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To assess the structural characteristics involved in the design of high-volume low-pressure endotracheal tube cuffs that are associated with fluid sealing effectiveness and to determine the extent of transmitted tracheal pressures upon cuff inflation.In vitro study.Pneumology laboratories.Eight high-volume low-pressure cuffs of cylindrical or tapered shape, made of polyvinylchloride or polyurethane, were studied. Cuffs were tested within a tracheal model, oriented 30° above horizontal to assess 1 hr leakage of oropharyngeal secretions simulant at cuff internal pressures of 15–30 cm H2O. The four best performing cuffs were evaluated for 24 hrs using an internal pressure of 30 cm H2O. The extent of transmitted tracheal wall pressure throughout the cuff–trachea contact area was determined using an internal pressure sensor within a tracheal model upon cuff inflation up to 30 cm H2O.Outer diameter, length, and compliance of each cuff were assessed. Multivariate regression analysis was performed to identify the main determinants of simulant leakage rate. The cuff–trachea contact area and the percentage of tracheal wall pressure measurements greater than 50 cm H2O were computed. Cuff design characteristics significantly differ among tubes. The cuffs made of polyurethane showed the best short- and long-term sealing efficacy. Nevertheless, in the multivariate analysis, the cuff outer diameter (n: 288, p = 0.003) and length (n: 288, p < 0.001), along with the internal pressure (n: 288, p < 0.001), were the only predictors of simulant leakage rate. The tapered cuffs showed the lowest tracheal wall contact area (n: 96, p < 0.001). The tracheal wall pressure distribution pattern was heterogeneous, and the percentage of high tracheal wall pressure significantly differs among the cuffs (n: 96, p < 0.001).The high-volume low-pressure cuffs’ outer diameter, length, material, and internal pressure are the main determinants of sealing efficacy. Despite internal pressure within the safe range, transmitted tracheal pressure is extremely heterogeneous and differs among cuffs, occasionally reaching localized, very high, unsafe levels.