Endotracheal intubation is indispensable in general anesthesia, pre-hospital emergency care, and intensive care units for airway control. The endotracheal tube (ETT) cuff, a crucial component, not only maintains airway seal for assisted ventilation but also effectively prevents aspiration (1). However, establishing appropriate ETT cuff pressure poses challenges for anesthesiologists. Insufficient pressure increases the risk of ventilator-associated leaks and fails to prevent leakage of oropharyngeal secretions into the lower airways, closely linked to ventilator-associated pneumonia (VAP) (2). Conversely, excessively high cuff pressures pose significant patient risks. Even brief periods of elevated cuff pressure can lead to tracheal mucosal damage, including ischemia, ulcers, necrosis, tracheoesophageal fistula, and potentially fatal tracheal rupture (3, 4). The safety threshold for ETT cuff pressure remains contentious; currently, 30 cmH₂O is considered safe, balancing prevention of aspiration against airway mucosal damage (5–7). However, perioperative factors frequently alter cuff pressures, and comprehensive data on the microstructural effects of 30 cmH₂O cuff pressure on tracheal mucosa are lacking (8). Reevaluating 30 cmH₂O as a safe threshold to prevent tracheal mucosal injury may be necessary.

The tracheal mucosa is extremely fragile. The hydrostatic pressure of the tracheal mucosal capillaries is approximately 24 cmH₂O in adults, and that of the lymphatic vessels is around 7 cmH₂O. When the internal pressure of the cuff exceeds 35 cmH₂O, the blood flow at the compressed section of the trachea significantly decreases, increasing the risk of tracheal injury (3). It is widely accepted that maintaining cuff pressure at or below 30 cmH₂O is crucial to prevent damage to the tracheal mucosa. However, current attention to ETT cuff pressure among anesthesiologists is inadequate, with numerous surveys indicating that the pressures set frequently exceed this safe threshold (9, 10). Moreover, various factors in clinical practice, such as the specifics of anesthesia and surgical procedures, patient-specific airway characteristics, and even altitude, can significantly elevate cuff pressure (11–19) (Figure 1A). Therefore, monitoring and appropriately adjusting cuff pressure is essential for the protection of the tracheal mucosa. Tools such as manometers, continuous cuff pressure monitoring and adjustment devices, mucosal blood flow monitors, and standard clinical pressure sensors support the careful monitoring and adjustment of cuff pressure (3, 20, 21) (Figure 1B). Nevertheless, there is a lack of clear threshold standards for cuff pressure, and a critical issue that demands close examination is the reference levels for cuff pressure adjustments, aimed at maximizing the prevention of VAP and tracheal mucosal damage.

It is generally believed that maintaining cuff pressure between 20–30 cmH₂O is appropriate for adult patients under normal circumstances (5). Pressures below 20 cmH₂O are independently associated with an increased risk of VAP, while 30 cmH₂O serves as a safe upper limit to prevent tracheal mucosal injury, and is currently a primary reference for adjusting cuff pressure (2). However, the safety margins regarding cuff pressure are based on theoretical deductions about mucosal perfusion pressure, and there is a lack of evidence to confirm whether 30 cmH₂O as a reference cuff pressure could cause damage to the mucosa in patients under prolonged general anesthesia. There is also a dearth of research on whether 30 cmH₂O could potentially harm the microstructure of the tracheal mucosa. This study aims to reassess the safety limits for cuff pressure to prevent tracheal mucosal damage through current status surveys, clinical imaging, and mechanical ventilation animal models.

This study was conducted as a multifaceted study comprising three parts. Ethical approvals were obtained from the Ethics Committee of the Zigong Fourth People’s Hospital (ID: 2022-090). In brief, the first part of the study utilized a web-based questionnaire survey among anesthesiologists primarily in Sichuan Province, China, to assess their methods and awareness regarding the establishment of ETT cuff pressures across different proficiency levels. Additionally, pressure monitoring was used to measure ETT cuff pressure values established by select anesthesiologists, and the impact of perioperative anesthesia and surgical procedures on cuff pressures was evaluated. The second part of the study involved a retrospective observational analysis of the condition of airway mucosa in mechanically ventilated general anesthesia patients maintained at a baseline ETT cuff pressure of 30 cmH₂O for varying durations. Correlation analyses were performed between the degree of mucosal damage and postoperative pharyngeal pain severity based on postoperative follow-up records. In the third part, an animal mechanical ventilation model was employed to maintain ETT cuff pressure at 30 cmH₂O. After 4 h of ventilation, microscopic structural changes in the airway mucosa were observed, and the sequential method was used to estimate the ED₅₀ of cuff pressure required to prevent airway mucosal injury.

A total of 634 valid questionnaires were obtained. The current method of establishing ETT cuff pressure by most anesthesiologists is incorrect, and pressure monitoring equipment is also lacking. Among these, only 1.84% of anesthesiologists inflated the cuff under the guidance of pressure monitoring devices. The predominant method still employed is the finger touch technique, with its usage frequency increasing progressively as professional titles advance (Figure 2A). In addition, most anesthesiologists have a poor understanding of ETT cuff pressure. There appears to be varying knowledge among surveyed anesthesiologists regarding the appropriate cuff pressure; 44.1% believe that a pressure range of 10–20 cm H₂O is most suitable, despite such pressure being insufficient to maintain airway seal integrity. Furthermore, 12.86% of anesthesiologists are unaware of the recommended cuff pressure range (Figure 2B). Alarmingly, 79.2% of the anesthesiologists surveyed never monitor or adjust cuff pressure intraoperatively (Figure 2C). The full questionnaire information and results are presented in Supplementary material S1.

The cuff pressures established by 294 anesthesiologists during elective surgeries was measured, and found that the average cuff pressure exceeded safe limits using 30 cmH₂O as a reference. The highest cuff pressure established by resident physicians was 42.98 ± 18.57 cmH₂O (95% CI of mean: 38.14 to 47.82 cmH₂O). We did not observe a decrease in cuff pressure with increasing professional degree (Figure 2D). Secondary analysis of pressure values across different surgical categories revealed significantly higher cuff pressures in oral surgery patients compared to other types of surgeries (Figure 2E). After initial pressure measurements, adjustments were uniformly made to 30 cmH₂O, and we examined the effects of various anesthesia and surgical procedures on cuff pressure. Coughing resulted in the most pronounced increase in cuff pressure at 77.7 ± 16.68 cmH₂O (95% CI of mean: 71.47 to 83.93 cmH₂O), with multiple anesthesia and surgical procedures significantly elevating cuff pressures (Figure 2F).

In the retrospective analysis, 119 of the 219 patients initially screened for inclusion in the study were excluded based on exclusion criteria. Therefore, a total of 100 patients were included in this retrospective study, and complete clinical data were obtained. The flowchart of the patient screening process is shown in Figure 3. At each time point, a total of patients who met the criteria were included in the cohorts. Demographic characteristics of enrolled patients refer to Table 1. For patients ventilated for less than 4 h, a cuff pressure of 30 cmH₂O did not significantly alter the incidence of airway injury. However, the degree of tracheal mucosal damage significantly increased over time, with the 6, 8, and 10 h cohorts showing significantly higher injury levels than the 2 h cohort (p < 0.05). A similar trend was observed in the postoperative sore throat severity among different cohorts (Figures 4A–C). The degree of injury was positively correlated with postoperative sore throat severity (r = 0.6232, 95% CI of r: 0.4863 to 0.7303, p < 0.0001) (Figure 4D).

TEM results of a rabbit mechanical ventilation model showed that a cuff pressure of 30 cmH₂O significantly damaged the airway mucosal ciliated columnar epithelial cells (n = 5). This damage was characterized by substantial loss of cilia, mitochondrial swelling, and the occurrence of partial autophagy. A mechanical ventilation duration of 4 h at a cuff pressure of 30 cmH₂O was sufficient to cause loss of airway mucosal epithelial cells and the tight connections between cells are broken (Figures 5A,B). H&E staining indicated that the pathological changes caused by a cuff pressure of 30 cmH₂O primarily consisted of significant epithelial congestion, continuity changes, accompanied by partial disruption and exudative injury (Figure 5C). Beyond mechanical-induced changes, TUNEL staining suggested that a cuff pressure of 30 cmH₂O could induce apoptotic changes in airway mucosal epithelial cells (Figure 5D). These findings suggest that maintaining cuff pressure at 30 cmH₂O may not be a safe limit to prevent airway mucosal damage in patients undergoing prolonged mechanical ventilation. In addition to the changes in airway mucosal epithelial cells damage, we observed that cuff pressures of 30 cmH₂O and 45 cmH₂O led to inflammatory cell infiltration, predominantly consisting of macrophages and neutrophils. At a pressure of 30 cmH₂O, notable damage to the mitochondria of macrophages was detected, characterized by mitochondrial swelling, reduced cristae, and partial disruption of the cell membrane. However, similar changes were not observed in neutrophils under the same cuff pressure of 30 cmH₂O (Figure 6).

A total of 20 adult rabbits were utilized in a sequential method to determine the minimum cuff pressure required to prevent airway mucosal damage (Figure 7A). Probit regression analysis revealed that the ED₅₀ for preventing airway mucosal injury was 25.64 cmH₂O (95% CI: 19.268–29.367 cmH₂O), while the ED95 was 19.455 cmH₂O (95% CI: 17.95–23.31 cmH₂O) (Figure 7B). The validity of this injury probability prediction was confirmed by Pearson’s goodness-of-fit test (χ² = 0.482, p = 0.923).

This study reevaluated the safety threshold of 30 cmH₂O for ETT cuff pressure. Our findings, based on a retrospective clinical analysis and mechanical ventilation animal models, suggest that a cuff pressure of 30 cmH₂O may be safe for airway mucosa during short-term mechanical ventilation. However, during prolonged mechanical ventilation, such pressures are likely to induce significant damage to the tracheal mucosal epithelium. Therefore, the traditionally recommended cuff pressure of 30 cmH₂O may not effectively prevent tracheal mucosal injury. Furthermore, our survey indicated that anesthesiologists frequently exceed this recommended safety limit in practice. Moreover, various perioperative maneuvers can further elevate cuff pressure, compounding the risk of mucosal damage. These findings highlight the necessity of reassessing current guidelines and implementing more precise pressure monitoring to mitigate risks associated with extended mechanical ventilation.

The airway mucosa beneath the cuff is extremely fragile, and excessive cuff pressure can rapidly lead to severe mucosal injury (22). Unfortunately, the current situation is concerning. Our survey suggests that monitoring cuff pressure may not be a priority for anesthesiologists, who often rely on the imprecise finger touch method to inflate the cuff, resulting in pressures averaging 57.19 ± 30.99 cmH₂O. In emergency surgeries and pre-hospital settings, higher cuff pressures are commonly used to prevent aspiration, making excessive initial cuff pressures a significant risk factor for mucosal injury (23). Furthermore, post-intubation changes in cuff pressure are critical. Our findings, consistent with prior studies, indicate that various intraoperative factors can increase cuff pressure, with coughing exerting the most significant impact. Nseir et al. (24) reported that about 73% of ICU patients experienced cuff over-inflation, highlighting the risks in scenarios without neuromuscular blocking agents, where coughing can severely damage the airways. Therefore, continuous monitoring and adjustment of cuff pressure are essential to prevent airway mucosal injury. A critical issue that demands attention is identifying the optimal safety threshold for cuff pressure. To balance effective airway sealing and prevention of mucosal damage, a commonly recommended safe limit remains at 30 cmH₂O. This threshold, however, may need reevaluation in light of our findings. Unfortunately, no definitive guidelines on ETT cuff pressure have been published so far. Our findings may provide some reference for the development of clinical guidelines.

The rationale for setting a cuff pressure limit of 30 cmH₂O as safe is based on the fact that the perfusion pressure of airway mucosal capillaries is approximately 35 cmH₂O, suggesting that pressures within this limit should not impair mucosal blood flow (5, 6). However, this guideline fails to account for the perioperative period, when significant reductions in systemic blood pressure can inadvertently decrease mucosal perfusion pressure in anesthetized patients, potentially causing a 30 cmH₂O cuff pressure to obstruct mucosal blood flow (25). Moreover, the venous hydrostatic pressure of the tracheal mucosa is about 24 cmH₂O, and lymphatic return pressure is only 7 cmH₂O (3). This disparity may explain the more pronounced damage caused by a cuff pressure of 30 cmH₂O in patients requiring prolonged ventilation compared to those with shorter durations. There are no studies yet on the effects of a 30 cmH₂O cuff pressure on the microscopic structure of the airway mucosa. Our observations suggest that significant mucosal injury can occur at this pressure during extended mechanical ventilation, indicating a need to reevaluate the safety limits of cuff pressure. It should be noted that airway mucosal injury caused by ETT cuff may be more serious in elderly patients, who are often complicated with airway inflammation and weaker cardiovascular function, which may lead to airway mucosal compression injury in elderly patients with ETT cuff replacement.

Based on animal models, we infer that the minimal cuff pressure to prevent airway mucosal injury is approximately 19.455 cmH₂O. However, securing an airtight seal is also critical, as studies show that cuff pressures below 20 cmH₂O increase the incidence of VAP by 2.5 times, making sub-20 cmH₂O pressures a risk factor for VAP (26). The challenge of reducing cuff pressure while maintaining seal integrity necessitates exploring protective methods for the mucosa. Inflating the ETT cuff with an alkalinized lidocaine solution has been suggested to mitigate pressure fluctuations effectively (27, 28). Additionally, intraoperative cuff pressure adjustments and repositioning can protect the airway mucosa (1, 29). Our research indicates that mucosal injury at 30 cmH₂O may involve inflammatory infiltration and cellular apoptosis. Therefore, developing drugs to enhance epithelial cell apoptosis tolerance could be crucial for protecting the airway mucosa. In addition, on the basis of our study, we would recommend continuous cuff pressure monitoring in patients undergoing prolonged mechanical ventilation, using an electronic manometer or arterial pressure sensor for continuous measurement, and adjusting the cuff pressure to less than 30 cmH₂O as often as possible, according to titration to prevent air leakage.

In our study, we observed that during prolonged mechanical ventilation, ETT cuff compression caused inflammatory cell infiltration. Tracheal mucosal damage caused by ETT cuff is essentially a type of ischemia-reperfusion injury, stemming from an interruption in the respiratory chain that leads to an accumulation of reactive oxygen species (ROS), resulting in cellular pyroptosis under oxidative stress. Sustained oxidative stress contributes to the onset and progression of various diseases, with ROS production being a critical step in NLRP3-mediated pyroptosis (30–32). Our recent research has identified that NLRP3 activation-mediated pyroptosis of tracheal mucosal cells was a primary cause of ETT cuff-related mucosal damage (33). Therefore, in view of the activation of airway mucosal inflammation caused by ETT, reducing ROS is the key to prevent airway damage. Using reducing substances to neutralize ROS or developing new ETT cuff materials and nanocoatings to reduce inflammatory activation may be a new direction for airway protection. Our previous study also demonstrated that the natural reducing agent hydrogen (H₂) was effective in reducing airway inflammation.

This study has several limitations. Firstly, our findings are based on data from selected areas within Sichuan Province, China, and did not utilize a rigorous stratified random sampling method. Secondly, strict exclusion criteria were formulated in the retrospective analysis, and a large proportion of patients were excluded, which may have excluded some important groups for the results of this study. The excluded population may have caused imbalance of potential influencing factors in different groups. Further expansion of the sample size for the retrospective analysis may be necessary. Additionally, our conclusion that a 30 cmH₂O cuff pressure may be unsafe for patients undergoing prolonged ventilation stems from a retrospective study, which may be influenced by uncontrolled variables affecting result reliability and lacks long-term follow-up data. A rigorous prospective randomized controlled trial is needed to further validate these findings. Finally, the pathological results of this study were based on the animal model, and the animal model cannot fully simulate the human body. It is possible that the detection of human samples can further increase the reliability of the results and the basis for clinical application.

Our study discovered a concerning level of attention that anesthesiologists pay to cuff pressure. Clinical retrospective analysis and animal models have linked the currently established cuff pressure of 30 cmH₂O to airway mucosal damage in patients on prolonged mechanical ventilation. Considering these findings, it may be necessary to lower the safety threshold for cuff pressures and enhance educational efforts on cuff pressure management among anesthesiologists to reduce the risk of mucosal injury, however, the occurrence of reflux and aspiration should be prevented according to the actual situation.