Tourniquet (TQ) use is a common practice in lower extremity orthopedic surgeries, such as foot and ankle surgeries, total knee arthroplasties, anterior cruciate ligament (ACL) reconstruction, meniscal repair, and open reduction internal fixation (ORIF) of fractures, to minimize blood loss, optimize surgical visualization, and reduce operative times [1-3]. However, while tourniquet use has been shown to reduce intraoperative blood loss, it does not affect postoperative or total blood loss [4-5]. Moreover, tourniquet use has not been demonstrated to improve functional outcomes, post-operative pain [6], or joint recovery [5], and may even impede post-operative mobility [1][3].

Tourniquet use carries significant intra-operative and post-operative risks, including ischemia-reperfusion injuries, which can be mitigated by strategies such as limiting tourniquet time to 2 hours, cooling the extremity, closer monitoring of blood pressure, and giving glucocorticoids [7-8].

The use of tourniquets has been linked to higher risks of deep vein thrombosis, pulmonary embolism, and perioperative wound hematomas [5][9]. Moreover, the effects of tourniquets may persist even after surgery, as studies have demonstrated that they can lead to increased muscle atrophy and potentially contribute to the development of chronic pain [2][10].

Although tourniquet use is widespread, its effects on the development and mechanisms of chronic pain are not yet fully understood. Orthopedic procedures have been linked to the occurrence of complex regional pain syndrome, a type of neuropathic pain that does not follow a dermatomal distribution [10].Earlier studies have suggested that the development of complex regional pain syndrome (CRPS) may be associated with early inflammatory responses, hyperactive sympathetic outflow, and metabolic hyper-reperfusion, all of which can lead to microvascular and ischemic injury [11]. These injuries, in turn, trigger chronic inflammatory and neuropathic pain processes [11]. Recent animal studies have shown that ischemic reperfusion injury, edema, and tissue inflammation occur following tourniquet release [11-13]. This suggests that tourniquet use may play a role in the development of CRPS.

Advancements in our understanding of the mechanisms underlying these changes may help decrease the incidence of persistent pain after limb surgeries. In addition to the use of tourniquets, other factors that contribute to chronic pain after total knee arthroplasty include psychological predictors, as well as preoperative distress and pain. The aim of our study was to investigate the incidence of PSCP and explore the potential factors associated with its onset following tourniquet application during orthopedic surgeries aimed at minimizing intraoperative blood loss.

In our retrospective chart review, we gathered clinical and surgical data on patients who underwent orthopedic limb surgery with a tourniquet at Massachusetts General Hospital between January 1st, 2012, and December 31st, 2013. We collected demographic information from electronic medical records (EPIC and QPID), including age, gender, race, height, weight, ASA status, and tourniquet time. No exclusion criteria were applied, and the cohort was not limited by age, sex, weight, ASA status, or tourniquet time.

We developed a survey to assess the incidence of PSCP in our patient cohort. This survey collected information on the occurrence and severity of chronic pain, as well as individual characteristics of the pain, and was conducted through phone interviews. A total of 111 patients were contacted, 64 of whom had received surgery in 2012 and 47 of whom had received surgery in 2013. From this group, 34 patients were included in the final cohort, as they had both clinical and follow-up data available. Unfortunately, 77 patients were lost to follow-up due to lack of contact availability, mortality, or decline to participate in the study Figure.

Figure: Inclusion procedure.

The data was subjected to several statistical analyses. Baseline characteristics were presented using frequency and percentage for both PSCP and non-PSCP groups. The demographic and surgical variables of these characteristics were compared using the standardized mean difference measure of effect. A generalized linear mixed model was employed to compare changes in tourniquet time, ASA status, weight, and surgeon between the PSCP and non-PSCP groups. The outcome of interest was the interaction between patients who developed PSCP and those who did not. All tests were two-sided, and statistical significance was set at p < 0.05. The statistical analysis was performed using R and Rstudio statistical software.

We examined individual demographic and surgical variables for patients who experienced PSCP and those who did not in our cohort (Table ). There was an even split of 17 patients who experienced PSCP and 17 patients who did not. Although none of the subgroups in the study were significant to the outcome of PSCP with a p-value <0.05, the standardized mean difference (SMD) for age, gender, race, height, weight, ASA class, and year of surgery resulted in values >0.2, indicating that the effect size of these variables may be meaningful to the prevalence of PSCP.

Table: Patient Demographics.

More specifically, the average age of patients with PSCP was 60, while that of patients without PSCP was 69. Of the patients with PSCP, 52.9% had a pre-operative ASA score of 2, compared to 82.4% of patients without PSCP. Among the patients who experienced PSCP, 82.4% (14 of 17) had received a lower extremity tourniquet, which was the same for patients who did not experience PSCP. None of the variables were found to be significant and predictive of PSCP outcome. However, as we used an SMD cutoff point of 0.2, the values >0.2 for age, gender, race, height, weight, ASA class, and year of surgery suggest that the effect size of these variables may be meaningful to the prevalence of PSCP outcome.

We also conducted a linear mixed-effects regression analysis, adjusted for tourniquet time, ASA class, weight, and surgeon, but the results were negative, indicating that these variables did not have a significant effect on the prevalence of PSCP.

Despite advances in understanding the clinical outcomes of PSCP, there is still a significant gap in the literature regarding the underlying mechanisms that contribute to its development. This study aims to identify relevant characteristics of the patient population to facilitate further research into the neuroimmunology of pain. Notably, PSCP has recently been recognized as an ICD-11 diagnosis, defined as pain persisting for at least three months following surgery, which was not present before surgery or has different characteristics or increased intensity from preoperative pain. This pain is localized to the surgical site or a referred area, and other possible causes of the pain were excluded (e.g., cancer recurrence, infection) [14].

It is widely accepted that the immune system produces pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, which play a role in the pathophysiology of pain [15-17]. The development of chronic pain is thought to be mediated by signaling pathways between peripheral and central nociceptor sensory communication [18] and sensitization to these nociceptors. In Coderre's animal model of complex regional pain syndrome, rats showed evidence of a neuropathic-like pain syndrome following prolonged ischemia and reperfusion, with the generation of free radical scavenger. However, the exact mechanism linking ischemia, reperfusion, and pain in the animal model remains unclear. In humans, the sensitization between nociceptor sensory neurons and other aspects of the nervous and immune system, such as neuronal support cells, glial cells, immune cell receptors, and biomarkers, is still poorly understood. Some studies have identified biomarkers involved in neuroinflammation and chronic pain states and have focused on endogenous receptor agonism to reduce pro-inflammatory signaling [19]. Additionally, current studies are investigating the role of cannabinoid receptors [17-18] and IgG autoantibodies [19] in immune modulation and signaling in pain.

Although multiple pathophysiological mechanisms have been proposed to explain why PSCP occurs, it is still not well understood clinically, and further research is required to identify relevant clinical factors and biomarkers for future therapeutic goals.According to current literature, the incidence of PSCP varies depending on the type of surgery, and studies have shown that it occurs in both invasive and non-invasive surgeries [14]. The incidence of PSCP after limb surgeries ranges from 30% to 85% for amputations, 7% to 23% for hip arthroplasties, and 13% to 44% for knee arthroplasties [20]. In hip and knee arthroplasties, which have seen an increase in volume due to risk factors such as obesity, inflammatory disease, and increased life expectancy, there has been a higher incidence of PSCP [20].

Among various acute surgeries, amputation remains associated with the highest incidence of PSCP, as supported by multiple studies. The prediction of PSCP is challenging, but the current literature suggests that independent risk factors include the type of surgical procedure, age, physical and mental health, and preoperative pain (20). Other studies have identified risk factors based on preoperative, intraoperative, and postoperative approaches [21]. Future research aims to reduce the incidence of PSCP by identifying modifiable risk factors, such as modifying surgical techniques, using pharmacological interventions, and utilizing non-pharmaceutical therapies, such as physiotherapy and psychological support. While identifiable risk factors for PSCP have been established, there is limited data on the use of tourniquets during limb surgery and the impact on PSCP outcomes.

Our study aimed to evaluate the incidence of PSCP in patients who underwent orthopedic surgery with tourniquet use, and to determine if tourniquet time was associated with a greater incidence of chronic pain. Our results indicate that while tourniquet time did not have a significant correlation with the development of PSCP, certain patient demographics such as age, weight, and ASA classification at the time of the procedure were significant factors in the outcome and incidence of PSCP. These findings are consistent with current literature that identifies age, physical health, and obesity as independent risk factors for PSCP.

Although our study did not yield significant results, it offers insight into future tourniquet use in practice, as animal studies have shown the potential complications of ischemic reperfusion injury and edema, and tissue inflammatory changes immediately after tourniquet release. The use of a tourniquet in lower extremity limb surgery remains a topic of debate.

There were limitations to our study, including a small sample size and challenges with long-term follow-up. As the sample was based on patients of a group of surgeons, this could introduce procedure and outcome bias. Difficulties in contacting patients for follow-up could also introduce bias.

Further investigation is needed to identify modifiable factors that can improve outcomes and decrease the incidence of post-surgical chronic pain and ischemic-reperfusion injury.

Our study found that there was no significant association between tourniquet time and the development of PSCP. However, we observed that certain patient demographics, such as age, weight, and ASA classification at the time of the procedure, were associated with the incidence and outcome of PSCP. These findings are consistent with previous research that has identified age, physical health, and obesity as independent risk factors for PSCP. Further studies are needed to identify modifiable factors that can decrease the incidence of PSCP and ischemic-reperfusion injury in orthopedic surgery patients.

Conflict of Interest

All the authors declare no competing interests.

 Authors Contributions

Jingping Wang: Conceptualization, Methodology. Karen Li: Writing- Original draft preparation. Yuxiang Liu: Investigation. He Ma: Software, Validation. Shihab Ahmed: Writing- Reviewing and Editing.

Acknowledgements

Not applicable.

Funding

This work was supported by the the project of the Jilin Science and Technology Department (YDZJ202201ZYTS613, 2022) to He Ma.

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