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Original Research: Critical Care |

Endotracheal Tubes for Critically Ill PatientsEndotracheal Tube-Associated Tracheal Injury: An In Vivo Analysis of Associated Tracheal Injury, Mucociliary Clearance, and Sealing Efficacy FREE TO VIEW

Gianluigi Li Bassi, MD, PhD; Nestor Luque, MD; Joan Daniel Martí, PhD, RPT; Eli Aguilera Xiol, MSc; Marta Di Pasquale, MD; Valeria Giunta, MD; Talitha Comaru, PhD, RPT; Montserrat Rigol, DVM, PhD; Silvia Terraneo, MD; Francesca De Rosa, MD; Mariano Rinaudo, MD; Ernesto Crisafulli, MD, PhD, FCCP; Rogelio Cesar Peralta Lepe, MD; Carles Agusti, MD, PhD; Carmen Lucena, MD; Miguel Ferrer, MD, PhD; Laia Fernández, PhD; Antoni Torres, MD, PhD, FCCP
Author and Funding Information

From the Division of Animal Experimentation (Drs Li Bassi, Luque, Martí, Di Pasquale, Giunta, Comaru, Rigol, Terraneo, De Rosa, Rinaudo, Crisafulli, Peralta Lepe, Ferrer, Fernández, and Torres and Ms Aguilera Xiol), Department of Pulmonary and Critical Care Medicine, Thorax Institute, Hospital Clínic, Barcelona, Spain; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (Drs Li Bassi, Rigol, Ferrer, Fernández, and Torres), Barcelona, Spain; Centro de Investigación Biomedica En Red-Enfermedades Respiratorias (CIBERES) (Drs Li Bassi, Martí, Rigol, Ferrer, Fernández, and Torres and Ms Aguilera Xiol), Barcelona, Spain; University of Milan (Drs Di Pasquale, Giunta, Terraneo, and De Rosa), Milan, Italy; Division of Bronchoscopy (Drs Agusti and Lucena), Department of Pulmonary Medicine, Thorax Institute, Hospital Clínic, Barcelona, Spain; and University of Barcelona (Dr Torres), Barcelona, Spain.

CORRESPONDENCE TO: Antoni Torres, MD, PhD, FCCP, Department of Pulmonary and Critical Care Medicine, Hospital Clínic, Calle Villarroel 170, Esc 6/8 Planta 2, 08036 Barcelona, Spain; e-mail: atorres@clinic.ub.es


Drs Li Bassi and Luque contributed equally to this work.

FUNDING/SUPPORT: Support was provided by Covidien Ltd.

Part of this article has been presented in abstract form [De Rosa F, Li Bassi G, Martí JD, et al. Histological evaluation of the recovery of cuff-induced tracheal injury: assessment at 72 hours from extubation. Intens Care Med. 2013;39(suppl 2):0680; Li Bassi G, Marti JD, Aguilera Xiol E, et al. Effects of high-volume low-pressure cuff designs and materials on mucociliary clearance. Crit Care Med. 2012;40(12)(suppl 1):440; and Li Bassi G, Aguilera Xiol E, Marti JD, et al. Assessment of cuff-induced tracheal injury by commercially available endotracheal tubes. Crit Care Med. 2012;40(12 suppl 1):443].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(5):1327-1335. doi:10.1378/chest.14-1438
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BACKGROUND:  Improvements in the design of the endotracheal tube (ETT) have been achieved in recent years. We evaluated tracheal injury associated with ETTs with novel high-volume low-pressure (HVLP) cuffs and subglottic secretions aspiration (SSA) and the effects on mucociliary clearance (MCC).

METHODS:  Twenty-nine pigs were intubated with ETTs comprising cylindrical or tapered cuffs and made of polyvinylchloride (PVC) or polyurethane. In specific ETTs, SSA was performed every 2 h. Following 76 h of mechanical ventilation, pigs were weaned and extubated. Images of the tracheal wall were recorded before intubation, at extubation, and 24 and 96 h thereafter through a fluorescence bronchoscope. We calculated the red-to-green intensity ratio (R/G), an index of tracheal injury, and the green-plus-blue (G+B) intensity, an index of normalcy, of the most injured tracheal regions. MCC was assessed through fluoroscopic tracking of radiopaque markers. After 96 h from extubation, pigs were killed, and a pathologist scored injury.

RESULTS:  Cylindrical cuffs presented a smaller increase in R/G vs tapered cuffs (P = .011). Additionally, cuffs made of polyurethane produced a minor increase in R/G (P = .012) and less G+B intensity decline (P = .022) vs PVC cuffs. Particularly, a cuff made of polyurethane and with a smaller outer diameter outperformed all cuffs. SSA-related histologic injury ranged from cilia loss to subepithelial inflammation. MCC was 0.9 ± 1.8 and 0.4 ± 0.9 mm/min for polyurethane and PVC cuffs, respectively (P < .001).

CONCLUSIONS:  HVLP cuffs and SSA produce tracheal injury, and the recovery is incomplete up to 96 h following extubation. Small, cylindrical-shaped cuffs made of polyurethane cause less injury. MCC decline is reduced with polyurethane cuffs.

Figures in this Article

Several improvements in the design of the endotracheal tube (ETT) have been achieved in recent years.1 Critically ill patients are often intubated with ETTs comprising tapered2 or polyurethane cuffs.3 These novel cuffs have shown enhanced sealing effectiveness28 compared with standard high-volume low-pressure (HVLP) cuffs of cylindrical shape and made of polyvinylchloride (PVC). Additionally, some ETTs are designed for subglottic secretions aspiration (SSA). In two clinical studies,9,10 patients intubated with ETT comprising polyurethane cuffs were at lower risk of developing ventilator-associated pneumonia (VAP). Likewise, there is compelling evidence that SSA decreases the risk of VAP.11

Nevertheless, the safety of these novel ETTs has not been extensively evaluated. We have demonstrated7 that HVLP cuffs inflated at the clinically recommended pressure range might transmit high pressure against the trachea. In particular, we found that folds form along the cuff’s surface, and the tracheal mucosa adjacent to a fold could be subject to potentially harmful transmitted pressure. As for the safety of SSA, only a few studies have shown tracheal injury associated with SSA, particularly when few secretions are present within the subglottic region12 or when continuous aspiration is applied.13,14 Finally, inflation of the cuff impairs the mucociliary escalator.15 The effects of these novel cuffs on the mucociliary clearance (MCC) rate, however, is largely unknown. Thus, we designed this prospective randomized study to evaluate in tracheally intubated pigs the effects of commercially available HVLP cuffs on tracheal injury, MCC, and prevention of leakage across the cuff. Additionally, injury associated with intermittent SSA was assessed.

The institutional ethics committee approved the protocol. Animals were managed according to the guidelines for the use and care of laboratory animals.16 Further methodologic details are provided in e-Appendix 1.

Randomization and Animal Handling

Large White-Landrace pigs (37.3 ± 3.6 kg) were randomized to be intubated with one of the ETTs listed in Table 1 connected to a mechanical ventilator (SERVO-i; MAQUET Holding BV & Co KG) and ventilated as previously reported.17 Anesthesia was maintained through infusion of propofol and remifentanil. Gases were conditioned to 37°C with a heated humidifier (Hudson RCI Conchatherm III; Teleflex Incorporated). The internal ETT cuff pressure was maintained at 28 cm H2O through a mechanical device18 to optimize sealing efficacy7 while avoiding tracheal ischemia.1924 In ETTs with SSA, the patency of the suction lumen was tested every 2 h and secretions aspirated with a syringe. In case of resistance upon aspiration, 10 mL air was insufflated into the suction lumen, and aspiration was attempted one additional time only. Importantly, the cuff was deflated every 6 h and the ETT gently rotated to ensure that the evacuation port was directed toward the most-dependent tracheal regions. Following 76 h of mechanical ventilation, pigs were weaned, extubated, and housed with water and food ad libitum (e-Fig 1).

Table Graphic Jump Location
TABLE 1 ]  Endotracheal Tube Features

We studied commercially available endotracheal tubes with high-volume low-pressure cuffs most commonly used in critically ill patients. These tubes comprise cuffs made of PVC or polyurethane and with a cylindrical or tapered shape. Five of seven endotracheal tubes allowed aspiration of subglottic secretions. PVC = polyvinylchloride.

Tracheal Injury
Fluorescence Bronchoscopy:

At baseline, extubation, and 24 and 96 h thereafter, images of the tracheal region where the cuff was located were recorded through a fluorescence bronchoscope (Pentax SAFE-3000; Ricoh Imaging Deutschland GmbH). White-light and fluorescence pictures were concomitantly recorded. Upon laser activation, normal tracheal regions appeared bluish/greenish, whereas injured regions were darker and brownish.25 We calculated through image analysis software (ImageJ; National Institutes of Health) the red-to-green intensity ratio (R/G),26,27 an index of injury, and the green-plus-blue (G+B) intensity, an index of normalcy, of the most injured tracheal region (100 × 100 pixels). Thus, tracheal injury was expected to increase R/G and decrease G+B intensity values. To correct for intersubject fluorescence variability, all values were adjusted per baseline values as follows: ([current – baseline value] / baseline value) × 100, namely R/G and G+B intensity differentials, and reported as percentage. Upon imaging analysis, the observers were blinded to treatment allocation.

White-Light Bronchoscopy:

The white-light bronchoscopy pictures were scored by two bronchoscopists blinded to treatment allocation (Fig 1).

Figure Jump LinkFigure 1 –  Fluorescence and white-light bronchoscopy assessments at intubation, extubation, and 24 and 96 h thereafter per endotracheal tube type. The white-light bronchoscopy pictures were scored as follows: 0, no injury; 1, mild; 2, moderate; 3, severe hyperemia, edema, or discoloration without ulceration; 4, superficial ulceration; 5, deep ulceration of the mucous membrane; and 6, deep ulceration with exposed cartilage. We only report bronchoscopic still images of tracheal regions with the worst cuff-related injury. A, Ruschelit Safety Clear Plus. B, Hi-Lo Evac. C, SACETT. D, TaperGuard. E, Sheridan/HVT. F, KimVent* MICROCUFF*. G, SealGuard Evac.Grahic Jump Location
Histopathology:

After 96 h from extubation, the pigs were killed, and the length of the trachea adjacent to the cuff was measured. The worst histologic injury of the first and last tracheal rings in contact with the cuff and every other ring between these two segments were scored (0, no injury; 1, epithelial layer compression; 2, cilia loss; 3, epithelial denudation; 4, subepithelial/glandular inflammation; 5, perichondrium inflammation) by a pathologist (e-Fig 2) blinded to treatment allocation. Injury of the area adjacent to the SSA opening was also studied by gross examination and microscopy.

Mucociliary Clearance

Following 28 h of mechanical ventilation, MCC was measured through fluoroscopic tracking of radiopaque markers, as previously described.17,28

Cuff Leakage

At 52 and 73 h from intubation, animals were placed prone, the bed was oriented 30° above horizontal, and positive end-expiratory pressure was reduced to 0 cm H2O. We instilled 2 mL methylene blue and 3 mL phosphate buffer solution with 1.5 μL of 2.0-μm Invitrogen fluorescent microspheres (Thermo Fisher Scientific Inc) into the subglottic region. One hour from instillation, leakage was estimated by the presence of methylene blue and quantification of microspheres in tracheal secretions.29 We calculated the percentage of recovered microspheres per gram of tracheal secretions per the total amount of instilled microspheres (aspirated microspheres).29

Statistical Analysis

One-way analysis of variance or the Kruskal-Wallis test with post hoc Student t test or Wilcoxon-Mann-Whitney test with Bonferroni correction were used to analyze continuous variables. Repeated one-way analysis of variance, Friedman test with post hoc paired t test, and Wilcoxon signed rank test with Bonferroni correction were used to detect differences between paired measurements. Association of tracheal injury scores between raters was tested using the κ-statistic. Linear regression was used to assess association between parameters. A two-sided P < .05 was considered statistically significant. All analyses were performed using SAS 9.2 software (SAS Institute Inc).

Study Population

Four animals were included in each group; whereas five animals were intubated with the KimVent* MICROCUFF* ETT. Twenty-seven animals completed the study; two animals intubated with the KimVent* MICROCUFF* ETT were killed during weaning due to pneumonia and cardiac arrest.

Cuff-Related Injury: Fluorescence and White-Light Bronchoscopy

Figure 1 shows images of fluorescence and white-light bronchoscopy per ETT type. As shown in Figure 2A, cylindrical cuffs presented a smaller increase in R/G differentials vs tapered cuffs. Additionally, cuffs made of polyurethane produced a minor degree of injury (Fig 2B) and less deterioration of tracheal normalcy (Fig 3B) vs PVC cuffs. As for the comparison among ETTs, the R/G differential did not vary but did significantly increase upon extubation (15.2% ± 16.0%) and 24 h later (15.2% ± 15.4%) and then reverted to baseline values (3.4% ± 12.5%) after 96 h (P < .001, Friedman test) (Fig 2C). The G+B intensity differential changed significantly among ETTs (Fig 3C); in particular, the SACETT presented the greatest degree of injury (−43.2 ± 20.4%) and the KimVent* MICROCUFF* the least (−10.1 ± 21.8%).

Figure Jump LinkFigure 2 –  R/G differential, which is an index of tracheal injury, vs time of intubation (%). In each box plot, the median value of the R/G differential is indicated by the center horizontal line, the mean by the dashed line, and the 25th and 75th percentiles by the lower and upper box horizontal lines. Whiskers above and below the box indicate the 90th and 10th percentiles. Dots above and below whiskers show the 95th and fifth percentiles. A, Cylindrical cuffs presented a smaller increase in R/G differentials vs tapered cuffs (t test). B, Additionally, cuffs made of polyurethane produced a minor increase in R/G differentials compared with polyvinylchloride cuffs (Wilcoxon-Mann-Whitney test). C, The R/G differential did not significantly vary among endotracheal tube types (one-way analysis of variance). The R/G differential was higher upon extubation and 24 h thereafter and decreased after 96 h (P < .001, Friedman test). aP < .001 vs 24 and 96 h after extubation (Wilcoxon sign rank test with Bonferroni correction). R/G = red-to-green intensity ratio.Grahic Jump Location
Figure Jump LinkFigure 3 –  G+B intensity differential, which is an index of tracheal normalcy, vs time of intubation (%). In each box plot, the median value of the G+B intensity differential is indicated by the center horizontal line, the mean by the dashed line, and the 25th and 75th percentiles by the lower and upper box horizontal lines. Whiskers above and below the box indicate the 90th and 10th percentiles. Dots above and below whiskers show the 95th and fifth percentiles. A, Cuff shape did not affect the G+B intensity differential (t test). B, Cuffs made of polyurethane produced less G+B intensity differential decline vs polyvinylchloride cuffs (Wilcoxon-Mann-Whitney test). C, The G+B intensity differential was different among endotracheal tube types (P = .047, Kruskal-Wallis test). Additionally, the G+B intensity differential differed throughout the time of the study (P < .001, one-way repeated-measures analysis of variance). aP < .001 vs 24 and 96 h after extubation (repeated-measures t test with Bonferroni correction). G+B = green plus blue.Grahic Jump Location

As for the white-light bronchoscopy, the κ-score indicated substantial agreement (weighted κ = 0.69; 95% CI, 0.61-0.76; P < .001) between observers. The white-light bronchoscopy score did not differ between cuffs of cylindrical or tapered shape (P = .513, Wilcoxon-Mann-Whitney test) and polyurethane or PVC cuffs (P = .198, Wilcoxon-Mann-Whitney test). Likewise, there were no differences among ETTs (P = .453, Kruskal-Wallis test); whereas, the white-light bronchoscopy score was 2.2 ± 1.1, 1.4 ± 1.3, and 0.3 ± 0.5 at extubation, 24 h, and 96 h, respectively (P < .001, Friedman test). The R/G differential was linearly correlated with the white-light bronchoscopy score (r2 = 0.14, P < .001); likewise, the G+B intensity decline was associated with the bronchoscopy score (r2 = 0.19, P < .001).

Cuff-Related Injury: Gross Examination and Histologic Assessment

Data are reported in Table 2 and e-Figure 3. The length of the excised trachea differed among groups, yet it did not vary between cuffs of different shapes (P = .071, t test) or made of different materials (P = .105, t test). The shortest excised trachea was 2.6 ± 0.4 cm in the SACETT group. The histologic injury score of the cylindrical and tapered cuffs was 2.6 ± 0.7 and 2.7 ± 0.6, respectively (P = .802, Wilcoxon-Mann-Whitney test), whereas in polyurethane and PVC cuffs, it was 2.7 ± 0.6 and 2.6 ± 0.7, respectively (P = .987, Wilcoxon-Mann-Whitney test). No significant differences were found among groups. Importantly, at 96 h from extubation, the injury recovery was incomplete but only ranged from compression of the epithelial layer to epithelial loss.

Table Graphic Jump Location
TABLE 2 ]  Postmortem Assessment of Tracheal Injury

Data are presented as mean ± SD unless otherwise indicated. The length of the excised trachea, which was in contact with the cuff during the study, varied among endotracheal tubes because the cuffs were of different lengths. The first and last rings of the excised trachea and every other ring between these two segments were analyzed. As a result, the number of analyzed rings also differed among endotracheal tubes. NA = not available; SSA = subglottic secretions aspiration.

a 

P < .05.

b 

Kruskal-Wallis test.

c 

One-way analysis of variance.

SSA-Related Injury

The volume of subglottic secretions per aspiration varied among tubes (Fig 4). Additionally, aspirated secretions linearly increased with the study days (slope, 0.052; y intercept, 0.157; r2 = 0.37; P < .001). Injury caused by SSA was found in 12.2% of the bronchoscopic assessments (Fig 5), whereas upon autopsy, 25% of the tracheas presented gross findings of mucosal injury. Histologic assessment was carried out in 2.0 ± 0.7 tracheal rings in proximity with the evacuation port. Histologic tracheal injury ranged from cilia loss to subepithelial/glandular inflammation and did not differ among groups (Table 2).

Figure Jump LinkFigure 4 –  Aspirated subglottic secretions per ETT type. In each box plot, the median value of aspirated subglottic secretions is indicated by the center horizontal line, the mean by the dashed line, and the 25th and 75th percentiles by the lower and upper box horizontal lines. Whiskers above and below the box indicate the 90th and 10th percentiles. Dots above and below whiskers show the 95th and fifth percentiles. The volume of subglottic secretions per aspiration varied among tubes (Hi-Lo Evac, 0.12 ± 0.19 mL; SACETT, 0.21 ± 0.33 mL; SealGuard Evac, 0.34 ± 0.53 mL; TaperGuard, 0.26 ± 0.30 mL; P = .013, Kruskal-Wallis test). ETT = endotracheal tube.Grahic Jump Location
Figure Jump LinkFigure 5 –  A-D, Upon autopsy, tracheal mucosal erythema and edema in proximity of the evacuation lumen was observed in one animal (A) and mucosal erosion in three animals (B-D). The same mucosal injury was often observed during bronchoscopy (B and C, top pictures). A, SACETT. B, SACETT. C, TaperGuard. D, Hi-Lo Evac. The arrows highlight the injured tracheal regions.Grahic Jump Location
Mucociliary Clearance

Overall, 138 disks were tracked (4.9 ± 2.2 disks per ETT type; P = .495). As shown in Figure 6C, MCC rates differed among groups. Cuff material significantly affected MCC rate (P < .001, Wilcoxon-Mann-Whitney test) (Fig 6B). Conversely, cuff shape did not affect MCC rate (P = .129, Wilcoxon-Mann-Whitney test) (Fig 6A). In particular, the KimVent* MICROCUFF* was associated with the fastest rates (1.1 ± 2.1 mm/min, 0-9.7 mm/min); whereas the Ruschelit Safety Clear Plus presented the slowest rate (0.2 ± 0.3 mm/min, 0-1.1 mm/min).

Figure Jump LinkFigure 6 –  Mucociliary clearance by ETT type. In each box plot, the median value of disk movement is indicated by the center horizontal line, the mean by the dashed line, and the 25th and 75th percentiles by the lower and upper box horizontal lines. Whiskers above and below the box indicate the 90th and 10th percentiles. Dots above and below whiskers show the 95th and fifth percentiles. A, Cuff shape did not affect the mucociliary clearance rate (Wilcoxon-Mann-Whitney test). B, Cuffs made of polyurethane were associated with faster mucociliary clearance velocity compared with the polyvinylchloride cuffs (Wilcoxon-Mann-Whitney test). C, Mucociliary movements differed among ETT types (P < .001, Kruskal-Wallis test). aP ≤ .008 vs Ruschelit Safety Clear Plus and Hi-Lo Evac; bP = .002 vs Ruschelit Safety Clear Plus, Hi-Lo Evac, and SACETT (Wilcoxon-Mann-Whitney test with Bonferroni correction). See Figure 4 legend for expansion of abbreviation.Grahic Jump Location
Leakage Across the ETT Cuff

Methylene blue dye was never found in aspirated secretions. Aspirated microspheres did not differ between cuffs of different material (P = .545, Wilcoxon-Mann-Whitney test) or shape (P = .222, Wilcoxon-Mann-Whitney test). However, as shown in Figure 7, the percentage of aspirated microspheres varied among ETTs (P = .006, Kruskal-Wallis test). The TaperGuard showed the best sealing performance (aspirated microspheres, 0.008 ± 0.004%), whereas the SACETT showed the worst (0.356 ± 0.650%).

Figure Jump LinkFigure 7 –  Aspirated microspheres (percentage of recovered microspheres per gram of tracheal secretions of the total amount of instilled microspheres) per ETT type. Percentage of aspirated microspheres differed among groups (P = .006, Kruskal-Wallis test). See Figure 4 legend for expansion of abbreviation.Grahic Jump Location

We found that commercially available HVLP cuffs cause tracheal injury, and the recovery is incomplete up to 96 h following extubation. Of note, the KimVent* MICROCUFF*, which is a cylindrical-shaped cuff of small outer diameter3,7 and made of polyurethane, causes less injury. Additionally, the MCC rate is less impaired with polyurethane cuffs. Finally, intermittent SSA increases the risk of tracheal injury, and subepithelial/glandular inflammation may be present even at 96 h following extubation.

Cuff-Related Tracheal Injury

HVLP cuffs seal the trachea without being stretched; consequently, their internal pressure estimates the pressure transmitted against the mucosa.30,31 Based on fluorescence bronchoscopy assessment, we found that cuffs made of polyurethane and with a cylindrical shape caused less injury. In particular, as shown in Figures 2 and 3, the KimVent* MICROCUFF* and the SACETT were the best and worst outliers, respectively, suggesting that specific features in the design of these superior-performing and underperforming cuffs could play a critical role in the development of tracheal injury. Indeed, we previously demonstrated7 that the pressure transmitted by HVLP cuffs might be higher than expected, particularly using very large cuffs such as the SACETT because this cuff’s surface becomes highly irregular due to the formation of folds. Conversely, the KimVent* MICROCUFF* has a thickness of approximately 5 μm and a very small outer diameter3,7; thus, upon inflation, fewer thin folds are formed, and the cuff’s surface is more homogeneous. However, the tapered cuffs presented smaller contact areas compared with the cylindrical ones (Table 2). This factor should be taken into account because it could limit the extent of tracheal injury.

Fluorescence bronchoscopy has been used for the diagnosis of early stage airway cancers.32,33 To our knowledge, this report is the first to use this technique to quantify cuff-related tracheal injury. When the trachea is excited by blue light (408 nm), chromophore elements (ie, tryptophan, collagen, elastin) emit fluorescent light in the greenish/bluish spectra. Autofluorescence is diminished in pathologic states, such as inflammation and injury due to thickened epithelium, reduced density of chromophore elements, and hyperemic mucosa; consequently, the bronchoscope light is attenuated. Additionally, the red surface completely absorbs blue and green light. Based on these concepts, we calculated the R/G, as previously reported,26,27 and the G+B intensity to quantify the severity of injury. As shown by the association of these parameters with the white-light bronchoscopy scores, fluorescence bronchoscopy could be a potential tool to quantify in vivo tracheal injury.

SSA-Related Tracheal Injury

In line with previous investigations,1214,34 we found important injury associated with SSA, irrespective of our attempts to avoid mucosal invagination, through intermittent aspiration and hasty interruption of aspiration if resistance was encountered. A potential explanation for these results is that few secretions were present upon aspiration, particularly during the first days of ventilation. This may have been related to the use of the lateral Trendelenburg position. Another potential reason is related to the design of the evacuation port. Ideally, the suction port should be as close as possible to the cuff to allow, upon cuff inflation, a safe distance between the port and mucosa35 and to avoid mucosal invagination. Unfortunately, in all tested ETTs, the suction port was not in full proximity of the cuff.

Mucociliary Clearance

Previous studies have shown that the MCC rate decreases following intubation.15,28,36 In healthy pigs, the MCC rate ranges between 7 and 15 mm/min.37 Thus, in line with prior findings,15,28,36 the present study showed MCC to be highly depressed. Sackner et al15 suggested the activation of a neurogenic reflex arc upon cuff inflation, but the exact mechanism for this impairment is still unknown. In this context, we found that polyurethane cuffs, in particular the KimVent* MICROCUFF*, caused less tracheal injury and impairment in MCC velocity.

Tracheal Sealing Efficacy

Interestingly, according to our previous in vitro findings,7 we found that the sealing efficacy of the SACETT was highly limited. The SACETT is a tapered cuff with a very large outer diameter, and we first hypothesized that the sealing circumference of a large tapered cuff is inefficient. The current study supports this theory; indeed, the conical-shaped TaperGuard cuff, which has a very small outer diameter, performed better than the SACETT.

Clinical Implications

In past decades, postintubation complications have drastically reduced with HVLP cuffs.38,39 Nevertheless, Touat et al34 found tracheal ischemic lesions in 83% of critically ill patients intubated with these cuffs. These data highlight that prevention of cuff-related tracheal injury often is overlooked in clinical practice. The present study also calls attention to the severe reduction in MCC rate during tracheal intubation. The pathophysiologic mechanisms underlying this impairment should be identified to develop new preventive and therapeutic strategies. As for SSA, undoubtedly this technology plays an important role in the prevention of VAP.11 Nonetheless, the design of these ETTs should be further improved to ensure safety.

This study has a few limitations. First, the small sample size may have limited the power of the observations. Second, the study animals were healthy and ventilated for a limited number of days; thus, we speculate that a long-term use of these cuffs in critically ill patients would cause even greater tracheal damage, and further laboratory and clinical studies should corroborate these assumptions. Third, throughout the study, the ETT depth of insertion was strictly monitored and the internal cuff pressure kept at 28 cm H2O. Conversely, in clinical settings, position of the ETT40 and internal cuff pressure may vary41,42; consequently, we may have underestimated the extent and severity of tracheal injury.

We found that HVLP cuffs cause tracheal injury and that the KimVent* MICROCUFF*, which is a small cylindrical cuff made of polyurethane, reduces this risk. Additionally, HVLP cuffs made of PVC impair MCC, and the sealing efficacy of very large tapered PVC cuffs is highly limited. Finally, intermittent SSA frequently causes tracheal lesions, and recovery is incomplete up to 96 h from extubation.

Author contributions: G. L. B. and N. L. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. G. L. B., N. L., M. F., and A. T. contributed to study concept and design; G. L. B., N. L., J. D. M., E. A. X., M. D. P., V. G., T. C., M. Rigol, S. T., F. D. R., M. Rinaudo, E. C., R. C. P. L., and L. F. contributed to acquisition of data; G. L. B., N. L., J. D. M., E. A. X., M. D. P., V. G., T. C., F. D. R., C. A., and C. L. contributed to analysis and interpretation of data; G. L. B. and N. L. contributed to drafting of the manuscript; J. D. M., E. A. X., M. D. P., V. G., T. C., M. Rigol, S. T., F. D. R., M. Rinaudo, E. C., R. C. P. L., C. A., C. L., M. F., L. F., and A. T. contributed critical revision of the manuscript for important intellectual content; G. L. B. contributed statistical analysis; and L. F. contributed administrative, technical, or material support.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Li Bassi received research grants through his affiliated institutions from Covidien Ltd. Dr Torres received research grants through his affiliated institutions and consulting fees from Covidien Ltd. Drs Luque, Martí, Di Pasquale, Giunta, Comaru, Rigol, Terraneo, De Rosa, Rinaudo, Crisafulli, Peralta Lepe, Agusti, Lucena, Ferrer, and Fernández and Ms Aguilera Xiol have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: Covidien Ltd provided some insights for the design of the study. Covidien Ltd did not have any role in the conduction of the study, acquisition of the data, interpretation of the results or drafting of the manuscript.

Other contributions: We thank Marco Carbonara, MD, for his support with the fluorescence bronchoscopy figures and Otavio Tavares Ranzani, MD, for critical review. Finally, we acknowledge Ulf Borg, MD, for his insightful suggestions in the design of the study.

Additional information: The e-Appendix and e-Figures can be found in the Supplemental Materials section of the online article.

ETT

endotracheal tube

G+B

green plus blue

HVLP

high volume low pressure

MCC

mucociliary clearance

PVC

polyvinylchloride

R/G

red-to-green intensity ratio

SSA

subglottic secretions aspiration

VAP

ventilator-associated pneumonia

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Ouanes I, Lyazidi A, Danin PE, et al. Mechanical influences on fluid leakage past the tracheal tube cuff in a benchtop model. Intensive Care Med. 2011;37(4):695-700. [CrossRef] [PubMed]
 
Zanella A, Scaravilli V, Isgrò S, et al. Fluid leakage across tracheal tube cuff, effect of different cuff material, shape, and positive expiratory pressure: a bench-top study. Intensive Care Med. 2011;37(2):343-347. [CrossRef] [PubMed]
 
Pitts R, Fisher D, Sulemanji D, Kratohvil J, Jiang Y, Kacmarek R. Variables affecting leakage past endotracheal tube cuffs: a bench study. Intensive Care Med. 2010;36(12):2066-2073. [CrossRef] [PubMed]
 
Li Bassi G, Ranzani OT, Marti JD, et al. An in vitro study to assess determinant features associated with fluid sealing in the design of endotracheal tube cuffs and exerted tracheal pressures. Crit Care Med. 2013;41(2):518-526. [CrossRef] [PubMed]
 
Young PJ, Ridley SA, Downward G. Evaluation of a new design of tracheal tube cuff to prevent leakage of fluid to the lungs. Br J Anaesth. 1998;80(6):796-799. [CrossRef] [PubMed]
 
Lorente L, Lecuona M, Jiménez A, Mora ML, Sierra A. Influence of an endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia. Am J Respir Crit Care Med. 2007;176(11):1079-1083. [CrossRef] [PubMed]
 
Poelaert J, Depuydt P, De Wolf A, Van de Velde S, Herck I, Blot S. Polyurethane cuffed endotracheal tubes to prevent early postoperative pneumonia after cardiac surgery: a pilot study. J Thorac Cardiovasc Surg. 2008;135(4):771-776. [CrossRef] [PubMed]
 
Muscedere J, Rewa O, McKechnie K, Jiang X, Laporta D, Heyland DK. Subglottic secretion drainage for the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care Med. 2011;39(8):1985-1991. [CrossRef] [PubMed]
 
Suys E, Nieboer K, Stiers W, De Regt J, Huyghens L, Spapen H. Intermittent subglottic secretion drainage may cause tracheal damage in patients with few oropharyngeal secretions. Intensive Crit Care Nurs. 2013;29(6):317-320. [CrossRef] [PubMed]
 
Berra L, De Marchi L, Panigada M, Yu ZX, Baccarelli A, Kolobow T. Evaluation of continuous aspiration of subglottic secretion in an in vivo study. Crit Care Med. 2004;32(10):2071-2078. [CrossRef] [PubMed]
 
Harvey RC, Miller P, Lee JA, Bowton DL, MacGregor DA. Potential mucosal injury related to continuous aspiration of subglottic secretion device. Anesthesiology. 2007;107(4):666-669. [CrossRef] [PubMed]
 
Sackner MA, Hirsch J, Epstein S. Effect of cuffed endotracheal tubes on tracheal mucous velocity. Chest. 1975;68(6):774-777. [CrossRef] [PubMed]
 
Committee for the Update of the Guide for the Care and Use of Laboratory Animals; Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals.8th ed. Washington, DC: National Research Council of the National Academies; 2011. [PubMed] [PubMed]
 
Li Bassi G, Saucedo L, Marti JD, et al. Effects of duty cycle and positive end-expiratory pressure on mucus clearance during mechanical ventilation*. Crit Care Med. 2012;40(3):895-902. [CrossRef] [PubMed]
 
Farré R, Rotger M, Ferre M, Torres A, Navajas D. Automatic regulation of the cuff pressure in endotracheally-intubated patients. Eur Respir J. 2002;20(4):1010-1013. [CrossRef] [PubMed]
 
Stenqvist O, Bagge U. Cuff pressure and microvascular occlusion in the tracheal mucosa. An intravital microscopic study in the rabbit. Acta Otolaryngol. 1979;88(5-6):451-454. [CrossRef] [PubMed]
 
Nordin U, Lindholm CE, Wolgast M. Blood flow in the rabbit tracheal mucosa under normal conditions and under the influence of tracheal intubation. Acta Anaesthesiol Scand. 1977;21(2):81-94. [CrossRef] [PubMed]
 
Nordin U. The trachea and cuff-induced tracheal injury. An experimental study on causative factors and prevention. Acta Otolaryngol Suppl. 1977;345:1-71. [PubMed]
 
Nordin U, Lindholm CE. The vessels of the rabbit trachea and ischemia caused by cuff pressure. Arch Otorhinolaryngol. 1977;215(1):11-24. [CrossRef] [PubMed]
 
Dobrin P, Canfield T. Cuffed endotracheal tubes: mucosal pressures and tracheal wall blood flow. Am J Surg. 1977;133(5):562-568. [CrossRef] [PubMed]
 
Seegobin RD, van Hasselt GL. Endotracheal cuff pressure and tracheal mucosal blood flow: endoscopic study of effects of four large volume cuffs. Br Med J (Clin Res Ed). 1984;288(6422):965-968. [CrossRef] [PubMed]
 
Gabrecht T, Lovisa B, van den Bergh H, Wagnières G. Autofluorescence bronchoscopy: quantification of inter-patient variations of fluorescence intensity. Lasers Med Sci. 2009;24(1):45-51. [CrossRef] [PubMed]
 
Lee P, van den Berg RM, Lam S, et al. Color fluorescence ratio for detection of bronchial dysplasia and carcinoma in situ. Clin Cancer Res. 2009;15(14):4700-4705. [CrossRef] [PubMed]
 
Nakanishi K, Ohsaki Y, Kurihara M, et al. Color auto-fluorescence from cancer lesions: improved detection of central type lung cancer. Lung Cancer. 2007;58(2):214-219. [CrossRef] [PubMed]
 
Li Bassi G, Zanella A, Cressoni M, Stylianou M, Kolobow T. Following tracheal intubation, mucus flow is reversed in the semirecumbent position: possible role in the pathogenesis of ventilator-associated pneumonia. Crit Care Med. 2008;36(2):518-525. [CrossRef] [PubMed]
 
Li Bassi G, Marti JD, Saucedo L, et al. Gravity predominates over ventilatory pattern in the prevention of ventilator-associated pneumonia. Crit Care Med. 2014;42(9):e620-e627. [CrossRef] [PubMed]
 
Carroll RG. Evaluation of tracheal tube cuff designs. Crit Care Med. 1973;1(1):45-46. [CrossRef] [PubMed]
 
Carroll RG, Grenvik A. Proper use of large diameter, large residual volume cuffs. Crit Care Med. 1973;1(3):153-154. [CrossRef] [PubMed]
 
Chen W, Gao X, Tian Q, Chen L. A comparison of autofluorescence bronchoscopy and white light bronchoscopy in detection of lung cancer and preneoplastic lesions: a meta-analysis. Lung Cancer. 2011;73(2):183-188. [CrossRef] [PubMed]
 
Sun J, Garfield DH, Lam B, et al. The value of autofluorescence bronchoscopy combined with white light bronchoscopy compared with white light alone in the diagnosis of intraepithelial neoplasia and invasive lung cancer: a meta-analysis. J Thorac Oncol. 2011;6(8):1336-1344. [CrossRef] [PubMed]
 
Touat L, Fournier C, Ramon P, Salleron J, Durocher A, Nseir S. Intubation-related tracheal ischemic lesions: incidence, risk factors, and outcome. Intensive Care Med. 2013;39(4):575-582. [CrossRef] [PubMed]
 
Diaz E, Rodríguez AH, Rello J. Ventilator-associated pneumonia: issues related to the artificial airway. Respir Care. 2005;50(7):900-906. [PubMed]
 
Trawöger R, Kolobow T, Cereda M, Sparacino ME. Tracheal mucus velocity remains normal in healthy sheep intubated with a new endotracheal tube with a novel laryngeal seal. Anesthesiology. 1997;86(5):1140-1144. [CrossRef] [PubMed]
 
Hoegger MJ, Awadalla M, Namati E, et al. Assessing mucociliary transport of single particles in vivo shows variable speed and preference for the ventral trachea in newborn pigs. Proc Natl Acad Sci U S A. 2014;111(6):2355-2360. [CrossRef] [PubMed]
 
Honeybourne D, Costello JC, Barham C. Tracheal damage after endotracheal intubation: comparison of two types of endotracheal tubes. Thorax. 1982;37(7):500-502. [CrossRef] [PubMed]
 
Arola MK, Anttinen J. Post-mortem findings of tracheal injury after cuffed intubation and tracheostomy. A clinical and histopathological study. Acta Anaesthesiol Scand. 1979;23(1):57-68. [CrossRef] [PubMed]
 
Minonishi T, Kinoshita H, Hirayama M, et al. The supine-to-prone position change induces modification of endotracheal tube cuff pressure accompanied by tube displacement. J Clin Anesth. 2013;25(1):28-31. [CrossRef] [PubMed]
 
Nseir S, Zerimech F, Fournier C, et al. Continuous control of tracheal cuff pressure and microaspiration of gastric contents in critically ill patients. Am J Respir Crit Care Med. 2011;184(9):1041-1047. [CrossRef] [PubMed]
 
Valencia M, Ferrer M, Farre R, et al. Automatic control of tracheal tube cuff pressure in ventilated patients in semirecumbent position: a randomized trial. Crit Care Med. 2007;35(6):1543-1549. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Fluorescence and white-light bronchoscopy assessments at intubation, extubation, and 24 and 96 h thereafter per endotracheal tube type. The white-light bronchoscopy pictures were scored as follows: 0, no injury; 1, mild; 2, moderate; 3, severe hyperemia, edema, or discoloration without ulceration; 4, superficial ulceration; 5, deep ulceration of the mucous membrane; and 6, deep ulceration with exposed cartilage. We only report bronchoscopic still images of tracheal regions with the worst cuff-related injury. A, Ruschelit Safety Clear Plus. B, Hi-Lo Evac. C, SACETT. D, TaperGuard. E, Sheridan/HVT. F, KimVent* MICROCUFF*. G, SealGuard Evac.Grahic Jump Location
Figure Jump LinkFigure 2 –  R/G differential, which is an index of tracheal injury, vs time of intubation (%). In each box plot, the median value of the R/G differential is indicated by the center horizontal line, the mean by the dashed line, and the 25th and 75th percentiles by the lower and upper box horizontal lines. Whiskers above and below the box indicate the 90th and 10th percentiles. Dots above and below whiskers show the 95th and fifth percentiles. A, Cylindrical cuffs presented a smaller increase in R/G differentials vs tapered cuffs (t test). B, Additionally, cuffs made of polyurethane produced a minor increase in R/G differentials compared with polyvinylchloride cuffs (Wilcoxon-Mann-Whitney test). C, The R/G differential did not significantly vary among endotracheal tube types (one-way analysis of variance). The R/G differential was higher upon extubation and 24 h thereafter and decreased after 96 h (P < .001, Friedman test). aP < .001 vs 24 and 96 h after extubation (Wilcoxon sign rank test with Bonferroni correction). R/G = red-to-green intensity ratio.Grahic Jump Location
Figure Jump LinkFigure 3 –  G+B intensity differential, which is an index of tracheal normalcy, vs time of intubation (%). In each box plot, the median value of the G+B intensity differential is indicated by the center horizontal line, the mean by the dashed line, and the 25th and 75th percentiles by the lower and upper box horizontal lines. Whiskers above and below the box indicate the 90th and 10th percentiles. Dots above and below whiskers show the 95th and fifth percentiles. A, Cuff shape did not affect the G+B intensity differential (t test). B, Cuffs made of polyurethane produced less G+B intensity differential decline vs polyvinylchloride cuffs (Wilcoxon-Mann-Whitney test). C, The G+B intensity differential was different among endotracheal tube types (P = .047, Kruskal-Wallis test). Additionally, the G+B intensity differential differed throughout the time of the study (P < .001, one-way repeated-measures analysis of variance). aP < .001 vs 24 and 96 h after extubation (repeated-measures t test with Bonferroni correction). G+B = green plus blue.Grahic Jump Location
Figure Jump LinkFigure 4 –  Aspirated subglottic secretions per ETT type. In each box plot, the median value of aspirated subglottic secretions is indicated by the center horizontal line, the mean by the dashed line, and the 25th and 75th percentiles by the lower and upper box horizontal lines. Whiskers above and below the box indicate the 90th and 10th percentiles. Dots above and below whiskers show the 95th and fifth percentiles. The volume of subglottic secretions per aspiration varied among tubes (Hi-Lo Evac, 0.12 ± 0.19 mL; SACETT, 0.21 ± 0.33 mL; SealGuard Evac, 0.34 ± 0.53 mL; TaperGuard, 0.26 ± 0.30 mL; P = .013, Kruskal-Wallis test). ETT = endotracheal tube.Grahic Jump Location
Figure Jump LinkFigure 5 –  A-D, Upon autopsy, tracheal mucosal erythema and edema in proximity of the evacuation lumen was observed in one animal (A) and mucosal erosion in three animals (B-D). The same mucosal injury was often observed during bronchoscopy (B and C, top pictures). A, SACETT. B, SACETT. C, TaperGuard. D, Hi-Lo Evac. The arrows highlight the injured tracheal regions.Grahic Jump Location
Figure Jump LinkFigure 6 –  Mucociliary clearance by ETT type. In each box plot, the median value of disk movement is indicated by the center horizontal line, the mean by the dashed line, and the 25th and 75th percentiles by the lower and upper box horizontal lines. Whiskers above and below the box indicate the 90th and 10th percentiles. Dots above and below whiskers show the 95th and fifth percentiles. A, Cuff shape did not affect the mucociliary clearance rate (Wilcoxon-Mann-Whitney test). B, Cuffs made of polyurethane were associated with faster mucociliary clearance velocity compared with the polyvinylchloride cuffs (Wilcoxon-Mann-Whitney test). C, Mucociliary movements differed among ETT types (P < .001, Kruskal-Wallis test). aP ≤ .008 vs Ruschelit Safety Clear Plus and Hi-Lo Evac; bP = .002 vs Ruschelit Safety Clear Plus, Hi-Lo Evac, and SACETT (Wilcoxon-Mann-Whitney test with Bonferroni correction). See Figure 4 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 7 –  Aspirated microspheres (percentage of recovered microspheres per gram of tracheal secretions of the total amount of instilled microspheres) per ETT type. Percentage of aspirated microspheres differed among groups (P = .006, Kruskal-Wallis test). See Figure 4 legend for expansion of abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Endotracheal Tube Features

We studied commercially available endotracheal tubes with high-volume low-pressure cuffs most commonly used in critically ill patients. These tubes comprise cuffs made of PVC or polyurethane and with a cylindrical or tapered shape. Five of seven endotracheal tubes allowed aspiration of subglottic secretions. PVC = polyvinylchloride.

Table Graphic Jump Location
TABLE 2 ]  Postmortem Assessment of Tracheal Injury

Data are presented as mean ± SD unless otherwise indicated. The length of the excised trachea, which was in contact with the cuff during the study, varied among endotracheal tubes because the cuffs were of different lengths. The first and last rings of the excised trachea and every other ring between these two segments were analyzed. As a result, the number of analyzed rings also differed among endotracheal tubes. NA = not available; SSA = subglottic secretions aspiration.

a 

P < .05.

b 

Kruskal-Wallis test.

c 

One-way analysis of variance.

References

Haas CF, Eakin RM, Konkle MA, Blank R. Endotracheal tubes: old and new. Respir Care. 2014;59(6):933-952. [CrossRef] [PubMed]
 
Young PJ, Blunt MC. Improving the shape and compliance characteristics of a high-volume, low-pressure cuff improves tracheal seal. Br J Anaesth. 1999;83(6):887-889. [CrossRef] [PubMed]
 
Dullenkopf A, Gerber A, Weiss M. Fluid leakage past tracheal tube cuffs: evaluation of the new Microcuff endotracheal tube. Intensive Care Med. 2003;29(10):1849-1853. [CrossRef] [PubMed]
 
Ouanes I, Lyazidi A, Danin PE, et al. Mechanical influences on fluid leakage past the tracheal tube cuff in a benchtop model. Intensive Care Med. 2011;37(4):695-700. [CrossRef] [PubMed]
 
Zanella A, Scaravilli V, Isgrò S, et al. Fluid leakage across tracheal tube cuff, effect of different cuff material, shape, and positive expiratory pressure: a bench-top study. Intensive Care Med. 2011;37(2):343-347. [CrossRef] [PubMed]
 
Pitts R, Fisher D, Sulemanji D, Kratohvil J, Jiang Y, Kacmarek R. Variables affecting leakage past endotracheal tube cuffs: a bench study. Intensive Care Med. 2010;36(12):2066-2073. [CrossRef] [PubMed]
 
Li Bassi G, Ranzani OT, Marti JD, et al. An in vitro study to assess determinant features associated with fluid sealing in the design of endotracheal tube cuffs and exerted tracheal pressures. Crit Care Med. 2013;41(2):518-526. [CrossRef] [PubMed]
 
Young PJ, Ridley SA, Downward G. Evaluation of a new design of tracheal tube cuff to prevent leakage of fluid to the lungs. Br J Anaesth. 1998;80(6):796-799. [CrossRef] [PubMed]
 
Lorente L, Lecuona M, Jiménez A, Mora ML, Sierra A. Influence of an endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia. Am J Respir Crit Care Med. 2007;176(11):1079-1083. [CrossRef] [PubMed]
 
Poelaert J, Depuydt P, De Wolf A, Van de Velde S, Herck I, Blot S. Polyurethane cuffed endotracheal tubes to prevent early postoperative pneumonia after cardiac surgery: a pilot study. J Thorac Cardiovasc Surg. 2008;135(4):771-776. [CrossRef] [PubMed]
 
Muscedere J, Rewa O, McKechnie K, Jiang X, Laporta D, Heyland DK. Subglottic secretion drainage for the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care Med. 2011;39(8):1985-1991. [CrossRef] [PubMed]
 
Suys E, Nieboer K, Stiers W, De Regt J, Huyghens L, Spapen H. Intermittent subglottic secretion drainage may cause tracheal damage in patients with few oropharyngeal secretions. Intensive Crit Care Nurs. 2013;29(6):317-320. [CrossRef] [PubMed]
 
Berra L, De Marchi L, Panigada M, Yu ZX, Baccarelli A, Kolobow T. Evaluation of continuous aspiration of subglottic secretion in an in vivo study. Crit Care Med. 2004;32(10):2071-2078. [CrossRef] [PubMed]
 
Harvey RC, Miller P, Lee JA, Bowton DL, MacGregor DA. Potential mucosal injury related to continuous aspiration of subglottic secretion device. Anesthesiology. 2007;107(4):666-669. [CrossRef] [PubMed]
 
Sackner MA, Hirsch J, Epstein S. Effect of cuffed endotracheal tubes on tracheal mucous velocity. Chest. 1975;68(6):774-777. [CrossRef] [PubMed]
 
Committee for the Update of the Guide for the Care and Use of Laboratory Animals; Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals.8th ed. Washington, DC: National Research Council of the National Academies; 2011. [PubMed] [PubMed]
 
Li Bassi G, Saucedo L, Marti JD, et al. Effects of duty cycle and positive end-expiratory pressure on mucus clearance during mechanical ventilation*. Crit Care Med. 2012;40(3):895-902. [CrossRef] [PubMed]
 
Farré R, Rotger M, Ferre M, Torres A, Navajas D. Automatic regulation of the cuff pressure in endotracheally-intubated patients. Eur Respir J. 2002;20(4):1010-1013. [CrossRef] [PubMed]
 
Stenqvist O, Bagge U. Cuff pressure and microvascular occlusion in the tracheal mucosa. An intravital microscopic study in the rabbit. Acta Otolaryngol. 1979;88(5-6):451-454. [CrossRef] [PubMed]
 
Nordin U, Lindholm CE, Wolgast M. Blood flow in the rabbit tracheal mucosa under normal conditions and under the influence of tracheal intubation. Acta Anaesthesiol Scand. 1977;21(2):81-94. [CrossRef] [PubMed]
 
Nordin U. The trachea and cuff-induced tracheal injury. An experimental study on causative factors and prevention. Acta Otolaryngol Suppl. 1977;345:1-71. [PubMed]
 
Nordin U, Lindholm CE. The vessels of the rabbit trachea and ischemia caused by cuff pressure. Arch Otorhinolaryngol. 1977;215(1):11-24. [CrossRef] [PubMed]
 
Dobrin P, Canfield T. Cuffed endotracheal tubes: mucosal pressures and tracheal wall blood flow. Am J Surg. 1977;133(5):562-568. [CrossRef] [PubMed]
 
Seegobin RD, van Hasselt GL. Endotracheal cuff pressure and tracheal mucosal blood flow: endoscopic study of effects of four large volume cuffs. Br Med J (Clin Res Ed). 1984;288(6422):965-968. [CrossRef] [PubMed]
 
Gabrecht T, Lovisa B, van den Bergh H, Wagnières G. Autofluorescence bronchoscopy: quantification of inter-patient variations of fluorescence intensity. Lasers Med Sci. 2009;24(1):45-51. [CrossRef] [PubMed]
 
Lee P, van den Berg RM, Lam S, et al. Color fluorescence ratio for detection of bronchial dysplasia and carcinoma in situ. Clin Cancer Res. 2009;15(14):4700-4705. [CrossRef] [PubMed]
 
Nakanishi K, Ohsaki Y, Kurihara M, et al. Color auto-fluorescence from cancer lesions: improved detection of central type lung cancer. Lung Cancer. 2007;58(2):214-219. [CrossRef] [PubMed]
 
Li Bassi G, Zanella A, Cressoni M, Stylianou M, Kolobow T. Following tracheal intubation, mucus flow is reversed in the semirecumbent position: possible role in the pathogenesis of ventilator-associated pneumonia. Crit Care Med. 2008;36(2):518-525. [CrossRef] [PubMed]
 
Li Bassi G, Marti JD, Saucedo L, et al. Gravity predominates over ventilatory pattern in the prevention of ventilator-associated pneumonia. Crit Care Med. 2014;42(9):e620-e627. [CrossRef] [PubMed]
 
Carroll RG. Evaluation of tracheal tube cuff designs. Crit Care Med. 1973;1(1):45-46. [CrossRef] [PubMed]
 
Carroll RG, Grenvik A. Proper use of large diameter, large residual volume cuffs. Crit Care Med. 1973;1(3):153-154. [CrossRef] [PubMed]
 
Chen W, Gao X, Tian Q, Chen L. A comparison of autofluorescence bronchoscopy and white light bronchoscopy in detection of lung cancer and preneoplastic lesions: a meta-analysis. Lung Cancer. 2011;73(2):183-188. [CrossRef] [PubMed]
 
Sun J, Garfield DH, Lam B, et al. The value of autofluorescence bronchoscopy combined with white light bronchoscopy compared with white light alone in the diagnosis of intraepithelial neoplasia and invasive lung cancer: a meta-analysis. J Thorac Oncol. 2011;6(8):1336-1344. [CrossRef] [PubMed]
 
Touat L, Fournier C, Ramon P, Salleron J, Durocher A, Nseir S. Intubation-related tracheal ischemic lesions: incidence, risk factors, and outcome. Intensive Care Med. 2013;39(4):575-582. [CrossRef] [PubMed]
 
Diaz E, Rodríguez AH, Rello J. Ventilator-associated pneumonia: issues related to the artificial airway. Respir Care. 2005;50(7):900-906. [PubMed]
 
Trawöger R, Kolobow T, Cereda M, Sparacino ME. Tracheal mucus velocity remains normal in healthy sheep intubated with a new endotracheal tube with a novel laryngeal seal. Anesthesiology. 1997;86(5):1140-1144. [CrossRef] [PubMed]
 
Hoegger MJ, Awadalla M, Namati E, et al. Assessing mucociliary transport of single particles in vivo shows variable speed and preference for the ventral trachea in newborn pigs. Proc Natl Acad Sci U S A. 2014;111(6):2355-2360. [CrossRef] [PubMed]
 
Honeybourne D, Costello JC, Barham C. Tracheal damage after endotracheal intubation: comparison of two types of endotracheal tubes. Thorax. 1982;37(7):500-502. [CrossRef] [PubMed]
 
Arola MK, Anttinen J. Post-mortem findings of tracheal injury after cuffed intubation and tracheostomy. A clinical and histopathological study. Acta Anaesthesiol Scand. 1979;23(1):57-68. [CrossRef] [PubMed]
 
Minonishi T, Kinoshita H, Hirayama M, et al. The supine-to-prone position change induces modification of endotracheal tube cuff pressure accompanied by tube displacement. J Clin Anesth. 2013;25(1):28-31. [CrossRef] [PubMed]
 
Nseir S, Zerimech F, Fournier C, et al. Continuous control of tracheal cuff pressure and microaspiration of gastric contents in critically ill patients. Am J Respir Crit Care Med. 2011;184(9):1041-1047. [CrossRef] [PubMed]
 
Valencia M, Ferrer M, Farre R, et al. Automatic control of tracheal tube cuff pressure in ventilated patients in semirecumbent position: a randomized trial. Crit Care Med. 2007;35(6):1543-1549. [CrossRef] [PubMed]
 
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