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Predictive value of the neutrophil-to-lymphocyte ratio for epidural labor analgesia-associated intrapartum fever: a retrospective single-center study

BMC Anesthesiology volume 25, Article number: 96 (2025) Cite this article

Abstract

Background

Studies have indicated that epidural analgesia increases the risk of maternal fever during labor, possibly due to non-infectious inflammation. The neutrophil-to-lymphocyte ratio (NLR) is a crucial indicator of inflammation, with a higher NLR potentially signaling worse patient adverse outcomes. The present study explores whether NLR has clinical predictive value for epidural analgesia-related maternal fever (ERMF).

Methods

A retrospective analysis was performed for 1602 women who voluntarily requested analgesia for epidural labor from January 2023 to June 2024. Univariate and multivariate logistic regression analyses were applied to identify the factors influencing intrapartum fever, and the association between NLR and ERMF was explored. The receiver operating characteristic (ROC) curve was used to assess the area under the curve (AUC) of NLR for intrapartum fever, and the nearest ascending index was utilized to determine the cut-off value.

Results

A total of 1602 parturients were included, of which 160 (10%) had intrapartum fever. Body mass index (BMI) (OR = 1.132, 95% CI: 1.027–1.246, P = 0.012), the duration of the first stage of labor (OR = 1.002, 95% CI: 1.001–1.003, P < 0.001), percentage of lymphocytes (OR = 1.205, 95%CI: 1.073–1.354, P = 0.012) and NLR (OR = 1.964, 95% CI: 1.462–2.639, P < 0.001) were independent risk factors for intrapartum fever. High NLR levels were associated with a higher incidence of ERMF at subgroups of ages < 35 years (OR = 1.343, 95%CI: 1.215–1.486, P < 0.001), ages ≥ 35 years (OR = 1.274, 95%CI: 1.105–1.468, P = 0.01), BMI < 24 kg/m2 (OR = 1.326, 95% CI: 1.176–1.495, P < 0.001), BMI ≥ 24 kg/m2 (OR = 1.515, 95%CI: 1.147-2.000, P = 0.003), first stage of labor < 600 min (OR = 1.466, 95%CI: 1.241–1.733, P < 0.001), and first stage of labor ≥ 600 min (OR = 1.257, 95%CI: 1.109–1.424, P < 0.001). Maternal NLR levels greater than 6.305 (AUC = 0.702, 95%CI: 0.634–0.768, P < 0.001) were good predicators of intrapartum fever.

Conclusions

High NLR is associated with EMRF, and NLR is a viable predictor of early identification of the occurrence of EMRF, which may be beneficial for pregnancy outcomes.

Peer Review reports

Introduction

Epidural analgesia is a widely commonly utilized analgesic technique during labor, which can safely and effectively alleviate uterine contraction pain, decrease the incidence of cesarean deliveries, and enhance neonatal outcomes [1]. However, the incidence of epidural-related maternal fever (ERMF) has risen to 15–25% with the increased utilization of labor analgesia [2]. ERMF is a common complication after labor analgesia and is associated with adverse maternal and neonatal outcomes. This complication results in higher maternal antibiotic usage, elevated cesarean section rates, and increased risk of fetal distress, intrauterine fetal infection, and neonatal intensive care [3, 4]. Identifying reliable predictors and recognizing parturients at heightened risk of ERMF, coupled with suitable interventions to lessen its occurrence, is crucial for enhancing maternal and fetal outcomes.

The exact mechanism of ERMF remains unclear. Current evidence indicates that ERMF is associated with a non-infectious etiology, with the pathological process characterized by inflammatory responses and immune regulation [2, 5, 6]. Furthermore, researches have demonstrated that parturients exhibiting elevated levels of interleukin (IL-6) before the administration of epidural labor analgesia are at a heightened risk of developing ERMF [7, 8]. Glucocorticoids reduced IL-6 and ERMF, but prophylactic antibiotics or acetaminophen did not [9,10,11]. Therefore, a non-infectious inflammatory state may be a potential cause of ERMF. White blood cells play a vital role in the immune system, contributing to the inflammatory response and immune regulation. Low lymphocyte (LYM) and high neutrophil (NEU) counts predict poor outcomes in patients with pneumonia, tuberculosis, and cancer [12]. In addition, lymphocytopenia predicts adverse outcomes in healthy individuals and hospitalized patients [12,13,14,15]. As a highly sensitive inflammatory marker, NLR is of great value in the diagnosis and prognosis of various diseases [16, 17]. Relevant studies have confirmed the predictive value of NLR in obstetric diseases, which can effectively predict gestational diabetes mellitus, postpartum depression, preeclampsia and histological chorioamniotitis [12, 18,19,20,21]. However, the association between NLR in maternal blood and ERMF has been poorly studied and has not been fully validated. We hypothesized that elevated levels of NLR in maternal blood prior to epidural labor analgesia were associated with a higher risk of ERMF. The current study explored the association between inflammatory biomarkers and intrapartum fever, aiming to offer obstetricians and anesthesiologists more clinical evidence for predicting intrapartum fever.

Methods

General information

The study was approved by the Ethics Committee of Sichuan Women and Children’s Hospital (20240723-320). Given the retrospective nature of this study, maternal informed consent was waived. The study was conducted according to the Declaration of Helsinki, as revised in 2013. All data were anonymized to ensure patient privacy was protected. Consent was obtained from patients by telephone and they were clearly informed of their right to opt out of the study at any time. If a patient expresses disapproval of the continued use of their data during the conduct of the study, we will immediately discontinue the use of that data and remove it from the study. The entire study process will be supervised and reviewed by the Ethics Review Committee of Sichuan Women and Children’s Hospital, and the ethics review committee will have the authority to terminate the study immediately if any violation of ethical guidelines is found. Inclusion criteria: Full-term (gestational age > 37 weeks) vaginal delivery, head presentation, and singleton live pregnancy; voluntary epidural labor analgesia; American Society of Anesthesiologists (ASA) physical status classification I-II; and complete the clinical data. Exclusion criteria: Parturients with labor analgesia to cesarean section, multiparity, or induced labor (Induced labor refers to initiating the labor process through physical or pharmacological stimulation before the onset of natural childbirth. It can cause an inflammatory response within the body, resulting in an increase in inflammatory markers [22, 23]. This study focuses on the relationship between NLR and intrapartum fever during natural labor; therefore, parturients who have undergone induction of labor are excluded); prenatal fever (Definition of prenatal fever: Axillary temperature was measured every 2 h from the time the women arrived in the labor room until epidural labor analgesia was administered. If the axillary temperature reaches 37.5 °C or higher, the temperature should be remeasured after 10 min. If the axillary temperature was still high, prenatal fever was determined); fetal malformations or congenital defects; maternal severe familial disease or immune disease; use of glucocorticoids, antibiotics, and other medications that affect the white blood cell (WBC) count in the week before delivery; and no WBCs were recorded within 24 h.

Epidural labor analgesia procedure

All patients who requested epidural labor analgesia were evaluated by an obstetrician and an anesthesiologist and signed an informed consent for anesthesia. The baseline temperature was recorded after the mother was admitted to the labor room. Patients received 500 ml of intravenous Ringer’s lactate, and maternal/fetal monitoring (electrocardiogram, noninvasive blood pressure measurement, pulse oximetry, or fetal heart monitoring) was initiated. Labor analgesia was performed in the left lateral decubitus position in the L3-L4 or L2-L3 interspace. The epidural space was accessed by puncture with a 16-gauge Tuohy needle. An epidural catheter was inserted 4 cm into the epidural space. After withdrawing the bloodless, cerebrospinal fluid, 3 ml of 1.5% lidocaine was injected as the test dose. Labor analgesia was initiated with a 10 mL infusion of 0.1% ropivacaine containing 0.3 µg/mL sufentanil over 2 min. The pump delivered 8 ml per hour intermittently after the first hour, and analgesia was maintained using 5 ml patient-controlled epidural analgesia (PCEA) with a 20-minute lockout interval. The midwife measured the axillary temperature every 2 h after the mother entered the labor room; if the axillary temperature was ≥ 38 °C, the obstetrician diagnosed accordingly. After the diagnosis of maternal fever, the mother’s temperature was checked every hour, with the obstetrician implementing appropriate treatment based on the mother’s clinical symptoms.

Data acquisition

All data were collected by researchers involved in the study, and all members underwent rigorous training to ensure the quality of the collected data. Researchers extracted electronic medical record data from women who voluntarily requested epidural labor analgesia from January 2023 to June 2024. Clinical data were collected, including age, body mass index (BMI), cervical orifice size at the start of labor analgesia, neonatal birth weight, premature membrane rupture, amniotic fluid contamination, number of vaginal examinations, duration of the first stage of labor, and total duration of labor. Routine blood test results included WBC count, NEU count, LYM count, and lymphocyte percentage (LYM%). The duration of the first stage of labor was defined as the time from the start of labor analgesia to cervical dilation of 10 cm. The total duration of labor was defined as the time from the start of labor analgesia to the delivery of the placenta. The results of the most recent blood routine within 24 h before the start of epidural labor analgesia were used for analysis. Raw data were blindly collected to ensure study objectivity.

Statistical analysis

Data analysis was performed using SPSS version 27.0 (IBM, Armonk, NY, USA). Receiver operating characteristics (ROC) curves were generated using GraphPad Prism 9.4.1 (GraphPad, San Diego, CA, USA). The Shapiro-Wilk test was used to determine the normal distribution of continuous variables. Normally distributed continuous variables were expressed as mean ± standard deviation (SD) or the median and interquartile ranger (IQR). Normally distributed data were compared using an independent t-test, and the Mann-Whitney test was used to compare non-normally distributed data. Count variables were presented as percentages (%) and compared using the χ2 test. Univariate and multivariate logistic regression analyses were utilized to identify the factors influencing epidural labor analgesia-related intrapartum fever. Subsequently, three regression models were constructed based on the results of univariate and multivariate logistic regression to evaluate the association between NLR and intrapartum fever. This association was further investigated in subgroups of age, BMI, and duration of the first stage of labor. ROC curve analysis was performed, and the maximum Youden index in the ROC was used to identify the cut-off value. The significance threshold, sensitivity, specificity, and odds ratio (OR) and its associated 95% confidence interval (CI) were calculated to explore the predictive value of NLR cut-off value for ERMF. P < 0.05 was considered statistically significant.

Results

Patient screening for epidural labor analgesia

A total of 2041 parturients with labor analgesia were initially recruited. Figure 1 shows a flow chart of the screening process. After inclusion and exclusion criteria, 1602 women who received epidural labor analgesia were finally included in the analysis, of whom 160 (10%) had fever during labor.

Fig. 1
figure 1

Participant flow chart

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Characteristics of patients who received labor epidural analgesia

The parturients were divided into two groups based on the presence or absence of fever during epidural labor analgesia. The baseline WBC counts and other characteristics of parturients with or without intrapartum fever are shown in Table 1. The maternal WBC count (fever group: 10.05 × 109/L vs. non-fever group: 8.76 × 109/L; P < 0.001), WBC count > 9.5 × 109/L (58.1% vs. 35.9%; P < 0.001), NEU count (7.9 × 109/L vs. 6.58 × 109/L; P < 0.001), NEU count > 6.3 × 109/L (73.1% vs. 54.4%; P < 0.001) were significantly higher in the fever than in the non-fever group. LYM count (1.32 × 109/L vs. 1.47 × 109/L; P < 0.001) and LYM% (12.5 vs. 16.95; P < 0.001) were significantly lower in the fever than in the non-fever group, whereas LYM count < 1.1 × 109/L was markedly higher in the fever than in the non-fever group (35.6% vs. 13.5%; P < 0.001). BMI was significantly higher in the fever than in the non-fever group (27 ± 3.02 kg/m2 vs. 26.17 ± 2.789 kg/m2; P = 0.018). The duration of the first stage of labor ( (696.6 ± 196.8 min vs. 591.3 ± 239.7 min; P <0.001) and total delivery time (770.4 ± 203.6 min vs. 688.4 ± 338.3; P <0.001 ) were significantly longer in fever than in the non-fever group. The cervical orifice ≤ 2 cm at the beginning of epidural labor analgesia was significantly higher in the fever than in the non-fever group (86.9% vs. 66.8%; P < 0.001). No significant difference was found between the two groups in maternal age, premature rupture of membranes (PROM) and neonatal birth weight.

Table 1 Baseline demographic and clinical characteristics of participants, as stratified by the presence or absence of fever
Full size table

Association between NLR levels and ERMF

Variables with P < 0.1 in univariate analysis were used as independent variables, and the occurrence of ERMF served as a dependent variable. By multicollinearity analysis, we found that the variance expansion factor (VIF) of white blood cell count, neutrophil count, lymphocyte count, lymphocyte percentage, and NLR were > 5, and there was multicollinearity between the independent variables. A multivariate logistic regression model was constructed by stepwise forward method to assess risk factors of fever during epidural labor analgesia. The results showed that BMI (OR = 1.132, 95% CI: 1.027–1.246, P = 0.012), the duration of the first stage of labor (OR = 1.002, 95% CI: 1.001–1.003, P<0.001), LYM% (OR = 1.205, 95% CI: 1.073–1.354, P = 0.012), and NLR (OR = 1.964, 95% CI: 1.462–2.639, P<0.001) were independent risk factors for ERMF (Table 2).

Table 2 Multivariate logistic regression analysis of factors associated with intrapartum fever during epidural labor analgesia
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Association between NLR and intrapartum fever

Three models were developed to determine the correlation between NLR and thermogenesis. Model 1 was an unadjusted univariate regression model. Model 2 was developed after adjusting for WBC count, NUE count, LYM count, LYM%, and their outcome stratification. Model 3 was established based on model 2 after adjusting the duration of the first stage of labor, cervical orifice size, amniotic fluid contamination, number of cervical examinations, and total duration of labor. Results showed that NLR (OR = 1.334, 95%CI: 1.209–1.471, P<0.001; OR = 1.684, 95%CI: 1.087–2.608, P = 0.02; OR = 1.724, 95%CI: 1.099–2.705, P = 0.018) was independently associated with intrapartum fever in the three multivariate regression models (Table 3).

Table 3 Association between the neutrophil-to-lymphocyte ratio and thermogenesis based on three logistic regression models
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ROC curve analysis of maternal NLR for predicting ERMF before epidural analgesia

ROC curve analysis was performed to explore the NLR cut-off value before epidural analgesia in predicting ERMF. Figure 2 shows the ROC curve of maternal NLR for predicting ERMF before epidural analgesia. ROC analysis showed that NLR had an area under the curve (AUC) of 0.702 (95% CI: 0.634–0.768, P < 0.001) and a cut-off value of 6.305, which could identify high-risk parturients with maternal fever. We determined a cut-off value of 6.305 for NLR with a sensitivity of 61.43% (95%CI: 58.22-64.63%) and specificity of 58.75% (95%CI: 54.78-62.73%). In addition, NLR has a positive likelihood ratio (LR+) of 3.00 and a negative likelihood ratio (LR-) of 0.58. Maternal NLR > 6.305 (AUC = 0.702, positive predictive value = 0.515, negative predictive value = 0.827) was a predictor of ERMF.

Fig. 2
figure 2

ROC curve analysis for maternal NLR for predicting ERMF before epidural analgesia

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Correlation between NLR and ERMF in subgroups of age, BMI, and duration of the first stage of labor

The correlation between NLR and ERMF was further analyzed. Subgroup heterogeneity was investigated according to age, BMI and time of the first stage of labor. Forest plots show the results of NLR versus ERMF in relation to age, BMI, and time to first stage of labor (Fig. 3). High NLR level was related to higher odds of ERMF in subgroups of ages < 35 years (OR = 1.343, 95%CI: 1.215–1.486, P < 0.001), ages ≥ 35 years (OR = 1.274, 95%CI: 1.105–1.468, P = 0.01), BMI < 24 kg/m2 (OR = 1.326, 95% CI: 1.176–1.495, P < 0.001), BMI ≥ 24 kg/m2 (OR = 1.515, 95%CI: 1.147-2.000, P = 0.003), first stage of labor < 600 min (OR = 1.466, 95%CI: 1.241–1.733, P < 0.001), and first stage of labor ≥ 600 min (OR = 1.257, 95%CI: 1.109–1.424, P < 0.001). That is, the effect of NLR on intrapartum fever was consistent across the three subgroups.

Fig. 3
figure 3

Association between NLR levels and the incidence of ERMF in subgroups of age, BMI, and duration of the first stage of labor

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Discussion

The present retrospective study investigated the association between NLR levels and ERMF in parturients undergoing epidural analgesia. It was found that elevated NLR 24 h before labor analgesia was associated with an increased incidence of ERMF and was an independent risk factor for intraparty fever. More importantly, NLR exhibited a good predictive ability for maternal fever during labor.

Typically, NLR is a readily available biomarker for assessing the overall condition of inflammation. Our findings showed that NLR changes before intrapartum fever develops. NLR showed good predictive power for intrapartum fever, suggesting that parturients with a high inflammatory state before painless labor are prone to intrapartum fever. The levels of WBCs, NEUs, and NLR before delivery were higher in the fever than in the non-fever group. However, the LYM count and LYM% were lower in the fever than in the non-fever group. Chai et al. [24] observed that LYM counts were reduced in parturients experiencing intrapartum fever compared with those without fever, which aligns with our results. Additionally, other studies have demonstrated that maternal WBC levels increase during fever episodes [25], consistent with our findings. However, further analysis revealed that WBC, NEU, and LYM were not independent risk factors for intrapartum fever. This may be because there is a multiple linear relationship between them and there is mutual influence between independent variables, which is less stable than ratio parameters, making them unreliable in the thermogenic inflammatory state.

Epidural labor analgesia is the most common and safest technique worldwide. However, this technique has been associated with an increased risk of maternal fever [26]. Clinical studies have shown that the incidence of ERMF is about 20% [2, 27, 28], which is higher than the 10% fever rate observed in the current study. This discrepancy may be because only patients with body temperatures ≥ 38 °C were selected in the present study, excluding fever patients with body temperatures < 38 °C. Our study also exclusively included patients who underwent vaginal deliveries, excluding individuals with fever who were deemed unsuitable for a trial of labor due to fetal distress or maternal considerations and subsequently underwent cesarean sections. The primary reason was that delivery timing for cesarean affected key labor covariates and duration. Another reason is the timing of the start of epidural labor analgesia. In our study, epidural analgesia was performed in most parturients when cervical dilatation exceeded 3.0 cm. Studies have shown that shortening epidural analgesia duration reduces intrapartum fever rates compared with early epidural labor analgesia [29].

The mechanism of action of epidural analgesia in maternal fever remains unknown [30, 31]. Studies have demonstrated that maternal weight gain can influence the loss of body temperature in mothers. Additionally, higher BMI leads to thicker subcutaneous fat, which hinders heat dissipation and promotes a faster metabolism and increased heat production, consequently raising maternal body temperature [32]. The current study found that the BMI of parturients was significantly higher in the fever group than in the non-fever group, which was an independent risk factor for EMRF. Research indicates that the size of the maternal cervical opening influences the duration of labor analgesia. A cervical orifice < 3.0 cm increases maternal fever and cesarean rates [31]. The extension of labor duration results in a corresponding increase in maternal body temperature. ERMF risk is higher in patients with > 6 h of epidural labor analgesia compared to those with < 6 h [32], consistent with our findings that a longer first stage of labor increases ERMF risk in women. The failure of prophylactic antibiotic therapy and the effectiveness of glucocorticoids suggest a non-infectious cause [33,34,35]. Most patients experiencing intrapartum fever do not exhibit placental infection; thus, infection cannot be considered a causative factor for ERMF [4, 36]. Previous studies found that parturients with higher IL-6 and IL-8 on admission had a higher incidence of ERMF [2]. Research has also indicated that levels of IL-6 and TNF-α in maternal blood are elevated in women with ERMF [37]. These pieces of evidence suggest that a systemic inflammatory state underlies ERMF.

NLR is a highly sensitive indicator of inflammation [10, 11]. The application of epidural labor analgesia during labor may induce an inflammatory response [38]. Elevated NLR may predispose parturients to fever, potentially explaining the higher incidence of elevated NLR and ERMF. We established three models and subgroups to analyze the correlation between NLR and thermogenesis, revealing a stable relationship.

The NLR is an inflammatory index that can be readily measured in a clinical setting. When a pregnant woman chooses epidural analgesia with an NLR of exceeding 6.305, the anesthesiologist should inform her of the higher risk of developing fever, and obstetricians and nurses should closely monitor and implement individualized interventions. We suggest that the level of NLR should be evaluated before the start of labor analgesia. The anesthesiologist may wait until the cervical orifice is ≥ 3 cm to administer epidural analgesia if the NLR is significantly elevated. Simultaneously, midwives may assist in expediting the labor process and mitigating the likelihood of fever occurrence.

Nonetheless, this study has some limitations. First, given that this is a single-center regression study, with limited enrollment. Some patients who converted to cesarean due to intrapartum fever were excluded, possibly leading to missing data and selection bias. In addition, our study excluded multipara, whose labor course was shorter than that of primipara, and the incidence of intrapartum fever in multipara was significantly lower than that of nonparturients [36], so the results could not be extended to multipara. These may affect the comprehensive interpretation of ERMF. Larger multicenter studies are needed to validate our findings.

Conclusion

In summary, NLR is an independent risk factor for ERMF, with a good predictive power for intrapartum fever. NLR may serve as a simple and feasible index for identifying patients with a higher risk of ERMF, thereby guiding clinical decision-making and improving pregnancy outcomes.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

NLR:

Neutrophil-to-lymphocyte ratio

ERMF:

Epidural analgesia-related intrapartum fever

BMI:

Body mass index

OR:

Odds ratio

CI:

Confidence interval

AUC:

Area under the curve

ROC:

Receiver operating characteristic

AUC:

Area under the curve

PROM:

Premature rupture of membranes

MSF:

Meconium Stained Fluid

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Acknowledgements

The authors would like to thank all the reviewers who participated in the review.

Funding

The study was supported by the “Innovation Team Scientific Research Projects of Health Commission of Sichuan Province, China(Grant Number: 24CXTD18)”.

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Authors and Affiliations

  1. Department of Anesthesiology, Sichuan Provincial Women’s and Children’s Hospital, the Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, Sichuan, China

    Lei Li, Xiao-tong Yang, Jiang Zou, Jian Zhang, Xiao-hai Xie, Jing-hui Liu & Ben-zhen Chen

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  1. Lei Li
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  2. Xiao-tong Yang
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  7. Ben-zhen Chen
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Contributions

LL and BZC conceptualized and designed the study. XTY, JZ, XHX, and JHL collected and organized the data, performed the initial analysis. LL drafted the manuscript. BZC and JZ reviewed and revised the manuscript for important intellectual content and reviewed the initial analyses. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Ben-zhen Chen.

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Ethics approval and consent to participate

The study was approved by the Ethics Committee of Sichuan Women and Children’s Hospital (20240723-320). The need for informed consent was waived by the Sichuan Provincial Women and Children’s Hospital Review Board because no protected health information was used in this retrospective study.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Li, L., Yang, Xt., Zou, J. et al. Predictive value of the neutrophil-to-lymphocyte ratio for epidural labor analgesia-associated intrapartum fever: a retrospective single-center study. BMC Anesthesiol 25, 96 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12871-025-02972-9

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12871-025-02972-9

Keywords

BMC Anesthesiology

ISSN: 1471-2253

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