Role of high‑dose methylprednisolone in Zargar Grade IIB corrosive esophageal burns: A randomized control study

Abstract

OBJECTIVE: The objective of the study is to test the efficacy of high dose methylprednisolone in the prevention of esophageal stricture after corrosive ingestion.

METHODS: This study was a single center, randomized controlled single blinded study. Simple randomization was done with 15 adult patients (>18 years) in each arm, who presented with a history of corrosive ingestion within the past 24 h and had esophageal injury of Zargar Grade IIB on endoscopy. Intravenous methylprednisolone 1 g/day for 3 days was given to the intervention arm while 100 mL of normal saline was given as placebo in control arm. Follow up to diagnose esophageal stricture was done at 8 weeks.

RESULTS: Thirty patients (15 in each arm) were recruited for the study. As per the intention to treat analysis, 33% and 46.6% developed stricture in the intervention and control arm, respectively (relative risk [RR] = 0.714; 95% confidence interval 0.29–1.75; P = 0.462). 40% patients in control group and 7.7% in intervention group had undergone feeding jejunostomy, which was statistically significant with a p-value of 0.048. Airway injury showed significant clinical improvement in the intervention arm but the difference was nonsignificant statistically (P = 0.674). There was no increased incidence of hypertension, hyperglycemia, hyponatremia, hyperkalemia, or infections in intervention arm.

CONCLUSION: Methylprednisolone does not help in the prevention of stricture formation in corrosive esophageal injury, but it significantly reduces the requirement of feeding jejunostomy and has a beneficial role in treating airway injury.

Introduction

Corrosive ingestion is a grave public health problem. In contrast to pediatric population, ingestion in adults is more often suicidal in intent and frequently life threatening. It is a medical emergency and has devastating effects on the upper gastrointestinal(GI) and upper respiratory tract leading to mortality due to acute complications and esophageal stricture formation causing long term morbidity and mortality. Majority of the esophageal strictures develop within 8 weeks of corrosive ingestion.[1]

Approximately 1%–2% of corrosive ingestions develop stricture, the likelihood of which primarily depends on the depth of the burn injury.[2] Zargar classification on upper GI endoscopy (UGIE) has been used to grade the severity of corrosive injury.[3] Most of the patients with Zargar Grade I and IIA do not develop stricture.[2] Up to 70% of patients with Grade IIB and ≥90% of patients with Grade III injury will develop esophageal stricture.[4] Corticosteroid therapy in the management of corrosive substance ingestion is controversial. There is a low risk of stricture formation in lower grades of injury (Zargar IIA or lower) and high risk of infection and perforation in Zargar III or higher injuries which may be exacerbated by steroids.[5] Different corticosteroids (dexamethasone, prednisolone, and methylprednisolone) have been used at different doses through different routes of administration (oral or intravenous) in children with corrosive esophagitis with variable results.[6 8]

The utility of corticosteroids for postcorrosive stricture prevention is controversial. While various meta analyses did not find any benefit of steroid administration in terms of stricture prevention,[9 11] few studies have demonstrated improved outcomes with steroids.[7,12 14]

Hence, we performed a randomized control trial in adult population to test the efficacy of methylprednisolone in preventing stricture formation after corrosive ingestion.

Material and Methods

This single center, randomized, parallel group, single blinded, placebo controlled study was conducted at emergency department (ED) of a tertiary care teaching hospital from September 2020 to March 2022. The study was approved by the Institute Ethics Committee (Ref No: IECPG 212/June 24, 2020) and was registered with the National Clinical Trial Registry (CTRI/2020/09/027532).

All consecutive patients aged≥18 years having a history of corrosive ingestion within the past 24 h of presentation to ED were screened. They underwent UGIE within 24 h of ED presentation. Patients having esophageal lesion of Zargar endoscopic Grade of IIB were recruited to the study after acquiring their valid informed consent to participate in the study. Patients with other grades of esophageal injury, i.e., Zargar Grades I, IIA, and III, hemodynamic unstable, unconscious on arrival, those who received cardiopulmonary resuscitation (CPR), needing mechanical ventilation, pregnant females, or history of corrosive ingestion of >24 h were excluded from the study [Supplementary Section 1].

On the basis of a study conducted by Usta et al.,[7] we estimated 11% stricture development in the intervention group and we anticipated 50% esophageal stricture development in the control group. To detect a difference of 39% with 80% power at 5% level of significance, we required 21 patients each in the intervention and control group. The total number of patients (sample size) required for this study was 42 (21 each in intervention and control group). However, due to the COVID 19 pandemic, the number of corrosive ingestion patients presenting to ED drastically reduced from August 2020 to December 2021. Hence, the sample size was reduced to 30 (15 in each arm) after getting permit for the same from Institute Ethics Committee (Ref No: F.4 1/2020 Acad. 1).

Randomization and blinding

Simple randomization allocation sequence chart was generated using online software for allocating patients to the control and intervention arm. The eligible patients were randomized to intervention and control group on 1:1 basis. The study was a single blinded (blinded to patient) with blinded endpoint (the specialist performing the endoscopy initially and after 8 weeks along with reporting radiologist for barium studies was blinded regarding the intervention and the control group) to avoid any reporting bias (PROBE design). Sequentially numbered, opaque, sealed envelope technique was used for allocation concealment. Patients getting allocated to intervention arm received intravenous (IV) methylprednisolone 1 g/day diluted in 100 mL normal saline, which was infused over 30 min. This was administered once a day for a total of 3 days. Patients in control arm received 100 mL of normal saline (placebo) instead of methylprednisolone. Patients in both arms also received IV pantoprazole, IV antibiotics, and IV fluids along with other supportive therapy if needed. No steroids were administered to patients in control group.

Patients were monitored for complications secondary to corrosive ingestion (stridor, hoarseness of voice, upper GI bleed, acute respiratory distress syndrome, acute kidney injury, perforation peritonitis, and mediastinitis) during the ED stay. Clinical presence of hoarseness/ change in voice, stridor, and/or inability to vocalize was considered for the presence of airway injury. For complications related to methylprednisolone, blood pressure and blood sugar levels (pre and postprandial levels at breakfast, lunch, and dinner) were monitored every sixth hourly. Serum electrolytes were assayed daily for evaluating the effect of methylprednisolone on electrolytes. Patients were monitored for infection with daily 6 hourly temperature charting and by rise in total leukocyte count on arrival and at day 4 were recorded [Supplementary Table 1].

Those who were hemodynamically stable and tolerating oral fluids were discharged after 5 days. Patients who were not tolerating oral fluids, GI surgery were consulted for possible feeding jejunostomy [Supplementary Section 2 and 3]. UGIE and barium swallow was done 8 week postcorrosive ingestion. At follow up, both intervention and control group were assessed for the presence of esophageal stricture on endoscopy and radiological imaging. Patients who were not able to tolerate even fluids were not taken for barium swallow study, provided the risk of aspiration. The demonstration of stricture either on UGIE or barium swallow was labeled as having an esophageal stricture. All the endoscopies in both groups were either performed or reviewed by a single specialist (consultant gastroenterologist) and the barium swallow was interpreted by a single radiologist, both blinded to the treatment.

All the demographic profiles, symptoms, physical examination, laboratory evaluation, endoscopy, and radiological examination reports were recorded in Microsoft Excel spreadsheet. Analysis was done as per intention to treat for all the parameters except two secondary outcomes – “Underwent Invasive Procedure” and “Mortality at 8 weeks.” Baseline characteristics of the patients were summarized as mean and standard deviations, median and ranges, or numbers and percentages. The endpoint (rate of esophageal stricture) was expressed as relative risk (RR). For the comparison of the quantitative data, Student’s t test was used to compare the normally distributed quantitative variables between the groups and the Mann–Whitney U test was used to compare nonnormally distributed variables between both the groups. Chi square test was used for the comparison of the qualitative data. All the analyses were conducted on IBM SPSS version 24, and a two tailed P < 0.05 was considered statistically significant.

Results

Between July 2020 and March 2022, a total of 230 adult patients with corrosive ingestion underwent endoscopic screening, of whom 45 had esophageal Zargar Grade IIB and 30 were eligible for randomization [inclusion and exclusion criteria in Supplementary Section 1]. Details about the randomization and follow up of the patients are provided in Figure 1. The characteristics of the patients at baseline were well balanced between the two groups [Table 1]. Most of the patients were discharged from ED at day 5 with no significant difference in admission rates between the two arms [Table 1]. None of the patients included in the study had past history of corrosive ingestion or any esophageal surgery.

Figure 1. Consolidated Standards of Reporting Trials diagram showing progress through the phases of trial. ED: Emergency department, n: Frequency, Inj.: Injection, NS: Normal saline, OD: Once a day, BD: Twice a day, IV: Intravenous, UGIE: Upper gastrointestinal endoscopy

Table 1. Baseline characteristics of subjects

Primary endpoint

On follow up at 8 weeks, two participants could not be contacted and were lost to follow up in the intervention arm. There was no attrition in control arm. As per intention to treat analysis, esophageal stricture developed in 5 of 15 patients (33.3%) in the intervention group and in 7 of 15 (46.6%) in the placebo group [RR = 0.714; 95% confidence interval 0.29–1.75; P = 0.462, Table 2 and 3]. None of the patients without stricture at 8 weeks had a history of undergoing balloon dilatation before the follow up.

Table 2. Clinical, endoscopic, and radiological findings on follow‑up at 8 weeks

Table 3. Primary and secondary endpoints of the study

Secondary endpoint

On arrival to ED, a total of 6 patients presented with clinical airway injury, 3 each in control and intervention arm. At the time of disposition from ED, all the 3 patients in intervention arm had complete resolution of airway injury while 3 in control arm had persistent hoarseness. Although clinically there was significant clinical improvement in intervention arm, statistically this difference was nonsignificant with a P = 0. 674. On arrival to ED, a total of six patients (3 in each arm) presented with upper GI bleed (hematemesis) which had resolved in all of them; by the time, they were disposed from ED [Table 3].

None of the patients developed infection, sepsis, acute respiratory distress syndrome (ARDS), perforation, peritonitis, or mediastinitis. On follow up at 8 weeks, 40% patients in control group (n = 15) and 7.7% in intervention group (n = 13) had undergone feeding jejunostomy, which was statistically significant with a P = 0.048. All the three cases with balloon dilatation mentioned in the study underwent the procedure before follow up at 8 weeks. No mortality was reported in either of the groups at 8 weeks [Table 3].

No difference in the safety outcomes (rate of infection, hyperglycemia, or electrolyte disturbances) was observed between the study arms [Supplementary Figure 1 and Supplementary Table 2 and 3].

Discussion

Our study was a randomized controlled, open label trial intended to compare the efficacy of high dose methylprednisolone against placebo in the prevention of esophageal stricture formation in corrosive esophageal Zargar Grade IIB injury. Results from our study showed that there was no significant reduction in the development of esophageal stricture with methylprednisolone (RR = 0.714, P = 0.462). Systematic review and meta analysis by Katibe et al. [9] reported no benefit of corticosteroids in the prevention of esophageal strictures following the ingestion of caustic materials. Another systematic analysis conducted by Fulton and Hoffman[10] including Zargar Grade II injury patients treated with corticosteroids versus no corticosteroids for at least 10 days also reported similar results. Pelclová and Navrátil[11] included Zargar Grades II and III injury patients treated with corticosteroids for at least 8 days also suggested that systemic corticosteroids are not beneficial for the second and third degree corrosive esophageal burns. While prospective studies conducted by Usta et al.,[7] Boukthir et al.,[12] Bautista et al.,[13] and systematic analysis by Howell et al. [14] have suggested the beneficial role of systemic steroids in preventing stricture development in corrosive esophageal injury.

All the patients in control and intervention groups had comparable clinical profile such as presenting symptoms, disposition from ED, and feeding status at disposition. The most common complaint was dysphagia (n = 26) followed by vomiting (n = 24). Least common was hoarseness of voice (n = 4) and hematemesis (n = 6) [Supplementary Figure 2]. 57% of study subjects were discharged from ED. There was no significant difference in the ability to tolerate feeds at disposition in control and intervention groups. In a study published by Usta et al.,[7] vomiting and respiratory symptoms were the most and the least common symptoms, respectively. Although not statistically significant, all three patients with airway injury in intervention arm had resolution of airway symptoms after therapy while symptoms persisted in control arm at the same time interval. Systemic analysis conducted by Pelclová and Navrátil[11] and Fulton and Hoffman[10] supported the use of corticosteroids for patients with symptoms of respiratory tract edema secondary to corrosive burns.

The need for feeding jejunostomy and balloon dilation for esophageal stricture was assessed in both groups at 8 weeks. Requirement of feeding jejunostomy was significantly reduced in intervention group compared to control group (7.7% vs. 40%) with P = 0.048. There was no significant difference in requirement of balloon dilation at 8 weeks for both arms. Anderson et al. [6] reported less frequent requirement of esophageal replacement in steroid treated group. Bautista et al. [13] reported decreased requirement of dilation procedure for stricture in dexamethasone treated group in their study.

We did not observe any significant deviation in systolic or diastolic blood pressure over 3 days in both groups. The pre and post prandial blood sugar levels did not show an increasing trend in intervention arm. There was no increase in the incidence of electrolyte imbalances (hypernatremia, hypokalemia, and hypocalcemia) in intervention arm. These findings were consistent with studies published by Anderson et al. [6] and Usta et al.,[7] which reported no side effects associated with the high dose methylprednisolone treatment.

Studies have shown a mortality rate of 8%–10% in corrosive ingestion secondary to upper respiratory tract injury causing airway obstruction, perforation peritonitis, esophageal perforation, and mediastinitis with delayed mortality attributed mainly to its complication of esophageal stricture formation.[15 17] In contrast to this, there was no mortality at 8 weeks in either of the groups in our study. This could be due to the exclusion of more severe grades of esophageal injuries (Zargar Grades III and IV), intubated patients, hemodynamically unstable, and post CPR patients from our study.

Limitations

1. Reduction of sample size due to the COVID 19 pandemic further reduced the power of the study to detect a significant difference
2. It was a single center trial conducted at a tertiary care hospital in urban setup which might affect the patient profile
3. It was a single blinded study because of which some of the secondary outcomes could have reporting bias
4. Various studies have reported mortality 1–2 years postingestion which was not assessed in our study due to time restriction.

Conclusion

In our study, we found that IV methylprednisolone therapy does not help in the prevention of stricture formation in Zargar Grade IIB esophageal injury after corrosive ingestion, but it significantly reduced the requirement of feeding jejunostomy (though study was not powered to detect this relation) and might have a beneficial role in treating airway injury secondary to corrosive agents. Methylprednisolone use was found to be safe and was not associated with increased incidence of hypertension, hyperglycemia, and dyselectrolytemia. We did not find any increased incidence of infection or mortality with steroid use.

To better test the effectiveness of methylprednisolone in stricture prevention, role in airway injury, and reduction of need for invasive therapies, more double blinded RCTs with larger sample size can be planned in the future.

Suppl. F.1. Line diagram depicting the trend of TLCs. TLC: Total leukocyte counts

Suppl. F.2. Bar graph showing frequency of presenting symptoms

Supplementary Section

Supplementary section 1

Inclusion criteria

• All consecutive patients with a history of acute corrosive ingestion with Zargar Grade IIB esophageal injury on endoscopy

• Age ≥18 years

• Valid consent given by the patient for the study.

Exclusion criteria

• Esophageal injury other than endoscopic Zargar Grade IIB (Zargar Grades I, IIA, and III)

• Hemodynamically unstable patient

• Patients who are not conscious

• Patients who have received CPR

• Patients who need Endotracheal intubation and mechanical ventilation

• H/O corrosive ingestion of >24 h ago

• Pregnant females

• Age <18 years

• Patients who refused to give valid consent for the study.

Supplementary section 2

Admission criteria

Admission criteria • Complications not resolving during ED stay (stridor, hoarseness of voice, upper gastrointestinal bleed, acute respiratory distress syndrome, acute kidney injury, perforation peritonitis, and mediastinitis)

• Unable to tolerate oral liquids at disposition

• Requiring TPN (TPN was not started in our ED)

• Other concurrent injuries/conditions requiring admission and management (e.g., – ocular burns, complications secondary to comorbidities, persistent suicidal intent).

Discharge criteria

Tolerating oral liquids (trial given after Day 3 of corrosive ingestion if patient able to swallow their oral secretions).

Follow up of patients discharged from Ed or later after admission from hospital was done on outpatient basis in Gastroenterology OPD.

Supplementary section 3

Stopping guideline

Treating physician could stop the ongoing steroid therapy if patient had features suggestive of perforation, peritonitis, mediastinitis, infection, or developed adverse effects to corticosteroids.

Supplementary Tables

UHID

Area/bed number (in ED)

Suppl. T.1. Monitoring chart

Suppl. T.2. Monitored clinical parameters

Suppl. T.3. Monitored laboratory parameters

How to cite this article: Sheikh I, Jamshed N, Neseem A, Aggarwal P, Kedia S, Khan MA, et al. Role of high-dose methylprednisolone in Zargar Grade IIB corrosive esophageal burns: A randomized control study. Turk J Emerg Med 2024;24(1):20-6.

The study was approved by Institute Ethics Committee (Ref No: IECPG‑212/June 24, 2020) on June 25, 2020, and the protocol was registered with the National Clinical Trial Registry (CTRI/2020/09/027532).

• IS: Methodology, Investigation, Data curation, Formal analysis, Writing Original Draft, Visualization
• NJ: Conceptualization, Data curation, Methodology, Writing Review and Editing, Visualization, Supervision
• AN: Investigation, Writing Original Draft, Review and Editing, Data curation
• PA: Conceptualization, Supervision, Resources
• SK: Data curation, Supervision, Project administration, Resources
• MK Formal analysis, Project administration, Resources
• CJD: Methodology, Supervision, Project administration
• AK: Formal analysis, Writing Review and Editing.

None Declared.

None.

References

1. Contini S, Scarpignato C. Caustic injury of the upper gastrointestinal tract: A comprehensive review. World J Gastroenterol 2013;19:3918 30.
2. Rollin M, Jaulim A, Vaz F, Sandhu G, Wood S, Birchall M, et al. Caustic ingestion injury of the upper aerodigestive tract in adults. Ann R Coll Surg Engl 2015;97:304 7.
3. Zargar SA, Kochhar R, Mehta S, Mehta SK. The role of fiberoptic endoscopy in the management of corrosive ingestion and modified endoscopic classification of burns. Gastrointest Endosc 1991;37:165 9.
4. Lurie Y, Slotky M, Fischer D, Shreter R, Bentur Y. The role of chest and abdominal computed tomography in assessing the severity of acute corrosive ingestion. Clin Toxicol (Phila) 2013;51:834 7.
5. Kluger Y, Ishay OB, Sartelli M, Katz A, Ansaloni L, Gomez CA, et al. Caustic ingestion management: World society of emergency surgery preliminary survey of expert opinion. World J Emerg Surg 2015;10:48.
6. Anderson KD, Rouse TM, Randolph JG. A controlled trial of corticosteroids in children with corrosive injury of the esophagus. N Engl J Med 1990;323:637 40.
7. Usta M, Erkan T, Cokugras FC, Urganci N, Onal Z, Gulcan M, et al. High doses of methylprednisolone in the management of caustic esophageal burns. Pediatrics 2014;133:E1518 24.
8. Tuncer R, Soyupak S, Sen N , Okur H, Keskin E, Zorludemir Ü, et al. Does steroid treatment prevent caustic esophageal stricture? A prospective study. Annals of Medical Sciences 2000;9:56-8.
9. KatibeR, AbdelgadirI, McGroganP, AkobengAK. Corticosteroids for preventing caustic esophageal strictures: Systematic review and meta analysis. J Pediatr Gastroenterol Nutr 2018;66:898 902.
10. Fulton JA, Hoffman RS. Steroids in second degree caustic burns of the esophagus: A systematic pooled analysis of fifty years of human data: 1956 2006. Clin Toxicol (Phila) 2007;45:402 8.
11. Pelclová D, Navrátil T. Do corticosteroids prevent oesophageal stricture after corrosive ingestion? Toxicol Rev 2005;24:125 9.
12. Boukthir S, Fetni I, Mazigh Mrad S, Mongalgi MA, Debbabi A, Barsaoui S. High-dose corticosteroid therapy in the treatment of severe caustic esophagitis in children. Pediatric Archives 2004;11:13 7.
13. Bautista A, Varela R, Villanueva A, Estevez E, Tojo R, Cadranel S. Effects of prednisolone and dexamethasone in children with alkali burns of the oesophagus. Eur J Pediatr Surg 1996;6:198 203.
14. Howell JM, Dalsey WC, Hartsell FW, Butzin CA. Steroids for the treatment of corrosive esophageal injury: A statistical analysis of past studies. Am J Emerg Med 1992;10:421 5.
15. Ekpe EE, Ette V. Morbidity and mortality of caustic ingestion in rural children: Experience in a new cardiothoracic surgery unit in Nigeria. ISRN Pediatr 2012;2012:210632.
16. Ertekin C, Alimoglu O, Akyildiz H, Guloglu R, Taviloglu K. The results of caustic ingestions. Hepatogastroenterology 2004;51:1397 400.
17. Libuit JM, Carpio GCA, Razon Gonzalez EVB, Lomboy ARB, Vicente IMG, Madrid APM, et al. Predictors of mortality in caustic ingestion: A single, tertiary center study. Clin Gastroenterol Hepatol 2015;13:e78.