Dexamethasone versus Hyaluronidase as an Adjuvant to Local Anesthetics in the Ultrasound-guided Hydrodissection of the Median Nerve for the Treatment of Carpal Tunnel Syndrome Patients.

BACKGROUND: Carpal tunnel syndrome (CTS) is one of the most common focal entrapment neuropathies. Although the exact etiology remains unclear, high-pressure-related intracarpal tunnel compression of the median nerve (MN), progressing ischemia, and mechanical strangulation are common mechanisms. The therapeutic managements for CTS depend on the disease severity, varying from a conservative treatment to surgical interventions. Conservative treatment is helpful for most of the patients with mild-to-moderate CTS. Hydrodissection is a minimally invasive procedure of injecting solutions into some anatomical spaces to facilitate dissection and adhesiolysis. Steroids as an anti-inflammatory drugs are used to treat chronic pain conditions. Hyaluronidase as an adhesolysis agent can also be used for epidural injections with local anesthetics (LAs) and steroids for control of chronic back pain. AIM OF THE STUDY: This study was carried out to compare the efficacy of hyaluronidase versus dexamethasone as adjuvants to the mixture of LAs in ultrasound (US)-guided hydrodissection of the median nerve in mild to moderate cases of carpal tunnel syndrome. SETTINGS AND
DESIGN: This study was a prospective randomized controlled double-blinded clinical study.
METHODS: 40 patients aged from 20 to 60 years old with clinical, electrophysiologic, and ultrasonographic evidence of mild to moderate CTS were included in this study. Each patient was assessed at the baseline (prior to injection) and at 1 week, 1 month, 3 months, and 6 months intervals after injection: (1) The Boston Carpal Tunnel Syndrome Questionnaire (BCTQ) which is a frequently used patient-based questionnaire for measurement of CTS. primary outcome. (2) Median motor and sensory nerve conduction studies (NCS) secondary outcome. (3) Median nerve ultrasonography. The ultrasound examination included measurement of the median nerve cross-sectional area (CSA) at the distal wrist crease (DWC). Also, the median nerve echogenicity, mobility, and vascularity at the DWC were assessed by US. Secondary outcome. All outcome assessments were assessed by single investigator who was blinded to the study details. All patients received US guided hydrodissection of the median nerve at the distal wrist crease. The selected patients were randomly allocated into 2 groups containing 20 patients each according to the study drugs; Group (D) received 5 mL (3 mL plain bupivacaine 0.5% and 2 mL (8 mg) dexamethasone), and Group (H) received 5 mL (3 mL plain bupivacaine 0.5% and 2 mL normal saline containing 300 international units (IU) hyaluronidase. Ultrasound-guided intracarpal injection using ultrasonography (Sono Scape A5; Shinzhen, China) with a 10-18-MHZ linear array transducer was performed by the same physician who was not aware of study groups, the MN was observed at the inlet of the carpal tunnel, 3 ml of solution was injected via the in-plane ulnar approach, to detach the MN from the transverse carpal ligament and an additional 2 ml was injected to separate the MN from underlying flexor tendons. All patients were observed for 30 minutes post injection for possible side effects before discharge. Normally distributed numerical data are presented as mean ± standard deviation, and differences between the groups were compared using the independent Student's t-test. Chi-square test was used for categorical data. Intragroup data at different follow up time points were evaluated using paired Student's t-test. All statistical tests were two-tailed, with P < 0.05 being considered statistically significant.
RESULTS: The demographic data of the patients in both groups were statistically insignificant (P-value >0.05). In the pre-injection time, there were no statistically significant differences between both groups as regards BCTQ (SSS, FSS), electrophysiological studies (SNCV, DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score). The comparison between both groups showed that measured parameters as regards BCTQ (SSS, FSS), electrophysiological studies (SNCV, DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score) were significantly improved in group H compared with group D in the follow up periods at 1 week, 1 month, 3 months and 6 months post-injection (P-value <0.05). The comparison within each group showed that in group D, the measured parameters; BCTQ (SSS, FSS), electrophysiological studies (SNCV, DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score) were statistically significantly improved at 1 week, 1 month and 3 months follow up post-injection times but they were not significantly improved at 6 months post-injection time compared with the pre-injection data (P-value >0.05). While in group H, these measured parameters were statistically significantly improved in the all follow up post-injection times; at 1 week, 1 month, 3 months and even at 6 months periods compared with the baseline pre-injection data (P-value < 0.05).
CONCLUSION: In this study, it was concluded that MN hydrodissction using hyaluronidase (as an adhesolysis agent) significantly improved patients with mild to moderate CTS compared to steroid (as an anti-inflammatory agents) hydrodissection of MN as regards BCTQ (SSS, FSS), electrophysiological studies (SNCV, DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score) not only at 1 week, 1 month and 3 months follow up post-injection times but these parameters were also significantly improved at 6 months post-injection time in bupivacaine- hyaluronidase hydrodissection group compared to bupivacaine-steroid hydrodissection group. Copyright:

INTRODUCTION

Carpal tunnel syndrome (CTS) is one of the most common focal entrapment neuropathies. Although the exact etiology remains unclear, high-pressure-related intracarpal tunnel compression of the median nerve (MN), progressing ischemia, and mechanical strangulation are common mechanisms.[12] Peripheral nerve entrapments are common, but they are often underrecognized as causes of pain. An entrapment neuropathy is defined as a pressure-induced segmental injury to a peripheral nerve due to an anatomical compression or pathological process.[34] The defining criteria of an entrapment, according to Kashuk,[5] include altered transmission because of mechanical irritation from impingement of near structures. Many nerve entrapments occur at sites where the nerve travels through a canal, channel, or tunnel, but they also occur because of trauma or scar “strangulation” of the nerve.[6] The therapeutic managements for CTS depend on the disease severity, varying from a conservative treatment to surgical interventions. Although conservative treatment is helpful for most of the patients with mild-to-moderate CTS, a Cochrane Review suggested that there was limited efficacy of such treatments.[7] Surgical decompression is indicated mainly for severe CTS or patients who have an unsatisfactory pain relief after conservative treatments.[8] Therefore, we need to study more novel interventions during the presurgical stages of CTS. Hydrodissection is a minimally invasive procedure of injecting solutions into some anatomical spaces to facilitate dissection and adhesiolysis during surgery.[9] Smith et al.[10] described ultrasound (US)-guided injection of lidocaine and corticosteroids in patients with CTS and suggested the concept of nerve hydrodissection by injecting the fluid between the MN and transverse carpal ligament and underlying tendons, which may interrupt the adhesions of MN and decrease the symptoms.[10] Furthermore, nerve hydrodissection is useful in preventing unintended direct injection into the nerve. The therapeutic effect of nerve hydrodissection depends on the theory that separating the compressed nerve from nearby soft tissue may decrease the risk of adhesions and chronic constriction injuries.[11] Nerve entrapments can cause clinical symptoms that range from mild discomfort to numbness, paralysis, or incapacitating pain. Injections have a unique role in the treatment of peripheral nerve entrapments. Injections can help in diagnosis, but they can also treat the underlying nerve entrapment, presumably by the anti-inflammatory effect of injected corticosteroids, hydrodissection of the constricting tissues, and the dilution and flushing out of inflammatory mediators.[3] The technique of hydrodissection requires both the skill of the identification of nerves under US as well as the safe and accurate manipulation of the US-guided needle. The goal is to place the needle tip on each side of the nerve (perineural) but not inside the nerve (intraneural).[12] Hyaluronidase acts by catalyzing the hydrolysis of hyaluronan, a constituent of the extracellular matrix. Hyaluronidase lowers the viscosity of hyaluronan, thereby increasing tissue permeability. It is, therefore, used in medicine in conjunction with other drugs to improve their dispersion and delivery. Common applications are ophthalmic surgery, in combination with local anesthetics (LA). It is also used as an adjunct in subcutaneous urography for improving the resorption of radiopaque agents. Hyaluronidase is also used to treat extravasation of hyperosmolar solutions.[13] This study was carried out to compare the efficacy of hyaluronidase versus dexamethasone as adjuvants to the mixture of LA in US-guided hydrodissection of the MN in mild-to-moderate cases of CTS.

PATIENTS AND METHODS

This prospective, randomized, controlled, double-blind study was conducted in Fayoum University Hospital at the pain management department between February 2018 and April 2019. After obtaining approval from the university ethical committee and written informed consents from the patients, 40 patients aged from 20 to 60 years with clinical, electrophysiologic, and ultrasonographic evidence of mild-to-moderate CTS were included in this study. Inclusion criteria were numbness or pain in the MN distribution, nerve conduction studies (NCS) consistent with CTS as per the AANEM guidelines,[14] and an MN cross-sectional area (CSA) at the wrist >12 mm2. Exclusion criteria were patients with severe symptoms as this is an indication for surgery, patients who show improvement on medical treatment, patients with previous surgical or injectional CTS treatment, coexistence of brachial plexopathy, or thoracic outlet syndrome, and patients with infection at the site of injection.

Each patient was assessed at the baseline (before injection) and at 1-week, 1-month, 3-month, and 6-month intervals after injection:

The Boston Carpal Tunnel Syndrome Questionnaire (BCTQ) is a frequently used patient-based questionnaire for the measurement of CTS, which encompasses two components.[15] In total, 11 questions and 8 items were evaluated for rating on the Symptom Severity Scale (SSS) and Functional Status Scale (FSS), respectively. Both the subscales score from 1 to 5, with higher scores indicating a greater degree of disability and a more severe form of the disease, primary outcome

Median motor and sensory NCS: the grade of CTS, determined via electrophysiological study, was classified as mild (abnormal sensory nerve conduction velocity [SNCV] and normal distal motor latency [DML]), moderate (both abnormal SNCV and DML), or severe (absence of sensory response and abnormal DML).[16] Only participants with mildtomoderate CTS were included in the study, secondary outcome

MN ultrasonography: The US examination included measurement of the MN CSA at the distal wrist crease (DWC); where the swelling of the MN presents a reliable measure for postinjection follow-up. Furthermore, by US, we assessed the MN echogenicity, mobility, and vascularity at the DWC. Echogenicity was assessed subjectively and rated as “normal,” (2), “slightly decreased” (1), or “decreased” (0), based on visual inspection of the image, with normal nerve echogenicity showing a honeycomb pattern with a mixture of dark fascicles interspersed among a brighter background. To assess MN mobility, the participant was asked to repeatedly flex and extend the fingers and wrist, while the transducer was kept over the DWC. Mobility was also rated as “normal” (2), “slightly decreased” (1), or “decreased” (0). Normal mobility is seen when the MN dives deep to the flexor tendons during finger and wrist flexion. Vascularity was assessed by placing the power Doppler box over the MN and slowly increasing the gain. If color flow was seen in the nerve prior to other structures (in particular, the flexor tendons), then vascularity was rated as either “increased” (2) or “slightly increased” (1), based on the degree of color flow, and “normal” (0) when there was no early color doppler signal in the nerve compared with the surrounding structures, the secondary outcome. All outcome assessments were assessed by single investigator who was blinded to the study details.

All patients received US-guided hydrodissection of the MN at the DWC. The selected patients were randomly allocated using computer-generated method and opaque, sealed envelopes into two groups containing 20 patients each according to the study drugs: Group D received 5 mL (3 mL plain bupivacaine 0.5% and 2 mL [8 mg] dexamethasone) and Group H received 5 mL (3 mL plain bupivacaine 0.5% and 2 mL normal saline containing 300 international units (i.u.) hyaluronidase. US-guided intracarpal injection using ultrasonography (SonoScape A5; Shenzhen, China) with a 10–18 MHz linear array transducer was performed by the same physician who was not aware of study groups, a 23G needle was inserted at the proximal wrist crease, just ulnar to the palmaris longus tendon, at a 30° angle to the skin and aiming toward the index finger, the MN was observed at the inlet of the carpal tunnel, 3 mL of solution was injected through the in-plane ulnar approach, to detach the MN from the transverse carpal ligament, and an additional 2 mL was injected to separate the MN from the underlying flexor tendons. All patients were observed for 30-min postinjection for possible side effects before discharge.

Statistical analysis

Sample size: On the basis of comparing the between-group change of BCTQ score between the baseline and the 6th-month postinjection, a preliminary power analysis by Mann–Whitney U-test with G*Power version 3.1.9.2 (UCLA, Los Angeles, California, USA) was performed.[17] At least 34 wrists were required to achieve sufficient power ([1− β] = 0.8; α = 0.05; because no preliminary data were available, we used a medium-level effect size of 0.50); our sample size was chosen as 40 patients to replace any missing data

Data analysis: SPSS version 22 (IBM Corp., Armonk, New York, USA) was used for statistical analysis. Normally distributed numerical data are presented as mean ± standard deviation, and differences between the groups were compared using the independent Student's t-test. Chi-square test was used for categorical data. Intragroup data at different follow up time points were evaluated using paired Student's t- test. All statistical tests were two-tailed, with P < 0.05 being considered statistically significant.

RESULTS

The demographic data of the patients in both the groups were statistically insignificant (P > 0.05) [Table 1]. In the preinjection time, there were no statistically significant differences between both the groups as regards BCTQ (SSS and FSS), electrophysiological studies (SNCV and DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score) [Tables 2–5]. The comparison between both the groups showed that measured parameters as regards BCTQ (SSS and FSS), electrophysiological studies (SNCV and DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score) were significantly improved in Group H compared with Group D in the follow-up periods at 1-week, 1-month, 3-month, and 6-month postinjection (P < 0.05) [Tables 2–5]. The comparison within each group showed that in Group D, the measured parameters: BCTQ (SSS and FSS), electrophysiological studies (SNCV and DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score) were statistically significantly improved at 1-week, 1-month, and 3-month follow-up postinjection times, but they were not significantly improved at 6-month postinjection time compared with the preinjection data (P > 0.05) [Tables 2–5]. Whereas in Group H, these measured parameters were statistically significantly improved in the all follow-up postinjection times: at 1-week, 1-month, 3-month, and even at 6-month periods compared with the baseline preinjection data (P < 0.05) [Tables 2–5].

Table 1

Demographic data

	Group D (n=20)	Group H (n=20)	P
Age (years), mean±SD	40.18±10.5	42.76±8.3	0.5
Sex (male/female), n	9/11	10/10	0.52
Height (cm), mean±SD	160.11±10.3	164.7±4.5	0.3
Weight (kg), mean±SD	68.59±9.7	67.49±9.33	0.72
Degree of CTS (Padua) (mild/moderate), n	10/10	11/9	0.27

Data are presented as mean±SD or ratio of patients. P>0.05 is considered statistically nonsignificant. SD=Standard deviation, CTS=Carpal tunnel syndrome

Table 2

The Boston Carpal Tunnel Syndrome Questionnaire, Symptom Severity Scale, and Functional Status Scale

	Group D (n=20)		Group H (n=20)		P**
	SSS	FSS	SSS	FSS	SSS	FSS
Preinjection	2.8±0.2	2.7±0.3	2.7±0.1	2.6±0.4	0.456	0.243
Postinjection 1 week	2±0.1	1.9±0.2	1.6±0.2	1.4±0.4	<0.05**	0.046**
P*	<0.05*	0.01*	<0.05*	0.045*
Postinjection 1 month	1.9±0.2	1.8±0.1	1.4±0.3	1.1±0.3	0.029**	<0.05**
P*	<0.05*	0.034*	0.023*	<0.05*
Postinjection 3 months	1.7±0.3	1.8±0.3	1.3±0.2	1±0.6	0.048**	0.019**
P*	0.012*	<0.05*	0.041*	0.037*
Postinjection 6 months	2.7±0.3	2.6±0.1	1.7±0.5	1.8±0.4	<0.05**	0.033**
P*	0.213	0.2	<0.05*	0.028*

Data are presented as mean±SD. *P<0.05 is considered significant for intragroup comparison **P<0.05 is considered significant for comparison between groups. SSS=Symptom Severity Scale, FSS=Functional Status Scale, SD=Standard deviation

Table 5

Sonographic data median nerve echogenicity score, mobility score, and vascularity score

	Group D (n=20)			Group H (n=20)			P**
	ES	MS	VS	ES	MS	VS	ES	MS	VS
Preinjection	1.4±0.1	1±0.3	1.8±0.5	1.5±0.2	1.2±0.4	1.9±0.9	0.84	0.32	0.19
1-week postinjection	1.6±0.2	1.3±0.6	1.5±0.1	1.8±0.5	1.8±0.8	1.1±0.7	0.046**	<0.05**	0.037**
P*	0.04*	0.045*	0.03*	0.046*	0.034*	<0.05*
1-month postinjection	1.7±0.5	1.5±0.6	1.3±0.3	1.9±0.7	1.9±0.8	0.7±0.3	<0.05**	0.029**	0.014**
P*	<0.05*	0.032*	0.041*	0.048*	<0.05*	0.02*
3-month postinjection	1.7±0.9	1.7±0.9	1±0.9	2	1.9±0.9	0.6±0.5	0.041**	<0.05**	0.036**
P*	0.021*	0.037*	<0.05*	<0.05*	0.027*	0.01*
6-month postinjection	1.4±0.8	1.1±0.1	1.7±0.8	2	2	0.4±0.1	<0.05**	<0.05**	0.039**
P*	0.21	0.32	0.07	0.048*	<0.05*	<0.05*

Data are presented as mean±SD. *Wilcoxon signed-rank test for the intragroup data (each time point vs. baseline), **Mann–Whitney U-test (change between groups). P<0.05 is considered significant. ES=Echogenicity score, MS=Mobility score, VS=Vascularity score, SD=Standard deviation

DISCUSSION

Pathological edema and inflammation-induced thickened flexor tenosynovium are the most common causes of increased pressure which leads to the reduction of MN mobility within the carpal tunnel.[18] Furthermore, “hourglass” configuration distortion of the MN, due to elevated pressure and fixation in subsynovial connective tissue, could decrease MN excursion and potentiate traction neuropathy.[19] Fixation in fibrosed tissue for long time periods has also been implicated in increasing the risk of nerve strangulation, which could further impair nerve functions.[20] Many studies have tried to find better therapeutic solutions for mild and moderate (presurgical) cases of CTS. One of those studies was that the study done in 2019 by Wu et al.,[21] who concluded that nerve hydrodissection had a therapeutic effect in patients with mild-to-moderate CTS and that nerve hydrodissection was shown to be potentially beneficial for CTS patients presurgery when compared with noninterventional patients, but they also demonstrated that there was a need for future researches to compare nerve hydrodissection with traditional management techniques, such as splint, physical therapy, and corticosteroid injection in CTS patients. Steroid injections in the carpal tunnel, as an anti-inflammatory and anti-edematous drugs, have been used successfully in different studies to treat mild-to-moderate CTS patients as in the studies done by Bland and Armstrong et al.,[2223] but there were some limitations for using steroids in patients suffering from uncontrolled diabetes, osteoporosis, and hypertension. Hence, in this study, the author have tried to find alternative safe therapeutic solutions for those patients and it was found that MN hydrodissction using hyaluronidase significantly improved patients with mild-to-moderate CTS compared to steroid hydrodissection of MN as regards BCTQ (SSS and FSS), electrophysiological studies (SNCV and DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score) not only at 1-week, 1-month, and 3-month follow-up postinjection times but also these parameters were also significantly improved at 6-month postinjection time compared to steroid hydrodissection group. Our findings is concordant with the results of the study done in 2011 by Cartwright et al.,[24] who studied the MN changes following steroid injections in CTS and they concluded that US and electrophysiological measurements of the MN at the DWC demonstrated significant improvement after steroid injection for CTS. However, this study had some limitations: first, the sample size was not large, as only 19 individuals (29 wrists) were studied and second, all the participants received steroid injections and there was no control group. Hyaluronidase is widely used as an adjuvant to LAs in ocular blocks for ophthalmic surgery, where it can reduce onset time and increase the success rate.[25] Hyaluronidase can also be used for epidural injections with LAs and steroids for control of chronic back pain.[26] The optimal dose of hyaluronidase is not known. In ocular surgeries, it varies from 3.75 to 30 IU/mL for successful retrobulbar or peribulbar blocks.[25] For adhesiolysis in epidural injection in chronic back pain, 1500 IU was used.[26] The most common side effect of hyaluronidase is allergy[27] which did not happen in this study.

CONCLUSION

In this study, it was concluded that MN hydrodissction using hyaluronidase (as an adhesiolysis agent) significantly improved patients with mild-to-moderate CTS compared to steroid (as an anti-inflammatory agent) hydrodissection of MN as regards BCTQ (SSS and FSS), electrophysiological studies (SNCV and DML), and sonographic data (CSA, echogenicity score, mobility score, and vascularity score) not only at 1-week, 1-month, and 3-month follow-up postinjection times but also these parameters were also significantly improved at 6-month postinjection time in bupivacaine-hyaluronidase hydrodissection group compared to bupivacaine-steroid hydrodissection group.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 3

Electrophysiological changes sensory nerve conduction velocity in millimeter/seconds distal motor latency in milliseconds

	Group D (n=20)		Group H (n=20)		P**
	SNCV	DML	SNCV	DML	SNCV	DML
Preinjection	30.1±0.3	4.9±0.5	31.1±0.4	4.8±0.7	0.31	0.74
Postinjection 1 week	31.4±0.4	4.5±0.4	32.9±0.1	4.1±0.1	<0.05**	0.024**
P*	<0.05*	0.044*	0.039*	<0.05*
Postinjection 1 month	31.9±0.6	4.1±0.6	32.5±0.6	3.7±0.7	0.011**	<0.05**
P*	0.042*	<0.05*	0.022*	<0.05*
Postinjection 3 months	32±0.7	4±0.3	32.7±0.4	3.5±0.2	0.048**	0.036**
P*	0.49*	0.012*	<0.05*	0.03*
Postinjection 6 months	30±0.2	4.8±0.7	32.2±0.9	3.9±0.8	<0.05**	0.029**
P*	0.12	0.45	0.041*	<0.05*

Data are presented as mean±SD. *P<0.05 is considered significant for intragroup comparison. **P<0.05 is considered significant for comparison between groups. ES=Echogenicity score, MS=Mobility score, VS=Vascularity score, SD=Standard deviation

Table 4

Sonographic data – cross-sectional area of the median nerve (mm2)

	Group D (n=20)	Group H (n=20)	P**
Preinjection	13.2±0.8	13±0.5	0.21
1-week postinjection	12.5±0.3	12.6±0.1	<0.05**
P*	<0.05*	0.012*
1-month postinjection	12.3±0.9	12.1±0.2	0.045**
P*	0.033*	<0.05*
3-month postinjection	12.1±0.7	12±0.5	<0.05**
P*	0.023*	0.019*
6-month postinjection	12.9±0.8	12.4±0.7	0.034**
P*	0.31	<0.05*

Data are presented as mean±SD. *P<0.05 is considered significant for intragroup comparison. **P<0.05 is considered significant for comparison between groups. SD=Standard deviation