Effectiveness and Safety of Nasal Herbal Steam Therapy for Post-Extubation Respiratory Symptoms: A Methodology of Pragmatic Randomized Controlled, Parallel Grouped Study

Abstract

Post-extubastion respiratory symptoms (PERS) are a common sequelae of endotracheal intubation, impeding postoperative recovery. Despite the widespread use of prophylactic corticosteroids and symptomatic management, these approaches have limitations in alleviating PERS. In this study, we aim to evaluate the efficacy and safety of nasal herbal steam therapy (NHST), a traditional Korean medicine intervention, in managing PERS among patients with thyroid cancer following endotracheal intubation. In this pragmatic, parallel-group randomized controlled trial, 66 post-thyroidectomy patients with thyroid cancer who underwent endotracheal intubation will be randomly assigned in a 1:1 ratio to either the NHST group or the standard care group. The intervention group will receive personalized NHST for 5 consecutive days, whereas the control group will follow conventional postoperative care protocols. The primary endpoint is the change in Wisconsin Upper Respiratory Symptom Survey scores from baseline to day 5. Secondary endpoints included patient-reported symptom relief, safety assessments, and adherence rates. By investigating the therapeutic potential of NHST, this study will establish its role as a non-invasive, adjunctive intervention for improving intubation-related complications, potentially contributing to broadening integrative treatment strategies and optimizing recovery outcomes for patients with PERS. The study will be conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of CHA Ilsan Medical Center (ICHA 2024-011-006, date of approval 2024-09-04).

Introduction

Endotracheal intubation during general anesthesia induces mechanical irritation of the larynx, trachea, and upper bronchi. ¹ These symptoms range from mild discomforts, such as sore throat and coughing, to serious complications like respiratory failure, laryngeal edema with airway obstruction, and ventilator-associated pneumonia. ² Several factors increase the risk of PERS, including prolonged intubation, larger endotracheal tube size, excessive cuff pressure, emergency intubation, and female sex due to narrower upper airways. ³

Current PERS management strategies focus on close monitoring and symptomatic pharmacologic treatment. Prophylactic interventions may be applied when significant airway edema is anticipated. ⁴ Non-pharmacological measures—such as educating patients on humidification techniques, maintaining optimal indoor humidity, and promoting frequent fluid intake—are commonly recommended. ⁵ However, despite their frequent use, the evidence supporting these interventions, particularly humidification, remains limited. ⁶ This highlights the need for novel, evidence-based strategies to enhance post-extubation recovery.

Nasal herbal steam therapy (NHST), also referred to as steam inhalation, involves inhaling vapor infused with medicinal herbal extracts or essential oils. ⁷ Traditionally practiced in East Asia and other regions, NHST has been used to relieve upper respiratory symptoms and support mucosal protection. ⁷ Though explored as an adjunctive therapy in integrative cancer care—especially for hypopharyngeal cancer—its role in managing PERS has not been systematically investigated.^8,9 Considering the challenges of conducting conventional explanatory randomized controlled trials (RCTs) in the immediate postoperative setting, a pragmatic RCT design is well-suited to assess the real-world effectiveness and safety of NHST. ¹⁰ Thus, a pragmatic RCT framework is warranted to assess the real-world applicability and therapeutic potential of NHST in PERS management. This study aims to evaluate NHST as a complementary intervention for PERS, comparing its outcomes with those of standard clinical care.

Methods

Study Design

This study is a pragmatic, parallel-group RCT designed to investigate the efficacy and safety of NHST for PERS. Participants will include adult patients (≥19 years) diagnosed with thyroid cancer who have undergone surgical resection under general anesthesia with endotracheal intubation. A total of 66 eligible patients who meet the inclusion criteria and provide informed consent will be randomly allocated in a 1:1 ratio to either the NHST intervention group (n = 33) or the standard care group (n = 33). The intervention will be conducted over 5 consecutive days of outpatient treatment, with administration parameters guided by the clinical judgment of healthcare providers.

 The study protocol adheres to the Consolidated Standards of Reporting Trials (CONSORT) statement and its extensions for the pragmatic trials (CONSORT-extension for pragmatic trials). Investigational review board approval has been obtained. This study was registered at Clinicaltrials.gov (registration identifier: NCT06840106) and CRiS (registration identifier: KCT0010374, registered on 2025-04-02). The study will be conducted in accordance with the Declaration of Helsinki, domestic laws, and Korean Good Clinical Practice standards. This manuscript was based on protocol version 1.1. The detailed study flow diagram is presented in Figure 1.

Figure 1.

Flow diagram of the trial.

Abbreviations: ASA, American Society of Anesthesiologists; URE, Upper respiratory event; GERD: gastroesophageal reflux disease; MO: months.

Eligibility Criteria

Eligible participants will be adult patients (aged 19-69 years) diagnosed with thyroid cancer who have undergone thyroidectomy under general anesthesia requiring endotracheal intubation and subsequently developed upper respiratory tract symptoms. The specific inclusion criteria are as follows: (1) age between 19 and 69 years, (2) American Society of Anesthesiologists classification of I or II, (3) surgical thyroidectomy performed for thyroid tumors under general anesthesia with endotracheal intubation, (4) presence of PERS, and (5) voluntarily participation in the clinical trial and provision of written informed consent. All participants will be required to provide informed consent after receiving a detailed explanation of the study protocol, and a designated investigator or trial coordinator will obtain consent forms.

Participants meeting any of the following criteria will be excluded: (1) presence of symptomatic gastroesophageal reflux disease; (2) history of chronic cough persisting at least 3 months before surgery, including those with bronchial asthma or chronic obstructive pulmonary disease; (3) diagnosis of acute respiratory infection within 1 month prior to enrollment; (4) current or planned use of medications that may confound treatment effects or outcomes; (5) anticipation of additional major treatments during the study period, including repeat surgery, chemotherapy, or radiotherapy; (6) pregnancy, breastfeeding patients, or planned pregnancy during the trial period; and (7) any condition considered by investigator to interfere with adherence to study procedures, including difficulty attending scheduled visit completing or study-related questionnaires. All inclusion and exclusion assessments will be performed by the study investigators to ensure rigorous participant selection and adherence to the protocol.

Randomization and Allocation

Upon obtaining informed consent, participants undergo eligibility screening. Those meeting the inclusion/exclusion criteria will be randomly assigned in a 1:1 ratio using a randomization list generated by a statistical expert with R 4.1 (© the R foundation for statistical computing, Auckland, New Zealand). Randomization will be performed through block randomization, with each block size 2, 4, or 6 assigned at random. As this study follows a pragmatic clinical trial design, participants will be randomly allocated to either the NHST group or the standard care group. Given the real-world nature of the intervention, specific procedural details will not be strictly predefined but will be tailored according to the clinical judgment of the attending physicians or traditional Korean medicine practitioners, ensuring individualized patient care. All interventions during the trial will be documented through case report files.

To ensure allocation concealment, the randomization sequence will be secured in sealed, opaque envelopes and stored in a double-locked cabinet by an independent third party. A designated clinical staff member at each trial center will open the sealed envelope upon patient enrollment to determine group allocation. Given the nature of the intervention, double-blinding is not feasible; however, outcome assessors (research nurses, healthcare providers, or trial investigators) will remain blinded to the patient’s group assignment. All assessments will be performed in a separate setting before intervention commencement.

Intervention

Standard care group: participants assigned to the standard care group will receive usual postoperative care, which includes patient education, symptoms-based medication, and supportive therapies. Treatment strategies, such as drug selection and dosage, will be determined by the physicians based on clinical symptoms. All medications currently used in routine clinical practice will be permitted, and their administration will adhere to standard therapeutic guidelines. Supportive therapy, respiratory rehabilitation, hydration recommendations, and symptom management strategies for severe cough or excessive mucus production will also be provided. The intervention periods will last for 5 days, although symptom-based treatment may continue beyond the trial duration, depending on a clinical decision.

NHST group: participants allocated to the NHST group will receive a combination of nasal herbal steam therapy, targeting basic acupoints: Yingxiang (LI20), Shangyingxiang (EX-HN8), and Neiyingxiang (EX-HN9). This integrative approach, administered under the supervision of a Korean medicine practitioner, aims to enhance symptom relief and optimize therapeutic outcomes for PERS. In addition, clinicians may extend the steam application to other acupuncture point areas recommended by the World Health Organization (WHO) for upper respiratory tract symptom management, depending on the patient’s condition. This refers to the application of herbal steam over those areas.

Details of the NHST procedure are as follows: The selected herbal medicines were subjected to solvent extraction, and the resulting extract was quantitatively measured. Sterile normal saline was added to the extract, followed by adjustment of pH and osmolarity to physiological levels. The solution was subsequently sterilized by passage through a sterilizing-grade filter to remove microorganisms and particulate matter. The sterile filtrate was aseptically dispensed into sterile vials, stoppered with rubber stoppers, and sealed with aluminum caps. Terminal sterilization of all vials was performed using a high-pressure steam sterilizer (autoclave). Following sterilization, quality control tests, including visible inspection for insoluble particulates and standard microbiological assays, were conducted to ensure sterility and clarity. The final product was stored at low temperature until use.

Although the extract was derived from pharmacopuncture preparations, its mode of administration in this study did not involve injection into acupuncture points. Rather, the vaporized solution was externally applied to nasal regions anatomically corresponding to specific acupoint areas. This approach constitutes a non-invasive adaptation of pharmacopuncture, preserving its underlying therapeutic rationale while obviating the need for needle penetration.

For patient administration, the sterile herbal extract solution was diluted with sterile normal saline to achieve a concentration ratio of 1:20 to 1:30. A volume of 10 mL of the diluted preparation was placed in an inhalation device (Omron, Kyoto, Japan) and vaporized. Each session was conducted for 40 minutes at room temperature (20°C-30°C). Patients were instructed to perform inhalation sessions once every other day. The list of herbs used and their concentrations are detailed below, with modifications made based on clinical judgment and patient needs.

• Jungsong-ouhyul phamacopuncture: Biancaea sappan L. (0.8 mg/mL), Salvia miltiorrhiza (1.2 mg/mL), Paeonia lactiflora (1.2 mg/mL), Boswellia carterii (1.7 mg/mL), Corydalis yanhusuo (1.7 mg/mL), Commiphora myrrha (1.7 mg/mL), Gardenia jasminoides (4.0 mg/mL). The extract was prepared using a distillation-based extraction method, yielding a total volume of 10 mL for clinical application.

• Wild ginseng pharmacopuncture: Panax ginseng (0.4 mg/mL). The extract was prepared using a distillation-based extraction method, yielding a total volume of 10 mL for clinical application

• Cordyceps militaris pharmacopuncture: Cordyceps militaris (0.4 mg/mL). The extract was prepared using a distillation-based extraction method, yielding a total volume of 10 mL for clinical application

Treatment will consist of a total of 3 sessions, with 1 session performed every other day over the 5-day intervention period. Any rescue therapy will not be restricted in either group. If necessary, any types of rescue medication will be permitted and documented in the case report form to ensure comprehensive data collection and analysis. A separate subgroup analysis will be performed for patients who received corticosteroids, respiratory support therapy or restricted antibiotics. Every intervention will be administered by a qualified Korean medicine doctor with 5 years of clinical experience and may be adjusted in accordance with individualized clinical assessments.

Outcome Measurement

The primary endpoint will be the Wisconsin Upper Respiratory Symptom Survey-Korean version (WURSS-24). The WURSS-24 was originally developed for patients with upper respiratory tract infections and has been validated for assessing symptom severity and health-related quality of life. ¹¹ The questionnaire consists of 24 items rated on a 7-point Likert scale, evaluating symptom severity, functional impairment, quality of life, and overall patient satisfaction. Although the WURSS-24 was initially validated for upper respiratory tract infections, its structured assessment of airway-related symptoms may offer a feasible interim solution for evaluating post-operative, intubation-related symptoms, particularly in the absence of validated instruments tailored to this clinical context. By utilizing this tool, daily changes in PERS will be systematically quantified, and the impact of NHST on patient-reported quality of life will be thoroughly analyzed.

 Secondary endpoints will include a comprehensive assessment of treatment-related effects, including cough frequency, cough severity, throat discomfort, dysphagia, the Thyroid Cancer-Specific Quality of Life (THYCA-QoL) index, global assessment scale (Patient Global Impression of Change [PGIC] scale), and adverse events. Cough frequency will be recorded as the number of coughing episodes per day, while cough severity, throat discomfort, and dysphagia will be evaluated using a numerical rating scale (NRS). The THYCA-QoL questionnaire, developed following methodologically validated guidelines, serves as a standardized tool for assessing symptom burden, treatment efficacy, follow-up management, and disease experiences in thyroid cancer patients. The PGIC, a 7-point subjective scale, will be used to assess patient’s subjective improvement following the intervention.

Concomitant Care and Safety Assessment

The use of concomitant medications will be documented at each follow-up visit. Any adverse events will be recorded and assessed for their causal relationship to the treatment method using the WHO-Uppsala Monitoring Center causality assessment system, which categorizes event on a 6-point scale (1 = definitely related, 2 = probably related, 3 = possibly related, 4 = probably not related, 5 = definitely not related, and 6 = unknown). The severity of adverse events will be graded according to Common Terminology Criteria for Adverse Events version 5.0, incorporating both subjective and objective symptomatology.

Baseline demographic data will be collected, including sex, age, height, body weight, vital signs, pre-existing comorbidities, and medication history. The overall trial procedure and schedule of assessments are outlined in Table 1.

Table 1.

Timetable and Outcome Measurements.

	Screening	Enrollment/allocation	Treat			Follow up			Unscheduled visit
Time point	V0	V1 (D1)	V2 (D2)	V3 (D3)	V4 (D4)	V5 (D5)	V6 (D8)	V7 (D15)
Visit window	−30–0	Control point					±2	±3
Enrollment
Written informed consent	○
Screening number	○
Vital signs	○	◎	△	△	△	△	△	△	○
Sociodemographic characteristics	○
Medical history	○	◎
ASA status	○	◎
Eligibility screening	○	◎
Randomized allocation		○
Intervention
Nasal steam/usual care		○		○		○
Assessment
WURSS-24		○	○	○	○	○	○	○	△
Incidence-cough		○			○		○	○	△
NRS-cough		○			○		○	○	△
NRS-throat		○			○		○	○	△
NRS-dysphagia		○			○		○	○	△
THYCA-QoL		○			○		○	○	△
PGIC							○
Drug consumption		○	○	○	○	○	○	○	○
Adverse events		○	○	○	○	○	○	○	○

Abbreviations: ASA, American Society of Anesthesiologists; WURSS-24, Wisconsin Upper Respiratory Symptom Survey-24; NRS, Numerical Rating Scale; THYCA-QoL, Thyroid Cancer-specific Quality of Life questionnaire; PGIC, Patient Global Impression of Change.

○This measurement can be replaced with data from visit 0 if the visit 1 was conducted on the same day as v0.

△This measurement can be omitted only in the case of remote surveys, but data collection is recommended whenever possible.

Sample Size Calculation

The sample size for this study was determined based on findings from prior trials evaluating the effectiveness of lidocaine spray for post-extubation cough, which shows approximately 70% of patients experienced post-extubation cough, and the intervention led to a 50% reduction in symptoms. ¹² According to the study results, we estimated that enrolling 30 participants per group would provide statistical power (80%) to detect differences, with a significance level of 0.05. To account for a 10% dropout rate, we plan to recruit 33 participants per group, bringing the total study population to 66 patients. The statistical analysis was performed using G*power 3.1.9.7.

Statistical Analysis

 Both intention-to-treat (ITT) and per-protocol (PP) analyses will be performed, with ITT designated as the primary analytic approach. To address missing data, a mixed model for repeated measures will be employed. Sensitivity analyses will incorporate multiple imputations and last observation carried forward (LOCF) methods. For time-to-event analyses, dropout patients will be handled via right censoring, whereas intermittent censoring will assume the absence of event occurrence within the given time.

Baseline sociodemographic characteristics and treatment expectancy will be assessed across groups. Continuous variables will be summarized as mean (standard deviation) or median (interquartile range), with between-group comparisons conducted using Student’s t-test or the Wilcoxon rank sum test, depending on data distribution. Categorical variables will be expressed as frequency (%), with group differences evaluated using the chi-square test or Fisher’s exact test as appropriate.

The primary efficacy endpoint will be the between-group difference in change from baseline in continuous outcomes (eg, WURSS, NRS, THYCA-QoL) at each time point. A linear mixed-effects model with a random intercept at the patient level will be used, incorporating baseline values of each outcome, group allocation, time point, and the interaction terms to assess differential changes over time. Clinically relevant baseline covariates showing significant between-group differences will be included as fixed effects. Sensitivity analyses will be conducted for MI and LOCF datasets, applying the same covariates as the primary analysis while treating the group as a fixed factor. To compare cumulative difference in each outcome over a specified period (treatment phase or total trial duration), the area under the curve will be calculated at each time point after randomization, which will be tested utilizing analysis of covariance with multiple imputations. For NRS cough severity, the proportion of patients achieving the minimal clinically important difference (MCID) will be compared between groups. Time to MCID achievement will be analyzed using Kaplan–Meier survival analysis, with between-group differences assessed via the log-rank test. Additionally, hazard ratios will be estimated using the Cox proportional hazards model.

All statistical analyses will be performed using SAS 9.4 (© SAS Institute, Inc., Cary, NC, USA) or R 4.1.1 (© the R foundation for statistical computing, Auckland, New Zealand). Statistical significance will be defined as P < .05. If the superiority test fails, a non-inferiority test will be performed with a non-inferiority margin at 0.9, corresponding to half the MCID for acute cough (NRS-based), given the MCID for acute cough VAS is 1.7 and for chronic cough VAS is 3. If the lower bound of the 95% confidence interval (CI) for the between-group difference in NRS reduction does not exceed this margin, NHST will be considered non-inferior to the standard care group.

Data and Safety Monitoring Board

To ensure the integrity and safety of this clinical trial, a data and safety monitoring board (DSMB) will be established. The DSMB will be composed of at least 1 healthcare professional with relevant clinical expertise and 1 statistical expert. The board will operate independently from the study investigators and will be responsible for periodic safety review, interim efficacy assessments, and overall trial oversight to ensure adherence to ethical and scientific standards. The composition, responsibilities, and operational framework of the DSMB will be clearly defined in the operating procedure, outlining the frequency of meetings, decision-making processes, and criteria for trial modifications or termination, if necessary.

Discussion

Endotracheal intubation is a routine but invasive procedure in surgical settings and often results in post-extubation respiratory symptoms (PERS) following general anesthesia. Mechanical irritation of the airway may lead to a broad spectrum of symptoms, from mild sore throat and cough to more serious complications such as laryngeal edema, upper airway obstruction, or ventilator-associated pneumonia. ¹³ The severity and clinical presentation of PERS vary substantially among patients. Given its potential to delay recovery and compromise postoperative outcomes, effective management of PERS remains a significant challenge in perioperative care.

Thyroidectomy remains a primary treatment modality for thyroid cancer. ¹⁴ According to recent thyroid nodule management guidelines, ¹⁵ surgical resection is recommended for malignant or suspicious nodules, including follicular neoplasms. Given the anatomical proximity of the thyroid gland to upper airway structures, patients undergoing thyroidectomy are especially susceptible to PERS, highlighting the need for targeted preventive strategies. ¹⁶

 Nasal herbal steam therapy (NHST) has emerged as a promising intervention for post-extubation respiratory symptoms. Traditionally, it has been employed for upper airway care across various medical systems, including those in Hungary, ¹⁷ the Middle East, ¹⁸ and India. ¹⁹ In Hungary, mineral-rich geothermal steam has long been used in respiratory therapy as part of traditional healing practices. ²⁰

In the hot and arid climate of the Middle East, nasal steam therapy has long played a central role in supporting upper respiratory health. In Unani medicine, the nasal route is regarded as a key conduit for delivering both local and systemic therapeutic effects, and has traditionally been used to treat conditions such as asthma and bronchitis. ²¹ This technique typically involves inhalation of steam infused with herbs or therapeutic smoke derived from the controlled combustion of medicinal botanicals. ²²

Similarly, in Ayurvedic medicine, nasal steam therapy is a key component of the Swedana procedure, a traditional therapeutic modality that combines the effects of heat and medicinal herbs. ²³ Widely practiced in Ayurvedic hospitals, Swedana involves exposing patients to herbal steam in a prone position within a specialized chamber, ²⁴ allowing for targeted treatment of upper respiratory conditions. Reported benefits include enhanced mucociliary clearance, improved regional circulation, and immune modulation via stimulation of cutaneous and neuronal receptors. ²⁵ Recent Indian studies have further supported the efficacy of steam inhalation in improving mucociliary function, reinforcing its therapeutic relevance. ²⁶

In South Korea, nasal steam therapy has developed in parallel with global practices while maintaining unique features rooted in traditional Korean medicine, especially acupuncture and herbal remedies. Korean NHST involves the direct application of herbal steam to the upper respiratory tract and has been used to manage conditions ranging from acute airway obstruction to chronic inflammatory diseases. Traditionally, it has been applied to patients with impaired consciousness, upper respiratory infections, and certain gynecological conditions. ⁷ Recent clinical studies have also reported its potential benefits in managing sequelae of hypopharyngeal cancer treatment, as well as in cases of sudden hearing loss, ²⁷ Bell’s palsy, ²⁸ asthma, and chronic obstructive pulmonary disease. ²⁹

Despite its long-standing use, evidence evaluating NHST as a standalone intervention for PERS remains limited. Most prior studies have examined its effects within multimodal treatment settings, leaving insufficient data on its independent therapeutic efficacy. Furthermore, no standardized protocol currently exists regarding key treatment parameters, including herbal extracts, duration of steaming exposure, and frequency of administration. This study aims to systematically evaluate NHST as a single intervention compared with conventional PERS management, in order to clarify its clinical effectiveness and potential integration into postoperative care. The inhalation of herbal steam is expected to confer dual benefits: mucosal hydration and the anti-inflammatory action of bioactive phytochemicals. Given its potential to relieve mucosal dryness, reduce irritation, and promote recovery, NHST may serve as a non-invasive adjunct to optimize post-extubation respiratory outcomes.

In conclusion, this study is anticipated to generate robust evidence supporting the clinical utility of nasal steam for PERS management. By demonstrating the independent therapeutic effects of NHST, our findings will provide future standardization and potential incorporation of NHST into evidence-based postoperative respiratory care strategies.