Effectiveness of Enzyme Spray Intervention on Thirst Relief in Patients With Endotracheal Intubation.

Research Background Thirst is one of the most common and distressing symptoms experienced by patients in intensive care units (ICUs). Endotracheal intubation causes inspired air to bypass the normal warming and humidification functions of the upper airway and may contribute to oral mucosal dryness. Nil per os (NPO) status, oxygen therapy, and medication-related effects may further aggravate thirst. Current clinical approaches include moistening the lips, water or saline sprays, and oral moisturizing agents; however, the relief provided by these approaches may be short-lived. Direct oral water administration in patients with endotracheal intubation may also increase the risk of choking or aspiration.

Enzyme-based saliva substitutes are designed to mimic components of natural saliva and may help maintain oral moisture and stabilize the oral environment. Although these products have been used primarily in populations with xerostomia, evidence regarding their effectiveness for thirst relief in ICU patients with endotracheal intubation remains limited. Therefore, further evaluation of enzyme-based oral moisturizing strategies in this population is warranted.

Study Objectives The primary objective was to compare the effectiveness of an enzyme-based oral spray with a distilled-water control spray in reducing thirst intensity, measured using the Numerical Rating Scale-Intensity (NRS-I), and thirst distress, measured using the Numerical Rating Scale-Distress (NRS-D), among patients with endotracheal intubation.

The secondary objective was to evaluate the time course and persistence of thirst relief over 240 minutes following the intervention.

Study Design and Setting This study was conducted as a randomized controlled trial in a surgical ICU at a medical center in southern Taiwan. The study was based on routine clinical oral care practices and did not involve additional invasive procedures.

Eligible participants were adults aged 18 years or older who were admitted to the ICU with endotracheal intubation and were expected to remain intubated for more than 24 hours. Participants were required to have a baseline thirst intensity score of NRS-I ≥3, a Richmond Agitation-Sedation Scale (RASS) score between -1 and +1, and the ability to communicate subjective sensations verbally or in writing. Written informed consent was obtained before enrollment.

The study excluded patients with known allergy to components of the enzyme-based spray, including relevant milk- or egg-derived components; pre-existing xerostomia; oral mucosal ulcers or active oral bleeding; a history of oral surgery; physician-diagnosed abnormal salivary secretion; or a clinically determined increased risk of aspiration or other complications associated with oral spray administration. These criteria were defined in the approved study protocol.

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

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

Allocation concealment was achieved using sequentially numbered, opaque, sealed envelopes (SNOSE). The independent research assistant prepared and sealed the envelopes according to the randomization sequence. After informed consent was obtained and eligibility was confirmed by the research nurse, the principal investigator opened the next sequentially numbered envelope to determine group assignment.

Interventions Participants in the experimental group received an enzyme-based oral spray (Oral7®), whereas participants in the control group received a distilled-water oral spray.

Both solutions were prepared in identical 30-mL opaque spray bottles. The bottles were completely covered with opaque tape and labeled only with randomization codes without indicating their contents. The spray nozzle was 6.5 cm in length and marked at 3 cm to standardize insertion depth. The solutions were maintained at room temperature (24-26°C) and checked before administration.

The intervention was conducted during a standardized daily time window between 13:00 and 15:00. Baseline thirst intensity (T0) was assessed before routine oral care to minimize the influence of oral cleaning on the baseline measurement. After routine oral care, the assigned oral spray was administered according to the standardized study protocol.

Before intervention, the patient's level of consciousness, communication ability, vital signs, and eligibility were confirmed. To reduce aspiration risk, the head of the bed was elevated to approximately 30°, and ventilator circuit condensate was drained before administration.

The spray nozzle was inserted approximately 3 cm into the oral cavity through the occlusal plane. Four intraoral sites were sprayed in a fixed sequence: the hard palate, left buccal mucosa, tongue surface, and right buccal mucosa. One spray at each site constituted one cycle. Three cycles were administered, with a 1-minute interval between cycles. A total of 12 sprays, corresponding to approximately 1.56 mL, were administered during each intervention. No additional study spray was administered after completion of the three cycles, and participants were followed for 4 hours according to the predefined assessment schedule.

Masking Participants were not informed of their group allocation. Both intervention solutions were administered using identical opaque spray bottles and standardized procedures to reduce the possibility of identifying group assignment from the appearance of the intervention.

However, because sensory or physical characteristics after oral administration could differ between the two solutions, complete participant blinding could not be assured.

Intervention delivery and outcome assessment were performed by separate personnel. The principal investigator administered the intervention, whereas trained research nurses who were blinded to group allocation performed the outcome assessments. The principal investigator did not participate in NRS-I or NRS-D assessment during the follow-up period.

Because the intervention administrator could potentially recognize differences between the two solutions during administration, complete masking of the administrator could not be guaranteed. To minimize performance and observer bias, intervention procedures were standardized and the intervention administrator did not participate in outcome assessment. The approved IRB protocol similarly separated the intervention administrator from the blinded outcome assessors.

Outcome Measures The co-primary outcomes were thirst intensity and thirst distress. Thirst intensity was assessed using the Numerical Rating Scale-Intensity (NRS-I), ranging from 0, indicating no thirst, to 10, indicating the worst possible thirst.

Thirst distress was assessed using the Numerical Rating Scale-Distress (NRS-D), ranging from 0, indicating no distress, to 10, indicating the worst possible thirst-related distress.

Both outcomes were assessed at five predefined time points: baseline before intervention (T0), 30 minutes after intervention (T1), 60 minutes after intervention (T2), 120 minutes after intervention (T3), and 240 minutes after intervention (T4).

These repeated measurements were used to evaluate changes in thirst intensity and thirst distress over time and to examine the time course and persistence of the intervention effect during the 240-minute observation period. The same T0-T4 schedule was specified in the approved study protocol.

Safety Monitoring The study was considered a minimal-risk intervention. Potential adverse effects included transient discomfort or mild choking associated with oral spray administration.

During the intervention, participants were monitored for respiratory status, vital-sign changes, discomfort, choking, oxygen desaturation, respiratory distress, pain, or other clinically significant deterioration. If a predefined safety event occurred, the intervention was to be discontinued immediately and routine clinical care resumed, with notification of the attending physician when clinically indicated.

Sample Size The planned sample size was 76 participants, with 38 participants allocated to each group. This sample size allowed for an estimated attrition rate of 20%, with a target of at least 30 completed participants per group.

Research Data and Specimens No biological specimens, such as DNA or serum, were collected as part of this study. Research data consisted primarily of participant-reported outcome measurements and selected clinical information obtained from existing medical records.

All study data were coded and de-identified. Paper research records and informed consent documents were stored in locked cabinets with restricted access. Electronic data were stored on password-protected computers with restricted access and were managed according to institutional data protection requirements.

Statistical Analysis Generalized estimating equations (GEE) were used to evaluate the effects of group, time, and the group-by-time interaction on the two co-primary outcomes, NRS-I and NRS-D, while accounting for within-participant correlations arising from repeated measurements.

Data analysis was conducted after completion of participant recruitment, consistent with the statistical analysis plan specified in the approved study protocol.