Comparison between continuous femoral–sciatic block with continuous epidural block on reduced level of high-sensitivity C-reactive protein, prostaglandin E2, interleukine-6, and visual analog scale in lower limb surgery: Randomized, pre, and post-test trials : Bali Journal of Anesthesiology

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Comparison between continuous femoral–sciatic block with continuous epidural block on reduced level of high-sensitivity C-reactive protein, prostaglandin E2, interleukine-6, and visual analog scale in lower limb surgery: Randomized, pre, and post-test trials

Widnyana, Made Gde; Senapathi, Tjokorda Gde Agung; Pradhana, Adinda Putra

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Bali Journal of Anesthesiology 7(2):p 66-75, April-June 2023. | DOI: 10.4103/bjoa.bjoa_14_23
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Continuous femoral–sciatic block and continuous epidural block have antinociceptive and anti-inflammatory effects through Na-K channel block at the peripheral level and spinal nerve. The anti-inflammatory effect in the continuous femoral–sciatic block is better than in continuous epidural block due to the block density, which could limit neurogenic inflammation to reduce cytokine production and postoperative pain severity.

Materials and Methods: 

This study was a clinical trial with randomized sampling in pre and post-test design. A total of 60 samples were used in this study and were divided into two groups: continuous anesthesia femoral–sciatic block and continuous anesthesia epidural block.


There was a decrease in the prostaglandin E2 (PGE2) level in group I, which was statistically significant than the control group (P < 0.05). However, there was an increased level of high-sensitivity C-reactive protein in both groups in which the gap was found lesser in the control group (P < 0.05). Meanwhile, the interleukin-6 (IL-6) level was only decreased on the third day postoperative in group I but was not statistically significant (P > 0.05) than the control group. Visual analog scale (VAS) score at rest was decreased on the third day postoperative, and VAS at movement in the first hour and on the third day of postoperative was much better in group I than group II in a statistically significant manner (P < 0.05).


The continuous femoral–sciatic block could reduce the level of PGE2 than the control group and attenuate the increased level of IL-6. However, the VAS score decreased at rest and on movement and was purely the effect of the continuous femoral–sciatic block.


Pain is a sign of existing tissue injury, infectious diseases, invading pathogens, and neuropathy. Orthopedic surgery generally involves tissue damage, such as muscles, bones, blood vessels, and nerves. Tissue damage due to surgery, through afferent input, activates a sympathetic response and pain, which then triggers neuroendocrine and cytokine response. Orthopedic surgery in the cruris region is a major action that results in a severe degree of pain due to a large number of nociceptors in deep somatic tissue (joints and muscles) that are sensitized by mechanical stimuli.[1] Around 50% of patients have inadequate pain management after surgery, and 20%–70% of patients report severe pain on the first day to the third day after surgery.[2–4] Pain also causes clinical problems such as delayed functional recovery, prolonged hospitalization, reduced patient satisfaction, causes chronic pain, and has negative consequences on the quality of life and the economy.[5–7]

Interleukin-6 (IL-6) is one of the primary inflammatory mediators produced when tissue damage occurs, and there is a significant relationship with the extent of tissue damage.[8] IL-6 has various biological activities, such as induction of acute-phase protein (high-sensitivity C-reactive protein [HsCRP]/CRP), immunoglobulin synthesis, T-cell activation, induction of adrenocorticotropic hormone synthesis, and increased platelets.[9,10] IL-6, together with IL-1, stimulates the release of cortisol and prostaglandin E2 (PGE2),[11] which subsequently PGE2 plays a dominant role in the process of pain and inflammation.[12,13] IL-6 is also known as a dominant cytokine in addition to IL-1 and TNF-α, triggering an acute-phase reaction that releases CRP/HsCRP from liver cells.[14] HsCRP/CRP is a marker of systemic inflammation associated with increased length of stay, the severity of pain, and recovery of patients undergoing orthopedic surgery.[15–19]

Continuous epidural block anesthesia is a technique that is frequently used, and sometimes combined with spinal anesthesia techniques, for lower-abdominal and lower-limb orthopedic surgery, and there is evidence that it can reduce the neuroendocrine response, risk of complications, and postoperative mortality.[20–25] However, continuous epidural block does not always result in suppression of adequate postoperative pain, and about 21% still with moderate to severe pain complaints.[26] In addition, despite the perioperative epidural block is already given, an increase in the acute phase inflammatory response, PGE2, and IL-6, could still persists.[27–31] Clinical application of the anesthetic method of the continuous epidural block in the lumbar region has limitations, such as the uneven distribution of local anesthetic drugs into the fifth lumbar (L5) to the fifth sacral (S5) because of the extensive nerve root size[32] and spread anteriorly due to the presence of the posterior longitudinal ligament membrane and fat in the midline area of the posterior pedicle[33] so that local anesthetic drugs cannot completely inhibit sensory input to the center,[34] which results in central sensitization still ongoing.[35]

Selective placement of local anesthetic drugs around the femoral and sciatic nerves causes nerve conduction blockages that serve the cruris region. Peripheral nerve blockade completely and adequately inhibits afferent and efferent nerves in the operating area to prevent primary and secondary hyperalgesia and inhibit the sensitization of microglia and astrocytes at the center.[36,37] The anesthetic method of peripheral nerve block is also known to have the effect of reducing neurogenic inflammation in the peripheral due to the inhibition of the release of neurogenic mediator substances P and CGRP from the sensory nerve terminals.[38,39]

Material and Methods

The study was conducted at our university hospital from September 2017 to August 2019 with ethical clearance number 2094/UN.14.2/KEP/2017. This study was approved by our university review board, and informed written consent was obtained from all subjects in the study. The research design used was an experimental design with randomized pre and post-test control group design.

Sampling was done by permuted block random sampling technique, and the sample size was calculated based on the Pocock formula, which is 60 samples separated into two groups, namely the femoral–sciatic nerve block (FSNB) and the epidural nerve block (ENB) method, eligible patients were selected until the required number of samples is met. Inclusion criteria were patients aged 17–65 years who suffered unilateral cruris region fractures and met the indications of surgery with simple fracture forms and with physical status ASA 1 and 2. Patients with a history of medical conditions that affect HsCRP, PGE2, and IL-6 responses based on medical records previously, for example, patients with chronic infections, malignancies, autoimmune diseases, diabetes mellitus, immunosuppressant therapy, and corticosteroids were excluded from the sample group. Patients who met the dropout criteria with massive bleeding (more than 1500 mL) during surgery, as well as patients who showed allergic reactions to local anesthetics, would also be excluded from the sample group.

The anesthetic method of continuous ENB is performed according to standard procedures using a 2% lidocaine regimen of 10–15 mL through an epidural catheter followed by a 1% lidocaine continuously with a syringe pump at a rate of 2 mL/h. The method of continuous FSNB is performed under ultrasound guidance. Scans were performed on the femoral nerve in the inguinal region and the sciatic nerve in the popliteal region. Puncture the needle using a 100-mm peripheral block needle, which is confirmed with ultrasound in real time to be near the nerve, then given an injection of lidocaine 2% as local anesthesia by 15 mL. The catheter is then placed with the tip of the catheter placed near the nerve and continued with lidocaine 1% continuously at a rate of 2 mL/h.

Examination of HsCRP levels is carried out using the immunoturbidimetric CRP latex Tina Quant assay method to quantitatively detect human HsCRP in plasma or serum. Examination of serum PGE2 levels was carried out using the chemiluminescent immunoassay technique to measure quantitative concentrations of PGE2 in serum. Examination of serum IL-6 levels was carried out using the enzyme-linked immunosorbent assay method and used a technique called quantitative sandwich immunoassay to obtain quantitative IL-6 values in serum.

Visual analog scale (VAS) assessment is done the day before surgery, in the morning in the preoperative room, followed 1 h after the patient arrives in the recovery room after surgery, and the third day after surgery at the ward, using the VAS scale. The value is interpreted and grouped into 5 scores.[40]


Clinical characteristics of the study subjects are shown in Table 1; of all the preoperative characteristics analyzed, there were no differences between the two study groups in terms of; age, sex, and ASA (P > 0.05). Both study groups had a mean age of 42.5 years, male sex 35 people (57.4%) and women 26 people (42.6%), ASA I 42 people (68.9%) and ASA II 19 people (31.1%).

Table 1::
Clinical characteristics of research subjects

HsCRP levels in each group are shown in Table 2. Preoperative HsCRP levels in the FSNB group were 7.88 (26.26) mg/L, and the ENB group was 5.56 (21.18) mg/L, and the two study groups did not show any significant difference with P > 0.05. The FSNB group did not show a decrease in the production of HsCRP levels at 4 h after-incision, and on the third day after surgery, but on the contrary, there was a significant increase in systemic inflammatory mediators and significantly different from preoperative conditions (P < 0.05). Slightly different conditions were found in the ENB group, where there was a decrease in HsCRP at the 4-h after incision, and it increased again on the third day after surgery, although it was not significantly different from the preoperative condition with a P value < 0.05.

Table 2::
Comparison of HsCRP Levels before surgery, 4 h after incision, and third day after surgery and mean differences in HsCRP levels

Based on log the data shown in Table 2, the difference in HsCRP levels in the FSNB group showed significant differences compared to the ENB group (P < 0.05), where the ENB group suppressed HsCRP production better in the 4-h after-incision period and the third day after surgery period.

The comparison of PGE2 levels is shown in Table 3. The preoperative PGE2 levels of the FSNB group with a median value of 220.59 (110.35) pg/dL and the ENB group of 187.50 (155.20) pg/dL with no significant difference (P > 0.05). PGE2 levels in the FSNB group showed a dynamic of decline at the time of 4 h after incision and the third day after surgery but did not show a significant difference from the before surgery (P > 0.05). The ENB group shows an increase in PGE2 production, but there was no significant difference compared to the before-surgery condition (P > 0.05). The FSNB group, based on the results of the statistical analysis, did not produce a significant decrease in PGE2 levels at the 4 h after incision and the third day after surgery compared to the ENB group with a P value > 0.05.

Table 3::
Comparison of PGE2 levels before surgery, 4 h after-incision, and third day after surgery and mean differences in PGE2 levels

Based on the data shown in the previous table, the difference in PGE2 levels in the FSNB group showed a dynamics of decline at 4 h after incision (-98.00 pg/dL) and on the third day after surgery (-100.76 pg/dL) compared to before surgery conditions while in the ENB group, there was also a dynamics decrease at the 4 h after incision (–59.39 pg/dL) and on the third day after surgery (-65.41 pg/dL). When compared to the difference between the two groups, the FSNB group reduced PGE2 levels significantly more than the ENB group with a P value < 0.05.

A comparison of IL-6 levels is shown in Table 4. The median value of preoperative IL-6 levels in the FSNB group with a median value of 32.81 (214.49) pg/dL, and ENB group of 194.00 (362.40) pg/dL, and there were no significant differences in the two-research group with P > 0.05. In the FSNB group, there was an increase in IL-6 level at 4 h after incision and decreased on the third day after surgery, although it was not significantly different from the before surgery condition (P > 0.05). In the ENB group, there was a slight in decrease at the after-surgery IL-6 levels and did not differ significantly compared to the before-surgery condition (P > 0.05). The FSNB group did not show any decrease in after-surgery IL-6 levels and did not differ significantly from the ENB group.

Table 4::
Comparison of IL-6 levels before surgery, 4 h after-incision, and the third day after surgery and mean differences in IL-6 levels

The FSNB and ENB groups showed an increase in IL-6 levels in the 4 h after the incision period, not significantly different between the two groups. On the third day after surgery, there was a decrease in the FSNB group (-1.98 pg/dL) and an increase in the ENB group (2.98 pg/dL), but the two study groups did not show any significant difference (P > 0.05).

The clinical outcome assessed was postoperative pain, using VAS parameters. Patient assessment is carried out when at rest and at movement. The measurement of VAS was carried out before surgery, 1 h after surgery and the third day after surgery. A comparison of VAS scores is shown in Tables 5 and 6.

Table 5::
Comparison of VAS before surgery, 1 h after surgery, and third day after surgery
Table 6::
VAS scores differences

VAS scores at rest on before surgery did not show significant differences in the two groups, with P > 0.05. The data shows a decrease in VAS scores at 1 h after surgery in both the FSNB group and in the ENB group. Analysis of VAS scores difference at rest on 1 h postsurgery and the third day after surgery between the two groups was carried out using the Mann–Whitney analysis method at the significance level α = 0.05. The FSNB group showed a significant decrease in VAS score at rest on the third day after surgery compared to the ENB group with P < 0.05.

The before-surgery VAS scores between the two study groups were not significantly different with P > 0.05. Observation of the VAS scores at movement after surgery in both study groups showed significant improvement with a value of P < 0.05. The FSNB group showed decrease in pain at movement in the 1 h after surgery period and on the third day after surgery. It showed a significant difference from the before-surgery condition with a P value <0.05. The same thing also happened in the ENB group at 1 h after surgery and on the third day after surgery with P value <0.05. The FSNB group produced a better improvement in VAS scores at movement in the 1 h after surgery period and third day after surgery compared to the ENB group, with a P value <0.05.

Based on the results of a significant relationship pattern of the FSNB group to the improvement of the VAS scores at rest and at movement, it was continued with a linear regression test to find the effect of the FSNB on the decrease in the VAS score at rest on the third day after surgery and the VAS score at movement on the 1 h after surgery and on the third day after surgery. Based on the results of the analysis obtained with a value of P < 0.05 on VAS score at rest and at movement on the third day after surgery and 1 h after surgery. This means that there is a pure influence of the FSNB on improving VAS scores.


HsCRP is a sensitive but not specific systemic inflammation marker, which is formed due to tissue injury or acute inflammation. Increased levels of HsCRP due to surgery are associated with tissue damage.[41] In addition, in another study, it was reported that elevated levels of CRP/HsCRP were also associated with pain and delayed recovery in orthopedic surgery of the lower limbs.[29] so did the study from Stürmer et al.,[42] found an association of HsCRP with severe pain in osteoarthritis patients. Postoperative pain is a result of tissue injury and sometimes has the character of acute and persistent pain in the incision area that could release pro-inflammatory cytokines, including IL-6 and IL-1, which could promote the incidence of hyperalgesia and allodynia. IL-6 is the predominant proinflammatory cytokine besides IL-1 and TNF-α in the formation of CRP or HsCRP by hepatocyte cells that play a role in the process of opsonization.[43,44]

In this study, HsCRP levels were significantly increased at 4 h after incision and on the third day after surgery in both study groups. This result is similar with research conducted by Chloropoulou et al.[45] comparing the spinal anesthesia technique and the continuous epidural blockade technique, as well as the research conducted by Ozkul et al.,[46] which reported no significant difference between peripheral nerve blockade and spinal anesthesia to increase the inflammatory response to orthopedic surgery. A meta-analysis study reported that regional anesthesia did not result in a decrease in CRP/HsCRP levels in the postoperative period.[47] What caused an increase in HsCRP levels in our study was the extent of tissue damage that occurred. As is well known, orthopedic surgery in the cruris region is a major action that results in injury to the bone and bone marrow and a growing number of nociceptors active in deep somatic tissue (joints and muscles) that are sensitized by mechanical stimuli.[14] According to Watt et al.,[48] there is a consistent relationship between proinflammatory cytokine levels, especially IL-6 and CRP, to the severity of surgical procedures and tissue injury. Increased CRP levels are significantly associated with the severity of tissue damage due to the type of surgery.[49] In our study, there were variants mainly of the surgical techniques in the cruris region as well as operating manipulation factors which varied and directly played a role in the extent and severity of tissue damage leading to an increase in inflammatory mediators.[4,50,51] Postoperative CRP levels increase in the blood until the third day and then decrease rapidly and return to normal on the 12th day as the stimulus ends and the inflammatory process begins.[52]

Methods of regional anesthesia In this instance, neither the peripheral nerve block (FSNB) nor the epidural block (ENB) techniques used in the study had any effect on the amount of HsCRP produced during regional cruris surgery. This is likely due to local anesthetics used in regional anesthesia having a slight effect on cytokine responses to tissue damage due to surgery. Specifically, the effect of local anesthetic drugs on the modulation of inflammation through its interaction with G-protein-coupled receptors. The anti-inflammatory effect of local anesthetics is related to its systemic effect, which directly influences inflammation in the injured tissue.[53,54] Inhibition of these receptors occurs systemically at the clinical concentration of local anesthetic drugs.[55] Our study is also anatomically based on the FSNB technique, the sciatic nerve in the popliteal region is not located in a single neurovascular layer, so it is very rare that rapid absorption of local anesthetic drugs results in very slow systemic effects.[56] Our study shows that the difference in elevated HsCRP levels over time is smaller in the ENB group and significantly different than in the FSNB group in regional cruris surgery.

However, a significant increase in HsCRP levels from preoperative conditions in the two study groups did not exceed 100 times. As it is already well known, HsCRP levels are based on median values in healthy young people ranging from 0.8 to 1.7 mg/L.[57] In conditions of acute injury and surgery, there can be an increase in concentration of more than 100 times, especially on the first and second postoperative days.[58] The rapid increase in production of HsCRP levels (more than 5 mg/L) occurs within the first 6 h of acute injury and reaches a peak in 48 h.[59] In research conducted by Kolomachenko,[60] it was found that the lowest increase in CRP levels occurred in surgeries performed with regional anesthetic methods.

Although pain is said to be independent of the increase in HsCRP,[16] Continuous regional anesthesia techniques such as in this study have caused suppression of acute pain response through inhibition of nerve signals to the center due to axonal conduction blockade. Pain itself has a negative effect on the body’s immune response.[61,62] Another thing that is thought to influence the decrease in inflammatory mediator levels in the use of regional anesthetic techniques is its ability to suppress acute pain. Pain is known to suppress the function of the immune system and stimulate the release of proinflammatory cytokines through their effect on the sympathetic nerves.[63,64] The sympathetic response itself is a control system for the systemic inflammatory response. However, in research conducted by Okamoto et al.,[65] found that increased sympathetic response did not cause elevated HsCRP levels, and yet only increased IL-6 levels.

Regional anesthesia, in this case, neuraxial anesthesia, could inhibit the stress response but its effect on the suppression of cytokine production is inconsistent. This is likely due to nerve signals under regional anesthesia not completely blocked to the center despite being able to produce significant pain suppression.[35] Sensitization to the center continues, although local anesthetics placed along the nerve are able to block nerve signals through physical mediators, but nerve signals can still spread to the center through energy or nonphysical signals.[66] The inflammatory response due to surgery is necessary for the body to start the healing process but must be controlled so as not to overdo it. Regional anesthesia, with its ability to inhibit pain transmission and decrease the neuroendocrine response, reduce the excessive response of the hypothalamus–pituitary–adrenal (HPA) axis and the sympathetic nervous system so as not to suppress the immune system. Continuous FSNB and continuous ENB methods in regional cruris surgery do not result in a reduction in HsCRP levels at 4 h after incision and on the third day after surgery. Conversely, there was an increase in HsCRP levels in the 4-h post-science period and the third postoperative day, but the difference in levels in the ENB group was smaller and significantly different than in the FSNB group.

Tissue damage due to injury-producing kinin and potassium, which can stimulate afferent nerves secreting neuropeptide substance P (SP). Kinin is transformed to produce bradykinin which will activate the enzyme phospholipase A2 (PLA2) to convert phospholipids from cell membranes to arachidonic acid. One of the most common prostaglandins (PG) isoforms formed from arachidonic acid by COX-1 or COX-2 is PGE2. During the inflammatory response, there is a meaningful production in both levels and types of prostaglandins. Prostaglandin production is very low in tissues that are not inflamed but soon increase when there is acute inflammation before releasing leukocytes into the tissues. The histamine released by mast cells binds to H1 receptors (Histamine 1) in sensory afferent neurons, which in turn produces PGE2 in the periphery. PGE2 is the dominant cytokine that is released during trauma either through the humoral or nerve pathways during surgery and is associated with inflammation and pain events.[12,67] The operation produces a complex systemic response with an increase in plasma PGE2 and IL-6 levels due to tissue injury. PGE2 activates the sensitivity of neurons to pain after incision. Meanwhile, stimulation of the nociceptive nerve will release substance P, which will cause an increase in PGE2 production.[68,69] Inhibition of pain through a regional anesthetic block is known to be able to suppress the release of inflammatory mediators. The effect of regional anesthesia inhibits the stress response through its effect on the HPA axis through the inhibition of afferent nerve signals and the sympathetic nervous system.[70–72]

The two regional anesthesia methods compared in this study are known to have the ability to inhibit superior postoperative pain responses when compared to general anesthesia techniques that manage postoperative pain using patient-controlled analgesia. This occurs because local anesthetic drugs on FSNB and ENB cause secondary hyperalgesia inhibition and local inflammation at the peripheral. The effect is related to the inhibition of signals at the peripheral level so that the expression of COX-2 expression in the dorsal root and spinal cord is reduced, while due to axonal conduction inhibition also causes inhibition of PGE2 production by the peripheral nerves, which also reduces the effect due to inflammation of the peripheral. Furthermore, PGE2 production in cerebrospinal fluid also does not occur.[73] Buvanendran et al.,[13] stated that the upregulation of prostaglandin E2 and IL-6 at the center is an important component in the occurrence of an inflammatory response due to surgery and can affect the final outcome.

PGE2 is one of the mediators produced predominantly in tissue injury and osteotomy, especially in long bone fractures and is allergic, in addition to histamine, bradykinin, serotonin, and substance P.[74] In addition, pain indirectly increases sympathetic nerve responses that cause the release of bradykinin and subsequently stimulate the enzyme PLA2 to form PGE2 from arachidonic acid.[63] Increased PGE2 production also occurs from stimulation of the sympathetic postganglionic nerve as well as during the activation of nociceptors from tissues around the afferent nerve and macrophage cells.[75–77] The suppression of the pain response through regional anesthetic methods indirectly causes inhibition of the sympathetic response and is partly involved in preventing the overproduction of inflammatory mediators.[55,60] The antipain and anti-inflammatory effects of continuous FSNB can reduce PGE2 levels at 4 h after incision and on the third day after surgery and are significantly different than the continuous ENB method in the surgery of the cruris region.

IL-6 is a proinflammatory cytokine that is released with IL-1 during tissue injury. IL-6 can be induced by TNF-α and IL-1 production so that it causes fever and activation of the HPA axis by using α receptor (IL-6Rα) and gp 130 subunits. IL-6 is one of the cytokines that occur early and is an induction and control mediator for the synthesis of acute-phase proteins released by hepatocytes during pain stimuli such as trauma, infection, surgery, and burns.[78,79] In addition to that, it also activates astrocytes and microglia.[11] The role of IL-6 in the pain pathway is not yet known. In some studies, both in vitro and in vivo have not consistently linked IL-6 directly with pain, more to the effect on microglia and astrocyte cells and PGE2 regulation.[11,78,80–82] IL-6 in circulation is related to the severity of tissue damage that occurs during surgery[50] and causes hyperalgesia.[83] The same thing we got in our study, the two regional anesthetic techniques, in this case, the continuous FSNB and the continuous ENB did not completely reduce IL-6 levels in the two observation periods as indicated by an increase in IL-6 levels despite the increase not significantly different from the condition before surgery. In a meta-analysis study conducted by Alhayyan et al.,[47] stated that only a type of total intravenous anesthesia propofol could reduce IL-6 and CRP levels. Local anesthetic drugs used in regional anesthesia techniques have the ability to suppress the inflammatory response by blocking nerve transmission on the side of tissue trauma, which further inhibits neurogenic inflammation; local anesthetics have systemic anti-inflammatory effects.[84] This results in an explanation that anesthetic drugs used for regional anesthesia are able to prevent the hyperactivity of the inflammatory response without affecting the body’s defenses or suppressing the normal inflammatory response.[55] In our study, the continuous FSNB and the continuous anesthetic epidural block anesthetic method did not produce a significant decrease in IL-6 levels but were able to suppress the increase in its production at 4 h after incision and on the third day after surgery.

The ability of regional anesthesia to suppress the pain response is produced by inhibiting the formation of axon action potentials due to the bonding of local anesthetic drugs with Na-K channels on protein membranes along peripheral nerve axons or dorsal horns in the spinal cord.[85–87] Upregulation of PGE2 at the center is prevented through comprehensive barriers at the peripheral level so that it affects clinical outcomes.[13] In research conducted by Davies et al.,[88] reported that the combination of the peripheral blockade method was an alternative to the practice of postoperative pain management compared to epidural blockade of analgesia. This results in an emphasis on superior pain response and increases the satisfaction of patients undergoing knee arthroplasty surgery. Álvarez et al.,[89] reported that the use of the continuous femoral–sciatic block method resulted in effective after-surgery analgesic effects and minimal side effects compared with spinal anesthesia techniques with morphine intrathecal. A compilation study examining the effects of analgesia and length of stay on orthopedic surgery between peripheral nerve blockade, epidural blockade, and postoperative patient-controlled analgesia use reported that the peripheral nerve blockade method produces more effective analgesia with shorter stays compared to the epidural blockade method and patient-controlled analgesia.[90,91]

The improvement of VAS score in this study is related to the anesthesia method of peripheral nerve blockade, which is able to reduce the release of neurotransmitter substance P and CGRP so that it inhibits neurogenic inflammation in the peripheral.[38,39] Another thing to note is the sensitization of inflammatory mediators to the peripheral nociceptors; the signal transmission cannot be continued because of the blockade of local anesthetic drugs on the Na-K canal. Perineural catheter placement in the FSNB technique, besides producing continuous dosages of local anesthetic drugs on the peripheral nerves, the quality of the blockade density is better than ENB because the sensory nerves in the peripheral are smaller, without myelin, and so then the penetration of local anesthetics is easier,[92] so it is more effective in inhibiting nerve transmission and inflammation in the peripheral, and it has the ability to prevent tissue edema thus prevent acute pain.[34,93] The practice of neuraxial anesthesia for orthopedic surgery using standard techniques of epidural (ENB) has been proven to provide clinical benefits[91]; however, the biological impact to date has not consistently provided meaningful results; another thing is that there are still weaknesses related to anatomic conditions, side effects and limited use in high-risk cases. And with USG guiding technique, the practice of regional anesthesia can be done much safer. Its use can be carried out in high-risk patients in the presence of comorbid conditions undergoing major surgery because of minimal influence on the hemodynamic system and respiration.[24] Other benefits are fewer side effects, mainly related to the use of opioids for postoperative analgesia, and the discovery of significant effects on the inflammatory response of peripherals which are mainly associated with postoperative motion pain, length of stay, and early mobilization.[94,95] Biologically adequate postoperative pain response also reduces provocation for the release of further proinflammatory cytokines[96–98] and prevents depressed immune system function.[61,62] The subsequent use of continuous femoral–sciatic blockade clinically results in increased patient satisfaction, reduced length of stay, and reduced use of resources in the hospital.[99]


The findings in this study prove that the continuous FSNB results in an improvement in its ability to inhibit the postoperative acute pain response compared to the continuous epidural blockade anesthesia method in regional cruris surgery. The effect of the pure intervention on VAS scores is that the placement of local anesthetic drugs around the femoral and sciatic nerves has a better density in inhibiting nerve transmission to the central nervous system.

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1. Campbell J, Meyer R. Neuropathic pain: From the nociceptor to the patient.Merkey H, Loeser J, Dubner R. The Paths of Pain 1975–2005. Seattle: IASP Press; 2005. 229-42
2. Sommer M, De Rijke JM, Van Kleef M, Kessels AGH, Peters ML, Geurts JWJM, et al. The prevalence of postoperative pain in a sample of 1490 surgical inpatients. Eur J Anaesthesiol 2008;25:267-74
3. Chou LB, Wagner D, Witten DM, Martinez-Diaz GJ, Brook NS, Toussaint M, et al. Postoperative pain following foot and ankle surgery: A prospective study. Foot Ankle Int 2008;29:1063-8
4. Gerbershagen HJ, Aduckathil S, van Wijck AJM, Peelen LM, Kalkman CJ, Meissner W. Pain intensity on the first day after surgery. Anesthesiology 2013;118:934-44
5. Joshi GP, Ogunnaike BO. Consequences of inadequate postoperative pain relief and chronic persistent postoperative pain. Anesthesiol Clin North Am 2005;23:21-36
6. Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health 2011;11:770
7. Correll DJ, Vlassakov KV, Kissin I. No evidence of real progress in treatment of acute pain, 1993–2012: Scientometric analysis. J Pain Res 2014;7:199-210
8. Okeny PK, Ongom P, Kituuka O. Serum interleukin-6 level as an early marker of injury severity in trauma patients in an urban low-income setting: A cross-sectional study. BMC Emerg Med 2015;15:22
9. Sun CH, Li Y, Zhang YB, Wang F, Zhou XL, Wang F. The effect of vitamin-mineral supplementation on CRP and IL-6: A systemic review and meta-analysis of randomised controlled trials. Nutr Metab Cardiovasc Dis 2011;21:576-83
10. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011;1813:878-88
11. de Oliveira CMB, Sakata RK, Issy AM, Gerola LR, Salomão R. Cytokine and pain. Rev Bras Anestesiol 2011;61:255-60
12. Baba H, Kohno T, Moore KA, Woolf CJ. Direct activation of rat spinal dorsal horn neurons by prostaglandin E2. J Neurosci 2001;21:1750-6
13. Buvanendran A, Kroin JS, Berger RA, Hallab NJ, Saha C, Negrescu C, et al. Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology 2006;104:403-10
14. Larsson S, Thelander U, Friberg S. C-reactive protein (CRP) levels after elective orthopedic surgery. Clin Orthop Relat Res 1992. 237-42
15. Hall GM, Salmon P. Physiological and psychological influences on postoperative fatigue. Anesth Analg 2002;95:1446-50
16. Stürmer T, Raum E, Buchner M, Gebhardt K, Schiltenwolf M, Richter W, et al. Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain. Ann Rheum Dis 2005;64:921-5
17. Ackland GL, Scollay JM, Parks RW, De Beaux I, Mythen MG. Pre-operative high sensitivity C-reactive protein and postoperative outcome in patients undergoing elective orthopaedic surgery. Anaesthesia 2007;62:888-94
18. Honsawek S, Deepaisarnsakul B, Tanavalee A, Sakdinakiattikoon M, Ngarmukos S, Preativatanyou K, et al. Relationship of serum IL-6, C-reactive protein, erythrocyte sedimentation rate, and knee skin temperature after total knee arthroplasty: A prospective study. Int Orthop 2011;35:31-5
19. Karakaya C, Noyan T, Ekin S, Babayev E. Serum IL-6 and CRP levels in patients with trauma involving low-extremity bone fractures. East J Med 2014;18:176-80
20. Kidd B, Urban L. Mechanisms of inflammatory pain. Br J Anaesth 2001;87:3-11
21. Beilin B, Bessler H, Mayburd E, Smirnov G, Dekel A, Yardeni I, et al. Effects of preemptive analgesia on pain and cytokine production in the postoperative period. Anesthesiology 2003;98:151-5
22. Kawasaki T, Ogata M, Kawasaki C, Okamoto K, Sata T. Effects of epidural anaesthesia on surgical stress-induced immunosuppression during upper abdominal surgery. Br J Anaesth 2007;98:196-203
23. Yardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H. The effect of perioperative intravenous lidocaine on postoperative pain and immune function. Anesth Analg 2009;109:1464-9
24. Power I, McCormack JG, Myles PS. Regional anaesthesia and pain management. Anaesthesia 2010;65:38-47
25. Jin J, Wang G, Gong M, Zhang H, Liu J. Retrospective comparison of the effects of epidural anesthesia versus peripheral nerve block on postoperative outcomes in elderly Chinese patients with femoral neck fractures. Clin Interv Aging 2015;10:1223-31
26. Dolin SJ, Cashman JN, Bland JM. Effectiveness of acute postoperative pain management: Evidence from published data. Br J Anaesth 2002;89:409-23
27. Schulze S. Humoral and neural mediators of the systemic response to surgery. Dan Med Bull 1993;40:365-77
28. Norman JG, Fink GW. The effects of epidural anesthesia on the neuroendocrine response to major surgical stress: A randomized prospective trial. Am Surg 1997;63:75-80
29. Hall G, Peerbhoy D, Shenkin A, Parker C, Salmon P. Relationship of the functional recovery after hip arthroplasty to the neuroendocrine and inflammatory responses. Br J Anaesth 2001;87:537-42
30. Fant F, Tina E, Sandblom D, Andersson S, Magnuson A, Hultgren-Hornkvist E, et al. Thoracic epidural analgesia inhibits the neuro-hormonal but not the acute inflammatory stress response after radical retropubic prostatectomy. Br J Anaesth 2013;110:747-57
31. Ahmad MR, Bisri T. Does preemptive epidural analgesia completely block surgical stress responses?. Majalah Kedokteran Bandung 2013;1:147-54
32. Arakawa M, Aoyama Y, Ohe Y. Block of the sacral segments in lumbar epidural anaesthesia. Br J Anaesth 2003;90:173-8
33. Hogan Q. Distribution of solution in the epidural space: examination by cryomicrotome section. Reg Anesth Pain Med 2002;27:150-6
34. Benzon H, Toleikis J, Dixit P, Goodman I, Hill J. Onset, intensity of blockade and somatosensory evoked potential changes of the lumbosacral dermatomes after epidural anesthesia with alkalinized lidocaine. Anesth Analg 1993;76:328-32
35. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Fischer M, Zbinden AM. Temporal summation during extradural anaesthesia. Br J Anaesth 1995;75:634-5
36. Wen YR, Suter MR, Kawasaki Y, Huang J, Pertin M, Kohno T, et al. Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model. Anesthesiology 2007;107:312-21
37. Xie W, Strong JA, Zhang JM. Early blockade of injured primary sensory afferents reduces glial cell activation in two rat neuropathic pain models. Neuroscience 2009;160:847-57
38. Yonehara N, Shibutani T, Inoki R. Contribution of substance P to heat-induced edema in rat paw. J Pharmacol Exp Ther 1987;242:1071-6
39. Guo-ming F, Sui-liang G, Jia-ping D, Hong-mei Z, Gang C. The change of sustance P level in serum rabbit model after femoral nerve block. Chin J Pain Med 2012;95:80-8
40. Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of clinical phenomena. Res Nurs Health 1990;13:227-36
41. Kugisaki H, Sonohata M, Komine M, Tsunoda K, Someya S, Honke H, et al. Serum concentrations of interleukin-6 in patients following unilateral versus bilateral total knee arthroplasty. J Orthop Sci 2009;14:437-42
42. Stürmer T, Brenner H, Koenig W, Günther KP. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis 2004;63:200-5
43. Lowe GDO. Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J Thromb Haemost 2005. 1618-27
44. Hughes SF, Hendricks BD, Edwards DR, Middleton JF. Tourniquet-applied upper limb orthopaedic surgery results in increased inflammation and changes to leukocyte, coagulation and endothelial markers. PLoS ONE 2010;5:e11846
45. Chloropoulou P, Iatrou C, Vogiatzaki T, Kotsianidis I, Trypsianis G, Tsigalou C, et al. Epidural anesthesia followed by epidural analgesia produces less inflammatory response than spinal anesthesia followed by intravenous morphine analgesia in patients with total knee arthroplasty. Med Sci Monit 2013;19:73-80
46. Ozkul S, Baki E, Ozcan O, Koca H. Comparing the effects of spinal anesthesia and peripheral block applications against postoperative stress and inflammatory response on patients undergoing total knee arthroplasty. ARC J Anesthesiol 2018;3:1-9
47. Alhayyan A, McSorley S, Roxburgh C, Kearns R, Horgan P, McMillan D. The effect of anesthesia on the postoperative systemic inflammatory response in patients undergoing surgery: A systematic review and meta-analysis. Surg Open Sci 2020;2:1-21
48. Watt DG, Horgan PG, McMillan DC. Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: A systematic review. Surgery (United States) 2015;157:362-80
49. Neumaier M, Metak G, Scherer MA. C-reactive protein as a parameter of surgical trauma: CRP response after different types of surgery in 349 hip fractures. Acta Orthop 2006;77:788-90
50. Cruickshank AM, Fraser WD, Burns HJG, Van Damme J, Shenkin A. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci 1990;79:161-5
51. McSorley ST, Roxburgh CS, McMillan DC, Horgan PG. Surgeon specific effects on the postoperative systemic inflammatory response and complications following surgery for colorectal cancer. J Clin Oncol 2018;36:799
52. Kang BU, Lee SH, Ahn Y, Choi WC, Choi YG. Surgical site infection in spinal surgery: Detection and management based on serial C-reactive protein measurements clinical article. J Neurosurg Spine 2010;13:158-64
53. Jonsson A, Cassuto J, Hanson B. Inhibition of burn pain by intravenous lignocaine infusion. Lancet 1991;338:151-2
54. Cassuto J, Tarnow P. Potent inhibition of burn pain without use of opiates. Burns 2003;29:163-6
55. Hollmann MW, Wieczorek KS, Berger A, Durieux ME. Local anesthetic inhibition of G protein-coupled receptor signaling by interference with Gαq protein function. Mol Pharmacol 2001;59:294-301
56. Gaertner E, Fouche E, Choquet O, Hadzic A, Vloka J. Sciatic nerve block.In: Hadzic A. Text Book of Regional Anesthesia and Acute Pain1st ed. New York: Mc Graw Hill; 2007. 517-24
57. Shine B, de Beer FC, Pepys MB. Solid phase radioimmunoassays for human C-reactive protein. Clin Chim Acta 1981;117:13-23
58. Foglar C, Lindsey R. C-reactive protein in orthopedics. Orthopedics 1998;21:692-3
59. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest 1993;91:1351-7
60. Kolomachenko V. C-reactive protein level in plasma and drainage blood depends on the method of anaesthesia and post-operative analgesia after hip surgery. Anaesthesiol Intensive Ther 2018;50:117-21
61. Page GG. Immunologic effects of opioids in the presence or absence of pain. J Pain Symp Manage 2005;29Suppl_5S25-31
62. Franchi S, Panerai AE, Sacerdote P. Buprenorphine ameliorates the effect of surgery on hypothalamus–pituitary–adrenal axis, natural killer cell activity and metastatic colonization in rats in comparison with morphine or fentanyl treatment. Brain Behav Immun 2007;21:767-74
63. Khasar SG, Miao FJP, Jänig W, Levine JD. Modulation of bradykinin-induced mechanical hyperalgesia in the rat by activity in abdominal vagal afferents. Eur J Neurosci 1998;10:435-44
64. Areda E, Shafshak W, Zanaty O, Hadidi A, Omar A. Comparison between effects of two anesthetic techniques on acute stress proteins and d-dimer in patients undergoing lower limb orthopedic surgery. Res Opin Anesth Intensive Care 2016;3:14
65. Okamoto LE, Raj SR, Gamboa A, Shibao CA, Arnold AC, Garland EM, et al. Sympathetic activation is associated with increased IL-6, but not CRP in the absence of obesity: Lessons from postural tachycardia syndrome and obesity. Am J Physiol Hear Circ Physiol 2015;309:H2098-107
66. Chaban VV, Cho T, Reid CB, Norris KC. Physically disconnected non-diffusible cell-to-cell communication between neuroblastoma SH-SY5Y and DRG primary sensory neurons. Am J Transl Res 2013;5:69-79
67. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, et al. Interleukin-1 β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410:471-5
68. Ulmann L, Hirbec H, Rassendren F. P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain. EMBO J 2010;29:2290-300
69. Ricciotti E, Fitzgerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 2011;31:986-1000
70. Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav Immun 2007;21:736-45
71. Cruz FF, Rocco PRM, Pelosi P. Anti-inflammatory properties of anesthetic agents. Crit Care BioMed Central Ltd 2017;21:67
72. Besedovsky H, Del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science (80-) 1986;233:652-4
73. Beloeil H, Gentili M, Benhamou D, Mazoit JX. The effect of a peripheral block on inflammation-induced prostaglandin E2 and cyclooxygenase expression in rats. Anesth Analg 2009;109:943-50
74. Blackwell KA, Raisz LG, Pilbeam CC. Prostaglandins in bone: Bad cop, good cop?. Trends Endocrinol Metab 2010;21:294-301
75. Gonzales R, Goldyne ME, Taiwo YO, Levine JD. Production of hyperalgesic prostaglandins by sympathetic postganglionic neurons. J Neurochem 1989;53:1595-8
76. Sauer SK, Averbeck B, Reeh PW. Denervation and NKI receptor block modulate stimulated CGRP and PGE2 release from rat skin. Neuroreport 2000;11:283-6
77. Yamada T, Hasegawa-Moriyama M, Kurimoto T, Saito T, Kuwaki T, Kanmura Y. Peripheral nerve block facilitates acute inflammatory responses induced by surgical incision in mice. Reg Anesth Pain Med 2016;41:593-600
78. Zhang JH, Huang YG. The immune system: A new look at pain. Chin Med J (Engl) 2006;119:930-8
79. Senapathi TGA, Suarjaya IPP, Aryabiantara IW, Pradhana AP, Berhimpon AM. Oxycodone intravenous for acute pain management in modified radical mastectomy. Bali J Anesthesiol 2020;4:11
80. De Jongh RF, Vissers KC, Meert TF, Booij LHDJ, De Deyne CS, Heylen RJ. The role of interleukin-6 in nociception and pain. Anesth Analg 2003;96:1096-103
81. Tekieh E, Zaringhalam J, Manaheji H, Maghsoudi N, Alani B, Zardooz H. Increased serum IL-6 level time-dependently regulates hyperalgesia and spinal mu opioid receptor expression during CFA-induced arthritis. EXCLI J 2011;10:23-33
82. Senapathi TGA, Widnyana IMG, Hartawan IGAGU, Ryalino C, Kusuma OI. Differences in the suppression of immune response between general anesthesia and spinal anesthesia in femoral bone surgery. Bali J Anesthesiol 2020;4:14
83. Watkins LR, Maier SF, Goehler LE. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 1995;63:289-302
84. Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: Review of clinical and experimental evidence. Pain 1993;52:259-85
85. Butterworth JF IV, Strichartz GR. Molecular mechanisms of local anesthesia: A review. Anesthesiology 1990;72:711-34
86. Olschewski A, Hempelmann G, Vogel W, Safronov BV. Blockade of Na+ and K+ currents by local anesthetics in the dorsal horn neurons of the spinal cord. Anesthesiology 1998;88:172-9
87. Wang CF, Pancaro C, Gerner P, Strichartz G. Prolonged suppression of postincisional pain by a slow-release formulation of lidocaine. Anesthesiology 2011;114:135-49
88. Davies AF, Segar EP, Murdoch J, Wright DE, Wilson IH. Epidural infusion or combined femoral and sciatic nerve blocks as perioperative analgesia for knee arthroplasty. Br J Anaesth 2004;93:368-74
89. Álvarez NER, Ledesma RJG, Hamaji A, Hamaji MWM, Vieira JE. Continuous femoral nerve blockade and single-shot sciatic nerve block promotes better analgesia and lower bleeding for total knee arthroplasty compared to intrathecal morphine: A randomized trial. BMC Anesthesiol 2017;17:64
90. Kerfeld MJ, Hambsch ZJ, Mcentire DM, Kirkpat-Rick, Cai J, Youngblood CF. Physiologic advantages of peripheral nerve blockade trans- late to decreased length of stay and improved patient satisfaction. Res Pract Anesthesiol Open J 2016;1:4-14
91. Senapathi TGA, Widnyana IMG, Wiryana M, Mahaalit Aribawa IGN, Panji PAS, Soetjipto S, et al. Programmed intermittent epidural bolus improves efficacy of patient controlled epidural analgesia in postoperative pain management. Bali J Anesthesiol 2017;1:44
92. Bryant B, Kinight K. Pharmacology for Health Professionals3rd ed.Chastwood: Elsevier; 2011. 113-5
93. Gentili ME, Mazoit JX, Samii K, Fletcher D. The effect of a sciatic nerve block on the development of inflammation in carrageenan injected rats. Anesth Analg 1999;89:979-84
94. Richman JM, Liu SS, Courpas G, Wong R, Rowlingson AJ, McGready J, et al. Does continuous peripheral nerve block provide superior pain control to opioids? A meta-analysis. Anesth Analg 2006;102:248-57
95. Sakai N, Inoue T, Kunugiza Y, Tomita T, Mashimo T. Continuous femoral versus epidural block for attainment of 120° knee flexion after total knee arthroplasty: A randomized controlled trial. J Arthroplasty 2013;28:807-14
96. Marbach JJ, Schleifer SJ, Keller SE. Facial pain, distress, and immune function. Brain Behav Immun 1990;4:243-54
97. Desborough JP. The stress response to trauma and surgery. Br J Anaesth 2000;85:109-17
98. Kehlet H, Holte K. Effect of postoperative analgesia on surgical outcome. Br J Anaesth 2001;87:62-72
99. Jeon YH. Easier and safer regional anesthesia and peripheral nerve block under ultrasound guidance. Korean J Pain. 2016;29:1-2

Continuous epidural block; continuous femoral–sciatic block; HsCRP; IL-6; PGE2; VAS

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