Common Salt versus Silver Nitrate for the Treatment of Umbilical Granuloma in Infants: An Open-label, Single-center, Pilot Randomized Controlled Trial

ABSTRACT

Aim:

This study aims to compare the efficacy and safety of topical application of common salt (CS) in comparison to silver nitrate (SN) for treating infants with umbilical granuloma (UG).

Materials and Methods:

We conducted an open-label, prospective, single-center, pilot randomized controlled trial. Thirty-seven infants with a clinical UG diagnosis were enrolled between October 2022 and July 2023, excluding those previously treated for UG. Patients were randomly assigned (using the Randomizer^® app) to receive either topical CS (applied thrice daily by caregivers at home for 5 days) or SN (applied by pediatric surgeon in clinic and kept under occlusive dressing for 48 h). Patients with partial/no healing received an additional session of the same treatment. Nonresponders transitioned from CS to SN, and vice versa, for two more applications. Healing rates were compared with a significance level of α =0.05.

Results:

Out of 34 patients (18 CS and 16 SN), 32 successfully completed the trial (17 CS and 15 SN). No significant differences were observed in baseline characteristics. Efficacy rates of CS (19/22; 86.36%) and SN (11/17; 64.71%) did not significantly differ (P = 0.056; 95% confidence interval [CI] −0.4832–0.0502). No major adverse events were reported. CS showed superior healing outcomes in infants below 3 months of age (19/22; 86.36%) compared to SN (11/17; 64.71%) (P = 0.056; 95% CI − 0.4832–0.0502). The timing of umbilical cord detachment did not significantly affect healing rates.

Conclusion:

Widespread availability, ease of access, suitability for safe home application, and cost-effectiveness make CS a primary treatment option for UG. Larger patient cohorts are needed for conclusive results.

INTRODUCTION

Umbilical granuloma (UG) is one of the most common umbilical abnormalities in infants. It presents as a small granulation tissue at the base of the umbilicus, consisting predominantly of fibroblasts, abundant small vessels, and endothelial and inflammatory cells. It is presumed to develop in response to a subclinical infection of the fibromuscular umbilical ring after the cord stump falls off, which leads to incomplete epithelialization of the umbilical ring and subsequent overgrowth of the granulation tissue.[1] The most commonly employed treatment for UG involves topical application of silver nitrate (SN) which has been associated with reports of chemical burns in the periumbilical area due to its astringent and caustic effects on the neighboring healthy epithelial tissue.[2] Consequently, various researchers have explored alternative treatment options, including common salt (CS), antiseptics/steroids, alcohol wipes, and even, doxycycline.[3] The topical application of CS has garnered significant attention as an inexpensive and easily accessible homemade remedy, owing to its noted advantages in terms of both effectiveness and safety.[4] Salt has a desiccant effect, attributable to its high sodium ion concentration, which results in the removal of water from the intracellular compartment. This leads to contraction and necrosis of the moist granulation tissue without causing harm to the adjacent normal stratum corneum. However, it is imperative to establish more robust evidence of the benefits of salt treatment before advocating its widespread use.

To address this need, we conducted an open-label, prospective, single-center pilot randomized controlled trial (RCT) to compare the efficacy and safety of CS versus SN in infants afflicted with UG.

Aim

This study aims to compare the efficacy and safety of the topical application of CS in comparison to SN for the treatment of infants with UG.

The primary objective was to compare the healing rates of topical application of CS versus SN for infants with newly diagnosed UG. The secondary objective was to study the safety of parental/caregiver home-based application of CS in comparison to SN application by health-care professionals in the management of UG in infants.

MATERIALS AND METHODS

Study design

This is an open-label, prospective, single-center, pilot RCT aimed at comparing the effects of topical CS versus SN application in infants newly diagnosed with UG. Ethical approval for this trial was granted by our hospital’s institutional review board, and written informed consent was obtained from the parents or legal guardians of each infant before their inclusion. The study was conducted in strict accordance with the ethical principles outlined in the 1964 Declaration of Helsinki.

Participant enrolment

A total of 38 infants diagnosed with UG, who sought treatment at our hospital between October 2022 and July 2023, were enrolled in the trial. Inclusion criteria encompassed children up to 1 year of age with a clinical diagnosis of UG, established by qualified pediatric surgeons during outpatient department (OPD) evaluations. Infants previously treated for UG or those with ultrasonographic evidence of a patent vitellointestinal duct or patent urachus were excluded from the study. Demographic and clinical parameters, including gender, gestational age at birth, age at UG diagnosis, birth weight, time to umbilical cord detachment, and duration of UG symptoms, were recorded for all enrolled patients.

Randomization

All eligible patients were randomly assigned to receive either topical CS or SN treatment, as illustrated in Figure 1. Randomization was accomplished using the Android app Randomizer^®. Given the nature of the treatments, blinding was not feasible for both physicians and parents involved in the study.

Figure 1.

CONSORT flow diagram: Progression of patients through the trial

Throughout the study, participants retained the option to withdraw from the research without any restrictions or conditions. Complete confidentiality and anonymity of patient information were maintained throughout the study.

Common salt treatment

Parents were instructed on the proper care of the umbilical region, which involved gently cleansing it with warm water, followed by the application of a minimal amount of CS just sufficient to cover the UG. No occlusive dressings were applied. This regimen was advised to be carried out three times daily for 5 days, performed by family members at home. After this period, patients were scheduled for a follow-up visit at the hospital.

Silver nitrate treatment

In the case of SN treatment, patients were managed within the OPD by a pediatric surgeon. Before commencing treatment, parents were provided with detailed information regarding potential side effects, including chemical burns and pigment changes in the cauterized area. After obtaining consent, the umbilical region was thoroughly dried, followed by the application of paraffin to shield the surrounding skin and prevent contact with healthy tissue. Then, SN was carefully applied to the granuloma using a clean stick applicator, and the treated region was covered with a sterile gauze and an occlusive dressing. A follow-up appointment at the OPD was scheduled 48 h after the procedure. Parents were advised to avoid giving the baby normal baths during this period to ensure dryness and prevent periumbilical burns resulting from SN exposure.

Follow-up assessments

At each visit, the medical team documented the presence of umbilical exudate, any discoloration, or signs of burns in the periumbilical skin. In the patients who exhibited partial or no healing in either treatment group, the same treatment was reapplied. After the second round of treatment, the nonresponders were transitioned from the CS treatment arm to the SN arm, and vice versa, for two additional applications of the respective treatment. Any persisting UG after this was surgically electrocauterized.

Endpoints and definitions

For the purpose of this study, “healing” was defined as the absence of any clinical sign of umbilical exudate, bleeding, or granulation tissue, as assessed by qualified pediatric surgeons during OPD evaluations. “Treatment failure” was designated when granulation tissue persisted at the base of the umbilicus at the conclusion of the treatment protocol, reaching a size significant enough for the pediatric surgeon to contemplate surgical intervention and/or in the event of the occurrence of adverse clinical events.

Measurements

The collection of baseline data encompassed key parameters such as gestational age at birth, birth weight, age at the time of enrolment, gender, age at the natural detachment of the umbilical cord stump, duration of symptoms, and the presence of any underlying medical conditions. After enrolment, the presence or absence of umbilical exudate, bleeding, and granulation was meticulously recorded during each follow-up visit to the OPD. The collected data were entered into a Microsoft Excel spreadsheet by the primary author.

Statistical analysis

In determining the required sample size for this trial, it was assumed that the healing rate would range between 80% and 85% for CS and between 90% and 95% for SN treatment groups.[4,5,6] To meet this criterion, a sample size of 211 patients per group was deemed necessary to attain a statistical power exceeding 80%, while maintaining a two-sided type 1 error rate of 5%, using the formula:[7]

and N₂ = K × N₁

where,

p₁, p₂ = Proportion (incidence) of Groups 1 and 2 (Group 1 – CS; Group 2 – SN)

Δ = |p₂ − p₁| = Absolute difference between two proportions

N₁ = Sample size for Group 1 (CS)

N₂ = Sample size for Group 2 (SN)

α = Probability of type I error (0.05)

β = Probability of type II error (0.2)

z = critical Z value for a given α or β

K = Ratio of sample size for group 2 (SN) to group 1 (CS).

All patients who were randomized and received either form of treatment were considered eligible for inclusion in the primary efficacy analysis. Those participants who lacked data concerning the primary endpoint, failed to meet all inclusion criteria, satisfied any exclusion criteria, or were lost to follow-up were excluded from the primary analysis. The primary efficacy analysis entailed a comparison of healing rates, accompanied by the calculation of 95% confidence intervals (CIs) for both treatment groups. The distributions of baseline characteristics were subjected to comparison through Fisher’s exact tests and t-tests. Importantly, all statistical comparisons were conducted utilizing two-sided tests with a significance level set at α =0.05.

RESULTS

A total of 38 patients met the inclusion criteria and underwent assessment for eligibility, with four patients being subsequently excluded, as illustrated in Figure 1. Ultimately, 34 patients were randomized into the two treatment groups – 18 patients in the CS group and 16 patients in the SN group. Among these 34 patients, 32 successfully completed the trial (17 CS patients and 15 SN patients) as one patient was lost to follow-up from each treatment arm.

No significant differences were observed in baseline characteristics between the two treatment groups, as detailed in Table 1.

Table 1.

Comparison of baseline characteristics of the patients enrolled for the study (data presented as n [%] or median [interquartile range])

	Common salt (n=18)	Silver nitrate (n=16)	Total (n=34)
Age at presentation (days)	39.5 (29.25–56)	46 (21.25–87.5)	40.5 (26.25–59.75)
Male gender	11 (61.1)	7 (43.8)	18 (52.9)
Duration of symptoms (days)	20 (6.25–44)	13 (4.25–30)	18.5 (4.75–42)
Preterm	2 (11.1)	2 (12.5)	4 (11.8)
Birth weight (kg)	2.7 (2.57–2.89)	2.73 (2.31–3.09)	2.7 (2.52–2.99)
Cord fall (days)*	9 (6.5–10)	8 (6.25–12.75)	8 (6.5–11)

*25 mothers could recall the day of cord fall - 13 from the CS group and 12 from the SN group. CS: Common salt, SN: Silver nitrate

The primary outcome is presented in Table 2. Cumulative healing rates were calculated by combining patients in the crossover arm with those initially allocated to each group, while the patients lost to follow-up were considered treatment failure. The efficacy rates of both treatments did not show any statistically significant difference after two rounds of treatment [Table 2]. No major adverse events occurred during the treatment in either group.

Table 2.

Summary of results

	Common salt	Silver nitrate	Statistical significance (95% CI)
Healing after 1st application, n (%)	12/18 (66.7)	11/16 (68.8)	P=0.448 (−0.2939–0.3359)
Healing after re-application, n (%)	4/18 (22.2)	-	-
Gross healing rate, n (%)	16/18 (88.9)	11/16 (68.8)	P=0.074 (−0.4732–0.0712)
Lost to follow-up, n (%)	1/18 (5.55)	1/18 (5.55)	-
Crossover patients (from the other arm)*, n (%)	4 (3 healed with CS application; 1 did not heal - cauterized)	1 (did not heal with SN application - cauterized)	-
Total patients analyzed, n (%)	22 (18+4)	17 (16+1)
Cumulative healing rate, n (%)	19/22 (86.36)	11/17 (64.71)	P=0.056 (−0.4832–0.0502)

*Among the 5 nonresponders after re-application, four patients from the SN group switched to CS treatment, and one patient transitioned from the CS group to SN treatment. CS: Common salt, SN: Silver nitrate, CI: Confidence interval

When we stratified the study population into different age groups, we observed superior healing outcomes with CS (18/20; 90%) in infants up to 3 months of age when compared to those treated with SN (8/13; 61.54%); [P = 0.025; 95% CI − 0.5701–0.0009].

DISCUSSION

This pilot RCT aimed to compare the effectiveness of the topical application of CS versus SN in infants newly diagnosed with UG. Although the overall healing rates are comparable even with the small sample size, it can be argued that CS may serve as an effective rescue treatment following initial SN application failure, while the reverse does not hold true. With the enrolment of a larger patient cohort to achieve the desired statistical power, CS could emerge as a potential first-line treatment for UG, especially due to its safety, simplicity (administered at home by caregivers), and favorable efficacy.

This study likely represents the first properly formulated RCT to comprehensively compare the effects of CS and SN treatments for UG. However, it is important to note that this is a pilot study and it does not demonstrate statistical noninferiority, equivalence, or superiority of CS over SN. This limitation also arises from the challenge of predefining a noninferiority or superiority margin based on previous research, as the only RCTs comparing CS and SN published till date carry a high risk of bias and a lack of standardized randomization protocols.[5,6]

While the healing rates observed in this study were consistent with previous research findings,[4] it is noteworthy that there were no cases of iatrogenic periumbilical SN burns, which have been documented in the literature.[2,8,9,10] It is essential to highlight that in our study, SN application was performed by a pediatric surgeon in a clinical setting, whereas in the study by Daniels et al., it was administered by parents at home.[9] Other authors have not explicitly mentioned whether the SN application was carried out by parents or medical professionals. This suggests that the topical application of SN should be in a supervised environment among health-care providers. Conversely, CS can be conveniently and safely applied at home by parents, irrespective of their educational background or understanding.

CS treatment is remarkably cost-effective. Ogawa et al. reported the cost of SN treatment to be <2 USD per treatment,[3] whereas the cost of CS in the USA is approximately 2.2 USD per kilogram.[11]

This study has several limitations. First, blinding of treatment allocation was not feasible in the outpatient setting. Moreover, we were unable to directly oversee the application of CS performed by caregivers at home. In addition, changes in treatment between CS and SN occurred in some patients, potentially affecting efficacy rate calculations and precluding the use of an intention-to-treat analysis. Furthermore, the absence of a placebo group leaves the natural progression of untreated UG uncharted. Further research is warranted to establish the necessity of treating UG, especially in the neonatal age group. Finally, the clinical appearance of UG (size, shape, protrusion, and discharge) was not considered. Pedunculated UGs may respond differently to ligation compared to sessile ones in which topical application of these agents is typically preferred. However, this pilot study paves the way for larger patient cohorts that can facilitate more robust comparisons between CS and SN treatments, establishing noninferiority, equivalence, or even superiority, conclusively.

CONCLUSION

Common salt is a safe and effective substitute for silver nitrate for treating infants with umbilical granuloma, while eliminating the risk of chemical burns associated with improper SN use. Its widespread availability, ease of access, suitability for safe home application, and cost-effectiveness make CS an appealing choice as the primary treatment option for UG. However, the recruitment of a larger patient cohort is imperative to definitively establish statistical superiority.

Protection of patients’ right to privacy

A written informed consent was obtained from the parents or legal guardians of each infant before their inclusion in the study. Identifying information is not presented anywhere in the manuscript. No patient images have been used in the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.