Clinical efficacy of CRN’s three-stage approach for the treatment of infected neuropathic diabetic foot：a retrospective study

Clinical efficacy of CRN’s three-stage approach for the treatment of infected neuropathic diabetic foot：a retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical efficacy of CRN’s three-stage approach for the treatment of infected neuropathic diabetic foot：a retrospective study Qiang Dong, Zhicheng Zuo, Qing Li, Zhenhua Zhu, Kailong Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4508942/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Currently, clearing infections and repairing wounds are the main treatment for diabetic foot. However, statistics indicate that most cases of diabetic foot are caused by neuropathy alone or combined with vascular disease. In such cases, follow-up Neurotherapy plays a crucial role in managing diabetic foot patients. This study aimed to investigate the efficacy of using the CRN’s (Control infection, C; Repair wound, R; Neurolysis, N) three-stage approach in treating infected neuropathic diabetic foot. Methods A retrospective analysis was conducted on 84 diabetic foot patients with infection, ulceration, local gangrene, and neuropathy who were admitted to the Second Affiliated Hospital of Soochow University between March 2019 and March 2022. The treatment protocol involved complete surgical debridement in the first stage, wound repair surgery in the second stage, and the performance of Dellon triple neurolysis treatment three months after complete wound healing. The rate of foot sensory relief and the change of two-point discernment were compared before and after the operation. Results Following the operations, out of the 84 diabetic foot patients, 3 patients were treated with amputation due to progressive aggravation of infection and necrotizing fasciitis, while 81 underwent stages 2 and 3 of the treatment. Over an 8–18 months follow-up period, 3 patients were lost to follow-up, leaving 78 patients for analysis. Among them, 70 patients experienced successful wound healing without diabetic foot recurrence after the three-stage treatment, leading to successful limb preservation. 6 patients had diabetic foot recurrence but were readmitted for further treatment, resulting in successful wound repair and limb preservation. 2 patients passed away due to complications. Post-operation, neurologic symptoms improved in 76 patients who were followed up successfully, with a 95.9% foot sensory relief rate three months after the surgery, indicating positive outcomes. Additionally, two-point discrimination significantly improved three months post-surgery compared to pre-surgery levels, with statistical significance (P < 0.01). Conclusion The CRN’s three-stage surgical approach proves to be an effective method for treating infected neuropathic diabetic foot. It can shorten the hospital stay, regulate the treatment course, improve the limb-saving rate, and reduce the recurrence of diabetic foot. infected neuropathic diabetic foot control infection repair wound neurolysis Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Diabetic foot (DF) is a kind of foot infection, ulcer, and deep tissue destruction caused by nerve abnormalities and different degrees of vascular lesions in the distal lower limbs of patients with diabetes mellitus (DM). With the increasing number of diabetic patients, the incidence of diabetic foot is increasing. Epidemiological studies have shown that about 10–15% of patients with DM are attacked by DF. [ 1 ] As one of the most serious complications of DM, DF has a high mortality and disability rate. It is estimated that approximately 50% of patients with DF will die within five years, and 80% of DF patients will undergo lower limb amputation. [ 2 ] Due to diabetic patients’ vascular disease and neuropathy, small trauma can easily cause rupture, infection, necrotizing fasciitis, and even gangrene. According to statistics, about 50% of diabetic foot patients are caused by neuropathy, 15% with simple vasculopathy, and the remaining 35% are formed by the concurrent development of neuropathy and vasculopathy. [ 3 , 4 ] Therefore, the common diabetic foot in the clinic is the infected neuropathic diabetic foot. The basic features of this type diabetic foot are fever, local redness, and swelling, pus accumulation, local ulceration, and exudation with a foul odor and bad taste, accompanied or not accompanied by gangrene of the foot ( Fig. 1 A, B ) . How to regulate the treatment of infected neuropathic diabetic foot, improve the limb preservation rate, and reduce recurrence? It's something that clinicians need to think about. From March 2019 to March 2022, our department received a total of 84 patients with neurodegenerative diabetic foot with infection as the first symptom, all of whom were treated by CRN’s three-stage surgical approach, and achieved good curative effect. 2. Materials and Methods 2.1. General information A total of 84 patients diagnosed with infection-related neurodegenerative diabetic foot conditions, involving 92 feet, were enrolled in the study. The cohort comprised 52 male and 32 female participants, with an average age of 56 years (28-79). The inclusion criteria for diabetic foot patients in the study encompassed a history of inadequate blood glucose control, high random blood glucose levels upon admission, and clinical manifestations such as redness, swelling, ulceration, infection, wet gangrene, and in some cases, malodor in the affected foot. Additionally, varying degrees of hypoalgesia and abnormal two-point discrimination were observed during sensory examinations of the foot. Vascular assessments of the lower extremities revealed the presence of at least one major vessel supplying blood to the foot. Notably, 63 of the diabetic foot patients included in the study exhibited elevated body temperatures. 2.2. Three stages of surgery 2.2.1. Stage Ⅰ (Control infection, C): average hospitalization time 7-14 days. Patients were first examined for the degree of infection of the affected limb and secretions from the wound were retained for culture. For patients with poor foot sensation, necrotizing fasciitis, or severe infection, emergency incision and drainage were performed at the bedside, and then fill the wound with gauze; for those with less severe infection, antibiotic anti-infection treatment was given first. All patients underwent thorough debridement, open drainage, and filling of the dead space with antibiotic-laden bone cement under nerve block anesthesia or general anesthesia within three days ( Fig. 2A, B) , and the secretions were cultured again during the operation. In patients with poor infection control, extended debridement was performed again 2-3 days after the initial debridement until the infection was controlled. Among them, 49 patients had satisfactory infection control after one debridement, 22 patients had experienced twice debridement, 10 patients had experienced third debridement, and 3 patients had amputation due to progressive infection, and all the patients were filled with antibiotic-laden bone cement in the wounds. After the operation, the patients were observed to have decreased redness and swelling at the edges of the wounds of the affected limbs, with less exudation, and the infection indexes such as white blood cell counts, C-reactive protein, and procalcitonin were significantly improved compared with those at the time of admission to the hospital, which was in line with the criteria for discharge from the hospital. 2.2.2. Stage Ⅱ (Repair wound, R): average hospitalization time 10-21 days. Patients were readmitted to the hospital 1 month after the first stage of debridement treatment, complete the preoperative examination, remove the cement in the wound of the affected limb, and observe the wound condition, if there was no obvious infection, wound repair treatment was performed after simple debridement (Fig. 3A, B) . A total of 81 cases of diabetic foot patients entered the second stage of treatment, of which 54 cases of direct wound closure after debridement or partial closure of the wound, platelet-rich plasma prepared into a gel, placed in the wound for adjuvant therapy; 18 cases of free skin grafting, 9 cases of island flap or free flap to repair the wound. After the postoperative observation of the grafted skin and flap were well survived, wound healing was good, and then discharged. For patients with remaining wounds, wet compress and dressing change therapy should be performed, until the wound completely healed. The complete healing time of the 81 patients who entered this stage of treatment was from 1 month to 6 months. 2.2.3. Stage Ⅲ (Neurolysis, N): average hospitalization time is 7-10 days. Patients can undergo the third stage of Dellon triple neurolysis treatment if they are admitted to the hospital with no abnormal inflammatory indexes, good healing of the foot wound, no redness, swelling, and oozing 3 months after complete healing of the affected limb wound. A total of 81 patients entered the third stage of treatment. Under general anesthesia, according to the surgical markers made before surgery (Fig. 4A, B, C) , the patients underwent decompression of the common peroneal nerve at the head of the fibula (Fig. 4D) , incision of the flexor support band at the ankle canal, relaxation of the tibial nerve and its branches (Fig. 4E) , and incision of the extensor support band at the dorsum of the foot for deep peroneal nerve relaxation (Fig. 4F) , and closure of the wound after complete relaxation. After the wound healed well, the patient was discharged from the hospital and continued to take oral methylcobalamin tablets for 2-3 months. Before the three stages of treatment and 3 months after the end of treatment, two-point discrimination was measured in the foot of the patient's affected limb. Patients were asked to close their eyes and measure the two-point discrimination of the affected foot with a contact test disk. If the patient had a two-point sensation, the distance was gradually reduced and measured again until the patient's sensation shifted from two points to one point, and record the distance that we could measure the two-point sensation in the patient's foot at the last time. Analyzing the two groups of data to compare whether there was a statistical difference with a t-test. 3. Results Among the 84 patients with diabetic foot included, 3 patients underwent amputation due to progressive exacerbation of infection during the first stage of infection control, and the remaining 81 patients entered the second and third stages of treatment. The follow-up period was from 8 to 18 months, in which 3 cases were lost to follow-up and 78 patients were followed up. During the follow-up period, 70 patients had good wound healing of the affected limbs, no recurrence of diabetic foot, and were successful in limb preservation; 6 patients had recurrence of diabetic foot after the third stage of treatment, and were re-admitted to the hospital for debridement and repair of trauma, and were successful in limb preservation; and 2 patients died due to comorbidities. The postoperative follow-up of nerve symptoms in 76 patients found that 3 months after nerve release surgery, 73 patients had improved foot sensation and 3 had no significant change in sensation, with a relief rate of 95.9%, which showed a good therapeutic effect; the two-point discrimination of 76 patients in the follow-up before surgery was (12.3±2.5) mm, and the two-point discrimination 3 months after surgery was (8.3±1.6) mm. Compared with the admission time, the sensory sensitivity of the affected foot after surgery was significantly enhanced, the sensory recovery was obvious, and the difference was statistically significant (P < 0.01). ( Table 1 ) Table 1 shows the comparison of patients with two-point discrimination at admission and 3 months after surgery. The two-point discrimination of the patients in the follow-up before surgery was (12.3±2.5) mm, and the two-point discrimination 3 months after surgery was (8.3±1.6) mm. Compared with the admission time, the two-point discrimination 3 months after surgery was significantly enhanced, and the difference was statistically significant (P < 0.01). 4. Discussion 4.1. Pathogenesis characteristics and treatment difficulties of the infected neuropathic diabetic foot Diabetic foot is one of the serious complications of diabetes mellitus, and improper treatment can lead to catastrophic consequences such as amputation, and even life-threatening in severe cases. [5] The typing of a diabetic foot can be divided into vasculopathy type, neuropathic type, and vascular-neuropathic composite type. [6] Among them, pure angiopathy, i.e., diabetic foot caused by peripheral artery occlusion accounts for only 15%; pure neuropathy accounts for 50%; and vascular-neuropathy complex accounts for 35%. It can be seen that clinically, diabetic foot is usually dominated by neuropathy, based on which foot infection, ulceration, and even gangrene is combined. Therefore, we call this type of diabetic foot infected neuropathic diabetic foot. The basic features of infected-neuropathy type diabetic foot are fever, local redness and swelling, pus accumulation, local ulceration and exudation with a foul odor, accompanied or not accompanied by gangrene of the foot, and high infection indexes such as white blood cell count, the proportion of neutrophils, C-reactive protein, and procalcitonin can be seen in the laboratory examination of the hospital, and the CTA or DSA examination of the lower limbs showed that the main blood vessels of the lower limbs were basically patent or with mild-moderate stenosis, and at least one of the main blood vessels led to the foot; the nerve examination of the foot showed different degrees of hyperalgesia, and sensory retardation. The treatment difficulties of the infected neuropathic diabetic foot include the following four points: (1) the patient's general condition is poor, some patients are accompanied by sepsis and infective shock, the serious ones are life-threatening; (2) the local infection of the affected limb is heavy, some patients are combined with wet gangrene and necrotizing fasciitis, [7] if it is not controlled in time, the infection will spread rapidly; (3) after debridement, the local area will be left with large skin defect, and the repair of the wound is the basis of limb preservation; (4) How to improve neuropathy, partially or even completely restore the sensory function of the affected foot and reduce the recurrence of the diabetic foot after successful limb preservation is the key to the treatment of infected neuropathic diabetic foot. 4.2. CRN’s three-stage approach for systemic treatment of infected neuropathic diabetic foot To address the different stages of infected neuropathic diabetic foot, we proposed the CRN’s three-stage systemic treatment approach, including infection control, trauma repair, and neurolysis, and achieved good efficacy. 4.2.1. Control infection stage : infection control is the first stage of treatment for infected neuropathic diabetic foot, [8] and it is also an important stage to determine whether the limb can be successfully preserved. If the infection of the foot is serious when the patient is admitted to the hospital, incision, and drainage will be performed at the bedside immediately, and the wound will be filled with iodophor gauze; if the infection is mild-moderate, antibiotics can be given to anti-infection treatment temporarily, and the wound secretion will be taken for culture, and then debridement operation was performed actively after perfecting preoperative examination. Because of the possibility of progressive spread of infection, it is best to control the time of foot debridement within three days of admission; because most of the patients have neuropathy and poor sensation in the plantar and dorsal foot, the surgery can be performed under the nerve block anesthesia in the thigh or ankle, which can minimize the effect of anesthesia on the general condition. [9, 10] In the first stage of treatment, the principle of "quick, accurate, and ruthless" should be followed. "Fast" has three meanings, firstly, it means to carry out debridement surgery as early as possible, and the faster the better in the case of preliminary perfection of examination; secondly, it means fast operation speed under the premise of ensuring thorough debridement, and minimize the operation time; thirdly, it means to carry out second debridement quickly after the first debridement if the infection control is still unsatisfactory, especially in patients accompanied by wet gangrene or necrotizing fasciitis, and so on until the infection control is satisfactory. "Accuracy" refers to the need to open the abscess cavity thoroughly during surgical debridement, and at the same time to avoid damage to important blood vessels. As there is a physiologic gap in the foot, the infection usually spreads along the tendons of the flexor and extensor toes, so the surgical debridement must completely open the muscle spacing and drain thoroughly, which is the key step to control the infection. "Ruthless" means that the tissue that has been judged to be infected and necrotic during the operation should be thoroughly debrided, especially the partially necrotic bone, infected tendon, as well as seriously infected toe that has no value for preservation. It is important that the dorsal and plantar skin of the affected foot should be preserved as much as possible for the second stage of wound repair. After thorough debridement, the wound is filled with antibiotic-laden bone cement, which completely fills the dead space and is secured with sutures, the bone cement is drilled for drainage before it hardens. [11] 4.2.2. Repair wound stage: Wound repair is the second stage in the treatment of infected neuropathic diabetic foot and is the basis for successful limb preservation. After the first stage of debridement surgery, antibiotic-laden bone cement fills the wound for 1 month, the infection has been effectively controlled, and wound repair treatment is feasible. Wound repair is mainly done by direct suture technique, skin grafting technique, and flap technique, assisted by platelet-rich plasma technique to accelerate the healing of the wound. For patients who still have a small skin defect of the affected foot, the wound can be healed by wet compress and changing dressing. It is worth noting that in the stage of wound repair, direct suturing is the mainstay, supplemented by skin grafting, and hindfoot wounds can be repaired with island flaps or free flaps. [12] 4.2.3. Neurolysis stage: Nerve release is the third stage in the treatment of infected neuropathic diabetic foot, and it is also the key stage in preventing the recurrence of this type of diabetic foot. Diabetic foot neuropathy can be categorized into sensory neuropathy, motor neuropathy, and autonomic neuropathy. Sensory loss due to sensory neuropathy is the most common risk factor for developing diabetic foot. [13] A small trauma can cause the skin of the affected foot to break down and not be easily detected, [4, 14] and then the infection occurs and spreads rapidly and eventually develops into a serious diabetic foot ulcer. Dellon Triple Neurolysis is a proven effective procedure for the treatment of diabetic foot neuropathy, and the results of a multicenter prospective study conducted by Dellon demonstrated that in 655 diabetic patients with no prior foot ulcers, the incidence of foot ulcers was reduced by 15% to 0.6% over the course of 2.5 years, and for 44 patients with previous foot ulcers, their foot ulcer prevalence decreased from 50% to 2.2%. [15] We also verified this in our research. Intraoperative exploration showed that the nerve had undergone significant degeneration, partial edema, and different degrees of adhesive entrapment around the nerve, and the relief rate of sensory impairment after nerve release reached 95.9%. We suggest that nerve release surgery should be performed as much as possible 3 months after complete healing of the wound, which can minimize the risk of postoperative infection of the nerve release incision in patients. 4.3. Advantages of the CRN’s three-stage approach for the treatment of infected neuropathic diabetic foot Currently, surgical treatments for diabetic foot mainly include thorough debridement and wound repair. Platelet-rich plasma, which is rich in vascular growth factors, is also commonly used in the treatment of DFU, and its acceleration of wound healing has been demonstrated. [16, 17] In addition to this, transverse tibial bone relocation proposed by Ilizarov [18] for the treatment of diabetic foot has also been shown to induce neovascular regeneration and microvascular network generation in the distal limb of patients with diabetic foot ulcers. Vascular interventions such as percutaneous angioplasty and balloon dilatation angioplasty of the lower limb arteries have also achieved satisfactory clinical results, but studies [19, 20] have shown that patients with DFUs still have a high rate of restenosis after vascular interventions. Recently, some studies have also confirmed that extracorporeal shock wave therapy can increase neovascularization in DFU patients, which is a novel treatment modality. [21] Meanwhile, hyperbaric oxygen therapy has a better effect on DFU patients in terms of reducing trauma areas and accelerating wound healing. [16] Compared with the above diabetic foot treatment modalities, CRN’s three-stage approach to treating diabetic foot has its unique advantages. (1) Shorten hospitalization time, reduce patient treatment costs, and improve doctor-patient trust. Diabetic foot limb preservation treatment is a long process, CRN’s three-phase treatment corresponds to different stages of diabetic foot treatment, greatly shortening the single hospitalization time of the patient, reducing the patient's medical costs; importantly, solving the main problems of different stages of diabetic foot in different phases of the treatment can increase the acceptance and recognition of the patient, and at the same time, it is conducive to cultivating trust, and establishing a good doctor-patient relationship. Most patients with diabetic foot, generally have depression and other psychological disorders, [22] Too long hospitalization will aggravate the patient's psychological and emotional problems, leading to the patient's non-cooperation in the treatment, reducing the therapeutic effect, and even leading to treatment failure. CRN’s three-stage treatment can be used to avoid prolonged hospitalization by phasing the treatment to reduce the emergence of psychological problems. It is worth noting that in the first stage of treatment, the antibiotic-laden bone cement used to fill the patient's foot wounds has a relatively accurate efficacy in controlling infection in the diabetic foot, which has been clinically confirmed. [23] It also facilitated the change of medication and nursing care for the patients after they are discharged from the hospital, and the patients can change the medication by themselves at home, which provides the basics for the phased treatment. (2) Standardizing the treatment process. For the infected neuropathic diabetic foot that was not treated by the CRN’s three-stage treatment method, we found that it was difficult to grasp the timing of wound repair if the first and second stages were combined. Sometimes, in order to shorten the hospitalization time, flap or skin graft repair is rushed when the infection has not been fully controlled, and necrosis of the skin graft or skin flap occurs after surgery, which not only leads to a longer treatment cycle but also further aggravates the patient's psychological problems. If the second and third stages are operated at the same time, we found that patients often have difficulty in healing the incision of nerve release, and persistent oozing often occurs. For patients who underwent only one or two stages of treatment without practicing the third stage of nerve release, we found that the chance of recurrence of diabetic foot one year after surgery was high. For patients with diabetic foot treated with the three-stage approach of CRN, we found that the probability of recurrence or reoccurrence of diabetic foot after surgery was greatly reduced. (3) Improving limb preservation. The amputation rate of diabetic foot is high, [24] with more than 1 million diabetic foot amputations worldwide each year, and improper treatment can lead to higher amputation rates. Through the first and second stages of CRN’s three-stage therapy, the infection can be effectively controlled, the wound can be reasonably covered, and then the nerve release treatment using the Dellon triple neurolysis method can positively and effectively improve the sensory function of the patient's foot, and prevent the recurrence of diabetic foot due to sensory deficits. At the same time, through long-term follow-up, publicity, and education in outpatient clinics, and control of blood glucose, the amputation rate of patients with the infected neuropathic diabetic foot can be significantly reduced to help patients preserve their limbs successfully. 5. Conclusion In summary, for patients with neuropathic diabetic foot with infection, ulceration and local gangrene as the first symptom, applying CRN’s surgical three-stage method systematically to treat diabetic foot can shorten the hospitalization time of patients, reduce the cost of patients' treatment, standardize the treatment process, improve the rate of patients' limb preservation, and most importantly, it can largely avoid the recurrence of patients' diabetic foot, which is an effective method of treating the infected neuropathic diabetic foot. Abbreviations DF Diabetic Foot DM Diabetes Mellitus CRN Control infection, Repair wound, Neurolysis Declarations Ethics approval and consent to participate Ethical approval for this study was obtained from Ethics Committee of the Second Affiliated Hospital of Soochow University. Consent for publication The personal data contained in this study has been obtained with the consent of the individual. Data availability Data will be made available on request. Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This study was supported by the Project of State Key Laboratory of Radiation Medicine and Protection, Soochow University (GZK12023047). Authors’ contributions Qiang Dong : Writing – original draft, Writing – review & editing, Design, Collection and analysis of data. Zhicheng Zuo : Writing – original draft, Collection and analysis of data, Investigation, Methodology. Qing Li : Investigation, Methodology, Formal analysis. Zhenhua Zhu : Formal analysis, Design, Methodology. Kailong Zhou : Conception and design, Writing – original draft, Writing – review & editing, Methodology. All authors contributed to the article and approved the submitted version. Acknowledgements Not applicable References Petrova N, Edmonds M. 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Clin Infect Dis, 2012. 54(12): pp. e132-73. Zhu G, et al. Effect of peripheral nerve block versus general anesthesia on the hemodynamics and prognosis of diabetic patients undergoing diabetic foot Surgery. Diabetol Metab Syndr. 2023;15(1):213. Jor O, et al. Hypotension after induction of general anesthesia: occurrence, risk factors, and therapy. A prospective multicentre observational study. J Anesth. 2018;32(5):673–80. Ding X, et al. Analysis of the Effect of Antibiotic Bone Cement in the Treatment of Diabetic Foot Ulcer through Tibia Transverse Transport. Orthop Surg. 2022;14(9):2141–9. Yang X, et al. Free vascularized fascia flap combined with skin grafting for deep toe ulcer in diabetic patients. J Surg Res. 2018;231:167–72. Peltier A, Goutman SA, Callaghan BC. Painful Diabet neuropathy Bmj. 2014;348:g1799. Boulton AJ. What you can't feel can hurt you. J Vasc Surg. 2010;52(3 Suppl):s28–30. Dellon AL. Diabetic neuropathy: review of a surgical approach to restore sensation, relieve pain, and prevent ulceration and amputation. Foot Ankle Int. 2004;25(10):749–55. Zhang Z, et al. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcers: An updated systematic review and meta-analysis. Asian J Surg. 2022;45(1):68–78. Huang X, et al. Hyperbaric oxygen potentiates diabetic wound healing by promoting fibroblast cell proliferation and endothelial cell angiogenesis. Life Sci. 2020;259:118246. Ilizarov GA. The tension-stress effect on the genesis and growth of tissues. Part I. The influence of stability of fixation and soft-tissue preservation. Clin Orthop Relat Res, 1989(238): p. 249–81. Schneider PA. Evolution and current use of technology for superficial femoral and popliteal artery interventions for claudication. J Vasc Surg. 2017;66(3):916–23. Armstrong EJ, et al. Nitinol self-expanding stents vs. balloon angioplasty for very long femoropopliteal lesions. J Endovasc Ther. 2014;21(1):34–43. Skov-Jeppesen SM et al. [Indications and application of extracorporeal shockwave therapy]. Ugeskr Laeger, 2019. 181(8). Fejfarová V et al. Does the diabetic foot have a significant impact on selected psychological or social characteristics of patients with diabetes mellitus? J Diabetes Res, 2014. 2014: p. 371938. Dong T, Huang Q, Sun Z. Antibiotic-laden bone cement for diabetic foot infected wounds: A systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023;14:1134318. Sen P, Demirdal T, Emir B. Meta-analysis of risk factors for amputation in diabetic foot infections. Diabetes Metab Res Rev. 2019;35(7):e3165. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4508942","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":312232671,"identity":"1cf4ffd2-bcde-48cf-9226-7f0209335d86","order_by":0,"name":"Qiang Dong","email":"","orcid":"","institution":"Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215000","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Dong","suffix":""},{"id":312232672,"identity":"c0a7331a-0244-4927-8b24-c76d7636e0dc","order_by":1,"name":"Zhicheng Zuo","email":"","orcid":"","institution":"Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215000","correspondingAuthor":false,"prefix":"","firstName":"Zhicheng","middleName":"","lastName":"Zuo","suffix":""},{"id":312232673,"identity":"a87dcfc8-fb1e-484e-9422-7b7f9f929793","order_by":2,"name":"Qing Li","email":"","orcid":"","institution":"State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Li","suffix":""},{"id":312232676,"identity":"f9ecf191-ea82-4b29-8598-5199e015d3e2","order_by":3,"name":"Zhenhua Zhu","email":"","orcid":"","institution":"Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215000","correspondingAuthor":false,"prefix":"","firstName":"Zhenhua","middleName":"","lastName":"Zhu","suffix":""},{"id":312232688,"identity":"3123cf82-3689-4561-85fd-0c491d32e7eb","order_by":4,"name":"Kailong Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIiWNgGAWjYDACCQYGxgYGCRkQ+8AHg39ybOztB4jSwgNkMj6cUXHAmI/nTAIxWhhAWpiNec4cSJwn4WCAV4f87OZjkjNqLHj4pduvSc5su5PeJsGQwPCjYhtOLYxzjqVJbjgmwSM550yZxMe2Z7lt0o0HGHvO3MaphVkix0zyAZsEj8GNnDSgLcy5bTIHEpgZ23BrYQNr+QfRIs3bxpzOJpFggFcLD0jLxjaQlvTDQO8fTiCoRUIiLdlyZh/QLzNyQIGcZtgGDOSD+PwiPyP54M2eb3Vy/BLpD4BRaSMv395+8MGPCtxakN2IiI4DxKgHAvYHRCocBaNgFIyCkQYA9S1YZ2h1z2EAAAAASUVORK5CYII=","orcid":"","institution":"Department of Hand and Foot Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215000","correspondingAuthor":true,"prefix":"","firstName":"Kailong","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2024-05-31 12:29:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4508942/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4508942/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58760293,"identity":"a10e9517-dbfd-49b6-8d08-345d1f677832","added_by":"auto","created_at":"2024-06-20 18:49:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":806055,"visible":true,"origin":"","legend":"\u003cp\u003eDiabetic foot on admission. (A) shows redness, swelling, and infection of the dorsum of the forefoot and the 2nd toe of the left foot. (B) shows ulceration and oozing at the 2nd metatarsal head of the left plantar foot.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4508942/v1/bbee7f11f642570a69a8e9d2.png"},{"id":58760292,"identity":"60f9f77f-88f4-4352-a782-3dc8c412c9e2","added_by":"auto","created_at":"2024-06-20 18:49:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":804061,"visible":true,"origin":"","legend":"\u003cp\u003eStage Ⅰ (Infection control, C). (A) Intraoperative thorough debridement to remove infected necrotic tissue.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4508942/v1/0a7cdf548c0aaec000127c8c.png"},{"id":58760295,"identity":"be64e300-59ac-49bb-aba4-c80f52e9b7cf","added_by":"auto","created_at":"2024-06-20 18:49:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":890860,"visible":true,"origin":"","legend":"\u003cp\u003eStage Ⅱ (Wound repair, R). (A) Wound condition after removal of bone cement with satisfactory infection control. (B) Direct closure of the wound after simple debridement.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4508942/v1/f95c2ac8e5bc4b539267c27d.png"},{"id":58760294,"identity":"f9b15511-cd20-49e7-9a54-1f59a39e9142","added_by":"auto","created_at":"2024-06-20 18:49:16","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1057479,"visible":true,"origin":"","legend":"\u003cp\u003eStage Ⅲ (Neurolysis, N). (A, B, C) Preoperative neurolysis incisions. (D) Release of the common peroneal nerve. (E) Release of the tibial nerve. (F). Release of the deep peroneal nerve.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4508942/v1/43c17396f0b44b234366d91b.png"},{"id":65545416,"identity":"86601a18-06b4-45ce-8443-c8e478fa5d58","added_by":"auto","created_at":"2024-09-29 18:46:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3860244,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4508942/v1/c00a7b68-e1d1-459c-9e0d-8e2fda81af44.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical efficacy of CRN’s three-stage approach for the treatment of infected neuropathic diabetic foot：a retrospective study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDiabetic foot (DF) is a kind of foot infection, ulcer, and deep tissue destruction caused by nerve abnormalities and different degrees of vascular lesions in the distal lower limbs of patients with diabetes mellitus (DM). With the increasing number of diabetic patients, the incidence of diabetic foot is increasing. Epidemiological studies have shown that about 10\u0026ndash;15% of patients with DM are attacked by DF. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] As one of the most serious complications of DM, DF has a high mortality and disability rate. It is estimated that approximately 50% of patients with DF will die within five years, and 80% of DF patients will undergo lower limb amputation. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eDue to diabetic patients\u0026rsquo; vascular disease and neuropathy, small trauma can easily cause rupture, infection, necrotizing fasciitis, and even gangrene. According to statistics, about 50% of diabetic foot patients are caused by neuropathy, 15% with simple vasculopathy, and the remaining 35% are formed by the concurrent development of neuropathy and vasculopathy. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Therefore, the common diabetic foot in the clinic is the infected neuropathic diabetic foot. The basic features of this type diabetic foot are fever, local redness, and swelling, pus accumulation, local ulceration, and exudation with a foul odor and bad taste, accompanied or not accompanied by gangrene of the foot \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, B\u003cem\u003e)\u003c/em\u003e. How to regulate the treatment of infected neuropathic diabetic foot, improve the limb preservation rate, and reduce recurrence? It's something that clinicians need to think about. From March 2019 to March 2022, our department received a total of 84 patients with neurodegenerative diabetic foot with infection as the first symptom, all of whom were treated by CRN\u0026rsquo;s three-stage surgical approach, and achieved good curative effect.\u003c/p\u003e \u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1. General information\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA total of 84 patients diagnosed with infection-related neurodegenerative diabetic foot conditions, involving 92 feet, were enrolled in the study. The cohort comprised 52 male and 32 female participants, with an average age of 56 years (28-79). The inclusion criteria for diabetic foot patients in the study encompassed a history of inadequate blood glucose control, high random blood glucose levels upon admission, and clinical manifestations such as redness, swelling, ulceration, infection, wet gangrene, and in some cases, malodor in the affected foot. Additionally, varying degrees of hypoalgesia and abnormal two-point discrimination were observed during sensory examinations of the foot. Vascular assessments of the lower extremities revealed the presence of at least one major vessel supplying blood to the foot. Notably, 63 of the diabetic foot patients included in the study exhibited elevated body temperatures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThree stages of surgery\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.1. Stage Ⅰ (Control infection, C):\u0026nbsp;\u003c/strong\u003eaverage hospitalization time 7-14 days. Patients were first examined for the degree of infection of the affected limb and secretions from the wound were retained for culture. For patients with poor foot sensation, necrotizing fasciitis, or severe infection, emergency incision and drainage were performed at the bedside, and then fill the wound with gauze; for those with less severe infection, antibiotic anti-infection treatment was given first. All patients underwent thorough debridement, open drainage, and filling of the dead space with antibiotic-laden bone cement under nerve block anesthesia or general anesthesia within three days \u003cem\u003e(\u003c/em\u003e\u003cem\u003eFig. 2A, B)\u003c/em\u003e, and the secretions were cultured again during the operation. In patients with poor infection control, extended debridement was performed again 2-3 days after the initial debridement until the infection was controlled. Among them, 49 patients had satisfactory infection control after one debridement, 22 patients had experienced twice debridement, 10 patients had experienced third debridement, and 3 patients had amputation due to progressive infection, and all the patients were filled with antibiotic-laden bone cement in the wounds. After the operation, the patients were observed to have decreased redness and swelling at the edges of the wounds of the affected limbs, with less exudation, and the infection indexes such as white blood cell counts, C-reactive protein, and procalcitonin were significantly improved compared with those at the time of admission to the hospital, which was in line with the criteria for discharge from the hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.2. Stage Ⅱ (Repair wound, R):\u0026nbsp;\u003c/strong\u003eaverage hospitalization time 10-21 days. Patients were readmitted to the hospital 1 month after the first stage of debridement treatment, complete the preoperative examination, remove the cement in the wound of the affected limb, and observe the wound condition, if there was no obvious infection, wound repair treatment was performed after simple debridement \u003cem\u003e(Fig. 3A, B)\u003c/em\u003e. A total of 81 cases of diabetic foot patients entered the second stage of treatment, of which 54 cases of direct wound closure after debridement or partial closure of the wound, platelet-rich plasma prepared into a gel, placed in the wound for adjuvant therapy; 18 cases of free skin grafting, 9 cases of island flap or free flap to repair the wound. After the postoperative observation of the grafted skin and flap were well survived, wound healing was good, and then discharged. For patients with remaining wounds, wet compress and dressing change therapy should be performed, until the wound completely healed. The complete healing time of the 81 patients who entered this stage of treatment was from 1 month to 6 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.3. Stage Ⅲ (Neurolysis, N):\u0026nbsp;\u003c/strong\u003eaverage hospitalization time is 7-10 days. Patients can undergo the third stage of Dellon triple neurolysis treatment if they are admitted to the hospital with no abnormal inflammatory indexes, good healing of the foot wound, no redness, swelling, and oozing 3 months after complete healing of the affected limb wound. A total of 81 patients entered the third stage of treatment. Under general anesthesia, according to the surgical markers made before surgery \u003cem\u003e(Fig. 4A, B, C)\u003c/em\u003e, the patients underwent decompression of the common peroneal nerve at the head of the fibula \u003cem\u003e(Fig. 4D)\u003c/em\u003e, incision of the flexor support band at the ankle canal, relaxation of the tibial nerve and its branches\u003cem\u003e\u0026nbsp;(Fig. 4E)\u003c/em\u003e, and incision of the extensor support band at the dorsum of the foot for deep peroneal nerve relaxation \u003cem\u003e(Fig. 4F)\u003c/em\u003e, and closure of the wound after complete relaxation. After the wound healed well, the patient was discharged from the hospital and continued to take oral methylcobalamin tablets for 2-3 months.\u003c/p\u003e\n\u003cp\u003eBefore the three stages of treatment and 3 months after the end of treatment, two-point discrimination was measured in the foot of the patient\u0026apos;s affected limb. Patients were asked to close their eyes and measure the two-point discrimination of the affected foot with a contact test disk. If the patient had a two-point sensation, the distance was gradually reduced and measured again until the patient\u0026apos;s sensation shifted from two points to one point, and record the distance that we could measure the two-point sensation in the patient\u0026apos;s foot at the last time. Analyzing the two groups of data to compare whether there was a statistical difference with a t-test.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eAmong the 84 patients with diabetic foot included, 3 patients underwent amputation due to progressive exacerbation of infection during the first stage of infection control, and the remaining 81 patients entered the second and third stages of treatment. The follow-up period was from 8 to 18 months, in which 3 cases were lost to follow-up and 78 patients were followed up. During the follow-up period, 70 patients had good wound healing of the affected limbs, no recurrence of diabetic foot, and were successful in limb preservation; 6 patients had recurrence of diabetic foot after the third stage of treatment, and were re-admitted to the hospital for debridement and repair of trauma, and were successful in limb preservation; and 2 patients died due to comorbidities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe postoperative follow-up of nerve symptoms in 76 patients found that 3 months after nerve release surgery, 73 patients had improved foot sensation and 3 had no significant change in sensation, with a relief rate of 95.9%, which showed a good therapeutic effect; the two-point discrimination of 76 patients in the follow-up before surgery was (12.3\u0026plusmn;2.5) mm, and the two-point discrimination 3 months after surgery was (8.3\u0026plusmn;1.6) mm. Compared with the admission time, the sensory sensitivity of the affected foot after surgery was significantly enhanced, the sensory recovery was obvious, and the difference was statistically significant (P \u0026lt; 0.01). (\u003cem\u003eTable 1\u003c/em\u003e)\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"900\" height=\"184\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 shows the comparison of patients with two-point discrimination at admission and 3 months after surgery. \u0026nbsp;The two-point discrimination of the patients in the follow-up before surgery was (12.3\u0026plusmn;2.5) mm, and the two-point discrimination 3 months after surgery was (8.3\u0026plusmn;1.6) mm. Compared with the admission time, the two-point discrimination 3 months after surgery was significantly enhanced, and the difference was statistically significant (P \u0026lt; 0.01).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e\u003cstrong\u003e4.1. Pathogenesis characteristics and treatment difficulties of the infected neuropathic diabetic foot\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDiabetic foot is one of the serious complications of diabetes mellitus, and improper treatment can lead to catastrophic consequences such as amputation, and even life-threatening in severe cases. [5] The typing of a diabetic foot can be divided into vasculopathy type, neuropathic type, and vascular-neuropathic composite type. [6] Among them, pure angiopathy, i.e., diabetic foot caused by peripheral artery occlusion accounts for only 15%; pure neuropathy accounts for 50%; and vascular-neuropathy complex accounts for 35%. It can be seen that clinically, diabetic foot is usually dominated by neuropathy, based on which foot infection, ulceration, and even gangrene is combined. Therefore, we call this type of diabetic foot infected neuropathic diabetic foot. The basic features of infected-neuropathy type diabetic foot are fever, local redness and swelling, pus accumulation, local ulceration and exudation with a foul odor, accompanied or not accompanied by gangrene of the foot, and high infection indexes such as white blood cell count, the proportion of neutrophils, C-reactive protein, and procalcitonin can be seen in the laboratory examination of the hospital, and the CTA or DSA examination of the lower limbs showed that the main blood vessels of the lower limbs were basically patent or with mild-moderate stenosis, and at least one of the main blood vessels led to the foot; the nerve examination of the foot showed different degrees of hyperalgesia, and sensory retardation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe treatment difficulties of the infected neuropathic diabetic foot include the following four points: (1) the patient\u0026apos;s general condition is poor, some patients are accompanied by sepsis and infective shock, the serious ones are life-threatening; (2) the local infection of the affected limb is heavy, some patients are combined with wet gangrene and necrotizing fasciitis, [7] if it is not controlled in time, the infection will spread rapidly; (3) after debridement, the local area will be left with large skin defect, and the repair of the wound is the basis of limb preservation; (4) How to improve neuropathy, partially or even completely restore the sensory function of the affected foot and reduce the recurrence of the diabetic foot after successful limb preservation is the key to the treatment of infected neuropathic diabetic foot.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.2. CRN\u0026rsquo;s three-stage approach for systemic treatment of infected neuropathic diabetic foot\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo address the different stages of infected neuropathic diabetic foot, we proposed the CRN\u0026rsquo;s three-stage systemic treatment approach, including infection control, trauma repair, and neurolysis, and achieved good efficacy. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.2.1. Control infection stage\u003c/strong\u003e: infection control is the first stage of treatment for infected neuropathic diabetic foot, [8] and it is also an important stage to determine whether the limb can be successfully preserved. If the infection of the foot is serious when the patient is admitted to the hospital, incision, and drainage will be performed at the bedside immediately, and the wound will be filled with iodophor gauze; if the infection is mild-moderate, antibiotics can be given to anti-infection treatment temporarily, and the wound secretion will be taken for culture, and then debridement operation was performed actively after perfecting preoperative examination. Because of the possibility of progressive spread of infection, it is best to control the time of foot debridement within three days of admission; because most of the patients have neuropathy and poor sensation in the plantar and dorsal foot, the surgery can be performed under the nerve block anesthesia in the thigh or ankle, which can minimize the effect of anesthesia on the general condition. [9, 10]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the first stage of treatment, the principle of \u0026quot;quick, accurate, and ruthless\u0026quot; should be followed. \u0026quot;Fast\u0026quot; has three meanings, firstly, it means to carry out debridement surgery as early as possible, and the faster the better in the case of preliminary perfection of examination; secondly, it means fast operation speed under the premise of ensuring thorough debridement, and minimize the operation time; thirdly, it means to carry out second debridement quickly after the first debridement if the infection control is still unsatisfactory, especially in patients accompanied by wet gangrene or necrotizing fasciitis, and so on until the infection control is satisfactory. \u0026quot;Accuracy\u0026quot; refers to the need to open the abscess cavity thoroughly during surgical debridement, and at the same time to avoid damage to important blood vessels. As there is a physiologic gap in the foot, the infection usually spreads along the tendons of the flexor and extensor toes, so the surgical debridement must completely open the muscle spacing and drain thoroughly, which is the key step to control the infection. \u0026quot;Ruthless\u0026quot; means that the tissue that has been judged to be infected and necrotic during the operation should be thoroughly debrided, especially the partially necrotic bone, infected tendon, as well as seriously infected toe that has no value for preservation. It is important that the dorsal and plantar skin of the affected foot should be preserved as much as possible for the second stage of wound repair. After thorough debridement, the wound is filled with antibiotic-laden bone cement, which completely fills the dead space and is secured with sutures, the bone cement is drilled for drainage before it hardens.\u0026nbsp;[11]\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.2.2. Repair wound stage:\u003c/strong\u003e Wound repair is the second stage in the treatment of infected neuropathic diabetic foot and is the basis for successful limb preservation. After the first stage of debridement surgery, antibiotic-laden bone cement fills the wound for 1 month, the infection has been effectively controlled, and wound repair treatment is feasible. Wound repair is mainly done by direct suture technique, skin grafting technique, and flap technique, assisted by platelet-rich plasma technique to accelerate the healing of the wound. For patients who still have a small skin defect of the affected foot, the wound can be healed by wet compress and changing dressing. It is worth noting that in the stage of wound repair, direct suturing is the mainstay, supplemented by skin grafting, and hindfoot wounds can be repaired with island flaps or free flaps. [12]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.2.3. Neurolysis stage:\u0026nbsp;\u003c/strong\u003eNerve release is the third stage in the treatment of infected neuropathic diabetic foot, and it is also the key stage in preventing the recurrence of this type of diabetic foot. Diabetic foot neuropathy can be categorized into sensory neuropathy, motor neuropathy, and autonomic neuropathy. Sensory loss due to sensory neuropathy is the most common risk factor for developing diabetic foot.\u0026nbsp;[13]\u0026nbsp;A small trauma can cause the skin of the affected foot to break down and not be easily detected,\u0026nbsp;[4, 14]\u0026nbsp;and then the infection occurs and spreads rapidly and eventually develops into a serious diabetic foot ulcer. Dellon Triple Neurolysis is a proven effective procedure for the treatment of diabetic foot neuropathy, and the results of a multicenter prospective study conducted by Dellon demonstrated that in 655 diabetic patients with no prior foot ulcers, the incidence of foot ulcers was reduced by 15% to 0.6% over the course of 2.5 years, and for 44 patients with previous foot ulcers, their foot ulcer prevalence decreased from 50% to 2.2%.\u0026nbsp;[15]\u0026nbsp;We also verified this in our research. Intraoperative exploration showed that the nerve had undergone significant degeneration, partial edema, and different degrees of adhesive entrapment around the nerve, and the relief rate of sensory impairment after nerve release reached 95.9%. We suggest that nerve release surgery should be performed as much as possible 3 months after complete healing of the wound, which can minimize the risk of postoperative infection of the nerve release incision in patients.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.3. Advantages of the CRN\u0026rsquo;s three-stage approach for the treatment of infected neuropathic diabetic foot\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCurrently, surgical treatments for diabetic foot mainly include thorough debridement and wound repair. Platelet-rich plasma, which is rich in vascular growth factors, is also commonly used in the treatment of DFU, and its acceleration of wound healing has been demonstrated. [16, 17] In addition to this, transverse tibial bone relocation proposed by Ilizarov [18] for the treatment of diabetic foot has also been shown to induce neovascular regeneration and microvascular network generation in the distal limb of patients with diabetic foot ulcers. Vascular interventions such as percutaneous angioplasty and balloon dilatation angioplasty of the lower limb arteries have also achieved satisfactory clinical results, but studies [19, 20] have shown that patients with DFUs still have a high rate of restenosis after vascular interventions. Recently, some studies have also confirmed that extracorporeal shock wave therapy can increase neovascularization in DFU patients, which is a novel treatment modality. [21] Meanwhile, hyperbaric oxygen therapy has a better effect on DFU patients in terms of reducing trauma areas and accelerating wound healing. [16] Compared with the above diabetic foot treatment modalities, CRN\u0026rsquo;s three-stage approach to treating diabetic foot has its unique advantages.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(1) Shorten hospitalization time, reduce patient treatment costs, and improve doctor-patient trust. Diabetic foot limb preservation treatment is a long process, CRN\u0026rsquo;s three-phase treatment corresponds to different stages of diabetic foot treatment, greatly shortening the single hospitalization time of the patient, reducing the patient\u0026apos;s medical costs; importantly, solving the main problems of different stages of diabetic foot in different phases of the treatment can increase the acceptance and recognition of the patient, and at the same time, it is conducive to cultivating trust, and establishing a good doctor-patient relationship. Most patients with diabetic foot, generally have depression and other psychological disorders, [22] Too long hospitalization will aggravate the patient\u0026apos;s psychological and emotional problems, leading to the patient\u0026apos;s non-cooperation in the treatment, reducing the therapeutic effect, and even leading to treatment failure. CRN\u0026rsquo;s three-stage treatment can be used to avoid prolonged hospitalization by phasing the treatment to reduce the emergence of psychological problems. It is worth noting that in the first stage of treatment, the antibiotic-laden bone cement used to fill the patient\u0026apos;s foot wounds has a relatively accurate efficacy in controlling infection in the diabetic foot, which has been clinically confirmed. [23] It also facilitated the change of medication and nursing care for the patients after they are discharged from the hospital, and the patients can change the medication by themselves at home, which provides the basics for the phased treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(2) Standardizing the treatment process. For the infected neuropathic diabetic foot that was not treated by the CRN\u0026rsquo;s three-stage treatment method, we found that it was difficult to grasp the timing of wound repair if the first and second stages were combined. Sometimes, in order to shorten the hospitalization time, flap or skin graft repair is rushed when the infection has not been fully controlled, and necrosis of the skin graft or skin flap occurs after surgery, which not only leads to a longer treatment cycle but also further aggravates the patient\u0026apos;s psychological problems. If the second and third stages are operated at the same time, we found that patients often have difficulty in healing the incision of nerve release, and persistent oozing often occurs. For patients who underwent only one or two stages of treatment without practicing the third stage of nerve release, we found that the chance of recurrence of diabetic foot one year after surgery was high. For patients with diabetic foot treated with the three-stage approach of CRN, we found that the probability of recurrence or reoccurrence of diabetic foot after surgery was greatly reduced.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(3) Improving limb preservation. The amputation rate of diabetic foot is high, [24] with more than 1 million diabetic foot amputations worldwide each year, and improper treatment can lead to higher amputation rates. Through the first and second stages of CRN\u0026rsquo;s three-stage therapy, the infection can be effectively controlled, the wound can be reasonably covered, and then the nerve release treatment using the Dellon triple neurolysis method can positively and effectively improve the sensory function of the patient\u0026apos;s foot, and prevent the recurrence of diabetic foot due to sensory deficits. At the same time, through long-term follow-up, publicity, and education in outpatient clinics, and control of blood glucose, the amputation rate of patients with the infected neuropathic diabetic foot can be significantly reduced to help patients preserve their limbs successfully.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn summary, for patients with neuropathic diabetic foot with infection, ulceration and local gangrene as the first symptom, applying CRN\u0026rsquo;s surgical three-stage method systematically to treat diabetic foot can shorten the hospitalization time of patients, reduce the cost of patients' treatment, standardize the treatment process, improve the rate of patients' limb preservation, and most importantly, it can largely avoid the recurrence of patients' diabetic foot, which is an effective method of treating the infected neuropathic diabetic foot.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.370705244122966%\" valign=\"top\"\u003e\n \u003cp\u003eDF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.62929475587704%\" valign=\"top\"\u003e\n \u003cp\u003eDiabetic Foot\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.370705244122966%\" valign=\"top\"\u003e\n \u003cp\u003eDM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.62929475587704%\" valign=\"top\"\u003e\n \u003cp\u003eDiabetes Mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.370705244122966%\" valign=\"top\"\u003e\n \u003cp\u003eCRN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.62929475587704%\" valign=\"top\"\u003e\n \u003cp\u003eControl infection, Repair wound, Neurolysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was obtained from Ethics Committee of the Second Affiliated Hospital of Soochow University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe personal data contained in this study has been obtained with the consent of the individual.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be made available on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Project of State Key Laboratory of Radiation Medicine and Protection, Soochow University (GZK12023047).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQiang Dong\u003c/strong\u003e: Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Design, Collection and analysis of data. \u003cstrong\u003eZhicheng Zuo\u003c/strong\u003e: Writing \u0026ndash; original draft, Collection and analysis of data, Investigation, Methodology. \u003cstrong\u003eQing Li\u003c/strong\u003e: Investigation, Methodology, Formal analysis. \u003cstrong\u003eZhenhua Zhu\u003c/strong\u003e: Formal analysis, Design, Methodology. \u003cstrong\u003eKailong Zhou\u003c/strong\u003e: Conception and design, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Methodology. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePetrova N, Edmonds M. Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006;11(4):709\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMishra SC, et al. Diabet foot Bmj. 2017;359:j5064.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVibha SP, et al. Community based study to assess the prevalence of diabetic foot syndrome and associated risk factors among people with diabetes mellitus. BMC Endocr Disord. 2018;18(1):43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVolmer-Thole M, Lobmann R. Neuropathy and Diabetic Foot Syndrome. Int J Mol Sci, 2016. 17(6).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang Y, et al. A cohort study of diabetic patients and diabetic foot ulceration patients in China. Wound Repair Regen. 2015;23(2):222\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoor S, Zubair M, Ahmad J. Diabetic foot ulcer\u0026ndash;A review on pathophysiology, classification and microbial etiology. Diabetes Metab Syndr. 2015;9(3):192\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Z, et al. Necrotizing fasciitis caused by diabetic foot. Int J Infect Dis. 2021;103:3\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLipsky BA et al. 2012 \u003cem\u003eInfectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections.\u003c/em\u003e Clin Infect Dis, 2012. 54(12): pp. e132-73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu G, et al. Effect of peripheral nerve block versus general anesthesia on the hemodynamics and prognosis of diabetic patients undergoing diabetic foot Surgery. Diabetol Metab Syndr. 2023;15(1):213.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJor O, et al. Hypotension after induction of general anesthesia: occurrence, risk factors, and therapy. A prospective multicentre observational study. J Anesth. 2018;32(5):673\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDing X, et al. Analysis of the Effect of Antibiotic Bone Cement in the Treatment of Diabetic Foot Ulcer through Tibia Transverse Transport. Orthop Surg. 2022;14(9):2141\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang X, et al. Free vascularized fascia flap combined with skin grafting for deep toe ulcer in diabetic patients. J Surg Res. 2018;231:167\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeltier A, Goutman SA, Callaghan BC. Painful Diabet neuropathy Bmj. 2014;348:g1799.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoulton AJ. What you can't feel can hurt you. J Vasc Surg. 2010;52(3 Suppl):s28\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDellon AL. Diabetic neuropathy: review of a surgical approach to restore sensation, relieve pain, and prevent ulceration and amputation. Foot Ankle Int. 2004;25(10):749\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Z, et al. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcers: An updated systematic review and meta-analysis. Asian J Surg. 2022;45(1):68\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang X, et al. Hyperbaric oxygen potentiates diabetic wound healing by promoting fibroblast cell proliferation and endothelial cell angiogenesis. Life Sci. 2020;259:118246.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIlizarov GA. The tension-stress effect on the genesis and growth of tissues. Part I. The influence of stability of fixation and soft-tissue preservation. Clin Orthop Relat Res, 1989(238): p. 249\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchneider PA. Evolution and current use of technology for superficial femoral and popliteal artery interventions for claudication. J Vasc Surg. 2017;66(3):916\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmstrong EJ, et al. Nitinol self-expanding stents vs. balloon angioplasty for very long femoropopliteal lesions. J Endovasc Ther. 2014;21(1):34\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSkov-Jeppesen SM et al. [Indications and application of extracorporeal shockwave therapy]. Ugeskr Laeger, 2019. 181(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFejfarov\u0026aacute; V et al. \u003cem\u003eDoes the diabetic foot have a significant impact on selected psychological or social characteristics of patients with diabetes mellitus?\u003c/em\u003e J Diabetes Res, 2014. 2014: p. 371938.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDong T, Huang Q, Sun Z. Antibiotic-laden bone cement for diabetic foot infected wounds: A systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023;14:1134318.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSen P, Demirdal T, Emir B. Meta-analysis of risk factors for amputation in diabetic foot infections. Diabetes Metab Res Rev. 2019;35(7):e3165.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"infected neuropathic diabetic foot, control infection, repair wound, neurolysis","lastPublishedDoi":"10.21203/rs.3.rs-4508942/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4508942/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCurrently, clearing infections and repairing wounds are the main treatment for diabetic foot. However, statistics indicate that most cases of diabetic foot are caused by neuropathy alone or combined with vascular disease. In such cases, follow-up Neurotherapy plays a crucial role in managing diabetic foot patients. This study aimed to investigate the efficacy of using the CRN\u0026rsquo;s (Control infection, C; Repair wound, R; Neurolysis, N) three-stage approach in treating infected neuropathic diabetic foot.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e A retrospective analysis was conducted on 84 diabetic foot patients with infection, ulceration, local gangrene, and neuropathy who were admitted to the Second Affiliated Hospital of Soochow University between March 2019 and March 2022. The treatment protocol involved complete surgical debridement in the first stage, wound repair surgery in the second stage, and the performance of Dellon triple neurolysis treatment three months after complete wound healing. The rate of foot sensory relief and the change of two-point discernment were compared before and after the operation.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFollowing the operations, out of the 84 diabetic foot patients, 3 patients were treated with amputation due to progressive aggravation of infection and necrotizing fasciitis, while 81 underwent stages 2 and 3 of the treatment. Over an 8\u0026ndash;18 months follow-up period, 3 patients were lost to follow-up, leaving 78 patients for analysis. Among them, 70 patients experienced successful wound healing without diabetic foot recurrence after the three-stage treatment, leading to successful limb preservation. 6 patients had diabetic foot recurrence but were readmitted for further treatment, resulting in successful wound repair and limb preservation. 2 patients passed away due to complications. Post-operation, neurologic symptoms improved in 76 patients who were followed up successfully, with a 95.9% foot sensory relief rate three months after the surgery, indicating positive outcomes. Additionally, two-point discrimination significantly improved three months post-surgery compared to pre-surgery levels, with statistical significance (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe CRN\u0026rsquo;s three-stage surgical approach proves to be an effective method for treating infected neuropathic diabetic foot. It can shorten the hospital stay, regulate the treatment course, improve the limb-saving rate, and reduce the recurrence of diabetic foot.\u003c/p\u003e","manuscriptTitle":"Clinical efficacy of CRN’s three-stage approach for the treatment of infected neuropathic diabetic foot：a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-20 18:49:11","doi":"10.21203/rs.3.rs-4508942/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c2378588-079c-4d7a-9b5b-030452bdf5f5","owner":[],"postedDate":"June 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-29T18:38:22+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-20 18:49:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4508942","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4508942","identity":"rs-4508942","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}