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Year : 2020  |  Volume : 4  |  Issue : 1  |  Page : 18-21

Comparative effects of remifentanil and fentanyl on inflammatory stress response in mastectomy surgery with general anesthesia: A case series

Department of Anesthesiology, Intensive Care and Pain Management, Medical Faculty of Udayana University, Sanglah General Hospital, Denpasar, Bali, Indonesia

Date of Submission10-Dec-2019
Date of Decision11-Feb-2020
Date of Acceptance17-Feb-2020
Date of Web Publication16-Mar-2020

Correspondence Address:
Dr. Adi Dharma Thius
Department of Anesthesiology, Intensive Care and Pain Management, Medical Faculty of Udayana University, Sanglah General Hospital, Jl. Kesehatan No. 1, Denpasar, Bali 80114
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/BJOA.BJOA_15_19

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Malignancy associated with chronic inflammation and stress response events by the surgical procedure. The use of an opioid such as remifentanil can decrease stress response that may be measured by leukocyte, neutrophil-to-lymphocyte ratio (NLR), platelet-to -lymphocyte ratio (PLR), mean platelet volume, blood sugar, and C-reactive protein (CRP). This was a randomized, single-blind study, with a total sample of ten patients, and they were divided into two groups: 1.remifentanil group (0.1–0.3 mcg/kg body weight [BW]/min) and fentanyl group (intermittent 0.5–1 mcg/kg BW every 60 min). The patients' blood were collected two times before and 24 h after surgery. Inflammation markers such as total leukocyte value, NLR, PLR, and dan CRP were increased in two groups.Even PLR postoperative remains high in both group, but in remifentanil group was lower than fentanyl group. There were no differences between the two groups, but remifentanil was found better to suppress the postoperative PLR rather than in the fentanyl group.

Keywords: C-reactive protein, fentanyl, mean platelet volume, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, remifentanil

How to cite this article:
Agung Senapathi TG, Subagiartha I M, Utara Hartawan I G, Thius AD. Comparative effects of remifentanil and fentanyl on inflammatory stress response in mastectomy surgery with general anesthesia: A case series. Bali J Anaesthesiol 2020;4:18-21

How to cite this URL:
Agung Senapathi TG, Subagiartha I M, Utara Hartawan I G, Thius AD. Comparative effects of remifentanil and fentanyl on inflammatory stress response in mastectomy surgery with general anesthesia: A case series. Bali J Anaesthesiol [serial online] 2020 [cited 2020 Mar 29];4:18-21. Available from: http://www.bjoaonline.com/text.asp?2020/4/1/18/280811

  Introduction Top

Surgery causes a change in systemic leukocytes. Measuring the total of leukocyte, neutrophils, lymphocytes, platelet, and C-reactive protein (CRP) as a stress response indicator. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers that can be assessed easily to indicate systemic inflammation.[1],[2]

Remifentanil is an ultrashort-acting synthetic opioid that is more potent than fentanyl. The unique of remifentanil is expected to suppress the response of inflammatory stress due to surgical trauma by suppressing the nociceptive process modulation in the hypothalamus–pituitary–adrenal (HPA) axis.[3],[4]

The present study aims to compare remifentanil to fentanyl in suppressing the leukocytes, NLR, PLR, MVP, blood sugar, and CRP after surgery as stress response on the mastectomy procedure.

  Case Report Top

The number of samples participating in this pilot study was ten participants. Participants are women aged 18–65 years old who will undergo a mastectomy surgery with the physical status of the American Society of Anesthesiologists 1 and 2. Participants were divided into two groups, namely the remifentanil (R) group and fentanyl group (F). The sample of this study was collected by prospective randomized. Patients were given informed consent in advance. In the preparation room, the participants were given the premedication of midazolam 0.05 mg/kg body weight (BW), ketorolac 30 mg, and ketamine 0.1 mg/kg BW intravenously. In the R group, remifentanil administered at a dose of 1 mcg/kg BW in 60 s, propofol 2–3 mg/kg BW, atracurium 0.5 mg/kg BW, 5 min after performed intubation, the patient were monitored with the maintenance during procedure with sevoflurane 2 volume% with remifentanil continuous at a dose of 0.1–0.3 mcg/kg BW/min. In the Group F, fentanyl administered at a dose of 2 mcg/Kg BW, propofol 2–3 mg/kg BW, atracurium 0.5 mg/kg BW, after 5 min performed intubation, the patients were monitored with the maintenance during the procedure with fentanyl intermittent 0.5–1 mcg/ KgBW every 60 min intravenous and sevoflurane 2% volume. Morphine is given for analgetics after surgery in the ward. The inflammatory stress response due to surgical procedure uses total leukocytes, neutrophil-to-lymphocytes ratio, PLRs, mean platelet volume (MPV), and random blood sugar. Blood samples were taken through peripheral blood with two different times, preoperative and 24-h postoperative.

  Results Top

In both R and F groups, the inflammatory marker is a change in the number of leukocytes compared to the baseline preoperative value. [Graph 1] presents the preoperative and postoperative comparison data in both groups.

The inflammatory stress response assessed from NLR and PLR increases in both groups. However, on PLR, remifentanil is better at suppressing the increase in postoperative PLR value. This increases due to stress response in the form of an increase in neutrophil count and decreased lymphocytes due to cytokines released by surgical trauma. [Graph 2] and [Graph 3] represent the comparisons of NLR and PLR values between the two groups when pre- and postoperative. The CRP value is associated with an acute-phase response as the impact of the production of interleukin-6 (IL). The CRP's value in this study showed that the fentanyl group was better at suppressing the postoperative CRP compared to the remifentanil group [Graph 4]. As for MPV and blood sugar values [Graph 5] and [Table 1] between the two groups do not indicate any difference.
Table 1: Table of preoperative random blood sugar values and postoperative between groups remifentanil and fentanyl

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  Discussion Top

Malignancy is an abnormal growth of tumor cells, and many of the inflammatory mediators involved, for example, cytokines, chemokines, prostaglandins, and cyclooxygenase cause tumor growth by the suppression of the system immunity, increasing resistance to apoptosis, and promotion of angiogenesis. Anesthesia procedure in a cancer patient is associated with this inflammatory response.[1]

The surgical stress response can trigger systemic leukocyte changes after surgery, namely leukocytosis, neutrophilia, or lymphopenia. The neuroendocrine activated system during anesthesia and surgery results in the release of neuroendocrine and cytokine hormones. During anesthesia and surgery, there is a change in the immune system that affects the physiological response, which relates to the expansion of surgery, the patient's age, general health conditions, medication, and blood transfusions.

In this study, both groups showed an increase in total leukocytes. There is nothing dominant in both groups in suppressing the total increase in leukocytes from baseline values. In a subclass of leukocytes, NLR and PLR are increased. This may be caused by a surgical stress response causing an increase in neutrophil production and an increase in apoptosis lymphocytes. NLR and PLR enhancements may be associated with poor outcome and complications in the carcinoma surgery.

NLR and PLR in peripheral blood are a simple marker for systemic inflammatory response. NLR is essential for the diagnosis in some pathological circumstances, characterized by systemic inflammatory responses, such as diabetes mellitus, coronary artery disease, ulcerative colitis, and inflammatory arthritis. Several subclasses of leukocytes show that an increase of neutrophils and a decrease of lymphocytes will increase the NLR associated with the acceleration of mortality and morbidity in carcinoma patients. The NLR increase from baseline values demonstrates a poor prognosis for survival in any type of carcinoma patients. NLR is not only a provider of patient's data but also a patient's prognosis.[5] Endogenous anti-inflammatory anticancer and precoagulation responses can be detected with PLR. PLR is also more sensitive as a prognostic factor for breast cancer cases.

Neutrophils are associated with the state of the hypercoagulation and viscosity of blood that causes endothelial layer damage to the microvascular. Lymphocytes have a significant role in chronic inflammation, and the low number of lymphocytes is associated with morbidity and mortality rates. Platelet has an active role in plaque destabilization, rupture cascade plaque, and clotting. Some studies show an increase in NLR numbers, and PLR shows increased inflammatory and associated with organ damage, cardiovascular risk, and death in case of malignancy.[6]

Cytokines play an important role in the inflammatory response due to trauma and surgery. Cytokines have localized effects in mediation and maintain an inflammatory response due to trauma, as well as initiating systemic changes occurring. After a major surgery, the main cytokines released include IL-1, tumor necrosis factor α (TNF-α), and IL-6. IL-1 and TNF-α are released from the activation of macrophages and monocytes in damaged tissues. This will further stimulate the production and release, especially IL-6, as the primary cytokine responsible for systemic changes known as the acute-phase response. The CRP value will increase with IL-6 parallelly.[7]

PLR develops into a marker that provides information on shifting the number of platelets and lymphocytes due to acute inflammatory and prothrombotic state. PLR has been widely evaluated on a state of malignancy related to immune suppression and thrombosis, which can be predicted by the calculation of numbers and ratios.[8] The MPV describes the platelet size and to find out platelet function. Platelet size in circulation is associated with inflammatory intensity. In some chronic inflammatory conditions, MPV is used as a chronic inflammatory marker of disease and monitoring of anti-inflammatory therapy.[9]

The opioid is extensively used as an anesthetic agent on a wide range of operations. The opioid is used as an analytic and sedation. Besides, opioid also modulates immune responses through an opioid receptor that are directly expressed to the immune cell itself. Nowadays, the receptor of opioid kappa is believed to have a role in modulating various inflammatory conditions. The discovery of opioid receptors which are an expression in a variety of immune cells gives the idea that opioid has a direct effect on the immune system. Both endogenous and exogenous opioids affect the antibody's response, cell-mediated immunity, phagocytosis, chemotaxis, neutrophil response, and mononuclear phagocytes. Opioid also inhibits all phases of the HPA axis. In addition to suppressing the production corticotropin-releasing hormone (CRH), opioid also lowers the sensitivity of pituitary anterior to the CRH. Opioid, especially remifentanil, may inhibit cortisol plasma according to the administered dose.[10],[11],[12]

This study shows no difference between remifentanil and fentanyl for inhibiting the increase of NLR and PLR from the baseline values. The remifentanil group is better in preventing the increase in postoperative PLR as compared to the fentanyl group. This is different from the research done by Lee et al. The another study proved that remifentanil was more effective in suppressing cytokines and oxidative stress response in cardiac surgery such as cardiopulmonary bypass.[13] In the previous study found remifentanil able to suppress increased IL-6, IL-8 da malondialdehyde after reopening aortic clamp is better than fentanyl. The activation of central opioid receptors provides an influence on the peripheral immune system through the stimulation of the sympathetic nervous system and lymphoid organs.

Among the various types of opioids, only remifentanil can inhibit the activation of neutrophil expose to the lipopolysaccharide by lowering the activation of inflammatory cytokines and p38 MAPKs in vitro. The suppression of neuroendocrine stress response by remifentanil during surgery also affects the functioning of the immune system, resulting in a good prognosis as long as the patient is done treatment in the intensive care unit.[14]

More research needs to be done with more sample quantities to see the effect of remifentanil on the response of the inflammation of surgery and perform other inflammatory marker examination.

  Conclusion Top

In this study, there was no difference between the two groups in suppressing the increased marker of inflammatory stress response in postoperative. The remifentanil group is better in suppressing the platelet value to human ratio postoperation than that of the fentanyl group.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images, and other clinical information to be reported in the journal. The patients understand that their name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.


I would like to express my special thanks of gratitude to my wife, my family, and my teacher who helped me a lot in finishing this project within the limited time.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Memary E, Alireza M, Mahshid G, Mehrdad T, Ali AD, Atiye K. The effect of lidocaine infusion during general anesthesia on neutrophillymphocyteratio in breast cancer patients candidate for mastectomy: A clinical tria. J Cell Mol Anesth 2016;1:146-53. Available from: http://journals.sbmu.ac.ir/jcma/article/ view/13519. [Last accessed on 2019 Nov 08].  Back to cited text no. 1
Stojkovic Lalosevic M, Pavlovic Markovic A, Stankovic S, Stojkovic M, Dimitrijevic I, Radoman Vujacic I,et al. Combined diagnostic efficacy of neutrophiltolymphocyte ratio (NLR), platelettolymphocyte ratio (PLR), and mean platelet volume (MPV) as biomarkers of systemic inflammation in the diagnosis of colorectal cancer. Dis Markers 2019;1-7.  Back to cited text no. 2
Lee HJ, Tin TD, Kim JY, Chung SS, Kwak SH. Remifentanil Attenuates Systemic Inflammatory Response in Patients undergoing Cardiac Surgery with Cardiopulmonary Bypass. Arch Med 2017;9:5. [doi: 10.21767/1989-5216.1000237].  Back to cited text no. 3
Seo KH, Choi JW, Jung HS, Yoo H, Joo JD. The effects of remifentanil on expression of high mobility group box 1 in septic rats. J Korean Med Sci 2017;32:542-51.  Back to cited text no. 4
Kim WH, Jin HS, Ko JS, Hahm TS, Lee SM, Cho HS, et al. The effect of anesthetic techniques on neutrophil-to-lymphocyte ratio after laparoscopy-assisted vaginal hysterectomy. Acta Anaesthesiol Taiwan 2011;49:83-7.  Back to cited text no. 5
İlgün E, Ömer A, Ali OK, Fethi D, Mehmet D, Mustafa B. Neutrophil/Lymphocyte Ratio and Platelet/Lymphocyte Ratio in Fibromyalgia. Eur J Gen Med 2016;13:100-4.  Back to cited text no. 6
Desborough JP. The stress response to trauma and surgery. Br J Anaesth 2000;85:109-17.  Back to cited text no. 7
Gasparyan AY, Ayvazyan L, Mukanova U, Yessirkepov M, Kitas GD. The platelet-to-lymphocyte ratio as an inflammatory marker in rheumatic diseases. Ann Lab Med 2019;39:345-57.  Back to cited text no. 8
Gunluoglu G, Yazar EE, Veske NS, Seyhan EC, Altin S. Mean platelet volume as an inflammation marker in active pulmonary tuberculosis. Multidiscip Respir Med 2014;9:11.  Back to cited text no. 9
Haroutounian S. Postoperative opioids, endocrine changes, and immunosuppression. Pain Rep 2018;3:e640.  Back to cited text no. 10
Cıcek E, Demırel B, Cıcek IE, Kıraç AS, Eren I. Increased neutrophil-lymphocyte and platelet-lymphocyte ratios in male heroin addicts: A prospective controlled study. Clin Psychopharmacol Neurosci 2018;16:190-6.  Back to cited text no. 11
Guzel D, Yazici AB, Yazici E, Erol A. Evaluation of immunomodulatory and hematologic cell outcome in heroin/opioid addicts. J Addict 2018: 1-8.  Back to cited text no. 12
Surhonne N, Hebri C, Kannan S, Duggappa DR, Rao RR, Mapari CG. The effect of anesthetic techniques on neutrophil to lymphocyte ratio in patients undergoing infraumbilical surgeries. Korean J Anesthesiol 2019;72:458-65.  Back to cited text no. 13
Finnerty CC, Mabvuure NT, Ali A, Kozar RA, Herndon DN. The surgically induced stress response. JPEN J Parenter Enteral Nutr 2013;37:21S-9S.  Back to cited text no. 14


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