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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 1  |  Page : 10-19

Utilization of Neutrophils-to-Lymphocytic Ratio as a Marker for Post-operative Pain in Patients Undergoing Harmonic Cholecystectomy: A Single-center Study


1 Department of General Surgery, Mansura University Hospitals, Mansura, Egypt; Department of General Surgery, Saudi German Hospital, Jeddah, Saudi Arabia
2 Department of General Surgery, Saudi German Hospital, Jeddah, Saudi Arabia; Medicine and Surgery, Batterjee Medical College, Jeddah, Saudi Arabia
3 Department of General Surgery, Saudi German Hospital, Jeddah, Saudi Arabia; Department of Surgery, Faculty of Medicine, Suez Canal University Hospitals, Ismailia, Egypt

Date of Submission10-Dec-2021
Date of Acceptance12-Feb-2022
Date of Web Publication8-May-2022

Correspondence Address:
Ahmed Hafez Mousa
Medicine and Surgery, Batterjee Medical College, Jeddah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AMJM.AMJM_51_21

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  Abstract 

Objectives: Our study aimed to investigate the pre-operative neutrophils-lymphocytes ratio (NLR) in patients who underwent cholecystectomy and to identify whether it discriminates between chances of developing pain or not and at what interval. Materials and Methods: A cross-sectional study was conducted in a single center in Saudi Arabia over a period of 2 months. Analysis was conducted using SPSS 22nd edition; numeric variables were presented in mean ± standard deviation and compared using the Mann–Whitney U-test after normality testing. Results: The study included 69 patients diagnosed with acute cholecystitis and underwent cholecystectomy. The minimum identified NLR in our study was 0.3 and the maximum identified variable was 15.0. Highest sensitivity and specificity were found to be 93.8% and 24.5% after 36 h of performing the procedure, respectively. Conclusion: NLR utilization as a pain marker post-operatively has promising outcomes which will highly impact the reduction of disease burden on patients.

Keywords: Gallbladder, laparoscopic cholecystectomy, pain, surgery


How to cite this article:
Tarabay A, Mousa AH, Radwan HA, Khaled I. Utilization of Neutrophils-to-Lymphocytic Ratio as a Marker for Post-operative Pain in Patients Undergoing Harmonic Cholecystectomy: A Single-center Study. Amrita J Med 2022;18:10-9

How to cite this URL:
Tarabay A, Mousa AH, Radwan HA, Khaled I. Utilization of Neutrophils-to-Lymphocytic Ratio as a Marker for Post-operative Pain in Patients Undergoing Harmonic Cholecystectomy: A Single-center Study. Amrita J Med [serial online] 2022 [cited 2022 May 21];18:10-9. Available from: https://www.ajmonline.org.in/text.asp?2022/18/1/10/344948




  Introduction Top


Gallstones form when there is a lack of balance between the composition of bile leading to precipitation of one of its components or more.[1] Gallbladder disease is a popular and serious pathology. The development of gallbladder disease changes among population groups around the world.[2] The prevalence of gallbladder disease in Western cultures is similar to that in the USA, but it seems to be slightly lower in Asia and Africa.[3] In Saudi Arabia, the high predominance of gallbladder diseases is more shown in developed societies spanning from 10% to 20.8%. However, it is less common in developing nations and remaining as low as 4.1%.[3] Consequently, the number of procedures for gallstone disease has progressed with cholecystectomy becoming the most common elective surgical procedure.[2] Gallstones disease does not need to be treated if they are not causing problems. Patients who have cholecystitis or are distressed by symptoms of gallstones are treated with surgical removal of the gallbladder.[4] Laparoscopic cholecystectomy is a minimally invasive procedure done surgically to remove a pathologic gallbladder.[5] The utilization of advanced energy sources, such as the harmonic scalpel, though costly, provides an advantage of minimized procedure time and reduced perioperative complications rate.[6] Among the complications that can occur after the procedure, pain is one of those which has variable tolerance between patients, some view it devastating and others which show minimal affection. Pain control post-operatively is becoming an increasingly important topic to study.[7] The cause of pain of post-operative cholecystectomy is the visceral cavity insufflation with CO2 and phrenic nerve irritation. The patients complain of shoulder, back, and regional pain. Directors of non-steroidal anti-inflammatory drugs and narcotics can reduce the pain after laparoscopic cholecystectomy, although the uses of these methods for relieving the pain after surgery can lead to a lot of side effects so that the clinical signs of pain control are still controversial.[8] The predictive value of pre-operative neutrophil-to-lymphocyte ratio (NLR) in patients with gallbladder disease has not yet been established.[9] Our study aims to investigate the pre-operative NLR in patients who underwent cholecystectomy and to identify whether it discriminates between chances of developing pain or not and at what intervals. The NLR, lymphocyte–monocyte ratio, platelet–lymphocyte ratio, and mean platelet volume can be used as factors to determine the prognosis of patients in various clinical situations.[10]


  Materials and Methods Top


Study design and setting

This was a cross-sectional study conducted in a single center in Saudi Arabia over a period of 2 months from January 1, 2021 to March 1, 2021.

Study population

Inclusion criteria for our study were patients (i) with gallbladder disease, (ii) aged between 18 and 60 years, and (iii) had no co-morbidities preventing a laparoscopic approach in surgery in which it is eligible to participate in the study. Exclusion criteria for our study included (i) presentation with acute pancreatitis, (ii) presence of co-morbidities interfering with patient safety under anesthesia, (iii) presence of contraindications to laparoscopic approaches, and (iv) unfit for surgery.

Study tool

Data obtained were all collected on a pre-set Excel Sheet accessible only by the researchers to ensure utmost patient confidentiality. Demographics such as age, gender, and body mass index (BMI) were obtained. Additionally, pre-operative complete blood count was done from which the neutrophils and lymphocyte counts were obtained. Post-operative pain was assessed using a visual assistance scale at 12-, 24-, 36-, and 72-h intervals.

Ethical considerations

Informed consent was obtained from all participants. All participating individuals had the right to withdraw from the study at any time.

Statistical analysis

The analysis was conducted using SPSS 22nd edition; numeric variables were presented in mean ± standard deviation and compared using the Mann–Whitney U-test after normality testing. Categorical variables were presented in frequency and percentage and compared using the χ2 test. The Spearman correlation test was used for correlating numeric variables that are non-normally distributed, whereas binary logistic regression was conducted to determine the risk factors for developing pain post-operatively. Sensitivity analysis using receiver operating characteristics (ROC) curves was conducted to detect the predictability of neutrophil–lymphocytes ratio for post-operative pain. Any P-value less than 0.05 was considered significant.


  Results Top


In our study, we have included 69 patients diagnosed with acute cholecystitis and underwent cholecystectomy. The baseline demographic data are listed in [Table 1]. Operative details were obtained for the usage of drains, presence of adhesions, gallbladder perforation, conversion rate, and mean operative time in minutes listed in [Table 2]. Among the patients included in the study, 50 (72.5%) presented with biliary colic, and 17 (24.6%) presented and got diagnosed with acute cholecystitis. Majority of the study participants had no evidence of jaundice 66 (95.7%), as shown in [Table 3].
Table 1: Demographic data

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Table 2: Operative details

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Table 3: Diagnosis of the included patients

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Follow-up of the patient post-operatively for the assessment of pain has been done at intervals of 12, 24, and 36 h and 7 days, as displayed in [Table 4]. Around 43.8% of the patients showed evidence of pain 12 h after the operation. This number has decreased down to 7.426% at 7 days post-operatively, as displayed in [Figure 1]. Assessment for the levels of pain was done with the Visual–Analog Scale (VAS) of pain presented to the patients at various intervals, as displayed in [Table 5]. Box-plot display of the VAS is shown in [Figure 2], showing the decrease in severity of pain throughout the course of 7 days post-operatively.
Table 4: Post-operative pain incidence at 12, 24, and 36 h post-operatively and at the first visit if follow-up after 7 days

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Figure 1: Bar chart showing incidence of pain post-operatively

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Table 5: VAS for pain 12, 24, 36 h post-operatively and after 7 days

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Figure 2: Box plot showing VAS for pain distribution post-operatively

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Spearman’s correlation coefficient was done to determine the pattern between the N/L ratio and the patient’s demographics in addition to the VAS of pain. Moreover, P-values were determined as well. Significance (P < 0.05) was detected between the age and N/L ratio, as shown in [Table 6]. Results of correlation between the age and N/L ratio were displayed on a scatter plot [Figure 3] and showed a direct correlation between the two variables.
Table 6: Spearman’s correlation test between N/L ratio with demographics and VAS for pain

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Figure 3: Scatter plot showing correlation between age and NLR

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The mean N/L ratio for the participating individuals determined pre-operatively was 2.3 (S.D 2.8).

The minimum identified N/L ratio in our study was 0.3, and the maximum identified variable was 15.0 [Table 7]. The highest sensitivity and specificity were found to be 93.8% and 24.5% after 36 h of performing the procedure, respectively. In contrast, the lowest specificity and sensitivity for the N/L ratio were found to be 80% and 10.9%, determined at 7 days post-operatively, respectively. Sensitivity analysis using ROC curves was conducted to detect the predictability of neutrophil–lymphocytes ratio for post-operative pain at the intervals stated previously. The results were graphed for 12 h [Figure 4], 24 h [Figure 5], 36 h [Figure 6], and 7 days [Figure 7]. [Table 8] and [Table 9] show an in-depth analysis of post-operative pain metrics. [Table 8] assesses the individual predictors for pain. [Table 9] assesses sensitivity of NLR at different post-operative time intervals.
Table 7: NLR among included patients

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Figure 4: ROC curve showing predictability of NLR to incidence of pain 12 h post-operatively

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Figure 5: ROC curve showing predictability of NLR to incidence of pain 24 h post-operatively

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Figure 6: ROC curve showing predictability of NLR to incidence of pain 36 h post-operatively

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Figure 7: ROC curve showing predictability of NLR to incidence of pain 7 days after operation

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Table 8: Binary logistic regression model assessing the predictors for pain incidence after 12 h post-operatively

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Table 9: Sensitivity analysis of neutrophils–lymphocytes ratio in predicting pain post-operatively

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  Discussion Top


Cholecystectomy is the gold standard treatment for benign biliary disease.[11]

Pain is a relatively common complication after cholecystectomy, and the origin of the pain is multifactorial.[12] A study conducted by Bisgaard et al. found in their study that pain was the most common complaint about patients on the first day post-operatively.[13] The hematological and biochemical data about the severe inflammation are white blood cells (WBCs), C-reactive protein, and platelet-to-lymphocytes ratio. The WBC is a good indicator of inflammation but it did not access the severity of the disease.[9] Most of the patients who attend the hospital with biliary colic may have high NLR. This shows the importance of post-operative NLR values in predicting pain after laparoscopic cholecystectomy.[14] NLR is a recognized marker of clinical inflammation and is thought to indicate the balance between innate (neutrophils) and adaptive (lymphocytes) immune responses.[15] A study done by Cuff et al. estimates the parameters that affect post-operative pain that was done on 181 patients who underwent arthroscopic rotator cuff repair. They showed that circumstances, such as pre-operative narcotic use, smoking, and the young age of patients, were associated with high pain scores in the first post-operative week.[8] In contrast to our study, the demographic data affect post-operative pain. For example, most of the patients were females with high BMI and they are not smoking and most of them do not have a chronic disease but some of the patients have DM and HTN. A study done by Ikard[16] found that there is no relation between cholecystitis and diabetes patients, but the cholecystitis and gallbladder stone can be worse in patients with diabetes. In our study, we found that most of the patients have multiple numbers of stones and presence of adhesions, and gallbladder perforation can affect post-operative pain. The presence of adhesions can be attributed to predominantly acute nature of the presenting cases. In contrast, research was done which found the most important outcome that estimates many factors, which affect pain. The author established predictors that affect post-operative pain, young age, obesity, gender, fear from surgery, and the type of surgery (orthopedic, joint, abdominal, thoracic surgery).[15] The study done by Feride et al. found the relation among NLR, WBCs, PLT on patients who were admitted to the emergency department (ED) with abdominal pain, who had an NLR cut-off value for positive patients with sensitivity 59.57% and specificity 61.86%. So they admitted that NLR was a simple method in differentiating pain post-operatively.[17] NLR, which is used as a predictor for diagnosing simple acute cholecystitis, is higher than WBCs and is also a powerful predictor for severe acute cholecystitis than WBCs and CPR.[9] Some studies are using ratios such as 2, 3, and 4 as a cut-off ratio. Concerning the studies correlated with post-operative pain, we also arranged the cut-off value as ≥2 in this study[16] with sensitivity 93.8% and specificity 24.5% and was high at 36 h. In this study, we used a cut-off value of NLR ≥ 2 to be significantly associated with the inflammatory condition and post-operative pain. NLR has been used in many clinical investigations with or without other inflammatory markers to determine inflammation and/or disease prognostication and diagnosis, and it results in many different clinical entities.[15] Therefore, elevated NLR shows to be an accurate indicator of up-regulation of the innate immune response.[8] The research done by Daoudia et al.[14] found the pre-operative pain regarding the attitude and post-operative analgesic use. In this study, 60 patients undergo laparoscopic cholecystectomy. They described the total amount of analgesics required for post-operative pain in the first 48 h as “unitary dosage.” They found how post-operative analgesic elements of the patients have high-onset pain scale scores and low NLR.[14] In the end, they reported that there was a relationship between post-operative analgesic dose and pre-operative pain scale and hospital stress and depression scale and NLR that represents the inflammatory state and its relationship with post-operative pain.[18] The research done by Turgut et al.[15] evaluated pre-operative NLR and post-operative pain; this study was conducted on 140 cases who underwent orthognathic surgery. They discovered the cases with NLR and a high significant analgesic requirement, and they reported the relationship of high NLR with increased post-operative pain. On the contrary, the research done by Kim and co-workers[19] estimates VAS of 84 patients with 12-month follow-up who underwent rotator cuff repair, and they found high-onset pain and high VAS score in relation to high pain patterns.

In contrast to our study that estimates the VAS for pain of 69 patients who were followed at intervals of 12, 24, 36 h and 7 days underwent laparoscopic cholecystectomy, we found that the high pain patterns start at 12 h post-operatively and after that the pattern of pain decreases till 7 days.

In the study done by Sang Kuon et al., in 503 patients who appear with cholecystitis, the NLR is not only the marker for identifying severe cholecystitis, but also served as a marker of the length of hospital stay. They divide the NLR into low risk for severe cholecystitis (NLR <3.0) and high risk for severe cholecystitis (NLR ≥3.0), according to its value.[19] In contrast to our study, which considered the data on 69 patients who went to laparoscopic cholecystectomy, most of the cases had acute cholecystitis that the NLR was 2.1 and some of them had biliary colic that the NLR was > 2.3; in both cases, patients had acute pain and did not have any complications. A summary of key findings from 3 articles sharing similar objectives is shown in [Table 10].
Table 10: Summary of key findings from three article models that share similar objectives to our study

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  Limitations Top


Our study was conducted in a phase in which COVID-19 cases were utilizing a significant portion of hospitals resources, based on that the sample size included 69 patients only who were eligible to participate in the study.


  Conclusion Top


In conclusion, our study found that there is a relatively reasonable potential for the utilization of the NLR as a marker for pain. We recommend future studies to be done on a wider scale assessing the utilization of NLR due to its promising potential for pain detection and reduction of post-operative pain.

Acknowledgments

Not applicable.

Financial support and sponsorship

No funds were received to fulfill this work.

Conflicts of interest

The authors declare that they have no competing interests.

Authors’ contributions

All authors contributed to this manuscript equally.

Ethics approval and consent to participate

All procedures performed in the study were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Approval was obtained from the General Surgery Department, Saudi German Hospital, Jeddah, Saudi Arabia.

Availability of data and material

The datasets used in the current study are available with the corresponding author and can be obtained upon reasonable request.



 
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Lee JY, Keane MG, Pereira S. Diagnosis and treatment of gallstone disease. Practitioner 2015;259:15-9, 2.  Back to cited text no. 1
    
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Ndong A, Gaye NF, Tendeng JN, Diao ML, Diallo AC, Niang FG, et al. Profile of patients with gallstone disease in a sub-Saharan African General Surgery Department: A retrospective cohort study protocol. Int J Surg Protoc 2021;25:61-5.  Back to cited text no. 2
    
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Gallstones (Cholelithiasis): Practice Essentials, Background, Pathophysiology [Internet]. Emedicine.medscape.com. 2021. Available from: https://emedicine.medscape.com/article/175667-overview. [Last accessed on 20 Aug 2021].  Back to cited text no. 3
    
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Kim SS, Donahue TR. Laparoscopic cholecystectomy. JAMA 2018;319:1834.  Back to cited text no. 4
    
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Hassler KR, Collins JT, Philip K, Jones MW. Laparoscopic cholecystectomy. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. PMID: 28846328.  Back to cited text no. 5
    
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Rajnish K, Sureshkumar S, Ali MS, Vijayakumar C, Sudharsanan S, Palanivel C. Harmonic scalpel-assisted laparoscopic cholecystectomy vs. conventional laparoscopic cholecystectomy—A non-randomized control trial. Cureus 2018;10:e2084.  Back to cited text no. 6
    
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Zhao T, Shen Z, Sheng S. The efficacy and safety of nefopam for pain relief during laparoscopic cholecystectomy: A meta-analysis. Medicine (Baltimore) 2018;97:e0089.  Back to cited text no. 7
    
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Rasmussen JK, Nikolajsen L, Bjørnholdt KT. Acute postoperative pain after arthroscopic rotator cuff surgery: A review of methods of pain assessment. SICOT J 2018;4:49.  Back to cited text no. 8
    
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Micić D, Stanković S, Lalić N, Đukić V, Polovina S. Prognostic value of preoperative neutrophil-to-lymphocyte ratio for prediction of severe cholecystitis. J Med Biochem 2018;37:121-7.  Back to cited text no. 9
    
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Lee JS, Kim NY, Na SH, Youn YH, Shin CS. Reference values of neutrophil–lymphocyte ratio, lymphocyte–monocyte ratio, platelet–lymphocyte ratio, and mean platelet volume in healthy adults in South Korea. Medicine (Baltimore) 2018;97:e11138.  Back to cited text no. 10
    
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Bisgaard T, Klarskov B, Kehlet H, Rosenberg J. Preoperative dexamethasone improves surgical outcome after laparoscopic cholecystectomy: A randomized double-blind placebo-controlled trial. Ann Surg 2003;238:651.  Back to cited text no. 13
    
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Daoudia M, Decruynaere C, Le Polain de Waroux B, Thonnard JL, Plaghki L, Forget P. Biological inflammatory markers mediate the effect of preoperative pain-related behaviours on postoperative analgesics requirements. BMC Anesthesiol 2015;15:183.  Back to cited text no. 14
    
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Turgut HC, Alkan M, Ataç MS, Altundağ SK, Bozkaya S, Şimşek B, et al. Neutrophil lymphocyte ratio predicts postoperative pain after orthognathic surgery. Niger J Clin Pract 2017;20:1242-5.  Back to cited text no. 15
[PUBMED]  [Full text]  
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Ikard RW. Gallstones, cholecystitis and diabetes. Surg Gynecol Obstet 1990;171:528-32.  Back to cited text no. 16
    
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Chandrashekara S, Mukhtar Ahmad M, Renuka P, Anupama KR, Renuka K. Characterization of neutrophil-to-lymphocyte ratio as a measure of inflammation in rheumatoid arthritis. Int J Rheum Dis 2017;20:1457-67.  Back to cited text no. 17
    
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Öner K, Okutan AE, Ayas MS, Paksoy AE, Polat F. Predicting postoperative pain with neutrophil/lymphocyte ratio after arthroscopic rotator cuff repair. Asia Pac J Sports Med Arthrosc Rehabil Technol 2020;20:24-7.  Back to cited text no. 18
    
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Lee SK, Lee SC, Park JW, Kim SJ. The utility of the preoperative neutrophil-to-lymphocyte ratio in predicting severe cholecystitis: A retrospective cohort study. BMC Surg 2014;14:100.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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