Effect of airway constriction on ventilation inhomogeneity: multiple-breath washout indices and intrapulmonary...

Small airway dysfunction is an early and clinically important feature of many respiratory diseases but remains difficult to detect using conventional physiological tests. Multiple-breath washout (MBW) is widely used to assess ventilation heterogeneity; however, its sensitivity to the specific location and severity of airway narrowing is not fully understood.

Nitrogen MBW was simulated using a physiologically realistic computational airway model reconstructed from high-resolution chest CT imaging. Sixty-four airway constriction scenarios were examined, varying systematically by airway generation, constriction ratio, and constricted branch ratio. Standard MBW indices (LCI, S_acin, and S_cond) were evaluated alongside a novel intrapulmonary reverse flow (RF) metric. Sensitivity to airway structural changes was assessed using Spearman's rank correlation and multiple linear regression analyses.

MBW indices were predominantly sensitive to severe proximal constriction (Gen 5-9, ≥ 75% severity) with minimal changes observed in distal scenarios. RF showed strong correlations with all MBW indices, particularly S_acin (ρ = 0.93, p < 0.0001), and consistently increased with constriction at any given airway location. Notably, while S_acin has long been regarded as a marker of peripheral convective-diffusive heterogeneity at the acinar level, our findings demonstrate that convective heterogeneities arising from more proximal airway constrictions generate significant RF, which in turn influences the S_acin signal. In multivariable regression, RF emerged as the most sensitive marker of ventilation heterogeneity arising from airway structural alterations, explaining the greatest proportion of variance (Adj. R² = 0.933, p < 0.001), exceeding that of S_acin (0.826), LCI (0.732), and S_cond (0.564).

In simulations, RF was sensitive to ventilation abnormalities arising from mild and distal airway narrowing. As a physiologically interpretable, flow-based marker, RF offers a novel and complementary means of enhancing the sensitivity of MBW for the early detection and motivates further experimental and clinical validation. Importantly, by identifying RF as a convective link between central airway narrowing and peripheral washout behaviour, our study suggests that S_acin reflects a broader spectrum of ventilation disturbances than previously assumed, providing a new mechanistic basis for interpreting MBW indices.