Ignite Creation Date:
2024-05-06 @ 6:57 PM
Last Modification Date:
2024-10-26 @ 2:57 PM
Study NCT ID:
NCT05840276
Status:
RECRUITING
Last Update Posted:
2023-09-25
First Post:
2023-04-21
Brief Title:
Cryoneurolysis Prior to Total Knee Arthroplasty
Sponsor:
Hospital of South West Jutland
Organization:
Hospital of South West Jutland
Study Overview
Official Title:
Cryoneurolysis Prior to Total Knee Arthroplasty for the Management of Postoperative Pain A Randomized Sham-controlled Trial
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Knee osteoarthritis is a major issue worldwide with limited treatment options Many patients receive knee joint replacement surgery which is considered effective and safe Nonetheless the period post-surgery is characterized by moderate to severe pain inhibiting early ambulation motivation and range of motion compromising rehabilitation patient satisfaction and overall outcomes An optimal strategy of postoperative pain treatment after knee replacement surgery has not yet been established
Recently our research center and others have shown that is possible to target the nerves surrounding the knee with a novel treatment called cryoneurolysis Cryoneurolysis apply low temperatures -20C -100C to a target nerve which disrupts nerve function and provides potential pain relief This suggest a potential for cryoneurolysis to significantly improve rehabilitation reduce opioid intake and overall outcomes after knee replacement surgery
The primary objective of the current project is to determine the effectiveness of cryoneurolysis in its proposed ability to reduce opioid intake and postoperative pain after knee replacement surgery
The study is a randomized controlled study with two groups Group CRYO receives cryoneurolysis prior to knee replacement surgery and group SHAM receives a sham treatment prior to knee replacement surgery Both groups receive surgery analgesics and postoperative rehabilitation as per usual
Efficacy of treatment is evaluated using the change in opioid intake in the CRYO group compared to the SHAM group 14 days after knee replacement surgery Participants will also be assessed at 90 and 180 days after knee replacement surgery and will include measures on pain quality of life and function
Recently our research center and others have shown that is possible to target the nerves surrounding the knee with a novel treatment called cryoneurolysis Cryoneurolysis apply low temperatures -20C -100C to a target nerve which disrupts nerve function and provides potential pain relief This suggest a potential for cryoneurolysis to significantly improve rehabilitation reduce opioid intake and overall outcomes after knee replacement surgery
The primary objective of the current project is to determine the effectiveness of cryoneurolysis in its proposed ability to reduce opioid intake and postoperative pain after knee replacement surgery
The study is a randomized controlled study with two groups Group CRYO receives cryoneurolysis prior to knee replacement surgery and group SHAM receives a sham treatment prior to knee replacement surgery Both groups receive surgery analgesics and postoperative rehabilitation as per usual
Efficacy of treatment is evaluated using the change in opioid intake in the CRYO group compared to the SHAM group 14 days after knee replacement surgery Participants will also be assessed at 90 and 180 days after knee replacement surgery and will include measures on pain quality of life and function
Detailed Description:
INTRODUCTION In Denmark and the rest of Europe 20 of all chronic pain conditions is related to osteoarthritis OA and the incidence of this pathology is likely to increase significantly The treatment of knee OA typically focuses on pain relief however the effects of current conservative treatment options remain small to moderate and most are associated with side effects In many cases patients alternatively may be subjected to partialtotal knee arthroplasty TKA The number of TKA procedures in the US is projected to grow by 85 126 million procedures by 2030 TKA is considered to be an effective treatment for end-stage knee osteoarthritis however the period post-surgery is characterized by moderate to severe pain Postoperative pain inhibits early ambulation motivation and range of motion compromising rehabilitation patient satisfaction and overall outcomes In this regard more than 20 of patients have been shown to experience persistent and unchanged pain post-surgery In an attempt to attenuate postoperative pain many multimodal approaches have been proposed and implemented with mixed results however an optimal strategy of postoperative pain treatment after TKA has not yet been established
Reviewing these results focus should be on low-risk minimally invasive pain management Novel advances in the ability to target the genicular nerves are in that respect promising Cryoneurolysis has made it possible to apply low temperatures -20C -100C to a target percutaneous peripheral nerve causing Wallerian degeneration This disrupts nerve function while structural elements of the nerve bundle remain intact allowing for complete regeneration and functional recovery of the nerve over time Cryoneurolysis on peripheral nerves has been shown to provide pain relief in a variety of chronic pain conditions such as lumbar facet joint pain plantar fasciitis occipital neuralgia post thoracotomy pain syndrome and Mortons neuroma
Recently our research center and others have shown that is possible to target the superficial genicular nerves with cryoneurolysis and studies have observed a statistically significant reduction in hospital stay a decrease in prescribed opioids and less knee symptoms after TKA when cryoneurolysis was provided prior to operation These results suggest a potential for cryoneurolysis to significantly improve rehabilitation and overall outcomes Nevertheless these studies lack adequate power and a control group to confirm its efficacy and safety In addition the optimal freezing protocol for cryoneurolysis remains to be outlined This involves number of cycles duration intensity and thaw time which also depends on crucial factors such as nerve target identification probe placement and anatomical location of the target tissue
The present study is the first to utilize methodology that allows for accurate control of the ablation zone in relation to the target genicular nerves The nerves are identified using electrical nerve stimulation and ultra-sound which allows for the identification of nerve structures specific for each patient independent of the inherent variation of neural structures and also from a patient security point of view considers adjacent neurovascular structures and variations in anatomical structures We have in our center performed 500 ablations using the framework without any serious adverse events
If cryoneurolysis successfully attenuates postoperative pain and as a results opioid use earlier ambulation improved rehabilitation and overall outcomes - it would have massive socioeconomic implications Finally developing and establishing an efficacious and safe protocol for the treatment of pain with cryoneurolysis is an initial step for its implementation in a much broader context within the field of pain medicine and cryoanalgesia
OBJECTIVES The primary objective of the current project is to determine the effectiveness of cryoneurolysis in its proposed ability to reduce opioid intake and postoperative pain after TKA
The secondary objective is to evaluate whether such treatment affects functional performance quality of life and patient satisfaction
Finally development of safe and efficacious freezing protocols for upcoming studies and future research
TRIAL DESIGN This study is a single center randomized controlled trial designed to test the efficacy of cryoneurolysis treatment in patients undergoing TKA The patients will be randomly allocated in either a cryoneurolysis intervention group CRYO or a sham group SHAM and will be assessed at baseline and after 14 days 90 days and 180 days post TKA The tests will include both patient-reported outcomes PRO and objective functional measurements
Randomization will be performed as computer-generated block randomization with a 11 allocation ratio using random block sizes of 2 4 and 6 in either group CRYO or group SHAM The randomization restrictions will not be disclosed to ensure allocation concealment and the sequence will be performed by an external co-investigator
To account for the placebo effect and reduce the risk of bias the patients therapists and data-manager will be blinded to the allocation The allocation code will be concealed in a sealed envelope that will be available for the surgeon performing the cryoneurolysis procedure only Blinding will be assured using a sham trial that includes the same procedures as cryoneurolysis treatment but without any freezing temperatures Thus visible marks as a result of the procedures in both groups will be similar
In case of unexpected issues and if deemed absolutely necessary by the investigators and physician unblinding will occur according to emergency unblinding procedures that will maintain the integrity and confidentiality of the study
INTERVENTIONS The groups will be allocated to receive either sham or cryoneurolysis treatment Following intervention and TKA both the SHAM and CRYO group will receive standard rehabilitation programs standard analgesics and opioids
Cryoneurolysis Cryoneurolysis is a minimally invasive procedure and has been in use since the 1960s The methodology has developed over time and alongside the advent of ultrasound guided probe insertion it has become possible to treat multiple chronic pain conditions The current project involves the novel application and test of cryoneurolysis in the treatment of OA related pain The device used to perform the cryoneurolysis treatment is the VISUAL-ICE Galil Medical Arden Hills MN The rationale behind this device is based on previous reports showing that low temperature conditions can alter nerve function This technology allows for reversible destruction of nerves also known as Wallerian degeneration that prevents nerve signaling and potentially alleviate pain and motor dysfunction in a number of medical conditions The severity of nerve damage is dependent on the temperatures used to perform cryoneurolysis The goal in the current study is the apply temperatures between -20C to -100C at which the original structural scaffold of the nerve is preserved allowing for predictable regrowth of the axon along the epineurium and endoneurium allowing for the reinnervation of the sensory receptors over time This regeneration of the nerve is a well-established principle and means that the nerves sensory capabilities return
The VISUAL-ICE uses a combination of argon and helium to create a highly localized cold zone with temperatures between -20 and -100C A probe will be inserted percutaneously at the target AFCN and IBSN guided by ultrasound visualization to accurately determine the location of the nerve and to account for adjacent neurovascular structures and variations in anatomical structures The target locations are drawn directly on the patients skin prior to treatment along which a dose of local anesthetic will be injected subcutaneously before treatment Cryoneurolysis at each target site requires 2 freeze cycles with a duration of 3 mins and with thaw cycles between 20-40 seconds A temperature probe will be inserted adjacent to the target nerve and cryoneurolysis-probe to ensure a controlled cooling effect and to control nerve damage
The sham intervention includes the same procedures as described above but using a sham probe that does not allow for any freezing temperatures
Total Knee Arthroplasty Primary TKA is performed by trained orthopedic surgeons using an anterior midline incision and medial parapatellar arthrotomy Other than cryoneurolysis for CRYO group all patients received similar perioperative pain management
Rehabilitation All patients will be subjected to a standard rehabilitation protocol On the operation day the patients begin to be mobilized with the help of the physiotherapists and the nursing staff and are instructed in standard exercises All patients receive the exercise plan in written form If needed the patients receive more intensive rehabilitation during the stay andor have a longer stay After the discharge from the hospital all patients are invited to a two-week and a three-month control with a physiotherapist
Analgesics and opioids During TKA all patients receive a standard protocol of local infiltrative anesthesia LIA with 150ml 2mgml Ropivacain with Adrenalin 50 ml in the posterior capsule before the cementing 25 ml in the medial ligaments 25 ml in the lateral ligaments and 50 ml in subcutis during the skin closure
After the operation all eligible patients receive standard protocol pain medication Paracetamol 1000 mg x 4 Ibuprofen 400 mg x 4 Morphine 10 mg if necessary max 80 mg per day Patients who reach maximal dose of Morphine tablets begin to receive depot from the next day
DATA COLLECTION METHODS Intake of analgesic medicine Opioid intake will be evaluated during the first 14 days after knee arthroplasty and will be assessed using a patient medicine intake questionnaire Further use and prescriptions will be controlled via national recorded medical records Fælles Medicin Kort of prescribed medicine during the project period Patients receive a standard analgesic prescription post TKA comprising ibuprofen paracetamol morphine and if needed depot morphine
Pain Pain intensity will be assessed using the VAS pain intensity score VAS is a research and clinical tool widely used in diverse populations33 VAS consists of a continuous scale typically 100 mm in length anchored by two verbal descriptors no pain for the score of zero and worst pain imaginable for the score of 100 VAS is a self-reported tool where the respondent is asked to mark the point representing their current pain intensity This provides a score the distance between 0 and the respondents mark in the range 0-100mm which takes 1 minute to complete requires little training to administer and score and has been reported to be reliable34 In addition to intensity other pain characteristics such as location duration and type will be recorded as well
Functional performance Functional performance will be evaluated by the 30 second chair-stand test the 40m fast-paced walk test the 9-step stair-climb test and MVC force The 30 second chair-stand test consists of repeated sit-to-stand movement for a duration of 30 s The starting position is seated with feet placed flat on the floor shoulder width apart and with the arms crossed on the chest The position change to standing with hips and knees fully extended followed by sitting back down with bottom fully touching the seat The test is performed with usual footwear and the chair should be with a straight back with no arms seat height 43 cm placed against a wall In cases where the movement cannot be performed even once the hands are allowed to be placed on the legs or a regular mobility aid can be used - the result is then reported as an adapted test score The outcome is the total number of complete chair stands performed for the duration of the task one chair stand represents a stand followed by a sit movement
The 40m fast paced walk test consists of walking as fast as possible but still safely along a 10 m marked walkway then turning around a cone tape and return This is then repeated for a total distance of 40 m The test is performed with usual footwear and regular walking aid is allowed and recorded The outcome is expressed as speed ie walking distance 40m divided by the time to perform the task s Timing is paused during turns
The 9-step stair-climb test consists of the ascend and descend a flight of stairs as fast as possible but still safely The flight of stairs preferably has 9 steps step height appx 20 cm with hand rails The test is performed with usual footwear and regular walking aid is allowed and recorded The outcome is the total time to perform the task s
Quadriceps strength will be assessed measuring isometric MVC force of the knee extensors Patients will be seated in a chair with knee and hip flexed at 90 and with the pelvis and chest restrained by straps A non-extensile chain attached to the back of the chair and connected to a force transducer will be placed just proximal to the malleolus The patient will then be asked to perform three knee extensions pushing as hard as possible against the chain with 1 min rest in between The highest peak value out of the three MVCs will be taken as the MVC force
PRO-data PRO-data will be recorded using the Oxford Knee Score OKS developed and validated specifically to asses pain and function after knee arthroplasty The OKS consists of 12 questions about the patients level of function activities of daily living and pain over the preceding four weeks
Health-related quality of life will be assessed using the SF-36 questionnaire The SF-36 includes eight dimensions physical functioning role physical bodily pain general health vitality social functioning role emotional and mental health Its a validated and widely used questionnaire
Pain catastrophizing will be assessed using the pain catastrophizing scale Questions indicate thoughts and feelings when experiencing pain and also includes subscales on rumination magnification and helplessness
Adverse effects All adverse effects will be recorded using both prespecified symptom inventories and open-ended questions on both cryoneurolysis and morphine intake
STATISTICAL METHODS To evaluate the empirical distributions of the continuous outcomes visual inspection of the studentized residuals will be applied to evaluate whether the assumption of normality is reasonable
The treatment groups will be examined for comparability based on baseline demographic and prognostic measures An Intention-To-Treat ITT analysis will be used for all allocated patients and a mixed effects model will be used on the continuous outcome measures to determine the effects of cryoneurolysis treatment from baseline to post treatment and follow-ups Between groups factor CRYO vs SHAM within groups factor time The model will use robust estimation methods to account for outliers All P-values 005 will be considered statistically significant
HARMS Any adverse effects will be recorded and reported according to the guidelines of the Regional Committee on Health Research Ethics for Southern Denmark within 7 days Once a year the investigator will report all expected and unexpected adverse effects that have occurred during that period with an evaluation of patient safety
Cryoneurolysis Cryoneurolysis is a minimally invasive procedure that cause Wallerian degeneration where the nerve structure and conduction are disrupted while structural elements of the nerve bundle remain intact by applying temperatures between -20C to -100C This temperature range results in reversible destruction of the nerves that allow for complete regeneration and functional recovery In a preclinical study Hsu and Stevenson 39 examined the nerves in rats histologically post cryoneurolysis treatment and observed significant axonal regeneration and remyelination after 8 weeks and complete axonal regeneration 16 weeks post cryoneurolysis as compared to baseline Thus the target nerves suffer no permanent damage in rats The regeneration of sensory peripheral nerves after damage is a well-established principle but depends on the nature of the nerve damage Regeneration predominantly depends on the integrity of the surrounding endoneurial perineurial and epineurial structures which has been shown to be unaffected in animal models at the temperature range -20C to -100 This is likely explained by a remarkable resilience of collagen and fibroblasts to hypothermia In contrast to other therapies such as ablation with heat cryoneurolysis induces a mild lesion No studies have investigated the histological results of cryoneurolysis in humans however studies investigating human clinical results concurrently with animal models suggests that the effect of cryoneurolysis is comparable This also means that pain sensation might return over time and studies do show a gradual increase in sensory capabilities after cryoneurolysis treatment Cryoneurolysis is not a curative to chronic pain The current study will insert a temperature probe using ultra-sound adjacent to the target nerve and cryoneurolysis-probe to ensure a controlled cooling effect at the specified temperatures to control nerve damage and increase safety In addition the nerves of interest IBSN AFCN is located on the opposite side of the knee than the proprioceptive nerves surrounding the knee Proprioception will therefore not be affected
Adverse effects associated with cryoneurolysis treatment include frostbite to skin alopecia depigmentation of skin and damage to surrounding structures These effects are often mild and can be avoided with careful technique during the procedure with prober thaw options and meticulous skin precautions The procedure in the current study will be performed by a trained orthopedic surgeon Because cryoneurolysis is an invasive procedure however minimal adverse effects also include bleeding bruising redness infection and development of an insensate area at the site of treatment A recent study investigating cryoneurolysis in knee OA n180 observed side effects such as altered sensation 20 crusting 5 itching 5 local pain 21 numbness 53 swelling 36 tenderness on palpation 178 and tingling 11 in addition to the aforementioned The majority of these effects were categorized as mild in severity and were resolved within 30 days Another study reported no complaints of persistent numbness or other neurologic effect at the three-months follow-up
The current project will use ultrasound visualization to accurately determine the location of the nerve and to account for adjacent neurovascular structures and variations in anatomical structures
There is a risk for neuroma formation or neuritis however these are very rare Two different reviews stated that there has been no reported cases of permanent nerve damage as a result of cryoneurolysis and so far there is only one reported case of neuritis after cryoneurolysis treatment47 This is in line with what the authors of the current clinical protocol have observed in their search through the literature The investigators in the present study have extensive experience providing treatment with cryoneurolysis having performed 500 ablations as part of a similar and previously approved protocol S-20180089 and have not reported any serious adverse events
Analgesics and opioids Opioids are widely used to attenuate both moderate and severe pain Nevertheless these have important limitations that should be taken into account Opioid-related adverse effects include but are not limited to opioid use disorder nausea constipation dry mouth dizziness drowsiness falls lack of energy postoperative infection endocrinopathy altered immune function respiratory depression misuse abuse
RESARCH ETHICS The project will be conducted according to the declaration of Helsinki Furthermore the project will be registered in ClinicalTrialsgov
Given the study design eligibility criteria and safety measures the current project does not include special risks for the participating patients The majority of risks does not require medical attention and serious adverse effects as a result of local anesthetics and cryoneurolysis are very rare A clinical expert will be available to respond to any enquiries or adverse effects If adverse effects are identified patients will be referred to the relevant clinical department and care will be provided as needed as part of the Danish health security system The project is covered in accordance with Danish Patient Compensation Act The investigators will review the trial processes and data continuously
The potential benefits of the current project include increased functional capacity and quality of life as a result of significant pain relief reduced opioid intake and improved rehabilitation This could have a significant impact on patients lives as well as significant socioeconomic consequences
The inclusion of a sham group is necessary to test the hypothesis because of the large reported placebo effects in OA trials51 In addition the associated risks are minimal and the nature of misleading in regards to the administration of the sham trial will be adequately disclosed and accepted by the patient during the informed consent process The sham group is implemented according to current standards
PROTOCOL AMENDMENTS To maintain trial integrity changes to the protocol that might impact the conduct of the study including changes of study objectives design patient population sample size or other relevant procedures will be formally reported to the Regional Committee on Health Research Ethics for Southern Denmark and trial registries
DATA MANAGEMENT All data will be kept electronically and filed according to a participant code Data entry will always be handled by the same investigator who will use unambiguous and standard terminology based on predefined study forms Complete back-up of all data will be performed regularly and stored on secured servers in the Region of Southern Denmark via encrypted connection and restricted access that fulfil the demands for data security Data will be stored for a duration of 10 years
CONFIDENTIALITY All information related to the study including patient information will be stored securely with restricted access at the Hospital of South West Jutland University hospital of Southern Denmark Esbjerg Denmark The data will be identified by a coded identity number to maintain participant confidentiality and stored separately The investigators are under duty of confidentiality
The project will be reported to the Danish Data Protection Agency and will be handled according to the General Data Protection Regulation GDPR and the Danish Data Protection Act
ACCESS TO DATA The full data set will be available on request to the lead investigators All shared data will be fully anonymized
ECONOMY The current project was initiated by Carsten Kock-Jensen MD CRPS Center South Hospital of South West Justland and is funded by Boston Scientific Funds are paid to a specific research account administered by the Hospital of South West Jutland University hospital of Southern Denmark Esbjerg Denmark and is subject to public audit under Rigsrevisionen
The current project is independent of the grants listed and there are no conflicts of interests
Reviewing these results focus should be on low-risk minimally invasive pain management Novel advances in the ability to target the genicular nerves are in that respect promising Cryoneurolysis has made it possible to apply low temperatures -20C -100C to a target percutaneous peripheral nerve causing Wallerian degeneration This disrupts nerve function while structural elements of the nerve bundle remain intact allowing for complete regeneration and functional recovery of the nerve over time Cryoneurolysis on peripheral nerves has been shown to provide pain relief in a variety of chronic pain conditions such as lumbar facet joint pain plantar fasciitis occipital neuralgia post thoracotomy pain syndrome and Mortons neuroma
Recently our research center and others have shown that is possible to target the superficial genicular nerves with cryoneurolysis and studies have observed a statistically significant reduction in hospital stay a decrease in prescribed opioids and less knee symptoms after TKA when cryoneurolysis was provided prior to operation These results suggest a potential for cryoneurolysis to significantly improve rehabilitation and overall outcomes Nevertheless these studies lack adequate power and a control group to confirm its efficacy and safety In addition the optimal freezing protocol for cryoneurolysis remains to be outlined This involves number of cycles duration intensity and thaw time which also depends on crucial factors such as nerve target identification probe placement and anatomical location of the target tissue
The present study is the first to utilize methodology that allows for accurate control of the ablation zone in relation to the target genicular nerves The nerves are identified using electrical nerve stimulation and ultra-sound which allows for the identification of nerve structures specific for each patient independent of the inherent variation of neural structures and also from a patient security point of view considers adjacent neurovascular structures and variations in anatomical structures We have in our center performed 500 ablations using the framework without any serious adverse events
If cryoneurolysis successfully attenuates postoperative pain and as a results opioid use earlier ambulation improved rehabilitation and overall outcomes - it would have massive socioeconomic implications Finally developing and establishing an efficacious and safe protocol for the treatment of pain with cryoneurolysis is an initial step for its implementation in a much broader context within the field of pain medicine and cryoanalgesia
OBJECTIVES The primary objective of the current project is to determine the effectiveness of cryoneurolysis in its proposed ability to reduce opioid intake and postoperative pain after TKA
The secondary objective is to evaluate whether such treatment affects functional performance quality of life and patient satisfaction
Finally development of safe and efficacious freezing protocols for upcoming studies and future research
TRIAL DESIGN This study is a single center randomized controlled trial designed to test the efficacy of cryoneurolysis treatment in patients undergoing TKA The patients will be randomly allocated in either a cryoneurolysis intervention group CRYO or a sham group SHAM and will be assessed at baseline and after 14 days 90 days and 180 days post TKA The tests will include both patient-reported outcomes PRO and objective functional measurements
Randomization will be performed as computer-generated block randomization with a 11 allocation ratio using random block sizes of 2 4 and 6 in either group CRYO or group SHAM The randomization restrictions will not be disclosed to ensure allocation concealment and the sequence will be performed by an external co-investigator
To account for the placebo effect and reduce the risk of bias the patients therapists and data-manager will be blinded to the allocation The allocation code will be concealed in a sealed envelope that will be available for the surgeon performing the cryoneurolysis procedure only Blinding will be assured using a sham trial that includes the same procedures as cryoneurolysis treatment but without any freezing temperatures Thus visible marks as a result of the procedures in both groups will be similar
In case of unexpected issues and if deemed absolutely necessary by the investigators and physician unblinding will occur according to emergency unblinding procedures that will maintain the integrity and confidentiality of the study
INTERVENTIONS The groups will be allocated to receive either sham or cryoneurolysis treatment Following intervention and TKA both the SHAM and CRYO group will receive standard rehabilitation programs standard analgesics and opioids
Cryoneurolysis Cryoneurolysis is a minimally invasive procedure and has been in use since the 1960s The methodology has developed over time and alongside the advent of ultrasound guided probe insertion it has become possible to treat multiple chronic pain conditions The current project involves the novel application and test of cryoneurolysis in the treatment of OA related pain The device used to perform the cryoneurolysis treatment is the VISUAL-ICE Galil Medical Arden Hills MN The rationale behind this device is based on previous reports showing that low temperature conditions can alter nerve function This technology allows for reversible destruction of nerves also known as Wallerian degeneration that prevents nerve signaling and potentially alleviate pain and motor dysfunction in a number of medical conditions The severity of nerve damage is dependent on the temperatures used to perform cryoneurolysis The goal in the current study is the apply temperatures between -20C to -100C at which the original structural scaffold of the nerve is preserved allowing for predictable regrowth of the axon along the epineurium and endoneurium allowing for the reinnervation of the sensory receptors over time This regeneration of the nerve is a well-established principle and means that the nerves sensory capabilities return
The VISUAL-ICE uses a combination of argon and helium to create a highly localized cold zone with temperatures between -20 and -100C A probe will be inserted percutaneously at the target AFCN and IBSN guided by ultrasound visualization to accurately determine the location of the nerve and to account for adjacent neurovascular structures and variations in anatomical structures The target locations are drawn directly on the patients skin prior to treatment along which a dose of local anesthetic will be injected subcutaneously before treatment Cryoneurolysis at each target site requires 2 freeze cycles with a duration of 3 mins and with thaw cycles between 20-40 seconds A temperature probe will be inserted adjacent to the target nerve and cryoneurolysis-probe to ensure a controlled cooling effect and to control nerve damage
The sham intervention includes the same procedures as described above but using a sham probe that does not allow for any freezing temperatures
Total Knee Arthroplasty Primary TKA is performed by trained orthopedic surgeons using an anterior midline incision and medial parapatellar arthrotomy Other than cryoneurolysis for CRYO group all patients received similar perioperative pain management
Rehabilitation All patients will be subjected to a standard rehabilitation protocol On the operation day the patients begin to be mobilized with the help of the physiotherapists and the nursing staff and are instructed in standard exercises All patients receive the exercise plan in written form If needed the patients receive more intensive rehabilitation during the stay andor have a longer stay After the discharge from the hospital all patients are invited to a two-week and a three-month control with a physiotherapist
Analgesics and opioids During TKA all patients receive a standard protocol of local infiltrative anesthesia LIA with 150ml 2mgml Ropivacain with Adrenalin 50 ml in the posterior capsule before the cementing 25 ml in the medial ligaments 25 ml in the lateral ligaments and 50 ml in subcutis during the skin closure
After the operation all eligible patients receive standard protocol pain medication Paracetamol 1000 mg x 4 Ibuprofen 400 mg x 4 Morphine 10 mg if necessary max 80 mg per day Patients who reach maximal dose of Morphine tablets begin to receive depot from the next day
DATA COLLECTION METHODS Intake of analgesic medicine Opioid intake will be evaluated during the first 14 days after knee arthroplasty and will be assessed using a patient medicine intake questionnaire Further use and prescriptions will be controlled via national recorded medical records Fælles Medicin Kort of prescribed medicine during the project period Patients receive a standard analgesic prescription post TKA comprising ibuprofen paracetamol morphine and if needed depot morphine
Pain Pain intensity will be assessed using the VAS pain intensity score VAS is a research and clinical tool widely used in diverse populations33 VAS consists of a continuous scale typically 100 mm in length anchored by two verbal descriptors no pain for the score of zero and worst pain imaginable for the score of 100 VAS is a self-reported tool where the respondent is asked to mark the point representing their current pain intensity This provides a score the distance between 0 and the respondents mark in the range 0-100mm which takes 1 minute to complete requires little training to administer and score and has been reported to be reliable34 In addition to intensity other pain characteristics such as location duration and type will be recorded as well
Functional performance Functional performance will be evaluated by the 30 second chair-stand test the 40m fast-paced walk test the 9-step stair-climb test and MVC force The 30 second chair-stand test consists of repeated sit-to-stand movement for a duration of 30 s The starting position is seated with feet placed flat on the floor shoulder width apart and with the arms crossed on the chest The position change to standing with hips and knees fully extended followed by sitting back down with bottom fully touching the seat The test is performed with usual footwear and the chair should be with a straight back with no arms seat height 43 cm placed against a wall In cases where the movement cannot be performed even once the hands are allowed to be placed on the legs or a regular mobility aid can be used - the result is then reported as an adapted test score The outcome is the total number of complete chair stands performed for the duration of the task one chair stand represents a stand followed by a sit movement
The 40m fast paced walk test consists of walking as fast as possible but still safely along a 10 m marked walkway then turning around a cone tape and return This is then repeated for a total distance of 40 m The test is performed with usual footwear and regular walking aid is allowed and recorded The outcome is expressed as speed ie walking distance 40m divided by the time to perform the task s Timing is paused during turns
The 9-step stair-climb test consists of the ascend and descend a flight of stairs as fast as possible but still safely The flight of stairs preferably has 9 steps step height appx 20 cm with hand rails The test is performed with usual footwear and regular walking aid is allowed and recorded The outcome is the total time to perform the task s
Quadriceps strength will be assessed measuring isometric MVC force of the knee extensors Patients will be seated in a chair with knee and hip flexed at 90 and with the pelvis and chest restrained by straps A non-extensile chain attached to the back of the chair and connected to a force transducer will be placed just proximal to the malleolus The patient will then be asked to perform three knee extensions pushing as hard as possible against the chain with 1 min rest in between The highest peak value out of the three MVCs will be taken as the MVC force
PRO-data PRO-data will be recorded using the Oxford Knee Score OKS developed and validated specifically to asses pain and function after knee arthroplasty The OKS consists of 12 questions about the patients level of function activities of daily living and pain over the preceding four weeks
Health-related quality of life will be assessed using the SF-36 questionnaire The SF-36 includes eight dimensions physical functioning role physical bodily pain general health vitality social functioning role emotional and mental health Its a validated and widely used questionnaire
Pain catastrophizing will be assessed using the pain catastrophizing scale Questions indicate thoughts and feelings when experiencing pain and also includes subscales on rumination magnification and helplessness
Adverse effects All adverse effects will be recorded using both prespecified symptom inventories and open-ended questions on both cryoneurolysis and morphine intake
STATISTICAL METHODS To evaluate the empirical distributions of the continuous outcomes visual inspection of the studentized residuals will be applied to evaluate whether the assumption of normality is reasonable
The treatment groups will be examined for comparability based on baseline demographic and prognostic measures An Intention-To-Treat ITT analysis will be used for all allocated patients and a mixed effects model will be used on the continuous outcome measures to determine the effects of cryoneurolysis treatment from baseline to post treatment and follow-ups Between groups factor CRYO vs SHAM within groups factor time The model will use robust estimation methods to account for outliers All P-values 005 will be considered statistically significant
HARMS Any adverse effects will be recorded and reported according to the guidelines of the Regional Committee on Health Research Ethics for Southern Denmark within 7 days Once a year the investigator will report all expected and unexpected adverse effects that have occurred during that period with an evaluation of patient safety
Cryoneurolysis Cryoneurolysis is a minimally invasive procedure that cause Wallerian degeneration where the nerve structure and conduction are disrupted while structural elements of the nerve bundle remain intact by applying temperatures between -20C to -100C This temperature range results in reversible destruction of the nerves that allow for complete regeneration and functional recovery In a preclinical study Hsu and Stevenson 39 examined the nerves in rats histologically post cryoneurolysis treatment and observed significant axonal regeneration and remyelination after 8 weeks and complete axonal regeneration 16 weeks post cryoneurolysis as compared to baseline Thus the target nerves suffer no permanent damage in rats The regeneration of sensory peripheral nerves after damage is a well-established principle but depends on the nature of the nerve damage Regeneration predominantly depends on the integrity of the surrounding endoneurial perineurial and epineurial structures which has been shown to be unaffected in animal models at the temperature range -20C to -100 This is likely explained by a remarkable resilience of collagen and fibroblasts to hypothermia In contrast to other therapies such as ablation with heat cryoneurolysis induces a mild lesion No studies have investigated the histological results of cryoneurolysis in humans however studies investigating human clinical results concurrently with animal models suggests that the effect of cryoneurolysis is comparable This also means that pain sensation might return over time and studies do show a gradual increase in sensory capabilities after cryoneurolysis treatment Cryoneurolysis is not a curative to chronic pain The current study will insert a temperature probe using ultra-sound adjacent to the target nerve and cryoneurolysis-probe to ensure a controlled cooling effect at the specified temperatures to control nerve damage and increase safety In addition the nerves of interest IBSN AFCN is located on the opposite side of the knee than the proprioceptive nerves surrounding the knee Proprioception will therefore not be affected
Adverse effects associated with cryoneurolysis treatment include frostbite to skin alopecia depigmentation of skin and damage to surrounding structures These effects are often mild and can be avoided with careful technique during the procedure with prober thaw options and meticulous skin precautions The procedure in the current study will be performed by a trained orthopedic surgeon Because cryoneurolysis is an invasive procedure however minimal adverse effects also include bleeding bruising redness infection and development of an insensate area at the site of treatment A recent study investigating cryoneurolysis in knee OA n180 observed side effects such as altered sensation 20 crusting 5 itching 5 local pain 21 numbness 53 swelling 36 tenderness on palpation 178 and tingling 11 in addition to the aforementioned The majority of these effects were categorized as mild in severity and were resolved within 30 days Another study reported no complaints of persistent numbness or other neurologic effect at the three-months follow-up
The current project will use ultrasound visualization to accurately determine the location of the nerve and to account for adjacent neurovascular structures and variations in anatomical structures
There is a risk for neuroma formation or neuritis however these are very rare Two different reviews stated that there has been no reported cases of permanent nerve damage as a result of cryoneurolysis and so far there is only one reported case of neuritis after cryoneurolysis treatment47 This is in line with what the authors of the current clinical protocol have observed in their search through the literature The investigators in the present study have extensive experience providing treatment with cryoneurolysis having performed 500 ablations as part of a similar and previously approved protocol S-20180089 and have not reported any serious adverse events
Analgesics and opioids Opioids are widely used to attenuate both moderate and severe pain Nevertheless these have important limitations that should be taken into account Opioid-related adverse effects include but are not limited to opioid use disorder nausea constipation dry mouth dizziness drowsiness falls lack of energy postoperative infection endocrinopathy altered immune function respiratory depression misuse abuse
RESARCH ETHICS The project will be conducted according to the declaration of Helsinki Furthermore the project will be registered in ClinicalTrialsgov
Given the study design eligibility criteria and safety measures the current project does not include special risks for the participating patients The majority of risks does not require medical attention and serious adverse effects as a result of local anesthetics and cryoneurolysis are very rare A clinical expert will be available to respond to any enquiries or adverse effects If adverse effects are identified patients will be referred to the relevant clinical department and care will be provided as needed as part of the Danish health security system The project is covered in accordance with Danish Patient Compensation Act The investigators will review the trial processes and data continuously
The potential benefits of the current project include increased functional capacity and quality of life as a result of significant pain relief reduced opioid intake and improved rehabilitation This could have a significant impact on patients lives as well as significant socioeconomic consequences
The inclusion of a sham group is necessary to test the hypothesis because of the large reported placebo effects in OA trials51 In addition the associated risks are minimal and the nature of misleading in regards to the administration of the sham trial will be adequately disclosed and accepted by the patient during the informed consent process The sham group is implemented according to current standards
PROTOCOL AMENDMENTS To maintain trial integrity changes to the protocol that might impact the conduct of the study including changes of study objectives design patient population sample size or other relevant procedures will be formally reported to the Regional Committee on Health Research Ethics for Southern Denmark and trial registries
DATA MANAGEMENT All data will be kept electronically and filed according to a participant code Data entry will always be handled by the same investigator who will use unambiguous and standard terminology based on predefined study forms Complete back-up of all data will be performed regularly and stored on secured servers in the Region of Southern Denmark via encrypted connection and restricted access that fulfil the demands for data security Data will be stored for a duration of 10 years
CONFIDENTIALITY All information related to the study including patient information will be stored securely with restricted access at the Hospital of South West Jutland University hospital of Southern Denmark Esbjerg Denmark The data will be identified by a coded identity number to maintain participant confidentiality and stored separately The investigators are under duty of confidentiality
The project will be reported to the Danish Data Protection Agency and will be handled according to the General Data Protection Regulation GDPR and the Danish Data Protection Act
ACCESS TO DATA The full data set will be available on request to the lead investigators All shared data will be fully anonymized
ECONOMY The current project was initiated by Carsten Kock-Jensen MD CRPS Center South Hospital of South West Justland and is funded by Boston Scientific Funds are paid to a specific research account administered by the Hospital of South West Jutland University hospital of Southern Denmark Esbjerg Denmark and is subject to public audit under Rigsrevisionen
The current project is independent of the grants listed and there are no conflicts of interests
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None