Bench and mathematical modeling of the effects of breathing a helium/oxygen mixture on expiratory time constants in the presence of heterogeneous airway obstructions
- Andrew R Martin^{1}Email author,
- Ira M Katz^{2, 3},
- Karine Terzibachi^{2},
- Laure Gouinaud^{2},
- Georges Caillibotte^{2} and
- Joëlle Texereau^{2}
DOI: 10.1186/1475-925X-11-27
© Martin et al.; licensee BioMed Central Ltd. 2012
Received: 3 April 2012
Accepted: 7 May 2012
Published: 30 May 2012
Abstract
Background
Expiratory time constants are used to quantify emptying of the lung as a whole, and emptying of individual lung compartments. Breathing low-density helium/oxygen mixtures may modify regional time constants so as to redistribute ventilation, potentially reducing gas trapping and hyperinflation for patients with obstructive lung disease. In the present work, bench and mathematical models of the lung were used to study the influence of heterogeneous patterns of obstruction on compartmental and whole-lung time constants.
Methods
A two-compartment mechanical test lung was used with the resistance in one compartment held constant, and a series of increasing resistances placed in the opposite compartment. Measurements were made over a range of lung compliances during ventilation with air or with a 78/22% mixture of helium/oxygen. The resistance imposed by the breathing circuit was assessed for both gases. Experimental results were compared with predictions of a mathematical model applied to the test lung and breathing circuit. In addition, compartmental and whole-lung time constants were compared with those reported by the ventilator.
Results
Time constants were greater for larger minute ventilation, and were reduced by substituting helium/oxygen in place of air. Notably, where time constants were long due to high lung compliance (i.e. low elasticity), helium/oxygen improved expiratory flow even for a low level of resistance representative of healthy, adult airways. In such circumstances, the resistance imposed by the external breathing circuit was significant. Mathematical predictions were in agreement with experimental results. Time constants reported by the ventilator were well-correlated with those determined for the whole-lung and for the low-resistance compartment, but poorly correlated with time constants determined for the high-resistance compartment.
Conclusions
It was concluded that breathing a low-density gas mixture, such as helium/oxygen, can improve expiratory flow from an obstructed lung compartment, but that such improvements will not necessarily affect time constants measured by the ventilator. Further research is required to determine if alternative measurements made at the ventilator level are predictive of regional changes in ventilation. It is anticipated that such efforts will be aided by continued development of mathematical models to include pertinent physiological and pathophysiological phenomena that are difficult to reproduce in mechanical test systems.
Keywords
Helium Heliox Exhalation Time constant Hyperinflation Gas trapping Ventilation distribution Airway resistance Mechanical ventilation LungBackground
Resistance to expiratory flow is a concern for patients with obstructive lung disease. Thickening of airway walls, partial occlusion of lumen due to excessive mucus production, and airway narrowing associated with smooth muscle contraction can all contribute to increased airway resistance, which impedes expiratory flow and can lead to dynamic hyperinflation and dyspnea [1–4]. Previous studies have explored the hypothesis that breathing low-density helium/oxygen (He/O_{2}) mixtures improves lung emptying in patients with obstructive lung disease [5–9]. From these investigations, coupled with analysis of the underlying respiratory fluid mechanics, it may be gathered that the potential for He/O_{2} to influence expiratory flow rates is highly dependent on the location of obstruction [5, 6]. Moving from the upper airways to the peripheral lung, as the gas Reynolds number decreases by several orders of magnitude, airway resistance becomes less influenced by flow inertia (which depends in turn on gas density) and more influenced by viscous effects [5, 10, 11].
In addition to their depth along the respiratory tract, airway obstructions may also vary in their severity across different airways at the same depth in the lung [12, 13]. Variation in airway resistance between lung regions leads to regional differences in ventilation, including differences in expiratory time constants. In such circumstances, end-expiratory volumes and pressures will also vary regionally [5, 14]. As noted recently by Diehl and colleagues [15], breathing He/O_{2} may hypothetically modify regional time constants so as to redistribute ventilation. Previously, we employed a dual chamber mechanical test lung to demonstrate that, in the presence of heterogeneous airway resistance representative of conducting airway obstruction, the ventilation distribution between chambers on inspiration was more homogeneous for He/O_{2} than for air [11]. In the present work, we used a similar approach to investigate the influence of He/O_{2} on expiratory flow, with attention paid to differences between the behavior of an individual, obstructed lung compartment and the lung as a whole. Additional measurements were made to assess the expiratory resistance imposed by the breathing circuit of the ventilator used to supply gas to the test lung, and these data were used as input in the development of an analytical model describing the test system.
Methods
Bench experiments
The test lung was ventilated in volume-control mode with either dry medical air (78% N_{2}/22% O_{2}; Air Liquide, France) or He/O_{2} (78% He/22% O_{2}; Air Liquide, France) using a Hamilton G5 ventilator (Hamilton Medical AG, Switzerland). Two breathing patterns were used: a 500 ml tidal volume at 12 breaths/min, producing a minute ventilation (V_{E}) of 6 l/min, and a 1000 ml tidal volume at 20 breaths/min, producing a minute ventilation of 20 l/min. In either case, the inspiratory/expiratory ratio was ½, and flow was set as constant over the inspiratory phase (i.e., a square wave).
Loss Coefficients (k) and Equivalent Linear Resistances (R) for the Rp5, Rp20, and Rp50 Parabolic Resistors
R[cmH _{2}OI ^{-1} s] | ||||
---|---|---|---|---|
Resistor | k | Q[I/min] | Air | He/O _{ 2 } |
Rp5 | 3.3 | 20 | 0.9 | 0.3 |
60 | 2.7 | 0.9 | ||
Rp20 | 21.5 | 20 | 5.8 | 2.0 |
60 | 17.5 | 6.1 | ||
Rp50 | 132.9 | 20 | 36.1 | 12.7 |
60 | 108.4 | 38.0 |
Finally, in order to provide input data for the analytical model, additional measurements were performed to assess the resistance imposed by the flow sensors and the expiratory limb of the breathing circuit. The pressure drop across either a single flow sensor, from inlet to outlet, or the entire expiratory circuit, from the patient end of the ventilator’s proximal flow sensor through the expiratory valve, was measured using a digital manometer (PR-201; Eurolec, Ireland) over a range of steady flow rates of medical air or He/O_{2} supplied by the mass flow controller.
Calculation of time constants
where ΔP is the driving pressure, V is the volume of the compartment, Q is the volumetric flow rate into or out of the system, and R and C are constants representing, respectively, the resistance and compliance of the system. The resistance is specified as the pressure drop across the airway per unit flow rate, whereas the compliance is the change in compartment volume per unit pressure.
where V _{ e }(t) is the exhaled volume at time t.
where V _{ e,tot } is the total exhaled volume, and t _{ e } is the exhalation time.
The solution described in Equations (7) and (8) was implemented in Microsoft Excel, with input values of V _{ e,tot }, Q _{ e,p }, and t _{ e } obtained from flow versus time data acquired for each compartment, and the whole lung, as described above. It was found that the time constant calculated in this manner typically varied between iterations by less than 1% after no more than 3 or 4 iterations.
Under the controlled experimental conditions described above, there was only very small variation in the calculated time constant between repetitions performed with all parameters held constant; therefore, for the experimental time constants reported below, uncertainty in measurement was estimated as the maximum difference between values determined for the right and left compartment when an Rp5 was inserted in both limbs (in which cases the time constants for the left and right compartments should ideally have been identical, and differences were attributed mainly to experimental uncertainties in the set left and right chamber compliances).
Analytical model
where the subscript i indicates the left or right chamber, the subscript j indicates the opposite chamber, P is the chamber pressure, V is the volume of gas in the chamber, C is the chamber compliance, Q is the volumetric flow rate out of the chamber, A is the cross-sectional area of the airway, and k _{ i }, k _{ fs }, and k _{ cct } represent loss coefficients for the parabolic resistor, the flow sensor, and the expiratory circuit, respectively. Of note, unlike the loss coefficients for the parabolic resistors provided in Table 1, loss coefficients for the flow sensors and expiratory limb of the breathing circuit depended on gas density and flow rate. Therefore, the measurements described above in Section 2.1 for the resistances imposed by these components were fit with second order polynomials for use in the analytical model.
Equation (9) was solved for either chamber with the initial chamber volume and pressure at the start of exhalation calculated using the inhalation model of Katz et al. [11]. The analysis consisted of a quasi-steady solution for the flow rates at each time step, progressing until the expiratory time limit was reached. Time constants for the left and right chambers were again determined according to equations (7) and (8), in this case using the peak flow and exhaled volume determined by the model.
Results and discussion
Time constants determined experimentally
Comparing Figure 2 and Figure 3 further, it is clear that, all else being equal, measured time constants were greater at higher minute ventilation, and lower for He/O_{2} than for air. The former effect is no doubt due to the flow-dependence of resistance exhibited by the parabolic resistors used in the present study, as evidenced above in Table 1. Regarding the effect of He/O_{2}, the pressure drop across these resistors results from phenomena that are inertial in nature, and therefore density-dependant [11]. By substituting He/O_{2} in place of air, the low density of the mixture reduces resistance, in turn reducing expiratory time constants. The applicability of these results to the human respiratory tract, where airway resistance contains both inertial and viscous components, will clearly depend on the nature and severity of airway disease, with obstructions occurring in more proximal airways favoring inertial effects, and those in the distal airways favoring viscous effects. However, as discussed below, it should be noted that the resistances imposed by healthy, conducting airways, and by common components of external breathing circuits, are both flow- and density-dependent.
Resistance imposed by the external breathing circuit
Comparison with analytical model
Conclusions
In summary, where inertial phenomena contribute to airway resistance, He/O_{2} reduces expiratory time constants compared to air. Regional variation in resistance leads to regional variation in expiratory flow, and the behavior of obstructed lung compartments has only minor influence on the time constant derived from flow data collected by the ventilator. Accordingly, such measurements may not permit a full appreciation of the effects of He/O_{2} on regional lung ventilation. Finally, results of experiments performed using a mechanical test lung were reproduced by a mathematical model that can be readily extended to include further physiological and pathophysiological phenomena pertinent to the assessment of He/O_{2} therapy for specific diseases and phenotypes.
Declarations
Authors’ Affiliations
References
- Farré R, Navajas D: Assessment of expiratory flow limitation in chronic obstructive pulmonary disease: a new approach. Eur Respir J 2004, 23: 187–188. 10.1183/09031936.04.00131804View ArticleGoogle Scholar
- O'Donnell DE: Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease. Proc Am Thoracic Soc 2006, 3: 180–184. 10.1513/pats.200508-093DOView ArticleGoogle Scholar
- Permutt S: The role of the large airways on smooth muscle contraction in asthma. J Appl Physiol 2007, 103: 1457–1458. 10.1152/japplphysiol.00568.2007View ArticleGoogle Scholar
- Barbini P, Brighenti C, Gnudi G: A simulation study of expiratory flow limitation in obstructive patients during mechanical ventilation. Annals of Biomed Eng 2006, 34: 1879–1889. 10.1007/s10439-006-9213-6View ArticleGoogle Scholar
- Brighenti C, Barbini P, Gnudi G, Cevenini G, Pecchiari M, D'Angelo E: Helium-oxygen ventilation in the presence of expiratory flow-limitation: A model study. Respir Physiol Neurobiol 2007, 157: 326–334. 10.1016/j.resp.2006.12.012View ArticleGoogle Scholar
- D'Angelo E, Santus P, Civitillo MF, Centanni S, Pecchiari M: Expiratory flow-limitation and heliox breathing in resting and exercising COPD patients. Respir Physiol Neurobiol 2009, 169: 291–296. 10.1016/j.resp.2009.09.009View ArticleGoogle Scholar
- Pecchiari M, Pelucchi A, D'Angelo E, Foresi A, Milic-Emili J, D'Angelo E: Effect of heliox breathing on dynamic hyperinflation in COPD patients. Chest 2004, 125: 2075–2082. 10.1378/chest.125.6.2075View ArticleGoogle Scholar
- Palange P, Valli G, Onorati P, Antonucci R, Paoletti P, Rosato A, Manfredi F, Serra P: Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients. J Appl Physiol 2004, 97: 1637–1642. 10.1152/japplphysiol.01207.2003View ArticleGoogle Scholar
- Manthous CA, Hall JB, Melmed A, Caputo MA, Walter J, Klocksieben JM, Schmidt GA, Wood LDH: Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated patients with severe asthma. Am J Respir Crit Care Med 1995, 151: 310–314.View ArticleGoogle Scholar
- Papamoschou D: Theoretical validation of the respiratory benefits of helium-oxygen mixtures. Respir Physiol 1995, 99: 183–190. 10.1016/0034-5687(94)00071-7View ArticleGoogle Scholar
- Katz IM, Martin AR, Muller P-A, Terzibachi K, Feng C-H, Caillibotte G, Sandeau J, Texereau J: The ventilation distribution of helium-oxygen mixtures and the role of inertial losses in the presence of heterogeneous airway obstructions. J Biomechanics 2011, 44: 1137–1143. 10.1016/j.jbiomech.2011.01.022View ArticleGoogle Scholar
- de Lange EE, Altes TA, Patrie JT, Battiston JJ, Juersvich AP, Mugler JP III, Platts-Mills TA: Changes in regional airflow obstruction over time in the lungs of patients with asthma: Evaluation with 3He MR imaging. Radiology 2009, 250: 567–575. 10.1148/radiol.2502080188View ArticleGoogle Scholar
- Venegas JG, Schroeder T, Harris S, Winkler RT, Melo MFV: The distribution of ventilation during bronchoconstriction is patchy and bimodal: A PET imaging study. Resp Physiol Neurobiol 2005, 148: 57–64. 10.1016/j.resp.2005.05.023View ArticleGoogle Scholar
- Kurahashi K, Ohtsuka M, Usuda Y: Central airway occlusion underestimates intrinsic positive end-expiratory pressure: a numerical and physical simulation. Exp Lung Res 2009, 35: 756–769. 10.3109/01902140902878496View ArticleGoogle Scholar
- Diehl J-L, Peigne V, Guérot E, Faisy C, Lecourt L, Mercat A: Helium in the adult critical care setting. Annals of Intensive Care 2011, 1: 24. 10.1186/2110-5820-1-24View ArticleGoogle Scholar
- Otis AB, McKerrow CB, Bartlett RA, Mead J, McIlroy MB, Selverstone NJ, Radford EP: Mechanical factors in distribution of pulmonary ventilation. J Appl Physiol 1956, 8: 427–443.Google Scholar
- Silva CA M, Ventura CE: A simple model illustrating the respiratory system’s time constant concept. Adv Physiol Educ 2006, 30: 129–130. 10.1152/advan.00011.2006View ArticleGoogle Scholar
- Brunner JX, Laubscher TP, Banner MJ, Iotti G, Braschi A: Simple method to measure total expiratory time constant based on the passive expiratory flow-volume curve. Crit Care Med 1995, 23: 1117–1122. 10.1097/00003246-199506000-00019View ArticleGoogle Scholar
- Despas PJ, Leroux M, Macklem PT: Site of airway obstruction in asthma as determined by measuring maximal expiratory flow breathing air and a helium-oxygen mixture. J Clin Investig 1972, 51: 3235–3243. 10.1172/JCI107150View ArticleGoogle Scholar
- Hamilton Medical: Hamilton G5 Operator's Manual. 2008, 6–22. 624074/02Google Scholar
- Katz IM, Martin AR, Feng C-H, Majoral C, Caillibotte G, Marx T, Bazin J-E, Daviet C: Airway pressure distribution during xenon anesthesia: the insufflation phase at constant flow (volume controlled mode). Appl Cardiopulm Pathophysiol 2012, 16: 5–16.Google Scholar
- Lichtwarck-Aschoff M, Helmer A, Kawati R, Lattuada M, Sjostrand UH, Zugel N, Guttman J, Hedenstierna G: Good short-term agreement between measured and calculated tracheal pressure. Brit J Anesth 2003, 91: 239–48. 10.1093/bja/aeg169View ArticleGoogle Scholar
- Jarreau P-H, Louis B, Dassieu G, Desfrere L, Blanchard PW, Moriette G, Isabey D, Harf A: Estimation of inspiratory pressure drop in neonatal and pediatric endotracheal tubes. J Appl Physiol 1999, 87: 36–46.Google Scholar
- Katz I, Caillibotte G, Martin AR, Arpentinier P: Property value estimation for inhaled therapeutic binary gas mixtures: He, Xe, N2O, and N2 with O2. Med Gas Res 2011, 1: 28. 10.1186/2045-9912-1-28View ArticleGoogle Scholar
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