Addition of Hyaluronidase Reduces Failure of Regional Block in Ophthalmic Surgery: Meta-Analysis of Randomized Clinical Trials

Objetive: To evaluate the efficacy of hyaluronidase in preventing total/partial failure of regional block in ophthalmic surgery. Method: Meta-analysis of randomized clinical trials, with patients undergoing ophthalmic procedures under peribulbar/subtenonian block, who received local anesthetic associated with hyaluronidase. The search for articles on PubMed used terms such as hyaluronidase, hyaluronoglucosaminidase and ophthalmology, or synonyms, using AND and OR interlocutors. Two independent researchers evaluated titles and abstracts. For those selected, there was complete reading of the text for inclusion in the sample. Manual search of references was also carried out. A random effects model (DerSimonian-Laird test) and Odds Ratios Calculation (OR) with 95% confidence intervals (95% CI) were used. Results: 242 studies identified, 12 were selected, including 1,328 patients (689 cas es and 639 controls). The use of hyaluronidase was considered a protective factor against ocular akinesia failure in regional anesthesia (OR: 0.55; 95% CI: 0.32-0.93; p=0.027). The same was observed in the subgroups analysis with a hyaluronidase dose >100 IU / mL (OR: 0.43; 95% CI: 0.20-0.90; p=0.02) and association with bupivacaine (OR: 0.53; 95% CI: 0.33-0.84; p=0.01). Conclusion: This meta-analysis shows the efficacy of hyaluronidase associated with local anesthetics in preventing regional block failure in ophthalmic surgery.


Introduction
Hyaluronidase is an enzyme that has been used as an adjunct to Local Anesthetics (LA) aiming to improve the speed of onset of blocks, dispersion, depth, better akinesia and analgesia. Its main action is depolymerization of extracellular hyaluronic acid, the intercellular cement of connective tissues, allowing anesthetic agents to spread more easily along the orbit through fine septal barriers of connective tissue [1]. When hyaluronidase is not used with local LA, increased concentrations of the anesthetic agent has the potential to accumulate around the extraocular muscles, leading to myotoxicity, increased orbital extracellular pressure and ischemic damage by decreasing blood flow in the branches of the ophthalmic artery [2]. The development of less invasive surgical techniques in ophthalmology has contributed to the replacement of general anesthesia by regional block techniques. Peribulbar (PB) and subtenonian blocks (SB) are commonly practiced, providing excellent conditions for operating the eye, but they have their inherent risks, such as eye perforation, hemorrhages, and even cardiorespiratory arrest, among others [3]. Less invasive techniques to provide local anesthesia, such as subconjunctival or topical application, present less risk of complications, but fail to provide adequate immobility [akinesia] of the eye and postoperative analgesia [3]. Among all LAs used in clinical practice, ropivacaine, bupivacaine, lidocaine and the association of bupivacaine and lidocaine stand out [4][5][6]. There is still no consensus on the efficacy and the most adequate dose of hyaluronidase in association with LA in ophthalmic blocks [7]. Thus, this meta-analysis aims to assess the effectiveness of hyaluronidase in preventing total or partial failure of regional block in ophthalmic surgery.

Method
Meta-analysis of randomized clinical trials that evaluated the efficacy of hyaluronidase associated with LA in preventing total or partial failure of PB or SB in patients undergoing eye surgery.
The PRISMA Guidelines [8] were followed for the elaboration and reporting of a systematic review and meta-analysis of randomized clinical trials. Articles published up to April 2020 in the PubMed databases were selected using terms such as hyaluronidase, hyaluronoglucosaminidase and ophthalmology, or their synonyms, separated by AND and OR interlocutors. To complement the search, a manual analysis of the references of the studies that met the inclusion criteria was performed, aiming to identify original studies that were not previously found. Randomized, double-blind clinical trials with patients over 18 years old under eye surgery. Studies using retrobulbar block in animals, techniques combined with sedation, different comparison groups and unavailable full text were excluded.
Two independent researchers performed a preliminary assessment of the titles/abstracts and extracted the data. For those selected, there was a complete reading of the text, obeying the inclusion and exclusion criteria. In case of disagreement, a third researcher made the final assessment. The data referring to the patients were: age and physical status classification and (B). To explore sources of heterogeneity among studies, we planned sensitivity analysis by subgroups containing the same LA, LA concentration and/or association with hyaluronidase, doses of hyaluronidase greater than and less than 100 IU/ml, and different blocking techniques (PB or SB). Statistical heterogeneity was calculated using the chi-square method (χ2) and the Higgins test (I2) [10]. The odds ratio (OR) and a 95% confidence interval (95% CI) were used to assess the dichotomous variables differences between groups. The random effects model was adopted using the DerSimonian-Laird test [11] and statistical analysis using the Comprehensive Meta-analyzes® software v.3.3. Evaluation of potential publication bias was performed by visual analysis of the funnel graph and also Begg [12] and Egger [13] tests, adopting statistical significance of 5%.   Table 1. Six studies were carried out in England [7,18,[20][21][22][23], two in Scotland [15,16], and the others in Iran [14] Wales [17], New
With the techniques used, satisfactory ocular akinesia was obtained and adverse events were minimal, even in different concentrations of added LA. Hyaluronidase has been used for many decades as an adjunct to the local anesthetic solution, aiming to improve the speed of onset of regional blocks in ophthalmic surgeries and to provide better akinesia and analgesia [1]. Reaffirming this thesis, a study proved, by means of ultrasound, that the addition of hyaluronidase results in faster dispersion of LA [3]. Another benefit of hyaluronidase is to change the pH of the solution due to the presence of phosphate buffers in the preparation. The pH of the bupivacaine solution changes from 5.3 to 6.3 after the addition of hyaluronidase and can maintain the solubility of AL during the alkalinization process, generating less pain on application [25].
Studies that evaluate the dose of hyaluronidase in ophthalmic anesthesia are conflicting, with no consensus on the effective dose. This makes it difficult to standardize the enzyme's use and reduces adherence to its adoption [21]. On the group that used a hyaluronidase dose greater than 100IU/mL, its presence behaved as a protective factor against block failure. The main hypotheses for this are due to the fact that there is a dose-dependent effect, which facilitates the dispersion of LA and a consequent decrease in the failure rate [1].
When the two subgroups of LA type were analyzed, the studies that used sole bupivacaine comparing the presence or absence of hyaluronidase versus the studies that used only lidocaine in the presence or absence of hyaluronidase, the reduction in the block failure could only be found in the association containing the bupivacaine. This may be possibly due to the pharmacokinetic and pharmacodynamic properties of bupivacaine [6,26]. Since it is more potent and has a longer duration of action, it promotes absent eye movement for a longer time compared to lidocaine.
This finding is consistent with the results of other studies [6,26].
On the other hand, a disadvantage of bupivacaine relies in its more evident cardiotoxicity than lidocaine [27]. Lidocaine has a pKa closer to the physiological one, which implies shorter latency, faster onset of action, but also shorter duration, with the need to repeat supplementary doses, including intraoperatively [6,28]. This, in theory, can justify the non-association shown in this meta-analysis.
Another possibility would be the small number of studies that used lidocaine.  [29]. An adequate meta-analysis should include relevant studies, of low heterogeneity and detect potential biases [8]. Despite the different strategies adopted in this study to minimize possible biases, such as analysis by subgroups, those cannot be ruled out. Double-blind, randomized clinical studies were included, but the search was performed in only one database, which in fact did not compromise the result since we did not find publication bias in the Begg [12] and Egger [13] tests. The inclusion of different doses of hyaluronidase, types and concentrations of LA and varied regional blocking technique, corroborated for the presence of clinical heterogeneity in the studies that justified the use of the random effects model. No studies were found to describe the economic impact of hyaluronidase use. In the current climate of financial constraints, this information would be very valuable, and any future study must incorporate this aspect.

Conclusion
This meta-analysis shows the efficacy of hyaluronidase associated with local anesthetics in preventing failure of regional block in ophthalmic surgery.