Abstract: We included seven trials involving 500 participants that studied the effect of hyaluronidase on intraoperative pain. Four of the seven trials with 289 participants reported the primary outcome in a dichotomous manner, and we proceeded to meta-analyse the findings which showed a moderate heterogeneity that could not be explained (I2 = 41% ). The pooled risk ratio (RR) for these four trials was 0.83 with the 95% confidence interval ranging from 0.48 to 1.42. The reduction in intraoperative pain scores in the hyaluronidase group were not statistically significant. Among the three trials that reported the primary outcome in a continuous manner, the presence of missing data made it difficult to conduct a meta-analysis. To further explore the data, we imputed standard deviations for the other studies from another included RCT (Sedghipour 2012). However, this resulted in substantial heterogeneity between study estimates (I² = 76% ). The lack of reported relevant data in two of the three remaining trials made it difficult to assess the direction of effect in a clinical setting. Overall, there was no statistical difference regarding the intraoperative reduction of pain scores between the hyaluronidase and control group. All seven included trials had a low risk of bias. According to GRADE, we found the quality of evidence was low and downgraded the trials for serious risk of inconsistency and imprecision. Therefore, the results should be analysed with caution. Participant satisfaction scores were significantly higher in the hyaluronidase group in two high quality trials with 122 participants. Surgical satisfaction was also superior in two of three high quality trials involving 141 participants. According to GRADE, the quality of evidence was moderate for participant and surgical satisfaction as the trials were downgraded for imprecision due to the small sample sizes. The risk of bias in these trials was low. There was no reported harm due to the addition of hyaluronidase in any of the studies. No study reported on the cost of hyaluronidase in the context of eye surgery. The effects of adding hyaluronidase to local anaesthetic fluid on pain outcomes in people undergoing eye surgery are uncertain due to the low quality of evidence available. A well designed RCT is required to address inconsistency and imprecision among the studies and to determine the benefit of hyaluronidase to improve analgesia during eye surgery. Participant and surgical satisfaction is higher with hyaluronidase compared to the control groups, as demonstrated in moderate quality studies. There was no harm attributed to the use of hyaluronidase in any of the studies. Considering that harm was only rarely defined as an outcome measure, and the overall small number of participants, conclusions cannot be drawn about the incidence of harmful effects of hyaluronidase. None of the studies undertook cost calculations with regards to use of hyaluronidase in local anaesthetic eye blocks.

Plain-language summary: We included seven randomized controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) in our review. These involved 500 adults undergoing eye surgery under local anaesthesia. We looked at any additional effect of adding hyaluronidase to local anaesthetic on the pain experienced during eye surgery. We also looked at participant and surgical satisfaction scores and if any harms were reported after using hyaluronidase in the injection solution. None of the studies reported on costs. Of the seven included trials, we pooled the results of four trials (289 participants) as the results were reported in a similar manner. They found that addition of hyaluronidase did not significantly reduce pain during surgery. Among the three remaining trials (211 participants) lack of data reporting in two trials made it difficult to pool the results. The overall result of looking at all these trials together suggests there was no significant reduction of pain with using hyaluronidase in eye nerve blocks. We found moderate quality evidence from two trials (122 participants) to suggest that addition of hyaluronidase increased participant satisfaction scores. Three studies involving 141 participants looked at surgical satisfaction, which was reported as superior with hyaluronidase in the two larger studies and not significantly different in one small study (19 participants). None of the included studies reported any harmful effects of hyaluronidase. The included trials that reported on pain during surgery were at low risk for bias. The overall quality of evidence was low because of variations in the effect on pain reduction. We contacted all trial authors to request more information on the trials, but the data were not available. Moderate quality studies reported greater participant and surgical satisfaction with hyaluronidase. Analgesia alone does not take into account the full spectrum of the beneficial effects of hyaluronidase. Patient comfort with the eye surgery is also likely to be improved by a speedy onset and reduced eye movements due to hyaluronidase.