The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model

Abstract

Background: Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH₂O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain).

Methods: Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + H_DS, n = 6) and (2) over-distension + low dynamic strain (OD + L_DS, n = 6). OD was caused by setting the inspiratory pressure at 40 cmH₂O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy.

Results: In normal tissue (N_T), OD + L_DS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + H_DS. In acutely injured tissue (ALI_T), OD + L_DS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + H_DS.

Conclusions: Both N_T and ALI_T are resistant to VILI caused by OD alone, but when combined with a H_DS, significant tissue injury develops.

Keywords: Acute lung injury; Acute respiratory distress syndrome (ARDS); Alveolar collapse and reexpansion; Alveolar over-distension; Atelectasis; Dynamic strain; Heterogeneous lung; Heterogeneous lung inflation; Over-distension; Static strain; Strain; Stress; Ventilator-induced lung injury (VILI).

Fig. 1

a) Schematic representing trachea as well as mainstem, lobar, and sublobar bronchi in pigs. Numbers label b) representative bronchoscopic images at those specific points in the tracheobronchial tree. The airway was visualized, and the bronchoscope was advanced down the right mainstem bronchus first, until reaching point 6. 0.75 mL/kg of 1% Tween was instilled at this point in order to specifically target dependent lung regions. The bronchoscope was withdrawn to the carina and then advanced down the left mainstem bronchus until reaching point 9, and another 0.75 mL/kg of 1% Tween was administered. The bronchoscope was completely withdrawn at this point and the animals randomized into two groups. (Reprinted with permission) [15]

Fig. 2

a Typical airway pressure release ventilation (APRV) airway Pressure and Flow curves. Correctly set APRV has a very brief duration at expiration (time at low pressure (T _Low)) and extended inspiratory duration (time at high pressure (T _High)) [17]. The T_High is ~90% of each breath. The two other APRV settings are the pressure at inspiration (P _High) and at expiration (P _Low). P_High is set sufficiently high to recruit and open alveoli, and P_Low is always set at 0 cmH₂O to facilitate expiratory flow. However, T_Low is sufficiently short such that end-expiratory pressure (P_Low) never reaches 0 cmH₂O identified by the tracheal pressure (green line) maintaining a level of PEEP. b This figure summarizes our novel method to maintain alveolar stability by adaptively adjusting the expiratory duration as directed by the expiratory flow curve. The rate of lung collapse is seen in the Normal (slope 45°) and acutely injured lung (ARDS, slope 30°). ARDS causes a more rapid lung collapse due to decreased lung compliance. Our preliminary studies have shown that if the ratio of the peak expiratory flow (PEF, 60 L/min) to the end-expiratory flow (EEF, 45 L/min) (EEF/PEF) is equal to 75%, this expiratory duration (0.5 s) is sufficiently brief to stabilize alveoli [14, 38]. The lung with ARDS collapses more rapidly such that the EEF/PEF of 75% identifies a shorter expiratory duration of 0.45s is necessary to stabilize alveoli. Although the EEF/PEF is fixed, the expiratory duration is not, but rather is adaptive and will stabilize alveoli regardless of lung injury severity. Thus, this method of setting expiratory duration is adaptive to changes in lung pathophysiology and personalizes the mechanical breath to each individual patient. The values presented in this legend are just an example and may not reflect the actual values obtained in real life situations. (Reprinted with permission) [18]

Fig. 3

The effect of both high (OD + H _DS) and low (OD + L _DS) dynamic strain on total protein concentration, matrix metalloproteinase-9 (MMP-9) activity, and both surfactant protein A (SP-A) and B (SP-B) levels in bronchoalveolar lavage fluid (BALF) of normal (N _T) and acutely injured (ALI _T) lung tissue. a Low dynamic strain (OD + L_DS) prevented the increase in total protein in normal lung tissue (N_T). b Low dynamic strain (OD + L_DS) prevented the increase in MMP-9 activity in N_T. c High dynamic strain (OD + H_DS) caused a decrease in SP-A in N_T. d No differences in SP-B were seen with high or low dynamic strain or in normal or acutely injured lung tissue. Data mean ± SD

Fig. 4

Pulmonary edema measured as a lung wet/dry weight ratio following ventilation with high (OD + H _DS) and low (OD + L _DS) dynamic strain and in normal (N _T) and acutely injured (ALI _T) lung tissue. Data mean ± SD

Fig. 5

The percent change in both the duration at expiration (T _Low), which is set by changes in lung physiology (see Fig. 2b) and the tidal volume (Vt) over time in both the high (OD + H _DS) and low (OD + L _DS) dynamic strain groups. a T_Low is set by changing lung physiology and will require shortening with increasing lung pathology/elastance. This suggests worsening lung injury with time in the OD + H_DS group but not in the OD + L_DS group. b Shortening T_Low, with increasing lung pathology, will necessitate a reduction in Vt over time, which was seen in the OD + H_DS group but not in the OD + L_DS group. (○, mean of the distribution)

Fig. 6

a–d (6a) low (OD +L_DS)  and (6b) high (OD + H_DS) dynamic strain and in normal (N_T) and acutely injured (ALI_T) lung tissue of the entire lung and the cut lung surface (6c–d) at necropsy. Lungs were inflated to 25 cmH₂O to standardize lung volume history

Fig. 7

Histopathology following ventilation with high (OD + H _DS) and low (OD + L _DS) dynamic strain and in normal (N _T) and acutely injured (ALI _T) lung tissue. Arrows indicate cell infiltration, while arrowheads indicate the presence of fibrin deposits in the air compartment; both had higher incidence with H_DS irrespective of injury. Stars highlight alveolar patency, which was greater with L_DS