The basic goals and objectives of ventilator management for acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are aimed at providing adequate gas exchange and minimizing barotraumas in the injured lung. Recently, strategies for the clinical management of ARDS have also focused on attempts to improve outcomes by preventing ventilator-associated lung injury (VALI).1–6 VALI refers to the additional injury imposed on a previously injured lung by mechanical ventilation, whereas ventilator-induced lung injury (VILI) refers to experimental models in which lung injury is induced by an injurious ventilation strategy.7 High tidal volume, positive end-expiratory pressure (PEEP), and recruitment manoeuvres are crucial for recruiting nonaerated lung regions. However, these strategies may simultaneously induce overinflation of normally aerated lung regions, which increases the risk of VALI. Lung stress and strain are the primary determinants of lung injury caused by a ventilator8 and avoiding overstress by adopting low tidal volume ventilation (LTV) is strongly recommended in the management of ARDS/ALI.5 In addition to overdistension, experimental models suggest that repeated opening and collapse of atelectatic lungs can also be another mechanism of lung injury through shear stress of peripheral airways.9,10 Thus, it is important to note that the reversal of atelectasis is an essential step in ventilatory support, and the so-called ‘open lung’ approach in managing ARDS is thought to attenuate the mechanical amplification of existing lung injury and improve patients' outcomes.1,11 However, the required mean airway pressure used in the open lung approach may be associated with haemodynamic side effects,12 and the effects of PEEP depend on the recruitability of lung tissue. Use of higher PEEP levels in patients with a lower percentage of potentially recruitable lung provides little benefit and may actually be harmful.13
Airway pressure release ventilation (APRV) is a pressure regulated and time cycle ventilator mode that allows spontaneous breathing at any phase of the ventilatory cycle. Reduction of intrathoracic pressure is expected during APRV, which favours haemodynamic stability.14 APRV may provide better alveolar recruitment at a lower peak airway pressure than conventional mechanical ventilation (CMV).15,16 APRV may also reduce the risk of both barotrauma and atelectrauma in patients with ALI/ARDS, as well as provide better ventilation–perfusion matching than other types of controlled mechanical ventilation.17,18 APRV may be one of the lung protective strategies in the management of ALI/ARDS.
The roles of biological markers in VILI or VALI have been investigated in both experimental and clinical studies. Interleukin-8 (IL-8) and other related CXC chemokines, IL-6, IL-1β, and tumour necrosis factor-α (TNF-α), have been found to decrease with protective ventilation strategies in experimental19,20 and clinical studies.4,21,22 High-mobility group box-1 (HMGB1), which is a 30 kDa, nonhistone chromatin-associated protein,23 has potent inflammatory properties.24 It has not only been identified as a late mediator of endotoxin-induced ALI,25–28 but it has also been suggested as a marker of VILI.29 To date, there has been no clinical or experimental study that investigates the effects of ventilator strategies on HMGB1 levels in ALI/ARDS. We hypothesized that APRV and LTV with high PEEP (10 cmH2O) may reduce bronchoalveolar fluid HMGB1 levels in comparison with CMV with low PEEP (3 cmH2O) in an experimental model of ALI induced by whole lung lavage (LAV).
All experimental protocols were reviewed and approved by the Animal Care and Use Committee of Tokyo Medical & Dental University and they were performed according to US National Institutes of Health guidelines. Twenty-one Japanese white rabbits that weighed between 3.1 and 3.3 kg were anaesthetized using intramuscular ketamine hydrochloride (20 mg kg−1) and pentobarbital (15 mg kg−1). With the animals supine, a midline cervical incision followed by tracheostomy was performed after subcutaneous infiltration with 1% lidocaine. The trachea was intubated using a tracheal tube (inner diameter, 3.5 mm). Mechanical ventilation [tidal volume, 10 ml kg−1; respiratory rate, 30 breaths min−1; inspiratory: expiratory (I/E) ratio, 1: 2; FIO2, 0.5; PEEP, 0] was started using the Evita XL (Dräger, Lübeck, Germany). The animals were paralysed by intramuscular injection of pancuronium (0.1 mg kg−1). A 20 G venous catheter was introduced through a jugular vein for fluid and drug infusion. Lactated Ringer's solution was infused intravenously at a rate of 10 ml kg−1 h−1 throughout the study. Anaesthesia was maintained using ketamine hydrochloride at 10 mg kg−1 h−1 and propofol at 10 mg kg−1 h−1. An arterial catheter was placed in the carotid artery to monitor arterial pressure and sample arterial blood. The arterial pressure was recorded on a polygraph system (RM6000, Nihon Kohden, Tokyo, Japan). Mean airway pressures obtained from the ventilator monitor reflected the average of the pressure throughout the entire breathing cycle. Blood sampling and baseline measurements of lung mechanics, haemodynamics, and arterial blood gases were performed after stabilization. Following baseline measurements, the FIO2 was increased to 1.0 and lung lavage was performed using warmed (37°C) normal saline (60 ml) to produce lung injury. The animals were disconnected from the ventilator and saline was instilled directly into the lungs via the tracheal tube. The animals were ventilated using the previous settings for 15 s, and 10 ml of lavaged fluid was recovered for the analysis of HMGB1 levels (baseline). Then, ventilation was continued for 60 s and the rest of the saline was recovered by gentle suctioning. This lavage procedure was repeated every 10 min until the PaO2/FIO2 was less than 150 torr. Sixty minutes after confirming the establishment of lung injury, control measurements were taken.
After establishment of lung injury, the animals were randomly assigned to three groups of seven animals each (CMV, LTV, and APRV groups). The animals in the LTV group and the CMV group were paralysed with pancuronium at 0.1 mg kg−1 h−1 intravenously, and animals in the APRV group were allowed spontaneous breathing. The animals in the CMV group were ventilated with a tidal volume of 10 ml kg−1, a respiratory rate of 30 breaths min−1, an I: E ratio of 1: 2, and a PEEP of 3 cmH2O, but the respiratory rate was allowed to increase to up to 40 breaths min−1 when the PaCO2 exceeded 50 torr. The animals in the LTV group were ventilated with a tidal volume of 6 ml kg−1, a respiratory rate of 40 breaths min−1, an I: E ratio of 1: 2, and a PEEP of 10 cmH2O. The animals in the APRV group were ventilated with a Phigh of 20 cmH2O, a Thigh of 2.9 s, a Plow of 5 cmH2O, and a Tlow of 0.15 s (Table 1).
Arterial blood samples were obtained before and after lung injury, as well as 60, 120, and 240 min after randomization to ventilation strategy to determine blood gases and plasma HMGB1 levels. Arterial blood specimens were analysed for PaO2, PaCO2, and pH (ABL700; Radiometer Medical ApS, Copenhagen, Denmark). Four hours after ventilatory treatment, the animals were sacrificed by injection of a pentobarbital overdose. The lungs and heart were then excised en bloc. Bronchoalveolar lavage fluid (BALF) was harvested from the left lung with 25 ml of normal saline. The solution was flushed in and out of the lung five times. The BALF, together with the fluid recovered on inducing lung injury, was then centrifuged at 3000 r.p.m. for 15 min at 4°C. Cell-free supernatant and serum were divided into several aliquots and stored at −80°C for measurement of HMGB1 levels. Serum and BALF HMGB1 levels were measured using enzyme-linked immunosorbent assay (HMGB1 ELISA Kit II; Shino-Test Co., Kanagawa, Japan). The right upper lobe of the lung was sampled for analysis of the wet-to-dry (W/D) weight ratio.
The right lower lobe of the lung was fixed by instillation of formaldehyde solution through the right main bronchus at 20 cmH2O. At least 48 h after fixation, the lung was embedded in paraffin. Then, 4 μm thick sections were stained with haematoxylin and eosin and examined under light microscopy. Three observers, who were blinded to the nature of the experiment, scored lung injury from 0 (no damage) to 3 (maximal damage), according to four assessment categories: alveolar congestion; oedema; infiltration/aggregation of neutrophils in the airspace or vessel walls; and alveolar distension or destruction. In addition, a total lung injury score was calculated by summing the histopathological scores.
Data values are expressed as means ± SD. All statistical analyses of recorded data were performed using the StatView statistical software package (J 4.5; Abacus Concepts, Berkeley, California, USA). All data except for histopathological, BALF HMGB1, and W/D weight ratio data were analysed using repeated-measures analysis of variance (ANOVA) to determine the effect of treatment. The intragroup comparisons of control data (after injury) and data obtained at 60, 120, and 240 min, and the intergroup comparisons at each time interval were performed using repeated-measures ANOVA. When a significant difference was noted, post-hoc analysis using Scheffe's method was performed within and between groups. Because BALF HMBG1 and W/D weight ratio data were collected at the end of experiment, they were analysed by one-way ANOVA followed by Scheffe's test for the comparison among three groups. For histopathological data, statistical significance was determined by ANOVA using the Kruskal–Wallis test, followed by the Mann–Whitney U-test. Values of P less than 0.05 were considered statistically significant.
Saline lavage produced a significant decrease in PaO2 and a significant increase in peak and plateau airway pressures (Tables 2 and 3). Lung injury showed progressive deterioration, as shown in the changes in values of PaO2, PaCO2, and plateau pressure in the CMV group.
The decreased PaO2/FIO2 values following induction of lung injury were significantly increased after treatment using LTV with high PEEP and APRV (Table 2). The PaO2/FIO2 values were higher in the LTV and APRV groups than in the CMV group. The PaCO2 values 60 and 120 min after treatment were higher in the APRV group than in the LTV group. The arterial blood pH decreased at the end of the study in the CMV group; this was considered to be due to PaCO2 elevation. The pH values were significantly higher in the LTV group than in the CMV group at the end of the experiment.
The values of heart rate (HR) were significantly higher in the APRV group than in the CMV and LTV groups after treatment. The mean blood pressure in the LTV group was transiently decreased following the start of treatment; the values were significantly lower than those in the CMV group. The values of mean blood pressure in the APRV group were almost identical to those in the CMV group.
The mean airway pressure was significantly elevated after starting LTV with high PEEP (from 6.7 ± 0.5 to 14.4 ± 1.4 cmH2O) or APRV (from 6.4 ± 1.4 to 18 ± 1.4 cmH2O), and the values were higher in the APRV group than in the LTV group (Table 3). There were no significant differences in plateau airway pressures among the three groups. The minute volume was increased in the APRV group; this was due to allowance for spontaneous breathing. As the spontaneous breathing rates changed every moment and were variable between the animals, the data are not shown.
Lung injury and barotraumas
Serum HMGB1 levels were unchanged before and after lung injury; however, BALF HMGB1 levels were elevated at the end of the experiment (Table 4). The BALF HMGB1 levels were significantly lower in the APRV and LTV groups at the end of the experiment than in the CMV group (P < 0.0001), and the values of the APRV group were also lower than those of the LTV group (P = 0.0391; Fig. 1).
Representative microscopic images are shown in Fig. 2. When individual injury variables were analysed, there were no significant differences in the histopathological evidence of atelectasis and alveolar/interstitial neutrophil infiltration between the groups (Table 5). The APRV-treated animals suffered less injury, as evidenced by the bleeding score, than the LTV-treated or CMV-treated animals (P = 0.0157 and P = 0.0128, respectively), but the total lung injury score of the APRV group compared with the animals ventilated with CMV with low PEEP or LTV with high PEEP was not significantly different.
The W/D weight ratios for the three groups of animals are shown in Fig. 3. The W/D weight ratios were significantly lower in the APRV group than in the CMV and LTV groups (6.81 ± 0.73 vs. 8.61 ± 1.06 and 8.63 ± 0.98, P = 0.0058 and P = 0.0050, respectively).
The present results indicate that APRV seemed more protective than the other CMVs in an experimental model of ARDS, because increases in BALF HMGB1 and pulmonary oedema caused by ALI were significantly attenuated in the APRV group.
At present, IL-6, IL-8, and TNF-α are known to modulate the inflammatory response in VILI/VALI,7 but, unfortunately, measurements of these mediators are difficult in rabbits, because ELISA kits for rabbits are not commercially available. As the amino acid sequence of HMGB1 is highly conserved among mammalian cells, HMGB1 may be used as a good marker of lung injury in rabbits. There was a trace of HMGB1 detected in the serum and BALF before injury, and serum HMGB1 levels were not elevated even after induction of lung injury. The reasons for no change in serum HMGB1 before and after lung injury can be explained by the origin of HMGB1 in this model. Unlike sepsis, bronchoalveolar lavage primarily injures peripheral airways and activates alveolar macrophages, which may be the source of HMGB1; thus, the changes in concentrations were more prominent in BALF than in serum. Ogawa et al.29 showed that alveolar macrophages and neutrophils were intensely immunoreactive for HMGB1 in the rabbit lung ventilated with a high tidal volume of 30 ml kg−1, and HMGB1 was increased in the cytoplasm of those inflammatory cells. In the same study, they showed the serum HMGB1 was undetectable or nearly undetectable even in the high tidal volume group, although the BALF HMGB1 in the high tidal volume group was significantly higher than in the small tidal volume or normal control groups. The present study demonstrated that prevention of atelectasis by application of high PEEP or Phigh with short Tlow reduced HMGB1 production in the lungs.
Recently, a lung stress and strain concept on lung injury caused by a ventilator has been advocated by Chiumello et al.8 ‘Stress’ is defined as the internal distribution of the counterforce per unit of area that balances and reacts to an external load and was represented by transpulmonary pressure. The associated deformation of the structure is called ‘strain’, which was represented by the ratio of volume change to the resting lung volume. APRV might reduce both stress and strain because APRV uses a longer inflation duration in recruited lung rather than a larger tidal volume or PEEP to recruit atelectatic lung units. In the present study, we determined the Phigh levels of the APRV group to be identical to the plateau airway pressures of the LTV group. From the results of histopathology, overdistension was not definitely significant in the APRV group compared with the LTV group, despite the higher mean airway pressure. Certainly, the alveolar stresses associated with a long inflation time and/or the rapid flow reversals associated with the deflation–reinflation APRV pattern may have an injurious effect,30 but we do not expect complete lung deflation in this mode in order to maintain oxygenation. And the frequency of pressure release was less in the APRV group compared with the respiratory rate in the LTV group (20 vs. 40 min−1). Therefore, it is speculated that the lower BALF HMGB1 levels in the APRV group may be partly explained by a reduction in the frequency and degree of shear stress during ventilation. It is important to remember that the intrathoracic inflation pressure generated by the respiratory muscles during the spontaneous breaths will add to the end-inflation volume and stretching pressure during APRV.30 End-inflation transpulmonary pressure (stress) would be higher than the applied inflation airway pressure and could be higher than other conventional assist-control modes. Sarge and Talmor31,32 suggested that measurement of oesophageal pressure, which estimates intrathoracic pressure, would provide useful information regarding transpulmonary pressure and optimal PEEP during the ventilatory management of ALI/ARDS. The optimal PEEP level in the LTV group might be provided by oesophageal pressure.
In the present study, the PaCO2 levels were significantly higher in the APRV group than in the LTV group. As it has been suggested that hypercapnic acidosis attenuates VALI,33–35 APRV might have been less protective with PaCO2 levels similar to those observed in LTV. Certainly, this also remains speculative and addressing the issue would have required another study group (i.e. low tidal volume with permissive hypercapnia), which was beyond the scope of the present investigation.
Although the mean airway pressure was kept higher, the blood pressure in the APRV group was well maintained in comparison with the LTV group. Mild respiratory acidosis might contribute to haemodynamic stability, because the HR was significantly elevated in the APRV group. The negative effects of mechanical ventilation on haemodynamics were also ameliorated by the spontaneous breathing component of APRV.36,37 The animals can breathe throughout the entire ventilator cycle and spontaneous breathing may reduce intrathoracic pressure compared with LTV with high PEEP despite identical mean airway pressures. Kaplan et al.37 demonstrated that the cardiac index rose from 3.2 to 4.6 l min−1 m−2 when patients with ARDS who were managed with inverse ratio pressure control ventilation were switched to APRV with spontaneous breathing. Furthermore, intrinsic PEEP due to high ventilatory rates in the LTV group might affect intrathoracic pressure and reduce mean arterial pressure.
Although there was no difference in lung histology except for bleeding scores, the lower W/D ratio of the lungs in the APRV group seems surprising. Mechanical ventilation with high intrathoracic pressure can impede lymphatic return.38 Lattuada and Hedenstierna39 demonstrated that spontaneous breathing, compared with mechanical ventilation, increased lymph flow from the abdomen to the central circulation in an endotoxin sepsis model. Preserved respiratory muscle activity might account for the difference between the APRV group and the LTV group.
There are several limitations to the comparison between LTV and APRV as used in the study that should be addressed. First, there has been no information on the extent to which APRV, LTV, or CMV induces HMGB1 release in normal healthy lungs. Clinically, APRV and LTV with high PEEP are not performed in normal healthy lungs; however, this information may be necessary in order to evaluate how much APRV, LTV, or CMV by themselves induce HMGB1 release in the injured lung. Unfortunately, we cannot conclude whether CMV with low PEEP enhanced existing lung injury or APRV attenuated progression of lung injury, but APRV was the most protective among the three ventilator strategies, at least in the atelectatic lungs.
Second, this study was undertaken using small animals in the acute phase of lung injury induced by saline lavage. The present results may not be applicable to adult patients with ALI/ARDS, but they suggest that APRV can be done in infants or paediatric patients with ALI/ARDS. Clinical trials with APRV have been conducted almost exclusively on adults, with only a few paediatric reports in the literature.40,41 A comparative study with high-frequency oscillatory ventilation (HFOV) would be attractive in paediatric patients with ALI/ARDS.
Third, the present study's duration was short, as per the experimental protocol, and could not examine the changes in intrapulmonary HMGB1 over time. The histopathological findings did not show overdistension in the APRV group, but the effect of high mean airway pressure over a prolonged, sustained period should be investigated in long-term studies.
Fourth, we demonstrated that HMGB1 might be a good marker for the inflammatory response in VALI in the current study, but the relationship between HMGB1 and other inflammatory cytokines is still unknown, especially with respect to which one comes first in the inflammatory cascades of biotrauma. In order to substantiate the claim that APRV reduces the inflammatory response, the inflammatory response should be characterized in greater detail by measuring more pro-inflammatory and anti-inflammatory mediators; however, it is difficult to clarify the overall responses in rabbits.
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