Prognostic Accuracy of Blood Cell Count Ratios in Predicting Adverse Outcomes in Crush Syndrome Patients

doi:10.21203/rs.3.rs-4686608/v1

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Prognostic Accuracy of Blood Cell Count Ratios in Predicting Adverse Outcomes in Crush Syndrome Patients

https://doi.org/10.21203/rs.3.rs-4686608/v1

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Purpose

The rationale behind this study was the lack of an accurate predictor to facilitate treatment management and anticipate prognosis in crush syndrome. Our research aimed to investigate the following: 1) Is there a correlation between the ratios of blood cell counts upon admission and the adverse outcomes of crush syndrome? and 2) if such a correlation exists, what are the precise thresholds of blood cell count ratios for predicting these adverse outcomes?

Methods

In this single-centered and retrospective design study, we analyzed all patients admitted to our hospital after Kahramanmaras Earthquake.The data on length of stay in the ICU and mortality status were obtained using our hospital system. Ratios of blood cell count were calculated and recorded at the time of admission.

Results

The NLR values in admission were significantly higher in patients with amputation, patients who received intensive care unit (ICU) and patients who died. (p < 0.001, p < 0.001 and p = 0.001, respectively). The MLR values were found to be significantly increased in patients who underwent amputation and patients who received ICU (p < 0.001 and p = 0.003, respectively). NAR values in admission were significantly higher in patients with amputation, patients who received intensive care unit (ICU) and patients who died (p < 0.001, p < 0.001 and p = 0.002,respectively). In addition, according to binary logistic regression analysis, with a CLR value of > 109.844, the risk of amputation increases 8.188 fold; with a CLR value of > 64.518, the possibility of ICU admission requirement increases 10.117 fold, and with a CLR value of > 116.00, the risk of death increases 5.519 fold.

Conclusion

Ratios of blood cell count such as NLR, MLR, NAR, and CLR offer a reasonable prognostic accuracy in predicting adverse outcomes and mortality in patients with crush syndrome. Therefore, for better disaster management in the future, the determination of these values at admission should be used as an adjunct tool for predicting prognosis in patients with crush syndrome.

Earthquake

Crush Syndrome

Mortality

Prognosis

Blood Cell Count Ratios

Predictor

Earthquakes are catastrophic natural disasters that have a global impact, causing numerous fatalities and injuries each year within a short period[1, 2]. In contrast to other types of catastrophic events, an earthquake is characterized by the significant dissipation of energy it involves [3]. It is primarily mechanical energy; therefore, most victims suffer crush injuries [4]. Furthermore, collapsed buildings prolong extrication time and increase the severity of crush injuries.

‘Crush injury’ is characterized by traumatic rhabdomyolysis, which occurs when a muscle group subjected to continuous pressure for an extended period, resulting in extensive tissue damage [5]. Additionally, ‘crush syndrome’ defined as a crush injury with systemic complications such as hypovolemic shock, metabolic acidosis, and an increased risk of acute renal failure (ARF) [6]. Studies indicate that crush injury occurs in 2–15% of cases after major earthquakes [7]. Furthermore, the high-energy impact leads to increased pressure within the muscle compartments, restricting blood flow and causing a condition known as acute compartment syndrome (ACS) [8]. Crush syndrome is one of the most frequent causes of death after earthquakes [6]. The mortality rate for crush syndrome patients requiring dialysis treatment has been documented to exceed 40% [9]. Due to the presence of chaotic disaster conditions and inadequate information, healthcare professionals may not consistently identify crush syndrome [2].

Several blood cell count ratios have generated significant attention over the previous decade. For instance, a recent study identified Monocyte to lymphocyte ratio (MLR) could serve as a predictor of survival in patients with different types of malignant diseases[10]. Similarly, Neutrophile to Lymphocyte ratio (NLR) has been linked to adverse outcomes like amputation and early mortality in patients requiring urgent revascularization due to acute limb ischemia [11]. The rationale behind this study was the lack of an accurate predictor to facilitate treatment management and anticipate prognosis in crush syndrome which presents a wide-ranging prognostic spectrum.

Our research aimed to investigate the following: 1) Is there a correlation between the ratios of blood cell counts upon admission and the adverse outcomes of crush syndrome? and 2) if such a correlation exists, what are the precise thresholds of blood cell count ratios for predicting these adverse outcomes?

Study Design

In this single-centerred and retrospective design study, we analyzed all patients admitted to our hospital after Kahramanmaras Earthquake between February 6, 2023, and April 5, 2023. The design and protocol of the current study (E1-23-3402) have been approved by our institutional review board. All researchers have signed the latest version of the Helsinki Declaration. Consent forms obtained from all the patients assigned in the study. This study is reported based on The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [12].

Inclusion and Exclusion Criteria

The study included all earthquake victims who initially sought medical intervention at our hospital and diagnosed with crush syndrome. The exclusion criteria applied; 1) patients who did not diagnosed with crush syndrome, 2) initially admitted another institution, 3) patients with vascular injury requiring surgical intervention, and 4) patients with active infection (Fig. 1).

Patient Care and Surgical Interventions

Following the devastating event, a considerable number of patients from the earthquake region were admitted to our facility, which serves as a tertiary referral center. The majority of the admitted individuals presented with compromised general healthand compartment syndrome caused by advanced crush syndrome. Crush syndrome, characterized by a combination of crush injury and systemic symptoms such as shock, acidosis and ARF [13], was diagnosed by internal medicine specialists. Our internal medicine department implemented preventive measures, particularly focusing on addressing traumatic rhabdomyolysis and ARF, during regular patient visits. Patients who developed ARF were evaluated for the need for hemodialysis treatment.

Urgent fasciotomy has become the standard procedure for managing ACS. However, in cases where fasciotomy is contraindicated, such as when extrication time is prolonged, limb sensation is lost, and there is no active movement [14], primary amputations were also performed, taking into account the risk of rhabdomyolysis and infections, mainly due to delayed fasciotomy interventions [5, 6, 14]. The decision to proceed with primary amputation was made based on surgeon's experience and consultation with cardiovascular surgery, especially in life-threatening sepsis cases where limb salvage was not feasible [6]. Infectious disease specialists were consulted, and appropriate antibiotic therapies were administered to patients. The open wounds of the patients were treated with the cooperation of the Plastic and Reconstructive Surgery Department. In cases where infection could not be adequately controlled despite multiple debridements and antibiotic therapy, or when achieving sufficient blood circulation was not possible, amputations were carried out at the proper level in collaboration with divisions of infectious disease and cardiovascular sugery. Patients with worsening general health were closely monitored and treated in the intensive care unit (ICU).

Data collection

Demographic data of the patients, such as age, sex, and comorbidities, were recorded. The data on length of stay in the ICU and mortality status were obtained using our hospital system. All blood results, including inflammatory mediators, were collected at the time of admission. Ratios of blood cell count such as NLR, MLR, C-reactive protein (CRP) to Lymphocyte ratio (CLR), and Neutrophile to Albumin ratio (NAR) were calculated and recorded. In order to ensure impartiality, an autonomous research aide meticulously documented all data pertaining to the ongoing study.

Outcome of Interest

The primary outcome of this study is to reveal the influence of blood parameters at the time of admission on the adverse outcomes of crush syndrome. For this purpose, patients were examined in three main headings according to their prognosis; 1) mortality, 2) extremity amputation 3) ICU admission requirement. To give a cut-off value in blood parameters that affect these three consequences using ROC (Receiver Operating Characteristics) curve and binary logistic regression analysis as a secondary outcome.

Statistics

The statistical analysis was carried out using the SPSS version 22.0 software program. Categorical variables were represented by percentage and frequency values, while numerical variables were described using mean, standard deviation, median, and min-max values.

As the quantitative data did not display a normal distribution based on the Shapiro-Wilk Test, non-parametric test procedures were employed. To examine the relationships between paramters, both the Mann Whitney U Test and Spearman’s Rho Correlation Test were utilized. Fort he analysis for categorical data, the chi-square test was applied. Furthermore, Receiver Operation Characteristic (ROC) Analysis was used to identify the cut-off value, and Binary Logistic Regression Analysis was conducted for additional investigation.

The results were evaluated within the 95% confidence interval, and statistical significance was considered for p < 0.05.

After exclusion criteria applied, the remaining 94 patients ( 45 male and 49 female), mean age of 38.17 ± 15.3 years (range 18 to 85 years), were included in the study. During the follow-ups, a total of 21 patients (22.3%) underwent amputation of any extremity, 54 patients (57.4%) were received to the ICU, and 13 patients (13.8%) died (Figure 1). The number of patients who received fasciotomy due to acute compartment syndrome was fifty-seven. The patients' blood parameters were assessed categorically for three distinct prognosis groups: 1) patients with and without amputation, 2) patients who were admitted to the intensive care unit (ICU) and those who were not, and 3) patients who were deceased and those who were not.

Amputation

There was no significant difference in age and sex between the patient group with and without amputation (p=0.229 and p=0.284, respectively). The NLR, MLR, CLR, and NAR were significantly higher in patients who underwent amputation (p<0.001, p<0.001, p=0.011, and p<0.002, respectively). ROC analysis calculated the cut-off NLR value for amputation as 7.005 for this group. The area under the curve (AUC) was 0.817 with 0.857 sensitivity and 0.667 specificity (Figure 2A). The MLR cut-off value was 0.566, AUC was 0.792, and sensitivity and specificity were 0.810 and 0.700, respectively (Figure 2B). The cut-off CLR value was 109.844 for amputation. The AUC was 0.750 with 0.583 sensitivity and 0.848 specificity (Figure 2C). The NAR cut-off value was 0.453, AUC was 0.894, and sensitivity and specificity were 0.857 and 0.867, respectively (Figure 2D). Table 1 comprised further information about patients with amputation.

ICU Admission

Table 2 represents detailed information in patients with ICU admission. During the follow-up period, no significant difference was determined between the groups regarding age and gender when comparing patients who received ICU care with those who did not require ICU admission (p=0.668 and p=0.950, respectively). NLR, MLR, CLR, and NAR were statistically significantly higher in patients who received ICU (p<0.001, p=0.003, p=0.001, and p<0.001, respectively). We also compared the patients who received ICU regarding the length of stay in ICU, and NLR, MLR, and NAR were statistically significantly higher in patients with prolonged ICU stay (p=0.003, p=0.001, and p=0.032, respectively). Interestingly, total protein and albumin values were also significantly higher in patients with prolonged ICU stay (p=0.020 and p=0.006, respectively). ROC analysis calculated the cut-off NLR value for ICU admission requirement as 7.078 for this group. The AUC was 0.750 with 0.722 sensitivity and 0.750 specificity (Figure 3A). The MLR cut-off value for ICU admission requirement was 0.497, with 0.682 AUC, and sensitivity and specificity were 0.704 and 0.625, respectively (Figure 3B). The cut-off CLR value was 64.518 for amputation. The AUC was 0.766 with 0.833 sensitivity and 0.632 specificity (Figure 3C). The NAR cut-off value was 0.447, AUC was 0.769, and sensitivity and specificity were 0.574 and 0.875, respectively (Figure 3D).

Mortality

There was no difference in age and gender between deceased and control patients (p=0.218 and p=0.894, respectively). NLR, CLR, and NAR were statistically significantly higher in patients with mortality (p=0.001, p=0.021, and p=0.002, respectively) (Table 3). According to ROC analysis, the cut-off NLR value was 10.651 for the mortal group. The AUC was 0.779 with 0.769 sensitivity and 0.728 specificity (Figure 4A). The cut-off CLR value was 116.00, AUC was 0.736, and sensitivity and specificity were 0.700 and 0.778, respectively (Figure 4B). The NAR cut-off value was 0.518 for the mortal group. The AUC was 0.767 with 0.692 sensitivity and 0.790 specificity (Figure 4C). The mortality statistics are presented in Table 3.

Binary Logistic Regression Analysis

In Table 4, comprehensive data pertaining to the binary logistic regression analysis is presented. The independent variables NLR, MLR, CLR, and NAR, were associated with three prognostic categories in the logistic regression model. A stepwise approach was used to construct the model, wherein the likehood of amputation, ICU admission necessity, and death were modeled. Notably, among all variables, only CLR demonstrated a notable impact on enhancing the model’s explanatory capacity. The result of the analysis showed an odds ratio of 8.188 (95% confidence interval 1.39 to 48.17) for the association of amputation and CLR, 10.117 (95% confidence interval 1.19 to 85.93) for the relation of ICU admission requirement and CLR, and, 5.519 (95% confidence interval 1.01 to 30.13) for the association of mortality and CLR. These results showed that with a CLR value of >109.844, the risk of amputation increases 8.188 fold; with a CLR value of >64.518, the possibility of ICU admission requirement increases 10.117 fold, and with a CLR value of >116.00, the risk of death increases 5.519 fold.

The key finding of this study was that the CLR value was a highly reliable predictive indicator for amputation, ICU admission requirement, and mortality in patients with crush syndrome. In addition, NLR, MLR, and NAR values were also found to be statistically significant predictors for adverse outcomes in crush syndrome.

Neutrophils serve as the primary agents in the innate immune system [15]. Upon activation, they initiate the release of neutrophil extracellular traps (NETs), which possess potent antimicrobial and immune-modulating properties. However, excessive local concentrations of NETs can cause substantial tissue damage, resulting in subsequent organ dysfunction [16]. Lymphocytes play a crucial role in regulating an proper inflammatory response, and their decrease due to apoptosis can lead to inconvenient state of inflammation. Zahorec et al. [17] reported that the NLR value might indicate a patient's response to an inflammatory insult. When faced with stress, neutrophil levels increase in response, but when the stress becomes overwhelming, it induces apoptosis in lymphocytes [17].

A recent observational cohort study demonstrated that NLR measured upon admission to the ICU was associated with mortality in patients without sepsis [18]. Coelho et al. reported that elevated preoperative NLR was associated with early mortality and amputation in patients with acute limb ischemia [11]. Karadeniz et al. concluded that a high NLR value was a significant risk factor for one-year mortality in elderly patients operated for hip fractures [19]. Many recent studies demonstrated that NLR value emerged as an independent predictor for postoperative complications and mortality in non-orthopedic surgeries [20, 21]. The current study found that NLR value was significantly higher in patients with adverse outcomes following crush syndrome.

Monocytes play a vital role in the innate immune system and serve as a connecting link between the adaptive immune system by presenting antigens to lymphocytes [22]. The MLR has been proposed to be related with survival rate in patients with malignancy[10]. Moreover, Bingol et al. reported that admission MLR is valuable data for predicting mortality in geriatric hip fracture patients [23]. The admission MLR value was statistically correlated with adverse outcomes such as amputation, ICU admission requirement, and prolonged ICU stay in this study.

The serum albumin levels indicate both the nutritional status and organ function, wherein inflammation causes a decrease in hepatic albumin secretion and increases the generation of pro-inflammatory substances [24, 25]. The biological processes of albumin have yet to be comprehensively defined. However, its association with shorter hospital stays, decreased mortality, and complication rates for patients with acute conditions is well-established [26]. Several recent studies have proposed the use of the NAR value as a predictor of prognosis [27, 28]. For example, Hu et al. concluded that elevated neutrophil percentage to albumin ratio (NPAR) values were correlated with an increased risk of early mortality in patients with sepsis [25]. The study found that elevated NAR values were linked with adverse outcomes in patients with crush syndrome, consistent with literature.

C-reactive protein (CRP) is an acute-phase protein synthesized by the liver, and its levels increase in response to inflammation. The inverse relationship between elevated CRP levels and a decrease in lymphocyte cell count during inflammation may account fort he high diagnostic value of CLR. Recent studies on CLR have predominantly focused on its prognostic implications for various cancer and its potential role in disease progression of COVID-19[29, 30]. However, no research has yet explored the relationship between CLR and crush syndome. This study found that the elevated admission CLR value was highly correlated with amputation, ICU admission requirement, and mortality. Moreover, according to binary logistic regression analysis, with a CLR value of > 109.844, the risk of amputation increases 8.188 fold; with a CLR value of > 64.518, the possibility of ICU admission requirement increases 10.117 fold; with a CLR value of > 116.00, the risk of death rises 5.519 fold.

This study has some limitations. First, this was a retrospective design, and the results should be further verified in randomized controlled trials. In addition, this retrospective design brings with it a potential bias in patient selection by authors. Nevertheless, in an effort to reduce such bias, strict criteria for inclusion and exclusion were implemented. Second, the current study was a single-centered design and had relatively small sample size. However, in order to maintain standardization, it was necessary to exclude patients who had initially sought treatment at another healthcare institution. Third, in this study, our evaluation focused on short-term outcomes following crush syndrome. Consequently, we did not have access to data concerning patients who experienced adverse events post-discharge.

Author Contribution

Taner Karlidag- Wrote the main manuscript, editing, data collection, proofreading, conceptualizationOlgun Bingol- Editing, proofreading, conceptualizationBaran Sarikaya- Conceptualization, supervisionOmer Halit Keskin- Data collection, editing, data collectionAtahan Durgal- Data collection, editing, data collectionGuzelali Ozdemir- Conceptualization, supervision

Conflicts of Interest and Source of Funding: The authors declared no conflict of interest with respect to the authorship and/or publication of this article. The authors received no financial support for the research and/or authorship of this article.

Ethical Approval: The local ethics committee authorized the study (E1-23-3402), which was performed in accordance with the ethical standards of the Declaration of Helsinki.

Informed consent : Patients gave written informed consent prior to participation. Acknowledgments: There are no acknowledgments for this article.

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Tables 1 to 4 are available in the Supplementary Files section.

No competing interests reported.

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You are reading this latest preprint version

Prognostic Accuracy of Blood Cell Count Ratios in Predicting Adverse Outcomes in Crush Syndrome Patients

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Methods

Study Design

Inclusion and Exclusion Criteria

Patient Care and Surgical Interventions

Data collection

Outcome of Interest

Statistics

Results

Disscussion

Conclusion

Declarations

Author Contribution

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1