key: cord-0739776-g4yrerlh
authors: Reese, Adam D; Keyloun, John W; Garg, Gaurav; McLawhorn, Melissa M; Moffatt, Lauren T; Travis, Taryn E; Johnson, Laura S; Shupp, Jeffrey W
title: Compounded Cerium Nitrate—Silver Sulfadiazine Cream is Safe and Effective for the Treatment of Burn Wounds: A Burn Center’s Four-Year Experience
date: 2021-09-20
journal: J Burn Care Res
DOI: 10.1093/jbcr/irab180
sha: 12a2af894a30417c0473e8bf8eb8e78578145fc2
doc_id: 739776
cord_uid: g4yrerlh

Wound infections and sepsis are significant causes of morbidity after burn injury and can be alleviated by early excision and grafting. In situations that preclude early surgery, topical agents allow for a safer delay. Cerium nitrate compounded with silver sulfadiazine (Ce-SSD) is a burn cream that provides broad antibacterial activity, forms a temporary barrier, and promotes re-epithelialization. Methemoglobinemia is a rare, but oft-cited, systemic complication of Ce-SSD. In this retrospective review, 157 patients treated with Ce-SSD between July 2014 - July 2018 were identified and the monitoring protocol for methemoglobinemia during Ce-SSD treatment was evaluated. Median age was 59 years (IQR, 47-70.5 years), with total body surface area burn (TBSA) of 8.5% (IQR, 3-27), adjusted Baux score of 76 (IQR, 59-94), and inhalation injury present in 9.9% of patients. Primary endpoints included incidence of symptomatic and asymptomatic methemoglobinemia. Of the 9.6% (n = 15) of patients with methemoglobinemia, 73.3% (n=11) had maximum methemoglobin levels ≥ 72 hours from time of first application. One patient developed clinically significant methemoglobinemia. Patients with TBSA ≥ 20% were more likely to develop methemoglobinemia (OR 9.318, 95% CI 2.078 to 65.73, p = 0.0078), however neither Ce-SSD doses nor days of exposure were significant predictors. Ce-SSD application to temporize burn wounds until excision and grafting is safe, effective, and, in asymptomatic patients with TBSA < 20%, can be used without serial blood gas monitoring. Vigilant monitoring for symptoms should be performed in patients with TBSA ≥ 20%, but routine blood gases are not necessary.

Wound infection and sepsis are prominent causes of morbidity and mortality after burn injury. Despite the benefits of early excision and grafting (1) (2) (3) , certain situations preclude early surgical management. These include patient inability to tolerate anesthesia, lack of suitable skin coverage material, and burns sustained in battle and mass casualty events, among others (2) . To address these limitations, topical antimicrobial agents for burn wound management have been employed with varying success and side-effect profiles (4) (5) (6) (7) .

The rare-earth element cerium, an inexpensive and nontoxic metal, has historically been used in its cerium salt form as a topical burn treatment due to its broad antibacterial activity and poor systemic absorption (8) . Likewise, silver sulfadiazine has been used as a topical treatment due to the antimicrobial activity of silver ions after dissociation (9) . In 1976, a combination of the two was first introduced and reported to have superior antimicrobial activity than either substance alone(10). This enhanced activity against gram-negative bacteria, gram-positive bacteria, and fungi (11) has been attributed to Ce-SSD's ability to bind and neutralize the immunosuppressive lipid protein complex (LPC) that is created in and around burned tissue (2, 12) . Ce-SSD treated areas develop a tough, leathery eschar that acts as an occlusive layer, promoting a moist wound healing environment and preventing bacterial invasion (2) . Recent findings by Qian et al. suggest that cerium nitrate improves the quality of burn eschar via attenuation of burn-induced DAMPs, tissue inflammatory responses, and regrowth of resident skin flora(20). In addition, Ce-SSD is purported to have a local effect on calcium homeostasis, altering extracellular calcium concentrations in the wound bed, and ultimately playing a role in keratinocyte proliferation, maturation, and re-epithelialization (2, 8) . Previous A c c e p t e d M a n u s c r i p t 4 studies have provided evidence of a synergistic relationship between silver and cerium, yielding a superior topical agent in the treatment of burns. A study of 853 patients with burns treated with Flammacerium (cerium nitrate-silver sulphadizine) and staged surgery by Scholten-Jaegers et al. found a lower overall mortality rate and fewer instances of sepsis and septic shock in comparison with the literature(21). Methemoglobinemia (MetHba) is a commonly cited, but rarely occurring, systemic complication of Ce-SSD (13) . Clinical consequences are dependent on the degree of MetHba, and range from headache and cyanosis to cardiac ischemia, hypotension, and even death (14) . institution enacted a screening protocol to monitor Methemoglobin (MetHb) in Ce-SSD-treated burns via serial ABGs drawn before Ce-SSD application, at 24 hours after Ce-SSD application, and at 72 hours after Ce-SSD application. This retrospective cohort study adds to the findings of Kath et al. by assessing the utility of the screening protocol and further characterizing the toxicity of Ce-SSD(15). We hypothesize that days exposed to Ce-SSD, doses of Ce-SSD, and %TBSA will be the main determinants for developing MetHba.

Following local institutional review board approval, medical and pharmacy records were queried for all patients admitted to a regional burn center between July 2014 and July 2018 who had Ce-SSD-treated burns. Data including demographics, A c c e p t e d M a n u s c r i p t 5 admission/discharge information, mechanism of injury and management, symptoms, complications, timing of Ce-SSD administration, surgical information, laboratory values, and methemoglobin trends were extracted. Primary endpoints included incidence and management of MetHba. Physiologic levels of MetHb are dynamic and range from 0-3% [17] , therefore MetHb greater than 3.0% was defined as MetHba.

Ce-SSD is prepared by compounding 22mL of 100% Ce(NO 3 ) 3 filtered stock solution with 1,000g of SSD cream. Typically, the Ce-SSD cream is kneaded into the matrix of a standard dry dressing and applied twice daily to a patient's burn wound(15).

Statistical analyses were performed using Prism 8 (GraphPad Software Inc., La Jolla, CA). Descriptive statistics were used to summarize the distributions and proportions of study variables. Analysis of continuous variables was performed using the Wilcoxon rank sum test and categorical variables analyzed via the Χ 2 or Fisher's exact test, as appropriate, with a p-value < 0.05 considered statistically significant.

Receiver-operating characteristic (ROC) curves were generated for continuous variables to determine sensitivity and specificity for predicting MetHba. A sensitivity of 100% was preferred for screening protocol and Youden Index (J = max {Se (c) + Sp (c) − 1}) was used to determine optimal cut-offs, where applicable. p < 0.05 was considered statistically significant. Simple logistic regression modeling was used to determine the ability of selected variables to predict MetHba and an adjusted model, selected using Akaike's Information Criterion, was created using multivariate logistic regression modeling.

A c c e p t e d M a n u s c r i p t 6

One hundred and fifty-seven patients had burn injuries that were treated with Ce-SSD. Table 1 summarizes patient demographics and Table 2 The need for a safe alternative to early excision and grafting in thermally injured patients has never been more apparent than it is now in the era of COVID-19.

The COVID-19 pandemic has impacted patients, providers, and standard practices of hospitals around the world. The typical insult to a burn patient's respiratory tract due to inhalation injury, inflammatory mediators associated with infection, sepsis, or the burn wound itself (19) has been further compounded by the respiratory sequelae of COVID-19. Prevention of burn wound infection and sepsis when patients cannot A c c e p t e d M a n u s c r i p t 10 safely undergo operative intervention is critical, and the use of Ce-SSD offers a safe option that requires no additional monitoring by providers. This group's experience with COVID-19 and thermally injured patients has reinforced this practice, as we believe it has minimized the additional insult to the respiratory tract that can come from an unprotected burn wound. The potential to minimize surgical intervention in periods after mass casualties, natural disasters, and other resource limited scenarios is significant.

This study is limited as a retrospective chart review from a single institution.

Additionally, the absence of wound and blood culture data limits further analysis based on different pathogenic organisms which may affect our results. However, burn wound cultures are not routinely obtained at this institution. While MetHb levels were acquired relatively early in the hospital course, other previously administered medications, such as copper supplementation or anesthetic agents, might have impacted the MetHb levels. Note that while both genetic abnormalities and nitrite ingestion can lead to methemoglobinemia, no patients in this cohort had known elevated levels prior to their Ce-SSD administration.

At this institution, a screening protocol for Methemoglobinemia was successfully implemented, and demonstrated an extremely low incidence of both asymptomatic and symptomatic MetHba in patients being treated with Ce-SSD.

Given this data, monitoring for MetHba is not necessary in patients with a TBSA < 20%; in patients with a TBSA > 20%, clinical vigilance is important, but serial laboratory data can be avoided. This study supports that Ce-SSD can be safely used to temporize burn wound excision and grafting without the need for routine monitoring for MetHba. A c c e p t e d M a n u s c r i p t 16 M a n u s c r i p t 17 M a n u s c r i p t 

The use of Flammacerium in British Burns Units

Cerium nitrate in the management of burns

Antibacterial effect of dressings containing multivalent silver ion carried by zirconium phosphate on experimental rat burn wounds

Topical application of mafenide acetate. Its association with erythema multiforme and cutaneous reactions

Silver sulfadiazine--a new topical therapy for Pseudomonas in burns. Therapy of Pseudomonas infection in burns

Topical chemotherapy for burns using cerium salts and silver sulfadiazine

Treatment of Large Human Burns with 0.5 Per Cent Silver Nitrate Solution

A reappraisal of the role of cerium in burn wound management

Mechanism of silver sulfadiazine action on burn wound infections

Cerium nitrate: a new topical antiseptic for extensive burns

An open study comparing topical silver sulfadiazine and topical silver sulfadiazine-cerium nitrate in the treatment of moderate and severe burns

Treating mass burns in warfare, disaster or terrorist strikes

Methemoglobinemia in critically ill burned patients

Methemoglobinemia: a review and recommendations for management

Incidence of methemoglobinemia in patients receiving cerium nitrate and silver sulfadiazine for the treatment of burn wounds: a burn center's experience

Methemoglobinemia: Etiology, Pharmacology and Clinical Management

Comparing the effects of silver sulfadiazine and cerium nitrate silver sulfadiazine on burn-wound healing and survival rate of rat animal model