Relationship between neutrophil-lymphocyte ratio and postoperative pain in cesarean section patients done under subarachnoid block: A prospective observational study

Abstract

Background and Aims:

Cesarean section is one of the most commonly performed surgeries in obstetrics. Various methods have been employed to assess postoperative pain. Surgical trauma causes acute phase response with neutrophilia and relative lymphopenia. Hence neutrophil lymphocyte ratio (NLR) can be taken as an objective tool to measure acute pain. The primary objective of the study was to evaluate the relationship between postoperative NLR and pain, which was assessed using visual analogue scale (VAS).

Material and Methods:

A prospective observational study was conducted on 120 pregnant women aged between 18 to 38 years belonging to American Society of Anesthesiologists Physical Status II undergoing elective cesarean section under subarachnoid block, in a tertiary care hospital over 18 months. Postoperatively pain was assessed using VAS. Blood samples were sent and NLR was calculated preoperatively and postoperatively. Injection diclofenac and tramadol was administered for postoperative pain and total doses of respective drugs were noted. The correlation between NLR and VAS was assessed using Spearman’s rank correlation analysis.

Results:

The postoperative NLR was higher than the preoperative NLR. There was significant correlation between VAS score and NLR score at 12^th, 24^th and 48^th h [(Spearman’s rank correlation coefficient), r = 0.462, P < 0.001; r = 0.519 P < 0.001; r = 0.455 P < 0.001]. The diclofenac requirement was significantly high at 24 h among the repeat cesarean section patients (P = 0.023).

Conclusion:

The postoperative NLR correlated significantly with VAS. NLR can be used as a surrogate marker for pain assessment.

Introduction

Cesarean section is one of the most commonly performed surgeries in obstetrics. In spite of numerous measures adopted to reduce postoperative pain, the incidence of inadequate analgesia is as high as 50%.[1,2,3] Despite the current in-depth understanding of pain mechanisms, managing postoperative pain remains challenging for physicians. Adequate analgesia helps the parturient in breastfeeding, increases comfort and early ambulation, decreases pulmonary and cardiovascular complications, enables faster recovery, and poses less financial burden. Unrelieved postoperative pain increases the risk of morbidity and mortality. Inadequate pain management results in chronic pain syndromes, which may have a profound impact on the quality of life.[4]

One of the main goals of pain management is to provide adequate pain relief with the lowest possible doses of analgesia, thereby eliminating unwanted side effects of the drugs, besides early rehabilitation and improved patient compliance.

There are numerous tools for assessing pain both subjectively and objectively. Pain is commonly assessed subjectively by the visual analog scale (VAS), numerical rating scale (NRS), and verbal rating scale (VRS). Objective methods include heart rate (HR) variability assessment, cardiovascular depth of analgesia (CARDEAN) index, surgical plethysmography index, skin conductance, and pupillometry. Sophisticated techniques such as neuroimaging and biomarkers have also been used.[5,6,7]

Higher costs and other limitations of these sophisticated methods have resulted in the emergence of simple markers such as neutrophil-lymphocyte ratio (NLR). Inflammation seen with surgical trauma secondary to incision, dissection, suturing, nerve stretching, or nerve compression is the mechanism behind postoperative pain. Surgical trauma causes acute phase response with neutrophilia and relative lymphopenia; thus, NLR, which is a relatively newly recognized inflammatory marker, can be taken as an objective tool to measure acute pain.[8]

The primary objective of the study was to evaluate the relationship between postoperative NLR and pain, which was assessed using VAS. The secondary objective was to compare NLR and postoperative pain among primary and repeat cesarean section patients under spinal anesthesia (SA).

Material and Methods

After obtaining institutional ethical committee approval (reference: KIMS: ETHICS COMM 412:2020-2021 dated January 22, 2021) the study was registered in the Clinical Trials Registry of India (CTRI) [vide registration number: CTRI/2021/09/036235]. The study was conducted in a tertiary care hospital over 18 months following the ethical principles laid down for medical research by the Declaration of Helsinki, 2013. Informed written consent was obtained from all the patients. The study included 120 pregnant women aged between 18 and 38 years, belonging to the American Society of Anesthesiologists Physical Status II (ASA-PS), scheduled to undergo elective cesarean section under subarachnoid block. Patients with pregnancy-induced hypertension, abruptio placenta, multiple pregnancy, preterm pregnancy, diabetes mellitus, anemia, liver, renal, cardiovascular diseases, existing acute infection or postoperative infection, those in labor, chronic inflammatory disease or on corticosteroids, emergency cesarean section, and cesarean section under general anesthesia (GA) were excluded from the study.

All pregnant women fulfilling the inclusion criteria were evaluated a day before surgery, and details of the patients were noted. Routine investigations were obtained as per the institutional protocol. A blood sample for complete blood count was sent in the preoperative period and at the 12^th, 24^th, and 48^th hour after completion of surgery. NLR was calculated by dividing the neutrophil count by the lymphocyte count. Patients were kept nil by mouth as per standard guidelines. An intravenous (IV) access was secured using an 18-G cannula and was co-loaded with Ringer’s lactate solution. Patients were premedicated with injection ranitidine 50 mg IV and injection metoclopramide 10 mg IV. Monitoring included electrocardiography (ECG), peripheral oxygen saturation (SpO₂), and non-invasive blood pressure (NIBP). SA was administered in the left lateral position with a 25/26-G Quincke needle, under aseptic precautions using 2 mL bupivacaine heavy (0.5%) in L3–L4 or L4–L5 interspace. Immediately after SA, the patient was repositioned with maintenance of left uterine displacement. The duration of surgery was noted. Postoperatively, the VAS score was noted at the 6^th, 12^th, 24^th, and 48^th hour. Injection tramadol 1.5 mg/kg was administered as an analgesic if the VAS was more than 3. Injection diclofenac 1.5 mg/kg was administered as a rescue analgesic if the patient complained of pain despite administering tramadol. The total doses of the respective drugs were noted.

Based on the previous studies, the anticipated correlation coefficient between NLR and pain score is 0.7. To estimate the true correlation coefficient with a 95% confidence interval and a half width of 0.1, a minimum sample of 103 was required.[9,10] Considering 10% dropouts, the sample size estimated was 120. Statistical analysis was performed using SPSS for Windows version 19.0 (SPSS Inc., Chicago, IL) software. P value < 0.05 was considered statistically significant. The results of the study were expressed as mean (SD). Demographic data were analyzed using a t-test. A comparison of VAS scores and NLR scores between the two groups was done using an independent t-test and Mann-Whitney U test. The correlation between VAS scores and NLR was assessed using Spearman’s rank correlation analysis.

Results

A total of 120 parturients were recruited for the study, of which 10 patients were excluded because of intraoperative blood transfusion or postoperative infection [Figure 1]. The NLR of 110 patients at different time points is shown in Figure 2. Table 1 shows the correlation between postoperative NLR and postoperative pain as assessed by VAS.

Figure 1.

The flowchart of the study group. LSCS: lower-segment cesarean section

Figure 2.

Comparison of NLR scores at different treatment time points. NLR: neutrophil-lymphocyte ratio, LSCS: lower-segment cesarean section

Table 1.

Correlation between NLR and VAS at different time points (n=110)

Time points	r	P
12 h	0.462	<0.001*
24 h	0.519	<0.001*
48 h	0.455	<0.001*

NLR: neutrophil-lymphocyte ratio, n: number of patients, VAS: visual analog scale, r: Spearman’s rank correlation coefficient *P<0.05: significant

The mean weight was 70.3 ± 3.7 kg in the primary cesarean section group and 69.7 ± 3.5 kg in the repeat cesarean section group (P = 0.384). The mean height was 155.0 ± 2.9 cm in the primary cesarean section group and 155.0 ± 3.0 cm in the repeat cesarean section group (P = 0.975). The mean body mass index (BMI) of patients was 29.2 ± 1.8 kg/m² in the primary cesarean section group and 29.0 ± 1.8 kg/m² in the repeat cesarean section group (P = 0.482). The study groups were comparable with respect to height, weight, and BMI.

Figure 2 shows the comparison of NLR between the study groups. The preoperative NLR was comparable among the study groups (P = 0.574). The NLR was higher at the 12^th h (P = 0.061) and significantly higher at the 24^th h (P = 0.002) in repeat cesarean patients. The NLR was higher in primary cesarean patients at the 48^th h (P = 0.598). The comparison of VAS among the study group is shown in Figure 3. The VAS was significantly higher in primary cesarean patients at the 6^th h (P = 0.018) and higher at the 12^th h (P = 0.532). The VAS was significantly higher in repeat cesarean patients at the 24^th h (P = 0.047) and higher at the 48^th h (P = 0.910).

Figure 3.

Comparison of VAS between the two study groups (n = 110). n: number of patients, VAS: visual analog scale, LSCS: lower-segment cesarean section

Table 2 shows the analgesic requirements at the 24^th and 48^th h. The diclofenac requirement was significantly high at the 24^th h among the repeat cesarean section patients (P = 0.023). The duration of surgery is shown in Table 3.

Table 2.

Comparison of postoperative analgesic requirement between the study groups at 24 h and 48h

Postoperative analgesic requirement	Primary cesarean section (n=55)	Repeat cesarean section (n=55)	Total (n=110)	P
Tramadol requirement at 24 h
Not required	0	1 (1.82%)	1 (0.91%)	0.504
1 dose	54 (98.18%)	52 (94.55%)	106 (96.36%)
2 doses	1 (1.82%)	2 (3.64%)	3 (2.73%)
Diclofenac requirement at 24 h
Not required	50 (90.91%)	41 (74.55%)	91 (82.73%)	0.023*
1 dose	5 (9.09%)	14 (25.45%)	19 (17.27%)
Tramadol requirement at 48 h
Not required	9 (16.36%)	15 (27.27%)	24 (21.82%)	0.166
1 dose	46 (83.64%)	40 (72.73%)	86 (78.18%)

n: number of patients, *P<0.05: significant

Table 3.

Comparison of duration of surgery between the study groups (n=110)

	Primary cesarean section (n=55)	Repeat cesarean section (n=55)	Total (n=110)	P
Duration of surgery (minutes)	45.8±3.9	50.0±3.9	47.9±4.4	>0.001*

Discussion

In our study, we have demonstrated an increase in the postoperative NLR when compared to the preoperative NLR. Inflammation is a very important aspect of the pain mechanism, and NLR may be a marker of inflammation. Surgical incision, dissection, and nerve stretching cause inflammatory changes, resulting in neutrophilia and relative lymphopenia, which increase NLR in the postoperative period. The normal range of NLR is between 1.65 ± 0.79 and 2.8 ± 1.6 across different populations.[11,12] Prior studies have shown NLR >2 to indicate inflammatory status and hence may be related pain.[13,14,15,16]

We also observed a positive correlation between postoperative VAS and NLR at the 12^th, 24^th, and 48^th h. Our results were similar to those of the study conducted by Canbolat et al.[10] They found a statistically significant difference between preoperative and postoperative NLR (P = 0.018) and significantly higher postoperative NLR in total hip arthroplasty compared to total knee arthroplasty patients. They attributed the results to the prolonged surgical duration in hip arthroplasty patients. Though the authors found a significant difference in the NLR scores between total hip arthroplasty and total knee arthroplasty, the VAS and morphine consumption were similar.

We compared NLR and VAS values between parturients who underwent primary and repeat cesarean section. Though the preoperative NLR did not show a statistically significant difference among the study groups (P = 0.574), the NLR score was higher at the 12^th h and significantly higher at the 24^th h only for repeat cesarean section compared to primary cesarean section. Longer duration and greater operating difficulties due to severe adhesions are seen in repeat cesarean-section patients, which may have resulted in higher NLR in repeat cesarean patients.

In our study, IV tramadol was administered if the patient complained of pain, and IV diclofenac was administered if pain persisted even after tramadol injection. The tramadol requirement was not statistically significant at the 24^th and 48^th h as both primary and repeat cesarean-section patients had been treated with tramadol for postoperative pain. The diclofenac requirement in both study groups was statistically significant (P = 0.009) at the 24^th h, wherein repeat cesarean-section patients had persistent pain with IV tramadol and had been treated with IV diclofenac. The analgesic requirement was consistent with higher NLR values in repeat cesarean-section patients.

We also compared VAS values in both study groups and found that the comparison was significant only at the 6^th and 24^th h, with VAS values higher in the primary LSCS group at the 6^th h and in the repeat LSCS group at the 24^th h. The VAS values were contrary to the NLR values. We attribute the results to the VAS, which is a subjective unidimensional method of assessing pain.

The study by Ülger G et al.[17] found no significant correlation between preoperative NLR and VAS values in patients undergoing video-assisted thoracoscopic surgeries, and a low degree of positive correlation was found between postoperative NLR and VAS values for the 1^st, 2^nd, 4^th, 8^th, and 16^th h.

Surhonne et al.[18] found that the postoperative total leucocyte count and NLR values were significantly higher in patients administered GA compared to SA at 2 h and 24 h post surgery.

NLR is not only affected by surgical trauma but also by anesthetic methods. Volatile anesthetic agents have been found to modulate both pro- and anti-inflammatory mediators, resulting in low lymphocyte count. In addition, neuroendocrine response is less in regional anesthesia compared to GA.[19]

In our study, as the cesarean section was performed under SA, we presumed a less neuroendocrine response, which explains relatively less increase in the postoperative NLR.

Tarabay et al.[20] conducted a study to investigate the preoperative NLR as a marker of postoperative pain in patients undergoing harmonic cholecystectomy, wherein they used a cutoff value of NLR ≥2 to be significantly associated with postoperative pain.

Duan et al.[21] compared postoperative pain in primary and repeated cesarean-section parturients; the relative risk for multiparas was 0.42, and the mean incision pain VAS score in the repeat cesarean-section group was significantly lower than that in the primary cesarean-section group at several time points, including 4, 12, and 24 h post surgery. Further studies are required to evaluate the degree of pain and analgesic requirement among primary and repeat cesarean-section patients.

In the study conducted by Öner et al.,[22] the preoperative NLR was found to be a strong predictor of postoperative NRS (P < 0.001), and there was a correlation between the NLR and mean analgesic intake. In their study, patients with a preoperative NLR of 2 had high NRS and short block duration. Higher preoperative NLR suggests increased cytokine production. The inflammatory mediators play a significant role in the transmission and transduction of pain. Patients with higher NLR and thus higher systemic inflammation may be exposed to non-resolution of pain and altered inflammatory balance within the central nervous system (CNS), and this high inflammatory status could result in increased analgesic requirements in the postoperative period. We included patients who underwent elective cesarean section in our study.

In another study conducted by Turgut et al.,[23] the mean amount of tenoxicam administered was significantly higher in patients with preoperative NLR ≥2 than those patients with NLR ≤2 in patients undergoing orthognathic surgeries (P < 0.0001).

The mean duration of the primary cesarean section was 45.8 ± 3.9 minutes, and for the repeat cesarean section was 50.0 ± 3.9 minutes (P < 0.001). Longer duration of surgery may be the cause for higher NLR values in repeat cesarean-section patients in our study.

The study has certain limitations. It is an observational study with a limited sample size and is subjected to various biases such as observer bias, selection bias, and statistical errors. We included only ASA PS 2 patients. Further studies are required to know the effect of comorbid conditions that affect NLR. Further randomized trials are necessary to compare VAS and NLR for analgesic administration.

Conclusions

The postoperative NLR was higher than the preoperative NLR. The NLR correlated with VAS at the 12^th, 24^th, and 48^th h after surgery. Hence, NLR can be used as a surrogate marker for pain assessment. The longer duration of surgery and greater operative difficulties in repeat cesarean-section patients may cause greater pain compared to primary cesarean-section patients, hence requiring adequate pain management, as shown by higher NLR values in repeat cesarean-section patients.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.