Ventilation Patterns Influence Airway Secretion Movement Marcia S Volpe, Alexander B Adams MPH RRT FAARC, Marcelo B P Amato MD, and John J Marini MD

Original Contributions

BACKGROUND: Retention of airway secretions is a common and serious problem in ventilated patients. Treating or avoiding secretion retention with mucus thinning, patient-positioning, airway suctioning, or chest or airway vibration or percussion may provide short-term benefit. METHODS: In a series of laboratory experiments with a test-lung system we examined the role of ventilator settings and lung-impedance on secretion retention and expulsion. Known quantities of a synthetic dye-stained mucus simulant with clinically relevant properties were injected into a transparent tube the diameter of an adult trachea and exposed to various mechanical-ventilation conditions. Mucus- simulant movement was measured with a photodensitometric technique and examined with image- analysis software. We tested 2 mucus-simulant viscosities and various peak flows, inspiratory/ expiratory flow ratios, intrinsic positive end-expiratory pressures, ventilation waveforms, and impedance values. RESULTS: Ventilator settings that produced flow bias had a major effect on mucus movement. Expiratory flow bias associated with intrinsic positive end-expiratory pressure generated by elevated minute ventilation moved mucus toward the airway opening, whereas intrinsic positive end-expiratory pressure generated by increased airway resistance moved the mucus toward the lungs. Inter-lung transfer of mucus simulant occurred rapidly across the “carinal divider” between interconnected test lungs set to radically different compliances; the mucus moved out of the low-compliance lung and into the high-compliance lung. CONCLUSIONS: The movement of mucus simulant was influenced by the ventilation pattern and lung impedance. Flow bias obtained with ventilator settings may clear or embed mucus during mechanical ventilation. Key words: airway clearance, mechanical ventilation, mucus, secretions. [Respir Care 2008;53(10):1287– 1294. © 2008 Daedalus Enterprises]

Introduction tained mucus narrows or occludes airways, causes breath- Retention of airway secretions can present a serious ing discomfort, and, if extensive, leads to atelectasis and clinical problem during mechanical ventilation because re- gas-exchange impairment. Mucus retention can lead to mortality in chronic bronchitis.1,2 In the acute-care setting, airway clearance of retained mucus is an acknowledged, important problem for critically ill patients,3-6 and is as- Marcia S Volpe is affiliated with the Respiratory Intensive Care Unit, sociated with significantly higher mortality and morbidi- University of Saõ Paulo School of Medicine, Brazil. Marcelo B P Amato ty.7-10 When cough is inhibited and the mucociliary esca- MD is affiliated with the Pulmonary Division, Hospital das Clıńicas, lator is impaired by intubation, retained secretions are a University of Saõ Paulo, Brazil. Alexander B Adams MPH RRT FAARC and John J Marini MD are affiliated with the Department of Critical Care and Pulmonary Medicine, Regions Hospital, St Paul, Minnesota. SEE THE RELATED EDITORIAL ON PAGE 1276 This research was supported by Healthpartners Research Foundation and Laborato´rio de Pneumologia Experimental, Faculdade de Medicina, Univer- sity of Saõ Paulo, Brazil, and Coordenaçaõ de Aperfeiçoamento de Pessoal sequestered growth medium for bacteria, which increases de Nı´vel Superior, Brazilian Ministry of Education, Brazil. The authors report no other conflicts of interest related to the content of this paper. the risk of pneumonia. Though secretions in the proximal large airways are accessible to suctioning, airways beyond Mr Adams presented a version of this paper at the OPEN FORUM at the 52nd International Respiratory Congress of the American Association for the 3rd generation are beyond the suction catheter’s reach Respiratory Care, held December 11-14, 2006, in Las Vegas, Nevada. and must be cleared by other methods. Correspondence: Alexander B Adams MPH RRT FAARC, Department There are several approaches to clearing retained secre- of Critical Care and Pulmonary Medicine, Regions Hospital, 640 Jackson tions, but they are often only marginally or temporarily Street, St Paul MN 55101. E-mail: [email protected]. effective and frequently treat the result rather than the

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Fig. 2. Movement of simulated mucus before (A) and after (B) applying a ventilation pattern that favors inspiratory flow (to the left). The image-analysis software colored the changed object (green mucus simulant) red. The center of mass is determined by optical densitometry. The displacement of the center of mass (CM) is the difference between CM1 and CM2. The extreme distance (ED) is the difference between ED1 and ED2. The volume displacement (difference between volume 2 and volume 1) is expressed as the percentage of volume moved in relation to the total initial volume.

gators of high-frequency oscillation,19-22 we propose that peak airflow bias (ie, the tidal differential tendency of peak flow and its duration to favor one direction of movement) is an important factor in airway secretion movement. We investigated the effect of ventilator settings and Fig. 1. Method of determining expiratory-inspiratory flow differ- the resulting flow bias on secretion movement. ence and ratio. The upper panel displays an example of a flow pattern that gives a positive value for the expiratory-inspiratory flow difference (ie,B–AϾ 0) and the expiratory-inspiratory flow Methods ratio (B/A Ͼ 1), which would create an expiratory flow bias and therefore tend to expel mucus. In that example, intrinsic positive Mucus Simulant end-expiratory pressure is generated by the ventilator settings. The lower panel shows a flow pattern whereB–AϽ 0 and B/A Ͻ 1, which favors mucus retention because of inspiratory flow bias and We formulated synthetic solutions with standardized vis- increased expiratory resistance. In that example, intrinsic positive coelastic properties similar to human mucus, according to end-expiratory pressure is generated by impedance, as in chronic previously described methods.23 We dissolved either 1.5 g obstructive pulmonary disease. or 3.0 g of polyethylene oxide powder (Sentry Polyox WSR Coagulant, Dow Chemicals, Wilmington, Delaware) cause of secretion retention. Cough effectively clears the in 100 mL of filtered water, at 100°C. The solution thick- major airways, but cough is frequently weakened by ill- nesses at the 2 concentrations (1.5% and 3.0%) simulated ness, and glottis closure is prevented by endotracheal in- normal and thick airway mucus. We colored the mucus tubation. Repeated catheter suctioning risks airway dam- simulant to allow quantitative photodensitometry, de- age, deoxygenation, and atelectasis.6 High-frequency chest- scribed below. wall or airway-pressure vibration has not been proven effective.11 Bland or muco-active aerosol or direct instil- Mucus-Movement Measurements lation of fluid can dilute, lubricate, and thin mucus and thus help to centralize secretions.12,13 Postural drainage is We positioned transparent tubing (inner diameter 1 cm, frequently prescribed to enlist the assistance of gravity in length 30 cm) horizontally on a light box and photographed moving secretions.14 Manual lung hyperinflation (an in- mucus movement with a 12 megapixel camera (Nikon) creased tidal volume [VT] with a slow inspiratory flow and fixed 1.30 m above and perpendicular to the light box a fast expiratory flow) can aid secretion clearance.15-17 (Fig. 2). Photographs of mucus simulant position were Chest-wall vibration also improves expiratory flow and, obtained before and after initiating specific ventilation pat- therefore, secretion clearance.18 terns. We used image-analysis software (Sigmascan, Sta- In airways there is a continuous “to and fro” movement tistical Solutions, Saugus, Massachusetts) to evaluate mu- of gas that affects the underlying secretion layers. Aver- cus movement, by measuring the mucus area in number of aged over several breaths, the net volume of gas moved in pixels. A ruler was positioned next to the tubing to cali- either direction must be equal, but the peak or mean flow brate the area of 1 pixel in square centimeters. The product of the inspiratory and expiratory phases can differ sub- of 1 pixel area unit and the measured number of pixels stantially, and this “flow bias” can be toward the lungs or gave the mucus area in cm2. The image-analysis software toward the mouth (Fig. 1). Following the lead of investi- can also measure the color intensity of each pixel in a

1288 RESPIRATORY CARE • OCTOBER 2008 VOL 53 NO 10 VENTILATION PATTERNS INFLUENCE AIRWAY SECRETION MOVEMENT measured object. The color intensity provides an indirect flow, we added one-way valves and a separate expiratory measure of mucus depth. Mucus volume was estimated as limb to the circuitry. the product of the average estimated depth by the corresponding mucus area. Experiment 1-2: Effect of Peak Flow. This experiment Mucus displacement after applying specific ventilation compared the effects of mean and peak inspiratory flow, patterns was evaluated in 3 ways: the displacement of the VT, and inspiratory time (TI) on mucus movement. We center of mass; the most extreme distance traveled from used flow-controlled, volume-cycled ventilation, a respi- the point of mucus injection; and the percent volume dis- ratory rate of 12 breaths/min, and VT of 375 mL and placement from the original center of mass. The image- 750 mL. At identical TI, constant square-wave and decel- analysis software calculates the center of mass by deter- erating inspiratory flow patterns were tested at mean flows mining a central location of the “object” after multiplying of 20, 40, 60, and 80 L/min. all pixels by their relative intensities. The extreme distance was the most distant point of the analyzed object along the Experiment 1-3: Flow Bias. This experiment studied major axis of the studied object (see Fig. 2). the relationship between inspiratory and expiratory flow and mucus displacement. We used a respiratory rate of Study Protocol 15 breaths/min and a VT of 750 mL. To adjust the differences (and ratios) between the inspiratory and expiratory The first stage comprised 3 experiments on the general flows, we kept compliance constant at 0.04 L/cm H2O) to effects of airflow and airflow bias on mucus movement. maintain a peak expiratory flow of approximately 60 L/ The second stage comprised 2 experiments in which we min, with 10 inspiratory flows from 35 L/min to 117 L/ tracked mucus displacement following specific clinical ven- min. We report the averages of Ն 2 measurements for each tilation scenarios. A test lung (Training and Test Lung, test condition. Michigan Instruments, Grand Rapids, Michigan) was ventilated via transparent tubing (inner diameter 1.0 cm, length 30 cm, held horizontal on the light box) with a mechanical Stage 2: Simulated Clinical Conditions ventilator (model 840, Puritan Bennett/Tyco, Carlsbad, Cal- ifornia). Experiment 2-1: Dynamic Hyperinflation. This exper- In each experiment, 1 mL of mucus simulant was in- iment investigated the effects of dynamic hyperinflation jected into the center of the tubing and was allowed to (and associated intrinsic positive end-expiratory pressure settle for 3–5 min before taking the initial photograph. [auto-PEEP]) generated by a high minute ventilation (ven- Then we connected the tubing to the mechanical ventila- tilator-generated auto-PEEP) or elevated airway resistance tor. After applying a specific ventilation pattern for 5 min (impedance-generated auto-PEEP). In both experiments the we took another photograph. We analyzed the photographs settings were: compliance 0.08 L/cm H2O, VT 1,000 mL, ϭ to assess the ventilation pattern’s effect on mucus move- constant inspiratory flow 30 L/min, and TI 2.00 s. Auto- ment. In the stage-1 experiments we tested both mucus PEEP values of 7, 11, and 17 cm H2O were induced with simulant concentrations. In the stage-2 experiments we respiratory rates of 18, 20, and 21 breaths/min, respec- used only the 1.5% mucus. After each experiment the tube tively. Similar levels of impedance-generated auto-PEEP was washed, air-dried, and repositioned on the light box were generated at a rate of 12 breaths/min by adjusting a for the next experiment. Inspiratory and expiratory flows variable resistor. and VT were measured with a pneumatic sensor (NICO, Respironics, Murrysville, Pennsylvania). In experiment 2 Experiment 2-2: Inter-Lung Mucus Transfer. This of stage 2 we used a separate pneumatic sensor for each experiment studied the possibility that mucus might move test-lung chamber to detect pendelluft with its respective between lungs of different compliance under certain ven- effect on interlung mucus transfer. tilation patterns. We tested 3 compliance combinations: one lung was set at a compliance of 0.01 L/cm H2O and Stage 1: Flow Effects and Relationships the other lung was set 0.02, 0.04, or 0.08 L/cm H2O. The ventilator settings were: VT 1,000 mL, respiratory rate Experiment 1-1: Mucus Displacement Flow Thresholds. 12 breaths/min, and TI 0.5 s. This experiment was designed to identify the flow threshold required to move the mucus simulant. We used a sin- Statistical Analysis gle-lung circuit, volume-control ventilation, square-wave inspiratory flows of 5, 10, 15, 20, 40, and 60 L/min, a In experiment 1-1, differences in response between the respiratory frequency of 12 breaths/min, and VT of 375 mL 2 mucus preparations were tested with repeated-measures and 750 mL. To isolate the influence of unidirectional analysis of variance with post hoc contrasts to identify

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Table 1. Univariate and Multivariate Analysis of Variables Associated With Mucus Simulant Displacement as the Dependent Variable

Univariate Analysis Multivariate Analysis

Variable r b* P rb* P Peak flow 0.938 0.048 Ͻ .001 0.976 0.049 Ͻ .001 Mean flow 0.853 0.057 Ͻ .001 0.196 0.006 .268 Ͻ TI –0.585 –1.241 .001 0.011 0.008 .949

VT 0.193 0.527 .245 0.121 0.292 .496 Waveform 0.342 0.461 .036 –0.150 –0.047 .398

* slope of the regression line TI ϭ inspiratory time VT ϭ tidal volume

mucus formed waves on its surface layer with all flows Ն Fig. 3. Center-of-mass displacement with various flows. The 1.5% 20 L/min. The extreme-distance and volume-displace- mucus simulant moved significantly more than the 3.0% mucus ment data show tendencies similar to the center-of-mass simulant at 40 L/min and 60 L/min (P Ͻ .007). displacement data.

Experiment 1-2: Effect of Peak Flow. A total of 38 thresholds. We used univariate and multivariate linear re- measurements (4 per condition) were made of each vari- gression analyses to study the influence of mucus thick- able: peak inspiratory flow (PIF), mean inspiratory flow, ness, inspiratory and expiratory flow, VT, and TI on mucus TI,VT, and waveform. Table 1 shows the results for the movement. For all comparisons, P Յ .05 was considered univariate and multivariate analysis with mucus center-of- significant. Analysis was performed with statistics soft- mass displacement as the dependent variable. During uni- ware (SPSS 12.0, SPSS, Chicago, Illinois). variate analysis, PIF, mean inspiratory flow, TI, and waveform each correlated with mucus displacement. Results Multivariate analysis, however, revealed that only PIF significantly correlated with center-of-mass displacement Validation of Photometric Method (r ϭ 0.976, P Ͻ .001). The strong association between PIF and mucus movement suggested that: We evaluated 190 mucus volumes (1 mL injected) via • After adjusting the regression model for PIF, other vari- our photometric method. The mean calculated volumes ables did not provide additional information to explain before and after application of the ventilation patterns were mucus displacement. 0.94 Ϯ 0.02 mL and 1.03 Ϯ 0.02 mL, respectively, which indicates that that the calculated mucus volume was well • On the contrary, when the regression model was pre- estimated by this technique. adjusted for the influence of these variables (mean in-

spiratory flow, TI,VT, and waveform), PIF always Stage 1: Flow Effects and Relationships emerged as an important variable, which explains a significant portion (P Ͻ .001) of the residual difference in Experiment 1-1: Mucus Displacement Flow Thresholds. mucus movement. The extreme-distance and volume- Figure 3 suggests a mucus-movement unidirectional flow displacement variables had a similar relationship to PIF. threshold of 10–20 L/min. The center-of-mass displace- However, multivariate analysis showed that the center- ment of the 1.5% mucus simulant was more evident than of-mass displacement (r2 ϭ 0.952) produced the most with the 3.0% preparation (P ϭ .007 for the overall dif- consistent results, compared to the extreme-distance ference, and P ϭ .013 for the interaction between the (r2 ϭ 0.922) and volume-displacement (r2 ϭ 0.703). mucus-concentration and flow factors). Compared to the Figure 4 illustrates the correlation curve between PIF 5 L/min condition, the center-of-mass mucus-displacement and mucus center-of-mass displacement. Waveform ef- only occurred at Ն 40 L/min with the 1.5% mucus simu- fects were not identified in this experiment. lant (P Ͻ .001) and at 60 L/min with the 3.0% preparation (P ϭ .007). However, the 1.5% mucus formed waves on Experiment 1-3: Flow Bias. The tested expiratory/in- its surface layer with all flows Ն 15 L/min. The 3.0% spiratory flow ratio (E/I) range was 2.4–0.7, and the ex-

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mucus movement (center of mass) to change direction. Differences moved mucus toward the mouth if E-I was Ͼ 17 L/min, or toward the lungs if I-E was Ͼ 17 L/min (see Fig. 5). With the 3% mucus simulant the E-I difference threshold was slightly higher. There was also a strong interaction between flow bias and mucus thickness (P Ͻ .001): a smaller flow bias difference moved the thinner mucus.

Stage 2: Simulated Clinical Conditions

Experiment 2-1: Dynamic Hyperinflation. Similar levels of auto-PEEP generated in different ways (ventilator- generated or impedance-generated) produced I-E flow dif- Fig. 4. The center-of-mass displacement of the mucus simulant ferences (see Figure 1). As a result, auto-PEEP caused by was directly related to the inspiratory peak flow in experiment 1-2 (r ϭ 0.94). increasing ventilatory frequency produced an expiratory flow bias that moved mucus out of the simulated lung. In contrast, auto-PEEP generated by increasing expiratory piratory-inspiratory flow difference (E-I) range was ϩ50 resistance caused an inspiratory flow bias that moved mu- to –45 L/min. Univariate analysis revealed that both E/I cus into the simulated lung (Table 2). In agreement with ratio (r2 ϭ 0.766, P Ͻ .001) and E-I difference (r2 ϭ 0.845, the results of experiment 1-3, a greater E-I flow difference P Ͻ .001) were important correlates of mucus movement. tended to displace mucus further. In multivariate analysis, however, with both ratio and difference variables forced into the regression model, the E-I Experiment 2-2: Inter-Lung Mucus Transfer. The first difference showed a stronger correlation with center-of- compliance combination tested was 0.01 L/cm H2O and ϭ Ͻ mass displacement (r 0.91, P .001), whereas E/I no 0.02 L/cm H2O, which had mean observed E-I flow dif- longer correlated with mucus movement (r ϭ 0.09, ferences of 29 L/min with the test lung set at 0.01 L/ ϭ Ϫ P .637). Moreover, the curve-fitting analysis suggests a cm H2O and 13 L/min for the test lung set at 0.02 L/ linear relationship between E-I difference and mucus dis- cm H2O. The second combination was compliances of placement, whereas the E/I ratio plot suggests a curvilinear 0.01 L/cm H2O and 0.04 L/cm H2O, which had E-I flow relationship (Fig. 5). These observations held true for both differences of 27 L/min and –28 L/min, respectively. The tested mucus viscosities, which suggests a slightly better last combination was compliances of 0.01 L/cm H2O and behavior for the E-I difference as an explanatory variable 0.08 L/cm H2O, which had observed E-I peak flow dif- for mucus displacement. An E-I flow difference of 17 L/ ferences of 40 L/min and –45 L/min, respectively. After min with the 1.5% mucus seems to be a threshold for 5 min of ventilation the leading edge of mucus had moved

Fig. 5. Relationship of center-of-mass displacement to expiratory/inspiratory flow ratio and expiratory-inspiratory flow difference. A negative displacement indicates mucus movement toward the test lungs. Across the tested range there is a curvilinear relationship between the expiratory/inspiratory flow ratio and mucus movement, whereas the relationship between mucus movement and the expiratory-inspiratory flow difference is linear.

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Table 2. Effect of Auto-PEEP on Mucus Movement*

Amount of Auto-PEEP Flow Bias (PEF–PIF) Center-of-Mass Extreme Distance Volume Type of Auto-PEEP (cmH2O) (L/min) Displacement (cm) (cm) (%) Impedance-generated 8 –4 –0.8 –1.5 –47 12 –5 –0.8 –1.1 –45 18 –5 –0.6 –0.9 –36 Ventilator-generated 7 27 2.6 3.4 46 11 45 3.2 5.3 61 17 51 3.1 4.5 68

* Negative values indicate mucus movement toward the test lung. auto-PEEP ϭ intrinsic positive end-expiratory pressure PEF ϭ peak expiratory flow PIF ϭ peak inspiratory flow

ward or away from the airway opening. Moreover, flow differences resulting from mechanical heterogeneity can transfer secretions between lung regions. In intubated patients, few problems are more prevalent than secretion retention, because intubation compromises both cough ability and the mucociliary escalator.7,24 Intu- bation also contaminates the lower airway with inoculates from the oropharynx.24 Although the consequences of intubation on impaired gas exchange, increased breathing Fig. 6. Tubing circuitry primed with 1 mL of mucus simulant before work load, and ventilator-associated pneumonia have been (A) and after (B) 10 min of mechanical ventilation with a heteroge- neous lung model. Tube segment 1 was connected to the lung well recognized, the role of ventilation pattern in secretion chamber set to a compliance of 0.01 L/cm H2O. Tube segment 2 retention has not. In selecting the ventilation mode and was connected to the lung chamber set to a compliance of 0.08 L/ settings, clinicians usually target specific values for infla- cm H O. Ventilation transferred the mucus that was injected into 2 tion pattern (PEEP and plateau pressure and/or flow pro- the lower-compliance circuit from the lower-compliance lung to the higher-compliance lung. file and magnitude). Quantitatively studying secretion movement in the setting of critical illness is difficult, which partly explains why so little information on the topic is from the lower-compliance lung into the higher-compli- solidified. With the paucity of data for guidance, perhaps ance lung in each case. As expected, E-I peak flow dif- it is not surprising that clinicians seldom consider the im- ferences of 29, 27, and 40 L/min (bias to expel mucus) plications of ventilator settings on secretion clearance. Yet, moved the mucus simulant toward the ventilator. Mucus when viewed against the background of the existing in- that reached the artificial carina (Y-piece) moved into the triguing but largely ignored experimental work, our find- more compliant lung with the E-I differences Ϫ13, Ϫ28, ings strongly suggest that this subject needs a closer and Ϫ45 (the negative values indicate a bias to retain look.19-22 mucus). With greater E-I differences, the extreme distance Our initial experiments led to predictable associations moved further into the more compliant lung: 1.3 cm, 2.5 cm, between flow-specific bias conditions and mucus move- and 3.1 cm for the 3 conditions, respectively. Figure 6 ment. The lower-viscosity mucus simulant moved further displays mucus displacement during the third compliance than the high-viscosity mucus simulant under otherwise combination. identical conditions, which verifies the previously reported importance of secretion viscosity.6,13 This effect was clearly Discussion shown in the flow-threshold study (experiment 1-1, see Fig. 3) and the E-I ratio/E-I difference study (experiment Our results suggest that ventilation settings and lung 1-3, see Fig. 5). Thus, thinning secretions should encour- impedance affect secretion mobilization. Once the flow- age secretion mobility, and, logically, increasing the PIF magnitude and phase-differential thresholds are exceeded, should drive mucus deeper, and, conversely, increasing the the relationship of tidal expiratory flow to peak inspiratory expiratory flow (ie, under reduced-compliance conditions) flow (factors affected by the ventilation mode, flow pro- should expel mucus from the airways. This might explain file, VT, and breathing frequency) may move mucus to- the impression that there are fewer secretion problems in

1292 RESPIRATORY CARE • OCTOBER 2008 VOL 53 NO 10 VENTILATION PATTERNS INFLUENCE AIRWAY SECRETION MOVEMENT acute respiratory distress syndrome (ARDS), which in- drainage is the central tenet of chest physiotherapy, and in volves low compliance and elevated expiratory flow. Re- the acute-care setting postural drainage is often an unin- tarding expiratory flow with an airway resistor has the tended benefit of prone positioning.26 Recent work from opposite effect. Schortgen and colleagues demonstrated the potential for Several aspects of the present study generate provoca- ventilation patterns to either reinforce or offset the fluid- tive points of consideration regarding mucus movement in mobilizing effects of adverse gravitational orientation.27 ventilated patients. As reported in previous laboratory stud- Given that perhaps two thirds or more of ARDS cases ies, settings that invert the I-E ratio tend to produce an begin on the airway side of the alveolus (ie, primary or expiratory flow bias that directs mucus away from the pulmonary ARDS, as opposed to secondary or extrapul- lungs.19,20 We observed that effect in experiment 1-3 (see monary ARDS28), it is a point of interest and concern that Fig. 5). Manipulating the I-E ratio with the ventilator set- the low-VT, lung-protection ventilation strategy would re- tings to direct mucus movement is not a common clinical tain rather than expel secretions. practice, but the present study confirms a rationale for that strategy. The effects of induced flow bias (due to auto- Limitations PEEP) on the simulated mucus appeared to depend on the cause of the auto-PEEP. Auto-PEEP generated by elevated Our experiment, designed as a step in establishing con- minute ventilation under normal impedance conditions ceptual, qualitative principles to direct further research caused flow bias that directed mucus away from the lungs into an important set of clinical problems, was not under- (experiment 2-1, see Table 2)—an effect of induced expi- taken to definitively answer them. The clinical relevance ratory flow bias. When expiratory resistance was imposed of our findings should be questioned on several fronts. Our (as in obstructive disease) to increase auto-PEEP, mucus simulated mucus, although previously used by others,23 is migrated toward the lungs—an effect of the relatively high not equivalent to real mucus, which differs and varies inspiratory flow bias. That mechanism could contribute to markedly in consistency and composition in and among secretion retention in patients with airway obstruction, patients. Our mucus simulant does not have a sol and gel which is a serious, common problem caused by persistent layer, it does not have the same cohesion and adherence inspiratory flow bias. properties of pathological mucus, and it was not applied to To summarize, the role of auto-PEEP and expiratory a dynamic, corrugated, lubricated mucosal surface. Only a single tube diameter similar in overall dimension to the flow intensity and duration may be the direct factor related trachea was examined, and the behavior of our mucus to secretion expulsion, however controlled or effected. And simulant in a biologically branched network was not stud- our experiment on the potential for inter-lung mucus trans- ied and should be considered a limitation, because a suc- fer found that mucus moved from the lower-compliance tion catheter can often be employed to evacuate the central lung to the higher-compliance lung. Mucus is propelled airways. from the lower-compliance units toward the carina be- Secretion movement depends on the secretions’ adher- cause of the relatively high expiratory flow, but is then ence to the airway surface, the cohesiveness and stickiness driven into the higher-compliance lung by the relatively of the secretions, and the forces that compete to move the rapid inspiratory flow to that side. We contend that inter- secretions in one direction or the other. The shearing and lung, interlobe, and intersegmental transfer of infectious propelling forces depend on overall flow rate and the di- materials could be accelerated by this mechanism, which ameter of the airway. Inferences drawn from our experi- might explain pneumonia propagation and/or occlusion of ments with a larger-diameter tube of uniform diameter major airways (especially in heavily sedated or paralyzed may not apply to smaller distal airways, where velocities, patients). resistances, and pressure gradients are different. We also That ventilation pattern influences secretion movement did not investigate the role of position, gravity, or cough has been reported in laboratory experiments with high- on mucus movement, and those are likely cofactors in the frequency ventilation—a setting in which I-E ratio influ- expulsion or embedding of mucus. ences the flow direction of mucus simulant.5 Our work confirms and extends that of Benjamin et al19 and Kim Conclusions et al,19,20 who emphasized the importance of expiratory- to-inspiratory peak flow bias in their high-frequency-ven- Although we hope our work will raise awareness and tilation model. Undeniably important as a cofactor is the stimulate interest among clinical investigators and clini- powerful gravitational effect of body positioning,14 which cians, we are not advocating direct application of these was not tested in our study. Panigada and colleagues il- results to the care of patients. The principles of clearance lustrated this principle convincingly in sheep.25 Postural and retention developed here, however, are consistent with

RESPIRATORY CARE • OCTOBER 2008 VOL 53 NO 10 1293 VENTILATION PATTERNS INFLUENCE AIRWAY SECRETION MOVEMENT the findings of prior studies of ventilation pattern and se- 14. Pryor JA. Physiotherapy for airway clearance in adults. Eur Respir J cretion movement. When considered together with physi- 1999;14(6):1418-1424. cal principles and experimental reports, our data strongly 15. Maxwell L, Ellis ER. The effects of three manual hyperventilation techniques on pattern of ventilation in a test lung model. Anesth suggest untapped therapeutic potential and the opportunity Intensive Care 2002;30(3):283-288. to avoid iatrogenesis. Well-conceived biological experi- 16. Denehy L. The use of manual hyperinflation in airway clearance. Eur ments must now be conducted to confirm or refute those Respir J 1999;14(4):958-965. possibilities. 17. Savian C, Paratz J, Davies A. 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