Mol Biol Rep (2014) 41:1325–1333 DOI 10.1007/s11033-013-2978-4
Effects of recruitment maneuvers with PEEP on lung volume distribution in canine models of direct and indirect lung injury Yi Yang • Qiuhua Chen • Songqiao Liu • Yingzi Huang • Ling Liu • Xiaoyan Wu • Guangjian Chen • Jiyang Jin • Gaojun Teng • Haibo Qiu
Received: 19 October 2012 / Accepted: 24 December 2013 / Published online: 4 January 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Lung recruitment maneuvers can help open collapsed lung units for sufficient oxygenation, and positive end expiratory pressure (PEEP) is used to keep the lung open after recruitment. However, the application of high PEEP levels may play a significant role in causing regional lung hyperinflation during mechanical ventilation. The authors sought to study the effects of PEEP targeting optimal oxygenation on regional lung volume distribution in a direct and an indirect acute respiratory distress syndrome (ARDS) model. ARDS was induced by either surfactant depletion or oleic acid injection in dogs. After lung recruitment, PEEP was decreased from 20 to 10 cmH2O in 2 cmH2O steps every 10 min to examine regional lung aeration by using computed tomography. Lung injury appeared to be localized in the model of surfactant depletion while it widely diffused after oleic acid infusion. At PEEP levels that achieved optimal oxygenation, nonaerated lung units decreased and normally aerated lung units enhanced, but hyperinflated areas increased significantly in both models (P \ 0.05). Hyperinflated areas were greater in the surfactant depletion model than in the oleic acid model at PEEP levels applied (P \ 0.05). Optimal oxygenation guided PEEP may cause hyperinflated in both
focal lung injury and diffused lung injury post lung recruitment. Hyperinflation was more susceptible in focal lung injury than in diffused lung injury post lung recruitment. Keywords ARDS Mechanical ventilation PEEP Hyperinflation Abbreviations ARDS Acute respiratory distress syndrome PEEP Positive end expiratory pressure VT Tidal volume FiO2 Fraction of inspired oxygen CPAP Continuous positive airway pressure Ppeak Peak airway pressure R Airway resistance Pplat Airway plateau pressure Cst,rs Static compliance HR Heart rate MAP Mean arterial pressure CI Cardiac index SVR Systemic vascular resistance
Yi Yang and Qiuhua Chen have contributed equally to this work.
Introduction Y. Yang Q. Chen S. Liu Y. Huang L. Liu X. Wu G. Chen H. Qiu (&) Department of Critical Care Medicine, Nanjing Zhong-Da Hospital, Southeast University, 87 Dingjiaqiao Rd, Nanjing 210009, People’s Republic of China e-mail: [email protected] J. Jin G. Teng Department of Radiology, Nanjing Zhong-Da Hospital, Southeast University, Nanjing, People’s Republic of China
Acute respiratory distress syndrome (ARDS) is associated with altered gas exchange and refractory hypoxia as a result of alveolar collapse [1]. Mechanical ventilation at low tidal volume with lung recruitment maneuvers provides an effective strategy in the treatment of acute lung injury [2, 3]. Lung recruitment maneuver helps open lung units for greater oxygenation, and positive end-expiratory
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pressure (PEEP) is used to keep the lung open after recruitment. However, increasing PEEP can also simultaneously result in overinflation of previously normally ventilated lung regions, leading to worsens heterogeneity [4]. A recent study reported hyperinflation of the normally aerated compartment in ARDS patients despite the use of carefully limited tidal volume and plateau pressure [5], suggesting that while keeping lung open PEEP plays a crucial role causing hyperinflation. An optimal range of PEEP levels during recruitment would allow the lung to be open for optimal or sufficient oxygenation while minimizing overdistension of normally aerated lung units [6, 7]. The assessment of regional lung aeration by CT scan provides a useful tool for evaluating the balance between alveolar collapse and overdistension [8, 9]. Most previous studies focused the investigation of lung recruitments on a given lung injury model, while the lung volume distribution in response to a given recruitment maneuver was not well addressed simultaneously in direct and indirect lung injury models. We hypothesized that PEEP targeting optimal oxygenation results in heterogeneous distribution of hyperinflation in models of primary and secondary acute lung injury. We show in dog models that the lung is prone to develop hyperinflation after direct (primary) lung injury induced by surfactant depletion while it becomes more resistant to hyperinflation during indirect (secondary) lung injury induced by oleic acid injection, in response to a given recruitment maneuver.
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Munich, Germany) for measurement of cardiac output. The PiCCO system was calibrated at each PEEP level during the subsequent PEEP trial. After 30 min of stabilization, the animals were randomly divided into two groups and received either surfactant depletion by repeated lung lavage using normal saline to achieve a PaO2/FiO2 ratio below 100 mmHg defined as ARDS [10], or oleic acid infusion i.v. at 0.2 mL/ kg mixed with an equal amount of autologous blood. This dose of oleic acid was sufficient to obtain a PaO2/FiO2 ratio less than 100 mmHg [11]. A stable lung injury model was considered when the PaO2/FiO2 value remained \100 mmHg within the next 30 min. All animals met the criteria. Lung recruitment maneuver and decremental PEEP trial Lung recruitment maneuvers were performed by applying 40 cmH2O PEEP for 30 s. in continuous positive airway pressure (CPAP) mode [12]. This maneuver was repeated every 5 min until PaO2/FiO2 reached C400 mmHg defined as maximal oxygenation, or until there was\10 % changes in PaO2/FiO2 values between two consecutive measurements defined as maximal lung recruitment [13]. PEEP was set at 20 cmH2O after the lung recruitment maneuver, and PEEP decremental trial was followed (PEEP reduction by 2 cmH2O steps every 10 min until 10 cmH2O was reached). Measurement of gas exchange and lung mechanics
Materials and methods Animal preparation The protocol was approved by the Institutional Animal Use and Care Committee of Southeast University, Nanjing, People’s Republic of China. 16 healthy mongrel dogs (9 males and 7 females) weighing 15 ± 1 kg (Jiangsu Academy of Agricultural Sciences, Jiangsu, China) were anesthetized with intravenous (i.v.) injection of sodium pentobarbital (30 mg/kg) followed by a continuous infusion at 1–2 mg/kg h-1. Muscle relaxation was achieved by the administration of succinylcholine chloride at a loading dose of 10 mg i.v. followed by continuous infusion at 1 mg/kg h-1. Normal saline was administered at 6 mL/ kg h-1 in all animals. A tracheotomy was performed for intratracheal intubation in all animals who were mechanically ventilated (Evita XL ventilator, Dra¨ger, Germany) with volume-control at a tidal volume (VT) of 10 mL/kg, a respiratory rate of 30 breaths/min, a fraction of inspired oxygen (FiO2) 1.0, and PEEP 5 cmH2O. The right femoral artery and the right jugular vein were catheterized and connected to a PiCCO system (Pulsion Medical System,
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Arterial blood gases were measured at all PEEP levels (Nova-M, Waltham, MA, USA). The volume of blood draw was 0.5 mL each time for a total of 20 times for a dog of total blood volume of *80 mL/kg of body weight [14]. Peak airway pressure (Ppeak) and airway resistance (R) were continuously monitored by the ventilator. Airway plateau pressure (Pplat) was measured at the end of an inspiratory pause of 5 s. Static compliance (Cst,rs) was calculated according to formula VT/(Pplat–PEEP). CT protocol and analysis The CT scans were performed in the supine position for the whole lung from apex to bottom. The endotracheal tube connected to the Y-piece of the ventilator circuit was occluded by a clamp at end-expiration while lung morphology by CT scan was conducted at baseline, induction of lung injury, completion of recruitment and at all PEEP levels. A 64-slice spiral CT (Siemens, Germany) was set at 120 kV, currency of 140 mA; collimation of 0.6 mm, rotation time of 0.33 s, pitch 1.2, field of view 204 mm, and bed speed of 23.78 mm/s. The lung aeration was constructed by scanning slices at a thickness of 3 mm,
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interval at 3 mm with matrix pixels of 512 9 512. In general, 70–100 slices were scanned per lung, depending on the lung volume. Lung volumes were calculated from the lung density and expressed in Hounsfield units. Three-dimensional lung was reconstructed by Pulmo software (Siemens, Germany). The regions were classified as nonaerated (density between ?100 and -99 Hounsfield units), poorly aerated (-100 and -499), normally aerated (-500 and -899), and hyperinflated (-900 and -1,000) [15]. The fraction of recruitment and hyperinflation induced by PEEP were calculated as previously described [16].
number of normally aerated and hyperinflated lung units (Fig. 3). Hyperinflated areas were greater in the surfactant depletion model than in the oleic acid model at all PEEP levels (P \ 0.05). Using three-dimensional lung reconstruction, it showed that hyperinflation occurred frequently in non-dependent zones, whereas recruitment lung units mostly occurred in dependent zones (Fig. 4). Figure 5 shows the fraction of recruitment and hyperinflation induced by PEEP in both groups, a balanced ratio of recruitment and hyperinflation took place at PEEP 10 and 14 cmH2O in the surfactant depletion and oleic acid model, respectively.
Statistical analysis
Gas exchange, hemodynamics and lung mechanics
Statistics were performed using SPSS (SPSS Inc., Chicago, IL, USA). Kolmogorov–Smirnov Tests were conducted for normality testing, followed by t tests for analysis between groups or by general linear model of repeated-measurements for analysis within a group. In the case that the data was not normally distributed, such as nonareated and hyperinflated lung areas, nonparametric tests were used. The Two Independent Samples Test was used for comparison between two groups, and the Tests for Several Related Samples was used for comparison within a group. Data are reported as mean ± SD. Significance was considered as P \ 0.05.
Twelve animals reached optimal oxygenation defined as the PaO2/FiO2 ratio C400 mmHg, and four animals achieved optimal lung recruitment defined as PaO2/FiO2 \10 % between two consecutive maneuvers. A similar optimal oxygenation was achieved at a PEEP 12 and 18 cmH2O in the surfactant depletion and the oleic acid group, respectively (P \ 0.05). The maximal values of Cst,rs was achieved at a PEEP level of 12 cmH2O in the surfactant depletion model, while Similar optimal oxygenation was obtained at PEEP 18 cmH2O and the highest compliance occurred at PEEP 10 cmH2O in the oleic acid model (18 vs. 10 cmH2O, P \ 0.05) (Table 2).
Results Discussion Acute lung injury models There was no difference in hemodynamics, gas exchange, or respiratory parameters at baseline between two kind models of ARDS (Tables 1, 2). Heart rate (HR), mean arterial pressure (MAP), cardiac index (CI) and systemic vascular resistance (SVR) were stable in the surfactant depletion model, while after oleic acid injection, CI decreased, but HR and MAP maintained relatively stable as a result of an increased SVR (Table 1). Lung injury was heterogeneously distributed following surfactant depletion: normal aerated alveoli were seen mostly in ventral areas (non-dependent), while atelectasis and poorly aerated alveoli were frequently found in dorsal areas. Alveolar collapse appeared to be gravity-dependent (dependent). On the contrary, lung injury appeared to be widely diffused in the oleic acid model (Figs. 1, 2). Lung volume distribution during PEEP trial In general, a higher PEEP level was associated with a lower number of nonaerated lung units and an increased
There are several novel findings in the present study: (1) PEEP titrated to achieve optimal oxygenation induced lung hyperinflation in both the surfactant depletion and the oleic acid model; (2) The lung was prone to develop heterogeneous hyperinflation after lavage injury, while it was resistant to recruitment maneuver following oleic acid induced-injury; and (3) The balanced ratio of recruitment and hyperinflation fraction took place at PEEP 10 and 14 cmH2O in the surfactant depletion and oleic acid model, much lower than PEEP titrated to achieve optimal oxygenation. Our models shows that lung injury was localized in the surfactant depletion model and was widely diffuse in the oleic acid infusion model. This observation may be explained by an uneven distribution of the lavage fluids administered within the lung in the surfactant depletion model, while a relatively equal allocation of disruption within the lung following intravenous infusion of oleic acid. Our results are consistent with a previous study showing significant heterogeneous lung injury after surfactant depletion in sheep [4]. The investigators reported
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123
16.6 ± 8.1
2,654 ± 1,501
Oleic acid
4,125 ± 2,084
2,933 ± 1,152
35.9 ± 10.9
#
38.1 ± 12.2#
3.8 ± 1.1 2.9 ± 1.0#
5.0 ± 1.3
5.0 ± 2.1
133 ± 30
133 ± 27
140 ± 21
115 ± 28
Injury
4,312 ± 3,430
5,133 ± 2,742#
41.0 ± 9.4
#
40.4 ± 10.2#
2.2 ± 1.1#* 3.0 ± 1.4#
3,921 ± 2,146
4,283 ± 1,888
41.3 ± 9.5
#
35.7 ± 12.2#
2.4 ± 0.7#* 2.7 ± 1.0#
10.1 ± 3.3
#*
#*
9.6 ± 4.6
10.1 ± 2.3#*
122 ± 38
127 ± 29
138 ± 29
124 ± 22
18
9.4 ± 3.0#*
124 ± 28
121 ± 28
138 ± 27
116 ± 20
20
Decremental PEEP trial (cmH2O)
3,851 ± 1,463
5,613 ± 2,781#
43.0 ± 9.9
#
35.7 ± 10.7#
1.9 ± 0.7#* 2.7 ± 1.0#
9.1 ± 2.6
#*
8.6 ± 2.1#*
127 ± 32
124 ± 27
140 ± 33
122 ± 27
16
4,304 ± 2,248
4,318 ± 1,765
44.0 ± 9.3
#
34.9 ± 10.5#
2.4 ± 0.7#* 2.6 ± 1.0#
8.6 ± 3.0
#*
8.6 ± 1.7#*
127 ± 31
125 ± 27
142 ± 37
124 ± 28
14
4,118 ± 2,161
4,423 ± 1,916
44.9 ± 7.4
#
35.4 ± 9.6#
2.4 ± 0.6#* 2.8 ± 1.1#
8.6 ± 2.3
#*
7.0 ± 2.4
129 ± 41
126 ± 26
144 ± 38
121 ± 26
12
#
P \ 0.05 vs. Baseline *P \ 0.05 vs. Injury;
P \ 0.05 vs. PEEP 20 cmH2O. N = 8
PEEP positive end-expiratory pressure, HR heart rate, MAP mean arterial pressure, CVP central venous pressure, CI cardiac index, EVLWI extra vascular lung water index
2,364 ± 858
Surfactant depletion
SVRI (dyn.s m cm )
-5
Oleic acid
2
13.8 ± 4.1
4.7 ± 2.2 5.2 ± 2.9
Surfactant depletion
EVLWI (mL/kg)
Surfactant depletion Oleic acid
CI (L min
m)
5.8 ± 1.3
2
Oleic acid
-1
5.6 ± 0.9
Surfactant depletion
CVP (mmHg)
128 ± 23
136 ± 18
Surfactant depletion
Oleic acid
MAP (mmHg)
141 ± 19
162 ± 10
Surfactant depletion
Oleic acid
HR (bpm)
Baseline
Table 1 Hemodynamic variables before and during decremental PEEP trial
3,284 ± 1,300
5,287 ± 3,445#
40.8 ± 9.0#
36.3 ± 7.3#
2.4 ± 1.0#* 3.2 ± 1.0#
8.5 ± 1.9#*
6.4 ± 2.3
129 ± 32
130 ± 24
139 ± 35
123 ± 24
10
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Table 2 Blood gas exchange and respiratory variables during decremental PEEP trial Baseline
Decremental PEEP trial (cmH2O)
Injury
20
18
16
14
12
10
PaO2/FiO2 Surfactant depletion
487 ± 66
74 ± 23#
492 ± 71*
438 ± 53*
423 ± 101*
424 ± 62*
401 ± 63#*
365 ± 89#*
Oleic acid
510 ± 68
83 ± 23#
455 ± 65*
394 ± 67#*
356 ± 80#*
306 ± 140#*
245 ± 128#* à
211 ± 127#* à
PaCO2 Surfactant depletion
43 ± 16
51 ± 10
65 ± 14
62 ± 17
65 ± 18
60 ± 24
55 ± 20
48 ± 16
Oleic acid
47 ± 15
68 ± 18
78 ± 14
80 ± 20
77 ± 16
74 ± 20
75 ± 19
62 ± 19
13 ± 2
21 ± 7#
39 ± 7#*
36 ± 9#*
32 ± 8#*
29 ± 7#
26 ± 6#
24 ± 6#
13 ± 4
18 ± 3#
36 ± 3#*
33 ± 3#*
30 ± 3#*
28 ± 3#*
25 ± 4#*
23 ± 3#*
11 ± 1
19 ± 7#
36 ± 7#*
33 ± 8#*
30 ± 8#*
26 ± 6#
23 ± 6#
21 ± 6#
12 ± 3
16 ± 2
#
#*
6±1
12 ± 3#
6±1
13 ± 4
#
29 ± 9
17 ± 11#
Ppeak (cmH2O) Surfactant depletion Oleic acid Pplat (cmH2O) Surfactant depletion Oleic acid
35 ± 3
31 ± 2
#*
#*
#*
28 ± 2
26 ± 3
9 ± 2#*
8 ± 2#*
22 ± 2
#*
20 ± 2#*
-1
R (cmH2O/s L ) Surfactant depletion Oleic acid
9 ± 2#* 10 ± 3
#*
9 ± 2#* 10 ± 3
#*
9±3
#*
10 ± 3
#*
9 ± 2#* 9±3
#*
9 ± 3#* 10 ± 3#*
Cst (mL/cmH2O) Surfactant depletion Oleic acid
26 ± 9
14 ± 2
#
11 ± 4#
12 ± 4#
14 ± 5#
16 ± 6#
18 ± 7#
#
#
#
#
#
11 ± 3
12 ± 3
13 ± 3
14 ± 4
15 ± 4
17 ± 7# 16 ± 5#
PEEP positive end-expiratory pressure, PaO2/FiO2 arterial oxygen tension/fraction of inspiratory oxygen, Ppeak peak airway pressure, Pplat plateau pressure, R airway resistance, Cst static compliance #
P \ 0.05 versus Baseline
*
P \ 0.05 versus Injury; P \ 0.05 versus PEEP 20 cmH2O;
that the regional P–V curves closely resembled the overall P–V curve in terms of the shape and inflection points in the diffused injury, but were dramatically different from the overall P–V curve in localized alveolar injury [4]. Our CT scan results provide direct evidence to show heterogeneous alveolar injury. However, another study showed no difference in the pattern of lung injury following surfactant depletion and oleic acid injection in pigs [17]. The different observations may be due to different definitions of lung injury and the methods of data analysis used. ARDS was defined as a PaO2/FiO2 ratio \100 mmHg in our study, whereas a ratio of 200 mmHg was used in the previous study [17]. Moreover, a whole-lung CT scan was performed to analyze a total of 70–100 slices per lung in our study, while two slices per lung were scanned and analyzed in the previous study that might have missed some detailed lung structure [17]. The heterogeneity of lung injury may have contributed to the greater response of hyperinflated area during recruitment after lung lavage. In ARDS patient, Nieszkowska et al. [18] reported lung overinflation in caudal and nondependent lung regions after recruitment maneuver in more than one-third population studied. Grasso et al. [19] also found evidence of alveolar hyperinflation in patients with focal ARDS who were ventilated with the ARDSnet protocol. A likely explanation is that the
à
P \ 0.05 versus Surfactant depletion. N = 8
collapsed lung regions were recruited in a PEEP-dependent manner while the previously normal regions were prone to develop overinflation in response to a given recruitment maneuver. Hence, the overinflation was a consequence of the underlying disease process as well as a result of the use of excessive PEEP and driving pressure. We demonstrated that the oleic acid-induced lung injury model responded differently than the lavage model for a given PEEP level. Higher PEEP levels were required to recruit the lung in the oleic acid model perhaps due to more severe damage and stiffer lungs, thus hyperinflation was less dramatic compared to the lavage model. Taken together, these animal and human studies suggest the use of PEEP levels following recruitment maneuver should be individualized based on different types of lung injury, and hyperinflation occurred more frequently in heterogeneous alveolar injury conditions such as surfactant deficiency. CT scan techniques have been used to study lung volume changes under mechanical ventilation in animal models and in human with ARDS [20–22]. In healthy anesthetized piglets, the use of PEEP at 16 cmH2O resulted in hyperinflation that was decreased when PEEP was progressively reduced to zero [20]. In a rabbit model of lung lavage, the application of dynamic CT detected changes of lung aeration in response to mechanical ventilation under either positive or negative pressure [21]. In patients with
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Fig. 1 Pathologic appearance following induction of acute lung injury. Surfactant depletion induced localized injury and oleic acid injection produced widely diffused injury
Fig. 2 Representative CT scan illustration during a decremental PEEP trial in surfactant depletion and oleic acid models
ARDS a thoracic spiral CT scan was performed at zero PEEP and PEEP 15 cmH2O. A significant correlation was found between PEEP-induced alveolar recruitment and increase in PaO2 [22]. Our results are in agreement with previous reports showing that CT scans provide a useful tool for evaluation of lung volume distribution. The present study may help us to search for optimal PEEP levels by which significant recruitment and oxygenation would be achieved without causing significant
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hyperinflation. We found that PEEP titrated to achieve optimal oxygenation resulted in great hyperinflated lung units in both the surfactant depletion and oleic acid model. A balanced ratio of recruitment and hyperinflation took place at PEEP 10 and 14 cmH2O in the surfactant depletion and oleic acid model, respectively, which were lower than the PEEP levels achieving optimal oxygen. This finding might suggest that the measurement of the balanced ratio of recruitment and hyperinflation can be used to choose the optimal range of
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Fig. 3 Lung volume distribution during a decremental PEEP trial in surfactant depletion and oleic acid infusion models. PEEP positive endexpiratory pressure. * P \ 0.05 versus Injury; P \ 0.05 versus PEEP 20 cmH2O; à P \ 0.05 versus Surfactant depletion. N = 8 per model Fig. 4 A representative alveolar aeration constructed by CT scan during a PEEP decremental trial after surfactant depletion or oleic acid injection. Hyperinflation occurred in nondependent lung regions, whereas recruitment occurred in dependent regions, hyperinflated areas were increased much more in surfactant depletion model than oleic acid model. Hyperinflation (yellow), normal aeration (blue), poorly aeration (red), nonaeration (deep red). (Color figure online)
PEEP levels. But a further study should be performed to demonstrate that compared to ARDSNet strategy, setting PEEP level based on a balanced ratio of recruitment and hyperinflation will decrease the expression of the injury markers such as inflammatory biomarkers or will improve clinical outcomes. We further extend the previous observation by demonstrating that hyperinflated areas were greater in the surfactant depletion model than in the oleic acid model
at PEEP levels achieving optimal oxygen. So for a given recruitment maneuver, different types of lung injury respond differently and the beneficial effects maybe underweighted by unwanted side effects. There are limitations in this study: (1) a normal control group without lung injury was not included as we focused on defining optimal PEEP levels following recruitment maneuvers in injured lung conditions. It is possible that a
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Compare to the stepwise increasing PEEP maneuver up to 45 cmH2O (plateau pressure 60 cmH2O), alveolar recruitment was inadequate in 20 s 40 cmH2O CPAP maneuvers [7, 24]. It might be possible that optimal oxygenation PEEP caused hyperinflation might be less pronounced if the stepwise increasing PEEP maneuver was used in the present study. (6) Finally, the study was conducted in a relative narrow rage of PEEP levels and further studies may help to understand the lung volume distribution at lower PEEP levels especially in the surfactant depletion model.
Conclusions
Fig. 5 Fractions of hyperinflation (FHyper, open blue circles) and recruitment (FRec, solid pink circles) induced by PEEP. The ‘‘potential for recruitment’’ was defined as the greatest amount of nonaerated tissue minus the least amount of nonaerated tissue and defined the ‘‘potential for hyperinflation’’ as the greatest amount of hyperinflated tissue minus the least amount of hyperinflated tissue recorded in any given dog. The fractions of recruitment induced by PEEP was expressed as: (observed inspiratory nonaerated tissueleast amount of nonaerated tissue)/potential for recruitment. The fractions of hyperinflation induced by PEEP was expressed as: (observed inspiratory hyperinflated tissue-least amount of hyperinflated tissue)/potential for hyperinflation. A balance between recruitment and hyperinflation occurred at PEEP 10 and 14 cmH2O in surfactant depletion model than oleic acid model. (Color figure online)
normal lung responds differently than an injured lung to a given recruitment maneuver. (2) We employed a relatively high VT in the setting of ventilator-induced lung injury to examine the effects of lung recruitment. It would be important to understand the effects of low VT on oxygenation and compliance in response to the same recruitment maneuver applied in the present study. (3) Further studies measuring transpulmonary pressure are warranted to reflect more closely alveolar pressure compared to plateau pressure. (4) We did not examine inflammatory responses in the present study, but it has been shown that the mechanisms of ventilator-induced lung injury involve both biophysical and biochemical stresses [23]. (5)
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In summary, our study shows that lung injury appeared to be localized in the surfactant depletion model while it was widely diffused in the oleic acid model. Optimal oxygenation guided PEEP may cause hyperinflated in both model post lung recruitment. The lung was prone to develop heterogeneous hyperinflation after lavage injury, while it was resistant to recruitment maneuver following oleic acid induced-injury. The application of recruitment maneuvers should be individualized based on the types of lung injury. Our study also suggests that the measurements of the balanced ratio of recruitment and hyperinflation provide a useful tool to choose PEEP level during recruitment maneuvers. Acknowledgments We are grateful to Min Wu in the Department of Radiology, Zhongda Hospital, Southeast University, for his help with CT scanning and image analysis, and to Dr. Haibo Zhang, Interdepartmental Division of Critical Care Medicine, University of Toronto for his critical review and edition of the manuscript. This work was supported by Project of National Key Clinical Specialty Construction (2100299), Health Research Special Funds for Public Welfare Projects (201202011), the Projects of Jiangsu Province’s Medical Key Discipline (889-KJXW11.3), Natural Science Foundation of Jiangsu Province Grant (BK2008298), and Medical Science and Technology Development Foundation of Jiangsu Province (BS2007045). Conflict of interests The authors declare that they have no conflcit of interests.
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1333 15. Malbouisson LM, Preteux F, Puybasset L, Grenier P, Coriat P, Rouby JJ (2001) Validation of a software designed for computed tomographic (CT) measurement of lung water. Intensive Care Med 27:602–608 16. Carvalho AR, Spieth PM, Pelosi P, Vidal Melo MF, Koch T, Jandre FC, Giannella-Neto A, de Abreu MG (2008) Ability of dynamic airway pressure curve profile and elastance for positive end-expiratory pressure titration. Intensive Care Med 34:2291–2299 17. Luecke T, Meinhardt JP, Herrmann P, Weiss A, Quintel M, Pelosi P (2006) Oleic acid vs saline solution lung lavage-induced acute lung injury. Chest 130:392–401 18. Nieszkowska A, Lu Q, Vieira S, Elman M, Fetita C, Rouby JJ (2004) Incidence and regional distribution of lung overinflation during mechanical ventilation with positive end-expiratory pressure. Crit Care Med 32:1496–1503 19. Grasso S, Stripoli T, De Michele M, Bruno F, Moschetta M, Angelelli G, Munno I, Ruggiero V, Anaclerio R, Cafarelli A, Driessen B, Fiore T (2007) ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir Crit Care Med 176:761–767 20. Carvalho ARS, Jandre FC, Pino AV, Bozza FA, Salluh JI, Rodrigues RS (2006) Effects of descending positive end-expiratory pressure on lung mechanics and aeration in healthy anaesthetized piglets. Crit Care 10:R122 21. Helm E, Talakoub O, Grasso F, Engelberts D, Alirezaie J, Kavanagh BP (2009) Use of dynamic CT in acute respiratory distress syndrome (ARDS) with comparison of positive and negative pressure ventilation. Eur Radiol 19:50–57 22. Malbouisson LM, Muller JC, Constantin JM, Lu Q, Puybasset L, Rouby JJ (2001) CT Scan ARDS Study Group. Computed tomography assessment of positive end-expiratory pressureinduced alveolar recruitment in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 163:1444–1450 23. Slutsky AS (2005) Ventilator-induced lung injury: from barotraumas to biotrauma. Respir Care 50:646–659 24. de Matos GF, Stanzani F, Passos RH, Fontana MF, Albaladejo R, Caserta RE, Santos DC, Borges JB, Amato MB, Barbas CS (2012) How large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography. Crit Care 16:R4
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Effects of recruitment maneuvers with PEEP on lung volume distribution in canine models of direct and indirect lung injury Yi Yang • Qiuhua Chen • Songqiao Liu • Yingzi Huang • Ling Liu • Xiaoyan Wu • Guangjian Chen • Jiyang Jin • Gaojun Teng • Haibo Qiu
Received: 19 October 2012 / Accepted: 24 December 2013 / Published online: 4 January 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Lung recruitment maneuvers can help open collapsed lung units for sufficient oxygenation, and positive end expiratory pressure (PEEP) is used to keep the lung open after recruitment. However, the application of high PEEP levels may play a significant role in causing regional lung hyperinflation during mechanical ventilation. The authors sought to study the effects of PEEP targeting optimal oxygenation on regional lung volume distribution in a direct and an indirect acute respiratory distress syndrome (ARDS) model. ARDS was induced by either surfactant depletion or oleic acid injection in dogs. After lung recruitment, PEEP was decreased from 20 to 10 cmH2O in 2 cmH2O steps every 10 min to examine regional lung aeration by using computed tomography. Lung injury appeared to be localized in the model of surfactant depletion while it widely diffused after oleic acid infusion. At PEEP levels that achieved optimal oxygenation, nonaerated lung units decreased and normally aerated lung units enhanced, but hyperinflated areas increased significantly in both models (P \ 0.05). Hyperinflated areas were greater in the surfactant depletion model than in the oleic acid model at PEEP levels applied (P \ 0.05). Optimal oxygenation guided PEEP may cause hyperinflated in both
focal lung injury and diffused lung injury post lung recruitment. Hyperinflation was more susceptible in focal lung injury than in diffused lung injury post lung recruitment. Keywords ARDS Mechanical ventilation PEEP Hyperinflation Abbreviations ARDS Acute respiratory distress syndrome PEEP Positive end expiratory pressure VT Tidal volume FiO2 Fraction of inspired oxygen CPAP Continuous positive airway pressure Ppeak Peak airway pressure R Airway resistance Pplat Airway plateau pressure Cst,rs Static compliance HR Heart rate MAP Mean arterial pressure CI Cardiac index SVR Systemic vascular resistance
Yi Yang and Qiuhua Chen have contributed equally to this work.
Introduction Y. Yang Q. Chen S. Liu Y. Huang L. Liu X. Wu G. Chen H. Qiu (&) Department of Critical Care Medicine, Nanjing Zhong-Da Hospital, Southeast University, 87 Dingjiaqiao Rd, Nanjing 210009, People’s Republic of China e-mail: [email protected] J. Jin G. Teng Department of Radiology, Nanjing Zhong-Da Hospital, Southeast University, Nanjing, People’s Republic of China
Acute respiratory distress syndrome (ARDS) is associated with altered gas exchange and refractory hypoxia as a result of alveolar collapse [1]. Mechanical ventilation at low tidal volume with lung recruitment maneuvers provides an effective strategy in the treatment of acute lung injury [2, 3]. Lung recruitment maneuver helps open lung units for greater oxygenation, and positive end-expiratory
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pressure (PEEP) is used to keep the lung open after recruitment. However, increasing PEEP can also simultaneously result in overinflation of previously normally ventilated lung regions, leading to worsens heterogeneity [4]. A recent study reported hyperinflation of the normally aerated compartment in ARDS patients despite the use of carefully limited tidal volume and plateau pressure [5], suggesting that while keeping lung open PEEP plays a crucial role causing hyperinflation. An optimal range of PEEP levels during recruitment would allow the lung to be open for optimal or sufficient oxygenation while minimizing overdistension of normally aerated lung units [6, 7]. The assessment of regional lung aeration by CT scan provides a useful tool for evaluating the balance between alveolar collapse and overdistension [8, 9]. Most previous studies focused the investigation of lung recruitments on a given lung injury model, while the lung volume distribution in response to a given recruitment maneuver was not well addressed simultaneously in direct and indirect lung injury models. We hypothesized that PEEP targeting optimal oxygenation results in heterogeneous distribution of hyperinflation in models of primary and secondary acute lung injury. We show in dog models that the lung is prone to develop hyperinflation after direct (primary) lung injury induced by surfactant depletion while it becomes more resistant to hyperinflation during indirect (secondary) lung injury induced by oleic acid injection, in response to a given recruitment maneuver.
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Munich, Germany) for measurement of cardiac output. The PiCCO system was calibrated at each PEEP level during the subsequent PEEP trial. After 30 min of stabilization, the animals were randomly divided into two groups and received either surfactant depletion by repeated lung lavage using normal saline to achieve a PaO2/FiO2 ratio below 100 mmHg defined as ARDS [10], or oleic acid infusion i.v. at 0.2 mL/ kg mixed with an equal amount of autologous blood. This dose of oleic acid was sufficient to obtain a PaO2/FiO2 ratio less than 100 mmHg [11]. A stable lung injury model was considered when the PaO2/FiO2 value remained \100 mmHg within the next 30 min. All animals met the criteria. Lung recruitment maneuver and decremental PEEP trial Lung recruitment maneuvers were performed by applying 40 cmH2O PEEP for 30 s. in continuous positive airway pressure (CPAP) mode [12]. This maneuver was repeated every 5 min until PaO2/FiO2 reached C400 mmHg defined as maximal oxygenation, or until there was\10 % changes in PaO2/FiO2 values between two consecutive measurements defined as maximal lung recruitment [13]. PEEP was set at 20 cmH2O after the lung recruitment maneuver, and PEEP decremental trial was followed (PEEP reduction by 2 cmH2O steps every 10 min until 10 cmH2O was reached). Measurement of gas exchange and lung mechanics
Materials and methods Animal preparation The protocol was approved by the Institutional Animal Use and Care Committee of Southeast University, Nanjing, People’s Republic of China. 16 healthy mongrel dogs (9 males and 7 females) weighing 15 ± 1 kg (Jiangsu Academy of Agricultural Sciences, Jiangsu, China) were anesthetized with intravenous (i.v.) injection of sodium pentobarbital (30 mg/kg) followed by a continuous infusion at 1–2 mg/kg h-1. Muscle relaxation was achieved by the administration of succinylcholine chloride at a loading dose of 10 mg i.v. followed by continuous infusion at 1 mg/kg h-1. Normal saline was administered at 6 mL/ kg h-1 in all animals. A tracheotomy was performed for intratracheal intubation in all animals who were mechanically ventilated (Evita XL ventilator, Dra¨ger, Germany) with volume-control at a tidal volume (VT) of 10 mL/kg, a respiratory rate of 30 breaths/min, a fraction of inspired oxygen (FiO2) 1.0, and PEEP 5 cmH2O. The right femoral artery and the right jugular vein were catheterized and connected to a PiCCO system (Pulsion Medical System,
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Arterial blood gases were measured at all PEEP levels (Nova-M, Waltham, MA, USA). The volume of blood draw was 0.5 mL each time for a total of 20 times for a dog of total blood volume of *80 mL/kg of body weight [14]. Peak airway pressure (Ppeak) and airway resistance (R) were continuously monitored by the ventilator. Airway plateau pressure (Pplat) was measured at the end of an inspiratory pause of 5 s. Static compliance (Cst,rs) was calculated according to formula VT/(Pplat–PEEP). CT protocol and analysis The CT scans were performed in the supine position for the whole lung from apex to bottom. The endotracheal tube connected to the Y-piece of the ventilator circuit was occluded by a clamp at end-expiration while lung morphology by CT scan was conducted at baseline, induction of lung injury, completion of recruitment and at all PEEP levels. A 64-slice spiral CT (Siemens, Germany) was set at 120 kV, currency of 140 mA; collimation of 0.6 mm, rotation time of 0.33 s, pitch 1.2, field of view 204 mm, and bed speed of 23.78 mm/s. The lung aeration was constructed by scanning slices at a thickness of 3 mm,
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interval at 3 mm with matrix pixels of 512 9 512. In general, 70–100 slices were scanned per lung, depending on the lung volume. Lung volumes were calculated from the lung density and expressed in Hounsfield units. Three-dimensional lung was reconstructed by Pulmo software (Siemens, Germany). The regions were classified as nonaerated (density between ?100 and -99 Hounsfield units), poorly aerated (-100 and -499), normally aerated (-500 and -899), and hyperinflated (-900 and -1,000) [15]. The fraction of recruitment and hyperinflation induced by PEEP were calculated as previously described [16].
number of normally aerated and hyperinflated lung units (Fig. 3). Hyperinflated areas were greater in the surfactant depletion model than in the oleic acid model at all PEEP levels (P \ 0.05). Using three-dimensional lung reconstruction, it showed that hyperinflation occurred frequently in non-dependent zones, whereas recruitment lung units mostly occurred in dependent zones (Fig. 4). Figure 5 shows the fraction of recruitment and hyperinflation induced by PEEP in both groups, a balanced ratio of recruitment and hyperinflation took place at PEEP 10 and 14 cmH2O in the surfactant depletion and oleic acid model, respectively.
Statistical analysis
Gas exchange, hemodynamics and lung mechanics
Statistics were performed using SPSS (SPSS Inc., Chicago, IL, USA). Kolmogorov–Smirnov Tests were conducted for normality testing, followed by t tests for analysis between groups or by general linear model of repeated-measurements for analysis within a group. In the case that the data was not normally distributed, such as nonareated and hyperinflated lung areas, nonparametric tests were used. The Two Independent Samples Test was used for comparison between two groups, and the Tests for Several Related Samples was used for comparison within a group. Data are reported as mean ± SD. Significance was considered as P \ 0.05.
Twelve animals reached optimal oxygenation defined as the PaO2/FiO2 ratio C400 mmHg, and four animals achieved optimal lung recruitment defined as PaO2/FiO2 \10 % between two consecutive maneuvers. A similar optimal oxygenation was achieved at a PEEP 12 and 18 cmH2O in the surfactant depletion and the oleic acid group, respectively (P \ 0.05). The maximal values of Cst,rs was achieved at a PEEP level of 12 cmH2O in the surfactant depletion model, while Similar optimal oxygenation was obtained at PEEP 18 cmH2O and the highest compliance occurred at PEEP 10 cmH2O in the oleic acid model (18 vs. 10 cmH2O, P \ 0.05) (Table 2).
Results Discussion Acute lung injury models There was no difference in hemodynamics, gas exchange, or respiratory parameters at baseline between two kind models of ARDS (Tables 1, 2). Heart rate (HR), mean arterial pressure (MAP), cardiac index (CI) and systemic vascular resistance (SVR) were stable in the surfactant depletion model, while after oleic acid injection, CI decreased, but HR and MAP maintained relatively stable as a result of an increased SVR (Table 1). Lung injury was heterogeneously distributed following surfactant depletion: normal aerated alveoli were seen mostly in ventral areas (non-dependent), while atelectasis and poorly aerated alveoli were frequently found in dorsal areas. Alveolar collapse appeared to be gravity-dependent (dependent). On the contrary, lung injury appeared to be widely diffused in the oleic acid model (Figs. 1, 2). Lung volume distribution during PEEP trial In general, a higher PEEP level was associated with a lower number of nonaerated lung units and an increased
There are several novel findings in the present study: (1) PEEP titrated to achieve optimal oxygenation induced lung hyperinflation in both the surfactant depletion and the oleic acid model; (2) The lung was prone to develop heterogeneous hyperinflation after lavage injury, while it was resistant to recruitment maneuver following oleic acid induced-injury; and (3) The balanced ratio of recruitment and hyperinflation fraction took place at PEEP 10 and 14 cmH2O in the surfactant depletion and oleic acid model, much lower than PEEP titrated to achieve optimal oxygenation. Our models shows that lung injury was localized in the surfactant depletion model and was widely diffuse in the oleic acid infusion model. This observation may be explained by an uneven distribution of the lavage fluids administered within the lung in the surfactant depletion model, while a relatively equal allocation of disruption within the lung following intravenous infusion of oleic acid. Our results are consistent with a previous study showing significant heterogeneous lung injury after surfactant depletion in sheep [4]. The investigators reported
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16.6 ± 8.1
2,654 ± 1,501
Oleic acid
4,125 ± 2,084
2,933 ± 1,152
35.9 ± 10.9
#
38.1 ± 12.2#
3.8 ± 1.1 2.9 ± 1.0#
5.0 ± 1.3
5.0 ± 2.1
133 ± 30
133 ± 27
140 ± 21
115 ± 28
Injury
4,312 ± 3,430
5,133 ± 2,742#
41.0 ± 9.4
#
40.4 ± 10.2#
2.2 ± 1.1#* 3.0 ± 1.4#
3,921 ± 2,146
4,283 ± 1,888
41.3 ± 9.5
#
35.7 ± 12.2#
2.4 ± 0.7#* 2.7 ± 1.0#
10.1 ± 3.3
#*
#*
9.6 ± 4.6
10.1 ± 2.3#*
122 ± 38
127 ± 29
138 ± 29
124 ± 22
18
9.4 ± 3.0#*
124 ± 28
121 ± 28
138 ± 27
116 ± 20
20
Decremental PEEP trial (cmH2O)
3,851 ± 1,463
5,613 ± 2,781#
43.0 ± 9.9
#
35.7 ± 10.7#
1.9 ± 0.7#* 2.7 ± 1.0#
9.1 ± 2.6
#*
8.6 ± 2.1#*
127 ± 32
124 ± 27
140 ± 33
122 ± 27
16
4,304 ± 2,248
4,318 ± 1,765
44.0 ± 9.3
#
34.9 ± 10.5#
2.4 ± 0.7#* 2.6 ± 1.0#
8.6 ± 3.0
#*
8.6 ± 1.7#*
127 ± 31
125 ± 27
142 ± 37
124 ± 28
14
4,118 ± 2,161
4,423 ± 1,916
44.9 ± 7.4
#
35.4 ± 9.6#
2.4 ± 0.6#* 2.8 ± 1.1#
8.6 ± 2.3
#*
7.0 ± 2.4
129 ± 41
126 ± 26
144 ± 38
121 ± 26
12
#
P \ 0.05 vs. Baseline *P \ 0.05 vs. Injury;
P \ 0.05 vs. PEEP 20 cmH2O. N = 8
PEEP positive end-expiratory pressure, HR heart rate, MAP mean arterial pressure, CVP central venous pressure, CI cardiac index, EVLWI extra vascular lung water index
2,364 ± 858
Surfactant depletion
SVRI (dyn.s m cm )
-5
Oleic acid
2
13.8 ± 4.1
4.7 ± 2.2 5.2 ± 2.9
Surfactant depletion
EVLWI (mL/kg)
Surfactant depletion Oleic acid
CI (L min
m)
5.8 ± 1.3
2
Oleic acid
-1
5.6 ± 0.9
Surfactant depletion
CVP (mmHg)
128 ± 23
136 ± 18
Surfactant depletion
Oleic acid
MAP (mmHg)
141 ± 19
162 ± 10
Surfactant depletion
Oleic acid
HR (bpm)
Baseline
Table 1 Hemodynamic variables before and during decremental PEEP trial
3,284 ± 1,300
5,287 ± 3,445#
40.8 ± 9.0#
36.3 ± 7.3#
2.4 ± 1.0#* 3.2 ± 1.0#
8.5 ± 1.9#*
6.4 ± 2.3
129 ± 32
130 ± 24
139 ± 35
123 ± 24
10
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Table 2 Blood gas exchange and respiratory variables during decremental PEEP trial Baseline
Decremental PEEP trial (cmH2O)
Injury
20
18
16
14
12
10
PaO2/FiO2 Surfactant depletion
487 ± 66
74 ± 23#
492 ± 71*
438 ± 53*
423 ± 101*
424 ± 62*
401 ± 63#*
365 ± 89#*
Oleic acid
510 ± 68
83 ± 23#
455 ± 65*
394 ± 67#*
356 ± 80#*
306 ± 140#*
245 ± 128#* à
211 ± 127#* à
PaCO2 Surfactant depletion
43 ± 16
51 ± 10
65 ± 14
62 ± 17
65 ± 18
60 ± 24
55 ± 20
48 ± 16
Oleic acid
47 ± 15
68 ± 18
78 ± 14
80 ± 20
77 ± 16
74 ± 20
75 ± 19
62 ± 19
13 ± 2
21 ± 7#
39 ± 7#*
36 ± 9#*
32 ± 8#*
29 ± 7#
26 ± 6#
24 ± 6#
13 ± 4
18 ± 3#
36 ± 3#*
33 ± 3#*
30 ± 3#*
28 ± 3#*
25 ± 4#*
23 ± 3#*
11 ± 1
19 ± 7#
36 ± 7#*
33 ± 8#*
30 ± 8#*
26 ± 6#
23 ± 6#
21 ± 6#
12 ± 3
16 ± 2
#
#*
6±1
12 ± 3#
6±1
13 ± 4
#
29 ± 9
17 ± 11#
Ppeak (cmH2O) Surfactant depletion Oleic acid Pplat (cmH2O) Surfactant depletion Oleic acid
35 ± 3
31 ± 2
#*
#*
#*
28 ± 2
26 ± 3
9 ± 2#*
8 ± 2#*
22 ± 2
#*
20 ± 2#*
-1
R (cmH2O/s L ) Surfactant depletion Oleic acid
9 ± 2#* 10 ± 3
#*
9 ± 2#* 10 ± 3
#*
9±3
#*
10 ± 3
#*
9 ± 2#* 9±3
#*
9 ± 3#* 10 ± 3#*
Cst (mL/cmH2O) Surfactant depletion Oleic acid
26 ± 9
14 ± 2
#
11 ± 4#
12 ± 4#
14 ± 5#
16 ± 6#
18 ± 7#
#
#
#
#
#
11 ± 3
12 ± 3
13 ± 3
14 ± 4
15 ± 4
17 ± 7# 16 ± 5#
PEEP positive end-expiratory pressure, PaO2/FiO2 arterial oxygen tension/fraction of inspiratory oxygen, Ppeak peak airway pressure, Pplat plateau pressure, R airway resistance, Cst static compliance #
P \ 0.05 versus Baseline
*
P \ 0.05 versus Injury; P \ 0.05 versus PEEP 20 cmH2O;
that the regional P–V curves closely resembled the overall P–V curve in terms of the shape and inflection points in the diffused injury, but were dramatically different from the overall P–V curve in localized alveolar injury [4]. Our CT scan results provide direct evidence to show heterogeneous alveolar injury. However, another study showed no difference in the pattern of lung injury following surfactant depletion and oleic acid injection in pigs [17]. The different observations may be due to different definitions of lung injury and the methods of data analysis used. ARDS was defined as a PaO2/FiO2 ratio \100 mmHg in our study, whereas a ratio of 200 mmHg was used in the previous study [17]. Moreover, a whole-lung CT scan was performed to analyze a total of 70–100 slices per lung in our study, while two slices per lung were scanned and analyzed in the previous study that might have missed some detailed lung structure [17]. The heterogeneity of lung injury may have contributed to the greater response of hyperinflated area during recruitment after lung lavage. In ARDS patient, Nieszkowska et al. [18] reported lung overinflation in caudal and nondependent lung regions after recruitment maneuver in more than one-third population studied. Grasso et al. [19] also found evidence of alveolar hyperinflation in patients with focal ARDS who were ventilated with the ARDSnet protocol. A likely explanation is that the
à
P \ 0.05 versus Surfactant depletion. N = 8
collapsed lung regions were recruited in a PEEP-dependent manner while the previously normal regions were prone to develop overinflation in response to a given recruitment maneuver. Hence, the overinflation was a consequence of the underlying disease process as well as a result of the use of excessive PEEP and driving pressure. We demonstrated that the oleic acid-induced lung injury model responded differently than the lavage model for a given PEEP level. Higher PEEP levels were required to recruit the lung in the oleic acid model perhaps due to more severe damage and stiffer lungs, thus hyperinflation was less dramatic compared to the lavage model. Taken together, these animal and human studies suggest the use of PEEP levels following recruitment maneuver should be individualized based on different types of lung injury, and hyperinflation occurred more frequently in heterogeneous alveolar injury conditions such as surfactant deficiency. CT scan techniques have been used to study lung volume changes under mechanical ventilation in animal models and in human with ARDS [20–22]. In healthy anesthetized piglets, the use of PEEP at 16 cmH2O resulted in hyperinflation that was decreased when PEEP was progressively reduced to zero [20]. In a rabbit model of lung lavage, the application of dynamic CT detected changes of lung aeration in response to mechanical ventilation under either positive or negative pressure [21]. In patients with
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Fig. 1 Pathologic appearance following induction of acute lung injury. Surfactant depletion induced localized injury and oleic acid injection produced widely diffused injury
Fig. 2 Representative CT scan illustration during a decremental PEEP trial in surfactant depletion and oleic acid models
ARDS a thoracic spiral CT scan was performed at zero PEEP and PEEP 15 cmH2O. A significant correlation was found between PEEP-induced alveolar recruitment and increase in PaO2 [22]. Our results are in agreement with previous reports showing that CT scans provide a useful tool for evaluation of lung volume distribution. The present study may help us to search for optimal PEEP levels by which significant recruitment and oxygenation would be achieved without causing significant
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hyperinflation. We found that PEEP titrated to achieve optimal oxygenation resulted in great hyperinflated lung units in both the surfactant depletion and oleic acid model. A balanced ratio of recruitment and hyperinflation took place at PEEP 10 and 14 cmH2O in the surfactant depletion and oleic acid model, respectively, which were lower than the PEEP levels achieving optimal oxygen. This finding might suggest that the measurement of the balanced ratio of recruitment and hyperinflation can be used to choose the optimal range of
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Fig. 3 Lung volume distribution during a decremental PEEP trial in surfactant depletion and oleic acid infusion models. PEEP positive endexpiratory pressure. * P \ 0.05 versus Injury; P \ 0.05 versus PEEP 20 cmH2O; à P \ 0.05 versus Surfactant depletion. N = 8 per model Fig. 4 A representative alveolar aeration constructed by CT scan during a PEEP decremental trial after surfactant depletion or oleic acid injection. Hyperinflation occurred in nondependent lung regions, whereas recruitment occurred in dependent regions, hyperinflated areas were increased much more in surfactant depletion model than oleic acid model. Hyperinflation (yellow), normal aeration (blue), poorly aeration (red), nonaeration (deep red). (Color figure online)
PEEP levels. But a further study should be performed to demonstrate that compared to ARDSNet strategy, setting PEEP level based on a balanced ratio of recruitment and hyperinflation will decrease the expression of the injury markers such as inflammatory biomarkers or will improve clinical outcomes. We further extend the previous observation by demonstrating that hyperinflated areas were greater in the surfactant depletion model than in the oleic acid model
at PEEP levels achieving optimal oxygen. So for a given recruitment maneuver, different types of lung injury respond differently and the beneficial effects maybe underweighted by unwanted side effects. There are limitations in this study: (1) a normal control group without lung injury was not included as we focused on defining optimal PEEP levels following recruitment maneuvers in injured lung conditions. It is possible that a
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Compare to the stepwise increasing PEEP maneuver up to 45 cmH2O (plateau pressure 60 cmH2O), alveolar recruitment was inadequate in 20 s 40 cmH2O CPAP maneuvers [7, 24]. It might be possible that optimal oxygenation PEEP caused hyperinflation might be less pronounced if the stepwise increasing PEEP maneuver was used in the present study. (6) Finally, the study was conducted in a relative narrow rage of PEEP levels and further studies may help to understand the lung volume distribution at lower PEEP levels especially in the surfactant depletion model.
Conclusions
Fig. 5 Fractions of hyperinflation (FHyper, open blue circles) and recruitment (FRec, solid pink circles) induced by PEEP. The ‘‘potential for recruitment’’ was defined as the greatest amount of nonaerated tissue minus the least amount of nonaerated tissue and defined the ‘‘potential for hyperinflation’’ as the greatest amount of hyperinflated tissue minus the least amount of hyperinflated tissue recorded in any given dog. The fractions of recruitment induced by PEEP was expressed as: (observed inspiratory nonaerated tissueleast amount of nonaerated tissue)/potential for recruitment. The fractions of hyperinflation induced by PEEP was expressed as: (observed inspiratory hyperinflated tissue-least amount of hyperinflated tissue)/potential for hyperinflation. A balance between recruitment and hyperinflation occurred at PEEP 10 and 14 cmH2O in surfactant depletion model than oleic acid model. (Color figure online)
normal lung responds differently than an injured lung to a given recruitment maneuver. (2) We employed a relatively high VT in the setting of ventilator-induced lung injury to examine the effects of lung recruitment. It would be important to understand the effects of low VT on oxygenation and compliance in response to the same recruitment maneuver applied in the present study. (3) Further studies measuring transpulmonary pressure are warranted to reflect more closely alveolar pressure compared to plateau pressure. (4) We did not examine inflammatory responses in the present study, but it has been shown that the mechanisms of ventilator-induced lung injury involve both biophysical and biochemical stresses [23]. (5)
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In summary, our study shows that lung injury appeared to be localized in the surfactant depletion model while it was widely diffused in the oleic acid model. Optimal oxygenation guided PEEP may cause hyperinflated in both model post lung recruitment. The lung was prone to develop heterogeneous hyperinflation after lavage injury, while it was resistant to recruitment maneuver following oleic acid induced-injury. The application of recruitment maneuvers should be individualized based on the types of lung injury. Our study also suggests that the measurements of the balanced ratio of recruitment and hyperinflation provide a useful tool to choose PEEP level during recruitment maneuvers. Acknowledgments We are grateful to Min Wu in the Department of Radiology, Zhongda Hospital, Southeast University, for his help with CT scanning and image analysis, and to Dr. Haibo Zhang, Interdepartmental Division of Critical Care Medicine, University of Toronto for his critical review and edition of the manuscript. This work was supported by Project of National Key Clinical Specialty Construction (2100299), Health Research Special Funds for Public Welfare Projects (201202011), the Projects of Jiangsu Province’s Medical Key Discipline (889-KJXW11.3), Natural Science Foundation of Jiangsu Province Grant (BK2008298), and Medical Science and Technology Development Foundation of Jiangsu Province (BS2007045). Conflict of interests The authors declare that they have no conflcit of interests.
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