This study addresses the high prevalence (66%-70%) of thirst among intensive care unit (ICU) patients with endotracheal intubation, a symptom associated with oral mucosal dryness, nil per os (NPO) status, high-flow oxygen therapy, and medication effects. Unrelieved thirst may contribute to anxiety, delirium, and unplanned extubation. Current clinical practices, such as cold water or saline sprays, provide only transient relief and may pose aspiration risks. Enzyme-based saliva substitutes, which mimic natural saliva and stabilize the oral environment, show potential benefits; however, evidence in ICU populations remains limited.

A single-blind randomized controlled trial (RCT) will be conducted in an ICU of a medical center in southern Taiwan. Eligible participants are adult patients (≥18 years) with endotracheal intubation expected to exceed 24 hours, a baseline thirst intensity score (NRS-I) ≥3, and the ability to communicate. A total of 76 participants will be recruited and randomly assigned in a 1:1 ratio to either the experimental group (enzyme-based oral spray) or the control group (distilled water spray), using sequentially numbered, opaque, sealed envelopes (SNOSE) to ensure allocation concealment.

The intervention will be administered following routine oral care within a standardized time window (13:00-15:00). Both solutions will be prepared in identical opaque spray bottles to maintain blinding. The protocol includes 12 sprays per session (approximately 1.56 mL), delivered to four standardized intraoral sites, with outcomes monitored over a 4-hour period.

Primary outcomes include thirst intensity (Numerical Rating Scale-Intensity, NRS-I) and thirst distress (Numerical Rating Scale-Distress, NRS-D), assessed at baseline (T0) and at 30, 60, 120, and 240 minutes post-intervention (T1-T4) by blinded outcome assessors. No biological specimens will be collected; data will be obtained from self-reported measures and electronic medical records, with strict de-identification and secure storage procedures.

This study is considered minimal risk. Any adverse events, such as discomfort or choking, will result in immediate discontinuation of the intervention. Data will be analyzed using generalized estimating equations (GEE) to evaluate group, time, and interaction effects. The findings are expected to provide evidence-based guidance for improving thirst management, enhancing patient comfort, and optimizing the quality of critical care nursing.

Research Background Disease Status and Natural Course Thirst is one of the most prevalent and distressing symptoms among patients admitted to intensive care units (ICUs), with a reported prevalence of approximately 66%-70%. Endotracheal intubation causes inhaled air to bypass the upper airway's natural warming and humidification mechanisms, resulting in oral mucosal dryness. In addition, therapeutic fasting (nil per os, NPO), high-flow oxygen therapy, and medication-related adverse effects may further exacerbate thirst, leading to anxiety, feelings of helplessness, and an increased risk of delirium and unplanned extubation.

Available Therapeutic Approaches Current clinical practice primarily relies on moistening the lips with cotton swabs, or administering cold water or cold normal saline sprays, which typically provide thirst relief for approximately 30 minutes. Oral moisturizing agents can be categorized into simple moisturizing formulations-most commonly containing carboxymethyl cellulose (CMC)-which aim to simulate salivary viscosity; however, their effects are generally short-lived, lasting approximately 27 ± 25 minutes.

Alternatively, direct oral water instillation in intubated patients may increase the risk of aspiration and choking. For patients requiring prolonged intubation or fasting, hydration alone is often insufficient to maintain oral moisture. Enzyme-based saliva substitutes, which mimic the composition of natural saliva and help stabilize the oral microenvironment, have been developed to address these limitations. Although such products are primarily used in patients with radiation-induced xerostomia, their salivary-mimicking properties and moisture-retaining mechanisms suggest potential applicability to other populations, including ICU patients at high risk of oral dryness or prolonged airway maintenance. Further empirical validation in this population is warranted.

Prognosis Effective thirst management may reduce physiological stress responses, decrease agitation, improve sleep quality, and enhance overall quality of critical care.

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1. Study Objectives Primary Objective To compare the effectiveness of enzyme-based oral spray versus distilled water (DW) spray in alleviating thirst intensity (Numerical Rating Scale-Intensity, NRS-I) and thirst distress (Numerical Rating Scale-Distress, NRS-D) in patients with endotracheal intubation.

   Secondary Objective To evaluate the duration of the thirst-relieving effect of the enzyme-based oral spray.

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2. Study Design

1. Study Type and Design Framework This study adopts a single-blind randomized controlled trial (RCT) design to compare the effects of enzyme-based oral spray and distilled water (DW) spray on thirst relief among intubated ICU patients.

   The intervention is conducted based on routine clinical oral care practices without introducing additional invasive procedures, and is therefore classified as a low-risk study design.

2. Study Population and Setting The study is conducted in the intensive care unit of a medical center. Eligible participants are adult ICU patients with endotracheal intubation. The principal investigator explains the study procedures to patients and their family members and obtains written informed consent. Participants are screened according to predefined inclusion and exclusion criteria. Only patients with a baseline thirst intensity score (NRS-I) ≥ 3 at T0 are eligible for randomization; this criterion is clearly communicated prior to consent. Eligible participants are subsequently enrolled in the study.

3. Randomization and Allocation Concealment a. Randomization Participants are randomly assigned in a 1:1 ratio to either the experimental group (enzyme-based oral spray) or the control group (distilled water spray).

   The randomization sequence is generated by an independent research assistant who is not involved in participant recruitment, intervention delivery, or outcome assessment, using a computerized random number generator. The resulting master randomization list is concealed from all clinical research personnel throughout the study.

   b. Allocation Concealment Allocation concealment is achieved using sequentially numbered, opaque, sealed envelopes (SNOSE).

   The independent research assistant places group assignment codes into correspondingly numbered envelopes and seals them securely. After informed consent is obtained and eligibility is confirmed by the research nurse, the principal investigator opens the envelopes sequentially to determine group allocation, ensuring that the assignment process remains free from human interference.

4. Intervention

   a. Experimental Group Participants receive an enzyme-based oral spray following completion of routine oral care, administered by the principal investigator according to the study protocol.

   b. Control Group Participants receive a distilled water (DW) oral spray administered at the same time points, frequency, and procedures as the experimental group.

   Intervention Standardization Both solutions are prefilled by an independent research assistant into identical 30-mL opaque spray bottles fully wrapped with opaque tape. Only randomization codes are displayed; solution contents are not labeled.

   All interventions are conducted during a fixed daily time window (13:00-15:00) to minimize time-related confounding effects.

5. Blinding

   1. Participant Blinding Spray bottles for both groups are identical in appearance, and the solutions are colorless and odorless. Participants cannot distinguish group allocation based on appearance, smell, or administration method, thus achieving participant blinding.

   2. Outcome Assessor Blinding To minimize measurement bias, intervention delivery and outcome assessment are performed by separate personnel.

      The principal investigator administers the intervention, while outcome assessments (T0-T4) are conducted by trained research nurses who are blinded to group allocation. The principal investigator refrains from participating in outcome assessments to prevent observer bias.

   3. Control of Operator Bias Although complete blinding of the intervention administrator may not be feasible due to potential physical differences between solutions, strict role separation ensures that the administrator does not participate in outcome assessment, thereby minimizing experimenter effects.

6. Outcome Measures and Data Collection Time Points Primary outcome measures include thirst intensity (Numeric Rating Scale for Thirst Intensity, NRS-I) and thirst distress (Numeric Rating Scale for Thirst Distress, NRS-D).

   Assessments are conducted at baseline (T0), and at 30 minutes (T1), 60 minutes (T2), 120 minutes (T3), and 240 minutes (T4) post-intervention by blinded assessors following standardized guidelines.

7. Study Quality and Safety Monitoring If participants experience discomfort, choking, or clinical deterioration during the study, the intervention will be immediately discontinued and routine medical care resumed. After study completion, audits of the randomization process and data completeness will be conducted to ensure research quality.

   • Participants Inclusion Criteria

1. Adult patients aged ≥18 years admitted to the ICU with endotracheal intubation and an expected intubation duration >24 hours.
2. Thirst intensity score (NRS-I) ≥3.
3. Conscious and able to communicate subjective sensations verbally, in Mandarin, Taiwanese, or in written form.
4. Richmond Agitation-Sedation Scale (RASS) score between -1 and +1.
5. Willingness to participate and provision of written informed consent after full explanation.

Exclusion Criteria

1. Known allergy to enzyme spray components (e.g., lysozyme, lactoperoxidase, glucanase, xylitol).
2. Known allergy to milk or eggs.
3. Pre-existing xerostomia.
4. Oral mucosal ulcers or active oral bleeding.
5. History of oral surgery.
6. Physician-diagnosed abnormal salivary secretion.
7. Physician-determined increased risk of aspiration or other complications related to oral spray administration.

Sample Size A total of 76 participants are planned (38 per group), with a target of 30 participants per group completing the study, accounting for an estimated 20% attrition rate.

• Handling of Specimens and Research Data Specimen Type This study does not involve the collection of biological specimens (e.g., DNA, serum). Data include self-reported scale measurements and existing physiological indicators retrieved from medical records (e.g., serum sodium, APACHE II score, 24-hour fluid balance).

  External Review Data are collected at a medical center in southern Taiwan and are not transferred to external institutions or overseas.

  Data Management All data are de-identified and coded. Paper documents, including signed informed consent forms and research records, are stored in locked cabinets in the nurse manager's office of Unit 10B.

  Electronic data are stored on password-protected, encrypted computers in the same office with restricted access. Data transmission also follows de-identification principles.

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• Research Methods Interventions Experimental group: Enzyme-based oral spray (Oral7®). Control group: Distilled water spray. Spray Preparation Both solutions are placed in 30-mL plastic spray bottles fully wrapped with opaque tape to maintain blinding. The spray nozzle length is 6.5 cm, with a depth marker at 3 cm to ensure consistency. Solutions are stored at room temperature (24-26 °C) and inspected prior to administration.

  Patient Condition Verification Before intervention, research nurses confirm patient consciousness, communication ability (verbal or non-verbal), stable vital signs, and eligibility criteria.

  Airway Safety Measures To reduce aspiration risk, the head of the bed is elevated to approximately 30°, and ventilator circuit condensate is drained prior to intervention.

  Intervention Procedure (Based on the Eight Dimensions of the Symptom Management Model) Baseline thirst intensity (NRS-I) at T0 is assessed prior to oral care to avoid confounding effects.

  • What: Alleviation of thirst intensity and distress in intubated ICU patients.

  • Who: Intervention administered by the principal investigator after eligibility confirmation by research nurses.

  • Whom: Eligible intubated ICU patients.

  • Where: ICU bedside (Unit 3B).

  • When: Following baseline assessment (T0) and routine oral care performed with clean water between 13:00-15:00; outcome assessments at T1, T2, T3, and T4.

  • Why: Enzyme-based oral spray mimics salivary components, improves oral mucosal moisture, stabilizes the oral environment, and enhances subjective comfort.

  • How: The spray nozzle is inserted 3 cm into the oral cavity via the occlusal plane. Four fixed sites are sprayed sequentially: hard palate, left buccal mucosa, tongue surface, and right buccal mucosa. One spray per site constitutes one cycle. Three cycles are administered with 1-minute intervals between cycles.

  • How Much: A total of 12 sprays per intervention, corresponding to approximately 1.56 mL. No additional spray is administered, and outcomes are monitored for 4 hours.

• Management of Adverse Effects This is a minimal-risk study. Potential adverse effects include transient discomfort or mild choking.

  During intervention, research nurses continuously monitor respiratory status and vital signs. If oxygen desaturation, respiratory distress, severe choking, or pain occurs, the intervention is immediately discontinued and the attending physician notified.

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• Statistical Analysis Generalized estimating equations (GEE) will be used to evaluate the effects of group, time, and group × time interaction on thirst outcomes, accounting for correlations in repeated measures data.

  All analyses will be conducted after completion of participant recruitment.

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• Participant Data Protection and Safety Monitoring Privacy protection is ensured through coded identifiers. Paper records are stored in locked cabinets, and electronic files are encrypted with restricted access.

Safety monitoring includes ensuring head-of-bed elevation and removal of ventilator condensate prior to intervention. Trained research nurses remain present throughout the intervention to monitor patient tolerance.

________________________________________ 9. Appendices Appendix I. Demographic Data Form

Inclusion Criteria:

• Adult patients aged ≥18 years admitted to the intensive care unit (ICU) with endotracheal intubation, and an expected duration of intubation >24 hours.
• Thirst intensity score ≥3 on the Numerical Rating Scale for Thirst Intensity (NRS-I).
• Conscious and able to communicate subjective sensations verbally (Mandarin or Taiwanese) or in written form.
• Richmond Agitation-Sedation Scale (RASS) score between -1 and +1.
• Willingness to participate and provision of written informed consent after a full explanation of the study.

Exclusion Criteria:

• Known allergy to enzyme spray components (e.g., lysozyme, lactoperoxidase, glucanase, xylitol).
• Known allergy to milk or eggs.
• Pre-existing xerostomia.
• Presence of oral mucosal ulcers or active oral bleeding.
• History of oral surgery.
• Physician-diagnosed abnormal salivary secretion.
• Physician-determined increased risk of aspiration or other complications associated with oral spray administration.

This study adopts a single-blind design. Participants are blinded to group allocation, as both intervention solutions are colorless, odorless, and administered using identical opaque spray bottles. Outcome assessors are also blinded to group assignment to minimize measurement bias. No additional parties are masked beyond those specified.