A Prospective Cohort Study: Platelet-Rich Plasma Combined with Carpal Tunnel Release Treating Carpal Tunnel Syndrome short (running) title: PRP-CTR Treating Carpal Tunnel Syndrome

doi:10.21203/rs.3.rs-1443905/v2

Background

PRP injection was proved to promote the health condition of individuals with mild to moderate Carpal Tunnel Syndrome (CTS). However, carpal tunnel release (CTR) was still an important treatment for individuals with moderate, as well as severe CTS.

Methods

To explore whether adjuvant PRP treatment would improve the prognosis while using CTR, we included 82 patients in this study. Preoperative and postoperative visual analog scale (VAS), Boston carpal tunnel syndrome questionnaire-symptom severity scale (BCTQ-SSS), Boston carpal tunnel syndrome questionnaire-functional status scale (BCTQ-FSS), and grip strength was used to examine the patient's symptoms and function.

Results

CTR combined with PRP treatment improved the VAS (1.9 ± 0.5 versus 1.4 ± 0.4, P < .05), BCTQ-SSS (1.8 ± 0.4versus 1.5 ± 0.3, P < .05) and BCTQ-FSS (1.8 ± 0.5 versus 1.4 ± 0.6, P < .05) in patients with moderate symptoms within one month after surgery. At the same time, it does not show any advantages in treating individuals with severe carpal tunnel syndrome.

Conclusions

The use of PRP does not affect long-term prognosis while increasing the surgery cost. To conclude, PRP as an adjuvant treatment of CTR has limited effect. Considering the additional financial burden on patients, CTR combined with PRP should be cautious in CTS treatment.

carpal tunnel syndrome (CTS)

carpal tunnel release (CTR)

Platelet-Rich Plasma (PRP)

BCTQ

Carpal tunnel syndrome (CTS) constitutes the commonest compressive neuropathy of the upper limbs, usually via the abnormal flexor retinaculum thickening ^1,2. Pain, numbness, and muscle weakness caused by CTS seriously affect patients’ function and quality of life³. Although splinting and corticosteroid injections were proven effective, strong evidence supported that the carpal tunnel release (CTR) decompresses the median nerve by dividing the transverse carpal ligament and should have a better treatment advantage at 6 and 12 months, especially in patients with moderate or severe symptoms^3–5.

Platelet-rich plasma (PRP) has been utilized as a safe treatment form in divergent settings⁶. It is an analogous biologic agent constituting concentrated platelets, the primary component of which is believed to be products of degradation consisting of transforming growth factor (TGF), the insulin-like growth factor-1 (IGF-1), Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF)⁷. An extensive bulk of the researches supported that PRP injection enhanced the clinical outcomes of the individuals with mild-to-moderate CTS⁸. Research-based on in vitro as well as in vivo studies supported the neurotrophic impact of PRP in peripheral nerves^9,10. Following a PRP injection, diverse growth factors are released and activated, which leads to median nerve rejuvenation and improves the supply of neural blood via protection of the blood-nerve barrier¹¹. There is limited clinical information on the utilization of PRP in peripheral neuropathies in humans^8,12. A recent systematic review indicated that PRP is proven effective for mild to moderate carpal tunnel syndrome individuals, while PRP injection alone is not recommended for severe carpal tunnel syndrome patients ⁸. No studies have pointed out whether additional PRP infusion is necessary for patients with severe symptoms who require surgical treatment.

For the lack of correlational studies, we tried to explore whether adjuvant PRP treatment could improve the prognosis of individuals with moderate to severe carpal tunnel syndrome while applying CTR. Further exploration is needed to provide robust research evidence by which surgeons should establish guidelines for utilizing this treatment in CTS patients.

2.1 Ethical approval

This study is a prognostic study constituting a prospective cohort. The ethics committee at Shanghai Sixth People’s Hospital approved the study. In addition, this study was conducted as per the Code of Ethics of the World Medical Association (Declaration of Helsinki) for procedures involving humans.

2.2 Patients

Between 2015 and 2018, 94 patients underwent CTR for CTS treatment in our hospital. Twelve patients declined to participate in the cohort, and we included the remaining 82 patients prospectively in this cohort. Before the operation, every patient underwent a nerve conduction study for definite diagnosis and severity evaluation¹³. The demographic data consisting of age, body mass index (BMI), gender, along with preoperative evaluation by visual analog scale (VAS), Boston carpal tunnel syndrome questionnaire- symptom severity scale (BCTQ-SSS), Boston carpal tunnel syndrome questionnaire- functional status scale (BCTQ-FSS) and grip strength. Follow up was performed at one, three and six months after surgery. The CTS diagnosis was centered on the typical history constituting pain, sensory disturbances, as well as weakness entailing the median nerve distribution. All subjects included in the study were with moderate to severe symptoms or failed conservative treatment with steroid injections¹⁴. Patients were excluded if they aged＞70 or＜18, with a course of CTS is less than two months, space-occupying lesions within the carpal tunnel, pregnancy, diabetes mellitus, rheumatoid arthritis, traumatic CTS, or had previous CTS surgery.

2.3 Operative procedure

Experienced surgeons performed all Surgical procedures. Regarding the conventional method, the approach documented by Taleisnik was applied ¹⁵. In brief, a palmar longitudinal incision starting at the ring finger axis was made passing through thenar and hypothenar eminences and proceeded proximally into the wrist proximal flexor crease. Following the exposure of the underlying transverse carpal ligament, its ulnar region was longitudinally cut. Identification of the median nerve was done for protection, and then the incision was closed in a routine way (Figure 1).

At the time of surgery, 15mL of analogous venous blood sample was drawn from every subject's contralateral (non-impacted) hand, followed by centrifugation at two successive density gradient centrifugations (800g-10min and 1100g-10min) at our hospital laboratory. In the initial centrifugation, separation of the red blood cells was achieved, whereas in the second centrifugation, separation of PRP from the platelet-poor plasma (PPP) was performed and then introduced into a sterile injector. 2 mL PRP was injected from the sutured incision, and then the incision was bandaged (Figure 1).

No brace or splint was used following the operation. Restricted wrist movement was permitted for 24 hours. We encouraged the patients to return to their daily activities. Non-steroidal inflammatory drug use was limited in both groups.

Symptom Typing¹⁶. 1. Low Severity (nighttime pain/sensory disturbances, and/or episodic/infrequent symptoms) 2. Moderate Severity (pain/sensory disturbances, tingling, frequent activity-related symptoms, and/or difficulty with fine motor coordination) 3. High Severity (constant sensory loss, motor clinical findings [eg, muscle weakness], and/or thenar atrophy).

2.4 Outcome measures

Postoperative follow-up visits were held by a third physician (blinded to the groups) after 3 and 6 months, during which the VAS, BCTQ and grip strength were repeated. Digital pain severity and paresthesia were determined via VAS, with 10 points designating extremely severe pain, while 0 points designated no pain. BCTQ constitutes a symptom severity scale (SSS), as well as a functional status scale (FSS). The lower scores on the BCTQ imply lesser symptom severity and better functional status of the patient¹⁷. Determination of strength of the grip was conducted with the flexion of elbow at 90 degrees and in neutral rotation for the forearm.

Six months after the operation, the remission was evaluated according to the clinical symptoms of the patients in the last two weeks. Remission was defined as the significant reduction of symptoms, including numbness, pain, sensory disturbance, and muscle weakness. Patients with no preoperative symptoms were defined as entirely asymptomatic.

2.5 Statistical analyses

Continuous variables were indicated as mean ± standard deviation; categorical data were shown as a number (percentage). For a continuous variable, demographic data were assessed via the independent t-test for continuous data, while X² test was employed for the categorical data. The repeated-measures ANOVA followed by post hoc tests was carried out for the data at various follow-ups. All statistical analysis was conducted using SPSS 22.0 in this study. All statistical evaluations were two-sided. P< .05 signified statistical significance.

A total of 82 patients (35 males and 47 females) were enrolled for analysis. All of the study surgeons were hand surgery specialists. All subjects were followed up for more than 6 months. In our cases, 35 of the 82 cases were male, and the average age of this series was 42.1±11.7 (19 to 69). The right hand was affected in 46, and the left hand was affected in 35 cases. The mean BMI was 25.2±4.7. The mean symptom duration of the two groups was 25.6±22.8. Table 1 shows the preoperative assessment of VAS, BCTQ-SSS, BCTQ-FSS, and grip strength. The data in Table 1 statistically showed no remarkable difference in demographics between the two groups.

Table 1 Patient features.

	Control Group N=39	PRP Group N=43	P
Gender
Male	17(43.6%)	18(41.8%)	0.874
Female	22 (56.4%)	25(58.2%)	0.874
Age	42.5±11.7	41.9±11.7	0.839
BMI	25.6±4.1	25.0±5.1	0.608
Affected side
Right	20 (51.2%)	26(60.4%)	0.402
Left	19(48.8%)	17(39.6%)	0.402
Symptom duration (month)	24.3±21.7	26.8±23.6	0.613
Grading
Moderate	26	26	0.560
Severe	13	17	0.560
VAS	4.51±1.27	4.58±1.36	0.817
BCTQ-SSS	2.62±0.51	2.80±0.65	0.189
BCTQ-FSS	2.70±0.68	2.86±0.58	0.250
Grip strength(g/mm²)	16.74±5.36	16.04±5.15	0.556

PRP= platelet-rich plasma, VAS=visual analog scale

BCTQ-SSS= Boston carpal tunnel syndrome questionnaire- symptom severity scale

BCTQ-FSS= Boston carpal tunnel syndrome questionnaire- functional status scale

Table 2 Clinical outcomes in all patients

	1 month after surgery			3 months after surgery			6 months after surgery
	Control Group N=39	PRP Group N=43	P	Control Group N=39	PRP Group N=43	P	Control Group N=39	PRP Group N=43	P
VAS	2.61±1.19	2.39±1.18	0.410	1.38±1.05	1.46±1.16	0.747	0.71±1.10	0.81±1.16	0.707
BCTQ-SSS	2.13±0.58	1.91±0.59	0.097	1.46±0.64	1.39±0.67	0.630	1.02±0.86	0.93±0.85	0.665
BCTQ-FSS	2.11±0.63	1.94±0.78	0.290	1.60±0.69	1.64±0.71	0.824	1.14±0.87	1.20±0.83	0.740
Grip strength (g/mm²)	18.01±5.24	17.88±5.05	0.852	20.68±5.15	21.81±5.12	0.909	22.87±5.10	24.34±5.59	0.222

Table 2 shows the clinical outcomes within 6 months after surgery. The results showed that there was no remarkable difference between the two groups in VAS, BCTQ-SSS, BCTQ-FSS and grip strength in 1 month, 3 months, as well as 6 months after surgery. However, the further analysis of patients with moderate preoperative symptoms showed that the PRP patient group showed a better outcome in VAS (2.42±1.30 versus 1.69±0.66, P<.05), BCTQ-SSS (1.90±0.54 versus 1.57±0.35, P<.05) and BCTQ-FSS (1.83±0.57 versus 1.54±0.37, P<.05) in 1 month after surgery. There was no marked difference between the two groups in VAS, BCTQ-SSS, BCTQ-FSS, and grips strength in 3 months and 6 months after surgery (Table 3, Figure 2).

Table 3 Clinical outcomes in patients with moderate preoperative symptoms

	Control Group N=26	PRP Group N=26	P *significant
VAS preoperative	4.00±1.07	3.84±1.16	0.630
VAS 1 month following surgery	2.42±1.30	1.69±0.66	0.016*
VAS 3 months following surgery	1.12±0.93	1.00±0.83	0.647
VAS 6 months following surgery	0.46±0.69	0.42±0.63	0.838
BCTQ-SSS preoperative	2.36±0.41	2.41±0.43	0.701
BCTQ-SSS 1 month following surgery	1.90±0.54	1.57±0.35	0.016*
BCTQ-SSS 3 months following surgery	1.25±0.51	1.06±0.48	0.201
BCTQ-SSS 6 months following surgery	0.80±0.67	0.66±0.61	0.438
BCTQ-FSS preoperative	2.42±0.58	2.51±0.41	0.521
BCTQ-FSS 1 month following surgery	1.83±0.57	1.54±0.37	0.037*
BCTQ-FSS 3 months following surgery	1.33±0.56	1.29±0.45	0.773
BCTQ-FSS 6 months following surgery	0.95±0.73	0.87±0.53	0.659
Grip strength preoperative (g/mm²)	19.47±3.71	18.68±4.36	0.470
Grip strength 1 month after surgery(g/mm²)	20.86±3.53	20.44±4.41	0.710
Grip strength 3 months after surgery (g/mm²)	23.19±4.06	23.21±4.87	0.983
Grip strength 6 months after surgery(g/mm²)	24.79±4.04	26.25±5.79	0.303

Table 4 showed that 35 (89.7%) and 40 (93%) individuals in the control group and PRP group, respectively, revealed remission 6 months after surgery. 16 (41.0%) and 19(44.1%) individuals in the control group and PRP group, respectively were found completely asymptomatic. Nonetheless, there was no remarkable difference between the two groups.

Table 4 Symptom Remission

	Moderate Symptom			Severe Symptom
	Control Group N=26	PRP Group N=26	P	Control Group N=13	PRP Group N=17	P
Remission	25(96.1%)	26(100.0%）	0.312	10(76.9%)	14(82.4%)	0.712
Non-remission	1(3.9%)	0(0%)	0.312	3(23.1%)	3(17.6%)	0.712
Completely asymptomatic	12(46.2%)	13(50.0%）	0.781	4(30.8%)	6(35.2%)	0.794

As shown in Table 5, the PRP treatment increased the costs of the surgery (12363.2±901.2 versus 16206.4±1131.0, CNY, P < .001). There was no statistic difference in hospitalization between the two groups (3.56±0.59 versus 3.46±0.54 days, P =0.29).

Table 5 Economic analysis.

Control Group

N=39

PRP Group

N=43

P

*significant

Hospitalization (Days)

3.56±0.59

3.46±0.54

0.437

Cost (CNY)

12363.2±901.2

16206.4±1131.0

<0.001*

CNY = China Yuan.

In this study, CTR combined with PRP treatment has been reported to better the health outcomes and functions of patients with moderate symptoms within one month after surgery, but it does not show an advantage in the treating individuals with severe carpal tunnel syndrome. At the same time, PRP's use does not affect long-term prognosis while increasing the surgery cost.

A large number of clinical and basic studies support PRP's role in the repair of peripheral nerve injury¹⁸, with the continuous study of PRP treatment, different researchers have proposed that the effect of PRP in the CTS treatment is limited. A placebo-controlled clinical study indicated that a single PRP injection has positive impacts on individuals with mild to moderate CTS. However, comparing to the VAS of the placebo group, PRP showed no statistical difference in their success ratios¹¹. In addition, some researchers believe that PRP injection did not add remarkably to the effects of a wrist splint. A randomized controlled trial pointed out that a single injection of PRP had no marked influence on the improvement effect of wrist splints to individuals with CTS¹². However, in almost all PRP treatment studies for CTS, a severe form of CTS was excluded, and treatment of PRP combined with CTR was not mentioned.

CTR is still the most recommended treatment for individuals with severe carpal tunnel syndrome and some patients with no improvement after glucocorticoid injection⁴. This study came to a similar conclusion that CTR is effective in treating persons with moderate or severe carpal tunnel syndrome, which can effectively improve the symptoms and functions, and even some patients' symptoms disappear entirely. The combined treatment of PRP does not increase the long-term effect of surgery, but it can accelerate the recovery after the operation in a short time.

In this study, patients with PRP treatment were not treated blindly. However, because of the surgery, the bias could be significantly reduced. Moreover, compared with a large number of multicenter clinical studies, the number of subjects in this study is relatively small, which needs further research. Besides, lack of randomization constitutes another limitation of the present study. Subjects who were apportioned into the PRP group but declined injection treatment were allowed to participate in the control group, which elevated the risk of selection bias.

To conclude, PRP as an adjuvant treatment of CTR has limited effect. Considering the additional financial burden on patients, CTR combined with PRP should be cautious in the treatment of CTS.

Ethics approval and consent to participate

This study was approved by Medical Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards

Consent for publication

Not applicable.

Availability of data and materials

The final dataset will be available from the corresponding author.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was funded by the Interdisciplinary Program of Shanghai Jiao Tong University (YG2021QN98) and Shanghai "Science and Technology Innovation Action Plan" Morning Star Cultivation: Sailing Program (22YF1447500).

Authors' contributions

Yanchun Gao revising substantial contributions to research design and revising the paper critically; Qiyang Wang acquisition, analysis, interpretation of data and drafting the paper; Chenchen Wang acquisition, analysis, and interpretation of data; Hua Chen approval of the submitted and final versions. All authors have read and approved the final submitted manuscript.

Acknowledgements

Authors disclose no conflicts of interest or acknowledgments.

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No competing interests reported.

A Prospective Cohort Study: Platelet-Rich Plasma Combined with Carpal Tunnel Release Treating Carpal Tunnel Syndrome short (running) title: PRP-CTR Treating Carpal Tunnel Syndrome

Status:

Version 2

Abstract

Background

Methods

Results

Conclusions

Figures

1. Background

2. Patients And Methods

3. Results

4. Discussion

Declarations

References

Additional Declarations

Status:

Version 2