Role of Strain Rate in the Pathogenesis of Ventilator-Induced Lung Edema.

OBJECTIVE: Lungs behave as viscoelastic polymers. Harms of mechanical ventilation could then depend on not only amplitude (strain) but also velocity (strain rate) of lung deformation. Herein, we tested this hypothesis. DESIGN: Laboratory investigation. SETTING: Animal unit. SUBJECTS: Thirty healthy piglets. INTERVENTIONS: Two groups of animals were ventilated for 54 hours with matched lung strains (ratio between tidal volume and functional residual capacity) but different lung strain rates (ratio between strain and inspiratory time). Individual strains ranged between 0.6 and 3.5 in both groups. Piglets ventilated with low strain rates had an inspiratory-to-expiratory time ratio of 1:2-1:3. Those ventilated with high strain rates had much lower inspiratory-to-expiratory time ratios (down to 1:9). Respiratory rate was always 15 breaths/min. Lung viscoelastic behavior, with ventilator setting required per protocol, was "quantified" as dynamic respiratory system hysteresis (pressure-volume loop [in Joules]) and stress relaxation (airway pressure drop during an end-inspiratory pause [in cm H2O]). Primary outcome was the occurrence of pulmonary edema within 54 hours. MEASUREMENTS AND MAIN RESULTS: On average, the two study groups were ventilated with well-matched strains (2.1 ± 0.9 vs 2.1 ± 0.9; p = 0.864) but different strain rates (1.8 ± 0.8 vs 4.6 ± 1.5 s; p < 0.001), dynamic respiratory system hysteresis (0.6 ± 0.3 vs 1.4 ± 0.8 J; p = 0.001), and stress relaxation (3.1 ± 0.9 vs 5.0 ± 2.3 cm H2O; p = 0.008). The prevalence of pulmonary edema was 20% among piglets ventilated with low strain rates and 73% among those ventilated with high strain rates (p = 0.010). CONCLUSIONS: High strain rate is a risk factor for ventilator-induced pulmonary edema, possibly because it amplifies lung viscoelastic behavior.

Lung anatomy, energy load, and ventilator-induced lung injury.

BACKGROUND: High tidal volume can cause ventilator-induced lung injury (VILI), but positive end-expiratory pressure (PEEP) is thought to be protective. We aimed to find the volumetric VILI threshold and see whether PEEP is protective per se or indirectly. METHODS: In 76 pigs (22 ± 2 kg), we examined the lower and upper limits (30.9-59.7 mL/kg) of inspiratory capacity by computed tomography (CT) scan at 45 cmH2O pressure. The pigs underwent a 54-h mechanical ventilation with a global strain ((tidal volume (dynamic) + PEEP volume (static))/functional residual capacity) from 0.45 to 5.56. The dynamic strain ranged from 18 to 100 % of global strain. Twenty-nine pigs were ventilated with end-inspiratory volumes below the lower limit of inspiratory capacity (group "Below"), 38 within (group "Within"), and 9 above (group "Above"). VILI was defined as death and/or increased lung weight. RESULTS: "Below" pigs did not develop VILI; "Within" pigs developed lung edema, and 52 % died before the end of the experiment. The amount of edema was significantly related to dynamic strain (edema 188-153 × dynamic strain, R (2) = 0.48, p < 0.0001). In the "Above" group, 66 % of the pigs rapidly died but lung weight did not increase significantly. In pigs ventilated with similar tidal volume adding PEEP significantly increased mortality. CONCLUSIONS: The threshold for VILI is the lower limit of inspiratory capacity. Below this threshold, VILI does not occur. Within these limits, severe/lethal VILI occurs depending on the dynamic component. Above inspiratory capacity stress at rupture may occur. In healthy lungs, PEEP is protective only if associated with a reduced tidal volume; otherwise, it has no effect or is harmful.

Validation of computed tomography for measuring lung weight.

BACKGROUND: Lung weight characterises severity of pulmonary oedema and predicts response to mechanical ventilation. The aim of this study was to evaluate the accuracy of quantitative analysis of thorax computed tomography (CT) for measuring lung weight in pigs with or without pulmonary oedema. METHODS: Thirty-six pigs were mechanically ventilated with different tidal volumes and positive end-expiratory pressures that did or did not induce pulmonary oedema. After 54 h, they underwent thorax CT (CT in vivo ) and were then sacrificed and exsanguinated. Fourteen pigs underwent a second thorax CT (CTpost-exsang.) after exsanguination. Lungs were excised and weighed with a balance (balancepost-exsang.). Agreement between lung weights measured with the balance (considered as reference) and those estimated by quantitative analysis of CT was assessed with Bland-Altman plots. RESULTS: One animal unexpectedly died before CT in vivo . In 35 pigs, lung weight measured with balancepost-exsang. was 371 ± 184 g and that estimated with CT in vivo was 481 ± 189 g (p < 0.001). Bias between methods was -111 g (-35%) and limits of agreement were -176 (-63%) and -46 g (-8%). Measurement error was similar in animals with (-112 ± 45 g; n = 11) or without (-110 ± 27 g; n = 24) pulmonary oedema (p = 0.88). In 14 pigs with thorax CT after exsanguination, lung weight measured with balancepost-exsang. was 342 ± 165 g and that estimated with CTpost-exsang. was 352 ± 160 g (p = 0.02). Bias between methods was -9 g (-4%) and limits of agreement were -36 (-11%) and 17 g (3%). Measurement errors were similar in pigs with (-1 ± 26 g; n = 11) or without (-12 ± 7 g; n = 3) pulmonary oedema (p = 0.12). CONCLUSIONS: Compared to the balance, CT obtained in vivo constantly overestimated the lung weight, as it included pulmonary blood (whereas the balance did not). By contrast, CT obtained after exsanguination provided accurate and reproducible results.

High positive end-expiratory pressure: only a dam against oedema formation?

INTRODUCTION: Healthy piglets ventilated with no positive end-expiratory pressure (PEEP) and with tidal volume (VT) close to inspiratory capacity (IC) develop fatal pulmonary oedema within 36 h. In contrast, those ventilated with high PEEP and low VT, resulting in the same volume of gas inflated (close to IC), do not. If the real threat to the blood-gas barrier is lung overinflation, then a similar damage will occur with the two settings. If PEEP only hydrostatically counteracts fluid filtration, then its removal will lead to oedema formation, thus revealing the deleterious effects of overinflation. METHODS: Following baseline lung computed tomography (CT), five healthy piglets were ventilated with high PEEP (volume of gas around 75% of IC) and low VT (25% of IC) for 36 h. PEEP was then suddenly zeroed and low VT was maintained for 18 h. Oedema was diagnosed if final lung weight (measured on a balance following autopsy) exceeded the initial one (CT). RESULTS: Animals were ventilated with PEEP 18 ± 1 cmH2O (volume of gas 875 ± 178 ml, 89 ± 7% of IC) and VT 213 ± 10 ml (22 ± 5% of IC) for the first 36 h, and with no PEEP and VT 213 ± 10 ml for the last 18 h. On average, final lung weight was not higher, and actually it was even lower, than the initial one (284 ± 62 vs. 347 ± 36 g; P = 0.01). CONCLUSIONS: High PEEP (and low VT) do not merely impede fluid extravasation but rather preserve the integrity of the blood-gas barrier in healthy lungs.