Anesthesia via peripheral nerve blocks during total knee replacement has no effect on postoperative inflammation in elderly patients

Abstract

Background

We have previously shown that, compared with general anesthesia (GA), the procedure of peripheral nerve blocks (PNB) facilitates faster recovery of elderly patients from total knee replacement (TKR). Here, we investigated whether the faster recovery is associated with decreased perioperative stress and inflammation and decreased incidences of postoperative complications.

Methods

After randomization, 165 patients aged ≥65 years underwent TKR under GA or PNB. The primary outcomes were the perioperative inflammation and stress levels, based on the serum C-reactive protein and interleukin-6 levels, erythrocyte sedimentation rate, white-blood cell and neutrophil counts, and blood-sugar level. The secondary outcomes were the postoperative complications, including cardiovascular, respiratory, and hepatic or renal complications, insomnia, delirium, electrolyte disturbances, and nausea and vomiting.

Results

The two groups were not significantly demographically different (p > .05). Of the cytokines related to stress and inflammation, the differences of time points were statistically significant between the two groups (p < .01), but two-way ANOVA revealed no interaction between the time points and groups. Incidences of postoperative complications were far lower in PNB group than in GA group (p = .006). Incidences of postoperative respiratory complications (p = .005) and postoperative nausea and vomiting (p = .040) were significantly lower in PNB group than in GA group. There were no significant differences in other complications between the two groups (p > .05).

Conclusions

PNB does not alleviate the stress and inflammation in elderly patients post TKR but significantly reduces the incidences of postoperative complications, especially respiratory complications, and nausea and vomiting. (ClinicalTrials.gov Identifier: NCT01871012)

Keywords

general anesthesia nerve block inflammation complications

Introduction

Total knee replacement (TKR) is the most common and effective surgical option for moderate-to-severe knee arthritis. The frequency of this surgery in a society is proportional to the percentage of the elderly population with comorbidities and complications, which has been increasing with the aging of modern societies.^1,2 To date, either general anesthesia (GA) or local anesthesia (LA) has been used for knee arthroplasty. However, with the increased application of ultrasound and nerve-detection technologies in the clinic, a new procedure called peripheral nerve blocks (PNB) has recently emerged as an alternative approach to the spinal anesthesia during knee surgery, and most likely, it will gradually replace GA and LA as the primary anesthetic during knee arthroplasty.^3,4

PNB has emerged as a safe and effective anesthesia method and is widely used in lower limb surgery to provide the optimal perioperative analgesia.⁵ There is evidence of the effects of regional anesthesia, such as PNB, on the neuroendocrine response on the functions of immune cells, on gene expression, and on the secretion of inflammatory mediators including cytokines, with considerable advantages over general anesthesia in various surgical procedures.^6,7 During surgical procedures, nerve signals at the surgical site are usually completely or partially interrupted by nerve blocks with local anesthetics, and C-fiber blockade may inhibit peripheral inflammation in the corresponding innervated zone.⁸ Furthermore, in postoperative patients, peripheral nerve blocks have been shown to attenuate postoperative inflammatory response in knee arthroplasty.^9,10

We have previously found that, compared with GA, lumbar plexus and sciatic blocks facilitate faster recovery of the physiological functions, including the cognitive function, of elderly patients post TKR.^11–15Perioperative inflammatory response has central involvement in both postoperative complications and postoperative recovery.¹⁶ However, it is currently unclear whether the rapid postoperative recovery of elderly patients who underwent TKR under PNB is associated with reduced perioperative inflammatory response or postoperative complications. Thus, this study aimed to clarify this association. The primary goal of this study was the assessment of the surgery-induced stress and inflammation. The secondary goal was the assessment of the postoperative complications.

Methods

This cohort study (ClinicalTrials.gov Identifier: NCT01871012) was performed at the Chinese People’s Liberation Army General Hospital between June 2013 and September 2013. The research protocol was approved by the Ethics Committee of the hospital.

Interventions management

PNB, GA, and postoperative pain management were performed as we have previously reported.¹¹

Randomization, sample-size estimation, and outcome measures

Randomization was performed as we have previously reported.¹¹ The sample sizes were estimated using the Cochran–Mantel–Haenszel test.

The primary outcomes were perioperative stress and inflammation levels, based on the serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESRs), white-blood cell (WBC) counts, neutrophil (N) percentages, and blood-sugar levels before the surgery (baseline, BL) and on day 1 (D₁), D₃, D₅, and D₇ after the surgery. The secondary outcomes were the postoperative complications, including postoperative cardiovascular, respiratory, and hepatic or renal complications, insomnia, delirium, electrolyte disturbances, and PONV.

Statistical analysis

The variables were presented as percentages, numbers, or means ± SDs. Biological data were compared between the groups and time points via two-way ANOVA. The categorical variables (i.e., comorbidities, complications, and gender) were compared using the chi-square test. All the statistical tests were two-sided with a significance level of p < .05.

Results

A total of 356 patients aged ≥65 years were recruited from the Chinese People’s Liberation Army General Hospital between June 2013 and September 2013. Of them, 138 patients failed the inclusion criteria, did not consent to the study, or voluntarily withdrew before the randomization, and the remaining 218 patients completed the enrollment. Additionally, 5 patients were discharged <7 d after the surgery and were lost to follow-up. We excluded 27 patients from the remaining 213 elderly patients because of having used corticosteroids or nonsteroidal anti-inflammatory drugs within 14 d before the surgery. Finally, 186 patients were included in the study (96 in GA group and 90 in PNB group) (Figure 1).

Figure 1.

Flowchart showing subjects enrollment and analysis.

Patient characteristics

The demographic data about the patients in each group are shown in Table 1. There were more women than men in both groups, but no significant difference in gender was found between the two groups (p = .754), which were not significantly different in age or preoperative comorbidities, or according to the guidelines of the American Society of Anesthesiologists, either (p > .05). The most frequent comorbidity in both groups was hypertension, followed by coronary heart disease, and diabetes.

Table 1.

Demographic and preoperative data of the study patients.

	GA group (n = 96)	PNB group (n = 90)	χ²	p
Male sex (N, %)	21 (21.9%)	18 (20.0%)	0.099	0.754
Age (years), (mean ± SD)
65-75	62 (64.6%)	57 (63.3%)	0.032	0.859
75-85	28 (29.2%)	26 (28.9%)	0.002	0.967
86-89	6 (6.3%)	7 (7.8%)	0.167	0.683
ASA score (N, %)
I	6 (6.3%)	7 (7.8%)	0.167	0.683
II	75 (78.1%)	68 (75.6%)	0.173	0.678
III	15 (15.6%)	15 (16.7%)	0.037	0.847
Comorbidities (N, %)
Hypertension	56 (58.3%)	57 (63.3%)	0.487	0.485
CAD	22 (22.9%)	15 (16.7%)	1.139	0.286
Diabetes	21 (21.9%)	21 (23.3%)	0.057	0.812
COPD	10 (10.4%)	8 (8.9%)	0.124	0.725

ASA, American Society of Anesthesiologists; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease. Chi-square test.

Levels of inflammation-related cytokines and organ-injury markers

The mean level of each inflammation-related cytokine per group of patients is shown in Figure 2. The mean serum CRP levels in both groups started rising on D₁, reached the highest levels on D₃, and gradually decreased with time. Although the mean ESRs started rising on D₁ as well, they reached the highest levels on D₅. Other markers of inflammation, such as WBC count, N percentage, serum IL-6, and blood sugar reached their highest levels on D₁ and gradually decreased with time in both groups. Of the cytokine levels, two-way repeated-measures ANOVA revealed that the differences of time points were statistically significant between the two groups (p < .01), and there was no interaction between the time points and groups (Figure 2).

Figure 2.

Cytokine levels of inflammation between GA group and PNBs group.

Mean serum level of creatine kinase isoenzyme-MB gradually rose during the perioperative period but started decreasing on D₅ in both groups. Mean levels of HB and protein content gradually declined after the surgery in both groups. The levels of LDH and creatinine were not significantly different between the two groups. Of the levels of organ-injury markers, two-way repeated-measures ANOVA revealed that the differences of time points were statistically significant between the two groups (p < .01), and there was no interaction between the time points and groups (Figure 3).

Figure 3.

Organ injury markers between GA group and PNBs group.

Perioperative complications

Incidences of perioperative complications were far lower in PNB group than in GA group (41.1% vs 61.5%; p = .006). The common perioperative complications in both groups were as follows: PONV, cardiovascular complications, delirium, and insomnia. Incidences of perioperative respiratory complications (15.6% vs 3.3%; p = .005) and PONV (33.3% vs 20.0%; p = .040) were dramatically higher in GA group than in PNB group. Although the incidence of perioperative cardiovascular complications was also higher in GA group, the difference between the two groups was not statistically significant (24.0% vs 13.3%; p = .064). Incidence of perioperative delirium was 15.6% in GA group and 20.0% in PNB group (p = .435). There were no significant differences in perioperative insomnia, hepatic and renal functions, or electrolyte levels between the two groups (p > .05) (Table 2).

Table 2.

Perioperative complications of the subjects between GA group and PNB group.

	GA group (n = 96)	PNB group (n = 90)	χ2	p
Complications (N., %)	59 (61.5%)	37 (41.1%)	7.701	0.006
Respiratory system	15 (15.6%)	3 (3.3%)	8.029	0.005
Cardiovascular system	23 (24.0%)	12 (13.3%)	3.433	0.064
PONV	32 (33.3%)	18 (20.0%)	4.204	0.040
Insomnia	13 (13.5%)	20 (22.2%)	2.398	0.122
Delirium	15 (15.6%)	18 (20.0%)	0.609	0.435
Liver dysfunction	8 (8.3%)	7 (7.8%)	0.019	0.889
Renal dysfunction	2 (2.1%)	2 (2.2%)	0.194	0.660
Electrolyte disturbances	8 (8.3%)	11 (12.2%)	0.766	0.382

GA: General Anesthesia; PNB: Peripheral Nerve Blocks; PONV: Postoperative Nausea and Vomiting. Chi-square test.

Discussion

This study demonstrated that the application of PNB instead of GA during TKR does not affect the postoperative stress and inflammation levels but can significantly reduce the incidences of postoperative complications, especially respiratory complications, as well as nausea and vomiting in elderly Chinese patients.

Inflammatory mediators and stress are usually implicated in the physiological responses of the body or in the pathogeneses of several chronic diseases associated with aging or osteoarthritis, and their levels can dramatically increase by trauma or surgery. Negative consequences of surgical trauma or stress include insomnia, fatigue, prolonged recovery, and postoperative complications.¹⁷ Naturally, elderly patients generally have reduced functional reserves of organ systems, and thus they are less tolerant to surgical trauma than young patients. Consequently, perioperative complications more frequently occur in elderly patients than in young patients.¹⁸

Several studies have shown that postoperative changes in serum levels of certain cytokines are correlated with the degree of postoperative systemic inflammatory response. Substances released by sensory nerve endings produce inflammation in the target tissue after surgical procedures, which is a progress of neurogenic inflammation response.¹⁹ The key point of neurogenic inflammation is the activation of the primary afferent, which cause dorsal root reflexes in the spinal cord. In addition, Blocking the nerve through local anesthetics can reduce the release of substances, such as substance P and calcitonin gene–related peptide, and block neural transmission at the site of tissue injury, thereby alleviating the neurogenic inflammatory response.²⁰ However, the exact mechanisms are still largely unclear.

Serum levels of IL-6 and CRP are considered excellent markers for the inflammatory phase and prognosis after knee or hip replacement.^21–23 Nevertheless, other studies have shown that pre-mature assessment of the IL-6 and CRP levels is not helpful in the diagnosis of sepsis and that fluctuations in the levels after a trauma or surgery should be evaluated with caution.²⁴ Multiple animal or human experiments have suggested that the physiological advantages of PNB are beyond its pharmacological effects on inflammation.^25,26

Other studies have shown that PNB has no positive effect in reducing inflammation in the body.²⁵ The effects of neuraxial blockade with local anesthetics on postoperative inflammatory response are still controversial. For example, a previous study suggested that a combined continuous lumbar plexus and sciatic nerve blocks with 0.2% ropivacaine contributed to the attenuation of postoperative inflammatory response, which was demonstrated by decreased CRP and IL-6 concentrations in plasma 24 and 48 h postoperatively.⁽⁹ Another clinical study using more extensive nerve blocks, have also indicated attenuated ex vivo pro-inflammatory cytokine IL-6 and anti-inflammatory cytokine IL-10 production after visceral surgery.²⁷ However, Moore and coworkers found that the circulating CRP and IL-6 response to pelvic surgery was unaffected by extradural analgesia,²⁸ which is consistent with the present study where PNB has no positive effect in reducing inflammation.

Several investigators have reported that postoperative changes in serum IL-6 level are not associated with increases in post-operative serum CRP level.²⁹ PNB does not affect plasma IL-6 level, but this observation may result from the limited sensitivity of ELISA to detect cytokine concentrations.³⁰ In addition, plasma cytokine levels in patients after a knee operation may be insensitive to the clinical anti-inflammatory treatments. The anti-inflammatory effect of PNB may be related to inhibition of neurogenic inflammation rather than systemic inflammation. It is also possible that the inflammation and tissue damage caused by knee surgery is too strong to outweigh the anti-inflammatory effect of PNB. Another study has found that epidural analgesia instead of GA during abdominal surgery can decrease the postoperative levels of inflammatory factors.^31,32

The effect of PNB on biological indicators of inflammation appears to depend on several factors, such as the types of inflammatory markers, the assays used for the assessment, anesthesia techniques, age, and types of surgery. In addition, the therapeutics used and the pathological states of patients may also influence inflammation. Several studies have indicated that corticosteroids or nonsteroidal anti-inflammatory drugs may affect the systemic inflammatory response. Therefore, this study excluded 27 patients who took such drugs within 2 weeks before the surgery, in case these drugs may affect the postoperative inflammatory response.

This study did not find any serious organ dysfunction in the assessed elderly patients after the surgery. Additionally, there was no significant difference in levels of organ-injury markers between the two groups. However, incidences of postoperative complications were significantly higher in GA group than in PNB group. The incidence of pulmonary complications after mechanical ventilation was significantly higher in GA group than in PNB group. Laryngeal masks irritate the pharynx, causing significant increases in oral secretions during GA. Since the airway protective reflex is suppressed, some secretions may enter the trachea and bronchi, resulting in pulmonary inflammation. Furthermore, the reduced dosage of general anesthetics during the perioperative period may be another reason underlying the reduced incidences of postoperative pulmonary complications and PONV.

Conclusion

This study demonstrated that PNB has no significant effect on post-TKR stress and inflammation but significantly reduces the incidences of postoperative complications, especially postoperative respiratory complications and PONV, in elderly Chinese patients.

Footnotes

Acknowledgments

The authors acknowledge Hong Zhang for proofreading activity. Participating Investigator: The authors acknowledge Wei Pan who served as scientific advisor. Participating Investigator: The authors acknowledge Ying Zhao who collected data.

Authors’ contributions

Author Jianwen Jin and author Junle Liu have given substantial contributions to the conception or the design of the manuscript, author Maowei Gong and author Bin Lu to acquisition, analysis and interpretation of the data. All authors have participated to drafting the manuscript, author Shujun Pei revised it critically. All authors read and approved the final version of the manuscript. All authors contributed equally to the manuscript and read and approved the final version of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work.

Ethical statement

ORCID iD

Junle Liu

Appendix

References

Dennis

Wylde

Gooberman-Hill

, et al. Effects of presurgical interventions on chronic pain after total knee replacement: a systematic review and meta-analysis of randomised controlled trials. BMJ Open 2020; 10(1): e033248.

Samsuddin

Karim

Salim

. The outcomes of health education programme on stress level among the caregivers of post total knee replacement surgery. Front Psychiatr 2021; 12.

Yugal Karkhur Ramneek , et al. Adductor canal block%femoral nerve block%peripheral nerve blockade%total knee arthroplasty. J Anaesthesiol Clin Pharmacol 2019; 34(4): 433–438.

Gaukhman

Garceau

Ran

, et al. Evidence-based review of periarticular injections and peripheral nerve blocks in total knee arthroplasty. Open Orthop J 2020; 14(1): 69–72.

Nielsen

. Peripheral nerve blocks for analgesia after elective total hip arthroplasty. Acta Anaesthesiol Scand 2020; 64.

Tsukinaga

Mihara

. Effects of melatonin on postoperative sleep quality: a systematic review, meta-analysis, and trial sequential analysis. Can J Anaesth. 2023; 70(5): 901–914.

Abdallah

Laffey

Halpern

, et al. Duration of analgesic effectiveness after the posterior and lateral transversus abdominis plane block techniques for transverse lower abdominal incisions: a meta-analysis. Br J Anaesth 2013; 111(5): 721–735.

Gentili

Mazoit

Samii

, et al. The effect of a sciatic nerve block on the development of inflammation in carrageenan injected rats. Anesth Analg 1999; 89(4): 979–984.

Bagry

de la Cuadra Fontaine

Asenjo

, et al. Effect of a continuous peripheral nerve block on the inflammatory response in knee arthroplasty. Reg Anesth Pain Med 2008; 33(1): 17–23.

10.

Martin

Martinez

Mazoit

, et al. Antiinflammatory effect of peripheral nerve blocks after knee surgery: clinical and biologic evaluation. Anesthesiology 2008; 109(3): 484–490.

11.

Hong

Liu

Yuan

, et al. Peripheral nerve blocks versus general anesthesia for total knee replacement in elderly patients on the postoperative quality of recovery. Clin Interv Aging 2014; 2014: 341–350.

12.

Clark

Malcangio

. Microglial signalling mechanisms: cathepsin S and fractalkine. Exp Neurol 2012; 234(2): 283–292.

13.

Betz

Penzel

Rosen

, et al. Relationships between childhood trauma and perceived stress in the general population: a network perspective. Psychol Med. 2021; 51(15): 2696–2706.

14.

Ricardo Bonfante Marcelo , et al. The P2X7 receptor, cathepsin S and fractalkine in the trigeminal subnucleus caudalis signal persistent hypernociception in temporomandibular rat joints. Neurosci. 2018; 391: 120–130.

15.

Klivinyi

Rumpold-Seitlinger

Dorn

, et al. Perioperative use of physostigmine to reduce opioid consumption and peri-incisional hyperalgesia: a randomised controlled trial. BJA British J of Anaesthesia 2020; 126(3).

16.

Saxena

Lai

, et al. Neuroinflammation is a putative target for the prevention and treatment of perioperative neurocognitive disorders. Br Med Bull 2019; 130(1): 125–135.

17.

Thorn

. Effects of epidural analgesia on gastroduodenal motility Experimental and clinical studies with epidural morphine and epidural bupivacaine. Acta Anaesthesiol Scand 2010; 40(8): 957–957.

18.

Watson

Redmond

M Cc Arthy

, et al. Exposure of the peritoneal cavity to air regulates early inflammatory responses to surgery in a murine model. Br J Surg 2010; 82.

19.

Dansereau

Bégin-Lavallée

, et al. Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity. J Neuroinflammation. 2021; 18(1): 79.

20.

Luz

Lima

. Contralateral afferent input to lumbar lamina I neurons as a neural substrate for mirror-image pain. J Neurosci. 2023; 43(18): 3245–3258.

21.

Palmer

Pandit

Zeeshan

, et al. The acute inflammatory response after trauma is heightened by frailty: a prospective evaluation of inflammatory and endocrine system alterations in frailty. J Trauma Acute Care Surg 2019; 87.

22.

Hall

Peerbhoy

Shenkin

, et al. Hip and knee arthroplasty: a comparison and the endocrine, metabolic and inflammatory responses. Clin Sci 2000; 98(1): 71.

23.

Edwards

Kronfli

Haythornthwaite

, et al. Association of catastrophizing with interleukin-6 responses to acute pain. Pain 2008; 140(1): 135–144.

24.

Xiao

Zhuo

Huang

, et al. Predictive value of serum PCT,CRP and IL-6 on lung infection in elderly patients with severe brain injury. Chinese Journal of Cri Care Med. 2019; 39(05): 408–411.

25.

Leduc

Gentili

Estèbe

J-P

, et al. The effect of local anesthetics and amitriptyline on peroxidation in vivo in an inflammatory rat model: preliminary reports, Anesthesia & Analgesia 2002; 95.

26.

Martin

Narjoz

Decleves

, et al. Dextromethorphan analgesia in a human experimental model of hyperalgesia. Anesthesiology 2019; 131(2): 1.

27.

Beilin

Bessler

Mayburd

, et al. Effects of preemptive analgesia on pain and cytokine production in the postoperative period. Anesthesiology 2003; 98(1): 151–155.

28.

Moore

Desborough

Powell

, et al. Effects of extradural anaesthesia on interleukin-6 and acute phase response to surgery. Br J Anaesth 1994; 72(3): 272–279.

29.

Bagry

Carlos

Asenjo

, et al. Effect of a continuous peripheral nerve block on the inflammatory response in knee arthroplasty. Reg Anesth Pain Med 2008; 33(1): 17–23.

30.

Liou

Lee

Lin

, et al. P-selectin is required for neutrophils and macrophage infiltration into injured site and contributes to generation of behavioral hypersensitivity following peripheral nerve injury in mice. Pain 2013; 154(10): 2150–2159.

31.

Sun

Nan

, et al. Perioperative systemic lidocaine for postoperative analgesia and recovery after abdominal surgery: a meta-analysis of randomized controlled trials. Dis Colon Rectum 2013; 56(11): 271–271.

32.

Spolverato

Maqsood

Kim

, et al. Neutrophil-lymphocyte and platelet-lymphocyte ratio in patients after resection for hepato-pancreatico-biliary malignancies. J Surg Oncol 2015; 111(7): 868–874.