day 3– SeMo ratio at admission. The primary outcome of this study was inhospital mortality rate.

Statistical analyses

All statistical analyses were performed using IBM SPSS Statistics for Windows (version 23.0; IBM Corp., Armonk, NY, USA). Categorical data were compared using Pearson's Chi-square test or two-sided Fisher's exact test. Levene's test was used to assess the homogeneity of variance in the continuous variables. Continuous data were analyzed using one-way analysis of variance with the Games–Howell post hoc test. The results were expressed as mean ± standard deviation, with GCS and ISS presented as the median and interquartile range (IQR) (Q1–Q3). The odds ratio (OR) of mortality was calculated using a 95% confidence interval (CI). A plot of specific receiver operating characteristic (ROC) curves was used to evaluate the best cutoff value for the delta-SeMo ratio that predicted the patient's probability of mortality. The cutoff point was derived from the ROC curves based on the maximal Youden's index, which was calculated as sensitivity + specificity −1, to reflect the maximal classification accuracy. An area under the curve (AUC) of more than 0.9 was defined as high accuracy, between 0.9 and 0.7 as moderate accuracy, and <0.7 as low accuracy.[23] The adjusted odds ratio (AOR) of mortality was calculated using logistic regression analysis by controlling for sex, age, GCS score, and ISS. Statistical significance was set at P < 0.05.

  Results 

Characteristics of the death and survival patients

As shown in [Table 1], patients who died were significantly older than those who survived (62.0 ± 19.9 vs. 53.6 ± 19.5, P < 0.001). There was no significant difference in sex, prevalence of preexisting comorbidities, neutrophil count, and monocyte count at admission into ICU and at 72–96 h after death and survival. There was no significant difference in the SeMo ratio at admission between patients who died and those who survived (SeMo ratio at admission, 18.7 ± 11.0 vs. 18.7 ± 18.4, respectively, P = 0.974). However, the SeMo ratio at day 3 and delta-SeMo ratio of the patients who died were significantly higher than those of the surviving patients (SeMo ratio at day 3, 20.3 ± 15.5 vs. 15.7 ± 16.0, respectively, P = 0.002; delta-SeMo ratio, 1.6 ± 19.5 vs.–3.0 ± 24.2, respectively, P = 0.034). A significantly lower GCS but higher ISS was found in patients who died than in those who survived (GCS, median [IQR]: 8 [3–15] vs. 15 [9–15], respectively; P < 0.001; ISS, 25 [16–29] vs. 20 [16–25], respectively; P < 0.001). Stratification of ISS revealed that, for the patients who died, there were fewer patients with an ISS of 1–15, but more patients had an ISS of 16–24 and ≥25 than those who survived. The patients who died had a significantly shorter hospital stay than the survivors (17.1 days vs. 22.7 days, respectively; P = 0.010).

Table 1: Characteristics and outcomes of adult patients with trauma who died and those who survived after admitted to intensive care unit

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Prediction of death by the delta-segmented neutrophil-to-monocyte ratio with area under the curve

According to the analysis of the plotted AUC curve, a delta-SeMo ratio of 1.038 as the cutoff point had the highest AUC of 0.577, with a sensitivity of 0.474 and specificity of 0.693 [Figure 2]. Accuracy of the discriminating power of the delta-SeMo ratio in predicting patient's death was low.

Figure 2: ROC curve analysis to identify the cutoff levels of delta-SeMo ratio for the probability of death. ROC: Receiver operating characteristic, SeMo: Segmented neutrophil-to-monocyte

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Characteristics and outcomes of patients divided by delta-segmented neutrophil-to-monocyte ratio of 1.038

As shown in [Table 2], with 1.038 as the best cutoff point of a delta-SeMo ratio, the study patient population was divided into two groups (delta-SeMo ratio ≥1.038, n = 476 and delta-SeMo ratio <1.038, n = 1000). There were significantly lower rates of delta-SeMo ratio ≥1.038 in men than in delta-SeMo ratio <1.038. There were significantly lower GCS scores in patients with a delta-SeMo ratio ≥1.038 than in those with a delta-SeMo ratio <1.038. Nonetheless, there was no difference in the ISS between the two groups of patients. Patients with a delta-SeMo ratio ≥1.038 sustained a higher mortality than those with a delta-SeMo ratio <1.038 (OR: 2.03, 95% CI: 1.42–2.91, P < 0.001). When controlled for sex, age, GSC, and ISS, patients with a delta-SeMo ratio ≥1.038 sustained a higher adjusted mortality rate than those with a delta-SeMo ratio <1.038 (AOR: 1.84, 95% CI: 1.27–2.66, P = 0.001). The patients with delta-SeMo ratio ≥1.038 stayed longer in the ICU (12.7 days vs. 10.2 days, respectively; P < 0.001) and in the hospital (24.3 days vs. 21.2 days, respectively; P = 0.001) than those patients with delta-SeMo ratio <1.038.

Table 2: Characteristics and outcomes of adult patients with trauma and delta-neutrophil-to-monocyte ratio ≥1.038 and <1.038 in the intensive care unit

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Characteristics and outcomes of patients divided by delta-segmented neutrophil-to-monocyte ratio of 0

For these patients, the SeMo ratio at admission between patients who died and those who survived was rather similar [SeMo ratio at admission, 18.7 ± 11.0 vs. 18.7 ± 18.4, as shown in [Table 1]]. However, the SeMo ratio at day 3 tended to be elevated for those who died (SeMo ratio at day 3: 20.3 ± 15.5), but decreased for those who survived (SeMo ratio at day 3: 15.7 ± 16.0), leading to a higher SeMo ratio and delta-SeMo ratio of patients who died and those who survived. Therefore, we were interested in determining the mortality outcome of patients divided by a delta-SeMo ratio of 0, indicating a different status with increasing or decreasing values. The study patient population was divided into two groups (delta-SeMo ratio ≥0, n = 546 and delta-SeMo ratio <0, n = 930), and the results were similar to those divided by the delta-SeMo ratio of 1.038 [Table 3]. Patients with delta-SeMo ratio ≥0 were less likely to be male, had lower GCS scores, and had no significant difference in ISS than those with delta-SeMo ratio <0. Patients with a delta-SeMo ratio ≥0 sustained a higher mortality rate than those with a delta-SeMo ratio <0 (OR: 1.83, 95% CI: 1.28–2.61, P = 0.001). When controlled for sex, age, GSC, and ISS, patients with delta-SeMo ratio ≥0 sustained a higher adjusted mortality rate than those with delta-SeMo ratio <0 (AOR: 1.70, 95% CI: 1.18–2.46, P = 0.004). Patients with delta-SeMo ratio ≥0 stayed longer in the ICU (12.3 days vs. 10.3 days, respectively; P = 0.003) and in the hospital (24.0 days vs. 21.1 days, respectively; P = 0.002) than those patients with delta-SeMo ratio <0.

Table 3: Characteristics and outcomes of adult patients with trauma and delta-neutrophil-to-monocyte ratio ≥0 and <0 in the intensive care unit

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  Discussion 

Our study results revealed that patients with a delta-SeMo ratio ≥1.038 sustained approximately 2-fold higher mortality rate and adjusted mortality rate than those with a delta-SeMo ratio <1.038. In addition, when the cutoff value of the delta-SeMo ratio was set to 0, a threshold value indicating an increase or decrease in the SeMo ratio at day 3 in comparison with the SeMo ratio at admission, there was also a similar a 2-fold higher mortality rate and adjusted mortality rate. In addition, patients with a delta-SeMo ratio ≥0 stayed longer in the ICU and hospital than those with delta-SeMo ratios <0. However, using solely the delta-SeMo ratio as a discriminator for determining mortality presented low accuracy.

Previous studies have revealed that the dynamic change in SeMo is associated with immune status and cytokine expression in septic patients in the ICU.[22] A key feature of the anti-inflammatory state in patients is a change in the responsiveness of monocytes that has been termed “deactivation of monocyte.”[24] Immunodeficiency with a dysregulated host response in patients with sepsis can potentially affect every organ system and serve as a prognostic factor. Patients dying of sepsis may have marked immunosuppression associated with sepsis-induced monocyte deactivation. In contrast, recovery of subjects is characterized by the resolution of inflammation and recovery of paresis of the immune cells.[25]

As a pathogenic organism, traumatic injury may also affect immune defense mechanisms. Severe trauma may lead to systemic release of proinflammatory cytokines and inflammatory mediators into circulation, with profound acute-phase responses.[26],[27] These hyperinflammatory responses include the release of TNF-α, IL-1, and IL-6 cytokines, as well as activation of neutrophils with microvascular adherence and uncontrolled burst of polymorphonuclear cells and macrophages.[12] In patients with trauma, monocyte deactivation correlates with injury severity[24] and those patients who survive the initial trauma and posttraumatic resuscitation are at risk for immune dysregulation, accounting for approximately 20% of mortality following traumatic injury. This posttraumatic immunosuppressed state has been attributed to the overexpression of anti-inflammatory mediators to restore host homeostasis.[26] The excessive release of these mediators may also play an important role in the pathogenesis of shock.[28] It is not surprising that circulating neutrophils and monocytes, as an immune defense mechanism, may respond not only to pathogenic organisms in patients with sepsis but also to the stress associated with trauma injury. However, this study cannot account for the mechanism of changes in the delta-SeMo ratio in patients with trauma and critical illness, and additional studies are required to determine the functional role of these neutrophils and monocytes in the regulation of immune system following trauma.

This study has some limitations. First, selection bias may exist in the retrospective design of the study and after excluding incomplete data. Second, the trauma database did not record patients who were declared dead upon arrival at the emergency room. Therefore, only inhospital mortality was considered in this study. This might have led to a selection bias during data analysis. Third, the platelets and WBC subtypes might fluctuate dynamically during the treatment course and interfere with the resuscitation process. Blood was drawn upon patient arrival at the emergency room in this study; thus, blood transfusion was less likely to occur at that time. However, fluid challenge did not adhere to specific protocol and the amount of infused fluid was unknown; these might lead to bias in outcome measurement. Similarly, interventions, such as resuscitation and surgery, could lead to different outcomes. We could only assume that the outcome of management was uniform across the studied patients. Finally, the population in this study was limited to a single urban trauma center, and the results might not be generalizable to other regions.

  Conclusions 

Following traumatic injury, critically ill patients with an increased SeMo ratio present with a higher rate of mortality and longer stay in the hospital and ICU than those with a decreased SeMo ratio. The use of the delta-SeMo ratio may help physicians quickly identify patients at a higher risk of inhospital mortality.

Acknowledgment

We appreciate the statistical analyses assisted by the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital.

Financial support and sponsorship

This research was supported by grants from CMRPG8K1041 CMRPG8L1321 to Ching-Hua Tsai.

Conflicts of interest

There are no conflicts of interest.

 

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  [Figure 1], [Figure 2]
 
 
  [Table 1], [Table 2], [Table 3]