A systematic review and meta-analysis of randomised controlled trials of surgical treatments for ingrown toenails part II: healing time, post-operative complications, pain, and participant satisfaction

Background When performing nail surgery, clinicians must choose from a multitude of procedures and variations within each procedure. Much has been published to guide this decision making, but there are a lack of up to date robust systematic reviews to assess the totality of this evidence. Methods Five databases (MEDLINE, Embase, CINAHL, Web of Science and CENTRAL) and two registers (Clinicaltrials.gov and ISRCTN) were searched to January 2022 for randomised trials evaluating the effects of a surgical intervention(s) for ingrown toenails. Two independent reviewers screened records, extracted data, assessed risk of bias and certainty of evidence. Data on co-primary outcomes of symptom relief and symptomatic regrowth were presented in our first paper. This paper presents data for the secondary outcomes and further discussion. Results Of 3,928 records identified, 36 randomised trials were included in the systematic review. Healing time appears to be reduced with shorter application of phenol. A reduced healing time was also apparent was with the addition of curettage, although this may also increase the risk of post-operative bleeding and pain. Post operative bleeding was also reportedly lower in people who received local anaesthetic with epinephrine but no tourniquet. Use of phenol with nail bed excision may decrease the risk of infection. Lower pain scores were reported when using partial matrixectomy and surgical interventions with phenol. Shorter duration of pain was reported with phenolisation and wedge resection. Participant satisfaction was high overall. Conclusion This second paper reports secondary outcomes from a robust systematic review of randomised trials on surgical treatment of ingrown toenails. Despite the large volume of clinical trials conducted on the topic, few clinical conclusions can be drawn due to the poor quality of these studies. Further high-quality clinical trials are needed to answer fundamental questions in the surgical treatment of ingrown toenails. Supplementary Information The online version contains supplementary material available at 10.1186/s13047-023-00655-7.


Introduction
Ingrown toenails (onychocryptoses) are one of the most common nail pathologies.It has been suggested that they have a prevalence of between 2.5% and 5% with a bimodal distribution of age with peaks at 15 and 50 years [1,2].Patients typically present with pain as their main symptom and this can often cause difficulty with footwear and walking [3].As the nail plate pierces the periungual tissue, it leads to local inflammation and frequently secondary bacterial infection with associated serosanguinous or purulent discharge [3].Over time, this can become chronic as the nail plate continues to grow causing hypergranulation tissue to proliferate and protrude from the nail sulcus [4].
Mild early cases can often be treated with conservative interventions, but many cases require some form of nail surgery.Indeed, nail surgery is so frequently performed that it has been identified as the tenth most common procedure performed by podiatrists [5].Although there are multiple procedures and options on how to perform such surgery, it typically aims to remove the problem part of the nail and destroy the underlying matrix to avoid recurrence [6][7][8].As with many interventions in healthcare, nail surgery can be considered a complex intervention as it contains multiple interacting components that often need tailoring to the needs of individual patients [9][10][11].When deciding on each of these components for a given patient, clinicians must make multiple decisions based on the available evidence.
A large number of papers have been published on the treatment of ingrown toenails including many narrative or scoping reviews, but with the most recent Cochrane review now over a decade old, there is a lack of current high quality systematic reviews and meta-analyses [7,[12][13][14].The authors therefore aimed to systematically search and synthesise the literature relating to the effectiveness/efficacy of surgical methods for treating ingrown toenails.Given the volume of studies and data on this topic, the review has been split into two parts with the linked paper reporting in detail the results from the co-primary outcomes of recurrence and relief of symptoms [15].This paper presents the secondary outcomes: healing time, post-operative complications (infection and haemorrhage), pain of operation/ post-operative pain and participant satisfaction.

Methods
The conduct and reporting of this review were guided by the Cochrane Handbook for Systematic Reviews of Interventions [16] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [17].It was prospectively registered [PROSPERO: CRD42021251938].

Eligibility criteria
Randomised controlled trials (RCT) were included if they evaluated the effects of a surgical intervention(s) for ingrown toenails with a follow-up period of at least one month.Our inclusion criteria were broad, and we did not restrict eligibility based on the trial setting, age, or gender of participants.Studies were restricted to English, pertaining to human participants, and must have reported one of the pre-defined outcomes for inclusion.Our co-primary outcomes were relief of symptoms, and symptomatic regrowth (nail spicules/nail spikes), which are reported elsewhere [15].Secondary outcomes: healing time, post-operative complications (e.g., infection and haemorrhage), pain of operation, post-operative pain (duration and intensity) and participant satisfaction are reported herein.

Search strategy
We searched MEDLINE (Ovid), EMBASE (Ovid), CINAHL, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to January 2022 using a multifaceted search strategy (Supplementary File 1).We also searched trial registers (International Clinical Trials Registry and Clinicaltrials.gov)and forward and backward citations of included studies.
Results were exported into Rayyan for de-duplication.Title, abstract, and full text screening were conducted independently by two reviewers and any discrepancies were assessed by a third reviewer and resolved by consensus.

Data extraction
Two reviewers independently extracted data using a modified Cochrane data extraction form.Disagreements were resolved through consensus with a third author.Data extracted included: (a) general information such as author(s), title, journal and study funding; (b) trial characteristics such as study aim and objectives, study design, unit of allocation and ethical approvals; (c) participant characteristics such as setting, inclusion/exclusion criteria, sample size (number of participants and nail folds), age, gender, baseline imbalances, severity of ingrown toenails; (d) intervention and comparison group(s); (e) outcome measures including as time points, unit of measurement, outcome definition, data at baseline/follow-up and statistical methods.Where data were missing or unclear, clarification was sought via email to the corresponding author(s).At least one follow-up email was sent if a response was not forthcoming.

Risk of bias
The Cochrane Risk of Bias tool (RoB 2.0) was used to evaluate risk of bias [18].

Data synthesis and analysis
Despite, intending to conduct meta-analyses on these secondary outcomes, unfortunately this was not possible due to a combination of studies not conducting intention to treat analysis, poor reporting, heterogeneity in the intervention and timepoints at which the outcomes were captured, and unavailability of data.Thus, these secondary outcomes could only be reported narratively, and conclusions are therefore limited.

Results
The PRISMA flow chart (Supplementary File 2), study characteristics (Supplementary Table 1) and interventions are detailed in paper 1 [15].
Few studies reported any statistically significant findings.Redness and exudate was found to be reduced when comparing nail bracing to matrix excision [46] and the use of phenol over trichloroacetic acid appeared to reduce oozing at week two and four [34].The addition of curettage to chemical matrixectomy [32] increased bleeding but showed lower infection rates.Two studies [33,38] found the addition of phenol led to significantly lower infection rates.

Participant satisfaction
Participant satisfaction was reported in nine studies [20, 21, 33, 36, 40-42, 47, 53] (Table 5).All studies reported improvements in satisfaction, although how that was defined and measured was generally unclear.Two studies [40,47] measured this using a VAS of 0-10 and only three studies [40,47,51] undertook statistical analysis.'Satisfaction with scar' was found to be higher with chemical matrixectomy than matrix excision [47] at 1 month but this difference was no longer significant by 3 and 12 months.The same study also measured 'satisfaction with cosmetic results' and found no significant difference at any of the timepoints.In a comparison of nail bracing to matrix excision [40], satisfaction was higher in the matrix excision group at 4 and 26 weeks.

Risk of bias
We used the used the Cochrane RoB 2.0 tool and assessed six domains for each study.No study was rated as low risk, for reasons such as not or providing information surrounding the randomisation process, not including all participants in the final analysis and failing to provide information on blinding of participants or the outcome assessor.Risk of bias summaries are presented in Fig. 1 and risk of bias table in Supplementary Table 2.

Discussion
This is the second paper from this systematic review and meta-analysis of randomised controlled rials of surgical treatments for ingrown toenails.The first reported the methods used in the review and reported results from the primary outcomes of recurrence and   2.0 ± 0.8 weeks relief of symptoms [15].This second paper focusses on the secondary outcomes of healing time, postoperative complications (e.g., infection and haemorrhage), postoperative pain (duration and intensity) and participant satisfaction.Although a large number of trials were identified for inclusion in the review, the poor reporting, heterogeneity of the studies and differences in outcome measures/timepoints, meant a meta-analysis was not possible on these secondary outcomes.Perhaps the most obvious clinical finding from this, is the lack of robust clinical conclusions that can be drawn from all these studies.Possibly the clearest pattern to emerge was around the use of phenol.Shorter application of phenol during the chemical matrixectomy was linked to shorter time to healing in two studies, but application duration appeared to have little effect on post operative complications [26,28].Although this may suggest that clinicians should use a shorter duration of phenol, this must be balanced against the meta-analysis in the first paper which indicate higher rates of regrowth are associated with shorter application times [15].The optimal balance of effectiveness and sequalae is yet to be determined and clinicians may opt to vary application times to meet the needs of individual patients.
Curettage has been explored in several studies.Alvarez-Jimenez et al. reported that using a Martini bone curette following partial nail avulsion and destruction of the nail matrix with phenol reduced healing time by a third (7.5 ± 1.8 days compared to 12.4 ± 3 days, p = 0.001) [32].They also found that it reduced rates of post operative infection, but increased post operative bleeding and as reported previously had no effect on recurrence [15].However, with only 51 patients, and that this has not been tested in multiple trials, care must be taken not to overinterpret these findings.It is notable that whilst interventions such as curettage may benefit some outcomes such as healing, it may increase others such as post operative bleeding.A similar pattern was found with phenol where longer durations of application were linked to reduced likelihood of regrowth but increase healing times [15,26,28].Clinicians and future studies should prioritise these competing risks and benefits in a way that prioritises what is important to patients.
Many studies report infection rates following nail surgery but combining these isn't yet possible as case definitions are unclear and inconsistent.Standardised definitions of surgical site infections, and severity classifications exist and have been used in other fields of surgical research, but they have not yet been validated Table 2 Healing definitions Akkus (2018) [18] No definition provided AlGhamdi (2014) [19] No definition provided Altinyazar (2010) [30] No definition provided Alvarez-Jimenez (2011) [31] The clinical criteria of early healing time were considered to be absence of drainage (no exudate evident), granulation tissue covered by a scab (no evidence of hyper granulation tissue), and no signs of infection (i.e.pain and clinical evidence of discharge in association with redness extending proximally).The patient was then allowed to bathe.All criteria had to be met before the wound was considered cicatrized (healed) Awad (2020) [20] Healing was inspected for the complete re-epithelialization of nail bad and regression of edema Gem (1990) a [21] No definition provided Gem (1990) b [21] No definition provided Kavoussi (2020) [22] No definition provided Misiak (2014) [23] Healing was defined as the complete reepithelialization of nail bed, regression of oedema and cessation of discharge Muriel-Sánchez (2020) [24] The healing time was measured paying attention to the previously described criteria, considering it to be the period of time between the surgical action and the solving of the draining and/or inflammatory changes.The criteria are absence of exudate in the gauze; the forming of a scab which covers the granulation tissue; the wound must be kept uncovered; a lack of signs of infection or inflammation in the zone operated; there are no signs of erythematosus tissue or of hyper granulation Muriel-Sánchez (2021) [25] The healing time was measured as previously described criteria, considering the period of time between ending surgical procedure and resolution of the postoperative period.These criteria were absence of exudate at gauze; formation of scab covering the wound; the wound must be kept uncovered; no signs of infection or inflammation at nail folds; no signs of erythema or hypergranulation tissue Reyzelman (2000) [26] Healing time was defined as the interval between the day the phenol matrixectomy was performed and the resolution of drainage and inflammatory changes surrounding the nail border.In every case, healing was identified by the principal investigator of the trial Tatlican (2009) [27] Complete healing was defined as the complete reepithelialization of the nail bed and the cessation of drainage Van der Ham (1990) [28] No definition provided Varma (1983) [29] No definition provided         and applied to nail surgery [54][55][56].Despite the clear interest in post operative infection as an outcome, only one trial explored the use of oral antibiotics and found no evidence that they reduced the rate of post operative infection.However, with only 50 to 53 participants per group, it would only have been powered to identify a large effect.Other post operative sequalae, such as haemorrhage also had unclear case definitions and were poorly reported.With some studies only capturing data for some outcomes up to 48 h post procedure [32], there is not enough time to meaningfully assess the effect of an intervention on complication rates.Perhaps more worryingly, there was a lack of information on the reporting of adverse events in general despite clear legal and governance frameworks being in place for many years.
Another frequently captured outcome was patient satisfaction.This is a widely used, but poorly defined concept in healthcare and although definitions vary, they generally centre on satisfaction being the extent to which an individual's experience meets their expectations [57][58][59].However, patient expectations are not a stable trait and change over time as has been recognised elsewhere [60].Evidence from randomised trials have shown that patient expectations can be deliberately modified, and that patient expectations can be guided towards what clinicians consider achievable [60,61].Modification of patient's expectations would in turn influence their final level of satisfaction, which brings into question its value as a measure of treatment effectiveness.
Given the limitations of the studies identified in this review, it's clear that many fundamental questions remain unanswered around the surgical treatment of ingrown toenails: Is destruction of the nail matrix always necessary?What is the optimal technique to prevent symptomatic regrowth?How should patients be reviewed and monitored post-operatively?Are different procedures more appropriate for subgroups of patients?Further high-quality collaborative trials are needed to answer these questions.
Findings from this paper should be interpreted in line with the assessments of risk of bias and certainty of evidence reported in the first paper [15].All studies included in the review were assessed as having either high risk or having some concerns about bias when assessed with the Cochrane ROB 2.0 tool.Similarly, none of the comparisons were considered to have high certainty when assessed with the GRADE system in the first paper [15].These issues could have been averted at the protocol development stage of each trial and there is a large body of literature to guide the development and conduct of such trials [62][63][64][65][66]. Similarly, frameworks exist that would aid reporting and peer review of such studies [67,68].This is a clear case of what the late Prof Doug Altman, who perhaps did more to improve healthcare research than anyone else, referred to when he said "We

Conclusion
This paper reports the narrative synthesis of the secondary outcomes from a systematic review and meta-analysis of randomised trials on surgical treatments for ingrown toenails.Despite the large volume of trials published in this area, poor design and reporting of studies prevented meta-analysis of these outcomes and limits the clinical conclusions that can be drawn.What is clear is that further robust, patient centred, clinical trials are urgently needed to fill the vacuum of quality evidence around such a commonly performed procedure.

(
time between the surgical action and the solving of the draining and/or inflammatory changes 21.3 ± 3.1 days [95% CI 20.20 to 22.39] p < 0.001 B: "Aesthetic reconstruction" (describes partial nail ablation with wedge excision of matrix) (n = 24) 8.2 ± 1.4 days [95% CI 7.92 to 8.55] Chemical v' s Other chemical (n = 1 study) Gem (1990) Study 1[21] A: Chemical ablation with 3-min application of 80% phenol (n = 109) Until healing occurred The average time to complete healing was 40 days, again with no statistical difference between the groups No statistical analysis information provided B: Chemical ablation with 2-min application of 10% sodium hydroxide (n = 110) The average time to complete healing was 40 days, again with no statistical difference between the groups Chemical timings (n = 3 studies) Gem (1990) Study 2[21] A: Chemical ablation with 2-min application of 10% sodium hydroxide (n = 110) Until healing occurred The average time to complete healing was 40 days, again with no statistical difference between the groups No statistical analysis information provided B: Chemical ablation with 1-min application of 10% sodium hydroxide (n = 93) The average time to complete healing was 40 days, again with no statistical difference between the groups Tatlican (2009) [28] A: Partial nail avulsion with 1 min phenol cauterisation (n = 37) Patients were examined on alternate days until the complete healing was achieved 13.5 ± 3.9 days A vs B = p = < 0.001 B: Partial nail avulsion with 2-min phenol cauterisation (n = 36) 17.5 ± 2.8 days A vs C = p = < 0.001 C: Partial nail avulsion with 3-min phenol cauterisation (n = 37) 17.1 ± 2.6 days B vs C = p = 0.853 Exley et al.Journal of Foot and Ankle Research (2023) 16:55 SD Standard Deviation, CI Confidence Interval, OR Odds Ratio, NaOH Sodium Hydroxide * Unless otherwise specified a Unclear on the timepoints included in the analysis

Fig. 1
Fig. 1 Risk of bias summary plot: RoB

Table 1
Outcome measure: Healing Time (n

Table 3
Outcome measure: Post-operative complications (infection and haemorrhage) (n

Table 4
(continued) SD Standard Deviation, CI Confidence Interval, OR Odds Ratio, NaOH Sodium Hydroxide * Unless otherwise specified a Unclear on the timepoints included in the analysis

Table 5
Outcome measure: Participant Satisfaction (n